Use of N-substituted benzylpyrazole derivatives as β2-adrenergic receptor modulators, antagonists and agonists

Abstract

The present invention belongs to the field of medicinal chemistry and relates to the application of N-substituted benzylpyrazole derivatives as allosteric modulators, antagonists, and agonists of the β2-adrenergic receptor. The present invention uses acetophenone or acetophenone with different substituents as raw materials, undergoes a Claisen condensation reaction, cyclization, and then substitution and hydrolysis reactions, followed by an amide coupling reaction to finally obtain a series of new pyrazole derivatives with the structure shown in formula (1), where R1 is a hydrogen atom, a halogen atom, a nitro group, or a methoxy group; R2 is a hydrogen atom, a halogen atom, a cyano group, a nitro group, or a methoxy group; and R3 is a halogen atom. Functional activity screening of the G protein-dependent signaling pathway was performed on all synthesized compounds, and it was found that these new derivatives can act as agonists, positive allosteric modulators (PAMs), antagonists, and negative allosteric modulators (NAMs) of the β2-adrenergic receptor. #imgabs0#

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and particularly relates to a preparation method of N-substituted benzylpyrazole derivatives and their application as allosteric modulators of β2-adrenergic receptors. Background Art

[0002] G-protein coupled receptors (GPCRs) are a class of membrane receptor proteins with a seven-transmembrane structure and are also key drug targets. Currently, more than 30% of the drugs approved by the FDA target GPCRs. GPCRs can be divided into six categories, but only four categories (A, B, C, and F) exist in humans. Among them, class A (rhodopsin) contains the largest number of GPCRs (719 in humans). Approximately half of the class A GPCRs are sensory receptors involved in olfaction (pheromone receptors) or vision (rhodopsin). Adrenergic receptors (ARs) are a class of class A GPCR subfamily and play an important role in the sympathetic nervous system. For example, β1-adrenergic receptor (β1AR) antagonists are used for cardiovascular diseases, while β2-adrenergic receptor (β2AR) antagonists are used to treat asthma.

[0003] Among the existing GPCR drugs, the vast majority target the orthosteric binding sites of GPCRs. At this site, the binding of endogenous ligands induces signal transduction. The compounds produced by this method either directly activate the target GPCR (agonist) or block the action of endogenous ligands (antagonist or inverse agonist). Therefore, the high conservation among different subtypes poses a great challenge to the development of selective drugs.

[0004] Allosteric ligands (also known as allosteric ligands) affect receptor activity by binding to a conformationally different site from the orthosteric ligand binding site. Allosteric ligands regulate their effects by inducing conformational changes in the GPCR protein. These changes are transferred from the allosteric binding pocket to the orthosteric site or directly to the effector protein coupling site. Due to their relatively low binding position conservation, they may have better subtype selectivity. Compared with traditional drugs, allosteric drugs targeting GPCRs not only have better selectivity but also can reduce potential drug side effects caused by off-target effects. In addition, allosteric modulators can also act synergistically with orthosteric ligands, locking the receptor in a specific conformation, thereby enabling the receptor to exhibit specific signal transduction, and further endowing the allosteric modulator with pharmacodynamic characteristics different from those of orthosteric ligands. β2AR antagonists are very classic GPCR drugs and play an important role in the treatment of diseases such as heart failure, hypertension, coronary heart disease, arrhythmia, and angina pectoris. They are the cornerstone for the treatment of cardiovascular diseases. Therefore, the development and design of β2AR allosteric antagonists are of great significance for the treatment of various cardiovascular diseases.

[0005] In 2017, our laboratory collaborated with scientists from Duke University in the United States and reported a small molecule negative allosteric modulator, Compound 15 (Cmpd-15, as shown in Formula 2), which is the first intracellular allosteric antagonist of the β2-adrenergic receptor (Proc. Natl. Acad. Sci. USA, 2017, 114: 1708-1713; Nature, 2017, 548: 480-484). However, since Cmpd-15 is a peptide compound with poor water solubility and relatively low biological activity, its relatively unstable structure may affect its drugability.

[0006]

[0007] Pyrazole (C3H3N2H) is a nitrogen-containing heterocyclic compound with good stability and broad-spectrum pharmacological properties and has become an attractive core skeleton in drug design.

[0008] In order to expand the structural types of lead compounds, improve their activity, stability, and drugability, the present invention uses the scaffold hopping strategy to replace the peptide core structure of Cmpd-15 with a pyrazole skeleton. Based on the scaffold hopping strategy, the key functional groups at three positions of Cmpd-15 are retained to form a heterocyclic derivative with a pyrazole as the core structure, and the activity and specificity of the new heterocyclic derivative against β2AR are evaluated. The design idea of the new heterocyclic derivative is shown in Formula 3. The pharmacophores on the left, middle, and right sides of Cmpd-15 are respectively connected to the pyrazole ring, thus forming a pyrazole type compound. It is expected that the stability of the designed heterocyclic derivative is better than that of Cmpd-15, which may improve the binding ability to β2AR and has better drugability.

[0009]

[0010] Considering that the amide bond prepared from α-substituted phenylacetic acid is extremely easy to hydrolyze and cannot exist stably. Therefore, it was decided to remove the amide bond and connect benzyl groups with different substituents (Formula 4), so as to make the final target compound exist stably.

[0011] Summary of the Invention

[0012] The present invention uses acetophenones with different substituents as raw materials, undergoes Claisen condensation, cyclization, and then substitution, ester hydrolysis, and amide coupling reactions to finally obtain a series of new pyrazole derivatives. The purpose of the present invention is to prepare N-substituted pyrazole derivatives to develop new heterocyclic derivatives with stable chemical structures, high biological activities, good receptor subtype selectivity, and improved water solubility, as allosteric modulators of β2-AR, providing a new direction for the research and development of new drugs for cardiovascular and cerebrovascular diseases, diabetes, and cancer.

[0013] N-Substituted benzyl pyrazole ring analog structure:

[0014]

[0015] Table 1 Structures of N-substituted benzyl pyrazole derivatives

[0016]

[0017]

[0018]

[0019] Synthetic route of N-substituted benzyl pyrazole ring derivatives:

[0020]

[0021] The specific synthesis method steps of N-substituted benzyl pyrazole derivatives are as follows:

[0022] The specific synthesis steps are:

[0023] (1) Under ice bath, dissolve substituted acetophenone 1 and diethyl oxalate in ethanol, add sodium ethoxide, and react at room temperature overnight to form β-ketoester compound 2. The molar ratio of acetophenone 1: diethyl oxalate: sodium ethoxide is 1: 1.2: 3.

[0024] (2) Under ice bath, react compound 2 with hydrazine monohydrate in acetic acid overnight to form pyrazole ring structure compound 3. The molar ratio of compound 2: hydrazine monohydrate is 1: 1.2.

[0025] (3) Under heating and reflux conditions, dissolve compound 3, potassium carbonate and substituted benzyl chloride in acetonitrile to form compound 4. The molar ratio of compound 3: potassium carbonate: substituted benzyl chloride is 1: 1.2: 1.3; wherein the substituent R2 of the substituted benzyl chloride is a halogen atom, a methoxy group, a nitro group, a cyano group, etc.

[0026] (4) At room temperature, dissolve compound 4 in methanol, add 4N sodium hydroxide solution, and react overnight to form compound 5.

[0027] (5) Under an ice bath, compound 5 and compound (S)-2-amino-3-(3-bromophenyl)-N-methylpropanamide (Bioorganic & Medicinal Chemistry, 2018, 26: 2320-2330) underwent an amide coupling reaction in DMF under the action of a coupling reagent (HOAT, NMM, EDCI) to obtain compound 6. The molar ratio of compound 5: HOAT: compound (S)-2-amino-3-(3-bromophenyl)-N-methylpropanamide: NMM: EDCI was 1: 1.2: 1: 0.7: 1.2.

[0028] The new derivatives of N-substituted benzylpyrazole can be used as agonists, antagonists, allosteric agonists, and allosteric antagonists of β2-AR;

[0029] Furthermore, compound H in Table 1 30 、H 31 、H 32 has agonist activity and can be used as an agonist of β2-AR;

[0030] Furthermore, compound H in Table 1 31 has both agonist activity and allosteric activity and can be used as an allosteric agonist of β2-AR;

[0031] Furthermore, compounds H2, H3, H5, H6, H8, H9, H 10 、H 11 、H 12 、H 17 、H 22 、H 23 、H 34 、H 35 、H 54 、H 55 、I2, I4, I6 have β2AR antagonistic effects and can be used as antagonists of β2-AR;

[0032] Furthermore, compounds H2, H 22 、H 23 、H 34 、H 54 、H 55 、I2, I4, I6 have both antagonistic activity and allosteric activity and can be used as allosteric antagonists of β2-AR;

[0033] Furthermore, compounds H2, H4, H7, H 13 、H 16 、H 22 、H 23 、H 24 、H 25 、H 26 、H27 , H 28 , H 29 , H 31 , H 33 , H 34 , H 37 , H 38 , H 43 , H 44 , H 45 , H 46 , H 47 , H 48 , H 49 , H 50 , H 51 , H 52 , H 53 , H 54 , H 55 , I2, I3, I4, I6, I7, I8, I9, have allosteric activity and can be used as allosteric modulators of β2-AR.

[0034] The beneficial effects of the present invention are as follows:

[0035] The N-substituted benzylpyrazole new derivatives can be used as agonists, antagonists, allosteric agonists, and allosteric antagonists of β2-AR, providing a new direction for the research and development of new drugs for cardiovascular and cerebrovascular diseases, diabetes, and cancer. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 is the structural diagram and ISO concentration-dependent curve of H 31 ;

[0037] Figure 2 is the EC 30 , H 31 , H 32 curve of 50 . DETAILED DESCRIPTION OF THE INVENTION

[0038] Preparation of N-substituted benzylpyrazole derivatives:

[0039] Example 1:

[0040] Preparation of (S)-1-benzyl-N-[3-(3-bromophenyl)-1-acylated methylamino-2-yl]-3-phenyl-1H-pyrazole-5-carboxamide H1

[0041] Step 1: Preparation of ethyl 2,4-dioxo-4-phenylbutyrate

[0042] Under an ice bath, acetophenone (500 mg, 3.4 mmol), diethyl oxalate (0.61 mL, 5.2 mmol) and sodium ethoxide (5 mL, 20% mass content, 0.01 mmol) were successively added to the reactor, and the mixture was vigorously stirred in ethanol until completely dissolved. The reaction was carried out overnight at room temperature. Under an ice bath, the pH was adjusted to 2 - 3 with 4N hydrochloric acid, and the mixture was extracted with ethyl acetate (30 mL). The organic phase was washed with saturated brine and concentrated to obtain the crude product ethyl 2,4-dioxo-4-phenylbutyrate.

[0043] Step 2: Preparation of 4-phenylpyrazole-1-carboxylate

[0044] The crude product from Step 1 was dissolved in 10 mL of acetic acid. Hydrazine monohydrate (0.3 mL, 6.2 mmol) was slowly added dropwise under an ice bath. After reacting at room temperature for 10 h, the mixture was extracted with ethyl acetate (30 mL). The organic phase was washed with saturated brine and concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain 740.6 mg of a milky white solid compound 4-phenylpyrazole-1-carboxylate. The total yield of the two steps was 82%. 1 H NMR (400 MHz, CDCl3): δ 7.73 - 7.67 (m, 2H), 7.40 - 7.29 (m, 3H), 6.97 (s, 1H), 4.17 (q, J = 7.1 Hz, 2H), 1.19 (t, J = 7.1 Hz, 3H).

[0045] Step 3: Preparation of N-2-benzyl-phenylpyrazole-1-carboxylate

[0046] 4-Phenylpyrazole-1-carboxylate (500 mg, 2.3 mmol) was dissolved in 10 mL of acetonitrile. Potassium carbonate (415.4 mg, 3 mmol) and benzyl chloride (0.27 mL, 2.3 mmol) were added, and the mixture was heated to reflux at 90 °C for 12 h. The mixture was extracted with ethyl acetate (30 mL). The organic phase was washed with saturated brine and concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 50:1) to obtain 538.4 mg of a white solid compound N-2-benzyl-phenylpyrazole-1-carboxylate with a yield of 76%. 1 H NMR (300 MHz, DMSO-d6): δ 7.90 - 7.86 (m, 2H), 7.45 - 7.40 (m, 3H), 7.37 - 7.24 (m, 4H), 7.21 - 7.18 (m, 2H), 5.77 (s, 2H), 4.30 (q, J = 7.1 Hz, 2H), 1.28 (t, J = 7.1 Hz, 3H). 1313C NMR (75 MHz, DMSO-d6): δ 159.0, 149.5, 137.4, 133.5, 132.0, 128.8, 128.6, 128.2, 127.6, 127.0, 125.3, 108.4, 61.1, 54.4, 14.0.

[0047] Step 4: Preparation of N-2-benzyl-phenylpyrazole-1-carboxylic acid

[0048] Dissolve N-2-benzyl-phenylpyrazole-1-carboxylate (538.4 mg, 1.8 mmol) in 12 mL of methanol, add 4 mL of 4N sodium hydroxide solution, and stir at room temperature for 10 h. Adjust the pH to 4 with 4N hydrochloric acid under ice bath conditions, extract with ethyl acetate (30 mL), wash the organic phase with saturated brine, and concentrate to obtain 425.5 mg of white solid compound N-2-benzyl-phenylpyrazole-1-carboxylic acid with a yield of 87%.

[0049] Step 5: Preparation of (S)-1-benzyl-N-[3-(3-bromophenyl)-1-acylated methylamino-2-yl]-3-phenyl-1H-pyrazole-5-carboxamide

[0050] Dissolve N-2-benzyl-phenylpyrazole-1-carboxylic acid (30 mg, 0.1 mmol) and HOAT (24.5 mg, 0.2 mmol) in 5 mL of DMF, stir at room temperature for 10 min under nitrogen protection, add compound (S)-2-amino-3-(3-bromophenyl)-N-methylpropanamide (38.5 mg, 0.1 mmol) at 0 °C, continue to stir for 10 min, add N-methylmorpholine (0.009 mL, 0.08 mmol) at 0 °C, stir for 10 min, add EDCI (24.8 mg, 0.1 mmol), maintain stirring at 0 °C for 1 h, and react at room temperature for 12 h. Extract with ethyl acetate (30 mL), wash the organic phase with saturated brine, and concentrate by column chromatography (dichloromethane:methanol = 40:1) to obtain 19 mg of white solid compound (S)-1-benzyl-N-[3-(3-bromophenyl)-1-acylated methylamino-2-yl]-3-phenyl-1H-pyrazole-5-carboxamide with a yield of 34%. 1HNMR(300MHz, DMSO-d6): δ 8.78 (d, J = 8.6 Hz, 1H), 8.09 (q, J = 4.5 Hz, 1H), 7.76 (d, J = 7.2 Hz, 2H), 7.57 (s, 1H), 7.47 - 7.20 (m, 10H), 7.13 - 7.11 (m, 2H), 5.73 - 5.56 (m, 2H), 4.63 (ddd, J = 10.4, 8.6, 4.4 Hz, 1H), 3.11 (dd, J = 13.6, 4.4 Hz, 1H), 2.92 (dd, J = 13.6, 10.6 Hz, 1H), 2.63 (d, J = 4.6 Hz, 3H). 13 C NMR(75MHz, DMSO-d6): δ 170.8, 159.0, 148.9, 141.0, 137.7, 136.4, 132.4, 132.0, 130.2, 129.2, 128.9, 128.4, 128.2, 128.0, 127.3, 125.0, 121.4, 104.9, 54.2, 53.7, 36.9, 25.7. HRMS(ESI, m / z): Calcd. for C 27 H 25 BrN4O2 [M + Na] + 539.1059, found: 539.1056.

