WO2023165168A1 - APPLICATION OF PYRAZOLE DERIVATIVE AS β2 ADRENERGIC RECEPTOR ALLOSTERIC MODULATOR, ANTAGONIST AND AGONIST - Google Patents

APPLICATION OF PYRAZOLE DERIVATIVE AS β2 ADRENERGIC RECEPTOR ALLOSTERIC MODULATOR, ANTAGONIST AND AGONIST Download PDF

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WO2023165168A1
WO2023165168A1 PCT/CN2022/132704 CN2022132704W WO2023165168A1 WO 2023165168 A1 WO2023165168 A1 WO 2023165168A1 CN 2022132704 W CN2022132704 W CN 2022132704W WO 2023165168 A1 WO2023165168 A1 WO 2023165168A1
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nmr
dmso
pyrazole
bromophenyl
preparation
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French (fr)
Chinese (zh)
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陈新
黑晓源
雒智杰
戚颖
钱明成
赵帅
李晴
洪美龄
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常州大学
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Priority claimed from CN202211403416.9A external-priority patent/CN115745891A/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms

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  • the invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of pyrazole derivatives and their application as allosteric regulators of ⁇ 2 adrenergic receptors.
  • GPCR G-protein coupled receptor
  • rhodopsin rhodopsin
  • Adrenergic receptors (AR) are a type A subfamily of GPCRs that play an important role in the sympathetic nervous system. For example, ⁇ 1 -adrenoceptor ( ⁇ 1 AR) antagonists are used in cardiovascular disease, while ⁇ 2 -adrenergic receptor ( ⁇ 2 AR) antagonists are used in the treatment of asthma.
  • Allosteric ligands (also known as allosteric ligands) affect receptor activity by differing in conformation from the orthosteric ligand binding site. Allosteric ligands mediate the action of GPCR proteins by inducing conformational changes in their proteins, which shift from the allosteric binding pocket to the orthosteric site or directly to the effector protein coupling site. Due to the relatively low conservation of their binding sites, it is possible with better subtype selectivity. Drugs targeting allosteric classes in GPCRs not only have better selectivity than traditional drugs, but also reduce potential drug side effects caused by off-target effects.
  • allosteric modulators can also act synergistically with orthosteric ligands to lock the receptor in a specific conformation, so that the receptor exhibits specific signal transduction, which in turn makes the allosteric modulator different from the orthosteric ligand.
  • Pharmacodynamic properties of ligands. ⁇ 2 AR antagonists are very classic GPCRs drugs, which play an important role in the treatment of heart failure, hypertension, coronary heart disease, arrhythmia, angina pectoris and other diseases, and are the cornerstone of the treatment of cardiovascular diseases. Therefore, the development and design of ⁇ 2 AR allosteric antagonists is of great significance to the treatment of various cardiovascular diseases.
  • Cmpd-15 small molecule negative allosteric modulator compound 15
  • Cmpd-15 shown in formula 2
  • Cmpd-15 is a peptide compound with poor water solubility and low biological activity, the relative instability of its structure may affect its druggability.
  • Pyrazole (C 3 H 3 N 2 H) is a nitrogen-containing heterocyclic compound with good stability and broad-spectrum pharmacological properties, and has become an attractive core skeleton in drug design.
  • the present invention uses a scaffold-hopping strategy to replace the peptide core structure of Cmpd-15 with a pyrazole skeleton. Based on the skeleton transition strategy, the key functional groups of the three parts of Cmpd-15 were retained to form heterocyclic derivatives with pyrazole as the core structure, and the activity and specificity of the new heterocyclic derivatives on ⁇ 2 AR were evaluated.
  • the design idea of the new heterocyclic derivatives is shown in Formula 3.
  • the pharmacophore on the left, middle and right side of Cmpd-15 is respectively connected to the pyrazole ring to form a pyrazole type compound. It is estimated that the stability of the designed heterocyclic derivatives is better than that of Cmpd-15, and it is possible to improve the ability to combine with ⁇ 2 AR, and the druggability is also relatively good.
  • the invention uses acetophenones with different substituents as raw materials, undergoes Claisen condensation, ring formation, substitution, ester hydrolysis and amide coupling reactions to finally obtain a series of new pyrazole derivatives.
  • the purpose of the present invention is to develop a new heterocyclic derivative with stable chemical structure, high biological activity, good receptor subtype selectivity and improved water solubility, as an allosteric regulator of ⁇ 2 -AR, for the development of cardiovascular and cerebrovascular, New medicines for diabetes and cancer diseases offer new directions.
  • the solvent is N,N-dimethylformamide; the activator is 1-hydroxy-7-azabenzotriazole (HOAT); the acid-binding agent is N-methylmorpholine (NMM); the amide coupling Agent 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI); Compound 5: HOAT: Compound A: NMM: The molar ratio of EDCI is 1:1.2:1:0.7: 1.2; react in ice bath for 1.5h, and react at room temperature for 12h.
  • New pyrazole derivatives can be used as agonists, antagonists, allosteric agonists and allosteric antagonists of ⁇ 2 -AR;
  • compounds H 30 , H 31 , and H 32 in Table 1-1 have agonist activity and can be used as ⁇ 2 -AR agonists;
  • the compound H 31 in Table 1-1 has both agonistic activity and allosteric activity, and can be used as an allosteric agonist of ⁇ 2 -AR;
  • H 2 , H 22 , H 23 , H 34 , H 54 , H 55 , I 2 , I 4 , I 6 and compounds L 1 -L 22 in Table 1-1 and Table 1-2 have both antagonistic activity and Allosteric activity, can be used as an allosteric antagonist of ⁇ 2 -AR.
  • New pyrazole derivatives can be used as agonists, antagonists, allosteric agonists and allosteric antagonists of ⁇ 2 -AR, providing new directions for the development of new drugs for cardiovascular and cerebrovascular diseases, diabetes and cancer diseases.
  • Fig. 1 is the structural diagram and ISO dose-response curve of H31 ;
  • Figure 2 is the EC 50 curves of compounds H 30 , H 31 , and H 32 .
  • Figure 3 is a dose-response curve of ISO mediated by L1, L4, and L14.
  • Figure 4 is a graph partially representative of pyrazole compound-mediated antagonism.
  • Step 1 Preparation of ethyl 2,4-dioxo-4-phenylbutyrate
  • Step 4 Preparation of N-2 benzyl-phenylpyrazole-1-carboxylic acid
  • N-2 benzyl-phenylpyrazole-1-carboxylic acid (30mg, 0.1mmol) and HOAT (24.5mg, 0.2mmol) were dissolved in 5mL DMF, stirred at room temperature for 10min under nitrogen protection, and compound ( S)-2-amino-3-(3-bromophenyl)-N-methylpropionamide (38.5mg, 0.1mmol), after stirring for 10min, N-methylmorpholine (0.009mL, 008mmol), stirred for 10min, added EDCI (24.8mg, 0.1mmol), kept stirring at 0°C for 1h, and reacted at room temperature for 12h.
  • Embodiment 6 is a diagrammatic representation of Embodiment 6
  • Embodiment 7 is a diagrammatic representation of Embodiment 7:
  • Embodiment 8 is a diagrammatic representation of Embodiment 8
  • Embodiment 9 is a diagrammatic representation of Embodiment 9:
  • Example 2 change benzyl chloride into 3-bromobenzyl chloride, change compound (S)-2-amino-3-(3-bromophenyl)-N-methylpropionamide into compound ( S)-2-amino-3-(3,5-dichlorophenyl)-N-methylpropanamide, the product is a white solid, and the yield is 73%.
  • Example 2 change benzyl chloride into 3-bromobenzyl chloride, change compound (S)-2-amino-3-(3-bromophenyl)-N-methylpropionamide into compound ( S)-2-amino-3-(3,5-difluorophenyl)-N-methylpropanamide, the product is a white solid, and the yield is 72%.
  • Example 2 change benzyl chloride into 3-bromobenzyl chloride, change compound (S)-2-amino-3-(3-bromophenyl)-N-methylpropionamide into compound ( S)-2-amino-3-(3-bromo-5-fluorophenyl)-N-methylpropanamide, the product is a white solid with a yield of 74%.
  • Example 2 change benzyl chloride into 3-bromobenzyl chloride, change compound (S)-2-amino-3-(3-bromophenyl)-N-methylpropionamide into compound ( S)-2-amino-3-(2-bromophenyl)-N-methylpropanamide, the product is a white solid, and the yield is 66%.
  • Example 2 change benzyl chloride into 3-bromobenzyl chloride, change compound (S)-2-amino-3-(3-bromophenyl)-N-methylpropionamide into compound ( S)-2-amino-3-(4-bromophenyl)-N-methylpropanamide, the product is a white solid, and the yield is 70%.
  • Example 2 change benzyl chloride into 3-bromobenzyl chloride, change compound (S)-2-amino-3-(3-bromophenyl)-N-methylpropionamide into compound 2 -Amino-3-(3-bromophenyl)-N-methylpropanamide, the product is a white solid with a yield of 73%.
  • Step 1 Preparation of ethyl 4-(2-bromophenyl)-2,4-dioxobutanoate
  • Step 3 Preparation of ethyl 1-benzyl-5-(2-bromophenyl)-1H-pyrazole-3-carboxylate
  • Step 5 (S)-1-Benzyl-5-(2-bromophenyl)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropane-2 Preparation of -yl)-1H-pyrazole-3-carboxamide
  • Example 57 Other conditions were the same as in Example 57, except that 2-bromoacetophenone was changed to acetophenone, benzyl chloride was changed to 3-fluorobenzyl chloride, and the product was a white solid with a yield of 73%.
  • Step 1 Preparation of ethyl 4-(2-fluorophenyl)-2,4-dioxobutanoate
  • Step 4 (S)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-(2-fluorophenyl)-1H- Preparation of pyrazole-5-carboxamide
  • Example 66 Other conditions were the same as in Example 66, and 4-fluoroacetophenone was substituted for 2-fluoroacetophenone to obtain a white solid with a yield of 35%.
  • Example 66 Other conditions were the same as in Example 66, and 4-chloroacetophenone was substituted for 2-fluoroacetophenone to obtain a white solid with a yield of 35%.
  • Example 66 Other conditions were the same as in Example 66, and 3-methylacetophenone was substituted for 2-fluoroacetophenone to obtain a white solid with a yield of 35%.
  • Example 66 Other conditions are the same as in Example 66, replacing 2-fluoroacetophenone with acetophenone, and replacing (S)-2-amino-3-(3-bromophenyl)-N-methylpropionamide with (S)- 2-Amino-3-(3,5-difluorophenyl)-N-methylpropanamide, a white solid was obtained with a yield of 37%.
  • Example 66 Other conditions are the same as in Example 66, replacing 2-fluoroacetophenone with acetophenone, and replacing (S)-2-amino-3-(3-bromophenyl)-N-methylpropionamide with (S)- 2-Amino-3-(3,5-dichlorophenyl)-N-methylpropanamide, a white solid was obtained with a yield of 38%.
  • Example 66 Other conditions are the same as in Example 66, replacing 2-fluoroacetophenone with acetophenone, and replacing (S)-2-amino-3-(3-bromophenyl)-N-methylpropionamide with (S)- 2-Amino-3-(3,5-dibromophenyl)-N-methylpropanamide was obtained as a white solid with a yield of 39%.
  • Example 66 Other conditions are the same as in Example 66, replacing 2-fluoroacetophenone with acetophenone, and replacing (S)-2-amino-3-(3-bromophenyl)-N-methylpropionamide with (S)- 2-Amino-3-(3-bromo-5-fluorophenyl)-N-methylpropanamide, a white solid was obtained with a yield of 35%.
  • Example 66 Other conditions are the same as in Example 66, replacing 2-fluoroacetophenone with acetophenone, and replacing (S)-2-amino-3-(3-bromophenyl)-N-methylpropionamide with (S)- 2-Amino-3-(2-bromophenyl)-N-methylpropanamide, a white solid was obtained with a yield of 37%.
  • Example 66 Other conditions are the same as in Example 66, replacing 2-fluoroacetophenone with acetophenone, and replacing (S)-2-amino-3-(3-bromophenyl)-N-methylpropionamide with (S)- 2-Amino-3-(4-bromophenyl)-N-methylpropanamide, a white solid was obtained with a yield of 35%.
  • cAMP a bioluminescence based cAMP biosensor (Promega).
  • HEK293T cells in good condition were planted in 6-well plates or 35MM cell culture dishes, and placed in a 37°C, 5% CO 2 incubator for 24 hours to allow the cells to adhere to the wall and grow.
  • the ⁇ 2 adrenoreceptor plasmid and the pGloSensor TM -22FcAMP plasmid were transferred into the cells with a transfection reagent, and placed in a 5% CO 2 incubator at 37°C for 24 hours to allow the transcription and expression of the target gene.
  • the cells transfected with the plasmid were evenly seeded in a 96-well plate, and cultured at 37° C. in a 5% CO 2 incubator for 24 hours. Finally, discard the old culture medium in the 96-well plate, wash the cells with new culture medium, and then add the balanced culture medium containing GloSensor TM cAMP Reagent, serum and CO 2 -independent medium at 37°C, 5% CO 2 incubator Incubate for 1-2 hours or until a stable background signal is obtained.
  • Isoproterenol (ISO) was dissolved in DMSO, and after sterile filtration, it was used as the compound mother solution and diluted with culture medium to different concentration gradients (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 plate containing HEK293T cells to start administration stimulation.
  • the bioluminescent signal after adding the compound can be observed by a multi-functional microplate reader. When the signal value rises to the peak and no longer increases, immediately add the compound with different concentration gradients (8 ⁇ M, 20 ⁇ M, 50 ⁇ M, 100 ⁇ M).
  • the bioluminescent signal was collected immediately with a multifunctional microplate reader, and the value of the bioluminescent signal increased with the increase of the compound concentration.
  • the data was sorted and processed with GraphPad Prism8 software, with the concentration as the abscissa, and the signal value, multiple value response value as the ordinate, to obtain the dose-effect relationship curve of the agonist, antagonist and allosteric modulator and the EC 50 or IC 50 of the compound value.
  • compound H 31 not only has the effect of agonizing ⁇ 2 AR, but also can positively regulate the functional activity of ⁇ 2 AR agonist ISO .
  • the dose-effect curve of ISO showed a limited upward trend ( Figure 1).
  • Compounds L 1 , L 4 , and L 14 can negatively regulate the functional activity of ⁇ 2 AR endogenous ligand ISO, and are allosteric antagonists of ⁇ 2 -adrenergic receptors.
  • the dose-effect curve of ISO showed a limited downward trend ( Figure 3).

Abstract

The present invention relates to an application of a pyrazole derivative as a β 2 adrenergic receptor allosteric modulator, antagonist and agonist. An acetophenone or an acetophenone containing different substituents is used as an initial raw material, and eventually the pyrazole derivative as shown in the formula (1) is obtained.

Description

[根据细则26改正 09.01.2023]吡唑衍生物在作为β2肾上腺素受体别构调节剂，拮抗剂和激动剂的应用[Corrected under Rule 26 09.01.2023] Use of pyrazole derivatives as allosteric modulators, antagonists and agonists of β2 adrenergic receptors 技术领域technical field
本发明属于药物化学领域，特别涉及一种吡唑类衍生物的制备方法以及其作为β2肾上腺素受体别构调节剂的应用。The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of pyrazole derivatives and their application as allosteric regulators of β2 adrenergic receptors.
背景技术Background technique
G蛋白偶联受体(G-protein coupled receptor，GPCR)是一类具有七次跨膜结构的膜受体蛋白,也是关键的药物靶标，目前FDA批准的药物中有超过30％是靶向GPCR的。GPCR可分为六类，但只有四类(A,B,C和F)存在于人类中。其中，A类(视紫红质)含有最多数量的GPCR(人类中有719个)。大约一半的A类GPCR是涉及气味(信息素受体)或视觉(视紫红质)的感觉受体。肾上腺素受体(AR)是一类A型亚家族的GPCR，在交感神经系统中发挥着重要功能。例如，β 1-肾上腺素受体(β 1AR)拮抗剂用于心血管疾病，而β 2-肾上腺素受体(β 2AR)拮抗剂用于治疗哮喘。 G-protein coupled receptor (GPCR) is a kind of membrane receptor protein with seven transmembrane structures, and it is also a key drug target. More than 30% of FDA-approved drugs target GPCR of. GPCRs can be divided into six classes, but only four (A, B, C and F) are present in humans. Of these, class A (rhodopsin) contains the highest number of GPCRs (719 in humans). About half of class A GPCRs are sensory receptors involved in odor (pheromone receptors) or vision (rhodopsin). Adrenergic receptors (AR) are a type A subfamily of GPCRs that play an important role in the sympathetic nervous system. For example, β 1 -adrenoceptor (β 1 AR) antagonists are used in cardiovascular disease, while β 2 -adrenergic receptor (β 2 AR) antagonists are used in the treatment of asthma.
现有GPCR类药物中，绝大多数是靶向GPCRs的正构结合位点，在该位点上，内源性配体结合诱导信号转导,这种方法产生的化合物要么直接激活目标GPCR(激动剂)，要么阻断内源性配体的作用(拮抗剂或反向激动剂),因此在不同亚型之间的高度保守给研发选择性药物带来了很大挑战。The vast majority of existing GPCR drugs target the orthosteric binding site of GPCRs where endogenous ligand binding induces signal transduction, and compounds generated by this approach either directly activate the target GPCR ( agonists), or block the action of endogenous ligands (antagonists or inverse agonists), so the high degree of conservation between different subtypes has brought great challenges to the development of selective drugs.
别构配体(也称变构配体)是通过与正构配体结合位点在构象上不同而影响受体活性。别构配体通过诱导GPCR蛋白的构象变化来调节其作用，这些变化从变构结合囊转移到正构位点或直接到效应蛋白偶联位点,由于其结合位置保守性相对较低，可能具有更好的亚型选择性。靶向GPCR中的别构类的药物相比传统的药物除了有更好的选择性,还能降低因脱靶效应引起的潜在药物副作用。此外，别构调节剂也可以与正构配体协同作用，能够将受体锁定在特定的构象，从而使得受体表现出特异性的信号转导，进而使得别构调节剂具有不同于正构配体的药效特点。β 2AR拮抗剂是非常经典的GPCRs药物，在心力衰竭、高血压、冠心病、心律失常、心绞痛等疾病的治疗中扮演着重要的角色，是治疗心血管类 疾病的基石。因此，β 2AR别构拮抗剂的开发和设计对各类心血管类疾病的治疗具有重要的意义。 Allosteric ligands (also known as allosteric ligands) affect receptor activity by differing in conformation from the orthosteric ligand binding site. Allosteric ligands mediate the action of GPCR proteins by inducing conformational changes in their proteins, which shift from the allosteric binding pocket to the orthosteric site or directly to the effector protein coupling site. Due to the relatively low conservation of their binding sites, it is possible with better subtype selectivity. Drugs targeting allosteric classes in GPCRs not only have better selectivity than traditional drugs, but also reduce potential drug side effects caused by off-target effects. In addition, allosteric modulators can also act synergistically with orthosteric ligands to lock the receptor in a specific conformation, so that the receptor exhibits specific signal transduction, which in turn makes the allosteric modulator different from the orthosteric ligand. Pharmacodynamic properties of ligands. β 2 AR antagonists are very classic GPCRs drugs, which play an important role in the treatment of heart failure, hypertension, coronary heart disease, arrhythmia, angina pectoris and other diseases, and are the cornerstone of the treatment of cardiovascular diseases. Therefore, the development and design of β 2 AR allosteric antagonists is of great significance to the treatment of various cardiovascular diseases.
2017年,本实验室同美国杜克大学科学家合作，报道了一个小分子负向别构调节剂化合物15(Cmpd-15，如式2所示),它是第一个β 2-肾上腺素受体胞内别构拮抗剂(Proc.Natl.Acad.Sci.USA,2017,114:1708-1713；Nature,2017,548:480-484)。不过，由于Cmpd-15是一个肽类化合物，水溶性较差，且生物活性不太高，其结构的相对不稳定性可能会影响其成药性。 In 2017, our laboratory cooperated with scientists from Duke University in the United States to report a small molecule negative allosteric modulator compound 15 (Cmpd-15, shown in formula 2), which is the first β 2 -adrenergic receptor In vivo allosteric antagonists (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 low biological activity, the relative instability of its structure may affect its druggability.
Figure PCTCN2022132704-appb-000001
Figure PCTCN2022132704-appb-000001
式2：Cmpd-15的结构Equation 2: Structure of Cmpd-15
吡唑(C 3H 3N 2H)是含氮杂环化合物，具有良好的稳定性和广谱药理性质，已成为药物设计中很有吸引力的核心骨架。 Pyrazole (C 3 H 3 N 2 H) is a nitrogen-containing heterocyclic compound with good stability and broad-spectrum pharmacological properties, and has become an attractive core skeleton in drug design.
本发明为了拓展先导物的结构类型，提高其活性、稳定性和成药性，利用骨架跃迁(Scaffoldhopping)策略，将Cmpd-15的肽类核心结构替换为吡唑骨架。基于骨架跃迁策略，保留Cmpd-15三个部位的关键官能团，形成以吡唑为核心结构的杂环衍生物，并评价新杂环衍生物对β 2AR的活性和特异性。新杂环衍生物的设计思路如式3所示，将Cmpd-15左侧、中间和右侧的药效团分别连接于吡唑环上，则形成吡唑类(pyrazole type)化合物。预计所设计杂环衍生物的稳定性好于Cmpd-15，有可能提高与β 2AR相结合能力，成药性也比较好。 In order to expand the structure type of the lead and improve its activity, stability and druggability, the present invention uses a scaffold-hopping strategy to replace the peptide core structure of Cmpd-15 with a pyrazole skeleton. Based on the skeleton transition strategy, the key functional groups of the three parts of Cmpd-15 were retained to form heterocyclic derivatives with pyrazole as the core structure, and the activity and specificity of the new heterocyclic derivatives on β 2 AR were evaluated. The design idea of the new heterocyclic derivatives is shown in Formula 3. The pharmacophore on the left, middle and right side of Cmpd-15 is respectively connected to the pyrazole ring to form a pyrazole type compound. It is estimated that the stability of the designed heterocyclic derivatives is better than that of Cmpd-15, and it is possible to improve the ability to combine with β 2 AR, and the druggability is also relatively good.
Figure PCTCN2022132704-appb-000002
Figure PCTCN2022132704-appb-000002
式3：将Cmpd-15骨架跃迁为吡唑类化合物反应式Formula 3: The reaction formula for transitioning the Cmpd-15 skeleton to pyrazole compounds
考虑到由α-取代苯乙酸制备的酰胺键极易水解，无法稳定存在。于是决定去除酰胺键，连接不同取代基的苄基(式4)，从而使最终目标化合物稳定存在。Considering that the amide bond prepared by α-substituted phenylacetic acid is easily hydrolyzed, it cannot exist stably. Then it was decided to remove the amide bond and connect benzyl groups with different substituents (Formula 4), so that the final target compound could exist stably.
Figure PCTCN2022132704-appb-000003
Figure PCTCN2022132704-appb-000003
式4：吡唑类目标化合物的设计Formula 4: Design of pyrazole target compounds
发明内容Contents of the invention
本发明以不同取代基的苯乙酮为原料，经克莱森缩合，成环，再经取代，酯水解和酰胺偶联反应最终得到一系列新的吡唑类衍生物。本发明的目的在于开发出化学结构稳定、生物活性高、受体亚型选择性好和水溶性改善的全新杂环衍生物，作为β 2-AR的别构调节剂，为研发心脑血管、糖尿病和癌症疾病的新药提供新的方向。 The invention uses acetophenones with different substituents as raw materials, undergoes Claisen condensation, ring formation, substitution, ester hydrolysis and amide coupling reactions to finally obtain a series of new pyrazole derivatives. The purpose of the present invention is to develop a new heterocyclic derivative with stable chemical structure, high biological activity, good receptor subtype selectivity and improved water solubility, as an allosteric regulator of β 2 -AR, for the development of cardiovascular and cerebrovascular, New medicines for diabetes and cancer diseases offer new directions.
吡唑环类似物结构：Pyrazole ring analog structure:
Figure PCTCN2022132704-appb-000004
Figure PCTCN2022132704-appb-000004
表1-1 H、I类吡唑类衍生物的结构Table 1-1 Structures of class H and class I pyrazole derivatives
Figure PCTCN2022132704-appb-000005
Figure PCTCN2022132704-appb-000005
Figure PCTCN2022132704-appb-000006
Figure PCTCN2022132704-appb-000006
Figure PCTCN2022132704-appb-000007
Figure PCTCN2022132704-appb-000007
表1-2 L类吡唑类衍生物的结构Table 1-2 Structure of L-like pyrazole derivatives
Figure PCTCN2022132704-appb-000008
Figure PCTCN2022132704-appb-000008
H、I类吡唑环衍生物的合成路线：The synthetic route of H, class I pyrazole ring derivatives:
Figure PCTCN2022132704-appb-000009
Figure PCTCN2022132704-appb-000009
吡唑H、I类衍生物的具体合成方法步骤如下：The concrete synthetic method step of pyrazole H, I class derivative is as follows:
具体合成步骤为：Concrete synthetic steps are:
(1)冰浴下，将取代苯乙酮1和草酸二乙酯溶解在乙醇中，加入乙醇钠后室温反应过夜，生成β-酮酸酯化合物2。苯乙酮1：草酸二乙酯：乙醇钠的摩尔比为1：1.2：3。(1) Dissolve substituted acetophenone 1 and diethyl oxalate in ethanol under ice bath, add sodium ethoxide and react overnight at room temperature to generate β-ketoester compound 2. The molar ratio of acetophenone 1: diethyl oxalate: sodium ethoxide is 1:1.2:3.
(2)冰浴下，将化合物2在肼一水合物的作用下，于乙酸中反应过夜，生成吡唑环结构化合物3。化合物2：肼一水合物的摩尔比为1：1.2。(2) Under the ice bath, compound 2 was reacted overnight in acetic acid under the action of hydrazine monohydrate to generate compound 3 with pyrazole ring structure. The molar ratio of compound 2:hydrazine monohydrate is 1:1.2.
(3)加热回流条件下，将化合物3，碳酸钾和取代氯化苄溶解于乙腈中，生成化合物4。化合物3：碳酸钾：取代氯化苄的摩尔比为1：1.2：1.3；其中所述取代基氯化苄的取代基R 2为卤原子，甲氧基，硝基，氰基等。 (3) Compound 3, potassium carbonate and substituted benzyl chloride were dissolved in acetonitrile under heating to reflux to generate compound 4. Compound 3: The molar ratio of potassium carbonate: substituted benzyl chloride is 1:1.2:1.3; wherein the substituent R2 of the substituent benzyl chloride is a halogen atom, methoxy, nitro, cyano, etc.
(4)在室温下，将化合物4溶解于甲醇中，加入4N氢氧化钠溶液，反应过夜，生成化合物5。(4) Dissolve compound 4 in methanol at room temperature, add 4N sodium hydroxide solution, and react overnight to generate compound 5.
(5)冰浴下，将化合物5和化合物(S)-2-氨基-3-(3-溴苯基)-N-甲基丙酰胺(Bioorganic&Medicinal Chemistry,2018,26:2320-2330)在偶联试剂(HOAT，NMM，EDCI)的作用下，于DMF中发生酰胺偶联反应，得到化合物6。化合物5：HOAT：化合物(S)-2-氨基-3-(3-溴苯基)-N-甲基丙酰胺：NMM：EDCI的摩尔比例为1： 1.2：1：0.7：1.2。(5) Under ice bath, compound 5 and compound (S)-2-amino-3-(3-bromophenyl)-N-methylpropionamide (Bioorganic & Medicinal Chemistry, 2018, 26:2320-2330) Under the action of coupling reagents (HOAT, NMM, EDCI), the amide coupling reaction occurred in DMF to obtain compound 6. Compound 5: HOAT: Compound (S)-2-amino-3-(3-bromophenyl)-N-methylpropionamide: NMM: EDCI in a molar ratio of 1: 1.2: 1: 0.7: 1.2.
L类吡唑环衍生物的合成路线：The synthetic route of L class pyrazole ring derivatives:
Figure PCTCN2022132704-appb-000010
Figure PCTCN2022132704-appb-000010
吡唑L类衍生物的具体合成方法步骤如下：The concrete synthetic method step of pyrazole L class derivative is as follows:
具体合成步骤为：Concrete synthetic steps are:
(1)冰浴下，将取代苯乙酮1和草酸二乙酯溶解在溶剂中，加入新鲜制备的乙醇钠，继续搅拌至变为室温，生成β酮酸酯化合物2。其中溶剂为无水乙醇；苯乙酮1：草酸二乙酯：乙醇钠的摩尔比为1：1.2：3；冰浴下搅拌30min，室温搅拌10h。(1) Dissolve the substituted acetophenone 1 and diethyl oxalate in the solvent in an ice bath, add freshly prepared sodium ethoxide, and continue stirring until it becomes room temperature to generate β-ketoester compound 2. The solvent is absolute ethanol; the molar ratio of acetophenone 1: diethyl oxalate: sodium ethoxide is 1:1.2:3; stir in ice bath for 30 min, and stir at room temperature for 10 h.
(2)冰浴下，将化合物2溶解在溶剂中，加入肼一水合物，继续搅拌至室温。关环形成吡唑环结构化合物3。其中溶剂为乙酸；化合物2：肼一水合物的摩尔比为1：1.2；冰浴下搅拌10min，室温搅拌8h。(2) Dissolve compound 2 in the solvent under ice bath, add hydrazine monohydrate, and continue stirring to room temperature. Ring closure forms pyrazole ring structure compound 3. The solvent is acetic acid; the molar ratio of compound 2:hydrazine monohydrate is 1:1.2; stir in ice bath for 10min, and stir at room temperature for 8h.
(3)将化合物3溶解在溶剂中，加入碱溶液，室温反应，加入酸调pH，生成化合物4。其中溶剂为甲醇；碱溶液为4N氢氧化钠溶液；室温搅拌10h。(3) Dissolving compound 3 in a solvent, adding alkali solution, reacting at room temperature, adding acid to adjust pH, and generating compound 4. The solvent is methanol; the alkali solution is 4N sodium hydroxide solution; stir at room temperature for 10 h.
