Amide compound as well as preparation method and application thereof

Abstract

The invention provides an amide compound as well as a preparation method and application thereof, and relates to the technical field of chemical synthesis. The amide compound has a structural formula as shown in a formula I, wherein R1 is selected from substituted or unsubstituted C6-C15 aryl groups; the substituent is selected from at least one of halogen and halogenated alkyl; r2 is selected from a substituted or unsubstituted alkyl group with 1 to 10 carbon atoms, an aryl group with 6 to 20 carbon atoms, and a heterocyclic ring with 3 to 10 carbon atoms; the substituent is selected from at least one of C1-C5 alkyl, C1-C5 alkoxy, halogen, halogenated alkyl or amino; or R2 and R3 form a 5-8 membered carbocyclic ring or heterocyclic ring together with the atoms to which R2 and R3 are attached, said heterocyclic ring optionally containing 1-3 heteroatoms selected from O, N or S. The amide compound with the novel structure, provided by the invention, has relatively good antibacterial activity. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the technical field of chemical synthesis, and particularly relates to an amide compound, a preparation method thereof, and an application thereof. Background Art

[0002] Bacteria play a crucial role in the environment, but at the same time pose a great threat to human life and health. The extensive use of clinical antibiotics now exerts a huge selective pressure on bacteria, inevitably leading to the emergence of drug resistance. The alarming increase in the drug resistance of bacteria to existing clinically used drugs is a serious problem faced by antimicrobial drug selection, and at the same time, the drug resistance of bacteria to existing antibacterial agents has also become one of the main causes of morbidity and mortality worldwide.

[0003] Chinese Patent Application CN114478474A discloses an amide compound and a preparation method thereof. The amide compound has the following structural formula:

[0004]

[0005] wherein R represents one of C1-C 16 alkyl, C6-C 15 aryl, and C4-C7 heterocycle. It has a relatively large binding energy with FabH, can be used as a FabH inhibitor to inhibit the growth of bacteria, and has advantages such as good antibacterial activity, low toxicity, and low hemolysis.

[0006] Amide, as a class of nitrogen-containing carboxylic acid derivatives, specifically refers to a compound formed by the connection of an acyl group and a nitrogen atom. In the medical field, amide derivatives have shown great promise, especially in antibacterial aspects. It can not only effectively inhibit and kill bacteria, but also has excellent anti-tumor and antiviral capabilities. Its antibacterial spectrum is very broad, which means it can fight against many different types of bacteria. More importantly, compared with other antibacterial drugs, amide derivatives have significant advantages, and it is extremely difficult for bacteria to develop drug resistance to them. Therefore, amide derivatives have extremely high application value in the medical antibacterial field, providing a new direction and hope for solving the increasingly serious problem of bacterial drug resistance.

[0007] Therefore, it is of research significance to develop a new-structured amide compound as an antibacterial compound. Summary of the Invention

[0008] The first object of the present invention is to provide a compound. The compound is an amide compound containing a benzene ring and 1,4-dioxepane. The compound is designed by a computer-aided drug design method, and it is detected by a molecular docking method that it has a relatively high binding energy with FabH, can be used as a FabH inhibitor, and has advantages such as good antibacterial activity, low toxicity, and low hemolysis.

[0009] The second object of the present invention is to provide a preparation method of the compound, which has a reasonable design and the synthesized compound is stable.

[0010] The third object of the present invention is to provide the application of the above compound.

[0011] To achieve the above object, the technical solution adopted by the present invention is as follows:

[0012] In the first aspect, the present invention provides an amide compound with the structural formula shown in Formula I:

[0013]

[0014] Wherein,

[0015] R1 is selected from substituted or unsubstituted C6-C 15 aryl; the substituent is selected from at least one of halogen and haloalkyl;

[0016] R2 and R3 are each independently selected from substituted or unsubstituted C1-C 10 alkyl, C6-C 20 aryl, C 3- C 10 heterocycle; the substituent is selected from at least one of C1-C5 alkyl, C1-C5 alkoxy, halogen, haloalkyl or amino; or R2 and R3 together with the atoms to which they are attached form a 5- to 8-membered carbocyclic or heterocyclic ring, and the heterocyclic ring optionally contains 1-3 heteroatoms selected from O, N or S.

[0017] Preferably,

[0018] R1 is selected from substituted or unsubstituted C6-C 12 aryl; the substituent is selected from at least one of F, Cl, Br and fluoroalkyl;

[0019] R2 and R3 are each independently selected from substituted or unsubstituted C1-C8 alkyl, C6-C 18 aryl, C4-C8 heterocycle; the substituent is selected from at least one of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, I, fluoroalkyl or amino; or R2 and R3 together with the atoms to which they are attached form a 5- to 7-membered carbocyclic or heterocyclic ring, and the heterocyclic ring optionally contains 1-3 heteroatoms selected from O or S.

[0020] More preferably,

[0021] R1 is selected from substituted or unsubstituted C6-C 10 aryl; the substituent is selected from at least one of F and CF3;

[0022] R2 and R3 are each independently selected from substituted or unsubstituted C1-C5 alkyl, C6-C 15 aryl, C4-C7 heterocycle; the substituent is selected from at least one of C1-C3 alkyl, C1-C3 alkoxy, F, Cl, Br, CF3 or amino; or R2 and R3 together with the atoms to which they are attached form a 5- to 6-membered carbocyclic or heterocyclic ring, and the heterocyclic ring optionally contains 1 to 3 O atoms.

[0023] Preferably, the amide compound has the structural formula as described in Formula II:

[0024]

[0025] wherein,

[0026] R2 and R3 are as described in any one of claims 1-3;

[0027] R4 is selected from substituted or unsubstituted C1-C5 alkyl, C6-C 15 aryl, C4-C7 heterocycle; the substituent is selected from at least one of C1-C3 alkyl, C1-C3 alkoxy, F, Cl, Br, CF3 or amino.

[0028] More preferably, the amide compound is selected from the following structural formulas:

[0029]

[0030]

[0031]

[0032]

[0033] More preferably, the amide compound is selected from the following structural formulas:

[0034]

[0035]

[0036]

[0037]

[0038] Even more preferably, the amide compound is selected from the following structural formulas:

[0039]

[0040]

[0041]

[0042] In a second aspect, the present invention provides a method for preparing the above-mentioned amide compounds. The reaction equation is as follows and includes the following steps:

[0043]

[0044] S1: Compound A reacts with 1,3-dibromopropane to obtain compound B;

[0045] S2: Compound B reacts with dimethyl oxalate and sodium methoxide / methanol solution to obtain compound C;

[0046] S3: Compound C undergoes an esterification reaction with a substituted benzene derivative hydrochloride and then hydrolysis under alkaline conditions to obtain compound E;

[0047] S4: Compound E reacts with an amine in the presence of a condensing agent to obtain compound F.

[0048] Preferably, in step S1, a solvent is involved, and the solvent is an alcohol.

[0049] Preferably, step S1 further includes a post-treatment step.

[0050] Preferably, in step S2, a solvent is involved, and the solvent is an alcohol.

[0051] Preferably, in step S2, the molar ratio of compound B to dimethyl oxalate is 1:2 - 4.

[0052] Preferably, in step S3, the molar ratio of compound C to the substituted benzene derivative hydrochloride is 1:1 - 1.1.

[0053] Preferably, in step S3, the substituted benzene derivative hydrochloride is selected from at least one of phenylhydrazine hydrochloride, trifluoromethylphenyl hydrochloride, or p-fluorophenyl hydrochloride.

[0054] Preferably, in step S3, the base used under the alkaline conditions is sodium hydroxide.

[0055] Preferably, in step S4, the condensing agent is a combination of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl) and 4-dimethylaminopyridine (DMAP) or a combination of 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) and N,N-diisopropylethylamine (DIPEA).

[0056] In a third aspect, the present invention provides the application of the above-mentioned amide compounds in antibacterial.

[0057] In the present invention, EDC·HCl refers to 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride; DMAP refers to 4-dimethylaminopyridine.

[0058] In the present invention, C1-C6, C4-C7, etc. all refer to the number of carbon atoms contained in the group.

[0059] In the present invention, the term "hydrocarbyl group" refers to a group formed by removing any one hydrogen atom from a hydrocarbon compound molecule; the hydrocarbon compounds include alkane compounds, alkene compounds, alkyne compounds, and aromatic hydrocarbon compounds. For example, the p-tolyl group formed by removing the hydrogen atom at the para position of the methyl group on the benzene ring of toluene, or the benzyl group formed by removing any one hydrogen atom from the methyl group of toluene, etc.

[0060] In the present invention, the term "alkyl group" refers to a group formed by removing any one hydrogen atom from an alkane compound molecule.

[0061] In the present invention, the term "aryl group" refers to a group formed by removing one hydrogen atom from an aromatic ring of an aromatic compound molecule; for example, the p-tolyl group formed by removing the hydrogen atom at the para position of the methyl group on the benzene ring of toluene.

[0062] In the present invention, the term "halogen" refers to at least one of fluorine, chlorine, bromine, and iodine.

[0063] In the present invention, the term "non-hydrocarbon substituent" refers to a group formed by removing any one hydrogen atom from a compound containing other elements (such as halogen, S, O, P, N, etc.) in addition to H and C. For example, alkoxy group, halogen, ether group, amide group, phenoxy group, phenyl group, diazacyclic ring, etc.

[0064] In the present invention, the term "heterocyclic ring" refers to a group formed by removing any one hydrogen atom from an organic compound containing a heterocyclic structure in the molecule. In addition to carbon atoms, the atoms constituting the ring also contain at least one heteroatom, including nitrogen atom, sulfur atom, and oxygen atom.

[0065] Compared with the prior art, the present invention has the following beneficial effects:

[0066] A novel amide compound provided by the present invention has good antibacterial activity and has good inhibitory effects on both Gram-negative bacteria and Gram-positive bacteria. Detailed implementation manners

[0067] In order to make the technical means, creative features, achieved objectives and functions of the present invention easy to understand, the present invention will be further illustrated below in conjunction with specific embodiments. However, the following embodiments are only the preferred embodiments of the present invention, not all of them. Based on the embodiments in the implementation manner, other embodiments obtained by those skilled in the art without creative labor all fall within the protection scope of the present invention. It is worth noting that the raw materials used in the present invention are all ordinary commercially available products, and no specific limitation is made on their sources. The technical and scientific terms used in the embodiments have the meanings commonly understood by those of ordinary skill in the technical field to which the present invention belongs.

[0068] Unless otherwise specified, the raw materials and catalysts in the embodiments of the present invention are all purchased through commercial channels.

[0069] Among them:

[0070] Benzaldehyde dioxane is from Shanghai Aladdin Biochemical Technology Co., Ltd.

[0071] EDC·HCl is from Shanghai Aladdin Biochemical Technology Co., Ltd.

[0072] DMAP is from Shanghai Aladdin Biochemical Technology Co., Ltd.

[0073] All kinds of primary amines are from Shanghai Aladdin Biochemical Technology Co., Ltd.

[0074] The instrument for nuclear magnetic resonance test is Bruker DPX 400, and the test condition is room temperature.

[0075] The instrument for mass spectrometry test is Mariner System 5304 mass spectrometer.

[0076] Example 1

[0077]

[0078] 5-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-1-phenyl-N-propyl-1H-pyrazole-3-carboxamide:

[0079] Add benzo[b][1,4]dioxepin-7-ylpyrazolecarboxylic acid (1.0 mmol), DMAP (1.1 equivalents), and EDC·HCl (1.1 equivalents) to a 25 mL dry round-bottom flask and dissolve them in 4 mL of dichloromethane. After stirring at room temperature for 15 minutes, add n-propylamine (1.1 mmol), and continue stirring for 8 hours. After the reaction stops, filter through diatomaceous earth, and then extract with water and dichloromethane three times. The organic layer is dried with Na2SO4, the solvent of the dried organic layer is evaporated, and the corresponding product is purified by column chromatography.

[0080] Milky white oil, yield 77%.

[0081] 1 1H NMR (400 MHz, Chloroform-d) δ 7.42 - 7.35 (m, 3H), 7.31 (dd, J = 7.6, 2.1 Hz, 2H), 6.98 (s, 1H), 6.88 - 6.83 (m, 2H), 6.72 (dd, J = 8.3, 2.2 Hz, 1H), 4.23 (t, J = 5.6 Hz, 2H), 4.18 (t, J = 5.7 Hz, 2H), 3.45 - 3.37 (m, 2H), 2.18 (p, J = 5.7 Hz, 2H), 1.61 (s, 2H), 0.99 (t, J = 7.4 Hz, 3H).

[0082] 13 13C NMR (101 MHz, Chloroform-d) δ 161.89, 151.44, 150.91, 147.26, 144.21, 139.61, 129.09, 128.25, 125.42, 124.81, 123.80, 122.04, 121.72, 107.76, 70.52, 70.44, 40.89, 31.49, 23.01, 11.49.

[0083] MS (ESI): m / z C 22 H 24 N3O3 + [M + H] + : Calculated: 378.18, Found: 378.30.

[0084] Example 2

[0085]

[0086] N-Cyclohexyl-5-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-1-phenyl-1H-pyrazole-3-carboxamide: Replace n-propylamine with cyclohexylamine, and other experimental procedures are the same as in Example 1.

