WO2014146486A1 - Three-level cyclic amine alk kinase inhibitor for treating cancer - Google Patents

Three-level cyclic amine alk kinase inhibitor for treating cancer Download PDF

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WO2014146486A1
WO2014146486A1 PCT/CN2014/000288 CN2014000288W WO2014146486A1 WO 2014146486 A1 WO2014146486 A1 WO 2014146486A1 CN 2014000288 W CN2014000288 W CN 2014000288W WO 2014146486 A1 WO2014146486 A1 WO 2014146486A1
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何伟
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浙江导明医药科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
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  • the F1174L activation point mutation has a more potent transformation activity in vivo than the second most common activating mutation, R1275Q, which is also the only ALK inhibitor on the market for ALK-positive tumors, Cristinib (Xalkori, Pfizer) , the cause of congenital and acquired resistance.
  • ALK inhibitors including crizoziltin, have proven to be effective on preclinical models of neuroblastoma.
  • Q is CO or S0 2 .
  • the IC50 values of the compounds of the examples of the present invention were determined by the above methods as shown in the following table:
  • the solid composition for oral administration may be in the form of a tablet, a powder, a granule or the like.
  • one or more active substances are combined with at least one inert excipient (eg, lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, poly Mixing vinylpyrrolidone, magnesium aluminum silicate, etc.).
  • the composition may also contain inert additives such as a lubricant (e.g., magnesium stearate), a disintegrant (e.g., sodium carboxymethyl starch), and a dissolution aid, according to conventional methods.
  • Tablets or pills may also be coated with a sugar coating or a gastric or enteric coating as needed.
  • Steps To the solution of the compound 4-(1H-pyrazol-4-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (200 mg, 0.8 mmol, 1.0 eq.) in ethanol (30 mL) Palladium on carbon (100 mg) was added to the solution. The mixture was stirred at 40 °C for 16 hours under a hydrogen atmosphere of 15 psi. The reaction mixture was filtered and evaporated to dryness to give the title compound (180 mg, yield: 90%). Step C:
  • reaction mixture was diluted with methylene chloride.
  • the organic layer was washed once with sodium bicarbonate solution and brine, dried over sodium sulfate and then evaporated to dryness. Separation (mobile phase: acetonitrile/water/0.5% ammonium bicarbonate, gradient elution 36% to 66% by volume), evaporation of the volatile components under reduced pressure and lyophilization to give the title compound (33.5 mg, yield It is 33.5%).
  • reaction solution was diluted with dichloromethane, and the organic layer was back-washed once with sodium hydrogen carbonate solution and brine, dried over sodium sulfate and then evaporated to dryness. Separation (mobile phase: acetonitrile/water/0.5% ammonium bicarbonate, gradient elution 36% to 66% (volume ratio; )), evaporation of the volatile components under reduced pressure, and lyophilization to give the title compound (7.2 mg, The yield was 90%).
  • This compound was prepared by the method described previously.
  • Example 88 Animal Experimental Methods and Activity Data The pharmacokinetic test of male SD rats within 24 hours was divided into two groups, intravenous and oral, with 3 animals in each group. The time of blood collection in the intravenous group was before administration. After the drug, 0.0833, 0.167, 0.5, 1, 2, 4, 8, 24 hours; the oral administration time was taken before administration, 0.167, 0.5, 1, 2, 4, 8, 24 hours after administration. After blood collection, bioassay was performed by HPLC-MS/MS to report the plasma concentration of the compound. The calculated pharmacokinetic parameters were the mean clearance rate (Clp) of the venous group, and the average apparent volume of distribution (Vdss).
  • Clp mean clearance rate
  • Vdss average apparent volume of distribution

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Abstract

Provided are substituted cyclic amine compounds, and pharmaceutically acceptable salts and pharmaceutical preparations thereof as an anaplastic lymphoma kinase (ALK) inhibitor. Also provided is the use of the compound and pharmaceutical preparations thereof in the preparation of drugs for the treatment and inhibition of diseases including non-small cell lung cancer (NSCLC), neuroblastomas, anaplastic large cell lymphoma (ALCL), liver cancer and other diseases caused by the rise of the ALK activity level.

Description

用于治疗癌症的三级环状胺 ALK激酶抑制剂  A tertiary amine amine for the treatment of cancer ALK kinase inhibitor
发明的技术领域 Technical field of invention
本发明涉及一系列新的被取代的环状胺类化合物及其制备方法， 包含它们作为有效成份 的药物组合物及其在治疗肿瘤等疾病中的应用。  The present invention relates to a series of novel substituted cyclic amine compounds and processes for their preparation, pharmaceutical compositions containing them as active ingredients and their use in the treatment of diseases such as tumors.
发明背景 Background of the invention
间变性淋巴瘤激酶 （ALK ) 是胰岛素受体家族的成员。 在人类中， 它是一种由 ALK基因 编码的一种激酶。 作为一种受体酪氨酸激酶， 它是 ώ一个胞外结构域， 跨膜区和胞内酪氨酸 激酶域组成。 ALK在脑和中枢神经系统的发展中起着重要的作用。 然而， ALK在成人中的功 能尚不清楚。  Anaplastic lymphoma kinase (ALK) is a member of the insulin receptor family. In humans, it is a kinase encoded by the ALK gene. As a receptor tyrosine kinase, it is composed of an extracellular domain, a transmembrane region and an intracellular tyrosine kinase domain. ALK plays an important role in the development of the brain and central nervous system. However, the function of ALK in adults is unclear.
在人体内， 异常的 ALK信号传导同多种癌症的发病有关。 这些异常的 ALK信号活性是由 ALK基因重排（包括易位， 放大扩增和突变）和 ALK激酶过度表达造成的。 ALK活性异常最 早在间变性大细胞淋巴瘤 （ALCL ) 中发现。 另外， ALK基因重排在炎症性肌纤维母细胞瘤， 神经母细胞瘤和非小细胞肺癌中被发现。  In the human body, abnormal ALK signaling is associated with the onset of multiple cancers. These abnormal ALK signaling activities are caused by ALK gene rearrangements (including translocation, amplification amplification and mutation) and overexpression of ALK kinase. Abnormal ALK activity was first detected in anaplastic large cell lymphoma (ALCL). In addition, ALK gene rearrangements were found in inflammatory myofibroblastoma, neuroblastoma and non-small cell lung cancer.
ALK基因易位会导致同激活配体无关的 ALK激酶的无控性激活。 这种 ALK激酶的无控性 激活和其引起的下游信号会导致细胞增殖， 存活和细胞周期的无控状态。 已被证明在非小细 胞肺癌中的 EML4 ALK易位导致了 ERK及 STAT3信号转导通路的活化， 从而引起细胞的增殖。 在 EML4-ALK阳性肺癌的小鼠模型中， 研究结果表明， ALK抑制剂会引起由 ERK-BIM和 STATE3 的信号转导阻断为诱因的癌细胞凋亡。  ALK gene translocation results in uncontrolled activation of ALK kinase independent of activation of the ligand. The uncontrolled activation of this ALK kinase and its downstream signaling leads to uncontrolled cell proliferation, survival and cell cycle. The EML4 ALK translocation in non-small cell lung cancer has been shown to cause activation of ERK and STAT3 signaling pathways, resulting in cell proliferation. In a mouse model of EML4-ALK-positive lung cancer, the results suggest that ALK inhibitors cause apoptosis in cancer cells that are blocked by ERK-BIM and STATE3 signaling.
间变性大细胞淋巴瘤（ALCL )是一种于 1985年首次发现的先前未知的淋巴肿瘤。 ALCL已 被证明主要是由两个涉及 ALK的易位 （ΝΡΜ- ALK: 60 % -80 % ; TP 3-ALK: 12-18 % ) 来引发。 实验证明， NPM-ALK易位的致癌效应是通过 STAT3的活化途径。 在 ALCL小鼠模型上， 已经 证明， 具有生物相容性的 ALK抑制剂有抗肿瘤效果。  Anaplastic large cell lymphoma (ALCL) is a previously unknown lymphoid tumor that was first discovered in 1985. ALCL has been shown to be mainly caused by two translocations involving ALK (ΝΡΜ- ALK: 60% -80%; TP 3-ALK: 12-18%). Experiments have shown that the carcinogenic effect of NPM-ALK translocation is through the activation pathway of STAT3. In the ALCL mouse model, biocompatible ALK inhibitors have been shown to have antitumor effects.
神经母细胞瘤是第二个最常见的儿童恶性肿瘤。 现已发现， 在所有神经母细胞瘤中， 8 % 的病人有 ALK激酶的激活点突变。 而且， 这些激活点突变的比例均匀地分布在不同的临床阶 段。 然而， 最常见的体细胞突变 F1 174L , 是与 MYCN原癌基因的扩增相关联。 这两种蛋白的 功能组合为病因的癌症的病情会比单独 ώ MYCN基因扩增引起的癌症要严重，这是由在神经母 细胞瘤的发展中的协同效应所造成。 F1174L激活点突变在体内具有比第二种最常见的活化突 变， R1275Q, 更有效的转化活性， 这也是 ALK阳性肿瘤对市场上唯一的 ALK抑制剂， 克里 唑蒂尼 （Xalkori, 辉瑞公司） ， 产生先天性和获得性抗药性的原因。 在神经母细胞瘤的临 床前模型上， ALK抑制剂， 包括克里唑蒂尼被证明是有效的。 Neuroblastoma is the second most common malignancy in children. It has been found that in all neuroblastomas, 8% of patients have activation point mutations in ALK kinase. Moreover, the proportion of these activation point mutations is evenly distributed in different clinical stages. However, the most common somatic mutation, F1 174L, is associated with amplification of the MYCN proto-oncogene. The combination of the functions of these two proteins is the cause of the cancer, which is more serious than the cancer caused by the amplification of the ώ MYCN gene alone. Caused by synergistic effects in the development of cell tumors. The F1174L activation point mutation has a more potent transformation activity in vivo than the second most common activating mutation, R1275Q, which is also the only ALK inhibitor on the market for ALK-positive tumors, Cristinib (Xalkori, Pfizer) , the cause of congenital and acquired resistance. ALK inhibitors, including crizoziltin, have proven to be effective on preclinical models of neuroblastoma.
克里唑蒂尼为间变性淋巴瘤激酶 （ALK ) 和 R0S1激酶的抑制剂。 在 2011年， 在美国和其 他一些国家， 它被批准用于治疗 ALK阳性的非小细胞肺癌 （NSCLC ) 。 现在， 正在进行它在 间变性大细胞淋巴瘤， 神经母细胞瘤， 以及其它晚期实体肿瘤在成人和儿童中的安全性和有 效性的临床试验评价。尽管克里唑蒂尼对 ALK阳性的非小细胞肺癌出色的疗效。 它也有很多 副作用， 包括严重的头晕， 昏厥， 心跳快或冲击；视力问题， 如视力模糊， 眼睛的光敏反应， 或看到闪烁光或 "飞蚊" ； 胸痛， 干咳， 咳嗽或有粘液， 喘鸣， 呼吸急促的感觉， 容易挫伤， 不寻常的出血 （鼻， 口腔， 阴道或直肠） ， 紫色或红色的精确点， 发烧， 寒战， 全身酸痛， 感冒症状， 口腔和喉咙溃疡， 或恶心， 上腹部疼痛， 瘙痒， 食欲不振， 尿色深， 大便陶土色， 黄疸（皮肤或眼睛发黄） 等。 比较轻的副作用还包括： 轻度头晕， 疲倦的感觉， 恶心， 呕吐， 胃痛， 食欲不振， 腹泻， 便秘， 轻度皮疹或瘙痒;感冒的症状， 如鼻塞， 打喷嚏， 咽喉痛， 麻 木， 或手或脚肿胀等。  Crizotinib is an inhibitor of anaplastic lymphoma kinase (ALK) and R0S1 kinase. In 2011, in the United States and other countries, it was approved for the treatment of ALK-positive non-small cell lung cancer (NSCLC). Now, it is undergoing clinical trial evaluations for the safety and efficacy of anaplastic large cell lymphoma, neuroblastoma, and other advanced solid tumors in adults and children. Despite the excellent efficacy of crizotinib on ALK-positive non-small cell lung cancer. It also has many side effects, including severe dizziness, fainting, rapid heartbeat or shock; vision problems such as blurred vision, photoreaction of the eye, or seeing flashing light or "flying mosquitoes"; chest pain, dry cough, coughing or mucus, asthma Feeling, shortness of breath, easy bruising, unusual bleeding (nose, mouth, vagina or rectum), precise point of purple or red, fever, chills, body aches, cold symptoms, mouth and throat ulcers, or nausea, upper Abdominal pain, itching, loss of appetite, dark urine, terracotta color, jaundice (yellow skin or eyes). Lighter side effects include: mild dizziness, feeling tired, nausea, vomiting, stomach pain, loss of appetite, diarrhea, constipation, mild rash or itching; symptoms of a cold, such as stuffy nose, sneezing, sore throat, numbness, or Swelling of hands or feet, etc.
在这些副作用中， 克里唑蒂尼对眼睛及视觉的副作用尤其让人担忧， 因为它在眼睛中的 高浓度及 ALK激酶在神经系统中高表达。  Among these side effects, the side and visual side effects of crizotinib are particularly worrying because of its high concentration in the eye and high expression of ALK kinase in the nervous system.
美国食品药物管理局的审查报告指出， "在克里唑蒂尼的临床试验中， 159例患者（62 % ) 出现了视力障碍， 包括视觉障碍， 视力模糊， 闪光幻觉， 玻璃体漂浮物， 畏光， 复视" 。 审 查报告还指出， "在人类临床试验中， 克里唑蒂尼在患者眼睛中的高浓度和长半衰期可能是 造成它对眼睛的毒性和视障的原因 "。 克里唑蒂尼在眼睛中的浓度是非常高的， 估计消除的 半衰期 （t l/2 ) 为 576小时， 明显长于它在血液中的半衰期 （42小时） 。 它的 Cmax (血药 达峰浓度） 比例为 8. 9: 1 ( B艮： 血液） 而 AUC (血液浓度 -时间曲线下面积） 比例为 278: 1 ( B艮:血液） 。 所以， 发明在眼睛中低浓度的新型 ALK化合物是非常可取的。 附图说明- 图 1 : 化合物 18对肿瘤抑制作用： 肿瘤体积及接瘤天数  According to a review by the US Food and Drug Administration, "In the clinical trials of crizotinib, 159 patients (62%) developed visual impairment, including visual impairment, blurred vision, flash illusion, vitreous floatation, photophobia , Diplopia" . The review report also stated that "in human clinical trials, the high concentration and long half-life of crizotinib in the patient's eye may be responsible for its toxicity to the eye and visual impairment." The concentration of crizotinib in the eye is very high, and the estimated half-life (t l/2 ) is 576 hours, which is significantly longer than its half-life in the blood (42 hours). Its Cmax (blood peak concentration) ratio is 8. 9: 1 (B艮: blood) and the AUC (blood concentration-time curve area) ratio is 278: 1 (B艮: blood). Therefore, it is highly desirable to invent a novel concentration of a novel ALK compound in the eye. BRIEF DESCRIPTION OF THE DRAWINGS - Figure 1: Tumor inhibition by Compound 18: Tumor volume and number of days of tumor
图 2: 化合物 18 在 4小时和 8小时在肿瘤， 血液， 脑， 及眼的分布， 其中各对比栏中， 左侧 为 4小时， 右侧为 8小时 发明的内容 Figure 2: Distribution of tumor 18 in tumor, blood, brain, and eye at 4 hours and 8 hours, in each comparison column, 4 hours on the left and 8 hours on the right Content of the invention
本发明涉及的治疗或抑制癌症的方法， 包括， 但并不限于非小细胞肺癌 （NSCLC) ， 间变 性大细胞淋巴瘤 （ALCL) ， 肝癌 （HCC)和神经母细胞瘤， 包括给所述患者施用有效剂量由通 式 ( I ) 或 （II ) 表达的化合物， 或其药学上可接受的盐。  The invention relates to a method for treating or inhibiting cancer, including, but not limited to, non-small cell lung cancer (NSCLC), anaplastic large cell lymphoma (ALCL), liver cancer (HCC) and neuroblastoma, including the patient An effective amount of a compound expressed by the formula (I) or (II), or a pharmaceutically acceptable salt thereof, is administered.
Figure imgf000004_0001
Figure imgf000004_0001
式中， Ar进一步定义为式 （III )  Wherein Ar is further defined as formula (III)
Figure imgf000004_0002
式中， A2， A3， 和^为（：或！^。 为 N 时， 其上无取代基连接 ;
Figure imgf000004_0002
Wherein A 2 , A 3 , and ^ are (: or !^. When N is present, no substituent is attached thereto ;
Ar最优选取自下式：
Figure imgf000004_0003
Ar is optimally selected from the following formula:
Figure imgf000004_0003
Xi , X2, X3， 和 X5各自独立地是 C, N, 0, S; 当为 C或者 N时， 其上可被氘， 卤素， 氨基， 羟基， 硝基， 氰基， （C1-C6) 垸基， （C1-C6 ) 垸氧基所取代。 Xi, X 2 , X 3 , and X 5 are each independently C, N, 0, S; when C or N, they may be deuterated, halogen, amino, hydroxy, nitro, cyano, (C1 -C6) fluorenyl, (C1-C6) substituted by decyloxy.
M【是一个饱和的或不饱和的 CI- C8碳链， 芳基， 杂环垸基或杂芳基。 这些碳链， 芳基， 杂环烷基或杂芳基的碳或氮原子上的氢原子可任选被烷基， 环烷基， 垸氧基， 环烷氧基， 氨 基， CN， 酰氨基， 卤素所取代。  M [is a saturated or unsaturated CI-C8 carbon chain, aryl, heterocyclic fluorenyl or heteroaryl. The hydrogen atom of the carbon or nitrogen atom of these carbon chain, aryl, heterocycloalkyl or heteroaryl group may be optionally alkyl, cycloalkyl, decyloxy, cycloalkoxy, amino, CN, acylamino , replaced by halogen.
其中， M1还可以同 Q或 R6形成 3-8元的芳基或杂芳基。 Among them, M 1 may form a 3-8 membered aryl or heteroaryl group with Q or R 6 .
Μ^Π Μ3各自独立地为式 （IV) 或 （V) ：
Figure imgf000005_0001
Μ^Π Μ 3 are each independently of formula (IV) or (V):
Figure imgf000005_0001
IV V 优选 M2和 M3同时为亚乙基链。 Preferably, IV V is M 2 and M 3 are both ethylene chains.
其中， Q是 CO或 S02。 Where Q is CO or S0 2 .
其中， R R2， R3， R4， R5, R6, R7， R8, R9， R,o, Rn, R12， R,3) R14和 Y可独立表示氢， 氘， 氨基， 卤素， 羟基， 羧基， 硝基， 氰基， （C2- C6) 烯基， （C2-C6 ) 炔基， 三氟甲基， 三氟 甲氧基， （C1-C6)垸基， （C1-C6) 垸氧基， （C3-C10) 环烷基； 其中的烷基， 烯基， 炔基， 垸氧基或环垸基可任选被下列基团所取代：氘，卤素，氨基，羟基，羧基，硝基，氰基， （C1-C6) 垸基， （CI- C6) 垸氧基。 其中， R6还可以是芳基或杂芳基。 Wherein RR 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R,o, Rn, R 12 , R, 3) R 14 and Y independently represent hydrogen, hydrazine, Amino, halogen, hydroxy, carboxy, nitro, cyano, (C2-C6) alkenyl, (C2-C6) alkynyl, trifluoromethyl, trifluoromethoxy, (C1-C6) fluorenyl, C1-C6) decyloxy, (C3-C10)cycloalkyl; wherein alkyl, alkenyl, alkynyl, decyloxy or cyclodecyl may be optionally substituted by hydrazine, halogen, amino , hydroxy, carboxy, nitro, cyano, (C1-C6) fluorenyl, (CI-C6) decyloxy. Wherein R 6 may also be an aryl group or a heteroaryl group.
其中， ！^还可以同 0或 形成 3-8元的芳基或杂芳基。  among them, ! ^ It is also possible to form a 3-8 membered aryl or heteroaryl group with 0 or.
所述芳基或杂芳基的碳或氮原子上的氢原子可任选被垸基， 环垸基， 烷氧基， 环垸氧基， 氨基， CN， 酰氨基， 卤素所取代。 其中， R8优选甲基。 The hydrogen atom on the carbon or nitrogen atom of the aryl or heteroaryl group may be optionally substituted by a mercapto group, a cyclodecyl group, an alkoxy group, a cyclodecyloxy group, an amino group, a CN, an acylamino group, or a halogen. Among them, R 8 is preferably a methyl group.
优选地， R7 为氢原子， M2, M3， N和 CH—起形成哌啶环而构成 （VI ) 或 （VH ) ：
Figure imgf000005_0002
Preferably, R 7 is a hydrogen atom, and M 2 , M 3 , N and CH form a piperidine ring to form (VI) or (VH):
Figure imgf000005_0002
中: 优选为吡唑基， 更优选为 或  Medium: preferably pyrazolyl, more preferably or
¾中:
Figure imgf000005_0003
从而构成 （VI I I ) 或 （IX )
Figure imgf000006_0001
3⁄4 in:
Figure imgf000005_0003
Thus forming (VI II ) or (IX )
Figure imgf000006_0001
最优先地， （VIII )和（IX)式中的 Q为羰基， 为亚甲基或不存在而形成（X)和（XI) :  Most preferably, Q in (VIII) and (IX) is a carbonyl group, which is a methylene group or is absent to form (X) and (XI):
Figure imgf000006_0002
Figure imgf000006_0002
其中： Ar, R6, ！^和 Y的定义如前所定义. 其中： R6优选为甲胺基或 1 基 . Of which: Ar, R 6 , ! The definitions of ^ and Y are as defined above. Among them: R 6 is preferably a methylamino group or a 1 group.
其中： 优选为甲基.  Wherein: preferred is methyl.
其中： Y优选为氨基. 在本发明中， "垸基" ， "烯基"和 "炔基" ， 优选是一至六个碳原子直链或支链的浣 基或二到六个碳原子直链或支链的链烯基和炔基， 例如， 甲基， 乙基， 丙基， 丁基， 戊基或 己基， 乙烯基， 丙烯基， 丁烯基， 戊烯基或己烯基及它们的异构体。  Wherein Y is preferably an amino group. In the present invention, "mercapto", "alkenyl" and "alkynyl" are preferably straight or branched fluorenyl groups of one to six carbon atoms or two to six carbon atoms straight. Chain or branched alkenyl and alkynyl groups, for example, methyl, ethyl, propyl, butyl, pentyl or hexyl, vinyl, propenyl, butenyl, pentenyl or hexenyl and their Isomers.
术语 "羟基"是指具有结构式 -0H的基团。  The term "hydroxy" refers to a group of the formula -0H.
术语 "卤素"或 "卤"是指氟， 氯， 溴或碘基。  The term "halogen" or "halo" means fluoro, chloro, bromo or iodo.
术语 "环垸基"是指单-或多环碳环， 其中每个环中含有 3至 10个碳原子数的， 并且其 中的任何环可以包含一个或多个双键或叁键。 实例包括基团如环丙基， 环丁基， 环戊基， 环 己基， 环烯基， 和环庚基。 术语 "环烷基" 附加地包括螺环系统， 其中的环垸基环上有一个 共同的碳环原子。  The term "cycloalkyl" refers to a mono- or polycyclic carbocyclic ring wherein each ring contains from 3 to 10 carbon atoms, and any of the rings may contain one or more double or triple bonds. Examples include groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloalkenyl, and cycloheptyl. The term "cycloalkyl" additionally includes a spiro ring system in which a cyclic fluorenyl ring has a common carbon ring atom.
术语 "杂环垸基" 为五元至六元的非芳香族饱和或不饱和杂环， 该杂环垸基可具有选自 氮原子、 氧原子和硫原子 （其可任选被氧化） 中的一个或多个相同或不同的杂原子。 杂环浣 基可分为不饱和的， 或者可以与苯环稠合。 但是， 不包括氮杂桥环烃类在内。 所述杂环烷基 可包括 （例如） 氮杂环丙基、 氮杂环丁基、 ¾咯烷基、 哌啶基、 高哌啶基、 吗啉基、 硫代吗 啉基、 哌 嗪基、 四氢呋喃基、 四氢噻吩基、 二氢噁唑基、 四氢吡喃基、 四氢噻喃基、 二氢吲 哚基、 四氢喹 啉基、 四氢异喹琳基以及苯并噁嗪基， 优选的是二氢噁唑基、 噁二唑基、 oxadiazolanyl禾口咲喃基。 The term "heterocyclic fluorenyl" is a five- to six-membered non-aromatic saturated or unsaturated heterocyclic ring which may have a nitrogen atom, an oxygen atom and a sulfur atom which may optionally be oxidized. One or more of the same or different heteroatoms. The heterocyclic fluorenyl group can be classified as unsaturated or can be fused to a benzene ring. However, nitrogen-bridged hydrocarbons are not included. The heterocycloalkyl group may include, for example, azacyclopropyl, azetidinyl, 3⁄4 alkyl, piperidinyl, homopiperidinyl, morpholinyl, thio? Polinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, indanyl, tetrahydroquinolyl, tetrahydroisoquineline And benzoxazinyl, preferably dihydrooxazolyl, oxadiazolyl, oxadiazolanyl and bromo.
术语 "环氨基"为在 "杂环烷基"所限定的基团中 3元至 8元的非芳香族环胺， 其具有 至少一个氮原子， 并可具有选自氮原子、 氧原子和硫原子 （其可被氧化） 中的一个或多个相 同或不同的杂原子， 其中至少一个氮原子成键。 但是， 不包括氮杂桥环烃类。 所述 "环氨基" 可包括 （例如） 氮丙啶基、 氮丁啶基、 吡咯烷基、 哌啶基、 高哌啶基、 吗啉基、 硫代吗啉基 以及哌嗪基。  The term "cyclic amino" is a 3- to 8-membered non-aromatic cyclic amine in the group defined by "heterocycloalkyl" which has at least one nitrogen atom and may have a nitrogen atom, an oxygen atom and sulfur. One or more of the same or different heteroatoms in the atom (which may be oxidized), wherein at least one of the nitrogen atoms is bonded. However, nitrogen bridged hydrocarbons are not included. The "cyclic amino group" may include, for example, aziridine, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, and piperazinyl.
术语"芳基"为芳香烃基， 优选苯基、萘基以及茚基， 更优选为碳原子数为 6-10的芳基， 最优选为苯基。  The term "aryl" is an aromatic hydrocarbon group, preferably a phenyl group, a naphthyl group and an anthracenyl group, more preferably an aryl group having 6 to 10 carbon atoms, and most preferably a phenyl group.
术语 "杂芳基"为一价的五元或六元芳香族杂环基， 其具有选自氮原子、 氧原子和 硫原 子中的一个或多个相同或不同的杂原子， 并且可与苯环稠合。 "杂芳基"可包括 （例如） 吡 啶基、 吡嗪基、 嘧啶基、 哒嗪基、 吡咯基、 吡唑基、 咪唑基、 噁唑基、 噻唑基、 噻吩基、 呋 喃基、 噁二唑基、 噻二唑基、 喹啉基、 异喹啉基、 苯并噻唑基、 苯并噁唑基、 吲哚基、 吲唑 基、 喹喔啉 基和喹唑啉基， 优选的是哒嗪基、 吡啶基、 吡嗪基、 噻唑基、 吡唑基和硫代噁唑 基。  The term "heteroaryl" is a monovalent five- or six-membered aromatic heterocyclic group having one or more of the same or different heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, and is compatible with benzene. The ring is fused. "Heteroaryl" may include, for example, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, thienyl, furanyl, oxadiazole Base, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, fluorenyl, oxazolyl, quinoxalinyl and quinazolinyl, preferably pyridazine Base, pyridyl, pyrazinyl, thiazolyl, pyrazolyl and thiooxazolyl.
术语 "桥环基"表示 "桥环烃基"和 "氮杂桥环烃基"  The term "bridged ring group" means "bridged cyclic hydrocarbon group" and "aza bridged hydrocarbon group"
术语 "桥环烃基"为饱和或不饱和的双环或多环桥联烃基， 这些烃基具有两个或三个碳 原子数为 3- 10的环垸基环。非桥联的环烷基不包括在内。尤其优选的是双环或多环的碳原子 数为 4-16的桥联烃基。 所述桥环烃基可包括 （例如） 双环 [2. 1. 1]己基、 双环 [2. 2. 1 ] 庚基、 双环 [2. 2. 2]辛基、 双环 [4. 3. 1]癸基、 双环 [3. 3. 1]壬基、 冰片基、 冰片烯基、 降冰片基、 降冰片烯基、 6， 6-二甲基双环 [3. 1. 1]庚基、三环丁基以及金刚垸基， 优选为 金 刚烷基或双环 [2. 2. 1]庚基。 The term "bridged hydrocarbyl" is a saturated or unsaturated bicyclic or polycyclic bridged hydrocarbyl group having two or three cyclodecyl rings having from 3 to 10 carbon atoms. Non-bridged cycloalkyl groups are not included. Particularly preferred are bicyclic or polycyclic bridged hydrocarbon groups having 4 to 16 carbon atoms. The bridged cyclic hydrocarbon group may include, for example, a bicyclo[2.1.1]hexyl, a bicyclo[2.2.1]heptyl group, a bicyclo[2.2.2]octyl group, a bicyclo[4.3.1] decyl, bicyclo [3.3.1] nonyl, bornyl, norbornenyl, norbornyl, norbornenyl, 6, 6-dimethyl-bicyclo [3.1.1] heptyl, tricyclo Butyl and adamantyl, preferably adamantyl or bicyclo[2.2.1]heptyl.
术语 "硝基"是指具有 -N02的基团。 The term "nitro" refers to a group having -N0 2 .
术语"氨基"是指具有结构 -NH2的基团， 其中氨基上的氢原子可被一个、 两个或三个基团 所取代， 所述取代基优选为垸基， 链烯基， 炔基， 芳基， 和类似物。 The term "amino" refers to a group having the structure -NH 2 wherein the hydrogen atom on the amino group may be substituted by one, two or three groups, preferably a fluorenyl group, an alkenyl group, an alkynyl group. , aryl, and the like.
术语 "氰基"是指具有结构式 -CN的基团。  The term "cyano" refers to a group of the formula -CN.
术语 "垸氧基"是指含有垸基的基团同一个氧原子连接， 如甲氧基团的部分结构。 垸氧 基部分的垸氧基的氧原子键合到分子的其他部分。 这样的基团的实例包括甲氧基， 乙氧基， 丙氧基， 异-丙氧基， 丁氧基和叔丁氧基。 术语 "酰基"表示具有 "-" = 0)-" 的基团， 优选为 - C( = 0)-烷基、 - C( = 0)-环垸基、 -C( = 0)-杂环烷 基、 - C( = 0)-芳基、 - C( = 0)-杂芳基、 氨基甲酰基、 烷基氨基甲酰基、 - C( = 0)- C (- 0)-NH 烷基、 环垸基氨基甲酰基、 杂环垸基氨基甲酰基、 芳基氨基甲酰基以 及杂芳基氨 基甲酰基。 术语 "垸基" 、 "环垸基" 、 "杂环垸基" 、 "芳基"和 "杂芳基" 的定义如上所述。 The term "decyloxy" means that the group containing a thiol group is bonded to the same oxygen atom, such as a partial structure of a methoxy group. The oxygen atom of the methoxy group of the methoxy moiety is bonded to the other part of the molecule. Examples of such groups include methoxy, ethoxy, propoxy, iso-propoxy, butoxy and tert-butoxy. The term "acyl" denotes a radical having "-" = 0)-", preferably -C(=0)-alkyl, -C(=0)-cyclodecyl, -C(=0)-heterocycle Alkyl, -C(=0)-aryl, -C(=0)-heteroaryl, carbamoyl, alkylcarbamoyl, -C(=0)-C(-0)-NHalkyl , cyclodecylcarbamoyl, heterocycloalkylcarbamoyl, arylcarbamoyl and heteroarylcarbamoyl. The terms "mercapto", "cycloalkyl", "heterocycloalkyl", "aryl" The definitions of "and" heteroaryl are as described above.
术语 "羧基"是指羧基基团， _C02H， 或它的盐。 The term "carboxy" refers to a carboxyl group, _C0 2 H, or a salt thereof.
当组合使用时， 例如， "烷芳基"或 "芳烷基" ， 上面列出的各个条款有上面所指出的 意义。  When used in combination, for example, "alkaryl" or "aralkyl", the various terms listed above have the meaning indicated above.
术语 "药学上可接受的盐" 指的是以酸或碱形式存在的盐， 其非受限的实例为（a)酸性 加成盐， 无机酸 (例如， 盐酸、 氢溴酸、 硫酸、 磷酸、 硝酸等）， 有机酸的盐， 有机酸例如醋 酸、 草酸（oxalicacid)、 酒石酸（tartaric acid)、 號珀酸（succinic acid) , 苹果酸  The term "pharmaceutically acceptable salt" refers to a salt which is present in acid or base form, non-limiting examples of which are (a) acidic addition salts, inorganic acids (eg, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid) , nitric acid, etc., organic acid salts, organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid
(malic acid)、抗坏血酸、苯甲酸 (benzoic acid)、驟酸 (tannic acid)、 扑酸 (pamoic acid)、 海藻酸（alginic acid)及聚麸胺酸（poly glutamicacid)等； （b)碱性加成盐 (malic acid), ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid and poly glutamic acid; (b) alkaline Addition salt
(base addition salts), 形成有金属阳离子， 如锌、 钙、 钠、 钾等。 合成方法 (base addition salts), formed with metal cations such as zinc, calcium, sodium, potassium, and the like. resolve resolution
本发明通过实施例和本文中所公开的化合物来例示。 在本发明的具体化合物选自下组被 公开的实施例中的化合物和它们的药学上可接受的盐及它们的单独的非对映体的化合物或 ±卜。  The invention is illustrated by the examples and the compounds disclosed herein. The specific compounds of the present invention are selected from the group consisting of the compounds of the disclosed examples and their pharmaceutically acceptable salts and their individual diastereomeric compounds or ±.
下面的反应方案阐述了本发明化合物的制备路径。  The following reaction scheme illustrates the route of preparation of the compounds of the invention.
除非另有说明， 在下面的反应方案和讨论中， Ar， M„ M2， M3, R R2， R3, R„ R5， R6， R7， R8， R9， R,„, Ru, R12, R13， R,,, Q, X1; X2， , 和 X5的定义如上述。 反应式方案 1
Figure imgf000009_0001
BOC Unless otherwise stated, in the following reaction schemes and discussion, Ar, M M 2 , M 3 , RR 2 , R 3 , R „ R 5 , R 6 , R 7 , R 8 , R 9 , R, „ , R u , R 12 , R 13 , R,,, Q, X 1; X 2 , , and X 5 are as defined above.
Figure imgf000009_0001
BOC
Figure imgf000009_0002
Figure imgf000009_0002
在碱的存在下， 如三乙胺， 并在适当的溶剂中， 如二氯甲垸， Boc保护的起始材料41可以 与甲磺酸氯的反应下， 生成中间体 B,。 在适当的碱， 如三乙胺的存在下， 并在适当的溶剂， 如 DMF中， 中间体 ^上的甲磺酰基团可以由一个适当的亲核试剂 C,来取代而产生以提供中 m D10 在适当的溶剂中， 如 THF， 中间体 Ι 可与频哪醇乙硼垸在适当的催化剂 （如醋酸钯） 作用下进行反应得到中间体 Ε。 中间体 Ε与芳基卤化物的 F1被连接在适当的条件下和催化剂 进行 Suzuki反应，形成中间体 G。在酸性条件下， 可以除去 01的^(基团，得到胺化合物 H。 胺化合物 H可以分别与亲电子试剂 或 反应， 得到产物 （I ) 或 （II ) 。 反应式方案 2 In the presence of a base, such as triethylamine, and in a suitable solvent, such as starting materials of dichloromethane, Boc-protected 41 can be reacted with methanesulfonic acid chloride to form an intermediate B ,. In the presence of a suitable base, such as triethylamine, and in a suitable solvent, such as DMF, the methanesulfonyl group on the intermediate can be replaced by a suitable nucleophile C to provide The D 10 can be reacted with a pinacol ethionium under a suitable catalyst (e.g., palladium acetate) in a suitable solvent such as THF to give the intermediate oxime. The intermediate hydrazine and the aryl halide F 1 are attached under appropriate conditions and the catalyst is subjected to a Suzuki reaction to form the intermediate G. Under acidic conditions, the group of 0 1 can be removed to give the amine compound H. The amine compound H can be reacted with an electrophile or separately to obtain the product (I) or (II).
0
Figure imgf000010_0001
0
Figure imgf000010_0001
Figure imgf000010_0002
在适当的溶剂如 （THF) 中， 在强碱 （如 LHMDS) 的存在下， Boc保护的环酮 A2可以与试 剂 PhNTf2反应产生中间体 B2。 在合适的溶剂 （如 DMF) 中， 在适当的催化剂 （如钯 （三苯基 膦） 4) 作用下， 中间体 B2和杂环硼酸酯 C2的 TfO组可发生 Suzuki交叉偶联反应得到中间体 D2。 在适当的溶剂如 （THF) 中， 在适当的催化剂 （如钯碳） 作用下， 被氢化得到中间体 E2。 在适当的条件下， 中间体 与芳基卤化物在催化剂 （如 Oil ) 作用下可以进行交叉偶联反应 形成中间体 G2。 在酸性条件下， 可以除去 G2的 Boc基团， 得到胺化合物 H。 胺化合物 H可以 分别与亲电子试剂 或 反应， 得到产物 （I ) 或 （II ) 。 反应式方案 3
Figure imgf000010_0002
In a suitable solvent (THF) in e.g., in the presence of a strong base (eg LHMDS), the ring A Boc protected 2-one can be produced PhNTf2 reagent 2 is reacted with intermediate B 2. Suzuki cross-coupling reaction can occur in the TfO group of intermediate B 2 and heterocyclic boronate C 2 under the action of a suitable catalyst such as palladium (triphenylphosphine) 4 in a suitable solvent such as DMF. Intermediate D 2 was obtained. Hydrogenation to give intermediate E 2 in a suitable solvent such as (THF) under the action of a suitable catalyst such as palladium on carbon. Under appropriate conditions, the intermediate and the aryl halide can be cross-coupled to form the intermediate G 2 under the action of a catalyst such as Oil. Under acidic conditions, the Boc group of G 2 can be removed to give the amine compound H. The amine compound H can be reacted with an electrophile, respectively, to give the product (I) or (II). Reaction Scheme 3
Figure imgf000011_0001
Figure imgf000011_0001
化合物八3在浓硫酸和浓硝酸的存在下， 进行硝化反应得到中间体 。 在合适的溶剂（如 DMF)中， 在适当的催化剂（如钯（三苯基膦） 4 )作用下， 中间体 B3和中间体 E可发生 Suzuki 交叉偶联反应得到中间体 C3. 中间体 上 的 Boc基团，可以在酸性条件下除去而得到环状胺 中间体 D3。 中间体 D3可与一个适当的亲电子试剂 YC1 or YBr产生中间体 E3。 在试剂三苯基 膦和 DEAD作用下， 中间体 E3和醇 F3可发生 Mistunobu反应得到芳醚中间体 G:i。 中间体 F3的 硝基基团可以在适当试剂 （如 Fe和氯化钹） 作用下， 得到产品 。 当 Y基团合适的基团时， 即 （I ) 或 （I I ) 。 ALK酶抑制剂活性测量方法： Compound octa 3 is subjected to nitration in the presence of concentrated sulfuric acid and concentrated nitric acid to obtain an intermediate. In a suitable solvent (such as DMF), intermediate B 3 and intermediate E can undergo Suzuki cross-coupling reaction under the action of a suitable catalyst (such as palladium (triphenylphosphine) 4 ) to obtain intermediate C 3 . Boc group on the body, may be a cyclic amine intermediate D 3 was removed under acidic conditions. Intermediate D3 with an appropriate electrophile YC1 or YBr yielding intermediate E 3. Under the action of the reagents triphenylphosphine and DEAD, the intermediate E 3 and the alcohol F 3 can undergo a Mistunobu reaction to obtain an aryl ether intermediate G :i . The nitro group of the intermediate F 3 can be obtained by the action of a suitable reagent such as Fe and cesium chloride. When the Y group is a suitable group, that is, (I) or (II). ALK enzyme inhibitor activity measurement method:
在聚丙烯板中加入 ALK (2纳摩尔） ， 生物素标记的肽底物， Km浓度的 ATP ( 34 uM) 和 试验化合物（1毫摩尔）在激酶反应缓冲液（HEPES250妈妈液（pH7. 0)，叠氮化钠在 BSA0. 05% , 0. 1 % , 钒酸 0. 5毫米） 一起温育 1小时。  In the polypropylene plate, ALK (2 nanomolar), biotin-labeled peptide substrate, Km concentration of ATP (34 uM) and test compound (1 mmol) in kinase reaction buffer (HEPES250 mother solution (pH 7. 0) were added. ), sodium azide was incubated for 1 hour at BSA0. 05%, 0.1%, vanadic acid 0.5 mm).
反应结束后， 由含有 EDTA, 抗体共轭与 Strephavdin-XL665， 穴状化合物铕的 HTRF检测 缓冲液 （50mM的 HEPES (pH值 7. 0) ， 添加剂， lOOmM浓度的 IxDTT西格玛 # D0632的水溶 液， 氯化镁（西格玛# 028， 1M) , 氯化锰（西格玛# 787， 1M) 来停止。 孵育一小时后， 进 行分析。  After the reaction, an aqueous solution of HTRF detection buffer containing EDTA, antibody conjugated with Strephavdin-XL665, cryptate compound (50 mM HEPES (pH 7.0), additive, 100 mM concentration of IxDTT Sigma # D0632, magnesium chloride (Sigma #028, 1M), manganese chloride (Sigma #787, 1M) to stop. After one hour of incubation, analyze.
该板用 Perkin Elmer公司 的 Envision通过 TR-FRET模式来分析。 高比例的 665/620表 示没有激酶抑制反应， 而低比例的 665/620表示完全激酶抑制反应。酶的酶活性由相对于标 准样品的测量值来计算， 表达为 IC50。  The plate was analyzed by Perkin Elmer's Envision in TR-FRET mode. A high ratio of 665/620 indicates no kinase inhibition reaction, while a low ratio of 665/620 indicates complete kinase inhibition. The enzymatic activity of the enzyme is calculated from the measured value relative to the standard sample and expressed as IC50.
通过以上方法测得本发明实施例的化合物的 IC50值如下表所示： 本发明实施例化合物抑制 ALK酶的活性数据表  The IC50 values of the compounds of the examples of the present invention were determined by the above methods as shown in the following table: The activity data of the compounds of the present invention inhibiting the activity of the ALK enzyme
Figure imgf000012_0001
13 53 45 58 77 38
Figure imgf000012_0001
13 53 45 58 77 38
14 147 46 27 78 11614 147 46 27 78 116
15 62 47 4 79 94615 62 47 4 79 946
16 28 48 4 80 3216 28 48 4 80 32
17 3 49 6 81 3417 3 49 6 81 34
18 5 50 187 82 9218 5 50 187 82 92
19 45 51 2 83 12019 45 51 2 83 120
20 9 52 11 84 11820 9 52 11 84 118
21 32 53 8 85 10321 32 53 8 85 103
22 258 54 10 86 21722 258 54 10 86 217
23 358 55 4 87 24323 358 55 4 87 243
24 330 56 32 24 330 56 32
25 56 57 1  25 56 57 1
26 48 58 7  26 48 58 7
27 38 59 5  27 38 59 5
28 130 60 6  28 130 60 6
29 13 61 16  29 13 61 16
30 243 62 30  30 243 62 30
31 8 63 8  31 8 63 8
32 873 64 49  32 873 64 49
本发明提供了由通式 （I ) 至 （XI ) 所述化合物， 及它们的对映体和非对映体或其可药 用的盐。 The present invention provides the compounds of the formulae (I) to (XI), and their enantiomers and diastereomers or their pharmaceutically acceptable salts.
本发明提供了制备由通式 （I ) 至 （XI ) 所述化合物， 及它们的对映体和非对映体的方 法。  The present invention provides a process for the preparation of the compounds of the formulae (I) to (XI), and their enantiomers and diastereomers.
本发明提供了一种用于治疗和抑制癌症和其他疾病的方法。 经证实， 本发明的化合物对 The present invention provides a method for treating and inhibiting cancer and other diseases. It has been confirmed that the compound of the present invention is
ALK活性具有抑制作用， 本发明提供了 通式 （I ) 至 （XI ) 所述化合物用于治疗和 /或预防 以下疾病的药剂中的活性成分， 所述的疾病为由不利的细胞因子信号传导引发的疾病， 这些 疾病包括， 但不限于， 非小细胞肺癌 （NSCLC ) ， 肝癌， 间变性大细胞淋巴瘤 （ALCL ) ， 神 经母细胞瘤， 以及其他抑制 ALK激酶活性对病人有益处的疾病。 所述方法包括给需要的患者 有效剂量的如权利要求 1 7中的化合物。 其他抑制 ALK激酶活性对病人有益处的疾病包括但不限于： 脑瘤， 膀胱癌， 胃癌， 卵巢 癌， 胰腺癌， 乳腺癌， 头颈癌， 子宫颈癌， 子宫内膜癌， 直肠癌， 肾癌， 食道癌， 前例腺癌， 甲状腺癌， 骨癌， 皮肤癌， 结肠癌， 雌性生殖道瘤， 淋巴瘤， 多发性骨髓瘤和睾丸癌 等。 更具体地， 本发明提供了一种用于治疗和抑制非小细胞 UNG肺癌 （NSCLC ) 方法。 The ALK activity has an inhibitory effect, and the present invention provides an active ingredient in a medicament for the treatment and/or prevention of a compound of the formula (I) to (XI), which is caused by adverse cytokine signaling The diseases caused, including, but not limited to, non-small cell lung cancer (NSCLC), liver cancer, anaplastic large cell lymphoma (ALCL), god Transblastoblasts, as well as other diseases that inhibit the activity of ALK kinase, are beneficial to patients. The method comprises administering to a patient in need thereof an effective amount of a compound of claim 17. Other diseases that inhibit ALK kinase activity are beneficial to patients including, but not limited to: brain tumors, bladder cancer, gastric cancer, ovarian cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, rectal cancer, kidney cancer , esophageal cancer, pre-existing adenocarcinoma, thyroid cancer, bone cancer, skin cancer, colon cancer, female genital tract tumor, lymphoma, multiple myeloma and testicular cancer. More specifically, the present invention provides a method for treating and inhibiting non-small cell UNG lung cancer (NSCLC).
更具体地， 本发明提供了一种用于治疗和抑制肝癌方法。  More specifically, the present invention provides a method for treating and inhibiting liver cancer.
更具体地， 本发明提供了一种用于治疗和抑制亚洲患者肝癌方法。  More specifically, the present invention provides a method for treating and inhibiting liver cancer in an Asian patient.
更具体地， 本发明提供了一种用于治疗和抑制间变性大细胞淋巴瘤 （ALCL) 方法。 更具体地， 本发明提供了一种用于治疗和抑制神经母细胞瘤方法。  More specifically, the present invention provides a method for treating and inhibiting anaplastic large cell lymphoma (ALCL). More specifically, the present invention provides a method for treating and inhibiting neuroblastoma.
可以根据标准的药学实践， 将本发明的化合物（ALK抑制剂） 的药物制剂单独使用或者与 一种或多种另外的药剂联合使用， 所述 ALK抑制剂的药物制剂与所述另外的药剂的给药途径 可以相同或不同， 并且给药时间可以相同或不同。 所述的另外的药剂包括 (但不限于） 酰胺 The pharmaceutical preparation of the compound of the present invention (ALK inhibitor) may be used alone or in combination with one or more additional pharmaceutical agents according to standard pharmaceutical practice, the pharmaceutical preparation of the ALK inhibitor and the additional pharmaceutical agent The routes of administration may be the same or different, and the administration times may be the same or different. Said additional agents include, but are not limited to, amides
(CTX) 、 异环磷酰胺 （IF0) 、 阿霉素 （ADM) 、 长春新碱 （VCR ) 、 长春花碱 （VBL) 、 依托 泊甙 （VP16 ) 、 威猛 （Vumon ) 、 卡铂 （CBP) 和甲氨蝶呤 （MTX) 环孢菌素 A、 他克莫司、 西 罗莫司、 依维莫司、 硫唑嘌呤、 布喹那、 来氟米特、 鞘氨醇 1 磷酸受体激动剂 （例如芬戈莫 德、 KRP-203等） 、 LEA-29Y、 抗 IL_2受体的抗体（例如达利珠单抗等） 、 抗 (3)3抗体（例 如 0KT3等） 、 抗 T细胞免疫球蛋白 （例如 AtGam等） 、 阿司匹林、 （3)28-B7阻断分子 （例如 Belatacept , Abatacept等）、 CD40-CD154阻断分子（例如抗 CD40抗体等）、 蛋白激酶 C抑制 剂 （例如 AEB-071等） 、 扑热息痛、 布洛芬、 萘普生、 吡罗昔康和抗炎甾体类 （例如氢化泼 尼松或地塞米松） 。 (CTX), ifosfamide (IF0), doxorubicin (ADM), vincristine (VCR), vinblastine (VBL), etoposide (VP16), virgin (Vumon), carboplatin (CBP) And methotrexate (MTX) cyclosporin A, tacrolimus, sirolimus, everolimus, azathioprine, benzoquine, leflunomide, sphingosine 1 phosphate receptor Agonists (eg, fingolimod, KRP-203, etc.), LEA-29Y, antibodies against the IL-2 receptor (eg, daclizumab, etc.), anti-CD3 antibodies (eg, 0KT3, etc.), anti-T cells Immunoglobulins (eg AtGam, etc.), aspirin, (3) 28-B7 blocking molecules (eg Belatacept, Abatacept, etc.), CD40-CD154 blocking molecules (eg anti-CD40 antibodies, etc.), protein kinase C inhibitors (eg AEB) -071, etc.), paracetamol, ibuprofen, naproxen, piroxicam and anti-inflammatory steroids (such as prednisolone or dexamethasone).
可使用载体、 赋形剂和其它通常用于药物制剂的添加剂， 来制备含有一种或两种或多种 式 （I ) ( XI ) 所示的化合物或其可药用盐作为活性成分的药物组合物。  A carrier, an excipient, and other additives conventionally used in pharmaceutical preparations can be used to prepare a medicament containing one or two or more compounds represented by the formula (I) (XI) or a pharmaceutically acceptable salt thereof as an active ingredient. combination.
可采用片剂、 丸剂、 胶囊、 颗粒剂、 散剂、 液体制剂等的口服给药的剂型， 或者采用静 脉注射或肌肉注射、 栓剂、 透皮剂、 经鼻剂、 吸入剂等的非经口给药的剂型， 来进行治疗给 药。 应考虑要治疗的各个患者的症状、 年龄、 性别等以便适当地确定化合物的剂量。 通常来 说， 在口服给药的情况下， 成人患者每曰服用的化合物剂量为 0. 001 mg/kg至 100 mg/kg左 右， 并将该剂量一次服用或分为 2— 4次服用。 在根据症状需要采用静脉给药的情况中， 通常 来说， 成人患者按照每次 0. 0001 mg/kg至 10 mg/kg的剂量范围， 每円一次至多次给药。 另 外， 在采用吸入剂给药的情况中， 通常来说， 成人患者按照每次 0. 0001 mg/kg至 1 mg/kg 的剂量范围， 每日一次至多次给药。 It can be administered orally in the form of tablets, pills, capsules, granules, powders, liquid preparations, etc., or by intravenous or intramuscular injection, suppositories, transdermal agents, nasal preparations, inhalants, etc. The dosage form of the drug is used for therapeutic administration. The symptoms, age, sex, etc. of each patient to be treated should be considered in order to appropriately determine the dose of the compound. Generally, in the case of oral administration, the dosage of the compound administered per adult is from 0.001 mg/kg to 100 mg/kg, and the dose is taken once or divided into 2-4 times. In the case of intravenous administration depending on the symptoms, usually In general, adult patients are administered once or more times per dose range of from 0.0001 mg/kg to 10 mg/kg. Further, in the case of administration by inhalation, in general, an adult patient is administered once or more times per day in a dose range of from 0.0001 mg/kg to 1 mg/kg.