(4)将化合物4和活化剂溶解在溶剂中，冰浴下加入(S)-2-氨基-3-(3-溴苯基)-N-甲基丙酰胺，再加入缚酸剂和酰胺偶联剂后继续搅拌至室温，得到吡唑类酰胺衍生物5。其中溶剂为N,N-二甲基甲酰胺；活化剂为1-羟基-7-氮杂苯并三氮唑(HOAT)；缚酸剂为N-甲基吗啡啉(NMM)；酰胺偶联剂1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDCI)；化合物5：HOAT：化合物A：NMM：EDCI的摩尔比例为1：1.2：1：0.7：1.2；冰浴下反应1.5h，至室温下反应12h。(4) Dissolve compound 4 and activator in solvent, add (S)-2-amino-3-(3-bromophenyl)-N-methylpropionamide under ice bath, then add acid-binding agent and amide Continue stirring to room temperature after the coupling agent to obtain pyrazole amide derivative 5. The solvent is N,N-dimethylformamide; the activator is 1-hydroxy-7-azabenzotriazole (HOAT); the acid-binding agent is N-methylmorpholine (NMM); the amide coupling Agent 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI); Compound 5: HOAT: Compound A: NMM: The molar ratio of EDCI is 1:1.2:1:0.7: 1.2; react in ice bath for 1.5h, and react at room temperature for 12h.
吡唑类新衍生物可作为β 2-AR的激动剂、拮抗剂、别构激动剂、别构拮抗剂； New pyrazole derivatives can be used as agonists, antagonists, allosteric agonists and allosteric antagonists of β 2 -AR;
进一步，表1-1中化合物H 30、H 31、H 32有激动活性，可作为β 2-AR的激动剂； Furthermore, compounds H 30 , H 31 , and H 32 in Table 1-1 have agonist activity and can be used as β 2 -AR agonists;
进一步，表1-1中化合物H 31同时具有激动活性和别构活性，可作为β 2-AR的别构激动剂； Furthermore, the compound H 31 in Table 1-1 has both agonistic activity and allosteric activity, and can be used as an allosteric agonist of β 2 -AR;
进一步，表1-1和表1-2中化合物H 2、H 3、H 5、H 6、H 8、H 9、H 10、H 11、H 12、 H 17、H 22、H 23、H 34、H 35、H 54、H 55、I 2、I 4、I 6、L 1、L 2、L 3、L 4、L 5、L 6、L 7、L 8、L 9、L 10、L 11、L 12、L 13、L 14、L 15、L 16、L 17、L 18、L 19、L 20、L 21、L 22，具有β 2AR拮抗作用，可作为β 2-AR的拮抗剂； Further, compounds H 2 , H 3 , H 5 , H 6 , H 8 , H 9 , H 10 , H 11 , H 12 , H 17 , H 22 , H 23 , H in Table 1-1 and Table 1-2 34 , H 35 , H 54 , H 55 , I 2 , I 4 , I 6 , L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 , L 8 , L 9 , L 10 , L 11 , L 12 , L 13 , L 14 , L 15 , L 16 , L 17 , L 18 , L 19 , L 20 , L 21 , L 22 , have β 2 AR antagonistic effect and can be used as β 2 -AR Antagonist;
进一步，表1-1和表1-2中H 2、H 22、H 23、H 34、H 54、H 55、I 2、I 4、I 6、化合物L 1-L 22同时具有拮抗活性和别构活性，可作为β 2-AR的别构拮抗剂。 Further, H 2 , H 22 , H 23 , H 34 , H 54 , H 55 , I 2 , I 4 , I 6 and compounds L 1 -L 22 in Table 1-1 and Table 1-2 have both antagonistic activity and Allosteric activity, can be used as an allosteric antagonist of β 2 -AR.
本发明的有益效果为：The beneficial effects of the present invention are:
吡唑新衍生物可作为β 2-AR的激动剂、拮抗剂、别构激动剂、别构拮抗剂，为研发心脑血管、糖尿病和癌症疾病的新药提供新的方向。 New pyrazole derivatives can be used as agonists, antagonists, allosteric agonists and allosteric antagonists of β 2 -AR, providing new directions for the development of new drugs for cardiovascular and cerebrovascular diseases, diabetes and cancer diseases.
附图说明Description of drawings
图1为H 31的结构图和ISO剂量-响应曲线； Fig. 1 is the structural diagram and ISO dose-response curve of H31 ;
图2为化合物H 30、H 31、H 32的EC 50曲线。 Figure 2 is the EC 50 curves of compounds H 30 , H 31 , and H 32 .
图3为L1、L4、L14介导的ISO剂量-响应曲线图。Figure 3 is a dose-response curve of ISO mediated by L1, L4, and L14.
图4为部分代表吡唑化合物介导的拮抗曲线图。Figure 4 is a graph partially representative of pyrazole compound-mediated antagonism.
具体实施方式Detailed ways
吡唑类衍生物的制备：Preparation of pyrazole derivatives:
实施例1：
Figure PCTCN2022132704-appb-000011
Example 1:
Figure PCTCN2022132704-appb-000011
(S)-1-苄基-N-[3-(3-溴苯基)-1-酰化甲氨基-2-基]-3-苯基-1H-吡唑-5-甲酰胺H 1的制备 (S)-1-Benzyl-N-[3-(3-bromophenyl)-1-acylated methylamino-2-yl]-3-phenyl-1H-pyrazole-5-carboxamide H 1 preparation of
步骤一：2,4-二氧代-4-苯基丁酸乙酯的制备Step 1: Preparation of ethyl 2,4-dioxo-4-phenylbutyrate
冰浴下，将苯乙酮(500mg，3.4mmo1)，草酸二乙酯(0.61Ml，5.2mmol)和乙醇钠(5mL，20％质量含量，0.0lmmol)依次加入反应器中，于乙醇中剧烈搅拌至全部溶解，室温反应过夜。冰浴下，用4N盐酸调pH至2-3，乙酸乙酯(30mL)萃取，用饱和食盐水洗涤有机相，浓缩得粗产物2,4-二氧代-4-苯基丁酸乙酯。Under ice bath, acetophenone (500mg, 3.4mmol), diethyl oxalate (0.61Ml, 5.2mmol) and sodium ethoxide (5mL, 20% mass content, 0.01mmol) were successively added to the reactor, and the Stir until completely dissolved, and react overnight at room temperature. Under ice-cooling, adjust the pH to 2-3 with 4N hydrochloric acid, extract with ethyl acetate (30 mL), wash the organic phase with saturated brine, and concentrate to obtain the crude product ethyl 2,4-dioxo-4-phenylbutyrate .
步骤二：4-苯基吡唑-1-甲酸酯的制备Step 2: Preparation of 4-phenylpyrazole-1-carboxylate
将步骤一的粗产物溶解在10mL乙酸中，冰浴下缓慢滴加肼一水合物(0.3mL，6.2mmol)，室温反应10h后，乙酸乙酯(30mL)萃取，用饱和食盐水洗涤有机相， 浓缩柱层析纯化(石油醚：乙酸乙酯＝5:1)，得到740.6mg乳白色固体化合物4-苯基吡唑-1-甲酸酯，两步产率共82％。 1H NMR(400MHz,CDCl 3):δ7.73-7.67(m,2H),7.40-7.29(m,3H),6.97(s,1H),4.17(q,J＝7.1Hz,2H),1.19(t,J＝7.1Hz,3H). The crude product from Step 1 was dissolved in 10 mL of acetic acid, and hydrazine monohydrate (0.3 mL, 6.2 mmol) was slowly added dropwise under an ice bath. After reacting at room temperature for 10 h, it was extracted with ethyl acetate (30 mL), and the organic phase was washed with saturated brine. , Purified by concentration and column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain 740.6 mg of milky white solid compound 4-phenylpyrazole-1-carboxylate, with a total yield of 82% in two steps. 1 H NMR (400MHz, CDCl 3 ): δ7.73-7.67(m, 2H), 7.40-7.29(m, 3H), 6.97(s, 1H), 4.17(q, J=7.1Hz, 2H), 1.19 (t,J=7.1Hz,3H).
步骤三:N-2苄基-苯基吡唑-1-甲酸酯的制备Step 3: Preparation of N-2 benzyl-phenylpyrazole-1-carboxylate
将苯基吡唑-1-甲酸酯(500mg，2.3mmol)溶解在10mL乙腈中，加入碳酸钾(415.4mg，3mmol)和氯化苄(0.27ml，2.3mmol)，90℃加热至回流，反应12h。乙酸乙酯(30mL)萃取，用饱和食盐水洗涤有机相，浓缩柱层析(石油醚：乙酸乙酯＝50:1)，得到538.4mg白色固体化合物N-2苄基-苯基吡唑-1-甲酸酯，产率为76％。 1H NMR(300MHz,DMSO-d 6):δ7.90-7.86(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＝7.1Hz,2H),1.28(t,J＝7.1Hz,3H). 13C NMR(75MHz,DMSO-d 6):δ159.0,149.5,137.4,133.5,132.0,128.8,128.6,128.2,127.6,127.0,125.3,108.4,61.1,54.4,14.0. Dissolve phenylpyrazole-1-carboxylate (500mg, 2.3mmol) in 10mL of acetonitrile, add potassium carbonate (415.4mg, 3mmol) and benzyl chloride (0.27ml, 2.3mmol), heat to reflux at 90°C, Reaction 12h. Extracted with ethyl acetate (30 mL), washed the organic phase with saturated brine, concentrated column chromatography (petroleum ether: ethyl acetate = 50:1), and obtained 538.4 mg of white solid compound N-2 benzyl-phenylpyrazole- 1-Carboxylate, 76% yield. 1 H NMR(300MHz,DMSO-d 6 ):δ7.90-7.86(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=7.1Hz, 2H), 1.28(t, J=7.1Hz, 3H). 13 C NMR(75MHz, DMSO-d 6 ): δ159.0, 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.
步骤四：N-2苄基-苯基吡唑-1-羧酸的制备Step 4: Preparation of N-2 benzyl-phenylpyrazole-1-carboxylic acid
将N-2苄基-苯基吡唑-1-甲酸酯(538.4mg，1.8mmol)溶解在12mL甲醇中，加入4mL4N氢氧化钠溶液，室温搅拌10h。冰浴条件下加入4N盐酸调pH至4，乙酸乙酯(30mL)萃取，用饱和食盐水洗涤有机相，浓缩，得到425.5mg白色固体化合物N-2苄基-苯基吡唑-1-羧酸，产率为87％。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. Add 4N hydrochloric acid to adjust the pH to 4 under ice-cooling 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-carboxylate acid, the yield was 87%.
步骤五：(S)-1-苄基-N-[3-(3-溴苯基)-1-酰化甲氨基-2-基]-3-苯基-1H-吡唑-5-甲酰胺的制备Step 5: (S)-1-Benzyl-N-[3-(3-bromophenyl)-1-acylated methylamino-2-yl]-3-phenyl-1H-pyrazole-5-methanol Preparation of amides
将N-2苄基-苯基吡唑-1-羧酸(30mg，0.1mmol)和HOAT(24.5mg，0.2mmo1)溶解于5mLDMF中，氮气保护下室温搅拌10min后，0℃下加入化合物(S)-2-氨基-3-(3-溴苯基)-N-甲基丙酰胺(38.5mg，0.1mmo1)，继续搅拌10min后，0℃下加入N-甲基吗啡啉(0.009mL，008mmol)，搅拌10min，加入EDCI(24.8mg，0.1mmo1)，保持0℃搅拌1h，至室温反应12h。乙酸乙酯(30mL)萃取，用饱和食盐水洗涤有机相，浓缩柱层析(二氯甲烷：甲醇＝40:1)，得到19mg白色固体化合物(S)-1-苄基-N-[3-(3-溴苯基)-1-酰化甲氨基-2-基]-3-苯基-1H-吡唑-5-甲酰胺，产率为34％。 1HNMR(300MHz,DMSO-d 6):δ8.78(d,J＝8.6Hz,1H),8.09(q,J＝4.5Hz,1H),7.76(d,J＝7.2Hz,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＝10.4,8.6,4.4Hz,1H),3.11(dd,J＝13.6,4.4Hz,1H),2.92(dd,J＝13.6,10.6Hz,1H),2.63(d,J＝4.6Hz,3H). 13C NMR(75 MHz,DMSO-d 6):δ170.8,159.0,148.9,141.0,137.7,136.4,132.4,132.0,130.2,129.2,128.9,128.4,128.2,128.0,127.3,125.0,121.4,104.9,54.2,53.7,36.9,25.7.HRMS(ESI,m/z):Calcd.for C 27H 25BrN 4O 2[M+Na] +539.1059,found:539.1056. N-2 benzyl-phenylpyrazole-1-carboxylic acid (30mg, 0.1mmol) and HOAT (24.5mg, 0.2mmol) were dissolved in 5mL DMF, stirred at room temperature for 10min under nitrogen protection, and compound ( S)-2-amino-3-(3-bromophenyl)-N-methylpropionamide (38.5mg, 0.1mmol), after stirring for 10min, N-methylmorpholine (0.009mL, 008mmol), stirred for 10min, added EDCI (24.8mg, 0.1mmol), kept stirring at 0°C for 1h, and reacted at room temperature for 12h. Extracted with ethyl acetate (30 mL), washed the organic phase with saturated brine, concentrated column chromatography (dichloromethane:methanol=40:1), and obtained 19 mg of white solid compound (S)-1-benzyl-N-[3 -(3-Bromophenyl)-1-acylated methylamino-2-yl]-3-phenyl-1H-pyrazole-5-carboxamide, yield 34%. 1 HNMR (300MHz, DMSO-d 6 ): δ8.78(d, J=8.6Hz, 1H), 8.09(q, J=4.5Hz, 1H), 7.76(d, J=7.2Hz, 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＝10.4,8.6,4.4Hz,1H),3.11 (dd, J=13.6, 4.4Hz, 1H), 2.92(dd, J=13.6, 10.6Hz, 1H), 2.63(d, J=4.6Hz, 3H). 13 C NMR (75 MHz, DMSO-d 6 ):δ170.8,159.0,148.9,141.0,137.7,136.4,132.4,132.0,130.2,129.2,128.9,128.4,128.2,128.0,127.3,125.0,121.4,104.9,54.2,53.7, 36.9, 25.7. HRMS (ESI, m/z): Calcd.for C 27 H 25 BrN 4 O 2 [M+Na] + 539.1059, found: 539.1056.
实施例2：
Figure PCTCN2022132704-appb-000012
Example 2:
Figure PCTCN2022132704-appb-000012
(S)-1-苄基-1[3-(3-溴苯基)-1-酰化甲氨基-2-基]-3-邻甲基苯基-1H-吡唑-5-甲酰胺H 2的制备 (S)-1-Benzyl-1[3-(3-bromophenyl)-1-acylated methylamino-2-yl]-3-o-methylphenyl-1H-pyrazole-5-carboxamide Preparation of H2
其他条件同实施例1，将苯乙酮改为2-甲基苯乙酮，产物为白色固体，产率为29％。 1H NMR(400MHz,DMSO-d 6)：δ8.91(dd,J＝34.6,8.7Hz,1H),8.19-8.16(m,1H),7.57-7.45(m,2H),7.37-7.17(m,10H),7.12(d,J＝6.8Hz,2H),5.77-5.60(m,2H),4.63(td,J＝10.8,10.1,6.5Hz,1H),3.11(dd,J＝13.6,4.4Hz,1H),2.94(t,J＝12.2Hz,1H),2.62(d,J＝4.5Hz,3H),2.47(s,3H). 13C NMR(75MHz,DMSO-d 6)δ170.9,159.1,149.2,141.1,137.8,135.4,135.2,132.0,132.0,131.0,130.2,129.2,128.5,128.3,128.3,127.8,127.4,127.3,126.0,121.4,107.8,54.20,53.6,36.9，25.7,21.2.HRMS(ESI,m/z):Calcd.for C 28H 27BrN 4O 2[M+Na] +553.1215,found:553.1210. Other conditions were the same as in Example 1, except that acetophenone was changed to 2-methylacetophenone, and the product was a white solid with a yield of 29%. 1 H NMR (400MHz, DMSO-d 6 ): δ8.91 (dd, J=34.6, 8.7Hz, 1H), 8.19-8.16(m, 1H), 7.57-7.45(m, 2H), 7.37-7.17( m,10H),7.12(d,J=6.8Hz,2H),5.77-5.60(m,2H),4.63(td,J=10.8,10.1,6.5Hz,1H),3.11(dd,J=13.6, 4.4Hz, 1H), 2.94(t, J=12.2Hz, 1H), 2.62(d, J=4.5Hz, 3H), 2.47(s, 3H). 13 C NMR (75MHz, DMSO-d 6 ) δ170. 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 BrN 4 O 2 [M+Na] + 553.1215, found: 553.1210.
实施例3：
Figure PCTCN2022132704-appb-000013
Example 3:
Figure PCTCN2022132704-appb-000013
(S)-1-苄基-N-(3-(3-溴苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-3-(间甲苯基)-1H-吡唑-5-甲酰胺H 3的制备 (S)-1-Benzyl-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-(m-tolyl)-1H - Preparation of pyrazole-5-carboxamide H3
其他条件同实施例1，将苯乙酮改为3-甲基苯乙酮，产物为白色固体，产率为32％。 1H NMR(300MHz,DMSO-d 6)：δ8.84(d,J＝8.7Hz,1H),8.17(d,J＝4.6Hz,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＝10.6,8.6,4.3Hz,1H),3.12(dd,J＝13.6,4.4Hz,1H),2.95(dd,J＝13.6,10.7Hz,1H),2.62(d,J＝4.5Hz,3H),2.35(s,3H). 13C NMR(75MHz,DMSO-d 6)：δ170.9,159.0,149.0,141.1,138.0,137.7,136.3,132.3,132.0,130.2,129.2,128.8,128.6,128.4,128.3,127.3,125.5,122.2,121.4,105.1,54.2,53.6,36.9,25.7,21.1.HRMS(ESI,m/z):Calcd.for C 28H 27BrN 4O 2[M+Na] +553.1215,found:553.1210. Other conditions were the same as in Example 1, except that acetophenone was changed to 3-methylacetophenone, and the product was a white solid with a yield of 32%. 1 H NMR (300MHz, DMSO-d 6 ): δ8.84(d, J=8.7Hz, 1H), 8.17(d, J=4.6Hz, 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＝10.6,8.6,4.3Hz,1H),3.12(dd,J＝13.6,4.4Hz,1H ), 2.95(dd, J＝13.6, 10.7Hz, 1H), 2.62(d, J＝4.5Hz, 3H), 2.35(s, 3H). 13 C NMR (75MHz, DMSO-d 6 ): δ170.9, 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 BrN 4 O 2 [M+Na] + 553.1215,found:553.1210.
实施例4：
Figure PCTCN2022132704-appb-000014
Example 4:
Figure PCTCN2022132704-appb-000014
(S)-1-苄基-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-3-(对甲苯基)-1H-吡唑-5-甲酰胺H 4的制备 (S)-1-Benzyl-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-(p-tolyl)-1H- Preparation of pyrazole-5-carboxamide H4
其他条件同实施例1，将苯乙酮改为4-甲基苯乙酮，产物为白色固体，产率为34％。 1H NMR(400MHz,DMSO-d 6)：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). 13C NMR(75MHz,DMSO-d 6)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 28H 27BrN 4O 2[M+Na] +553.1215,found:553.1210. Other conditions were the same as in Example 1, except that acetophenone was changed to 4-methylacetophenone, and the product was a white solid with a yield of 34%. 1 H NMR (400MHz, DMSO-d 6 ): 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=4.5 Hz,3H),2.32(s,3H). 13 C NMR(75MHz,DMSO-d 6 )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 BrN 4 O 2 [M+Na] + 553.1215,found:553.1210 .
实施例5：
Figure PCTCN2022132704-appb-000015
Example 5:
Figure PCTCN2022132704-appb-000015
(S)-1-苄基-N-(3-(3-溴苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-3-(4-甲氧基苯基)-1H-吡唑-5-甲酰胺H 5的制备 (S)-1-benzyl-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-(4-methoxybenzene Base)-1H-pyrazole-5-carboxamide H 5 Preparation
其他条件同实施例1，将苯乙酮改为对甲氧基苯乙酮，产物为白色固体，产率为32％。 1H NMR(400MHz,DMSO-d 6)：δ8.75(d,J＝8.6Hz,1H),8.09(d,J＝4.7Hz,1H),7.68(d,J＝8.8Hz,2H),7.57(s,1H),7.38(d,J＝7.9Hz,1H),7.29-7.19(m,6H),7.11-7.10(m,2H),7.01(d,J＝8.9Hz,2H),5.70-5.54(m,2H),4.62(ddd,J＝10.6,8.5,4.4Hz,1H),3.78(s,1H),3.10(dd,J＝13.6,4.4Hz,1H),2.92(dd,J＝13.6,10.6Hz,1H),2.62(d,J＝4.5Hz,3H). 13C NMR(75MHz,DMSO-d 6)δ170.9,159.1,159.1,148.8,141.0,137.8,136.3,132.0,130.3,129.2,128.4,128.2,127.3,127.3,126.3,125.1,121.4,114.3,104.4,55.2,54.1,53.5,36.9,25.7.HRMS(ESI,m/z):Calcd.for C 28H 27BrN 4O 2[M+Na] +569.1154,found:569.1160. Other conditions were the same as in Example 1, except that acetophenone was changed to p-methoxyacetophenone, and the product was a white solid with a yield of 32%. 1 H NMR (400MHz, DMSO-d 6 ): δ8.75(d, J=8.6Hz, 1H), 8.09(d, J=4.7Hz, 1H), 7.68(d, J=8.8Hz, 2H), 7.57(s,1H),7.38(d,J=7.9Hz,1H),7.29-7.19(m,6H),7.11-7.10(m,2H),7.01(d,J=8.9Hz,2H),5.70 -5.54(m,2H),4.62(ddd,J＝10.6,8.5,4.4Hz,1H),3.78(s,1H),3.10(dd,J＝13.6,4.4Hz,1H),2.92(dd,J =13.6,10.6Hz,1H),2.62(d,J=4.5Hz,3H). 13 C NMR (75MHz,DMSO-d 6 )δ170.9,159.1,159.1,148.8,141.0,137.8,136.3,132.0,130.3, 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 BrN 4 O 2 [M+Na] + 569.1154, found: 569.1160.
实施例6：
Figure PCTCN2022132704-appb-000016
Embodiment 6:
Figure PCTCN2022132704-appb-000016
(S)-1-苄基-N-(3-(3-溴苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-3-(2-氟苯基)-1H-吡唑-5-甲酰胺H 6的制备 (S)-1-Benzyl-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-(2-fluorophenyl) - Preparation of 1H-pyrazole-5-carboxamide H 6
其他条件同实施例1，将苯乙酮改为2-氟苯乙酮，产物为白色固体，产率为33％。 1HNMR(400MHz,DMSO-d 6)δ8.93(d,J＝8.6Hz,1H),8.11(d,J＝4.8Hz,1H),7.94(t,J＝6.9Hz,1H),7.56(s,1H),7.45-7.17(m,10H),7.12(d,J＝6.4Hz,2H),5.77-5.61(m,2H),4.64(td,J＝9.4,8.6,4.4Hz,1H),3.10(dd,J＝13.6,4.4Hz,1H),2.95(t,J＝12.2Hz,1H),2.63(d,J＝4.5Hz,3H). 13C NMR(75MHz,DMSO-d 6)δ170.9,160.9,158.9,157.6,143.4,141.1,137.6,136.1,,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 27H 24BrFN 4O 2[M+Na] +557.0964,found:557.0964. Other conditions were the same as in Example 1, except that acetophenone was changed to 2-fluoroacetophenone, and the product was a white solid with a yield of 33%. 1 HNMR (400MHz, DMSO-d 6 ) δ8.93(d, J=8.6Hz, 1H), 8.11(d, J=4.8Hz, 1H), 7.94(t, J=6.9Hz, 1H), 7.56( s,1H),7.45-7.17(m,10H),7.12(d,J=6.4Hz,2H),5.77-5.61(m,2H),4.64(td,J=9.4,8.6,4.4Hz,1H) , 3.10(dd, J=13.6, 4.4Hz, 1H), 2.95(t, J=12.2Hz, 1H), 2.63(d, J=4.5Hz, 3H). 13 C NMR (75MHz, DMSO-d 6 ) δ170.9, 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 BrFN 4 O 2 [M+Na] + 557.0964,found:557.0964.
实施例7：
Figure PCTCN2022132704-appb-000017
Embodiment 7:
Figure PCTCN2022132704-appb-000017
(S)-1-苄基-N-(3-(3-溴苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-3-(3-氟苯基)-1H-吡唑-5-甲酰胺H 7的制备 (S)-1-Benzyl-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-(3-fluorophenyl) - Preparation of 1H-pyrazole-5-carboxamide H 7
其他条件同实施例1，将苯乙酮改为3-氟苯乙酮，产物为白色固体，产率为34％。 1H NMR(400MHz,DMSO-d 6)δ8.78(d,J＝8.6Hz,1H),8.10(d,J＝4.8Hz,1H),7.65(d,J＝7.9Hz,2H),7.57(s,1H),7.38-7.18(m,9H),7.11(d,J＝6.2Hz,2H),5.71-5.54(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). 13C NMR(75MHz,DMSO-d 6)δ170.8,164.2,161.0,158.9,147.9,147.7,141.0,137.5,136.7,134.9,134.8,132.0,131.1,131.0,130.3,129.2,128.4,128.3,127.4,127.4,121.4,121.10,114.9,114.6,111.6,111.3,105.4,54.2,53.8,37.0,25.7.HRMS(ESI,m/z):Calcd.for C 27H 24BrFN 4O 2[M+Na] +557.0964,found:557.0964. Other conditions were the same as in Example 1, except that acetophenone was changed to 3-fluoroacetophenone, and the product was a white solid with a yield of 34%. 1 H NMR (400MHz, DMSO-d 6 ) δ8.78(d, J=8.6Hz, 1H), 8.10(d, J=4.8Hz, 1H), 7.65(d, J=7.9Hz, 2H), 7.57 (s,1H),7.38-7.18(m,9H),7.11(d,J=6.2Hz,2H),5.71-5.54(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-d 6 )δ170.8,164.2,161.0,158.9,147.9,147.7,141.0,137.5,136.7,134.9,134.8,132.0,131.1,131.0,130.3,129.2,128.4,128 .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 BrFN 4 O 2 [M+Na] + 557.0964, found: 557.0964.
实施例8：
Figure PCTCN2022132704-appb-000018
Embodiment 8:
Figure PCTCN2022132704-appb-000018
(S)-1-苄基-N-(3-(3-溴苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-3-(4-氟苯基)-1H-吡唑-5-甲酰胺H 8的制备 (S)-1-Benzyl-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-(4-fluorophenyl) - Preparation of 1H-pyrazole-5-carboxamide H 8
其他条件同实施例1，将苯乙酮改为4-氟苯乙酮，产物为白色固体，产率为33％。 1H NMR(400MHz,DMSO-d6)δ8.78(d,J＝8.6Hz,1H),8.10(d,J＝4.6Hz,1H),7.78(dd,J＝8.7,5.6Hz,2H),7.56(s,1H),7.37(d,J＝8.0Hz,2H),7.30-7.19(m,7H),7.12-7.01(m,2H),5.71-5.55(m,2H),4.63(ddd,J＝10.6,8.6,4.4Hz,1H),3.10(dd,J＝13.6,4.4Hz,1H),2.91(dd,J＝13.6,10.6Hz,1H),2.63(d,J＝4.5Hz,3H). 13C NMR(75MHz,DMSO-d6)δ171.3,159.4,148.5,141.5,138.1,137.0,132.4,130.7,129.7,129.5,129.4,128.8,128.7,127.8,127.5,127.4,121.8,116.4,116.1,105.3,54.6,54.1,37.4,26.1.HRMS(ESI,m/z):Calcd.for C 27H 24BrFN 4O 2[M+Na] +557.0964,found:557.0964. Other conditions were the same as in Example 1, except that acetophenone was changed to 4-fluoroacetophenone, and the product was a white solid with a yield of 33%. 1 H NMR (400MHz, DMSO-d6) δ 8.78 (d, J = 8.6Hz, 1H), 8.10 (d, J = 4.6Hz, 1H), 7.78 (dd, J = 8.7, 5.6Hz, 2H), 7.56(s,1H),7.37(d,J＝8.0Hz,2H),7.30-7.19(m,7H),7.12-7.01(m,2H),5.71-5.55(m,2H),4.63(ddd, J=10.6,8.6,4.4Hz,1H),3.10(dd,J=13.6,4.4Hz,1H),2.91(dd,J=13.6,10.6Hz,1H),2.63(d,J=4.5Hz,3H ). 13 C NMR (75MHz, DMSO-d6) δ171.3, 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 BrFN 4 O 2 [M+Na] + 557.0964, found: 557.0964.
实施例9：
Figure PCTCN2022132704-appb-000019
Embodiment 9:
Figure PCTCN2022132704-appb-000019
(S)-1-苄基-N-(3-(3-溴苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-3-(3-氯苯基)-1H-吡唑-5-甲酰胺H 9的制备 (S)-1-Benzyl-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-(3-chlorophenyl) - Preparation of 1H-pyrazole-5-carboxamide H9
其他条件同实施例1，将苯乙酮改为3-氯苯乙酮，产物为白色固体，产率为29％。 1H NMR(300MHz,DMSO-d 6)δ8.78(d,J＝8.7Hz,1H),8.12(d,J＝4.7Hz,1H),7.77(t,J＝1.8Hz,1H),7.71(d,J＝7.6Hz,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＝7.6,1.9Hz,2H),5.73-5.56(m,2H),4.64(ddd,J＝10.4,8.6,4.4Hz,1H),3.11(dd,J＝13.6,4.5Hz,1H),2.92(dd,J＝13.6,10.6Hz,1H),2.63(d,J＝4.5Hz,3H). 13C NMR(75MHz,DMSO-d 6)δ170.8,158.8,147.5,141.0,137.5,136.7,134.5,133.7,132.0,131.0,130.2,129.2,128.4,128.3,127.8,127.4,124.5,123.5,121.4,105.4,54.2,53.8,37.0,25.7.HRMS(ESI,m/z):Calcd.for C 27H 24BrClN 4O 2[M+Na] +573.0669,found:573.0667. Other conditions were the same as in Example 1, except that acetophenone was changed to 3-chloroacetophenone, and the product was a white solid with a yield of 29%. 1 H NMR (300MHz, DMSO-d 6 ) δ8.78(d, J=8.7Hz, 1H), 8.12(d, J=4.7Hz, 1H), 7.77(t, J=1.8Hz, 1H), 7.71 (d,J=7.6Hz,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 =7.6,1.9Hz,2H),5.73-5.56(m,2H),4.64(ddd,J=10.4,8.6,4.4Hz,1H),3.11(dd,J=13.6,4.5Hz,1H),2.92( dd, J＝13.6, 10.6Hz, 1H), 2.63 (d, J＝4.5Hz, 3H). 13 C NMR (75MHz, DMSO-d 6 ) δ170.8, 158.8, 147.5, 141.0, 137.5, 136.7, 134.5, 133.7 , 132.0,131.0,130.2,129.2,128.4,127.8,127.4,124.5,121.4,105.4,54.2,53.8,37.0, 25.7.7.7.7.7.hrms (ESI, M/Z): CALCD.FOR C 27 H 24 B 24 B 24 B 24 B RCLN 4 O 2 [M+Na] + 573.0669, found: 573.0667.