[0051] Example 2:

[0052] (S)-1-Benzyl-1[3-(3-bromophenyl)-1-acylated methylamino-2-yl]-3-o-tolyl-1H-pyrazole-5-carboxamide H2 Preparation

[0053] Under other conditions the same as in Example 1, changing acetophenone to 2-methylacetophenone, the product is a white solid with a yield of 29%. 1 HNMR(400MHz, DMSO-d6): δ 8.91 (dd, J = 34.6, 8.7 Hz, 1H), 8.19 - 8.16 (m, 1H), 7.57 - 7.45 (m, 2H), 7.37 - 7.17 (m, 10H), 7.12 (d, J = 6.8 Hz, 2H), 5.77 - 5.60 (m, 2H), 4.63 (td, J = 10.8, 10.1, 6.5 Hz, 1H), 3.11 (dd, J = 13.6, 4.4 Hz, 1H), 2.94 (t, J = 12.2 Hz, 1H), 2.62 (d, J = 4.5 Hz, 3H), 2.47 (s, 3H). 1313C NMR (75 MHz, DMSO-d6) δ 170.9, 159.1, 149.2, 141.1, 137.8, 135.4, 135.2, 132.0, 132.0, 131.0, 130.2, 129.2, 128.5, 128.3, 128.3, 127.8, 127.4, 127.3, 126.0, 121.4, 107.8, 54.20, 53.6, 36.9, 25.7, 21.2. HRMS (ESI, m / z): Calcd. for C 28 H 27 BrN4O2 [M+Na] + 553.1215, found: 553.1210.

[0054] Example 3:

[0055] (S)-1-Benzyl-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-(m-tolyl)-1H-pyrazole-5-carboxamide H3 Preparation

[0056] Under other conditions the same as in Example 1, acetophenone was changed to 3-methylacetophenone, and the product was a white solid with a yield of 32%. 1 1H NMR (300 MHz, DMSO-d6): δ 8.84 (d, J = 8.7 Hz, 1H), 8.17 (d, J = 4.6 Hz, 1H), 7.59 - 7.54 (m, 3H), 7.45 (s, 1H), 7.39 - 7.09 (m, 10H), 5.73 - 5.55 (m, 2H), 4.63 (ddd, J = 10.6, 8.6, 4.3 Hz, 1H), 3.12 (dd, J = 13.6, 4.4 Hz, 1H), 2.95 (dd, J = 13.6, 10.7 Hz, 1H), 2.62 (d, J = 4.5 Hz, 3H), 2.35 (s, 3H). 13 13C NMR (75 MHz, DMSO-d6): δ 170.9, 159.0, 149.0, 141.1, 138.0, 137.7, 136.3, 132.3, 132.0, 130.2, 129.2, 128.8, 128.6, 128.4, 128.3, 127.3, 125.5, 122.2, 121.4, 105.1, 54.2, 53.6, 36.9, 25.7, 21.1. HRMS (ESI, m / z): Calcd. for C 28 H 27 BrN4O2 [M+Na] +553.1215, found: 553.1210.

[0057] Example 4:

[0058] (S)-1-Benzyl-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-(p-tolyl)-1H-pyrazole-5-carboxamide H4 Preparation

[0059] Under other conditions the same as in Example 1, acetophenone was changed to 4-methylacetophenone, and the product was a white solid with a yield of 34%. 1 HNMR(400MHz, DMSO-d6): δ8.78(d, J = 8.6Hz, 1H), 8.10(d, J = 4.6Hz, 1H), 7.65(d, J = 8.0Hz, 2H), 7.57(s, 1H), 7.37(d, J = 10.3Hz, 2H), 7.31 - 7.18(m, 7H), 7.11(d, J = 6.7Hz, 2H), 5.71 - 5.55(m, 2H), 4.63(ddd, J = 10.7, 8.6, 4.3Hz, 1H), 3.11(dd, J = 13.6, 4.4Hz, 1H), 2.93(dd, J = 13.6, 10.7Hz, 1H), 2.63(d, J = 4.5Hz, 3H), 2.32(s, 3H). 13 C NMR(75MHz, DMSO-d6) δ170.9, 159.1, 149.0, 141.1, 137.8, 137.3, 136.4, 132.0, 130.3, 129.7, 129.5, 129.2, 128.4, 128.3, 127.4, 125.0, 121.4, 104.7, 54.2, 53.6, 36.9, 25.7, 20.8. HRMS(ESI, m / z): Calcd. for C 28 H 27 BrN4O2[M + Na] + 553.1215, found: 553.1210.

[0060] Example 5:

[0061] (S)-1-Benzyl-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-(4-methoxyphenyl)-1H-pyrazole-5-carboxamide H5 Preparation

[0062] Under other conditions the same as in Example 1, acetophenone was changed to p-methoxyacetophenone, and the product was a white solid with a yield of 32%. 11H NMR (400 MHz, DMSO-d6): δ 8.75 (d, J = 8.6 Hz, 1H), 8.09 (d, J = 4.7 Hz, 1H), 7.68 (d, J = 8.8 Hz, 2H), 7.57 (s, 1H), 7.38 (d, J = 7.9 Hz, 1H), 7.29 - 7.19 (m, 6H), 7.11 - 7.10 (m, 2H), 7.01 (d, J = 8.9 Hz, 2H), 5.70 - 5.54 (m, 2H), 4.62 (ddd, J = 10.6, 8.5, 4.4 Hz, 1H), 3.78 (s, 1H), 3.10 (dd, J = 13.6, 4.4 Hz, 1H), 2.92 (dd, J = 13.6, 10.6 Hz, 1H), 2.62 (d, J = 4.5 Hz, 3H). 13 13C NMR (75 MHz, DMSO-d6) δ 170.9, 159.1, 159.1, 148.8, 141.0, 137.8, 136.3, 132.0, 130.3, 129.2, 128.4, 128.2, 127.3, 127.3, 126.3, 125.1, 121.4, 114.3, 104.4, 55.2, 54.1, 53.5, 36.9, 25.7. HRMS (ESI, m / z): Calcd. for C 28 H 27 BrN4O2 [M + Na] + 569.1154, found: 569.1160.

[0063] Example 6:

[0064] (S)-1-Benzyl-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-(2-fluorophenyl)-1H-pyrazole-5-carboxamide H6 Preparation

[0065] Under other conditions the same as in Example 1, acetophenone was replaced with 2-fluorophenacyl, and the product was a white solid with a yield of 33%. 1HNMR(400MHz, DMSO-d6) δ 8.93 (d, J = 8.6 Hz, 1H), 8.11 (d, J = 4.8 Hz, 1H), 7.94 (t, J = 6.9 Hz, 1H), 7.56 (s, 1H), 7.45 - 7.17 (m, 10H), 7.12 (d, J = 6.4 Hz, 2H), 5.77 - 5.61 (m, 2H), 4.64 (td, J = 9.4, 8.6, 4.4 Hz, 1H), 3.10 (dd, J = 13.6, 4.4 Hz, 1H), 2.95 (t, J = 12.2 Hz, 1H), 2.63 (d, J = 4.5 Hz, 3H). 13 C NMR(75MHz, DMSO-d6) δ 170.9, 160.9, 158.9, 157.6, 143.4, 141.1, 137.6, 136.1,, 131.9, 130.2, 129.9, 129.8, 129.8, 129.2, 128.4, 128.2, 127.9, 127.4, 124.8, 121.4, 120.1, 120.0, 116.4, 116.2, 108.2, 108.0, 54.2, 53.8, 36.7, 25.7. HRMS(ESI, m / z): Calcd. for C 27 H 24 BrFN4O2[M+Na] + 557.0964, found: 557.0964.

[0066] Example 7:

[0067] (S)-1-Benzyl-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-(3-fluorophenyl)-1H-pyrazole-5-carboxamide H7 Preparation

[0068] Under other conditions the same as in Example 1, changing acetophenone to 3-fluorophenacyl, the product is a white solid with a yield of 34%. 1HNMR (400 MHz, DMSO-d6) δ 8.78 (d, J = 8.6 Hz, 1H), 8.10 (d, J = 4.8 Hz, 1H), 7.65 (d, J = 7.9 Hz, 2H), 7.57 (s, 1H), 7.38 - 7.18 (m, 9H), 7.11 (d, J = 6.2 Hz, 2H), 5.71 - 5.54 (m, 2H), 4.63 (ddd, J = 10.7, 8.6, 4.3 Hz, 1H), 3.11 (dd, J = 13.6, 4.4 Hz, 1H), 2.93 (dd, J = 13.6, 10.7 Hz, 1H), 2.63 (d, J = 4.5 Hz, 3H), 2.32 (s, 3H). 13 C NMR (75 MHz, DMSO-d6) δ 170.8, 164.2, 161.0, 158.9, 147.9, 147.7, 141.0, 137.5, 136.7, 134.9, 134.8, 132.0, 131.1, 131.0, 130.3, 129.2, 128.4, 128.3, 127.4, 127.4, 121.4, 121.10, 114.9, 114.6, 111.6, 111.3, 105.4, 54.2, 53.8, 37.0, 25.7. HRMS (ESI, m / z): Calcd. for C 27 H 24 BrFN4O2 [M+Na] + 557.0964, found: 557.0964.

[0069] Example 8:

[0070] (S)-1-Benzyl-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide H8 Preparation

[0071] Under other conditions the same as in Example 1, acetophenone was changed to 4-fluoroacetophenone, and the product was a white solid with a yield of 33%. 1HNMR (400 MHz, DMSO-d6) δ 8.78 (d, J = 8.6 Hz, 1H), 8.10 (d, J = 4.6 Hz, 1H), 7.78 (dd, J = 8.7, 5.6 Hz, 2H), 7.56 (s, 1H), 7.37 (d, J = 8.0 Hz, 2H), 7.30 - 7.19 (m, 7H), 7.12 - 7.01 (m, 2H), 5.71 - 5.55 (m, 2H), 4.63 (ddd, J = 10.6, 8.6, 4.4 Hz, 1H), 3.10 (dd, J = 13.6, 4.4 Hz, 1H), 2.91 (dd, J = 13.6, 10.6 Hz, 1H), 2.63 (d, J = 4.5 Hz, 3H). 13 C NMR (75 MHz, DMSO-d6) δ 171.3, 159.4, 148.5, 141.5, 138.1, 137.0, 132.4, 130.7, 129.7, 129.5, 129.4, 128.8, 128.7, 127.8, 127.5, 127.4, 121.8, 116.4, 116.1, 105.3, 54.6, 54.1, 37.4, 26.1. HRMS (ESI, m / z): Calcd. for C 27 H 24 BrFN4O2 [M+Na] + 557.0964, found: 557.0964.

[0072] Example 9:

[0073] (S)-1-Benzyl-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-(3-chlorophenyl)-1H-pyrazole-5-carboxamide H9 Preparation

[0074] Under the same conditions as in Example 1, changing acetophenone to 3-chloroacetophenone, the product is a white solid with a yield of 29%. 1HNMR(300MHz, DMSO-d6) δ 8.78 (d, J = 8.7 Hz, 1H), 8.12 (d, J = 4.7 Hz, 1H), 7.77 (t, J = 1.8 Hz, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.57 (s, 1H), 7.51 - 7.46 (m, 2H), 7.42 - 7.36 (m, 2H), 7.31 - 7.18 (m, 5H), 7.12 (dd, J = 7.6, 1.9 Hz, 2H), 5.73 - 5.56 (m, 2H), 4.64 (ddd, J = 10.4, 8.6, 4.4 Hz, 1H), 3.11 (dd, J = 13.6, 4.5 Hz, 1H), 2.92 (dd, J = 13.6, 10.6 Hz, 1H), 2.63 (d, J = 4.5 Hz, 3H). 13 C NMR(75MHz, DMSO-d6) δ 170.8, 158.8, 147.5, 141.0, 137.5, 136.7, 134.5, 133.7, 132.0, 131.0, 130.2, 129.2, 128.4, 128.3, 127.8, 127.4, 124.5, 123.5, 121.4, 105.4, 54.2, 53.8, 37.0, 25.7. HRMS(ESI, m / z): Calcd. for C 27 H 24 BrClN4O2 [M+Na] + 573.0669, found: 573.0667.

[0075] Example 10:

[0076] (S)-1-Benzyl-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-(4-chlorophenyl)-1H-pyrazole-5-carboxamide H 10 Preparation

[0077] Under other conditions the same as in Example 1, acetophenone was replaced with 4-chloroacetophenone, and the product was a white solid with a yield of 30%. 1HNMR(300MHz,DMSO-d6)δ8.80(d,J=8.6Hz,1H),8.10(q,J=4.1Hz,1H),7.78-7.76(m,2H),7.57(s,1H),7.52-7.49(m,2H),7.41-7.36(m,2H),7.31-7.18(m,5H),7.12(dd,J=7.9,2.1Hz,2H),5.73-5.55(m,2H),4.64(ddd,J=10.5,8.5,4.4Hz,1H),3.11(dd,J=13.7,4.4Hz,1H),2.92(dd,J=13.5,10.7Hz,1H),2.63(d,J=4.6Hz,3H). 13 C NMR(75MHz,DMSO-d6)δ170.8,158.9,147.8,141.0,137.5,136.6,132.5,132.0,131.3,130.3,129.2,129.0,128.4,128.2,127.4,126.7,121.4,105.1,54.9,54.2,53.7,36.9,25.7.HRMS(ESI,m / z):Calcd.for C 27 H 24 BrClN4O2[M+Na] + 573.0669,found:573.0667.