在本发明中， 用于经口给药的固体组合物可以采用片剂、 散剂、 颗粒剂等剂型。 在这种 固体组合物中， 将一种或一种以上的活性物质与至少一种惰性赋形剂（例如乳糖、 甘露糖醇、 葡萄糖、 羟丙基纤维素、 微晶纤维素、 淀粉、 聚乙烯吡咯垸酮、 硅酸镁铝等） 混合。 按照常 规方法， 组合物中也可以含有惰性添加剂， 如润滑剂 （如硬脂酸镁） 、 崩解剂 （如羧甲基淀 粉钠）和溶解助剂。 根据需要， 片剂或丸剂也可以被糖衣或者胃溶性或肠溶性包衣剂所包覆。  In the present invention, the solid composition for oral administration may be in the form of a tablet, a powder, a granule or the like. In such a solid composition, one or more active substances are combined with at least one inert excipient (eg, lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, poly Mixing vinylpyrrolidone, magnesium aluminum silicate, etc.). The composition may also contain inert additives such as a lubricant (e.g., magnesium stearate), a disintegrant (e.g., sodium carboxymethyl starch), and a dissolution aid, according to conventional methods. Tablets or pills may also be coated with a sugar coating or a gastric or enteric coating as needed.
用于经口给药的液体组合物包括可药用的乳液剂、 溶液制剂、 混悬剂、 糖浆剂、 或酏剂 等， 并含有通常可使用的惰性稀释剂 （例如纯化水、 乙醇） 。 除所述惰性稀释剂以外， 该组 合物中也可以含有诸如增溶剂、润湿剂、悬浮剂之类的助剂以及甜味剂、矫味剂、芳香剂、 防 腐剂。  The liquid composition for oral administration includes pharmaceutically acceptable emulsions, solution preparations, suspensions, syrups, elixirs, and the like, and contains an inert diluent (e.g., purified water, ethanol) which can be usually used. In addition to the inert diluent, the composition may also contain adjuvants such as solubilizers, wetting agents, suspending agents, and sweetening, flavoring, perfuming, and preservatives.
用于非经口给药的注射剂包括无菌的水性或非水性溶液制剂、 混悬剂、 乳剂。 用于水性 溶液的稀释剂可（例如）包括注射用蒸馏水和生理盐水。 用于非水性溶液的稀释剂可 （例如） 包括丙二醇、 聚乙二醇、 植物油 （如橄榄油） 、 醇类 （如乙醇） 和聚山梨醇酯 80。 这样的组 合物中还可以含有诸如等渗剂、 防腐剂、 润湿剂、 乳化剂、 分散剂、 稳定剂、 溶解助剂之类 的添加剂。 可以采用通过可截留细菌的过滤器进行过滤、 添加杀菌剂或进行光辐射的方法来 对所述组合物进行灭菌。 此外， 也可以将这些组合物制成无菌的固体组合物， 在使用前再用 无菌水或无菌的注射用溶剂来使其溶解或混悬而使用。  Injections for parenteral administration include sterile aqueous or nonaqueous solutions, suspensions, emulsions. The diluent for the aqueous solution may, for example, include distilled water for injection and physiological saline. The diluent for the non-aqueous solution may, for example, include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80. Such compositions may also contain additives such as isotonic agents, preservatives, wetting agents, emulsifying agents, dispersing agents, stabilizers, and solubilizing aids. The composition may be sterilized by filtration through a bacteria-retaining filter, addition of a bactericide, or light irradiation. Further, these compositions may be prepared into a sterile solid composition which is dissolved or suspended by using sterile water or a sterile injectable solvent before use.
诸如吸入剂和经鼻剂之类的经粘膜剂， 可以以固体、 液体、 或半固体的状态使用， 并且 可以按照以往公知的方法来制备这些经粘膜剂。 例如， 可以根据需要而添加赋形剂 （如乳糖 和淀粉） 、 pH调节剂、 防腐齐 IJ、 表面活性剂、 润滑齐 IJ、 稳定剂和增稠剂等。 给药时可 以 使用合适的吸入或吹送用装置。例如，可以使用计量给药吸入装置等公知的装置或喷雾器， 将化合物单独地或作为配方后的混合物粉末来给药。 此外， 也可以将化合物与可药用的载体 组合后， 作为溶液或混悬液来给药。 干燥粉末吸入器等可以用于单次给药或多次给药， 并可 以使用干燥粉末或含有粉末的胶囊。 另外， 也可以采用加压气溶胶喷雾等形式， 通过使用适 当的抛射剂 （例如， 氯氟烷烃、 氢氟垸烃、 或二氧化碳等适当的气体） 来给药。 实施例 1
Figure imgf000016_0001
Transmucosal agents such as inhalants and nasal sprays can be used in a solid, liquid, or semi-solid state, and these transmucosal agents can be prepared according to a conventionally known method. For example, excipients (such as lactose and starch), pH adjusters, antiseptic agents, surfactants, lubricating agents, stabilizers, thickeners, and the like can be added as needed. A suitable inhalation or insufflation device can be used for administration. For example, the compound can be administered alone or as a mixture powder after formulation, using a known device such as a metered dose inhalation device or a nebulizer. Alternatively, the compound may be combined with a pharmaceutically acceptable carrier and administered as a solution or suspension. A dry powder inhaler or the like can be used for single administration or multiple administration, and a dry powder or a capsule containing a powder can be used. Alternatively, it may be administered by a pressurized aerosol spray or the like by using a suitable propellant (for example, a suitable gas such as chlorofluoroalkane, hydrofluorocarbon, or carbon dioxide). Example 1
Figure imgf000016_0001
2-[4-[4-[6-氨基 -5-[l-(2,6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基] P比唑  2-[4-[4-[6-Amino-5-[l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]P-pyrazole
-1-基] -1-哌啶基]乙酸 步骤 A:  -1-yl]-1-piperidinyl]acetic acid Step A:
Figure imgf000016_0002
Figure imgf000016_0002
2-[4-[4-[6-氨基 -5-[1-(2,6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基]吡唑  2-[4-[4-[6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazole
-1-基]小哌啶基]乙酸甲酯  Methyl-1-pyridinyl]acetate
操作步骤： Steps:
将化合物甲基 2-氯乙酸（11毫克， 0.12毫摩尔， 1.2个当量）， 碳酸钾（0.5毫摩尔， 5个当量） 和碘化钠（2毫克）加入到化合物 3-[1-(2,6-二氯 -3-氟-苯基)乙氧基 ]-5-[1-(4-哌啶基) P比唑 -4-基] 吡啶 -2-胺（45毫克， 0.1毫摩尔， 1个当量） 的 2毫升的甲醇溶液中， 加热回流 2个小时后用 水淬灭， 后加入水层和二氯甲烷， 分层， 水层再用二氯甲烷萃取三次， 有机相合并后， 干燥 旋干， 产物直接应用于下一歩 （40毫克， 收率为 77%)。 步骤 B:
Figure imgf000016_0003
Add the compound methyl 2-chloroacetic acid (11 mg, 0.12 mmol, 1.2 equivalents), potassium carbonate (0.5 mmol, 5 equivalents) and sodium iodide (2 mg) to the compound 3-[1-(2) ,6-Dichloro-3-fluoro-phenyl)ethoxy]-5-[1-(4-piperidinyl)P-pyrazol-4-yl]pyridin-2-amine (45 mg, 0.1 mmol) , 1 equivalent) in 2 ml of methanol, heated under reflux for 2 hours, quenched with water, then aqueous layer and methylene chloride, layered, and the aqueous layer was extracted three times with dichloromethane. Dry and spin dry, the product was applied directly to the next layer (40 mg, yield 77%). Step B:
Figure imgf000016_0003
2—[4-[4- [6-氨基 -5-[1-(2,6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基基] P比唑  2-[4-[4-[6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]P-pyrazole
-1-基] -1-哌啶基]乙酸  -1-yl]-1-piperidinyl]acetate
操作步骤： Steps:
将氢氧化钠 （30毫克， 0.76毫摩尔， 10个当量） 和 0.5毫升水加入到化合物 2-[4-[4-[6-氨基 -5-[1-(2,6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基基] P比唑 -1-基] -1-哌啶基]乙酸甲酯中 ( 40 毫克， 0.076毫摩尔， 1 个当量） 的乙醇 （1.5毫升） 溶液中， 然后室温搅拌过夜， 反应液再用盐酸 溶液中和后用 HPLC纯化（流动相： 乙腈 /水 /0.5%碳酸氢氨， 梯度洗脱 36%至 66% (体积比）） 得到目标化合物 （16毫克， 收率为 42%)。 Add sodium hydroxide (30 mg, 0.76 mmol, 10 equivalents) and 0.5 ml of water to the compound 2-[4-[4-[6-amino-5-[1-(2,6-dichloro-3) -Fluoro-phenyl)ethoxy]-3-pyridyl]P-pyrazol-1-yl]-1-piperidinyl]acetate in methyl (40 mg, 0.076 mmol, 1 equivalent) of ethanol (1.5 ml) in a solution, then stirred at room temperature overnight, and the reaction solution was neutralized with a hydrochloric acid solution and purified by HPLC (mobile phase: acetonitrile / water / 0.5% aqueous ammonium hydrogen carbonate, gradient elution 36% to 66% by volume) The target compound was obtained (16 mg, yield 42%).
光谱数据： LC/MS (方法： UFLC): RT = 2.925 分钟； m/z = 508.0 [M+H]+; 总的运行时间为 7.00 分钟。 Ή NMR (400MHz, DMSO- 6) δ 8.12 (s, 1H), 7.89-7.82 (m， 2H), 7.69 (s, 1H)， 7.63 (dd, J - 4.8, 8.8 Hz, 1H)， 7.53 (t, J = 8.8 Hz, 1H)， 7.17 (s, 1H), 6.30 (q, J = 6.4 Hz, 1H), 4.49-4.44 (m, 1H), 4.18 (s, 2H), 3.78 - 3.59 (m， 5H)， 2.38-2.20 (m,3H), 1.85 (d, J= 6,8 Hz, 3H). 实施例 2
Figure imgf000017_0001
Spectral data: LC/MS (method: UFLC): RT = 2.925 min; m/z = 508.0 [M+H]+; The total run time was 7.00 min. NMR NMR (400MHz, DMSO- 6 ) δ 8.12 (s, 1H), 7.89-7.82 (m, 2H), 7.69 (s, 1H), 7.63 (dd, J - 4.8, 8.8 Hz, 1H), 7.53 (t , J = 8.8 Hz, 1H), 7.17 (s, 1H), 6.30 (q, J = 6.4 Hz, 1H), 4.49-4.44 (m, 1H), 4.18 (s, 2H), 3.78 - 3.59 (m, 5H), 2.38-2.20 (m, 3H), 1.85 (d, J = 6,8 Hz, 3H). Example 2
Figure imgf000017_0001
2—[4-[4-[6—氨基—5—[1—(2, 6-二氯-3-氟-苯基） 乙氧基 ]-3-吡啶基] 吡唑 2- [4-[ 4 -[ 6 —Amino-5-[1—( 2 , 6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazole
-1-基]- 哌啶基] 乙酰胺  -1-yl]-piperidinyl]acetamide
操作步骤： Steps:
将 2-氣乙酰胺 （132毫克， 1. 44毫摩尔， 1. 2个当量）， 碳酸钾 （4. 8毫摩尔， 4当量） 和碘 化钠 （12毫克） 加入到化合物 3-[1-(2，6-二氯 -3-氟-苯基)乙氧基 ]-5-[1-(4-哌啶基)吡唑 -4 -基]吡 啶 -2-胺 （0. 54毫克， 1. 2毫摩尔， 1当量） 的 15毫升的乙醇溶液中， 加热回流 2个小时后用 水淬灭， 后加入水和二氯甲垸， 分层， 水层再用二氯甲烷萃取三次， 有机相合并后， 干燥旋 干，粗品用色谱仪纯化（仪器： SHIMADZU LC 8A， 色谱柱： synergi-10 μ m， 250 X 50圍 I. D.， 流 动相： A 为 水 （含 1%。 TFA, v/v) , B 为 乙腈， 浓度梯度： B 30-80%， 流速： 80mL /分钟）。 HPLC纯化液用碳酸氢钠调节 ra值为 7-8后水层用二氯甲垸萃取三次， 有机层合并后用饱和 食盐水反洗， 干燥旋干后得到目标化合物 （320毫克， 收率为 53%)。 Add 2-oxoacetamide (132 mg, 1.44 mmol, 1.2 equivalents), potassium carbonate (4.8 mmol, 4 equivalents) and sodium iodide (12 mg) to compound 3-[1 -(2,6-Dichloro-3-fluoro-phenyl)ethoxy]-5-[1-(4-piperidinyl)pyrazole-4-yl]pyridin-2-amine (0. 54 mg , 1. 2 mmol, 1 equivalent) in 15 ml of ethanol, heated under reflux for 2 hours, quenched with water, then added with water and dichloromethane, layered, and then extracted twice with dichloromethane. After the organic phases are combined, dry and spin dry, and the crude product is purified by a chromatograph (instrument: SHIMADZU LC 8A, column: synergi-10 μ m, 250 X 50 ID, mobile phase: A is water (containing 1%. TFA, v /v) , B is acetonitrile, concentration gradient: B 30-80%, flow rate: 80mL / min). The HPLC purification solution was adjusted to a raine value of 7-8 with sodium hydrogen carbonate, and then the aqueous layer was extracted three times with dichloromethane. The organic layer was combined and washed with saturated brine, dried and dried to give the title compound (320 mg, yield 53%).
光谱数据： Spectral data:
LC/MS (方法： UFLC): RT = 2.56 分钟； m/z = 507.2 [M+H]+; 总的运行时间为 7.00分钟。 1H NMR (400 MHz, CDC13) δ 1.80 (d, 3 H), 2.10 (m, 4 H), 2.40 (t, 2 H), 3.00-3.10 (m, 4 H)， 4.10 (m, 1 H), 4.75 (s, 2 H), 5.60 (br, 1 H)， 6.05 (q, 1H), 6.85 (s, 1 H), 7.19 (t, 2 H)， 7.25 (m， 1 H)， 7.48 (s, 1 H), 7.55 (s, 1 H)， 7.70 (s, 1H). 实施例 3
Figure imgf000017_0002
LC/MS (method: UFLC): RT = 2.56 min; m/z = 507.2 [M+H]+; The total run time was 7.00 min. 1H NMR (400 MHz, CDC1 3 ) δ 1.80 (d, 3 H), 2.10 (m, 4 H), 2.40 (t, 2 H), 3.00-3.10 (m, 4 H), 4.10 (m, 1 H ), 4.75 (s, 2 H), 5.60 (br, 1 H), 6.05 (q, 1H), 6.85 (s, 1 H), 7.19 (t, 2 H), 7.25 (m, 1 H), 7.48 (s, 1 H), 7.55 (s, 1 H), 7.70 (s, 1H). Example 3
Figure imgf000017_0002
2-[4-[4-[6-氨基 -5-[l-(2,6-二氯 -3-氟-苯基)乙氧基 ]-3-P比啶基] P比唑 -1 -基]- 1  2-[4-[4-[6-Amino-5-[l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-Ppyridinyl]P-pyrazole-1 -基]- 1
-哌啶基 ]-N-甲基-乙酰胺 操作步骤： -piperidinyl]-N-methyl-acetamide Steps:
将化合物 2-[4-[4-[6-氨基 -5-[1-(2,6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基]吡唑- 基] -1-哌啶基]乙 酸甲酯 （0.8克， 1.53毫摩尔， 1.0当量）溶于甲胺的四氢呋喃溶液中。 然后在微波 80度反 应 45分钟后旋干溶剂。粗品用 HPLC纯化得到目标化合物 (仪器： SHIMADZU LC-8A, 色谱 柱： synergi-10mi, 250x50mmI.D.， 流动相： A为 水 （Add 1%。 TFA， v/v)， 流动相 B为乙腈， 浓 度梯度： B 30-80%, 流速： 80mL /分钟)。 HPLC纯化液用碳酸氢钠调节 PH值为 7-8后， 水层 用二氯甲垸萃取三次， 有机层合并后用饱和食盐水反洗， 干燥旋干得到目标化合物 （582.4 毫克， 收率为 73%)。 The compound 2-[4-[4-[6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazole-yl] Methyl 1-(piperidinyl)acetate (0.8 g, 1.53 mmol, 1.0 eq.) was dissolved in methylamine in tetrahydrofuran. The solvent was then spun off after 45 minutes of microwave reaction at 80 degrees. The crude product was purified by HPLC to give the title compound (yield: SHIMADZU LC-8A, column: synergi-10mi, 250x50mmI.D., mobile phase: A is water (Add 1%. TFA, v/v), mobile phase B is acetonitrile , Concentration gradient: B 30-80%, flow rate: 80mL / min). After the HPLC purification solution was adjusted to pH 7-8 with sodium hydrogencarbonate, the aqueous layer was extracted three times with dichloromethane. The organic layer was combined and washed with saturated brine, dried and dried to give the title compound (582.4 mg, yield 73%).
光谱数据： Spectral data:
LC/MS (方法： UFLC): RT = 3.006 分钟； m/z = 521.1 [M+H]+; 总的运行时间为 7.00 分钟。 1H NMR (400MHz, DMSO- 6) δ 7.92 (s, 1H), 7.73-7.70 (m, 2H), 7.58 (dd, J = 4.8, 8.8 Hz, 1H), 7.52 (s, 1H), 7.45 (t,J= 8.8 Hz, 1H), 6.88 (s, 1H), 6.09 (q,J= 6.4 Hz, 1H)， 5.65 (s, 2H)， 4.12-4.04 (m, 1H), 2.91 (s, 2H)， 2.86-2.83 (m, 2H), 2.61 (d,J=4.4 Hz, 3H), 2.24-2.18 (m, 2H), 2.02-1.93 (m, 4H), 1.79 (d,J=6.8Hz, 3H). LC/MS (method: UFLC): RT = 3.006 min; m/z = 521.1 [M+H] + ; The total run time was 7.00 min. 1H NMR (400MHz, DMSO- 6 ) δ 7.92 (s, 1H), 7.73-7.70 (m, 2H), 7.58 (dd, J = 4.8, 8.8 Hz, 1H), 7.52 (s, 1H), 7.45 (t , J= 8.8 Hz, 1H), 6.88 (s, 1H), 6.09 (q, J= 6.4 Hz, 1H), 5.65 (s, 2H), 4.12-4.04 (m, 1H), 2.91 (s, 2H) , 2.86-2.83 (m, 2H), 2.61 (d, J=4.4 Hz, 3H), 2.24-2.18 (m, 2H), 2.02-1.93 (m, 4H), 1.79 (d, J=6.8Hz, 3H ).
实施例 4
Figure imgf000018_0001
Example 4
Figure imgf000018_0001
2-[4-[4-[6-氨基 -5-[l-(2,6-二氯 -3-氟-苯基)乙氧基 ]-3-P比啶基] P比唑- 基] 2-[4-[4-[6-Amino-5-[l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-Ppyridinyl]P-pyrazole-yl ]
- 1-哌啶基] -Ν,Ν-二甲基-乙酰胺  - 1-piperidinyl]-indole, hydrazine-dimethyl-acetamide
操作步骤： Steps:
将化合物 2-[4-[4-[6-氨基 -5-[ (2，6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基]吡唑 -1-基]小哌啶基乙 酸（20毫克， 0.04毫摩尔， 1 当量）， 二甲胺盐酸盐（3.5毫克， 0.044毫摩尔， 1.1 当量）和 Ν,Ν,Ν' ,Ν' -四甲基 -0- (7-氮杂苯并三唑 -1 基）六氟磷酸脲 （22毫克， 0.06毫摩尔， 1.5当 量)溶于 5毫升二氯甲垸。 然后搅拌、 冰浴和氮气保护下， 继续缓慢加入 Ν,Ν' -二异丙基乙 胺（51毫克， 0.4毫摩尔， 10当量）。 反应在室温下继续搅拌 3小时。 反应结束后， 将反应液 用二氯甲烷稀释， 有机层用碳酸氢钠溶液和食盐水各反洗一次， 再用硫酸钠干燥后旋干， 得 到粗品采用高效液相（仪器： LC 8Α & Gilson 215 馏分收集器， 色谱柱： Ge 分钟 i 200*25 *5um,流动相 A: BASE 水， 流动相 B: 乙腈， 流速： 30mL/分钟，浓度梯度： B 38 68%: 0-12分钟）分离得到目标化合物 （ 8毫克， 产率为 40 The compound 2-[4-[4-[6-amino-5-[(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazol-1-yl] Small piperidinyl acetic acid (20 mg, 0.04 mmol, 1 eq.), dimethylamine hydrochloride (3.5 mg, 0.044 mmol, 1.1 eq.) and hydrazine, hydrazine, Ν', Ν'-tetramethyl- - (7-Azabenzotriazol-1-yl) hexafluorophosphate (22 mg, 0.06 mmol, 1.5 eq.) was dissolved in 5 mL of dichloromethane. Then, under stirring, ice bath and nitrogen, continue to slowly add hydrazine, Ν'-diisopropylethylamine (51 mg, 0.4 mmol, 10 eq.). The reaction was stirred at room temperature for 3 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane, and the organic layer was washed back once with sodium bicarbonate solution and brine, dried over sodium sulfate and then evaporated to dryness to give a crude product using high-performance liquids (instrument: LC 8 Α & Gilson 215 Fraction collector, column: Ge min i 200*25 *5um, mobile phase A: BASE water, mobile phase B: acetonitrile, flow rate: 30mL/min, concentration gradient: B 38 68%: 0-12 minutes) Target compound (8 mg, yield 40
HPLC (方法： UFLC)： RT = 2.84 分钟； m/z = 535.1 [M+H]+; 总的运行时间为 6.00分钟。 光谱数据： HPLC (method: UFLC): RT = 2.84 min; m/z = 535.1 [M+H]+; Spectral data:
1H NMR (400MHz, OMSO-d6) δ 7.96 (s, 1H), 7.75 (s, 1H), 7.59 (dd, J = 5.2, 8.8 Hz, 1H), 7.53 (s， 1H), 7.46 (t, J = 8.8 Hz, 1H), 6.90 (d, J = 1.8 Hz, 1H)， 6.09 (q, J = 6.4 Hz, 1H), 5.65 (s, 2H), 4.17 - 3.98 (m, 1H)， 3.18 (s, 2H), 3.04 (s， 3H), 2.96 - 2.85 (m, 2H), 2.82 (s， 3H), 2.32 - 2.17 (m, 2H)， 2.02 - 1.86 (m, 4H), 1.80 (d， J = 6.8 Hz, 3H). 1H NMR (400MHz, OMSO-d 6 ) δ 7.96 (s, 1H), 7.75 (s, 1H), 7.59 (dd, J = 5.2, 8.8 Hz, 1H), 7.53 (s, 1H), 7.46 (t, J = 8.8 Hz, 1H), 6.90 (d, J = 1.8 Hz, 1H), 6.09 (q, J = 6.4 Hz, 1H), 5.65 (s, 2H), 4.17 - 3.98 (m, 1H), 3.18 ( s, 2H), 3.04 (s, 3H), 2.96 - 2.85 (m, 2H), 2.82 (s, 3H), 2.32 - 2.17 (m, 2H), 2.02 - 1.86 (m, 4H), 1.80 (d, J = 6.8 Hz, 3H).
实施例 5
Figure imgf000019_0001
Example 5
Figure imgf000019_0001
2-[4- [4- [6-氨基 -5-Π-(2，6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基] P比唑 -1-基] 2-[4-[4- [6-Amino-5-indole-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]P-pyrazol-1-yl]
-1-哌啶基 ]-1-吗啉基 -乙酮  1-piperidinyl]-1-morpholinyl-ethanone
操作步骤： Steps:
将化合物 2-[4-[4-[6-氨基 -5- [ (2,6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基]吡唑 -1-基] -1-哌啶基]乙 酸 (20毫克， 0.04毫摩尔， 1当量)， 吗啉 (3.8毫克， 0.044毫摩尔， 1.1当量)和 Ν,Ν,Ν',Ν'-四甲基 -0-(7-氮杂苯并三唑 -1-基)六氟磷酸脲 （22毫克, 0.06毫摩尔，1.5当量)溶于 5 毫升二氯甲烷。 然后搅拌、 冰浴和氮气保护下， 继续缓慢加入 Ν，Ν'-二异丙基乙胺 (51毫克， 0.4毫摩尔， 10当 量)。 反应在室温下继续搅拌 3小时。 反应结束后， 将反应液用二氯甲烷稀释， 有机层用碳酸 氢钠溶液和食盐水各反洗一次， 再用硫酸钠干燥后旋干， 得到粗品采用高效液相分离 (仪器： LC 8Α & Gilson 215 馏分收集器， 色谱柱： Ge分钟 i 200*25mm*5um, 流动相 A: BASE 水, 流动相 B: 乙腈， 流速： 30mL/分钟 浓度梯度： 38-68%B, 0-12分钟)得到目标化合物 （10毫克， 产率为 40 %)。 The compound 2-[4-[4-[6-amino-5-[(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazol-1-yl] -1-piperidinyl]acetic acid (20 mg, 0.04 mmol, 1 eq.), morpholine (3.8 mg, 0.044 mmol, 1.1 eq.) and hydrazine, hydrazine, hydrazide, Ν'-tetramethyl- (7-Azabenzotriazol-1-yl) hexafluorophosphate (22 mg, 0.06 mmol, 1.5 eq.) was dissolved in 5 mL dichloromethane. Then, stirring, ice bath and nitrogen protection were continued, and hydrazine, Ν'-diisopropylethylamine (51 mg, 0.4 mmol, 10 equivalents) was added slowly. The reaction was stirred at room temperature for 3 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane, and the organic layer was back-washed once with sodium bicarbonate solution and brine, dried over sodium sulfate and then dried to give a crude product which was subjected to high-performance liquid separation (instrument: LC 8 Α & Gilson 215 Fraction collector, column: Ge min i 200*25mm*5um, mobile phase A: BASE water, mobile phase B: acetonitrile, flow rate: 30mL/min concentration gradient: 38-68%B, 0-12 minutes) The target compound (10 mg, 40% yield).
光谱数据： Spectral data:
HPLC (方法： UFLC): RT = 2.80 分钟； m/z = 577.1 [M+H]+; 总的运行时间为 7 分钟。  HPLC (method: UFLC): RT = 2.80 min; m/z = 577.1 [M+H]+;
Ή NMR (400MHz, OMSO-d6) δ 7.96 (s, 1H), 7.76 (d, J = 2.0 Hz, 1H), 7.62 - 7.50 (m, 2H), 7.48 (t, J = 8.8 Hz, 1H), 6.90 (d, J = 1.6 Hz, 1H), 6.09 (q, J = 6.4 Hz, 1H), 5.65 (s, 2H)， 4.16 - 4.04 (m, 1H), 3.67 - 3.51 (m, 6H), 3.49 - 3.42 (2, 3H)， 3.20 (s, 2H)， 2.92-2.89 (m, 2H)， 2.28 - 2.12 (m, 2H), 2.05 - 1.84 (m, 4H)， 1.81 (d, J = 6.8 Hz, 3H)0 实施例 6NMR NMR (400MHz, OMSO-d 6 ) δ 7.96 (s, 1H), 7.76 (d, J = 2.0 Hz, 1H), 7.62 - 7.50 (m, 2H), 7.48 (t, J = 8.8 Hz, 1H) , 6.90 (d, J = 1.6 Hz, 1H), 6.09 (q, J = 6.4 Hz, 1H), 5.65 (s, 2H), 4.16 - 4.04 (m, 1H), 3.67 - 3.51 (m, 6H), 3.49 - 3.42 (2, 3H), 3.20 (s, 2H), 2.92-2.89 (m, 2H), 2.28 - 2.12 (m, 2H), 2.05 - 1.84 (m, 4H), 1.81 (d, J = 6.8 Hz, 3H) 0 Example 6
Figure imgf000020_0001
Figure imgf000020_0001
[4-[4-[6-氨基 -5-[l-(2，6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基] B比唑 -1-基]  [4-[4-[6-Amino-5-[l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]B-pyrazole-1-yl]
小哌啶基 ]-(5-甲基异恶唑基 -4-基)甲酮  Small piperidinyl]-(5-methylisoxazolyl-4-yl)methanone
操作步骤： Steps:
将化合物 3-[1-(2,6 -二氯 -3-氟-苯基)乙氧基 ]-5- [ (4 -哌啶基)吡唑 -4 -基]吡啶 -2-胺 (300 毫克, 0.666 毫摩尔， 1 当量)， 化合物 5-甲基异恶唑 -4-羧酸 (0.093 克， 0.733 毫摩尔， 1.2 当量)和 Ν,Ν,Ν',Ν'-四甲基 -0-(7-氮杂苯并三唑 -1-基)六氟磷酸脲 （0.38克， 0.999毫摩尔， 1.5当量)溶于 2毫升二氯甲垸。 然后搅拌、 冰浴和氮气保护下， 继续缓慢加入 Ν,Ν'-二异丙基乙胺 (0.516克, 3.996毫摩尔， 4当量.；)。 反应在室温下继续搅拌 12小时。 反应结束后将反应液旋干， 得到的 粗品用 HPLC纯化纯化 (仪器： SHIMADZU LC-8A, 色谱柱： synergi-10/mi， 250 <50mmI.D.流 动相： A为 水 （Add 1%ο TFA, v/v),流动相 B为乙腈， 浓度梯度： B 30-80%，流速： 80mL /分钟)。 用 HPLC纯化液用碳酸氢钠调节 PH值为 7-8后水层用二氯甲垸萃取三次，有机层合并后用饱 和食盐水反洗， 干燥旋干得到目标化合物 （130毫克， 收率： 37.6%)。 The compound 3-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-5-[(4-piperidinyl)pyrazole-4-yl]pyridin-2-amine ( 300 mg, 0.666 mmol, 1 eq), compound 5-methylisoxazole-4-carboxylic acid (0.093 g, 0.733 mmol, 1.2 eq.) and hydrazine, hydrazine, hydrazine, Ν'-tetramethyl- 0-(7-Azabenzotriazol-1-yl)hexafluorophosphate (0.38 g, 0.999 mmol, 1.5 eq.) was dissolved in 2 mL of dichloromethane. Then, stirring, ice bath and nitrogen protection were continued, and hydrazine, Ν'-diisopropylethylamine (0.516 g, 3.996 mmol, 4 eq.;) was slowly added. The reaction was stirred at room temperature for further 12 hours. After completion of the reaction, the reaction solution was spun dry, and the obtained crude product was purified by HPLC (PLC: SHIMADZU LC-8A, column: synergi-10/mi, 250 <50mmI.D. mobile phase: A is water (Add 1%ο TFA, v/v), mobile phase B is acetonitrile, concentration gradient: B 30-80%, flow rate: 80 mL / min). After the pH was adjusted to 7-8 with sodium hydrogencarbonate, the aqueous layer was extracted three times with dichloromethane. The organic layer was combined and washed with saturated brine, dried and dried to give the title compound (130 mg, yield: 37.6%).
光谱数据： Spectral data:
LC/MS (方法： UFLC): RT =3.749 分钟； m/z = 559.1 [M+H]+; 总的运行时间为 7.00 分钟。 Ή NMR (400MHz, METHANOL-^) δ 8.52 (s, 1H), 8.00 (s, 1H), 7.68 (s, 1H), 7.63 (d, J= 1.6 Hz, 1H), 7.53 (dd, J = 4.8, 8.8 Hz, 1H), 7.32 (t, J = 8.8 Hz, 1H), 7.19 (d, J = 1.6 Hz, 1H), 6.38 (q， J = 6.8 Hz, 1H), 4.59-4.51 (m, 1H), 4.10-3.99 (m, 2H), 3.15-3.05 (m, 2H), 2.56 (s, 3H), 2.21-2.19 (m, 2H), 2.10 - 2.00 (m, 2H), 1.97 (d, J= 6.5 Hz, 3H). 实施例  LC/MS (method: UFLC): RT = 3.749 min; m/z = 559.1 [M+H]+; The total run time was 7.00 minutes. NMR NMR (400MHz, METHANOL-^) δ 8.52 (s, 1H), 8.00 (s, 1H), 7.68 (s, 1H), 7.63 (d, J= 1.6 Hz, 1H), 7.53 (dd, J = 4.8 , 8.8 Hz, 1H), 7.32 (t, J = 8.8 Hz, 1H), 7.19 (d, J = 1.6 Hz, 1H), 6.38 (q, J = 6.8 Hz, 1H), 4.59-4.51 (m, 1H ), 4.10-3.99 (m, 2H), 3.15-3.05 (m, 2H), 2.56 (s, 3H), 2.21-2.19 (m, 2H), 2.10 - 2.00 (m, 2H), 1.97 (d, J = 6.5 Hz, 3H). Example
Figure imgf000020_0002
Figure imgf000020_0002
2-[4-[4-[6-氨基 -5-Π-(2,6-二氯- 3-氟-苯基)乙氧基 ]- 3-吡啶基]吡唑 -1-基] 2-[4-[4-[6-Amino-5-indole-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazole-1-yl]
哌啶 -1-羰基] -3-氧代 -丁腈  Piperidine-1-carbonyl]-3-oxo-butyronitrile
操作步骤： Steps:
将甲醇钠（12毫克， 0.214毫摩尔， 1.5当量）溶于 2毫升甲醇中，然后慢慢滴加到化合物 [4-[4-[6- 氨基 -5- [ (2,6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基]吡唑小基] -1-哌啶基 ]-(5-甲基异恶唑基 -4-基) 甲酮 （0.08克， 0.143毫摩尔， 1.0当量） 的 5毫升四氢呋喃溶液中。 反应在常温下搅拌 3个 小时。反应液旋干后溶于水， 用 1摩尔 /升的盐酸调节 pH到 3-4 后用 HPLC纯化 （仪器： LC 8A & Gilson 215 馏分收集器 色谱柱： Ge分钟 i 200*25mm*5um，流动相 A: HC1 水,流动相 B: 乙腈， 流速： 30mL/分钟 浓度梯度： B 17-27%, 0-12分钟)后得到目标化合物 (54.7毫克， 产率 68.3 Sodium methoxide (12 mg, 0.214 mmol, 1.5 eq.) was dissolved in 2 mL of methanol and then slowly added dropwise to the compound [4-[4-[6- Amino-5-[(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazole small group]-1-piperidinyl]-(5-methyl isoxine Azyl-4-yl) ketone (0.08 g, 0.143 mmol, 1.0 eq.) in 5 mL of THF. The reaction was stirred at room temperature for 3 hours. The reaction solution was spun dry, dissolved in water, adjusted to pH 3-4 with 1 mol/L hydrochloric acid and purified by HPLC (instrument: LC 8A & Gilson 215 fraction collector column: Ge min i 200*25 mm*5 um, flowing Phase A: HC1 water, mobile phase B: acetonitrile, flow rate: 30 mL/min concentration gradient: B 17-27%, 0-12 minutes) to give the target compound (54.7 mg, yield 68.3
光谱数据： Spectral data:
LC/MS (方法： UFLC): RT = 4.091分钟； m/z = 559.1 [M+H]+ ; 总的运行时间为 7.00 分钟。 Ή NMR (400MHz, METHANOL-d4) δ 7.85 (s, 1H), 7.65 (s, 1H), 7.57 (s, 1H), 7.47 (dd， J = 4.8， 8.8 Hz, 1H), 7.24 (t, J= 8.4 Hz, 1H), 6.98 (s, 1H), 6.21 (q, J= 6.8 Hz, 1H), 4.80 (s， 1H), 4.55 - 4.45 (m, 3H), 3.20-3.13 (m, 2H), 2.29 (s, 3H), 2.23 - 2.11 (m, 2H), 2.10 - 1.95 (m, 2H), 1.89 (d, J = 6.8 Hz, 3H LC/MS (method: UFLC): RT = 4.091 min; m/z = 559.1 [M+H] + ; NMR NMR (400MHz, METHANOL-d 4 ) δ 7.85 (s, 1H), 7.65 (s, 1H), 7.57 (s, 1H), 7.47 (dd, J = 4.8, 8.8 Hz, 1H), 7.24 (t, J= 8.4 Hz, 1H), 6.98 (s, 1H), 6.21 (q, J= 6.8 Hz, 1H), 4.80 (s, 1H), 4.55 - 4.45 (m, 3H), 3.20-3.13 (m, 2H) ), 2.29 (s, 3H), 2.23 - 2.11 (m, 2H), 2.10 - 1.95 (m, 2H), 1.89 (d, J = 6.8 Hz, 3H
实施例 8  Example 8
Figure imgf000021_0001
Figure imgf000021_0001
2-[4-[4-[6-氨基 -5-[l-(2，6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基] P比唑 -1-基 2-[4-[4-[6-Amino-5-[l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]P-pyrazol-1-yl
-4-哌啶基]乙腈 步骤 A:  4-piperidinyl]acetonitrile Step A:
Figure imgf000021_0002
Figure imgf000021_0002
4 - (氰基亚甲基)哌啶- 1-甲酸叔丁酯  4-(cyanomethylene)piperidine-1-carboxylic acid tert-butyl ester
操作步骤： Steps:
向冰浴冷却和氮气保护的含有氢化钠 （0.264 克， 0.011 摩尔， 1.1 当量， 在矿物油 60%的含量) 的无水四氢呋喃溶液 (64 毫升)滴加化合物 2-二乙氧基磷酰乙腈 (2.04 克， 0.0115 摩尔， U5当 量)。此混合液在 20度下搅拌 45分钟再冷却到 0度，滴加化合物 4-氣代哌啶 -1-甲酸叔丁酯 (1.99 克， 0.0115 摩尔， 1当量） 的四氢呋喃溶液 (15 毫升)。 此混合物在室温下搅拌过夜。 在 0度 下加入食盐水 (40 毫升)并用乙酸乙酯 （50 毫升 *3)萃取。 有机层用碳酸氢钠溶液和食盐水各 反洗一次， 再用硫酸钠干燥后旋干， 得到的目标化合物 (2.27 克， 收率 100%)。 步骤 B: To the ice bath and nitrogen-protected solution of sodium hydride (0.264 g, 0.011 mol, 1.1 eq. in 60% of mineral oil) in anhydrous tetrahydrofuran (64 mL) was added dropwise to compound 2-diethoxyphosphoryl acetonitrile. (2.04 g, 0.0115 mol, U5 equivalent). The mixture was stirred at 20 °C for 45 minutes and then cooled to 0 °, and then a solution of compound 4-di-piperidine-l-carboxylic acid tert-butyl ester (1.99 g, 0.0115 mol, 1 eq.) in tetrahydrofuran (15 ml). This mixture was stirred at room temperature overnight. At 0 degrees Saline solution (40 ml) was added and extracted with ethyl acetate (50 ml*3). The organic layer was back-washed once with sodium bicarbonate solution and brine, dried over sodium sulfate and then evaporated to give the desired compound ( 2.27 g, yield 100%). Step B:
Figure imgf000022_0001
Figure imgf000022_0001
4-[4-[6-氨基 -5-[ (2, 6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基]吡唑 -1-基] -4- 4-[4-[6-Amino-5-[(2,6-Dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazole-1-yl]-4-
(氰甲基)哌啶 -1-甲酸叔丁酯 (cyanomethyl) piperidine-1-carboxylic acid tert-butyl ester
操作步骤： Steps:
在室温下向溶有化合物 4- (氰基亚甲基)哌啶 -1-甲酸叔丁酯 （20 毫克， 0.09 毫摩尔， 1 当量)的 乙腈 (5 毫升)中加入化合物 3-[1-(2,6-二氯 -3-氟-苯基)乙氧基 ]-5-[1Η-吡唑 -4-基]吡啶 -2-胺 (36 毫克， 0.1 毫摩尔， 1.1 当量） 和 1.8-二氮杂二环 [5.4.0] ^—垸- 7-烯 (27 毫克， 0.18 摩尔， 2.0 当 量)。此混合液在室温下搅拌 10小时。反应液减压旋干后加入乙酸乙酯 （20 毫升)并依次用饱 和碳酸氢钠和食盐水洗涤后用无水硫酸钠干燥。 有机相减压旋干用制备层析薄板 (石油醚： 乙 酸乙酯 =1 :1) 纯化得目标化合物 （30毫克， 收率： 51.7 %)。 步骤 C: To the solution of the compound 4-(cyanomethylene)piperidine-1-carboxylic acid tert-butyl ester (20 mg, 0.09 mmol, 1 eq.) in acetonitrile (5 mL) (2,6-Dichloro-3-fluoro-phenyl)ethoxy]-5-[1Η-pyrazol-4-yl]pyridin-2-amine (36 mg, 0.1 mmol, 1.1 eq.) and 1.8 - Diazabicyclo[5.4.0]^-垸-7-ene (27 mg, 0.18 mol, 2.0 eq.). This mixture was stirred at room temperature for 10 hours. The reaction mixture was evaporated to drynessnessnessnessnessnessnessnessnessnessnessnessness The organic phase was purified by EtOAc (EtOAc:EtOAc:EtOAc) Step C:
Figure imgf000022_0002
Figure imgf000022_0002
2-[4-[4-[6-氨基 -5- [ (2, 6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基]吡唑 -1-基]  2-[4-[4-[6-Amino-5-[(2,6-Dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazole-1-yl]
-4-哌啶基]乙腈  -4-piperidinyl]acetonitrile
操作步骤： Steps:
向用冰浴冷却的溶有化合物 4- [4-[6-氨基 -5-[1-(2, 6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基]吡唑- 1- 基] -4- (氰甲基)哌啶 -1-甲酸叔丁酯 (30 毫克， 0.05 毫摩尔， 1 当量） 的二氯甲垸 (20 毫升)溶液 中加入盐酸二氧六环 （0.5毫升, 4摩尔每升)。加完后， 此混合液在室温下搅拌一个小时。反应 液浓缩得到的粗品采用高效液相色谱在 C18反相柱上分离 (流动相： 乙腈 /水 /0.5%HC1， 梯度 洗脱 5%至 35% (体积比))， 减压蒸除易挥发的组分后冻干得到目标化合物的盐酸盐 (5.8 毫克, 收率 23.3%)。 Dissolved in the ice bath with the compound 4-[4-[6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyr Add oxazolidine hydrochloride to a solution of tert-butyl 4-(cyanomethyl)piperidine-1-carboxylate (30 mg, 0.05 mmol, 1 eq.) in dichloromethane (20 mL) Ring (0.5 ml, 4 mol per liter). After the addition was completed, the mixture was stirred at room temperature for one hour. The crude product obtained by concentration of the reaction liquid was separated by high performance liquid chromatography on a C18 reverse phase column (mobile phase: acetonitrile/water/0.5% HC1, gradient). The 5% to 35% by volume (volume ratio) was eluted, and the volatile component was evaporated under reduced pressure, followed by lyophilization to give the title compound hydrochloride (yield: 5.8 mg, yield: 23.3%).
光谱数据： Spectral data:
LC/MS (方法： UFLC): RT = 2.67 分钟； m/z = 507.1 [M+H]+; 总的运行时间为 为 7.0 分钟。 Ή NMR (400 MHz, methanol-^) δ 8.35 (s， IH) 7.79 (s, IH) 7.72 (s, IH) 7.51 (dd, J= 4.8， 9.2 Hz, IH) 7.25 - 7.33 (t, J= 8.8 Hz, IH), 7.22 (s, 1H)， 6.38 (q, J= 6.4 Hz, IH), 3.46-3.42 (m， 2H)， 3.12 (s 2H), 2.98-2.95 (m, 4H), 2.38-2.34 (m， 2H)， 1.96 (d, J= 6.8 Hz, 3H). LC/MS (method: UFLC): RT = 2.67 min; m/z = 507.1 [M+H] + ; NMR NMR (400 MHz, methanol-^) δ 8.35 (s, IH) 7.79 (s, IH) 7.72 (s, IH) 7.51 (dd, J= 4.8, 9.2 Hz, IH) 7.25 - 7.33 (t, J= 8.8 Hz, IH), 7.22 (s, 1H), 6.38 (q, J= 6.4 Hz, IH), 3.46-3.42 (m, 2H), 3.12 (s 2H), 2.98-2.95 (m, 4H), 2.38 -2.34 (m, 2H), 1.96 (d, J= 6.8 Hz, 3H).
实施例 9Example 9
Figure imgf000023_0001
Figure imgf000023_0001
2-[3-[4-[6-氨基 -5-[l- (2,6-二氯 -3-氟-苯基)乙氧基 ]- 3-吡啶基] P比唑 -1-基:  2-[3-[4-[6-Amino-5-[l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]P-pyrazol-1-yl :
氮杂环丁烷 -3-基]乙腈 步骤 A:  Azetidin-3-yl]acetonitrile Step A:
Boc
Figure imgf000023_0002
Boc
Figure imgf000023_0002
3- (氰基亚甲基)氮杂环丁烷 -1-甲酸叔丁酯 操作步骤：  3-(cyanomethylene)azetidin-1-carboxylic acid tert-butyl ester Procedure:
向冰浴冷却和氮气保护的含有氢化钠 （0.514 克， 0.0128 摩尔， 1.1 当量， 在矿物油 60%的含 量)的无水四氢呋喃 (64 毫升)滴加化合物 2-二乙氧基磷酰乙腈 (2.38 克， 0.0134 摩尔， 1.15 当 量)。 此混合液在 20度下搅拌 45分钟再冷却到零度， 滴加化合物 3-氧代氮杂环丁垸 -1-屮酸 叔丁酯 (2 克， 0.0117 摩尔， 1当量） 的四氢呋喃溶液 (15 毫升)。 此混合物在室温下搅拌过夜。 在零度下加入食盐水 (40 毫升)并用乙酸乙酯 （50 毫升 *3)萃取。 有机层用碳酸氢钠溶液和食 盐水各反洗一次， 再用硫酸钠干燥后旋干， 得到的目标化合物 （2.27 克， 收率 100%)。 步骤 B:
Figure imgf000024_0001
To the ice bath and nitrogen-protected sodium hydride (0.514 g, 0.0128 mol, 1.1 eq. in 60% of mineral oil) of anhydrous tetrahydrofuran (64 mL) was added dropwise to compound 2-diethoxyphosphoryl acetonitrile ( 2.38 g, 0.0134 mol, 1.15 eq.). The mixture was stirred at 20 °C for 45 minutes and then cooled to zero. A solution of the compound 3-oxoazetidin-1-decanoic acid tert-butyl ester (2 g, 0.0117 mol, 1 equivalent) in tetrahydrofuran (15) ML). This mixture was stirred at room temperature overnight. Saline solution (40 ml) was added at 0 °C and extracted with ethyl acetate (50 mL * 3). The organic layer was back-washed once with sodium bicarbonate solution and brine, dried over sodium sulfate and then evaporated to give the desired compound ( 2.27 g, yield 100%). Step B:
Figure imgf000024_0001
3-[4-[6-氨基 -5-[ l-(2, 6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基]吡唑小基] -3- (氰甲基) 3-[ 4 -[6-Amino-5-[ l-(2, 6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazole small group] -3- (cyano methyl)
氮杂环丁烷 -1-甲酸叔丁酯 操作步骤：  Azetidine azetidine-1-carboxylate Procedure:
在室温下向溶有化合物 3- (^基亚 Ψ¾)氮杂环丁烷 -1- 酸叔丁酯 (11 毫克， 0.06 毫摩尔， 1 当 量)的乙腈 (5 毫升)溶液中加入化合物 3-[1 -(2,6-二氯 -3-氟-苯基)乙氧基 ]-5-(1Η-吡唑 -4-基)吡啶 -2-胺 (22 毫克， 0.06 毫摩尔， 1 当量） 和 1.8-二氮杂二环 [5.4.0] ^—垸 -7-烯 (18 毫克， 0.12 摩 尔， 2.0 当量)。 此混合液在室温下搅拌 10小时。 反应液减压旋干后加入乙酸乙酯 （20 毫升) 并依次用饱和碳酸氢钠和食盐水洗涤后用无水硫酸钠干燥。 有机相减压旋干， 用制备层析薄 板 (石油醚： 乙酸乙酯 =1 : 1)纯化得目标化合物 (28 毫克， 收率：84.8 %)。 步骤 C: Add compound 3 to a solution of the compound 3-(^- yttrium) azetidine (10 mg, 0.06 mmol, 1 eq.) in EtOAc (5 mL) [1-(2,6-Dichloro-3-fluoro-phenyl)ethoxy]-5-(1Η-pyrazol-4-yl)pyridin-2-amine (22 mg, 0.06 mmol, 1 eq. And 1.8-diazabicyclo[5.4.0]^-垸-7-ene (18 mg, 0.12 mol, 2.0 eq.). This mixture was stirred at room temperature for 10 hours. The reaction mixture was dried over anhydrous sodium The organic phase was dried under reduced pressure, and purified (yield: ethyl ether: ethyl acetate = 1:1) to afford the title compound (28 mg, yield: 84.8 %). Step C:
Figure imgf000024_0002
Figure imgf000024_0002
2-[3- [4-[6-氨基 -5-[1-(2，6-二氯 -3-氟-苯基)乙氧基 ]- 3-吡啶基] P比唑 -1-基]  2-[3-[4-[6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]P-pyrazol-1-yl ]
氮杂环丁垸 -3-基]乙腈  Azetidin-3-yl]acetonitrile
操作步骤： Steps:
向用冰浴冷却的溶有化合物 3-[4-[6-氨基 -5-[ (2, 6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基]吡 小 基] -3- (氰甲基)氮杂环丁垸 -1-甲酸叔丁酯 (40 毫克， 0.07 毫摩尔， 1 当量） 的二氯甲垸 (20 毫升) 溶液中加入盐酸二氧六环 （0.5毫升, 4摩尔每升)。 加完后， 此混合液在室温下搅拌一个小时。 反应液浓缩得到的粗品采用高效液相色谱在 C18反相柱上分离 (流动相： 乙腈 /水 /弱碱， 梯度 洗脱 40%至 60% (体积比))， 减压蒸除易挥发的组分后冻干得到目标化合物 （9.5 毫克， 收率 30%)。 Dissolved in the ice bath, the compound 3-[4-[6-amino-5-[(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyridyl Add -3-(cyanomethyl)azetidin-1-carboxylic acid tert-butyl ester (40 mg, 0.07 mmol, 1 eq.) in dichloromethane (20 mL) 0.5 ml, 4 mol per liter). After the addition was completed, the mixture was stirred at room temperature for one hour. The crude product obtained by concentration of the reaction liquid was separated by high performance liquid chromatography on a C18 reverse phase column (mobile phase: acetonitrile/water/weak base, gradient elution 40% to 60% (volume ratio)), and the volatiles were evaporated under reduced pressure. The fractions were lyophilized to give the title compound (9.5 mg, yield 30%).
