CN117050075A - Biaryl ring BET inhibitor and synthetic method and application thereof - Google Patents

Abstract

The invention discloses biaryl ring BET inhibitors, a synthesis method and application thereof. The biaryl ring structure compound provided by the invention has a novel structure and an excellent inhibition effect on BET proteins. Those skilled in the art know that BET protein is a target for tumor or inflammation treatment, and therefore, the biaryl compound provided by the invention can be used for preparing an anti-tumor drug or an anti-inflammation drug independently, or can be used for preparing an anti-tumor drug in combination with other anti-tumor components, such as a PARP inhibitor, a CDK4/6 inhibitor, an ATR inhibitor, a PD-1 antibody or a small molecule inhibitor, a PD-L1 antibody or a small molecule inhibitor, an EZH2 inhibitor or an AR inhibitor.

Description

Translated fromChinese

一类联芳环类BET抑制剂及合成方法与用途A type of biaryl ring BET inhibitor and its synthesis method and use

技术领域Technical Field

本发明属于药物化学领域，具体涉及一类联芳环类BET抑制剂及合成方法与用途。The present invention belongs to the field of medicinal chemistry, and specifically relates to a class of biaryl ring BET inhibitors and a synthesis method and use thereof.

背景技术Background Art

表观遗传靶点溴结构域和超末端结构域(BET)蛋白家族在肿瘤及炎症治疗中是一个极其重要的靶点。BET蛋白家族包含4种亚型，分别是BRD2、BRD3、BRD4和BRDT。BET家族蛋白都包含了两个高度保守的N端串联溴构域BD1和BD2，以BRD4为例，BRD4 N末端第一个溴结构域以BRD4(1)表示，BRD4 N末端第二个溴结构域以BRD4(2)表示。BET蛋白通过溴结构域识别组蛋白和其它蛋白的乙酰化赖氨酸残基，在调控基因表达和控制细胞生长方面起着重要作用。人类许多疾病都与BET蛋白过表达有密切的联系，如肿瘤、炎症性疾病、自身免疫性疾病及病毒感染等。开发BET蛋白抑制剂在抗肿瘤和抗炎等领域有着极大的价值因而被各大制药公司和研究机构广泛研究。The epigenetic target bromodomain and extra-terminal domain (BET) protein family is an extremely important target in the treatment of tumors and inflammation. The BET protein family includes four subtypes, namely BRD2, BRD3, BRD4 and BRDT. BET family proteins all contain two highly conserved N-terminal tandem bromodomains, BD1 and BD2. Taking BRD4 as an example, the first bromodomain at the N-terminus of BRD4 is represented by BRD4(1), and the second bromodomain at the N-terminus of BRD4 is represented by BRD4(2). BET proteins recognize acetylated lysine residues of histones and other proteins through bromodomains, and play an important role in regulating gene expression and controlling cell growth. Many human diseases are closely related to the overexpression of BET proteins, such as tumors, inflammatory diseases, autoimmune diseases and viral infections. The development of BET protein inhibitors has great value in the fields of anti-tumor and anti-inflammatory, and has therefore been widely studied by major pharmaceutical companies and research institutions.

为了提供更优前景的BET抑制剂，特提出本发明创造。In order to provide a BET inhibitor with better prospects, the present invention is proposed.

发明内容Summary of the invention

本发明第一目的在于提供一类联芳环结构的化合物，第二目的在于提供该类联芳环结构化合物的制备方法，第三目的在于在于提供该类联芳环结构化合物的用途。The first purpose of the present invention is to provide a class of biaryl ring structure compounds, the second purpose is to provide a preparation method of the biaryl ring structure compounds, and the third purpose is to provide the use of the biaryl ring structure compounds.

本发明上述目的通过如下技术方案实现：The above-mentioned purpose of the present invention is achieved through the following technical solutions:

一类联芳环结构的化合物，为式Ⅰ所示化合物或其药学上可接受的盐：A class of compounds with biaryl ring structures is a compound represented by formula I or a pharmaceutically acceptable salt thereof:

其中：in:

A环选自苯基、5-10元芳杂基；R_a独立选自氢、卤素、C_1-5烷基、C_3-7环烷基、C_1-3烷氧基；n＝1-5；B环选自5-10元芳杂基，R_b独立选自氢、卤素、C_1-5烷基、C_3-7环烷基、C_1-3烷氧基；m＝1-5；The A ring is selected from phenyl, 5-10 membered aromatic hetero groups;_Ra is independently selected from hydrogen, halogen,_C1-5 alkyl,_C3-7 cycloalkyl,_C1-3 alkoxy; n=1-5; the B ring is selected from 5-10 membered aromatic hetero groups,_Rb is independently selected from hydrogen, halogen,_C1-5 alkyl,_C3-7 cycloalkyl,_C1-3 alkoxy; m=1-5;

R₁、R₂、R₃、R₄独立选自氢、卤素、C_1-5烷基、C_1-3烷氧基、-S(O)_pR^*、-NRR^*S(O)_pR^*、-NRR^*S(O)_pNRR^*、-C(O)OR^*、-C(O)R^*、-OC(O)R^*、-OC(O)NRR^*、-NRC(O)R^*、-NRC(O)NRR^*、-C(O)NRR^*、-NRR^*、-OR^*、-SR^*；R和R^*独立选自氢、C_1-5烷基、C_2-6烯基、C_2-6烯基、C_2-6炔基，或者R和R^*与它们连接的氮原子形成4-7元杂环烷基；p＝1或2。_R1 ,_R2 ,_R3 , and_R4 are independently selected from hydrogen, halogen,_C1-5 alkyl,_C1-3 alkoxy, -S(O)_pR^* , -NRR^* S(O)_pR^* , -NRR^* S(O)_pNRR^* , -C(O)OR^* , -C(O)R^* , -OC(O)R^* , -OC(O)NRR^* , -NRC(O)R^* , -NRC(O)NRR^* , -C(O)NRR^* , -NRR^* , -OR^* , and -SR^* ; R and R^* are independently selected from hydrogen,_C1-5 alkyl,_C2-6 alkenyl,_C2-6 alkenyl, and_C2-6 alkynyl, or R and R^* and the nitrogen atom to which they are attached form a 4-7 membered heterocycloalkyl; p=1 or 2.

优选地，所述药学上可接受的盐为式Ⅰ化合物的酸加成盐，其中用于成盐的酸包括氯化氢、硫酸、溴化氢、草酸、柠檬酸、琥珀酸、酒石酸、磷酸、马来酸、甲磺酸、苯磺酸和对甲苯磺酸。Preferably, the pharmaceutically acceptable salt is an acid addition salt of the compound of formula I, wherein the acid used for salt formation includes hydrogen chloride, sulfuric acid, hydrogen bromide, oxalic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, maleic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid.

一种上述化合物的合成方法，化合物结构如目标1～目标14所示，合成路线如下：A method for synthesizing the above compound, the compound structures are shown in Target 1 to Target 14, and the synthesis route is as follows:

一种上述化合物的合成方法，化合物结构如目标15～目标20所示，合成路线如下：A method for synthesizing the above compound, the compound structures are shown in target 15 to target 20, and the synthesis route is as follows:

一种上述化合物的合成方法，化合物结构如目标21～目标24所示，合成路线如下：A method for synthesizing the above compound, the compound structures are shown in Target 21 to Target 24, and the synthesis route is as follows:

一种上述化合物的合成方法，化合物结构如目标25～目标30所示，合成路线如下：A method for synthesizing the above compound, the compound structure is shown in target 25 to target 30, and the synthesis route is as follows:

上述化合物用于制备BET抑制剂药物的用途。The compound is used for preparing BET inhibitor drugs.

上述化合物用于制备抗肿瘤药物或抗炎症药物的用途。The compound is used for preparing anti-tumor drugs or anti-inflammatory drugs.

优选地，所述抗肿瘤药物中还含有其它抗肿瘤成分，所述其它抗肿瘤成分为PARP抑制剂、CDK4/6抑制剂、ATR抑制剂、PD-1抗体或小分子抑制剂、PD-L1抗体或小分子抑制剂、EZH2抑制剂或AR抑制剂。Preferably, the anti-tumor drug also contains other anti-tumor components, and the other anti-tumor components are PARP inhibitors, CDK4/6 inhibitors, ATR inhibitors, PD-1 antibodies or small molecule inhibitors, PD-L1 antibodies or small molecule inhibitors, EZH2 inhibitors or AR inhibitors.

有益效果：Beneficial effects:

本发明提供的联芳环结构的化合物结构新颖，对BET蛋白具有优异的抑制作用。本领域技术人员知道，BET蛋白为肿瘤或炎症治疗的靶点，因此，本发明提供的联芳环结构的化合物可以单独用于制备抗肿瘤药物或抗炎症药物，也可以与其他抗肿瘤成分联合用于制备抗肿瘤药物，如PARP抑制剂、CDK4/6抑制剂、ATR抑制剂、PD-1抗体或小分子抑制剂、PD-L1抗体或小分子抑制剂、EZH2抑制剂或AR抑制剂。The compounds with biaryl ring structures provided by the present invention have novel structures and excellent inhibitory effects on BET proteins. Those skilled in the art know that BET proteins are targets for tumor or inflammation treatment. Therefore, the compounds with biaryl ring structures provided by the present invention can be used alone to prepare anti-tumor drugs or anti-inflammatory drugs, or can be used in combination with other anti-tumor ingredients to prepare anti-tumor drugs, such as PARP inhibitors, CDK4/6 inhibitors, ATR inhibitors, PD-1 antibodies or small molecule inhibitors, PD-L1 antibodies or small molecule inhibitors, EZH2 inhibitors or AR inhibitors.

附图说明BRIEF DESCRIPTION OF THE DRAWINGS

图1为实施例26与PARP抑制剂联合用药对乳腺癌和卵巢癌细胞增殖的抑制作用。FIG1 shows the inhibitory effect of Example 26 combined with a PARP inhibitor on the proliferation of breast cancer and ovarian cancer cells.

具体实施方式DETAILED DESCRIPTION

下面结合实施例具体介绍本发明实质性内容，但并不以此限定本发明的保护范围。下列实施例中未注明具体条件的实验方法，按照行业现有方法和条件实施。The following examples are combined to specifically describe the essential contents of the present invention, but the protection scope of the present invention is not limited thereto. The experimental methods in the following examples without specifying specific conditions are implemented according to the existing methods and conditions in the industry.

化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10^-6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-300核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)、氘代氯仿(CDCl3)、氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)。The structure of the compound is determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). NMR shift (δ) is given in units of 10^-6 (ppm). NMR measurements are performed using a Bruker AVANCE-300 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD) as the measuring solvent, and tetramethylsilane (TMS) as the internal standard.

MS的测定用MS液质联用仪(生产商：Agilent，MS型号：6110/6120Quadrupole MS)。HRMS使用Aglient 6230。MS was measured using a liquid chromatography-mass spectrometer (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS). Aglient 6230 was used for HRMS.

薄层层析硅胶板使用青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。其他本发明公开的起始原料可以按照本领域已知的方法来合成，或者来自市售产品。The thin layer chromatography silica gel plate uses Qingdao GF254 silica gel plate, the silica gel plate used in thin layer chromatography (TLC) uses a specification of 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm. Other starting materials disclosed in the present invention can be synthesized according to methods known in the art, or from commercially available products.

实施例中无特殊说明，反应能够均在氩气气氛或氮气气氛下进行。Unless otherwise specified in the examples, the reactions can be carried out under argon or nitrogen atmosphere.

实施例中无特殊说明，反应的温度为室温，为20℃～30℃。Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

合成路线1：Synthetic route 1:

实施例1～14按照Scheme 1合成。Examples 1 to 14 were synthesized according to Scheme 1.

将商业化原料1～13分别和15、碳酸铯及[1,1-双(二苯基磷)二茂铁]二氯化钯二氯甲烷复合物(Pd(dppf)Cl₂·CH₂Cl₂)置于史莱克管中，在100℃加热及氩气保护条件下经Suzuki偶联反应得到实施例1～实施例13。商业化原料16和N,N′-羰基二咪唑17在四氢呋喃中经加热得到中间体14，14和15同上述条件经Suzuki偶联反应得到实施例14。Commercial raw materials 1 to 13 were placed in a Shrek tube with 15, cesium carbonate and [1,1-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (Pd(dppf)Cl₂ ·CH₂ Cl₂ ) respectively, and heated at 100° C. under argon protection to obtain Examples 1 to 13 by Suzuki coupling reaction. Commercial raw material 16 and N,N′-carbonyldiimidazole 17 were heated in tetrahydrofuran to obtain intermediate 14, and 14 and 15 were subjected to Suzuki coupling reaction under the same conditions to obtain Example 14.

Scheme 1.Reagents and conditions：(a)Cs₂CO₃,Pd(dppf)Cl₂·CH₂Cl₂,1,4-Dioxane,H₂O,100℃,3h；(b)THF,80℃,4h.Scheme 1.Reagents and conditions: (a)Cs₂ CO₃ ,Pd(dppf)Cl₂ ·CH₂ Cl₂ ,1,4-Dioxane,H₂ O,100℃,3h; (b)THF,80℃, 4h.

实施例1：Embodiment 1:

5-(3,4,5-三甲氧基苯基)-1H-吡咯并[2,3-b]吡啶(实施例1)的合成Synthesis of 5-(3,4,5-trimethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine (Example 1)

5-(3,4,5-trimethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine(实施例1)5-(3,4,5-trimethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine (Example 1)

常规路线A：将5-溴-1H-吡咯并[2,3-b]吡啶1(300mg，1.52mmol)，3,4,5-三甲氧基苯基硼酸15(419.64mg，1.98mmol)，碳酸铯(992.17mg，3.05mmol)和[1,1-双(二苯基磷)二茂铁]二氯化钯二氯甲烷复合物(124.38mg，0.152mmol)加入到史莱克管中，随后加入9mL二氧六环和3mL水作为反应溶剂。用氩气充分置换史莱克管中的空气，100℃反应3h后TLC监测反应完全结束。待反应冷却至室温后，加入等体积的乙酸乙酯和水分液萃取3次，合并有机层并低压浓缩除去溶剂，残留物经过柱层析得到目标产物实施例1(317mg，产率：73.2％)。¹HNMR(300MHz,DMSO-d₆)δ11.74(s,1H),8.58(d,J＝2.2Hz,1H),8.26(dd,J＝2.2,0.7Hz,1H),7.54(dd,J＝3.5,2.5Hz,1H),6.99(s,2H),6.53(dd,J＝3.4,1.9Hz,1H),3.91(s,6H),3.73(s,3H).Conventional route A: 5-bromo-1H-pyrrolo[2,3-b]pyridine 1 (300 mg, 1.52 mmol), 3,4,5-trimethoxyphenylboronic acid 15 (419.64 mg, 1.98 mmol), cesium carbonate (992.17 mg, 3.05 mmol) and [1,1-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (124.38 mg, 0.152 mmol) were added to a Shrek tube, followed by 9 mL of dioxane and 3 mL of water as reaction solvents. The air in the Shrek tube was fully replaced with argon, and the reaction was completely completed after TLC monitoring at 100°C for 3 hours. After the reaction was cooled to room temperature, an equal volume of ethyl acetate and water were added for liquid extraction 3 times, the organic layers were combined and concentrated at low pressure to remove the solvent, and the residue was subjected to column chromatography to obtain the target product Example 1 (317 mg, yield: 73.2%).¹ HNMR (300MHz, DMSO-d₆ ) δ11.74(s,1H),8.58(d,J＝2.2Hz,1H),8.26(dd,J＝2.2,0.7Hz,1H),7.54(dd,J＝3.5,2.5Hz,1H),6.99(s,2H),6.53(dd,J＝3.4,1.9Hz ,1H),3.91(s,6H),3.73(s,3H).

实施例2：Embodiment 2:

6-(3,4,5-三甲氧基苯基)-1H-吡咯并[2,3-b]吡啶(实施例2)的合成Synthesis of 6-(3,4,5-trimethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine (Example 2)

6-(3,4,5-trimethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine(实施例2)6-(3,4,5-trimethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine (Example 2)

按常规路线A，以6-溴-1H-吡咯并[2,3-b]吡啶2(300mg，1.52mmol)为反应原料，得到目标产物实施例2(297mg，产率：68.75％)。¹H NMR(300MHz,)δ11.78(s,1H),8.05(d,J＝8.3Hz,1H),7.73(d,J＝8.3Hz,1H),7.50(dd,J＝3.5,2.5Hz,1H),7.42(s,2H),6.49(dd,J＝3.4,1.8Hz,1H),3.92(s,6H),3.75(s,3H).According to the conventional route A, 6-bromo-1H-pyrrolo[2,3-b]pyridine 2 (300 mg, 1.52 mmol) was used as the reaction raw material to obtain the target product Example 2 (297 mg, yield: 68.75%).¹ H NMR (300 MHz,) δ 11.78 (s, 1H), 8.05 (d, J = 8.3 Hz, 1H), 7.73 (d, J = 8.3 Hz, 1H), 7.50 (dd, J = 3.5, 2.5 Hz, 1H), 7.42 (s, 2H), 6.49 (dd, J = 3.4, 1.8 Hz, 1H), 3.92 (s, 6H), 3.75 (s, 3H).