实施例10：
Figure PCTCN2022132704-appb-000020
Example 10:
Figure PCTCN2022132704-appb-000020
(S)-1-苄基-N-(3-(3-溴苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-3-(4-氯苯基)-1H-吡唑-5-甲酰胺H 10的制备 (S)-1-Benzyl-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-(4-chlorophenyl) - Preparation of 1H-pyrazole-5-carboxamide H 10
其他条件同实施例1，将苯乙酮改为4-氯苯乙酮，产物为白色固体，产率为30％。 1H NMR(300MHz,DMSO-d 6)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). 13C NMR(75MHz,DMSO-d 6)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 27H 24BrClN 4O 2[M+Na] +573.0669,found:573.0667. Other conditions were the same as in Example 1, except that acetophenone was changed to 4-chloroacetophenone, and the product was a white solid with a yield of 30%. 1 H NMR (300MHz, DMSO-d 6 )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-d 6 ) 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 BrClN 4 O 2 [M+Na] + 573.0669, found: 573.0667.
实施例11：
Figure PCTCN2022132704-appb-000021
Example 11:
Figure PCTCN2022132704-appb-000021
(S)-1-苄基-3-(2-溴苯基)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-1H-吡唑-5-甲酰胺H 11的制备 (S)-1-Benzyl-3-(2-bromophenyl)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)- Preparation of 1H-pyrazole-5-carboxamide H11
其他条件同实施例1，将苯乙酮改为2-溴苯乙酮，产物为白色固体，产率为33％。 1H NMR(300MHz,DMSO-d 6)δ8.91(d,J＝8.6Hz,1H),8.14(q,J＝4.5Hz,1H),7.74(dd,J＝8.0,1.2Hz,1H),7.66(dd,J＝7.7,1.8Hz,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＝10.6,8.4,4.4Hz,1H),3.09(dd,J＝13.5,4.4Hz,1H),2.94(dd,J＝13.6,10.7Hz,1H),2.62(d,J＝4.6Hz,3H). 13C NMR(75MHz,DMSO-d 6)δ170.9,158.9,148.0,141.1,137.6,135.4,133.5,133.4,132.0,131.0,130.2,129.9,129.2,128.4,128.3,127.9,127.4,127.4,121.4,121.0,108.5,54.3,53.8,36.8,25.6.HRMS(ESI,m/z):Calcd.for C 27H 24Br 2N 4O 2[M+Na] +619.0164,found:619.0147. Other conditions were the same as in Example 1, except that acetophenone was changed to 2-bromoacetophenone, and the product was a white solid with a yield of 33%. 1 H NMR (300MHz, DMSO-d 6 ) δ8.91(d, J=8.6Hz, 1H), 8.14(q, J=4.5Hz, 1H), 7.74(dd, J=8.0, 1.2Hz, 1H) ,7.66(dd,J＝7.7,1.8Hz,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=10.6,8.4,4.4Hz,1H),3.09(dd,J=13.5,4.4Hz,1H),2.94(dd,J=13.6,10.7Hz,1H ), 2.62 (d, J=4.6Hz, 3H). 13 C NMR (75MHz, DMSO-d 6 ) δ170.9, 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 Br 2 N 4 O 2 [M+ Na] + 619.0164, found: 619.0147.
实施例12：
Figure PCTCN2022132704-appb-000022
Example 12:
Figure PCTCN2022132704-appb-000022
(S)-1-苄基-3-(3-溴苯基)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-1H-吡唑-5-甲酰胺H 12的制备 (S)-1-Benzyl-3-(3-bromophenyl)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)- Preparation of 1H-pyrazole-5-carboxamide H12
其他条件同实施例1，将苯乙酮改为3-溴苯乙酮，产物为白色固体，产率为30％。 1H NMR(300MHz,DMSO-d 6)δ8.84(d,J＝8.7Hz,1H),8.18(d,J＝4.6Hz,1H),7.91(t,J＝1.6Hz,1H),7.75(d,J＝7.8Hz,1H),7.58-7.52(m,3H),7.44-7.36(m,2H),7.32-7.2(m,5H),7.11(dd,J＝7.5,1.8Hz,2H),5.73-5.56(m,2H),4.64(ddd, J＝10.6,8.6,4.4Hz,1H),3.12(dd,J＝13.6,4.4Hz,1H),2.94(dd,J＝13.6,10.6Hz,1H),2.63(d,J＝4.5Hz,3H). 13C NMR(75MHz,DMSO-d 6)δ170.8,158.8,147.4,141.0,137.5,136.6,134.7,132.0,131.2,130.7,130.3,129.2,128.4,128.3,127.4,123.9,122.3,1214,105.5,54.2,53.8,37.0,25.7. Other conditions were the same as in Example 1, except that acetophenone was changed to 3-bromoacetophenone, and the product was a white solid with a yield of 30%. 1 H NMR (300MHz, DMSO-d 6 ) δ8.84(d, J=8.7Hz, 1H), 8.18(d, J=4.6Hz, 1H), 7.91(t, J=1.6Hz, 1H), 7.75 (d,J=7.8Hz,1H),7.58-7.52(m,3H),7.44-7.36(m,2H),7.32-7.2(m,5H),7.11(dd,J=7.5,1.8Hz,2H ),5.73-5.56(m,2H),4.64(ddd, J＝10.6,8.6,4.4Hz,1H),3.12(dd,J＝13.6,4.4Hz,1H),2.94(dd,J＝13.6,10.6 Hz, 1H), 2.63 (d, J=4.5Hz, 3H). 13 C NMR (75MHz, DMSO-d 6 ) δ170.8, 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.
实施例13：
Figure PCTCN2022132704-appb-000023
Example 13:
Figure PCTCN2022132704-appb-000023
(S)-1-苄基-3-(4-溴苯基)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-1H-吡唑-5-甲酰胺H 13的制备 (S)-1-Benzyl-3-(4-bromophenyl)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)- Preparation of 1H-pyrazole-5-carboxamide H13
其他条件同实施例1，将苯乙酮改为4-溴苯乙酮，产物为白色固体，产率为34％。 1H NMR(300MHz,DMSO-d 6)δ8.84(d,J＝8.6Hz,1H),8.14(d,J＝4.5Hz,1H),7.72-7.63(m,4H),7.57(s,1H),7.44(s,1H),7.37(d,J＝7.9Hz,1H),7.32-7.17(m,5H),7.13-7.10(m,2H),5.72-5.54(m,2H),4.63(td,J＝9.5,8.6,4.3Hz,1H),3.11(dd,J＝13.6,4.4Hz,1H),2.97-2.88(m,1H),2.62(d,J＝4.5Hz,3H). 13C NMR(75MHz,DMSO-d 6)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. Other conditions were the same as in Example 1, except that acetophenone was changed to 4-bromoacetophenone, and the product was a white solid with a yield of 34%. 1 H NMR (300MHz, DMSO-d 6 )δ8.84(d, J=8.6Hz, 1H), 8.14(d, J=4.5Hz, 1H), 7.72-7.63(m, 4H), 7.57(s, 1H),7.44(s,1H),7.37(d,J=7.9Hz,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, 4.3Hz, 1H), 3.11(dd, J=13.6, 4.4Hz, 1H), 2.97-2.88(m, 1H), 2.62(d, J=4.5Hz, 3H). 13 C NMR (75MHz, DMSO-d 6 )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.
实施例14：
Figure PCTCN2022132704-appb-000024
Example 14:
Figure PCTCN2022132704-appb-000024
(S)-1-苄基-N-(3-(3-溴苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-3-(2-硝基苯基)-1H-吡唑-5-甲酰胺H 14的制备 (S)-1-Benzyl-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-(2-nitrophenyl )-1H-pyrazole-5-carboxamide H 14 preparation
其他条件同实施例1，将苯乙酮改为2-硝基苯乙酮，产物为白色固体，产率为36％。 1H NMR(300MHz,DMSO-d 6)：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),7.30-7.17(m,6H),7.10-7.07(m,2H),5.61(q,J＝14.7Hz,2H),4.62(dt,J＝13.2,4.6Hz,1H),3.09(dd,J＝13.6,4.5Hz,1H),2.95-2.87(m,1H),2.62(d,J＝4.6Hz,3H). 13C NMR(75MHz,DMSO-d 6)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 27H 24BrN 5O 4[M+Na] +584.0909,found:584.0900. Other conditions were the same as in Example 1, except that acetophenone was changed to 2-nitroacetophenone, and the product was a white solid with a yield of 36%. 1 H NMR (300MHz, DMSO-d 6 ): 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),7.30-7.17(m,6H),7.10-7.07(m,2H),5.61( q,J=14.7Hz,2H),4.62(dt,J=13.2,4.6Hz,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-d 6 ) 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 BrN 5 O 4 [M+Na] + 584.0909, found: 584.0900.
实施例15：
Figure PCTCN2022132704-appb-000025
Example 15:
Figure PCTCN2022132704-appb-000025
(S)-1-苄基-N-(3-(3-溴苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-3-(3-硝基苯基)-1H-吡唑-5-甲酰胺H 15的制备 (S)-1-Benzyl-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-(3-nitrophenyl )-1H-pyrazole-5-carboxamide H 15 preparation
其他条件同实施例1，将苯乙酮改为3-硝基苯乙酮，产物为白色固体，产率为34％。 1H NMR(300MHz,DMSO-d 6)：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). 13C NMR(75MHz,DMSO-d 6)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. Other conditions were the same as in Example 1, except that acetophenone was changed to 3-nitroacetophenone, and the product was a white solid with a yield of 34%. 1 H NMR (300MHz, DMSO-d 6 ): 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-d 6 ) 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.
实施例16：
Figure PCTCN2022132704-appb-000026
Example 16:
Figure PCTCN2022132704-appb-000026
(S)-1-苄基-N-(3-(3-溴苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-3-(4-硝基苯基)-1H-吡唑-5-甲酰胺H 16的制备 (S)-1-Benzyl-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-(4-nitrophenyl )-1H-pyrazole-5-carboxamide H 16 preparation
其他条件同实施例1，将苯乙酮改为4-硝基苯乙酮，产物为白色固体，产率为35％。H NMR(300MHz,DMSO-d 6)δ8.78(d,J＝8.6Hz,1H),8.12(d,J＝4.7Hz,1H),7.69(d,J＝8.8Hz,2H),7.57(s,1H),7.39-7.18(m,7H),7.11(dd,J＝7.6,1.9Hz,2H),7.01(d,J＝8.8Hz,2H),5.71-5.53(m,2H),4.63(ddd,J＝10.5,8.5,4.3Hz,1H),3.78(s,3H),3.11(dd,J＝13.6,4.4Hz,1H),2.93(dd,J＝13.6,10.6Hz,1H),2.63(d,J＝4.5Hz,3H).. 13C NMR(75MHz,DMSO-d 6)δ171.0,159.2,148.9,141.1,137.8,136.4,136.3,132.0,130.3,129.3,128.4,128.3,127.4,126.4,125.1,121.4,114.3,104.4,55.2,53.6,36.9,25.7. Other conditions were the same as in Example 1, except that acetophenone was changed to 4-nitroacetophenone, and the product was a white solid with a yield of 35%. H NMR (300MHz, DMSO-d 6 )δ8.78(d, J=8.6Hz, 1H), 8.12(d, J=4.7Hz, 1H), 7.69(d, J=8.8Hz, 2H), 7.57( s,1H),7.39-7.18(m,7H),7.11(dd,J=7.6,1.9Hz,2H),7.01(d,J=8.8Hz,2H),5.71-5.53(m,2H),4.63 (ddd,J=10.5,8.5,4.3Hz,1H),3.78(s,3H),3.11(dd,J=13.6,4.4Hz,1H),2.93(dd,J=13.6,10.6Hz,1H), 2.63(d,J=4.5Hz,3H).. 13 C NMR(75MHz,DMSO-d 6 )δ171.0,159.2,148.9,141.1,137.8,136.4,136.3,132.0,130.3,129.3,128.4,128.3,127.4, 126.4, 125.1, 121.4, 114.3, 104.4, 55.2, 53.6, 36.9, 25.7.
实施例17：
Figure PCTCN2022132704-appb-000027
Example 17:
Figure PCTCN2022132704-appb-000027
(S)-1-苄基-N-(3-(3-溴苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-3-(3-氰基苯基)-1H-吡唑-5-甲酰胺H 17的制备 (S)-1-Benzyl-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-(3-cyanophenyl) )-1H-pyrazole-5-carboxamide H 17 preparation
其他条件同实施例1，将苯乙酮改为3-氰基苯乙酮，产物为白色固体，产率为29％。 1H NMR(300MHz,DMSO-d 6)δ8.79(d,J＝8.6Hz,1H),8.13-8.06(m,3H),7.81(d,J＝7.7Hz,1H),7.66(t,J＝7.8Hz,1H),7.53(d,J＝17.1Hz,2H),7.39-7.11(m,8H),5.73-5.56(m,2H),4.65(dq,J＝8.7,4.6Hz,1H),3.11(dd,J＝13.6,4.5Hz,1H),2.95-2.87(m,1H),2.63(d,J＝4.2Hz,3H). 13C NMR(75MHz,DMSO-d 6)δ170.8,158.8,147.0,140.9,137.4,136.9,133.6,132.0,131.5,130.3,130.3,129.5,129.3,128.4,128.3,127.4,121.4,118.6,112.1,105.5,54.2,53.9,37.0,25.7.HRMS(ESI,m/z):Calcd.for C 28H 24BrN 5O 2[M+Na] +564.1011,found:564.1008. Other conditions were the same as in Example 1, except that acetophenone was changed to 3-cyanoacetophenone, and the product was a white solid with a yield of 29%. 1 H NMR (300MHz, DMSO-d 6 )δ8.79(d, J=8.6Hz, 1H), 8.13-8.06(m, 3H), 7.81(d, J=7.7Hz, 1H), 7.66(t, J＝7.8Hz, 1H), 7.53(d, J＝17.1Hz, 2H), 7.39-7.11(m, 8H), 5.73-5.56(m, 2H), 4.65(dq, J＝8.7, 4.6Hz, 1H ), 3.11(dd, J＝13.6, 4.5Hz, 1H), 2.95-2.87(m, 1H), 2.63(d, J＝4.2Hz, 3H). 13 C NMR (75MHz, DMSO-d 6 ) δ170. 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 BrN 5 O 2 [M+Na] + 564.1011, found: 564.1008.
实施例18：
Figure PCTCN2022132704-appb-000028
Example 18:
Figure PCTCN2022132704-appb-000028
(S)-1-苄基-N-(3-(3-溴苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-3-(4-氰基苯基)-1H-吡唑-5-甲酰胺H 18的制备 (S)-1-Benzyl-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-(4-cyanophenyl )-1H-pyrazole-5-carboxamide H 18 preparation
其他条件同实施例1，将苯乙酮改为4-氰基苯乙酮，产物为白色固体，产率为30％。 1H NMR(300MHz,DMSO-d 6)δ8.84(d,J＝8.6Hz,1H),8.11(d,J＝4.7Hz,1H),7.95-7.89(m,4H),7.56(s,1H),7.52(s,1H),7.37(d,J＝7.8,2.1Hz,1H),7.31-7.18(m,5H),7.12(dd,J＝7.6,2.0Hz,2H),5.74-5.57(m,2H),4.65(dq,J＝10.5,4.5Hz,1H),3.11(dd,J＝13.6,4.5Hz,1H),2.91(dd,J＝13.6,10.6Hz,1H),2.63(d,J＝4.6Hz,3H). 13C NMR(75MHz,DMSO-d 6)δ170.8,158.8,147.2,140.9,137.3,136.9,136.7,133.0,132.0,130.3,129.2,128.4,128.3,127.5,127.4,125.6,121.4,118.8,110.2,105.9,54.2,53.9,37.0,25.7. Other conditions were the same as in Example 1, except that acetophenone was changed to 4-cyanoacetophenone, and the product was a white solid with a yield of 30%. 1 H NMR (300MHz, DMSO-d 6 )δ8.84(d, J=8.6Hz, 1H), 8.11(d, J=4.7Hz, 1H), 7.95-7.89(m, 4H), 7.56(s, 1H),7.52(s,1H),7.37(d,J=7.8,2.1Hz,1H),7.31-7.18(m,5H),7.12(dd,J=7.6,2.0Hz,2H),5.74-5.57 (m,2H),4.65(dq,J=10.5,4.5Hz,1H),3.11(dd,J=13.6,4.5Hz,1H),2.91(dd,J=13.6,10.6Hz,1H),2.63( D, J = 4.6Hz, 3H). 13 C NMR (75MHz, DMSO-D 6 ) Δ170.8,158,147.2,140.9,136.9,136.7,133.0,130.3,128.4, 128.3,127.5,1,1 27.4 ,125.6,121.4,118.8,110.2,105.9,54.2,53.9,37.0,25.7.
实施例19：
Figure PCTCN2022132704-appb-000029
Example 19:
Figure PCTCN2022132704-appb-000029
(S)-N-(3-(3-溴苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-1-(2-甲基苄基)-3-苯基-1H-吡唑-5-甲酰胺H 19的制备 (S)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-1-(2-methylbenzyl)-3-benzene Preparation of base-1H-pyrazole-5-carboxamide H19
其他条件同实施例1，将氯化苄改为2-甲基氯化苄，产物为白色固体，产率为39％。 1H NMR(300MHz,DMSO-d 6)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). 13C NMR(75MHz,DMSO-d 6)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.for C 28H 27BrN 4O 2[M+Na] +553.1215,found:553.1210. Other conditions were the same as in Example 1, except that 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-d 6 ) 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-d 6 ) 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.for C 28 H 27 BrN 4 O 2 [M+Na] + 553.1215, found: 553.1210.
实施例20：
Figure PCTCN2022132704-appb-000030
Example 20:
Figure PCTCN2022132704-appb-000030
(S)-N-(3-(3-溴苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-1-(3-甲基苄基)-3-苯基-1H-吡唑-5-甲酰胺H 20的制备 (S)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-1-(3-methylbenzyl)-3-benzene Preparation of base-1H-pyrazole-5-carboxamide H20
其他条件同实施例1，将氯化苄改为3-甲基氯化苄，产物为白色固体，产率为39％。 1H NMR(300MHz,DMSO-d 6)δ8.79(d,J＝8.6Hz,1H),8.10(d,J＝4.7Hz,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＝7.5Hz,1H),6.96(s,1H),6.89(d,J＝7.6Hz,1H),5.66-5.54(m,2H),4.62(ddd,J＝10.5,8.5,4.4Hz,1H),3.10(dd,J＝13.6,4.4Hz,1H),2.93(dd,J＝13.6,10.6Hz,1H),2.63(d,J＝4.5Hz,3H),2.22(s,3H). 13C NMR(75MHz,DMSO-d 6)δ170.9,159.1,148.8,141.1,137.6,137.5,136.5,132.4,132.0,130.2,129.2,128.9,128.3,128.2,128.0,127.9,125.0,124.5,121.4,104.9,54.2,53.6,36.9,25.6,21.0. Other conditions were the same as in Example 1, except that benzyl chloride was changed to 3-methylbenzyl chloride, and the product was a white solid with a yield of 39%. 1 H NMR (300MHz, DMSO-d 6 )δ8.79(d, J=8.6Hz, 1H), 8.10(d, J=4.7Hz, 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=7.5Hz, 1H), 6.96(s, 1H), 6.89(d, J=7.6Hz, 1H ),5.66-5.54(m,2H),4.62(ddd,J=10.5,8.5,4.4Hz,1H),3.10(dd,J=13.6,4.4Hz,1H),2.93(dd,J=13.6,10.6 Hz, 1H), 2.63(d, J=4.5Hz, 3H), 2.22(s, 3H). 13 C NMR (75MHz, DMSO-d 6 ) δ170.9, 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.
实施例21：
Figure PCTCN2022132704-appb-000031
Example 21:
Figure PCTCN2022132704-appb-000031
(S)-N-(3-(3-溴苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-1-(4-甲基苄基)-3-苯基-1H-吡唑-5-甲酰胺H 21的制备 (S)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-1-(4-methylbenzyl)-3-benzene Preparation of base-1H-pyrazole-5-carboxamide H 21
其他条件同实施例1，将氯化苄改为4-甲基氯化苄，产物为白色固体，产率为45％。 1H NMR(300MHz,DMSO-d 6)δ8.77(d,J＝8.6Hz,1H),8.10(d,J＝4.7Hz,1H),7.76(d,J＝7.1Hz,2H),7.57(s,1H),7.46-7.29(m,6H),7.21(t,J＝7.7Hz,1H),7.05(dd,J＝9.6,4.6Hz,4H),5.67-5.50(m,2H),4.67-4.59(m,1H),3.11(dd,J＝13.6,4.4Hz,1H),2.92(dd,J＝13.6,10.6Hz,1H),2.63(d,J＝4.4Hz,3H),2.23(s, 3H). 13C NMR(75MHz,DMSO-d 6)δ170.9,159.1,148.8,141.0,136.5,136.3,134.7,132.4,132.0,130.3,129.2,128.9,128.2,128.0,127.4,125.0,121.4,104.9,54.2,53.4,36.91,25.7,20.7. Other conditions were the same as in Example 1, except that benzyl chloride was changed to 4-methylbenzyl chloride, and the product was a white solid with a yield of 45%. 1 H NMR (300MHz, DMSO-d 6 ) δ8.77(d, J=8.6Hz, 1H), 8.10(d, J=4.7Hz, 1H), 7.76(d, J=7.1Hz, 2H), 7.57 (s,1H),7.46-7.29(m,6H),7.21(t,J=7.7Hz,1H),7.05(dd,J=9.6,4.6Hz,4H),5.67-5.50(m,2H), 4.67-4.59(m,1H),3.11(dd,J=13.6,4.4Hz,1H),2.92(dd,J=13.6,10.6Hz,1H),2.63(d,J=4.4Hz,3H),2.23 (s, 3H). 13 C NMR(75MHz,DMSO-d 6 )δ170.9,159.1,148.8,141.0,136.5,136.3,134.7,132.4,132.0,130.3,129.2,128.9,128.2,128.0,127.4,125. 0,121.4 ,104.9,54.2,53.4,36.91,25.7,20.7.
实施例22：
Figure PCTCN2022132704-appb-000032
Example 22:
Figure PCTCN2022132704-appb-000032
(S)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-1-(3-甲氧基苄基)-3-苯基-1H-吡唑-5-甲酰胺H 22的制备 (S)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-1-(3-methoxybenzyl)-3-benzene Preparation of base-1H-pyrazole-5-carboxamide H 22
其他条件同实施例1，将氯化苄改为3-甲氧基氯化苄，产物为白色固体，产率为55％。 1H NMR(400MHz,DMSO-d 6)δ8.84(d,J＝8.6Hz,1H),8.14(d,J＝4.7Hz,1H),7.77(d,J＝7.6Hz,2H),7.57(d,J＝1.9Hz,1H),7.47-7.39(m,3H),7.33(dt,J＝14.4,8.0Hz,3H),7.18(dt,J 1＝10.6,J 2＝7.8Hz,2H),6.79(dd,J 1＝8.1,J 2＝2.6Hz,1H),6.71(t,J＝2.0Hz,1H),6.65(d,J＝7.6Hz,1H),5.68-5.55(m,2H),4.63(m,1H),3.67(s,3H),3.11(dd,J 1＝13.6,J 2＝4.4Hz,1H),2.94(dd,J 1＝13.6,J 2＝10.6Hz,1H),2.63(d,J＝4.5Hz,3H). 13C NMR(101MHz,DMSO-d 6)δ170.76,158.99,158.83,148.73,140.81,139.03,136.28,132.19,131.80,130.05,129.30,129.04,128.73,128.02,127.83,124.79,121.20,119.19,112.91,112.38,104.78,54.71,54.06,53.39,36.71,25.47. Other conditions were the same as in Example 1, except that benzyl chloride was changed to 3-methoxybenzyl chloride, and the product was a white solid with a yield of 55%. 1 H NMR (400MHz, DMSO-d 6 ) δ8.84(d, J=8.6Hz, 1H), 8.14(d, J=4.7Hz, 1H), 7.77(d, J=7.6Hz, 2H), 7.57 (d, J = 1.9Hz, 1H), 7.47-7.39 (m, 3H), 7.33 (dt, J = 14.4, 8.0Hz, 3H), 7.18 (dt, J 1 = 10.6, J 2 = 7.8Hz, 2H ), 6.79(dd, J 1 =8.1, J 2 =2.6Hz, 1H), 6.71(t, J=2.0Hz, 1H), 6.65(d, J=7.6Hz, 1H), 5.68-5.55(m, 2H), 4.63(m, 1H), 3.67(s, 3H), 3.11(dd, J 1 =13.6, J 2 =4.4Hz, 1H), 2.94(dd, J 1 =13.6, J 2 =10.6Hz, 1H), 2.63 (d, J=4.5Hz, 3H). 13 C NMR (101MHz, DMSO-d 6 ) δ170.76, 158.99, 158.83, 148.73, 140.81, 139.03, 136.28, 132.19, 131.80, 130.05, 129.30, 1 29.04, 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.
实施例23：
Figure PCTCN2022132704-appb-000033
Example 23:
Figure PCTCN2022132704-appb-000033
(S)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-1-(4-甲氧基苄基)-3-苯基-1H-吡唑-5-甲酰胺H 23的制备 (S)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-1-(4-methoxybenzyl)-3-benzene Preparation of base-1H-pyrazole-5-carboxamide H 23
其他条件同实施例1，将氯化苄改为4-甲氧基氯化苄，产物为白色固体，产率为53％。 1H NMR(400MHz,DMSO-d 6)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,J 1＝13.7,J 2＝4.4Hz,1H),2.95-2.90(m,1H),2.64(d,J＝4.5Hz,3H). 13C NMR(101 MHz,DMSO-d 6)：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. Other conditions were the same as in Example 1, except that 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-d 6 ) 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, J 1 =13.7, J 2 =4.4Hz, 1H), 2.95-2.90(m, 1H), 2.64(d, J=4.5Hz, 3H). 13 C NMR (101 MHz, DMSO-d 6 ): 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.
实施例24：
Figure PCTCN2022132704-appb-000034
Example 24:
Figure PCTCN2022132704-appb-000034
(S)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-1-(2-氟苄基)-3-苯基-1H-吡唑-5-甲酰胺H 24的制备 (S)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-1-(2-fluorobenzyl)-3-phenyl- Preparation of 1H-pyrazole-5-carboxamide H 24
其他条件同实施例1，将氯化苄改为2-氟氯化苄，产物为白色固体，产率为64％。 1H NMR(400MHz,DMSO-d 6)δ8.84(d,J＝8.6Hz,1H),8.12(d,J＝4.9Hz,1H),7.76(d,J＝7.6Hz,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＝7.5Hz,1H),6.81(t,J＝7.6Hz,1H),5.82-5.61(m,2H),4.62(m,1H),3.11(dd,J 1＝13.7,J 2＝4.4Hz,1H),2.98-2.86(m,1H),2.63(d,J＝4.5Hz,3H). 13C NMR(101MHz,DMSO-d 6)δ170.93,158.93,149.18,141.03,136.79,132.34,132.04,130.29,129.27,128.97,128.28,128.13,125.06,124.90,124.54,121.43,115.34,115.13,105.05,54.23,36.98,25.71. Other conditions were the same as in Example 1, except that benzyl chloride was changed to 2-fluorobenzyl chloride, and the product was a white solid with a yield of 64%. 1 H NMR (400MHz, DMSO-d 6 ) δ8.84(d, J=8.6Hz, 1H), 8.12(d, J=4.9Hz, 1H), 7.76(d, J=7.6Hz, 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=7.5Hz,1H),6.81(t,J=7.6 Hz, 1H), 5.82-5.61(m, 2H), 4.62(m, 1H), 3.11(dd, J 1 ＝13.7, J 2 ＝4.4Hz, 1H), 2.98-2.86(m, 1H), 2.63( d, J＝4.5Hz, 3H). 13 C NMR (101MHz, DMSO-d 6 ) δ170.93, 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.
实施例25：
Figure PCTCN2022132704-appb-000035
Example 25:
Figure PCTCN2022132704-appb-000035
(S)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-1-(3-氟苄基)-3-苯基-1H-吡唑-5-甲酰胺H 25的制备 (S)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-1-(3-fluorobenzyl)-3-phenyl- Preparation of 1H-pyrazole-5-carboxamide H 25
其他条件同实施例1，将氯化苄改为3-氟氯化苄，产物为白色固体，产率为65％。 1H NMR(400MHz,DMSO-d 6)δ8.83(d,J＝8.7Hz,1H),8.12(d,J＝4.7Hz,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＝7.8Hz,1H),7.07(m,1H),6.97-6.89(m,2H),5.76-5.56(m,2H),4.64(ddd,J 1＝10.7,J 2＝8.5,J 3＝4.4Hz,1H),3.12(dd,J 1＝13.6,J 2＝4.4Hz,1H),2.94(m,1H),2.64(d,J＝4.5Hz,3H). 13C NMR(101MHz,DMSO-d 6)δ170.60,163.00,160.58,158.69,148.87,140.74,140.25,140.18,136.26,132.06,131.75,130.17,130.09,129.95,128.96,128.67,127.95,127.82,124.77,123.02,121.13,114.04,113.90,113.68,104.77,53.93,52.93,36.66,25.40. Other conditions were the same as in Example 1, except that benzyl chloride was changed to 3-fluorobenzyl chloride, and the product was a white solid with a yield of 65%. 1 H NMR (400MHz, DMSO-d 6 )δ8.83(d, J=8.7Hz, 1H), 8.12(d, J=4.7Hz, 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＝7.8Hz,1H),7.07(m,1H),6.97-6.89(m,2H),5.76 -5.56 (m, 2H), 4.64 (ddd, J 1 = 10.7, J 2 = 8.5, J 3 = 4.4Hz, 1H), 3.12 (dd, J 1 = 13.6, J 2 = 4.4Hz, 1H), 2.94 (M, 1H), 2.64 (d, J = 4.5Hz, 3H). 13 C NMR (101MHz, DMSO-D 6 ) Δ170.60, 163.00, 158.58.69,148.87,140.25,140.18,136,132.06,131. 75 ,130.17,130.09,129.95,128.96,128.67,127.95,127.82,124.77,123.02,121.13,114.04,113.90,113.68,104.77,53.93,52.93,36.66,25.4 0.