光谱数据： Spectral data:
LC/MS (方法： UFLC): RT = 2.578 分钟； m/z = 461.2 [M+H]+; 总的运行时间为 7.00 分钟. 'H NMR (400 MHz, CDC13) δ 7.76 (s, 1H), 7.65 (s, 1H)， 7.64 (s, 1H), 7.31 (dd, J= 4.8, 8.4 Hz, 1H) 7.06 (t, J = 8.4 Hz, 1H)， 6.88 (s, 1H), 6.08 (q, J = 6.8 Hz, 1H), 4.92 (br. s" 2H), 4.22 (d， J = 8.0 Hz, 1H), 3.85 (d, J= 8.0 Hz, 1H), 3.33 (s, 2H), 1.87 (d, J= 6.4 Hz, 3H). 实施例 10 LC/MS (method: UFLC): RT = 2.578 min; m/z = 461.2 [M+H] + ; The total run time is 7.00 min. 'H NMR (400 MHz, CDC1 3 ) δ 7.76 (s, 1H), 7.65 (s, 1H), 7.64 (s, 1H), 7.31 (dd, J= 4.8, 8.4 Hz, 1H) 7.06 (t, J = 8.4 Hz, 1H), 6.88 (s, 1H), 6.08 (q, J = 6.8 Hz, 1H), 4.92 (br. s" 2H), 4.22 (d, J = 8.0 Hz, 1H), 3.85 (d , J = 8.0 Hz, 1H), 3.33 (s, 2H), 1.87 (d, J = 6.4 Hz, 3H). Example 10
Figure imgf000025_0001
Figure imgf000025_0001
3- [ (2，6-二氯 -3-氟-苯基)乙氧基 ]-5-[4-(4-哌啶基) P比唑 -1-基] 3-[ (2,6-Dichloro-3-fluoro-phenyl)ethoxy]-5-[4-(4-piperidinyl)P-pyrazole-1-yl]
吡啶基 -2-胺  Pyridyl-2-amine
步骤 A:
Figure imgf000025_0002
Step A:
Figure imgf000025_0002
4 吡唑—4-基) -5, 6 -二氢吡啶 -1(2//)-甲酸叔丁酯  4 pyrazole-4-yl)-5,6-dihydropyridine -1(2//)-tert-butyl formate
操作步骤： Steps:
在氮气保护下， 向溶有化合物 4 - (三氟甲基磺酰氧基 )- 5， 6 -二氢吡啶 -1(2H)-甲酸叔丁酯 (1 克, 3.0 毫摩尔， 当量)和化合物 4-(4，4，5,5-四甲基 -1，3，2-二氧杂环戊硼垸 -2-基)- 1H-吡唑 （756 毫 克， 3.9 毫摩尔， 1.3 当量)的饱和的碳酸氢钠水溶液 （5 毫升)和乙腈 （5 毫升） 的混合溶液中 加入 1，1'-双 (二苯基磷)二茂铁氯化钯 （122毫克， 0.15毫摩尔， 5%当量)。 加完后， 混合物在微 波中 110度下反应 30 分钟。 反应液冷却到室温并倒入 20 毫升水中并用乙酸乙酯 （30毫升 *2)萃取。 合并的有机相用食盐水反洗一次， 再用硫酸钠干燥后旋干后得到粗品化合物。 此粗 品化合物用快速柱纯化 （石油醚： 乙酸乙酯 =1 : 1) 得到目标化合物 （400 毫克， 53.5 %)。 步骤 B:
Figure imgf000025_0003
Under the protection of nitrogen, the compound 4 - (trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1 g, 3.0 mmol, equivalent) and Compound 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (756 mg, 3.9 mmol, 1.3 eq.) Add 1,1'-bis(diphenylphosphino)ferrocene palladium chloride (122 mg, 0.15 mmol, 5%) to a mixed solution of saturated aqueous sodium bicarbonate (5 mL) and acetonitrile (5 mL) equivalent). After the addition was completed, the mixture was reacted at 110 °C for 30 minutes in the microwave. The reaction solution was cooled to room temperature and poured into water (20 ml) The combined organic phases were backwashed once with brine, dried over sodium sulfate and dried to give a crude compound. The crude compound was purified by flash column (EtOAc (EtOAc:EtOAc) Step B:
Figure imgf000025_0003
4-(lH-吡唑 -4-基)哌啶小甲酸叔丁酉 i  4-(lH-pyrazol-4-yl)piperidineminic acid tert-butyl hydrazine i
操作步骤： 向溶有化合物 4 -(1H-吡唑 -4-基) -5， 6 -二氢吡啶- 1(2H)-甲酸叔丁酯 (200 毫克， 0.8毫摩尔， 1.0当 量） 的乙醇 （30 毫升） 溶液中加入钯碳 （100 毫克). 此混合液在 15 psi 氢气环境下在 40度 搅拌 16个小时. 反应液过滤减压旋干得到目标化合物 (180毫克， 收率 90%) 。 步骤 C:
Figure imgf000026_0001
Steps: To the solution of the compound 4-(1H-pyrazol-4-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (200 mg, 0.8 mmol, 1.0 eq.) in ethanol (30 mL) Palladium on carbon (100 mg) was added to the solution. The mixture was stirred at 40 °C for 16 hours under a hydrogen atmosphere of 15 psi. The reaction mixture was filtered and evaporated to dryness to give the title compound (180 mg, yield: 90%). Step C:
Figure imgf000026_0001
4-[1-[6-氨基 -5- [ (2， 6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基]吡唑 -4-基]哌啶小甲酸叔丁酯 操作步骤：  4-[1-[6-Amino-5-[(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazol-4-yl]piperidine Butyl ester operation steps:
向含有化合物 4-(lH-吡唑 -4-基)哌啶 -1-甲酸叔丁酯 （100 毫克， 0.4 毫摩尔， 1 当量)， 化合物 3-[1-(2，6-二氯 -3-氟-苯基)乙氧基 ]-5-碘-卩比啶 -2-胺 (182 毫克， 0.48 毫摩尔， 1.2 当量), 碘化亚 铜 （76 毫克， 0.4 毫摩尔， 1当量)， 碳酸钾 （1 16 毫克， 0.86 毫摩尔，2.1当量)的甲苯 (20 毫升) 溶液中加入反式-二甲基环己基 -1 ,2-二胺 (56 毫克， 0.4 毫摩尔， 1.0当量)。 此混合液在闷罐中 在 110度下搅拌 48小时。 待反应液冷却后过滤。 滤液倒入水中 (10 毫升） 用乙酸乙酯 (20 毫 升 *2)萃取。合并的有机相用食盐水反洗一次，再用硫酸钠干燥后旋干后得到目标化合物 (130 毫克， 收率为 59%)。 步骤 D: To the compound containing 4-(lH-pyrazol-4-yl)piperidine-1-carboxylic acid tert-butyl ester (100 mg, 0.4 mmol, 1 eq.), compound 3-[1-(2,6-dichloro- 3-fluoro-phenyl)ethoxy]-5-iodo-indolepyridin-2-amine (182 mg, 0.48 mmol, 1.2 eq.), cuprous iodide (76 mg, 0.4 mmol, 1 eq.) , Potassium carbonate (1 16 mg, 0.86 mmol, 2.1 eq.) in toluene (20 mL) was added to the solution of trans-dimethylcyclohexyl-1,2-diamine (56 mg, 0.4 mmol, 1.0 eq.) . This mixture was stirred at 110 °C for 48 hours in a stuffing tank. The reaction solution was cooled and filtered. The filtrate was poured into water (10 ml) and extracted with ethyl acetate (20 mL). The combined organic phases were back-washed once with brine, dried over sodium sulfate and dried to give the title compound (130 mg, yield 59%). Step D:
Figure imgf000026_0002
Figure imgf000026_0002
3-[1-(2,6-二氯 -3-氟-苯基)乙氧基 ]-5- [4-(4-哌啶基)吡唑小基] 3-[1-(2,6-Dichloro-3-fluoro-phenyl)ethoxy]-5-[4-(4-piperidyl)pyrazole small group]
吡啶 -2-胺  Pyridine-2-amine
操作步骤： Steps:
向用冰浴冷却的溶有化合物 4- [ [6-氨基 -5-[1 -(2,6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基] 吡唑 -4-基]哌啶 -1-甲酸叔丁酯 （130 毫克， 0.236 毫摩尔） 的二氯甲垸 （20 毫升)溶液中加入盐酸 二氧六环 （1.5毫升, 4摩尔每升)。加完后， 此混合液在室温下搅拌一个小时。反应液浓缩得到 的粗品采用高效液相色谱在 C18 反相柱上分离 (流动相： 乙腈 /水 /0.5%HC1， 梯度洗脱 8%至 38% (体积比))， 减压蒸除易挥发的组分后冻干得到目标化合物的盐酸盐 （72.7 毫克， 收率 68.5%) Dissolved in the ice bath with the compound 4-[[6-amino-5-[1 -(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazole- To a solution of 4-yl]piperidine-1-carboxylic acid tert-butyl ester (130 mg, 0.236 mmol) in dichloromethane (20 mL) was added EtOAc (EtOAc m. After the addition was completed, the mixture was stirred at room temperature for one hour. The crude product obtained by concentration of the reaction liquid was separated by high performance liquid chromatography on a C18 reverse phase column (mobile phase: acetonitrile/water/0.5% HC1, gradient elution 8% to 38% (by volume)), the volatile component was distilled off under reduced pressure and lyophilized to give the title compound hydrochloride (72.7 mg, yield 68.5%)
光谱数据： Spectral data:
LC/MS (方法： UFLC): RT = 2.74 分钟； m/z = 450.3 [M+H]+. 总的运行时间为 7.00 分钟. 'HNMR (400 MHz, D20) δ 7.68 (s, 1H), 7.60 (s, 1H), 7.57 (d,J=2.0 Hz, 1H)， 7.31 (dd,J=5.2, 9.2 Hz, 1H), 7.14 (d，J= 2.0 Hz, 1H), 7.07 (t,J=8.8Hz, 1H), 6.18 (q,J= 6.4 Hz, 1H), 3.40-3.37 (m， 2H), 3.07-3.00 (m, 2H), 2.89-2.81 (m， 1H), 2.11-2.08 (m， 2H), 1.78 (d, J =6.4 Hz, 3H), 1.75 - 1.63 (m, 2H)。 实施例 11 和实施例 12 LC/MS (method: UFLC): RT = 2.74 min; m/z = 450.3 [M+H] + . The total run time is 7.00 min. 'HNMR (400 MHz, D 2 0) δ 7.68 (s, 1H ), 7.60 (s, 1H), 7.57 (d, J=2.0 Hz, 1H), 7.31 (dd, J=5.2, 9.2 Hz, 1H), 7.14 (d, J= 2.0 Hz, 1H), 7.07 (t , J=8.8Hz, 1H), 6.18 (q, J= 6.4 Hz, 1H), 3.40-3.37 (m, 2H), 3.07-3.00 (m, 2H), 2.89-2.81 (m, 1H), 2.11- 2.08 (m, 2H), 1.78 (d, J = 6.4 Hz, 3H), 1.75 - 1.63 (m, 2H). Example 11 and Example 12
Figure imgf000027_0001
Figure imgf000027_0001
3-[(lR)- 1-(2,6-二氯 -3-氟-苯基)乙氧基 ]-5-[4-(4-哌啶基) P比唑 - 基 3-[(lR)- 1-(2,6-Dichloro-3-fluoro-phenyl)ethoxy]-5-[4-(4-piperidinyl)P-pyrazole-yl
吡啶基 -2-胺  Pyridyl-2-amine
Figure imgf000027_0002
Figure imgf000027_0002
3-[(lS)-l-(2,6-二氯 -3-氟-苯基)乙氧基 ]-5-[4-(4-哌啶基) P比唑 -1-基] 3-[(lS)-l-(2,6-Dichloro-3-fluoro-phenyl)ethoxy]-5-[4-(4-piperidinyl)P-pyrazole-1-yl]
吡啶基 -2-胺 操作步骤：  Pyridyl-2-amine Procedure:
将化合物 3-[ (2,6-二氯- 3-氟-苯基)乙氧基 ]-5-[4-(4-哌啶基)吡唑小基]吡啶基 -2-胺 （ 32毫克， 0.071 毫摩尔）进行手性 SFC 分离得到目标化合物 3-[(lR)-l-(2,6-二氯 -3-氟-苯基）乙氧 基]— 5-[4-(4-哌啶基)吡唑- 基] (实施例 11, 10 毫克） 和 3-[(lS)-l-(2，6-二氯 -3-氟-苯基)乙氧 基 ]— 5 [4-(4-哌啶基) P比唑 -1-基]吡啶基 -2-胺 （实施例 12， 9毫克）。 The compound 3-[(2,6-dichloro-3-fluoro-phenyl)ethoxy]-5-[4-(4-piperidinyl)pyrazole small group]pyridin-2-amine (32 The target compound 3-[(lR)-l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-5-[4-(4) was isolated by chiral SFC. -piperidinyl)pyrazole-yl] (Example 11, 10 mg) and 3-[(lS)-l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]- 5 [ 4-(4-piperidinyl)P-pyrazol-1-yl]pyridin-2-amine (Example 12, 9 mg).
实施例 13
Figure imgf000028_0001
Example 13
Figure imgf000028_0001
3-[l-(2，6-二氯 -3-氟-苯基)乙氧基 ]-5-[l-(l-甲基磺酰基- 4-哌啶基) P比唑 -4-基] 吡啶 -2-胺 3-[l-(2,6-Dichloro-3-fluoro-phenyl)ethoxy]-5-[l-(l-methylsulfonyl-4-piperidinyl)P-pyrazole-4- Pyridin-2-amine
操作步骤： Steps:
将化合物甲磺酰氯（3毫克， 0.026毫摩尔， 1.2当量）加入到化合物 3-[1-(2，6 -二氯 -3-氟-苯基) 乙氧基 ]-5-[1-(4 -哌啶基)吡唑 -4 -基]吡啶- 2-胺 （10 毫克， 0.022毫摩尔， 1.0当量） 和二异丙基 乙胺 （5.67毫克， 0.044毫摩尔， 2.0当量） 的 1毫升的二氯甲烷的溶液中， 反应在室温搅拌 1个小时后旋干过柱纯化 （石油醚： 乙酸乙酯 =1 :1 ) 得到目标化合物 （2.5毫克）。 The compound methanesulfonyl chloride (3 mg, 0.026 mmol, 1.2 eq.) was added to the compound 3-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-5-[1-( 4 -piperidinyl)pyrazole-4-yl]pyridine-2-amine (10 mg, 0.022 mmol, 1.0 eq.) and 1 ml of diisopropylethylamine (5.67 mg, 0.044 mmol, 2.0 eq.) The solution was stirred at room temperature for 1 hour and then purified by EtOAc (EtOAc:EtOAc)
光谱数据： Spectral data:
LC/MS (方法： UFLC): RT = 1.135分钟； m/z = 528.0 [M+H]+; 总的运行时间为 2.00 分钟。 Ή NM (400MHz, CD3OD): δ 8.00 (s, 1H)， 7.67 (s， 1H), 7.63 (s， 1H)， 7.55 (dd, J = 4.8， 8.8 Hz, 1H), 7.33 (t, J = 8.4 Hz, 1H)， 7.20 (s, 1H), 6.45 (q， J = 6.4 Hz, 1H)， 4.40-4.34 (m, 1H), 3.89-3.86 (m, 2H), 3.04-2.97 (m, 2H), 2.90 (s, 3H), 2.24-2.10 (m, 2H)， 2.00 - 2.30 (m, 2H), 1.95 (d， J = 6.4 Hz, 3H). 实施例 14
Figure imgf000028_0002
LC/MS (method: UFLC): RT = 1.135 min; m/z = 528.0 [M+H]+; The total run time was 2.00 min. Ή NM (400MHz, CD 3 OD): δ 8.00 (s, 1H), 7.67 (s, 1H), 7.63 (s, 1H), 7.55 (dd, J = 4.8, 8.8 Hz, 1H), 7.33 (t, J = 8.4 Hz, 1H), 7.20 (s, 1H), 6.45 (q, J = 6.4 Hz, 1H), 4.40-4.34 (m, 1H), 3.89-3.86 (m, 2H), 3.04-2.97 (m , 2H), 2.90 (s, 3H), 2.24-2.10 (m, 2H), 2.00 - 2.30 (m, 2H), 1.95 (d, J = 6.4 Hz, 3H). Example 14
Figure imgf000028_0002
3-[l-(2,6-二氯 -3-氟-苯基)乙氧基 ]-5-[l-(l-乙烯磺酰基 -4-哌啶基） 3-[l-(2,6-Dichloro-3-fluoro-phenyl)ethoxy]-5-[l-(l-vinylsulfonyl-4-piperidinyl)
吡唑 -4-基]吡啶 -2-胺  Pyrazole-4-yl]pyridine-2-amine
操作步骤： Steps:
将 3-[1-(2,6 -二氯 -3-氟-苯基)乙氧基 ]-5-[1-(4 -哌啶基)吡唑 -4 -基] P比啶 -2-胺 （23毫克， 0.05毫摩 尔， 1当量)， Ν,Ν'-二异丙基乙胺 (14毫克， 0.11毫摩尔，2.2当量)和 4-二甲氨基吡啶 (催化量) 溶于 5毫升二氯甲烷。然后搅拌、冰浴和氮气保护下将乙烯基磺酰氯 (7毫克， 0.06毫摩尔， 1.1 当量)逐滴加入。 得到反应液在室温下继续搅拌 15 小时。 反应结束后， 将反应液用二氯甲垸 稀释， 有机层用碳酸氢钠溶液和食盐水各反洗一次， 再用硫酸钠干燥后旋干， 得到的粗品采 用高效液相色谱在 C18反相柱上分离 (流动相： 乙腈 /水 /0.5%盐酸，梯度洗脱 25%至 55% (体积 比；))， 减压蒸除易挥发的组分后冻干得到目标化合物盐酸盐 (7毫克， 产率为 26%)。 光谱数据： 3-[1-(2,6-Dichloro-3-fluoro-phenyl)ethoxy]-5-[1-(4-piperidyl)pyrazole-4-yl]P-pyridin-2 -amine (23 mg, 0.05 mmol, 1 equivalent), hydrazine, Ν'-diisopropylethylamine (14 mg, 0.11 mmol, 2.2 eq.) and 4-dimethylaminopyridine (catalytic amount) dissolved in 5 Milliliter of dichloromethane. Vinylsulfonyl chloride (7 mg, 0.06 mmol, 1.1 eq.) was then added dropwise with stirring, ice bath and nitrogen. The reaction solution was stirred at room temperature for further 15 hours. After the reaction was completed, the reaction solution was diluted with dichloromethane, and the organic layer was back-washed once with sodium hydrogen carbonate solution and brine, dried over sodium sulfate and then evaporated to dryness. Separation (mobile phase: acetonitrile / water / 0.5% hydrochloric acid, gradient elution 25% to 55% (volume The target compound hydrochloride (7 mg, yield 26%) was obtained by evaporation of the volatile component under reduced pressure. Spectral data:
LC/MS (方法： UFLC): RT = 3.87 分钟； m/z = 540.1 [M+H]+; 总的运行时间为 7.00分钟。 实施例 15
Figure imgf000029_0001
LC/MS (method: UFLC): RT = 3.87 min; m/z = 540.1 [M+H] + ; Example 15
Figure imgf000029_0001
1— [4— [4— [6—氨基—5— [1— (2,6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基]吡唑 -1-基]  1-[4-[4-[6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazol-1-yl]
-1-哌啶基]丙 -2-烯小酮  -1-piperidinyl]prop-2-enionone
操作步骤： Steps:
将 3- [1-(2，6 -二氯 -3-氟-苯基)乙氧基 ]-5-[1-(4 -哌啶基)吡唑 -4 -基]吡啶 -2-胺 （50毫克， 0.11毫摩 尔， 1当量)， Ν,Ν'-二异丙基乙胺 (28.7毫克， 0.22毫摩尔， 2当量)溶于 1毫升二氯甲垸。然后搅 拌、 冰浴和氮气保护下将化合物丙 -2-烯酰基氯 （11毫克，0.12毫摩尔， 1.1当量)逐滴加入。 得 到反应液在室温下继续搅拌 10分钟。 反应结束后， 将反应液用二氯甲垸稀释， 有机层用碳酸 氢钠溶液和食盐水各反洗一次，再用硫酸钠干燥后旋干，得到的粗品采用高效液相色谱在 C18 反相柱上分离 (流动相： 乙腈 /水 /0.5%碳酸氢氨， 梯度洗脱 36%至 66% (体积比; ))， 减压蒸除易 挥发的组分后冻干得到目标化合物（6毫克， 产率为 10.7%)。 3-[1-(2,6-Dichloro-3-fluoro-phenyl)ethoxy]-5-[1-(4-piperidinyl)pyrazole-4-yl]pyridin-2-amine (50 mg, 0.11 mmol, 1 eq.), hydrazine, Ν'-diisopropylethylamine (28.7 mg, 0.22 mmol, 2 eq.) was dissolved in 1 ml of dichloromethane. The compound propyl-2-enoyl chloride (11 mg, 0.12 mmol, 1.1 eq.) was then added dropwise with stirring, ice bath and nitrogen. The reaction solution was stirred at room temperature for further 10 minutes. After the reaction was completed, the reaction solution was diluted with dichloromethane, and the organic layer was back-washed once with sodium hydrogen carbonate solution and brine, dried over sodium sulfate and then dried. The obtained crude product was subjected to high performance liquid chromatography on C18 reversed phase column. Separation (mobile phase: acetonitrile/water/0.5% ammonium bicarbonate, gradient elution 36% to 66% (volume ratio; )), evaporation of the volatile components under reduced pressure, and lyophilization to give the target compound (6 mg, The yield was 10.7%).
光谱数据： Spectral data:
LC/MS (方法： UFLC): RT=3.66 分钟； m/z=503.1 [M+H]+; 总的运行时间为 7.00分钟. LC/MS (method: UFLC): RT = 3.66 min; m/z = 503.1 [M+H] + ;
1H NMR (400 MHz, CD3OD) δ 7.88 (s, 1H), 7.64 (s, 1H)， 7.55 (s, 1H), 7.45 (dd, dd, J= 4.8, 8.8 Hz: 1H)， 7.23 (t， J = 8.8 Hz, 1H)， 6.93 (s， 1H)， 6.82 (dd, J = 10.8, 16.8 Hz, 1 H)， 6.13-6.26 (m, 2H), 5.76 (dd, J = 1.6, 10.8 Hz, 1 H)， 4.75-4.46 (m, 3H), 4.30-4.20 (m, 1H)， 2.98-2.86 (m, 1H), 2.25-2.15 (m， 2H)， 2.10-1.90 (m, 2H)， 1.87 (d, J = 6.8 Hz, 3 H). 1H NMR (400 MHz, CD 3 OD) δ 7.88 (s, 1H), 7.64 (s, 1H), 7.55 (s, 1H), 7.45 (dd, dd, J= 4.8, 8.8 Hz: 1H), 7.23 ( t, J = 8.8 Hz, 1H), 6.93 (s, 1H), 6.82 (dd, J = 10.8, 16.8 Hz, 1 H), 6.13-6.26 (m, 2H), 5.76 (dd, J = 1.6, 10.8 Hz, 1 H), 4.75-4.46 (m, 3H), 4.30-4.20 (m, 1H), 2.98-2.86 (m, 1H), 2.25-2.15 (m, 2H), 2.10-1.90 (m, 2H) , 1.87 (d, J = 6.8 Hz, 3 H).
Figure imgf000029_0002
l-[4-[4-[6-氨基 -5-[ l - (2,6-二氯 -3-氟-苯基)乙氧基 ]- 3-吡啶基] P比唑 -1-基
Figure imgf000029_0002
1-[4-[4-[6-Amino-5-[l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]P-pyrazol-1-yl
-1 -哌啶基 ]-2-羟基 -乙酮 操作步骤： -1 -piperidinyl]-2-hydroxy-ethanone Steps:
将 3-[1-(2，6-二氯 -3-氟-苯基)乙氧基 ]-5-[1-(4-哌啶基)吡唑 -4-基]吡啶 -2-胺 (20.1毫克， 0.04毫摩 尔， 1.0当量)， 2-羟基乙酸 （28.5毫克， 0.38毫摩尔， 8.5当量） 和 N, N， N，， N，-四甲基 -0-(7- 氮杂苯并三唑 -1-基)六氟磷酸脲 （53.5毫克， 0.14毫摩尔， 3.1当量） 溶于 10毫升二氯甲垸。 然后搅拌、 冰浴和氮气保护下将 N，N-二异丙基乙胺 (74毫克， 0.57毫摩尔， 12.8当量)逐滴加 入。 得到反应液在室温下继续搅拌 10分钟。 反应结束后， 将反应液用二氯甲烷稀释， 有机层 用碳酸氢钠溶液和食盐水各反洗一次， 再用硫酸钠干燥后旋干， 得到的粗品采用高效液相色 谱在 C18反相柱上分离 (柱子： synergi-150*30mm*5u, 流动相： A为盐酸水溶液， B为乙腈， 洗 脱梯度： B， 17-47%, 流速： 30 mL /分钟， 检测器： UV Detector 220nm)， 减压蒸除易挥发的组分 后冻干得到目标化合物盐酸盐 （9.3 毫克， 产率为 40.9%)。 3-[1-(2,6-Dichloro-3-fluoro-phenyl)ethoxy]-5-[1-(4-piperidinyl)pyrazol-4-yl]pyridin-2-amine (20.1 mg, 0.04 mmol, 1.0 eq.), 2-hydroxyacetic acid (28.5 mg, 0.38 mmol, 8.5 eq.) and N, N, N, N,-tetramethyl- 0-(7-azabenzene And triazol-1-yl) hexafluorophosphate (53.5 mg, 0.14 mmol, 3.1 equivalent) was dissolved in 10 ml of dichloromethane. Then, N,N-diisopropylethylamine (74 mg, 0.57 mmol, 12.8 equivalent) was added dropwise with stirring, ice bath and nitrogen. The reaction solution was stirred at room temperature for further 10 minutes. After the reaction was completed, the reaction mixture was diluted with methylene chloride. The organic layer was washed once with sodium bicarbonate solution and brine, dried over sodium sulfate and then evaporated to dryness. Separation (column: synergi-150*30mm*5u, mobile phase: A is aqueous hydrochloric acid, B is acetonitrile, elution gradient: B, 17-47%, flow rate: 30 mL / min, detector: UV Detector 220 nm), The volatile component was evaporated under reduced pressure and lyophilized to give the title compound hydrochloride (9.3 mg, yield 40.9%).
光谱数据： Spectral data:
LC/MS (方法： UFLC): RT = 3.240 分钟； m/z = 508.2 [M+H]+; 总的运行时间为 7.00 分钟。 Ή NMR (400MHz, DMSO- 6): δ 8.06 (s, 1H), 7.78 (s, 1H)， 7.64-7.55 (m, 2H), 7.51-7.41 (m, 1H), 7.35 (s, 0.5H), 7.11 (s, 0.5H), 7.04 (s, 1H)， 6.19 (q, J = 6.4 Hz, 1H), 4.50-4.40 (m, 2H), 4.20-4.06 (m, 2H)， 3.85-3.75 (m, 1H)， 3.17-3.1 1 (m, 1H), 2.86-2.80 (m, 1H), 2.06-2.03 (m, 2H), 1.92― 1.89-1.73 (m, 5H)。 LC/MS (method: UFLC): RT = 3.240 min; m/z = 508.2 [M+H]+; The total run time was 7.00 min. NMR NMR (400MHz, DMSO- 6 ): δ 8.06 (s, 1H), 7.78 (s, 1H), 7.64-7.55 (m, 2H), 7.51-7.41 (m, 1H), 7.35 (s, 0.5H) , 7.11 (s, 0.5H), 7.04 (s, 1H), 6.19 (q, J = 6.4 Hz, 1H), 4.50-4.40 (m, 2H), 4.20-4.06 (m, 2H), 3.85-3.75 ( m, 1H), 3.17-3.1 1 (m, 1H), 2.86-2.80 (m, 1H), 2.06-2.03 (m, 2H), 1.92- 1.89-1.73 (m, 5H).
Figure imgf000030_0001
Figure imgf000030_0001
2-氨基- 1-[4-[4-[6-氨基 -5-[l-(2，6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基]吡唑- 基] 2-Amino- 1-[4-[4-[6-amino-5-[l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazole- Base
-1-哌啶基]乙酮  -1-piperidinyl]ethanone
操作步骤： Steps:
将化合物 3-[1-(2,6-二氯 -3-氟-苯基)乙氧基 ]-5-[1-(4-哌啶基)吡唑 -4-基] P比啶 -2-胺 (80毫克， 0.178 毫摩尔， 1当量)，2- (叔丁氧羰基氨基)乙酸 (34.2毫克， 0.196毫摩尔， 1.1当量)和 Ν,Ν,Ν',Ν'-四甲 基 -0-(7-氮杂苯并三唑 -1-基)六氟磷酸脲 （101毫克， 0.267毫摩尔， 1.5当量)溶于 2毫升二氯甲 垸。 然后搅拌、 冰浴和氮气保护下， 继续缓慢加入 Ν,Ν'-二异丙基乙胺 (115毫克， 0.89毫摩尔, 5当量)。 反应在室温下继续搅拌 1 小时。 反应结束后将反应液旋干， 置于盐酸 /二氧六环 （5 毫升） 中室温搅拌 3小时。 反应结束后， 将反应液旋干得到的粗品采用高效液相色谱在 C18 反相柱上分离 (流动相： 乙腈 /水 /0.5%碳酸氢氨， 梯度洗脱 36%室 66% (体积比))， 减压蒸除易 挥发的组分后冻干得到目标化合物 （10.1毫克， 总产率为 11.2%)。 The compound 3-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-5-[1-(4-piperidinyl)pyrazol-4-yl]P is pyridine- 2-Amine (80 mg, 0.178 mmol, 1 eq.), 2-(tert-butoxycarbonylamino)acetic acid (34.2 mg, 0.196 mmol, 1.1 eq.) and hydrazine, hydrazine, hydrazine, Ν'-tetramethyl -0-(7-Azabenzotriazol-1-yl) hexafluorophosphate (101 mg, 0.267 mmol, 1.5 eq.) was dissolved in 2 mL of dichloromethane. Then, stirring, ice bath and nitrogen protection were continued, and hydrazine, Ν'-diisopropylethylamine (115 mg, 0.89 mmol, 5 eq.) was slowly added. The reaction was stirred at room temperature for an additional 1 hour. After completion of the reaction, the reaction mixture was evaporated to dryness mjjjjjjjjjj After the reaction is completed, the crude liquid obtained by spinning the reaction solution is subjected to high performance liquid chromatography at C18. Separation on a reversed-phase column (mobile phase: acetonitrile/water/0.5% ammonium bicarbonate, gradient elution 36% chamber 66% (by volume)), evaporation of volatile components under reduced pressure, and lyophilization to obtain the target compound (10.1) Mg, the total yield was 11.2%).
光谱数据： Spectral data:
LC/MS (方法： UFLC): RT = 2.74 分钟； m/z = 506.1 [M+H]+. 总的运行时间为 7.00 分钟. Ή NMR (400 MHz, CD3OD) δ 8.00 (s, 1H), 7.70 (s， 1H)， 7.59 (s, 1H), 7.55 (dd, J = 4.8, 8.8 Hz, 1H), 7.29 (t， J = 8.8 Hz, 1 H)， 7.16 (s, 1 H)， 6.36 (q, J = 6.8 Hz, 1 H), 4.61-4.44 (m, 2H), 4.13-3.82 (m, 3H), 3.30-3.20 (m, 1H)， 3.02-2.89 (m, 1H), 2.22-2.10 (m, 2H), 2.10-1.87 (m， 5H). 实施例 18
Figure imgf000031_0001
LC/MS (method: UFLC): RT = 2.74 min; m/z = 506.1 [M+H] + . The total run time is 7.00 min. NMR NMR (400 MHz, CD 3 OD) δ 8.00 (s, 1H ), 7.70 (s, 1H), 7.59 (s, 1H), 7.55 (dd, J = 4.8, 8.8 Hz, 1H), 7.29 (t, J = 8.8 Hz, 1 H), 7.16 (s, 1 H) (6,6,6 = 6.8 Hz, 1 H), 2.22-2.10 (m, 2H), 2.10-1.87 (m, 5H). Example 18
Figure imgf000031_0001
2-[4-[4- [6-氨基 -5-[(lR)-l-(2,6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基] P比唑 -1-基] 2-[4-[4-[6-Amino-5-[(lR)-l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl] P-pyrazole -1-base]
-1-哌啶基] -N-甲基-乙酰胺  -1-piperidinyl]-N-methyl-acetamide
操作步骤： Steps:
将 440 毫克的化合物 2- [4-[4-[6-氨基 -5-[1 -(2,6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基]吡唑- 1-基] -1- 哌啶基] -N-甲基-乙酰胺 （见实施例 3 )，用 SFC手性分离得到的 2-[4-[4-[6-氨基 -5-[(lR)-l-(2，6- 二氯 -3-氟-苯基）乙氧基 ]-3-吡啶基]吡唑 -1 -基] -1 -哌啶基] -N-甲基-乙酰胺 (137.7 毫克， 收率 62.5%, 实施例 18). 440 mg of compound 2-[4-[4-[6-amino-5-[1 -(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazole 1- 1-[4-piperidinyl]-N-methyl-acetamide (see Example 3), 2-[4-[4-[6-amino-5-[ (lR)-l-(2,6-Dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazole-1-yl]-1 -piperidinyl]-N-methyl - acetamide (137.7 mg, yield 62.5%, Example 18).
光谱数据： Spectral data:
LC/MS (方法： UFLC): RT = 2.763分钟； m/z = 521.2 [M+H]+. 总的运行时间为 7.00 分钟. 1H NMR (400MHz, OMSO-d6): δ 7.95 (s, 1H), 7.70-7.80 (m, 2H)， 7.55 (m, 2H), 7.49 (t, J= 8.8 Hz, 1H), 6.90 (s, 1H), 6.10 (q, 6.36 (q, J = 6.8 Hz, 1H)， 5.65 (s, 2H), 4.15-4.07 (m, 1H), 3.10 (s, 2H), 2.95-2.80 (m， 2H), 2.60 (d, J = 6.4 Hz, 3H), 2.30-2.20 (m, 2H)， 2.00-2.10 (m, 4H), 1.75 (d，J = 6.8 Hz, 3H). 实施例 19 LC/MS (method: UFLC): RT = 2.763 min; m/z = 521.2 [M+H] + . The total run time is 7.00 min. 1H NMR (400 MHz, OMSO-d 6 ): δ 7.95 (s, 1H), 7.70-7.80 (m, 2H), 7.55 (m, 2H), 7.49 (t, J= 8.8 Hz, 1H), 6.90 (s, 1H), 6.10 (q, 6.36 (q, J = 6.8 Hz) , 1H), 5.65 (s, 2H), 4.15-4.07 (m, 1H), 3.10 (s, 2H), 2.95-2.80 (m, 2H), 2.60 (d, J = 6.4 Hz, 3H), 2.30- 2.20 (m, 2H), 2.00-2.10 (m, 4H), 1.75 (d, J = 6.8 Hz, 3H). Example 19
Figure imgf000031_0002
Figure imgf000031_0002
2-[4-[4-[6-氨基- 5-Π-(2，6-二氯 -3-氟-苯基)乙氧基 ]-3-P比啶基]吡唑小基] -1-哌啶基] -N-乙基-乙酰胺 2-[4-[4-[6-amino-5-indole-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-Ppyridinyl]pyrazole small group] -1-piperidinyl]-N-ethyl-acetamide
操作步骤： Steps:
将化合物 2-[4-[4-[6-氨基 -5-[1-(2,6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基基]吡唑 -1-基]小哌啶基] 乙酸 （37毫克， 0.073毫摩尔， 1当量)，乙胺盐酸盐（7毫克， 0.087毫摩尔， 1.2当量）和 Ν,Ν,Ν',Ν'- 四甲基 -0-(7-氮杂苯并三唑 -1-基)六氟磷酸脲（41毫克， 0.109毫摩尔， 1.5当量）溶于 2 毫升二 氯甲垸。 然后搅拌、 冰浴和氮气保护下， 继续缓慢加入 Ν,Ν'-二异丙基乙胺 (47毫克, 0.364毫 摩尔， 5当量)。 反应在室温下继续搅拌 2小时。 反应结束后， 将反应液用二氯甲垸稀释， 有机 层用碳酸氢钠溶液和食盐水各反洗一次，再用硫酸钠干燥后旋干，得到粗品采用 HPLC在 C18 反相柱上分离 (柱子： synergi-150*30mm*5u, 流动相: A为盐酸水溶液， B为乙腈， 洗脱梯度： B， 17-47%, 流速： 30 mL /分钟， 检测器: UV Detector 220nm)， 减压蒸除易挥发的组分后冻干得到 目标化合物盐酸盐 (3.3毫克， 产率为 8.6 %). The compound 2-[4-[4-[6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazole-1 -yl]piperidinyl]acetic acid (37 mg, 0.073 mmol, 1 eq.), ethylamine hydrochloride (7 mg, 0.087 mmol, 1.2 eq.) and hydrazine, hydrazine, Ν', Ν'- The base-0-(7-azabenzotriazol-1-yl)hexafluorophosphate (41 mg, 0.109 mmol, 1.5 eq.) was dissolved in 2 mL of dichloromethane. Then, stirring, ice bath and nitrogen protection were continued, and hydrazine, Ν'-diisopropylethylamine (47 mg, 0.364 mmol, 5 eq.) was slowly added. The reaction was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was diluted with dichloromethane, and the organic layer was washed once with sodium bicarbonate solution and brine, dried over sodium sulfate and then evaporated to give a crude product which was separated by HPLC on C18 reverse column (column) : synergi-150*30mm*5u, mobile phase: A is aqueous hydrochloric acid, B is acetonitrile, elution gradient: B, 17-47%, flow rate: 30 mL / min, detector: UV Detector 220nm), steam distillation The target compound hydrochloride (3.3 mg, yield 8.6%) was obtained after lyophilization with the volatile component.
光谱数据： Spectral data:
LC/MS (方法： UFLC): RT = 2.81 分钟； m/z = 534.1 [M+H]+; 总的运行时间为 7.00 分钟. Ή NMR (400 MHz, CD3OD) δ 7.98 (s, 1H), 7.71 (s, 1H), 7.64 (s, 1H), 7.56-7.49 (m, 1H), 7.31 (t， J = 8.4 Hz, 1H), 7.18 (s, 1H), 6.38 (q, J = 6.8 Hz, 1H), 4.69-4.64 (m, 1H), 4.06 (s, 2H), 3.80-3.70 (m, 2H), 3.63-3.52 (m, 2H), 3.33-3.30 (m, 2H), 2.48-2.38 (m, 4H), 1.97-1.93 (d, J = 6.4 Hz, 3H)， 1.19 (t, J = 7.2 Hz, 3H)。 LC/MS (method: UFLC): RT = 2.81 min; m/z = 534.1 [M+H]+; The total run time is 7.00 min. NMR NMR (400 MHz, CD 3 OD) δ 7.98 (s, 1H ), 7.71 (s, 1H), 7.64 (s, 1H), 7.56-7.49 (m, 1H), 7.31 (t, J = 8.4 Hz, 1H), 7.18 (s, 1H), 6.38 (q, J = 6.8 Hz, 1H), 4.69-4.64 (m, 1H), 4.06 (s, 2H), 3.80-3.70 (m, 2H), 3.63-3.52 (m, 2H), 3.33-3.30 (m, 2H), 2.48 -2.38 (m, 4H), 1.97-1.93 (d, J = 6.4 Hz, 3H), 1.19 (t, J = 7.2 Hz, 3H).
实施例 20
Figure imgf000032_0001
Example 20
Figure imgf000032_0001
2-[4-[4-[6-氨基 -5- [ (2，6-二氯 -3-氟-苯基)乙氧基 ]- 3-吡啶基]吡唑 -1-基]  2-[4-[4-[6-Amino-5-[(2,6-Dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazole-1-yl]
-1-哌啶基] -N-(2-羟基乙基)乙酰胺  -1-piperidinyl]-N-(2-hydroxyethyl)acetamide
操作步骤： Steps:
将化合物 2-[4-[4-[6-氨基 -5-[ 1 -(2，6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基]吡唑 -1 -基]- 1 -哌啶基]乙 酸 (37毫克， 0.073毫摩尔， 1当量)， 2-氨基乙醇（5毫克， 0.088毫摩尔， 1.2当量）和 Ν,Ν,Ν',Ν'- 四甲基 -0-(7-氮杂苯并三唑小基)六氟磷酸脲 （41毫克， 0.11毫摩尔， 1.5当量） 溶于 2毫升二 氯甲烷。 然后搅拌、 冰浴和氮气保护下， 继续缓慢加入 Ν,Ν'-二异丙基乙胺 （47毫克， 0.367 毫摩尔， 5当量）。 反应在室温下继续搅拌 2小时。 反应结束后， 将反应液用二氯甲垸稀释， 有机层用碳酸氢钠溶液和食盐水各反洗一次， 再用硫酸钠千燥后旋干， 得到的粗品采用高效 液相色谱在 C18反相柱上分离 (流动相： 乙腈 /水 /0.5%碳酸氢氨， 梯度洗脱 36%至 66% (体积 比; ))， 减压蒸除易挥发的组分后冻干得到目标化合物 （14毫克， 产率为 35%). The compound 2-[4-[4-[6-amino-5-[ 1 -(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazole-1 - ]]- 1 -piperidinyl]acetic acid (37 mg, 0.073 mmol, 1 eq.), 2-aminoethanol (5 mg, 0.088 mmol, 1.2 eq.) and hydrazine, hydrazine, hydrazine, Ν'- Base-0-(7-azabenzotriazole small) urea hexafluorophosphate (41 mg, 0.11 mmol, 1.5 eq.) was dissolved in dichloromethane (2 mL). Then, stirring, ice bath and nitrogen protection were continued, and hydrazine, Ν'-diisopropylethylamine (47 mg, 0.367 mmol, 5 eq.) was slowly added. The reaction was stirred at room temperature for 2 hours. After the reaction is completed, the reaction solution is diluted with dichloromethane, and the organic layer is backwashed once with sodium bicarbonate solution and brine, dried over sodium sulfate and then dried to give a crude product. Liquid chromatography was separated on a C18 reverse phase column (mobile phase: acetonitrile/water/0.5% ammonium bicarbonate, gradient elution 36% to 66% (volume ratio; )), and the volatile components were evaporated under reduced pressure. Dry to give the target compound (14 mg, yield 35%).
光谱数据： Spectral data:
LC/MS (方法： UFLC): RT = 2.62 分钟； m/z = 550.1 [M+H]+; 总的运行时间为为 7.00分钟. Ή NMR (400 MHz, METHANOL-^) δ 8.03 (s, 1H), 7.68 (s, 1H), 7.65 (s, 1H)， 7.51 (dd, J = 4.8, 8.8 Hz, 1H), 7.30 (t, J= 8.4 Hz, 1H), 7.17 (s, 1H)， 6.37 (q, J = 6.4 Hz, 1H), 4.63 (br. s.， 1H)， 4.02 (s, 2H), 3.79-3.72 (m, 2H), 3.65 (t，J= 6.4 Hz, 3H), 3.45-3.33 (m, 4H)， 2.50-2.30 (m, 4H), 1.95 (d, J = 6.4 Hz, 3H). 实施例 21 LC/MS (method: UFLC): RT = 2.62 min; m/z = 550.1 [M+H] + ; s s s s s s s s s s s s s s s s s s s s s s s s 1H), 7.68 (s, 1H), 7.65 (s, 1H), 7.51 (dd, J = 4.8, 8.8 Hz, 1H), 7.30 (t, J= 8.4 Hz, 1H), 7.17 (s, 1H), 6.37 (q, J = 6.4 Hz, 1H), 4.63 (br. s., 1H), 4.02 (s, 2H), 3.79-3.72 (m, 2H), 3.65 (t, J = 6.4 Hz, 3H), 3.45-3.33 (m, 4H), 2.50-2.30 (m, 4H), 1.95 (d, J = 6.4 Hz, 3H). Example 21
Figure imgf000033_0001
Figure imgf000033_0001
2-[4-[4-[6-氨基 -5-[(-l-(2，6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基] P比唑 -1-基] 2-[4-[4-[6-Amino-5-[(-l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]P-pyrazole-1 -base]
-1-哌啶基] -N-异丙基-乙酰胺  -1-piperidinyl]-N-isopropyl-acetamide
操作步骤： Steps:
将 2-[4-[4-[6-氨基 -5-[1-(2，6-二氯 -3-氟-苯基）乙氧基 ]-3-吡啶基基]吡唑 -1-基] -1-哌啶基]乙酸 (40 毫克， 0.073毫摩尔， 1当量.)， 丙垸 -2-胺 （9毫克， 0.147毫摩尔， 2当量） 和 Ν,Ν,Ν',Ν'- 四甲基 -0-(7-氮杂苯并三唑 -1-基)六氟磷酸脲 （42毫克， 0.11毫摩尔，1.5当量)溶于 2毫升二氯 甲垸。 然后搅拌、 冰浴和氮气保护下， 继续缓慢加入 Ν,Ν'-二异丙基乙胺（47毫克， 0.364毫 摩尔， 5当量)逐滴加入。 得到反应液在室温下继续搅拌 1小时。 反应结束后， 将反应液用二氯 甲烷稀释， 有机层用碳酸氢钠溶液和食盐水各反洗一次， 再用硫酸钠干燥后旋干， 得到的粗 品采用高效液相色谱在 C18反相柱上分离 (流动相：乙腈 /水 /0.5%盐酸，梯度洗脱 36%至 66% (体 积比; ))， 减压蒸除易挥发的组分后冻干得到目标化合物 （31毫克， 产率为 72.6%)。 2-[4-[4-[6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazole-1- ]]-1-piperidinyl]acetic acid (40 mg, 0.073 mmol, 1 eq.), propidin-2-amine (9 mg, 0.147 mmol, 2 eq.) and hydrazine, hydrazine, hydrazine Tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate (42 mg, 0.11 mmol, 1.5 eq.) was dissolved in 2 mL of dichloromethane. Then, stirring, ice bath and nitrogen protection were continued, and hydrazine was added slowly, and Ν'-diisopropylethylamine (47 mg, 0.364 mmol, 5 eq.) was added dropwise. The reaction solution was stirred at room temperature for further 1 hour. After the reaction was completed, the reaction mixture was diluted with methylene chloride. The organic layer was washed once with sodium bicarbonate solution and brine, dried over sodium sulfate and then evaporated to dryness. Separation (mobile phase: acetonitrile / water / 0.5% hydrochloric acid, gradient elution 36% to 66% (by volume; )), the volatile component was evaporated under reduced pressure and lyophilized to give the title compound (31 mg, yield 72.6%).
光谱数据： Spectral data:
LC/MS (方法： UFLC): RT = 2.81 分钟； m/z = 549.3 [M+H]+ ; 总的运行时间为 7.00 分钟. Ή NMR (400 MHz, METHANOL-^) δ 8.04 (s, 1H)， 7.70 (s, 1H), 7.67 (s， 1H), 7.60-7.52 (m, 1H), 7.31 (t, J= 8.4 Hz, 1H), 7.19 (s, 1H), 6.38 (q, J= 6.4 Hz, 1H), 4.65 (br. s., 1 H)， 4.12-3.92 (m, 3H), 3.83-3.78 (m, 1H), 3.66-3.51 (m, 1H), 3.42-3.38 (m, 1H), 2.39-2.31 (m, 4H), 1.97 (d, J = 6.0 Hz, 3H), 1.21 (d, J= 6.4 Hz, 6H). 实施例 22 LC/MS (method: UFLC): RT = 2.81 min; m/z = 549.3 [M+H] + ; </ RTI>< / RTI> NMR (400 MHz, METHANOL-^) δ 8.04 (s, 1H ), 7.70 (s, 1H), 7.67 (s, 1H), 7.60-7.52 (m, 1H), 7.31 (t, J= 8.4 Hz, 1H), 7.19 (s, 1H), 6.38 (q, J= 6.4 Hz, 1H), 4.65 (br. s., 1 H), 4.12-3.92 (m, 3H), 3.83-3.78 (m, 1H), 3.66-3.51 (m, 1H), 3.42-3.38 (m, 1H), 2.39-2.31 (m, 4H), 1.97 (d, J = 6.0 Hz, 3H), 1.21 (d, J = 6.4 Hz, 6H). Example 22
Figure imgf000034_0001
Figure imgf000034_0001
2—[4-[4-[6-氨基 -5- [ (2,6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基] P比唑 -1-基] 2-[4-[4-[6-Amino-5-[(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]P-pyrazole-1-yl]
-1-哌啶基] -N,2-二甲基-丙酰胺  -1-piperidinyl]-N,2-dimethyl-propionamide
操作步骤： Steps:
将化合物 3-[1-(2，6-二氯 -3-氟-苯基)乙氧基 ]-5-[1-(4 -哌啶基)吡唑 -4-基] P比啶 -2-胺 (41 毫克， 0.09 毫摩尔， 1当量)， 2-溴 -N,2-二甲基-丙酰胺 (0.019 毫克， 0.11 毫摩尔， 1.2当量)、 氢氧化钠 (2.5 毫升， 50%水溶液） 和四丁基碘化钹 (0.029 毫克， 0.12 毫摩尔， 1.3当量)溶于 2.5毫升二氯甲 烷。 然后将反应液在室温下剧烈搅拌反应 20小时。 结束反应后， 将反应分层， 水层用二氯甲 烷 （加入 10%甲醇） 萃取三次。 合并有机层用食盐水反洗一次， 再用硫酸钠干燥后旋干， 得 到的粗品采用高效液相色谱在 RP18反相柱上分离 (柱子：synergi-150*30mm*5u， 流动相 : A为 0.05%HC1水溶液， 流动相 B为乙腈， 洗脱梯度： B 6-36%， 流速： 30 mL /分钟， 检测器： UV Detector 220nm), 减压蒸除易挥发的组分后， 剩余水相用饱和碳酸氢钠溶液中和， 然后用 二氯甲垸萃取， 再用硫酸钠干燥后冻干得到目标化合物 (10毫克， 产率为 20%)。 The compound 3-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-5-[1-(4-piperidyl)pyrazol-4-yl]P is pyridine- 2-Amine (41 mg, 0.09 mmol, 1 eq.), 2-bromo-N,2-dimethyl-propionamide (0.019 mg, 0.11 mmol, 1.2 eq.), sodium hydroxide (2.5 mL, 50%) Aqueous solution) and tetrabutylphosphonium iodide (0.029 mg, 0.12 mmol, 1.3 eq.) were dissolved in 2.5 mL dichloromethane. The reaction solution was then vigorously stirred at room temperature for 20 hours. After the reaction was completed, the reaction was separated and the aqueous layer was extracted three times with dichloromethane (with 10% methanol). The combined organic layers were backwashed once with saline solution, dried over sodium sulfate and then spun dry. The obtained crude product was separated by high performance liquid chromatography on RP18 reverse phase column (column: synergi-150*30mm*5u, mobile phase: A 0.05% HCl aqueous solution, mobile phase B is acetonitrile, elution gradient: B 6-36%, flow rate: 30 mL / min, detector: UV Detector 220 nm), after evaporation of volatile components under reduced pressure, residual aqueous phase It was neutralized with a saturated sodium hydrogencarbonate solution, and then extracted with dichloromethane, dried over sodium sulfate and lyophilized to give the title compound (10 mg, yield 20%).
光谱数据： Spectral data:
LC/MS (方法： UFLC): RT = 2.847 分钟； m/z = 275.1 [M/2+H]+ ;总的运行时间为为 7.00 分钟. Ή NMR (400MHz, METHANOL-d4) δ 8.05 (br. s., 1H), 7.76-7.60 (m, 2H), 7.54 (br. s.， 1H), 7.32 (t, J= 8.0 Hz, 1H), 7.19 (s, 1H), 6.39 (d, J = 6.0 Hz, 1H), 4.66 (br. s" 1H), 3.58 (br. s" 2H), 2.99- 2.77 (m, 5H), 2.63-2.33 (m, 4H)， 1.97 (d， J = 5.8 Hz, 3H), 1.78-1.56 (m, 6H), 1.45-1.22 (m, 1H). 实施例 23 LC/MS (method: UFLC): RT = 2.847 min; m/z = 275.1 [M / 2+H] + ; the total run time is 7.00 min. NMR (400 MHz, METHANOL-d 4 ) δ 8.05 ( Br. s., 1H), 7.76-7.60 (m, 2H), 7.54 (br. s., 1H), 7.32 (t, J= 8.0 Hz, 1H), 7.19 (s, 1H), 6.39 (d, J = 6.0 Hz, 1H), 4.66 (br. s" 1H), 3.58 (br. s" 2H), 2.99- 2.77 (m, 5H), 2.63-2.33 (m, 4H), 1.97 (d, J = 5.8 Hz, 3H), 1.78-1.56 (m, 6H), 1.45-1.22 (m, 1H). Example 23
Figure imgf000034_0002
Figure imgf000034_0002
2-[4-[4-[6-氨基 -5-[(lR)-卜 (2,6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基] P比唑 -1-基] 2-[4-[4-[6-Amino-5-[(lR)-bu(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]P-pyrazole- 1-base]
-1-哌啶基] -N,2-二甲基-丙酰胺  -1-piperidinyl]-N,2-dimethyl-propionamide
操作步骤： Steps:
将 2-[4-[4-[6-氨基 -5- [ (2,6-二氯 -3-氟-苯基）乙氧基 ]-3-吡啶基]吡唑 -1 -基]小哌啶基] -N,2-二甲 基-丙酰胺 （实施例 23， 49 毫克， 0.041毫摩尔， 1当量)用 SFC手性分离， 分离后的组分旋干 得到化合物 2-[4-[4-[6-氨基 -5-[(lR)-l-(2，6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基]吡唑- 基] -1-哌 啶基] -N,2-二甲基-丙酰胺 （5.1 毫克)。 2- [4-[4-[6-Amino-5-[(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazole-1-yl] Piperidinyl]-N,2-dimethyl The base-propionamide (Example 23, 49 mg, 0.041 mmol, 1 equivalent) was isolated by SFC chiral separation, and the separated fractions were dried to give compound 2-[4-[4-[6-amino-5-[ (lR)-l-(2,6-Dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazole-yl]-1-piperidinyl]-N,2-dimethyl Base-propionamide (5.1 mg).