[0078] Example 11:

[0079] (S)-1-Benzyl-3-(2-bromophenyl)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-1H-pyrazole-5-carboxamide H 11 Preparation

[0080] Under other conditions the same as in Example 1, acetophenone was replaced with 2-bromoacetophenone, and the product was a white solid with a yield of 33%. 1HNMR(300MHz, DMSO-d6) δ 8.91 (d, J = 8.6 Hz, 1H), 8.14 (q, J = 4.5 Hz, 1H), 7.74 (dd, J = 8.0, 1.2 Hz, 1H), 7.66 (dd, J = 7.7, 1.8 Hz, 1H), 7.56 (s, 1H), 7.48 - 7.42 (m, 2H), 7.38 - 7.19 (m, 7H), 7.17 - 7.12 (m, 2H), 5.75 - 5.57 (m, 2H), 4.62 (ddd, J = 10.6, 8.4, 4.4 Hz, 1H), 3.09 (dd, J = 13.5, 4.4 Hz, 1H), 2.94 (dd, J = 13.6, 10.7 Hz, 1H), 2.62 (d, J = 4.6 Hz, 3H). 13 C NMR(75MHz, DMSO-d6) δ 170.9, 158.9, 148.0, 141.1, 137.6, 135.4, 133.5, 133.4, 132.0, 131.0, 130.2, 129.9, 129.2, 128.4, 128.3, 127.9, 127.4, 127.4, 121.4, 121.0, 108.5, 54.3, 53.8, 36.8, 25.6. HRMS(ESI, m / z): Calcd. for C 27 H 24 Br2N4O2[M + Na] + 619.0164, found: 619.0147.

[0081] Example 12:

[0082] (S)-1-Benzyl-3-(3-bromophenyl)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-1H-pyrazole-5-carboxamide H 12 Preparation

[0083] Under other conditions the same as in Example 1, changing acetophenone to 3-bromoacetophenone, the product is a white solid with a yield of 30%. 1HNMR (300 MHz, DMSO-d6) δ 8.84 (d, J = 8.7 Hz, 1H), 8.18 (d, J = 4.6 Hz, 1H), 7.91 (t, J = 1.6 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.58 - 7.52 (m, 3H), 7.44 - 7.36 (m, 2H), 7.32 - 7.2 (m, 5H), 7.11 (dd, J = 7.5, 1.8 Hz, 2H), 5.73 - 5.56 (m, 2H), 4.64 (ddd, J = 10.6, 8.6, 4.4 Hz, 1H), 3.12 (dd, J = 13.6, 4.4 Hz, 1H), 2.94 (dd, J = 13.6, 10.6 Hz, 1H), 2.63 (d, J = 4.5 Hz, 3H). 13 C NMR (75 MHz, DMSO-d6) δ 170.8, 158.8, 147.4, 141.0, 137.5, 136.6, 134.7, 132.0, 131.2, 130.7, 130.3, 129.2, 128.4, 128.3, 127.4, 123.9, 122.3, 1214, 105.5, 54.2, 53.8, 37.0, 25.7.

[0084] Example 13:

[0085] (S)-1-Benzyl-3-(4-bromophenyl)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-1H-pyrazole-5-carboxamide H 13 Preparation

[0086] Under other conditions the same as in Example 1, acetophenone was replaced with 4-bromoacetophenone, and the product was a white solid with a yield of 34%. 1 HNMR (300 MHz, DMSO-d6) δ 8.84 (d, J = 8.6 Hz, 1H), 8.14 (d, J = 4.5 Hz, 1H), 7.72 - 7.63 (m, 4H), 7.57 (s, 1H), 7.44 (s, 1H), 7.37 (d, J = 7.9 Hz, 1H), 7.32 - 7.17 (m, 5H), 7.13 - 7.10 (m, 2H), 5.72 - 5.54 (m, 2H), 4.63 (td, J = 9.5, 8.6, 4.3 Hz, 1H), 3.11 (dd, J = 13.6, 4.4 Hz, 1H), 2.97 - 2.88 (m, 1H), 2.62 (d, J = 4.5 Hz, 3H). 13C NMR(75MHz,DMSO-d6)δ170.8,158.9,147.8,141.0,137.5,136.6,132.0,131.9,131.6, 130.2,129.2,128.4,128.2,127.4,127.0,121.4,121.0,105.1,54.2,53.7,36.9,25.7.

[0087] Example 14:

[0088] (S)-1-Benzyl-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-(2-nitrophenyl)-1H-pyrazole-5-carboxamide 14 Preparation

[0089] Other conditions were the same as in Example 1, except that acetophenone was replaced with 2-nitroacetophenone. The product was a white solid with a yield of 36%. 1 HNMR (300MHz, DMSO-d6): δ8.89(d,J=8.6Hz,1H),8.12(d,J=4.7Hz,1H),7.88(d ,J=7.9Hz,1H),7.78-7.72(m,2H),7.64-7.54(m,2H),7.37(d,J=7.9Hz,1H),7.3 0-7.17(m,6H),7.10-7.07(m,2H),5.61(q,J=14.7Hz,2H),4.62(dt,J=13.2,4.6 Hz,1H),3.09(dd,J=13.6,4.5Hz,1H),2.95-2.87(m,1H),2.62(d,J=4.6Hz,3H). 13 C NMR(75MHz,DMSO-d6)δ170.8,158.6,148.6,144.7,141.0,137.3,136.3,132.5,131.9,130.2,130.1,129.4,129 .2,128.3,128.2,127.4,127.4,125.5,123.8,121.4,107.0,54.2,53.9,36.8,25.6.HRMS(ESI,m / z):Calcd.for C 27 H 24 BrN5O4[M+Na] + 584.0909,found:584.0900.

[0090] Example 15:

[0091] (S)-1-Benzyl-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-(3-nitrophenyl)-1H-pyrazole-5-carboxamide H 15 Preparation

[0092] Under other conditions the same as in Example 1, acetophenone was replaced with 3-nitroacetophenone, and the product was a white solid with a yield of 34%. 1 HNMR(300MHz, DMSO-d6): δ8.87(d, J = 8.7Hz, 1H), 8.52(t, J = 2.0Hz, 1H), 8.2 - 8.13(m, 3H), 7.75(t, J = 8.0Hz, 1H), 7.64(s, 1H), 7.57(d, J = 1.8Hz, 1H), 7.39 - 7.36(m, 1H), 7.32 - 7.18(m, 5H), 7.12(dd, J = 7.7, 1.9Hz, 2H), 5.78 - 5.59(m, 2H), 4.65(ddd, J = 10.5, 8.7, 4.4Hz, 1H), 3.12(dd, J = 13.6, 4.5Hz, 1H), 2.93(dd, J = 13.6, 10.5Hz, 1H), 2.63(d, J = 4.5Hz, 3H). 13 C NMR(75MHz, DMSO-d6)δ170.8, 158.7, 148.3, 146.9, 140.9, 137.4, 136.9, 134.0, 132.0, 131.1, 130.7, 130.3, 129.2, 128.4, 128.3, 127.5, 127.4, 122.6, 121.4, 119.2, 105.7, 54.2, 53.9, 37.0, 25.7.

[0093] Example 16:

[0094] (S)-1-Benzyl-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-(4-nitrophenyl)-1H-pyrazole-5-carboxamide H 16 Preparation

[0095] Under the same conditions as in Example 1, acetophenone was replaced with 4-nitroacetophenone, and the product was a white solid with a yield of 35%. 1H NMR (300 MHz, DMSO-d6) δ 8.78 (d, J = 8.6 Hz, 1H), 8.12 (d, J = 4.7 Hz, 1H), 7.69 (d, J = 8.8 Hz, 2H), 7.57 (s, 1H), 7.39 - 7.18 (m, 7H), 7.11 (dd, J = 7.6, 1.9 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 5.71 - 5.53 (m, 2H), 4.63 (ddd, J = 10.5, 8.5, 4.3 Hz, 1H), 3.78 (s, 3H), 3.11 (dd, J = 13.6, 4.4 Hz, 1H), 2.93 (dd, J = 13.6, 10.6 Hz, 1H), 2.63 (d, J = 4.5 Hz, 3H).. 13 13C NMR (75 MHz, DMSO-d6) δ 171.0, 159.2, 148.9, 141.1, 137.8, 136.4, 136.3, 132.0, 130.3, 129.3, 128.4, 128.3, 127.4, 126.4, 125.1, 121.4, 114.3, 104.4, 55.2, 53.6, 36.9, 25.7.

[0096] Example 17:

[0097] (S)-1-Benzyl-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-(3-cyanophenyl)-1H-pyrazole-5-carboxamide H 17 Preparation

[0098] Under the same conditions as in Example 1, acetophenone was replaced with 3-cyanoacetophenone, and the product was a white solid with a yield of 29%. 1 1H NMR (300 MHz, DMSO-d6) δ 8.79 (d, J = 8.6 Hz, 1H), 8.13 - 8.06 (m, 3H), 7.81 (d, J = 7.7 Hz, 1H), 7.66 (t, J = 7.8 Hz, 1H), 7.53 (d, J = 17.1 Hz, 2H), 7.39 - 7.11 (m, 8H), 5.73 - 5.56 (m, 2H), 4.65 (dq, J = 8.7, 4.6 Hz, 1H), 3.11 (dd, J = 13.6, 4.5 Hz, 1H), 2.95 - 2.87 (m, 1H), 2.63 (d, J = 4.2 Hz, 3H). 1313C NMR (75 MHz, DMSO-d6) δ 170.8, 158.8, 147.0, 140.9, 137.4, 136.9, 133.6, 132.0, 131.5, 130.3, 130.3, 129.5, 129.3, 128.4, 128.3, 127.4, 121.4, 118.6, 112.1, 105.5, 54.2, 53.9, 37.0, 25.7. HRMS (ESI, m / z): Calcd. for C 28 H 24 BrN5O2 [M+Na] + 564.1011, found: 564.1008.

[0099] Example 18:

[0100] (S)-1-Benzyl-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-(4-cyanophenyl)-1H-pyrazole-5-carboxamide H 18 Preparation

[0101] Under other conditions the same as in Example 1, acetophenone was replaced with 4-cyanophenylethanone, and the product was a white solid with a yield of 30%. 1 1H NMR (300 MHz, DMSO-d6) δ 8.84 (d, J = 8.6 Hz, 1H), 8.11 (d, J = 4.7 Hz, 1H), 7.95 - 7.89 (m, 4H), 7.56 (s, 1H), 7.52 (s, 1H), 7.37 (d, J = 7.8, 2.1 Hz, 1H), 7.31 - 7.18 (m, 5H), 7.12 (dd, J = 7.6, 2.0 Hz, 2H), 5.74 - 5.57 (m, 2H), 4.65 (dq, J = 10.5, 4.5 Hz, 1H), 3.11 (dd, J = 13.6, 4.5 Hz, 1H), 2.91 (dd, J = 13.6, 10.6 Hz, 1H), 2.63 (d, J = 4.6 Hz, 3H). 13 13C NMR (75 MHz, DMSO-d6) δ 170.8, 158.8, 147.2, 140.9, 137.3, 136.9, 136.7, 133.0, 132.0, 130.3, 129.2, 128.4, 128.3, 127.5, 127.4, 125.6, 121.4, 118.8, 110.2, 105.9, 54.2, 53.9, 37.0, 25.7.

[0102] Example 19:

[0103] (S)-N-(3-(3-Bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-1-(2-methylbenzyl)-3-phenyl-1H-pyrazole-5-carboxamide H 19 Preparation

[0104] Under other conditions the same as in Example 1, benzyl chloride was changed to 2-methylbenzyl chloride, and the product was a white solid with a yield of 39%. 1 H NMR(300MHz,DMSO-d6)δ8.78(d,J=8.6Hz,1H),8.08(d,J=4.7Hz,1H),7.76(d,J=7.1Hz,2H),7.56(s,1H),7.44(t,J=7.1Hz,3H),7.38-7.27(m,3H),7.22-7.09(m,3H),7.02(t,J=7.2Hz,1H),6.56(d,J=7.6Hz,1H),5.65(q,J=15.4Hz,2H),4.60(td,J=9.4,8.6,4.4Hz,1H),3.09(dd,J=13.6,4.5Hz,1H),2.91(dd,J=13.6,10.5Hz,1H),2.62(d,J=4.2Hz,3H),2.31(s,3H). 13 C NMR(75MHz,DMSO-d6)δ170.9,159.0,148.8,141.0,136.8,136.3,135.1,132.4,132.0,130.2,129.9,129.2,128.9,128.2,128.0,127.1,126.5,125.9,124.9,121.4,104.9,54.2,51.5,36.9,25.6,18.8.HRMS(ESI,m / z):Calcd.forC 28 H 27 BrN4O2[M+Na] + 553.1215,found:553.1210.

[0105] Example 20:

[0106] (S)-N-(3-(3-Bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-1-(3-methylbenzyl)-3-phenyl-1H-pyrazole-5-carboxamide H 20 Preparation

[0107] Under other conditions the same as in Example 1, benzyl chloride was changed to 3-methylbenzyl chloride, and the product was a white solid with a yield of 39%. 11H NMR (300 MHz, DMSO-d6) δ 8.79 (d, J = 8.6 Hz, 1H), 8.10 (d, J = 4.7 Hz, 1H), 7.78 - 7.75 (m, 2H), 7.58 (s, 1H), 7.47 - 7.30 (m, 6H), 7.23 - 7.11 (m, 2H), 7.04 (d, J = 7.5 Hz, 1H), 6.96 (s, 1H), 6.89 (d, J = 7.6 Hz, 1H), 5.66 - 5.54 (m, 2H), 4.62 (ddd, J = 10.5, 8.5, 4.4 Hz, 1H), 3.10 (dd, J = 13.6, 4.4 Hz, 1H), 2.93 (dd, J = 13.6, 10.6 Hz, 1H), 2.63 (d, J = 4.5 Hz, 3H), 2.22 (s, 3H). 13 13C NMR (75 MHz, DMSO-d6) δ 170.9, 159.1, 148.8, 141.1, 137.6, 137.5, 136.5, 132.4, 132.0, 130.2, 129.2, 128.9, 128.3, 128.2, 128.0, 127.9, 125.0, 124.5, 121.4, 104.9, 54.2, 53.6, 36.9, 25.6, 21.0.