实施例26：
Figure PCTCN2022132704-appb-000036
Example 26:
Figure PCTCN2022132704-appb-000036
(S)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-1-(4-氟苄基)-3-苯基-1H-吡唑-5-甲酰胺H 26的制备 (S)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-1-(4-fluorobenzyl)-3-phenyl- Preparation of 1H-pyrazole-5-carboxamide H 26
其他条件同实施例1，将氯化苄改为4-氟氯化苄，产物为白色固体，产率为65％。 1H NMR(400MHz,DMSO-d 6)δ8.81(d,J＝8.6Hz,1H),8.12(q,J＝4.6Hz,1H),7.80-7.73(m,2H),7.57(s,1H),7.44(t,J＝7.6Hz,2H),7.41-7.29(m,4H),7.24-7.16(m,3H),7.12-7.06(m,2H),5.68(d,J＝14.7Hz,1H),5.55(d,J＝14.7Hz,1H),4.64(ddd,J 1＝10.7,J 2＝8.6,J 3＝4.4Hz,1H),3.12(dd,J 1＝13.6,J 2＝4.4Hz,1H),2.93(m,1H),2.64(d,J＝4.5Hz,3H). 13C NMR(101MHz,DMSO-d 6)δ170.91,159.04,149.02,141.06,136.36,133.88,132.39,132.03,130.27,129.63,129.55,129.24,128.93,128.28,128.06,125.03,121.41,115.27,115.06,105.02,54.22,25.70. Other conditions were the same as in Example 1, except that benzyl chloride was changed to 4-fluorobenzyl chloride, and the product was a white solid with a yield of 65%. 1 H NMR (400MHz, DMSO-d 6 )δ8.81(d, J=8.6Hz, 1H), 8.12(q, J=4.6Hz, 1H), 7.80-7.73(m, 2H), 7.57(s, 1H), 7.44(t, J=7.6Hz, 2H), 7.41-7.29(m, 4H), 7.24-7.16(m, 3H), 7.12-7.06(m, 2H), 5.68(d, J=14.7Hz ,1H),5.55(d,J=14.7Hz,1H),4.64(ddd,J 1 =10.7,J 2 =8.6,J 3 =4.4Hz,1H),3.12(dd,J 1 =13.6,J 2 ＝4.4Hz, 1H), 2.93(m, 1H), 2.64(d, J＝4.5Hz, 3H). 13 C NMR (101MHz, DMSO-d 6 ) δ170.91, 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.
实施例27：
Figure PCTCN2022132704-appb-000037
Example 27:
Figure PCTCN2022132704-appb-000037
(S)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-1-(2-氯苄基)-3-苯基-1H-吡唑-5-甲酰胺H 27的制备 (S)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-1-(2-chlorobenzyl)-3-phenyl- Preparation of 1H-pyrazole-5-carboxamide H 27
其他条件同实施例1，将氯化苄改为2-氯代氯化苄，产物为白色固体，产率为68％。 1H NMR(400MHz,DMSO-d 6)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,J 1＝8.4,J 2＝7.1Hz,3H),7.38-7.32(m,2H),7.31-7.22(m,2H),7.22-7.13(m,2H),6.53(dd,J 1＝7.7,J 2＝1.7Hz,1H),5.82-5.64(m,2H),4.59(ddd,J 1＝10.6,J 2＝8.6,J 3＝4.4Hz,1H),3.10(dd,J 1＝13.6,J 2＝4.5Hz,1H),2.93(dd,J＝13.6,10.6Hz,1H),2.62(d,J＝4.5Hz,3H). 13C NMR(101MHz,DMSO-d 6)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. Other conditions were the same as in Example 1, except that benzyl chloride was changed to 2-chlorobenzyl chloride, and the product was a white solid with a yield of 68%. 1 H NMR (400MHz, DMSO-d 6 )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, J 1 =8.4, J 2 =7.1Hz, 3H), 7.38-7.32(m, 2H), 7.31-7.22(m, 2H), 7.22-7.13( m, 2H), 6.53 (dd, J 1 =7.7, J 2 =1.7Hz, 1H), 5.82-5.64 (m, 2H), 4.59 (ddd, J 1 =10.6, J 2 =8.6, J 3 =4.4 Hz, 1H), 3.10(dd, J 1 ＝13.6, J 2 ＝4.5Hz, 1H), 2.93(dd, J＝13.6, 10.6Hz, 1H), 2.62(d, J＝4.5Hz, 3H). 13 C NMR(101MHz,DMSO-d 6 )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.
实施例28：
Figure PCTCN2022132704-appb-000038
Example 28:
Figure PCTCN2022132704-appb-000038
(S)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-1-(3-氯苄基)-3-苯基-1H-吡唑-5-甲酰胺H 28的制备 (S)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-1-(3-chlorobenzyl)-3-phenyl- Preparation of 1H-pyrazole-5-carboxamide H 28
其他条件同实施例1，将氯化苄改为3-氯代氯化苄，产物为白色固体，产率为67％。 1H NMR(400MHz,DMSO-d 6)δ8.83(d,J＝8.6Hz,1H),8.10(q,J＝4.5Hz,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＝15.0Hz,1H),5.59(d,J＝15.0Hz,1H),4.63(ddd,J 1＝10.6,J 2＝8.6,J 3＝4.4Hz,1H),3.11(dd,J 1＝13.6,J 2＝4.4Hz,1H),2.94(dd,J 1＝14.5,J 2＝3.9Hz,1H),2.63(d,J＝4.5Hz,3H). 13C NMR(101MHz,DMSO-d 6)δ170.89,158.98,149.20,141.02,140.16,136.57,133.03,132.03,130.37,129.00,128.25,127.43,127.18,126.00,125.07,121.43,105.08,54.23,36.94,25.72. Other conditions were the same as in Example 1, except that benzyl chloride was changed to 3-chlorobenzyl chloride, and the product was a white solid with a yield of 67%. 1 H NMR (400MHz, DMSO-d 6 )δ8.83(d, J=8.6Hz, 1H), 8.10(q, J=4.5Hz, 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=15.0Hz, 1H), 5.59(d, J=15.0Hz, 1H), 4.63(ddd, J 1 =10.6, J 2 =8.6, J 3 =4.4Hz, 1H), 3.11(dd, J 1 = 13.6, J 2 =4.4Hz, 1H), 2.94 (dd, J 1 =14.5, J 2 =3.9Hz, 1H), 2.63 (d, J = 4.5Hz, 3H). 13 C NMR (101MHz, DMSO-d 6 ) δ170.89, 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, 105.0 8, 54.23, 36.94, 25.72.
实施例29：
Figure PCTCN2022132704-appb-000039
Example 29:
Figure PCTCN2022132704-appb-000039
(S)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-1-(4-氯苄基)-3-苯基-1H-吡唑-5-甲酰胺H 29的制备 (S)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-1-(4-chlorobenzyl)-3-phenyl- Preparation of 1H-pyrazole-5-carboxamide H 29
其他条件同实施例1，将氯化苄改为4-氯代氯化苄，产物为白色固体，产率为70％。 1H NMR(400MHz,DMSO-d 6)δ8.79(d,J＝8.6Hz,1H),8.09(q,J＝4.6Hz,1H),7.76(dd,J 1＝8.3,J 2＝1.3Hz,2H),7.55(d,J＝1.9Hz,1H),7.44(m,3H),7.38-7.27(m,5H),7.20(t,J＝7.8Hz,1H),7.15-7.11(m,2H),5.68(d,J＝14.9Hz,1H),5.56(d,J＝14.9Hz,1H),4.61(ddd,J 1＝10.8,J 2＝8.7,J 3＝4.3Hz,1H),3.10(dd,J 1＝13.7,J 2＝4.4Hz,1H),2.91(m,1H),2.62(d,J＝4.5Hz,3H). Other conditions were the same as in Example 1, except that benzyl chloride was changed to 4-chlorobenzyl chloride, and the product was a white solid with a yield of 70%. 1 H NMR (400MHz, DMSO-d 6 ) δ8.79 (d, J=8.6Hz, 1H), 8.09 (q, J=4.6Hz, 1H), 7.76 (dd, J 1 =8.3, J 2 =1.3 Hz, 2H), 7.55(d, J=1.9Hz, 1H), 7.44(m, 3H), 7.38-7.27(m, 5H), 7.20(t, J=7.8Hz, 1H), 7.15-7.11(m ,2H),5.68(d,J=14.9Hz,1H),5.56(d,J=14.9Hz,1H),4.61(ddd,J 1 ＝10.8,J 2 ＝8.7,J 3 ＝4.3Hz,1H) ,3.10(dd,J 1 =13.7,J 2 =4.4Hz,1H),2.91(m,1H),2.62(d,J=4.5Hz,3H).
实施例30：
Figure PCTCN2022132704-appb-000040
Example 30:
Figure PCTCN2022132704-appb-000040
(S)-1-(2-溴苄基)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-3-苯基-1H-吡唑-5-甲酰胺H 30的制备 (S)-1-(2-bromobenzyl)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-phenyl- Preparation of 1H-pyrazole-5-carboxamide H 30
其他条件同实施例1，将氯化苄改为2-溴氯化苄，产物为白色固体，产率为70％。 1H NMR(300MHz,DMSO-d 6)δ8.87(d,J＝8.7Hz,1H),8.13(d,J＝4.7Hz,1H),7.78-7.76(m,2H),7.61(dd,J＝7.3,1.9Hz,1H),7.55(s,2H),7.45(t,J＝7.4Hz,2H),7.37-7.16(m,6H),6.45(dd,J＝7.1,2.2Hz,1H),5.69(q,J＝16.0Hz,2H),4.58(ddd,J＝10.5,8.6,4.4Hz,1H),3.10(dd,J＝13.5,4.5Hz,1H),2.93(dd,J＝13.6,10.6Hz,1H). 13C NMR(75MHz,DMSO-d 6)δ170.8,158.7,149.3,141.0,137.1,137.1,132.4,132.3,132.0,130.2,129.2,129.1,128.9,128.2,128.1,127.9,127.8,125.0,121.4,121.3,105.0,54.9,54.2,36.9,25.6.HRMS(ESI,m/z):Calcd.for C 27H 24Br 2N 4O 2[M+Na] +619.0164,found:619.0147. Other conditions were the same as in Example 1, except that benzyl chloride was changed to 2-bromobenzyl chloride, and the product was a white solid with a yield of 70%. 1 H NMR (300MHz, DMSO-d 6 )δ8.87(d, J=8.7Hz, 1H), 8.13(d, J=4.7Hz, 1H), 7.78-7.76(m, 2H), 7.61(dd, J=7.3,1.9Hz,1H),7.55(s,2H),7.45(t,J=7.4Hz,2H),7.37-7.16(m,6H),6.45(dd,J=7.1,2.2Hz,1H ), 5.69(q, J=16.0Hz, 2H), 4.58(ddd, J=10.5, 8.6, 4.4Hz, 1H), 3.10(dd, J=13.5, 4.5Hz, 1H), 2.93(dd, J= 13.6,10.6Hz,1H). 13 C NMR(75MHz,DMSO-d 6 )δ170.8,158.7,149.3,141.0,137.1,137.1,132.4,132.3,132.0,130.2,129.2,129.1,128.9,128.2,12 8.1,127.9 ,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 Br 2 N 4 O 2 [M+Na] + 619.0164,found :619.0147.
实施例31：
Figure PCTCN2022132704-appb-000041
Example 31:
Figure PCTCN2022132704-appb-000041
(S)-1-(3-溴苄基)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-3-苯基-1H-吡唑-5-甲酰胺H 31的制备 (S)-1-(3-bromobenzyl)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-phenyl- Preparation of 1H-pyrazole-5-carboxamide H 31
其他条件同实施例1，将氯化苄改为3-溴氯化苄，产物为白色固体，产率为68％。 1H NMR(300MHz,DMSO-d 6)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). 13C NMR(75MHz,DMSO-d 6)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. Other conditions were the same as in Example 1, except that benzyl chloride was changed to 3-bromobenzyl chloride, and the product was a white solid with a yield of 68%. 1 H NMR (300MHz, DMSO-d 6 ) 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- d 6 )δ170.8,158.9,149.1,141.0,140.4,136.5,132.3,132.0,130.6,130.3,130.2,130.0,129.2,129.0,128.2,128.1,126.4,125.0,121.6,12 1.4, 105.1, 54.2, 53.1, 36.9 ,25.7.
实施例32：
Figure PCTCN2022132704-appb-000042
Example 32:
Figure PCTCN2022132704-appb-000042
(S)-1-(4-溴苄基)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-3-苯基-1H-吡唑-5-甲酰胺H 32的制备 (S)-1-(4-bromobenzyl)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-phenyl- Preparation of 1H-pyrazole-5-carboxamide H 32
其他条件同实施例1，将氯化苄改为4-溴氯化苄，产物为白色固体，产率为70％。 1H NMR(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). 13C 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. Other conditions were the same as in Example 1, except that benzyl chloride was changed to 4-bromobenzyl chloride, and the product was a white solid with a yield of 70%. 1 H NMR (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.
实施例33：
Figure PCTCN2022132704-appb-000043
Example 33:
Figure PCTCN2022132704-appb-000043
(S)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-1-(3-碘苄基)-3-苯基-1H-吡唑-5-甲酰胺H 33的制备 (S)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-1-(3-iodobenzyl)-3-phenyl- Preparation of 1H-pyrazole-5-carboxamide H 33
其他条件同实施例1，将氯化苄改为3-碘氯化苄，产物为白色固体，产率为71％。 1H NMR(400MHz,DMSO-d 6)δ8.82(d,J＝8.6Hz,1H),8.11(d,J＝4.6Hz,1H),7.81-7.72(m,2H),7.63-7.52(m,3H),7.45(t,J＝7.6Hz,2H),7.40(s,1H),7.38-7.32(m,2H),7.29(d,J＝7.9Hz,1H),7.20(t,J＝7.8Hz,1H),7.08(m,2H),5.64(d,J＝15.0Hz,1H),5.54(d,J＝14.9Hz,1H),4.62(m,1H),3.11(dd,J 1＝13.7,J 2＝4.4Hz,1H),2.92(m,1H),2.63(d,J＝4.5Hz,3H). 13C NMR(101MHz,DMSO-d 6)δ170.96,159.04,149.24,141.04,140.30,136.58,136.23,136.00,132.35,132.08,130.72,130.35,129.35,129.04,128.29,128.22,126.81,125.12,121.49,105.11,94.82,54.28,53.03,48.72,36.99,25.80. Other conditions were the same as in Example 1, except that benzyl chloride was changed to 3-iodobenzyl chloride, and the product was a white solid with a yield of 71%. 1 H NMR (400MHz, DMSO-d 6 ) δ8.82(d, J=8.6Hz, 1H), 8.11(d, J=4.6Hz, 1H), 7.81-7.72(m, 2H), 7.63-7.52( m,3H),7.45(t,J=7.6Hz,2H),7.40(s,1H),7.38-7.32(m,2H),7.29(d,J=7.9Hz,1H),7.20(t,J =7.8Hz,1H),7.08(m,2H),5.64(d,J=15.0Hz,1H),5.54(d,J=14.9Hz,1H),4.62(m,1H),3.11(dd,J 1 ＝13.7, J 2 ＝4.4Hz, 1H), 2.92(m, 1H), 2.63(d, J＝4.5Hz, 3H). 13 C NMR(101MHz, DMSO-d 6 )δ170.96, 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.
实施例34：
Figure PCTCN2022132704-appb-000044
Example 34:
Figure PCTCN2022132704-appb-000044
(S)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-1-(2-硝基苄基)-3-苯基-1H-吡唑-5-甲酰胺H 34的制备 (S)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-1-(2-nitrobenzyl)-3-phenyl - Preparation of 1H-pyrazole-5-carboxamide H 34
其他条件同实施例1，将氯化苄改为2-硝基氯化苄，产物为白色固体，产率为71％。 1H NMR(400MHz,DMSO-d 6)δ8.83(d,J＝8.7Hz,1H),8.08(dd,J 1＝8.0,J 2＝1.5Hz,2H),7.82-7.74(m,2H),7.58(m,1H),7.55-7.49(m,3H),7.46(t,J＝7.6Hz, 2H),7.38-7.32(m,2H),7.26(d,J＝7.6Hz,1H),7.17(t,J＝7.8Hz,1H),6.64(dd,J 1＝7.8,J 2＝1.5Hz,1H),6.05(d,J＝16.6Hz,1H),5.93(d,J＝16.6Hz,1H),4.55(ddd,J 1＝10.5,J 2＝8.6,J 3＝4.5Hz,1H),3.09(dd,J 1＝13.6,J 2＝4.5Hz,1H),2.90(m,1H),2.61(d,J＝4.5Hz,3H). 13C NMR(101MHz,DMSO-d 6)δ170.79,158.63,149.47,147.34,140.93,136.89,134.13,133.28,132.20,132.00,130.22,129.24,128.99,128.64,128.24,125.09,124.73,121.37,105.23,54.11,51.42,36.95,25.67. Other conditions were the same as in Example 1, except that benzyl chloride was changed to 2-nitrobenzyl chloride, and the product was a white solid with a yield of 71%. 1 H NMR (400MHz, DMSO-d 6 ) δ8.83 (d, J=8.7Hz, 1H), 8.08 (dd, J 1 =8.0, J 2 =1.5Hz, 2H), 7.82-7.74 (m, 2H ),7.58(m,1H),7.55-7.49(m,3H),7.46(t,J＝7.6Hz, 2H),7.38-7.32(m,2H),7.26(d,J＝7.6Hz,1H) ,7.17(t,J=7.8Hz,1H),6.64(dd, J1 =7.8, J2 =1.5Hz,1H),6.05(d,J=16.6Hz,1H),5.93(d,J=16.6 Hz, 1H), 4.55(ddd, J 1 =10.5, J 2 =8.6, J 3 =4.5Hz, 1H), 3.09(dd, J 1 =13.6, J 2 =4.5Hz, 1H), 2.90(m, 1H), 2.61 (d, J=4.5Hz, 3H). 13 C NMR (101MHz, DMSO-d 6 ) δ170.79, 158.63, 149.47, 147.34, 140.93, 136.89, 134.13, 133.28, 132.20, 132.00, 130.22, 1 29.24, 128.99, 128.64, 128.24, 125.09, 124.73, 121.37, 105.23, 54.11, 51.42, 36.95, 25.67.
实施例35：
Figure PCTCN2022132704-appb-000045
Example 35:
Figure PCTCN2022132704-appb-000045
(S)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-1-(3-硝基苄基)-3-苯基-1H-吡唑-5-甲酰胺H 35的制备 (S)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-1-(3-nitrobenzyl)-3-phenyl - Preparation of 1H-pyrazole-5-carboxamide H 35
其他条件同实施例1，将氯化苄改为3-硝基氯化苄，产物为白色固体，产率为70％。 1H NMR(300MHz,DMSO-d 6)δ8.85(d,J＝8.7Hz,1H),8.14-8.10(m,2H),8.02(d,J＝1.6Hz,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＝7.7Hz,1H),5.85-5.69(m,2H),4.65-4.57(m,1H),3.10(dd,J＝13.6,4.4Hz,1H),2.91(dd,J＝13.6,10.7Hz,1H),2.62(d,J＝4.5Hz,3H). 13C NMR(75MHz,DMSO-d 6)δ170.8,158.9,149.3,147.7,141.0,139.9,136.6,134.0,132.2,132.0,130.2,130.0,129.2,129.0,128.2,125.1,122.4,122.0,121.4,105.2,54.2,53.1,36.9,25.6.HRMS(ESI,m/z):Calcd.for C 27H 24BrN 5O 4[M+Na] +584.0909,found:584.0900. Other conditions were the same as in Example 1, except that benzyl chloride was changed to 3-nitrobenzyl chloride, and the product was a white solid with a yield of 70%. 1 H NMR (300MHz, DMSO-d 6 ) δ8.85(d, J=8.7Hz, 1H), 8.14-8.10(m, 2H), 8.02(d, J=1.6Hz, 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＝7.7Hz,1H),5.85-5.69(m, 2H), 4.65-4.57(m, 1H), 3.10(dd, J＝13.6, 4.4Hz, 1H), 2.91(dd, J＝13.6, 10.7Hz, 1H), 2.62(d, J＝4.5Hz, 3H ). 13 C NMR (75MHz, DMSO-d 6 ) δ170.8, 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 BrN 5 O 4 [M+Na] + 584.0909,found:584.0900.
实施例36：
Figure PCTCN2022132704-appb-000046
Example 36:
Figure PCTCN2022132704-appb-000046
(S)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-1-(4-硝基苄基)-3-苯基-1H-吡唑-5-甲酰胺H 36的制备 (S)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-1-(4-nitrobenzyl)-3-phenyl - Preparation of 1H-pyrazole-5-carboxamide H 36
其他条件同实施例1，将氯化苄改为4-硝基氯化苄，产物为白色固体，产率为72％。 1H NMR(300MHz,DMSO-d 6):δ8.83(d,J＝8.7Hz,1H),8.09-8.06(m,2H),7.78-7.76(m,2H),7.62-7.43(m,6H),7.36(t,J＝7.3Hz,2H),7.26(d,J＝7.7Hz,1H),7.17(t,J＝7.7Hz,1H),6.65-6.62(m,1H),6.07-5.89(m,2H),4.55(ddd,J＝10.4,8.6,4.5Hz,1H),3.09(dd,J＝13.6,4.5Hz,1H),2.90(dd,J＝13.6,10.5Hz,1H), 2.60(d,J＝4.5Hz,3H). 13C NMR(75MHz,DMSO-d 6):δ170.7,158.6,149.4,147.3,140.9,136.9,134.1,133.3,132.3,132.0130.2,129.2,129.0,128.6,128.2,125.1,124.7,121.3,105.2,54.1,51.4,36.9,25.6. Other conditions were the same as in Example 1, except that benzyl chloride was changed to 4-nitrobenzyl chloride, and the product was a white solid with a yield of 72%. 1 H NMR (300MHz, DMSO-d 6 ): δ8.83 (d, J=8.7Hz, 1H), 8.09-8.06 (m, 2H), 7.78-7.76 (m, 2H), 7.62-7.43 (m, 6H), 7.36(t, J=7.3Hz, 2H), 7.26(d, J=7.7Hz, 1H), 7.17(t, J=7.7Hz, 1H), 6.65-6.62(m, 1H), 6.07- 5.89(m,2H),4.55(ddd,J=10.4,8.6,4.5Hz,1H),3.09(dd,J=13.6,4.5Hz,1H),2.90(dd,J=13.6,10.5Hz,1H) , 2.60(d,J＝4.5Hz,3H). 13 C NMR(75MHz,DMSO-d 6 ):δ170.7,158.6,149.4,147.3,140.9,136.9,134.1,133.3,132.3,132.0130.2,129.2,129.0,128 .6 ,128.2,125.1,124.7,121.3,105.2,54.1,51.4,36.9,25.6.
实施例37：
Figure PCTCN2022132704-appb-000047
Example 37:
Figure PCTCN2022132704-appb-000047
(S)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-1-(2-氰基苄基)-3-苯基-1H-吡唑-5-甲酰胺H 37的制备 (S)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-1-(2-cyanobenzyl)-3-phenyl - Preparation of 1H-pyrazole-5-carboxamide H 37
其他条件同实施例1，将氯化苄改为2-氰基氯化苄，产物为白色固体，产率为74％。 1H NMR(400MHz,DMSO-d 6)δ8.84(d,J＝8.7Hz,1H),8.09(q,J＝4.6Hz,1H),7.86-7.72(m,3H),7.58-7.41(m,6H),7.35(m,2H),7.28(d,J＝7.8Hz,1H),7.18(t,J＝7.8Hz,1H),6.85(d,J＝7.9Hz,1H),5.91(d,J＝15.7Hz,1H),5.79(d,J＝15.7Hz,1H),4.61(ddd,J 1＝10.5,J 2＝8.6,J 3＝4.4Hz,1H),3.11(dd,J 1＝13.6,J 2＝4.5Hz,1H),2.91(m,1H),2.62(d,J＝4.5Hz,3H). 13C NMR(101MHz,DMSO-d 6)δ170.94,158.87,149.52,141.21,141.01,136.77,133.63,133.06,132.23,132.08,130.34,129.33,129.07,128.34,127.43,125.16,121.46,117.32,110.44,105.24,54.22,52.23,37.01,25.78. Other conditions were the same as in Example 1, except that benzyl chloride was changed to 2-cyanobenzyl chloride, and the product was a white solid with a yield of 74%. 1 H NMR (400MHz, DMSO-d 6 ) δ8.84 (d, J = 8.7Hz, 1H), 8.09 (q, J = 4.6Hz, 1H), 7.86-7.72 (m, 3H), 7.58-7.41 ( m, 6H), 7.35(m, 2H), 7.28(d, J=7.8Hz, 1H), 7.18(t, J=7.8Hz, 1H), 6.85(d, J=7.9Hz, 1H), 5.91( d, J = 15.7Hz, 1H), 5.79 (d, J = 15.7Hz, 1H), 4.61 (ddd, J 1 = 10.5, J 2 = 8.6, J 3 = 4.4Hz, 1H), 3.11 (dd, J 1 ＝13.6, J 2 ＝4.5Hz, 1H), 2.91(m, 1H), 2.62(d, J＝4.5Hz, 3H). 13 C NMR(101MHz, DMSO-d 6 )δ170.94, 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.
实施例38：
Figure PCTCN2022132704-appb-000048
Example 38:
Figure PCTCN2022132704-appb-000048
(S)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-1-(4-氰基苄基)-3-苯基-1H-吡唑-5-甲酰胺H 38的制备 (S)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-1-(4-cyanobenzyl)-3-phenyl - Preparation of 1H-pyrazole-5-carboxamide H 38
其他条件同实施例1，将氯化苄改为4-氰基氯化苄，产物为白色固体，产率为73％。 1H NMR(300MHz,DMSO-d 6)δ8.84(d,J＝8.6Hz,1H),8.11(d,J＝4.7Hz,1H),7.95-7.89(m,4H),7.56(s,1H),7.52(s,1H),7.37(d,J＝7.8,2.1Hz,1H),7.31-7.18(m,5H),7.12(dd,J＝7.6,2.0Hz,2H),5.74-5.57(m,2H),4.65(dq,J＝10.5,4.5Hz,1H),3.11(dd,J＝13.6,4.5Hz,1H),2.91(dd,J＝13.6,10.6Hz,1H),2.63(d,J＝4.6Hz,3H). 13C NMR(101MHz,DMSO-d 6)δ170.83,158.82,149.32,143.36, 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. Other conditions were the same as in Example 1, except that benzyl chloride was changed to 4-cyanobenzyl chloride, and the product was a white solid with a yield of 73%. 1 H NMR (300MHz, DMSO-d 6 )δ8.84(d, J=8.6Hz, 1H), 8.11(d, J=4.7Hz, 1H), 7.95-7.89(m, 4H), 7.56(s, 1H),7.52(s,1H),7.37(d,J=7.8,2.1Hz,1H),7.31-7.18(m,5H),7.12(dd,J=7.6,2.0Hz,2H),5.74-5.57 (m,2H),4.65(dq,J=10.5,4.5Hz,1H),3.11(dd,J=13.6,4.5Hz,1H),2.91(dd,J=13.6,10.6Hz,1H),2.63( d, J＝4.6Hz, 3H). 13 C NMR (101MHz, DMSO-d 6 ) δ170.83, 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.
实施例39：
Figure PCTCN2022132704-appb-000049
Example 39:
Figure PCTCN2022132704-appb-000049
(S)-N-(3-(3-溴苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-1-(3-甲基苄基)-3-(间甲苯基)-1H-吡唑-5-甲酰胺H 39的制备 (S)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-1-(3-methylbenzyl)-3-( Preparation of m-tolyl)-1H-pyrazole-5-carboxamide H 39
其他条件同实施例1，将苯乙酮改为3-甲基苯乙酮，氯化苄改为3-甲基氯化苄，得到30mg白色固体化合物，产率为34％。 1H NMR(300MHz,DMSO-d 6)：δ8.78(d,J＝8.5Hz,1H),8.11(d,J＝4.4Hz,1H),7.56(d,J＝14.6Hz,3H),7.39-7.30(m,4H),7.23-7.12(m,3H),7.03(d,J＝7.3Hz,1H),6.95(s,1H),6.88(d,J＝7.5Hz,1H),5.66-5.54(m,2H),4.63(dq,J＝9.0,4.5Hz,1H),3.10(dd,J＝13.6,4.1Hz,1H),2.93(t,J＝12.0Hz,1H),2.63(d,J＝4.4Hz,3H),2.35(s,3H),2.22(s,3H). 13C NMR(75MHz,DMSO-d 6)：δ170.9,159.1,148.9,141.1,138.0,137.7,137.5136.4,132.4,132.0,130.3,129.2,128.8,128.6,128.3,128.2,128.0,127.9,125.5,124.4,122.2,121.4,105.0,54.2,53.6,36.9,25.7,21.1,21.0.HRMS(ESI,m/z):Calcd.for C 29H 29BrN 4O 2[M+Na] +631.0320,found:631.0313. Other conditions were the same as in Example 1, except that 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 (300MHz, DMSO-d 6 ): δ8.78(d, J=8.5Hz, 1H), 8.11(d, J=4.4Hz, 1H), 7.56(d, J=14.6Hz, 3H), 7.39-7.30(m,4H),7.23-7.12(m,3H),7.03(d,J=7.3Hz,1H),6.95(s,1H),6.88(d,J=7.5Hz,1H),5.66 -5.54(m,2H),4.63(dq,J=9.0,4.5Hz,1H),3.10(dd,J=13.6,4.1Hz,1H),2.93(t,J=12.0Hz,1H),2.63( d, J=4.4Hz, 3H), 2.35(s, 3H), 2.22(s, 3H). 13 C NMR (75MHz, DMSO-d 6 ): δ170.9, 159.1, 148.9, 141.1, 138.0, 137.7, 137.5136. 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 BrN 4 O 2 [M+Na] + 631.0320, found: 631.0313.
实施例40：
Figure PCTCN2022132704-appb-000050
Example 40:
Figure PCTCN2022132704-appb-000050
(S)-N-(3-(3-溴苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-1-(4-甲基苄基)-3-(间甲苯基)-1H-吡唑-5-甲酰胺H 40的制备 (S)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-1-(4-methylbenzyl)-3-( Preparation of m-tolyl)-1H-pyrazole-5-carboxamide H 40
其他条件同实施例1，将苯乙酮改为3-甲基苯乙酮，氯化苄改为4-甲基氯化苄，产物为白色固体，产率为73％。 1H NMR(300MHz,DMSO-d 6)：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). 13C NMR(75MHz,DMSO-d 6)：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. Other conditions were the same as in Example 1, except that acetophenone was changed to 3-methylacetophenone, benzyl chloride was changed to 4-methylbenzyl chloride, and the product was a white solid with a yield of 73%. 1 H NMR (300MHz, DMSO-d 6 ): 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-d 6 ): 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.