实施例3：Embodiment 3:

5-(3,4,5-三甲氧基苯基)-1H-吡咯并[2,3-b]吡啶(实施例3)的合成Synthesis of 5-(3,4,5-trimethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine (Example 3)

5-(3,4,5-trimethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine(实施例3)5-(3,4,5-trimethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine (Example 3)

按常规路线A，以4-溴-1H-吡咯并[2,3-b]吡啶3(300mg，1.52mmol)为反应原料，得到目标产物实施例3(327mg，产率：75.7％)。¹H NMR(300MHz,)δ11.82(s,1H),8.30(d,J＝5.0Hz,1H),7.57(t,J＝3.0Hz,1H),7.26(d,J＝5.0Hz,1H),7.05(s,2H),6.72(dd,J＝3.5,1.8Hz,1H),3.91(s,6H),3.77(s,3H).According to the conventional route A, 4-bromo-1H-pyrrolo[2,3-b]pyridine 3 (300 mg, 1.52 mmol) was used as the reaction raw material to obtain the target product Example 3 (327 mg, yield: 75.7%).¹ H NMR (300 MHz,) δ 11.82 (s, 1H), 8.30 (d, J = 5.0 Hz, 1H), 7.57 (t, J = 3.0 Hz, 1H), 7.26 (d, J = 5.0 Hz, 1H), 7.05 (s, 2H), 6.72 (dd, J = 3.5, 1.8 Hz, 1H), 3.91 (s, 6H), 3.77 (s, 3H).

实施例4：Embodiment 4:

3-(3,4,5-三甲氧基苯基)-1H-吡咯并[2,3-b]吡啶(实施例4)的合成Synthesis of 3-(3,4,5-trimethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine (Example 4)

3-(3,4,5-trimethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine(实施例4)3-(3,4,5-trimethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine (Example 4)

按常规路线A，以4-溴-1H-吡咯并[2,3-b]吡啶4(300mg，1.52mmol)为反应原料，得到目标产物实施例4(288mg，产率：66.7％)。¹H NMR(300MHz,)δ11.92(s,1H),8.42–8.24(m,2H),7.90(d,J＝2.7Hz,1H),7.19(dd,J＝8.0,4.7Hz,1H),6.97(s,2H),3.91(s,6H),3.72(s,3H).According to the conventional route A, 4-bromo-1H-pyrrolo[2,3-b]pyridine 4 (300 mg, 1.52 mmol) was used as the reaction raw material to obtain the target product Example 4 (288 mg, yield: 66.7%).¹ H NMR (300 MHz,) δ11.92 (s, 1H), 8.42–8.24 (m, 2H), 7.90 (d, J=2.7 Hz, 1H), 7.19 (dd, J=8.0, 4.7 Hz, 1H), 6.97 (s, 2H), 3.91 (s, 6H), 3.72 (s, 3H).

实施例5：Embodiment 5:

4-(3,4,5-三甲氧基苯基)-1H-吡咯并[2,3-c]吡啶(实施例5)的合成Synthesis of 4-(3,4,5-trimethoxyphenyl)-1H-pyrrolo[2,3-c]pyridine (Example 5)

4-(3,4,5-trimethoxyphenyl)-1H-pyrrolo[2,3-c]pyridine(实施例5)4-(3,4,5-trimethoxyphenyl)-1H-pyrrolo[2,3-c]pyridine (Example 5)

按常规路线A，以4-溴-1H-吡咯并[2,3-c]吡啶5(300mg，1.52mmol)为反应原料，得到目标产物实施例5(293mg，产率：67.8％)。¹H NMR(300MHz,DMSO-d₆)δ11.80(s,1H),8.76(s,1H),8.28(s,1H),7.70(t,J＝2.8Hz,1H),6.99(s,2H),6.83–6.65(m,1H),3.89(s,6H),3.75(s,3H).According to the conventional route A, 4-bromo-1H-pyrrolo[2,3-c]pyridine 5 (300 mg, 1.52 mmol) was used as the reaction raw material to obtain the target product Example 5 (293 mg, yield: 67.8%).¹ H NMR (300 MHz, DMSO-d₆ ) δ 11.80 (s, 1H), 8.76 (s, 1H), 8.28 (s, 1H), 7.70 (t, J = 2.8 Hz, 1H), 6.99 (s, 2H), 6.83-6.65 (m, 1H), 3.89 (s, 6H), 3.75 (s, 3H).

实施例6：Embodiment 6:

4-(3,4,5-三甲氧基苯基)-1H-苯并[d]咪唑(实施例6)的合成Synthesis of 4-(3,4,5-trimethoxyphenyl)-1H-benzo[d]imidazole (Example 6)

4-(3,4,5-trimethoxyphenyl)-1H-benzo[d]imidazole(实施例6)4-(3,4,5-trimethoxyphenyl)-1H-benzo[d]imidazole (Example 6)

按常规路线A，以4-溴-1H-苯并[d]咪唑6(300mg，1.52mmol)为反应原料，得到目标产物实施例6(339mg，产率：78.4％)。¹HNMR(300MHz,DMSO-d₆)δ12.63(s,1H),8.29(d,J＝23.4Hz,1H),7.72–7.26(m,5H),6.92(s,1H),3.76(s,3H).According to the conventional route A, 4-bromo-1H-benzo[d]imidazole 6 (300 mg, 1.52 mmol) was used as the reaction raw material to obtain the target product Example 6 (339 mg, yield: 78.4%).¹ HNMR (300 MHz, DMSO-d₆ ) δ 12.63 (s, 1H), 8.29 (d, J = 23.4 Hz, 1H), 7.72-7.26 (m, 5H), 6.92 (s, 1H), 3.76 (s, 3H).

实施例7：Embodiment 7:

4-(3,4,5-三甲氧基苯基)-1H-吲唑(实施例7)的合成Synthesis of 4-(3,4,5-trimethoxyphenyl)-1H-indazole (Example 7)

4-(3,4,5-trimethoxyphenyl)-1H-indazole(实施例7)4-(3,4,5-trimethoxyphenyl)-1H-indazole (Example 7)

按常规路线A，以4-溴-1H-吲唑7(300mg，1.52mmol)为反应原料，得到目标产物实施例7(323mg，产率：74.7％)。¹H NMR(300MHz,DMSO-d₆)δ12.63(s,1H),8.29(d,J＝23.4Hz,1H),7.72–7.26(m,5H),6.92(s,1H),3.76(s,3H).According to conventional route A, 4-bromo-1H-indazole 7 (300 mg, 1.52 mmol) was used as the reaction raw material to obtain the target product Example 7 (323 mg, yield: 74.7%).¹ H NMR (300 MHz, DMSO-d₆ ) δ 12.63 (s, 1H), 8.29 (d, J = 23.4 Hz, 1H), 7.72-7.26 (m, 5H), 6.92 (s, 1H), 3.76 (s, 3H).

实施例8：Embodiment 8:

4-(3,4,5-三甲氧基苯基)苯并[d]异恶唑(实施例8)的合成Synthesis of 4-(3,4,5-trimethoxyphenyl)benzo[d]isoxazole (Example 8)

4-(3,4,5-trimethoxyphenyl)benzo[d]isoxazole(实施例8)4-(3,4,5-trimethoxyphenyl)benzo[d]isoxazole (Example 8)

按常规路线A，以4-溴苯并[d]异恶唑8(250mg，1.26mmol)为反应原料，得到目标产物实施例8(216mg，产率：76.1％)。¹H NMR(300MHz,DMSO-d₆)δ11.21(d,J＝4.5Hz,1H),7.57(td,J＝7.9,2.7Hz,1H),7.14–6.82(m,4H),3.88(s,6H),3.81–3.74(m,3H).According to the conventional route A, 4-bromobenzo[d]isoxazole 8 (250 mg, 1.26 mmol) was used as the reaction raw material to obtain the target product Example 8 (216 mg, yield: 76.1%).¹ H NMR (300 MHz, DMSO-d₆ ) δ 11.21 (d, J = 4.5 Hz, 1H), 7.57 (td, J = 7.9, 2.7 Hz, 1H), 7.14-6.82 (m, 4H), 3.88 (s, 6H), 3.81-3.74 (m, 3H).

实施例9：Embodiment 9:

8-(3,4,5-三甲氧基苯基)-[1,2,4]三唑并[4,3-a]吡啶(实施例9)的合成Synthesis of 8-(3,4,5-trimethoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine (Example 9)

8-(3,4,5-trimethoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine(实施例9)8-(3,4,5-trimethoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine (Example 9)

按常规路线A，以8-溴-[1,2,4]三唑并[4,3-a]吡啶9(250mg，1.26mmol)为反应原料，得到目标产物实施例9(178mg，产率：62.4％)。¹H NMR(300MHz,DMSO-d₆)δ9.40(d,J＝3.5Hz,1H),8.70–8.52(m,1H),7.77(dd,J＝7.2,3.6Hz,1H),7.63(d,J＝3.7Hz,2H),7.19–7.03(m,1H),3.91(d,J＝3.5Hz,6H).According to the conventional route A, 8-bromo-[1,2,4]triazolo[4,3-a]pyridine 9 (250 mg, 1.26 mmol) was used as the reaction raw material to obtain the target product Example 9 (178 mg, yield: 62.4%).¹ H NMR (300 MHz, DMSO-d₆ ) δ 9.40 (d, J = 3.5 Hz, 1H), 8.70–8.52 (m, 1H), 7.77 (dd, J = 7.2, 3.6 Hz, 1H), 7.63 (d, J = 3.7 Hz, 2H), 7.19–7.03 (m, 1H), 3.91 (d, J = 3.5 Hz, 6H).

实施例10：Embodiment 10:

5-(3,4,5-三甲氧基苯基)-[1,2,4]三唑并[4,3-a]吡啶(实施例10)的合成Synthesis of 5-(3,4,5-trimethoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine (Example 10)

5-(3,4,5-trimethoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine(实施例10)5-(3,4,5-trimethoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine (Example 10)

按常规路线A，以5-溴-[1,2,4]三唑并[4,3-a]吡啶10(250mg，1.26mmol)为反应原料，得到目标产物实施例10(165mg，产率：57.8％)。¹HNMR(300MHz,DMSO-d₆)δ9.39(s,1H),7.82(d,J＝9.2Hz,1H),7.49(dd,J＝9.2,6.8Hz,1H),7.11(s,2H),7.09–7.05(m,1H),3.90(s,6H),3.79(s,3H).According to the conventional route A, 5-bromo-[1,2,4]triazolo[4,3-a]pyridine 10 (250 mg, 1.26 mmol) was used as the reaction raw material to obtain the target product Example 10 (165 mg, yield: 57.8%).¹ HNMR (300 MHz, DMSO-d₆ ) δ 9.39 (s, 1H), 7.82 (d, J = 9.2 Hz, 1H), 7.49 (dd, J = 9.2, 6.8 Hz, 1H), 7.11 (s, 2H), 7.09–7.05 (m, 1H), 3.90 (s, 6H), 3.79 (s, 3H).

实施例11：Embodiment 11:

4-(3,4,5-三甲氧基苯基)-1H-吡唑并[3,4-b]吡啶(实施例11)的合成Synthesis of 4-(3,4,5-trimethoxyphenyl)-1H-pyrazolo[3,4-b]pyridine (Example 11)

4-(3,4,5-trimethoxyphenyl)-1H-pyrazolo[3,4-b]pyridine(实施例11)4-(3,4,5-trimethoxyphenyl)-1H-pyrazolo[3,4-b]pyridine (Example 11)

按常规路线A，以4-溴-1H-吡唑并[3,4-b]吡啶11(200mg，1.01mmol)为反应原料，得到目标产物实施例11(152mg，产率：53.1％)。¹HNMR(300MHz,DMSO-d₆)δ13.81(s,1H),8.60(d,J＝4.8Hz,1H),8.45(s,1H),7.44(d,J＝4.8Hz,1H),7.14(s,2H),3.79(s,3H).According to the conventional route A, 4-bromo-1H-pyrazolo[3,4-b]pyridine 11 (200 mg, 1.01 mmol) was used as the reaction raw material to obtain the target product Example 11 (152 mg, yield: 53.1%).¹ HNMR (300 MHz, DMSO-d₆ ) δ 13.81 (s, 1H), 8.60 (d, J = 4.8 Hz, 1H), 8.45 (s, 1H), 7.44 (d, J = 4.8 Hz, 1H), 7.14 (s, 2H), 3.79 (s, 3H).

实施例12：Embodiment 12:

7-(3,4,5-三甲氧基苯基)-3H-咪唑并[4,5-b]吡啶(实施例12)的合成Synthesis of 7-(3,4,5-trimethoxyphenyl)-3H-imidazo[4,5-b]pyridine (Example 12)

7-(3,4,5-trimethoxyphenyl)-3H-imidazo[4,5-b]pyridine(实施例12)7-(3,4,5-trimethoxyphenyl)-3H-imidazo[4,5-b]pyridine (Example 12)

按常规路线A，以7-氯-3H-咪唑并[4,5-b]吡啶12(200mg，1.3mmol)为反应原料，得到目标产物实施例12(121mg，产率：42.4％)。¹HNMR(300MHz,DMSO-d₆)δ13.25(s,1H),8.53(s,1H),8.40(d,J＝5.1Hz,1H),7.75(s,2H),7.65(d,J＝5.3Hz,1H),3.92(d,J＝3.3Hz,6H),3.77(s,3H).According to the conventional route A, 7-chloro-3H-imidazo[4,5-b]pyridine 12 (200 mg, 1.3 mmol) was used as the reaction raw material to obtain the target product Example 12 (121 mg, yield: 42.4%).¹ HNMR (300 MHz, DMSO-d₆ ) δ 13.25 (s, 1H), 8.53 (s, 1H), 8.40 (d, J = 5.1 Hz, 1H), 7.75 (s, 2H), 7.65 (d, J = 5.3 Hz, 1H), 3.92 (d, J = 3.3 Hz, 6H), 3.77 (s, 3H).

实施例13：Embodiment 13:

4-(3,4,5-三甲氧基苯基)-7H-吡咯并[2,3-d]嘧啶(实施例13)的合成Synthesis of 4-(3,4,5-trimethoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine (Example 13)

4-(3,4,5-trimethoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine(实施例13)4-(3,4,5-trimethoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine (Example 13)

按常规路线A，以4-溴-7H-吡咯并[2,3-d]嘧啶13(200mg，1.01mmol)为反应原料，得到目标产物实施例13(169mg，产率：59.3％)。¹HNMR(300MHz,DMSO-d₆)δ12.28(s,1H),8.85(s,1H),7.68(dd,J＝3.6,2.3Hz,1H),7.46(s,2H),6.96(dd,J＝3.7,1.7Hz,1H),3.94(s,6H),3.79(s,3H).According to the conventional route A, 4-bromo-7H-pyrrolo[2,3-d]pyrimidine 13 (200 mg, 1.01 mmol) was used as the reaction raw material to obtain the target product Example 13 (169 mg, yield: 59.3%).¹ HNMR (300 MHz, DMSO-d₆ ) δ 12.28 (s, 1H), 8.85 (s, 1H), 7.68 (dd, J = 3.6, 2.3 Hz, 1H), 7.46 (s, 2H), 6.96 (dd, J = 3.7, 1.7 Hz, 1H), 3.94 (s, 6H), 3.79 (s, 3H).

实施例14：Embodiment 14:

4-(3,4,5-三甲氧基苯基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮(实施例14)的合成Synthesis of 4-(3,4,5-trimethoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (Example 14)

4-(3,4,5-trimethoxyphenyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one(实施例14)4-(3,4,5-trimethoxyphenyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (Example 14)

按常规路线A，以7-氯-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮14(283mg，1.67mmol)为反应原料，得到目标产物实施例14(293mg，产率：53.3％)。¹H NMR(300MHz,DMSO-d₆)δ11.47(s,1H),11.08(s,1H),7.95(d,J＝5.5Hz,1H),7.11(d,J＝5.5Hz,1H),6.87(s,2H),3.91(s,6H),3.74(s,3H).According to the conventional route A, 7-chloro-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one 14 (283 mg, 1.67 mmol) was used as the reaction raw material to obtain the target product Example 14 (293 mg, yield: 53.3%).¹ H NMR (300 MHz, DMSO-d₆ ) δ 11.47 (s, 1H), 11.08 (s, 1H), 7.95 (d, J = 5.5 Hz, 1H), 7.11 (d, J = 5.5 Hz, 1H), 6.87 (s, 2H), 3.91 (s, 6H), 3.74 (s, 3H).