[0087] Pale yellow solid, yield 72%.

[0088] 11H NMR (400 MHz, Chloroform-d) δ 7.43 - 7.35 (m, 3H), 7.32 (dd, J = 7.7, 2.1 Hz, 2H), 6.98 (s, 1H), 6.88 (d, J = 4.1 Hz, 1H), 6.85 (d, J = 2.0 Hz, 2H), 6.71 (dd, J = 8.3, 2.2 Hz, 1H), 4.22 (s, 2H), 4.18 (t, J = 5.7 Hz, 2H), 3.98 (dddd, J = 14.6, 10.5, 8.1, 4.0 Hz, 1H), 2.18 (p, J = 5.7 Hz, 2H), 2.02 (dq, J = 11.8, 3.5 Hz, 2H), 1.76 (dt, J = 13.3, 3.7 Hz, 2H), 1.72 - 1.62 (m, 2H), 1.48 - 1.35 (m, 2H), 1.32 - 1.25 (m, 2H).

[0089] 13 13C NMR (101 MHz, Chloroform-d) δ 160.34, 150.86, 150.34, 146.90, 143.64, 139.08, 128.53, 127.68, 124.94, 124.32, 123.25, 121.48, 121.14, 107.29, 69.96, 69.88, 47.45, 32.70, 30.95, 25.06, 24.47.

[0090] MS (ESI): m / z C 25 H 28 N3O3 + [M + H] + : Calculated: 418.21, Found: 418.30.

[0091] Example 3

[0092]

[0093] (5-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-1-phenyl-1H-pyrazol-3-yl)(pyrrolidin-1-yl)methanone:

[0094] Replace n-propylamine with pyrrolidine, and other experimental procedures are the same as in Example 1.

[0095] Off-white solid, yield 80%.

[0096] 11H NMR (400 MHz, Chloroform-d) δ 7.45 - 7.28 (m, 5H), 6.96 (s, 1H), 6.92 - 6.81 (m, 2H), 6.74 (dd, J = 8.3, 2.2 Hz, 1H), 4.21 (dt, J = 17.4, 5.6 Hz, 4H), 4.02 (t, J = 6.6 Hz, 2H), 3.70 (t, J = 6.7 Hz, 2H), 2.18 (p, J = 5.6 Hz, 2H), 1.93 (dt, J = 17.8, 6.5 Hz, 4H).

[0097] 13 13C NMR (101 MHz, Chloroform-d) δ 161.89, 151.35, 150.90, 148.56, 142.81, 139.85, 128.93, 127.83, 125.18, 125.09, 123.90, 122.10, 121.68, 109.86, 70.54, 70.47, 48.93, 46.89, 31.54, 26.58, 23.96.

[0098] MS (ESI): m / z C 23 H 24 N3O3 + [M + H] + : Calculated: 390.18, Found: 390.30.

[0099] Example 4

[0100]

[0101] (5-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-1-phenyl-1H-pyrazol-3-yl)(piperidin-1-yl)methanone:

[0102] Replace n-propylamine with piperidine, and other experimental procedures are the same as in Example 1.

[0103] White solid, yield 75%.

[0104] 11H NMR (400 MHz, Chloroform-d) δ 7.42 - 7.28 (m, 5H), 6.92 - 6.83 (m, 2H), 6.78 (s, 1H), 6.74 (dd, J = 8.3, 2.2 Hz, 1H), 4.20 (dt, J = 17.1, 5.6 Hz, 4H), 3.93 (t, J = 5.3 Hz, 2H), 3.74 (t, J = 5.0 Hz, 2H), 2.18 (p, J = 5.7 Hz, 2H), 1.79 - 1.56 (m, 6H).

[0105] 13 13C NMR (101 MHz, Chloroform-d) δ 162.91, 151.37, 150.90, 147.74, 142.92, 139.69, 128.93, 127.85, 125.28, 125.00, 123.87, 122.06, 121.69, 109.38, 70.54, 70.46, 48.32, 43.63, 31.52, 26.76, 25.72, 24.74.

[0106] MS (ESI): m / z C 24 H 26 N3O3 [M + H] + : Calculated: 404.19, Found: 404.25.

[0107] Example 5

[0108]

[0109] (5-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-1-phenyl-1H-pyrazol-3-yl)(morpholino)methanone:

[0110] Replace n-propylamine with morpholine, and the other experimental procedures are the same as in Example 1.

[0111] White solid, yield 81%.

[0112] 1 1H NMR (400 MHz, Chloroform-d) δ 7.42 - 7.32 (m, 3H), 7.29 (dd, J = 7.6, 2.2 Hz, 2H), 6.95 - 6.79 (m, 3H), 6.73 (dd, J = 8.3, 2.2 Hz, 1H), 4.21 (dt, J = 17.4, 5.7 Hz, 6H), 3.91 - 3.66 (m, 6H), 2.18 (p, J = 5.7 Hz, 2H).

[0113] 1313C NMR (101 MHz, Chloroform-d) δ 162.58, 151.45, 150.92, 147.21, 143.16, 139.60, 129.01, 128.06, 125.30, 124.75, 123.85, 122.06, 121.73, 110.18, 70.53, 70.45, 67.28, 66.98, 47.73, 42.99, 31.49.

[0114] MS (ESI): m / z C 23 H 24 N3O4 [M+H] + : Calculated: 406.17, Found: 406.25.

[0115] Example 6

[0116]

[0117] 5-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-N,1-diphenyl-1H-pyrazole-3-carboxamide:

[0118] Replace n-propylamine with aniline, and the other experimental procedures are the same as in Example 1.

[0119] White solid, yield 83%.

[0120] 1 1H NMR (400 MHz, Chloroform-d) δ 8.79 (s, 1H), 7.74 - 7.67 (m, 2H), 7.45 - 7.39 (m, 3H), 7.39 - 7.33 (m, 4H), 7.16 - 7.09 (m, 1H), 7.07 (s, 1H), 6.88 (dd, J = 5.2, 3.1 Hz, 2H), 6.74 (dd, J = 8.3, 2.2 Hz, 1H), 4.24 (t, J = 5.6 Hz, 2H), 4.20 (t, J = 5.7 Hz, 2H), 2.19 (p, J = 5.7 Hz, 2H).

[0121] 13 13C NMR (101 MHz, Chloroform-d) δ 158.67, 150.52, 149.90, 146.10, 143.69, 138.44, 136.86, 128.13, 127.99, 127.44, 124.45, 123.54, 123.04, 122.80, 121.05, 120.74, 118.73, 106.98, 69.49, 69.41, 30.43.

[0122] MS (ESI): m / z C 25 H 22 N3O3 + [M + H] + : Calculated value: 412.16, Measured value: 412.25.

[0123] Example 7

[0124]

[0125] 5-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-1-phenyl-N-(p-tolyl)-1H-pyrazole-3-carboxamide:

[0126] Replace n-propylamine with p-toluidine, and other experimental procedures are the same as in Example 1.

[0127] Yellow solid, yield 79%.

[0128] 1 H NMR (400 MHz, Chloroform-d) δ 8.74 (s, 1H), 7.62 - 7.55 (m, 2H), 7.44 - 7.38 (m, 3H), 7.38 - 7.32 (m, 2H), 7.20 - 7.13 (m, 2H), 7.06 (s, 1H), 6.88 (dd, J = 5.2, 3.1 Hz, 2H), 6.74 (dd, J = 8.3, 2.2 Hz, 1H), 4.23 (t, J = 5.6 Hz, 2H), 4.19 (t, J = 5.7 Hz, 2H), 2.33 (s, 3H), 2.19 (p, J = 5.7 Hz, 2H).

[0129] 13 C NMR (101 MHz, Chloroform-d) δ 159.57, 151.54, 150.95, 147.28, 144.68, 139.54, 135.36, 133.66, 129.53, 129.16, 128.43, 125.51, 124.66, 123.85, 122.09, 121.76, 119.79, 107.99, 70.53, 70.45, 31.48, 20.90.

[0130] MS (ESI): m / z C 26 H 24 N3O3 + [M + H] + : Calculated value: 426.18, Measured value: 426.30.

[0131] Example 8

[0132]

[0133] 5-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-N-(4-methoxyphenyl)-1-phenyl-1H-pyrazole-3-carboxamide:

[0134] Replace n-propylamine with p-methoxyaniline, and keep other experimental procedures the same as in Example 1.

[0135] Grayish-brown solid, yield 77%.

[0136] 1 H NMR(400MHz,Chloroform-d)δ8.69(s,1H),7.66 - 7.56(m,2H),7.47 - 7.38(m,3H),7.38 - 7.30(m,2H),7.06(s,1H),6.96 - 6.84(m,4H),6.74(dd,J=8.3,2.2Hz,1H),4.27 - 4.22(m,2H),4.22 - 4.15(m,2H),3.81(s,3H),2.19(dq,J=7.3,5.6Hz,2H).

[0137] 13 C NMR(101MHz,Chloroform-d)δ159.51,156.28,151.54,150.95,147.27,144.65,139.54,131.09,129.16,128.43,125.50,124.66,123.84,122.09,121.76,121.47,114.22,107.96,70.53,70.45,55.50,31.49.

[0138] MS(ESI):m / z C 26 H 24 N3O4 + [M+H] + : Calculated value: 442.17, Measured value: 442.25.

[0139] Example 9

[0140]

[0141] 5-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-N-(3,4-dimethoxyphenyl)-1-phenyl-1H-pyrazole-3-carboxamide:

[0142] Replace n-propylamine with 3,4-dimethoxyaniline, and keep other experimental procedures the same as in Example 1.

[0143] Greyish-black solid, yield 80%.

[0144] 1 H NMR (400 MHz, Chloroform-d) δ 8.71 (s, 1H), 7.55 (d, J = 2.5 Hz, 1H), 7.47 - 7.32 (m, 5H), 7.09 (dd, J = 8.6, 2.4 Hz, 1H), 7.06 (s, 1H), 6.91 - 6.81 (m, 3H), 6.74 (dd, J = 8.3, 2.2 Hz, 1H), 4.24 (t, J = 5.6 Hz, 2H), 4.20 (t, J = 5.7 Hz, 2H), 3.93 (s, 3H), 3.88 (s, 3H), 2.19 (p, J = 5.7 Hz, 2H).

[0145] 13 C NMR (101 MHz, Chloroform-d) δ 159.58, 151.57, 150.95, 149.06, 147.18, 145.68, 144.73, 139.49, 131.59, 129.19, 128.49, 125.51, 124.56, 123.83, 122.08, 121.78, 111.63, 111.41, 107.89, 104.62, 70.54, 70.45, 56.13, 55.92, 31.47.

[0146] MS (ESI): m / z C 29 H 28 N3O5 + [M + H] + : Calculated: 472.18, Found: 472.30.

[0147] Example 10

[0148]

[0149] 5-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-N-(2-fluorophenyl)-1-phenyl-1H-pyrazole-3-carboxamide:

[0150] Replace n-propylamine with o-fluoroaniline, and the other experimental procedures are the same as in Example 1.

[0151] Yellow solid, yield 71%.

[0152] 11H NMR (400 MHz, Chloroform-d) δ 9.06 (s, 1H), 8.51 (td, J = 8.1, 1.7 Hz, 1H), 7.45 - 7.32 (m, 5H), 7.21 - 7.10 (m, 2H), 7.10 - 7.02 (m, 2H), 6.89 (dd, J = 5.2, 3.0 Hz, 2H), 6.75 (dd, J = 8.3, 2.2 Hz, 1H), 4.22 (dt, J = 17.3, 5.7 Hz, 4H), 2.20 (p, J = 5.7 Hz, 2H).

[0153] 13 13C NMR (101 MHz, Chloroform-d) δ 159.81, 153.84, 151.58, 151.42, 150.96, 146.82, 144.71, 139.45, 129.11, 128.40, 126.52, 126.42, 125.43, 124.62, 124.60, 124.56, 124.16, 124.08, 123.87, 122.12, 121.79, 121.63 (d, J = 262 Hz), 114.99, 114.80, 108.06, 70.55, 70.46, 31.48.

[0154] MS (ESI): m / z C 25 H 21 FN3O3 + [M + H] + : Calculated: 430.15, Found: 430.20.

[0155] Example 11

[0156]

[0157] 5-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-N-(4-fluorophenyl)-1-phenyl-1H-pyrazole-3-carboxamide:

[0158] Replace n-propylamine with 4-fluoroaniline, and other experimental procedures are the same as in Example 1.

[0159] Yellow solid, yield 73%.

[0160] 11H NMR (400 MHz, Chloroform-d) δ 8.78 (s, 1H), 7.70 - 7.63 (m, 2H), 7.45 - 7.39 (m, 3H), 7.35 (dd, J = 7.2, 2.2 Hz, 2H), 7.09 - 7.02 (m, 3H), 6.92 - 6.81 (m, 3H), 6.74 (dt, J = 8.4, 1.6 Hz, 1H), 4.24 (t, J = 5.7 Hz, 2H), 4.19 (t, J = 5.6 Hz, 2H), 2.19 (p, J = 5.7 Hz, 2H).

[0161] 13 13C NMR (101 MHz, Chloroform-d) δ 160.48, 159.66, 158.06, 151.59, 150.96, 146.97, 144.80, 139.48, 133.95, 133.92, 129.19, 128.52, 125.49, 124.53, 123.82, 122.08, 121.79, 121.50, 121.43 (d, J = 265 Hz), 115.77, 115.54, 107.99, 70.53, 70.44, 31.47.