实施例41：
Figure PCTCN2022132704-appb-000051
Example 41:
Figure PCTCN2022132704-appb-000051
(S)-1-(3-溴苄基)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-3-(间甲苯基)-1H-吡唑-5-甲酰胺H 41的制备 (S)-1-(3-bromobenzyl)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-(m-toluene Base)-1H-pyrazole-5-carboxamide H 41 Preparation
其他条件同实施例1，将苯乙酮改为3-甲基苯乙酮，氯化苄改为3-溴氯化苄，产物为白色固体，产率为73％。 1H NMR(300MHz,DMSO-d 6)δ8.83(d,J＝8.6Hz,1H),8.13(q,J＝4.5Hz,1H),7.66(t,J＝8.2Hz,3H),7.45-7.42(m,2H),7.38-7.15(m,7H),7.08(d,J＝7.9Hz,1H),5.71-5.55(m,2H),4.62(ddd,J＝10.4,8.5,4.4Hz,1H),3.11(dd,J＝13.6,4.4Hz,1H),2.93(dd,J＝13.5,10.7Hz,1H),2.63(d,J＝4.6Hz,3H),2.35(s,3H). 13C NMR(75MHz,DMSO-d 6)δ170.8,158.9,149.2,141.0,140.4,138.0,136.4,132.2,132.0,130.6,130.2,130.0,129.2,128.9,128.8,128.2,126.3,125.6,122.2,121.6,121.4,105.1,54.2,53.0,36.9,25.7,21.1. Other conditions were the same as in Example 1, except that acetophenone was changed to 3-methylacetophenone, benzyl chloride was changed to 3-bromobenzyl chloride, and the product was a white solid with a yield of 73%. 1 H NMR (300MHz, DMSO-d 6 )δ8.83(d, J=8.6Hz, 1H), 8.13(q, J=4.5Hz, 1H), 7.66(t, J=8.2Hz, 3H), 7.45 -7.42(m,2H),7.38-7.15(m,7H),7.08(d,J=7.9Hz,1H),5.71-5.55(m,2H),4.62(ddd,J=10.4,8.5,4.4Hz ,1H),3.11(dd,J=13.6,4.4Hz,1H),2.93(dd,J=13.5,10.7Hz,1H),2.63(d,J=4.6Hz,3H),2.35(s,3H) . 13 C NMR (75MHz, DMSO-d 6 ) δ170.8, 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.
实施例42：
Figure PCTCN2022132704-appb-000052
Example 42:
Figure PCTCN2022132704-appb-000052
(S)-1-(4-溴苄基)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-3-(间甲苯基)-1H-吡唑-5-甲酰胺H 42的制备 (S)-1-(4-bromobenzyl)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-(m-toluene Base)-1H-pyrazole-5-carboxamide H 42 Preparation
其他条件同实施例1，将苯乙酮改为3-甲基苯乙酮，氯化苄改为4-溴氯化苄，产物为白色固体，产率为73％。 1H NMR(300MHz,DMSO-d 6)δ8.79(d,J＝8.6Hz,1H),8.11(d,J＝4.6Hz,1H),7.56(t,J＝8.7Hz,3H),7.47-7.42(m,3H),7.38-7.28(m,3H),7.22-7.14(m,2H),7.06(d,J＝8.4Hz,2H),5.69-5.51(m,2H),4.62(ddd,J＝10.6,8.6,4.4Hz,1H),3.11(dd,J＝13.6,4.4Hz,1H),2.92(dd,J＝13.0,10.1Hz,1H),2.62(d,J＝4.5Hz,3H),2.35(s,3H). 13C NMR(75MHz,DMSO-d 6)δ171.3,159.4,149.6,141.5,138.5,137.6,136.8,132.7,132.4,131.7,130.7,130.0,129.7,129.3,129.2,128.7,126.0,122.6,121.8,121.0,105.5,54.6,53.6,37.4,26.1,21.5. Other conditions were the same as in Example 1, except that acetophenone was changed to 3-methylacetophenone, benzyl chloride was changed to 4-bromobenzyl chloride, and the product was a white solid with a yield of 73%. 1 H NMR (300MHz, DMSO-d 6 ) δ8.79(d, J=8.6Hz, 1H), 8.11(d, J=4.6Hz, 1H), 7.56(t, J=8.7Hz, 3H), 7.47 -7.42(m,3H),7.38-7.28(m,3H),7.22-7.14(m,2H),7.06(d,J＝8.4Hz,2H),5.69-5.51(m,2H),4.62(ddd ,J=10.6,8.6,4.4Hz,1H),3.11(dd,J=13.6,4.4Hz,1H),2.92(dd,J=13.0,10.1Hz,1H),2.62(d,J=4.5Hz, 3H),2.35(s,3H). 13 C NMR(75MHz,DMSO-d 6 )δ171.3,159.4,149.6,141.5,138.5,137.6,136.8,132.7,132.4,131.7,130.7,130.0,129.7,129.3,12 9.2 ,128.7,126.0,122.6,121.8,121.0,105.5,54.6,53.6,37.4,26.1,21.5.
实施例43：
Figure PCTCN2022132704-appb-000053
Example 43:
Figure PCTCN2022132704-appb-000053
(S)-1-(3-溴苄基)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-3-(4-氟苯基)-1H-吡唑-5-甲酰胺H 43的制备 (S)-1-(3-bromobenzyl)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-(4- Preparation of fluorophenyl)-1H-pyrazole-5-carboxamide H 43
其他条件同实施例1，将苯乙酮改为4-氟苯乙酮，氯化苄改为3-溴氯化苄，产物为白色固体，产率为73％。 1H NMR(400MHz,DMSO-d 6)δ8.83(d,J＝8.6Hz,1H),8.12(q,J＝4.6Hz,1H),7.79(dd,J 1＝8.6,J 2＝5.7Hz,2H),7.56(s,1H),7.45-7.33(m,4H),7.32-7.17(m,5H),7.09(d,J＝7.7Hz,1H),5.67(d,J＝15.1Hz,1H),5.57(d,J＝15.0Hz,1H),4.63(ddd,J 1＝10.6,J 2＝8.5,J 3＝4.4Hz,1H),3.11(dd,J 1＝13.6,J 2＝4.5Hz,1H),2.92(m,1H),2.63(d,J＝4.5Hz,3H). 13C NMR(101MHz,DMSO-d 6)δ170.87,158.93,148.34,140.99,140.33,136.66,132.03,130.66,130.35,130.28,130.11,129.29,128.25,127.14,127.06,126.41,121.63,121.44,116.02,115.81,104.98,54.23,53.10,36.96,25.72. Other conditions were the same as in Example 1, except that acetophenone was changed to 4-fluoroacetophenone, benzyl chloride was changed to 3-bromobenzyl chloride, and the product was a white solid with a yield of 73%. 1 H NMR (400MHz, DMSO-d 6 ) δ8.83 (d, J = 8.6Hz, 1H), 8.12 (q, J = 4.6Hz, 1H), 7.79 (dd, J 1 = 8.6, J 2 = 5.7 Hz, 2H), 7.56(s, 1H), 7.45-7.33(m, 4H), 7.32-7.17(m, 5H), 7.09(d, J=7.7Hz, 1H), 5.67(d, J=15.1Hz ,1H),5.57(d,J=15.0Hz,1H),4.63(ddd,J 1 =10.6,J 2 =8.5,J 3 =4.4Hz,1H),3.11(dd,J 1 =13.6,J 2 =4.5Hz, 1H), 2.92(m, 1H), 2.63(d, J=4.5Hz, 3H). 13 C NMR (101MHz, DMSO-d 6 ) δ170.87, 158.93, 148.34, 140.99, 140.33, 136.66, 132.03 ,130.66,130.35,130.28,130.11,129.29,128.25,127.14,127.06,126.41,121.63,121.44,116.02,115.81,104.98,54.23,53.10,36.96,25.7 2.
实施例44：
Figure PCTCN2022132704-appb-000054
Example 44:
Figure PCTCN2022132704-appb-000054
(S)-1-(3-溴苄基)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-3-(2-氯苯基)-1H-吡唑-5-甲酰胺H 44的制备 (S)-1-(3-bromobenzyl)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-(2- Preparation of chlorophenyl)-1H-pyrazole-5-carboxamide H44
其他条件同实施例1，将苯乙酮改为2-氯苯乙酮，氯化苄改为3-溴氯化苄，产物为白色固体，产率为73％。 1H NMR(400MHz,DMSO-d 6)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,J 1＝7.7,J 2＝1.3Hz,1H),7.24(t,J＝7.8Hz,1H),7.19(t,J＝7.8Hz,1H),7.11(dt,J 1＝7.9,J 2＝1.3Hz,1H),5.67(q,J＝14.9Hz,2H),4.63(ddd,J 1＝10.7,J 2＝8.6,J 3＝4.4Hz,1H),3.10(dd,J 1＝13.6,J 2＝4.4Hz,1H),2.94(m,1H),2.63(d,J＝4.6Hz,3H). 13C NMR(101MHz,DMSO-d 6)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. Other conditions were the same as in Example 1, except that acetophenone was changed to 2-chloroacetophenone, benzyl chloride was changed to 3-bromobenzyl chloride, and the product was a white solid with a yield of 73%. 1 H NMR (400MHz, DMSO-d 6 ) 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,J 1 =7.7,J 2 =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, J 1 = 10.7, J 2 = 8.6, J 3 = 4.4Hz, 1H), 3.10 (dd, J 1 = 13.6, J 2 = 4.4Hz, 1H), 2.94 (m, 1H), 2.63 (d, J = 4.6 Hz,3H). 13 C NMR(101MHz,DMSO-d 6 )δ170.90,158.85,146.71,141.07,140.20,135.63,131.99,131.05,131.00,130.62,130.38,130.33,130.18,12 9.70, 129.24, 128.22, 127.47, 126.46, 121.60, 121.39, 108.68, 54.26, 53.16, 36.77, 25.68.
实施例45：
Figure PCTCN2022132704-appb-000055
Example 45:
Figure PCTCN2022132704-appb-000055
(S)-1-(3-溴苄基)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-3-(3-氯苯基)-1H-吡唑-5-甲酰胺H 45的制备 (S)-1-(3-bromobenzyl)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-(3- Preparation of Chlorophenyl)-1H-pyrazole-5-carboxamide H 45
其他条件同实施例1，将苯乙酮改为3-氯苯乙酮，氯化苄改为3-溴氯化苄，产物为白色固体，产率为73％。 1H NMR(400MHz,DMSO-d 6)δ8.81(d,J＝8.6Hz,1H),8.12(q,J＝4.5Hz,1H),7.78(t,J＝1.9Hz,1H),7.72(dt,J 1＝7.9,J 2＝1.4Hz,1H),7.56(t,J＝1.8Hz,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,J 1＝15.6,J 2＝7.8Hz,2H),7.11-7.07(m,1H),5.73-5.54(m,2H),4.64(ddd,J 1＝10.5,J 2＝8.6,J 3＝4.5Hz,1H),3.11(dd,J 1＝13.6,J 2＝4.5Hz,1H),2.92(m,1H),2.63(d,J＝4.5Hz,3H). 13C NMR(101MHz,DMSO-d 6)δ170.76,158.77,147.75,140.92,140.15,136.74,134.36,133.75,132.01,130.99,130.65,130.36,130.26,130.10,129.26,128.22,127.89,126.40,124.61,123.58,121.61,121.40,105.49,54.19,53.19,25.68. Other conditions were the same as in Example 1, except that acetophenone was changed to 3-chloroacetophenone, benzyl chloride was changed to 3-bromobenzyl chloride, and the product was a white solid with a yield of 73%. 1 H NMR (400MHz, DMSO-d 6 ) δ8.81(d, J=8.6Hz, 1H), 8.12(q, J=4.5Hz, 1H), 7.78(t, J=1.9Hz, 1H), 7.72 (dt, J 1 =7.9, J 2 =1.4Hz, 1H), 7.56(t, J=1.8Hz, 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,J 1 =15.6,J 2 =7.8Hz,2H),7.11-7.07(m,1H),5.73-5.54(m,2H),4.64 (ddd, J 1 =10.5, J 2 =8.6, J 3 =4.5Hz, 1H), 3.11(dd, J 1 =13.6, J 2 =4.5Hz, 1H), 2.92(m, 1H), 2.63(d , J＝4.5Hz, 3H). 13 C NMR (101MHz, DMSO-d 6 ) δ170.76, 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.
实施例46：
Figure PCTCN2022132704-appb-000056
Example 46:
Figure PCTCN2022132704-appb-000056
(S)-1-(3-溴苄基)-3-(2-溴苯基)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-1H-吡唑-5-甲酰胺H 46的制备 (S)-1-(3-bromobenzyl)-3-(2-bromophenyl)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropane- Preparation of 2-yl)-1H-pyrazole-5-carboxamide H46
其他条件同实施例1，将苯乙酮改为2-溴苯乙酮，氯化苄改为3-溴氯化苄，产物为白色固体，产率为73％。 1H NMR(400MHz,DMSO-d 6)：δ8.92(d,J＝8.6Hz,1H),8.12(q,J＝4.5Hz,1H),7.74(dd,J 1＝8.0,J 2＝1.2Hz,1H),7.65(dd,J 1＝7.8,J 2＝1.8Hz,1H),7.55(t,J＝1.8Hz,1H),7.48-7.42(m,3H),7.39-7.28(m,4H),7.25(t,J＝7.8Hz,1H),7.19(t,J＝7.8Hz,1H),7.12(dt,J 1＝7.9,J 2＝1.3Hz,1H),5.66(q,J＝15.0Hz,2H),4.62(ddd,J 1＝10.7,J 2＝8.5,J 3＝4.4Hz,1H),3.09(dd,J 1＝13.6,J 2＝4.4Hz,1H),2.93(m,1H),2.63(d,J＝4.5Hz,3H). 13C NMR(101MHz,DMSO-d 6)： δ170.91,158.86,148.33,141.07,140.23,135.46,133.56,133.32,131.99,131.01,130.62,130.33,130.18,130.03,129.26,128.24,127.97,126.46,121.61,121.40,121.09,108.56,54.30,25.69. Other conditions were the same as in Example 1, except that acetophenone was changed to 2-bromoacetophenone, benzyl chloride was changed to 3-bromobenzyl chloride, and the product was a white solid with a yield of 73%. 1 H NMR (400MHz, DMSO-d 6 ): δ8.92 (d, J = 8.6Hz, 1H), 8.12 (q, J = 4.5Hz, 1H), 7.74 (dd, J 1 = 8.0, J 2 = 1.2Hz, 1H), 7.65(dd, J 1 ＝7.8, J 2 ＝1.8Hz, 1H), 7.55(t, J＝1.8Hz, 1H), 7.48-7.42(m, 3H), 7.39-7.28(m ,4H),7.25(t,J=7.8Hz,1H),7.19(t,J=7.8Hz,1H),7.12(dt,J 1 =7.9,J 2 =1.3Hz,1H),5.66(q, J=15.0Hz, 2H), 4.62 (ddd, J 1 =10.7, J 2 =8.5, J 3 =4.4Hz, 1H), 3.09 (dd, J 1 =13.6, J 2 =4.4Hz, 1H), 2.93 (m, 1H), 2.63 (d, J=4.5Hz, 3H). 13 C NMR (101MHz, DMSO-d 6 ): δ170.91, 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.
实施例47：
Figure PCTCN2022132704-appb-000057
Example 47:
Figure PCTCN2022132704-appb-000057
(S)-1-(3-溴苄基)-3-(3-溴苯基)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-1H-吡唑-5-甲酰胺H 47的制备 (S)-1-(3-bromobenzyl)-3-(3-bromophenyl)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropane- Preparation of 2-yl)-1H-pyrazole-5-carboxamide H47
其他条件同实施例1，将苯乙酮改为3-溴苯乙酮，氯化苄改为3-溴氯化苄，产物为白色固体，产率为73％。 1H NMR(400MHz,DMSO-d 6)δ8.80(d,J＝8.7Hz,1H),8.11(q,J＝4.5Hz,1H),7.92(t,J＝1.8Hz,1H),7.76(dt,J＝7.8,1.3Hz,1H),7.55(m,2H),7.49(s,1H),7.46-7.40(m,2H),7.36(m,2H),7.29(dt,J 1＝7.7,J 2＝1.4Hz,1H),7.22(dt,J 1＝15.8,J 2＝7.8Hz,2H),7.11-7.07(m,1H),5.68(d,J＝15.0Hz,1H),5.58(d,J＝15.0Hz,1H),4.63(ddd,J 1＝10.4,J 2＝8.5,J 3＝4.5Hz,1H),3.11(dd,J 1＝13.6,J 2＝4.5Hz,1H),2.91(m,1H),2.63(d,J＝4.5Hz,3H). 13C NMR(101MHz,DMSO-d 6)δ170.74,158.74,147.63,140.91,140.15,136.72,134.57,132.01,131.26,130.78,130.65,130.36,130.26,130.09,129.25,128.21,127.48,126.39,123.93,122.31,121.60,121.39,105.48,54.17,53.17,36.98,25.67. Other conditions were the same as in Example 1, except that acetophenone was changed to 3-bromoacetophenone, benzyl chloride was changed to 3-bromobenzyl chloride, and the product was a white solid with a yield of 73%. 1 H NMR (400MHz, DMSO-d 6 ) δ8.80(d, J=8.7Hz, 1H), 8.11(q, J=4.5Hz, 1H), 7.92(t, J=1.8Hz, 1H), 7.76 (dt,J=7.8,1.3Hz,1H),7.55(m,2H),7.49(s,1H),7.46-7.40(m,2H),7.36(m,2H),7.29(dt,J 1 = 7.7, J 2 ＝1.4Hz, 1H), 7.22(dt, J 1 ＝15.8, J 2 ＝7.8Hz, 2H), 7.11-7.07(m, 1H), 5.68(d, J＝15.0Hz, 1H), 5.58(d, J=15.0Hz, 1H), 4.63(ddd, J 1 ＝10.4, J 2 ＝8.5, J 3 ＝4.5Hz, 1H), 3.11(dd, J 1 ＝13.6, J 2 ＝4.5Hz, 1H),2.91(m,1H),2.63(d,J=4.5Hz,3H). 13 C NMR(101MHz,DMSO-d 6 )δ170.74,158.74,147.63,140.91,140.15,136.72,134.57,132.01,131.26 ,130.78,130.65,130.36,130.26,130.09,129.25,128.21,127.48,126.39,123.93,122.31,121.60,121.39,105.48,54.17,53.17,36.98,25.6 7.
实施例48：
Figure PCTCN2022132704-appb-000058
Example 48:
Figure PCTCN2022132704-appb-000058
(S)-1-(3-溴苄基)-3-(4-溴苯基)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-1H-吡唑-5-甲酰胺H 48的制备 (S)-1-(3-bromobenzyl)-3-(4-bromophenyl)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropane- Preparation of 2-yl)-1H-pyrazole-5-carboxamide H48
其他条件同实施例1，将苯乙酮改为4-溴苯乙酮，氯化苄改为3-溴氯化苄，产物为白色固体，产率为73％。 1H NMR(400MHz,DMSO-d 6)δ8.84(d,J＝8.6Hz,1H),8.11(q,J＝4.5Hz,1H),7.71(d,J＝8.5Hz,2H),7.65(d,J＝8.6Hz,2H),7.56(t,J＝1.8Hz,1H),7.44(m,2H),7.38-7.33(m,2H),7.29(d,J＝7.6Hz,1H),7.22(dt,J 1＝15.5,J 2＝7.8Hz,2H),7.09(d,J＝7.7Hz,1H),5.68(d,J＝14.9Hz,1H),5.57(d,J＝15.0Hz,1H),4.63(ddd,J 1＝10.6,J 2＝8.6,J 3＝4.5Hz,1H),3.11(dd,J 1＝13.7,J 2＝ 4.5Hz,1H),2.92(m,1H),2.63(d,J＝4.5Hz,3H). 13C NMR(101MHz,DMSO-d 6)δ170.79,158.82,148.09,140.96,140.20,136.71,132.00,131.94,131.51,130.64,130.35,130.24,130.11,129.25,128.21,127.02,126.41,121.60,121.40,121.18,105.19,54.20,53.13,36.94,25.68. Other conditions were the same as in Example 1, except that acetophenone was changed to 4-bromoacetophenone, benzyl chloride was changed to 3-bromobenzyl chloride, and the product was a white solid with a yield of 73%. 1 H NMR (400MHz, DMSO-d 6 )δ8.84(d, J=8.6Hz, 1H), 8.11(q, J=4.5Hz, 1H), 7.71(d, J=8.5Hz, 2H), 7.65 (d, J=8.6Hz, 2H), 7.56(t, J=1.8Hz, 1H), 7.44(m, 2H), 7.38-7.33(m, 2H), 7.29(d, J=7.6Hz, 1H) ,7.22(dt,J 1 =15.5,J 2 =7.8Hz,2H),7.09(d,J=7.7Hz,1H),5.68(d,J=14.9Hz,1H),5.57(d,J=15.0 Hz, 1H), 4.63(ddd, J 1 ＝10.6, J 2 ＝8.6, J 3 ＝4.5Hz, 1H), 3.11(dd, J 1 ＝13.7, J 2 ＝4.5Hz, 1H), 2.92(m, 1H), 2.63 (d, J=4.5Hz, 3H). 13 C NMR (101MHz, DMSO-d 6 ) δ170.79, 158.82, 148.09, 140.96, 140.20, 136.71, 132.00, 131.94, 131.51, 130.64, 130.35, 1 30.24, 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.
实施例49：
Figure PCTCN2022132704-appb-000059
Example 49:
Figure PCTCN2022132704-appb-000059
(S)-1-(3-溴苄基)-N-(3-(3-溴苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-3-(2-硝基苯基)-1H-吡唑-5-甲酰胺H 49的制备 (S)-1-(3-bromobenzyl)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-(2 Preparation of -nitrophenyl)-1H-pyrazole-5-carboxamide H49
其他条件同实施例1，将苯乙酮改为2-硝基苯乙酮，氯化苄改为3-溴氯化苄，产物为白色固体，产率为73％。 1H NMR(400MHz,DMSO-d 6)δ8.91(d,J＝8.6Hz,1H),8.11(q,J＝4.5Hz,1H),7.89(dd,J 1＝8.0,J 2＝1.1Hz,1H),7.79-7.71(m,2H),7.62(ddd,J 1＝8.5,J 2＝6.9,J 3＝2.0Hz,1H),7.53(t,J＝1.8Hz,1H),7.44(dt,J 1＝8.0,J 2＝1.5Hz,1H),7.36(dt,J 1＝8.0,J 2＝1.5Hz,1H),7.31-7.16(m,5H),7.05(d,J＝7.7Hz,1H),5.60(q,J＝15.0Hz,2H),4.60(ddd,J 1＝10.5,J 2＝8.5,J 3＝4.5Hz,1H),3.09(dd,J 1＝13.7,J 2＝4.6Hz,1H),2.90(m,1H),2.62(d,J＝4.5Hz,3H). 13C NMR(101MHz,DMSO-d 6)δ170.78,158.53,148.62,144.94,140.95,139.93,136.32,132.51,131.94,130.53,130.37,130.22,130.15,130.06,129.49,129.26,128.21,126.33,125.42,123.89,121.63,121.39,107.08,54.23,53.31,36.83,25.66. Other conditions were the same as in Example 1, except that acetophenone was changed to 2-nitroacetophenone, benzyl chloride was changed to 3-bromobenzyl chloride, and the product was a white solid with a yield of 73%. 1 H NMR (400MHz, DMSO-d 6 ) δ8.91 (d, J=8.6Hz, 1H), 8.11 (q, J=4.5Hz, 1H), 7.89 (dd, J 1 =8.0, J 2 =1.1 Hz, 1H), 7.79-7.71 (m, 2H), 7.62 (ddd, J 1 = 8.5, J 2 = 6.9, J 3 = 2.0Hz, 1H), 7.53 (t, J = 1.8Hz, 1H), 7.44 (dt, J 1 =8.0, J 2 =1.5Hz, 1H), 7.36(dt, J 1 =8.0, J 2 =1.5Hz, 1H), 7.31-7.16(m, 5H), 7.05(d, J= 7.7Hz, 1H), 5.60 (q, J = 15.0Hz, 2H), 4.60 (ddd, J 1 = 10.5, J 2 = 8.5, J 3 = 4.5Hz, 1H), 3.09 (dd, J 1 = 13.7, J 2 =4.6Hz,1H),2.90(m,1H),2.62(d,J=4.5Hz,3H). 13 C NMR(101MHz,DMSO-d 6 )δ170.78,158.53,148.62,144.94,140.95,139.93 ,136.32,132.51,131.94,130.53,130.37,130.22,130.15,130.06,129.49,129.26,128.21,126.33,125.42,123.89,121.63,121.39,107.08,5 4.23, 53.31, 36.83, 25.66.
实施例50：
Figure PCTCN2022132704-appb-000060
Example 50:
Figure PCTCN2022132704-appb-000060
(S)-1-(3-溴苄基)-N-(3-(3,5-二溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-3-苯基-1H-吡唑-5-甲酰胺H 50的制备 (S)-1-(3-bromobenzyl)-N-(3-(3,5-dibromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3- Preparation of phenyl-1H-pyrazole-5-carboxamide H 50
其他条件同实施例1，将氯化苄改为3-溴氯化苄，化合物(S)-2-氨基-3-(3-溴苯基)-N-甲基丙酰胺改为化合物(S)-2-氨基-3-(3,5-二溴苯基)-N-甲基丙酰胺，产物为白色固体，产率为76％。 1H NMR(400MHz,DMSO-d 6)δ8.84(d,J＝8.7Hz,1H),8.11(q,J＝4.6Hz,1H),7.78-7.75(m,2H),7.63(t,J＝1.8Hz,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＝7.8Hz,1H),7.08(d,J＝7.9Hz,1H),5.69(d,J＝15.0Hz,1H),5.57(d,J＝15.0Hz,1H),4.62(ddd,J 1＝10.7,J 2＝8.6,J 3＝4.4Hz,1H),3.11(dd,J 1＝13.5,J 2＝4.4Hz,1H),2.91(m,1H),2.63(d,J＝4.6Hz,3H). 13C NMR(101MHz,DMSO-d 6)δ170.59,158.95,149.18,143.00,140.33,136.47,132.27,131.33,130.60,130.30,130.06,128.98,128.12,126.31,125.00,122.05,121.60,105.01,53.94,53.08,36.59,25.68. Other conditions are the same as embodiment 1, change benzyl chloride into 3-bromobenzyl chloride, compound (S)-2-amino-3-(3-bromophenyl)-N-methyl propionamide is changed into compound (S )-2-amino-3-(3,5-dibromophenyl)-N-methylpropanamide, the product is a white solid, and the yield is 76%. 1 H NMR (400MHz, DMSO-d 6 ) δ8.84(d, J=8.7Hz, 1H), 8.11(q, J=4.6Hz, 1H), 7.78-7.75(m, 2H), 7.63(t, J＝1.8Hz, 1H), 7.57(d, J＝1.8Hz, 2H), 7.48-7.40(m, 4H), 7.37-7.31(m, 2H), 7.23(t, J＝7.8Hz, 1H), 7.08(d, J=7.9Hz, 1H), 5.69(d, J=15.0Hz, 1H), 5.57(d, J=15.0Hz, 1H), 4.62(ddd, J 1 =10.7, J 2 =8.6, J 3 ＝4.4Hz, 1H), 3.11(dd, J 1 ＝13.5, J 2 ＝4.4Hz, 1H), 2.91(m, 1H), 2.63(d, J＝4.6Hz, 3H). 13 C NMR ( 101MHz,DMSO-d 6 )δ170.59,158.95,149.18,143.00,140.33,136.47,132.27,131.33,130.60,130.30,130.06,128.98,128.12,126.31,125.00,12 2.05, 121.60, 105.01, 53.94, 53.08, 36.59, 25.68 .
实施例51：
Figure PCTCN2022132704-appb-000061
Example 51:
Figure PCTCN2022132704-appb-000061
(S)-1-(3-溴苄基)-N-(3-(3,5-二氯苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-3-苯基-1H-吡唑-5-甲酰胺H 51的制备 (S)-1-(3-bromobenzyl)-N-(3-(3,5-dichlorophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3- Preparation of phenyl-1H-pyrazole-5-carboxamide H51
其他条件同实施例1，将氯化苄改为3-溴氯化苄，将化合物(S)-2-氨基-3-(3-溴苯基)-N-甲基丙酰胺改为化合物(S)-2-氨基-3-(3,5-二氯苯基)-N-甲基丙酰胺，产物为白色固体，产率为73％。 1H NMR(400MHz,DMSO-d 6)：δ8.85(d,J＝8.7Hz,1H),8.11(q,J＝4.6Hz,1H),7.79-7.73(m,2H),7.48-7.44(m,2H),7.43(d,J＝4.3Hz,2H),7.39(q,J＝1.7Hz,3H),7.37-7.32(m,2H),7.23(t,J＝7.8Hz,1H),7.08(d,J＝7.7Hz,1H),5.69(d,J＝15.0Hz,1H),5.57(d,J＝15.0Hz,1H),4.64(ddd,J 1＝10.7,J 2＝8.7,J 3＝4.4Hz,1H),3.13(dd,J 1＝13.6,J 2＝4.5Hz,1H),2.93(m,1H),2.63(d,J＝4.5Hz,3H). 13C NMR(101MHz,DMSO-d 6)：δ170.60,158.94,149.18,142.48,140.35,136.45,133.57,132.27,130.60,130.30,130.04,128.98,128.10,126.29,126.12,125.00,121.60,105.02,53.87,53.09,36.66,25.68. Other conditions are the same as Example 1, change benzyl chloride into 3-bromobenzyl chloride, change compound (S)-2-amino-3-(3-bromophenyl)-N-methylpropionamide into compound ( S)-2-amino-3-(3,5-dichlorophenyl)-N-methylpropanamide, the product is a white solid, and the yield is 73%. 1 H NMR (400MHz, DMSO-d 6 ): δ8.85 (d, J = 8.7Hz, 1H), 8.11 (q, J = 4.6Hz, 1H), 7.79-7.73 (m, 2H), 7.48-7.44 (m,2H),7.43(d,J=4.3Hz,2H),7.39(q,J=1.7Hz,3H),7.37-7.32(m,2H),7.23(t,J=7.8Hz,1H) ,7.08(d,J=7.7Hz,1H),5.69(d,J=15.0Hz,1H),5.57(d,J=15.0Hz,1H),4.64(ddd,J 1 ＝10.7,J 2 ＝8.7 ,J 3 ＝4.4Hz, 1H), 3.13(dd, J 1 ＝13.6, J 2 ＝4.5Hz, 1H), 2.93(m, 1H), 2.63(d, J＝4.5Hz, 3H). 13 C NMR (101MHz, DMSO-d 6 ): δ170.60, 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, 1 25.00, 121.60, 105.02, 53.87, 53.09, 36.66 ,25.68.