其中，化合物14通过如下方法合成：Among them, compound 14 was synthesized by the following method:

7-氯-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮(14)的合成Synthesis of 7-chloro-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (14)

7-bromo-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(14)7-bromo-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one(14)

将4-氯吡啶-2,3-二胺16(300mg,2.09mmol)与N,N'-羰基二咪唑17(677mg，4.18mmol)加入到含有10mL四氢呋喃的圆底烧瓶中，80℃加热4h后，TLC检测完全反应结束。减压浓缩除去四氢呋喃，加入10mL二氯甲烷溶解残留物，有大量红色粉末析出，抽滤后得到14(283mg，产率：79.9％)。4-Chloropyridine-2,3-diamine 16 (300 mg, 2.09 mmol) and N,N'-carbonyldiimidazole 17 (677 mg, 4.18 mmol) were added to a round-bottom flask containing 10 mL of tetrahydrofuran, and heated at 80°C for 4 h. The reaction was complete after TLC detection. The tetrahydrofuran was removed by concentration under reduced pressure, and 10 mL of dichloromethane was added to dissolve the residue. A large amount of red powder was precipitated, and 14 (283 mg, yield: 79.9%) was obtained after filtration.

合成路线2：Synthetic route 2:

实施例15～实施例20依据scheme 2合成，商业化购买的化合物19a～19f，以Pd(dppf)Cl₂·CH₂Cl₂为催化剂，碳酸铯作为碱，二氧六环与H₂O(3:1)为溶剂，100℃加热及氩气保护条件下，与1-溴-3-碘苯18在史莱克管中进行Suzuki偶联反应得到中间体20a～20f。中间体20f与溴甲基环丙烷24在碳酸铯存在下，通过亲和取代反应得到中间体20g。中间体20a～20e及20g与21在Pd(dppf)Cl₂·CH₂Cl₂和叔丁醇钾催化下，以无水二氧六环作为溶剂，在氩气保护及加热条件下反应得到硼酸酯中间体22a～22e和22g，本步骤要求在严格无水无氧条件下进行。22a～22e和22g分别与23在Pd(dppf)Cl₂·CH₂Cl₂作为催化剂，碳酸铯作为碱，以二氧六环与H₂O(3:1)作为溶剂，在氩气保护下100℃加热7h后得到实施例15～实施例20。Examples 15 to 20 were synthesized according to Scheme 2. Commercially purchased compounds 19a to 19f were reacted with 1-bromo-3-iodobenzene 18 in a Shrek tube under the conditions of heating at 100°C and argon protection by Suzuki coupling reaction using Pd(dppf)Cl₂ ·CH₂ Cl₂ as a catalyst, cesium carbonate as a base, dioxane and H₂ O (3:1) as a solvent to obtain intermediates 20a to 20f. Intermediate 20f reacted with bromomethylcyclopropane 24 in the presence of cesium carbonate by affinity substitution reaction to obtain intermediate 20g. Intermediates 20a to 20e and 20g reacted with 21 under the conditions of Pd(dppf)Cl₂ ·CH₂ Cl₂ and potassium tert-butoxide catalysis, anhydrous dioxane as a solvent, argon protection and heating to obtain borate intermediates 22a to 22e and 22g. This step requires to be carried out under strictly anhydrous and oxygen-free conditions. 22a-22e and 22g were respectively reacted with 23 in Pd(dppf)Cl₂ ·CH₂ Cl₂ as a catalyst, cesium carbonate as a base, and dioxane and H₂ O (3:1) as a solvent, and heated at 100° C. for 7 h under argon protection to obtain Examples 15-20.

Scheme 2.Reagents and conditions：(a)Cs₂CO₃,Pd(dppf)Cl₂·CH₂Cl₂,1,4-Dioxane,H₂O,100℃,3h；(b)AcOK,Pd(dppf)Cl₂·CH₂Cl₂,dry 1,4-Dioxane,100℃,3h；(c)Cs₂CO₃,Pd(dppf)Cl₂·CH₂Cl₂,1,4-Dioxane,H₂O,100℃,7h；(d)Cs₂CO₃,DMF,r.t.,5h.Scheme 2.Reagents and conditions: (a)Cs₂ CO₃ ,Pd(dppf)Cl₂ ·CH₂ Cl₂ ,1,4-Dioxane,H₂ O,100℃,3h; (b)AcOK,Pd(dppf )Cl₂ ·CH₂ Cl₂ ,dry 1,4-Dioxane,100℃,3h; (c)Cs₂ CO₃ ,Pd(dppf)Cl₂ ·CH₂ Cl₂ ,1,4-Dioxane,H₂ O ,100℃,7h; (d)Cs₂ CO₃ ,DMF,rt,5h.

4-(3-溴苯基)-3,5-二甲基异恶唑(20a)的合成Synthesis of 4-(3-bromophenyl)-3,5-dimethylisoxazole (20a)

4-(3-bromophenyl)-3,5-dimethylisoxazole(20a)4-(3-bromophenyl)-3,5-dimethylisoxazole(20a)

常规合成路线B:将1-溴-3-碘苯18(500mg，1.77mmol)，3,5-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)异恶唑19a(512.54mg,2.30mmol)，碳酸铯(1.15g,3.53mmol)，和[1,1-双(二苯基磷)二茂铁]二氯化钯二氯甲烷复合物(143.90mg，0.177mmol)加入到史莱克管中，随后加入9mL二氧六环和3mL水作为反应溶剂。用氩气充分置换史莱克管中的空气，100℃反应3h后TLC监测反应完全结束。待反应冷却至室温后，加入等体积的乙酸乙酯和水分液萃取3次，合并有机层并低压浓缩除去溶剂，残留物经过柱层析得到目标产物20a(400mg，产率：89.8％)。¹H NMR(300MHz,Chloroform-d)δ7.73(m,1H),7.61(d,J＝7.5,1H),7.43(d,J＝7.5Hz,1H),7.41(t,J＝7.5Hz,1H),2.87(s,3H),2.66(s,3H).Conventional synthetic route B: 1-bromo-3-iodobenzene 18 (500 mg, 1.77 mmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole 19a (512.54 mg, 2.30 mmol), cesium carbonate (1.15 g, 3.53 mmol), and [1,1-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (143.90 mg, 0.177 mmol) were added to a Shrek tube, followed by 9 mL of dioxane and 3 mL of water as reaction solvents. The air in the Shrek tube was fully replaced with argon, and the reaction was completely completed after TLC monitoring at 100°C for 3 hours. After the reaction was cooled to room temperature, an equal volume of ethyl acetate and water were added for three times of separation and extraction, the organic layers were combined and concentrated under low pressure to remove the solvent, and the residue was subjected to column chromatography to obtain the target product 20a (400 mg, yield: 89.8%).¹ H NMR (300 MHz, Chloroform-d) δ7.73 (m, 1H), 7.61 (d, J = 7.5, 1H), 7.43 (d, J = 7.5 Hz, 1H), 7.41 (t, J = 7.5 Hz, 1H), 2.87 (s, 3H), 2.66 (s, 3H).

4-(3-溴苯基)-1,3,5-三甲基-1H-吡唑(20b)的合成Synthesis of 4-(3-bromophenyl)-1,3,5-trimethyl-1H-pyrazole (20b)

4-(3-bromophenyl)-1,3,5-trimethyl-1H-pyrazole(20b)4-(3-bromophenyl)-1,3,5-trimethyl-1H-pyrazole(20b)

按常规路线B，以1,3,5-三甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑19b(533mg，2.30mmol)为反应原料，得到目标产物20b(413mg，产率：88.13％)。¹HNMR(300MHz,Chloroform-d)δ7.70(t,J＝2.0Hz,1H),7.61(dt,J＝7.5,2.0Hz,1H),7.43(dt,J＝7.5,2.1Hz,1H),7.34(t,J＝7.5Hz,1H),3.92(s,3H),2.61(s,3H),2.37(s,3H).According to the conventional route B, 1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 19b (533 mg, 2.30 mmol) was used as the reaction raw material to obtain the target product 20b (413 mg, yield: 88.13%).¹ HNMR (300 MHz, Chloroform-d) δ 7.70 (t, J = 2.0 Hz, 1H), 7.61 (dt, J = 7.5, 2.0 Hz, 1H), 7.43 (dt, J = 7.5, 2.1 Hz, 1H), 7.34 (t, J = 7.5 Hz, 1H), 3.92 (s, 3H), 2.61 (s, 3H), 2.37 (s, 3H).

5-(3-溴苯基)-1,4-二甲基-1H-吡唑(20c)的合成Synthesis of 5-(3-bromophenyl)-1,4-dimethyl-1H-pyrazole (20c)

5-(3-bromophenyl)-1,4-dimethyl-1H-pyrazole(20c)5-(3-bromophenyl)-1,4-dimethyl-1H-pyrazole(20c)

按常规路线B，以1,4-二甲基-5-(4,4,5,5-四甲基-1,3,2-dioxaborolan-2-yl)-1H-吡唑(1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole)19c(510mg，2.30mmol)为反应原料，得到目标产物20c(398mg，产率：89.67％)。¹HNMR(300MHz,Chloroform-d)δ7.70(t,J＝2.0Hz,1H),7.61(dt,J＝7.3,2.1Hz,1H),7.42(dt,J＝7.5,2.0Hz,1H),7.39(s,1H),7.34(t,J＝7.5Hz,1H),3.85(s,3H),2.08(s,3H).According to conventional route B, 1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 19c (510 mg, 2.30 mmol) was used as the reaction raw material to obtain the target product 20c (398 mg, yield: 89.67%).¹ HNMR(300MHz,Chloroform-d)δ7.70(t,J＝2.0Hz,1H),7.61(dt,J＝7.3,2.1Hz,1H),7.42(dt,J＝7.5,2.0Hz,1H),7.39(s,1H),7.34(t,J＝7.5Hz,1H),3.85(s,3H ),2.08(s,3H).

3'-溴-2,6-二甲基-1,1'-联苯(20d)的合成Synthesis of 3'-bromo-2,6-dimethyl-1,1'-biphenyl (20d)

3'-bromo-2,6-dimethyl-1,1'-biphenyl(20d)3'-bromo-2,6-dimethyl-1,1'-biphenyl(20d)

按常规路线B，以2-(2,6-二甲基苯基)-4,4,5,5-四甲基-1,3,2-二氧硼烷19d(533mg，2.30mmol)为反应原料，得到目标产物20d(430mg，产率：93.16％)。¹H NMR(300MHz,Chloroform-d)δ7.70–7.59(m,2H),7.40(dt,J＝7.6,2.0Hz,1H),7.31(dt,J＝15.4,7.5Hz,2H),7.16(d,J＝7.5Hz,2H),2.27(s,6H).According to the conventional route B, 2-(2,6-dimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane 19d (533 mg, 2.30 mmol) was used as the reaction raw material to obtain the target product 20d (430 mg, yield: 93.16%).¹ H NMR (300 MHz, Chloroform-d) δ7.70–7.59 (m, 2H), 7.40 (dt, J＝7.6, 2.0 Hz, 1H), 7.31 (dt, J＝15.4, 7.5 Hz, 2H), 7.16 (d, J＝7.5 Hz, 2H), 2.27 (s, 6H).

8-(3-溴苯基)喹啉(20e)的合成Synthesis of 8-(3-bromophenyl)quinoline (20e)

8-(3-bromophenyl)quinoline(20e)8-(3-bromophenyl)quinoline(20e)

按常规路线B，以8-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)喹啉19e(586mg，2.30mmol)为反应原料，得到目标产物20e(410mg，产率：81.64％)。¹H NMR(300MHz,Chloroform-d)δ9.00(dd,J＝7.5,1.5Hz,1H),8.31(dt,J＝7.5,1.5Hz,1H),7.89(dt,J＝7.6,1.5Hz,1H),7.86–7.79(m,2H),7.67–7.57(m,2H),7.55(dt,J＝7.5,2.0Hz,1H),7.38(dt,J＝14.7,7.5Hz,2H).According to the conventional route B, 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline 19e (586 mg, 2.30 mmol) was used as the reaction raw material to obtain the target product 20e (410 mg, yield: 81.64%).¹ H NMR (300 MHz, Chloroform-d) δ 9.00 (dd, J = 7.5, 1.5 Hz, 1H), 8.31 (dt, J = 7.5, 1.5 Hz, 1H), 7.89 (dt, J = 7.6, 1.5 Hz, 1H), 7.86-7.79 (m, 2H), 7.67-7.57 (m, 2H), 7.55 (dt, J = 7.5, 2.0 Hz, 1H), 7.38 (dt, J = 14.7, 7.5 Hz, 2H).

4-(3-溴苯基)-3,5-二甲基-1H-吡唑(20f)的合成Synthesis of 4-(3-bromophenyl)-3,5-dimethyl-1H-pyrazole (20f)

4-(3-bromophenyl)-3,5-dimethyl-1H-pyrazole(20f)4-(3-bromophenyl)-3,5-dimethyl-1H-pyrazole(20f)

按常规路线B，以3,5-二甲基4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑19f(510.28mg，2.30mmol)为反应原料，得到目标产物20f(356mg，产率：80.21％)。According to conventional route B, 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 19f (510.28 mg, 2.30 mmol) was used as the reaction raw material to obtain the target product 20f (356 mg, yield: 80.21%).

4-(3-溴苯基)-1-(环丙基甲基)-3,5-二甲基-1H-吡唑(20g)的合成Synthesis of 4-(3-bromophenyl)-1-(cyclopropylmethyl)-3,5-dimethyl-1H-pyrazole (20 g)

4-(3-bromophenyl)-1-(cyclopropylmethyl)-3,5-dimethyl-1H-pyrazole(20g)4-(3-bromophenyl)-1-(cyclopropylmethyl)-3,5-dimethyl-1H-pyrazole(20g)

室温下，将4-(3-溴苯基)-3,5-二甲基-1H-吡唑20f(500mg，1.99mmol)，(溴甲基)环丙烷24(403.19mg，2.99mmol)和碳酸铯(1.30g，3.98mmol)加入到圆底烧瓶中，随后加入15mLDMF作为反应溶剂。室温搅拌4h后，TLC检测，反应完全结束。加入等体积的乙酸乙酯和水分液萃取3次，合并有机层，以饱和氯化钠溶液再次分液萃取，取有机层，用无水硫酸钠干燥1h后，浓缩除去溶剂。经柱层析分离后得到白色油状物质20g(467mg，76.9％)。At room temperature, 4-(3-bromophenyl)-3,5-dimethyl-1H-pyrazole 20f (500 mg, 1.99 mmol), (bromomethyl)cyclopropane 24 (403.19 mg, 2.99 mmol) and cesium carbonate (1.30 g, 3.98 mmol) were added to a round-bottom flask, followed by 15 mL of DMF as a reaction solvent. After stirring at room temperature for 4 h, the reaction was completely completed by TLC detection. An equal volume of ethyl acetate and water were added for three times of separation, the organic layers were combined, and the separation was performed again with a saturated sodium chloride solution. The organic layer was taken, dried with anhydrous sodium sulfate for 1 h, and then concentrated to remove the solvent. After column chromatography, 20 g (467 mg, 76.9%) of a white oily substance was obtained.

3,5-二甲基-4-(3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)异恶唑(22a)的合成Synthesis of 3,5-dimethyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazole (22a)

3,5-dimethyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazole(22a)3,5-dimethyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazole(22a)

常规合成路线C:将4-(3-溴苯基)-3,5-二甲基异恶唑20a(334mg，1.33mmol),4,4,4',4',5,5,5',5'-八甲基-2,2'-二(1,3,2-二氧杂硼烷)21(438.07mg，1.73mmol)，乙酸钾(260.47mg，2.65mmol)和[1,1-双(二苯基磷)二茂铁]二氯化钯二氯甲烷复合物(108.79mg，0.13mmol)加入到史莱克管中，随后加入10mL无水二氧六环作为反应溶剂。用氩气充分置换史莱克管中的空气，100℃反应3h后TLC监测反应完全结束。待反应冷却至室温后，加入等体积的乙酸乙酯和水分液萃取3次，合并有机层并低压浓缩除去溶剂，得到残留物320mg。未经进一步纯化，直接投下一步。Conventional synthetic route C: 4-(3-bromophenyl)-3,5-dimethylisoxazole 20a (334 mg, 1.33 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-di(1,3,2-dioxaborolane) 21 (438.07 mg, 1.73 mmol), potassium acetate (260.47 mg, 2.65 mmol) and [1,1-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (108.79 mg, 0.13 mmol) were added to a Shrek tube, followed by 10 mL of anhydrous dioxane as a reaction solvent. The air in the Shrek tube was fully replaced with argon, and the reaction was completely completed after TLC monitoring at 100°C for 3 hours. After the reaction was cooled to room temperature, an equal volume of ethyl acetate and water were added for liquid extraction 3 times, the organic layers were combined and concentrated at low pressure to remove the solvent to obtain a residue of 320 mg. Without further purification, it was directly used for the next step.