[0162] MS (ESI): m / z C 25 H 21 FN3O3 + [M + H] + : Calculated: 430.15, Found: 430.20.

[0163] Example 12

[0164]

[0165] 5-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-N-(4-methoxybenzyl)-1-phenyl-1H-pyrazole-3-carboxamide:

[0166] Replace n-propylamine with 4-methoxybenzylamine, and other experimental procedures are the same as in Example 1.

[0167] White solid, yield 83%.

[0168] 11H NMR (400 MHz, Chloroform-d) δ 7.39 - 7.32 (m, 3H), 7.28 (td, J = 5.9, 5.1, 2.9 Hz, 4H), 7.01 (s, 1H), 6.91 - 6.80 (m, 4H), 6.71 (dd, J = 8.3, 2.2 Hz, 1H), 4.57 (d, J = 5.9 Hz, 2H), 4.22 (t, J = 5.6 Hz, 2H), 4.18 (t, J = 5.7 Hz, 2H), 3.79 (s, 3H), 2.18 (p, J = 5.7 Hz, 2H).

[0169] 13 13C NMR (101 MHz, Chloroform-d) δ 161.71, 159.01, 151.47, 150.92, 147.00, 144.26, 139.56, 130.45, 129.34, 129.07, 128.26, 125.40, 124.77, 123.82, 122.05, 121.73, 114.05, 107.88, 70.53, 70.45, 55.31, 42.70, 31.49.

[0170] MS (ESI): m / z C 27 H 26 N3O4 [M + H] + : Calculated: 456.19, Found: 456.25.

[0171] Example 13

[0172]

[0173] 5-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-1-phenyl-N-(4-(trifluoromethyl)benzyl)-1H-pyrazole-3-carboxamide:

[0174] Replace n-propylamine with 4-(trifluoromethyl)benzylamine, and other experimental procedures are the same as in Example 1.

[0175] Orange-yellow solid, yield 78%.

[0176] 11H NMR (400 MHz, Chloroform-d) δ 7.59 (d, J = 8.1 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 7.37 (dt, J = 4.8, 2.5 Hz, 3H), 7.32 - 7.27 (m, 2H), 7.01 (s, 1H), 6.89 - 6.83 (m, 2H), 6.72 (dd, J = 8.3, 2.2 Hz, 1H), 4.70 (d, J = 6.2 Hz, 2H), 4.23 (t, J = 5.7 Hz, 2H), 4.21 - 4.13 (m, 2H), 2.19 (p, J = 5.7 Hz, 2H).

[0177] 13 13C NMR (101 MHz, Chloroform-d) δ 160.95, 150.49, 149.90, 145.62, 143.41, 141.54, 141.52, 138.46, 128.07, 127.33, 126.97, 124.59, 124.55, 124.51, 124.47, 124.45, 124.34, 123.58, 122.76, 121.00, 120.73, 106.87, 69.49, 69.40, 41.60, 30.42.

[0178] MS (ESI): m / z C 27 H 23 F3N3O3 [M + H] + : Calculated: 494.16, Found: 494.25.

[0179] Example 14

[0180]

[0181] (5-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-1-(4-fluorophenyl)-1H-pyrazol-3-yl)(pyrrolidin-1-yl)methanone: Benzofluoropyrazole carboxylic acid dioxane (1.0 mmol), DMAP (1.1 equiv), EDC·HCl (1.1 equiv) were dissolved in 4 mL of dichloromethane in a 25 mL dry round-bottom flask. After stirring at room temperature for 15 minutes, pyrrolidine (1.1 mmol) was added and stirring was continued for 8 hours. After the reaction stopped, it was filtered through diatomaceous earth, and then extracted with water and dichloromethane three times. The organic layer was dried over Na2SO4, the solvent of the dried organic layer was evaporated, and the corresponding product was purified by column chromatography.

[0182] White solid, yield 81%.

[0183] 11H NMR (400 MHz, Chloroform-d) δ 7.33 - 7.27 (m, 2H), 7.05 (t, J = 8.5 Hz, 2H), 6.98 (s, 1H), 6.93 - 6.82 (m, 2H), 6.74 (dd, J = 8.3, 2.2 Hz, 1H), 4.22 (dt, J = 16.2, 5.6 Hz, 4H), 4.00 (s, 2H), 3.72 (s, 2H), 2.20 (p, J = 5.7 Hz, 2H).

[0184] 13 13C NMR (101 MHz, Chloroform-d) δ 160.90, 159.59, 158.44, 149.30, 148.81, 146.52, 140.77, 133.89, 133.86, 124.84, 124.76, 122.67, 121.70 (d, J = 281 Hz), 119.92, 119.65, 113.87, 113.64, 107.72, 68.40, 68.31, 46.75, 44.75, 29.35, 24.44, 21.82.

[0185] MS (ESI): m / z C 23 H 23 FN3O3 [M + H] + : Calculated: 408.17, Found: 408.25.

[0186] Example 15

[0187]

[0188] (5-(3,4-Dihydro-2H-benzo[b][1,4]dioxino[7]hepten-7-yl)-1-(4-fluorophenyl)-1H-pyrazol-3-yl)(piperidin-1-yl)methanone:

[0189] Replace pyrrolidine with piperidine, and other experimental procedures are the same as in Example 14.

[0190] White solid, yield 76%.

[0191] 11H NMR (400 MHz, Chloroform-d) δ 7.31 - 7.26 (m, 2H), 7.08 - 7.00 (m, 2H), 6.91 - 6.83 (m, 2H), 6.77 (s, 1H), 6.73 (dd, J = 8.3, 2.2 Hz, 1H), 4.22 (dt, J = 16.0, 5.7 Hz, 4H), 3.90 (s, 2H), 3.75 (s, 2H), 2.20 (p, J = 5.7 Hz, 2H), 1.68 (s, 6H).

[0192] 13 13C NMR (101 MHz, Chloroform-d) δ 163.05, 162.77, 160.59, 151.44, 150.95, 147.90, 143.01, 135.89, 135.86, 127.09, 127.00, 124.75, 123.82, 122.03, 121.79 (d, J = 270 Hz), 116.00, 115.77, 109.35, 70.53, 70.44, 48.28, 43.61, 31.47, 26.77, 25.71, 24.74.

[0193] MS (ESI): m / z C 24 H 25 FN3O3 [M + H] + : Calculated: 422.18, Found: 422.30.

[0194] Example 16

[0195]

[0196] (5-(3,4-Dihydro-2H-benzo[b][1,4]dioxepino[7,6-c]pyrrol-7-yl)-1-(4-fluorophenyl)-1H-pyrazol-3-yl)(morpholin-4-yl)methanone:

[0197] Replace pyrrolidine with morpholine, and other experimental procedures are the same as in Example 14.

[0198] White solid, yield 72%.

[0199] 11H NMR (400 MHz, Chloroform-d) δ 7.28 (d, J = 4.8 Hz, 1H), 7.25 (s, 1H), 7.06 (t, J = 8.5 Hz, 2H), 6.93 - 6.82 (m, 3H), 6.72 (dd, J = 8.3, 2.2 Hz, 1H), 4.22 (dt, J = 16.2, 5.7 Hz, 4H), 4.16 (s, 2H), 3.78 (d, J = 24.4 Hz, 6H), 2.20 (p, J = 5.7 Hz, 2H).

[0200] 13 13C NMR (101 MHz, Chloroform-d) δ 163.17, 162.46, 160.70, 151.53, 150.97, 147.33, 143.27, 135.76, 135.73, 127.13, 127.04, 124.48, 123.79, 122.02, 121.84 (d, J = 276 Hz), 116.10, 115.87, 110.13, 70.53, 70.43, 67.25, 66.97, 47.69, 42.97, 31.44.

[0201] MS (ESI): m / z C 23 H 23 FN3O4 [M + H] + : Calculated: 424.16, Found: 424.30.

[0202] Example 17

[0203]

[0204] 5-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-1-(4-fluorophenyl)-N-phenyl-1H-pyrazole-3-carboxamide

[0205] Replace pyrrolidine with aniline, and the other experimental procedures are the same as in Example 14.

[0206] Yellow solid, yield 66%.

[0207] 11H NMR (400 MHz, Chloroform-d) δ 8.75 (s, 1H), 7.71 (d, J = 7.8 Hz, 2H), 7.35 (ddt, J = 12.2, 8.2, 2.5 Hz, 4H), 7.17 - 7.03 (m, 4H), 6.94 - 6.82 (m, 2H), 6.73 (ddd, J = 8.2, 3.6, 2.0 Hz, 1H), 4.22 (dq, J = 14.6, 4.3, 3.3 Hz, 4H), 2.27 - 2.11 (m, 2H).

[0208] 13 13C NMR (101 MHz, Chloroform-d) δ 163.38, 160.91, 159.55, 151.65, 151.00, 147.24, 144.85, 137.84, 135.64, 135.61, 129.06, 127.36, 127.27, 124.33, 124.15, 123.80, 122.06, 121.89 (d, J = 258 Hz), 119.76, 116.28, 116.05, 108.05, 70.55, 70.45, 31.43.

[0209] MS (ESI): m / z C 25 H 21 FN3O3 [M + H] + : Calculated: 430.15, Found: 430.25.

[0210] Example 18

[0211]

[0212] 5-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-1-(4-fluorophenyl)-N-(p-tolyl)-1H-pyrazole-3-carboxamide:

[0213] Replace pyrrolidine with p-toluidine, and other experimental procedures are the same as in Example 14.

[0214] Yellow solid, yield 75%.

[0215] 11H NMR (400 MHz, Chloroform-d) δ 8.70 (s, 1H), 7.64 - 7.53 (m, 2H), 7.38 - 7.29 (m, 2H), 7.20 - 7.07 (m, 4H), 7.05 (s, 1H), 6.93 - 6.82 (m, 2H), 6.74 (dd, J = 8.3, 2.2 Hz, 1H), 4.23 (dt, J = 15.8, 5.7 Hz, 4H), 2.34 (s, 3H), 2.20 (p, J = 5.6 Hz, 2H).

[0216] 13 13C NMR (101 MHz, Chloroform-d) δ 163.37, 160.89, 159.44, 151.64, 150.99, 147.34, 144.78, 135.66, 135.63, 135.28, 133.75, 129.64, 129.55, 127.35, 127.27, 124.37, 123.80, 122.06, 121.88 (d, J = 262 Hz), 119.79, 116.26, 116.03, 115.93, 108.02, 70.55, 70.45, 31.43, 20.91.

[0217] MS (ESI): m / z C 26 H 23 FN3O3 [M + H] + : Calculated: 444.17, Found: 444.30.

[0218] Example 19

[0219]

[0220] 5-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-N-(3,4-dimethylphenyl)-1-(4-fluorophenyl)-1H-pyrazole-3-carboxamide

[0221] Replace pyrrolidine with 3,4-dimethylaniline, and the other experimental procedures are the same as in Example 14.

[0222] Yellow solid, yield 78%.

[0223] 11H NMR (400 MHz, Chloroform-d) δ 8.67 (s, 1H), 7.66 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.3 Hz, 3H), 7.44 (dd, J = 8.1, 2.4 Hz, 1H), 7.12 (d, J = 8.1 Hz, 1H), 7.06 (s, 1H), 6.97 - 6.87 (m, 2H), 6.73 (dd, J = 8.3, 2.2 Hz, 1H), 4.26 (t, J = 5.7 Hz, 2H), 4.22 (t, J = 5.7 Hz, 2H), 2.31 - 2.16 (m, 8H).

[0224] 13 13C NMR (101 MHz, Chloroform-d) δ 156.92, 149.58, 148.85, 145.76, 142.61, 139.95, 135.03, 133.17, 130.35, 127.94, 127.78, 127.62, 125.47, 124.07, 124.04, 124.00, 123.96, 123.02, 122.76, 121.93, 121.61, 120.05, 119.85, 119.78, 118.84, 115.01, 106.58, 68.29, 68.20, 29.11, 27.87, 27.44, 17.66, 16.95, -2.27.

[0225] MS (ESI): m / z C 27 H 24 FN3O3 [M + H] + : Calculated value: 457.51, Measured value: 457.55.

[0226] Example 20

[0227]

[0228] 5-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-1-(4-fluorophenyl)-N-mesityl-1H-pyrazole-3-carboxamide:

[0229] Replace pyrrolidine with 2,4,6-trimethylaniline, and other experimental procedures are the same as in Example 14.

[0230] Grey solid, yield 71%.

[0231] 11H NMR (400 MHz, Chloroform-d) δ 8.20 (s, 1H), 7.41 - 7.31 (m, 2H), 7.14 - 7.04 (m, 3H), 6.97 - 6.82 (m, 4H), 6.75 (dd, J = 8.3, 2.2 Hz, 1H), 4.23 (dt, J = 16.2, 5.7 Hz, 4H), 2.28 (d, J = 5.4 Hz, 9H), 2.20 (p, J = 5.6 Hz, 2H).