实施例 25的光谱数据： Spectral data of Example 25:
LC/MS (方法： UFLC): RT = 2.810 分钟； m/z = 275.1 [M/2+H]+; 总的运行时间为 7.00 分钟. 1H NMR (400MHz, METHANOL-^) δ 7.83 (s， 1H), 7.68 (s， 1H), 7.57 (s, 1H), 7.49 (dd, J= 4.8, 8.8 Hz, 1H), 7.26 (t，J= 8.4 Hz, 1H), 6.95 (s, 1H), 6.24 (q, J= 6.8 Hz, 1H), 4.19-4.11 (m, 1H), 2.94-2.91 (m, 2H), 2.79 (s， 3H), 2.46-2.34 (m， 2H), 2.34-2.09 (m， 4H), 1.92 (d， J= 6.8 Hz, 3H), 1.19 (s, 6H). 实施例 24  LC/MS (method: UFLC): RT = 2.810 min; m/z = 275.1 [M/2+H]+; total run time is 7.00 min. 1H NMR (400 MHz, METHANOL-^) δ 7.83 (s, 1H), 7.68 (s, 1H), 7.57 (s, 1H), 7.49 (dd, J= 4.8, 8.8 Hz, 1H), 7.26 (t, J= 8.4 Hz, 1H), 6.95 (s, 1H), 6.24 (q, J= 6.8 Hz, 1H), 4.19-4.11 (m, 1H), 2.94-2.91 (m, 2H), 2.79 (s, 3H), 2.46-2.34 (m, 2H), 2.34-2.09 ( m, 4H), 1.92 (d, J = 6.8 Hz, 3H), 1.19 (s, 6H). Example 24
Figure imgf000035_0001
Figure imgf000035_0001
3-[4-[4-[6-氨基 -5-[(lR)-l-(2,6-二氯- 3-氟-苯基)乙氧基 ]-3-吡啶基]吡唑 -1-基] 3-[4-[4-[6-Amino-5-[(lR)-l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazole- 1-base]
-1-哌啶基 ]-1,1,1-三氟-丙 -2-酮 操作步骤：  -1-piperidinyl-1,1,1-trifluoro-propan-2-one Procedure:
目标化合物根据实施例 2的方法由 3-[1-(2,6-二氯 -3-氟-苯基)乙氧基 ]-5-[1-(4-吡啶基） 吡唑 -4- 基] 哌啶基 -2-胺为原料制备。 然后用 SFC 手性分离得到目标化合物 3-[4-[4-[6-氨基 -5-[(lR)- (2,6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基]吡唑 -1-基] -1-哌啶基 ]- 1,1，1-三氟-丙 -2-酮 光谱数据： The title compound was obtained according to the method of Example 2 from 3-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-5-[1-(4-pyridyl)pyrazole-4- The base piperidinyl-2-amine is prepared as a starting material. The title compound 3-[4-[4-[6-amino-5-[(lR)-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3 was obtained by chiral separation with SFC. -pyridyl]pyrazol-1-yl]-1-piperidinyl]- 1,1,1-trifluoro-propan-2-one spectral data:
LC/MS (方法： UFLC): m/z = 560 [M+H]+. 实施例 25 LC/MS (method: UFLC): m/z = 560 [M+H] + .
Figure imgf000035_0002
Figure imgf000035_0002
2-[4-[4-[6-氨基 -5- [ (2，6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基]吡唑 - 基  2-[4-[4-[6-Amino-5-[(2,6-Dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazole-yl
-1-哌啶基] -Ν-ί2-氯乙基)乙酰胺 操作步骤： -1-piperidinyl]-Ν-ί2-chloroethyl)acetamide Steps:
将 2-[4-[4-[6-氨基 -5-[1-(2,6-二氯 -3-氟-苯基)乙氧基 ]-3-P比啶基]吡唑 -1-基] -1-哌啶基]乙酸 （40 毫克， 0.073毫摩尔， 1当量)， 2-氯乙胺盐酸盐 (17毫克， 0.147毫摩尔， 2当量） 和 Ν,Ν,Ν',Ν'- 四甲基 -0-(7-氮杂苯并三唑 -1-基)六氟磷酸脲 （42毫克， 0.11毫摩尔， 1.5当量)溶于 2毫升二氯 甲垸。 然后搅拌、 冰浴和氮气保护下， 继续缓慢加入 Ν,Ν'-二异丙基乙胺（47毫克， 0.368毫 摩尔， 5当量)逐滴加入。得到反应液在室温下继续搅拌 1小时。 反应结束后， 将反应液用二氯 甲垸稀释， 有机层用碳酸氢钠溶液和食盐水各反洗一次， 再用硫酸钠千燥后旋干， 得到的粗 品采用高效液相色谱在 C18反相柱上分离 (流动相：乙腈 /水 /0.5%盐酸,梯度洗脱 36%至 66% (体 积比 ))， 减压蒸除易挥发的组分后冻干得到目标化合物盐酸盐（17毫克， 产率为 40.9%). 2-[4-[4-[6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-Ppyridyl]pyrazole-1 -yl]-1-piperidinyl]acetic acid (40 mg, 0.073 mmol, 1 eq.), 2-chloroethylamine hydrochloride (17 mg, 0.147 mmol, 2 eq.) Ν'-Tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate (42 mg, 0.11 mmol, 1.5 eq.) was dissolved in 2 mL of dichloromethane. Then, stirring, ice bath and nitrogen protection were continued, and hydrazine was added slowly, and Ν'-diisopropylethylamine (47 mg, 0.368 mmol, 5 eq.) was added dropwise. The reaction solution was stirred at room temperature for further 1 hour. After the reaction, the reaction solution was diluted with dichloromethane, and the organic layer was back-washed once with sodium bicarbonate solution and brine, dried over sodium sulfate and then dried, and the crude product was purified by high-performance liquid chromatography in C18. Separation on the column (mobile phase: acetonitrile/water/0.5% hydrochloric acid, gradient elution 36% to 66% by volume), evaporation of the volatile components under reduced pressure, and lyophilization to give the title compound hydrochloride (17 mg) , the yield is 40.9%).
光谱数据： Spectral data:
LC/MS (方法： UFLC): RT = 2.92 分钟； m/z = 569.1 [M+H]+; 总的运行时间为 7.00 分钟. 1H NMR (400 MHz, METHANOL-^) δ 7.96 (s， 1H), 7.70 (s, 1H), 7.61 (s, 1H), 7.55-7.50 (m, 1H), 7.31 (t, J = 8.8 Hz, 1H), 7.17 (s， 1H), 6.37 (q, J = 6.8 Hz, 1H), 4.03 (s, 2H), 3.73-3.84 (m, 1H), 3.77-3.50 (m, 4H)， 3.20-3.00 (m, 4H), 2.49-2.29 (m, 4H), 1.95 (d， J= 6.8 Hz, 1H). LC/MS (method: UFLC): RT = 2.92 min; m/z = 569.1 [M+H] + ; The total run time is 7.00 min. 1H NMR (400 MHz, METHANOL-^) δ 7.96 (s, 1H ), 7.70 (s, 1H), 7.61 (s, 1H), 7.55-7.50 (m, 1H), 7.31 (t, J = 8.8 Hz, 1H), 7.17 (s, 1H), 6.37 (q, J = 6.8 Hz, 1H), 4.03 (s, 2H), 3.73-3.84 (m, 1H), 3.77-3.50 (m, 4H), 3.20-3.00 (m, 4H), 2.49-2.29 (m, 4H), 1.95 (d, J = 6.8 Hz, 1H).
实施例 26 Example 26
Figure imgf000036_0001
Figure imgf000036_0001
2-[4-[4-[6-氨基 -5-[l-(2,6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基] P比唑 -1-基] 2-[4-[4-[6-Amino-5-[l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]P-pyrazol-1-yl ]
-1-哌啶基] -N-环丙基-乙酰胺 操作步骤： 将 2-[4-[4-[6-氨基 -5- [ (2，6-二氯 -3-氟-苯基）乙氧基 ]-3-吡啶基基] P比唑 -1-基]小哌啶基]乙酸 (40 毫克， 0.073毫摩尔， 1当量)， 环丙胺 (8毫克， 0.147毫摩尔, 2当量） 和 Ν,Ν,Ν',Ν'-四甲基 -0-(7-氮杂苯并三唑 -1-基)六氟磷酸脲 （42毫克， 0.11毫摩尔， 1.5当量)溶于 2毫升二氯甲垸。 然后搅拌、 冰浴和氮气保护下， 继续缓慢加入 Ν,Ν'-二异丙基乙胺（47毫克， 0.368毫摩尔，5 当量)。 得到反应液在室温下继续搅拌 1小时。 反应结束后， 将反应液用二氯甲垸稀释， 有机 层用碳酸氢钠溶液和食盐水各反洗一次， 再用硫酸钠干燥后旋干， 得到的粗品采用高效液相 色谱在 C18反相柱上分离 (流动相： 乙腈 /水 /0.5%盐酸， 梯度洗脱 36%至 66% (体积比; ))， 减压 (H8 'ω) '(Η '^)0Γζ-02'3 '(HI '^) S8 "16 '(HI '"1-(piperidinyl)-N-cyclopropyl-acetamide procedure: 2-[4-[4-[6-Amino-5-[(2,6-dichloro-3-fluoro-phenyl) Ethoxy]-3-pyridyl] P-pyrazol-1-yl]piperidinyl]acetic acid (40 mg, 0.073 mmol, 1 eq.), cyclopropylamine (8 mg, 0.147 mmol, 2 eq. And hydrazine, hydrazine, hydrazine, Ν'-tetramethyl- 0-(7-azabenzotriazol-1-yl) hexafluorophosphate (42 mg, 0.11 mmol, 1.5 eq.) dissolved in 2 ML dichloromethane. Then, stirring, ice bath and nitrogen protection were continued, and hydrazine, Ν'-diisopropylethylamine (47 mg, 0.368 mmol, 5 eq.) was slowly added. The reaction solution was stirred at room temperature for further 1 hour. After the reaction was completed, the reaction solution was diluted with dichloromethane, and the organic layer was back-washed once with sodium hydrogen carbonate solution and brine, dried over sodium sulfate and then evaporated to dryness. Separation (mobile phase: acetonitrile/water/0.5% hydrochloric acid, gradient elution 36% to 66% (volume ratio; )), decompression (H8 'ω) '(Η '^)0Γζ-02'3 '(HI '^) S8 "16 '(HI '"
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Figure imgf000037_0001
Figure imgf000037_0001
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Figure imgf000038_0001
l-[4-[4-[6-氨基 -5-[l-(2，6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基]吡唑- 基]小哌啶基] 88Z000/M0ZN3/X3d 98t9 / 0Z OAV
Figure imgf000038_0001
1-[4-[4-[6-Amino-5-[l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazole-yl]piperazine Pyridyl
-3-甲基-丁 -2-烯 -1-酮  -3-methyl-but-2-en-1-one
操作步骤： Steps:
将化合物 3-[1-(2,6-二氯 -3-氟-苯基）乙氧基 ]-5-[1-(4-哌啶基)吡唑 -4-基]吡啶 -2-胺 （64 毫克， 0.144毫摩尔，1当量)， 3 -甲基-丁 -2 -烯酸 (15.8毫克， 0.158毫摩尔， 1.1当量)和 Ν,Ν,Ν',Ν'-四甲 基 -0-(7-氮杂苯并三唑小基)六氟磷酸脲 （82毫克， 0.216毫摩尔， 1.5当量)溶于 2毫升二氯甲 垸。然后搅拌、冰浴和氮气保护下， 继续缓慢加入 Ν,Ν'-二异丙基乙胺 (92毫克, 0.72毫摩尔，5 当量)。 反应在室温下继续搅拌 2小时。 反应结束后， 将反应液用二氯甲垸稀释， 有机层用碳 酸氢钠溶液和食盐水各反洗一次， 再用硫酸钠干燥后旋干， 得到的粗品采用高效液相色谱在 C18反相柱上分离 (流动相： 乙腈 /水 /0.5%碳酸氢氨， 梯度洗脱 36%至 66% (体积比))， 减压蒸 除易挥发的组分后冻干得到目标化合物 （27毫克， 产率为 35.3%). The compound 3-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-5-[1-(4-piperidinyl)pyrazol-4-yl]pyridine-2- Amine (64 mg, 0.144 mmol, 1 eq.), 3-methyl-but-2-enoic acid (15.8 mg, 0.158 mmol, 1.1 eq.) and hydrazine, hydrazine, Ν', Ν'-tetramethyl- 0-(7-azabenzotriazole small group) Urea hexafluorophosphate (82 mg, 0.216 mmol, 1.5 equivalent) was dissolved in 2 ml of dichloromethane. Then, stirring, ice bath and nitrogen protection were continued, and hydrazine, Ν'-diisopropylethylamine (92 mg, 0.72 mmol, 5 eq.) was slowly added. The reaction was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was diluted with dichloromethane, and the organic layer was back-washed once with sodium hydrogen carbonate solution and brine, dried over sodium sulfate and then evaporated to dryness. Separation (mobile phase: acetonitrile/water/0.5% ammonium bicarbonate, gradient elution 36% to 66% by volume), evaporation of the volatile components under reduced pressure, and lyophilization to give the target compound (27 mg, yield The rate is 35.3%).
光谱数据： Spectral data:
LC/MS (方法： UFLC): RT = 3.79 分钟； m/z = 531.1[M+H]+; 总的运行时间为 7.00分钟. 1H NMR (400 MHz, METHANOL-^) δ 7.98 (s, IH), 7.74 (s, 1H)， 7.64 (s， IH), 7.52 (dd, J = 4.8, 8.8 Hz, IH), 7.31 (t, J = 8.4 Hz, IH), 7.16 (s， IH), 6.38 (q, J = 6.4 Hz, IH), 5.92 (s, IH), 4.70-4.58 (m, IH), 4.54-4.42 (m, IH), 4.20-4.06 (m, IH), 3.28-3.21 (m, IH), 2.97-2.83 (m, IH), 2.22-2.09 (m, 2H), 2.00-1.83 (m, 11H). 实施例 29
Figure imgf000038_0002
LC/MS (method: UFLC): RT = 3.79 min; m/z = 531.1 [M+H] + ; s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s ), 7.74 (s, 1H), 7.64 (s, IH), 7.52 (dd, J = 4.8, 8.8 Hz, IH), 7.31 (t, J = 8.4 Hz, IH), 7.16 (s, IH), 6.38 (q, J = 6.4 Hz, IH), 5.92 (s, IH), 4.70-4.58 (m, IH), 4.54-4.42 (m, IH), 4.20-4.06 (m, IH), 3.28-3.21 (m , IH), 2.97-2.83 (m, IH), 2.22-2.09 (m, 2H), 2.00-1.83 (m, 11H). Example 29
Figure imgf000038_0002
(E)-H4-[4-[6-氨基 -5-[ (2，6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基]吡唑 -1-基] (E)-H4-[4-[6-Amino-5-[(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazole-1-yl]
-1-哌啶基 ]-4- (二甲基氨基)丁 -2- - 酮  1-piperidinyl]-4-(dimethylamino)butan-2-one
操作步骤： Steps:
将化合物 3-[1-(2，6-二氯 -3-氟-苯基)乙氧基 ]-5-[1-(4-哌啶基)吡唑 -4-基]吡啶 -2-胺 (40毫克， 0.09 毫摩尔， 1当量），（Ε-4- (二甲基氨基）丁 -2-烯酸 (12.6毫克， 0.10毫摩尔，1.1当量)和 Ν,Ν,Ν',Ν'- 四甲基 -0-(7-氮杂苯并三唑 -1-基)六氟憐酸脲 ί51.3毫克， 0.135毫摩尔， 1.5当量)溶于 5 毫升二 氯甲垸。 然后搅拌、 冰浴和氮气保护下， 继续缓慢加入 N，N，-二异丙基乙胺 (116.1毫克, 0.9毫 摩尔， 10当量)。 反应在室温下继续搅拌 3小时。 反应结束后， 将反应液用二氯甲垸稀释， 有 机层用碳酸氢钠溶液和食盐水各反洗一次， 再用硫酸钠干燥后旋干， 得到粗品采用高效液相 分离 (仪器： LC 8 A & Gilson 215 馏分收集器 色谱柱： Ge分钟 i 200*25mm*5um，流动相 A: BASE水， 流动相 B: 乙腈， 流速： 30mL/分钟， 浓度梯度： 38-68%B, 0-12分钟)得到目标化合 物（ Π.4毫克， 收率： 34.8%) The compound 3-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-5-[1-(4-piperidinyl)pyrazol-4-yl]pyridine-2- Amine (40 mg, 0.09 mmol, 1 eq.), (Ε-4-(dimethylamino)but-2-enoic acid (12.6 mg, 0.10 mmol, 1.1 eq.) and hydrazine, hydrazine, hydrazine '-Tetramethyl-0-(7-azabenzotriazol-1-yl)hexafluorodiurea urea 51.3 mg, 0.135 mmol, 1.5 eq.) dissolved in 5 ml II Chloroformamidine. Then, N,N,-diisopropylethylamine (116.1 mg, 0.9 mmol, 10 equivalents) was added slowly under stirring, ice bath and nitrogen. The reaction was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was diluted with dichloromethane, and the organic layer was back-washed once with sodium bicarbonate solution and brine, dried over sodium sulfate and then dried to give a crude product. & Gilson 215 Fraction Collector Column: Ge min i 200*25mm*5um, mobile phase A: BASE water, mobile phase B: acetonitrile, flow rate: 30mL/min, concentration gradient: 38-68%B, 0-12 minutes Obtained the target compound (Π.4 mg, yield: 34.8%)
LC/MS (方法： UFLC): RT = 2.966 分钟； m/z = 561.4 [M+H]+; 总的运行时间为 7.00 分钟。  LC/MS (method: UFLC): RT = 2.966 min; m/z = 561.4 [M+H]+; The total run time is 7.00 minutes.
1H NMR (400MHz, METHANOL-i¾): δ 8.06 (s, 1H)， 7.82-7.69 (m, 3H)， 7.31-7.10 (m， 3H)， 6.76 (br, 1H)， 6.38 (br, IH), 4.67-4.59 (m, 2H), 4.30 (br, IH), 4.01 (br, 2H), 3.62-3.57 (m, IH), 2.94 (s， 6H), 2.75-2.70 (m, IH), 2.25-2.15 (m, 2H), 2.10-1.96 (m, 5H). 实施例 30和 施例 31
Figure imgf000039_0001
1H NMR (400MHz, METHANOL-i3⁄4): δ 8.06 (s, 1H), 7.82-7.69 (m, 3H), 7.31-7.10 (m, 3H), 6.76 (br, 1H), 6.38 (br, IH), 4.67-4.59 (m, 2H), 4.30 (br, IH), 4.01 (br, 2H), 3.62-3.57 (m, IH), 2.94 (s, 6H), 2.75-2.70 (m, IH), 2.25- 2.15 (m, 2H), 2.10-1.96 (m, 5H). Example 30 and Example 31
Figure imgf000039_0001
(E)小 [4-[4-[6-氨基 -5-[(lS)-l-(2， 6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基]吡唑 - 基 (E) Small [4-[4-[6-amino-5-[(lS)-l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyridinium Azole-based
-1-哌啶基 ]-4-(二甲基氨基)丁 -2-烯小酮
Figure imgf000039_0002
1-piperidinyl]- 4 -(dimethylamino)butan- 2 -enone
Figure imgf000039_0002
(E)-l-[4-[4-[6-氨基 -5-[(lR)-l-(2， 6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基]吡唑- 基] (E)-l-[4-[4-[6-Amino-5-[(lR)-l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl) Pyrazole-based]
-1-哌啶基 ]-4- (二甲基氨基)丁 -2-烯 - 酮  1-piperidinyl]-4-(dimethylamino)but-2-en-one
操作步骤： Steps:
将化合物 (E)-l-[4-[4-[6-氨基 -5-[1-(2,6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基]吡唑- 基]小哌啶基] -4- (二甲基氨基) -丁 -2-烯小酮 （16.1 毫克， 0.028 毫摩尔） 进行 SFC 分离得到目标化合物 (E)- [4-[4-[6-氨基 -5-[(lS)-l-(2，6-二氯 -3-氟-苯基）乙氧基 ]-3-吡啶基] P比唑- 1-基]小哌啶基] -4- (二甲基氨基） 丁 -2-烯小酮 ( 3毫克） 和 （E)-l-[4-[4-[6-氨基 -5-[(lR)-l-(2，6-二氯 -3-氟-苯基)乙 氧基] -3-吡啶基]吡唑- 基]小哌啶基 ]-4- (二甲基氨基)丁 -2-烯- 酮 （4毫克）。 Compound (E)-l-[4-[4-[6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyridin Imidazole-yl]piperidinyl]-4-(dimethylamino)-but-2-enionone (16.1 mg, 0.028 mmol) was subjected to SFC isolation to give the title compound (E)- [4-[4- [6-Amino-5-[(lS)-l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]P-pyrazole-1-yl]piperidine -4-(dimethylamino)but-2-enone (3 mg) and (E)-l-[4-[4-[6-amino-5-[(lR)-l-( 2,6-Dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazole-yl]piperidinyl]-4-(dimethylamino)but-2-en-one (4 mg).
实施例 30的光谱数据： Spectral data of Example 30:
LC/MS (方法： UFLC): RT = 2.966 分钟； m/z = 561.4 [M+H]+; 总的运行时间为 7.00 分钟。 实施例 31的光谱数据： LC/MS (method: UFLC): RT = 2.966 min; m/z = 561.4 [M+H]+; The total run time was 7.00 min. Spectral data of Example 31:
LC/MS (方法： UFLC): RT = 2.966 分钟； m/z = 561.4 [M+H]+; 总的运行时间为 7.00 分钟。 Ή NMR (400MHz, METHANOL-d4): δ 8.00 (s， IH), 7.65 (s, IH), 7.63 (s, IH), 7.52 (dd, J = 4.8， 8.8 Hz, IH), 7.31 (t, J = 8.4 Hz, 1H)， 7.16 (s, IH), 7.07 (d， J = 15.2 Hz, IH), 6.74-6.67 (m, 1H)， 6.38 (q, J = 6.4 Hz, IH), 4.68-4.65 (m, IH), 4.56-4.50 (m， IH), 4.28-4.24 (m, IH), 3.98 (d， J = 7.2 Hz, 2H), 3.41-3.34 (m,lH)， 3.01-2.92 (m, 7H), 2.21-2.05 (m， 2H), 2.01-1.95 (m, 5H). 实施例 32 LC/MS (method: UFLC): RT = 2.966 min; m/z = 561.4 [M+H] + ; The total run time was 7.00 min. NMR NMR (400MHz, METHANOL-d 4 ): δ 8.00 (s, IH), 7.65 (s, IH), 7.63 (s, IH), 7.52 (dd, J = 4.8, 8.8 Hz, IH), 7.31 (t , J = 8.4 Hz, 1H), 7.16 (s, IH), 7.07 (d, J = 15.2 Hz, IH), 6.74-6.67 (m, 1H), 6.38 (q, J = 6.4 Hz, IH), 4.68 -4.65 (m, IH), 4.56-4.50 (m, IH), 4.28-4.24 (m, IH), 3.98 (d, J = 7.2 Hz, 2H), 3.41-3.34 (m, lH), 3.01-2.92 (m, 7H), 2.21-2.05 (m, 2H), 2.01-1.95 (m, 5H). Example 32
Figure imgf000040_0001
Figure imgf000040_0001
3-[(2, 6-二氯苯基)甲氧基 ]-5-[l-(4-哌啶基) B比唑 -4-基] P比啶基 -2-胺 步骤 A:
Figure imgf000040_0002
3-[(2,6-Dichlorophenyl)methoxy]-5-[l-(4-piperidinyl) B-pyrazol-4-yl]P-pyridyl-2-amine Step A:
Figure imgf000040_0002
3 - [(2, 6 -二氯苯基)甲氧基 ]-2-硝基 -吡啶  3-[(2,6-Dichlorophenyl)methoxy]-2-nitro-pyridine
操作步骤： Steps:
将底物 2-硝基吡啶 -3-醇（437.5毫克， 3.125毫摩尔， 1.1当量）和 三苯基膦（ 1.116克， 4.216 毫摩尔， 1.5当量）加入到底物 (2,6 -二氯苯基)甲醇 (500毫克， 2.842毫摩尔， 1当量） 的 8 毫 升的四氢呋喃溶液中， 在零摄氏度下， 滴加溶解在 ImL四氢呋喃溶液中的 DIAD (746毫克， 3.693毫摩尔， 1.3当量)。 室温 25摄氏度搅拌过夜。 旋干， 加入水和二氯甲垸分层。 水相用 二氯甲垸萃取三遍， 将有机相合并干燥， 过滤， 旋干， 过柱得到目标化合物 （1.2 g) 。 The substrate 2-nitropyridin-3-ol (437.5 mg, 3.125 mmol, 1.1 eq.) and triphenylphosphine (1.1116 g, 4.216 mmol, 1.5 eq.) were added to the substrate (2,6-dichlorobenzene). DIAD (746 mg, 3.693 mmol, 1.3 eq.) dissolved in 1 mL of tetrahydrofuran solution was added dropwise to a solution of methanol (500 mg, 2.842 mmol, 1 eq.) in 8 mL of tetrahydrofuran. Stir at room temperature 25 ° C overnight. Spin dry, add water and dichloromethane stratified. The aqueous phase was extracted three times with dichloromethane, and the organic phase was combined, dried, filtered, and evaporated to give the title compound (1.2 g).
光谱数据. -Spectral data. -
LC/MS (方法： UFLC): RT = 0.773 分钟； m/z = 298.8 [M+H]+ ; 总的运行时间为 1.5分钟. 步骤 B:
Figure imgf000041_0001
LC/MS (method: UFLC): RT = 0.773 min; m/z = 298.8 [M+H] + ; the total run time is 1.5 min. Step B:
Figure imgf000041_0001
3-[(2, 6-二氯苯基)甲氧基]吡啶 -2-胺  3-[(2,6-Dichlorophenyl)methoxy]pyridine-2-amine
操作步骤： Steps:
将底物 3-[(2，6-二氯苯基)甲氧基 ]-2-硝基 -吡啶 （500毫克， 1.678毫摩尔， 1当量）和还原铁粉 ( 939毫克， 16.78毫摩尔， 10当量） 溶解在乙酸 （4毫升）和乙醇 （4毫升） 的混合体系中， 加热搅拌回流 1小时。 冷却到室温， 通过硅藻土过滤， 滤饼用二氯甲垸和水洗， 分层， 有机 相用饱和食盐水洗， 干燥， 过滤， 旋干得到目标化合物 （430毫克）。 The substrate 3-[(2,6-dichlorophenyl)methoxy]-2-nitro-pyridine (500 mg, 1.678 mmol, 1 eq.) and reduced iron powder (939 mg, 16.78 mmol, 10 equivalents) Dissolved in a mixed system of acetic acid (4 ml) and ethanol (4 ml), and stirred under reflux for 1 hour. The mixture was cooled to room temperature, filtered through celite, and filtered, and filtered and evaporated.
光谱数据： Spectral data:
LC/MS (方法： UFLC): RT = 0.730 分钟； m/z = 268.8 [M+H]+; 总的运行时间为 1.5分钟。 步骤 C:
Figure imgf000041_0002
LC/MS (method: UFLC): RT = 0.730 min; m/z = 268.8 [M+H]+; Step C:
Figure imgf000041_0002
5-溴 -3- [(2, 6-二氯苯基)甲氧基]吡啶 -2-胺  5-bromo-3-[(2,6-dichlorophenyl)methoxy]pyridine-2-amine
操作步骤： Steps:
将化合物 3-[(2,6-二氯苯基)甲氧基]吡啶 -2-胺 （430毫克， 1.604毫摩尔， 1当量） 溶解在乙腈The compound 3-[(2,6-dichlorophenyl)methoxy]pyridine-2-amine (430 mg, 1.604 mmol, 1 eq.) was dissolved in acetonitrile
( 5毫升） 中， 在 0摄氏度下分批加入 NBS ( 225毫克， 1.925毫摩尔， 1.15当量）。 加入完 毕后， 0摄氏度下搅拌 1小时。 旋干， 倒入水中， 用二氯甲烷萃取三次。 有机相干燥， 过滤， 旋干， 过柱得到目标化合物 （230毫克）。 In 5 ml, NBS (225 mg, 1.925 mmol, 1.15 equivalent) was added in portions at 0 °C. After the addition, the mixture was stirred at 0 ° C for 1 hour. Spin dry, pour into water and extract three times with dichloromethane. The organic phase was dried, filtered, dried and purified eluted eluted
光谱数据： Spectral data:
LC/MS (方法： UFLC): RT = 0.748 分钟； m/z = 348.7 [M+H]+. 总的运行时间为 1.5分钟. 步骤 D:
Figure imgf000041_0003
LC/MS (method: UFLC): RT = 0.748 min; m/z = 348.7 [M+H] + . The total run time is 1.5 minutes. Step D:
Figure imgf000041_0003
4-[4-[6-氨基 -5-[(2, 6 -二氯苯基)甲氧基 ]-3-吡啶基] P比唑 -1-基]哌啶 -1 -甲酸叔丁酉 I 操作步骤： 4-[4-[6-Amino-5-[(2,6-dichlorophenyl)methoxy]-3-pyridyl]P-pyrazol-1-yl]piperidine-1 -carboxylic acid tert-butyl hydrazine Steps:
将化合物 5-溴 -3-[(2,6-二氯苯基)甲氧基]吡啶 -2-胺 （50毫克， 0.145毫摩尔， 1当量）， 化合物 4—[4— (4,4,5,5-四甲基 -1，3，2 -二氧杂环戊硼烷 -2-基)吡唑 -1-基]哌啶 -1 -甲酸叔丁酯 （81.7毫克， 0.217毫摩尔， 1.5当量） 和碳酸钠 （31毫克， 0.289毫摩尔， 2当量） 溶解在二氧六环 （2.5 毫升） 和水 （2.5毫升） 的混合体系中并在氮气保护下加入四 (三苯基膦)钯 （8.3毫克， 0.007 毫摩尔， 0.05当量） 室温 26摄氏度下搅拌。 升温到 80摄氏度下回流 6小时。 将混合体系倒 入冰水中并用二氯甲垸萃取三遍， 合并有机相用饱和食盐水洗涤， 干燥， 过滤， 旋干， TLC 分离得到目标化合物 （40毫克）。 The compound 5-bromo-3-[(2,6-dichlorophenyl)methoxy]pyridin-2-amine (50 mg, 0.145 mmol, 1 eq.), Compound 4 - [4- (4, 4) ,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1 -carboxylic acid tert-butyl ester (81.7 mg, 0.217 mmol) , 1.5 equivalents) and sodium carbonate (31 mg, 0.289 mmol, 2 equivalents) dissolved in a mixture of dioxane (2.5 ml) and water (2.5 ml) and added tetrakis(triphenylphosphine) under nitrogen Palladium (8.3 mg, 0.007 mmol, 0.05 equivalent) Stir at room temperature 26 ° C. The temperature was raised to 80 ° C for 6 hours. The mixture was poured into ice water and extracted with dichloromethane (3 mL).
光谱数据： Spectral data:
LC/MS (方法： UFLC): RT = 0.753 分钟； m/z = 518.1 [M+H]+; 总的运行时间为 1.5分钟. 步骤 E:  LC/MS (method: UFLC): RT = 0.753 min; m/z = 518.1 [M+H]+; The total run time is 1.5 min. Step E:
Figure imgf000042_0001
Figure imgf000042_0001
3-[(2,6-二氯苯基)甲氧基 ]-5-[1-(4-哌啶基)吡唑 -4-基] P比啶基 -2-胺 操作步骤： 3-[(2,6-Dichlorophenyl)methoxy]-5-[1-(4-piperidinyl)pyrazol-4-yl]P-pyridyl-2-amine Procedure:
将化合物 4-[4-[6-氨基 -5-[(2， 6 -二氯苯基)甲氧基 ]-3-吡啶基]吡唑- 基]哌啶- 1 -甲酸叔丁酯 （40 毫克， 0.077毫摩尔） 溶解在盐酸乙酸乙酯 （4mL) 中， 在室温搅拌 1小时。 旋干得到目标化 合物 （17毫克）。 The compound 4-[4-[6-amino-5-[(2,6-dichlorophenyl)methoxy]-3-pyridyl]pyrazole-yl]piperidine-1-carboxylic acid tert-butyl ester ( 40 mg, 0.077 mmol) was dissolved in ethyl acetate (4 mL) and stirred at room temperature for 1 hour. The target compound (17 mg) was obtained by spin-drying.
光谱数据： Spectral data:
LC/MS (方法： UFLC): RT=2.363 分钟； m/z = 418.1 [M+H]+. 总的运行时间为 7分钟. 实施例 33 LC/MS (method: UFLC): RT = 2.336 min; m/z = 418.1 [M+H] + . The total run time was 7 min. Example 33
Figure imgf000042_0002
Figure imgf000042_0002
2— [4-[4-[6-氨基 -5-[( l R)-l -(2，6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基]吡唑小基 -1-哌啶基]乙酸乙酯 2- [4-[4-[6-Amino-5-[(l R)-l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazole Small base Ethyl-1-phenylpiperidinyl]
操作步骤： Steps:
将化合物甲基 2-氯乙酸（58毫克， 0.53毫摩尔， 1.2个当量）， 碳酸钾（0.49克， 3.55毫摩尔， 8当量) 和碘化钠 ( 8毫克) 加入到化合物 3-[(lR)小 (2,6 -二氯 -3-氟-苯基)乙氧基 ]-5-[1-(4 -哌 啶基) P比唑 -4-基]吡啶 -2-胺（200毫克， 0.44毫摩尔， 1当量） 的 2毫升的乙醇溶液中， 加热回 流 2个小时后用水淬灭， 后加入水层和二氯甲垸， 分层， 水层再用二氯甲垸萃取三次， 有机 相合并后， 干燥旋干， 粗品过柱纯化 (石油醚： 乙酸乙酯 =4:1)干燥旋干后得到目标化合物（6.6 毫克， 收率为 2.5%)。 The compound methyl 2-chloroacetic acid (58 mg, 0.53 mmol, 1.2 equivalents), potassium carbonate (0.49 g, 3.55 mmol, 8 equivalents) and sodium iodide (8 mg) were added to the compound 3-[(lR Small (2,6-dichloro-3-fluoro-phenyl)ethoxy]-5-[1-(4-piperidinyl)P-pyrazol-4-yl]pyridin-2-amine (200 mg) , 0.44 mmol, 1 equivalent) in 2 ml of ethanol solution, heated under reflux for 2 hours, quenched with water, then added aqueous layer and dichloromethane, layered, and the aqueous layer was extracted three times with dichloromethane. After the organic phases were combined, dried and dried, and then purified and evaporated, mjjjjjjjjj
LC/MS (方法： UFLC): RT=7.00 分钟； m/z = 536.3 [M+H]+; 总的运行时间为 1.798 分钟。 实施例 34  LC/MS (method: UFLC): RT = 7.00 min; m/z = 536.3 [M+H]+; The total run time was 1.798 minutes. Example 34
Figure imgf000043_0001
Figure imgf000043_0001
2-[4-[4-[6-氨基 -5-[(lR)小 (2，6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基] P比唑 -1-基] 2-[4-[4-[6-Amino-5-[(lR) small (2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl] P-pyrazole-1 -base]
-1-哌啶基] -Ν,Ν-二甲基-乙酰胺  -1-piperidinyl]-indole, hydrazine-dimethyl-acetamide
操作步骤： Steps:
将 2-[4-[4-[6-氨基 -5-[ (lR)-(2,6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基基]吡唑 -1-基]小哌啶基]乙酸 (400毫克， 0.73毫摩尔， 1当量)，化合物二甲胺 （295毫克， 1.47毫摩尔， 2当量） 和 Ν,Ν,Ν',Ν'- 四甲基 -0-(7-氮杂苯并三唑 -1-基)六氟磷酸脲 （415毫克， 1.1毫摩尔，1.5当量)溶于 5毫升二氯 甲垸。 然后搅拌、 冰浴和氮气保护下， 继续缓慢加入 Ν,Ν'-二异丙基乙胺 (380毫克, 2.94毫摩 尔， 5当量)逐滴加入。得到反应液在室温下继续搅拌 1小时。 反应结束后， 将反应液用二氯甲 垸稀释， 有机层用碳酸氢钠溶液和食盐水各反洗一次， 再用硫酸钠干燥后旋干， 得到的粗品 采用高效液相色谱在 C18反相柱上分离 (流动相： 乙腈 /水 /0.5%盐酸，梯度洗脱 36%至 66% (体 积比 ))， 减压蒸除易挥发的组分后冻干得到目标化合物盐酸盐 (60毫克， 产率为 15.4%)。 2-[4-[4-[6-Amino-5-[(lR)-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazole- 1-yl]piperidinyl]acetic acid (400 mg, 0.73 mmol, 1 eq.), compound dimethylamine (295 mg, 1.47 mmol, 2 eq.) and hydrazine, hydrazine, hydrazine, Ν'- Base-0-(7-azabenzotriazol-1-yl)hexafluorophosphate (415 mg, 1.1 mmol, 1.5 eq.) was dissolved in 5 mL of dichloromethane. Then, stirring, ice bath and nitrogen protection were continued, and hydrazine was added slowly, and Ν'-diisopropylethylamine (380 mg, 2.94 mmol, 5 eq.) was added dropwise. The reaction solution was stirred at room temperature for further 1 hour. After the reaction was completed, the reaction solution was diluted with dichloromethane, and the organic layer was back-washed once with sodium hydrogen carbonate solution and brine, dried over sodium sulfate and then evaporated to dryness. Separation (mobile phase: acetonitrile/water/0.5% hydrochloric acid, gradient elution 36% to 66% by volume), evaporation of the volatile components under reduced pressure, and lyophilization to give the title compound hydrochloride (60 mg, The yield was 15.4%).
LC/MS (方法： UFLC): RT = 2.75 分钟； m/z = 535.3 [Μ+Η]+; 总的运行时间为 7.00 分钟. Ή NMR (400 MHz, METHANOL-^) δ 8.28-8.02 (m, 1H), 7.73-7.70 (m, 2H)， 7.55 (dd, J = 4.4, 8.4 Hz, 1H)， 7.33 (t, J = 8.4 Hz, 1H), 7.19 (s, 1H), 6.41 (q, J = 6.4 Hz, 1H), 4.71-4.60 (m, 1H), 4.41-4.37 (m, 2H), 3.85-3.82 (m, 1H)， 3.62-3.60 (m, 1H), 3.42-3.36 (m, 2H), 3.02 (s, 6H), 2.52-2.38 (m, 4H), 1.97 (d, J= 6.4 Hz, 3 H) 实施例 35 LC/MS (method: UFLC): RT = 2.75 min; m/z = 535.3 [Μ+Η] + ; The total run time is 7.00 min. NMR NMR (400 MHz, METHANOL-^) δ 8.28-8.02 (m , 1H), 7.73-7.70 (m, 2H), 7.55 (dd, J = 4.4, 8.4 Hz, 1H), 7.33 (t, J = 8.4 Hz, 1H), 7.19 (s, 1H), 6.41 (q, J = 6.4 Hz, 1H), 4.71-4.60 (m, 1H), 4.41-4.37 (m, 2H), 3.85-3.82 (m, 1H), 3.62-3.60 (m, 1H), 3.42-3.36 (m, 2H), 3.02 (s, 6H), 2.52-2.38 (m, 4H), 1.97 (d, J= 6.4 Hz, 3 H) Example 35
Figure imgf000044_0001
μ [4— [4— [6—氨基— 5— [l-(2,6—二氯 -3—氟-苯基)乙氧基 ]-3-吡啶基] P比唑 -1-基] -1-哌啶基
Figure imgf000044_0001
μ [4- [4- [6- amino - 5- [l- (2, 6 - dichloro-3-fluoro-phenyl) - ethoxy] -3-pyridinyl] P-pyrazol-1-yl] 1-piperidinyl
-2- (二甲基氨基)乙酮  -2- (dimethylamino) ethyl ketone
操作步骤: Steps:
将化合物 3-[1-(2,6-二氯 -3-氟-苯基)乙氧基 ]-5-[1-(4-哌啶基)吡唑 -4-基] P比啶 -2-胺盐酸盐 (60毫克， 0.123毫摩尔，1当量) , 2- (二甲基氨基)乙酸 （15毫克， 0.147毫摩尔， 1.2当量)和 Ν,Ν,Ν',Ν'-四甲 基 -0-(7-氮杂苯并三唑 -1-基)六氟磷酸脲 （70毫克， 0.184毫摩尔， 1.5当量)溶于 2毫升二氯甲 垸。然后搅拌、冰浴和氮气保护下， 继续缓慢加入 Ν,Ν'-二异丙基乙胺 (79 毫克, 0.615毫摩尔， 5当量)。反应在室温下继续搅拌 12小时。反应结束后将反应液旋干，得到的目标化合物粗品， 用 HPLC纯化 (仪器： SHIMADZU LC-8A, 色谱柱： synergi-10 mi, 250x50mmI.D. , 流动相 A: 水 （1%。TFA, v/v)， 流动相 B: 乙腈， 浓度梯度： B 30-80%， 流速： 80mL /分钟)。 纯化液用碳 酸氢钠调节 PH值为 7-8后水层用二氯甲垸萃取三次，有机层合并后用饱和食盐水反洗，干燥 旋干得到目标化合物 （41.6毫克， 收率为 63%)。 The compound 3-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-5-[1-(4-piperidinyl)pyrazol-4-yl]P is pyridine- 2-amine hydrochloride (60 mg, 0.123 mmol, 1 eq.), 2-(dimethylamino)acetic acid (15 mg, 0.147 mmol, 1.2 eq.) and hydrazine, hydrazine, hydrazine Methyl-0-(7-azabenzotriazol-1-yl)hexafluorophosphate (70 mg, 0.184 mmol, 1.5 eq.) was dissolved in 2 mL of dichloromethane. Then, stirring, ice bath and nitrogen protection were continued, and hydrazine, Ν'-diisopropylethylamine (79 mg, 0.615 mmol, 5 eq.) was slowly added. The reaction was stirred at room temperature for further 12 hours. After completion of the reaction, the reaction mixture was dried to give a crude title compound, which was purified by HPLC (yield: SHIMADZU LC-8A, column: synergi-10 mi, 250x50mmI.D., mobile phase A: water (1%. TFA, v/v), mobile phase B: acetonitrile, concentration gradient: B 30-80%, flow rate: 80 mL / min). The purified liquid was adjusted to pH 7-8 with sodium hydrogencarbonate, and then the aqueous layer was extracted three times with methylene chloride. The organic layer was combined and washed with saturated brine, dried and dried to give the title compound (41.6 mg, yield 63%) ).
光谱数据： Spectral data:
LC/MS (方法： UFLC): RT = 2.820分钟； m/z = 535.3 [M+H]+; 总的运行时间为 7.00 分钟. Ή丽 R (400MHz, DMSO-i/6) δ 7.95 (s， 1H), 7.75 (d, J = 1.6 Hz, 1H), 7.61 -7.50 (m, 2H), 7.45 (t， J= 8.4 Hz, 1H), 6.89 (d, J= 1.6 Hz, 1H), 6.08 (q, J= 6.4 Hz, 1H)， 5.65 (s, 2H), 4.49-4.31 (m, 2H), 4.15-4.1 1 (m, 1H), 3.23-2.99 (m, 3H), 2.76-2.71 (m, 1H), 2.20 (s, 6H), 2.10-2.02 (m, 2H), 1.86- 1.69 (m, 5H). 实施例 36 LC/MS (method: UFLC): RT = 2.820 min; m/z = 535.3 [M+H]+; The total run time is 7.00 min. Ή R (400MHz, DMSO-i/ 6 ) δ 7.95 (s , 1H), 7.75 (d, J = 1.6 Hz, 1H), 7.61 -7.50 (m, 2H), 7.45 (t, J= 8.4 Hz, 1H), 6.89 (d, J= 1.6 Hz, 1H), 6.08 (q, J = 6.4 Hz, 1H), 5.65 (s, 2H), 4.49-4.31 (m, 2H), 4.15-4.1 1 (m, 1H), 3.23-2.99 (m, 3H), 2.76-2.71 ( m, 1H), 2.20 (s, 6H), 2.10-2.02 (m, 2H), 1.86- 1.69 (m, 5H). Example 36
Figure imgf000044_0002
l-[4-[4-[6-氨基- 5-[ (2，6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基]吡唑 -1-基] -1-哌啶基
Figure imgf000044_0002
1-[4-[4-[6-Amino-5-[(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazol-1-yl]-1 -piperidinyl
-2- (甲基氨基)乙酮 A: -2- (methylamino) ethyl ketone A:
Figure imgf000045_0001
Figure imgf000045_0001
N-[2-[4-[4-[6-氨基 -5-Π-(2，6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基]吡唑 -1-基] -1-哌啶基 ]-2-氧代-乙 基] -Ν-甲基氨基甲酸叔丁酯  N-[2-[4-[4-[6-Amino-5-indole-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazole-1- Tert-butyl 1-(piperidinyl)-2-oxo-ethyl]-indole-methylcarbamate
操作步骤： Steps:
将化合物 3-[1-(2,6-二氯 -3-氟-苯基)乙氧基 ]-5-[1-(4-哌啶基) Ρ比唑- 4-基]吡啶 -2-胺盐酸盐 (60毫克， 0.123毫摩尔， 1当量)， 2- [叔丁氧基羰基 (甲基)氨基]乙酸（ 27 毫克， 0.147毫摩尔， 1.2当量)和 Ν,Ν,Ν',Ν'-四甲基 -0-(7-氮杂苯并三唑 -1-基)六氟磷酸脲 （70 毫克， 0.184毫摩尔， 1.5当量)溶于 2毫升二氯甲垸。 然后搅拌、 冰浴和氮气保护下， 继续缓慢加入 Ν，Ν'-二异丙基乙胺 (79 毫克， 0.615毫摩尔，5当量)。 反应在室温下继续搅拌 12小时。 反应结束后将反应液旋干， 得到的目 标化合物粗品用 HPLC 纯化（仪器： SHIMADZU LC-8A, 色谱柱： synergi-10/mi， 250x50mmI.D. ， 流动相 A: 水 （1%。 TFA， v/v)， 流动相 B: 乙腈， 浓度梯度： B 30-80%， 流 速： 80mL /分钟 )。 HPLC纯化液用碳酸氢钠调节 PH值为 7-8后水层用二氯甲垸萃取三次， 有 机层合并后用饱和食盐水反洗， 干燥旋干得到目标化合物 （50毫克， 收率为 65.7%)。 The compound 3-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-5-[1-(4-piperidinyl)indoleazole-4-yl]pyridine-2 -amine hydrochloride (60 mg, 0.123 mmol, 1 eq.), 2-[tert-butoxycarbonyl(methyl)amino]acetic acid (27 mg, 0.147 mmol, 1.2 eq.) and oxime, Ν, Ν , Ν'-Tetramethyl-O-(7-azabenzotriazol-1-yl) hexafluorophosphate (70 mg, 0.184 mmol, 1.5 eq.) was dissolved in 2 mL of dichloromethane. Then, under stirring, ice bath and nitrogen, continue to slowly add hydrazine, Ν'-diisopropylethylamine (79 mg, 0.615 mmol, 5 eq.). The reaction was stirred at room temperature for further 12 hours. After completion of the reaction, the reaction solution was dried to dryness, and the obtained crude compound was purified by HPLC (yield: SHIMADZU LC-8A, column: synergi-10/mi, 250x50mmI.D., mobile phase A: water (1%. TFA, v/v), mobile phase B: acetonitrile, concentration gradient: B 30-80%, flow rate: 80 mL / min). The HPLC purification solution was adjusted to pH 7-8 with sodium hydrogen carbonate, and then the aqueous layer was extracted three times with methylene chloride. The organic layer was combined and washed with saturated brine, dried and dried to give the title compound (50 mg, yield 65.7) %).
Figure imgf000045_0002
Figure imgf000045_0002
1-[4- [4-[6-氨基 -5-[1-(2，6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基] P比唑- 基] -1-哌啶基] 1-[4-[4-[6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]P-pyrazole-yl]- 1-piperidinyl]
-2- (甲基氨基)乙酮  -2- (methylamino) ethyl ketone
操作步骤： Steps:
将化合物 N-[2-[4-[4-[6-氨基 -5-[1-(2,6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基] P比唑 -1-基]小哌啶基] - 2-氧代-乙基] -N-甲基氨基甲酸叔丁酯 （50毫克， 0.08毫摩尔， 1当量)溶于 2毫升甲醇中， 在The compound N-[2-[4-[4-[6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl] P ratio Tert-butyl ester of oxazol-1-yl]piperidinyl]-2-oxo-ethyl]-N-methylcarbamate (50 mg, 0.08 mmol, 1 eq.) dissolved in 2 mL of methanol
-30度下向该溶液中慢慢滴加盐酸 /二氧六环（2毫升）并在该温度下搅拌 3小时。反应结束后， 将反应液旋干得到目标化合物 (30毫克， 产率 71%)。 Hydrochloric acid / dioxane (2 ml) was slowly added dropwise to the solution at -30 ° C and stirred at this temperature for 3 hours. After completion of the reaction, the reaction mixture was evaporated to dryness crystals crystals crystals
光谱数据： LC/MS (方法： UFLC): RT =2.761 分钟； m/z = 521.3 [M+H]+; 总的运行时间为 7.00 分钟. Ή NMR (400 MHz, D20) δ 7.73 (s, IH), 7.49 (s, IH), 7.39 (d, J = 1.6 Hz, IH), 7.28 (dd, J= 4.8， 8.8 Hz, IH), 7.02 (t, J = 8.8 Hz, 1H)， 6.87 (d, J = 1.6 Hz, IH), 6.04 (q, J = 6.8 Hz, IH), 4.54-4.44 (m, IH), 4.17-3.98 (m, 3H), 3.77-3.66 (m, IH), 3.26-3.20 (m， IH), 2.89-2.78 (m， 1H)， 2.74 (s， 3H)， 2.11-2.02 (m, 2H), 1.88-1.71 (m, 5H). 实施例 37
Figure imgf000046_0001
Spectral data: LC / MS (Method: UFLC):. RT = 2.761 minutes; m / z = 521.3 [M + H] +; total run time of 7.00 minutes Ή NMR (400 MHz, D 2 0) δ 7.73 (s, IH ), 7.49 (s, IH), 7.39 (d, J = 1.6 Hz, IH), 7.28 (dd, J= 4.8, 8.8 Hz, IH), 7.02 (t, J = 8.8 Hz, 1H), 6.87 (d , J = 1.6 Hz, IH), 6.04 (q, J = 6.8 Hz, IH), 4.54-4.44 (m, IH), 4.17-3.98 (m, 3H), 3.77-3.66 (m, IH), 3.26- 3.20 (m, IH), 2.89-2.78 (m, 1H), 2.74 (s, 3H), 2.11-2.02 (m, 2H), 1.88-1.71 (m, 5H). Example 37
Figure imgf000046_0001
N-[2-[4-[4-[6-氨基 -5-[l-(2,6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基] P比唑 -1-基] 小哌啶基] -2-氧代-乙基]乙酰胺 N-[2-[4-[4-[6-amino-5-[l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]P-pyrazole- 1-yl]piperidinyl]-2-oxo-ethyl]acetamide
操作步骤： Steps:
将化合物 3-[1-(2，6-二氯 -3-氟-苯基)乙氧基 ]-5-[1-(4-哌啶基) P比唑 -4-基]吡啶 -2-胺 (40毫克， 0.09 毫摩尔， 1当量)， 2-乙酰氨基乙酸 (11.7毫克， 0.10毫摩尔， 1.1当量)和 Ν,Ν,Ν',Ν'-四甲基 -0-(7- 氮杂苯并三唑 -1-基)六氟磷酸脲 （51.3毫克， 0.135毫摩尔， 1.5当量)溶于 5 毫升二氯甲垸。 然 后搅拌、 冰浴和氮气保护下， 继续缓慢加入 Ν,Ν'-二异丙基乙胺 (116.1毫克， 0.9毫摩尔，10当 量)。 反应在室温下继续搅拌 3小时。 反应结束后， 将反应液用二氯甲垸稀释， 有机层用碳酸 氢钠溶液和食盐水各反洗一次， 再用硫酸钠千燥后旋干， 得到粗品采用高效液相分离 (仪器： LC 8A & Gilson 215 馏分收集器，色谱柱： Ge分钟 i 200*25mm*5um,流动相 A: 水， 流动相 B: 乙腈， 流速： 30mL/分钟 浓度梯度： 38-68%B， 0-12 分钟)得到目标化合物 (14.7 毫克， 收率为 30.6%)。 The compound 3-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-5-[1-(4-piperidinyl)P-pyrazol-4-yl]pyridine-2 -amine (40 mg, 0.09 mmol, 1 equivalent), 2-acetamidoacetic acid (11.7 mg, 0.10 mmol, 1.1 eq.) and hydrazine, hydrazine, hydrazine, Ν'-tetramethyl- 0-(7- Azabenzotriazol-1-yl)hexafluorophosphate (51.3 mg, 0.135 mmol, 1.5 eq.) was dissolved in 5 mL of dichloromethane. Then, stirring, ice bath and nitrogen protection were continued, and hydrazine, Ν'-diisopropylethylamine (116.1 mg, 0.9 mmol, 10 equivalents) was added slowly. The reaction was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was diluted with dichloromethane, and the organic layer was backwashed once with sodium bicarbonate solution and brine, then dried over sodium sulfate and then dried to give a crude product using high-performance liquid separation (instrument: LC 8A) & Gilson 215 Fraction Collector, Column: Ge min i 200*25mm*5um, mobile phase A: water, mobile phase B: acetonitrile, flow rate: 30mL/min Concentration gradient: 38-68%B, 0-12 minutes) The target compound was obtained (14.7 mg, yield 30.6%).