[0108] Example 21:

[0109] (S)-N-(3-(3-Bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-1-(4-methylbenzyl)-3-phenyl-1H-pyrazole-5-carboxamide H 21 [[ID=ll]]Preparation

[0110] Under the same conditions as in Example 1, benzyl chloride was changed to 4-methylbenzyl chloride, and the product was a white solid with a yield of 45%. 1 1H NMR (300 MHz, DMSO-d6) δ 8.77 (d, J = 8.6 Hz, 1H), 8.10 (d, J = 4.7 Hz, 1H), 7.76 (d, J = 7.1 Hz, 2H), 7.57 (s, 1H), 7.46 - 7.29 (m, 6H), 7.21 (t, J = 7.7 Hz, 1H), 7.05 (dd, J = 9.6, 4.6 Hz, 4H), 5.67 - 5.50 (m, 2H), 4.67 - 4.59 (m, 1H), 3.11 (dd, J = 13.6, 4.4 Hz, 1H), 2.92 (dd, J = 13.6, 10.6 Hz, 1H), 2.63 (d, J = 4.4 Hz, 3H), 2.23 (s, 3H). 1313C NMR (75 MHz, DMSO-d6) δ 170.9, 159.1, 148.8, 141.0, 136.5, 136.3, 134.7, 132.4, 132.0, 130.3, 129.2, 128.9, 128.2, 128.0, 127.4, 125.0, 121.4, 104.9, 54.2, 53.4, 36.91, 25.7, 20.7.

[0111] Example 22:

[0112] (S)-N-(3-(3-Bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-1-(3-methoxybenzyl)-3-phenyl-1H-pyrazole-5-carboxamide H 22 Preparation

[0113] Under other conditions the same as in Example 1, benzyl chloride was replaced with 3-methoxybenzyl chloride, and the product was a white solid with a yield of 55%. 1 1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J = 8.6 Hz, 1H), 8.14 (d, J = 4.7 Hz, 1H), 7.77 (d, J = 7.6 Hz, 2H), 7.57 (d, J = 1.9 Hz, 1H), 7.47 - 7.39 (m, 3H), 7.33 (dt, J = 14.4, 8.0 Hz, 3H), 7.18 (dt, J1 = 10.6, J2 = 7.8 Hz, 2H), 6.79 (dd, J1 = 8.1, J2 = 2.6 Hz, 1H), 6.71 (t, J = 2.0 Hz, 1H), 6.65 (d, J = 7.6 Hz, 1H), 5.68 - 5.55 (m, 2H), 4.63 (m, 1H), 3.67 (s, 3H), 3.11 (dd, J1 = 13.6, J2 = 4.4 Hz, 1H), 2.94 (dd, J1 = 13.6, J2 = 10.6 Hz, 1H), 2.63 (d, J = 4.5 Hz, 3H). 13 13C NMR (101 MHz, DMSO-d6) δ 170.76, 158.99, 158.83, 148.73, 140.81, 139.03, 136.28, 132.19, 131.80, 130.05, 129.30, 129.04, 128.73, 128.02, 127.83, 124.79, 121.20, 119.19, 112.91, 112.38, 104.78, 54.71, 54.06, 53.39, 36.71, 25.47.

[0114] Example 23:

[0115] (S)-N-(3-(3-Bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-1-(4-methoxybenzyl)-3-phenyl-1H-pyrazole-5-carboxamide H 23 Preparation

[0116] Under the same conditions as in Example 1, benzyl chloride was changed to 4-methoxybenzyl chloride, and the product was a white solid with a yield of 53%. 1 H NMR(400MHz,DMSO-d6)δ8.82(d,J=8.6Hz,1H),8.14(q,J=4.6Hz,1H),7.85-7.80(m,2H),7.78-7.71(m,2H),7.58(t,J=1.8Hz,1H),7.37-7.32(m,3H),7.30(s,1H),7.19(s,1H),7.12-7.08(m,2H),6.83-6.79(m,2H),5.62(d,J=14.4Hz,1H),5.49(d,J=14.4Hz,1H),4.65(m,1H),3.69(s,5H),3.12(dd,J1=13.7,J2=4.4Hz,1H),2.95-2.90(m,1H),2.64(d,J=4.5Hz,3H). 13 C NMR(101MHz,DMSO-d6):δ170.99,158.64,132.04,130.31,129.67,129.05,128.93,128.84,128.76,125.17,125.01,121.44,113.84,113.76,55.08,54.26,53.15,25.73.

[0117] Example 24:

[0118] (S)-N-(3-(3-Bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-1-(2-fluorobenzyl)-3-phenyl-1H-pyrazole-5-carboxamide H 24 Preparation

[0119] Under the same conditions as in Example 1, benzyl chloride was changed to 2-fluorobenzyl chloride, and the product was a white solid with a yield of 64%. 1HNMR(400MHz, DMSO-d6) δ 8.84 (d, J = 8.6 Hz, 1H), 8.12 (d, J = 4.9 Hz, 1H), 7.76 (d, J = 7.6 Hz, 2H), 7.56 (s, 1H), 7.44 (m, 3H), 7.39 - 7.26 (m, 4H), 7.24 - 7.12 (m, 2H), 7.06 (t, J = 7.5 Hz, 1H), 6.81 (t, J = 7.6 Hz, 1H), 5.82 - 5.61 (m, 2H), 4.62 (m, 1H), 3.11 (dd, J1 = 13.7, J2 = 4.4 Hz, 1H), 2.98 - 2.86 (m, 1H), 2.63 (d, J = 4.5 Hz, 3H). 13 C NMR(101MHz, DMSO-d6) δ 170.93, 158.93, 149.18, 141.03, 136.79, 132.34, 132.04, 130.29, 129.27, 128.97, 128.28, 128.13, 125.06, 124.90, 124.54, 121.43, 115.34, 115.13, 105.05, 54.23, 36.98, 25.71.

[0120] Example 25:

[0121] (S)-N-(3-(3-Bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-1-(3-fluorobenzyl)-3-phenyl-1H-pyrazole-5-carboxamide H 25 Preparation

[0122] Under the same conditions as in Example 1, changing benzyl chloride to 3-fluorobenzyl chloride, the product is a white solid with a yield of 65%. 1 HNMR(400MHz, DMSO-d6) δ 8.83 (d, J = 8.7 Hz, 1H), 8.12 (d, J = 4.7 Hz, 1H), 7.85 - 7.73 (m, 2H), 7.57 (s, 1H), 7.51 - 7.41 (m, 3H), 7.40 - 7.27 (m, 4H), 7.20 (t, J = 7.8 Hz, 1H), 7.07 (m, 1H), 6.97 - 6.89 (m, 2H), 5.76 - 5.56 (m, 2H), 4.64 (ddd, J1 = 10.7, J2 = 8.5, J3 = 4.4 Hz, 1H), 3.12 (dd, J1 = 13.6, J2 = 4.4 Hz, 1H), 2.94 (m, 1H), 2.64 (d, J = 4.5 Hz, 3H). 1313C NMR (101 MHz, DMSO-d6) δ 170.60, 163.00, 160.58, 158.69, 148.87, 140.74, 140.25, 140.18, 136.26, 132.06, 131.75, 130.17, 130.09, 129.95, 128.96, 128.67, 127.95, 127.82, 124.77, 123.02, 121.13, 114.04, 113.90, 113.68, 104.77, 53.93, 52.93, 36.66, 25.40.

[0123] Example 26:

[0124] (S)-N-(3-(3-Bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-1-(4-fluorobenzyl)-3-phenyl-1H-pyrazole-5-carboxamide H 26 Preparation

[0125] Under the same conditions as in Example 1, benzyl chloride was replaced with 4-fluorobenzyl chloride, and the product was a white solid with a yield of 65%. 1 1H NMR (400 MHz, DMSO-d6) δ 8.81 (d, J = 8.6 Hz, 1H), 8.12 (q, J = 4.6 Hz, 1H), 7.80 - 7.73 (m, 2H), 7.57 (s, 1H), 7.44 (t, J = 7.6 Hz, 2H), 7.41 - 7.29 (m, 4H), 7.24 - 7.16 (m, 3H), 7.12 - 7.06 (m, 2H), 5.68 (d, J = 14.7 Hz, 1H), 5.55 (d, J = 14.7 Hz, 1H), 4.64 (ddd, J1 = 10.7, J2 = 8.6, J3 = 4.4 Hz, 1H), 3.12 (dd, J1 = 13.6, J2 = 4.4 Hz, 1H), 2.93 (m, 1H), 2.64 (d, J = 4.5 Hz, 3H). 13 13C NMR (101 MHz, DMSO-d6) δ 170.91, 159.04, 149.02, 141.06, 136.36, 133.88, 132.39, 132.03, 130.27, 129.63, 129.55, 129.24, 128.93, 128.28, 128.06, 125.03, 121.41, 115.27, 115.06, 105.02, 54.22, 25.70.

[0126] Example 27:

[0127] (S)-N-(3-(3-Bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-1-(2-chlorobenzyl)-3-phenyl-1H-pyrazole-5-carboxamide H 27 Preparation

[0128] Under other conditions same as Example 1, changing benzyl chloride to 2-chlorobenzyl chloride, the product is a white solid with a yield of 68%. 1 H NMR(400MHz,DMSO-d6)δ8.85(d,J=8.7Hz,1H),8.11(q,J=4.6Hz,1H),7.79-7.73(m,2H),7.55(s,1H),7.51(s,1H),7.45(dd,J1=8.4,J2=7.1Hz,3H),7.38-7.32(m,2H),7.31-7.22(m,2H),7.22-7.13(m,2H),6.53(dd,J1=7.7,J2=1.7Hz,1H),5.82-5.64(m,2H),4.59(ddd,J1=10.6,J2=8.6,J3=4.4Hz,1H),3.10(dd,J1=13.6,J2=4.5Hz,1H),2.93(dd,J=13.6,10.6Hz,1H),2.62(d,J=4.5Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ170.90,158.79,149.34,140.98,137.05,135.55,132.29,132.03,131.25,130.25,129.25,129.15,128.96,128.91,128.26,128.16,127.82,127.37,125.06,121.41,104.99,54.19,51.72,36.97,25.68.

[0129] Example 28:

[0130] (S)-N-(3-(3-Bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-1-(3-chlorobenzyl)-3-phenyl-1H-pyrazole-5-carboxamide H 28 Preparation

[0131] Under other conditions same as Example 1, changing benzyl chloride to 3-chlorobenzyl chloride, the product is a white solid with a yield of 67%. 11H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J = 8.6 Hz, 1H), 8.10 (q, J = 4.5 Hz, 1H), 7.82 - 7.73 (m, 2H), 7.56 (s, 1H), 7.47 - 7.41 (m, 3H), 7.38 - 7.34 (m, 2H), 7.32 - 7.28 (m, 3H), 7.22 - 7.17 (m, 2H), 7.06 (m, 1H), 5.69 (d, J = 15.0 Hz, 1H), 5.59 (d, J = 15.0 Hz, 1H), 4.63 (ddd, J1 = 10.6, J2 = 8.6, J3 = 4.4 Hz, 1H), 3.11 (dd, J1 = 13.6, J2 = 4.4 Hz, 1H), 2.94 (dd, J1 = 14.5, J2 = 3.9 Hz, 1H), 2.63 (d, J = 4.5 Hz, 3H). 13 13C NMR (101 MHz, DMSO-d6) δ 170.89, 158.98, 149.20, 141.02, 140.16, 136.57, 133.03, 132.03, 130.37, 129.00, 128.25, 127.43, 127.18, 126.00, 125.07, 121.43, 105.08, 54.23, 36.94, 25.72.

[0132] Example 29:

[0133] (S)-N-(3-(3-Bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-1-(4-chlorobenzyl)-3-phenyl-1H-pyrazole-5-carboxamide H 29 Preparation

[0134] Under other conditions the same as in Example 1, changing benzyl chloride to 4-chlorobenzyl chloride, the product was a white solid with a yield of 70%. 11H NMR (400 MHz, DMSO-d6) δ 8.79 (d, J = 8.6 Hz, 1H), 8.09 (q, J = 4.6 Hz, 1H), 7.76 (dd, J1 = 8.3, J2 = 1.3 Hz, 2H), 7.55 (d, J = 1.9 Hz, 1H), 7.44 (m, 3H), 7.38 - 7.27 (m, 5H), 7.20 (t, J = 7.8 Hz, 1H), 7.15 - 7.11 (m, 2H), 5.68 (d, J = 14.9 Hz, 1H), 5.56 (d, J = 14.9 Hz, 1H), 4.61 (ddd, J1 = 10.8, J2 = 8.7, J3 = 4.3 Hz, 1H), 3.10 (dd, J1 = 13.7, J2 = 4.4 Hz, 1H), 2.91 (m, 1H), 2.62 (d, J = 4.5 Hz, 3H).

[0135] Example 30:

[0136] (S)-1-(2-Bromobenzyl)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-phenyl-1H-pyrazole-5-carboxamide H 30 Preparation

[0137] Under the same conditions as in Example 1, benzyl chloride was replaced with 2-bromobenzyl chloride, and the product was a white solid with a yield of 70%. 1 1H NMR (300 MHz, DMSO-d6) δ 8.87 (d, J = 8.7 Hz, 1H), 8.13 (d, J = 4.7 Hz, 1H), 7.78 - 7.76 (m, 2H), 7.61 (dd, J = 7.3, 1.9 Hz, 1H), 7.55 (s, 2H), 7.45 (t, J = 7.4 Hz, 2H), 7.37 - 7.16 (m, 6H), 6.45 (dd, J = 7.1, 2.2 Hz, 1H), 5.69 (q, J = 16.0 Hz, 2H), 4.58 (ddd, J = 10.5, 8.6, 4.4 Hz, 1H), 3.10 (dd, J = 13.5, 4.5 Hz, 1H), 2.93 (dd, J = 13.6, 10.6 Hz, 1H). 1313C NMR (75 MHz, DMSO-d6) δ 170.8, 158.7, 149.3, 141.0, 137.1, 137.1, 132.4, 132.3, 132.0, 130.2, 129.2, 129.1, 128.9, 128.2, 128.1, 127.9, 127.8, 125.0, 121.4, 121.3, 105.0, 54.9, 54.2, 36.9, 25.6. HRMS (ESI, m / z): Calcd. for C 27 H 24 Br2N4O2 [M+Na] + 619.0164, found: 619.0147.

[0138] Example 31:

[0139] (S)-1-(3-Bromobenzyl)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-phenyl-1H-pyrazole-5-carboxamide H 31 Preparation

[0140] Under other conditions the same as in Example 1, changing benzyl chloride to 3-bromobenzyl chloride, the product is a white solid with a yield of 68%. 1 1H NMR (300 MHz, DMSO-d6) δ 8.85 (d, J = 8.6 Hz, 1H), 8.13 (d, J = 4.7 Hz, 1H), 7.77 (d, J = 7.0 Hz, 2H), 7.56 (s, 1H), 7.48 - 7.17 (m, 10H), 7.09 (d, J = 7.7 Hz, 1H), 5.74 - 5.53 (m, 2H), 4.62 (ddd, J = 10.6, 8.6, 4.4 Hz, 1H), 3.12 (dd, J = 13.6, 4.5 Hz, 1H), 2.93 (dd, J = 13.6, 10.6 Hz, 1H), 2.63 (d, J = 4.5 Hz, 3H). 13 13C NMR (75 MHz, DMSO-d6) δ 170.8, 158.9, 149.1, 141.0, 140.4, 136.5, 132.3, 132.0, 130.6, 130.3, 130.2, 130.0, 129.2, 129.0, 128.2, 128.1, 126.4, 125.0, 121.6, 121.4, 105.1, 54.2, 53.1, 36.9, 25.7.