[0232] 13 13C NMR (101 MHz, Chloroform-d) δ 161.49, 159.02, 158.30, 149.77, 149.18, 145.22, 142.76, 135.10, 133.95, 133.92, 133.67, 129.00, 127.10, 125.50, 125.41, 122.72, 122.01, 120.24, 120.07 (d, J = 270 Hz), 114.39, 114.17, 106.42, 68.74, 68.63, 29.63, 27.90, 19.16, 16.69.

[0233] MS (ESI): m / z C 28 H 27 FN3O3 [M + H] + : Calculated: 472.20, Found: 472.30.

[0234] Example 21

[0235]

[0236] 5-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-1-(4-fluorophenyl)-N-(4-methoxyphenyl)-1H-pyrazole-3-carboxamide

[0237] Replace pyrrolidine with p-methoxyaniline, and other experimental procedures are the same as in Example 14.

[0238] Greyish-black solid, yield 71%.

[0239] 11H NMR (400 MHz, Chloroform-d) δ 8.66 (s, 1H), 7.66 - 7.57 (m, 2H), 7.40 - 7.29 (m, 2H), 7.16 - 7.02 (m, 3H), 6.94 - 6.81 (m, 4H), 6.74 (dd, J = 8.3, 2.2 Hz, 1H), 4.23 (dt, J = 15.9, 5.7 Hz, 4H), 3.81 (s, 3H), 2.20 (p, J = 5.7 Hz, 2H).

[0240] 13 13C NMR (101 MHz, Chloroform-d) δ 163.36, 160.88, 159.37, 156.32, 151.63, 150.99, 147.34, 144.76, 135.68, 135.65, 131.01, 127.34, 127.26, 124.38, 123.79, 122.05, 121.88, 121.47 (d, J = 254 Hz), 116.26, 116.03, 114.22, 107.99, 70.54, 70.45, 55.50, 31.43.

[0241] MS (ESI): m / z C 26 H 23 FN3O4 [M + H] + : Calculated: 460.16, Found: 460.25.

[0242] Example 22

[0243]

[0244] 5-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-N-(3,4-dimethoxyphenyl)-1-(4-fluorophenyl)-1H-pyrazole-3-carboxamide

[0245] Replace pyrrolidine with 3,4-dimethoxyaniline, and other experimental procedures are the same as in Example 14.

[0246] Greyish-black solid, yield 69%.

[0247] 11H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1H), 7.53 (d, J = 2.4 Hz, 1H), 7.52 - 7.41 (m, 3H), 7.35 (t, J = 8.8 Hz, 2H), 7.07 (s, 1H), 6.94 (dd, J = 14.1, 8.5 Hz, 2H), 6.90 - 6.81 (m, 2H), 4.13 (dt, J = 15.0, 5.5 Hz, 4H), 3.74 (d, J = 4.5 Hz, 6H), 2.09 (p, J = 5.4 Hz, 2H).

[0248] 13 13C NMR (101 MHz, DMSO-d6) δ 163.25, 160.80, 159.82, 151.79, 151.18, 150.30, 148.93, 147.73, 145.59, 144.40, 143.89, 140.48, 136.23, 136.21, 132.71, 128.76, 128.67, 124.52, 124.19, 122.35, 122.27, 116.70, 116.47, 115.14, 112.65, 112.36, 108.01, 105.97, 105.51, 100.40, 70.94, 70.87, 60.23, 57.17, 56.18, 55.86, 55.57, 31.64, 14.54.

[0249] MS (ESI): m / z C 27 H 24 FN3O5 [M + H] + : Calculated: 489.17, Found: 489.30.

[0250] Example 23

[0251]

[0252] 5-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-1-(4-fluorophenyl)-N-(3,4,5-trimethoxyphenyl)-1H-pyrazole-3-carboxamide:

[0253] Replace pyrrolidine with 3,4,5-trimethoxyaniline, and other experimental procedures are the same as in Example 14.

[0254] Black solid, yield 77%.

[0255] 11H NMR (400 MHz, Chloroform-d) δ 8.72 (s, 1H), 7.40 - 7.30 (m, 2H), 7.11 (t, J = 8.5 Hz, 2H), 7.04 (s, 3H), 6.95 - 6.82 (m, 2H), 6.73 (dd, J = 8.3, 2.2 Hz, 1H), 4.25 (t, J = 5.7 Hz, 2H), 4.21 (t, J = 5.7 Hz, 2H), 3.88 (s, 6H), 3.83 (s, 3H), 2.20 (p, J = 5.7 Hz, 2H).

[0256] 13 13C NMR (101 MHz, Chloroform-d) δ 162.99, 160.51, 159.11, 152.95, 151.26, 150.57, 146.71, 144.55, 135.18, 135.14, 134.13, 133.55, 126.97, 126.89, 123.77, 123.36, 121.62, 121.49, 115.89, 115.66, 107.46, 96.90, 70.13, 70.02, 60.57, 55.70, 30.97, 29.28.

[0257] MS (ESI): m / z C 28 H 26 FN3O6 [M + H] + : Calculated: 519.18, Found: 519.45.

[0258] Example 24

[0259]

[0260] N-(4-Aminophenyl)-5-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-1-(4-fluorophenyl)-1H-pyrazole-3-carboxamide

[0261] Replace pyrrolidine with p-phenylenediamine, and other experimental procedures are the same as in Example 14.

[0262] Yellow solid, yield 76%.

[0263] 11H NMR (400 MHz, Chloroform-d) δ 9.02 (d, J = 3.0 Hz, 1H), 8.51 (td, J = 8.1, 1.7 Hz, 1H), 7.34 (ddd, J = 10.7, 5.4, 3.0 Hz, 2H), 7.21 - 6.96 (m, 6H), 6.92 - 6.83 (m, 2H), 6.73 (ddd, J = 13.5, 8.3, 2.2 Hz, 1H), 4.25 (t, J = 5.5 Hz, 2H), 4.23 - 4.19 (m, 2H), 2.24 - 2.18 (m, 2H).

[0264] 13 13C NMR (101 MHz, Chloroform-d) δ 163.36, 162.35, 160.89, 159.66, 153.83, 151.67, 151.00, 146.90, 144.82, 135.60, 135.57, 127.59, 127.51, 127.27, 127.19, 126.46, 126.36, 124.62, 124.58, 124.33, 124.29, 124.21, 124.14, 123.82, 123.76, 122.08, 122.03, 121.90, 121.83, 121.61 (d, J = 254 Hz), 116.22, 116.09, 115.99, 115.86, 114.99, 114.80, 109.66, 108.07, 70.55, 70.45, 31.42.

[0265] MS (ESI): m / z C 25 H 20 F2N3O3 [M + H] + : Calculated: 448.14, Found: 448.25.

[0266] Example 25

[0267]

[0268] N-(2-Aminophenyl)-5-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-1-(4-fluorophenyl)-1H-pyrazole-3-carboxamide

[0269] Replace pyrrolidine with o-phenylenediamine, and other experimental procedures are the same as in Example 14.

[0270] White solid, yield 74%.

[0271] 11H NMR (400 MHz, Chloroform-d) δ 8.65 (s, 1H), 7.54 (d, J = 8.7 Hz, 2H), 7.35 - 7.28 (m, 2H), 7.09 (t, J = 8.5 Hz, 2H), 7.02 (s, 1H), 6.94 - 6.80 (m, 4H), 6.72 (dd, J = 8.3, 2.2 Hz, 1H), 4.22 (dt, J = 16.6, 5.7 Hz, 4H), 2.19 (p, J = 5.5 Hz, 2H).

[0272] 13 13C NMR (101 MHz, Chloroform-d) δ 163.33, 160.85, 159.30, 151.60, 150.98, 147.46, 144.67, 143.13, 135.70, 135.67, 129.30, 127.33, 127.25, 124.43, 123.80, 122.05, 121.86, 121.67 (d, J = 274 Hz), 116.24, 116.01, 115.53, 107.97, 70.55, 70.45, 31.44.

[0273] MS (ESI): m / z C 25 H 22 FN4O3 [M + H] + : Calculated: 445.16, Found: 445.30.

[0274] Example 26

[0275]

[0276] N-(4-Bromophenyl)-5-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide:

[0277] Replace pyrrolidine with p-bromoaniline, and other experimental procedures are the same as in Example 14.

[0278] White solid, yield 68%.

[0279] 11H NMR (400 MHz, Chloroform-d) δ 8.78 (s, 1H), 7.66 - 7.56 (m, 2H), 7.50 - 7.42 (m, 2H), 7.38 - 7.28 (m, 2H), 7.16 - 7.00 (m, 3H), 6.93 - 6.81 (m, 2H), 6.72 (dd, J = 8.3, 2.2 Hz, 1H), 4.24 (t, J = 5.7 Hz, 2H), 4.20 (t, J = 5.7 Hz, 2H), 2.20 (p, J = 5.7 Hz, 2H).

[0280] 13 13C NMR (101 MHz, Chloroform-d) δ 163.41, 160.94, 159.56, 151.70, 151.00, 146.93, 144.98, 136.95, 135.56, 135.53, 132.00, 127.35, 127.27, 124.18, 123.78, 122.06, 121.91, 121.28, 116.66, 116.31, 116.08, 108.04, 70.55, 70.45, 31.52, 31.40, 30.15, 29.71, 1.04.

[0281] MS (ESI): m / z C 25 H 19 BrFN3O3 [M + H] + : Calculated: 507.06, Found: 507.15.

[0282] Example 27

[0283]

[0284] N-(4-Chlorophenyl)-5-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-1-(4-fluorophenyl)-1H-pyrazole-3-carboxamide

[0285] Replace pyrrolidine with 4-chloroaniline, and other experimental procedures are the same as in Example 14.

[0286] Yellow solid, yield 60%.

[0287] 11H NMR (400 MHz, Chloroform-d) δ 8.69 (s, 1H), 7.65 - 7.53 (m, 2H), 7.33 - 7.22 (m, 4H), 7.12 - 6.92 (m, 3H), 6.87 - 6.74 (m, 2H), 6.66 (dd, J = 8.3, 2.2 Hz, 1H), 4.18 (t, J = 5.6 Hz, 2H), 4.14 (t, J = 5.7 Hz, 2H), 2.13 (p, J = 5.7 Hz, 2H).

[0288] 13 13C NMR (101 MHz, Chloroform-d) δ 163.42, 160.95, 159.51, 151.70, 151.01, 146.94, 144.98, 136.44, 135.56, 135.53, 129.07, 127.36, 127.27, 124.18, 123.78, 122.06, 121.91, 120.94, 116.31, 116.08, 108.04, 70.55, 70.45, 31.40, 29.72, 1.03.

[0289] MS (ESI): m / z C 25 H 19 ClFN3O3 [M + H] + : Calculated: 463.11, Found: 463.35.

[0290] Example 28

[0291]

[0292] 5-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-N,1-bis(4-fluorophenyl)-1H-pyrazole-3-carboxamide:

[0293] Replace pyrrolidine with p-fluoroaniline, and the other experimental procedures are the same as in Example 14.

[0294] Yellow solid, yield 82%.

[0295] 1 1H NMR (400 MHz, Chloroform-d) δ 8.79 (s, 1H), 7.69 (dt, J = 11.0, 2.2 Hz, 1H), 7.39 - 7.27 (m, 4H), 7.16 - 7.02 (m, 3H), 6.93 - 6.79 (m, 3H), 6.73 (dd, J = 8.3, 2.2 Hz, 1H), 4.23 (dt, J = 15.9, 5.7 Hz, 4H), 2.20 (p, J = 5.7 Hz, 2H).

[0296] 13 C NMR(101MHz, Chloroform-d) δ 164.31, 163.42, 161.88, 160.95, 159.59, 151.70, 151.01, 146.89, 144.99, 139.41, 139.30, 135.57, 135.54, 130.14, 130.04, 127.36, 127.27, 124.20, 123.79, 122.06, 121.91(d, J = 275Hz), 116.30, 116.07, 114.99, 114.96, 110.93, 110.72, 108.06, 107.33, 107.06, 70.55, 70.44, 31.41.

[0297] MS(ESI): m / z C 25 H 20 F2N3O3 [M + H] + : Calculated: 448.14, Found: 448.25.

[0298] Example 29

[0299]

[0300] 5-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-N,1-bis(3-fluorophenyl)-1H-pyrazole-3-carboxamide:

[0301] Replace pyrrolidine with 3-fluoroaniline, and other experimental procedures are the same as in Example 14.

[0302] Yellow solid, yield 80%.

[0303] 1 H NMR(400MHz, Chloroform-d) δ 8.73(s, 1H), 7.75 - 7.59(m, 2H), 7.40 - 7.30(m, 2H), 7.18 - 7.00(m, 5H), 6.96 - 6.82(m, 2H), 6.74(dd, J = 8.3, 2.2Hz, 1H), 4.23(dt, J = 16.0, 5.7Hz, 4H), 2.20(p, J = 5.7Hz, 2H).

[0304] 1313C NMR (101 MHz, Chloroform-d) δ 163.40, 160.92, 160.51, 159.51, 158.09, 151.67, 151.00, 147.05, 144.90, 135.61, 135.58, 133.87, 133.84, 127.35, 127.26, 124.25, 123.78, 122.05, 121.90, 121.49, 121.42 (d, J = 260 Hz), 116.29, 116.06, 115.80, 115.58, 108.02, 70.55, 70.44, 31.41.