光谱数据： Spectral data:
LC/MS (方法： UFLC): T = 3.297 分钟； m/z = 549.3 [M+H]+; 总的运行时间为 7.00 分钟. Ή NMR (400MHz, CD3OD): δ 8.02 (s, IH), 7.92 (s, IH), 7.74 (s， IH), 7.54 (dd, J = 4.8, 8.8 Hz, IH), 7.32 (t, J = 8.8 Hz, 1H)， 7.18 (s, 1H)， 6.40 (q, J = 6.4 Hz, IH), 4.60-4.54 (m, 2H), 4.23-3.95 (m, 3H), 3.33-3.24 (m ,1H), 3.03-2.89 (m, IH), 2.32-2.14 (m, 2H), 2.07-1.91 (m, 8H), 实施例 38和实施例 39LC/MS (method: UFLC): T = 3.297 min; m/z = 549.3 [M+H]+; total run time is 7.00 min. NMR NMR (400 MHz, CD 3 OD): δ 8.02 (s, IH ), 7.92 (s, IH), 7.74 (s, IH), 7.54 (dd, J = 4.8, 8.8 Hz, IH), 7.32 (t, J = 8.8 Hz, 1H), 7.18 (s, 1H), 6.40 (q, J = 6.4 Hz, IH), 4.60-4.54 (m, 2H), 4.23-3.95 (m, 3H), 3.33-3.24 (m ,1H), 3.03-2.89 (m, IH), 2.32-2.14 (m, 2H), 2.07-1.91 (m, 8H), Example 38 and Example 39
Figure imgf000046_0002
N_[2-[4— [4— [6-氨基 -5-[(lR)-l-(2，6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基
Figure imgf000046_0002
N _[2-[4-[4-[6-amino-5-[(lR)-l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl)
吡唑小基] -1-哌啶基 -2-氧代-乙基]乙酰胺
Figure imgf000047_0001
Pyrazole small group]-1-piperidinyl-2-oxo-ethyl]acetamide
Figure imgf000047_0001
N-[2-[4-[4- [6-氨基 -5-[(lS)-l-(2,6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基] N- [2-[4-[4-[6-amino-5-[(lS)-l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]
吡唑 -1-基] -1-哌啶基 ]-2-氧代-乙基]乙酰胺  Pyrazole-1-yl]-1-piperidinyl]-2-oxo-ethyl]acetamide
操作步骤： Steps:
将化合物 N-[2-[4-[4-[6-氨基 -5-[1-(2，6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基] P比唑 -1-基] -1-哌啶基] -2-氧代-乙基]乙酰胺 （13.4 毫克， 0.024 毫摩尔） 进行手性 SFC 分离得到目标化合物 N— [2— [4-[4-[6-氨基 -5-[(lR)小 (2,6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基]吡唑 -1-基] -1-哌啶基 ]-2-氧 代-乙基]乙酰胺 （2毫克） 和 N-[2-[4-[4-[6-氨基- 5-[(l S)-l-(2,6-二氯- 3-氟-苯基)乙氧基 ]-3-吡啶 基]吡唑 -1-基] -1-哌啶基 ]-2-氧代-乙基]乙酰胺 （3毫克）。 The compound N-[2-[4-[4-[6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl] P ratio Zyridin-1-yl]-1-piperidinyl]-2-oxo-ethyl]acetamide (13.4 mg, 0.024 mmol) was subjected to chiral SFC separation to give the target compound N - [2 - [4-[4 -[6-amino-5-[(lR) small (2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazol-1-yl]-1-piperidine 5-oxo-ethyl]acetamide (2 mg) and N-[2-[4-[4-[6-amino- 5-[(l S)-l-(2,6-di) Chloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazol-1-yl]-1-piperidinyl]-2-oxo-ethyl]acetamide (3 mg).
实施例 38的光谱数据： Spectral data of Example 38:
LC/MS (方法： UFLC): RT=3.297 分钟； m/z=549.4 [M+H]+; 总的运行时间为 7.00 分钟. Ή NMR (400MHz, METHANOL-^) δ 8.03 (s, 1H)， 7.74 - 7.60 (m, 2H)， 7.53 (dd, J= 4.8, 8.8 Hz, 1H), 7.31 (t, J= 8.7 Hz, 1H), 7.19 (s, 1H), 6.38 (q, J= 6.3 Hz, 1H), 4.69 - 4.46 (m, 2H), 4.24 - 3.98 (m, 3H), 3.03 (s, 1H)， 2.98 - 2.84 (m, 1H), 2.23 - 2.13 (m, 2H), 2.08 (s, 3H), 1.97 (d, J= 6.5 Hz, 3H). LC/MS (method: UFLC): RT = 3.297 min; m/z = 549.4 [M+H] + ; s s s s s s s s s s s s s s s s s s s s s s s s s s s s , 7.74 - 7.60 (m, 2H), 7.53 (dd, J= 4.8, 8.8 Hz, 1H), 7.31 (t, J= 8.7 Hz, 1H), 7.19 (s, 1H), 6.38 (q, J= 6.3 Hz, 1H), 4.69 - 4.46 (m, 2H), 4.24 - 3.98 (m, 3H), 3.03 (s, 1H), 2.98 - 2.84 (m, 1H), 2.23 - 2.13 (m, 2H), 2.08 ( s, 3H), 1.97 (d, J= 6.5 Hz, 3H).
实施例 39的光谱数据： Spectral data of Example 39:
LC/MS (方法： UFLC): RT = 3.707 分钟； m/z = 549.4 [M+H]+; 总的运行时间为 7.00 分钟. 实施例 40
Figure imgf000047_0002
LC/MS (method: UFLC): RT = 3.707 min; m/z = 549.4 [M+H]+; The total run time was 7.00 min. Example 40
Figure imgf000047_0002
3-氨基 -1-[4-[4-[6-氨基 -5-[1-(2,6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基  3-amino-1-[4-[4-[6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl
吡唑 -1-基]小哌啶基]丙 - 酮 步骤 A:
Figure imgf000047_0003
N— [3-[4-[4-[6-氨基 -5-[ (2,6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基: Pyrazol-1-yl]piperidinyl]propanone Step A:
Figure imgf000047_0003
N — [3-[4-[4-[6-Amino-5-[(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl:
吡唑 -1-基] -1-哌啶基 ]-3-氧代-丙基]氨基甲酸叔丁基酯 操作步骤:  Pyrazole-1-yl]-1-piperidinyl]-3-oxo-propyl]carbamic acid tert-butyl ester Procedure:
将化合物 3-[1-(2,6-二氯 -3-氟-苯基)乙氧基 ]-5-[1-(4-哌啶基) P比唑 -4-基]吡啶 -2-胺盐酸盐 （ 60毫 克， 0.123毫摩尔， 1当量)， 化合物 3- (叔丁氧羰基氨基)丙酸 (23 毫克， 0.147毫摩尔， 1.2当量.) 和 N,N，N，，N，-四甲基 -0-(7-氮杂苯并三唑 -1-基)六氟磷酸脲 (70毫克， 0.184毫摩尔， 1.5当量.)溶 于 2毫升二氯甲烷。 然后搅拌、 冰浴和氮气保护下， 继续缓慢加入 Ν,Ν'-二异丙基乙胺 (79毫 克， 0.615毫摩尔，5当量)。 反应在室温下继续搅拌 12小时。 反应结束后将反应液旋干， 得到 的粗品用 HPLC纯化 (仪器： SHIMADZU LC-8A, 色谱柱： synergi-ΙΟμιη, 250x50mmI.D.流动 相： A为 水 （加 l°/oo TFA, v/v), B为 乙腈， 浓度梯度： B 30-80%， 流速： 80mL /分钟） 得到 目标化合物 （50毫克， 收率为 65%)。 步骤 B: The compound 3-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-5-[1-(4-piperidinyl)P-pyrazol-4-yl]pyridine-2 -amine hydrochloride (60 mg, 0.123 mmol, 1 eq.), compound 3-(tert-butoxycarbonylamino)propanoic acid (23 mg, 0.147 mmol, 1.2 eq.) and N,N,N,,N ,-Tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate (70 mg, 0.184 mmol, 1.5 eq.) was dissolved in dichloromethane (2 mL). Then, stirring, ice bath and nitrogen protection were continued, and hydrazine, Ν'-diisopropylethylamine (79 mg, 0.615 mmol, 5 eq.) was slowly added. The reaction was stirred at room temperature for further 12 hours. After completion of the reaction, the reaction solution was spun dry, and the obtained crude product was purified by HPLC (PLC: SHIMADZU LC-8A, column: synergi-ΙΟμιη, 250×50 mm I.D. mobile phase: A is water (add l°/oo TFA, v/ v), B is acetonitrile, concentration gradient: B 30-80%, flow rate: 80 mL / min) The title compound (50 mg, yield 65%) was obtained. Step B:
Figure imgf000048_0001
Figure imgf000048_0001
3-氨基小 [4-[4-[6-氨基 -5-[l-(2,6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基: 3-Amino small [4-[4-[6-amino-5-[l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl:
吡唑 -1-基]小哌啶基]丙 -1-酮 操作步骤：  Pyrazole-1-yl]piperidinyl]propan-1-one Procedure:
将化合物 N-[3-[4-[4-[6-氨基 -5-[1-(2,6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基]吡唑 -1-基]小哌啶基] -3-氧代-丙基]氨基甲酸叔丁基酯（50毫克， 0.08毫摩尔， 1当量)置于盐酸 /二氧六环（2毫升） 中室温搅拌 3小时。 反应结束后， 将反应液旋干得到粗品。 用 HPLC纯化 （仪器： LC 8A & Gilson 215 熘分收集器色谱柱： Ge分钟 i 200*25mm*5um, 流动相 A: 水， 流动相 B: 乙腈, 流速： 30mL/分钟， 浓度梯度： 17-27%B, 0-12分钟)得到目标化合物 (5.2毫克， 产率 12.4%)。 光谱数据： The compound N-[3-[4-[4-[6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazole -1-yl]piperidinyl]-3-oxo-propyl]carbamic acid tert-butyl ester (50 mg, 0.08 mmol, 1 eq.) in HCl / dioxane (2 mL) Stir for 3 hours. After completion of the reaction, the reaction solution was spun to give a crude product. Purified by HPLC (Instrument: LC 8A & Gilson 215 Separation Collector column: Ge min i 200*25 mm*5 um, mobile phase A: water, mobile phase B: acetonitrile, flow rate: 30 mL/min, concentration gradient: 17- 27% B, 0-12 min) gave the title compound (5.2 mg, yield 12.4%). Spectral data:
LC/MS (方法： UFLC): RT = 0.626 分钟； m/z = 521.1 [M+H]+; 总的运行时间为 2.00 分钟. Ή NMR (400 MHz, D20) δ 7.80 (s, 1H), 7.70 (s， 1H), 7.50 (s, 1H), 7.40 (dd, J = 4.8, 8.8 Hz, 1H), 7.15 (t， J = 8.8 Hz, 1H), 7.05 (s, 1H), 6.30 (q, J = 6.4 Hz, 1H), 4.10-3.96 (m, 2H), 3.77-3.75 (m, 2H), 3.30-3.24 (m， 3H)， 2.89-2.84 (m, 2H)， 2.17-2.1 1 (m, 2H), 1.92-1.78 (m, 5H). 施例 41
Figure imgf000049_0001
LC/MS (method: UFLC): RT = 0.626 min; m/z = 521.1 [M+H]+; The total run time is 2.00 min. NMR (400 MHz, D 2 0) δ 7.80 (s, 1H ), 7.70 (s, 1H), 7.50 (s, 1H), 7.40 (dd, J = 4.8, 8.8 Hz, 1H), 7.15 (t, J = 8.8 Hz, 1H), 7.05 (s, 1H), 6.30 (q, J = 6.4 Hz, 1H), 4.10-3.96 (m, 2H), 3.77-3.75 (m, 2H), 3.30-3.24 (m, 3H), 2.89-2.84 (m, 2H), 2.17-2.1 1 (m, 2H), 1.92-1.78 (m, 5H). Example 41
Figure imgf000049_0001
4-氨基 -l-[4-[4-[6-氨基 -5-[l-(2,6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基  4-Amino-l-[4-[4-[6-amino-5-[l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl
吡唑 -1-基] -1-哌啶基]丁 -1-酮  Pyrazole-1-yl]-1-piperidinyl]butan-1-one
步骤 A:
Figure imgf000049_0002
Step A:
Figure imgf000049_0002
N-[4-[4- [4-[6-氨基 -5-[1-(2, 6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基 吡唑 -1-基] -1-哌啶基 ]-4-氧代丁基]氨基甲酸叔丁基酯 操作步骤: N- [4-[4-[4-[6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridylpyrazole-1- Tert-butyl 1-butylpiperidinyl]-4-oxobutyl]carbamate
将化合物 3-[1-(2,6-二氯 -3-氟-苯基)乙氧基 ]-5-[1-(4-哌啶基) B比唑 -4-基]吡啶 -2-胺盐酸盐 （ 50毫 克， 0.103毫摩尔， 1当量)， 化合物 4- (叔丁氧羰基氨基)丁酸 (27毫克， 0.133毫摩尔， 1.1当量)和 N,N，N，,N，-四甲基 -0-(7-氮杂苯并三唑 -1-基)六氟磷酸脲 (60毫克, 0.155 毫摩尔， 1.5 当量)溶于 10毫升二氯甲垸。 然后搅拌、 冰浴和氮气保护下， 继续缓慢加入 Ν,Ν'-二异丙基乙胺 (100毫 克, 1.03 毫摩尔， 10当量)。 反应在室温下继续搅拌 12小时。 反应结束后将反应液旋干， 得到 的目标化合物直接用于下一步。 步骤 B:
Figure imgf000049_0003
The compound 3-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-5-[1-(4-piperidinyl) B-pyrazol-4-yl]pyridine-2 -amine hydrochloride (50 mg, 0.103 mmol, 1 eq.), compound 4-(tert-butoxycarbonylamino)butyric acid (27 mg, 0.133 mmol, 1.1 eq.) and N,N,N,,N, Tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate (60 mg, 0.155 mmol, 1.5 eq.) was dissolved in 10 mL of dichloromethane. Then, stirring, ice bath and nitrogen protection were continued, and hydrazine, Ν'-diisopropylethylamine (100 mg, 1.03 mmol, 10 eq.) was slowly added. The reaction was stirred at room temperature for further 12 hours. After completion of the reaction, the reaction solution was spun dry, and the obtained target compound was used directly to the next step. Step B:
Figure imgf000049_0003
4-氨基- 1-[4-[4-[6-氨基 -5-[1- (2,6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基] 4-amino- 1-[4-[4-[6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]
吡唑 -1-基] -1-哌啶基]丁 - 酮  Pyrazole-1-yl]-1-piperidinyl]butanone
操作步骤: Steps:
将化合物 Ν-[4-[4-[4- [6-氨基 -5-[1-(2,6-二氯 -3-氟-苯基）乙氧基 ]-3-吡啶基]吡唑 -1-基]小哌啶 基] -4-氧代丁基]氨基甲酸叔丁基酯置于盐酸 /二氧六环 （10毫升） 中室温搅拌 3小时。 反应结 束后， 将反应液旋干得到粗品。 用 HPLC纯化 （仪器： LC 8Α & Gilson 215 馏分收集器 色 谱柱： Synergi 150*30匪 *5u, 流动相 A: 0. 05%HC1 水， 流动相 B: 乙腈， 流速： 30mL/分钟， 浓度梯度： 13-23%B, 0-1 1分钟） 后得到目标化合物 （5.9毫克， 产率为 9%)。 The compound Ν-[4-[4-[4-[6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazole The tert-butyl ester of -1-yl]piperidinyl]-4-oxobutyl]carbamate was stirred in hydrochloric acid / dioxane (10 ml) at room temperature for 3 hr. After completion of the reaction, the reaction solution was spun to give a crude product. Purified by HPLC (instrument: LC 8Α & Gilson 215 fraction collector) Column: Synergi 150*30匪*5u, mobile phase A: 0. 05% HC1 water, mobile phase B: acetonitrile, flow rate: 30 mL/min, concentration gradient: 13-23% B, 0-1 1 min) The title compound was obtained (5.9 mg, yield 9%).
光谱数据： Spectral data:
LC/MS (方法： UFLC): RT=1.636 分钟； m/z = 535.4 [M+H]+; 总的运行时间为 7.00分钟. 1H NMR (400MHz, METHANOL-^) δ 8.19 (s, IH), 7.67 (s, 2H)， 7.52 (br. s" IH), 7.31 (t, J = 8.0 Hz, 1H)， 7.19 (s, 1H)， 6.38 (br, IH), 4.70-4.60 (m, IH), 4.54 (br. s" IH), 4.15-4.10 (m ,1H), 3.35-3.25 (m, IH), 3.03 (br, 2H)， 2.90- 2.86 (m, IH), 2.65 (br, 2H), 2.33-1.96 (m, 9H). LC/MS (method: UFLC): RT = 1.636 min; m/z = 535.4 [M+H] + ; The total run time is 7.00 min. 1H NMR (400MHz, METHANOL-^) δ 8.19 (s, IH) , 7.67 (s, 2H), 7.52 (br. s" IH), 7.31 (t, J = 8.0 Hz, 1H), 7.19 (s, 1H), 6.38 (br, IH), 4.70-4.60 (m, IH ), 4.54 (br. s" IH), 4.15-4.10 (m , 1H), 3.35-3.25 (m, IH), 3.03 (br, 2H), 2.90- 2.86 (m, IH), 2.65 (br, 2H ), 2.33-1.96 (m, 9H).
实施例 42
Figure imgf000050_0001
Example 42
Figure imgf000050_0001
[4-[4-[6-氨基 -5-[ (2，6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基]吡唑 -卜基  [4-[4-[6-Amino-5-[(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazole-buji
-1-哌啶基 ]-(4-哌啶基)甲酮  -1-piperidinyl]-(4-piperidinyl)methanone
步骤 Α:
Figure imgf000050_0002
Step Α:
Figure imgf000050_0002
4-[4-[4-[6-氨基 -5-[ l-(2，6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基]吡唑 -1-基]  4-[4-[4-[6-Amino-5-[ l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazol-1-yl]
-1-哌啶基-羰基]哌啶 -1-甲酸叔丁酯操作步骤：  1-(piperidinyl-carbonyl)piperidine-1-carboxylic acid tert-butyl ester operation steps:
将化合物 3-[1-(2,6-二氯 -3-氟-苯基)乙氧基 ]-5- [1-(4-哌啶基)吡唑 -4-基]吡啶 -2-胺盐酸盐 (50毫克， 0.103 毫摩尔， 1 当量)， 1-叔丁氧基羰基哌啶 -4-羧酸 (26 毫克， 0.113 毫摩尔 ，1.1 当量)和 Ν,Ν,Ν',Ν'-四甲基 -0-(7-氮杂苯并三唑小基)六氟磷酸脲 (60毫克， 0.155 毫摩尔， 1.5当量)溶于 10 毫升二氯甲垸。 然后搅拌、 冰浴和氮气保护下， 继续缓慢加入 Ν,Ν'-二异丙基乙胺 (100毫 克， 1.03毫摩尔， 10当量)。 反应在室温下继续搅拌 12小时。 反应结束后将反应液旋干， 得到 的目标化合物直接用于下一歩。 步骤 Β:
Figure imgf000050_0003
The compound 3-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-5-[1-(4-piperidinyl)pyrazol-4-yl]pyridine-2- Amine hydrochloride (50 mg, 0.103 mmol, 1 eq.), 1-tert-butoxycarbonylpiperidine-4-carboxylic acid (26 mg, 0.113 mmol, 1.1 eq.) and oxime, oxime, Ν', Ν '-Tetramethyl-0-(7-azabenzotriazole small) hexafluorophosphate (60 mg, 0.155 mmol, 1.5 eq.) was dissolved in 10 mL of dichloromethane. Then, stirring, ice bath and nitrogen protection were continued, and hydrazine, Ν'-diisopropylethylamine (100 mg, 1.03 mmol, 10 eq.) was slowly added. The reaction was stirred at room temperature for further 12 hours. After the end of the reaction, the reaction solution was spun dry, and the obtained target compound was directly applied to the next. Step Β:
Figure imgf000050_0003
[4-[4-[6-氨基 -5-[1-(2, 6- 氯 -3-氟-苯基） 乙氧基 ]-3-吡啶基]吡唑小基: -1-哌啶基 ]-(4-哌啶基)甲酮 [4-[4-[6-Amino-5-[1-(2,6-chloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazole small group: 1-piperidinyl]-(4-piperidinyl)methanone
操作步骤： Steps:
将化合物 4-[4-[4-[6-氨基 -5-[1-(2,6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基] P比唑 -1-基] -1-哌啶基-羰 基]哌啶 -1-甲酸叔丁酯置于盐酸 /二氧六环 （10毫升） 中室温搅拌 3小时。 反应结束后， 将反 应液旋干得到粗品。用 HPLC纯化 （仪器： LC 8A & Gilson 215 馏分收集器 色谱柱： Synergi 150*30mm*5u, 流动相 A: 0. 05%HC1 水， 流动相 B: 乙腈， 流速： 30mL/分钟， 浓度梯度: 13-23%B, 0-11分钟） 后得到目标化合物盐酸盐 （3.6 毫克， 产率为 6%)。 The compound 4-[4-[4-[6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]P-pyrazole-1 Tert-butyl 1-(piperidinyl-carbonyl)piperidine-1-carboxylate was stirred in hydrochloric acid / dioxane (10 mL) for 3 hr. After the reaction was completed, the reaction solution was spun to obtain a crude product. Purified by HPLC (Instrument: LC 8A & Gilson 215 Fraction Collector Column: Synergi 150*30mm*5u, Mobile Phase A: 0. 05% HC1 Water, Mobile Phase B: Acetonitrile, Flow Rate: 30 mL/min, Concentration Gradient: The target compound hydrochloride (3.6 mg, 6% yield) was obtained after 13-23% B, 0-11 min.
光谱数据： Spectral data:
LC/MS (方法： UFLC): RT = 1.789分钟； m/z = 561.3 [M+H]+; 总的运行时间为 7.00 分钟。 Ή NMR (400MHz, METHANOL-^) δ 8.04 (s， 1H), 7.67 (s, 2H), 7.54 (dd， J = 4.8， 8.8 Hz, 1H), 7.32 (t, J = 8.8 Hz, 1H), 7.18 (s, 1H), 6.38 (q, J = 6.4 Hz, 1H), 5.00-4.80 (m, 2H), 4.73-4.46 (m, 2H), 4.27-4.23 (m, 0.5H), 4.05-4.00 (m, 0.5H), 3.46-3.36 (m, 2H), 3.18-2,84 (m, 3H), 2.22-1.80 (m, 9H), 1.55-1.51 (m, 2H). 实施例 43
Figure imgf000051_0001
LC/MS (method: UFLC): RT = 1.789 min; m/z = 561.3 [M+H]+; The total run time was 7.00 min. NMR NMR (400MHz, METHANOL-^) δ 8.04 (s, 1H), 7.67 (s, 2H), 7.54 (dd, J = 4.8, 8.8 Hz, 1H), 7.32 (t, J = 8.8 Hz, 1H), 7.18 (s, 1H), 6.38 (q, J = 6.4 Hz, 1H), 5.00-4.80 (m, 2H), 4.73-4.46 (m, 2H), 4.27-4.23 (m, 0.5H), 4.05-4.00 (m, 0.5H), 3.46-3.36 (m, 2H), 3.18-2, 84 (m, 3H), 2.22-1.80 (m, 9H), 1.55-1.51 (m, 2H). Example 43
Figure imgf000051_0001
3-氨基 -l-[4-[4-[6-氨基 -5-[l-(2，6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基] 3-Amino-l-[4-[4-[6-amino-5-[l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]
吡唑 -1-基]小哌啶基] -3-甲基-丁 - 酮  Pyrazole-1-yl]piperidinyl]-3-methyl-butanone
操作步骤： Steps:
将化合物 3-Π-(2，6-二氯 -3-氟-苯基)乙氧基 ]-5-[1 -(4-哌啶基)吡唑 -4-基] P比啶 -2-胺盐酸盐 (50毫克 : 0.103毫摩尔， 1当量)， 3- (叔丁氧羰基氨基) -3-甲基丁酸 （26毫克， 0.113毫摩尔， 1.1当量)和 Ν,Ν,Ν',Ν'-四甲基 -0-(7-氮杂苯并三唑 -1-基)六氟磷酸脲 （60毫克, 0.155 毫摩尔， 1.5当量)溶于 10毫升二氯甲垸。 然后搅拌、 冰浴和氮气保护下， 继续缓慢加入 Ν,Ν'-二异丙基乙胺（100毫 克 1.03毫摩尔， 10当量)。 反应在室温下继续搅拌 12小时。 反应结束后将反应液旋干， 置于 盐酸 /二氧六环（10毫升）中室温搅拌 3小时。反应结束后，将反应液旋干得到粗品。 用 HPLC 纯化 (仪器： LC 8Α & Gilson 215 馏分收集器 色谱柱： Synergi 150*30誦 *5u，流动相 A: 0. 05%HC1 水， 流动相 B: 乙腈， 流速： 30mL/分钟， 浓度梯度： 13-23%B， 0-1 1分钟)得到目标化 合物盐酸盐 (14.9 毫克， 产率为 25%)。 The compound 3-indole-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-5-[1-(4-piperidyl)pyrazol-4-yl]P is pyridine-2 -amine hydrochloride (50 mg : 0.103 mmol, 1 equivalent), 3-(tert-butoxycarbonylamino)-3-methylbutyric acid (26 mg, 0.113 mmol, 1.1 eq.) and hydrazine, hydrazine, hydrazine ', Ν'-tetramethyl- 0-(7-azabenzotriazol-1-yl) hexafluorophosphate (60 mg, 0.155 mmol, 1.5 eq.) was dissolved in 10 ml of dichloromethane. Then, stirring, ice bath and nitrogen protection were continued, and hydrazine, Ν'-diisopropylethylamine (100 mg 1.03 mmol, 10 eq.) was slowly added. The reaction was stirred at room temperature for further 12 hours. After completion of the reaction, the reaction mixture was evaporated to dryness mjjjjl After completion of the reaction, the reaction solution was spun to give a crude product. Purified by HPLC (Instrument: LC 8Α & Gilson 215 Fraction Collector Column: Synergi 150*30诵*5u, Mobile Phase A: 0. 05% HC1 Water, Mobile Phase B: Acetonitrile, Flow Rate: 30 mL/min, Concentration Gradient : 13-23% B, 0-1 1 min) gave the title compound hydrochloride (14.9 mg, yield 25%).
光谱数据： LC/MS (方法： UFLC): RT = 1.801 分钟； m/z = 549.4 [M+H]+; 总的运行时间为 7.00 分钟. 1H NMR (400MHz, METHANOL-^) δ 8.00 (s， IH), 7.64 (s， IH), 7.63 (s， 1H)， 7.51 (dd, J = 4.8, 8.8 Hz, IH), 7.29 (t, J = 8.8 Hz, IH), 7.16 (s， IH), 6.36 (q, J = 6.4 Hz, 1H)， 4.70-4.67 (m, IH), 4.54-4.49 (m, IH), 4.12-4.09 (m, IH), 3.40-3.20 (m, IH), 2.90 - 2.67 (m, 3H), 2.22 - 2.08 (m, 2H)， 2.05-1.90 (m, 5H), 1.45-1.43 (m, 6H). Spectral data: LC/MS (method: UFLC): RT = 1.801 min; m/z = 549.4 [M+H] + ; The total run time is 7.00 min. 1H NMR (400MHz, METHANOL-^) δ 8.00 (s, IH) , 7.64 (s, IH), 7.63 (s, 1H), 7.51 (dd, J = 4.8, 8.8 Hz, IH), 7.29 (t, J = 8.8 Hz, IH), 7.16 (s, IH), 6.36 ( q, J = 6.4 Hz, 1H), 4.70-4.67 (m, IH), 4.54-4.49 (m, IH), 4.12-4.09 (m, IH), 3.40-3.20 (m, IH), 2.90 - 2.67 ( m, 3H), 2.22 - 2.08 (m, 2H), 2.05-1.90 (m, 5H), 1.45-1.43 (m, 6H).
实施例 44
Figure imgf000052_0001
Example 44
Figure imgf000052_0001
[4-[4-[6-氨基 -5-[l-(2，6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基] P比唑 -1-基 [4-[4-[6-Amino-5-[l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]P-pyrazole-1-yl
-1-哌啶基]- (氮杂环丁烷 -3-基)甲酮  -1-piperidinyl]-(azetidin-3-yl)methanone
操作步骤: Steps:
将化合物 3-[l-(2,6-二氯 -3-氟-苯基)乙氧基 ]-5-[l-(4-哌啶基)吡唑 -4-基]吡啶 -2-胺盐酸盐 （ 50毫 克， 0.103毫摩尔， 1当量)， 1-叔丁氧基羰基氮杂环丁垸 -3-羧酸（ 23毫克， 0.133毫摩尔 ,1.1当量) 和 Ν,Ν,Ν',Ν'-四甲基 -0-(7-氮杂苯并三唑 -1-基)六氟磷酸脲 (60毫克， 0.155毫摩尔， 1.5当量)溶 于 10毫升二氯甲垸。 然后搅拌、 冰浴和氮气保护下， 继续缓慢加入 N，N，-二异丙基乙胺 （100 毫克， 1.03毫摩尔， 10当量)。 反应在室温下继续搅拌 12小时。 反应结束后将反应液旋干， 置 于盐酸 /二氧六环 （10毫升） 中室温搅拌 3 小时。 反应结束后， 将反应液旋干得到粗品。 用 HPLC纯化 （仪器： LC 8A & Gilson 215 馏分收集器 色谱柱： Synergi 150*30画 *5u, 流动相 A: 0. 05%HC1 水， 流动相 B: 乙腈， 流速： 30mL/分钟， 浓度梯度： 17-27%B, 0-12分钟) 后得到 目标化合物盐酸盐 （12.6毫克， 产率为 19%)。 The compound 3-[l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-5-[l-(4-piperidinyl)pyrazol-4-yl]pyridine-2- Amine hydrochloride (50 mg, 0.103 mmol, 1 eq.), 1-tert-butoxycarbonylazetidin-3-carboxylic acid (23 mg, 0.133 mmol, 1.1 eq.) ', Ν'-tetramethyl- 0-(7-azabenzotriazol-1-yl) hexafluorophosphate (60 mg, 0.155 mmol, 1.5 eq.) was dissolved in 10 ml of dichloromethane. Then, N,N,-diisopropylethylamine (100 mg, 1.03 mmol, 10 equivalents) was added slowly under stirring, ice bath and nitrogen. The reaction was stirred at room temperature for further 12 hours. After the reaction was completed, the reaction mixture was evaporated to dryness mjjjjd After completion of the reaction, the reaction solution was spun to give a crude product. Purified by HPLC (instrument: LC 8A & Gilson 215 fraction collector column: Synergi 150*30 draw *5u, mobile phase A: 0. 05% HC1 water, mobile phase B: acetonitrile, flow rate: 30 mL/min, concentration gradient : 17-27% B, 0-12 min) The title compound hydrochloride (12.6 mg, yield 19%) was obtained.
光谱数据: Spectral data:
LC/MS (方法： UFLC): RT = 1.646分钟； m/z = 533.3 [M+H]+ ; 总的运行时间为 7.00分钟。 Ή NMR (400MHz, METHANOL-d4) δ 8.03 (s, IH), 7.69 - 7.66 (m, 2H), 7.53 (dd, J = 4.8, 8.8 Hz, IH), 7.32 (t, J = 8.8 Hz, 1H)， 7.18 (s, IH), 6.46 - 6.31 (q, J = 6.8 Hz, IH), 4.65-4.62 (m, IH), 4.53 (br. s.， IH), 4.42 - 4.25 (m, 4H), 4.19-4.13 (m, IH), 3.80-3.77 (m, IH), 3.36-3.26 (m, IH), 2.98-2.92 (m, IH), 2.15-1.86 (m, 7H). 实施例 45
Figure imgf000052_0002
(1 -氨基环丁基) -[4-[4-[6-氨基 -5-[l-(2,6-二氯- 3-氟-苯基)乙氧基] LC/MS (method: UFLC): RT = 1.646 min; m/z = 533.3 [M+H] + ; NMR NMR (400MHz, METHANOL-d 4 ) δ 8.03 (s, IH), 7.69 - 7.66 (m, 2H), 7.53 (dd, J = 4.8, 8.8 Hz, IH), 7.32 (t, J = 8.8 Hz, 1H), 7.18 (s, IH), 6.46 - 6.31 (q, J = 6.8 Hz, IH), 4.65-4.62 (m, IH), 4.53 (br. s., IH), 4.42 - 4.25 (m, 4H ), 4.19-4.13 (m, IH), 3.80-3.77 (m, IH), 3.36-3.26 (m, IH), 2.98-2.92 (m, IH), 2.15-1.86 (m, 7H). Example 45
Figure imgf000052_0002
(1-Aminocyclobutyl)-[4-[4-[6-amino-5-[l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]
-3-吡啶基] P比唑小基] -1-哌啶基]甲酮  -3-pyridyl] P-pyridazinyl]-1-piperidinyl]methanone
操作步骤： Steps:
将化合物 3-[1-(2,6-二氯 -3-氟-苯基)乙氧基 ]-5-[1-(4-哌啶基)吡唑 -4-基]吡啶 -2-胺盐酸盐 (50毫克， 0.103毫摩尔， 1当量)， 化合物 1- (叔丁氧羰基氨基)环丁烷羧酸 (25毫克， 0.113毫摩尔， 1.1当 量)和 Ν,Ν,Ν',Ν'-四甲基 -0-(7-氮杂苯并三唑 -1-基)六氟磷酸脲 (60毫克， 0.155毫摩尔， 1.5当量） 溶于 10毫升二氯甲烷。然后搅拌、冰浴和氮气保护下，继续缓慢加入 Ν,Ν'-二异丙基乙胺 (100 毫克， 1.03毫摩尔 10当量)。 反应在室温下继续搅拌 12小时。 反应结束后将反应液旋干， 置 于盐酸二氧六环 (10毫升)中室温搅拌 3小时。反应结束后， 将反应液旋干得到粗品。用 HPLC 纯化 （仪器： LC 8Α & Gilson 215 馏分收集器 色谱柱： Synergi 150*30隱 *5u, 流动相 A: 0.05%HC1 水， 流动相 B: 乙腈， 流速： 30mL/分钟， 浓度梯度： 17-27%B， 0-12分钟） 后得到目 标化合物盐酸盐 （11.4毫克， 产率为 17%)。 The compound 3-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-5-[1-(4-piperidinyl)pyrazol-4-yl]pyridine-2- Amine hydrochloride (50 mg, 0.103 mmol, 1 eq.), Compound 1-(tert-butoxycarbonylamino)cyclobutanecarboxylic acid (25 mg, 0.113 mmol, 1.1 eq.) Ν'-Tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate (60 mg, 0.155 mmol, 1.5 eq.) was dissolved in 10 mL dichloromethane. Then, stirring, ice bath and nitrogen protection were continued, and hydrazine, Ν'-diisopropylethylamine (100 mg, 1.03 mmol, 10 equivalents) was added slowly. The reaction was stirred at room temperature for further 12 hours. After the reaction was completed, the reaction mixture was evaporated to dryness mjjjjjjjjjj After completion of the reaction, the reaction solution was spun to give a crude product. Purified by HPLC (Instrument: LC 8Α & Gilson 215 Fraction Collector Column: Synergi 150*30 Implicit *5u, Mobile Phase A: 0.05% HC1 Water, Mobile Phase B: Acetonitrile, Flow Rate: 30 mL/min, Concentration Gradient: 17 The target compound hydrochloride (11.4 mg, yield 17%) was obtained after -27% B, 0-12 min.
光谱数据： Spectral data:
LC/MS (方法： UFLC): RT = 1.778 分钟； m/z = 547.4 [M+H]+; 总的运行时间为 7.00 分钟. 1H NMR (400MHz, METHANOL- ） δ 8.03 (s, 1H), 7.70 - 7.59 (m, 2H), 7.51 (dd, J= 4.8, 8.8 Hz, 1H), 7.29 (t, J= 8.8 Hz, 1H)， 7.17 (s, 1H), 6.36 (q, J = 6,4 Hz, 1H), 4.60-4.52 (m, 1H), 4.40-4.20 (m, 1H), 3.36-3.09 (m, 3H), 2.97 - 2.86 (m, 2H), 2.41 - 2.30 (m, 3H), 2.21 -2.12 (m, 2H), 2.09-1.95 (m, 3H), 1.95 (d, J = 6.0 Hz, 3H). 实施例 46
Figure imgf000053_0001
LC/MS (method: UFLC): RT = 1.778 min; m/z = 547.4 [M+H] + ; </ RTI>< / RTI>< / RTI>< / RTI>< / RTI><RTIgt; 7.70 - 7.59 (m, 2H), 7.51 (dd, J= 4.8, 8.8 Hz, 1H), 7.29 (t, J= 8.8 Hz, 1H), 7.17 (s, 1H), 6.36 (q, J = 6, 4 Hz, 1H), 4.60-4.52 (m, 1H), 4.40-4.20 (m, 1H), 3.36-3.09 (m, 3H), 2.97 - 2.86 (m, 2H), 2.41 - 2.30 (m, 3H) , 2.21 -2.12 (m, 2H), 2.09-1.95 (m, 3H), 1.95 (d, J = 6.0 Hz, 3H). Example 46
Figure imgf000053_0001
l-[4-[4-[6-氨基 -5-[l-(2,6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基] P比唑 -1-基]  1-[4-[4-[6-Amino-5-[l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]P-pyrazol-1-yl ]
-1 -哌啶基 ]-2-甲基 -2-(甲基氨基)丙 -1 -酮 操作步骤：  -1 -piperidinyl]-2-methyl-2-(methylamino)propan-1-one
将化合物 3-[1 -(2，6-二氯 -3-氟-苯基)乙氧基 ]-5-[1 -(4-哌啶基)吡唑 -4-基]吡啶 -2-胺（ 50毫克， 0.11 1 毫摩尔 ,1 当量)， 2- [苄氧羰基 (甲基)氨基] -2-甲基丙酸（ 29 毫克， 0.122 毫摩尔， 1.1 当量)和 Ν,Ν,Ν',Ν'-四甲基 -0-(7-氮杂苯并三唑- 基)六氟磷酸脲 (64毫克， 0.166毫摩尔， 1.5当量)溶于 10 毫升二氯甲垸。 然后搅拌、 冰浴和氮气保护下， 继续缓慢加入 Ν，Ν'-二异丙基乙胺 (72 毫克，The compound 3-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-5-[1-(4-piperidyl)pyrazol-4-yl]pyridine-2- Amine (50 mg, 0.11 1 mmol, 1 eq.), 2-[benzyloxycarbonyl(methyl)amino]-2-methylpropanoic acid (29 mg, 0.122 mmol, 1.1 eq.) ', Ν'-tetramethyl- 0-(7-azabenzotriazol-yl) hexafluorophosphate (64 mg, 0.166 mmol, 1.5 eq.) was dissolved in 10 ml of dichloromethane. Then stir, ice bath and nitrogen protection, continue to slowly add Ν, Ν'-diisopropylethylamine (72 mg,
0.555毫摩尔，，5当量)。 反应在室温下继续 拌 12小时。 反应结束后将反应液旋干， 溶于甲 醇（10毫升） 中， 室温搅拌中加入氢氧化钯（0.2克)。 置换空气后， 将反应液置于氢气气氛下 反应搅拌 3小时。 反应结束后， 将反应液过滤、 旋干得到粗品， 用 HPLC纯化 (仪器： LC 8A & Gilson 215 馏分收集器 色谱柱： Synergi 150*30誦 *5u,流动相 A: 0. 05%HC1 水,流动相 B: 乙腈， 流速： 30mL/分钟， 浓度梯度： 13-23%B，0-1 1分钟)得到目标化合物盐酸盐 (10.2毫克， 产 率为 15%)。 0.555 mmol, 5 equivalents). The reaction was continued to mix for 12 hours at room temperature. After the reaction is over, the reaction solution is spun dry and dissolved in a Palladium hydroxide (0.2 g) was added to the alcohol (10 ml) with stirring at room temperature. After replacing the air, the reaction solution was placed under a hydrogen atmosphere and stirred for 3 hours. After the reaction was completed, the reaction mixture was filtered and dried to give a crude material, which was purified by HPLC ( Instrument: LC 8A & Gilson 215 fraction collector column: Synergi 150*30诵*5u, mobile phase A: 0.5% HCl water, Mobile phase B: acetonitrile, flow rate: 30 mL/min, concentration gradient: 13-23% B, 0-1 1 min) The title compound hydrochloride (10.2 mg, yield 15%) was obtained.
光谱数据： Spectral data:
LC/MS (方法： UFLC): RT = 1.757 分钟； m/z = 549.4 [M+H]+; 总的运行时间为 7.00 分钟。 Ή NMR (400MHz, METHANOL-^) δ 8.02 (s, 1H), 7.70 (s， 1H), 7.60 (s， 1H), 7.53 (dd, J = 4.8, 8.8 Hz, 1H), 7.31 (t, J= 8.8 Hz, 1H), 7.19 (d, J= 1.6 Hz, 1H), 6.38 (q, J= 6.4 Hz, 1H), 4.59-4.47 (m, 3H), 3.10 (br, 2H), 2.71 (s, 3H), 2.21-2.18 (m, 2H), 2.07 - 1.96 (m, 5H), 1.73 (s, 6H). 实施例 47
Figure imgf000054_0001
LC/MS (method: UFLC): RT = 1.757 min; m/z = 549.4 [M+H] + ; The total run time was 7.00 min. NMR NMR (400MHz, METHANOL-^) δ 8.02 (s, 1H), 7.70 (s, 1H), 7.60 (s, 1H), 7.53 (dd, J = 4.8, 8.8 Hz, 1H), 7.31 (t, J = 8.8 Hz, 1H), 7.19 (d, J= 1.6 Hz, 1H), 6.38 (q, J= 6.4 Hz, 1H), 4.59-4.47 (m, 3H), 3.10 (br, 2H), 2.71 (s , 3H), 2.21-2.18 (m, 2H), 2.07 - 1.96 (m, 5H), 1.73 (s, 6H). Example 47
Figure imgf000054_0001
[4-[4-[6-氨基 -5-[(lR)-l-(2，6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基] P比唑 -1-基] [4-[4-[6-Amino-5-[(lR)-l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl] P-pyrazole-1 -base]
-1 -哌啶基 ]-[(3R)-四氢吡咯 -3-基]甲酮 操作步骤:  -1 -piperidinyl]-[(3R)-tetrahydropyrrole-3-yl]methanone
将化合物 3-[(lR)-l -(2,6-二氯 -3-氟-苯基)乙氧基 ]-5-[l-(4-哌啶基)吡唑 -4-基] P比啶 -2-胺（ 50毫克, 0.111毫摩尔， 1当量)， （3R)-1-叔丁氧基羰基吡咯垸 -3-羧酸（ 27毫克， 0.122毫摩尔， 1.1当量) 和 N，N，N',N，-四甲基 -0-(7-氮杂苯并三唑 -1 -基)六氟磷酸脲 (64毫克， 0.166毫摩尔， 1.5当量)溶 于 10 毫升二氯甲烷。 然后搅拌、 冰浴和氮气保护下， 继续缓慢加入 Ν,Ν'-二异丙基乙胺 (72 毫克, 0.555 毫摩尔，5当量)。 反应在室温下继续搅拌 12小时。 反应结束后将反应液旋干， 置 于盐酸 /二氧六环 （10 毫升） 中室温搅拌 3 小时。 反应结束后， 将反应液旋干得到粗品， 用 HPLC纯化 (仪器： LC 8Α & Gilson 215 馏分收集器 色谱柱： Synergi 150*30mm*5u, 流动相 A: 0. 05%HC1 水,流动相 B: 乙腈， 流速： 30mL/分钟，浓度梯度： 13-23%B, 0- 1 1分钟) 得到目标 化合物的盐酸盐 (33.3mg， 收率为 50%)。 The compound 3-[(lR)-l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-5-[l-(4-piperidyl)pyrazol-4-yl] P-pyridin-2-amine (50 mg, 0.111 mmol, 1 eq.), (3R)-1-tert-butoxycarbonylpyrrole-3-carboxylic acid (27 mg, 0.122 mmol, 1.1 eq.) and N , N, N', N,-tetramethyl- 0-(7-azabenzotriazol-1-yl) hexafluorophosphate (64 mg, 0.166 mmol, 1.5 eq.) dissolved in 10 mL of dichloro Methane. Then, under stirring, ice bath and nitrogen, continue to slowly add hydrazine, Ν'-diisopropylethylamine (72 mg, 0.555 mmol, 5 eq.). The reaction was stirred at room temperature for further 12 hours. After the reaction was completed, the reaction mixture was evaporated to dryness mjjjjjjjjjjj After completion of the reaction, the reaction solution was dried to give a crude material, which was purified by HPLC (PLC: LC 8 Α & Gilson 215 fraction collector column: Synergi 150*30mm*5u, mobile phase A: 0.5% HCl water, mobile phase B : acetonitrile, flow rate: 30 mL/min, concentration gradient: 13-23% B, 0 - 1 1 min) The hydrochloride salt of the title compound (33.3 mg, yield 50%).
光谱数据： Spectral data:
LC/MS (方法： UFLC): RT = 1.573分钟； m/z = 547.3 [M+H]+; 总的运行时间为 7.00分钟. 1H NMR (400 MHz, METHANOL- ) δ 8.05 (s, IH), 7.68 (s, 2H)， 7.53 (dd, J = 4.8， 8.8 Hz, IH), 7.32 (t, J = 8.8 Hz, IH), 7.18 (s, IH), 6,38 (q, J = 6.4 Hz, IH), 4.66-4.50 (m, 2H), 4.22-4.19 (m, IH), 3.76-3.54 (m, 2H), 3.41-3.36 (m, 4H)， 2.96-2.90 (m, IH), 2.43 (br, IH), 2.22-1.96 (m, 8H). 实施例 48
Figure imgf000055_0001
LC/MS (method: UFLC): RT = 1.573 min; m/z = 547.3 [M+H] + ; The total run time is 7.00 min. 1H NMR (400 MHz, METHANOL-) δ 8.05 (s, IH), 7.68 (s, 2H), 7.53 (dd, J = 4.8, 8.8 Hz, IH), 7.32 (t, J = 8.8 Hz, IH), 7.18 (s, IH), 6,38 (q, J = 6.4 Hz, IH), 4.66-4.50 (m, 2H), 4.22-4.19 (m, IH), 3.76-3.54 (m, 2H), 3.41- 3.36 (m, 4H), 2.96-2.90 (m, IH), 2.43 (br, IH), 2.22-1.96 (m, 8H). Example 48
Figure imgf000055_0001
[4-[4-[6-氨基 -5-[(lR)- (2，6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基]吡唑小基]  [4-[4-[6-Amino-5-[(lR)-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazole small group]
-1-哌啶基 ]-[(3S)-四氢吡咯 -3-基]甲酮  -1-piperidinyl]-[(3S)-tetrahydropyrrole-3-yl]methanone
操作步骤： Steps:
将化合物 3-[(lR)-l-(2,6-二氯 -3-氟-苯基)乙氧基 ]-5-[1-(4-哌啶基)吡唑 -4-基]吡啶 -2-胺 （50毫克, 0.111毫摩尔， 1当量)， （3S)-1-叔丁氧基羰基吡咯垸 -3-羧酸 （27毫克， 0.122毫摩尔， 1.1当量) 和 Ν,Ν,Ν',Ν'-四甲基 -0- (7-氮杂苯并三唑 -1-基)六氟磷酸脲 (64毫克， 0.166毫摩尔， 1.5当量)溶 于 10 毫升二氯甲烷。 然后搅拌、 冰浴和氮气保护下， 继续缓慢加入 Ν，Ν'-二异丙基乙胺 （72 毫克, 0.555 毫摩尔，5当量.；)。 反应在室温下继续搅拌 12小时。 反应结束后将反应液旋干， 置 于盐酸 /二氧六环（10毫升）中室温搅拌 3小时。反应结束后，将反应液旋干得到粗品,用 HPLC 纯化 (仪器： LC 8Α & Gilson 215 馏分收集器 色谱柱： Synergi 150*30讓 *5u,流动相 A: 0. 05%HC1 水， 流动相 B: 乙腈， 流速： 30mL/分钟， 浓度梯度： 13-23%B, 0-1 1分钟)得到目标化 合物的盐酸盐 (21.6毫克， 产率为 32%). The compound 3-[(lR)-l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-5-[1-(4-piperidyl)pyrazol-4-yl] Pyridin-2-amine (50 mg, 0.111 mmol, 1 eq.), (3S)-1-tert-butoxycarbonylpyrrole-3-carboxylic acid (27 mg, 0.122 mmol, 1.1 eq.) , Ν', Ν'-tetramethyl-0-(7-azabenzotriazol-1-yl) hexafluorophosphate (64 mg, 0.166 mmol, 1.5 eq.) was dissolved in 10 mL of dichloromethane. Then, under stirring, ice bath and nitrogen, continue to slowly add hydrazine, Ν'-diisopropylethylamine (72 mg, 0.555 mmol, 5 eq.;). The reaction was stirred at room temperature for further 12 hours. After the reaction was completed, the reaction mixture was evaporated to dryness mjjjjjjjjjjjj After completion of the reaction, the reaction solution was dried to give a crude product which was purified by HPLC (PLC: LC 8 Α & Gilson 215 fraction collector column: Synergi 150*30 let *5u, mobile phase A: 0.5% HCl water, mobile phase B: acetonitrile, flow rate: 30 mL/min, concentration gradient: 13-23% B, 0-1 1 min) The title compound hydrochloride (21.6 mg, yield 32%).