实施例52：
Figure PCTCN2022132704-appb-000062
Example 52:
Figure PCTCN2022132704-appb-000062
(S)-1-(3-溴苄基)-N-(3-(3,5-二氟苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-3-苯基-1H-吡唑-5-甲酰胺H 52的制备 (S)-1-(3-bromobenzyl)-N-(3-(3,5-difluorophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3- Preparation of phenyl-1H-pyrazole-5-carboxamide H52
其他条件同实施例1，将氯化苄改为3-溴氯化苄，将化合物(S)-2-氨基-3-(3-溴苯基)-N-甲基丙酰胺改为化合物(S)-2-氨基-3-(3,5-二氟苯基)-N-甲基丙酰胺，产物为白色固体，产率为72％。 1H NMR(400MHz,DMSO-d 6)δ8.83(d,J＝8.7Hz,1H),8.10(q,J＝4.6Hz,1H),7.79-7.74(m,2H),7.49-7.42(m,4H),7.38-7.31(m,2H),7.23(t,J＝7.8Hz,1H),7.09(dt,J 1＝7.8,J 2＝1.3Hz,1H),7.06-6.97(m,3H),5.76-5.69(m,1H),5.60(d,J＝15.0Hz,1H),4.67(ddd,J 1＝10.6,J 2＝8.6,J 3＝4.5Hz,1H),3.15(dd,J 1＝13.6,J 2＝4.5Hz,1H),2.96(m,1H),2.63(d,J＝4.5Hz,3H). 13C NMR(101MHz,DMSO-d 6)δ170.64,158.91,149.18,140.37,136.39,132.26,130.59,130.30,130.04,128.98,128.14,126.29,125.01,121.60,112.42,112.17,105.03,53.89,53.11,25.69. Other conditions are the same as Example 1, change benzyl chloride into 3-bromobenzyl chloride, change compound (S)-2-amino-3-(3-bromophenyl)-N-methylpropionamide into compound ( S)-2-amino-3-(3,5-difluorophenyl)-N-methylpropanamide, the product is a white solid, and the yield is 72%. 1 H NMR (400MHz, DMSO-d 6 ) δ8.83 (d, J = 8.7Hz, 1H), 8.10 (q, J = 4.6Hz, 1H), 7.79-7.74 (m, 2H), 7.49-7.42 ( m, 4H), 7.38-7.31 (m, 2H), 7.23 (t, J = 7.8Hz, 1H), 7.09 (dt, J 1 = 7.8, J 2 = 1.3Hz, 1H), 7.06-6.97 (m, 3H), 5.76-5.69(m, 1H), 5.60(d, J=15.0Hz, 1H), 4.67(ddd, J 1 ＝10.6, J 2 ＝8.6, J 3 ＝4.5Hz, 1H), 3.15(dd , J 1 =13.6, J 2 =4.5Hz, 1H), 2.96 (m, 1H), 2.63 (d, J = 4.5Hz, 3H). 13 C NMR (101MHz, DMSO-d 6 ) δ170.64, 158.91, 149.18 .
实施例53：
Figure PCTCN2022132704-appb-000063
Example 53:
Figure PCTCN2022132704-appb-000063
(S)-N-(3-(3-溴-5-氟苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-1-(3-溴苄基)-3-苯基-1H-吡唑-5-甲酰胺H 53的制备 (S)-N-(3-(3-bromo-5-fluorophenyl)-1-(methylamino)-1-oxopropan-2-yl)-1-(3-bromobenzyl)- Preparation of 3-phenyl-1H-pyrazole-5-carboxamide H 53
其他条件同实施例1，将氯化苄改为3-溴氯化苄，将化合物(S)-2-氨基-3-(3-溴苯基)-N-甲基丙酰胺改为化合物(S)-2-氨基-3-(3-溴-5-氟苯基)-N-甲基丙酰胺，产物为白色固体，产率为74％。 1H NMR(400MHz,DMSO-d 6)：δ8.84(d,J＝8.7Hz,1H),8.11(q,J＝4.6Hz,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＝8.0Hz,1H),5.70(d,J＝15.0Hz,1H),5.59(d,J＝15.0Hz,1H),4.65(ddd,J 1＝10.6,J 2＝8.6,J 3＝4.5Hz,1H),3.14(dd,J 1＝13.6,J 2＝4.5Hz,1H),2.94(m,1H),2.63(d,J＝4.6Hz,3H). 13C NMR(101MHz,DMSO-d 6)：δ170.62,158.94,149.18,140.35,136.44,132.27,130.60,130.30,130.05,128.97,126.30,125.01,121.60,105.03,53.92,53.10,36.71,25.69. Other conditions are the same as Example 1, change benzyl chloride into 3-bromobenzyl chloride, change compound (S)-2-amino-3-(3-bromophenyl)-N-methylpropionamide into compound ( S)-2-amino-3-(3-bromo-5-fluorophenyl)-N-methylpropanamide, the product is a white solid with a yield of 74%. 1 H NMR (400MHz, DMSO-d 6 ): δ8.84 (d, J = 8.7Hz, 1H), 8.11 (q, J = 4.6Hz, 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=8.0Hz,1H),5.70(d,J=15.0Hz,1H),5.59( d, J = 15.0Hz, 1H), 4.65 (ddd, J 1 = 10.6, J 2 = 8.6, J 3 = 4.5Hz, 1H), 3.14 (dd, J 1 = 13.6, J 2 = 4.5Hz, 1H) , 2.94 (m, 1H), 2.63 (d, J=4.6Hz, 3H). 13 C NMR (101MHz, DMSO-d 6 ): δ170.62, 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.
实施例54：
Figure PCTCN2022132704-appb-000064
Example 54:
Figure PCTCN2022132704-appb-000064
(S)-1-(3-溴苄基)-N-(3-(2-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-3-苯基-1H-吡唑-5-甲酰胺H 54的制备 (S)-1-(3-bromobenzyl)-N-(3-(2-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-phenyl- Preparation of 1H-pyrazole-5-carboxamide H 54
其他条件同实施例1，将氯化苄改为3-溴氯化苄，将化合物(S)-2-氨基-3-(3-溴苯基)-N-甲基丙酰胺改为化合物(S)-2-氨基-3-(2-溴苯基)-N-甲基丙酰胺，产物为白色固体，产率为66％。 1H NMR(400MHz,DMSO-d 6)：δ8.85(d,J＝8.7Hz,1H),8.01(q,J＝4.5Hz,1H),7.80-7.74(m,2H),7.55(dd,J 1＝8.0,J 2＝1.3Hz,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＝15.0Hz,1H),5.58(d,J＝14.9Hz,1H),4.77(m,1H),3.05(dd,J 1＝14.1,J 2＝10.2Hz 1H),2.62(d,J＝4.6Hz,3H). 13C NMR(101MHz,DMSO-d 6)：δ170.55,158.90,149.16,140.42,137.09,136.45,132.48,132.29,131.34,130.65,130.30,130.04,128.97,128.62,128.13,127.43,126.42,125.06,124.27,121.62,105.13,53.10,52.17,37.48,25.88. Other conditions are the same as Example 1, change benzyl chloride into 3-bromobenzyl chloride, change compound (S)-2-amino-3-(3-bromophenyl)-N-methylpropionamide into compound ( S)-2-amino-3-(2-bromophenyl)-N-methylpropanamide, the product is a white solid, and the yield is 66%. 1 H NMR (400MHz, DMSO-d 6 ): δ8.85(d, J=8.7Hz, 1H), 8.01(q, J=4.5Hz, 1H), 7.80-7.74(m, 2H), 7.55(dd , J 1 =8.0, J 2 =1.3Hz,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=15.0Hz,1H),5.58(d,J=14.9Hz,1H),4.77(m,1H),3.05(dd,J 1 =14.1,J 2 =10.2Hz 1H),2.62(d,J =4.6Hz, 3H). 13 C NMR (101MHz, DMSO-d 6 ): δ170.55, 158.90, 149.16, 140.42, 137.09, 136.45, 132.48, 132.29, 131.34, 130.65, 130.30, 130.04, 128.9 7,128.62,128.13,127.43 ,126.42,125.06,124.27,121.62,105.13,53.10,52.17,37.48,25.88.
实施例55：
Figure PCTCN2022132704-appb-000065
Example 55:
Figure PCTCN2022132704-appb-000065
(S)-1-(3-溴苄基)-N-(3-(4-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-3-苯基-1H-吡唑-5-甲酰胺H 55的制备 (S)-1-(3-bromobenzyl)-N-(3-(4-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-phenyl- Preparation of 1H-pyrazole-5-carboxamide H 55
其他条件同实施例1，将氯化苄改为3-溴氯化苄，将化合物(S)-2-氨基-3-(3-溴苯基)-N-甲基丙酰胺改为化合物(S)-2-氨基-3-(4-溴苯基)-N-甲基丙酰胺，产物为白色固体，产率为70％。 1H NMR(400MHz,DMSO-d 6)：δ8.82(d,J＝8.6Hz,1H),8.10(q,J＝4.6Hz,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＝15.1Hz,1H),5.60(d,J＝15.0Hz,1H),4.63(ddd,J 1＝10.4,J 2＝8.5,J 3＝4.5Hz,1H),3.09(dd,J 1＝13.7,J 2＝4.5Hz,1H),2.92(m,1H),2.62(d,J＝4.6Hz,3H). 13C NMR(101MHz,DMSO-d 6)：δ170.87,158.93,149.17,140.41,137.61,136.51,132.29,131.36,131.01,130.63,130.27,130.02,128.94,128.11,126.32,125.07,121.61,119.58,105.09,54.20,25.69. Other conditions are the same as Example 1, change benzyl chloride into 3-bromobenzyl chloride, change compound (S)-2-amino-3-(3-bromophenyl)-N-methylpropionamide into compound ( S)-2-amino-3-(4-bromophenyl)-N-methylpropanamide, the product is a white solid, and the yield is 70%. 1 H NMR (400MHz, DMSO-d 6 ): δ8.82(d, J=8.6Hz, 1H), 8.10(q, J=4.6Hz, 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=15.1Hz,1H),5.60(d,J=15.0 Hz, 1H), 4.63 (ddd, J 1 = 10.4, J 2 = 8.5, J 3 = 4.5Hz, 1H), 3.09 (dd, J 1 = 13.7, J 2 = 4.5Hz, 1H), 2.92 (m, 1H), 2.62 (d, J=4.6Hz, 3H). 13 C NMR (101MHz, DMSO-d 6 ): δ170.87, 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.
实施例56：
Figure PCTCN2022132704-appb-000066
Example 56:
Figure PCTCN2022132704-appb-000066
1-(3-溴苄基)-N-(3-(3-溴苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-3-苯基-1H-吡唑-5- 甲酰胺H 56的制备 1-(3-bromobenzyl)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-phenyl-1H-pyridine Preparation of azole-5-carboxamide H 56
其他条件同实施例1，将氯化苄改为3-溴氯化苄，将化合物(S)-2-氨基-3-(3-溴苯基)-N-甲基丙酰胺改为化合物2-氨基-3-(3-溴苯基)-N-甲基丙酰胺，产物为白色固体，产率为73％。 1H NMR(400MHz,DMSO-d 6)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,J 1＝9.7,J 2＝4.3Hz,1H),3.11(dd,J 1＝14.0,J 2＝4.4Hz,1H),2.92(t,J＝12.1Hz,1H),2.63(d,J＝4.5Hz,3H). 13C NMR(101MHz,DMSO-d 6)δ170.82,141.00,132.00,130.64,130.28,130.06,128.96,126.36,125.03,54.20,25.68. Other conditions are the same as Example 1, change benzyl chloride into 3-bromobenzyl chloride, change compound (S)-2-amino-3-(3-bromophenyl)-N-methylpropionamide into compound 2 -Amino-3-(3-bromophenyl)-N-methylpropanamide, the product is a white solid with a yield of 73%. 1 H NMR (400MHz, DMSO-d 6 ) 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,J 1 = 9.7, J 2 = 4.3Hz, 1H), 3.11 (dd, J 1 = 14.0, J 2 = 4.4Hz, 1H), 2.92 (t, J = 12.1Hz, 1H), 2.63 (d, J = 4.5 Hz,3H). 13 C NMR(101MHz,DMSO-d 6 )δ170.82,141.00,132.00,130.64,130.28,130.06,128.96,126.36,125.03,54.20,25.68.
实施例57：
Figure PCTCN2022132704-appb-000067
Example 57:
Figure PCTCN2022132704-appb-000067
(S)-1-苄基-5-(2-溴苯基)-N-(3-(3-溴苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-1H-吡唑-3-甲酰胺I 1的制备 (S)-1-Benzyl-5-(2-bromophenyl)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl) - Preparation of 1H-pyrazole-3-carboxamide I 1
步骤一：4-(2-溴苯基)-2,4-二氧代丁酸乙酯的制备Step 1: Preparation of ethyl 4-(2-bromophenyl)-2,4-dioxobutanoate
冰浴下，将2-溴苯乙酮(500mg，2.5mmo1)，草酸二乙酯(0.6mL，5.5mmol)和乙醇钠(5mL，20％质量含量，0.0lmmol)依次加入反应器中，于乙醇中剧烈搅拌至溶解后，室温搅拌10h。冰浴下，用4N盐酸调pH至2-3，乙酸乙酯(30mL)萃取，再用饱和食盐水洗涤有机相，浓缩得粗产物4-(2-溴苯基)-2,4-二氧代丁酸乙酯。Under ice-cooling, 2-bromoacetophenone (500mg, 2.5mmol), diethyl oxalate (0.6mL, 5.5mmol) and sodium ethoxide (5mL, 20% mass content, 0.01mmol) were sequentially added to the reactor, and Stir vigorously in ethanol until dissolved, then stir at room temperature for 10 h. Under ice-cooling, adjust the pH to 2-3 with 4N hydrochloric acid, extract with ethyl acetate (30 mL), wash the organic phase with saturated brine, and concentrate to obtain the crude product 4-(2-bromophenyl)-2,4-di Ethyl oxobutyrate.
步骤二：5-(2-溴苯基)-1H-吡唑-3-甲酸乙酯的制备Step 2: Preparation of ethyl 5-(2-bromophenyl)-1H-pyrazole-3-carboxylate
将步骤一的粗产物溶解在10mL的乙酸中，冰浴下缓慢滴加肼一水合物(0.3mL，6.0mmol)，室温下搅拌8h。乙酸乙酯(30mL)萃取，再用饱和食盐水洗涤有机相，浓缩柱层析(石油醚：乙酸乙酯＝5:1)，得到740mg乳白色固体化合物5-(2-溴苯基)-1H-吡唑-3-甲酸乙酯，两步产率共80％。The crude product from Step 1 was dissolved in 10 mL of acetic acid, and hydrazine monohydrate (0.3 mL, 6.0 mmol) was slowly added dropwise under ice-cooling, and stirred at room temperature for 8 h. Extracted with ethyl acetate (30 mL), washed the organic phase with saturated brine, concentrated column chromatography (petroleum ether: ethyl acetate = 5:1), and obtained 740 mg of milky white solid compound 5-(2-bromophenyl)-1H - Ethyl pyrazole-3-carboxylate, 80% yield in two steps.
步骤三:1-苄基-5-(2-溴苯基)-1H-吡唑-3-甲酸乙酯的制备Step 3: Preparation of ethyl 1-benzyl-5-(2-bromophenyl)-1H-pyrazole-3-carboxylate
将5-(2-溴苯基)-1H-吡唑-3-甲酸乙酯500mg，1.7mmol)溶解在10mL乙腈中，加入碳酸钾(415.4mg，3mmol)和氯化苄(0.27ml，2.3mmol)，90℃加热至回流，反应12h。乙酸乙酯(20mL)萃取，再用饱和食盐水洗涤有机相，浓缩柱层析(石油醚：乙酸乙酯＝5:1)，得到130mg白色固体化合物1-苄基-5-(2-溴苯基)-1H-吡唑-3-甲 酸乙酯，产率为20％。Dissolve ethyl 5-(2-bromophenyl)-1H-pyrazole-3-carboxylate (500mg, 1.7mmol) in 10mL of acetonitrile, add potassium carbonate (415.4mg, 3mmol) and benzyl chloride (0.27ml, 2.3 mmol), heated at 90°C to reflux, and reacted for 12h. Extracted with ethyl acetate (20mL), washed the organic phase with saturated brine, concentrated column chromatography (petroleum ether:ethyl acetate=5:1), and obtained 130mg of white solid compound 1-benzyl-5-(2-bromo Ethyl phenyl)-1H-pyrazole-3-carboxylate, 20% yield.
步骤四：1-苄基-5-(2-溴苯基)-1H-吡唑-3-羧酸的制备Step 4: Preparation of 1-benzyl-5-(2-bromophenyl)-1H-pyrazole-3-carboxylic acid
将1-苄基-5-(2-溴苯基)-1H-吡唑-3-甲酸乙酯(130mg，0.3mmol)溶解在12mL甲醇中，加入4mL4N氢氧化钠溶液，室温搅拌10h。冰浴条件下加入4N盐酸调pH至4，乙酸乙酯(20mL)萃取，再用饱和食盐水洗涤有机相，浓缩，得到108mg白色固体1-苄基-5-(2-溴苯基)-1H-吡唑-3-羧酸，产率为90％。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. Add 4N hydrochloric acid to adjust the pH to 4 under ice-bath conditions, extract with ethyl acetate (20 mL), wash the organic phase with saturated brine, and concentrate to obtain 108 mg of white solid 1-benzyl-5-(2-bromophenyl)- 1H-Pyrazole-3-carboxylic acid, 90% yield.
步骤五：(S)-1-苄基-5-(2-溴苯基)-N-(3-(3-溴苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-1H-吡唑-3-甲酰胺的制备Step 5: (S)-1-Benzyl-5-(2-bromophenyl)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropane-2 Preparation of -yl)-1H-pyrazole-3-carboxamide
将1-苄基-5-(2-溴苯基)-1H-吡唑-3-羧酸(30mg，0.1mmol)和HOAT(24.5mg，0.2mmo1)溶解在5mLDMF中，氮气保护下室温搅拌10min后，0℃下加入化合物(S)-2-氨基-3-(3-溴苯基)-N-甲基丙酰胺(38.5mg，0.1mmo1)，继续搅拌10min后，0℃加入N-甲基吗啡啉(0.009mL，008mmol)，搅拌10min，加入EDCI(24.8mg，0.1mmo1)，保持0℃搅拌1h，至室温反应12h。乙酸乙酯(20mL)萃取，再用饱和食盐水洗涤有机相，浓缩柱层析(石油醚：乙酸乙酯＝1:1)，得到22mg白色固体化合物(S)-1-苄基-5-(2-溴苯基)-N-(3-(3-溴苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-1H-吡唑-3-甲酰胺，产率为44％。 1H NMR(300MHz,DMSO-d 6)：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). 13C NMR(101MHz,DMSO-d 6)：δ171.0,160.8,145.3,143.0,140.9,136.3,132.9,132.3,132.0,131.6,130.4,130.2,129.2,128.4,128.3,127.9,127.6,127.0,123.6,121.4,107.9,53.7,53.4,37.2,25.6. Dissolve 1-benzyl-5-(2-bromophenyl)-1H-pyrazole-3-carboxylic acid (30mg, 0.1mmol) and HOAT (24.5mg, 0.2mmol) in 5mL DMF, stir at room temperature under nitrogen protection After 10min, compound (S)-2-amino-3-(3-bromophenyl)-N-methylpropionamide (38.5mg, 0.1mmol) was added at 0°C, and after stirring was continued for 10min, N- Methylmorpholine (0.009 mL, 008 mmol), stirred for 10 min, added EDCI (24.8 mg, 0.1 mmol), kept stirring at 0°C for 1 h, and reacted at room temperature for 12 h. Extracted with ethyl acetate (20 mL), washed the organic phase with saturated brine, concentrated column chromatography (petroleum ether: ethyl acetate = 1:1), and obtained 22 mg of white solid compound (S)-1-benzyl-5- (2-bromophenyl)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-1H-pyrazole-3-carboxamide, The yield was 44%. 1 H NMR (300MHz, DMSO-d 6 ): 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-d 6 ): δ171.0, 160.8, 145.3, 143.0, 140.9, 136.3, 132.9, 132.3, 132.0, 131.6, 130.4, 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.
实施例58：
Figure PCTCN2022132704-appb-000068
Example 58:
Figure PCTCN2022132704-appb-000068
(S)-1-苄基-5-(3-溴苯基)-N-(3-(3-溴苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-1H-吡唑-3-甲酰胺I 2的制备 (S)-1-Benzyl-5-(3-bromophenyl)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl) - Preparation of 1H-pyrazole-3-carboxamide I 2
其他条件同实施例57,将2-溴苯乙酮改为3-溴苯乙酮，产物为白色固体，产率为73％。 1H NMR(400MHz,DMSO-d 6)δ8.12(t,J＝7.0Hz,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＝7.4Hz,2H),6.89(s, 1H),5.46(s,2H),4.69(td,J＝8.7,5.2Hz,1H),3.10–3.00(m,2H),2.61(d,J＝4.7Hz,3H). 13C NMR(101MHz,DMSO-d 6)δ171.0,160.6,145.5,143.4,140.9,136.9,132.0,131.9,131.5,131.1,131.0,130.2,129.2,128.7,128.4,127.7,127.6,126.6,122.0,121.4,107.4,53.6,53.5,37.2,25.6. Other conditions were the same as in Example 57, except that 2-bromoacetophenone was changed to 3-bromoacetophenone, and the product was a white solid with a yield of 73%. 1 H NMR (400MHz, DMSO-d 6 )δ8.12(t, J=7.0Hz, 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=7.4Hz,2H),6.89(s,1H),5.46(s,2H),4.69(td,J=8.7,5.2Hz,1H),3.10 –3.00(m,2H),2.61(d,J＝4.7Hz,3H). 13 C NMR(101MHz,DMSO-d 6 )δ171.0,160.6,145.5,143.4,140.9,136.9,132.0,131.9,131.5,131.1 ,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.
实施例59：
Figure PCTCN2022132704-appb-000069
Example 59:
Figure PCTCN2022132704-appb-000069
(S)-1-苄基-5-(4-溴苯基)-N-(3-(3-溴苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-1H-吡唑-3-甲酰胺I 3的制备 (S)-1-Benzyl-5-(4-bromophenyl)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl) - Preparation of 1H-pyrazole-3-carboxamide I 3
其他条件同实施例57，将2-溴苯乙酮改为4-溴苯乙酮，产物为白色固体，产率为73％。 1H NMR(400MHz,DMSO-d 6)δ8.12-8.06(m,2H),7.67-7.62(m,2H),7.47(t,J＝1.8Hz,1H),7.39-7.35(m,3H),7.33-7.23(m,4H),7.19(t,J＝7.7Hz,1H),7.00-6.96(m,2H),6.85(s,1H),5.45(s,2H),4.68(td,J 1＝8.8,J 2＝5.2Hz,1H),3.03(m,2H),2.61(d,J＝4.6Hz,3H). 13C NMR(101MHz,DMSO-d 6)δ170.94,160.63,145.55,143.83,140.85,136.88,131.99,131.89,130.61,130.18,129.21,128.65,128.48,128.33,127.60,126.52,122.58,121.37,107.15,53.59,25.59. Other conditions were the same as in Example 57, except that 2-bromoacetophenone was changed to 4-bromoacetophenone, and the product was a white solid with a yield of 73%. 1 H NMR (400MHz,DMSO-d 6 )δ8.12-8.06(m,2H),7.67-7.62(m,2H),7.47(t,J=1.8Hz,1H),7.39-7.35(m,3H ),7.33-7.23(m,4H),7.19(t,J＝7.7Hz,1H),7.00-6.96(m,2H),6.85(s,1H),5.45(s,2H),4.68(td, J 1 ＝8.8, J 2 ＝5.2Hz, 1H), 3.03(m, 2H), 2.61(d, J＝4.6Hz, 3H). 13 C NMR(101MHz, DMSO-d 6 )δ170.94, 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.
实施例60：
Figure PCTCN2022132704-appb-000070
Example 60:
Figure PCTCN2022132704-appb-000070
(S)-1-苄基-N-(3-(3-溴苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-5-(间甲苯基)-1H-吡唑-3-甲酰胺I 4的制备 (S)-1-Benzyl-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-5-(m-tolyl)-1H - Preparation of pyrazole-3-carboxamide I 4
其他条件同实施例57,将2-溴苯乙酮改为3-甲基苯乙酮，产物为白色固体，产率为73％。 1H NMR(300MHz,DMSO-d 6)δ8.11-8.08(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＝8.6,5.4Hz,1H),3.11-2.98(m,2H),2.62(d,J＝4.5Hz,3H),2.29(s,3H). 13C NMR(101MHz,DMSO-d 6)δ171.0,160.8,145.5,145.2,140.9,138.25,137.2,132.0,130.2,129.7,129.2,128.8,128.6,128.4,127.6,126.6,125.6,121.4,106.7,53.6,53.2,37.3,25.6,20.9. Other conditions were the same as in Example 57, except that 2-bromoacetophenone was changed to 3-methylacetophenone, and the product was a white solid with a yield of 73%. 1 H NMR (300MHz,DMSO-d 6 )δ8.11-8.08(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=8.6,5.4Hz,1H),3.11-2.98(m,2H),2.62(d,J=4.5Hz,3H),2.29(s, 3H). 13 C NMR (101MHz, DMSO-d 6 ) δ171.0, 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.
实施例61：
Figure PCTCN2022132704-appb-000071
Example 61:
Figure PCTCN2022132704-appb-000071
(S)-1-苄基-N-(3-(3-溴苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-5-(对甲苯基)-1H-吡唑-3-甲酰胺I 5的制备 (S)-1-Benzyl-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-5-(p-tolyl)-1H - Preparation of pyrazole-3-carboxamide I 5
其他条件同实施例57，将2-溴苯乙酮改为4-甲基苯乙酮，产物为白色固体，产率为73％。 1H NMR(300MHz,DMSO-d 6)δ8.11-8.08(m,2H),7.48(s,1H),7.38-7.16(m,10H),6.99(d,J＝6.7Hz,2H),6.79(s,1H),5.43(s,2H),4.70(td,J＝8.6,5.4Hz,1H),3.07-3.03(m,2H),2.62(d,J＝4.5Hz,3H),2.31(s,3H). 13C NMR(101MHz,DMSO-d 6)δ171.0,160.8,145.5,145.1,140.9,138.6,137.2,132.0,130.2,129.5,129.2,128.6,128.4,128.3,127.5,126.5,121.4,106.6,53.6,53.1,37.3,25.6,20.8. Other conditions were the same as in Example 57, except that 2-bromoacetophenone was changed to 4-methylacetophenone, and the product was a white solid with a yield of 73%. 1 H NMR (300MHz,DMSO-d 6 )δ8.11-8.08(m,2H),7.48(s,1H),7.38-7.16(m,10H),6.99(d,J=6.7Hz,2H), 6.79(s,1H),5.43(s,2H),4.70(td,J=8.6,5.4Hz,1H),3.07-3.03(m,2H),2.62(d,J=4.5Hz,3H),2.31 (s,3H). 13 C NMR(101MHz,DMSO-d 6 )δ171.0,160.8,145.5,145.1,140.9,138.6,137.2,132.0,130.2,129.5,129.2,128.6,128.4,128.3,127.5,126. 5,121.4 ,106.6,53.6,53.1,37.3,25.6,20.8.
实施例62：
Figure PCTCN2022132704-appb-000072
Example 62:
Figure PCTCN2022132704-appb-000072
(S)-1-苄基-N-(3-(3-溴苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-5-(3-甲氧基苯基)-1H-吡唑-3-甲酰胺I 6的制备 (S)-1-benzyl-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-5-(3-methoxybenzene Base)-1H-pyrazole-3-carboxamide I 6 preparation
其他条件同实施例57，将2-溴苯乙酮改为3-甲氧基苯乙酮，产物为白色固体，产率为73％。 11H NMR(400MHz,DMSO-d 6)δ8.19(q,J＝4.6Hz,1H),8.10(d,J＝8.6Hz,1H),7.48(t,J＝1.8Hz,1H),7.36(t,J＝7.9Hz,2H),7.31(dd,J 1＝8.1,J 2＝6.3Hz,2H),7.26(m,2H),7.19(t,J＝7.7Hz,1H),6.99(m,4H),6.91(t,J＝2.1Hz,1H),6.85(s,1H),5.45(s,2H),4.69(td,J 1＝8.8,J 2＝5.1Hz,1H),3.69(s,3H),3.17–2.97(m,2H),2.61(d,J＝4.5Hz,3H). 13C NMR(101MHz,DMSO-d 6)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. Other conditions were the same as in Example 57, except that 2-bromoacetophenone was changed to 3-methoxyacetophenone, and the product was a white solid with a yield of 73%. 11 H NMR (400MHz, DMSO-d 6 ) δ8.19(q, J=4.6Hz, 1H), 8.10(d, J=8.6Hz, 1H), 7.48(t, J=1.8Hz, 1H), 7.36 (t, J = 7.9Hz, 2H), 7.31 (dd, J 1 = 8.1, J 2 = 6.3Hz, 2H), 7.26 (m, 2H), 7.19 (t, J = 7.7Hz, 1H), 6.99 ( m, 4H), 6.91 (t, J = 2.1Hz, 1H), 6.85 (s, 1H), 5.45 (s, 2H), 4.69 (td, J 1 = 8.8, J 2 = 5.1Hz, 1H), 3.69 (s,3H),3.17–2.97(m,2H),2.61(d,J＝4.5Hz,3H). 13 C NMR(101MHz,DMSO-d 6 )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.