1,3,5-三甲基-4-(3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)-1H-吡唑(22b)的合成Synthesis of 1,3,5-trimethyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole (22b)

1,3,5-trimethyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole(22b)1,3,5-trimethyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole(22b)

按常规路线C，以4-(3-溴苯基)-1,3,5-三甲基-1H-吡唑20b(400mg，1.51mmol)为反应原料，得到目标产物22b(390mg，产率：82.8％)。According to conventional route C, 4-(3-bromophenyl)-1,3,5-trimethyl-1H-pyrazole 20b (400 mg, 1.51 mmol) was used as the reaction raw material to obtain the target product 22b (390 mg, yield: 82.8%).

1,4-二甲基-5-(3-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)苯基)-1H-吡唑(22c)的合成Synthesis of 1,4-dimethyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole (22c)

1,4-dimethyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole(22c)1,4-dimethyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole(22c)

按常规路线C，以5-(3-溴苯基)-1,4-二甲基-1H-吡唑20c(400mg，1.59mmol)为反应原料，得到目标产物22c(412mg，产率：86.74％)。According to conventional route C, 5-(3-bromophenyl)-1,4-dimethyl-1H-pyrazole 20c (400 mg, 1.59 mmol) was used as the reaction raw material to obtain the target product 22c (412 mg, yield: 86.74%).

2-(2',6'-二甲基-[1,1'-联苯]-3-基)-4,4,5,5-四甲基-1,3,2-二氧硼烷(22d)的合成Synthesis of 2-(2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (22d)

2-(2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(22d)2-(2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(22d)

按常规路线C，以3'-溴-2,6-二甲基-1,1'-联苯20d(400mg，2.30mmol)为反应原料，得到目标产物22d(417mg，产率：88.3％)。According to conventional route C, 3'-bromo-2,6-dimethyl-1,1'-biphenyl 20d (400 mg, 2.30 mmol) was used as the reaction raw material to obtain the target product 22d (417 mg, yield: 88.3%).

8-(3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)喹啉(22e)的合成Synthesis of 8-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinoline (22e)

8-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinoline(22e)8-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinoline(22e)

按常规路线C，以8-(3-溴苯基)喹啉20e(400mg，1.41mmol)为反应原料，得到目标产物22e(372mg，产率：83.31％)。According to conventional route C, 8-(3-bromophenyl)quinoline 20e (400 mg, 1.41 mmol) was used as the reaction raw material to obtain the target product 22e (372 mg, yield: 83.31%).

1-(环丙基甲基)-3,5-二甲基-4-(3-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)苯基)-1H-吡唑(22g)的合成Synthesis of 1-(cyclopropylmethyl)-3,5-dimethyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole (22 g)

1-(cyclopropylmethyl)-3,5-dimethyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole(22g)1-(cyclopropylmethyl)-3,5-dimethyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole(22g)

按常规路线C，以4-(3-溴苯基)-1-(环丙基甲基)-3,5-二甲基-1H-吡唑20g(400mg,1.31mmol)为反应原料，得到目标产物22g(383mg，产率：83.0％)。According to conventional route C, 20 g (400 mg, 1.31 mmol) of 4-(3-bromophenyl)-1-(cyclopropylmethyl)-3,5-dimethyl-1H-pyrazole was used as the reaction raw material to obtain 22 g (383 mg, yield: 83.0%) of the target product.

实施例15：Embodiment 15:

4-(3-(1H-咪唑并[4,5-b]吡啶-7-基)苯基)-3,5-二甲基异噁唑(实施例15)的合成Synthesis of 4-(3-(1H-imidazo[4,5-b]pyridin-7-yl)phenyl)-3,5-dimethylisoxazole (Example 15)

4-(3-(1H-imidazo[4,5-b]pyridin-7-yl)phenyl)-3,5-dimethylisoxazole(实施例15)4-(3-(1H-imidazo[4,5-b]pyridin-7-yl)phenyl)-3,5-dimethylisoxazole (Example 15)

常规合成路线D:将7-溴-1H-咪唑并[4,5-b]吡啶23(258mg，1.3mmol)，3,5-二甲基-4-(3-(4,4,5,5-四甲基-1,3,2-二恶硼烷-2-基)苯基)异恶唑22a(506.73mg，1.69mmol)，碳酸铯(848.66mg，2.60mmol)和[1,1-双(二苯基磷)二茂铁]二氯化钯二氯甲烷复合物(106.38mg，0.13mmol)加入到史莱克管中，随后加入9mL二氧六环和3mL水作为反应溶剂。用氩气充分置换史莱克管中的空气，100℃反应7h后TLC监测反应完全结束。待反应冷却至室温后，加入等体积的乙酸乙酯和水分液萃取3次，合并有机层并低压浓缩除去溶剂，残留物经过柱层析得到目标产物实施例15(197mg，产率：60.6％)。¹H NMR(300MHz,DMSO-d₆)δ13.29(s,1H),8.53(s,1H),8.48–8.37(m,2H),8.29(d,J＝7.9Hz,1H),7.72–7.61(m,2H),7.53(d,J＝7.7Hz,1H),3.41(s,3H),2.35(s,3H).Conventional synthetic route D: 7-bromo-1H-imidazo[4,5-b]pyridine 23 (258 mg, 1.3 mmol), 3,5-dimethyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazole 22a (506.73 mg, 1.69 mmol), cesium carbonate (848.66 mg, 2.60 mmol) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (106.38 mg, 0.13 mmol) were added to a Shrek tube, followed by 9 mL of dioxane and 3 mL of water as reaction solvents. The air in the Shrek tube was fully replaced with argon, and the reaction was completely completed after 7 h at 100°C monitored by TLC. After the reaction was cooled to room temperature, an equal volume of ethyl acetate and water were added for extraction three times, the organic layers were combined and concentrated under low pressure to remove the solvent, and the residue was subjected to column chromatography to obtain the target product Example 15 (197 mg, yield: 60.6%).¹ H NMR (300 MHz, DMSO-d₆ ) δ 13.29 (s, 1H), 8.53 (s, 1H), 8.48–8.37 (m, 2H), 8.29 (d, J=7.9 Hz, 1H), 7.72–7.61 (m, 2H), 7.53 (d, J=7.7 Hz, 1H), 3.41 (s, 3H), 2.35 (s, 3H).

实施例16：Embodiment 16:

7-(3-(1,3,5-三甲基-1H-吡唑-4-基)苯基)-1H-咪唑并〔4,5-b〕吡啶(实施例16)的合成Synthesis of 7-(3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-1H-imidazo[4,5-b]pyridine (Example 16)

7-(3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-1H-imidazo[4,5-b]pyridine(实施例16)7-(3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-1H-imidazo[4,5-b]pyridine (Example 16)

按常规路线D，以1,3,5-三甲基-4-(3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)-1H-吡唑22b(390mg，1.25mmol)为反应原料，得到目标产物实施例16(232mg，产率：79.7％)。¹H NMR(300MHz,Chloroform-d)δ8.58(d,J＝5.4Hz,1H),8.50(s,1H),8.10(d,J＝7.9Hz,1H),8.02(s,1H),7.65(t,J＝7.7Hz,1H),7.56(d,J＝5.1Hz,1H),7.42(d,J＝7.7Hz,1H),3.86(s,3H),2.36(d,J＝2.5Hz,6H).According to conventional route D, 1,3,5-trimethyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole 22b (390 mg, 1.25 mmol) was used as the reaction raw material to obtain the target product Example 16 (232 mg, yield: 79.7%).¹ H NMR (300MHz, Chloroform-d) δ8.58(d,J＝5.4Hz,1H),8.50(s,1H),8.10(d,J＝7.9Hz,1H),8.02(s,1H),7.65(t,J＝7.7Hz,1H),7.56(d,J＝5.1Hz,1H),7.42(d,J =7.7Hz,1H),3.86(s,3H),2.36(d,J=2.5Hz,6H).

实施例17：Embodiment 17:

7-(3-(1,4-二甲基-1H-吡唑-5-基)苯基)-1H-咪唑并[4,5-b]吡啶(实施例17)的合成Synthesis of 7-(3-(1,4-dimethyl-1H-pyrazol-5-yl)phenyl)-1H-imidazo[4,5-b]pyridine (Example 17)

7-(3-(1,4-dimethyl-1H-pyrazol-5-yl)phenyl)-1H-imidazo[4,5-b]pyridine(实施例17)7-(3-(1,4-dimethyl-1H-pyrazol-5-yl)phenyl)-1H-imidazo[4,5-b]pyridine (Example 17)

按常规路线D，以1,4-二甲基-5-(3-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)苯基)-1H-吡唑22c(412mg，1.38mmol)为反应原料，得到目标产物实施例17(192mg，产率：62.7％)。¹HNMR(300MHz,Chloroform-d)δ8.59(d,J＝5.2Hz,1H),8.43(s,1H),8.28(d,J＝7.9Hz,1H),8.17(s,1H),7.73(t,J＝7.7Hz,1H),7.57(d,J＝5.1Hz,1H),7.49(d,J＝7.6Hz,1H),7.47(s,1H),3.92(s,3H),2.14(s,3H).According to conventional route D, 1,4-dimethyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole 22c (412 mg, 1.38 mmol) was used as the reaction raw material to obtain the target product Example 17 (192 mg, yield: 62.7%).¹ HNMR (300MHz, Chloroform-d) δ8.59(d,J＝5.2Hz,1H),8.43(s,1H),8.28(d,J＝7.9Hz,1H),8.17(s,1H),7.73(t,J＝7.7Hz,1H),7.57(d,J＝5.1Hz,1H),7.49(d,J =7.6Hz,1H),7.47(s,1H),3.92(s,3H),2.14(s,3H).

实施例18：Embodiment 18:

7-(2',6'-二甲基-[1,1'-联苯]-3-基)-1H-咪唑并[4,5-b]吡啶(实施例18)的合成Synthesis of 7-(2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-1H-imidazo[4,5-b]pyridine (Example 18)

7-(2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-1H-imidazo[4,5-b]pyridine(实施例18)7-(2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-1H-imidazo[4,5-b]pyridine (Example 18)

按常规路线D，以2-(2',6'-二甲基-[1,1'-联苯]-3-基)-4,4,5,5-四甲基-1,3,2-二氧硼烷22d(417mg，1.35mmol)为反应原料，得到目标产物实施例18(229.1mg，产率：69.2％)。¹HNMR(300MHz,Chloroform-d)δ8.56(d,J＝5.1Hz,1H),8.45(s,1H),8.38–8.31(m,1H),7.91(s,1H),7.68(t,J＝7.6Hz,1H),7.55(d,J＝5.1Hz,1H),7.36–7.31(m,1H),7.21(q,J＝5.8Hz,3H),2.17(s,6H).According to the conventional route D, 2-(2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane 22d (417 mg, 1.35 mmol) was used as the reaction raw material to obtain the target product Example 18 (229.1 mg, yield: 69.2%).¹ HNMR (300 MHz, Chloroform-d) δ 8.56 (d, J = 5.1 Hz, 1H), 8.45 (s, 1H), 8.38-8.31 (m, 1H), 7.91 (s, 1H), 7.68 (t, J = 7.6 Hz, 1H), 7.55 (d, J = 5.1 Hz, 1H), 7.36-7.31 (m, 1H), 7.21 (q, J = 5.8 Hz, 3H), 2.17 (s, 6H).

实施例19：Embodiment 19:

8-(3-(1H-咪唑并〔4,5-b]吡啶-7-基)苯基)喹啉(实施例19)的合成Synthesis of 8-(3-(1H-imidazo〔4,5-b]pyridin-7-yl)phenyl)quinoline (Example 19)

8-(3-(1H-imidazo[4,5-b]pyridin-7-yl)phenyl)quinoline(实施例19)8-(3-(1H-imidazo[4,5-b]pyridin-7-yl)phenyl)quinoline (Example 19)

按常规路线D，以8-(3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)喹啉22e(372mg，1.17mmol)为反应原料，得到目标产物实施例19(201.7mg，产率：69.6％)。¹HNMR(300MHz,Chloroform-d)δ9.03(dd,J＝4.2,1.8Hz,1H),8.49(d,J＝5.2Hz,1H),8.37(t,J＝1.7Hz,1H),8.31–8.23(m,2H),8.10(d,J＝7.7Hz,1H),7.87(ddd,J＝14.3,7.6,1.5Hz,2H),7.79(dt,J＝7.7,1.4Hz,1H),7.66(t,J＝7.7Hz,2H),7.52–7.44(m,2H).According to conventional route D, 8-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinoline 22e (372 mg, 1.17 mmol) was used as the reaction raw material to obtain the target product Example 19 (201.7 mg, yield: 69.6%).¹ HNMR(300MHz,Chloroform-d)δ9.03(dd,J＝4.2,1.8Hz,1H),8.49(d,J＝5.2Hz,1H),8.37(t,J＝1.7Hz,1H),8.31–8.23(m,2H),8.10(d,J＝7.7Hz,1H),7.87(ddd,J＝ 14.3,7.6,1.5Hz,2H),7.79(dt,J＝7.7,1.4Hz,1H),7.66(t,J＝7.7Hz,2H),7.52–7.44(m,2H).

实施例20：Embodiment 20:

7-(3-(1-(环丙基甲基)-3,5-二甲基-1H-吡唑-4-基)苯基)-1H-咪唑并[4,5-b]吡啶(实施例20)的合成Synthesis of 7-(3-(1-(cyclopropylmethyl)-3,5-dimethyl-1H-pyrazol-4-yl)phenyl)-1H-imidazo[4,5-b]pyridine (Example 20)

7-(3-(1-(cyclopropylmethyl)-3,5-dimethyl-1H-pyrazol-4-yl)phenyl)-1H-imidazo[4,5-b]pyridine(实施例20)7-(3-(1-(cyclopropylmethyl)-3,5-dimethyl-1H-pyrazol-4-yl)phenyl)-1H-imidazo[4,5-b]pyridine (Example 20)

按常规路线D，以1-(环丙基甲基)-3,5-二甲基-4-(3-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)苯基)-1H-吡唑22g(387.68mg，1.10mmol)为反应原料，得到目标产物实施例20(149mg，产率：51.3％)。¹H NMR(300MHz,DMSO-d₆)δ13.24(s,1H),8.50(s,1H),8.44(d,J＝5.1Hz,1H),8.30(s,1H),8.17(d,J＝7.8Hz,1H),7.61(d,J＝6.1Hz,2H),7.41(d,J＝7.8Hz,1H),3.95(d,J＝6.9Hz,2H),2.35(s,3H),2.25(s,3H),1.27(s,1H),0.55(d,J＝7.6Hz,2H),0.41(d,J＝4.9Hz,2H).According to conventional route D, 1-(cyclopropylmethyl)-3,5-dimethyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole 22g (387.68mg, 1.10mmol) was used as the reaction raw material to obtain the target product Example 20 (149mg, yield: 51.3%).¹ H NMR (300MHz, DMSO-d₆ ) δ13.24 (s, 1H), 8.50 (s, 1H), 8.44 (d, J = 5.1Hz, 1H), 8.30 (s, 1H), 8.17 (d, J = 7.8Hz, 1H), 7.61 (d, J = 6.1Hz, 2H), 7.41 (d, J = 7.8Hz, 1H),3.95(d,J＝6.9Hz,2H),2.35(s,3H),2.25(s,3H),1.27(s,1H),0.55(d,J＝7.6Hz,2H),0.41(d,J＝4.9Hz,2H).

合成路线3：Synthetic route 3:

实施例21～实施例24依据scheme 3合成。商业化原料25a～25d和19b作为起始原料参考scheme 2合成路线a步骤反应得到中间体26a～26d，硼酸酯中间体27a～27d及目标化合物实施例21～实施例24的合成分别参考scheme 2合成路线b步骤和c步骤。Examples 21 to 24 were synthesized according to Scheme 3. Commercial raw materials 25a to 25d and 19b were used as starting materials to obtain intermediates 26a to 26d by referring to step a of the synthetic route of Scheme 2. The synthesis of borate intermediates 27a to 27d and target compounds Examples 21 to 24 were respectively referred to steps b and c of the synthetic route of Scheme 2.

Scheme 3.Reagents and conditions：(a)Cs₂CO₃,Pd(dppf)Cl₂·CH₂Cl₂,1,4-Dioxane,H₂O,100℃,3h；(b)AcOK,Pd(dppf)Cl₂·CH₂Cl₂,dry 1,4-Dioxane,100℃,3h；(c)Cs₂CO₃,Pd(dppf)Cl₂·CH₂Cl₂,1,4-Dioxane,H₂O,100℃,7h。Scheme 3.Reagents and conditions: (a)Cs₂ CO₃ ,Pd(dppf)Cl₂ ·CH₂ Cl₂ ,1,4-Dioxane,H₂ O,100℃,3h; (b)AcOK,Pd(dppf )Cl₂ ·CH₂ Cl₂ ,dry 1,4-Dioxane,100℃,3h; (c)Cs₂ CO₃ ,Pd(dppf)Cl₂ ·CH₂ Cl₂ ,1,4-Dioxane,H₂ O ,100℃,7h.