[0305] MS (ESI): m / z C 25 H 20 F2N3O3 [M+H] + : Calculated: 448.14, Found: 448.25.

[0306] Example 30

[0307]

[0308] 5-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-N,1-bis(2-fluorophenyl)-1H-pyrazole-3-carboxamide:

[0309] Replace pyrrolidine with 3-fluoroaniline, and the other experimental procedures are the same as in Example 14.

[0310] Yellow solid, yield 76%.

[0311] 1 1H NMR (400 MHz, Chloroform-d) δ 9.02 (d, J = 3.0 Hz, 1H), 8.51 (td, J = 8.1, 1.7 Hz, 1H), 7.34 (ddd, J = 10.7, 5.4, 3.0 Hz, 2H), 7.21 - 6.96 (m, 6H), 6.92 - 6.83 (m, 2H), 6.73 (ddd, J = 13.5, 8.3, 2.2 Hz, 1H), 4.25 (t, J = 5.5 Hz, 2H), 4.23 - 4.19 (m, 2H), 2.24 - 2.18 (m, 2H).

[0312] 1313C NMR (101 MHz, Chloroform-d) δ 163.36, 162.35, 160.89, 159.66, 153.83, 151.67, 151.00, 146.90, 144.82, 135.60, 135.57, 127.59, 127.51, 127.27, 127.19, 126.46, 126.36, 124.62, 124.58, 124.33, 124.29, 124.21, 124.14, 123.82, 123.76, 122.08, 122.03, 121.90, 121.83, 121.61 (d, J = 254 Hz), 116.22, 116.09, 115.99, 115.86, 114.99, 114.80, 109.66, 108.07, 70.55, 70.45, 31.42.

[0313] MS (ESI): m / z C 25 H 20 F2N3O3 [M+H] + : Calculated: 448.14, Found: 448.25.

[0314] Example 31

[0315]

[0316] 5-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-1-(4-fluorophenyl)-N-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide:

[0317] Replace pyrrolidine with p-trifluoromethylaniline, and other experimental procedures are the same as in Example 14.

[0318] Yellow solid, yield 72%.

[0319] 1 1H NMR (400 MHz, Chloroform-d) δ 8.92 (s, 1H), 7.84 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.5 Hz, 2H), 7.40 - 7.30 (m, 2H), 7.20 - 7.02 (m, 3H), 6.95 - 6.81 (m, 2H), 6.73 (dd, J = 8.3, 2.2 Hz, 1H), 4.25 (t, J = 5.7 Hz, 2H), 4.21 (t, J = 5.7 Hz, 2H), 2.20 (p, J = 5.7 Hz, 2H).

[0320] 1313C NMR (101 MHz, Chloroform-d) δ 163.47, 160.99, 159.75, 151.74, 151.02, 146.73, 145.12, 140.89, 135.52, 135.49, 127.38, 127.29, 126.39, 126.35, 126.31, 126.28, 126.01, 125.69, 125.51, 124.10, 123.79, 122.82, 122.06, 121.93, 119.30, 116.34, 116.11, 108.10, 70.56, 70.45, 31.39, 29.71.

[0321] MS (ESI): m / z C 26 H 19 F4N3O3 [M+H] + : Calculated: 497.14, Found: 497.45.

[0322] Example 32

[0323]

[0324] 5-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-1-(4-fluorophenyl)-N-(furan-2-yl)-1H-pyrazole-3-carboxamide:

[0325] Replace pyrrolidine with furfurylamine, and other experimental procedures are the same as in Example 14.

[0326] White solid, yield 82%.

[0327] 1 1H NMR (400 MHz, Chloroform-d) δ 7.39 - 7.32 (m, 1H), 7.32 - 7.21 (m, 3H), 7.06 (t, J = 8.5 Hz, 2H), 6.98 (s, 1H), 6.88 (d, J = 8.3 Hz, 1H), 6.83 (d, J = 2.1 Hz, 1H), 6.70 (dd, J = 8.3, 2.2 Hz, 1H), 6.38 - 6.26 (m, 2H), 4.63 (d, J = 5.8 Hz, 2H), 4.23 (t, J = 5.7 Hz, 2H), 4.19 (t, J = 5.7 Hz, 2H), 2.18 (p, J = 5.7 Hz, 2H).

[0328] 1313C NMR(101MHz,Chloroform-d)δ162.97,161.22,160.49,151.27,151.02,150.66,146.54,144.09,141.93,135.40,135.37,126.96,126.87,126.73,126.65,124.14,123.47,121.72,121.54,115.88,115.65,110.26,110.14,107.63,107.30,105.41,70.23,70.14,35.81,31.46,31.13,29.40,29.02,26.62,13.83.

[0329] MS(ESI):m / z C 23 H 18 FN3O4[M+H] + : Calculated: 419.13, Found: 419.40.

[0330] Example 33

[0331]

[0332] 5-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-1-(4-fluorophenyl)-N-(1H-indol-6-yl)-1H-pyrazole-3-carboxamide:

[0333] Replace pyrrolidine with 6-aminoindole, and other experimental procedures are the same as in Example 14.

[0334] Yellow oil, yield 80%.

[0335] 1 1H NMR(400MHz,Chloroform-d)δ8.87(s,1H),8.58(s,1H),8.43 - 8.27(m,1H),7.57(d,J = 8.4Hz,1H),7.41 - 7.29(m,2H),7.18(t,J = 2.8Hz,1H),7.15 - 7.06(m,3H),7.02(dd,J = 8.4,1.9Hz,1H),6.93 - 6.84(m,2H),6.74(dd,J = 8.3,2.2Hz,1H),6.50(t,J = 2.6Hz,1H),4.24(t,J = 5.6Hz,2H),4.20(t,J = 5.7Hz,2H),2.19(p,J = 5.7Hz,2H).

[0336] 1313C NMR (101 MHz, Chloroform-d) δ 162.21, 159.73, 158.41, 150.47, 149.84, 146.33, 143.62, 134.97, 134.53, 134.50, 131.40, 126.21, 126.12, 123.64, 123.33, 123.26, 123.23, 122.68, 120.92, 120.73, 119.58, 115.11, 114.88, 114.78, 112.06, 106.80, 101.80, 101.21, 69.40, 69.31, 33.84, 33.30, 30.36, 30.28, 28.99, 28.55, -1.15.

[0337] MS (ESI): m / z C 27 H 21 FN4O3 [M+H] + : Calculated: 468.16, Found: 468.40.

[0338] Example 34

[0339]

[0340] 5-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-1-(4-fluorophenyl)-N-(quinolin-4-yl)-1H-pyrazole-3-carboxamide:

[0341] Replace pyrrolidine with 4-aminoquinoline, and other experimental procedures are the same as in Example 14.

[0342] Yellow solid, yield 64%.

[0343] 1 1H NMR (400 MHz, Chloroform-d) δ 9.82 (d, J = 19.3 Hz, 1H), 8.91 (d, J = 5.1 Hz, 1H), 8.59 (d, J = 16.4 Hz, 1H), 8.24 (d, J = 24.3 Hz, 1H), 7.99 (d, J = 8.3 Hz, 1H), 7.80 (t, J = 7.9 Hz, 1H), 7.64 (q, J = 8.1 Hz, 1H), 7.46 - 7.31 (m, 2H), 7.21 - 7.09 (m, 3H), 6.97 - 6.84 (m, 2H), 6.76 (dd, J = 8.3, 2.2 Hz, 1H), 4.25 (dt, J = 15.8, 5.7 Hz, 4H), 2.22 (p, J = 5.7 Hz, 2H).

[0344] 1313C NMR (101 MHz, Chloroform-d) δ 163.51, 161.03, 159.96, 151.79, 151.39, 151.04, 148.86, 146.73, 145.34, 140.24, 135.57, 135.53, 130.57, 129.39, 127.41, 127.32, 126.46, 124.05, 123.82, 122.11, 121.97 (d, J = 270 Hz), 119.95, 119.22, 116.38, 116.15, 110.22, 108.17, 70.57, 70.45, 31.39.

[0345] MS (ESI): m / z C 28 H 22 FN4O3 [M+H] + : Calculated: 481.16, Found: 481.30.

[0346] Example 35

[0347]

[0348] N-Benzyl-5-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-1-(4-fluorophenyl)-N-1H-pyrazole-3-carboxamide:

[0349] Replace pyrrolidine with benzylamine, and other experimental procedures are the same as in Example 14.

[0350] Pale yellow solid, yield 83%.

[0351] 1 1H NMR (400 MHz, Chloroform-d) δ 7.42 - 7.30 (m, 4H), 7.28 (dt, J = 4.8, 1.8 Hz, 2H), 7.15 - 6.96 (m, 3H), 6.94 - 6.80 (m, 2H), 6.71 (dd, J = 8.3, 2.2 Hz, 1H), 4.65 (d, J = 6.0 Hz, 2H), 4.22 (dt, J = 16.0, 5.6 Hz, 4H), 2.19 (p, J = 5.7 Hz, 2H).

[0352] 1313C NMR (101 MHz, Chloroform-d) δ 160.77, 159.17, 158.29, 149.07, 148.48, 144.54, 141.91, 135.81, 133.23, 133.19, 126.20, 125.48, 124.99, 124.75, 124.66, 122.00, 121.29, 119.53, 119.36 (d, J = 281 Hz), 113.67, 113.44, 105.44, 68.05, 67.95, 40.74, 28.95.

[0353] MS (ESI): m / z C 26 H 23 FN3O3 [M+H] + : Calculated: 444.17, Found: 444.25.

[0354] Example 36

[0355]

[0356] 5-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-1-(4-fluorophenyl)-N-(4-methoxybenzyl)-1H-pyrazole-3-carboxamide:

[0357] Replace pyrrolidine with 4-methoxybenzylamine, and other experimental procedures are the same as in Example 14.

[0358] Grey solid, yield 80%.

[0359] 1 1H NMR (400 MHz, DMSO-d6) δ 8.80 (t, J = 6.3 Hz, 1H), 7.47 - 7.38 (m, 2H), 7.37 - 7.18 (m, 4H), 7.00 - 6.91 (m, 2H), 6.91 - 6.77 (m, 4H), 4.38 (d, J = 6.2 Hz, 2H), 4.11 (dt, J = 15.7, 5.5 Hz, 4H), 3.72 (s, 3H), 2.08 (p, J = 5.4 Hz, 2H).

[0360] 1313C NMR (101 MHz, DMSO-d6) δ 163.15, 161.37, 160.71, 158.64, 151.72, 151.16, 147.58, 144.14, 136.27, 136.24, 132.21, 129.22, 128.62, 128.53, 124.62, 124.14, 122.33, 122.20, 116.64, 116.41, 114.08, 107.65, 70.92, 70.85, 60.23, 55.50, 41.95, 31.64, 21.21, 14.54.

[0361] MS (ESI): m / z C 27 H 24 FN3O4 [M+H] + : Calculated: 473.18, Found: 473.30.

[0362] Example 37

[0363]

[0364] 5-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-1-(4-fluorophenyl)-N-(4-(trifluoromethyl)benzyl)-1H-pyrazole-3-carboxamide:

[0365] Replace pyrrolidine with 4-(trifluoromethyl)benzylamine, and other experimental procedures are the same as in Example 14.

[0366] Yellow solid, yield 75%.

[0367] 1 1H NMR (400 MHz, Chloroform-d) δ 7.58 (d, J = 8.1 Hz, 2H), 7.44 (dd, J = 22.1, 7.2 Hz, 3H), 7.32 - 7.22 (m, 2H), 7.13 - 6.94 (m, 3H), 6.92 - 6.80 (m, 2H), 6.71 (dd, J = 8.3, 2.2 Hz, 1H), 4.69 (d, J = 6.2 Hz, 2H), 4.23 (t, J = 5.7 Hz, 2H), 4.19 (t, J = 5.7 Hz, 2H), 2.19 (p, J = 5.7 Hz, 2H).

[0368] 1313C NMR (101 MHz, Chloroform-d) δ 163.07, 161.65, 160.59, 151.40, 150.76, 146.50, 144.34, 142.30, 142.29, 135.43, 135.39, 129.93, 129.60, 129.28, 127.78, 127.01, 126.92, 125.42, 125.38, 125.34, 125.31, 125.26, 124.11, 123.54, 122.55, 121.79, 121.65, 115.98, 115.75, 115.58, 107.71, 70.31, 70.21, 42.43, 31.19, 29.48.

[0369] MS (ESI): m / z C 27 H 21 F4N3O3 M+H] + : Calculated value: 511.15, Measured value: 511.25.

[0370] Example 38

[0371]

[0372] N-Butyl-5-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide: Add benzotrifluoromethylpyrazole carboxylic acid dioxane (1.0 mmol), DMAP (1.1 equiv), EDC·HCl (1.1 equiv) dissolved in 4 mL of dichloromethane to a 25 mL dry round-bottom flask. After stirring at room temperature for 15 minutes, add n-butylamine (1.1 mmol), and continue stirring for 8 hours. After the reaction stops, filter through diatomaceous earth, then extract with water and dichloromethane three times. The organic layer is dried over Na2SO4, the solvent of the dried organic layer is evaporated, and the corresponding product is purified by column chromatography.

[0373] Yellow oil, yield 77%.