实施例63：
Figure PCTCN2022132704-appb-000073
Example 63:
Figure PCTCN2022132704-appb-000073
(S)-1-苄基-N-(3-(3-溴苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-5-(4-甲氧基苯基)-1H-吡唑-3-甲酰胺I 7的制备 (S)-1-benzyl-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-5-(4-methoxybenzene Base)-1H-pyrazole-3-carboxamide I7 preparation
其他条件同实施例57，将2-溴苯乙酮改为4-甲氧基苯乙酮，产物为白色固体，产率为73％。 1H NMR(300MHz,DMSO-d 6)δ8.08(m,1H),7.47(t,J＝1.7Hz,1H),7.37(dt,J 1＝7.5,J 2＝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,J 1＝8.6,J 2＝5.2Hz,1H),3.12-2.94(m,2H),2.61(d,J＝4.5Hz,3H),2.32(s,3H). 13C NMR(75MHz,DMSO-d 6)δ171.02,160.84,145.50,145.16,140.88,138.70,137.18,132.03,130.24,129.54,129.27,128.68,128.48,128.38,127.57,126.50,126.45,121.42,106.61,53.63,53.13,37.28,25.64,20.85. Other conditions were the same as in Example 57, except that 2-bromoacetophenone was changed to 4-methoxyacetophenone, and the product was a white solid with a yield of 73%. 1 H NMR (300MHz, DMSO-d 6 )δ8.08 (m, 1H), 7.47 (t, J = 1.7Hz, 1H), 7.37 (dt, J 1 = 7.5, J 2 = 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,J 1 =8.6,J 2 =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-d 6 )δ171.02,160.84,145.50,145.16,140.88,138.70 ,137.18,132.03,130.24,129.54,129.27,128.68,128.48,128.38,127.57,126.50,126.45,121.42,106.61,53.63,53.13,37.28,25.64,20.85 .
实施例64：
Figure PCTCN2022132704-appb-000074
Example 64:
Figure PCTCN2022132704-appb-000074
(S)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-1-(3-甲基苄基)-5-苯基-1H-吡唑-3-甲酰胺I 8的制备 (S)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-1-(3-methylbenzyl)-5-phenyl - Preparation of 1H-pyrazole-3-carboxamide I 8
其他条件同实施例57，将2-溴苯乙酮改为苯乙酮，氯化苄改为3-甲基氯化苄，产物为白色固体，产率为73％。 1H NMR(400MHz,DMSO-d 6)：δ8.14-8.03(m,1H),7.44(m,3H),7.37(dt,J 1＝7.8,J 2＝1.6Hz,1H),7.25(dt,J 1＝7.7,J 2＝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,J 1＝8.7,J 2＝5.2Hz,1H),3.13–2.97(m,1H),2.62(d,J＝4.6Hz,2H),2.22(s,1H). 13C NMR(101MHz,DMSO-d 6)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. Other conditions were the same as in Example 57, except that 2-bromoacetophenone was changed to acetophenone, benzyl chloride was changed to 3-methylbenzyl chloride, and the product was a white solid with a yield of 73%. 1 H NMR (400MHz, DMSO-d 6 ): δ8.14-8.03 (m, 1H), 7.44 (m, 3H), 7.37 (dt, J 1 =7.8, J 2 =1.6Hz, 1H), 7.25( dt,J 1 =7.7,J 2 =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, J 1 = 8.7, J 2 = 5.2Hz, 1H), 3.13–2.97 (m, 1H), 2.62 ( D, j = 4.6Hz, 2H), 2.22 (s, 1H). 13 C NMR (101MHz, DMSO-D 6 ) Δ170.99,160.79,145.02,140.87,137.77,132.00,17,129.36,129.2 2, 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.
实施例65：
Figure PCTCN2022132704-appb-000075
Example 65:
Figure PCTCN2022132704-appb-000075
(S)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-1-(3-氟苄基)-5-苯基-1H-吡唑-3-甲酰胺I 9的制备 (S)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-1-(3-fluorobenzyl)-5-phenyl- Preparation of 1H-pyrazole-3-carboxamide I 9
其他条件同实施例57，将2-溴苯乙酮改为苯乙酮，氯化苄改为3-氟氯化苄，产物为白色固体，产率为73％。 1H NMR(400MHz,DMSO-d 6)δ8.10(m,2H),7.48-7.44(m,2H),7.41(dd,J 1＝7.3,J 2＝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). 13C NMR(101MHz,DMSO-d 6)δ170.97,160.73,145.71,145.16,140.87,139.90,139.83,132.02,130.76,130.68,130.17,129.23,129.15,128.99,128.57,128.35,122.55,121.39,114.55,114.35,113.55,113.33,106.92,54.94,53.63,52.67,37.23,25.62. Other conditions were the same as in Example 57, except that 2-bromoacetophenone was changed to acetophenone, benzyl chloride was changed to 3-fluorobenzyl chloride, and the product was a white solid with a yield of 73%. 1 H NMR (400MHz, DMSO-d 6 )δ8.10 (m, 2H), 7.48-7.44 (m, 2H), 7.41 (dd, J 1 =7.3, J 2 =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). 13 C NMR(101MHz,DMSO-d 6 )δ170.97,160.73,145.71,145.16,140.87,139.90,139.83 ,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.
实施例66：
Figure PCTCN2022132704-appb-000076
Example 66:
Figure PCTCN2022132704-appb-000076
(S)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-3-(2-氟苯基)-1H-吡唑-5-甲酰胺L 1的制备 (S)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-(2-fluorophenyl)-1H-pyrazole- Preparation of 5-formamide L1
步骤一：4-(2-氟苯基)-2,4-二氧代丁酸乙酯的制备Step 1: Preparation of ethyl 4-(2-fluorophenyl)-2,4-dioxobutanoate
冰浴下，将2-氟苯乙酮(1g，7.2mmo1)和草酸二乙酯(0.7mL，10.3mmol)溶解于乙醇钠(10mL，20％质量含量，0.01mmol)中，室温搅拌10h。冰浴下，用4N盐酸调pH至2-3，乙酸乙酯萃取，再用饱和食盐水洗涤有机相，浓缩得粗产物，直接进行下一步。Under ice-cooling, 2-fluoroacetophenone (1 g, 7.2 mmol) and diethyl oxalate (0.7 mL, 10.3 mmol) were dissolved in sodium ethoxide (10 mL, 20% by mass, 0.01 mmol), and stirred at room temperature for 10 h. Under ice-cooling, adjust the pH to 2-3 with 4N hydrochloric acid, extract with ethyl acetate, wash the organic phase with saturated brine, concentrate to obtain a crude product, and proceed directly to the next step.
步骤二：3-(2-氟苯基)-1H-吡唑-5-甲酸乙酯的制备Step 2: Preparation of ethyl 3-(2-fluorophenyl)-1H-pyrazole-5-carboxylate
将步骤一的粗产物溶解在10mL的乙酸中，冰浴下加入肼一水合物(0.3mL，4.0mmol)，室温下搅拌8h。乙酸乙酯萃取，再用饱和食盐水洗涤有机相，浓缩柱层析(石油醚：乙酸乙酯＝3：1)，得到750mg乳白色固体化合物3，两步产率共80％。The crude product from Step 1 was dissolved in 10 mL of acetic acid, hydrazine monohydrate (0.3 mL, 4.0 mmol) was added under ice-cooling, and stirred at room temperature for 8 h. After extraction with ethyl acetate, the organic phase was washed with saturated brine, and concentrated by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain 750 mg of compound 3 as a milky white solid, with a yield of 80% in two steps.
步骤三：3-(2-氟苯基)-1H-吡唑-5-羧酸的制备Step 3: Preparation of 3-(2-fluorophenyl)-1H-pyrazole-5-carboxylic acid
将3-(2-氟苯基)-1H-吡唑-5-甲酸乙酯(500mg，2.1mmol)溶解在12mL甲醇中，加入4mL4N氢氧化钠溶液，室温搅拌10h。冰浴条件下加入4N盐酸调pH至4，乙酸乙酯萃取，再用饱和食盐水洗涤有机相，干燥浓缩，得到396mg白色固体化合物5，产率为90％。Dissolve ethyl 3-(2-fluorophenyl)-1H-pyrazole-5-carboxylate (500 mg, 2.1 mmol) in 12 mL of methanol, add 4 mL of 4N sodium hydroxide solution, and stir at room temperature for 10 h. 4N hydrochloric acid was added under ice bath to adjust the pH to 4, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried and concentrated to obtain 396 mg of white solid compound 5 with a yield of 90%.
步骤四：(S)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-3-(2-氟苯基)-1H-吡唑-5-甲酰胺的制备Step 4: (S)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-(2-fluorophenyl)-1H- Preparation of pyrazole-5-carboxamide
将3-(2-氟苯基)-1H-吡唑-5-羧酸(150mg，0.73mmo1)。HOAT(119mg，0.87mmo1)溶解在10mLDMF中，搅拌10min后，加入化合物(S)-2-氨基-3-(3-溴苯基)-N-甲基丙酰胺(187mg，0.73mmol)，冰浴下加入N-甲基吗啡啉(0.057mL，0.51mmol)搅拌10min，加入EDCI(167mg，0.87mmol)，保持0℃搅拌1h，至室温反应12h。乙酸乙酯萃取，再用饱和食盐水洗涤有机相，浓缩柱层析(石油醚：乙酸乙酯＝1：1)，得到103mg白色固体产物，产率为32％。 1H NMR(400MHz,DMSO-d 6)：δ13.76(s,1H),8.23-7.80(m,3H),7.51-7.17(m,8H),4.66(s,1H),3.00(d,J＝52.8Hz,2H),2.62(d,J＝4.5Hz,3H). 13C NMR(100MHz,DMSO-d 6):δ171.1,132.0,130.2,129.2,128.3,121.4,25.7.HRMS(ESI,m/z):Calcd.for C 20H 18BrFN 4O 2[M+Na] +467.0489,found:467.0494. 3-(2-Fluorophenyl)-1H-pyrazole-5-carboxylic acid (150 mg, 0.73 mmol). HOAT (119mg, 0.87mmol) was dissolved in 10mL DMF, and after stirring for 10min, compound (S)-2-amino-3-(3-bromophenyl)-N-methylpropanamide (187mg, 0.73mmol) was added, ice Add N-methylmorpholine (0.057mL, 0.51mmol) under the bath and stir for 10min, add EDCI (167mg, 0.87mmol), keep stirring at 0°C for 1h, and react at room temperature for 12h. Extracted with ethyl acetate, washed the organic phase with saturated brine, concentrated column chromatography (petroleum ether: ethyl acetate = 1:1), and obtained 103 mg of a white solid product with a yield of 32%. 1 H NMR (400MHz, DMSO-d 6 ): δ13.76(s,1H),8.23-7.80(m,3H),7.51-7.17(m,8H),4.66(s,1H),3.00(d, J＝52.8Hz, 2H), 2.62 (d, J＝4.5Hz, 3H). 13 C NMR (100MHz, DMSO-d 6 ): δ171.1, 132.0, 130.2, 129.2, 128.3, 121.4, 25.7. HRMS (ESI, m/z): Calcd.for C 20 H 18 BrFN 4 O 2 [M+Na] + 467.0489, found: 467.0494.
实施例67：
Figure PCTCN2022132704-appb-000077
Example 67:
Figure PCTCN2022132704-appb-000077
(S)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-3-(3-氟苯基)-1H-吡唑-5-甲酰胺L 2的制备。 (S)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-(3-fluorophenyl)-1H-pyrazole- Preparation of 5-carboxamide L2 .
其他条件同实施例66，将3-氟苯乙酮代替2-氟苯乙酮，得到白色固体，产率为35％。 1H NMR(400MHz,DMSO-d 6):δ13.84-13.63(m,1H),8.17-8.02(m,2H),7.70-7.59(m,2H),7.57-7.45(m,3H),7.41-7.28(m,2H),7.27-7.11(m,3H),4.73-4.60(m,1H),3.15-2.87(m,2H),2.62(d,J＝4.5Hz,3H). Other conditions were the same as in Example 66, and 3-fluoroacetophenone was substituted for 2-fluoroacetophenone to obtain a white solid with a yield of 35%. 1 H NMR(400MHz,DMSO-d 6 ):δ13.84-13.63(m,1H),8.17-8.02(m,2H),7.70-7.59(m,2H),7.57-7.45(m,3H), 7.41-7.28(m,2H),7.27-7.11(m,3H),4.73-4.60(m,1H),3.15-2.87(m,2H),2.62(d,J=4.5Hz,3H).
实施例68：
Figure PCTCN2022132704-appb-000078
Example 68:
Figure PCTCN2022132704-appb-000078
(S)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-3-(4-氟苯基)-1H-吡唑-5-甲酰胺L 3的制备 (S)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-(4-fluorophenyl)-1H-pyrazole- Preparation of 5-formamide L3
其他条件同实施例66，将4-氟苯乙酮代替2-氟苯乙酮，得到白色固体，产率为35％。 1H NMR(400MHz,DMSO-d 6):δ13.62(d,J＝48.1Hz,1H),8.17-7.98(m,2H),7.82(s,2H),7.51(d,J＝30.0Hz,1H),7.39-7.17(m,6H),4.66(s,1H),3.18-2.90(m,2H),2.62(d,J＝4.5Hz,3H). 13C NMR(100MHz,DMSO-d 6):δ171.0,162.3,161.2,147.3,140.9,132.0,130.2,129.2,128.3,127.6,127.0,121.4,116.2,115.9,115.6,102.8,53.5,37.3,35.8,30.8,25.6. Other conditions were the same as in Example 66, and 4-fluoroacetophenone was substituted for 2-fluoroacetophenone to obtain a white solid with a yield of 35%. 1 H NMR (400MHz, DMSO-d 6 ): δ13.62(d, J=48.1Hz, 1H), 8.17-7.98(m, 2H), 7.82(s, 2H), 7.51(d, J=30.0Hz , 1H), 7.39-7.17(m, 6H), 4.66(s, 1H), 3.18-2.90(m, 2H), 2.62(d, J=4.5Hz, 3H). 13 C NMR (100MHz, DMSO-d 6 ): δ171.0, 162.3, 161.2, 147.3, 140.9, 132.0, 130.2, 129.2, 128.3, 127.6, 127.0, 121.4, 116.2, 115.9, 115.6, 102.8, 53.5, 37.3, 35.8, 30.8, 25.6.
实施例69：
Figure PCTCN2022132704-appb-000079
Example 69:
Figure PCTCN2022132704-appb-000079
(S)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-3-(2-氯苯基)-1H-吡唑-5-甲酰胺L 4的制备 (S)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-(2-chlorophenyl)-1H-pyrazole- Preparation of 5-formamide L4
其他条件同实施例66，将2-氯苯乙酮代替2-氟苯乙酮，得到白色固体，产率为35％。 1H NMR(400MHz,DMSO-d 6):δ13.74(d,J＝22.7Hz,1H),8.26-7.75(m,2H),7.68-7.59(m,1H),7.58-7.43(m,3H),7.42-7.25(m,3H),7.21(t,J＝7.9Hz,1H),4.67(s,1H),3.16-2.90(m,2H),2.62(d,J＝4.5Hz,3H). 13C NMR(100MHz,DMSO-d 6):δ171.1,132.0,130.3,129.2,128.3,121.4,25.7. Other conditions were the same as in Example 66, and 2-chloroacetophenone was substituted for 2-fluoroacetophenone to obtain a white solid with a yield of 35%. 1 H NMR (400MHz, DMSO-d 6 ): δ13.74(d, J=22.7Hz, 1H), 8.26-7.75(m, 2H), 7.68-7.59(m, 1H), 7.58-7.43(m, 3H), 7.42-7.25(m, 3H), 7.21(t, J=7.9Hz, 1H), 4.67(s, 1H), 3.16-2.90(m, 2H), 2.62(d, J=4.5Hz, 3H ). 13 C NMR (100MHz, DMSO-d 6 ): δ171.1, 132.0, 130.3, 129.2, 128.3, 121.4, 25.7.
实施例70：
Figure PCTCN2022132704-appb-000080
Example 70:
Figure PCTCN2022132704-appb-000080
(S)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-3-(3-氯苯基)-1H-吡唑-5-甲酰胺L 5的制备 (S)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-(3-chlorophenyl)-1H-pyrazole- Preparation of 5-formamide L5
其他条件同实施例66，将3-氯苯乙酮代替2-氟苯乙酮，得到白色固体，产率为37％。 1H NMR(400MHz,DMSO-d 6):δ13.77(d,J＝44.7Hz,1H),8.12-8.03(m,1H),7.95-7.70(m,2H),7.59-7.45(m,2H),7.45-7.29(m,3H),7.28-7.12(m,3H),4.67(d,J＝7.1Hz,1H),3.16-3.02(m,1H),2.94(q,J＝13.3,12.9Hz,1H),2.68-2.42(m,3H).HRMS(ESI,m/z):Calcd.for C 20H 18BrClN 4O 2[M+Na] +483.0194,found:483.0198. Other conditions were the same as in Example 66, and 3-chloroacetophenone was substituted for 2-fluoroacetophenone to obtain a white solid with a yield of 37%. 1 H NMR (400MHz, DMSO-d 6 ): δ13.77 (d, J=44.7Hz, 1H), 8.12-8.03 (m, 1H), 7.95-7.70 (m, 2H), 7.59-7.45 (m, 2H), 7.45-7.29(m, 3H), 7.28-7.12(m, 3H), 4.67(d, J=7.1Hz, 1H), 3.16-3.02(m, 1H), 2.94(q, J=13.3, 12.9Hz,1H),2.68-2.42(m,3H).HRMS(ESI,m/z):Calcd.for C 20 H 18 BrClN 4 O 2 [M+Na] + 483.0194,found:483.0198.
实施例71：
Figure PCTCN2022132704-appb-000081
Example 71:
Figure PCTCN2022132704-appb-000081
(S)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-3-(4-氯苯基)-1H-吡唑-5-甲酰胺L 6的制备 (S)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-(4-chlorophenyl)-1H-pyrazole- Preparation of 5-formamide L 6
其他条件同实施例66，将4-氯苯乙酮代替2-氟苯乙酮，得到白色固体，产率为35％。 1H NMR(400MHz,DMSO-d 6):δ13.74(d,J＝56.9Hz,1H),8.08(d,J＝28.1Hz,2H),7.81(s,2H),7.52(s,4H),7.40-7.16(m,4H),4.66(s,1H),3.07(s,2H),2.61(d,J＝4.5Hz,3H). 13C NMR(100MHz,DMSO-d 6):δ171.0,162.3,140.9,132.0,130.2,129.2,129.0,128.3,126.9,121.4,79.2,37.2,35.8,30.8,25.6.HRMS(ESI, m/z):Calcd.for C 20H 18BrClN 4O 2[M+Na] +483.0194,found:483.0196. Other conditions were the same as in Example 66, and 4-chloroacetophenone was substituted for 2-fluoroacetophenone to obtain a white solid with a yield of 35%. 1 H NMR (400MHz, DMSO-d 6 ): δ13.74(d, J=56.9Hz, 1H), 8.08(d, J=28.1Hz, 2H), 7.81(s, 2H), 7.52(s, 4H ),7.40-7.16(m,4H),4.66(s,1H),3.07(s,2H),2.61(d,J＝4.5Hz,3H). 13 C NMR(100MHz,DMSO-d 6 ):δ171 .0, 162.3, 140.9, 132.0, 130.2, 129.2, 129.0, 128.3, 126.9, 121.4, 79.2, 37.2, 35.8, 30.8, 25.6. HRMS (ESI, m/z): Calcd.for C 20 H 18 BrClN 4 O 2 [ M+Na] + 483.0194, found: 483.0196.
实施例72：
Figure PCTCN2022132704-appb-000082
Example 72:
Figure PCTCN2022132704-appb-000082
(S)-3-(3-溴苯基)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-1H-吡唑-5-甲酰胺L 7的制备 (S)-3-(3-bromophenyl)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-1H-pyrazole- Preparation of 5-formamide L 7
其他条件同实施例66，将3-溴苯乙酮代替2-氟苯乙酮，得到白色固体，产率为35％。 1H NMR(400MHz,DMSO-d 6):δ13.80(d,J＝49.0Hz,1H),8.16(dd,J1＝29.5,J2＝4.8Hz,1H),8.10-7.74(m,3H),7.58-7.46(m,2H),7.46-7.36(m,2H),7.33(d,J＝11.0Hz,1H),7.28-7.13(m,2H),4.67(t,J＝7.2Hz,1H),3.18-2.89(m,2H),2.62(d,J＝4.5Hz,3H). 13C NMR(100MHz,DMSO-d 6):δ132.0,131.2,130.2,129.2,128.3,121.4.HRMS(ESI,m/z):Calcd.for C 20H 18Br 2N 4O 2[M+Na] +528.9668,found:528.9678. Other conditions were the same as in Example 66, and 3-bromoacetophenone was substituted for 2-fluoroacetophenone to obtain a white solid with a yield of 35%. 1 H NMR (400MHz, DMSO-d 6 ): δ13.80(d, J=49.0Hz, 1H), 8.16(dd, J1=29.5, J2=4.8Hz, 1H), 8.10-7.74(m, 3H) ,7.58-7.46(m,2H),7.46-7.36(m,2H),7.33(d,J=11.0Hz,1H),7.28-7.13(m,2H),4.67(t,J=7.2Hz,1H ), 3.18-2.89 (m, 2H), 2.62 (d, J=4.5Hz, 3H). 13 C NMR (100MHz, DMSO-d 6 ): δ132.0, 131.2, 130.2, 129.2, 128.3, 121.4. HRMS (ESI ,m/z):Calcd.for C 20 H 18 Br 2 N 4 O 2 [M+Na] + 528.9668,found:528.9678.
实施例73：
Figure PCTCN2022132704-appb-000083
Example 73:
Figure PCTCN2022132704-appb-000083
(S)-3-(4-溴苯基)-N-(3-(3-溴苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-1H-吡唑-5-甲酰胺L 8的制备 (S)-3-(4-bromophenyl)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-1H-pyrazole - Preparation of 5-carboxamide L 8
其他条件同实施例66，将4-溴苯乙酮代替2-氟苯乙酮，得到白色固体，产率为37％。 1H NMR(400MHz,DMSO-d 6):δ13.73(d,J＝56.7Hz,1H),8.23-8.01(m,2H),7.73(d,J＝9.8Hz,2H),7.66(d,J＝10.2Hz,2H),7.52(d,J＝32.8Hz,1H),7.35(d,J＝8.2Hz,2H),7.27(d,J＝23.8Hz,1H),7.20(t,J＝7.7Hz,1H),4.66(s,1H),3.16–2.89(m,2H),2.62(d,J＝4.6Hz,3H). 13C NMR(100MHz,DMSO-d 6):δ171.0,132.0,130.2,129.2,128.3,121.4,25.7.HRMS(ESI,m/z):Calcd.for C 20H 18Br 2N 4O 2[M+Na]+528.9668,found:528.9675. Other conditions were the same as in Example 66, and 4-bromoacetophenone was substituted for 2-fluoroacetophenone to obtain a white solid with a yield of 37%. 1 H NMR (400MHz, DMSO-d 6 ): δ13.73(d, J=56.7Hz, 1H), 8.23-8.01(m, 2H), 7.73(d, J=9.8Hz, 2H), 7.66(d ,J=10.2Hz,2H),7.52(d,J=32.8Hz,1H),7.35(d,J=8.2Hz,2H),7.27(d,J=23.8Hz,1H),7.20(t,J ＝7.7Hz, 1H), 4.66(s, 1H), 3.16–2.89(m, 2H), 2.62(d, J＝4.6Hz, 3H). 13 C NMR (100MHz, DMSO-d 6 ): δ171.0, 132.0 ,130.2,129.2,128.3,121.4,25.7.HRMS(ESI,m/z): Calcd.for C 20 H 18 Br 2 N 4 O 2 [M+Na]+528.9668,found:528.9675.
实施例74：
Figure PCTCN2022132704-appb-000084
Example 74:
Figure PCTCN2022132704-appb-000084
(S)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-3-(2-硝基苯基)-1H-吡唑-5-甲酰胺L 9的制备 (S)-N-(3-(3-Bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-(2-nitrophenyl)-1H-pyrazole - Preparation of 5-carboxamide L 9
其他条件同实施例66，将2-硝基苯乙酮代替2-氟苯乙酮，得到白色固体，产率 为37％。 1H NMR(400MHz,DMSO-d 6):δ13.80(s,1H),8.51(d,J＝281.5Hz,2H),7.80(d,J＝42.5Hz,3H),7.57(d,J＝24.4Hz,2H),7.38-7.34(m,1H),7.30(d,J＝7.6Hz,1H),7.21(t,J＝7.8Hz,2H),4.67-4.61(m,1H),3.14-2.86(m,2H),2.62(d,J＝4.5Hz,3H).HRMS(ESI,m/z):Calcd.for C 20H 18BrN 5O 4[M+Na] +494.0434,found:494.0434. Other conditions were the same as in Example 66, and 2-nitroacetophenone was substituted for 2-fluoroacetophenone to obtain a white solid with a yield of 37%. 1 H NMR (400MHz, DMSO-d 6 ): δ13.80(s, 1H), 8.51(d, J=281.5Hz, 2H), 7.80(d, J=42.5Hz, 3H), 7.57(d, J =24.4Hz, 2H), 7.38-7.34(m, 1H), 7.30(d, J=7.6Hz, 1H), 7.21(t, J=7.8Hz, 2H), 4.67-4.61(m, 1H), 3.14 -2.86(m,2H),2.62(d,J＝4.5Hz,3H).HRMS(ESI,m/z): Calcd.for C 20 H 18 BrN 5 O 4 [M+Na] + 494.0434,found: 494.0434.
实施例75：
Figure PCTCN2022132704-appb-000085
Example 75:
Figure PCTCN2022132704-appb-000085
(S)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-3-(3-硝基苯基)-1H-吡唑-5-甲酰胺L 10的制备 (S)-N-(3-(3-Bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-(3-nitrophenyl)-1H-pyrazole - Preparation of 5-carboxamide L 10
其他条件同实施例66，将3-硝基苯乙酮代替2-氟苯乙酮，得到白色固体，产率为32％。 1H NMR(400MHz,DMSO-d 6):δ14.00(d,J＝89.9Hz,1H),8.93-8.50(m,2H),8.31-8.09(m,3H),7.77-7.73(m,1H),7.65-7.46(m,2H),7.35(d,J＝8.3Hz,1H),7.33-7.24(m,1H),7.21(t,J＝7.8Hz,1H),4.67(d,J＝8.0Hz,1H),3.14-3.04(m,1H),3.05-2.90(m,1H),2.62(d,J＝4.1Hz,3H). Other conditions were the same as in Example 66, and 3-nitroacetophenone was substituted for 2-fluoroacetophenone to obtain a white solid with a yield of 32%. 1 H NMR (400MHz, DMSO-d 6 ): δ14.00 (d, J=89.9Hz, 1H), 8.93-8.50 (m, 2H), 8.31-8.09 (m, 3H), 7.77-7.73 (m, 1H), 7.65-7.46(m, 2H), 7.35(d, J=8.3Hz, 1H), 7.33-7.24(m, 1H), 7.21(t, J=7.8Hz, 1H), 4.67(d, J =8.0Hz,1H),3.14-3.04(m,1H),3.05-2.90(m,1H),2.62(d,J=4.1Hz,3H).
实施例76：
Figure PCTCN2022132704-appb-000086
Example 76:
Figure PCTCN2022132704-appb-000086
(S)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-3-(3-羟基苯基)-1H-吡唑-5-甲酰胺L 11的制备 (S)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-(3-hydroxyphenyl)-1H-pyrazole- Preparation of 5-formamide L 11
其他条件同实施例66，将3-羟基苯乙酮代替2-氟苯乙酮，得到白色固体，产率为36％。 1H NMR(400MHz,DMSO-d 6):δ13.60(d,J＝53.3Hz,1H),9.72(s,1H),8.10(d,J＝45.2Hz,1H),7.50(s,1H),7.40-7.33(m,1H),7.32-7.25(m,2H),7.23-7.18(m,4H),6.86(d,J＝61.1Hz,2H),4.65(q,J＝8.4,7.8Hz,1H),3.14-2.93(m,2H),2.61(d,J＝4.5Hz,3H). Other conditions were the same as in Example 66, and 3-hydroxyacetophenone was substituted for 2-fluoroacetophenone to obtain a white solid with a yield of 36%. 1 H NMR (400MHz, DMSO-d 6 ): δ13.60(d, J=53.3Hz, 1H), 9.72(s, 1H), 8.10(d, J=45.2Hz, 1H), 7.50(s, 1H ),7.40-7.33(m,1H),7.32-7.25(m,2H),7.23-7.18(m,4H),6.86(d,J=61.1Hz,2H),4.65(q,J=8.4,7.8 Hz,1H),3.14-2.93(m,2H),2.61(d,J＝4.5Hz,3H).
实施例77：
Figure PCTCN2022132704-appb-000087
Example 77:
Figure PCTCN2022132704-appb-000087
(S)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-3-(4-羟基苯基)-1H-吡唑-5-甲酰胺L 12的制备 (S)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-(4-hydroxyphenyl)-1H-pyrazole- Preparation of 5-formamide L 12
其他条件同实施例66，将4-羟基苯乙酮代替2-氟苯乙酮，得到白色固体，产率为35％。 1H NMR(400MHz,DMSO-d 6)δ13.50(s,1H),9.82(s,1H),8.07(d,J＝58.8Hz,2H),7.63-7.45(m,3H),7.39-7.33(m,1H),7.30-7.17(m,2H),6.85(d,J＝8.3Hz,2H),4.69-4.63(m,1H),3.13-2.95(m,2H),2.61(d,J＝4.5Hz,3H). Other conditions were the same as in Example 66, and 4-hydroxyacetophenone was substituted for 2-fluoroacetophenone to obtain a white solid with a yield of 35%. 1 H NMR (400MHz, DMSO-d 6 ) δ13.50(s, 1H), 9.82(s, 1H), 8.07(d, J=58.8Hz, 2H), 7.63-7.45(m, 3H), 7.39- 7.33(m,1H),7.30-7.17(m,2H),6.85(d,J＝8.3Hz,2H),4.69-4.63(m,1H),3.13-2.95(m,2H),2.61(d, J＝4.5Hz,3H).
实施例78：
Figure PCTCN2022132704-appb-000088
Example 78:
Figure PCTCN2022132704-appb-000088
(S)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-3-(邻甲苯基)-1H-吡唑-5-甲酰胺L 13的制备 (S)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-(o-tolyl)-1H-pyrazole-5- Preparation of formamide L 13
制备方法同实施例66，将步骤一用2-甲基苯乙酮代替2-氟苯乙酮，得到白色固体，产率为33％。HRMS(ESI,m/z):Calcd.for C 21H 21BrN 4O 2[M+Na] +463.0740,found:463.0743. The preparation method was the same as in Example 66, except that 2-methylacetophenone was used instead of 2-fluoroacetophenone in Step 1 to obtain a white solid with a yield of 33%. HRMS (ESI, m/z): Calcd. for C 21 H 21 BrN 4 O 2 [M+Na] + 463.0740, found: 463.0743.