4-(3-溴-2-氟苯基)-1,3,5-三甲基-1H-吡唑(26a)的合成Synthesis of 4-(3-bromo-2-fluorophenyl)-1,3,5-trimethyl-1H-pyrazole (26a)

4-(3-bromo-2-fluorophenyl)-1,3,5-trimethyl-1H-pyrazole(26a)4-(3-bromo-2-fluorophenyl)-1,3,5-trimethyl-1H-pyrazole(26a)

按常规路线B，以1-溴-2-氟-3-碘苯25a(530mg，1.76mmol)，1,3,5-三甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)-1H-吡唑19b(540mg，2.29mmol)为反应原料。得到4-(3-溴-2-氟苯基)-1,3,5-三甲基-1H-吡唑26a(400mg，80.2％)。According to the conventional route B, 1-bromo-2-fluoro-3-iodobenzene 25a (530 mg, 1.76 mmol) and 1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 19b (540 mg, 2.29 mmol) were used as the reaction raw materials to obtain 4-(3-bromo-2-fluorophenyl)-1,3,5-trimethyl-1H-pyrazole 26a (400 mg, 80.2%).

4-(5-溴-2-氟苯基)-1,3,5-三甲基-1H-吡唑(26b)的合成Synthesis of 4-(5-bromo-2-fluorophenyl)-1,3,5-trimethyl-1H-pyrazole (26b)

4-(5-bromo-2-fluorophenyl)-1,3,5-trimethyl-1H-pyrazole(26b)4-(5-bromo-2-fluorophenyl)-1,3,5-trimethyl-1H-pyrazole(26b)

按常规路线B，以4-溴-1-氟-2-碘苯25b(530mg，1.76mmol)，1,3,5-三甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)-1H-吡唑19b(540mg，2.29mmol)为反应原料。得到目标产物26b(372mg，74.6％)。According to the conventional route B, 4-bromo-1-fluoro-2-iodobenzene 25b (530 mg, 1.76 mmol) and 1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 19b (540 mg, 2.29 mmol) were used as the reaction raw materials to obtain the target product 26b (372 mg, 74.6%).

4-(3-溴-2-氯苯基)-1,3,5-三甲基-1H-吡唑(26c)的合成Synthesis of 4-(3-bromo-2-chlorophenyl)-1,3,5-trimethyl-1H-pyrazole (26c)

4-(3-bromo-2-chlorophenyl)-1,3,5-trimethyl-1H-pyrazole(26c)4-(3-bromo-2-chlorophenyl)-1,3,5-trimethyl-1H-pyrazole(26c)

按常规路线B，以1-溴-2-氯-3-碘苯25c(530mg，1.67mmol)，1,3,5-三甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)-1H-吡唑19b(512mg，2.17mmol)为反应原料。得到目标产物26c(381mg，76.2％)。According to the conventional route B, 1-bromo-2-chloro-3-iodobenzene 25c (530 mg, 1.67 mmol) and 1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 19b (512 mg, 2.17 mmol) were used as the reaction raw materials to obtain the target product 26c (381 mg, 76.2%).

4-(5-溴-2,4-二氟苯基)-1,3,5-三甲基-1H-吡唑(26d)的合成Synthesis of 4-(5-bromo-2,4-difluorophenyl)-1,3,5-trimethyl-1H-pyrazole (26d)

4-(5-bromo-2,4-difluorophenyl)-1,3,5-trimethyl-1H-pyrazole(26d)4-(5-bromo-2,4-difluorophenyl)-1,3,5-trimethyl-1H-pyrazole(26d)

按常规路线B，以1-溴-2,4-二氯-5-碘苯25d(530mg，1.66mmol)，1,3,5-三甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)-1H-吡唑19b(510mg，2.16mmol)为反应原料。得到目标产物26d(391mg，78.1％)。According to the conventional route B, 1-bromo-2,4-dichloro-5-iodobenzene 25d (530 mg, 1.66 mmol) and 1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 19b (510 mg, 2.16 mmol) were used as the reaction raw materials to obtain the target product 26d (391 mg, 78.1%).

4-(2-氟-3-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)苯基)-1,3,5-三甲基-1H-吡唑(27a)的合成Synthesis of 4-(2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3,5-trimethyl-1H-pyrazole (27a)

4-(2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3,5-trimethyl-1H-pyrazole(27a)4-(2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3,5-trimethyl-1H-pyrazole(27a)

按常规路线C，以4-(3-溴-2-氟苯基)-1,3,5-三甲基-1H-吡唑26a(400mg,1.41mmol)为反应原料，得到目标产物27a(366mg，产率：78.5％)。According to conventional route C, 4-(3-bromo-2-fluorophenyl)-1,3,5-trimethyl-1H-pyrazole 26a (400 mg, 1.41 mmol) was used as the reaction raw material to obtain the target product 27a (366 mg, yield: 78.5%).

4-(2-氟-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)-1,3,5-三甲基-1H-吡唑(27b)的合成Synthesis of 4-(2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3,5-trimethyl-1H-pyrazole (27b)

4-(2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3,5-trimethyl-1H-pyrazole(27b)4-(2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3,5-trimethyl-1H-pyrazole(27b)

按常规路线C，以4-(5-溴-2-氟苯基)-1,3,5-三甲基-1H-吡唑26b(400mg,1.41mmol)为反应原料，得到目标产物27b(401mg，产率：85.9％)。According to conventional route C, 4-(5-bromo-2-fluorophenyl)-1,3,5-trimethyl-1H-pyrazole 26b (400 mg, 1.41 mmol) was used as the reaction raw material to obtain the target product 27b (401 mg, yield: 85.9%).

4-(2-氯-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)-1,3,5-三甲基-1H-吡唑(27c)的合成Synthesis of 4-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3,5-trimethyl-1H-pyrazole (27c)

4-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3,5-trimethyl-1H-pyrazole(27c)4-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3,5-trimethyl-1H-pyrazole(27c)

按常规路线C，以4-(3-溴-2-氯苯基)-1,3,5-三甲基-1H-吡唑26c(400mg,1.34mmol)为反应原料，得到目标产物27c(351mg，产率：75.8％)。According to conventional route C, 4-(3-bromo-2-chlorophenyl)-1,3,5-trimethyl-1H-pyrazole 26c (400 mg, 1.34 mmol) was used as the reaction raw material to obtain the target product 27c (351 mg, yield: 75.8%).

4-(2,4-二氟-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)-1,3,5-三甲基-1H-吡唑(27d)的合成Synthesis of 4-(2,4-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3,5-trimethyl-1H-pyrazole (27d)

4-(2,4-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3,5-trimethyl-1H-pyrazole(27d)4-(2,4-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3,5-trimethyl-1H-pyrazole(27d )

按常规路线C，以4-(5-溴-2,4-二甲基苯基)-1,3,5-三甲基-1H-吡唑26d(400mg,1.36mmol)为反应原料，得到目标产物27d(376mg，产率：79.2％)。According to conventional route C, 4-(5-bromo-2,4-dimethylphenyl)-1,3,5-trimethyl-1H-pyrazole 26d (400 mg, 1.36 mmol) was used as the reaction raw material to obtain the target product 27d (376 mg, yield: 79.2%).

实施例21：Embodiment 21:

7-(2-氟-3-(1,3,5-三甲基-1H-吡唑-4-基)苯基)-1H-咪唑并[4,5-b]吡啶(实施例21)的合成Synthesis of 7-(2-fluoro-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-1H-imidazo[4,5-b]pyridine (Example 21)

7-(2-fluoro-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-1H-imidazo[4,5-b]pyridine(实施例21)7-(2-fluoro-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-1H-imidazo[4,5-b]pyridine (Example 21)

按常规路线D，以4-(2-氟-3-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)苯基)-1,3,5-三甲基-1H-吡唑27a(279.5mg，0.85mmol)为反应原料。得到目标产物实施例21(138mg，66.0％)。¹H NMR(300MHz,Chloroform-d)δ8.59(s,1H),8.40(s,1H),7.89(d,J＝7.6Hz,1H),7.55(s,1H),7.38(p,J＝7.5Hz,2H),3.84(s,3H),2.26(s,3H),2.23(s,3H).According to the conventional route D, 4-(2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3,5-trimethyl-1H-pyrazole 27a (279.5 mg, 0.85 mmol) was used as the reaction material. The target product Example 21 (138 mg, 66.0%) was obtained.¹ H NMR (300 MHz, Chloroform-d) δ 8.59 (s, 1H), 8.40 (s, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.55 (s, 1H), 7.38 (p, J = 7.5 Hz, 2H), 3.84 (s, 3H), 2.26 (s, 3H), 2.23 (s, 3H).

实施例22：Embodiment 22:

7-(4-氟-3-(1,3,5-三甲基-1H-吡唑-4-基)苯基)-1H-咪唑并[4,5-b]吡啶(实施例22)的合成Synthesis of 7-(4-fluoro-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-1H-imidazo[4,5-b]pyridine (Example 22)

7-(4-fluoro-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-1H-imidazo[4,5-b]pyridine(实施例22)7-(4-fluoro-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-1H-imidazo[4,5-b]pyridine (Example 22)

按常规路线D，以4-(2-氟-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)-1,3,5-三甲基-1H-吡唑27b(279.5mg，0.85mmol)为反应原料。得到目标产物实施例22(113mg，54.1％)。¹H NMR(300MHz,Chloroform-d)δ8.62(s,1H),8.40(s,1H),8.21(s,1H),8.06(d,J＝6.9Hz,1H),7.52(s,1H),7.38(d,J＝9.0Hz,1H),3.85(s,3H),2.29(d,J＝5.9Hz,6H).According to the conventional route D, 4-(2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3,5-trimethyl-1H-pyrazole 27b (279.5 mg, 0.85 mmol) was used as the reaction material. The target product Example 22 (113 mg, 54.1%) was obtained.¹ H NMR (300 MHz, Chloroform-d) δ 8.62 (s, 1H), 8.40 (s, 1H), 8.21 (s, 1H), 8.06 (d, J = 6.9 Hz, 1H), 7.52 (s, 1H), 7.38 (d, J = 9.0 Hz, 1H), 3.85 (s, 3H), 2.29 (d, J = 5.9 Hz, 6H).

实施例23：Embodiment 23:

7-(2-氯-3-(1,3,5-三甲基-1H-吡唑-4-基)苯基)-1H-咪唑并[4,5-b]吡啶(实施例23)的合成Synthesis of 7-(2-chloro-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-1H-imidazo[4,5-b]pyridine (Example 23)

7-(2-chloro-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-1H-imidazo[4,5-b]pyridine(实施例23)7-(2-chloro-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-1H-imidazo[4,5-b]pyridine (Example 23)

按常规路线D，以4-(2-氯-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)-1,3,5-三甲基-1H-吡唑27c(292.9mg，0.85mmol)为反应原料。得到目标产物实施例23(96mg，43.7％)。¹H NMR(300MHz,Chloroform-d)δ8.59(s,1H),8.38(s,1H),7.61(d,J＝7.5Hz,1H),7.48(s,2H),7.35(d,J＝7.3Hz,1H),3.84(s,3H),2.21(s,3H),2.19(s,3H).According to the conventional route D, 4-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3,5-trimethyl-1H-pyrazole 27c (292.9 mg, 0.85 mmol) was used as the reaction material. The target product Example 23 (96 mg, 43.7%) was obtained.¹ H NMR (300 MHz, Chloroform-d) δ 8.59 (s, 1H), 8.38 (s, 1H), 7.61 (d, J = 7.5 Hz, 1H), 7.48 (s, 2H), 7.35 (d, J = 7.3 Hz, 1H), 3.84 (s, 3H), 2.21 (s, 3H), 2.19 (s, 3H).

实施例24：Embodiment 24:

7-(2,4-二氟-5-(1,3,5-三甲基-1H-吡唑-4-基)苯基)-1H-咪唑并[4,5-b]吡啶(实施例24)的合成Synthesis of 7-(2,4-difluoro-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-1H-imidazo[4,5-b]pyridine (Example 24)

7-(2,4-difluoro-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-1H-imidazo[4,5-b]pyridine(实施例24)7-(2,4-difluoro-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-1H-imidazo[4,5-b]pyridine (Example 24)

按常规路线D，以4-(2,4-二氟-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)-1,3,5-三甲基-1H-吡唑27d(294.2mg，0.85mmol)为反应原料。得到目标产物实施例24(105mg，47.6％)。¹H NMR(300MHz,Chloroform-d)δ8.59(s,1H),8.38(s,1H),7.89(t,J＝8.3Hz,1H),7.51(s,1H),7.12(t,J＝9.9Hz,1H),3.83(s,3H),2.26(s,3H),2.25(s,3H).According to the conventional route D, 4-(2,4-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3,5-trimethyl-1H-pyrazole 27d (294.2 mg, 0.85 mmol) was used as the reaction material. The target product Example 24 (105 mg, 47.6%) was obtained.¹ H NMR (300 MHz, Chloroform-d) δ 8.59 (s, 1H), 8.38 (s, 1H), 7.89 (t, J = 8.3 Hz, 1H), 7.51 (s, 1H), 7.12 (t, J = 9.9 Hz, 1H), 3.83 (s, 3H), 2.26 (s, 3H), 2.25 (s, 3H).

合成路线4：Synthetic route 4:

实施例25～实施例30依据scheme 4合成。28与商业化原料29a～29f在吡啶存在下经缩合反应得到中间体30a～30f。中间体31a～31f、硼酸酯中间体32a～32f及目标产物实施例25～实施例30的合成分别参照scheme 2合成路线a步骤、b步骤和c步骤。Examples 25 to 30 were synthesized according to Scheme 4. 28 and commercial raw materials 29a to 29f were subjected to condensation reaction in the presence of pyridine to obtain intermediates 30a to 30f. The synthesis of intermediates 31a to 31f, borate intermediates 32a to 32f and target products Examples 25 to 30 were respectively based on steps a, b and c of the synthetic route of Scheme 2.

Scheme 4.Reagents and conditions：(a)Pyridine,CH₂Cl₂,r.t.,4h；(b)Cs₂CO₃,Pd(dppf)Cl₂·CH₂Cl₂,1,4-Dioxane,H₂O,100℃,3h；(c)AcOK,Pd(dppf)Cl₂·CH₂Cl₂,dry1,4-Dioxane,100℃,3h；(d)Cs₂CO₃,Pd(dppf)Cl₂·CH₂Cl₂,1,4-Dioxane,H₂O,100℃,7h。Scheme 4.Reagents and conditions: (a)Pyridine,CH₂ Cl₂ ,rt,4h; (b)Cs₂ CO₃ ,Pd(dppf)Cl₂ ·CH₂ Cl₂ ,1,4-Dioxane,H₂ O ,100℃,3h; (c)AcOK,Pd(dppf)Cl₂ ·CH₂ Cl₂ ,dry1,4-Dioxane,100℃,3h; (d)Cs₂ CO₃ ,Pd(dppf)Cl₂ ·CH₂ Cl₂ ,1,4-Dioxane,H₂ O, 100℃, 7h.

N-(3,5-二溴-4-氟苯基)甲磺酰胺(30a)的合成Synthesis of N-(3,5-dibromo-4-fluorophenyl)methanesulfonamide (30a)

N-(3,5-dibromo-4-fluorophenyl)methanesulfonamide(30a)N-(3,5-dibromo-4-fluorophenyl)methanesulfonamide(30a)

常规合成路线E：室温下，将3,5-二溴-4-氟苯胺28(2.0g，7.44mmol)置于250mL圆底烧瓶中，并加入70mL二氯甲烷作为反应溶剂，随后加入吡啶(1.47g/1.49mL，18.6mmol)。在匀速搅拌状态下缓慢滴加甲基磺酰氯29a(937.1mg，8.18mmol)。滴加完毕后继续在室温下反应4h后TLC检测反应完全结束。在反应液中加入100mL 1M稀盐酸和等体积的乙酸乙酯分液萃取3次，合并有机层后以饱和氯化钠萃取一次，有机层以无水硫酸钠干燥1h后低压浓缩除去溶剂，残留物经柱层析得到目标产物30a(2.47g，95.7％)。Conventional synthetic route E: At room temperature, 3,5-dibromo-4-fluoroaniline 28 (2.0 g, 7.44 mmol) was placed in a 250 mL round-bottom flask, and 70 mL of dichloromethane was added as the reaction solvent, followed by pyridine (1.47 g/1.49 mL, 18.6 mmol). Methanesulfonyl chloride 29a (937.1 mg, 8.18 mmol) was slowly added dropwise under uniform stirring. After the addition was completed, the reaction was continued at room temperature for 4 h, and the reaction was completely completed after TLC detection. 100 mL of 1M dilute hydrochloric acid and an equal volume of ethyl acetate were added to the reaction solution, and the mixture was extracted three times. The organic layers were combined and extracted once with saturated sodium chloride. The organic layer was dried with anhydrous sodium sulfate for 1 h and then concentrated under low pressure to remove the solvent. The residue was subjected to column chromatography to obtain the target product 30a (2.47 g, 95.7%).