[0374] 11H NMR (400 MHz, Chloroform-d) δ 7.63 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.3 Hz, 2H), 6.98 (s, 1H), 6.94 - 6.85 (m, 2H), 6.71 (dd, J = 8.3, 2.2 Hz, 1H), 4.23 (dt, J = 17.3, 5.7 Hz, 4H), 3.46 (q, J = 6.8 Hz, 2H), 2.21 (h, J = 5.7, 5.0 Hz, 2H), 1.61 (p, J = 7.2 Hz, 2H), 1.41 (dt, J = 14.5, 7.4 Hz, 2H), 0.95 (t, J = 7.3 Hz, 3H).

[0375] 13 13C NMR (101 MHz, Chloroform-d) δ 158.58, 149.45, 148.79, 146.53, 142.19, 140.02, 127.72, 127.39, 123.95, 123.91, 123.88, 122.96, 122.16, 121.57, 119.77, 119.72, 106.18, 68.26, 68.17, 49.00, 29.11, 28.65, 27.43, 26.64.

[0376] MS (ESI): m / z C 24 H 25 F3N3O3 [M + H] + : Calculated: 460.18, Found: 460.30.

[0377] Example 39

[0378]

[0379] N-tert-Butyl-5-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide:

[0380] Replace n-butylamine with tert-butylamine, and other experimental procedures are the same as in Example 38.

[0381] Yellow solid, yield 73%.

[0382] 11H NMR (400 MHz, Chloroform-d) δ 7.63 (d, J = 8.3 Hz, 2H), 7.45 (d, J = 8.2 Hz, 2H), 6.95 (s, 1H), 6.93 - 6.85 (m, 2H), 6.70 (dd, J = 8.3, 2.2 Hz, 1H), 4.24 (dt, J = 16.3, 5.7 Hz, 4H), 2.21 (p, J = 5.7 Hz, 2H), 1.49 (s, 9H).

[0383] 13 13C NMR (101 MHz, Chloroform-d) δ 161.51, 151.76, 151.09, 147.96, 144.46, 142.32, 142.31, 126.28, 126.24, 126.20, 126.17, 125.18, 124.36, 123.84, 122.07, 122.01, 108.66, 70.55, 70.45, 38.96, 31.81, 31.39, 20.13, 13.78.

[0384] MS (ESI): m / z C 24 H 25 F3N3O3 [M + H] + : Calculated: 460.18, Found: 460.30.

[0385] Example 40

[0386]

[0387] (5-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)(pyrrolidin-1-yl)methanone:

[0388] Replace n-butylamine with pyrrolidine, and other experimental procedures are the same as in Example 38.

[0389] Pale yellow solid, yield 79%.

[0390] 1 1H NMR (400 MHz, Chloroform-d) δ 7.61 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 7.00 (s, 1H), 6.95 - 6.86 (m, 2H), 6.74 (dd, J = 8.3, 2.2 Hz, 1H), 4.24 (dt, J = 17.2, 5.6 Hz, 4H), 4.01 (s, 2H), 3.72 (s, 2H), 2.21 (p, J = 5.7 Hz, 2H).

[0391] 13 C NMR (101 MHz, Chloroform-d) δ 161.44, 151.68, 151.09, 149.32, 143.10, 142.56, 129.63, 129.30, 126.14, 126.10, 126.06, 124.86, 124.62, 123.91, 122.11, 121.98, 110.79, 70.56, 70.47, 48.87, 46.94, 31.43, 26.59, 23.94.

[0392] MS (ESI): m / z C 24 H 23 F3N3O3 [M+H] + : Calculated: 458.16, Found: 458.25.

[0393] Example 41

[0394]

[0395] (5-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)(piperidin-1-yl)methanone:

[0396] Replace n-butylamine with piperidine, and other experimental procedures are the same as in Example 29.

[0397] Yellow solid, yield 81%.

[0398] 1 H NMR (400 MHz, Chloroform-d) δ 7.54 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H), 6.89 - 6.80 (m, 2H), 6.72 (s, 1H), 6.66 (dd, J = 8.3, 2.2 Hz, 1H), 4.17 (dt, J = 17.0, 5.7 Hz, 4H), 3.84 (t, J = 5.4 Hz, 2H), 3.68 (t, J = 5.2 Hz, 2H), 2.14 (p, J = 5.7 Hz, 2H), 1.70 - 1.58 (m, 6H).

[0399] 1313C NMR (101 MHz, Chloroform-d) δ 161.45, 150.67, 150.06, 147.52, 142.17, 141.39, 125.14, 125.10, 125.06, 125.02, 123.91, 123.52, 122.86, 121.06, 120.96, 109.26, 69.53, 69.43, 47.25, 42.62, 30.39, 24.69, 23.68.

[0400] MS (ESI): m / z C 25 H 25 F3N3O3 [M+H] + : Calculated: 472.18, Found: 472.30.

[0401] Example 42

[0402]

[0403] 5-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-N-phenyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide:

[0404] Replace n-butylamine with aniline, and the other experimental procedures are the same as in Example 38.

[0405] Orange-yellow solid, yield 69%.

[0406] 1 1H NMR (400 MHz, Chloroform-d) δ 8.75 (s, 1H), 7.75 - 7.63 (m, 4H), 7.50 (d, J = 8.3 Hz, 2H), 7.41 - 7.33 (m, 2H), 7.18 - 7.11 (m, 1H), 7.08 (s, 1H), 6.98 - 6.86 (m, 2H), 6.74 (dd, J = 8.3, 2.2 Hz, 1H), 4.27 (t, J = 5.7 Hz, 2H), 4.23 (t, J = 5.7 Hz, 2H), 2.22 (p, J = 5.7 Hz, 2H).

[0407] 1313C NMR (101 MHz, Chloroform-d) δ 159.34, 151.89, 151.14, 147.87, 144.98, 142.20, 142.18, 137.75, 129.09, 126.37, 126.33, 126.29, 126.26, 125.31, 124.27, 124.13, 123.87, 122.13, 122.08, 119.79, 108.88, 70.57, 70.47, 31.38.

[0408] MS (ESI): m / z C 26 H 21 F3N3O3 [M+H] + : Calculated: 480.15, Found: 480.30.

[0409] Example 43

[0410]

[0411] 5-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-N-(p-tolyl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide:

[0412] Replace n-butylamine with p-toluidine, and other experimental procedures are the same as in Example 38.

[0413] Orange-yellow solid, yield 78%.

[0414] 1 1H NMR (400 MHz, Chloroform-d) δ 8.72 (s, 1H), 7.67 (ddt, J = 9.1, 2.8, 1.3 Hz, 4H), 7.50 (d, J = 8.2 Hz, 2H), 7.12 - 7.02 (m, 3H), 6.96 - 6.86 (m, 2H), 6.74 (dt, J = 8.3, 1.7 Hz, 1H), 4.31 - 4.25 (m, 2H), 4.25 - 4.20 (m, 2H), 2.22 (p, J = 5.4, 4.9 Hz, 2H).

[0415] 1313C NMR (101 MHz, Chloroform-d) δ 159.29, 151.90, 151.14, 147.67, 145.04, 142.16, 133.76, 133.73, 126.35, 126.31, 125.31, 124.06, 123.86, 122.12, 122.08, 121.53, 121.46, 115.84, 115.62, 108.85, 70.57, 70.46, 31.36.

[0416] MS (ESI): m / z C 27 H 23 F3N3O3 [M+H] + : Calculated: 494.16, Found: 494.25.

[0417] Example 44

[0418]

[0419] 5-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-N-(3,4-dimethylphenyl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide:

[0420] Replace n-butylamine with 3,4-dimethylaniline, and other experimental procedures are the same as in Example 38.

[0421] Orange-yellow solid, yield 70%.

[0422] 1 1H NMR (400 MHz, Chloroform-d) δ 8.60 (s, 1H), 7.42 (d, J = 2.3 Hz, 1H), 7.35 (dd, J = 8.1, 2.3 Hz, 1H), 7.29 - 7.20 (m, 2H), 7.08 - 6.92 (m, 4H), 6.87 - 6.74 (m, 2H), 6.65 (dd, J = 8.3, 2.2 Hz, 1H), 4.16 (t, J = 5.7 Hz, 2H), 4.12 (t, J = 5.7 Hz, 2H), 2.21 - 2.07 (m, 8H).

[0423] 1313C NMR (101 MHz, Chloroform-d) δ 162.48, 160.01, 158.56, 150.76, 150.13, 146.54, 143.88, 136.39, 134.81, 134.78, 134.69, 131.62, 129.16, 126.48, 126.39, 123.53, 122.95, 121.20, 121.01, 120.25, 116.41, 115.38, 115.15, 107.15, 69.69, 69.59, 30.66, 30.57, 29.29, 28.85, 19.07, 18.35.

[0424] MS (ESI): m / z C 28 H 24 F3N3O3 [M+H] + : Calculated: 507.18, Found: 507.25.

[0425] Example 45

[0426]

[0427] 5-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-N-mesityl-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide:

[0428] Replace n-butylamine with 2,4,6-trimethylaniline, and other experimental procedures are the same as in Example 38.

[0429] Yellow solid, yield 62%.

[0430] 1 1H NMR (400 MHz, DMSO-d6) δ 9.66 (s, 1H), 7.87 (d, J = 8.5 Hz, 2H), 7.64 (d, J = 8.4 Hz, 2H), 7.07 (s, 1H), 6.99 (d, J = 8.3 Hz, 1H), 6.95 - 6.81 (m, 4H), 4.17 (t, J = 5.4 Hz, 2H), 4.12 (t, J = 5.5 Hz, 2H), 2.25 (s, 3H), 2.15 (s, 8H).

[0431] 1313C NMR (101 MHz, DMSO-d6) δ 160.02, 151.99, 151.29, 148.10, 144.38, 142.87, 136.11, 135.82, 132.69, 128.94, 128.74, 128.62, 126.84, 126.80, 126.51, 125.70, 124.56, 124.42, 123.00, 122.52, 122.48, 108.94, 70.96, 70.90, 60.22, 31.64, 21.23, 21.00, 18.56, 14.56.

[0432] MS (ESI): m / z C 29 H 26 F3N3O3 [M+H] + : Calculated: 521.19, Found 521.30.

[0433] Example 46

[0434]

[0435] N-(4-Bromophenyl)-5-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide:

[0436] Replace n-butylamine with p-bromoaniline, and other experimental procedures are the same as in Example 38.

[0437] Dark yellow solid, yield 71%.

[0438] 1 1H NMR (400 MHz, Chloroform-d) δ 8.74 (s, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.65 - 7.59 (m, 2H), 7.53 - 7.45 (m, 4H), 7.07 (s, 1H), 6.95 - 6.87 (m, 2H), 6.73 (dd, J = 8.3, 2.3 Hz, 1H), 4.25 (dt, J = 17.3, 5.7 Hz, 4H), 2.22 (p, J = 5.7 Hz, 2H).

[0439] 1313C NMR (101 MHz, Chloroform-d) δ 159.31, 151.92, 151.14, 147.56, 145.11, 142.12, 136.84, 132.05, 130.38, 130.05, 126.36, 126.32, 126.28, 125.32, 123.99, 123.85, 122.12, 122.09, 121.28, 116.79, 108.85, 70.57, 70.46, 31.35.

[0440] MS (ESI): m / z C 26 H 19 BrF3N3O3 [M+H] + : Calculated: 557.06, Found: 557.30.

[0441] Example 47

[0442]

[0443] N-(4-Chlorophenyl)-5-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide:

[0444] Replace n-butylamine with 4-chloroaniline, and other experimental procedures are the same as in Example 38.

[0445] Yellow solid, yield 71%.

[0446] 1 1H NMR (400 MHz, Chloroform-d) δ 8.75 (s, 1H), 7.78 - 7.59 (m, 4H), 7.49 (d, J = 8.3 Hz, 2H), 7.39 - 7.28 (m, 2H), 7.07 (s, 1H), 6.99 - 6.84 (m, 2H), 6.73 (dd, J = 8.3, 2.2 Hz, 1H), 4.27 (t, J = 5.7 Hz, 2H), 4.22 (t, J = 5.7 Hz, 2H), 2.21 (p, J = 5.7 Hz, 2H).

[0447] 1313C NMR (101 MHz, Chloroform-d) δ 159.31, 151.92, 151.14, 147.57, 145.11, 142.12, 136.33, 130.38, 130.05, 129.20, 129.10, 126.39, 126.36, 126.32, 126.28, 125.32, 124.99, 124.00, 123.85, 122.29, 122.12, 122.09, 120.96, 108.85, 70.57, 70.46, 31.36, 29.72, 1.03.

[0448] MS (ESI): m / z C 26 H 19 ClF3N3O3 [M+H] + : Calculated: 513.11, Found: 513.30.

[0449] Example 48

[0450]

[0451] N-(4-Fluorophenyl)-5-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide:

[0452] Replace n-butylamine with p-fluoroaniline, and the other experimental procedures are the same as in Example 38.

[0453] Yellow solid, yield 76%.

[0454] 1 1H NMR (400 MHz, Chloroform-d) δ 8.69 (s, 1H), 7.67 (d, J = 8.5 Hz, 2H), 7.62 - 7.55 (m, 2H), 7.50 (d, J = 8.4 Hz, 2H), 7.21 - 7.13 (m, 2H), 7.07 (s, 1H), 6.95 - 6.86 (m, 2H), 6.74 (dd, J = 8.3, 2.2 Hz, 1H), 4.27 (t, J = 5.7 Hz, 2H), 4.22 (t, J = 5.7 Hz, 2H), 2.34 (s, 3H), 2.21 (p, J = 5.7 Hz, 2H).