光谱数据： Spectral data:
LC/MS (方法： UFLC): RT = 1.641分钟； m/z = 548.4 [M+H]+; 总的运行时间为 7.00分钟。 Ή NMR (400 MHz, METHANOL-d4) δ 8.03 (s, I H), 7.67 (s, 1H)， 7.65 (s， IH), 7.53 (dd, J= 4.8， 8.8 Hz, IH), 7.32 (t, J= 8.8 Hz, IH), 7.18 (d, J= 1.2 Hz, 1H)， 6.38 (q, J= 6.8 Hz, IH), 4.66-4.47 (m, 2H), 4.22-4.19 (m, 1H)， 3.69-3.63 (m， 2H), 3.43-3.33 (m, 4H), 2.96-2.89 (m,lH), 2.44-2.40 (m, 1H)， 2.22-1.92 (m, 8H). 实施例 49
Figure imgf000055_0002
LC/MS (method: UFLC): RT = 1.641 min; m/z = 548.4 [M+H]+; NMR NMR (400 MHz, METHANOL-d4) δ 8.03 (s, IH), 7.67 (s, 1H), 7.65 (s, IH), 7.53 (dd, J= 4.8, 8.8 Hz, IH), 7.32 (t, J = 8.8 Hz, IH), 7.18 (d, J = 1.2 Hz, 1H), 6.38 (q, J = 6.8 Hz, IH), 4.66-4.47 (m, 2H), 4.22-4.19 (m, 1H), 3.69-3.63 (m, 2H), 3.43-3.33 (m, 4H), 2.96-2.89 (m, lH), 2.44-2.40 (m, 1H), 2.22-1.92 (m, 8H). Example 49
Figure imgf000055_0002
[4— [4-[6-氨基 -5-[(lR)-l-(2,6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基]吡唑 -1-基  [4-[4-[6-Amino-5-[(lR)-l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazole-1- Base
小哌啶基] -[(3S)-吗啉 -3-基]甲酮 操作步骤： Small piperidinyl]-[(3S)-morpholin-3-yl]methanone Steps:
将化合物 3-[(lR)-l-(2 6-二氯 -3-氟-苯基)乙氧基 ]-5-[1-(4-哌啶基)吡唑 -4-基]吡啶 -2-胺 （50毫克， 0.111毫摩尔， 1 当量)， （3S)-4- (叔丁氧羰基)吗啉 -3-羧酸 （29毫克， 0.122毫摩尔， 1.1 当量)和 Ν,Ν,Ν',Ν'-四甲基 -0-(7-氮杂苯并三唑- 基)六氟磷酸脲 （64毫克， 0.166毫摩尔， 1.5当量)溶于 10毫升二氯甲垸。 然后搅拌、 冰浴和氮气保护下， 继续缓慢加入 Ν,Ν'-二异丙基乙胺 （72 毫 克， 0.555毫摩尔，5当量)。 反应在室温下继续搅拌 12小时。 反应结束后将反应液旋干， 置于 盐酸 /二氧六环（10毫升）中室温搅拌 3小时。反应结束后，将反应液旋干得到粗品。用 HPLC 纯化 （仪器： LC 8Α & Gilson 215 馏分收集器 色谱柱： Synergi 150*30 *5u， 流动相 A: 0. 05%HC1 水， 流动相 B: 乙腈， 流速： 30mL/分钟， 浓度梯度： 13-23%B, 0-1 1分钟） 得到目标 化合物的盐酸盐 (28.1mg， 收率为 42 The compound 3-[(lR)-l-(2 6-dichloro-3-fluoro-phenyl)ethoxy]-5-[1-(4-piperidinyl)pyrazol-4-yl]pyridine 2-Amine (50 mg, 0.111 mmol, 1 eq.), (3S)-4-(tert-butoxycarbonyl)morpholine-3-carboxylic acid (29 mg, 0.122 mmol, 1.1 eq.) , Ν', Ν'-tetramethyl- 0-(7-azabenzotriazol-yl) hexafluorophosphate (64 mg, 0.166 mmol, 1.5 eq.) was dissolved in 10 mL of dichloromethane. Then, under stirring, ice bath and nitrogen, continue to slowly add hydrazine, Ν'-diisopropylethylamine (72 mg, 0.555 mmol, 5 eq.). The reaction was stirred at room temperature for further 12 hours. After the reaction was completed, the reaction mixture was evaporated to dryness mjjjjjjjjjj After completion of the reaction, the reaction solution was spun to give a crude product. Purified by HPLC (instrument: LC 8 Α & Gilson 215 fraction collector column: Synergi 150*30 *5u, mobile phase A: 0. 05% HCl water, mobile phase B: acetonitrile, flow rate: 30 mL/min, concentration gradient: 13-23% B, 0-1 1 min) The hydrochloride salt of the title compound (28.1 mg, yield 42
光谱数据： Spectral data:
LC/MS (方法： UFLC): RT = 1.584分钟； m/z = 563.3 [M+H]+; 总的运行时间为 7.00 分钟。 1H NMR (400 MHz, Methanol-d4) δ 8.05 (s, 1H), 7.70-7.66 (m 2H), 7,54 (dd, J = 4.8, 8.8 Hz, 1H), 7.30 (t, J = 8.4 Hz, 1H), 7.19 (s, 1H), 6.40 (q, J = 6.4 Hz, 1H)， 4.70-4.56 (m, 3H), 4.29-4.25 (m, 1H), 4.09-4.05 (m, 2H), 3.83-3.59 (m, 2H), 3.39 (br, 3H), 3.06-2.92 (m 1H), 2.29-2.20 (m, 3H), 2.05-1.96 (m, 4H). LC/MS (method: UFLC): RT = 1.584 min; m/z = 563.3 [M+H] + ; 1H NMR (400 MHz, Methanol-d 4 ) δ 8.05 (s, 1H), 7.70-7.66 (m 2H), 7,54 (dd, J = 4.8, 8.8 Hz, 1H), 7.30 (t, J = 8.4 Hz, 1H), 7.19 (s, 1H), 6.40 (q, J = 6.4 Hz, 1H), 4.70-4.56 (m, 3H), 4.29-4.25 (m, 1H), 4.09-4.05 (m, 2H) , 3.83-3.59 (m, 2H), 3.39 (br, 3H), 3.06-2.92 (m 1H), 2.29-2.20 (m, 3H), 2.05-1.96 (m, 4H).
实施例 50  Example 50
Figure imgf000056_0001
Figure imgf000056_0001
2-氨基 -l-[4- [4-[6-氨基 -5-[(lR)-l-(2,6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基]  2-Amino-l-[4-[4-[6-amino-5-[(lR)-l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl) ]
吡唑 -1-基] -1-哌啶基 ]-3 3,3-三氟-丙 -卜酮  Pyrazole-1-yl]-1-piperidinyl]-3 3,3-trifluoro-propanone
操作步骤： Steps:
将化合物 3-[(lR)-l-(2,6-二氯 -3-氟-苯基)乙氧基 ]-5-[1-(4-哌啶基)吡唑 -4-基]口比啶 -2-胺 （10毫克, 0.0222毫摩尔， 1当量)，化合物 2- (叔丁氧羰基氨基) -3,3 3-三氟丙酸 (3.5毫克, 0.0244毫摩尔， 1.1 当量） 和 Ν,Ν,Ν',Ν'-四甲基 -0-(7-氮杂苯并三唑 -1 -基)六氟磷酸脲 （12.6毫克， 0.033毫摩尔， 1.5 当量)溶于 5毫升二氯甲垸。 然后搅拌、 冰浴和氮气保护下， 继续缓慢加入 Ν,Ν'-二异丙基乙 胺 （ 14.3毫克， 0.111毫摩尔， 5当量)。 反应在室温下搅拌 2小时。 反应结束后将反应液旋干， 置于盐酸 /二氧六环 （10毫升） 中室温搅拌 3小时。 反应结束后， 将反应液用二氯甲垸稀释， 有机层用碳酸氢钠溶液和食盐水各反洗一次， 再用硫酸钠干燥后旋干， 得到的粗品采用用 HPLC纯化 (仪器： LC 8Α & Gilson 215 馏分收集器 色谱柱： Synergi 150*30 *5u,流动相 A: 0. 05%HC1 水,流动相 B: 乙腈， 流速： 30mL/分钟， 浓度梯度： 13-23%B, 0-11分钟)得到目标化 合物的盐酸盐 （8毫克， 产率为 61%)。 The compound 3-[(lR)-l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-5-[1-(4-piperidyl)pyrazol-4-yl] Methylpyridin-2-amine (10 mg, 0.0222 mmol, 1 eq.), compound 2-(tert-butoxycarbonylamino)-3,3 3-trifluoropropionic acid (3.5 mg, 0.0244 mmol, 1.1 eq.) And hydrazine, hydrazine, hydrazine, Ν'-tetramethyl- 0-(7-azabenzotriazol-1-yl) hexafluorophosphate (12.6 mg, 0.033 mmol, 1.5 eq.) dissolved in 5 ml Dichloromethane. Then, stirring, ice bath and nitrogen protection were continued, and hydrazine, Ν'-diisopropylethylamine ( 14.3 mg, 0.111 mmol, 5 eq.) was slowly added. The reaction was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was evaporated to dryness mjjjjjjjjjj After completion of the reaction, the reaction mixture was diluted with dichloromethane, and the organic layer was washed with sodium bicarbonate solution and brine, then dried over sodium sulfate and then evaporated to dryness. The crude product was purified by HPLC (PLC: LC 8 Α & Gilson 215 Fraction Collector Column: Synergi 150*30 *5u, Mobile Phase A: 0. 05% HCl water, mobile phase B: acetonitrile, flow rate: 30 mL/min, concentration gradient: 13-23% B, 0-11 min) The desired compound hydrochloride (8 mg, yield 61%) .
光谱数据： Spectral data:
LC/MS (方法： UFLC): m/z = 575 [M+H]+. 实施例 51
Figure imgf000057_0001
LC/MS (method: UFLC): m/z = 575 [M+H] + .
Figure imgf000057_0001
[4-[4-[6-氨基 -5-[(lR)小 (2，6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基] P比唑 - 基  [4-[4-[6-Amino-5-[(lR) small (2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]P-pyrazole-yl
-1-哌啶基 ]-[(3S)-3-哌啶基]甲酮  -1-piperidinyl]-[(3S)-3-piperidinyl]methanone
操作步骤： Steps:
将化合物 3-[(lR)-l-(2,6-二氯 -3-氟-苯基)乙氧基 ]-5-[1-(4-哌啶基) P比唑 -4-基] P比啶 -2-胺 （300 毫 克， 0.666毫摩尔， 1当量)，(3S)-1 -叔丁氧基羰基哌啶 -3-羧酸 （168毫克， 0.733毫摩尔， 1.1当量) 和 N，N,N'，N，-四甲基 -0-(7-氮杂苯并三唑 -1 -基)六氟磷酸脲（384毫克, 0.999 毫摩尔， 1.5当量) 溶于 30 毫升二氯甲烷。然后搅拌、冰浴和氮气保护下，继续缓慢加入 Ν，Ν ' -二异丙基乙胺 （430 毫克, 3.33 毫摩尔，5当量)。 反应在室温下继续搅拌 12小时。 反应结束后将反应液旋千， 置于 盐酸 /二氧六环（30毫升）中室温搅拌 3小时。反应结束后，将反应液旋干得到粗品。用 HPLC 纯化 （仪器： LC 8Α & Gilson 215 馏分收集器 色谱柱： Synergi 150*30圍 *5u， 流动相 A: 0. 05%HC1 水， 流动相 B: 乙腈， 流速： 30mL/分钟， 浓度梯度： 13-23%B, 0-1 1分钟） 得到目标 化合物的盐酸盐 （213毫克， 产率为 53%)。 The compound 3-[(lR)-l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-5-[1-(4-piperidinyl)P-pyrazol-4-yl P-pyridin-2-amine (300 mg, 0.666 mmol, 1 equivalent), (3S)-1 -tert-butoxycarbonylpiperidine-3-carboxylic acid (168 mg, 0.733 mmol, 1.1 eq.) N,N,N',N,-tetramethyl-O-(7-azabenzotriazol-1-yl) hexafluorophosphate (384 mg, 0.999 mmol, 1.5 eq.) dissolved in 30 ml Methyl chloride. Then, under stirring, ice bath and nitrogen, continue to slowly add hydrazine, Ν'-diisopropylethylamine (430 mg, 3.33 mmol, 5 eq.). The reaction was stirred at room temperature for further 12 hours. After the completion of the reaction, the reaction mixture was stirred for 1 hour, and the mixture was stirred at room temperature for 3 hours under hydrochloric acid / dioxane (30 ml). After completion of the reaction, the reaction solution was spun to give a crude product. Purified by HPLC (instrument: LC 8 Α & Gilson 215 fraction collector column: Synergi 150*30 circumference *5u, mobile phase A: 0. 05% HCl water, mobile phase B: acetonitrile, flow rate: 30 mL/min, concentration gradient : 13-23% B, 0-1 1 min) The hydrochloride salt of the title compound (213 mg, yield: 53%).
光谱数据： Spectral data:
LC/MS (方法： UFLC): RT = 1.773分钟； m/z = 561.3 [M+H]+; 总的运行时间为 7.00分钟。 Ή NMR (400 MHz, METHANOL-^) δ 8.02 (s， 1H), 7.67-7.65 (m, 2H), 7.54 (dd, J= 4.8, 8.8 Hz, 1H), 7.33 (t, J= 8.8 Hz, 1H)， 7.18 (s, 1H), 6.40 (q, J= 6.4 Hz, 1H), 4.68-4.53 (m, 2H), 4.13-4.09 (m, 1 H), 3.41 -3.19 (m, 6H)， 2.93-2.84 (m, 1H)， 2.26-2.15 (m, 2H), 2.06-1.84 (m,9H). 实施例 52
Figure imgf000057_0002
LC/MS (method: UFLC): RT = 1.773 min; m/z = 561.3 [M+H]+; NMR NMR (400 MHz, METHANOL-^) δ 8.02 (s, 1H), 7.67-7.65 (m, 2H), 7.54 (dd, J = 4.8, 8.8 Hz, 1H), 7.33 (t, J = 8.8 Hz, 1H), 7.18 (s, 1H), 6.40 (q, J= 6.4 Hz, 1H), 4.68-4.53 (m, 2H), 4.13-4.09 (m, 1 H), 3.41 -3.19 (m, 6H), 2.93-2.84 (m, 1H), 2.26-2.15 (m, 2H), 2.06-1.84 (m, 9H). Example 52
Figure imgf000057_0002
[4-[4-[6-氨基 -5-[(lR)-l- (2,6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基] P比唑 - 基 -1 -哌啶基 ]-[(3R)-3-哌啶基]甲酮 [4-[4-[6-Amino-5-[(lR)-l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]P-pyrazole-yl -1 -piperidinyl]-[(3R)-3-piperidinyl]methanone
操作步骤： Steps:
将化合物 3-[(lR)-l -(2,6 -二氯 -3-氟-苯基)乙氧基 ]-5-[1 -(4 -哌啶基)吡唑 -4-基]吡啶 -2-胺 （ 50毫 克， 0.111毫摩尔， 1当量)， (3R)-1 -叔-丁氧基羰基哌啶 -3-羧酸 (28毫克， 0.122毫摩尔， 1.1当量） 和 Ν,Ν,Ν',Ν'-四甲基 -0-(7-氮杂苯并三唑 -1 -基)六氟磷酸脲 (64毫克， 0.166毫摩尔， 1.5当量)溶 于 10毫升二氯甲垸。然后搅拌、冰浴和氮气保护下， 继续缓慢加入 Ν,Ν ' -二异丙基乙胺 （72 毫克 , 0.555毫摩尔， 5当量)。 反应在室温下继续搅拌 12小时。 反应结束后将反应液旋干， 置 于盐酸 /二氧六环 （10毫升） 中室温搅拌 3小时。 反应结束后， 将反应液旋干得到粗品， 用 HPLC纯化 (仪器： LC 8Α & Gilson 215 馏分收集器 色谱柱： Ge分钟 i 200*25mm*5um，流动 相 A: HC1 水，流动相 B: 乙腈， 流速： 30mL/分钟， 浓度梯度： 17-27%B, 0-12分钟)得到目标化 合物的盐酸盐 （14.7毫克， 产率为 22%)。 The compound 3-[(lR)-l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-5-[1 -(4-piperidyl)pyrazol-4-yl] Pyridin-2-amine (50 mg, 0.111 mmol, 1 eq.), (3R)-1 -tert-butoxycarbonylpiperidine-3-carboxylic acid (28 mg, 0.122 mmol, 1.1 eq.) Ν,Ν',Ν'-tetramethyl- 0-(7-azabenzotriazol-1-yl) hexafluorophosphate (64 mg, 0.166 mmol, 1.5 eq.) dissolved in 10 ml of dichloromethane Hey. Then, under stirring, ice bath and nitrogen, continue to slowly add hydrazine, Ν'-diisopropylethylamine (72 mg, 0.555 mmol, 5 eq.). The reaction was stirred at room temperature for further 12 hours. After the reaction was completed, the reaction mixture was evaporated to dryness mjjjjjjjjjjj After completion of the reaction, the reaction solution was spun dry to give a crude material which was purified by HPLC (PLC: LC 8 Α & Gilson 215 fraction collector column: Ge min i 200*25 mm*5 um, mobile phase A: HC1 water, mobile phase B: acetonitrile , Flow rate: 30 mL/min, Concentration gradient: 17-27% B, 0-12 min) The hydrochloride salt of the title compound (14.7 mg, yield 22%).
光谱数据： Spectral data:
LC/MS (方法： UFLC): RT = 1.779分钟； m/z = 561.3 [M+H]+; 总的运行时间为 7.00 分钟。 Ή NMR (400 MHz, METHANOL-d4) δ 8.08 (s， IH), 7.65 (s, 2H)， 7.52 (br, I H), 7.43 (t, J= 9.2 Hz: I H), 7.16 (s, I H), 6.36 (q, J= 6.4 Hz, IH), 4.65-4.52 (m, 2H), 4.12-4.04 (m, I H), 3.47-3.18 (m, 6H); 2.89-2.80 (m, IH), 2.21 -2.13 (m, 2H)， 2.02-1.81 (m, 9H). 实施例 53
Figure imgf000058_0001
LC/MS (method: UFLC): RT = 1.779 min; m/z = 561.3 [M+H] + ; NMR NMR (400 MHz, METHANOL-d 4 ) δ 8.08 (s, IH), 7.65 (s, 2H), 7.52 (br, IH), 7.43 (t, J = 9.2 Hz : IH), 7.16 (s, IH) ), 6.36 (q, J = 6.4 Hz, IH), 4.65-4.52 (m, 2H), 4.12-4.04 (m, IH), 3.47-3.18 (m, 6H) ; 2.89-2.80 (m, IH), 2.21 -2.13 (m, 2H), 2.02-1.81 (m, 9H). Example 53
Figure imgf000058_0001
[4- [4-[6-氨基 -5-[(lR)-l-(2，6-二氯 -3-氟-苯基)乙氧基 ]- 3-吡啶基]吡唑 -1 -基]  [4- [4-[6-Amino-5-[(lR)-l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]- 3-pyridyl]pyrazole-1 - Base
- 1 -哌啶基 ]-[(2R)-吗啉 -2-基]甲酮  - 1 -piperidinyl]-[(2R)-morpholin-2-yl]methanone
操作步骤： Steps:
将化合物 3-[(l R)-l-(2,6-二氯 -3-氟-苯基)乙氧基 ]-5-[1 -(4-哌啶基) P比唑 -4-基] P比啶 -2-胺（ 50 毫 克, 0.1 1 1毫摩尔， 1当量)， （2R)-4- (叔丁氧羰基)吗啉 -2-羧酸（29毫克， 0.122毫摩尔， 1.1当量） 和 Ν,Ν,Ν',Ν'-四甲基 -0-(7-氮杂苯并三唑 -1 -基)六氟磷酸脲 （64毫克， 0.166毫摩尔，1.5 当量) 溶于 10毫升二氯甲垸。然后搅拌、冰浴和氮气保护下，继续缓慢加入 Ν，Ν'-二异丙基乙胺 （72 毫克， 0.555毫摩尔，5当量.；)。 反应在室温下继续搅拌 12小时。 反应结束后将反应液旋干， 置 于盐酸 /二氧六环 （10毫升） 中室温搅拌 3 小时。 反应结束后， 将反应液旋干得到粗品。 用The compound 3-[(l R)-l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-5-[1-(4-piperidinyl)P-pyrazole-4- P-pyridin-2-amine (50 mg, 0.11 mmol, 1 equivalent), (2R)-4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (29 mg, 0.122 mmol, 1.1 equivalents) and hydrazine, hydrazine, hydrazine, Ν'-tetramethyl- 0-(7-azabenzotriazol-1-yl) hexafluorophosphate (64 mg, 0.166 mmol, 1.5 eq.) In 10 ml of dichloromethane. Then, stirring, ice bath and nitrogen protection were continued, and hydrazine, Ν'-diisopropylethylamine (72 mg, 0.555 mmol, 5 eq.;) was slowly added. The reaction was stirred at room temperature for further 12 hours. After the reaction was completed, the reaction mixture was evaporated to dryness mjjjjd After completion of the reaction, the reaction solution was spun to give a crude product. use
HPLC纯化 （仪器： LC 8Α & Gilson 215 馏分收集器 色谱柱： Ge分钟 i 200*25mm*5um, 流 动相 A: HC1 7X, 流动相 B: 乙腈， 流速： 30mL/分钟， 浓度梯度： 17-27%B， 0-12分钟） 得到目 标化合物的盐酸盐 （13毫克， 产率为 20%)。 HPLC purification (instrument: LC 8 Α & Gilson 215 fraction collector column: Ge min i 200*25 mm*5 um, mobile phase A: HC1 7X, mobile phase B: acetonitrile, flow rate: 30 mL/min, concentration gradient: 17-27 %B, 0-12 minutes) Get the item The hydrochloride salt of the title compound (13 mg, 20% yield).
光谱数据-Spectral data -
LC/MS (方法： UFLC): RT = 1.687分钟； m/z = 563.3 [M+H]+; 总的运行时间为 7.00分钟。 Ή NMR (400 MHz, METHANOL-^) δ 8.00 (br, IH), 7.67 (s, 2H), 7.50 (br, 1H)， 7.31 (t, J = 8.8 Hz, IH), 7.16 (s, IH), 6.36 (q, J= 6.4 Hz, I H), 5.00- 4.87 (m, IH), 4.64-4.45 (m， 2H)， 4.18-3.90 (m, 3H), 3.40-3.24 (m, 5H), 3.13-2.89 (m, IH), 2.18-1.94 (m, 7H). 施例 54
Figure imgf000059_0001
LC/MS (method: UFLC): RT = 1.687 min; m/z = 563.3 [M+H] + ; NMR NMR (400 MHz, METHANOL-^) δ 8.00 (br, IH), 7.67 (s, 2H), 7.50 (br, 1H), 7.31 (t, J = 8.8 Hz, IH), 7.16 (s, IH) , 6.36 (q, J= 6.4 Hz, IH), 5.00- 4.87 (m, IH), 4.64-4.45 (m, 2H), 4.18-3.90 (m, 3H), 3.40-3.24 (m, 5H), 3.13 -2.89 (m, IH), 2.18-1.94 (m, 7H). Example 54
Figure imgf000059_0001
[4-[4-[6-氨基 -5-[(lR)-l-(2，6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基]吡唑 -1-基]  [4-[4-[6-Amino-5-[(lR)-l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazole-1- Base
-1-哌啶基 ]-[(2S)-吗啉 -2-基]甲酮  1-piperidinyl]-[(2S)-morpholin-2-yl]methanone
操作步骤： Steps:
将化合物 3-[(lR)-l-(2,6-二氯 -3-氟-苯基)乙氧基 ]-5-[1-(4-哌啶基)吡唑 -4-基]吡啶 -2-胺（ 50毫克, 0.111毫摩尔， 1当量)， （2S)-4- (叔丁氧羰基)吗啉 -2-羧酸 (29 毫克， 0.122毫摩尔， 1.1当量)和 N，N，N，，N，-四甲基 -0-(7-氮杂苯并三唑小基)六氟磷酸脲 (64 毫克， 0.166毫摩尔， 1.5当量)溶于 10毫升二氯甲垸。然后搅拌、冰浴和氮气保护下， 继续缓慢加入 Ν,Ν'-二异丙基乙胺 (72毫克, 0.555毫摩尔， 5当量)。 反应在室温下继续搅拌 12小时。 反应结束后将反应液旋千， 置于盐酸 /二氧六环（10毫升） 中室温搅拌 3小时。 反应结束后， 将反应液旋干得到粗品。 用 HPLC纯 化 （仪器： LC 8Α & Gilson 215 馏分收集器 色谱柱： Ge分钟 i 200*25mm*5um, 流动相 A: HC1 水， 流动相 B: 乙腈， 流速： 30mL/分钟，浓度梯度： 17-27%B, 0-12分钟） 得到目标化合物 的盐酸盐 （4毫克， 产率 6%)。 The compound 3-[(lR)-l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-5-[1-(4-piperidyl)pyrazol-4-yl] Pyridin-2-amine (50 mg, 0.111 mmol, 1 eq.), (2S)-4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (29 mg, 0.122 mmol, 1.1 eq.) and N, N,N,,N,-Tetramethyl-O-(7-azabenzotriazole small) urea hexafluorophosphate (64 mg, 0.166 mmol, 1.5 eq.) was dissolved in 10 mL of dichloromethane. Then, stirring, ice bath and nitrogen protection were continued, and hydrazine, Ν'-diisopropylethylamine (72 mg, 0.555 mmol, 5 eq.) was slowly added. The reaction was stirred at room temperature for further 12 hours. After the completion of the reaction, the reaction mixture was stirred for 1 hour, and the mixture was stirred at room temperature for 3 hours under hydrochloric acid / dioxane (10 ml). After completion of the reaction, the reaction solution was spun to give a crude product. Purified by HPLC (instrument: LC 8 Α & Gilson 215 fraction collector column: Ge min i 200*25 mm*5 um, mobile phase A: HC1 water, mobile phase B: acetonitrile, flow rate: 30 mL/min, concentration gradient: 17- 27% B, 0-12 min) The hydrochloride salt of the title compound (4 mg, yield 6%).
光谱数据： Spectral data:
1H NMR (400 MHz, Methanol-^) δ 7.90 (br, IH), 7.63 (s, IH), 7.61(s， IH), 7.50 (dd， J = 4.8, 8.8 Hz, IH), 7,29 (t, J = 8.8 Hz, IH), 7.06 (s, I H), 6.31 (q, J = 6.4 Hz, 1H)， 4.66-4.50 (m, 3H), 4.18-4.14 (m, IH), 4.01-3.96 (m, 2H), 3.48-3.22 (m, 5H), 3.20-2.89 (m, IH), 2.21 -1.89 (m, 7H).  1H NMR (400 MHz, Methanol-^) δ 7.90 (br, IH), 7.63 (s, IH), 7.61 (s, IH), 7.50 (dd, J = 4.8, 8.8 Hz, IH), 7,29 ( t, J = 8.8 Hz, IH), 7.06 (s, IH), 6.31 (q, J = 6.4 Hz, 1H), 4.66-4.50 (m, 3H), 4.18-4.14 (m, IH), 4.01-3.96 (m, 2H), 3.48-3.22 (m, 5H), 3.20-2.89 (m, IH), 2.21 -1.89 (m, 7H).
Figure imgf000059_0002
[4-[4-[6-氨基 -5-[(lR)-l-(2,6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基] P比唑-卜基]
Figure imgf000059_0002
[4-[4-[6-Amino-5-[(lR)-l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl] P-pyrazole-b base]
-1 -哌啶基 ]-[(2R)-四氢吡咯 -2-基]甲酮  -1 -piperidinyl]-[(2R)-tetrahydropyrrole-2-yl]methanone
操作步骤： Steps:
将化合物 3-[(lR)-l-(2,6-二氯 -3-氟-苯基)乙氧基 ]-5-[1-(4-哌啶基) P比唑 -4-基] P比啶 -2-胺 （ 50毫克, 0.111毫摩尔， 1当量)， （2R)-1- (叔丁氧羰基)吡咯垸 -2-羧酸（ Π毫克， 0.122毫摩尔， 1.1当量)和 Ν,Ν,Ν',Ν'-四甲基 -0-(7-氮杂苯并三唑 -1-基)六氟磷酸脲 (64毫克， 0.166毫摩尔， 1.5当量)溶于 10 毫升二氯甲垸。 然后搅拌、 冰浴和氮气保护下， 继续缓慢加入 Ν，Ν'-二异丙基乙胺（72毫 克 0.555 毫摩尔 ,5当量)。 反应在室温下继续搅拌 12小时。 反应结束后将反应液旋干， 置于 HC1/二氧六环（10毫升）中室温搅拌 3小时。反应结束后， 将反应液旋干得到粗品。用 HPLC 纯化 （仪器： LC 8Α & Gilson 215 馏分收集器 色谱柱： Synergi 150*30瞧 *5u， 流动相 A: 0. 05%HC1 水， 流动相 B: 乙腈， 流速： 30mL/分钟， 浓度梯度： 13-23%B, 0-1 1分钟) 得到目标 化合物 （11.8毫克， 产率为 18%). The compound 3-[(lR)-l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-5-[1-(4-piperidinyl)P-pyrazol-4-yl P-pyridin-2-amine (50 mg, 0.111 mmol, 1 equivalent), (2R)-1-(tert-butoxycarbonyl)pyrrole-2-carboxylic acid (mg mg, 0.122 mmol, 1.1 eq.) And hydrazine, hydrazine, Ν', Ν'-tetramethyl- 0-(7-azabenzotriazol-1-yl) hexafluorophosphate (64 mg, 0.166 mmol, 1.5 eq.) dissolved in 10 ml Dichloromethane. Then, stirring, ice bath and nitrogen protection were continued, and hydrazine, Ν'-diisopropylethylamine (72 mg, 0.555 mmol, 5 eq.) was slowly added. The reaction was stirred at room temperature for further 12 hours. After the reaction was completed, the reaction mixture was evaporated to dryness, mjjjjjjjjj After completion of the reaction, the reaction solution was spun to give a crude product. Purified by HPLC (Instrument: LC 8Α & Gilson 215 Fraction Collector Column: Synergi 150*30瞧*5u, Mobile Phase A: 0. 05% HC1 Water, Mobile Phase B: Acetonitrile, Flow Rate: 30 mL/min, Concentration Gradient : 13-23% B, 0-1 1 min) The title compound was obtained (11.8 mg, yield 18%).
光谱数据： Spectral data:
LC/MS (方法： UFLC): RT = 1.538分钟； m/z = 547.3 [M+H]+; 总的运行时间为 7.00分钟。 lH NMR (400MHz, METHANOL- d4) δ 8.05 (s， 1Η)， 7.68 (s, 2Η), 7.53 (dd， J = 4,8， 8,4 Hz, IH), 7.32 (t， J = 8.4 Hz, IH), 7.19 (s, IH), 6.38 (q, J = 6.8 Hz, IH), 4.84 - 4.71 (m, 2H), 4.68 - 4.48 (m, 2H), 4.11 - 3.96 (m, IH), 3.50 - 3.36 (m, 3H), 3.02-2.97 (m, IH), 2.58-2.54 (m, IH), 2.29 - 1.97 (m„ 9H). LC/MS (method: UFLC): RT = 1.538 min; m/z = 547.3 [M+H] + ; l H NMR (400MHz, METHANOL- d 4 ) δ 8.05 (s, 1Η), 7.68 (s, 2Η), 7.53 (dd, J = 4,8, 8,4 Hz, IH), 7.32 (t, J = 8.4 Hz, IH), 7.19 (s, IH), 6.38 (q, J = 6.8 Hz, IH), 4.84 - 4.71 (m, 2H), 4.68 - 4.48 (m, 2H), 4.11 - 3.96 (m, IH ), 3.50 - 3.36 (m, 3H), 3.02-2.97 (m, IH), 2.58-2.54 (m, IH), 2.29 - 1.97 (m„ 9H).
实施例 56
Figure imgf000060_0001
Example 56
Figure imgf000060_0001
[4-[4-[6-氨基 -5-[(l R)-l-(2，6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基] P比唑 -1 -基]  [4-[4-[6-Amino-5-[(l R)-l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl] P-pyrazole- 1 - base]
-1-哌啶基 ]-(2-哌啶基)甲酮  1-piperidinyl]-(2-piperidinyl)methanone
操作步骤： Steps:
将化合物 3-[(l R)-l-(2,6-二氯 -3-氟-苯基)乙氧基 ]-5-[1-(4-哌啶基) B比唑 -4-基] P比啶 -2-胺（ 50毫克,The compound 3-[(l R)-l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-5-[1-(4-piperidinyl) B-pyrazole-4- P]pyridin-2-amine (50 mg,
0.111毫摩尔， 1当量)， 1- (苄氧羰基)哌啶 -2-羧酸（ 33毫克， 0.122毫摩尔， 1.1当量.)和 Ν,Ν,Ν',Ν'- 四甲基 -0-(7-氮杂苯并三唑 -1-基)六氟磷酸脲 (64毫克， 0.166毫摩尔， 1.5当量)溶于 10毫升二 氯甲烷。 然后搅拌、 冰浴和氮气保护下， 继续缓慢加入 Ν，Ν'-二异丙基乙胺 （72 毫克， 0.555 毫摩尔 1， 5当量)。 反应在室温下继续搅拌 12小时。 反应结束后将反应液旋干， 溶于甲醇中， 室温搅拌中加入氢氧化钯 (0.2克)。 置换空气后， 将反应液置于氢气气氛下反应搅拌 3小时。 反应结束后， 将反应液过滤、 旋干得到粗品， 用 HPLC纯化 (仪器： LC 8Α & Gilson 215 馏 分收集器 色谱柱： Synergi 150*30mm*5u，流动相 A: 0.05%HC1 水，流动相 B: 乙腈， 流速: 30mL/分钟， 浓度梯度： 13-23%B, 0-11分钟)得到目标化合物的盐酸盐 (1毫克， 产率为 1.4%)。 光谱数据： 0.111 mmol, 1 equivalent), 1-(benzyloxycarbonyl)piperidine-2-carboxylic acid (33 mg, 0.122 mmol, 1.1 eq.) and hydrazine, hydrazine, hydrazine -(7-Azabenzotriazol-1-yl)hexafluorophosphate (64 mg, 0.166 mmol, 1.5 eq.) was dissolved in 10 mL dichloromethane. Then, under stirring, ice bath and nitrogen, continue to slowly add hydrazine, Ν'-diisopropylethylamine (72 mg, 0.555 mmol, 1, 5 eq.). The reaction was stirred at room temperature for further 12 hours. After completion of the reaction, the reaction mixture was dried and dissolved in methanol. After replacing the air, the reaction solution was placed under a hydrogen atmosphere and stirred for 3 hours. After completion of the reaction, the reaction solution was filtered and dried to give a crude product which was purified by HPLC (PLC: LC 8 Α & Gilson 215 distillation Separator column: Synergi 150*30mm*5u, mobile phase A: 0.05% HC1 water, mobile phase B: acetonitrile, flow rate: 30 mL/min, concentration gradient: 13-23% B, 0-11 minutes) The hydrochloride salt of the compound (1 mg, yield 1.4%). Spectral data:
LC/MS (方法： UFLC): RT = 1.884分钟； m/z=561.3 [M+H]+; 总的运行时间为 7.00 分钟。 施例 57
Figure imgf000061_0001
LC/MS (method: UFLC): RT = 1.884 min; m/z = 561.3 [M+H] + ; Example 57
Figure imgf000061_0001
(2S)-2-氨基 -1-[4-[4-[6-氨基 -5-[(lR)-l-(2，6-二氯 -3-氟-苯基)乙氧基  (2S)-2-Amino-1-[4-[4-[6-amino-5-[(lR)-l-(2,6-dichloro-3-fluoro-phenyl)ethoxy)
-3-吡啶基]吡唑小基] -1-哌啶基 ]-6- (二甲基氨基)己 - 酮 操作步骤：  -3-pyridyl]pyrazole small group]-1-piperidinyl]-6-(dimethylamino)hexan-one Procedure:
将化合物 3- [(lR)-l-(2,6-二氯 -3-氟-苯基)乙氧基 ]-5-[1-(4-哌啶基) P比唑 -4-基]吡啶 -2-胺 （ 500毫 克， 1.11毫摩尔， 1当量)，（2S)-6- (二甲基氨基 )-2-(9H-芴- 9-基甲氧羰基氨基)己酸 (530毫克， 1.22 毫摩尔， 1.1当量)和 Ν，Ν, Ν',Ν'-四甲基 -0-(7-氮杂苯并三唑 -1-基)六氟磷酸脲 （640m g， 1.66毫 摩尔， 1.5当量)溶于 50毫升二氯甲垸。 然后搅拌、 冰浴和氮气保护下， 继续缓慢加入 Ν,Ν'- 二异丙基乙胺 (720毫克， 5.55毫摩尔，5当量)。 反应在室温下继续搅拌 12小时。 反应结束后将 反应液旋干， 溶于甲醇（50毫升） 中， 室温搅拌中加入氢氧化钯 (0.1g)。 置换空气后， 将反应 液置于氢气气氛下反应搅拌 3小时。 反应结束后， 将反应液过滤、 旋干得到粗品， 高效液相 分离（仪器： LC 8A & Gilson 215 馏分收集器 色谱柱： Synergi 150*30mm*5u,流动相 A: 0.05%HC1 水，流动相 B: 乙腈， 流速： 30mL/分钟， 浓度梯度： 1-30%B, 0-8分钟)旋干后得到目 标化合物的盐酸盐 (379毫克， 收率为 50%)。 The compound 3-[(lR)-l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-5-[1-(4-piperidinyl)P-pyrazol-4-yl Pyridin-2-amine (500 mg, 1.11 mmol, 1 equivalent), (2S)-6-(dimethylamino)-2-(9H-indole-9-ylmethoxycarbonylamino)hexanoic acid (530 Mg, 1.22 mmol, 1.1 eq.) and hydrazine, hydrazine, Ν', Ν'-tetramethyl- 0-(7-azabenzotriazol-1-yl) hexafluorophosphate (640 m g, 1.66 m) Molar, 1.5 equivalents) was dissolved in 50 ml of dichloromethane. Then, stirring, ice bath and nitrogen protection were continued, and hydrazine, Ν'-diisopropylethylamine (720 mg, 5.55 mmol, 5 eq.) was slowly added. The reaction was stirred at room temperature for further 12 hours. After the reaction was completed, the reaction mixture was evaporated to dryness mjjjjjjjjjjj After replacing the air, the reaction solution was placed under a hydrogen atmosphere and stirred for 3 hours. After the reaction is completed, the reaction solution is filtered and spun dry to obtain a crude product, which is separated by high-performance liquid chromatography (instrument: LC 8A & Gilson 215 fraction collector column: Synergi 150*30 mm*5u, mobile phase A: 0.05% HC1 water, mobile phase B: acetonitrile, flow rate: 30 mL/min, concentration gradient: 1-30% B, 0-8 min) After spin-drying, the title compound salt (379 mg, yield 50%) was obtained.
光谱数据： Spectral data:
LC/MS (方法： UFLC): RT = 1.291分钟； m/z = 606.4 [M+H]+; 总的运行时间为 7.00分钟. Ή NMR (400 MHz, METHANOLS) δ 8.07-8.00 (m, 1H), 7.68-7.62 (m, 2H), 7.51 (dd, J = 4.8, 8.8 Hz, 1H), 7.30 (t, J= 8.8 Hz, 1H)， 7.17 (s, 1H)， 6.37 (q， J = 6.8 Hz, 1H), 4.69-4.49 (m, 3H), 4.07 (br, 1H), 3.42-3.33 (m, 1H), 3.25-3.14 (m, 2H), 2.99-2.95 (m, 1H), 2.89 (s, 6H), 2.21-1.77 (m, 11H), 1.53 (m, 2H). 实施例 58
Figure imgf000062_0001
LC/MS (method: UFLC): RT = 1.291 min; m/z = 606.4 [M+H]+; The total run time is 7.00 min. NMR NMR (400 MHz, METHANOLS) δ 8.07-8.00 (m, 1H) ), 7.68-7.62 (m, 2H), 7.51 (dd, J = 4.8, 8.8 Hz, 1H), 7.30 (t, J= 8.8 Hz, 1H), 7.17 (s, 1H), 6.37 (q, J = 6.8 Hz, 1H), 4.69-4.49 (m, 3H), 4.07 (br, 1H), 3.42-3.33 (m, 1H), 3.25-3.14 (m, 2H), 2.99-2.95 (m, 1H), 2.89 (s, 6H), 2.21-1.77 (m, 11H), 1.53 (m, 2H). Example 58
Figure imgf000062_0001
(2S)-2-氨基 -l-[4- [4-[6-氨基 -5-[(lR)- (2,6-二氯 -3-氟-苯基)乙氧基  (2S)-2-Amino-l-[4-[4-[6-amino-5-[(lR)-(2,6-dichloro-3-fluoro-phenyl)ethoxy)
-3-吡啶基]吡唑 -1-基]小哌啶基 ]-3-(lH-咪唑 -4-基)丙 -1-酮  -3-pyridyl]pyrazole-1-yl]piperidinyl]-3-(lH-imidazolyl-4-yl)propan-1-one
操作步骤: Steps:
将化合物 3-[(lR)-l-(2，6-二氯 -3-氟-苯基)乙氧基 ]-5-[1-(4-哌啶基) P比唑 -4-基] P比啶 -2-胺（ 50毫克， 0.111毫摩尔， 1当量)， （2S)-2- (叔丁氧基羰基氨基 )-3-(1Η-咪唑 -4-基)丙酸 (32毫克， 0.122毫摩 尔， 1.1当量)和 Ν,Ν，Ν，，Ν'-四甲基 -0- (7-氮杂苯并三唑 -1-基)六氟磷酸脲 (64毫克 0.166毫摩尔, 1.5当量)溶于 10毫升二氯甲烷。 然后搅拌、 冰浴和氮气保护下， 继续缓慢加入 Ν,Ν'-二异丙 基乙胺 （ 72毫克， 0.555毫摩尔， 5当量.；)。反应在室温下继续搅拌 12小时。反应结束后将反应 液旋干， 置于 HC1/二氧六环 （10毫升） 中室温搅拌 3小时。 反应结束后， 将反应液旋干得到 粗品。用 HPLC纯化 （仪器： LC 8Α & Gilson 215 馏分收集器 色谱柱： Synergi 150*30mm*5u, 流动相 A: 0. 05%HC1 水,流动相 B: 乙腈， 流速： 30mL/分钟，浓度梯度： 1 -30%Β, 0-8分钟)得到 目标化合物的盐酸盐 （6.9毫克， 产率为 9%)。 The compound 3-[(lR)-l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-5-[1-(4-piperidinyl)P-pyrazol-4-yl P-pyridin-2-amine (50 mg, 0.111 mmol, 1 equivalent), (2S)-2-(tert-butoxycarbonylamino)-3-(1Η-imidazol-4-yl)propanoic acid (32 Mg, 0.122 mmol, 1.1 eq.) and hydrazine, hydrazine, hydrazine, Ν'-tetramethyl-(7-azabenzotriazol-1-yl) hexafluorophosphate (64 mg 0.166 mmol) , 1.5 equivalents) dissolved in 10 ml of dichloromethane. Then, under stirring, ice bath and nitrogen, continue to slowly add hydrazine, Ν'-diisopropylethylamine (72 mg, 0.555 mmol, 5 eq.;). The reaction was stirred at room temperature for further 12 hours. After completion of the reaction, the reaction mixture was evaporated to dryness mjjjjjjjjjj After the reaction was completed, the reaction solution was spun to give a crude product. Purified by HPLC (instrument: LC 8 Α & Gilson 215 fraction collector column: Synergi 150*30 mm*5u, mobile phase A: 0. 05% HCl water, mobile phase B: acetonitrile, flow rate: 30 mL/min, concentration gradient: 1 -30% hydrazine, 0-8 minutes) The hydrochloride salt of the title compound (6.9 mg, 9% yield).
光谱数据： Spectral data:
LC/MS (方法： UFLC): RT =1.221分钟； m/z = 588.4 [M+H]+; 总的运行时间为 7.00分钟。 Ή NMR (400 MHz, METHANOL- ί¾) δ 9.00-8.95 (m， 1Η), 8.08 (s, 1H), 7.67-7.62 (m, 2H), 7.59-7.48 (m, 2H), 7.30 (t, J = 8.8 Hz, 1H), 7.17 (s, 1H), 6.37 (q, J = 6.8 Hz, 1 H), 4.82-4.53 (m, 2H), 4.19-4.15 (m, 1H), 3.69-3.53 (m, 3H), 3.42-3.29 (m, 3H), 3.07-2.91 (m, 1H), 2.20-2.10 (m， 2H), 1.95 (d, J = 6.4 Hz, 3H). 实施例 59
Figure imgf000062_0002
</ RTI>< RTI ID=0.0></RTI>< / RTI>< RTI ID=0.0></RTI>< / RTI>< / RTI><RTIgt; NMR NMR (400 MHz, METHANOL- ί3⁄4) δ 9.00-8.95 (m, 1Η), 8.08 (s, 1H), 7.67-7.62 (m, 2H), 7.59-7.48 (m, 2H), 7.30 (t, J = 8.8 Hz, 1H), 7.17 (s, 1H), 6.37 (q, J = 6.8 Hz, 1 H), 4.82-4.53 (m, 2H), 4.19-4.15 (m, 1H), 3.69-3.53 (m , 3H), 3.42-3.29 (m, 3H), 3.07-2.91 (m, 1H), 2.20-2.10 (m, 2H), 1.95 (d, J = 6.4 Hz, 3H). Example 59
Figure imgf000062_0002
(2R)-2-氨基小 [4-[4-[6-氨基 -5-[(lR)-l-(2, 6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基]吡唑- 基] -1-哌 啶基] -3-甲基-丁 -1-酮  (2R)-2-aminosodium [4-[4-[6-amino-5-[(lR)-l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3- Pyridyl]pyrazole-yl]-1-piperidinyl]-3-methyl-butan-1-one
操作步骤: Steps:
将化合物 3-[(lR)-l-(2，6-二氯 -3-氟-苯基)乙氧基 ]-5-[1-(4-哌啶基) P比唑 -4-基] P比啶- 2-胺 （50毫克， 0.111毫摩尔， 1当量)， （2R)-2- (叔丁氧基羰基氨基 )-3-甲基 -丁酸 (27毫克， 0.122毫摩尔， 1.1当 量)和 Ν,Ν,Ν',Ν'-四甲基 - 0-(7-氮杂苯并三唑- 基)六氟磷酸脲 （64毫克， 0.166毫摩尔， 1.5当量) 溶于 10毫升二氯甲垸。 然后搅拌、 冰浴和氮气保护下， 继续缓慢加入 Ν,Ν'-二异丙基乙胺 (72 毫克， 0.555毫摩尔，5当量)。 反应在室温下继续搅拌 12小时。 反应结束后将反应液旋干， 置 于盐酸 /二氧六环 （10毫升） 中室温搅拌 3小时。 反应结束后， 将反应液旋干得到粗品。 再将 粗品高效液相分离 (仪器： LC 8Α & Gilson 215 馏分收集器 色谱柱： Synergi 150*30mm*5u, 流动相 A: 0.05%HC1 水， 流动相 B: 乙腈， 流速： 30mL/分钟， 浓度梯度： 16-26%B， 0-8分钟) 旋干后得到目标化合物的盐酸盐 （28.1 毫克， 产率为 37%)。 The compound 3-[(lR)-l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-5-[1-(4-piperidinyl)P-pyrazol-4-yl P-pyridyl-2-amine (50 mg, 0.111 mmol, 1 eq.), (2R)-2-(tert-butoxycarbonylamino)-3-methyl-butyric acid (27 mg, 0.122 mmol, 1.1 equivalents) and hydrazine, hydrazine, hydrazine, Ν'-tetramethyl- 0-(7-azabenzotriazol-yl) hexafluorophosphate (64 mg, 0.166 mmol, 1.5 eq.) Dissolved in 10 ml of dichloromethane. Then, under stirring, ice bath and nitrogen, continue to slowly add hydrazine, Ν'-diisopropylethylamine (72 mg, 0.555 mmol, 5 eq.). The reaction was stirred at room temperature for further 12 hours. After completion of the reaction, the reaction mixture was evaporated to dryness mjjjjjjjjjj After completion of the reaction, the reaction solution was spun to give a crude product. The crude product was separated by high performance liquid chromatography (instrument: LC 8 Α & Gilson 215 fraction collector column: Synergi 150*30 mm*5u, mobile phase A: 0.05% HCl water, mobile phase B: acetonitrile, flow rate: 30 mL/min, concentration Gradient: 16-26% B, 0-8 min) The title compound salt (28.1 mg, yield 37%).
光谱数据： Spectral data:
LC/MS (方法： UFLC): RT = 1.800分钟； m/z = 550.4 [M+H]+; 总的运行时间为 7.00 分钟。 1H NMR (400 MHz, METHANOL-^) δ 8.04 (s， 1H), 7.68 (s, 2H), 7.52 (dd, J = 4.8, 8.8 Hz, 1H)， 7.33 (t， J = 8,8 Hz, 1H), 7.18 (s, 1H), 6.40 (q, J = 6.8 Hz, 1H), 4.67-4.56 (m, 2H), 4.44-4.38 (m, 1H), 4.15-4.09 (m, 1H), 3.48-3.33 (m, 1H), 3.02-2.93 (m, 1H)， 3.22-1.96 (m，8H), 1.18-0.98 (m, 6H). 实施例 60
Figure imgf000063_0001
LC/MS (method: UFLC): RT = 1.800 min; m/z = 550.4 [M+H]+; The total run time was 7.00 min. 1H NMR (400 MHz, METHANOL-^) δ 8.04 (s, 1H), 7.68 (s, 2H), 7.52 (dd, J = 4.8, 8.8 Hz, 1H), 7.33 (t, J = 8,8 Hz, 1H), 7.18 (s, 1H), 6.40 (q, J = 6.8 Hz, 1H), 4.67-4.56 (m, 2H), 4.44-4.38 (m, 1H), 4.15-4.09 (m, 1H), 3.48 -3.33 (m, 1H), 3.02-2.93 (m, 1H), 3.22-1.96 (m, 8H), 1.18-0.98 (m, 6H). Example 60
Figure imgf000063_0001
(2R)-2-氨基 -l -[4-[4-[6-氨基 -5-[(lR)-l-(2,6-二氯 -3-氟-苯基)乙氧基] (2R)-2-Amino-l-[4-[4-[6-amino-5-[(lR)-l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]
-3-吡啶基]吡唑小基] -1-哌啶基]丙小酮  -3-pyridyl]pyrazole small group]-1-piperidinyl]propanone
操作步骤： Steps:
将化合物 3-[(lR)-l-(2,6-二氯 -3-氟-苯基)乙氧基 ]-5-[1-(4-哌啶基)吡唑 -4-基]吡啶 -2-胺 （50毫克， 0.111 毫摩尔， 1 当量)， （2R)- 2- (叔丁氧羰基氨基)丙酸 (24 毫克， 0.122 毫摩尔， 1.1 当量)和 Ν,Ν,Ν'Ν'-四甲基 -0-(7-氮杂苯并三唑 -1-基)六氟磷酸脲 (64毫克， 0.166毫摩尔， 1.5当量)溶于 10 毫升二氯甲垸。 然后搅拌、 冰浴和氮气保护下， 继续缓慢加入 Ν,Ν ' -二异丙基乙胺 (72毫克， 0.555毫摩尔，5当量)。 反应在室温下继续搅拌 12小时。 反应结束后将反应液旋干， 置于盐酸 /二氧六环中室温搅拌 3小时。 反应结束后， 将反应液旋干得到粗品。 再将粗品用 HPLC纯化 (仪器： LC 8Α & Gilson 215 馏分收集器 色谱柱： Synergi 150*30mm*5u, 流动相 A: 0.05%HC1 水流动相 B: 乙腈， 流速： 30mL/分钟，浓度梯度： 13-23%B, 0-11分钟） 得到目标化 合物的盐酸盐 （12毫克， 产率为 18%)。 The compound 3-[(lR)-l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-5-[1-(4-piperidyl)pyrazol-4-yl] Pyridin-2-amine (50 mg, 0.111 mmol, 1 eq.), (2R)-2-(tert-butoxycarbonylamino)propionic acid (24 mg, 0.122 mmol, 1.1 eq.) Ν'-Tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate (64 mg, 0.166 mmol, 1.5 eq.) was dissolved in 10 mL of dichloromethane. Then, under stirring, ice bath and nitrogen, continue to slowly add hydrazine, Ν'-diisopropylethylamine (72 mg, 0.555 mmol, 5 eq.). The reaction was stirred at room temperature for further 12 hours. After completion of the reaction, the reaction mixture was evaporated to dryness. After completion of the reaction, the reaction solution was spun to give a crude product. The crude product was purified by HPLC (instrument: LC 8 Α & Gilson 215 fraction collector column: Synergi 150*30 mm*5u, mobile phase A: 0.05% HCl water mobile phase B: acetonitrile, flow rate: 30 mL/min, concentration gradient: 13-23% B, 0-11 min) The hydrochloride salt of the title compound (12 mg, yield 18%).