[0141] Example 32:

[0142] (S)-1-(4-Bromobenzyl)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-phenyl-1H-pyrazole-5-carboxamide H 32 Preparation

[0143] Under other conditions same as Example 1, changing benzyl chloride to 4-bromobenzyl chloride, the product is a white solid with a yield of 70%. 1 HNMR(300MHz,DMSO-d6):δ8.85(d,J=8.6Hz,1H),8.13(d,J=4.7Hz,1H),7.77(d,J=7.0Hz,2H),7.56(s,1H),7.48-7.17(m,10H),7.09(d,J=7.7Hz,1H),5.74-5.53(m,2H),4.62(ddd,J=10.6,8.6,4.4Hz,1H),3.12(dd,J=13.6,4.5Hz,1H),2.93(dd,J=13.6,10.6Hz,1H),2.63(d,J=4.5Hz,3H). 13 C NMR(75MHz,DMSO-d6):δ170.8,158.9,149.1,141.0,140.4,136.5,132.3,132.0,130.6,130.3,130.2,130.0,129.2,129.0,128.2,128.1,126.4,125.0,121.6,121.4,105.1,54.2,53.1,36.9,25.7.

[0144] Example 33:

[0145] (S)-N-(3-(3-Bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-1-(3-iodobenzyl)-3-phenyl-1H-pyrazole-5-carboxamide H 33 Preparation

[0146] Under other conditions same as Example 1, changing benzyl chloride to 3-iodobenzyl chloride, the product is a white solid with a yield of 71%. 1HNMR(400MHz, DMSO-d6) δ 8.82 (d, J = 8.6 Hz, 1H), 8.11 (d, J = 4.6 Hz, 1H), 7.81 - 7.72 (m, 2H), 7.63 - 7.52 (m, 3H), 7.45 (t, J = 7.6 Hz, 2H), 7.40 (s, 1H), 7.38 - 7.32 (m, 2H), 7.29 (d, J = 7.9 Hz, 1H), 7.20 (t, J = 7.8 Hz, 1H), 7.08 (m, 2H), 5.64 (d, J = 15.0 Hz, 1H), 5.54 (d, J = 14.9 Hz, 1H), 4.62 (m, 1H), 3.11 (dd, J1 = 13.7, J2 = 4.4 Hz, 1H), 2.92 (m, 1H), 2.63 (d, J = 4.5 Hz, 3H). 13 C NMR(101MHz, DMSO-d6) δ 170.96, 159.04, 149.24, 141.04, 140.30, 136.58, 136.23, 136.00, 132.35, 132.08, 130.72, 130.35, 129.35, 129.04, 128.29, 128.22, 126.81, 125.12, 121.49, 105.11, 94.82, 54.28, 53.03, 48.72, 36.99, 25.80.

[0147] Example 34:

[0148] (S)-N-(3-(3-Bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-1-(2-nitrobenzyl)-3-phenyl-1H-pyrazole-5-carboxamide H 34 Preparation

[0149] Under the same conditions as in Example 1, benzyl chloride was replaced with 2-nitrobenzyl chloride. The product was a white solid with a yield of 71%. 11H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J = 8.7 Hz, 1H), 8.08 (dd, J1 = 8.0, J2 = 1.5 Hz, 2H), 7.82 - 7.74 (m, 2H), 7.58 (m, 1H), 7.55 - 7.49 (m, 3H), 7.46 (t, J = 7.6 Hz, 2H), 7.38 - 7.32 (m, 2H), 7.26 (d, J = 7.6 Hz, 1H), 7.17 (t, J = 7.8 Hz, 1H), 6.64 (dd, J1 = 7.8, J2 = 1.5 Hz, 1H), 6.05 (d, J = 16.6 Hz, 1H), 5.93 (d, J = 16.6 Hz, 1H), 4.55 (ddd, J1 = 10.5, J2 = 8.6, J3 = 4.5 Hz, 1H), 3.09 (dd, J1 = 13.6, J2 = 4.5 Hz, 1H), 2.90 (m, 1H), 2.61 (d, J = 4.5 Hz, 3H). 13 13C NMR (101 MHz, DMSO-d6) δ 170.79, 158.63, 149.47, 147.34, 140.93, 136.89, 134.13, 133.28, 132.20, 132.00, 130.22, 129.24, 128.99, 128.64, 128.24, 125.09, 124.73, 121.37, 105.23, 54.11, 51.42, 36.95, 25.67.

[0150] Example 35:

[0151] (S)-N-(3-(3-Bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-1-(3-nitrobenzyl)-3-phenyl-1H-pyrazole-5-carboxamide H 35 Preparation

[0152] Under other conditions the same as in Example 1, benzyl chloride was replaced with 3-nitrobenzyl chloride, and the product was a white solid with a yield of 70%. 11H NMR (300 MHz, DMSO-d6) δ 8.85 (d, J = 8.7 Hz, 1H), 8.14 - 8.10 (m, 2H), 8.02 (d, J = 1.6 Hz, 1H), 7.80 - 7.77 (m, 2H), 7.61–7.52 (m, 3H), 7.48 - 7.43 (m, 3H), 7.38 - 7.27 (m, 3H), 7.18 (t, J = 7.7 Hz, 1H), 5.85 - 5.69 (m, 2H), 4.65 - 4.57 (m, 1H), 3.10 (dd, J = 13.6, 4.4 Hz, 1H), 2.91 (dd, J = 13.6, 10.7 Hz, 1H), 2.62 (d, J = 4.5 Hz, 3H). 13 13C NMR (75 MHz, DMSO-d6) δ 170.8, 158.9, 149.3, 147.7, 141.0, 139.9, 136.6, 134.0, 132.2, 132.0, 130.2, 130.0, 129.2, 129.0, 128.2, 125.1, 122.4, 122.0, 121.4, 105.2, 54.2, 53.1, 36.9, 25.6. HRMS (ESI, m / z): Calcd. for C 27 H 24 BrN5O4 [M+Na] + 584.0909, found: 584.0900.

[0153] Example 36:

[0154] (S)-N-(3-(3-Bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-1-(4-nitrobenzyl)-3-phenyl-1H-pyrazole-5-carboxamide H 36 Preparation

[0155] Under the same conditions as in Example 1, changing benzyl chloride to 4-nitrobenzyl chloride, the product was a white solid with a yield of 72%. 11H NMR (300 MHz, DMSO-d6): δ 8.83 (d, J = 8.7 Hz, 1H), 8.09 - 8.06 (m, 2H), 7.78 - 7.76 (m, 2H), 7.62 - 7.43 (m, 6H), 7.36 (t, J = 7.3 Hz, 2H), 7.26 (d, J = 7.7 Hz, 1H), 7.17 (t, J = 7.7 Hz, 1H), 6.65 - 6.62 (m, 1H), 6.07 - 5.89 (m, 2H), 4.55 (ddd, J = 10.4, 8.6, 4.5 Hz, 1H), 3.09 (dd, J = 13.6, 4.5 Hz, 1H), 2.90 (dd, J = 13.6, 10.5 Hz, 1H), 2.60 (d, J = 4.5 Hz, 3H). 13 13C NMR (75 MHz, DMSO-d6): δ 170.7, 158.6, 149.4, 147.3, 140.9, 136.9, 134.1, 133.3, 132.3, 132.0 130.2, 129.2, 129.0, 128.6, 128.2, 125.1, 124.7, 121.3, 105.2, 54.1, 51.4, 36.9, 25.6.

[0156] Example 37:

[0157] (S)-N-(3-(3-Bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-1-(2-cyanobenzyl)-3-phenyl-1H-pyrazole-5-carboxamide H 37 Preparation

[0158] Under the same conditions as in Example 1, replacing benzyl chloride with 2-cyanobenzyl chloride, the product was a white solid with a yield of 74%. 1 1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J = 8.7 Hz, 1H), 8.09 (q, J = 4.6 Hz, 1H), 7.86 - 7.72 (m, 3H), 7.58 - 7.41 (m, 6H), 7.35 (m, 2H), 7.28 (d, J = 7.8 Hz, 1H), 7.18 (t, J = 7.8 Hz, 1H), 6.85 (d, J = 7.9 Hz, 1H), 5.91 (d, J = 15.7 Hz, 1H), 5.79 (d, J = 15.7 Hz, 1H), 4.61 (ddd, J1 = 10.5, J2 = 8.6, J3 = 4.4 Hz, 1H), 3.11 (dd, J1 = 13.6, J2 = 4.5 Hz, 1H), 2.91 (m, 1H), 2.62 (d, J = 4.5 Hz, 3H). 1313C NMR (101 MHz, DMSO-d6) δ 170.94, 158.87, 149.52, 141.21, 141.01, 136.77, 133.63, 133.06, 132.23, 132.08, 130.34, 129.33, 129.07, 128.34, 127.43, 125.16, 121.46, 117.32, 110.44, 105.24, 54.22, 52.23, 37.01, 25.78.

[0159] Example 38:

[0160] (S)-N-(3-(3-Bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-1-(4-cyanobenzyl)-3-phenyl-1H-pyrazole-5-carboxamide H 38 Preparation

[0161] Under the same conditions as in Example 1, benzyl chloride was changed to 4-cyanobenzyl chloride, and the product was a white solid with a yield of 73%. 1 1H NMR (300 MHz, DMSO-d6) δ 8.84 (d, J = 8.6 Hz, 1H), 8.11 (d, J = 4.7 Hz, 1H), 7.95 - 7.89 (m, 4H), 7.56 (s, 1H), 7.52 (s, 1H), 7.37 (d, J = 7.8, 2.1 Hz, 1H), 7.31 - 7.18 (m, 5H), 7.12 (dd, J = 7.6, 2.0 Hz, 2H), 5.74 - 5.57 (m, 2H), 4.65 (dq, J = 10.5, 4.5 Hz, 1H), 3.11 (dd, J = 13.6, 4.5 Hz, 1H), 2.91 (dd, J = 13.6, 10.6 Hz, 1H), 2.63 (d, J = 4.6 Hz, 3H). 13 13C NMR (101 MHz, DMSO-d6) δ 170.83, 158.82, 149.32, 143.36, 140.99, 136.60, 132.39, 132.24, 131.99, 130.24, 129.21, 128.95, 128.26, 128.16, 127.93, 127.62, 127.00, 125.06, 121.38, 118.74, 110.15, 105.10, 54.18, 53.53, 36.93, 25.68.

[0162] Example 39:

[0163] (S)-N-(3-(3-Bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-1-(3-methylbenzyl)-3-(m-tolyl)-1H-pyrazole-5-carboxamide H 39 Preparation

[0164] Under other conditions the same as in Example 1, acetophenone was changed to 3-methylacetophenone and benzyl chloride was changed to 3-methylbenzyl chloride to obtain 30 mg of a white solid compound with a yield of 34%. 1 H NMR(300 MHz, DMSO-d6): δ 8.78 (d, J = 8.5 Hz, 1H), 8.11 (d, J = 4.4 Hz, 1H), 7.56 (d, J = 14.6 Hz, 3H), 7.39 - 7.30 (m, 4H), 7.23 - 7.12 (m, 3H), 7.03 (d, J = 7.3 Hz, 1H), 6.95 (s, 1H), 6.88 (d, J = 7.5 Hz, 1H), 5.66 - 5.54 (m, 2H), 4.63 (dq, J = 9.0, 4.5 Hz, 1H), 3.10 (dd, J = 13.6, 4.1 Hz, 1H), 2.93 (t, J = 12.0 Hz, 1H), 2.63 (d, J = 4.4 Hz, 3H), 2.35 (s, 3H), 2.22 (s, 3H). 13 C NMR(75 MHz, DMSO-d6): δ 170.9, 159.1, 148.9, 141.1, 138.0, 137.7, 137.5 136.4, 132.4, 132.0, 130.3, 129.2, 128.8, 128.6, 128.3, 128.2, 128.0, 127.9, 125.5, 124.4, 122.2, 121.4, 105.0, 54.2, 53.6, 36.9, 25.7, 21.1, 21.0. HRMS(ESI, m / z): Calcd. for C 29 H 29 BrN4O2 [M+Na] + 631.0320, found: 631.0313.

[0165] Example 40:

[0166] (S)-N-(3-(3-Bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-1-(4-methylbenzyl)-3-(m-tolyl)-1H-pyrazole-5-carboxamide H 40 Preparation

[0167] Under the same conditions as in Example 1, acetophenone was changed to 3-methylacetophenone, and benzyl chloride was changed to 4-methylbenzyl chloride. The product was a white solid with a yield of 73%. 1 H NMR(300MHz,DMSO-d6): δ8.80(d,J = 8.6Hz,1H),8.14(d,J = 4.6Hz,1H),7.58 - 7.53(m,3H),7.40 - 7.30(m,4H),7.23 - 7.13(m,2H),7.03(q,J = 8.1Hz,4H),5.66 - 5.50(m,2H),4.63(ddd,J = 10.7,8.5,4.4Hz,1H),3.11(dd,J = 13.6,4.3Hz,1H),2.97 - 2.89(m,1H),2.63(d,J = 4.4Hz,3H),2.35(s,3H),2.23(s,3H). 13 C NMR(75MHz,DMSO-d6): δ170.9,159.0,148.9,141.1,138.0,136.5,136.3,134.7,132.4,132.0,130.2,129.2,128.9,128.8,128.6,128.2,127.4,125.5,122.2,121.4,105.0,54.2,53.4,36.9,25.7,21.1,20.7.

[0168] Example 41:

[0169] (S)-1-(3-Bromobenzyl)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-(m-tolyl)-1H-pyrazole-5-carboxamide H 41 Preparation

[0170] Under the same conditions as in Example 1, acetophenone was changed to 3-methylacetophenone, and benzyl chloride was changed to 3-bromobenzyl chloride. The product was a white solid with a yield of 73%. 11H NMR (300 MHz, DMSO-d6) δ 8.83 (d, J = 8.6 Hz, 1H), 8.13 (q, J = 4.5 Hz, 1H), 7.66 (t, J = 8.2 Hz, 3H), 7.45 - 7.42 (m, 2H), 7.38 - 7.15 (m, 7H), 7.08 (d, J = 7.9 Hz, 1H), 5.71 - 5.55 (m, 2H), 4.62 (ddd, J = 10.4, 8.5, 4.4 Hz, 1H), 3.11 (dd, J = 13.6, 4.4 Hz, 1H), 2.93 (dd, J = 13.5, 10.7 Hz, 1H), 2.63 (d, J = 4.6 Hz, 3H), 2.35 (s, 3H). 13 13C NMR (75 MHz, DMSO-d6) δ 170.8, 158.9, 149.2, 141.0, 140.4, 138.0, 136.4, 132.2, 132.0, 130.6, 130.2, 130.0, 129.2, 128.9, 128.8, 128.2, 126.3, 125.6, 122.2, 121.6, 121.4, 105.1, 54.2, 53.0, 36.9, 25.7, 21.1.