[0455] 1313C NMR (101 MHz, Chloroform-d) δ 159.24, 151.87, 151.13, 147.96, 144.90, 142.22, 142.21, 135.20, 133.87, 129.57, 126.35, 126.31, 126.27, 126.23, 125.29, 124.17, 123.87, 122.12, 122.06, 119.83 (d, J = 276 Hz), 108.85, 70.57, 70.47, 31.38, 20.90.

[0456] MS (ESI): m / z C 26 H 20 F4N3O3 [M+H] + : Calculated: 498.14, Found: 498.25.

[0457] Example 49

[0458]

[0459] N-(3-Fluorophenyl)-5-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide:

[0460] Replace n-butylamine with m-fluoroaniline, and the other experimental procedures are the same as in Example 38.

[0461] Yellow solid, yield 82%.

[0462] 1 1H NMR (400 MHz, Chloroform-d) δ 8.79 (s, 1H), 7.72 - 7.63 (m, 3H), 7.50 (d, J = 8.4 Hz, 2H), 7.35 - 7.28 (m, 2H), 7.08 (s, 1H), 6.95 - 6.88 (m, 2H), 6.84 (ddt, J = 10.3, 8.0, 2.4 Hz, 1H), 6.74 (dd, J = 8.3, 2.2 Hz, 1H), 4.25 (dt, J = 17.3, 5.7 Hz, 4H), 2.22 (p, J = 5.7 Hz, 2H).

[0463] 1313C NMR (101 MHz, Chloroform-d) δ 162.44, 160.01, 157.52, 150.08, 149.30, 145.65, 143.26, 140.27, 140.25, 137.46, 137.36, 128.32, 128.23, 124.50, 124.46, 123.47, 122.14, 122.00, 120.27, 120.24 (d, J = 263 Hz), 113.17, 113.14, 109.18, 108.97, 107.02, 105.51, 105.24, 68.72, 68.61, 29.51.

[0464] MS (ESI): m / z C 26 H 20 F4N3O3 [M+H] + : Calculated: 498.14, Found: 498.35.

[0465] Example 50

[0466]

[0467] N-(2-Fluorophenyl)-5-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide:

[0468] Replace n-butylamine with o-fluoroaniline, and the other experimental procedures are the same as in Example 38.

[0469] Yellow solid, yield 88%.

[0470] 1 1H NMR (400 MHz, Chloroform-d) δ 9.03 (d, J = 3.0 Hz, 1H), 8.51 (td, J = 8.1, 1.6 Hz, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.3 Hz, 2H), 7.22 - 7.03 (m, 4H), 6.96 - 6.88 (m, 2H), 6.74 (dd, J = 8.3, 2.2 Hz, 1H), 4.31 - 4.18 (m, 4H), 2.22 (p, J = 5.6 Hz, 2H).

[0471] 1313C NMR (101 MHz, Chloroform-d) δ 159.40, 151.90, 151.14, 147.54, 144.98, 126.31, 126.27, 125.23, 124.65, 124.61, 124.31, 124.23, 124.14, 123.89, 122.14, 122.08, 121.58 (d, J = 258 Hz), 115.01, 114.82, 108.89, 70.57, 70.47, 31.37.

[0472] MS (ESI): m / z C 26 H 20 F4N3O3 [M+H] + : Calculated: 498.14, Found: 498.45.

[0473] Example 51

[0474]

[0475] 5-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-N-(2-fluoro-4-methoxyphenyl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide:

[0476] Replace n-butylamine with 2-fluoro-4-methoxyaniline, and other experimental procedures are the same as in Example 38.

[0477] Dark yellow solid, yield 76%.

[0478] 1 1H NMR (400 MHz, Chloroform-d) δ 8.81 (d, J = 2.5 Hz, 1H), 8.30 (t, J = 9.2 Hz, 1H), 7.66 (d, J = 8.5 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 7.06 (s, 1H), 6.96 - 6.87 (m, 2H), 6.78 - 6.68 (m, 3H), 4.25 (dt, J = 17.1, 5.7 Hz, 4H), 3.81 (s, 3H), 2.22 (p, J = 5.7 Hz, 2H).

[0479] 1313C NMR (101 MHz, Chloroform-d) δ 159.24, 156.73, 156.63, 154.83, 152.40, 151.87, 151.13, 147.63, 144.88, 142.17, 126.29, 126.25, 126.22, 125.22, 124.20, 123.89, 122.90, 122.87, 122.13, 122.06, 119.28, 119.17 (d, J = 275 Hz), 109.45, 109.42, 108.84, 101.97, 101.74, 70.56, 70.46, 55.72, 31.38.

[0480] MS (ESI): m / z C 27 H 22 F4N3O4 [M+H] + : Calculated: 528.15, Found: 528.30.

[0481] Example 52

[0482]

[0483] 5-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-N-(4-methoxyphenyl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide:

[0484] Replace n-butylamine with p-methoxyaniline, and the other experimental procedures are the same as in Example 38.

[0485] Dark yellow solid, yield 81%.

[0486] 1 1H NMR (400 MHz, Chloroform-d) δ 8.65 (s, 1H), 7.71 - 7.57 (m, 4H), 7.50 (d, J = 8.3 Hz, 2H), 7.07 (s, 1H), 6.96 - 6.86 (m, 4H), 6.74 (dd, J = 8.3, 2.3 Hz, 1H), 4.25 (dt, J = 17.1, 5.7 Hz, 4H), 3.82 (s, 3H), 2.22 (p, J = 5.7 Hz, 2H).

[0487] 1313C NMR (101 MHz, Chloroform-d) δ 159.16, 156.40, 151.86, 151.13, 147.96, 144.88, 142.22, 130.90, 126.35, 126.31, 126.28, 126.24, 125.28, 124.18, 123.87, 122.12, 122.06, 121.51, 114.24, 108.84, 70.57, 70.47, 55.49, 31.38.

[0488] MS (ESI): m / z C 27 H 23 F3N3O4 [M+H] + : Calculated: 510.16, Found: 510.30.

[0489] Example 53

[0490]

[0491] 5-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-N-(3,4-dimethoxyphenyl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide:

[0492] Replace n-butylamine with 3,4-dimethoxyaniline, and the other experimental procedures are the same as in Example 38.

[0493] Dark yellow solid, yield 73%.

[0494] 1 1H NMR (400 MHz, Chloroform-d) δ 8.67 (s, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 2.4 Hz, 1H), 7.50 (d, J = 8.3 Hz, 2H), 7.10 - 7.04 (m, 2H), 6.95 - 6.88 (m, 2H), 6.86 (d, J = 8.7 Hz, 1H), 6.74 (dd, J = 8.3, 2.2 Hz, 1H), 4.25 (dt, J = 16.8, 5.7 Hz, 4H), 3.91 (d, J = 17.9 Hz, 6H), 2.22 (p, J = 5.7 Hz, 2H).

[0495] 1313C NMR (101 MHz, Chloroform-d) δ 158.15, 150.84, 150.09, 148.09, 146.87, 144.80, 143.93, 141.17, 141.16, 130.38, 125.30, 125.26, 124.28, 123.08, 122.83, 121.08, 121.04, 110.61, 110.39, 107.71, 103.60, 69.53, 69.42, 55.10, 54.91, 30.33.

[0496] MS (ESI): m / z C 28 H 25 F3N3O5 [M+H] + : Calculated: 540.17, Found: 540.35.

[0497] Example 54

[0498]

[0499] 5-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-N-(3,4,5-trimethoxyphenyl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide:

[0500] Replace n-butylamine with 3,4,5-trimethoxyaniline, and the other experimental steps are the same as in Example 38.

[0501] Yellowish-black solid, yield 76%.

[0502] 1 1H NMR (400 MHz, Chloroform-d) δ 8.71 (s, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.3 Hz, 2H), 7.05 (d, J = 7.8 Hz, 3H), 6.98 - 6.84 (m, 2H), 6.73 (dd, J = 8.3, 2.2 Hz, 1H), 4.27 (t, J = 5.6 Hz, 2H), 4.23 (t, J = 5.7 Hz, 2H), 3.89 (s, 6H), 3.84 (s, 3H), 2.22 (p, J = 5.7 Hz, 2H).

[0503] 1313C NMR (101 MHz, Chloroform-d) δ 159.30, 153.40, 151.91, 151.13, 147.76, 145.10, 142.16, 134.66, 133.86, 130.69, 130.36, 130.03, 126.40, 126.36, 126.33, 126.29, 125.37, 124.99, 124.00, 123.86, 122.28, 122.11, 122.09, 108.70, 97.36, 70.57, 70.46, 60.99, 56.13, 31.51, 31.35, 29.70, 1.03.

[0504] MS (ESI): m / z C 29 H 26 F3N3O6 [M+H] + : Calculated: 569.18, Found: 569.40.

[0505] Example 55

[0506]

[0507] 5-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-N-(4-(trifluoromethyl)phenyl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide:

[0508] Replace n-butylamine with p-(trifluoromethyl)aniline, and other experimental procedures are the same as in Example 38.

[0509] Yellow solid, yield 79%.

[0510] 1 1H NMR (400 MHz, Chloroform-d) δ 8.91 (s, 1H), 7.84 (d, J = 8.4 Hz, 2H), 7.65 (dd, J = 21.2, 8.4 Hz, 4H), 7.50 (d, J = 8.4 Hz, 2H), 7.09 (s, 1H), 6.97 - 6.86 (m, 2H), 6.73 (dd, J = 8.3, 2.2 Hz, 1H), 4.27 (t, J = 5.7 Hz, 2H), 4.23 (t, J = 5.7 Hz, 2H), 2.22 (p, J = 5.7 Hz, 2H).

[0511] 1313C NMR (101 MHz, Chloroform-d) δ 159.47, 151.90, 151.09, 147.30, 145.19, 142.01, 140.73, 130.42, 130.09, 126.36, 126.33, 126.29, 126.25, 126.08, 125.76, 125.43, 125.30, 124.92, 124.32, 123.84, 123.79, 122.73, 122.21, 122.06, 119.28, 114.11, 108.84, 70.51, 70.40, 31.45, 31.38, 31.28, 30.08, 29.65.

[0512] MS (ESI): m / z C 27 H 19 F6N3O3 [M+H] + : Calculated: 547.13, Found: 547.30.

[0513] Example 56

[0514]

[0515] 5-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-N-(furan-2-yl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide:

[0516] Replace n-butylamine with furfurylamine, and other experimental procedures are the same as in Example 38.

[0517] Yellow solid, yield 81%.

[0518] 1 1H NMR (400 MHz, Chloroform-d) δ 7.62 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.37 (dd, J = 1.9, 0.9 Hz, 1H), 7.26 (d, J = 11.6 Hz, 1H), 7.00 (s, 1H), 6.94 - 6.83 (m, 2H), 6.71 (dd, J = 8.3, 2.2 Hz, 1H), 6.39 - 6.24 (m, 2H), 4.65 (d, J = 5.8 Hz, 2H), 4.25 (t, J = 5.6 Hz, 2H), 4.21 (t, J = 5.7 Hz, 2H), 2.20 (p, J = 5.7 Hz, 2H).

[0519] 1313C NMR (101 MHz, Chloroform-d) δ 161.29, 151.80, 151.24, 151.10, 147.47, 144.53, 142.29, 142.26, 142.24, 130.10, 129.77, 129.44, 126.29, 126.25, 126.21, 126.18, 125.18, 125.02, 124.26, 123.85, 122.32, 122.08, 122.03, 110.46, 108.79, 107.64, 70.55, 70.46, 36.15, 31.38, 29.71.

[0520] MS (ESI): m / z C 24 H 18 F3N3O4 [M+H] + : Calculated: 469.12, Found: 469.35.

[0521] Example 57

[0522]

[0523] 5-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-N-(1H-indol-6-yl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide:

[0524] Replace n-butylamine with 6-aminoindole, and other experimental procedures are the same as in Example 38.

[0525] Yellow oil, yield 69%.

[0526] 1 1H NMR (400 MHz, Chloroform-d) δ 8.86 (s, 1H), 8.41 (s, 1H), 8.36 - 8.28 (m, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 8.3 Hz, 2H), 7.20 (t, J = 2.8 Hz, 1H), 7.14 - 6.99 (m, 2H), 6.97 - 6.87 (m, 2H), 6.75 (dd, J = 8.3, 2.3 Hz, 1H), 6.52 (t, J = 2.7 Hz, 1H), 4.27 (t, J = 5.6 Hz, 2H), 4.23 (t, J = 5.7 Hz, 2H), 2.22 (p, J = 5.7 Hz, 2H).

[0527] 1313C NMR (101 MHz, Chloroform-d) δ 159.28, 151.86, 151.13, 148.13, 144.91, 142.24, 136.08, 132.54, 130.23, 129.91, 126.33, 126.29, 126.25, 125.30, 124.84, 124.47, 124.24, 123.90, 122.14, 122.07, 120.80, 113.21, 108.82, 102.88, 102.48, 70.58, 70.48, 53.43, 31.52, 31.39, 30.15, 29.71, 1.03.