光谱数据： Spectral data:
LC/MS (方法： UFLC): RT = 1.594分钟； m/z = 521.3 [M+H]+; 总的运行时间为 7.00分钟。 Ή NMR (400 MHz, METHANOL-d4) δ 8.02 (s， IH), 7.67 (s, IH), 7.65 (s, IH), 7,54 (dd, J = 4.8, 8.8 Hz, IH), 7.31 (t, J = 8.8 Hz, IH), 7.18 (d, J = 1.2 Hz, 1H)， 6.40 (q, J = 6.8 Hz, 1H)， 4.66-4.46 (m, 3H), 4.06-4.02 (m, 1H)， 3.42-3.33 (m, IH), 3.03-2.92 (m, IH), 2.27-1.96 (m, 7H), 1.55-1.49 (m, 3H). 实施例 61
Figure imgf000064_0001
LC/MS (method: UFLC): RT = 1.594 min; m/z = 521.3 [M+H]+; NMR NMR (400 MHz, METHANOL-d 4 ) δ 8.02 (s, IH), 7.67 (s, IH), 7.65 (s, IH), 7,54 (dd, J = 4.8, 8.8 Hz, IH), 7.31 (t, J = 8.8 Hz, IH), 7.18 (d, J = 1.2 Hz, 1H), 6.40 (q, J = 6.8 Hz, 1H), 4.66-4.46 (m, 3H), 4.06-4.02 (m, 1H), 3.42-3.33 (m, IH), 3.03-2.92 (m, IH), 2.27-1.96 (m, 7H), 1.55-1.49 (m, 3H). Example 61
Figure imgf000064_0001
(2S)-2-氨基小 [4-[4-[6-氨基 -5-[(lR)-l-(2,6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基] 吡唑 -1-基] -1-哌啶基]丙 -1-酮 操作步骤：  (2S)-2-Amino small [4-[4-[6-amino-5-[(lR)-l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3- Pyridyl]pyrazol-1-yl]-1-piperidinyl]propan-1-one Procedure:
将化合物 3-[(lR)-l-(2,6-二氯- 3-氟-苯基)乙氧基 ]-5-[1-(4-哌啶基)吡唑 -4-基]吡啶 -2-胺（ 50毫克, 0.111毫摩尔， 1当量)， （2S)-2- (叔丁氧羰基氨基)丙酸 (24毫克， 0.122毫摩尔， 1.1当量)和 N,N， Ν'Ν'-四甲基 -0-(7-氮杂苯并三唑 -1-基)六氟磷酸脲 (64毫克， 0.166毫摩尔， 1.5当量)溶于 10毫 升二氯甲垸中。 然后搅拌、 冰浴和氮气保护下， 继续缓慢加入 Ν, Ν，-二异丙基乙胺 (72毫克, 0.555毫摩尔，5当量)。 反应在室温下继续搅拌 12小时。 反应结束后将反应液旋干， 置于盐酸 /二氧六环 （10毫升） 中室温搅拌 3小时。 反应结束后， 将反应液旋干得到粗品。 用 HPLC纯 化 （仪器： LC 8Α & Gilson 215 馏分收集器 色谱柱： Synergi 150*30mm*5u, 流动相 A: 0.075%HC1 水,流动相 B: 乙腈， 流速： 30mL/分钟，浓度梯度： 13-23%B，0- 11分钟)得到目标化 合物的盐酸盐 (13.1毫克， 产率为 19%)。 The compound 3-[(lR)-l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-5-[1-(4-piperidyl)pyrazol-4-yl] Pyridin-2-amine (50 mg, 0.111 mmol, 1 eq.), (2S)-2-(tert-butoxycarbonylamino)propanoic acid (24 mg, 0.122 mmol, 1.1 eq.) and N,N, Ν Ν'-Tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate (64 mg, 0.166 mmol, 1.5 eq.) was dissolved in 10 mL of dichloromethane. Then, stirring, ice bath and nitrogen protection were continued, and hydrazine, hydrazine, and diisopropylethylamine (72 mg, 0.555 mmol, 5 eq. The reaction was stirred at room temperature for further 12 hours. After the reaction was completed, the reaction mixture was evaporated to dryness mjjjjjjjjjj After completion of the reaction, the reaction solution was spun to give a crude product. Purified by HPLC (instrument: LC 8 Α & Gilson 215 fraction collector column: Synergi 150*30 mm*5u, mobile phase A: 0.075% HCl water, mobile phase B: acetonitrile, flow rate: 30 mL/min, concentration gradient: 13- 23% B, 0 - 11 min) gave the title compound (13.1 mg, yield 19%).
光谱数据： Spectral data:
LC/MS (方法： UFLC): RT = 1.645分钟； m/z = 521.3 [M+H]+; 总的运行时间为 7.00 分钟。 Ή NMR (400MHz, METHANOLS) δ 8.03 (s, IH), 7.68-7.66 (m, 2H)， 7.53 (dd, J = 4.8, 8.8 Hz, IH), 7.32 (t, J = 8.8 Hz, IH), 7.19 (s, IH), 6.38 (q, J = 6.4 Hz, IH), 4.70 - 4.46 (m, 3H), 4.05-4.01 (m, IH), 3.46 - 3.37 (m, IH), 3.08 - 2.92 (m, IH), 2.191-1.96 (m, 7H), 1.55-1.49 (m, 3H). 实施例 62 LC/MS (method: UFLC): RT = 1.645 min; m/z = 521.3 [M+H] + ; NMR NMR (400MHz, METHANOLS) δ 8.03 (s, IH), 7.68-7.66 (m, 2H), 7.53 (dd, J = 4.8, 8.8 Hz, IH), 7.32 (t, J = 8.8 Hz, IH), 7.19 (s, IH), 6.38 (q, J = 6.4 Hz, IH), 4.70 - 4.46 (m, 3H), 4.05-4.01 (m, IH), 3.46 - 3.37 (m, IH), 3.08 - 2.92 ( m, IH), 2.191-1.96 (m, 7H), 1.55-1.49 (m, 3H). Example 62
Figure imgf000064_0002
(4S)-4-氨基 -5-[4-[4-[6-氨基 -5-[(lR)- (2，6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基]
Figure imgf000064_0002
(4S)-4-Amino-5-[4-[4-[6-amino-5-[(lR)-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3- Pyridyl]
吡唑 -1-基]小哌啶基 ]-5-氧代-戊酰胺  Pyrazole-1-yl]piperidinyl]-5-oxo-pentanamide
操作步骤： Steps:
将化合物 3-[(lR)-l-(2,6-二氯 -3-氟-苯基)乙氧基 ]- 5-[1 -(4-哌啶基) P比唑 -4-基] P比啶 -2-胺 (20毫克， 0.044毫摩尔， 1当量)， （2S)-5-氨基 -2- (叔丁氧羰基氨基) -5-氧代戊酸 (12毫克， 0.049毫摩尔， 1 .1 当量)， 1-羟基苯并三氮唑 (7毫克， 0.049毫摩尔， 1.1当量)和 Ν,Ν'-二环己基碳二亚胺 (13毫克， 0.05毫摩尔，1.1当量)溶于 5毫升四氢呋喃。 然后搅拌和氮气保护下， 继续缓慢加入 Ν, Ν'-二 异丙基乙胺 （26毫克， 0.2毫摩尔，5当量)。 反应在室温下继续搅拌 3小时。反应结束后， 将反 应液用二氯甲垸稀释， 有机层用碳酸氢钠溶液和食盐水各反洗一次， 再用硫酸钠干燥后旋干， 置于盐酸 /乙酸乙酯 (5毫升)中室温搅拌 3 小时。 反应结束后， 将反应液旋干得到得到粗品用 用 HPLC纯化 （仪器： LC 8Α & Gilson 215 馏分收集器 色谱柱： Synergi 150*30mm*5u, 流动 相 A: 0.075%HC1 水， 流动相 B: 乙腈， 流速： 30mL/分钟， 浓度梯度： 13-23%B, 0-11分钟)得 到目标化合物的盐酸盐 (4 毫克， 产率为 47%)。 The compound 3-[(lR)-l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-5-[1-(4-piperidinyl)P-pyrazol-4-yl P-pyridin-2-amine (20 mg, 0.044 mmol, 1 equivalent), (2S)-5-amino-2-(tert-butoxycarbonylamino)-5-oxopentanoic acid (12 mg, 0.049 m) Molar, 1.1 equivalents, 1-hydroxybenzotriazole (7 mg, 0.049 mmol, 1.1 equivalents) and hydrazine, Ν'-dicyclohexylcarbodiimide (13 mg, 0.05 mmol, 1.1 equivalents) ) dissolved in 5 ml of tetrahydrofuran. Then, under stirring and under nitrogen, continue to slowly add hydrazine, Ν'-diisopropylethylamine (26 mg, 0.2 mmol, 5 eq.). The reaction was stirred at room temperature for 3 hours. After the reaction was completed, the reaction mixture was diluted with dichloromethane, and the organic layer was washed with sodium bicarbonate and brine, and then dried over sodium sulfate and evaporated to dryness. Stir for 3 hours. After completion of the reaction, the reaction solution was spun to obtain a crude product which was purified by HPLC (PLC: LC 8 Α & Gilson 215 fraction collector column: Synergi 150*30 mm*5u, mobile phase A: 0.075% HCl water, mobile phase B: Acetonitrile, flow rate: 30 mL/min, concentration gradient: 13-23% B, 0-11 min) gave the title compound salt (4 mg, yield 47%).
光谱数据： Spectral data:
LC/MS (方法： UFLC): mix = 578 [M+H]+. 实施例 63
Figure imgf000065_0001
LC/MS (method: UFLC): mixture = 578 [M+H] + . Example 63
Figure imgf000065_0001
2—氨基— [4-[4-[6-氨基 -5-[(l R)-l -(2,6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基] P比唑 -1-基]小哌啶 基] -2-(3-吡啶基)乙酮  2-amino-[4-[4-[6-amino-5-[(l R)-l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl] P-pyrazol-1-yl]piperidinyl]-2-(3-pyridyl)ethanone
操作步骤： Steps:
将化合物 3-[( l R)小 (2,6-二氯 -3-氟-苯基)乙氧基 ]-5-[1 -(4_哌啶基)口比唑 -4_基] P比啶 -2-胺 （50毫克, 0.11毫摩尔， 1当量)， 2- (叔丁氧羰基氨基) -2-(3-吡啶基)乙酸 (31毫克， 0.12毫摩尔， 1.1当量)和 Ν,Ν,Ν',Ν' -四甲基 -0-(7-氮杂苯并三唑 -1 -基)六氟磷酸脲（ 64毫克， 0.17毫摩尔， 1.5当量)溶于The compound 3-[(l R) small (2,6-dichloro-3-fluoro-phenyl)ethoxy]- 5 -[1 -( 4 -piperidinyl)-portyrazole- 4 -yl] P-pyridin-2-amine (50 mg, 0.11 mmol, 1 eq.), 2-(tert-butoxycarbonylamino)-2-(3-pyridyl)acetic acid (31 mg, 0.12 mmol, 1.1 eq.) Ν,Ν,Ν',Ν'-tetramethyl-0-(7-azabenzotriazol-1-yl) hexafluorophosphate (64 mg, 0.17 mmol, 1.5 eq.) is soluble
10毫升二氯甲烷。 然后搅拌、 冰浴和氮气保护下， 继续缓慢加入 Ν,Ν'-二异丙基乙胺 （72毫 克， 0.56毫摩尔，5 当量)。 反应在室温下继续搅拌 3小时。 反应结束后， 将反应液用二氯甲烷 稀释， 有机层用碳酸氢钠溶液和食盐水各反洗一次， 再用硫酸钠干燥后旋干， 得到的粗品在 盐酸 /二氧六环（4Ν )中搅拌 30分钟后旋干得到粗品采用高效液相分离 (仪器： LC SA & Gilson 215 馏分收集器 色谱柱： Synergi 150*30mm*5u，流动相 A: 0.05%HC1 水,流动相 B: 乙腈， 流 速： 30mL/分钟， 浓度梯度： 13-35%B, 0-6分钟)后旋干得到目标化合物的盐酸盐 (25毫克， 产率 为 52%)。 10 ml of dichloromethane. Then, under stirring, ice bath and nitrogen, continue to slowly add hydrazine, Ν'-diisopropylethylamine (72 mg, 0.56 mmol, 5 eq.). The reaction was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was diluted with dichloromethane, and the organic layer was washed with sodium bicarbonate solution and brine, and dried over sodium sulfate and then dried to give the crude product in hydrochloric acid / dioxane (4 Ν) After stirring for 30 minutes, spin dry to obtain crude product by high performance liquid phase separation (instrument: LC SA & Gilson 215 fraction collector column: Synergi 150*30mm*5u, mobile phase A: 0.05% HC1 water, mobile phase B: acetonitrile, flow Speed: 30 mL/min, concentration gradient: 13-35% B, 0-6 min) was then dried to give the title compound (25 mg, yield 52%).
光谱数据： Spectral data:
LC/MS (方法： UFLC): RT = 1.695分钟； m/z = 584.1 [M+H]+ ; 总的运行时间为 7.00分钟。 Ή NMR (400MHz, METHANOL-^) δ 9.24-9.20 (m, IH), 9.06-9.05 (m, 1H)， 8.85-8.78 (m, 1H)， 8.34-8.19 (m, IH), 8.02-7.94 (m, 1H)， 7.66-7.47 (m, 3H)， 7.31-7.27 (m, 1H)， 7.16-7.1 1 (m, 1H)， 6.37-6.33 (m， IH), 6.11-6.05 (m, IH), 4.75-4.45 (m, 2H)， 4.05-3.90 (m, IH), 3.50-3.40 (m, 0.5H), 3.15-2.90 (m, 1.5H), 2.94-1.87 (m, 7H). 实施例 64和 65
Figure imgf000066_0001
LC/MS (method: UFLC): RT = 1.695 min; m/z = 584.1 [M+H] + ; NMR NMR (400MHz, METHANOL-^) δ 9.24-9.20 (m, IH), 9.06-9.05 (m, 1H), 8.85-8.78 (m, 1H), 8.34-8.19 (m, IH), 8.02-7.94 ( m, 1H), 7.66-7.47 (m, 3H), 7.31-7.27 (m, 1H), 7.16-7.1 1 (m, 1H), 6.37-6.33 (m, IH), 6.11-6.05 (m, IH) , 4.75-4.45 (m, 2H), 4.05-3.90 (m, IH), 3.50-3.40 (m, 0.5H), 3.15-2.90 (m, 1.5H), 2.94-1.87 (m, 7H). 64 and 65
Figure imgf000066_0001
(2R)-2-氨基 -1- [4-[4-[6-氨基 -5-[(lR)-l-(2,6-二氯- 3-氟-苯基)乙氧基 ]-3-吡啶基]吡唑 -1-基] -1-哌 啶基] -2-(3-吡啶基)乙酮  (2R)-2-Amino-1-[4-[4-[6-amino-5-[(lR)-l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]- 3-pyridyl]pyrazol-1-yl]-1-piperidinyl]-2-(3-pyridyl)ethanone
Figure imgf000066_0002
Figure imgf000066_0002
(2S)-2-氨基 -1-[4-[4-[6-氨基 -5-[(lR)小 (2，6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基]吡唑 -1-基]小哌 啶基] -2-(3-吡啶基)乙酮  (2S)-2-amino-1-[4-[4-[6-amino-5-[(lR) small (2,6-dichloro-3-fluoro-phenyl)ethoxy]-3- Pyridyl]pyrazol-1-yl]piperidinyl]-2-(3-pyridyl)ethanone
操作步骤： Steps:
将化合物 2-氨基 -1-[4-[4-[6-氨基 -5-[(lR)小 (2，6-二氯 -3-氟-苯基）乙氧基 ]-3-吡啶基]吡唑 -1- 基] -1-哌啶基 ]-2-(3-吡啶基)乙酮 (24毫克， 0.041毫摩尔， 1当量，实施例 63)进行手性 SFC分离 得到目标化合物 (2R)-2-氨基 -】-[4-[4-[6-氨基 -5-[( )-l-(2,6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基] 吡唑 -1 -基] -1 -哌啶基 ]-2-(3-吡啶基）乙酮 ( 3.6 毫克） 和 （2S)-2-氨基 -1-[4-[4-[6-氨基 - 5- [(lR)-l-(2，6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基] P比唑- 1-基]小哌啶基] -2-(3-吡啶基)乙酮 （5.8 毫克）。 The compound 2-amino-1-[4-[4-[6-amino-5-[(lR) small (2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl) Pyrazol-1-yl]-1-piperidinyl]-2-(3-pyridyl)ethanone (24 mg, 0.041 mmol, 1 eq., Example 63) was subjected to chiral SFC to afford the title compound ( 2R)-2-Amino-]-[4-[4-[6-amino-5-[()-l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3- Pyridyl]pyrazol-1-yl]-1 -piperidinyl]-2-(3-pyridyl)ethanone (3.6 mg) and (2S)-2-amino-1-[4-[4-[ 6-Amino-5-[(lR)-l-(2,6-Dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]P-pyrazole-1-yl]piperidinyl ]-2-(3-pyridyl)ethanone (5.8 mg).
实施例 64的光谱数据： Spectral data of Example 64:
LC/MS (方法： UFLC): m/z - 584.1 [M+H]+. 实施例 65的光谱数据-LC/MS (method: UFLC): m/z - 584.1 [M+H] + . Spectral data of Example 65 -
LC/MS (方法： UFLC): m/z = 584.1 [M+H]+. 实施例 66
Figure imgf000067_0001
LC/MS (method: UFLC): m/z = 584.1 [M+H] + .
Figure imgf000067_0001
氨基 -5-| (2,6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基]吡唑 -1-基]  Amino-5-|(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazole-1-yl]
- 哌啶基] -2-氧代-乙基] -3-甲基-脲 操作步骤：  - piperidinyl]-2-oxo-ethyl]-3-methyl-urea
将 2-氨基小 [4-[4-[6-氨基 -5- [卜 (2,6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基]吡唑 -1-基] -1-哌啶基] 乙 酮 （80 毫克， 0.157毫摩尔， 1当量， 实施例 17)， N，N，-二异丙基乙胺 (81毫克， 0.63毫摩尔， 4 当量)溶 5毫升二氯甲垸。然后搅拌、冰浴和氮气保护下将 N-甲基氨基甲酰氯（ 29毫克， 0.315 毫摩尔， 2当量)逐滴加入。 得到反应液在室温下继续搅拌 10分钟。 反应结束后， 将反应液 用二氯甲烷稀释， 有机层用碳酸氢钠溶液和食盐水各反洗一次， 再用硫酸钠干燥后旋干， 得 到的粗品采用高效液相色谱在 C18反相柱上分离 (流动相： 乙腈 /水 /0.5%碳酸氢氨， 梯度洗脱 36%至 66% (体积比))， 减压蒸除易挥发的组分后冻干得到目标化合物 (33.5 毫克， 产率为 33.5%)。 2-Amino small [4-[4-[6-amino-5-[b(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazole-1- Ethyl ketone ketone (80 mg, 0.157 mmol, 1 eq., Example 17), N,N,-diisopropylethylamine (81 mg, 0.63 mmol, 4 eq.) 5 ml of dichloromethane. N-methylcarbamoyl chloride (29 mg, 0.315 mmol, 2 eq.) was then added dropwise with stirring, ice bath and nitrogen. The reaction solution was stirred at room temperature for further 10 minutes. After the reaction was completed, the reaction mixture was diluted with methylene chloride. The organic layer was washed once with sodium bicarbonate solution and brine, dried over sodium sulfate and then evaporated to dryness. Separation (mobile phase: acetonitrile/water/0.5% ammonium bicarbonate, gradient elution 36% to 66% by volume), evaporation of the volatile components under reduced pressure and lyophilization to give the title compound (33.5 mg, yield It is 33.5%).
光谱数据： Spectral data:
LC/MS (方法： UFLC): RT = 3.368 分钟； m/z = 563.1 [M+H]+; 总的运行时间为 7.00 分钟。 LC/MS (method: UFLC): RT = 3.368 min; m/z = 563.1 [M+H] + ; The total run time was 7.00 min.
Ή NMR (400 MHz, METHANOL-^) δ 1.87 (d, J = 6.53 Hz, 4 H), 1.92 - 2.04 (m， 2 H), 2.08 - 2.20 (m, 2 H), 2.66 - 2.74 (m, 3 H), 2.81 - 2.93 (m, 1 H), 3.22 - 3.28 (m, 1 H)， 3.96 - 4.11 (m, 3 H), 4.40 - 4.48 (m, 1 H), 4.61 (br. s.， 1 H), 6.18 (q, J = 6.69 Hz, 1 H)， 6.93 (d, J = 1.51 Hz, 1 H), 7.23 (t, J = 8.66 Hz, 1 H)， 7.46 (dd, J = 9.03, 4.77 Hz, 1 H), 7.55 (s, 1 H), 7.67 (d, J = 1.51 Hz, 1 H)， 7.84 (s, 1 H). 实施例 67
Figure imgf000067_0002
NMR NMR (400 MHz, METHANOL-^) δ 1.87 (d, J = 6.53 Hz, 4 H), 1.92 - 2.04 (m, 2 H), 2.08 - 2.20 (m, 2 H), 2.66 - 2.74 (m, 3 H), 2.81 - 2.93 (m, 1 H), 3.22 - 3.28 (m, 1 H), 3.96 - 4.11 (m, 3 H), 4.40 - 4.48 (m, 1 H), 4.61 (br. s. , 1 H), 6.18 (q, J = 6.69 Hz, 1 H), 6.93 (d, J = 1.51 Hz, 1 H), 7.23 (t, J = 8.66 Hz, 1 H), 7.46 (dd, J = 9.03, 4.77 Hz, 1 H), 7.55 (s, 1 H), 7.67 (d, J = 1.51 Hz, 1 H), 7.84 (s, 1 H). Example 67
Figure imgf000067_0002
l-[2-[4-[4-[6-氨基 -5-[l-(2,6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基] P比唑 -1-基  1-[2-[4-[4-[6-Amino-5-[l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]P-pyrazole- 1-base
-1-哌啶基 ]-2-氧代-乙基] -3-乙基-脲 操作步骤： -1-piperidinyl]-2-oxo-ethyl]-3-ethyl-urea Steps:
将 2-氨基 -1-[4- [4-[6-氨基 -5- [1-(2,6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基]吡唑- 基]小哌啶基]乙 酮 (117 毫克, 0.22毫摩尔，1当量)溶于 3毫升二氯甲烷。然后搅拌、冰浴和氮气保护下乙基异 氰酸酯 (16毫克， 0.23毫摩尔， 1.1当量)逐滴加入。 得到反应液在室温下继续搅拌 10分钟。 反应结束后， 将反应液用二氯甲烷稀释， 有机层用碳酸氢钠溶液和食盐水各反洗一次， 再用 硫酸钠干燥后旋干，得到的粗品采用高效液相色谱在 C18反相柱上分离 (流动相：乙腈 /水 /0.5% 碳酸氢氨， 梯度洗脱 36%至 66% (体积比))， 减压蒸除易挥发的组分后冻干得到目标化合物 (4 毫克， 产率为 3.3%)。 2-Amino-1-[4-[4-[6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazole -Phenyl]piperidinyl]ethanone (117 mg, 0.22 mmol, 1 eq.) was dissolved in dichloromethane (3 mL). Ethyl isocyanate (16 mg, 0.23 mmol, 1.1 eq.) was then added dropwise with stirring, ice bath and nitrogen. The reaction solution was stirred at room temperature for further 10 minutes. After the reaction was completed, the reaction mixture was diluted with methylene chloride. The organic layer was washed once with sodium bicarbonate solution and brine, dried over sodium sulfate and then evaporated to dryness. Separation (mobile phase: acetonitrile/water/0.5% ammonium bicarbonate, gradient elution 36% to 66% by volume), evaporation of the volatile components under reduced pressure and lyophilization to give the title compound (4 mg, yield 3.3%).
光谱数据： Spectral data:
LC/MS (方法： UFLC): RT = 3.423分钟； m/z = 577.1 [M+H]+; 总的运行时间为 7.00分钟。 1H NMR (400 MHz, METHANOL-^) δ 7.98 (s, 1H)， 7.66 (s, 1H), 7.63 (d, J = 1.6 Hz, 1H), 7.55 (dd, J= 4.8, 9.2 Hz, 1H), 7.32 (t， J= 8.8 Hz, 1H)， 7.19 (d, J= 1.6 Hz, 1H), 6.40 (q, J= 6.4 Hz, 1H)， 4.63-4.47 (m, 2H), 4.16-4.01 (m, 3H), 3.36-3.32 (m, 1H), 3.22 (q, J - 6.4 Hz, 2H), 2.94-2.88 (m, 1H), 2.21-2.17 (m ,2H)， 2.06-1.91 (m， 5H)， 1.16 (t, J= 6.4 Hz, 3H). 施例 68
Figure imgf000068_0001
LC/MS (method: UFLC): RT = 3.423 min; m/z = 577.1 [M+H] + ; 1H NMR (400 MHz, METHANOL-^) δ 7.98 (s, 1H), 7.66 (s, 1H), 7.63 (d, J = 1.6 Hz, 1H), 7.55 (dd, J= 4.8, 9.2 Hz, 1H) , 7.32 (t, J= 8.8 Hz, 1H), 7.19 (d, J= 1.6 Hz, 1H), 6.40 (q, J= 6.4 Hz, 1H), 4.63-4.47 (m, 2H), 4.16-4.01 ( m, 3H), 3.36-3.32 (m, 1H), 3.22 (q, J - 6.4 Hz, 2H), 2.94-2.88 (m, 1H), 2.21-2.17 (m , 2H), 2.06-1.91 (m, 5H), 1.16 (t, J= 6.4 Hz, 3H). Example 68
Figure imgf000068_0001
N-[2-[4-[4-[6-氨基 -5-[l-(2,6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基] P比唑 -1-基]  N-[2-[4-[4-[6-amino-5-[l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]P-pyrazole- 1-base]
-1-哌啶基 ]-2-氧代-乙基]氨甲酸甲酯  Methyl 1-piperidinyl]-2-oxo-ethyl]carbamate
操作步骤： Steps:
将 2-氨基 - [4-[4- [6-氨基 -5-[1-(2,6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基]吡唑 -1-基]小哌啶基]乙 酮 (80 毫克， 0.158毫摩尔， 1当量)， Ν,Ν'-二异丙基乙胺 (40 毫克， 0.316毫摩尔， 2当量)溶于 3 毫升二氯甲垸。然后搅拌、冰浴和氮气保护下将氯甲酸甲酯 (300毫克， 0.32毫摩尔， 2当量) 逐滴加入。 得到反应液在室温下继续搅拌 10分钟。 反应结束后， 将反应液用二氯甲垸稀释， 有机层用碳酸氢钠溶液和食盐水各反洗一次， 再用硫酸钠干燥后旋干， 得到的粗品采用高效 液相色谱在 C18反相柱上分离 (流动相： 乙腈 /水 /0.5%碳酸氢氨， 梯度洗脱 36%至 66% (体积 比; ))， 减压蒸除易挥发的组分后冻干得到目标化合物 （7.2毫克， 产率为 90%)。 2-Amino-[4-[4-[6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazole-1 -yl)piperidinyl]ethanone (80 mg, 0.158 mmol, 1 eq.), hydrazine, Ν'-diisopropylethylamine (40 mg, 0.316 mmol, 2 eq.) dissolved in 3 mL of dichloro Hyperthyroidism. Methyl chloroformate (300 mg, 0.32 mmol, 2 eq.) was then added dropwise with stirring, ice bath and nitrogen. The reaction solution was stirred at room temperature for further 10 minutes. After the reaction was completed, the reaction solution was diluted with dichloromethane, and the organic layer was back-washed once with sodium hydrogen carbonate solution and brine, dried over sodium sulfate and then evaporated to dryness. Separation (mobile phase: acetonitrile/water/0.5% ammonium bicarbonate, gradient elution 36% to 66% (volume ratio; )), evaporation of the volatile components under reduced pressure, and lyophilization to give the title compound (7.2 mg, The yield was 90%).
光谱数据： Spectral data:
LC/MS (方法： UFLC): RT = 3.456 分钟； m/z = 564.1 [M+H]+ ; 总的运行时间为 7.00 分钟。 [養- ι-¾ ι [聲 ¾φ-ε- [聲 -ε- =-9 -ι -養) -9]寸
Figure imgf000069_0001
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Figure imgf000069_0001
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88i000/M0ZN3/X3d 操作步骤： 88i000/M0ZN3/X3d Steps:
将化合物 3-[1-(2，6-二氯 -3-氟-苯基)乙氧基 ]-5-[1-(4-哌啶基) P比唑 -4-基] P比啶 -2-胺 （23毫克， 0.05 毫摩尔， 1当量.；)， 2-脲基乙酸 (7毫克， 0.06毫摩尔， 1.2当量)和 Ν,Ν,Ν',Ν'-四甲基 -0-(7-氮杂 苯并三唑 -1-基)六氟磷酸脲 (29毫克, 0.075毫摩尔， 1.5当量)溶于 2毫升二氯甲垸。 然后搅拌、 冰浴和氮气保护下， 继续缓慢加入 Ν,Ν'-二异丙基乙胺 (33毫克, 0.25毫摩尔， 5当量)。 反应在 室温下继续搅拌 2小时。 反应结束后， 将反应液用二氯甲烷稀释， 有机层用碳酸氢钠溶液和 食盐水各反洗一次， 再用硫酸钠干燥后旋干， 得到的粗品采用高效液相色谱在 C18反相柱上 分离 (流动相： 乙腈 /水 /0.5%碳酸氢氨， 梯度洗脱 36%至 66% (体积比))， 减压蒸除易挥发的组 分后冻干得到目标化合物 （7 毫克， 产率为 25%)。 The compound 3-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-5-[1-(4-piperidinyl)P-pyrazol-4-yl]P is pyridine 2-Amine (23 mg, 0.05 mmol, 1 eq.;), 2-ureidoacetic acid (7 mg, 0.06 mmol, 1.2 eq.) and hydrazine, hydrazine, hydrazine, Ν'-tetramethyl- -(7-Azabenzotriazol-1-yl)hexafluorophosphate (29 mg, 0.075 mmol, 1.5 eq.) was dissolved in 2 mL of dichloromethane. Then, under stirring, ice bath and nitrogen, continue to slowly add hydrazine, Ν'-diisopropylethylamine (33 mg, 0.25 mmol, 5 eq.). The reaction was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was diluted with methylene chloride. The organic layer was washed once with sodium bicarbonate solution and brine, dried over sodium sulfate and then evaporated to dryness. Separation (mobile phase: acetonitrile/water/0.5% ammonium bicarbonate, gradient elution 36% to 66% by volume), evaporation of the volatile components under reduced pressure and lyophilization to give the title compound (7 mg, yield 25%).
光谱数据： Spectral data:
LC/MS (方法： UFLC): RT = 3.166 分钟； m/z = 549.1 [M+H]+; 总的运行时间为 7.00 分钟。 Ή NMR (400 MHz, METHANOL-^) δ 7.99 (s, 1H), 7.67 (s, 1H), 7.63 (s, 1H), 7.53 (dd, J = 4.8, 8.8 Hz, 1H), 7.36 (t, J = 8,4 Hz, 1H), 7.16 (s, 1H), 6.38 (q, J = 6.8 Hz, 1H), 4.61 -4.50 (m, 2H), 4.20-3.95 (m, 3H), 3.34-3.30 (m，1H)， 2.94-2.84 (m, 1H), 2.19-2.12 (m, 2H), 2.06-1.94 (m, 5H). 实施例 71
Figure imgf000070_0001
LC/MS (method: UFLC): RT = 3.166 min; m/z = 549.1 [M+H] + ; The total run time was 7.00 min. NMR NMR (400 MHz, METHANOL-^) δ 7.99 (s, 1H), 7.67 (s, 1H), 7.63 (s, 1H), 7.53 (dd, J = 4.8, 8.8 Hz, 1H), 7.36 (t, J = 8,4 Hz, 1H), 7.16 (s, 1H), 6.38 (q, J = 6.8 Hz, 1H), 4.61 -4.50 (m, 2H), 4.20-3.95 (m, 3H), 3.34-3.30 (m, 1H), 2.94-2.84 (m, 1H), 2.19-2.12 (m, 2H), 2.06-1.94 (m, 5H). Example 71
Figure imgf000070_0001
l-[4-[4-[6-氨基 -5-[(lR)-l- (2,6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基]吡唑- 1-基]  1-[4-[4-[6-Amino-5-[(lR)-l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazole- 1-base]
-1-哌啶基 ]-2-(3-吡啶基)乙酮  1-piperidinyl]-2-(3-pyridyl)ethanone
操作步骤： Steps:
将化合物 3-[(lR)-l-(2,6-二氯 -3-氟-苯基)乙氧基 ]-5-[1- (4-哌啶基)吡唑 -4-基] P比啶 -2-胺 （100 毫 克， 0.222毫摩尔， 1.0当量)， 2-(3-吡啶基）乙酸 (42毫克， 0.245毫摩尔， 1.1当量)和 Ν,Ν,Ν',Ν'- 四甲基- 0-(7-氮杂苯并三唑 -1-基)六氟磷酸脲 (126毫克， 0.334毫摩尔， 1.5当量)溶于 5毫升二氯 甲垸。 然后搅拌、 冰浴和氮气保护下， 继续缓慢加入 Ν,Ν'-二异丙基乙胺 (0.143毫克， 1.11毫 摩尔， 5当量)。 反应在室温下继续搅拌 2小时。 反应结束后， 将反应液用二氯甲垸稀释， 有机 层用碳酸氢钠溶液和食盐水各反洗一次， 再用硫酸钠干燥后旋干， 得到的粗品采用高效液相 色谱在 C18反相柱上分离 (流动相： 乙腈 /水 /0.5%碳酸氢氨， 梯度洗脱 36%至 66% (体积比))， 减压蒸除易挥发的组分后冻干得到目标化合物（23.3毫克， 产率为 18.5%)。 The compound 3-[(lR)-l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-5-[1-(4-piperidyl)pyrazol-4-yl] P-pyridin-2-amine (100 mg, 0.222 mmol, 1.0 eq.), 2-(3-pyridyl)acetic acid (42 mg, 0.245 mmol, 1.1 eq.) and hydrazine, hydrazine, hydrazine Tetramethyl- 0-(7-azabenzotriazol-1-yl)hexafluorophosphate (126 mg, 0.334 mmol, 1.5 eq.) was dissolved in 5 mL of dichloromethane. Then, stirring, ice bath and nitrogen protection were continued, and hydrazine, Ν'-diisopropylethylamine (0.143 mg, 1.11 mmol, 5 eq.) was slowly added. The reaction was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was diluted with dichloromethane, and the organic layer was back-washed once with sodium hydrogen carbonate solution and brine, dried over sodium sulfate and then evaporated to dryness. Separation (mobile phase: acetonitrile/water/0.5% ammonium bicarbonate, gradient elution 36% to 66% by volume), evaporation of the volatile components under reduced pressure, and lyophilization to give the target compound (23.3 mg, yield The rate is 18.5%).
光谱数据： LC/MS (方法： UFLC): RT = 3.127分钟； m/z = 568.1 [M+H]+; 总的运行时间为 7.00 分钟。 Ή NMR (400 MHz, METHANOL-^) δ 1.83 - 1.98 (m, 5 H), 2.12 (d, J = 3.26 Hz, 2 H)， 2.87 (t, J = 11.67 Hz, 1 H), 3.33 - 3.40 (m, 1 H)， 3.90 (s, 2 H), 4.20 (d， J = 13.80 Hz, 1 H)， 4.43 (tt， J = 11.42, 4.02 Hz, 1 H), 4.59 - 4.69 (m, 1 H)， 6.16 (q, J = 6.69 Hz, 1 H), 6.92 (d, J = 1.51 Hz, 1 H), 7.22 (t, J = 8.66 Hz, 1 H), 7.38 - 7.47 (m, 2 H), 7.55 (s， 1 H), 7.66 (d, J = 1.51 Hz, 1 H)， 7.72 - 7.79 (m， 1 H)， 7.79 - 7.84 (m, 1 H), 8.35 - 8.60 (m, 2 H). 施例 72 Spectral data: LC/MS (method: UFLC): RT = 3.127 min; m/z = 568.1 [M+H] + ; NMR NMR (400 MHz, METHANOL-^) δ 1.83 - 1.98 (m, 5 H), 2.12 (d, J = 3.26 Hz, 2 H), 2.87 (t, J = 11.67 Hz, 1 H), 3.33 - 3.40 (m, 1 H), 3.90 (s, 2 H), 4.20 (d, J = 13.80 Hz, 1 H), 4.43 (tt, J = 11.42, 4.02 Hz, 1 H), 4.59 - 4.69 (m, 1 H), 6.16 (q, J = 6.69 Hz, 1 H), 6.92 (d, J = 1.51 Hz, 1 H), 7.22 (t, J = 8.66 Hz, 1 H), 7.38 - 7.47 (m, 2 H ), 7.55 (s, 1 H), 7.66 (d, J = 1.51 Hz, 1 H), 7.72 - 7.79 (m, 1 H), 7.79 - 7.84 (m, 1 H), 8.35 - 8.60 (m, 2 H). Example 72
[4— [4-[6—氨基— 5—[(lR)— 1— (2,6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基]吡唑 -1-基] [4-[4-[ 6 -Amino-5-[(lR)-1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazole-1- base]
-1-哌啶基 ]-2-(4-吡啶基)乙酮  -1-piperidinyl]-2-(4-pyridyl)ethanone
操作步骤： Steps:
将化合物 3-[(lR)-l-(2，6-二氯 -3-氟-苯基)乙氧基 ]-5-[1-(4-哌啶基) P比唑 -4-基]吡啶 -2-胺 （100 毫 克， 0.227毫摩尔， 1当量)， 2-(4-吡啶基）乙酸 (42 毫克， 0.245毫摩尔， 1.1当量)禾卩 N,N，N，,N，- 四甲基 -0-(7-氮杂苯并三唑小基)六氟磷酸脲 (126毫克， 0.334毫摩尔， 1.5当量)溶于 5 毫升二 氯甲烷。 然后搅拌、 冰浴和氮气保护下， 继续缓慢加入 Ν，Ν'-二异丙基乙胺 （143毫克， 1.1 毫摩尔， 1当量)。 反应在室温下继续搅拌 3小时。 反应结束后， 将反应液用二氯甲垸稀释， 有机层用碳酸氢钠溶液和食盐水各反洗一次， 再用硫酸钠干燥后旋干， 得到的粗品采用高效 液相色谱在 C18反相柱上分离 (流动相： 乙腈 /水 /0.5%碳酸氢氨， 梯度洗脱 36%至 66% (体积 比))， 减压蒸除易挥发的组分后冻干得到目标化合物 (72毫克， 产率为 57%)。 The compound 3-[(lR)-l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-5-[1-(4-piperidinyl)P-pyrazol-4-yl Pyridin-2-amine (100 mg, 0.227 mmol, 1 eq.), 2-(4-pyridyl)acetic acid (42 mg, 0.245 mmol, 1.1 eq.), s, N, N, N, N, Tetramethyl-O-(7-azabenzotriazole small) hexafluorophosphate (126 mg, 0.334 mmol, 1.5 eq.) was dissolved in 5 mL of dichloromethane. Then, under stirring, ice bath and nitrogen, continue to slowly add hydrazine, Ν'-diisopropylethylamine (143 mg, 1.1 mmol, 1 eq.). The reaction was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was diluted with dichloromethane, and the organic layer was back-washed once with sodium hydrogen carbonate solution and brine, dried over sodium sulfate and then evaporated to dryness. Separation (mobile phase: acetonitrile/water/0.5% ammonium bicarbonate, gradient elution 36% to 66% (by volume)), evaporation of volatile components under reduced pressure, lyophilization to give the target compound (72 mg, yield The rate is 57%).
光谱数据： Spectral data:
LC/MS (方法： UFLC): RT = 2.977分钟； m/z = 568.1 [Μ+Η]+; 总的运行时间为 7,00 分钟。 Ή NMR (400 MHz, METHANOL-d4) δ 1.87 (d， J = 6.53 Hz, 3 H)， 1.89 - 1.99 (m, 2 H), 2.12 (d， J = 11.80 Hz, 2 H), 2.81 - 2.94 (m， 1 H), 3.24 - 3.35 (m, 2 H), 3.88 - 3.92 (m, 1 H), 4.13 (d, J = 14.05 Hz, 1 H)， 4.42 (tt, J = 1 1.36, 3.95 Hz, 1 H)， 4.67 (d, J = 13.05 Hz, 1 H), 6.16 (q, J = 6.53 Hz, 1 H)， 6.92 (d, J = 1.25 Hz, 1 H)， 7.21 (t, J = 8.53 Hz, 1 H), 7.38 (d, J = 6.02 Hz, 2 H), 7.43 (dd, J = 8.91, 4.89 Hz, 1 H), 7.52 - 7.60 (m, 2 H)， 7.61 - 7.71 (m, 2 H)， 7.81 (s, 1 H), 8.50 (d, J= 5.52 Hz, 2 H). 实施例 73
Figure imgf000072_0001
LC/MS (method: UFLC): RT = 2.977 min; m/z = 568.1 [Μ+Η] + ; The total run time is 7,00 minutes. NMR NMR (400 MHz, METHANOL-d 4 ) δ 1.87 (d, J = 6.53 Hz, 3 H), 1.89 - 1.99 (m, 2 H), 2.12 (d, J = 11.80 Hz, 2 H), 2.81 - 2.94 (m, 1 H), 3.24 - 3.35 (m, 2 H), 3.88 - 3.92 (m, 1 H), 4.13 (d, J = 14.05 Hz, 1 H), 4.42 (tt, J = 1 1.36, 3.95 Hz, 1 H), 4.67 (d, J = 13.05 Hz, 1 H), 6.16 (q, J = 6.53 Hz, 1 H), 6.92 (d, J = 1.25 Hz, 1 H), 7.21 (t, J = 8.53 Hz, 1 H), 7.38 (d, J = 6.02 Hz, 2 H), 7.43 (dd, J = 8.91, 4.89 Hz, 1 H), 7.52 - 7.60 (m, 2 H), 7.61 - 7.71 (m, 2 H), 7.81 (s, 1 H), 8.50 (d, J = 5.52 Hz, 2 H). Example 73
Figure imgf000072_0001
1-[4- [4-[6-氨基 -5-[(lR)-l-(2， 6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基] P比唑- 基]  1-[4-[4-[6-Amino-5-[(lR)-l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl] P-pyrazole - base]
-1-哌啶基 ]-2-(2-吡啶基)乙酮  -1-piperidinyl]-2-(2-pyridyl)ethanone
操作步骤： Steps:
将化合物 3-[(lR)-l-(2，6-二氯 -3-氟-苯基)乙氧基 ]- 5-[1-(4-哌啶基) P比唑 -4-基] P比啶 -2-胺 （100 毫 克， 0.227毫摩尔， 1.1当量)， 2-(2-吡啶基）乙酸 （42毫克， 0.245毫摩尔， 1.1当量)和 Ν，Ν,Ν'，Ν'- 四甲基 -0-(7-氮杂苯并三唑 -1-基)六氟磷酸脲 (126毫克， 0.334毫摩尔， 1.5当量)溶于 5 毫升二 氯甲垸。 然后搅拌、 冰浴和氮气保护下， 继续缓慢加入 Ν,Ν'-二异丙基乙胺 (143毫克， 1.11毫 摩尔， 5当量)。 反应在室温下继续搅拌 3小时。 反应结束后， 将反应液用二氯甲垸稀释， 有机 层用碳酸氢钠溶液和食盐水各反洗一次， 再用硫酸钠干燥后旋干， 得到的粗品采用高效液相 色谱在 C18反相柱上分离 (流动相： 乙腈 /水 /0.5%碳酸氢氨， 梯度洗脱 36%至 66% (体积比))， 减压蒸除易挥发的组分后冻干得到目标化合物 (109毫克， 产率为 86.5%)。 The compound 3-[(lR)-l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-5-[1-(4-piperidinyl)P-pyrazol-4-yl P-pyridin-2-amine (100 mg, 0.227 mmol, 1.1 eq.), 2-(2-pyridyl)acetic acid (42 mg, 0.245 mmol, 1.1 eq.) and Ν, Ν, Ν ', Ν' - Tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate (126 mg, 0.334 mmol, 1.5 eq.) was dissolved in 5 mL of dichloromethane. Then, under stirring, ice bath and nitrogen, continue to slowly add hydrazine, Ν'-diisopropylethylamine (143 mg, 1.11 mmol, 5 eq.). The reaction was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was diluted with dichloromethane, and the organic layer was back-washed once with sodium hydrogen carbonate solution and brine, dried over sodium sulfate and then evaporated to dryness. Separation (mobile phase: acetonitrile/water/0.5% ammonium bicarbonate, gradient elution 36% to 66% by volume), evaporation of the volatile components under reduced pressure, and lyophilization to give the title compound (109 mg, yield The rate is 86.5%).
光谱数据： Spectral data:
LC/MS (方法： UFLC): RT = 3.101分钟； m/z = 568.1 [Μ+Η]+; 总的运行时间为 7.00 分钟。 Ή NMR (400 MHz, METHANOL-^) δ 8.52 (d, J = 4.8 Hz, 1H)， 7.83-7.99 (m, 2H), 7.68 (d, J = 1.6 Hz, IH), 7.55 (s, IH), 7.46-7.40 (m, 2H)， 7.35 (dd, J = 4.8， 7.6 Hz, 1H)， 7.26 (t, J= 8.8 Hz, IH), 6.94 (s, IH), 6.20 (q, J = 6.8 Hz, 1H)， 4.69-4.65 (m, IH), 4.46-4.43 (m, IH), 4.25-4.20 (m, IH), 4.02-3.99 (m, IH), 3.34-3.28 (m，2H), 2.94-2.84 (m, IH), 2.14-2.12 (m, 2H), 1.96-1.87 (m， 5H). 实施例 74  LC/MS (method: UFLC): RT = 3.101 min; m/z = 568.1 [Μ+Η]+; The total run time is 7.00 minutes. NMR NMR (400 MHz, METHANOL-^) δ 8.52 (d, J = 4.8 Hz, 1H), 7.83-7.99 (m, 2H), 7.68 (d, J = 1.6 Hz, IH), 7.55 (s, IH) , 7.46-7.40 (m, 2H), 7.35 (dd, J = 4.8, 7.6 Hz, 1H), 7.26 (t, J= 8.8 Hz, IH), 6.94 (s, IH), 6.20 (q, J = 6.8 Hz, 1H), 4.69-4.65 (m, IH), 4.46-4.43 (m, IH), 4.25-4.20 (m, IH), 4.02-3.99 (m, IH), 3.34-3.28 (m, 2H), 2.94-2.84 (m, IH), 2.14-2.12 (m, 2H), 1.96-1.87 (m, 5H). Example 74
Figure imgf000072_0002
Figure imgf000072_0002
3- [l-(2, 6-二氯苯基)乙氧基 ]-5-[l- (4-哌啶基) P比唑 -4-基]吡啶基 -2-胺 操作步骤：  3-[l-(2,6-Dichlorophenyl)ethoxy]-5-[l-(4-piperidinyl)P-pyrazol-4-yl]pyridyl-2-amine
此化合物由前面描述的方法制备。 This compound was prepared by the method described previously.
光谱数据： Spectral data:
LC/MS (方法： UFLC): m/z = 432 [M+H]+. 实施例 75
Figure imgf000073_0001
LC/MS (method: UFLC): m/z = 432 [M+H] + . Example 75
Figure imgf000073_0001
2— [4-[4-[6-氨基 -5-[l-(2,6-二氯苯基)乙氧基 ]-3-吡啶基]吡唑 -1-基] -1-哌啶基  2-[4-[4-[6-Amino-5-[l-(2,6-dichlorophenyl)ethoxy]-3-pyridyl]pyrazole-1-yl]-1-piperidine Base
-N-甲基-乙酰胺  -N-methyl-acetamide
操作步骤： Steps:
此化合物由前面描述的方法制备。 This compound was prepared by the method described previously.