N-(3,5-二溴-4-氟苯基)乙磺酰胺(30b)的合成Synthesis of N-(3,5-dibromo-4-fluorophenyl)ethanesulfonamide (30b)

N-(3,5-dibromo-4-fluorophenyl)ethanesulfonamide(30b)N-(3,5-dibromo-4-fluorophenyl)ethanesulfonamide(30b)

按常规路线E，以乙基磺酰氯29b(1.04g，8.18mmol)为反应原料，得到目标产物30b(2.56g，产率：95.3％)。According to the conventional route E, ethylsulfonyl chloride 29b (1.04 g, 8.18 mmol) was used as the reaction raw material to obtain the target product 30b (2.56 g, yield: 95.3%).

N-(3,5-二溴-4-氟苯基)丙烷-1-磺酰胺(30c)的合成Synthesis of N-(3,5-dibromo-4-fluorophenyl)propane-1-sulfonamide (30c)

N-(3,5-dibromo-4-fluorophenyl)propane-1-sulfonamide(30c)N-(3,5-dibromo-4-fluorophenyl)propane-1-sulfonamide(30c)

按常规路线E，以乙基磺酰氯29c(1.17g，8.18mmol)为反应原料，得到目标产物30c(2.61g，产率：93.6％)。According to the conventional route E, ethylsulfonyl chloride 29c (1.17 g, 8.18 mmol) was used as the reaction raw material to obtain the target product 30c (2.61 g, yield: 93.6%).

N-(3,5-二溴-4-氟苯基)环丙磺酰胺(30d)的合成Synthesis of N-(3,5-dibromo-4-fluorophenyl)cyclopropanesulfonamide (30d)

N-(3,5-dibromo-4-fluorophenyl)cyclopropanesulfonamide(30d)N-(3,5-dibromo-4-fluorophenyl)cyclopropanesulfonamide(30d)

按常规路线E，以环丙基磺酰氯29d(1.15g，8.18mmol)为反应原料，得到目标产物30d(2.58g，产率：93.0％)。According to conventional route E, cyclopropylsulfonyl chloride 29d (1.15 g, 8.18 mmol) was used as the reaction raw material to obtain the target product 30d (2.58 g, yield: 93.0%).

N-(3,5-二溴-4-氟苯基)-1-甲基-1H-吡唑-4-磺酰胺(30e)的合成Synthesis of N-(3,5-dibromo-4-fluorophenyl)-1-methyl-1H-pyrazole-4-sulfonamide (30e)

N-(3,5-dibromo-4-fluorophenyl)-1-methyl-1H-pyrazole-4-sulfonamide(30e)N-(3,5-dibromo-4-fluorophenyl)-1-methyl-1H-pyrazole-4-sulfonamide(30e)

按常规路线E，以1-甲基-1H-吡唑-4-磺酰氯29e(1.48g，8.18mmol)为反应原料，得到目标产物30e(2.79g，产率：90.8％)。According to conventional route E, 1-methyl-1H-pyrazole-4-sulfonyl chloride 29e (1.48 g, 8.18 mmol) was used as the reaction raw material to obtain the target product 30e (2.79 g, yield: 90.8%).

N-(3,5-二溴-4-氟苯基)吡啶-2-磺酰胺(30f)的合成Synthesis of N-(3,5-dibromo-4-fluorophenyl)pyridine-2-sulfonamide (30f)

N-(3,5-dibromo-4-fluorophenyl)pyridine-2-sulfonamide(30f)N-(3,5-dibromo-4-fluorophenyl)pyridine-2-sulfonamide(30f)

按常规路线E，以1-甲基-1H-吡唑-4-磺酰氯29f(1.45g，8.18mmol)为反应原料，得到目标产物30f(2.63g，产率：86.3％)。According to conventional route E, 1-methyl-1H-pyrazole-4-sulfonyl chloride 29f (1.45 g, 8.18 mmol) was used as the reaction raw material to obtain the target product 30f (2.63 g, yield: 86.3%).

N-(3-溴-4-氟-5-(1,3,5-三甲基-1H-吡唑-4-基)苯基)甲磺酰胺(31a)的合成Synthesis of N-(3-bromo-4-fluoro-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)methanesulfonamide (31a)

N-(3-bromo-4-fluoro-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)methanesulfonamide(31a)N-(3-bromo-4-fluoro-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)methanesulfonamide(31a)

按常规路线B，以N-(3,5-二溴-4-氟苯基)甲磺酰胺30a(600mg，1.73mmol)为反应原料，得到目标产物31a(532mg，产率：81.8％)。According to conventional route B, N-(3,5-dibromo-4-fluorophenyl)methanesulfonamide 30a (600 mg, 1.73 mmol) was used as the reaction raw material to obtain the target product 31a (532 mg, yield: 81.8%).

N-(3-溴-4-氟-5-(1,3,5-三甲基-1H-吡唑-4-基)苯基)乙磺酰胺(31b)的合成Synthesis of N-(3-bromo-4-fluoro-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)ethanesulfonamide (31b)

N-(3-bromo-4-fluoro-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)ethanesulfonamide(31b)N-(3-bromo-4-fluoro-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)ethanesulfonamide(31b)

按常规路线B，以N-(3,5-二溴-4-氟苯基)乙磺酰胺30b(600mg，1.66mmol)为反应原料，得到目标产物31a(541mg，产率：83.4％)。According to conventional route B, N-(3,5-dibromo-4-fluorophenyl)ethanesulfonamide 30b (600 mg, 1.66 mmol) was used as the reaction raw material to obtain the target product 31a (541 mg, yield: 83.4%).

N-(3-溴-4-氟-5-(1,3,5-三甲基-1H-吡唑-4-基)苯基)丙烷-1-磺酰胺(31c)的合成Synthesis of N-(3-bromo-4-fluoro-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)propane-1-sulfonamide (31c)

N-(3-bromo-4-fluoro-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)propane-1-sulfonamide(31c)N-(3-bromo-4-fluoro-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)propane-1-sulfonamide(31c)

按常规路线B，以N-(3,5-二溴-4-氟苯基)丙烷-1-磺酰胺30c(600mg，1.60mmol)为反应原料，得到目标产物31c(554mg，产率：85.7％)。According to conventional route B, N-(3,5-dibromo-4-fluorophenyl)propane-1-sulfonamide 30c (600 mg, 1.60 mmol) was used as the reaction raw material to obtain the target product 31c (554 mg, yield: 85.7%).

N-(3-溴-4-氟-5-(1,3,5-三甲基-1H-吡唑-4-基)苯基)环丙磺酰胺(31d)的合成Synthesis of N-(3-bromo-4-fluoro-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)cyclopropanesulfonamide (31d)

N-(3-bromo-4-fluoro-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)cyclopropanesulfonamide(31d)N-(3-bromo-4-fluoro-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)cyclopropanesulfonamide(31d)

按常规路线B，以N-(3,5-二溴-4-氟苯基)环丙磺酰胺30d(600mg，1.61mmol)为反应原料，得到目标产物31d(547mg，产率：84.5％)According to the conventional route B, N-(3,5-dibromo-4-fluorophenyl)cyclopropanesulfonamide 30d (600 mg, 1.61 mmol) was used as the reaction raw material to obtain the target product 31d (547 mg, yield: 84.5%)

N-(3-溴-4-氟-5-(1,3,5-三甲基-1H-吡唑-4-基)苯基)-1-甲基-1H-吡唑-4-磺酰胺(31e)的合成Synthesis of N-(3-bromo-4-fluoro-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-1-methyl-1H-pyrazole-4-sulfonamide (31e)

N-(3-bromo-4-fluoro-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-1-methyl-1H-pyrazole-4-sulfonamide(31e)N-(3-bromo-4-fluoro-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-1-methyl-1H-pyrazole-4-sulfonamide(31e)

按常规路线B，以N-(3,5-二溴-4-氟苯基)环丙磺酰胺30e(600mg，1.45mmol)为反应原料，得到目标产物31e(542mg，产率：84.4％)。According to conventional route B, N-(3,5-dibromo-4-fluorophenyl)cyclopropanesulfonamide 30e (600 mg, 1.45 mmol) was used as the reaction raw material to obtain the target product 31e (542 mg, yield: 84.4%).

N-(3-溴-4-氟-5-(1,3,5-三甲基-1H-吡唑-4-基)苯基)吡啶-2-磺酰胺(31f)的合成Synthesis of N-(3-bromo-4-fluoro-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)pyridine-2-sulfonamide (31f)

N-(3-bromo-4-fluoro-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)pyridine-2-sulfonamide(31f)N-(3-bromo-4-fluoro-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)pyridine-2-sulfonamide(31f)

按常规路线B，以N-(3,5-二溴-4-氟苯基)环丙磺酰胺30f(600mg，1.46mmol)为反应原料，得到目标产物31f(517mg，产率：80.4％)。According to conventional route B, N-(3,5-dibromo-4-fluorophenyl)cyclopropanesulfonamide 30f (600 mg, 1.46 mmol) was used as the reaction raw material to obtain the target product 31f (517 mg, yield: 80.4%).

N-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-5-(1,3,5-三甲基-1H-吡唑-4-基)苯基)甲基磺酰胺(32a)的合成Synthesis of N-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)methylsulfonamide (32a)

N-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)methanesulfonamide(32a)N-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(1,3,5-trimethyl-1H-pyrazol-4- yl)phenyl)methanesulfonamide(32a)

按常规路线C，以N-(3-溴-4-氟-5-(1,3,5-三甲基-1H-吡唑-4-基)苯基)甲磺酰胺31a(400mg，1.06mmol)为反应原料，得到目标产物32a(351mg，产率：78.0％)。According to conventional route C, N-(3-bromo-4-fluoro-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)methanesulfonamide 31a (400 mg, 1.06 mmol) was used as the reaction raw material to obtain the target product 32a (351 mg, yield: 78.0%).

N-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-5-(1,3,5-三甲基-1H-吡唑-4-基)苯基)乙磺酰胺(32b)的合成Synthesis of N-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)ethanesulfonamide (32b)

N-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)ethanesulfonamide(32b)N-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(1,3,5-trimethyl-1H-pyrazol-4- yl)phenyl)ethanesulfonamide(32b)

按常规路线C，以N-(3-溴-4-氟-5-(1,3,5-三甲基-1H-吡唑-4-基)苯基)乙磺酰胺31b(400mg，1.02mmol)为反应原料，得到目标产物32b(347mg，产率：77.4％)。According to conventional route C, N-(3-bromo-4-fluoro-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)ethanesulfonamide 31b (400 mg, 1.02 mmol) was used as the reaction raw material to obtain the target product 32b (347 mg, yield: 77.4%).

N-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-5-(1,3,5-三甲基-1H-吡唑-4-基)苯基)丙烷-1-磺酰胺(32c)的合成Synthesis of N-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)propane-1-sulfonamide (32c)

N-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)propane-1-sulfonamide(32c)N-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(1,3,5-trimethyl-1H-pyrazol-4- yl)phenyl)propane-1-sulfonamide(32c)

按常规路线C，以N-(3-溴-4-氟-5-(1,3,5-三甲基-1H-吡唑-4-基)苯基)丙烷-1-磺酰胺31c(400mg，0.98mmol)为反应原料，得到目标产物32c(331mg，产率：74.1％)。According to conventional route C, N-(3-bromo-4-fluoro-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)propane-1-sulfonamide 31c (400 mg, 0.98 mmol) was used as the reaction raw material to obtain the target product 32c (331 mg, yield: 74.1%).

N-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-5-(1,3,5-三甲基-1H-吡唑-4-基)苯基)环丙磺酰胺(32d)的合成Synthesis of N-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)cyclopropanesulfonamide (32d)

N-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)cyclopropanesulfonamide(32d)N-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(1,3,5-trimethyl-1H-pyrazol-4- yl)phenyl)cyclopropanesulfonamide(32d)

按常规路线C，以N-(3-溴-4-氟-5-(1,3,5-三甲基-1H-吡唑-4-基)苯基)环丙磺酰胺31d(400mg，0.99mmol)为反应原料，得到目标产物32d(324mg，产率：72.5％)。According to conventional route C, N-(3-bromo-4-fluoro-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)cyclopropanesulfonamide 31d (400 mg, 0.99 mmol) was used as the reaction raw material to obtain the target product 32d (324 mg, yield: 72.5%).

N-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-5-(1,3,5-三甲基-1H-吡唑-4-基)苯基)-1-甲基-1H-吡唑-4-磺酰胺(32e)的合成Synthesis of N-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-1-methyl-1H-pyrazole-4-sulfonamide (32e)

N-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-1-methyl-1H-pyrazole-4-sulfonamide(32e)N-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(1,3,5-trimethyl-1H-pyrazol-4- yl)phenyl)-1-methyl-1H-pyrazole-4-sulfonamide(32e)

按常规路线C，以N-(3-溴-4-氟-5-(1,3,5-三甲基-1H-吡唑-4-基)苯基)-1-甲基-1H-吡唑-4-磺酰胺31e(400mg，0.91mmol)为反应原料，得到目标产物32e(324mg，产率：73.2％)。According to conventional route C, N-(3-bromo-4-fluoro-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-1-methyl-1H-pyrazole-4-sulfonamide 31e (400 mg, 0.91 mmol) was used as the reaction raw material to obtain the target product 32e (324 mg, yield: 73.2%).

N-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-5-(1,3,5-三甲基-1H-吡唑-4-基)苯基)吡啶-2-磺酰胺(32f)的合成Synthesis of N-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)pyridine-2-sulfonamide (32f)

N-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)pyridine-2-sulfonamide(32f)N-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(1,3,5-trimethyl-1H-pyrazol-4- yl)phenyl)pyridine-2-sulfonamide(32f)

按常规路线C，以N-(3-溴-4-氟-5-(1,3,5-三甲基-1H-吡唑-4-基)苯基)吡啶-2-磺酰胺31f(400mg，0.91mmol)为反应原料，得到目标产物32f(342mg，产率：77.2％)。According to conventional route C, N-(3-bromo-4-fluoro-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)pyridine-2-sulfonamide 31f (400 mg, 0.91 mmol) was used as the reaction raw material to obtain the target product 32f (342 mg, yield: 77.2%).

实施例25：Embodiment 25:

N-(4-氟-3-(1H-咪唑并[4,5-b]吡啶-7-基)-5-(1,3,5-三甲基-1H-吡唑-4-基)苯基)甲磺酰胺(实施例25)的合成Synthesis of N-(4-fluoro-3-(1H-imidazo[4,5-b]pyridin-7-yl)-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)methanesulfonamide (Example 25)

N-(4-fluoro-3-(1H-imidazo[4,5-b]pyridin-7-yl)-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)methanesulfonamide(实施例25)N-(4-fluoro-3-(1H-imidazo[4,5-b]pyridin-7-yl)-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)methanesulfonamide( Example 25)

按常规路线D，以N-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-5-(1,3,5-三甲基-1H-吡唑-4-基)苯基)甲基磺酰胺32a(300mg，0.71mmol)为反应原料。得到目标产物实施例25(193mg，65.7％)。¹H NMR(300MHz,DMSO-d₆)δ13.33(s,1H),9.96(d,J＝9.5Hz,1H),8.52(s,1H),8.45(d,J＝5.0Hz,1H),7.67(dd,J＝5.9,2.8Hz,1H),7.42(dd,J＝5.0,1.8Hz,1H),7.22(dd,J＝6.1,2.8Hz,1H),3.75(s,3H),3.12(s,3H),2.23(s,3H),2.14(s,3H).According to the conventional route D, N-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)methylsulfonamide 32a (300 mg, 0.71 mmol) was used as the reaction material to obtain the target product Example 25 (193 mg, 65.7%).¹ H NMR (300MHz, DMSO-d₆ ) δ13.33(s,1H),9.96(d,J＝9.5Hz,1H),8.52(s,1H),8.45(d,J＝5.0Hz,1H),7.67(dd,J＝5.9,2.8Hz,1H),7.42(dd,J＝5.0,1.8Hz,1H) ,7.22(dd,J＝6.1,2.8Hz,1H),3.75(s,3H),3.12(s,3H),2.23(s,3H),2.14(s,3H).