[0171] Example 42:

[0172] (S)-1-(4-Bromobenzyl)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-(m-tolyl)-1H-pyrazole-5-carboxamide H 42 Preparation

[0173] Under other conditions the same as in Example 1, acetophenone was changed to 3-methylacetophenone, and benzyl chloride was changed to 4-bromobenzyl chloride. The product was a white solid with a yield of 73%. 1 1H NMR (300 MHz, DMSO-d6) δ 8.79 (d, J = 8.6 Hz, 1H), 8.11 (d, J = 4.6 Hz, 1H), 7.56 (t, J = 8.7 Hz, 3H), 7.47 - 7.42 (m, 3H), 7.38 - 7.28 (m, 3H), 7.22 - 7.14 (m, 2H), 7.06 (d, J = 8.4 Hz, 2H), 5.69 - 5.51 (m, 2H), 4.62 (ddd, J = 10.6, 8.6, 4.4 Hz, 1H), 3.11 (dd, J = 13.6, 4.4 Hz, 1H), 2.92 (dd, J = 13.0, 10.1 Hz, 1H), 2.62 (d, J = 4.5 Hz, 3H), 2.35 (s, 3H). 1313C NMR (75 MHz, DMSO-d6) δ 171.3, 159.4, 149.6, 141.5, 138.5, 137.6, 136.8, 132.7, 132.4, 131.7, 130.7, 130.0, 129.7, 129.3, 129.2, 128.7, 126.0, 122.6, 121.8, 121.0, 105.5, 54.6, 53.6, 37.4, 26.1, 21.5.

[0174] Example 43:

[0175] (S)-1-(3-Bromobenzyl)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-(4-fluorophenyl)-1H-pyrazole-5-carboxamide H 43 Preparation

[0176] Under the same conditions as in Example 1, acetophenone was changed to 4-fluoroacetophenone and benzyl chloride was changed to 3-bromobenzyl chloride. The product was a white solid with a yield of 73%. 1 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J = 8.6 Hz, 1H), 8.12 (q, J = 4.6 Hz, 1H), 7.79 (dd, J1 = 8.6, J2 = 5.7 Hz, 2H), 7.56 (s, 1H), 7.45 - 7.33 (m, 4H), 7.32 - 7.17 (m, 5H), 7.09 (d, J = 7.7 Hz, 1H), 5.67 (d, J = 15.1 Hz, 1H), 5.57 (d, J = 15.0 Hz, 1H), 4.63 (ddd, J1 = 10.6, J2 = 8.5, J3 = 4.4 Hz, 1H), 3.11 (dd, J1 = 13.6, J2 = 4.5 Hz, 1H), 2.92 (m, 1H), 2.63 (d, J = 4.5 Hz, 3H). 13 13C NMR (101 MHz, DMSO-d6) δ 170.87, 158.93, 148.34, 140.99, 140.33, 136.66, 132.03, 130.66, 130.35, 130.28, 130.11, twelve9.29, 128.25, 127.14, 127.06, 126.41, 121.63, 121.44, 116.02, 115.81, 104.98, 54.23, 53.10, 36.96, 25.72.

[0177] Example 44:

[0178] (S)-1-(3-Bromobenzyl)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-(2-chlorophenyl)-1H-pyrazole-5-carboxamide H 44 Preparation

[0179] Under other conditions the same as in Example 1, acetophenone was changed to 2-chloroacetophenone, and benzyl chloride was changed to 3-bromobenzyl chloride. The product was a white solid with a yield of 73%. 1 H NMR(400MHz,DMSO-d6)δ8.95(d,J=8.6Hz,1H),8.12(q,J=4.5Hz,1H),7.80-7.75(m,1H),7.58-7.53(m,3H),7.46-7.43(m,1H),7.42-7.33(m,4H),7.30(dt,J1=7.7,J2=1.3Hz,1H),7.24(t,J=7.8Hz,1H),7.19(t,J=7.8Hz,1H),7.11(dt,J1=7.9,J2=1.3Hz,1H),5.67(q,J=14.9Hz,2H),4.63(ddd,J1=10.7,J2=8.6,J3=4.4Hz,1H),3.10(dd,J1=13.6,J2=4.4Hz,1H),2.94(m,1H),2.63(d,J=4.6Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ170.90,158.85,146.71,141.07,140.20,135.63,131.99,131.05,131.00,130.62,130.38,130.33,130.18,129.70,129.24,128.22,127.47,126.46,121.60,121.39,108.68,54.26,53.16,36.77,25.68.

[0180] Example 45:

[0181] (S)-1-(3-Bromobenzyl)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-(3-chlorophenyl)-1H-pyrazole-5-carboxamide H 45 Preparation

[0182] Under other conditions the same as in Example 1, acetophenone was changed to 3-chloroacetophenone, and benzyl chloride was changed to 3-bromobenzyl chloride. The product was a white solid with a yield of 73%. 11H NMR (400 MHz, DMSO-d6) δ 8.81 (d, J = 8.6 Hz, 1H), 8.12 (q, J = 4.5 Hz, 1H), 7.78 (t, J = 1.9 Hz, 1H), 7.72 (dt, J1 = 7.9, J2 = 1.4 Hz, 1H), 7.56 (t, J = 1.8 Hz, 1H), 7.52 - 7.46 (m, 2H), 7.46 - 7.39 (m, 2H), 7.36 (m, 2H), 7.31 - 7.27 (m, 1H), 7.22 (dt, J1 = 15.6, J2 = 7.8 Hz, 2H), 7.11 - 7.07 (m, 1H), 5.73 - 5.54 (m, 2H), 4.64 (ddd, J1 = 10.5, J2 = 8.6, J3 = 4.5 Hz, 1H), 3.11 (dd, J1 = 13.6, J2 = 4.5 Hz, 1H), 2.92 (m, 1H), 2.63 (d, J = 4.5 Hz, 3H). 13 13C NMR (101 MHz, DMSO-d6) δ 170.76, 158.77, 147.75, 140.92, 140.15, 136.74, 134.36, 133.75, 132.01, 130.99, 130.65, 130.36, 130.26, 130.10, 129.26, 128.22, 127.89, 126.40, 124.61, 123.58, 121.61, 121.40, 105.49, 54.19, 53.19, 25.68.

[0183] Example 46:

[0184] (S)-N-(1-(3-bromobenzyl)-3-(2-bromophenyl)-1H-pyrazole-5-carbonyl)-3-(3-bromophenyl)-1-(methylamino)propan-2-amine 46 Preparation

[0185] Under the same conditions as in Example 1, replace acetophenone with 2-bromoacetophenone and benzyl chloride with 3-bromobenzyl chloride. The product is a white solid with a yield of 73%. 11H NMR (400 MHz, DMSO-d6): δ 8.92 (d, J = 8.6 Hz, 1H), 8.12 (q, J = 4.5 Hz, 1H), 7.74 (dd, J1 = 8.0, J2 = 1.2 Hz, 1H), 7.65 (dd, J1 = 7.8, J2 = 1.8 Hz, 1H), 7.55 (t, J = 1.8 Hz, 1H), 7.48 - 7.42 (m, 3H), 7.39 - 7.28 (m, 4H), 7.25 (t, J = 7.8 Hz, 1H), 7.19 (t, J = 7.8 Hz, 1H), 7.12 (dt, J1 = 7.9, J2 = 1.3 Hz, 1H), 5.66 (q, J = 15.0 Hz, 2H), 4.62 (ddd, J1 = 10.7, J2 = 8.5, J3 = 4.4 Hz, 1H), 3.09 (dd, J1 = 13.6, J2 = 4.4 Hz, 1H), 2.93 (m, 1H), 2.63 (d, J = 4.5 Hz, 3H). 13 13C NMR (101 MHz, DMSO-d6): δ 170.91, 158.86, 148.33, 141.07, 140.23, 135.46, 133.56, 133.32, 131.99, 131.01, 130.62, 130.33, 130.18, 130.03, 129.26, 128.24, 127.97, 126.46, 121.61, 121.40, 121.09, 108.56, 54.30, 25.69.

[0186] Example 47:

[0187] (S)-1-(3-Bromobenzyl)-3-(3-bromophenyl)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-1H-pyrazole-5-carboxamide H 47 Preparation

[0188] Under the same conditions as in Example 1, acetophenone was changed to 3-bromoacetophenone, and benzyl chloride was changed to 3-bromobenzyl chloride. The product was a white solid with a yield of 73%. 11H NMR (400 MHz, DMSO-d6) δ 8.80 (d, J = 8.7 Hz, 1H), 8.11 (q, J = 4.5 Hz, 1H), 7.92 (t, J = 1.8 Hz, 1H), 7.76 (dt, J = 7.8, 1.3 Hz, 1H), 7.55 (m, 2H), 7.49 (s, 1H), 7.46 - 7.40 (m, 2H), 7.36 (m, 2H), 7.29 (dt, J1 = 7.7, J2 = 1.4 Hz, 1H), 7.22 (dt, J1 = 15.8, J2 = 7.8 Hz, 2H), 7.11 - 7.07 (m, 1H), 5.68 (d, J = 15.0 Hz, 1H), 5.58 (d, J = 15.0 Hz, 1H), 4.63 (ddd, J1 = 10.4, J2 = 8.5, J3 = 4.5 Hz, 1H), 3.11 (dd, J1 = 13.6, J2 = 4.5 Hz, 1H), 2.91 (m, 1H), 2.63 (d, J = 4.5 Hz, 3H). 13 13C NMR (101 MHz, DMSO-d6) δ 170.74, 158.74, 147.63, 140.91, 140.15, 136.72, 134.57, 132.01, 131.26, 130.78, 130.65, 130.36, 130.26, 130.09, 129.25, 128.21, 127.48, 126.39, 123.93, 122.31, 121.60, 121.39, 105.48, 54.17, 53.17, 36.98, 25.67.

[0189] Example 48:

[0190] (S)-1-(3-Bromobenzyl)-3-(4-bromophenyl)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-1H-pyrazole-5-carboxamide H 48 Preparation

[0191] Under other conditions the same as in Example 1, replace acetophenone with 4-bromoacetophenone and benzyl chloride with 3-bromobenzyl chloride. The product is a white solid with a yield of 73%. 11H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J = 8.6 Hz, 1H), 8.11 (q, J = 4.5 Hz, 1H), 7.71 (d, J = 8.5 Hz, 2H), 7.65 (d, J = 8.6 Hz, 2H), 7.56 (t, J = 1.8 Hz, 1H), 7.44 (m, 2H), 7.38 - 7.33 (m, 2H), 7.29 (d, J = 7.6 Hz, 1H), 7.22 (dt, J1 = 15.5, J2 = 7.8 Hz, 2H), 7.09 (d, J = 7.7 Hz, 1H), 5.68 (d, J = 14.9 Hz, 1H), 5.57 (d, J = 15.0 Hz, 1H), 4.63 (ddd, J1 = 10.6, J2 = 8.6, J3 = 4.5 Hz, 1H), 3.11 (dd, J1 = 13.7, J2 = 4.5 Hz, 1H), 2.92 (m, 1H), 2.63 (d, J = 4.5 Hz, 3H). 13 13C NMR (101 MHz, DMSO-d6) δ 170.79, 158.82, 148.09, 140.96, 140.20, 136.71, 132.00, 131.94, 131.51, 130.64, 130.35, 130.24, 130.11, 129.25, 128.21, 127.02, 126.41, 121.60, 121.40, 121.18, 105.19, 54.20, 53.13, 36.94, 25.68.

[0192] Example 49:

[0193] (S)-1-(3-Bromobenzyl)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-(2-nitrophenyl)-1H-pyrazole-5-carboxamide 49 Preparation

[0194] Under other conditions the same as in Example 1, acetophenone was replaced with 2-nitroacetophenone, and benzyl chloride was replaced with 3-bromobenzyl chloride. The product was a white solid with a yield of 73%. 11H NMR (400 MHz, DMSO-d6) δ 8.91 (d, J = 8.6 Hz, 1H), 8.11 (q, J = 4.5 Hz, 1H), 7.89 (dd, J1 = 8.0, J2 = 1.1 Hz, 1H), 7.79 - 7.71 (m, 2H), 7.62 (ddd, J1 = 8.5, J2 = 6.9, J3 = 2.0 Hz, 1H), 7.53 (t, J = 1.8 Hz, 1H), 7.44 (dt, J1 = 8.0, J2 = 1.5 Hz, 1H), 7.36 (dt, J1 = 8.0, J2 = 1.5 Hz, 1H), 7.31 - 7.16 (m, 5H), 7.05 (d, J = 7.7 Hz, 1H), 5.60 (q, J = 15.0 Hz, 2H), 4.60 (ddd, J1 = 10.5, J2 = 8.5, J3 = 4.5 Hz, 1H), 3.09 (dd, J1 = 13.7, J2 = 4.6 Hz, 1H), 2.90 (m, 1H), 2.62 (d, J = 4.5 Hz, 3H). 13 13C NMR (101 MHz, DMSO-d6) δ 170.78, 158.53, 148.62, 144.94, 140.95, 139.93, 136.32, 132.51, 131.94, 130.53, 130.37, 130.22, 130.15, 130.06, 129.49, 129.26, 128.21, 126.33, 125.42, 123.89, 121.63, 121.39, 107.08, 54.23, 53.31, 36.83, 25.66.

[0195] Example 50:

[0196] (S)-1-(3-Bromobenzyl)-N-(3-(3,5-dibromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-phenyl-1H-pyrazole-5-carboxamide H 50 Preparation

[0197] Under other conditions the same as in Example 1, changing benzyl chloride to 3-bromobenzyl chloride and changing the compound (S)-2-amino-3-(3-bromophenyl)-N-methylpropanamide to the compound (S)-2-amino-3-(3,5-dibromophenyl)-N-methylpropanamide, the product is a white solid with a yield of 76%. 11H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J = 8.7 Hz, 1H), 8.11 (q, J = 4.6 Hz, 1H), 7.78 - 7.75 (m, 2H), 7.63 (t, J = 1.8 Hz, 1H), 7.57 (d, J = 1.8 Hz, 2H), 7.48 - 7.40 (m, 4H), 7.37 - 7.31 (m, 2H), 7.23 (t, J = 7.8 Hz, 1H), 7.08 (d, J = 7.9 Hz, 1H), 5.69 (d, J = 15.0 Hz, 1H), 5.57 (d, J = 15.0 Hz, 1H), 4.62 (ddd, J1 = 10.7, J2 = 8.6, J3 = 4.4 Hz, 1H), 3.11 (dd, J1 = 13.5, J2 = 4.4 Hz, 1H), 2.91 (m, 1H), 2.63 (d, J = 4.6 Hz, 3H). 13 13C NMR (101 MHz, DMSO-d6) δ 170.59, 158.95, 149.18, 143.00, 140.33, 136.47, 132.27, 131.33, 130.60, 130.30, 130.06, 128.98, 128.12, 126.31, 125.00, 122.05, 121.60, 105.01, 53.94, 53.08, 36.59, 25.68.