实施例79：
Figure PCTCN2022132704-appb-000089
Example 79:
Figure PCTCN2022132704-appb-000089
(S)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-3-(间甲苯基)-1H-吡唑-5-甲酰胺L 14的制备 (S)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-(m-tolyl)-1H-pyrazole-5- Preparation of formamide L 14
其他条件同实施例66，将3-甲基苯乙酮代替2-氟苯乙酮，得到白色固体，产率为35％。 1H NMR(400MHz,DMSO-d 6):δ13.70(s,1H),8.18(s,1H),7.66-7.56(m,2H),7.51(s,1H),7.36-7.27(m,3H),7.24-7.12(m,2H),4.63-4.69(m,1H),3.20-2.90(m,2H),2.61(d,J＝4.5Hz,3H),2.35(s,3H). 13C NMR(75MHz,DMSO-d 6):δ171.1,141.0,132.0,130.3,129.3,128.9,128.4,125.8,122.4,121.4,102.7,37.2,25.7,21.1. Other conditions were the same as in Example 66, and 3-methylacetophenone was substituted for 2-fluoroacetophenone to obtain a white solid with a yield of 35%. 1 H NMR (400MHz,DMSO-d 6 ):δ13.70(s,1H),8.18(s,1H),7.66-7.56(m,2H),7.51(s,1H),7.36-7.27(m, 13 C NMR (75MHz, DMSO-d 6 ): δ171.1, 141.0, 132.0, 130.3, 129.3, 128.9, 128.4, 125.8, 122.4, 121.4, 102.7, 37.2, 25.7, 21.1.
实施例80：
Figure PCTCN2022132704-appb-000090
Example 80:
Figure PCTCN2022132704-appb-000090
(S)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-3-(对甲苯基)-1H-吡唑-5-甲酰胺L 15的制备 (S)-N-(3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-(p-tolyl)-1H-pyrazole-5- Preparation of formamide L 15
其他条件同实施例66，将4-甲基苯乙酮代替2-氟苯乙酮，得到白色固体，产率为36％。 1H NMR(400MHz,DMSO-d 6):δ8.53(d,J＝8.5Hz,1H),8.04(q,J＝4.5Hz,1H),7.75-7.69(m,2H),7.56(t,J＝1.8Hz,1H),7.37-7.29(m,2H),7.27-7.17(m, 3H),4.63(ddd,J 1＝10.6,J 2＝8.4,J 3＝4.3Hz,1H),3.08(dd,J 1＝13.6,J 2＝4.3Hz,1H),3.00-2.93(m,1H),2.62(d,J＝4.6Hz,3H),2.33(s,3H). 13C NMR(100MHz,DMSO-d 6):δ171.5,166.2,141.5,141.2,132.0,131.2,130.2,129.1,128.7,128.3,127.5,121.4,54.7,36.9,25.7,21.0.HRMS(ESI,m/z):Calcd.for C 21H 21BrN 4O 2[M+Na] +463.0740,found:463.0745. Other conditions were the same as in Example 66, and 4-methylacetophenone was substituted for 2-fluoroacetophenone to obtain a white solid with a yield of 36%. 1 H NMR (400MHz, DMSO-d 6 ): δ8.53(d, J=8.5Hz, 1H), 8.04(q, J=4.5Hz, 1H), 7.75-7.69(m, 2H), 7.56(t ,J＝1.8Hz,1H),7.37-7.29(m,2H),7.27-7.17(m,3H),4.63(ddd,J 1 ＝10.6,J 2 ＝8.4,J 3 ＝4.3Hz,1H), 13 C NMR ( 100MHz, DMSO-D 6 ): Δ171.5,166.2,141.5,141.2,132.0,130.2,129.1,128.7,127.5,121.4,54.7,25.7, 21.0.0.0.0.0.0.0.0.0.0.0.0.0.0.0.0.0.0.0.0.0.0.0.0.0.0.0.0.0.0.0. : CALCD .for C 21 H 21 BrN 4 O 2 [M+Na] + 463.0740,found: 463.0745.
实施例81：
Figure PCTCN2022132704-appb-000091
Example 81:
Figure PCTCN2022132704-appb-000091
(S)-N-(3-(3,5-二氟苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-3-苯基-1H-吡唑-5-甲酰胺L 16的制备 (S)-N-(3-(3,5-difluorophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-phenyl-1H-pyrazole-5 - Preparation of formamide L 16
其他条件同实施例66，将苯乙酮代替2-氟苯乙酮，将(S)-2-氨基-3-(3-溴苯基)-N-甲基丙酰胺替换为(S)-2-氨基-3-(3,5-二氟苯基)-N-甲基丙酰胺，得到白色固体，产率为37％。 1H NMR(400MHz,MeOH-d 4):δ7.78-7.57(m,3H),7.44(t,J＝7.5Hz,2H),7.36(dd,J 1＝8.3,J 2＝6.3Hz,1H),7.02(s,1H),6.90(h,J＝4.2Hz,2H),6.77(dd,J 1＝9.2,J 2＝2.4Hz,1H),4.82(dd,J 1＝8.6,J 2＝6.0Hz,1H),3.23(dd,J 1＝13.7,J 2＝6.0Hz,2H),2.74(d,J＝4.2Hz,3H). 13C NMR(100MHz,MeOH-d 4):δ130.1,126.6,113.4,113.1,103.7,103.070,55.407,26.507,26.4. Other conditions are the same as in Example 66, replacing 2-fluoroacetophenone with acetophenone, and replacing (S)-2-amino-3-(3-bromophenyl)-N-methylpropionamide with (S)- 2-Amino-3-(3,5-difluorophenyl)-N-methylpropanamide, a white solid was obtained with a yield of 37%. 1 H NMR (400MHz, MeOH-d 4 ): δ7.78-7.57 (m, 3H), 7.44 (t, J = 7.5Hz, 2H), 7.36 (dd, J 1 = 8.3, J 2 = 6.3Hz, 1H),7.02(s,1H),6.90(h,J=4.2Hz,2H),6.77(dd,J 1 =9.2,J 2 =2.4Hz,1H),4.82(dd,J 1 =8.6,J 2 = 6.0Hz, 1H), 3.23 (dd, J 1 = 13.7, J 2 = 6.0Hz, 2H), 2.74 (d, J = 4.2Hz, 3H). 13 C NMR (100MHz, MeOH-d 4 ): δ130.1, 126.6, 113.4, 113.1, 103.7, 103.070, 55.407, 26.507, 26.4.
实施例82：
Figure PCTCN2022132704-appb-000092
Example 82:
Figure PCTCN2022132704-appb-000092
(S)-N-(3-(3,5-二氯苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-3-苯基-1H-吡唑-5-甲酰胺L 17的制备 (S)-N-(3-(3,5-dichlorophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-phenyl-1H-pyrazole-5 - Preparation of formamide L 17
其他条件同实施例66，将苯乙酮代替2-氟苯乙酮，将(S)-2-氨基-3-(3-溴苯基)-N-甲基丙酰胺换为(S)-2-氨基-3-(3,5-二氯苯基)-N-甲基丙酰胺，得到白色固体，产率为38％。 1H NMR(400MHz,MeOH-d 4):δ7.76-7.57(m,3H),7.43(dd,J 1＝8.3,J 2＝6.7Hz,2H),7.38-7.32(m,1H),7.25(s,3H),6.97(d,J＝35.0Hz,1H),4.80(dd,J 1＝8.6,J 2＝6.0Hz,1H),3.19(dd,J 1＝13.7,J 2＝6.0Hz,1H),3.03(dd,J 1＝13.7,J 2＝8.6Hz,1H),2.73(s,3H). 13C NMR(100MHz,MeOH-d 4):δ173.3,142.5,135.9,130.1,129.1,127.8,126.6,103.7,55.4,26.4. Other conditions are the same as in Example 66, replacing 2-fluoroacetophenone with acetophenone, and replacing (S)-2-amino-3-(3-bromophenyl)-N-methylpropionamide with (S)- 2-Amino-3-(3,5-dichlorophenyl)-N-methylpropanamide, a white solid was obtained with a yield of 38%. 1 H NMR (400MHz, MeOH-d 4 ): δ7.76-7.57(m, 3H), 7.43(dd, J 1 =8.3, J 2 =6.7Hz, 2H), 7.38-7.32(m, 1H), 7.25(s,3H),6.97(d,J=35.0Hz,1H),4.80(dd, J1 =8.6, J2 =6.0Hz,1H),3.19(dd, J1 =13.7, J2 =6.0 Hz, 1H), 3.03 (dd, J 1 =13.7, J 2 =8.6Hz, 1H), 2.73 (s, 3H). 13 C NMR (100MHz, MeOH-d 4 ): δ173.3, 142.5, 135.9, 130.1, 129.1, 127.8, 126.6, 103.7, 55.4, 26.4.
实施例83：
Figure PCTCN2022132704-appb-000093
Example 83:
Figure PCTCN2022132704-appb-000093
(S)-N-(3-(3,5-二溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-3-苯基-1H-吡唑-5-甲酰胺L 18的制备 (S)-N-(3-(3,5-Dibromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-phenyl-1H-pyrazole-5- Preparation of formamide L 18
其他条件同实施例66，将苯乙酮代替2-氟苯乙酮，将(S)-2-氨基-3-(3-溴苯基)-N-甲基丙酰胺换为(S)-2-氨基-3-(3,5-二溴苯基)-N-甲基丙酰胺，得到白色固体，产率为39％。 1H NMR(400MHz,DMSO-d 6):δ13.77-13.49(m,1H),8.10(dd,J 1＝18.1,J 2＝6.8Hz,2H),7.82-7.75(m,2H),7.63(d,J＝1.9Hz,1H),7.59-7.50(m,2H),7.45(q,J＝7.9Hz,2H),7.40-7.33(m,1H),4.66(dd,J 1＝9.0,J 2＝5.4Hz,1H),3.15-2.87(m,2H),2.63(d,J＝4.5Hz,3H). 13C NMR(100MHz,DMSO-d 6):δ143.1,131.3,129.1,125.3,122.0,25.6.HRMS(ESI,m/z):Calcd.for C 20H 18Br 2N 4O 2[M+Na] +528.9668,found:528.9676. Other conditions are the same as in Example 66, replacing 2-fluoroacetophenone with acetophenone, and replacing (S)-2-amino-3-(3-bromophenyl)-N-methylpropionamide with (S)- 2-Amino-3-(3,5-dibromophenyl)-N-methylpropanamide was obtained as a white solid with a yield of 39%. 1 H NMR (400MHz, DMSO-d 6 ): δ13.77-13.49 (m, 1H), 8.10 (dd, J 1 = 18.1, J 2 = 6.8Hz, 2H), 7.82-7.75 (m, 2H), 7.63 (d, J = 1.9Hz, 1H), 7.59-7.50 (m, 2H), 7.45 (q, J = 7.9Hz, 2H), 7.40-7.33 (m, 1H), 4.66 (dd, J 1 = 9.0 , J 2 =5.4Hz, 1H), 3.15-2.87(m, 2H), 2.63(d, J=4.5Hz, 3H). 13 C NMR (100MHz, DMSO-d 6 ): δ143.1, 131.3, 129.1, 125.3 ,122.0,25.6.HRMS(ESI,m/z):Calcd.for C 20 H 18 Br 2 N 4 O 2 [M+Na] + 528.9668,found:528.9676.
实施例84：
Figure PCTCN2022132704-appb-000094
Example 84:
Figure PCTCN2022132704-appb-000094
(S)-N-(3-(3-溴-5-氟苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-3-苯基-1H-吡唑-5-甲酰胺L 19的制备 (S)-N-(3-(3-bromo-5-fluorophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-phenyl-1H-pyrazole- Preparation of 5-formamide L 19
其他条件同实施例66，将苯乙酮代替2-氟苯乙酮，将(S)-2-氨基-3-(3-溴苯基)-N-甲基丙酰胺换为(S)-2-氨基-3-(3-溴-5-氟苯基)-N-甲基丙酰胺，得到白色固体，产率为35％。 1H NMR(400MHz,DMSO-d 6):δ13.64(d,J＝55.7Hz,1H),8.09(dd,J 1＝17.3,J 2＝6.8Hz,2H),7.83-7.74(m,2H),7.50-7.29(m,5H),7.16(d,J＝10.1Hz,1H),4.69(q,J＝8.5,7.8Hz,1H),3.19-2.86(m,2H),2.63(d,J＝4.5Hz,3H). 13C NMR(100MHz,DMSO-d 6):δ129.1,128.5,125.3,37.0,25.7.HRMS(ESI,m/z):Calcd.for C 20H 18BrFN 4O 2[M+Na] +467.0489,found:467.0489. Other conditions are the same as in Example 66, replacing 2-fluoroacetophenone with acetophenone, and replacing (S)-2-amino-3-(3-bromophenyl)-N-methylpropionamide with (S)- 2-Amino-3-(3-bromo-5-fluorophenyl)-N-methylpropanamide, a white solid was obtained with a yield of 35%. 1 H NMR (400MHz, DMSO-d 6 ): δ13.64 (d, J = 55.7Hz, 1H), 8.09 (dd, J 1 = 17.3, J 2 = 6.8Hz, 2H), 7.83-7.74 (m, 2H), 7.50-7.29(m, 5H), 7.16(d, J=10.1Hz, 1H), 4.69(q, J=8.5, 7.8Hz, 1H), 3.19-2.86(m, 2H), 2.63(d , J＝4.5Hz, 3H). 13 C NMR (100MHz, DMSO-d 6 ): δ129.1, 128.5, 125.3, 37.0, 25.7. HRMS (ESI, m/z): Calcd.for C 20 H 18 BrFN 4 O 2 [M+Na] + 467.0489, found: 467.0489.
实施例85：
Figure PCTCN2022132704-appb-000095
Example 85:
Figure PCTCN2022132704-appb-000095
(S)-N-(3-(2-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-3-苯基-1H-吡唑-5-甲酰胺L 20的制备 (S)-N-(3-(2-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-phenyl-1H-pyrazole-5-carboxamide L Preparation of 20
其他条件同实施例66，将苯乙酮代替2-氟苯乙酮，将(S)-2-氨基-3-(3-溴苯基)-N-甲基丙酰胺换为(S)-2-氨基-3-(2-溴苯基)-N-甲基丙酰胺，得到白色固体，产率为37％。 1H NMR(400MHz,CDCl 3):δ9.69(d,J＝8.5Hz,1H),7.70(dd,J 1＝30.8,J 2＝7.7Hz,3H),7.37-7.30(m,3H),7.29-7.24(m,2H),7.20-7.14(m,1H),7.09(t,J＝7.4Hz,1H),6.96(s,1H),6.91(t,J＝7.7Hz,1H),5.06(q,J＝8.1Hz,1H),3.27-3.16(q,J＝11.6,9.3Hz,2H),2.80-2.70(m,3H). 13C NMR(100MHz,CDCl 3):δ136.3,133.1,129.2,128.9,128.7,125.6,29.8,26.6,1.1. Other conditions are the same as in Example 66, replacing 2-fluoroacetophenone with acetophenone, and replacing (S)-2-amino-3-(3-bromophenyl)-N-methylpropionamide with (S)- 2-Amino-3-(2-bromophenyl)-N-methylpropanamide, a white solid was obtained with a yield of 37%. 1 H NMR (400MHz, CDCl 3 ): δ9.69 (d, J = 8.5Hz, 1H), 7.70 (dd, J 1 = 30.8, J 2 = 7.7Hz, 3H), 7.37-7.30 (m, 3H) ,7.29-7.24(m,2H),7.20-7.14(m,1H),7.09(t,J=7.4Hz,1H),6.96(s,1H),6.91(t,J=7.7Hz,1H), 5.06(q, J=8.1Hz, 1H), 3.27-3.16(q, J=11.6, 9.3Hz, 2H), 2.80-2.70(m, 3H). 13 C NMR(100MHz, CDCl 3 ): δ136.3, 133.1 ,129.2,128.9,128.7,125.6,29.8,26.6,1.1.
实施例86：
Figure PCTCN2022132704-appb-000096
Example 86:
Figure PCTCN2022132704-appb-000096
(S)-N-(3-(4-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-3-苯基-1H-吡唑-5-甲酰胺L 21的制备 (S)-N-(3-(4-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)-3-phenyl-1H-pyrazole-5-carboxamide L Preparation of 21
其他条件同实施例66，将苯乙酮代替2-氟苯乙酮，将(S)-2-氨基-3-(3-溴苯基)-N-甲基丙酰胺换为(S)-2-氨基-3-(4-溴苯基)-N-甲基丙酰胺，得到白色固体，产率为35％。 1H NMR(400MHz,MeOH-d 4):δ7.69(d,J＝7.8Hz,2H),7.46-7.32(m,5H),7.19-7.15(m,2H),7.02(s,1H),4.79(dd,J 1＝8.2,J 2＝6.2Hz,1H),3.17(dd,J 1＝13.8,J 2＝6.2Hz,1H),3.02(dd,J 1＝13.7,J 2＝8.2Hz,1H),2.71(s,3H). 13C NMR(100MHz,MeOH-d 4):δ173.6,137.6,132.5,132.3,130.1,126.6,121.7,103.7,55.6,38.7,26.4. Other conditions are the same as in Example 66, replacing 2-fluoroacetophenone with acetophenone, and replacing (S)-2-amino-3-(3-bromophenyl)-N-methylpropionamide with (S)- 2-Amino-3-(4-bromophenyl)-N-methylpropanamide, a white solid was obtained with a yield of 35%. 1 H NMR (400MHz, MeOH-d 4 ): δ7.69 (d, J=7.8Hz, 2H), 7.46-7.32 (m, 5H), 7.19-7.15 (m, 2H), 7.02 (s, 1H) , 4.79 (dd, J 1 =8.2, J 2 =6.2Hz, 1H), 3.17 (dd, J 1 =13.8, J 2 =6.2Hz, 1H), 3.02 (dd, J 1 =13.7, J 2 =8.2 Hz,1H),2.71(s,3H). 13 C NMR(100MHz,MeOH-d 4 ):δ173.6,137.6,132.5,132.3,130.1,126.6,121.7,103.7,55.6,38.7,26.4.
生物活性测试Biological activity test
cAMP的累积水平主要利用GloSensor方法，一种基于生物发光的cAMP生物传感器(Promega)来测试。将状态良好的HEK293T细胞种于6孔板或者35MM细胞培养皿中，放置在37℃，5％CO 2培养箱培养24h，使细胞贴壁生长。后用转染试剂将β 2肾上腺素受体质粒和pGloSensor TM-22FcAMP质粒转入细胞内，放于37℃5％CO 2培养箱培养24h，使目的基因转录和表达。接着将转染了质粒的细胞均匀种于96孔板，在37℃，5％CO 2培养箱培养24h。最后，吸弃96孔板旧的培养液，用新的培养液洗一遍细胞，然后加入含GloSensor TM cAMP Reagent、血清和CO 2-independent medium的平衡培养液在37℃，5％CO 2培养箱培养1-2h或直到获得一个稳定的背景信号。将异丙肾上腺素(ISO)用DMSO溶解，除菌过 滤后作为化合物母液用培养液稀释到不同浓度梯度(所配制的化合物中DMSO浓度小于或等于0.1％)。将配制好的化合物迅速加入到含HEK293T细胞的96孔板中开始给药刺激。通过多功能酶标仪可以观测到加入化合物后的生物发光信号快速上升，当信号值上升到顶点不再升高时立即加入不同浓度梯度(8μM,20μM,50μM,100μM)的化合物。同时立即用多功能酶标仪收集生物发光信号，生物发光信号值随化合物浓度增加而升高。最后将数据整理后用GraphPad Prism8软件处理以浓度为横坐标，信号值、倍数值响应值为纵坐标获得激动剂、拮抗剂和别构调节剂的量效关系曲线和合物的EC 50或IC 50值。 The accumulation level of cAMP was mainly tested using the GloSensor method, a bioluminescence based cAMP biosensor (Promega). HEK293T cells in good condition were planted in 6-well plates or 35MM cell culture dishes, and placed in a 37°C, 5% CO 2 incubator for 24 hours to allow the cells to adhere to the wall and grow. Afterwards, the β2 adrenoreceptor plasmid and the pGloSensor TM -22FcAMP plasmid were transferred into the cells with a transfection reagent, and placed in a 5% CO 2 incubator at 37°C for 24 hours to allow the transcription and expression of the target gene. Then, the cells transfected with the plasmid were evenly seeded in a 96-well plate, and cultured at 37° C. in a 5% CO 2 incubator for 24 hours. Finally, discard the old culture medium in the 96-well plate, wash the cells with new culture medium, and then add the balanced culture medium containing GloSensor TM cAMP Reagent, serum and CO 2 -independent medium at 37°C, 5% CO 2 incubator Incubate for 1-2 hours or until a stable background signal is obtained. Isoproterenol (ISO) was dissolved in DMSO, and after sterile filtration, it was used as the compound mother solution and diluted with culture medium to different concentration gradients (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 plate containing HEK293T cells to start administration stimulation. The bioluminescent signal after adding the compound can be observed by a multi-functional microplate reader. When the signal value rises to the peak and no longer increases, immediately add the compound with different concentration gradients (8μM, 20μM, 50μM, 100μM). At the same time, the bioluminescent signal was collected immediately with a multifunctional microplate reader, and the value of the bioluminescent signal increased with the increase of the compound concentration. Finally, the data was sorted and processed with GraphPad Prism8 software, with the concentration as the abscissa, and the signal value, multiple value response value as the ordinate, to obtain the dose-effect relationship curve of the agonist, antagonist and allosteric modulator and the EC 50 or IC 50 of the compound value.
表2-1H、I类衍生物的生物活性测试结果统计表Table 2-1 Statistical table of biological activity test results of H and I derivatives
Figure PCTCN2022132704-appb-000097
Figure PCTCN2022132704-appb-000097
Figure PCTCN2022132704-appb-000098
Figure PCTCN2022132704-appb-000098
表2-2 L类衍生物的生物活性测试结果统计表Table 2-2 Statistical table of biological activity test results of L derivatives
Figure PCTCN2022132704-appb-000099
Figure PCTCN2022132704-appb-000099
Figure PCTCN2022132704-appb-000100
Figure PCTCN2022132704-appb-000100
注：其中“+”表示具有相应活性“-”表示无相应活性Note: "+" means corresponding activity, "-" means no corresponding activity
表3-1 H、I类衍生物的别构活性与Cmpd-15活性比较结果统计表Table 3-1 Statistical table of comparison results of allosteric activities of class H and class I derivatives and Cmpd-15 activity
Figure PCTCN2022132704-appb-000101
Figure PCTCN2022132704-appb-000101
Figure PCTCN2022132704-appb-000102
Figure PCTCN2022132704-appb-000102
表3-2 L类衍生物的别构活性与Cmpd-15活性比较结果统计表Table 3-2 Statistical table of comparison results of allosteric activity of L derivatives and Cmpd-15 activity
Figure PCTCN2022132704-appb-000103
Figure PCTCN2022132704-appb-000103
Figure PCTCN2022132704-appb-000104
Figure PCTCN2022132704-appb-000104
注： a数值表示为相对于Cmpd-15的阻断活性 Note: a value is expressed as the blocking activity relative to Cmpd-15
在Glosensor cAMP累积试验测试结果中，化合物H 31不仅具有激动β 2AR的作用，还能发挥正向别构调节β 2AR激动剂ISO的功能活性，是β 2-肾上腺素受体的别构激动剂，随着该化合物浓度的不断升高，ISO的量效曲线呈现有限的上移趋势(图1)。而化合物L 1，L 4，L 14能够负向别构调节β 2AR内源性配体ISO的功能活性，是β 2-肾上腺素受体的别构拮抗剂，随着该化合物浓度的不断升高，ISO的量效曲线呈现有限的下移趋势(图3)。 According to the test results of Glosensor cAMP accumulation test, compound H 31 not only has the effect of agonizing β 2 AR, but also can positively regulate the functional activity of β 2 AR agonist ISO . For agonists, with the continuous increase of the concentration of the compound, the dose-effect curve of ISO showed a limited upward trend (Figure 1). Compounds L 1 , L 4 , and L 14 can negatively regulate the functional activity of β 2 AR endogenous ligand ISO, and are allosteric antagonists of β 2 -adrenergic receptors. The dose-effect curve of ISO showed a limited downward trend (Figure 3).
同时，这些结果表明，Cmpd-15结构中右边(S)-2-氨基-3-(3-溴苯基)-N-甲基丙酰胺为重要活性部分，若将该部分换为其他不同取代的胺,所得化合物的拮抗活性较弱或没有。此外，吡唑苄基苯环上有吸电子取代基(例如，NO 2，F和Br等)的新化合物具有更好的别构活性,其中N-2位取代化合物别构拮抗活性均好N-1位取代化合物。而不含苄基的吡唑类化合物,当取代基为吸电子基团时(例如，NO 2，F和Cl等),则表现出更好的β 2-肾上腺素受体的拮抗活性。 At the same time, these results show that the right (S)-2-amino-3-(3-bromophenyl)-N-methylpropanamide in the Cmpd-15 structure is an important active part, if the part is replaced by other different amines, the antagonistic activity of the obtained compounds is weak or absent. In addition, the new compounds with electron-withdrawing substituents (for example, NO 2 , F and Br, etc.) on the pyrazole benzyl benzene ring have better allosteric activity, and the allosteric antagonistic activity of the N-2-substituted compounds is good. -1-position substituted compound. However, when the substituent is an electron-withdrawing group (for example, NO 2 , F and Cl, etc.), the pyrazole compounds without benzyl group exhibit better β 2 -adrenergic receptor antagonistic activity.

Claims (5)

  1. 一种吡唑类衍生物在作为β 2肾上腺素受体别构调节剂中的应用，其特征在于：所述吡唑类衍生物的结构如式1中化合物H或化合物I或化合物L所示： A kind of application of pyrazole derivatives as β2 adrenoreceptor allosteric modulator, it is characterized in that: the structure of described pyrazole derivatives is shown in compound H or compound I or compound L in formula 1 :
    Figure PCTCN2022132704-appb-100001
    Figure PCTCN2022132704-appb-100001
    所述R 1＝H,F,Cl,Br,I,NO 2,CH 3,OCH 3,OH中的任意一种； The R 1 = any one of H, F, Cl, Br, I, NO 2 , CH 3 , OCH 3 , OH;
    所述R 2＝H,F,Cl,Br,NO 2,OCH 3,CN中的任意一种； The R 2 = any one of H, F, Cl, Br, NO 2 , OCH 3 , CN;
    所述R 3＝H,F,Cl,Br中的任意一种； The R 3 = any one of H, F, Cl, Br;
    所述R 4＝H,F,Cl,Br中的任意一种。 The R 4 =any one of H, F, Cl, Br.
  2. 根据权利要求1所述一种吡唑类衍生物在作为β 2肾上腺素受体别构调节剂中的应用，其特征在于：所述β 2肾上腺素受体别构调节剂包括β 2肾上腺素受体别构激动剂和β 2肾上腺素受体别构拮抗剂；其中作为β 2肾上腺素受体别构激动剂的吡唑类衍生物的结构式为： According to claim 1, the application of a pyrazole derivative as a β2 adrenoceptor allosteric modulator, is characterized in that: the β2 adrenoceptor allosteric modulator includes β2 adrenaline Receptor allosteric agonist and β 2 adrenoceptor allosteric antagonist; wherein the structural formula of the pyrazole derivative as β 2 adrenoceptor allosteric agonist is:
    Figure PCTCN2022132704-appb-100002
    Figure PCTCN2022132704-appb-100002
  3. 根据权利要求2所述一种吡唑类衍生物在作为β 2肾上腺素受体别构调节剂中的应用，其特征在于：所述作为β 2肾上腺素受体别构拮抗剂的吡唑类衍生物为以下结构式中的一种： According to the application of a kind of pyrazole derivatives as β2 adrenoceptor allosteric modulator according to claim 2, it is characterized in that: the pyrazoles as β2 adrenergic receptor allosteric antagonist Derivatives are one of the following structural formulas:
    Figure PCTCN2022132704-appb-100003
    Figure PCTCN2022132704-appb-100003
    所述R 1＝H,F,Cl,Br,NO 2,CH 3,OCH 3,OH中的任意一种； The R 1 = any one of H, F, Cl, Br, NO 2 , CH 3 , OCH 3 , OH;
    所述R 2＝H,Br,NO 2,OCH 3中的任意一种； The R 2 = any one of H, Br, NO 2 , OCH 3 ;
    所述R 3＝H,Br中的任意一种； The R 3 = any one of H and Br;
    所述R 4＝H中的任意一种。 Any one of R 4 =H.
  4. 一种吡唑类衍生物在作为β 2肾上腺素受体激动剂中的应用，其特征在于：所述吡唑类衍生物为以下结构式中的一种： An application of a pyrazole derivative as a β2 adrenoceptor agonist, characterized in that: the pyrazole derivative is one of the following structural formulas:
    Figure PCTCN2022132704-appb-100004
    Figure PCTCN2022132704-appb-100004
  5. 一种吡唑类衍生物在作为β 2肾上腺素受体拮抗剂的应用，其特征在于：吡唑类衍生物的结构式为： A kind of application of pyrazole derivatives as β2 adrenoceptor antagonist is characterized in that: the structural formula of pyrazole derivatives is:
    Figure PCTCN2022132704-appb-100005
    Figure PCTCN2022132704-appb-100005
    所述R 1＝H,F,Cl,Br,I,NO 2,CH 3,OCH 3,OH中的任意一种； The R 1 = any one of H, F, Cl, Br, I, NO 2 , CH 3 , OCH 3 , OH;
    所述R 2＝H,F,Cl,Br,NO 2,OCH 3,CN中的任意一种； The R 2 = any one of H, F, Cl, Br, NO 2 , OCH 3 , CN;
    所述R 3＝F,Cl,Br中的任意一种； The R 3 = any one of F, Cl, Br;
    所述R 4＝H,F,Cl,Br中的任意一种。 The R 4 =any one of H, F, Cl, Br.
PCT/CN2022/132704 2022-10-27 2022-11-18 APPLICATION OF PYRAZOLE DERIVATIVE AS β2 ADRENERGIC RECEPTOR ALLOSTERIC MODULATOR, ANTAGONIST AND AGONIST WO2023165168A1 (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004104001A2 (en) * 2003-05-21 2004-12-02 Prosidion Limited Pyrrolopyridine-2-carboxylic acid amide inhibitors of glycogen phoshorylase
CN106749511A (en) * 2017-01-09 2017-05-31 常州大学 Phenylalanine dipeptide phenyl acetamide derivative and its production and use
CN114057646A (en) * 2021-12-14 2022-02-18 常州大学 Pyrazole derivative and application thereof in preparation of antitumor drugs

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004104001A2 (en) * 2003-05-21 2004-12-02 Prosidion Limited Pyrrolopyridine-2-carboxylic acid amide inhibitors of glycogen phoshorylase
CN106749511A (en) * 2017-01-09 2017-05-31 常州大学 Phenylalanine dipeptide phenyl acetamide derivative and its production and use
CN114057646A (en) * 2021-12-14 2022-02-18 常州大学 Pyrazole derivative and application thereof in preparation of antitumor drugs

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