实施例26：Embodiment 26:

N-(4-氟-3-(1H-咪唑并[4,5-b]吡啶-7-基)-5-(1,3,5-三甲基-1H-吡唑-4-基)苯基)乙磺酰胺(实施例26)的合成Synthesis of N-(4-fluoro-3-(1H-imidazo[4,5-b]pyridin-7-yl)-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)ethanesulfonamide (Example 26)

N-(4-fluoro-3-(1H-imidazo[4,5-b]pyridin-7-yl)-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)ethanesulfonamide(实施例26)N-(4-fluoro-3-(1H-imidazo[4,5-b]pyridin-7-yl)-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)ethanesulfonamide( Example 26)

按常规路线D，以N-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-5-(1,3,5-三甲基-1H-吡唑-4-基)苯基)乙磺酰胺32b(300mg，0.68mmol)为反应原料。得到目标产物实施例26(203mg，69.1％)。¹HNMR(300MHz,DMSO-d₆)δ13.32(s,1H),9.99(s,1H),8.57–8.41(m,2H),7.68(dd,J＝5.9,2.8Hz,1H),7.43–7.32(m,1H),7.22(dd,J＝6.0,2.8Hz,1H),3.75(s,3H),3.21(dd,J＝8.7,5.8Hz,2H),2.23(s,3H),2.13(s,3H),1.27(t,J＝7.2Hz,3H).According to the conventional route D, N-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)ethanesulfonamide 32b (300 mg, 0.68 mmol) was used as the reaction material to obtain the target product Example 26 (203 mg, 69.1%).¹ HNMR (300MHz, DMSO-d₆ ) δ13.32(s,1H),9.99(s,1H),8.57–8.41(m,2H),7.68(dd,J＝5.9,2.8Hz,1H),7.43–7.32(m,1H),7.22(dd,J＝6.0,2.8Hz,1H),3.7 5(s,3H),3.21(dd,J＝8.7,5.8Hz,2H),2.23(s,3H),2.13(s,3H),1.27(t,J＝7.2Hz,3H).

实施例27：Embodiment 27:

N-(4-氟-3-(1H-咪唑并[4,5-b]吡啶-7-基)-5-(1,3,5-三甲基-1H-吡唑-4-基)苯基)丙烷-1-磺酰胺(实施例27)的合成Synthesis of N-(4-fluoro-3-(1H-imidazo[4,5-b]pyridin-7-yl)-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)propane-1-sulfonamide (Example 27)

N-(4-fluoro-3-(1H-imidazo[4,5-b]pyridin-7-yl)-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)propane-1-sulfonamide(实施例27)N-(4-fluoro-3-(1H-imidazo[4,5-b]pyridin-7-yl)-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)propane- 1-sulfonamide (Example 27)

按常规路线D，以N-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-5-(1,3,5-三甲基-1H-吡唑-4-基)苯基)环丙磺酰胺32c(300mg，0.66mmol)为反应原料。得到目标产物实施例27(164mg，55.8％)。¹HNMR(300MHz,Chloroform-d)δ8.97(s,1H),8.54(d,J＝5.1Hz,1H),8.38(s,1H),7.77(s,1H),7.48(d,J＝4.5Hz,1H),3.78(s,3H),3.15(dd,J＝9.4,6.3Hz,2H),2.16(s,3H),2.14(s,3H),1.90(h,J＝7.4Hz,2H),1.03(d,J＝7.4Hz,3H).According to the conventional route D, N-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)cyclopropanesulfonamide 32c (300 mg, 0.66 mmol) was used as the reaction material to obtain the target product Example 27 (164 mg, 55.8%).¹ HNMR(300MHz,Chloroform-d)δ8.97(s,1H),8.54(d,J＝5.1Hz,1H),8.38(s,1H),7.77(s,1H),7.48(d,J＝4.5Hz,1H),3.78(s,3H),3.15(dd,J＝9.4,6.3Hz,2H), 2.16(s,3H),2.14(s,3H),1.90(h,J＝7.4Hz,2H),1.03(d,J＝7.4Hz,3H).

实施例28：Embodiment 28:

N-(4-氟-3-(1H-咪唑并[4,5-b]吡啶-7-基)-5-(1,3,5-三甲基-1H-吡唑-4-基)苯基)环丙烷磺酰胺(实施例28)的合成Synthesis of N-(4-fluoro-3-(1H-imidazo[4,5-b]pyridin-7-yl)-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)cyclopropanesulfonamide (Example 28)

N-(4-fluoro-3-(1H-imidazo[4,5-b]pyridin-7-yl)-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)cyclopropanesulfonamide(实施例28)N-(4-fluoro-3-(1H-imidazo[4,5-b]pyridin-7-yl)-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)cyclopropanesulfonamide( Example 28)

按常规路线D，以N-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-5-(1,3,5-三甲基-1H-吡唑-4-基)苯基)环丙磺酰胺32d(300mg，0.67mmol)为反应原料。得到目标产物实施例28(176mg，59.8％)。¹H NMR(300MHz,DMSO-d₆)δ9.92(s,1H),8.55(s,1H),8.47(d,J＝5.0Hz,1H),7.63(s,1H),7.39(dd,J＝5.0,1.4Hz,1H),7.25(dd,J＝6.2,2.8Hz,1H),3.75(s,3H),2.75(tt,J＝7.2,5.2Hz,1H),2.23(s,3H),2.14(s,3H),1.00(dq,J＝4.4,2.5Hz,4H).According to the conventional route D, N-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)cyclopropanesulfonamide 32d (300 mg, 0.67 mmol) was used as the reaction material to obtain the target product Example 28 (176 mg, 59.8%).¹ H NMR (300MHz, DMSO-d₆ ) δ9.92 (s, 1H), 8.55 (s, 1H), 8.47 (d, J = 5.0Hz, 1H), 7.63 (s, 1H), 7.39 (dd, J = 5.0, 1.4Hz, 1H), 7.25 (dd, J = 6.2, 2.8Hz, 1H), 3.75 (s, 3H), 2.75(tt,J＝7.2,5.2Hz,1H),2.23(s,3H),2.14(s,3H),1.00(dq,J＝4.4,2.5Hz,4H).

实施例29：Embodiment 29:

N-(4-氟-3-(1H-咪唑并[4,5-b]吡啶-7-基)-5-(1,3,5-三甲基-1H-吡唑-4-基)苯基)-1-甲基-1H-吡唑-4-磺酰胺(实施例29)的合成Synthesis of N-(4-fluoro-3-(1H-imidazo[4,5-b]pyridin-7-yl)-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-1-methyl-1H-pyrazole-4-sulfonamide (Example 29)

N-(4-fluoro-3-(1H-imidazo[4,5-b]pyridin-7-yl)-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-1-methyl-1H-pyrazole-4-sulfonamide(实施例29)N-(4-fluoro-3-(1H-imidazo[4,5-b]pyridin-7-yl)-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-1 -methyl-1H-pyrazole-4-sulfonamide (Example 29)

按常规路线D，以N-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-5-(1,3,5-三甲基-1H-吡唑-4-基)苯基)-1-甲基-1H-吡唑-4-磺酰胺32e(300mg，0.61mmol)为反应原料。得到目标产物实施例29(182mg，61.8％)。¹H NMR(300MHz,DMSO-d₆)δ13.31(s,1H),10.59(s,1H),8.56–8.41(m,2H),7.91(dd,J＝4.7,2.3Hz,1H),7.58(dd,J＝5.9,2.8Hz,1H),7.33(dd,J＝5.0,1.7Hz,1H),7.14(ddd,J＝15.1,6.1,2.8Hz,1H),6.71(d,J＝2.2Hz,1H),3.93(s,3H),3.73(s,3H),2.15(s,3H),2.05(d,J＝2.9Hz,3H).According to the conventional route D, N-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-1-methyl-1H-pyrazole-4-sulfonamide 32e (300 mg, 0.61 mmol) was used as the reaction material to obtain the target product Example 29 (182 mg, 61.8%).¹ H NMR (300MHz, DMSO-d₆ ) δ13.31 (s, 1H), 10.59 (s, 1H), 8.56–8.41 (m, 2H), 7.91 (dd, J = 4.7, 2.3Hz, 1H), 7.58 (dd, J = 5.9, 2.8Hz, 1H), 7.33 (dd, J = 5.0, 1.7Hz, 1H),7.14(ddd,J＝15.1,6.1,2.8Hz,1H),6.71(d,J＝2.2Hz,1H),3.93(s,3H),3.73(s,3H),2.15(s,3H),2.05(d,J＝2.9Hz,3H).

实施例30：Embodiment 30:

N-(4-氟-3-(1H-咪唑并[4,5-b]吡啶-7-基)-5-(1,3,5-三甲基-1H-吡唑-4-基)苯基)吡啶-2-磺酰胺(实施例30)的合成Synthesis of N-(4-fluoro-3-(1H-imidazo[4,5-b]pyridin-7-yl)-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)pyridine-2-sulfonamide (Example 30)

N-(4-fluoro-3-(1H-imidazo[4,5-b]pyridin-7-yl)-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)pyridine-2-sulfonamide(实施例30)N-(4-fluoro-3-(1H-imidazo[4,5-b]pyridin-7-yl)-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)pyridine- 2-sulfonamide (Example 30)

按常规路线D，以N-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-5-(1,3,5-三甲基-1H-吡唑-4-基)苯基)吡啶-2-磺酰胺32f(300mg，0.62mmol)为反应原料。得到目标产物实施例30(158mg，53.6％)。¹H NMR(300MHz,DMSO-d₆)δ13.35(s,1H),10.73(s,1H),9.09–8.78(m,2H),8.49(d,J＝25.0Hz,2H),8.24(d,J＝7.9Hz,1H),7.81–7.51(m,2H),7.33(s,1H),7.02(s,1H),3.72(s,3H),2.09(s,3H),1.99(s,3H).According to the conventional route D, N-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)pyridine-2-sulfonamide 32f (300 mg, 0.62 mmol) was used as the reaction raw material to obtain the target product Example 30 (158 mg, 53.6%).¹ H NMR (300MHz, DMSO-d₆ ) δ13.35(s,1H),10.73(s,1H),9.09–8.78(m,2H),8.49(d,J＝25.0Hz,2H),8.24(d,J＝7.9Hz,1H),7.81–7.51(m,2H),7.33(s,1H ),7.02(s,1H),3.72(s,3H),2.09(s,3H),1.99(s,3H).

药理活性评价：Evaluation of pharmacological activity:

1、对BRD4(1)和BRD4(2)的抑制率测试1. Inhibition test of BRD4(1) and BRD4(2)

以竞争性荧光偏振(FP)测定评估化合物对BRD4(1)和BRD4(2)的抑制活性。为了建立FP检测，我们设计并合成了一种基于(+)-JQ1(MedChemExpress(MCE))的FAM(MedChemExpress(MCE))标记的荧光探针(合成方法见表1下文)。通过在测定hepes(安耐吉化学)缓冲液中连续稀释，将实施例化合物(10mM在DMSO(国药集团化学试剂有限公司)母液中)制备成各种浓度的溶液。BRD4(1)和BRD4(2)以及荧光探针(FAM-(+)-JQ1)在测定缓冲液中稀释至所需浓度。该实验在384孔黑色平底聚苯乙烯板(康宁编号3575)中进行。对于每个测定，等体积的稀释化合物(20uL)、BRD4(1)(20uL,78nM final)或BRD4(2)(20uL,53nMfinal)和FAM-(+)-JQ1(20uL,2.33nM final)连续添加到孔中。将板盖上并在室温下摇动30分钟，使用SpectraMax多模式酶标仪(Molecular Devices)检测FP值，激发和发射波长分别为485和535nm。对于每个测定，空白对照(仅FAM-(+)-JQ1)的FP值记录为Pmin；阴性对照(FAM-(+)-JQ1和蛋白质)的FP值记为Pmax，测试孔(化合物、FAM-(+)-JQ1和蛋白质)的FP值记为Ptest。各浓度点化合物的抑制率计算公式如下：抑制率(％)＝[1-(Ptest-Pmin)/(Pmax-Pmin)]×100％。采用Graphpad Prism 8.0软件计算IC₅₀。The inhibitory activity of the compounds against BRD4(1) and BRD4(2) was evaluated by competitive fluorescence polarization (FP) assay. To establish FP detection, we designed and synthesized a FAM (MedChemExpress (MCE))-labeled fluorescent probe based on (+)-JQ1 (MedChemExpress (MCE)) (synthesis method is shown in Table 1 below). The example compounds (10mM in DMSO (Sinopharm Chemical Reagent Co., Ltd.) stock solution) were prepared into solutions of various concentrations by serial dilution in assay hepes (Annaiji Chemical) buffer. BRD4(1) and BRD4(2) and the fluorescent probe (FAM-(+)-JQ1) were diluted to the desired concentration in assay buffer. The experiment was performed in a 384-well black flat-bottom polystyrene plate (Corning No. 3575). For each assay, equal volumes of diluted compound (20uL), BRD4(1) (20uL, 78nM final) or BRD4(2) (20uL, 53nM final) and FAM-(+)-JQ1 (20uL, 2.33nM final) were added to the wells in succession. The plate was covered and shaken at room temperature for 30 min, and the FP values were measured using a SpectraMax multi-mode microplate reader (Molecular Devices) with excitation and emission wavelengths of 485 and 535nm, respectively. For each assay, the FP value of the blank control (FAM-(+)-JQ1 only) was recorded as Pmin; the FP value of the negative control (FAM-(+)-JQ1 and protein) was recorded as Pmax, and the FP value of the test well (compound, FAM-(+)-JQ1 and protein) was recorded as Ptest. The inhibition rate of the compound at each concentration point was calculated as follows: Inhibition rate (%) = [1-(Ptest-Pmin)/(Pmax-Pmin)] × 100%._IC50 was calculated using Graphpad Prism 8.0 software.

表1实施例化合物对BRD4(1)和BRD4(2)的抑制活性Table 1 Inhibitory activity of the compounds of the examples against BRD4(1) and BRD4(2)

荧光探针5-FAM-(+)-JQ1的合成方法：Synthesis method of fluorescent probe 5-FAM-(+)-JQ1:

(S)-2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂-6-基)乙酸(C1)的合成Synthesis of (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid (C1)

(S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]di(S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1 ,4]di

azepin-6-yl)acetic acid(C1)azepin-6-yl)acetic acid(C1)

将(+)-JQ1(300mg,656.47μM)溶于10mL二氯甲烷中，在上述溶液中室温缓慢滴加974μL(20eq)三氟乙酸，室温搅拌3h，然后用TLC反应完全。减压浓缩除去溶剂，得淡黄色油状物(262mg，99.6％)，无需进一步纯化，直接进入下一步。(+)-JQ1 (300 mg, 656.47 μM) was dissolved in 10 mL of dichloromethane, 974 μL (20 eq) of trifluoroacetic acid was slowly added dropwise to the above solution at room temperature, stirred at room temperature for 3 h, and then the reaction was completed by TLC. The solvent was removed by concentration under reduced pressure to obtain a light yellow oil (262 mg, 99.6%), which was directly transferred to the next step without further purification.

叔丁基(S)-(2-(2-(2-(2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2)),4]三唑并[4,3-a][1,4]二氮杂-6-基)乙酰氨基)乙氧基)乙氧基)乙基)氨基甲酸酯(C3)的合成Synthesis of tert-butyl (S)-(2-(2-(2-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2)),4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)ethoxy)ethoxy)ethyl)carbamate (C3)

tert-butyl(S)-(2-(2-(2-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)ethoxy)ethoxy)ethyl)carbamate(C3)tert-butyl(S)-(2-(2-(2-(2-(4-(4-chlorophenyl))-2,3,9-trimethyl-6H-thieno[3,2-f][1,2 ,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)ethoxy)ethoxy)ethyl)carbamate(C3)

室温下将C1(266mg，0.66mmol)溶于无水二氯甲烷中，向上述溶液中加入pyBOP(379mg，0.73mmol)和DIPEA(256mg，1.98mmol)，室温下搅拌30分钟，然后加入C2(164mg,0.66mmol)加入到反应混合物中。在室温下继续搅拌4h后，通过TLC监测反应材料的完全反应。有机层加水和二氯甲烷萃取3次，合并有机层，用饱和NaCl萃取，有机层用无水硫酸钠干燥30min，萃取浓缩除去溶剂，通过柱色谱分离得到白色粉末C3(295mg，67.1％)。¹H NMR(300MHz,DMSO-d₆)δ7.51(d,J＝8.8Hz,2H),7.45(d,J＝8.6Hz,2H),6.81(t,J＝5.7Hz,1H),4.54(dd,J＝7.9,6.2Hz,1H),3.61–3.51(m,8H),3.48(t,J＝5.8Hz,2H),3.41(t,J＝6.1Hz,2H),3.10(t,J＝5.9Hz,2H),3.06–2.98(m,1H),2.62(s,3H),2.46–2.40(s,3H),1.68–1.62(s,3H),1.39(s,9H).C1 (266 mg, 0.66 mmol) was dissolved in anhydrous dichloromethane at room temperature, pyBOP (379 mg, 0.73 mmol) and DIPEA (256 mg, 1.98 mmol) were added to the above solution, stirred at room temperature for 30 minutes, and then C2 (164 mg, 0.66 mmol) was added to the reaction mixture. After stirring at room temperature for 4 hours, the complete reaction of the reaction material was monitored by TLC. The organic layer was extracted with water and dichloromethane three times, the organic layers were combined, extracted with saturated NaCl, and the organic layer was dried over anhydrous sodium sulfate for 30 minutes. The extract was concentrated to remove the solvent and separated by column chromatography to obtain white powder C3 (295 mg, 67.1%).¹ H NMR (300MHz, DMSO-d₆ ) δ7.51(d,J＝8.8Hz,2H),7.45(d,J＝8.6Hz,2H),6.81(t,J＝5.7Hz,1H),4.54(dd,J＝7.9,6.2Hz,1H),3.61–3.51(m,8H),3.48(t,J＝5.8 Hz,2H),3.41(t,J＝6.1Hz,2H),3.10(t,J＝5.9Hz,2H),3.06–2.98(m,1H),2.62(s,3H),2.46–2.40(s,3H),1.68–1.62(s,3H),1.39(s,9H).