[0198] Example 51:

[0199] (S)-1-(3-Bromobenzyl)-N-(3-(3,5-dichlorophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-phenyl-1H-pyrazole-5-carboxamide H 51 Preparation

[0200] Under other conditions the same as in Example 1, replacing benzyl chloride with 3-bromobenzyl chloride and replacing the compound (S)-2-amino-3-(3-bromophenyl)-N-methylpropanamide with the compound (S)-2-amino-3-(3,5-dichlorophenyl)-N-methylpropanamide, the product is a white solid with a yield of 73%. 11H NMR (400 MHz, DMSO-d6): δ 8.85 (d, J = 8.7 Hz, 1H), 8.11 (q, J = 4.6 Hz, 1H), 7.79 - 7.73 (m, 2H), 7.48 - 7.44 (m, 2H), 7.43 (d, J = 4.3 Hz, 2H), 7.39 (q, J = 1.7 Hz, 3H), 7.37 - 7.32 (m, 2H), 7.23 (t, J = 7.8 Hz, 1H), 7.08 (d, J = 7.7 Hz, 1H), 5.69 (d, J = 15.0 Hz, 1H), 5.57 (d, J = 15.0 Hz, 1H), 4.64 (ddd, J1 = 10.7, J2 = 8.7, J3 = 4.4 Hz, 1H), 3.13 (dd, J1 = 13.6, J2 = 4.5 Hz, 1H), 2.93 (m, 1H), 2.63 (d, J = 4.5 Hz, 3H). 13 13C NMR (101 MHz, DMSO-d6): δ 170.60, 158.94, 149.18, 142.48, 140.35, 136.45, 133.57, 132.27, 130.60, 130.30, 130.04, 128.98, 128.10, 126.29, 126.12, 125.00, 121.60, 105.02, 53.87, 53.09, 36.66, 25.68.

[0201] Example 52:

[0202] (S)-1-(3-Bromobenzyl)-N-(3-(3,5-difluorophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-phenyl-1H-pyrazole-5-carboxamide H 52 Preparation

[0203] Under the same conditions as in Example 1, replace benzyl chloride with 3-bromobenzyl chloride, and replace compound (S)-2-amino-3-(3-bromophenyl)-N-methylpropanamide with compound (S)-2-amino-3-(3,5-difluorophenyl)-N-methylpropanamide. The product is a white solid with a yield of 72%. 11H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J = 8.7 Hz, 1H), 8.10 (q, J = 4.6 Hz, 1H), 7.79 - 7.74 (m, 2H), 7.49 - 7.42 (m, 4H), 7.38 - 7.31 (m, 2H), 7.23 (t, J = 7.8 Hz, 1H), 7.09 (dt, J1 = 7.8, J2 = 1.3 Hz, 1H), 7.06 - 6.97 (m, 3H), 5.76 - 5.69 (m, 1H), 5.60 (d, J = 15.0 Hz, 1H), 4.67 (ddd, J1 = 10.6, J2 = 8.6, J3 = 4.5 Hz, 1H), 3.15 (dd, J1 = 13.6, J2 = 4.5 Hz, 1H), 2.96 (m, 1H), 2.63 (d, J = 4.5 Hz, 3H). 13 13C NMR (101 MHz, DMSO-d6) δ 170.64, 158.91, 149.18, 140.37, 136.39, 132.26, 130.59, 130.30, 130.04, 128.98, 128.14, 126.29, 125.01, 121.60, 112.42, 112.17, 105.03, 53.89, 53.11, 25.69.

[0204] Example 53:

[0205] (S)-N-(3-(3-Bromo-5-fluorophenyl)-1-(methylamino)-1-oxopropan-2-yl)-1-(3-bromobenzyl)-3-phenyl-1H-pyrazole-5-carboxamide H 53 Preparation

[0206] Under other conditions the same as in Example 1, benzyl chloride was changed to 3-bromobenzyl chloride, and compound (S)-2-amino-3-(3-bromophenyl)-N-methylpropanamide was changed to compound (S)-2-amino-3-(3-bromo-5-fluorophenyl)-N-methylpropanamide. The product was a white solid with a yield of 74%. 11H NMR (400 MHz, DMSO-d6): δ 8.84 (d, J = 8.7 Hz, 1H), 8.11 (q, J = 4.6 Hz, 1H), 7.79 - 7.74 (m, 2H), 7.48–7.40 (m, 5H), 7.38 - 7.31 (m, 3H), 7.28 - 7.16 (m, 2H), 7.09 (d, J = 8.0 Hz, 1H), 5.70 (d, J = 15.0 Hz, 1H), 5.59 (d, J = 15.0 Hz, 1H), 4.65 (ddd, J1 = 10.6, J2 = 8.6, J3 = 4.5 Hz, 1H), 3.14 (dd, J1 = 13.6, J2 = 4.5 Hz, 1H), 2.94 (m, 1H), 2.63 (d, J = 4.6 Hz, 3H). 13 13C NMR (101 MHz, DMSO-d6): δ 170.62, 158.94, 149.18, 140.35, 136.44, 132.27, 130.60, 130.30, 130.05, 128.97, 126.30, 125.01, 121.60, 105.03, 53.92, 53.10, 36.71, 25.69.

[0207] Example 54:

[0208] (S)-1-(3-Bromobenzyl)-N-(3-(2-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-phenyl-1H-pyrazole-5-carboxamide H 54 Preparation

[0209] Under other conditions the same as in Example 1, replace benzyl chloride with 3-bromobenzyl chloride, and replace the compound (S)-2-amino-3-(3-bromophenyl)-N-methylpropanamide with the compound (S)-2-amino-3-(2-bromophenyl)-N-methylpropanamide. The product is a white solid with a yield of 66%. 1 1H NMR (400 MHz, DMSO-d6): δ 8.85 (d, J = 8.7 Hz, 1H), 8.01 (q, J = 4.5 Hz, 1H), 7.80 - 7.74 (m, 2H), 7.55 (dd, J1 = 8.0, J2 = 1.3 Hz, 1H), 7.45 (m, 4H), 7.39 - 7.31 (m, 3H), 7.29 - 7.17 (m, 2H), 7.11 (m, 2H), 5.71 (d, J = 15.0 Hz, 1H), 5.58 (d, J = 14.9 Hz, 1H), 4.77 (m, 1H), 3.05 (dd, J1 = 14.1, J2 = 10.2 Hz 1H), 2.62 (d, J = 4.6 Hz, 3H). 1313C NMR (101 MHz, DMSO-d6): δ 170.55, 158.90, 149.16, 140.42, 137.09, 136.45, 132.48, 132.29, 131.34, 130.65, 130.30, 130.04, 128.97, 128.62, 128.13, 127.43, 126.42, 125.06, 124.27, 121.62, 105.13, 53.10, 52.17, 37.48, 25.88.

[0210] Example 55:

[0211] (S)-1-(3-Bromobenzyl)-N-(3-(4-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-phenyl-1H-pyrazole-5-carboxamide H 55 Preparation

[0212] Under the same conditions as in Example 1, replace benzyl chloride with 3-bromobenzyl chloride, and replace the compound (S)-2-amino-3-(3-bromophenyl)-N-methylpropanamide with the compound (S)-2-amino-3-(4-bromophenyl)-N-methylpropanamide. The product is a white solid with a yield of 70%. 1 1H NMR (400 MHz, DMSO-d6): δ 8.82 (d, J = 8.6 Hz, 1H), 8.10 (q, J = 4.6 Hz, 1H), 7.80 - 7.74 (m, 2H), 7.44 (m, 6H), 7.38 - 7.31 (m, 2H), 7.28 - 7.20 (m, 3H), 7.11 - 7.05 (m, 1H), 5.70 (d, J = 15.1 Hz, 1H), 5.60 (d, J = 15.0 Hz, 1H), 4.63 (ddd, J1 = 10.4, J2 = 8.5, J3 = 4.5 Hz, 1H), 3.09 (dd, J1 = 13.7, J2 = 4.5 Hz, 1H), 2.92 (m, 1H), 2.62 (d, J = 4.6 Hz, 3H). 13 13C NMR (101 MHz, DMSO-d6): δ 170.87, 158.93, 149.17, 140.41, 137.61, 136.51, 132.29, 131.36, 131.01, 130.63, 130.27, 130.02, 128.94, 128.11, 126.32, 125.07, 121.61, 119.58, 105.09, 54.20, 25.69.

[0213] Example 56:

[0214] 1-(3-Bromobenzyl)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-phenyl-1H-pyrazole-5-carboxamide H 56 Preparation

[0215] Under other conditions same as Example 1, changing benzyl chloride to 3-bromobenzyl chloride and changing the compound (S)-2-amino-3-(3-bromophenyl)-N-methylpropanamide to the compound 2-amino-3-(3-bromophenyl)-N-methylpropanamide, the product is a white solid with a yield of 73%. 1 H NMR(400MHz,DMSO-d6)δ8.83(d,J=8.6Hz,1H),8.10(d,J=5.1Hz,1H),7.77(d,J=7.6Hz,2H),7.56(s,1H),7.48-7.40(m,4H),7.39-7.17(m,6H),7.09(d,J=7.8Hz,1H),5.73-5.54(m,2H),4.62(td,J1=9.7,J2=4.3Hz,1H),3.11(dd,J1=14.0,J2=4.4Hz,1H),2.92(t,J=12.1Hz,1H),2.63(d,J=4.5Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ170.82,141.00,132.00,130.64,130.28,130.06,128.96,126.36,125.03,54.20,25.68.

[0216] Example 57:

[0217] (S)-1-Benzyl-5-(2-bromophenyl)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-1H-pyrazole-3-carboxamide I1 Preparation

[0218] Step 1: Preparation of ethyl 4-(2-bromophenyl)-2,4-dioxobutyrate [[ID=2」]

[0219] Under an ice bath, 2-bromoacetophenone (500 mg, 2.5 mmol), diethyl oxalate (0.6 mL, 5.5 mmol) and sodium ethoxide (5 mL, 20% mass content, 0.01 mmol) were successively added to the reactor. After stirring vigorously in ethanol until dissolved, the mixture was stirred at room temperature for 10 h. Under an ice bath, the pH was adjusted to 2 - 3 with 4N hydrochloric acid, and the organic phase was extracted with ethyl acetate (30 mL), and then washed with saturated brine. The crude product ethyl 4-(2-bromophenyl)-2,4-dioxobutyrate was obtained by concentration.

[0220] Step 2: Preparation of Ethyl 5-(2-bromophenyl)-1H-pyrazole-3-carboxylate

[0221] Dissolve the crude product from Step 1 in 10 mL of acetic acid. Slowly add hydrazine monohydrate (0.3 mL, 6.0 mmol) dropwise under an ice bath, and stir at room temperature for 8 h. Extract with ethyl acetate (30 mL), wash the organic phase with saturated brine, concentrate, and perform column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain 740 mg of a milky white solid, ethyl 5-(2-bromophenyl)-1H-pyrazole-3-carboxylate. The total yield of the two steps is 80%.

[0222] Step 3: Preparation of Ethyl 1-benzyl-5-(2-bromophenyl)-1H-pyrazole-3-carboxylate

[0223] Dissolve 500 mg (1.7 mmol) of ethyl 5-(2-bromophenyl)-1H-pyrazole-3-carboxylate in 10 mL of acetonitrile. Add potassium carbonate (415.4 mg, 3 mmol) and benzyl chloride (0.27 mL, 2.3 mmol), heat to reflux at 90 °C, and react for 12 h. Extract with ethyl acetate (20 mL), wash the organic phase with saturated brine, concentrate, and perform column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain 130 mg of a white solid, ethyl 1-benzyl-5-(2-bromophenyl)-1H-pyrazole-3-carboxylate, with a yield of 20%.

[0224] Step 4: Preparation of 1-benzyl-5-(2-bromophenyl)-1H-pyrazole-3-carboxylic acid

[0225] Dissolve ethyl 1-benzyl-5-(2-bromophenyl)-1H-pyrazole-3-carboxylate (130 mg, 0.3 mmol) in 12 mL of methanol. Add 4 mL of 4N sodium hydroxide solution and stir at room temperature for 10 h. Adjust the pH to 4 with 4N hydrochloric acid under an ice bath, extract with ethyl acetate (20 mL), wash the organic phase with saturated brine, and concentrate to obtain 108 mg of a white solid, 1-benzyl-5-(2-bromophenyl)-1H-pyrazole-3-carboxylic acid, with a yield of 90%.

[0226] Step 5: Preparation of (S)-1-benzyl-5-(2-bromophenyl)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-1H-pyrazole-3-carboxamide

[0227] 1-Benzyl-5-(2-bromophenyl)-1H-pyrazole-3-carboxylic acid (30 mg, 0.1 mmol) and HOAT (24.5 mg, 0.2 mmol) were dissolved in 5 mL of DMF and stirred at room temperature for 10 min under nitrogen protection. Compound (S)-2-amino-3-(3-bromophenyl)-N-methylpropionamide (38.5 mg, 0.1 mmol) was added at 0°C. Stirring was continued for 10 min, and N-methylmorpholine (0.009 mL, 0.08 mmol) was added at 0°C. Stirring was continued for 10 min, and EDCI (24.8 mg, 0.1 mmol) was added. The mixture was stirred at 0°C for 1 h, and the reaction was allowed to proceed to room temperature for 12 h. The mixture was extracted with ethyl acetate (20 mL), and the organic phase was washed with saturated brine. The residue was concentrated and subjected to column chromatography (petroleum ether:ethyl acetate=1:1) to obtain 22 mg of the white solid compound (S)-1-benzyl-5-(2-bromophenyl)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-1H-pyrazole-3-carboxamide in a yield of 44%. 1 H NMR (300MHz, DMSO-d6): δ8.13(t,J=6.4Hz,2H),7.78-7.75(m,1H),7.50(s,1H),7.45-7.17(m,9H),6.92(t,J=3 .7Hz,2H),6.76(s,1H),5.22(t,J=16.5Hz,2H),4.70(q,J=8.4Hz,1H),3.07–2.98(m,2H),2.62(d,J=4.4Hz,3H). 13 C NMR (101MHz, DMSO-d6): δ171.0,160.8,145.3,143.0,140.9,136.3,132.9,132.3,132.0,131.6,13 0.4,130.2,129.2,128.4,128.3,127.9,127.6,127.0,123.6,121.4,107.9,53.7,53.4,37.2,25.6.