[0528] MS (ESI): m / z C 28 H 21 F3N4O3 [M+H] + : Calculated: 518.16, Found: 518.40.

[0529] Example 58

[0530]

[0531] 5-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-N-(quinolin-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide:

[0532] Replace n-butylamine with 4-aminoquinoline, and the other experimental procedures are the same as in Example 38.

[0533] Yellow solid, yield 66%.

[0534] 1 1H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H), 8.90 (d, J = 4.9 Hz, 1H), 8.21 - 8.11 (m, 1H), 8.10 - 7.99 (m, 2H), 7.92 (d, J = 8.4 Hz, 2H), 7.80 (ddd, J = 8.4, 6.9, 1.3 Hz, 1H), 7.76 - 7.59 (m, 3H), 7.26 (s, 1H), 7.05 - 6.94 (m, 2H), 6.89 (dd, J = 8.2, 2.2 Hz, 1H), 4.15 (dt, J = 17.8, 5.5 Hz, 4H), 2.12 (p, J = 5.4 Hz, 2H).

[0535] 1313C NMR(101MHz, DMSO-d6) δ 160.71, 152.12, 151.33, 151.24, 149.14, 147.50, 144.85, 142.76, 141.45, 130.09, 129.87, 129.23, 128.91, 127.00, 126.97, 126.93, 126.71, 126.63, 125.68, 124.44, 124.23, 122.98, 122.94, 122.58, 122.54, 122.29, 114.41, 109.30, 70.99, 70.92, 55.38, 31.62, 30.30, 29.47.

[0536] MS(ESI): m / z C 29 H 21 F3N4O3 [M+H] + : Calculated: 530.16, Found: 530.55.

[0537] Example 59

[0538]

[0539] N-Benzyl-5-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide:

[0540] Replace n-butylamine with benzylamine, and the other experimental procedures are the same as in Example 38.

[0541] White solid, yield 77%.

[0542] 1 1H NMR(400MHz, Chloroform-d) δ 7.61(d, J = 8.5Hz, 2H), 7.43(d, J = 8.4Hz, 2H), 7.39 - 7.34(m, 3H), 7.34 - 7.26(m, 2H), 7.02(s, 1H), 6.95 - 6.85(m, 2H), 6.71(dd, J = 8.3, 2.2Hz, 1H), 4.66(d, J = 6.0Hz, 2H), 4.24(dt, J = 17.1, 5.7Hz, 4H), 2.21(p, J = 5.7Hz, 2H).

[0543] 1313C NMR (101 MHz, Chloroform-d) δ 161.44, 151.80, 151.11, 147.66, 144.54, 142.26, 138.23, 128.72, 127.94, 127.53, 126.27, 126.23, 126.19, 126.16, 125.16, 124.31, 123.85, 122.08, 122.03, 108.80, 70.55, 70.46, 43.26, 31.39.

[0544] MS (ESI): m / z C 27 H 23 F3N3O3 [M+H] + : Calculated: 494.16, Found: 494.30.

[0545] Example 60

[0546]

[0547] 5-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-N-(4-methoxybenzyl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide:

[0548] Replace n-butylamine with 4-methoxybenzylamine, and the other experimental procedures are the same as in Example 38.

[0549] White solid, yield 71%.

[0550] 1 1H NMR (400 MHz, Chloroform-d) δ 7.61 (d, J = 8.5 Hz, 2H), 7.42 (d, J = 8.3 Hz, 2H), 7.33 - 7.28 (m, 2H), 7.01 (s, 1H), 6.94 - 6.83 (m, 4H), 6.71 (dd, J = 8.3, 2.2 Hz, 1H), 4.59 (d, J = 5.9 Hz, 2H), 4.24 (dt, J = 17.3, 5.7 Hz, 4H), 3.80 (s, 3H), 2.21 (p, J = 5.7 Hz, 2H).

[0551] 1313C NMR (101 MHz, Chloroform-d) δ 161.37, 159.06, 151.80, 151.11, 147.72, 144.50, 142.27, 142.25, 130.33, 129.31, 126.25, 126.21, 126.18, 126.14, 125.15, 124.31, 123.85, 122.08, 122.03, 114.08, 108.78, 70.55, 70.46, 55.29, 42.73, 31.39.

[0552] MS (ESI): m / z C 28 H 25 F3N3O4 [M+H] + : Calculated: 524.18, Found: 524.30.

[0553] Example 61

[0554]

[0555] 5-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-N-(4-(trifluoromethyl)benzyl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide:

[0556] Replace n-butylamine with 4-(trifluoromethyl)benzylamine, and the other experimental procedures are the same as in Example 38.

[0557] Yellow solid, yield 79%.

[0558] 1 1H NMR (400 MHz, Chloroform-d) δ 7.61 (dd, J = 10.9, 8.3 Hz, 4H), 7.49 (d, J = 8.0 Hz, 2H), 7.41 (dd, J = 21.0, 7.4 Hz, 3H), 7.02 (s, 1H), 6.95 - 6.84 (m, 2H), 6.71 (dd, J = 8.3, 2.2 Hz, 1H), 4.71 (d, J = 6.2 Hz, 2H), 4.26 (t, J = 5.6 Hz, 2H), 4.22 (t, J = 5.7 Hz, 2H), 2.21 (p, J = 5.7 Hz, 2H).

[0559] 1313C NMR (101 MHz, Chloroform-d) δ 160.94, 151.13, 150.41, 146.63, 144.00, 141.69, 141.48, 129.80, 129.48, 129.21, 129.15, 128.89, 127.44, 127.28, 125.60, 125.56, 125.52, 125.49, 124.98, 124.94, 124.91, 124.87, 124.75, 124.47, 124.28, 123.45, 123.13, 122.04, 121.57, 121.37, 121.35, 108.08, 69.85, 69.74, 41.98, 30.65, 28.99.

[0560] MS (ESI): m / z C 28 H 21 F6N3O3 [M+H] + : Calculated value: 561.15, Measured value: 561.20.

[0561] Test Example 1

[0562] Antibacterial test:

[0563] The medium required for the strain is Mueller-Hinton medium (MH medium: 17.5 g of casein hydrolysate, 1.5 g of soluble starch, 1000 ml of beef extract).

[0564] The minimum inhibitory concentration (MIC) value of the test compound is determined by the colorimetric method of MTT (3-(4,5-dimethylpyridin-2-yl)-2,5-diphenyl bromide).

[0565] The compound was dissolved in dimethyl sulfoxide (DMSO) to prepare a storage solution with a concentration of 100 μg / mL, and the storage solution was added to a specified volume of sterile liquid MH medium in gradient amounts. A specific volume of the compound solution containing the medium was added to a microtiter plate. A suspension with a bacterial count of approximately 105 cfu / mL was prepared and added dropwise to the microtiter plate, and incubated at 37 °C for 24 h together with the serially diluted compound. After measuring the MIC value of each microtiter plate by microscopy, phosphate buffer solution (PBS; 50 mL, 0.01 M, pH 7.4, 2.9 g Na2HPO4·12H2O, 0.2 g KH2PO4, 8.0 g NaCl, 0.2 g KCl, 1000 ml distilled water) with an MTT concentration of 2 mg / mL was added to each well. It was left at room temperature for 4 - 5 hours, the reaction solution in each well was removed, and 100 mL of isopropanol containing 5% HCl (final concentration of 1 M) was added to extract the dye. After incubation at room temperature for 12 hours, the microplate reader was set to measure the optical density (OD) at 550 nm. The test results are shown in Table 1:

[0566] Table 1. Antibacterial effect

[0567]

[0568]

[0569]

[0570]

[0571] As can be seen from Table 1, most compounds have certain antibacterial abilities against both Gram-positive and Gram-negative bacteria. By introducing different amine compounds, their antibacterial activities were evaluated. Taking kanamycin B as a reference, the inhibitory effects of various amide compounds on two Gram-negative bacteria (Escherichia coli and Pseudomonas fluorescens) and two Gram-positive bacteria (Staphylococcus aureus and Bacillus subtilis) were compared. When the amino group of the amide was modified with a hydrophobic region structure, the lipophilicity and membrane permeability did not significantly improve the antibacterial activity. However, fluorination of the benzene ring significantly improved the antibacterial activity, and the MIC values for the four common bacterial strains were between 12.5 μg / mL and 25 μg / mL, and the antibacterial activity was enhanced. In this regard, the antibacterial performance of derivatives with fluorine substitution at two different positions was also consistent with the previous results. Among halogen substitutions, fluorine-substituted derivatives had better antibacterial activities than the corresponding bromine- and chlorine-substituted derivatives. Derivatives containing a trifluoromethyl substituent had significantly better antibacterial activities than the corresponding derivatives without a substituent at the same position.

[0572] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than limiting the protection scope of the present invention. Any simple modification or equivalent replacement made by those of ordinary skill in the art to the technical solution of the present invention shall not depart from the essence and scope of the technical solution of the present invention.

Claims

1. An amide compound, characterized in that, Having the structural formula described in Formula I: Wherein, R1 is selected from substituted or unsubstituted C6-C 15 aryl; the substituents are selected from at least one of halogen and haloalkyl; R2 and R3 are each independently selected from substituted or unsubstituted C1-C 10 alkyl, C6-C 20 aryl, C 3- C 10 heterocycle; the substituents are selected from at least one of C1-C5 alkyl, C1-C5 alkoxy, halogen, haloalkyl or amino; or R2 and R3 together with the atoms to which they are attached form a 5- to 8-membered carbocyclic or heterocyclic ring, the heterocyclic ring optionally containing 1 to 3 heteroatoms selected from O, N or S.

2. The amide compound according to claim 1, wherein Wherein, R1 is selected from substituted or unsubstituted C6-C 12 aryl; the substituents are selected from at least one of F, Cl, Br, and fluoroalkyl; R2 and R3 are each independently selected from substituted or unsubstituted C1-C8 alkyl, C6-C 18 aryl, C4-C8 heterocycle; the substituent is selected from at least one of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, I, fluoroalkyl or amino; or R2 and R3 together with the atoms to which they are attached form a 5-7 membered carbocyclic or heterocyclic ring, and the heterocyclic ring optionally contains 1-3 heteroatoms selected from O or S.

3. The amide compound according to claim 2, wherein Wherein, R1 is selected from substituted or unsubstituted C6-C 10 aryl; the substituents are selected from at least one of F and CF3; R2 and R3 are each independently selected from substituted or unsubstituted C1-C5 alkyl, C6-C 15 aryl, C4-C7 heterocycle; the substituent is selected from at least one of C1-C3 alkyl, C1-C3 alkoxy, F, Cl, Br, CF3 or amino; or R2 and R3 together with the atoms to which they are attached form a 5-6 membered carbocyclic or heterocyclic ring, and the heterocyclic ring optionally contains 1-3 O atoms.

4. The amide compound according to claim 3, wherein The amide compound has the structural formula described in Formula II: Wherein, R2 and R3 are as described in any one of claims 1-3; R4 is selected from substituted or unsubstituted C1-C5 alkyl, C6-C 15 aryl, C4-C7 heterocycle; the substituent is selected from at least one of C1-C3 alkyl, C1-C3 alkoxy, F, Cl, Br, CF3 or amino.

5. The amide compound according to claim 4, wherein Selected from the following structural formulas:

6. The amide compound according to claim 5, wherein The amide compound is selected from the following structural formulas:

7. The amide compound according to claim 6, wherein The amide compound is selected from the following structural formulas:

8. A process for preparing the amide compound according to any one of claims 1 to 7, characterized in that, The reaction equation is as shown below and includes the following steps: S1: Compound A reacts with 1,3-dibromopropane to obtain Compound B; S2: Compound B reacts with dimethyl oxalate and sodium methoxide / methanol solution to obtain Compound C; S3: Compound C and phenylhydrazine hydrochloride undergo an esterification reaction and then hydrolysis under alkaline conditions to obtain Compound E; S4: Compound E and an amine react in the presence of a catalyst to obtain Compound F.

9. The preparation method according to claim 8, characterized in that In step S1, a solvent is involved, and the solvent is an alcohol.

10. The preparation method according to claim 8, characterized in that, Step S1 also includes a post-treatment step.

11. According to the preparation method described in claim 8, characterized in that, In step S2, a solvent is involved, and the solvent is an alcohol.

12. The preparation method according to claim 8, characterized in that In step S2, the molar ratio of Compound B to dimethyl oxalate is 1:2-4.

13. The preparation method according to claim 8, wherein, In step S3, the molar ratio of Compound C to the substituted benzene derivative hydrochloride is 1:1-1.

1.

14. The preparation method according to claim 8, characterized in that, In step S3, the substituted benzene derivative hydrochloride is selected from at least one of phenylhydrazine hydrochloride, trifluoromethylphenyl hydrochloride, or p-fluorophenyl hydrochloride.

15. The preparation method according to claim 8, characterized in that, In step S3, the base used under the alkaline condition is sodium hydroxide.

16. The preparation method according to claim 8, characterized in that, In step S4, the condensing agent is a combination of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and 4-dimethylaminopyridine or a combination of 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate and N,N-diisopropylethylamine.

17. Use of the amide compound according to any one of claims 1-7 in antibacterial.

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