(s)-2-(2-(2-(2-(4-(4-氯苯基))-2，3，9-三甲基-6H-噻吩[3,2-f][1,2,4]三唑[4,3-a][1,4]二氮杂卓-6-基)乙酰胺基)乙氧基)乙氧基)乙烷-1--2，2，2-三氟乙酸盐(C4)的合成(S)-2-(2-(2-(2-(4-(4-chlorophenyl))-2,3,9-trimethyl-6H-thiophene[3,2-f][1,2,4]triazol[4,3-a][1,4]diazepin-6-yl)acetamido)ethoxy)ethoxy)ethane-1- -Synthesis of 2,2,2-trifluoroacetate (C4)

(S)-2-(2-(2-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]dia zepin-6-yl)acetamido)ethoxy)ethoxy)ethan-1-aminium 2,2,2-trifluoroacetate(C4)(S)-2-(2-(2-(2-(4-(4-chlorophenyl))-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo [4,3-a][1,4]dia zepin-6-yl)acetamido)ethoxy)ethoxy)ethan-1-aminium 2,2,2-trifluoroacetate(C4)

室温下，将C3(295mg，0.44mmol)加入50mL圆底烧瓶中，加入10mL二氯甲烷作为反应溶剂，缓慢滴加2mL三氟乙酸，在3℃搅拌后用TLC监测原料反应。室温3h。减压除去溶剂，得到棕红色油状物(210mg)。无需进一步纯化，直接流延至下一步。At room temperature, C3 (295 mg, 0.44 mmol) was added to a 50 mL round-bottom flask, 10 mL of dichloromethane was added as the reaction solvent, 2 mL of trifluoroacetic acid was slowly added dropwise, and the reaction of the raw material was monitored by TLC after stirring at 3 ° C. Room temperature for 3 h. The solvent was removed under reduced pressure to obtain a brown-red oil (210 mg). No further purification was required and it was directly cast to the next step.

(S)-N-(2-(2-(2-(2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂卓-6-基)乙酰氨基)乙氧基)乙氧基)乙基)-3',6'-二羟基-3-氧代-3H-螺[异苯并呋喃-1,9'-蒽]-5-甲酰胺(5-FAM-(+)-JQ1)的合成Synthesis of (S)-N-(2-(2-(2-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)ethoxy)ethoxy)ethyl)-3',6'-dihydroxy-3-oxo-3H-spiro[isobenzofuran-1,9'-anthracene]-5-carboxamide (5-FAM-(+)-JQ1)

(S)-N-(2-(2-(2-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)ethoxy)ethoxy)ethyl)-3',6'-dihydroxy-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthene]-5-carboxamide(5-FAM-(+)-JQ1)(S)-N-(2-(2-(2-(2-(4-(4-chlorophenyl))-2,3,9-trimethyl-6H-thieno[3,2-f][1,2, 4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)ethoxy)ethoxy)ethyl)-3',6'-dihydroxy-3-oxo-3H-spiro[isobenzofuran-1, 9'-xanthene]-5-carboxamide(5-FAM-(+)-JQ1)

在室温下，将C4(210mg，0.37mmol)加入到50mL圆底烧瓶中，然后加入7mL无水DMF、HATU(154.7mg，0.41mmol)和DIPEA(144.5mg，1.1mmol)，反应进行N2保护下搅拌30分钟，反应变为浅棕色混合物，然后加入5-FAM(139.2mg，0.37mmol)，继续搅拌6小时。TLC监测原料的完全反应。有机层加水和二氯甲烷萃取3次，合并有机层，用饱和NaCl萃取，有机层用无水硫酸钠干燥30min，萃取浓缩除去溶剂，得通过柱色谱分离淡黄色粉末5-FAM-(+)-JQ1(267mg,81.4％)。¹H NMR(300MHz,DMSO-d₆)δ10.21(s,1H),8.95(t,J＝5.4Hz,1H),8.49(s,1H),8.35(s,1H),8.28(dd,J＝8.1,1.6Hz,1H),7.56–7.41(m,5H),7.39(d,J＝8.1Hz,1H),6.72(d,J＝2.2Hz,2H),6.61(d,J＝8.6Hz,2H),6.56(dd,J＝8.8,2.2Hz,2H),4.53(dd,J＝7.8,6.3Hz,1H),3.62–3.58(m,6H),3.50(q,J＝5.7,4.9Hz,4H),3.27(t,J＝7.2Hz,4H),2.62(s,3H),2.43(s,3H),1.63(s,3H).Purity:97.95％by HPLC(MeOH/H₂O＝75:25).纯度：97.93％by HPLC(MeOH/H₂O＝80:20,t_R＝3.535min).At room temperature, C4 (210 mg, 0.37 mmol) was added to a 50 mL round-bottom flask, and then 7 mL of anhydrous DMF, HATU (154.7 mg, 0.41 mmol) and DIPEA (144.5 mg, 1.1 mmol) were added. The reaction was stirred for 30 minutes under N2 protection. The reaction turned into a light brown mixture, and then 5-FAM (139.2 mg, 0.37 mmol) was added and continued to stir for 6 hours. TLC monitored the complete reaction of the raw material. The organic layer was extracted with water and dichloromethane three times, the organic layers were combined, extracted with saturated NaCl, and the organic layer was dried over anhydrous sodium sulfate for 30 min. The extract was concentrated to remove the solvent, and a light yellow powder 5-FAM-(+)-JQ1 (267 mg, 81.4%) was separated by column chromatography.¹ H NMR (300 MHz, DMSO-d₆ )δ10.21(s,1H),8.95(t,J＝5.4Hz,1H),8.49(s,1H),8.35(s,1H),8.28(dd,J＝8.1,1.6Hz,1H),7.56–7.41(m,5H),7.39(d,J＝8.1Hz,1H),6.72(d,J＝2.2Hz ,2H),6.61(d,J＝8.6Hz,2H),6 .56(dd,J＝8.8,2.2Hz,2H),4.53(dd,J＝7.8,6.3Hz,1H),3.62–3.58(m,6H),3.50(q,J＝5.7,4.9Hz,4H),3.27(t,J＝7.2Hz,4H),2.62(s,3H),2.43(s,3H), 1.63 (s, 3H). Purity: 97.95% by HPLC (MeOH/H₂ O = 75:25). Purity: 97.93% by HPLC (MeOH/H₂ O = 80:20, t_R = 3.535min).

2、细胞水平活性评价2. Evaluation of cell-level activity

人髓性单核细胞白血病细胞MV-4-11、人卵巢癌细胞SKOV3、人乳腺癌细胞MCF7从中科院上海细胞库购得，MV-4-11细胞培养在IMDM(Adamas)培养基中，SKOV3细胞培养自McCoy’s 5A培养基(Gibco)中，MCF7细胞培养在DMEM(Adamas)培养基中，培养时各类培养基添加10％胎牛血清，1％的100×青霉素链霉素双抗(15140-122,Gibco ThermoFisher,USA)，在37℃，5％CO₂条件下培养。将处于对数生长期的细胞以每孔5000个的密度接种至96孔板(Corning，型号3599)中，培养基体积为100μL，于37℃，5％CO₂的孵箱内过夜培养。次日，加入100μL培养基配制的不同浓度的药物溶液，每个浓度设三个复孔(记为RLU_test)，并设置对照孔和空白孔。对照孔为细胞、培养液与相同浓度的药物溶解介质(记为RLU_control),空白孔为培养液(记为RLU_blank)。96h后，每孔吸出100μL至96孔黑板中，每孔再加入100μL的CellTiter-Lumi发光法细胞活力检测试剂盒(Beyotime Biotechnology)检测试剂，放置在摇床上避光孵育10min后检测。贴壁细胞每孔吸出100μL培养基丢弃，在96孔板中各加入100μL的检测试剂，放置摇床上裂解2min后，将孔中溶液吸出至96孔黑板中，放置在摇床上避光孵育8min后检测。通过Thermo scientific varioskanflash上的化学发光模块检测化学发光值。通过下式计算细胞的存活百分比，计算公式为：细胞存活率(％)＝(RLU_test-RLU_blank)/(RLU_control-RLU_blank)×100％，采用Graphpad Prism 8.0软件计算IC₅₀。结果如表2和图1所示。Human myelomonocytic leukemia cells MV-4-11, human ovarian cancer cells SKOV3, and human breast cancer cells MCF7 were purchased from the Shanghai Cell Bank of the Chinese Academy of Sciences. MV-4-11 cells were cultured in IMDM (Adamas) medium, SKOV3 cells were cultured in McCoy's 5A medium (Gibco), and MCF7 cells were cultured in DMEM (Adamas) medium. During the culture, each culture medium was supplemented with 10% fetal bovine serum and 1% 100× penicillin-streptomycin antibody (15140-122, Gibco ThermoFisher, USA) and cultured at 37°C and 5% CO_2. Cells in the logarithmic growth phase were seeded into a 96-well plate (Corning, model 3599) at a density of 5,000 cells per well, with a culture medium volume of 100 μL, and cultured overnight in an incubator at 37°C and 5% CO₂ . The next day, 100 μL of drug solution prepared in culture medium of different concentrations was added, and three replicate wells were set for each concentration (recorded as RLU_test ), and control wells and blank wells were set. The control wells were cells, culture medium and drug dissolution medium of the same concentration (recorded as RLU_control ), and the blank wells were culture medium (recorded as RLU_blank ). After 96 hours, 100 μL was aspirated from each well to the 96-well black board, and 100 μL of CellTiter-Lumi luminescence cell viability detection kit (Beyotime Biotechnology) detection reagent was added to each well, and the cells were placed on a shaker to incubate in the dark for 10 minutes before detection. 100 μL of culture medium was aspirated from each well of the adherent cells and discarded, and 100 μL of detection reagent was added to each 96-well plate. After being placed on a shaker for 2 minutes, the solution in the well was aspirated to the 96-well black board, and the cells were placed on a shaker to incubate in the dark for 8 minutes before detection. The chemiluminescence value was detected by the chemiluminescence module on the Thermo scientific varioskanflash. The cell survival percentage was calculated by the following formula: Cell survival rate (%) = (RLU_test - RLU_blank )/(RLU_control - RLU_blank )×100%, and IC₅₀ was calculated using Graphpad Prism 8.0 software. The results are shown in Table 2 and FIG1 .

表2代表实施例对MV4-11细胞系的体外抗肿瘤活性Table 2 shows the in vitro antitumor activity of the examples against the MV4-11 cell line

上述实施例的作用在于具体介绍本发明的实质性内容，但本领域技术人员应当知道，不应将本发明的保护范围局限于该具体实施例。The purpose of the above-mentioned embodiments is to specifically introduce the essential content of the present invention, but those skilled in the art should know that the protection scope of the present invention should not be limited to the specific embodiments.

Claims (9)

Translated fromChinese

1.一类联芳环结构的化合物，其特征在于，为式Ⅰ所示化合物或其药学上可接受的盐：1. A class of compounds with a biaryl ring structure, which is characterized in that it is a compound represented by formula I or a pharmaceutically acceptable salt thereof:其中：in:A环选自苯基、5-10元芳杂基；R_a独立选自氢、卤素、C_1-5烷基、C_3-7环烷基、C_1-3烷氧基；n＝1-5；B环选自5-10元芳杂基，R_b独立选自氢、卤素、C_1-5烷基、C_3-7环烷基、C_1-3烷氧基；m＝1-5；Ring A is selected from phenyl, 5-10 membered aryl heteroyl; R_{a is} independently selected from hydrogen, halogen, C_1-5 alkyl, C_3-7 cycloalkyl, C_1-3 alkoxy; n=1 -5; Ring B is selected from 5-10 membered aryl heteroyl, R_b is independently selected from hydrogen, halogen, C_1-5 alkyl, C_3-7 cycloalkyl, C_1-3 alkoxy; m=1 -5;R₁、R₂、R₃、R₄独立选自氢、卤素、C_1-5烷基、C_1-3烷氧基、-S(O)_pR^*、-NRR^*S(O)_pR^*、-NRR^*S(O)_pNRR^*、-C(O)OR^*、-C(O)R^*、-OC(O)R^*、-OC(O)NRR^*、-NRC(O)R^*、-NRC(O)NRR^*、-C(O)NRR^*、-NRR^*、-OR^*、-SR^*；R和R^*独立选自氢、C_1-5烷基、C_2-6烯基、C_2-6烯基、C_2-6炔基，或者R和R^*与它们连接的氮原子形成4-7元杂环烷基；p＝1或2。R₁ , R₂ , R₃ , R₄ are independently selected from hydrogen, halogen, C_1-5 alkyl, C_1-3 alkoxy, -S(O)_p R^* , -NRR^* S(O)_p R^* , -NRR^* S(O)_p NRR^* , -C(O)OR^* , -C(O)R^* , -OC(O)R^* , -OC(O)NRR^* , -NRC(O )R^* , -NRC(O)NRR^* , -C(O)NRR^* , -NRR^* , -OR^* , -SR^* ; R and R^* are independently selected from hydrogen, C_1-5 alkyl, C_{2 -6} alkenyl, C_2-6 alkenyl, C_2-6 alkynyl, or R and R^* and the nitrogen atom to which they are connected form a 4-7 membered heterocycloalkyl group; p=1 or 2.2.根据权利要求1所述的化合物，其特征在于：所述药学上可接受的盐为式Ⅰ化合物的酸加成盐，其中用于成盐的酸包括氯化氢、硫酸、溴化氢、草酸、柠檬酸、琥珀酸、酒石酸、磷酸、马来酸、甲磺酸、苯磺酸和对甲苯磺酸。2. The compound according to claim 1, characterized in that: the pharmaceutically acceptable salt is an acid addition salt of the compound of formula I, wherein the acid used for salt formation includes hydrogen chloride, sulfuric acid, hydrogen bromide, and oxalic acid. , citric acid, succinic acid, tartaric acid, phosphoric acid, maleic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid.3.一种权利要求1所述化合物的合成方法，其特征在于，化合物结构如目标1～目标14所示，合成路线如下：3. A method for synthesizing the compound according to claim 1, characterized in that the compound structure is as shown in Target 1 to Target 14, and the synthesis route is as follows:4.一种权利要求1所述化合物的合成方法，其特征在于，化合物结构如目标15～目标20所示，合成路线如下：4. A method for synthesizing the compound of claim 1, characterized in that the compound structure is as shown in target 15 to target 20, and the synthesis route is as follows:5.一种权利要求1所述化合物的合成方法，其特征在于，化合物结构如目标21～目标24所示，合成路线如下：5. A method for synthesizing the compound of claim 1, characterized in that the compound structure is as shown in target 21 to target 24, and the synthesis route is as follows:6.一种权利要求1所述化合物的合成方法，其特征在于，化合物结构如目标25～目标30所示，合成路线如下：6. A method for synthesizing the compound of claim 1, characterized in that the compound structure is as shown in target 25 to target 30, and the synthesis route is as follows:7.权利要求1所述的化合物用于制备BET抑制剂药物的用途。7. Use of the compound of claim 1 for preparing BET inhibitor drugs.8.权利要求1所述的化合物用于制备抗肿瘤药物或抗炎症药物的用途。8. Use of the compound according to claim 1 for preparing anti-tumor drugs or anti-inflammatory drugs.9.根据权利要求8所述的用途，所述抗肿瘤药物中还含有其它抗肿瘤成分，所述其它抗肿瘤成分为PARP抑制剂、CDK4/6抑制剂、ATR抑制剂、PD-1抗体或小分子抑制剂、PD-L1抗体或小分子抑制剂、EZH2抑制剂或AR抑制剂。9. The use according to claim 8, the anti-tumor drug also contains other anti-tumor ingredients, and the other anti-tumor ingredients are PARP inhibitors, CDK4/6 inhibitors, ATR inhibitors, PD-1 antibodies or Small molecule inhibitors, PD-L1 antibodies or small molecule inhibitors, EZH2 inhibitors or AR inhibitors.