[0228] Example 58:

[0229] Preparation of (S)-1-benzyl-5-(3-bromophenyl)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-1H-pyrazole-3-carboxamide I2

[0230] Other conditions were the same as in Example 57, except that 2-bromoacetophenone was replaced with 3-bromoacetophenone. The product was a white solid with a yield of 73%. 11H NMR (400 MHz, DMSO-d6) δ 8.12 (t, J = 7.0 Hz, 2H), 7.63 - 7.59 (m, 2H), 7.48 (s, 1H), 7.43 - 7.36 (m, 3H), 7.32 - 7.18 (m, 5H), 6.99 (d, J = 7.4 Hz, 2H), 6.89 (s, 1H), 5.46 (s, 2H), 4.69 (td, J = 8.7, 5.2 Hz, 1H), 3.10–3.00 (m, 2H), 2.61 (d, J = 4.7 Hz, 3H). 13 13C NMR (101 MHz, DMSO-d6) δ 171.0, 160.6, 145.5, 143.4, 140.9, 136.9, 132.0, 131.9, 131.5, 131.1, 131.0, 130.2, 129.2, 128.7, 128.4, 127.7, 127.6, 126.6, 122.0, 121.4, 107.4, 53.6, 53.5, 37.2, 25.6.

[0231] Example 59:

[0232] (S)-1-Benzyl-5-(4-bromophenyl)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-1H-pyrazole-3-carboxamide I3 Preparation

[0233] Under other conditions the same as in Example 57, changing 2-bromoacetophenone to 4-bromoacetophenone, the product was a white solid with a yield of 73%. 1 1H NMR (400 MHz, DMSO-d6) δ 8.12 - 8.06 (m, 2H), 7.67 - 7.62 (m, 2H), 7.47 (t, J = 1.8 Hz, 1H), 7.39 - 7.35 (m, 3H), 7.33 - 7.23 (m, 4H), 7.19 (t, J = 7.7 Hz, 1H), 7.00 - 6.96 (m, 2H), 6.85 (s, 1H), 5.45 (s, 2H), 4.68 (td, J1 = 8.8, J2 = 5.2 Hz, 1H), 3.03 (m, 2H), 2.61 (d, J = 4.6 Hz, 3H). 1313C NMR (101 MHz, DMSO-d6) δ 170.94, 160.63, 145.55, 143.83, 140.85, 136.88, 131.99, 131.89, 130.61, 130.18, 129.21, 128.65, 128.48, 128.33, 127.60, 126.52, 122.58, 121.37, 107.15, 53.59, 25.59.

[0234] Example 60:

[0235] Preparation of (S)-1-benzyl-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-5-(m-tolyl)-1H-pyrazole-3-carboxamide I4

[0236] Under other conditions the same as in Example 57, replacing 2-bromoacetophenone with 3-methylacetophenone, the product was a white solid with a yield of 73%. 1 1H NMR (300 MHz, DMSO-d6) δ 8.11 - 8.08 (m, 2H), 7.48 (s, 1H), 7.38 - 7.17 (m, 10H), 7.02 - 7.00 (m, 2H), 6.80 (s, 1H), 5.44 (s, 2H), 4.69 (td, J = 8.6, 5.4 Hz, 1H), 3.11 - 2.98 (m, 2H), 2.62 (d, J = 4.5 Hz, 3H), 2.29 (s, 3H). 13 13C NMR (101 MHz, DMSO-d6) δ 171.0, 160.8, 145.5, 145.2, 140.9, 138.25, 137.2, 132.0, 130.2, 129.7, 129.2, 128.8, 128.6, 128.4, 127.6, 126.6, 125.6, 121.4, 106.7, 53.6, 53.2, 37.3, 25.6, 20.9.

[0237] Example 61:

[0238] Preparation of (S)-1-benzyl-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-5-(p-tolyl)-1H-pyrazole-3-carboxamide I5

[0239] Under other conditions the same as in Example 57, replacing 2-bromoacetophenone with 4-methylacetophenone, the product was a white solid with a yield of 73%. 11H NMR (300 MHz, DMSO-d6) δ 8.11 - 8.08 (m, 2H), 7.48 (s, 1H), 7.38 - 7.16 (m, 10H), 6.99 (d, J = 6.7 Hz, 2H), 6.79 (s, 1H), 5.43 (s, 2H), 4.70 (td, J = 8.6, 5.4 Hz, 1H), 3.07 - 3.03 (m, 2H), 2.62 (d, J = 4.5 Hz, 3H), 2.31 (s, 3H). 13 13C NMR (101 MHz, DMSO-d6) δ 171.0, 160.8, 145.5, 145.1, 140.9, 138.6, 137.2, 132.0, 130.2, 129.5, 129.2, 128.6, 128.4, 128.3, 127.5, 126.5, 121.4, 106.6, 53.6, 53.1, 37.3, 25.6, 20.8.

[0240] Example 62:

[0241] (S)-1-Benzyl-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-5-(3-methoxyphenyl)-1H-pyrazole-3-carboxamide I6 Preparation

[0242] Under other conditions the same as in Example 57, changing 2-bromoacetophenone to 3-methoxyacetophenone, the product is a white solid with a yield of 73%. 11 1H NMR (400 MHz, DMSO-d6) δ 8.19 (q, J = 4.6 Hz, 1H), 8.10 (d, J = 8.6 Hz, 1H), 7.48 (t, J = 1.8 Hz, 1H), 7.36 (t, J = 7.9 Hz, 2H), 7.31 (dd, J1 = 8.1, J2 = 6.3 Hz, 2H), 7.26 (m, 2H), 7.19 (t, J = 7.7 Hz, 1H), 6.99 (m, 4H), 6.91 (t, J = 2.1 Hz, 1H), 6.85 (s, 1H), 5.45 (s, 2H), 4.69 (td, J1 = 8.8, J2 = 5.1 Hz, 1H), 3.69 (s, 3H), 3.17–2.97 (m, 2H), 2.61 (d, J = 4.5 Hz, 3H). 13C NMR(101MHz,DMSO-d6)δ170.99,160.75,159.35,145.49,144.87,140.89,137.19,132.02,130.12 ,129.22,128.67,128.37,127.55,126.46,121.38,120.73,113.80,106.89,55.13,53.63,25.60.

[0243] Example 63:

[0244] Preparation of (S)-1-benzyl-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-5-(4-methoxyphenyl)-1H-pyrazole-3-carboxamide I7

[0245] Other conditions were the same as those in Example 57, except that 2-bromoacetophenone was replaced with 4-methoxyacetophenone. The product was a white solid with a yield of 73%. 1 H NMR (300MHz, DMSO-d6) δ8.08(m,1H),7.47(t,J=1.7Hz,1H),7.37(dt,J1=7.5,J2=1.8Hz,1H),7.34-7.21(m,9H),7.02-6.95 (m,2H),6.78(s,1H),5.43(s,2H),4.67(td,J1=8.6,J2=5.2Hz,1H),3.12-2.94(m,2H),2.61(d,J=4.5Hz,3H),2.32(s,3H). 13 C NMR(75MHz,DMSO-d6)δ171.02,160.84,145.50,145.16,140.88,138.70,137.18,132.03,130.24,129.54,12 9.27,128.68,128.48,128.38,127.57,126.50,126.45,121.42,106.61,53.63,53.13,37.28,25.64,20.85.

[0246] Example 64:

[0247] Preparation of (S)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-1-(3-methylbenzyl)-5-phenyl-1H-pyrazole-3-carboxamide I8

[0248] Under the same conditions as in Example 57, 2-bromoacetophenone was changed to acetophenone, and benzyl chloride was changed to 3-methylbenzyl chloride. The product was a white solid with a yield of 73%. 1 H NMR(400MHz,DMSO-d6): δ8.14-8.03(m,1H),7.44(m,3H),7.37(dt,J1=7.8,J2=1.6Hz,1H),7.25(dt,J1=7.7,J2=1.4Hz,1H),7.18(q,J=7.5Hz,1H),7.05(d,J=7.6Hz,1H),6.81(d,J=3.5Hz,2H),6.75(d,J=7.6Hz,1H),5.40(s,2H),4.69(td,J1=8.7,J2=5.2Hz,1H),3.13–2.97(m,1H),2.62(d,J=4.6Hz,2H),2.22(s,1H). 13 CNMR(101MHz,DMSO-d6)δ170.99,160.79,145.46,145.02,140.87,137.77,136.96,132.00,130.17,129.36,129.22,129.04,128.92,128.59,128.55,128.33,128.19,127.15,123.60,121.39,106.78,53.60,53.19,37.27,25.60,21.01.

[0249] Example 65:

[0250] (S)-N-(3-(3-Bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-1-(3-fluorobenzyl)-5-phenyl-1H-pyrazole-3-carboxamide I9 Preparation

[0251] Under the same conditions as in Example 57, 2-bromoacetophenone was changed to acetophenone, and benzyl chloride was changed to 3-fluorobenzyl chloride. The product was a white solid with a yield of 73%. 1 H NMR(400MHz,DMSO-d6)δ8.10(m,2H),7.48-7.44(m,2H),7.41(dd,J1=7.3,J2=2.5Hz,1H),7.39-7.31(m,4H),7.25(d,J=7.7,1H),7.19(t,J=7.7Hz,1H),7.09(m,1H),5.75(s,1H),5.47(s,1H),4.69(m,1H),3.05(m,2H),2.62(d,J=4.6Hz,3H). 1313C NMR (101 MHz, DMSO-d6) δ 170.97, 160.73, 145.71, 145.16, 140.87, 139.90, 139.83, 132.02, 130.76, 130.68, 130.17, 129.23, 129.15, 128.99, 128.57, 128.35, 122.55, 121.39, 114.55, 114.35, 113.55, 113.33, 106.92, 54.94, 53.63, 52.67, 37.23, 25.62.

[0252] Biological activity test

[0253] The cumulative level of cAMP was mainly measured using the GloSensor method, a bioluminescence-based cAMP biosensor (Promega). HEK293T cells in good condition were seeded in 6-well plates or 35 mm cell culture dishes and placed in an incubator at 37 °C and 5% CO2 for 24 h to allow the cells to adhere and grow. Then, β2-adrenergic receptor plasmid and pGloSensor TM -22FcAMP plasmid were transfected into the cells using a transfection reagent and cultured in an incubator at 37 °C and 5% CO2 for 24 h to allow transcription and expression of the target gene. Subsequently, the transfected cells were evenly seeded in 96-well plates and cultured in an incubator at 37 °C and 5% CO2 for 24 h. Finally, the old culture medium in the 96-well plates was aspirated, the cells were washed once with fresh culture medium, and then a balanced culture medium containing GloSensor TM cAMP Reagent, serum, and CO2-independent medium was added and cultured in an incubator at 37 °C and 5% CO2 for 1-2 h or until a stable background signal was obtained. Isoproterenol (ISO) was dissolved in DMSO, sterilized by filtration, and used as a compound stock solution, which was diluted to different concentration gradients with culture medium (the DMSO concentration in the prepared compound was less than or equal to 0.1%). The prepared compound was quickly added to the 96-well plates containing HEK293T cells to start drug stimulation. It was observed that the bioluminescence signal increased rapidly after the addition of the compound using a multifunctional microplate reader. When the signal value reached the peak and no longer increased, compounds with different concentration gradients (8 μM, 20 μM, 50 μM, 100 μM) were immediately added. At the same time, the bioluminescence signal was immediately collected using a multifunctional microplate reader, and the bioluminescence signal value increased with the increase in the compound concentration. Finally, after organizing the data, it was processed using GraphPad Prism8 software. With the concentration as the abscissa and the signal value, fold value, and response value as the ordinate, the dose-response curves of agonists, antagonists, and allosteric modulators and the EC 50 or IC 50 values of the compound were obtained.

[0254] Table 2 Statistical Table of Functional Activities of N-Substituted Benzyl Pyrazole Derivatives

[0255]

[0256]

[0257] Note: Among them, "+" indicates having the corresponding activity, and "-" indicates having no corresponding activity

[0258] Table 3 Comparison Results of Activities between New Derivatives with Allosteric Modulator Activity and Cmpd-15

[0259]

[0260] Note: a The values are expressed as the blocking activity relative to Cmpd-15

[0261] In the test results of the Glosensor cAMP accumulation assay, the new compounds H2, H3, H5, H6, H8, H9, H 10 ,H 11 ,H 12 ,H 17 ,H 22 ,H 23 ,H 34 ,H 35 ,H 54 ,H 55 I2, I4, I6 have β2AR antagonistic effects; H4, H7, H 13 ,H 16 ,H 24 ,H 25 and 38 other compounds have β2AR allosteric regulatory effects (see Table 2). Among them, the allosteric effects of H 16 ,H 24 ,H 25 ,H 33 ,H 43 ,H 44 ,H 45 ,H 49 ,H 50 are stronger than those of Cmpd-15 (see Table 3); when the substituent on the N-2 benzyl is Br (H 30 ,H 31 ,H 32 ), the activities of the new compounds are reversed and all have agonist effects (see Figure 2 ); especially the derivative H 31, not only has the effect of activating β2AR, but also can play a positive allosteric regulatory role in the functional activity of the β2AR agonist ISO. As the concentration of this compound continues to increase, the dose-effect curve of ISO shows a limited upward shift trend (see Figure 1 ), indicating that compound H 31 can positively allosterically regulate the functional activity of the β2AR agonist ISO, that is, H 31 is an agonist of β2AR and also an allosteric agonist of β2AR. H 30 , H 32 is a partial agonist of β2AR.

[0262] At the same time, these results indicate that the right (S)-2-amino-3-(3-bromophenyl)-N-methylpropanamide in the Cmpd-15 structure is an important active part. If this part is replaced with other differently substituted amines, the resulting compounds have weak or no antagonistic activity. In addition, new compounds with electron-withdrawing substituents (such as NO2, F, and Br, etc.) on the pyrazolylbenzyl benzene ring have better allosteric activity, and the allosteric antagonistic activity of N-2 substituted compounds is better than that of N-1 substituted compounds.

Claims

1. Use of an N-substituted benzylpyrazole derivative or a pharmaceutically acceptable salt thereof, characterized in that, When the N-substituted benzylpyrazole derivative is used for preparing a β2-AR receptor antagonist drug, it is selected from one of the following structural formulas: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ； When the N-substituted benzylpyrazole derivative is used for preparing a β2-AR receptor agonist drug, it is selected from one of the following structural formulas: ； ； 。

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