光谱数据： Spectral data:
LC/MS (方法： UFLC): m/z = 503 [M+H]+. 76
Figure imgf000073_0002
LC/MS (method: UFLC): m/z = 503 [M+H] + . 76
Figure imgf000073_0002
2— [4-[4-[6-氨基 -5-Π-(2-氯 -6-甲氧基-苯基)乙氧基 ]-3-吡啶基] P比唑 -1-基:  2-[4-[4-[6-Amino-5-indole-(2-chloro-6-methoxy-phenyl)ethoxy]-3-pyridyl]P-pyrazole-1-yl:
-1-哌啶基] -N-甲基-乙酰胺 步骤 A:  1-piperidinyl]-N-methyl-acetamide Step A:
Figure imgf000073_0003
Figure imgf000073_0003
2-(1-溴乙基) - 氯 -3-甲氧基-苯  2-(1-bromoethyl)-chloro-3-methoxy-benzene
操作步骤： Steps:
向冰浴冷却的溶有化合物 1-(2-氯 -6-甲氧基苯基)乙醇 (93 毫克， 0.5 毫摩尔， 1.0 当量)和 4-二 甲氨基吡啶 (6 毫克， 0.05 毫摩尔， 0.1 当量)的无水二氯甲垸 (5 毫升)溶液中滴加三溴化磷 (148 毫克， 0.55毫摩尔， 1.1当量). 此混合物在室温下搅拌 2小时。在零度下加入水 (10 毫升) 并用二氯甲垸 （10 毫升 *3)萃取. 有机层用用硫酸钠干燥后旋干， 得到的粗品化合物。 此粗 品化合物用薄层色谱层析制备板 （石油醚： 乙酸乙酯 =5:1) 得到目标化合物 （70 毫克， 50 %)。 步骤 B:
Figure imgf000074_0001
The compound was dissolved in an ice bath, 1-(2-chloro-6-methoxyphenyl)ethanol (93 mg, 0.5 mmol, 1.0 eq.) and 4-dimethylaminopyridine (6 mg, 0.05 mmol). To a solution of 0.1 equivalent of anhydrous dichloromethane (5 ml) was added dropwise phosphorus tribromide (148 mg, 0.55 mmol, 1.1 eq.). The mixture was stirred at room temperature for 2 hr. Water (10 ml) was added at 0 °C and extracted with dichloromethane (10 mL*3). This crude compound was purified by chromatography (yield: ethyl ether: ethyl acetate = 5:1) to give the title compound (70 mg, 50%). Step B:
Figure imgf000074_0001
2-[4-[4-[6-氨基 -5-[l-(2-氯 -6-甲氧基-苯基)乙氧基 ]-3-吡啶基]吡唑小基:  2-[4-[4-[6-Amino-5-[l-(2-chloro-6-methoxy-phenyl)ethoxy]-3-pyridyl]pyrazole small group:
-1-哌啶基] -N-甲基-乙酰胺  -1-piperidinyl]-N-methyl-acetamide
操作步骤: Steps:
向冰浴冷却和氮气保护的含有化合物 2-[4-[4-(6-氨基 -5-羟基 -3-吡啶基)吡唑 -1-基] -1-哌啶 基]—N—甲基-乙酰胺 (93 毫克， 0.28 毫摩尔， 1.0当量)的无水 Ν,Ν'-二甲基甲酰胺 （3 毫升)加入 氢化钠 （13毫克， 0.34毫摩尔， 1.2当量， 在矿物油 60%的含量)。 此混合液在 0度下搅拌 30 分钟后， 再滴加化合物 2-(1-溴乙基 )-1-氯 -3-甲氧基-苯 （70 毫克， 0.28 毫摩尔， 1.0当量） 的 Ν,Ν'-二甲基甲酰胺 (3 毫升)。 此混合物在室温下搅拌过夜。 在 0度下加入食盐水 (5 毫升)并 用乙酸乙酯 （10 毫升 *3)萃取。合并的有机层用碳酸氢钠溶液和食盐水各反洗一次，再用硫酸 钠干燥后旋干得到的粗品， 此粗品采用用 HPLC纯化采用高效液相色谱在 C18反相柱上分离 (流动相：乙腈 /水 /0.5%碳酸氢铰，梯度洗脱 25%至 55% (体积比))，得到目标化合物 (10毫克， 产 率为 7%)。 The compound containing 2-[4-[4-(6-amino-5-hydroxy-3-pyridyl)pyrazol-1-yl]-1-piperidinyl]-N-A was cooled to ice-cooled and nitrogen-protected Base-acetamide (93 mg, 0.28 mmol, 1.0 eq.) of anhydrous hydrazine, Ν'-dimethylformamide (3 mL), sodium hydride (13 mg, 0.34 mmol, 1.2 eq. % content). After the mixture was stirred at 0 °C for 30 minutes, the compound 2-(1-bromoethyl)-1-chloro-3-methoxy-benzene (70 mg, 0.28 mmol, 1.0 eq. , Ν'-dimethylformamide (3 ml). This mixture was stirred at room temperature overnight. Saline solution (5 ml) was added at 0 °C and extracted with ethyl acetate (10 ml *3). The combined organic layers were backwashed once with sodium bicarbonate solution and brine, dried over sodium sulfate and then evaporated to dryness. The crude product was purified by HPLC using high performance liquid chromatography on a C18 reversed phase column (mobile phase: Acetonitrile/water/0.5% hydrogencarbonate hinge, gradient elution from 25% to 55% (by volume)) gave the title compound (10 mg, yield 7%).
光谱数据: Spectral data:
LC/MS (方法： UFLC): RT,= 1.79 分钟； m/z = 499.2 [Μ+Η]+; 总的运行时间为 7.00 分钟。 Ή NMR (400 MHz, METHANOL-^) δ 7.85 (s, 1 H), 7.53 - 7.67 (m, 2 H), 7.18 - 7.31 (m, 1 H)， 7.11 (d, J = 1.76 Hz, 1 H)， 7.01 (dd, J = 8.16, 1.38 Hz, 2 H), 6.18 (q, J = 6.36 Hz, 1 H), 4.13 - 4.34 (m, 1 H)， 3.94 (s， 3 H), 3.17 (s, 2 H), 3.07 (d, J = 1 1.54 Hz, 2 H)， 2.82 (s, 3 H) 2.39 - 2.56 (m, 2 H): 2.01 - 2.31 (m, 4 H), 1.85 (d, J = 6.78 Hz, 3 H), 1.32 (br. s.， 3 H)。 实施例 77
Figure imgf000074_0002
LC/MS (method: UFLC): RT, = 1.79 min; m/z = 499.2 [Μ+Η] + ; The total run time is 7.00 min. NMR NMR (400 MHz, METHANOL-^) δ 7.85 (s, 1 H), 7.53 - 7.67 (m, 2 H), 7.18 - 7.31 (m, 1 H), 7.11 (d, J = 1.76 Hz, 1 H ), 7.01 (dd, J = 8.16, 1.38 Hz, 2 H), 6.18 (q, J = 6.36 Hz, 1 H), 4.13 - 4.34 (m, 1 H), 3.94 (s, 3 H), 3.17 ( s, 2 H), 3.07 (d, J = 1 1.54 Hz, 2 H), 2.82 (s, 3 H) 2.39 - 2.56 (m, 2 H) : 2.01 - 2.31 (m, 4 H), 1.85 (d , J = 6.78 Hz, 3 H), 1.32 (br. s., 3 H). Example 77
Figure imgf000074_0002
2-[4-[4-[6-氨基 -5-[l-(3, 5-二氯 -4-吡啶基） 乙氧基 ]-3-吡啶基]吡唑 -1-基  2-[4-[4-[6-Amino-5-[l-(3,5-dichloro-4-pyridyl)ethoxy]-3-pyridyl]pyrazole-1-yl
-1-哌啶基] -N-甲基-乙酰胺  -1-piperidinyl]-N-methyl-acetamide
步骤 A:
Figure imgf000075_0001
Step A:
Figure imgf000075_0001
3,5-二氯 -4-[l-[(2 -硝基 -3-吡啶基)氧]乙基]吡啶  3,5-Dichloro-4-[l-[(2-nitro-3-pyridyl)oxy]ethyl]pyridine
操作步骤： Steps:
在零度下往化合物 1-(3,5-二氯 -4-吡啶基)乙醇 (180毫克， 0.94毫摩尔， 1当量) , 2-硝基吡啶 -3-醇 (131毫克， 0.94毫摩尔， 1当量） 和 三苯基膦 （357毫克， 1.12毫摩尔， 1.5当量)的无水四氢呋 喃 10毫升溶液中加入偶氮二甲酸二异丙酯 （227毫克， 1.12毫摩尔， 1.5当量)。 反应液在室温 搅拌 12个小时后旋干. 然后向反应液中加入水 (20毫升)并用乙酸乙酯萃取 （3*20 毫升)。 有 机层合并后用硫酸钠干燥， 过滤旋干后用薄层色谱层析制备板 （石油醚： 乙酸乙酯 =2: 1 ) 纯 化得到目标化合物 (180毫克，收率为 61%)。 步骤 B:
Figure imgf000075_0002
Compound 0-(3,5-dichloro-4-pyridyl)ethanol (180 mg, 0.94 mmol, 1 eq.), 2-nitropyridin-3-ol (131 mg, 0.94 mmol, 1 eq.) To a solution of triphenylphosphine (357 mg, 1.12 mmol, 1.5 eq.) in anhydrous tetrahydrofuran (10 ml) was added isopropyl azodicarboxylate (227 mg, 1.12 mmol, 1.5 eq.). After the reaction mixture was stirred at room temperature for 12 hrs, EtOAc (EtOAc) The organic layer was combined, dried over sodium sulfate, filtered, and evaporated to silica gel eluting Step B:
Figure imgf000075_0002
3-[1-(3,5-二氯 -4-吡啶基)乙氧基]吡啶 -2-胺  3-[1-(3,5-Dichloro-4-pyridyl)ethoxy]pyridine-2-amine
操作步骤： Steps:
将化合物 3,5-二氯- 4- [1- [(2-硝基 -3-吡啶基)氧]乙基]吡啶 (180毫克， 0.57毫摩尔， 1当量）， 铁粉 (160毫克， 2.87毫摩尔，5当量)和氯化铵 (45.5毫克， 0.86毫摩尔， 1.5当量)溶解于 5毫升乙醇和 1毫升乙醇。 反应液回流 6个小时后硅藻土过滤并且用甲醇 （10毫升） 洗涤。 滤液减压浓缩 后加入水 （10 毫升)并用乙酸乙酯萃取 （3*20 毫升)。 有机层合并后用硫酸钠干燥， 过滤旋干 后用薄层色谱层析制备板 （石油醚： 乙酸乙酯 = 1 : 1 ) 纯化得到目标化合物 (100毫克，收率为 61.8%)。 步骤 C: The compound 3,5-dichloro-4-[1-[(2-nitro-3-pyridyl)oxy]ethyl]pyridine (180 mg, 0.57 mmol, 1 equivalent), iron powder (160 mg, 2.87 mmol, 5 equivalents) and ammonium chloride (45.5 mg, 0.86 mmol, 1.5 equivalents) were dissolved in 5 ml of ethanol and 1 ml of ethanol. After the reaction mixture was refluxed for 6 hours, celite was filtered and washed with methanol (10 ml). The filtrate was concentrated under reduced pressure. EtOAc (EtOAc) The organic layer was combined, dried over sodium sulfate, filtered and evaporated to dryness elution elution elution elution elution elution elution elution elution elution Step C:
Figure imgf000075_0003
Figure imgf000075_0003
5-溴- 3-[1-(3,5-二氯- 4-吡啶基)乙氧基]吡啶 -2-胺  5-bromo-3-[1-(3,5-dichloro-4-pyridyl)ethoxy]pyridine-2-amine
操作步骤： 在零度往化合物 3-[l-(3,5-二氯 -4-吡啶基)乙氧基]吡啶 -2-胺 (100毫克， 0.35毫摩尔， 1当量） 的 乙腈 （20毫升)溶液中分批加入 N-溴代丁二酰亚胺（75毫克， 0.42毫摩尔， 1.2当量。之后反应 在 0度下搅拌一个小时。 加入饱和碳酸氢钠水溶液 （5毫升)并用乙酸乙酯萃取 （3*20毫升)。 有机层合并后用硫酸钠干燥， 过滤旋干后用薄层色谱层析制备板 （石油醚： 乙酸乙酯 =1 : 1 ) 纯化得到目标化合物 (86毫克,收率为 93%)。 步骤 D: Steps: To a solution of the compound 3-[l-(3,5-dichloro-4-pyridyl)ethoxy]pyridin-2-amine (100 mg, 0.35 mmol, 1 eq.) in EtOAc (20 mL) N-Bromosuccinimide (75 mg, 0.42 mmol, 1.2 eq.) was added portionwise. The reaction was stirred at EtOAc (EtOAc) *20 ml). The organic layer was combined and dried over sodium sulfate, filtered and evaporated to dryness eluting %). Step D:
Figure imgf000076_0001
Figure imgf000076_0001
3-[1 -(3,5-二氯 -4-吡啶基)乙氧基 ]-5-[1-(4-哌啶基)吡唑 -4-基] P比啶 -2-胺 操作步骤：  3-[1-(3,5-Dichloro-4-pyridyl)ethoxy]-5-[1-(4-piperidinyl)pyrazol-4-yl]P-pyridin-2-amine Steps:
在氮气保护下， 向溶有化合物 5-溴 -3-[1-(3,5-二氯 -4-吡啶基)乙氧基]吡啶 -2-胺 (86 毫克， 0.24 毫摩尔， 1当量)和化合物 4-[4-(4,4,5,5-四甲基 -1，3，2-二氧杂环戊硼垸 -2-基)吡唑 -1-基]哌啶小甲 酸叔丁酯 (134 毫克， 0.35 毫摩尔， 1.5 当量)的饱和的碳酸氢钠水溶液 （5 毫升)和乙腈 （5 毫 升） 的混合溶液中加入 1，1'-双 (二苯基磷)二茂铁氯化钯 （17毫克， 0.024毫摩尔，10%当量)。 加 完后， 混合物在微波中 100 度下反应 30分钟。 将反应液冷却到室温并倒入 20 毫升水中并用 乙酸乙酯 （30 毫升 *2)萃取。 合并的有机相用食盐水反洗一次， 再用硫酸钠干燥后旋干后得 到粗品化合物。 此粗品化合物用快速柱纯化 （石油醚： 乙酸乙酯 = 1 : 1)， 然后溶在二氯甲烷 ( 10毫升） 溶液中并加入盐酸甲醇 （0.3毫升， 4摩尔每升）。 反应在 0度搅拌 3个小时。 直 接旋干得到目标化合物的盐酸盐 (35 毫克)。 步骤 E:
Figure imgf000076_0002
The compound was dissolved in the presence of 5-bromo-3-[1-(3,5-dichloro-4-pyridyl)ethoxy]pyridin-2-amine (86 mg, 0.24 mmol, 1 eq. And the compound 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine Add 1,1'-bis(diphenylphosphine) ferrocene to a mixed solution of tert-butyl ester (134 mg, 0.35 mmol, 1.5 eq.) in saturated aqueous sodium bicarbonate (5 mL) and acetonitrile (5 mL) Iron palladium chloride (17 mg, 0.024 mmol, 10% equivalent). After the addition was completed, the mixture was reacted at 100 °C for 30 minutes in the microwave. The reaction solution was cooled to room temperature and poured into 20 ml of water and extracted with ethyl acetate (30 ml*2). The combined organic phases were backwashed once with brine, dried over sodium sulfate and dried to give a crude compound. This crude compound was purified by flash column (EtOAc:EtOAc:EtOAc) The reaction was stirred at 0 degrees for 3 hours. Direct spin-drying gave the title compound hydrochloride (35 mg). Step E:
Figure imgf000076_0002
2-[4-[4- [6-氨基 -5-Π-(3,5-二氯 -4-吡啶基)乙氧基 ]-3-吡啶基] P比唑 -1 -基]  2-[4-[4-[6-amino-5-indole-(3,5-dichloro-4-pyridyl)ethoxy]-3-pyridyl]P-pyrazole-1-yl]
-1-哌啶基] -Ν-甲基-乙酰胺  -1-piperidinyl]-indole-methyl-acetamide
操作步骤： Steps:
将化合物 3-[1-(3,5-二氯 -4-吡啶基)乙氧基 ]-5-[1 -(4-哌啶基) Ρ比唑 -4-基] Ρ比啶 -2-胺（35毫克， 0.066 毫摩尔）， 2-溴 -Ν-甲基-乙酰胺（13毫克， 0.0S7毫摩尔， 1 .3当量）， 碘化钠（1毫克， 0.0067 毫摩尔， 0.1当量） 和碳酸钾 （73毫克， 0.54毫摩尔， 8.0当量） 溶于乙醇 （3毫升） 后在 80 度下反应 12个小时。 然后冷却到室温， 将反应液用饱和食盐水（10ml )稀释， 并用乙酸乙酯 (10毫升 *2)萃取。合并的有机相用食盐水反洗一次，再用硫酸钠干燥后旋干后得到粗品化合 物。 所得到的粗品采用用 HPLC纯化采用高效液相色谱在 C18反相柱上分离 (流动相： 乙腈 / 水 /0.5%氨水， 梯度洗脱 25%至 55% (体积比))， 得到目标化合物 (13毫克， 两歩产率为 39%)。 光谱数据： The compound 3-[1-(3,5-dichloro-4-pyridyl)ethoxy]-5-[1-(4-piperidinyl)indolezol-4-yl]pyridin-2 -Amine (35 mg, 0.066 mmol), 2-bromo-indole-methyl-acetamide (13 mg, 0.0S7 mmol, 1.3 equivalent), sodium iodide (1 mg, 0.0067) Millimol, 0.1 eq.) and potassium carbonate (73 mg, 0.54 mmol, 8.0 eq.) were dissolved in ethanol (3 mL) and reacted at 80 ° for 12 hours. Then it was cooled to room temperature, and the mixture was diluted with brine (10 ml). The combined organic phases were backwashed once with brine, dried over sodium sulfate and dried to give a crude compound. The obtained crude product was purified by HPLC using high performance liquid chromatography on a C18 reverse phase column (mobile phase: acetonitrile / water / 0.5% aqueous ammonia, gradient elution 25% to 55% by volume) to give the target compound ( 13 mg, yield of 39%). Spectral data:
LC/MS (方法： UFLC): RT = 2.41 分钟； m/z = 504.1 [M+H]+; 总的运行时间为 7.0 分钟。 Ή NMR (400 MHz, METHANOL^) δ 8.56 (s, 2 H), 7.85 (s, 1 H)， 7.71 (d, J = 1.76 Hz, 1 H), 7,59 (s, 1 H)， 6.94 (d, J = 1.51 Hz, 1 H)， 6.19 (q, J = 6.78 Hz, 1 H), 4.13 - 4.24 (m, 1 H), 3.08 (s， 2 H), 2.99 (d, J = 11.80 Hz, 2 H)， 2.82 (s, 3 H), 2.32 - 2.42 (m, 2 H), 2.04 - 2.23 (m， 4 H)， 1.89 (d, J =
Figure imgf000077_0001
实施例 78
Figure imgf000077_0002
LC/MS (method: UFLC): RT = 2.41 min; m/z = 504.1 [M+H]+; NMR NMR (400 MHz, METHANOL^) δ 8.56 (s, 2 H), 7.85 (s, 1 H), 7.71 (d, J = 1.76 Hz, 1 H), 7,59 (s, 1 H), 6.94 (d, J = 1.51 Hz, 1 H), 6.19 (q, J = 6.78 Hz, 1 H), 4.13 - 4.24 (m, 1 H), 3.08 (s, 2 H), 2.99 (d, J = 11.80 Hz, 2 H), 2.82 (s, 3 H), 2.32 - 2.42 (m, 2 H), 2.04 - 2.23 (m, 4 H), 1.89 (d, J =
Figure imgf000077_0001
Example 78
Figure imgf000077_0002
2-[4-[4-[6-氨基 -5-Π-[2-氯 -6- (环丙氧基)苯基]乙氧基 ]-3-吡啶基]吡唑小基] 2- [4-[4-[6-Amino-5-indole-[2-chloro-6-(cyclopropoxy)phenyl]ethoxy]-3-pyridyl]pyrazole small group]
-1-哌啶基] -Ν-甲基-乙酰胺  -1-piperidinyl]-indole-methyl-acetamide
步骤 Α: Step Α:
Figure imgf000077_0003
Figure imgf000077_0003
2- (1-溴乙基 )-1-氯 -3- (环丙基甲氧基)苯  2-(1-Bromoethyl)-1-chloro-3-(cyclopropylmethoxy)benzene
操作步骤： Steps:
向冰浴冷却的溶有化合物 1-[2-氯- 6- (环丙基甲氧基)苯基]乙醇 (113 毫克， 0.5 毫摩尔，1.0 当量) 和 4-二甲氨基吡啶 (6 毫克， 0.05 毫摩尔， 0.1 当量)的无水二氯甲垸 (5 毫升)溶液中滴加三溴 化磷 （148 毫克， 0.55毫摩尔， 1.1当量)。此混合物在室温下搅拌 2小时。在零度下加入水 (10 毫 升)并用二氯甲垸 （10 毫升 *3)萃取。 有机层用用硫酸钠干燥后旋干， 得到的粗品化合物。 此 粗品化合物用薄层色谱层析制备板 （石油醚 ： 乙酸乙酯 = 5: 1) 纯化得到目标化合物 （80 毫 克， 56 %)。 步骤 B:
Figure imgf000078_0001
The compound was dissolved in an ice bath, 1-[2-chloro-6-(cyclopropylmethoxy)phenyl]ethanol (113 mg, 0.5 mmol, 1.0 eq.) and 4-dimethylaminopyridine (6 mg). To a solution of 0.05 mmol, 0.1 eq. of anhydrous dichloromethane (5 mL) was added dropwise phosphorus tribromide (148 mg, 0.55 mmol, 1.1 eq.). This mixture was stirred at room temperature for 2 hours. Water (10 ml) was added at zero and extracted with dichloromethane (10 ml * 3). The organic layer was dried over sodium sulfate and dried to give a crude compound. The crude compound was purified by chromatography (yield: ethyl ether: ethyl acetate = 5:1) to afford the title compound (80 mg, 56%). Step B:
Figure imgf000078_0001
2-[4-[4-[6-氨基 -5-[l-[2-氯 -6- (环丙氧基)苯基]乙氧基 ]-3-吡啶基]吡唑 -1-基] 小哌啶基] -N-甲基-乙酰胺 2-[4-[4-[6-Amino-5-[l-[2-chloro-6-(cyclopropoxy)phenyl]ethoxy]- 3 -pyridyl]pyrazol-1-yl Small piperidinyl]-N-methyl-acetamide
操作步骤： Steps:
向冰浴冷却和氮气保护的含有化合物 2-[4-[4-(6-氨基 -5-羟基 -3-吡啶基)吡唑- 基] -1-哌啶 基] -N-甲基-乙酰胺 (91 毫克， 0.28 毫摩尔， 1.0当量)的无水 Ν,Ν'-二甲基甲酰胺 （3 毫升)加入 氢化钠 （13毫克， 0.34 毫摩尔， 1.2当量， 在矿物油 60%的含量)。此混合液在零度下搅拌 30分 钟后， 再滴加化合物 2- ( 溴乙基) -1-氯 -3- (环丙基甲氧基)苯 (70 毫克， 0.28 毫摩尔， 1.0当量) 的 Ν，Ν'-二甲基甲酰胺 (3 毫升)。 此混合物在室温下搅拌过夜。 在 0度下加入食盐水 (5 毫升) 并用乙酸乙酯 （10 毫升 *3)萃取。合并的有机层用碳酸氢钠溶液和食盐水各反洗一次，再用硫 酸钠干燥后旋干得到的粗品， 此粗品采用用 HPLC纯化采用高效液相色谱在 C18反相柱上分 离 (流动相： 乙腈 /水 /0.5%碳酸氢铵， 梯度洗脱 25%至 55% (体积比))， 得到目标化合物 (25毫 克， 产率为 16.8%)。 The compound containing 2-[4-[4-(6-amino-5-hydroxy-3-pyridyl)pyrazole-yl]-1-piperidinyl] -N -methyl--cooled and nitrogen-protected to ice-bath Acetylamine (91 mg, 0.28 mmol, 1.0 eq.) of anhydrous hydrazine, Ν'-dimethylformamide (3 ml) was added sodium hydride (13 mg, 0.34 mmol, 1.2 eq, 60% in mineral oil) content). After the mixture was stirred at 0 °C for 30 minutes, the compound 2-(bromoethyl)-1-chloro-3-(cyclopropylmethoxy)benzene (70 mg, 0.28 mmol, 1.0 eq.) was added dropwise. Ν, Ν '-dimethylformamide (3 ml). This mixture was stirred at room temperature overnight. Saline solution (5 ml) was added at 0 ° C and extracted with ethyl acetate (10 ml * 3). The combined organic layers were backwashed once with sodium bicarbonate solution and brine, dried over sodium sulfate and then evaporated to dryness. The crude product was purified by HPLC using high performance liquid chromatography on a C18 reversed phase column (mobile phase: Acetonitrile/water/0.5% ammonium hydrogencarbonate, gradient elution from 25% to 55% (by volume)) gave the title compound (25 mg, yield: 16.8%).
光谱数据： Spectral data:
LC/MS (方法： UFLC): RT = 3.40分钟； m/z = 539.2 [Μ+Η]+; 总的运行时间为 7.00 分钟。 Ή NMR (400 MHz, METHANOL-^) δ 7.82 (s, 1H), 7.63 (d, J= 1.6 Hz, 1H), 7.54 (s， 1H), 7.23 (t， J= 8.0 Hz, 1H)， 7.10 (d， J= 1.6 Hz, 1H), 6.99-6.95 (m, 2H), 6.20 (q, J= 6.8 Hz, 1H), 4.20-4.16 (m, 1H), 4.01-3.91 (m， 2H)， 3.07 (s, 2H)， 3.01-2.98 (m, 2H), 2.81 (s, 3H), 2.38-2.34 (m ,2H), 2.18-2.09 (m, 4H), 1.87 (d, J = 6.4 Hz, 3H), 1.40-1.36 (m, 1H)， 0.71-0.67 (m, 2H), 0.43-0.40 (m, 2H). 实施例 79
Figure imgf000078_0002
LC/MS (method: UFLC): RT = 3.40 min; m/z = 539.2 [Μ+Η]+; The total run time was 7.00 min. NMR NMR (400 MHz, METHANOL-^) δ 7.82 (s, 1H), 7.63 (d, J = 1.6 Hz, 1H), 7.54 (s, 1H), 7.23 (t, J = 8.0 Hz, 1H), 7.10 (d, J = 1.6 Hz, 1H), 6.99-6.95 (m, 2H), 6.20 (q, J = 6.8 Hz, 1H), 4.20-4.16 (m, 1H), 4.01-3.91 (m, 2H), 3.07 (s, 2H), 3.01-2.98 (m, 2H), 2.81 (s, 3H), 2.38-2.34 (m , 2H), 2.18-2.09 (m, 4H), 1.87 (d, J = 6.4 Hz, 3H), 1.40-1.36 (m, 1H), 0.71-0.67 (m, 2H), 0.43-0.40 (m, 2H). Example 79
Figure imgf000078_0002
2-[4-[4-[6-氨基 -5-[ (2，6-二氯苯基) -2，2，2-三氟-乙氧基 ]-3-吡啶基]吡唑 -1-基 2- [4-[4-[6-Amino-5-[(2,6-dichlorophenyl)-2,2,2-trifluoro-ethoxy]-3-pyridyl]pyrazole-1 -base
-1-哌啶基 1-N-甲基-乙酰胺  1-piperidinyl 1-N-methyl-acetamide
步骤 A:
Figure imgf000078_0003
l-(2, 6-二氯苯基) -2, 2, 2-三氟-乙基]三氟甲磺酸酯 Step A:
Figure imgf000078_0003
L-(2,6-Dichlorophenyl)-2,2,2-trifluoro-ethyl]trifluoromethanesulfonate
操作步骤： Steps:
在氮气保护下在零度下，将氢化钠（33毫克， 816微毫摩尔， 2当量）慢慢加入到化合物 1- (2,6- 二氯苯基) -2,2，2-三氟乙醇 （100毫克， 408微毫摩尔， 1当量） 的四氢呋喃 （8毫升） 中并且 在室温搅拌 1个小时， 然后将三氟甲磺酰氯 （138毫克， 816微毫摩尔， 2当量） 加入， 反应 继续在室温下搅拌过夜后反应加水稀释， 水层用二氯甲垸萃取， 有机层分出， 干燥旋干后直 接用于下一步。 步骤 B:
Figure imgf000079_0001
Sodium hydride (33 mg, 816 μmmol, 2 equivalents) was slowly added to the compound 1-(2,6-dichlorophenyl)-2,2,2-trifluoroethanol at zero temperature under nitrogen. (100 mg, 408 μmmol, 1 eq.) in tetrahydrofuran (8 ml) and stirred at room temperature for 1 hour, then trifluoromethanesulfonyl chloride (138 mg, 816 rnmol, 2 eq.). After stirring at room temperature overnight, the reaction was diluted with water, the aqueous layer was extracted with methylene chloride, and the organic layer was separated, dried and dried, Step B:
Figure imgf000079_0001
2-[4-[4-[6-氨基 -5-[1-(2，6-二氯苯基) -2,2,2-三氟-乙氧基 ]-3-吡啶基] P比唑 -1-基]  2-[4-[4-[6-Amino-5-[1-(2,6-dichlorophenyl)-2,2,2-trifluoro-ethoxy]-3-pyridyl] P ratio Zin-1-yl]
-1-哌啶基] -N-甲基-乙酰胺  -1-piperidinyl]-N-methyl-acetamide
操作步骤： Steps:
将化合物 2-[4 -[4 -(6 -氨基 -5-羟基 -3-吡啶基)吡唑 -1-基] -1-哌啶基] -N-甲基-乙酰胺 （50毫克， 151微毫摩尔， 1当量） 和碳酸铯 （60毫克， 184微毫摩尔， 1.2当量） 加入到化合物 1-(2， 6- 二氯苯基) -2， 2, 2-三氟-乙基]三氟甲磺酸酯 （57毫克， 151微毫摩尔， 1当量） 的 Ν,Ν-二甲基 甲酰胺 （20毫升） 的溶液中， 反应在 25度下反应 12个小时， 后反应加水稀释并且用乙酸乙 酯萃取三次， 有机层分出后用硫酸钠干燥旋干。 粗品用 HPLC 纯化 （仪器： LC 8A & Gilson 215 馏分收集器 色谱柱： Synergi 150*30誦 *5u， 流动相 A: 0. 05%HC1 水， 流动相 B: 乙腈， 流速： 30mL/分钟 浓度梯度： 13-23%B, 0-1 1分钟） 后得到目标化合物（6.7毫克，收率为 1.2%)。 光谱数据： The compound 2-[4-[4-(6-amino-5-hydroxy-3-pyridyl)pyrazol-1-yl]-1-piperidinyl]-N-methyl-acetamide (50 mg, 151 μmmol, 1 equivalent) and cesium carbonate (60 mg, 184 μmmol, 1.2 eq.) were added to the compound 1-(2,6-dichlorophenyl)-2,2,2-trifluoro-ethyl In a solution of trifluoromethanesulfonate (57 mg, 151 μmmol, 1 equivalent) in hydrazine, hydrazine-dimethylformamide (20 ml), the reaction was allowed to react at 25 °C for 12 hours, after which the reaction was added with water. It was diluted and extracted three times with ethyl acetate. The crude product was purified by HPLC (instrument: LC 8A & Gilson 215 fraction collector column: Synergi 150*30诵*5u, mobile phase A: 0. 05% HC1 water, mobile phase B: acetonitrile, flow rate: 30 mL/min concentration gradient : 13-23% B, 0-1 1 min) The title compound (6.7 mg, yield: 1.2%) was obtained. Spectral data:
LC/MS (方法： UFLC): RT = 2.77分钟； m/z = 557.2 [M+H]+ ; 总的运行时间为 6.00 分钟。 LC/MS (method: UFLC): RT = 2.77 min; m/z = 557.2 [M+H] + ;
实施例 80
Figure imgf000079_0002
Example 80
Figure imgf000079_0002
4-[4-[4-[6-氨基- 5-[(lR)小 (2,6-二氯- 3-氟-苯基)乙氧基 ]-3-吡啶基] P比唑- 1-基  4-[4-[4-[6-amino-5-[(lR) small (2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl] P-pyrazole-1 -base
-1-哌啶基] -N-甲基-丁酰胺 步骤 A:
Figure imgf000080_0001
1-piperidinyl]-N-methyl-butanamide Step A:
Figure imgf000080_0001
4-[4-[4-[6-氨基 -5-[(lR)- (2,6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基]吡唑- 基]  4-[4-[4-[6-Amino-5-[(lR)-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazole-yl]
-1-哌啶基] -丁酸乙酯  Ethyl-1-pyridinyl]-butyrate
操作步骤： Steps:
将 3-[(lR)-l-(2，6-二氯 -3-氟-苯基)乙氧基 ]-5-[1-(4-哌啶基)吡唑 -4-基]吡啶 -2-胺 (150毫克， 0.33 毫摩尔， 1当量)、 4-溴丁酸乙酯 (77毫克， 0.4毫摩尔， 1.2当量)、三乙胺 (67毫克, 0.66毫摩尔， 2 当量)溶于 N，N-二甲基甲酰胺 (2毫升)中 80'C反应 4小时。 毕， 水 (10毫升)加入反应液中， 经乙酸乙酯 (10毫升 X 3)萃取， 合并有机相， 减压蒸除溶剂得到目标化合物 (90毫克， 产率为 47.8%)。 步骤 B:
Figure imgf000080_0002
3-[(lR)-l-(2,6-Dichloro-3-fluoro-phenyl)ethoxy]-5-[1-(4-piperidinyl)pyrazol-4-yl]pyridine 2-Amine (150 mg, 0.33 mmol, 1 eq.), ethyl 4-bromobutyrate (77 mg, 0.4 mmol, 1.2 eq.), triethylamine (67 mg, 0.66 mmol, 2 eq.) The reaction was carried out in N,N-dimethylformamide (2 ml) at 80 ° C for 4 hours. After the addition of water (10 ml), EtOAc (EtOAc m. Step B:
Figure imgf000080_0002
4-[4-[4-[6-氨基 -5-[(lR)-l-(2，6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基] 吡唑小基] 4-[4-[4-[6-Amino-5-[(lR)-l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazole Base
-1-哌啶基] -丁酸  -1-piperidinyl]-butyric acid
操作步骤： Steps:
将化合物 4-[4-[4-[6-氨基 -5-[(lR)小 (2，6-二氯 -3-氟-苯基)乙氧基 ]- 3-吡啶基]吡唑- 基]小哌啶 基] -丁酸乙酯 （90毫克， 0.16毫摩尔， 1当量)溶于甲醇 (0.2毫升)中， 加入 2摩尔 /升的氢氧化 钠水溶液 (4毫升)搅拌 1小时， 然后加浓盐酸 (0.5毫升)调节 pH值为 2。 减压蒸除溶剂得目标 化合物。 步骤 C:
Figure imgf000080_0003
The compound 4-[4-[4-[6-amino-5-[(lR) small (2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazole- Ethyl hydrazinyl]-butyric acid ethyl ester (90 mg, 0.16 mmol, 1 eq.) was dissolved in methanol (0.2 mL). Then, concentrated hydrochloric acid (0.5 ml) was added to adjust the pH to 2. The solvent was evaporated under reduced pressure to give the title compound. Step C:
Figure imgf000080_0003
4-[4-[4-[6-氨基 -5-[(lR)- (2,6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基]吡唑- 基:  4-[4-[4-[6-Amino-5-[(lR)-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazole-yl:
-1-哌啶基] -N-甲基-丁酰胺  1-piperidinyl]-N-methyl-butanamide
操作步骤： 在冰水浴下， 将 2 摩尔 /升甲胺四氢呋喃溶液 (0.3 毫升， 0.6 毫摩尔， 4 当量)缓慢滴加溶有 ^^'-四甲基-0-(7-氮杂苯并三唑-1-基)六氟磷酸脲 （85毫克, 0.0.224毫摩尔 ,1.5当量 .)，化 合物 4-[4-[4-[6-氨基 -5-[(lR)-l-(2,6-二氯 -3-氟-苯基）乙氧基 ]- 3-吡啶基]吡唑- 基]小哌啶基] - 丁酸 (80毫克， 0.15毫摩尔， 1当量)， 滴毕， 在室温下继续搅拌 2小时， 反应液采用高效液相色 谱在 C18反相柱上分离 (流动相： 乙腈 /水 /0.5%碳酸氢铰， 梯度洗脱 43%至 53% (体积比))， 减 压蒸除易挥发的组分后冻干得到目标化合物 （13毫克， 总产率为 15.8%)。 Steps: 2 mol / liter of methylamine tetrahydrofuran solution (0.3 ml, 0.6 mmol, 4 equivalents) was slowly added dropwise to the solution of ^^'-tetramethyl-(7-azabenzotriazole) in an ice water bath. 1-yl) hexafluorophosphate (85 mg, 0.0.224 mmol, 1.5 eq.), compound 4-[4-[4-[6-amino-5-[(lR)-l-(2,6) -Dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazole-yl]piperidinyl]-butyric acid (80 mg, 0.15 mmol, 1 eq.), Stirring was continued for 2 hours at room temperature, and the reaction solution was separated by high performance liquid chromatography on a C18 reverse phase column (mobile phase: acetonitrile/water/0.5% hydrogencarbonate hinge, gradient elution 43% to 53% (volume ratio)), minus The volatile component was distilled off and lyophilized to give the title compound (13 mg, 15%).
光谱数据： Spectral data:
LC/MS (方法： UFLC): RT = 2.957 分钟； m/z = 549.1 [M+H]+; 总的运行时间为 7.00 分钟. Ή NMR (400MHz, METHANOL-^) δ 7.83 (s, 1H), 7.69 (d, J = 1.6 Hz, 1H), 7.57 (s, 1H)， 7.49 (dd, J = 4.8， 8.8 Hz, 1H), 7.27 (t, J= 8.8 Hz, 1H), 6.96 (d，J= 1.2 Hz, 1H), 6.22 (q, J= 6.8 Hz, 1H), 4.26-4.20 (m, 1H), 3.21-3.17 (m, 2H)， 2.74 (s, 3H), 2.58-2.54 (m, 2H)， 2.40-2.35 (m, 2H)， 2.29 (t, J = 7.2 Hz, 2H), 2.16-2.12 (m, 4H), 1.90-1.85 (m, 5H). 施例 81 LC/MS (method: UFLC): RT = 2.957 min; m/z = 549.1 [M+H]+; The total run time is 7.00 min. NMR (400MHz, METHANOL-^) δ 7.83 (s, 1H) , 7.69 (d, J = 1.6 Hz, 1H), 7.57 (s, 1H), 7.49 (dd, J = 4.8, 8.8 Hz, 1H), 7.27 (t, J = 8.8 Hz, 1H), 6.96 (d, J= 1.2 Hz, 1H), 6.22 (q, J= 6.8 Hz, 1H), 4.26-4.20 (m, 1H), 3.21-3.17 (m, 2H), 2.74 (s, 3H), 2.58-2.54 (m , 2H), 2.40-2.35 (m, 2H), 2.29 (t, J = 7.2 Hz, 2H), 2.16-2.12 (m, 4H), 1.90-1.85 (m, 5H).
Figure imgf000081_0001
Figure imgf000081_0001
5-[4-[4-[6-氨基 -5-[(lR) -(2,6-二氯 -3-氟-苯基)乙氧基 ]- 3-吡啶基] P比唑- 1-基]  5-[4-[4-[6-amino-5-[(lR)-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]P-pyrazole-1 -base]
-1-哌啶基] -N-甲基-戊酰胺  -1-piperidinyl]-N-methyl-pentanamide
操作步骤： Steps:
将化合物 3-[(lR)-l-(2,6-二氯 -3-氟-苯基)乙氧基 ]-5-[1-(4-哌啶基) P比唑 -4-基]吡啶 -2-胺 （ 50毫克， 0.11毫摩尔， 1.0当量)， 5-溴 -N-甲基戊酰胺（ Ύ1毫克， 0.12毫摩尔， 1.1当量)和碳酸钾 （I22毫 克， 0.88毫摩尔， 8当量)溶于 10毫升乙醇。 然后搅拌、 在氮气保护下， 继续加入碘化钠 （1.5 毫克 0.01 毫摩尔 ,0.1当量)。 反应在加热回流下继续搅拌 12小时。 反应结束后， 将溶剂旋干 后得到粗品化合物。 此得到的粗品采用用 HPLC纯化采用高效液相色谱在 C18反相柱上分 离 (流动相： 乙腈 /碱性水， 梯度洗脱 43%至 73% (体积比))， 得到目标化合物 (4毫克， 产率为 6%) o The compound 3-[(lR)-l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-5-[1-(4-piperidinyl)P-pyrazol-4-yl Pyridin-2-amine (50 mg, 0.11 mmol, 1.0 equivalent), 5-bromo-N-methylpentanamide (Ύ1 mg, 0.12 mmol, 1.1 eq.) and potassium carbonate (I 22 mg, 0.88 mmol) , 8 equivalents) was dissolved in 10 ml of ethanol. Stir iodide (1.5 mg 0.01 mmol, 0.1 eq.) was then added and stirred under nitrogen. The reaction was stirred for a further 12 hours under reflux with heating. After completion of the reaction, the solvent was dried to give a crude compound. The crude product obtained was purified by HPLC using high performance liquid chromatography on a C18 reverse phase column (mobile phase: acetonitrile/basic water, gradient elution 43% to 73% by volume) to give the target compound (4 mg) , yield 6%) o
光谱数据： Spectral data:
LC/MS (方法： UFLC): RT = 1.892 分钟； m/z = 563.2 [M+H]+; 总的运行时间为 7.00 分钟。 实施例 82
Figure imgf000082_0001
LC/MS (method: UFLC): RT = 1.892 min; m/z = 563.2 [M+H] + ; The total run time was 7.00 min. Example 82
Figure imgf000082_0001
4-[4-[4-[6-氨基 -5-[(lR)小 (2，6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基] P比唑小基  4-[4-[4-[6-amino-5-[(lR) small (2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl] P-pyrazole small group
- 哌啶基] -N-甲基 -4-氧代-丁酰胺  - piperidinyl]-N-methyl-4-oxo-butanamide
操作步骤: Steps:
将化合物 3-[(lR)-l-(2，6 -二氯 -3-氟-苯基)乙氧基 ]-5-[1-(4-哌啶基) P比唑 -4-基] P比啶 -2-胺（ 50毫克, 0.111毫摩尔， 1当量)， 4- (甲基氨基) -4 -氧代 -丁酸 (16毫克， 0.12毫摩尔， 1.1当量)和 N，N,N，N，- 四甲基 -0-(7-氮杂苯并三唑 -1-基)六氟磷酸脲 （ 63毫克， 0.16毫摩尔， 1.5当量.)溶于 10毫升二 氯甲垸。 然后搅拌、 冰浴和氮气保护下， 继续缓慢加入 Ν,Ν'-二异丙基乙胺（ 72毫克， 0.55毫 摩尔， 5当量)。反应在室温下继续搅拌 12小时。反应结束后将反应液旋干得到粗品，用 HPLC 纯化 (仪器： LC 8Α & Gilson 215 馏分收集器 色谱柱： Ge分钟 i 150*30mm*4um, 流动相 A: 0.05%HC1 水， 流动相 B: 乙腈 ， 流速： 30mL/分钟，浓度梯度： 15-40%B，0- 8分钟)得到目标化 合物的盐酸盐 （47 毫克， 产率为 74%)。 The compound 3-[(lR)-l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-5-[1-(4-piperidinyl)P-pyrazol-4-yl P-pyridin-2-amine (50 mg, 0.111 mmol, 1 equivalent), 4-(methylamino)-4-oxo-butyric acid (16 mg, 0.12 mmol, 1.1 eq.) and N,N ,N,N,-tetramethyl-(7-azabenzotriazol-1-yl)hexafluorophosphate (63 mg, 0.16 mmol, 1.5 eq.) dissolved in 10 ml of dichloromethane . Then, under stirring, ice bath and nitrogen, continue to slowly add hydrazine, Ν'-diisopropylethylamine (72 mg, 0.55 mmol, 5 eq.). The reaction was stirred at room temperature for further 12 hours. After completion of the reaction, the reaction solution was spun dry to give a crude product which was purified by HPLC (PLC: LC 8 Α & Gilson 215 fraction collector column: Ge min i 150*30 mm*4 um, mobile phase A: 0.05% HCl water, mobile phase B: Acetonitrile, flow rate: 30 mL/min, concentration gradient: 15-40% B, 0-8 min) gave the title compound as the hydrochloride salt (47 mg, yield 74%).
光谱数据: Spectral data:
LC/MS (方法： UFLC): RT = 2.321分钟； m/z = 563.1 [M+H]+; 总的运行时间为 2.321 分钟。 Ή NMR (400MHz, METHANOW4) δ 8.05 (s, 1H), 7.71 (s, 1H), 7.66 (d, J = 1.5 Hz, 1H), 7.53 (dd, J= 4.9, 8.9 Hz, 1H), 7.32 (t, J= 8.5 Hz, 1H), 7.19 (d, J= 1.5 Hz, 1H), 6.39 (q, J= 6.7 Hz, 1H), 4.64 (d, J= 1 1.0 Hz, 1H), 4.58 - 4.47 (m, 1H), 4.17 (d, J = 13.6 Hz, 1H), 3.00 - 2.76 (m, 7H), 2.72 - 2.57 (m, 2H)， 2.39 - 2.01 (m, 4H), 1.99 - 1.85 (m, 4H)。 实施例 83
Figure imgf000082_0002
LC/MS (method: UFLC): RT = 2.321 min; m/z = 563.1 [M+H]+; The total run time was 2.321 min. NMR NMR (400MHz, METHANOW 4 ) δ 8.05 (s, 1H), 7.71 (s, 1H), 7.66 (d, J = 1.5 Hz, 1H), 7.53 (dd, J= 4.9, 8.9 Hz, 1H), 7.32 (t, J = 8.5 Hz, 1H), 7.19 (d, J = 1.5 Hz, 1H), 6.39 (q, J = 6.7 Hz, 1H), 4.64 (d, J = 1 1.0 Hz, 1H), 4.58 - 4.47 (m, 1H), 4.17 (d, J = 13.6 Hz, 1H), 3.00 - 2.76 (m, 7H), 2.72 - 2.57 (m, 2H), 2.39 - 2.01 (m, 4H), 1.99 - 1.85 ( m, 4H). Example 83
Figure imgf000082_0002
2-[4-[4-[6-氨基 -5-[(lR)-l-(2,6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基] P比唑- 基  2-[4-[4-[6-Amino-5-[(lR)-l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl] P-pyrazole - base
-1-哌啶基] -N-甲基 -乙基磺酰胺  -1-piperidinyl]-N-methyl-ethylsulfonamide
步骤 A: Step A:
N-甲基乙烯磺酰胺 操作步骤: 在冰浴下，将 2-氯乙垸磺酰氯 (200毫克， 1.23毫摩尔， 1当量)缓慢滴加到 2摩尔 /升甲胺四氢呋 喃溶液 (0.68毫升, 1.36毫摩尔，1.1当量)和三乙胺 (249毫克， 2.46毫摩尔， 2当量)的二氯甲烷溶 液 (2毫升)中， 滴毕， 保持在冰浴下搅拌 2小时， 水 (10毫升)和二氯甲烷 (10毫升)加入反应瓶 中， 水相经二氯甲烷 (10毫升 X 3)萃取， 合并有机相， 减压蒸除溶剂得到目标化合物 (79毫克， 产率为 53%)。 步骤 B: N-methyl ethylene sulfonamide operation steps: 2-Chloroethanesulfonyl chloride (200 mg, 1.23 mmol, 1 eq.) was slowly added dropwise to a 2 mol/L methylamine tetrahydrofuran solution (0.68 mL, 1.36 mmol, 1.1 eq.) and tribr. A solution of the amine (249 mg, 2.46 mmol, 2 eq.) in dichloromethane (2 mL), EtOAc (2 mL) The mixture was extracted with EtOAc (EtOAc) (EtOAc) Step B:
Figure imgf000083_0001
Figure imgf000083_0001
2-[4-[4-[6-氨基 -5-[(lR)小 (2,6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基] P比唑 -1-基]  2-[4-[4-[6-Amino-5-[(lR) small (2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl] P-pyrazole-1 -base]
-1-哌啶基] -N-甲基 -乙基磺酰胺  -1-piperidinyl]-N-methyl-ethylsulfonamide
操作步骤： Steps:
将溶有 3-[(lR)-l-(2,6-二氯 -3-氟-苯基)乙氧基 ]-5-[1-(4-哌啶基)吡唑 -4-基]吡啶 -2-胺 （70毫克， 0.156毫摩尔， 1当量)，化合物 N-甲基乙烯磺酰胺 (37.7毫克， 0.312毫摩尔， 2当量)的甲醇 (0.5 毫升)溶液室温下搅拌 24小时， 反应液采用高效液相色谱在 C18反相柱上分离 (流动相： 乙腈 /水 /0.5%碳酸氢铵， 梯度洗脱 42%至 52% (体积比))， 减压蒸除易挥发的组分后冻干得到目标 化合物 (22毫克， 产率为 25%)。 Will be dissolved in 3-[(lR)-l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-5-[1-(4-piperidyl)pyrazol-4-yl Pyridine-2-amine (70 mg, 0.156 mmol, 1 eq.), mp EtOAc (EtOAc (EtOAc) The reaction solution was separated by high performance liquid chromatography on a C18 reverse phase column (mobile phase: acetonitrile/water/0.5% ammonium hydrogencarbonate, gradient elution 42% to 52% by volume), and the volatile group was distilled off under reduced pressure. After lyophilization, the title compound (22 mg, yield 25%) was obtained.
光谱数据： Spectral data:
LC/MS (方法： UFLC): RT = 3.043 分钟； m/z = 571.1 [M+H]+ ; 总的运行时间为 7.00 分钟。 LC/MS (method: UFLC): RT = 3.043 min; m/z = 571.1 [M+H] + ;
Ή NMR (400 MHz, METHANOL- ί¾ δ 7.80 (s, 1Η), 7.67 (s, 1H), 7.54 (s, 1H), 7.47 (dd, J = 4.8， 8.8 Hz, 1H)， 7.25 (t, J = 8.4 Hz, 1H)， 6.92 (s, 1H), 6.20 (q, J = 6.8 Hz, 1H), 4.19-4.14 (m, 1H), 3.34-3.25 (m, 2H), 3.09-3.06 (m, 2H), 2.86-2.83 (m, 2H)， 2.73 (s， 3H), 2.31-2.26 (m, 2H)， 2.09-2.04 (m， 4H), 1.88 (d, J= 6.8 Hz, 3H). 施例 84
Figure imgf000083_0002
NMR NMR (400 MHz, METHANOL- ί3⁄4 δ 7.80 (s, 1Η), 7.67 (s, 1H), 7.54 (s, 1H), 7.47 (dd, J = 4.8, 8.8 Hz, 1H), 7.25 (t, J = 8.4 Hz, 1H), 6.92 (s, 1H), 6.20 (q, J = 6.8 Hz, 1H), 4.19-4.14 (m, 1H), 3.34-3.25 (m, 2H), 3.09-3.06 (m, 2H), 2.86-2.83 (m, 2H), 2.73 (s, 3H), 2.31-2.26 (m, 2H), 2.09-2.04 (m, 4H), 1.88 (d, J = 6.8 Hz, 3H). Example 84
Figure imgf000083_0002
3-[4-[4-[6-氨基 -5-[(lR)-l-(2，6-二氯 -3-氟-苯基)乙氧基 ]- 3-吡啶基]吡唑 - 基  3-[4-[4-[6-Amino-5-[(lR)-l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]- 3-pyridyl]pyrazole- Base
小哌啶基] -N-甲基 -丙基 -1-磺酰胺  Small piperidinyl]-N-methyl-propyl-1-sulfonamide
操作步骤： 此化合物由前面描述的方法制备。 Steps: This compound was prepared by the method described previously.
光谱数据： Spectral data:
LC/MS (方法： UFLC): m/z = 585 [M+H] 施例 85 LC/MS (method: UFLC): m/z = 585 [M+H] Example 85
Figure imgf000084_0001
Figure imgf000084_0001
2— [4-[4-[6-氨基 -5-[(lR)-l-(2,6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基] P比唑 -1-基] 2 — [4-[4-[6-Amino-5-[(lR)-l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl] P-pyrazole -1-base]
-1-哌啶基]乙基磺酰胺  -1-piperidinyl]ethylsulfonamide
操作步骤： Steps:
此化合物由前面描述的方法制备。 This compound was prepared by the method described previously.
光谱数据： Spectral data:
LC/MS (方法： UFLC): m/z = 557 [M+H]+. 实施例 86LC/MS (method: UFLC): m/z = 557 [M+H] + .
Figure imgf000084_0002
Figure imgf000084_0002
3-[4-[4-[6-氨基 -5-[(lR) -(2，6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基] P比唑小基]  3-[4-[4-[6-Amino-5-[(lR)-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]P-pyrazole small group ]
-1-哌啶基]环戊 -2-烯小酮  1-piperidinyl]cyclopent-2-enone
操作步骤： Steps:
将 3-[(lR)-l-(2，6-二氯 -3-氟-苯基)乙氧基 ]- 5-[1-(4-哌啶基)卩比唑 - 4-基]卩比啶 -2-胺 （100毫克，0.222 毫摩尔， 1当量)， 1,3-环戊二酮 (23.7毫克， 0.267毫摩尔， 1.2当量)以及对甲苯磺酸 (3.8毫克, 0.022毫摩尔，0.1当量)于 0.5毫升甲苯中回流 14小时。 经 LCMS确定反应结束后， 减压蒸除 甲苯得到残余物，采用高效液相色谱在 C18的反相柱上分离 （流动相：乙腈 /水 /0.5%碳酸氢氨， 梯度洗脱 40%至 50% (体积比))，减压蒸除易挥发的组分后， 冻干得到目标化合物 (22毫克， 产 率为 18.8%)。 3-[(lR)-l-(2,6-Dichloro-3-fluoro-phenyl)ethoxy]-5-[1-(4-piperidinyl)indole-3-yl] Indole-2-amine (100 mg, 0.222 mmol, 1 equivalent), 1,3-cyclopentanedione (23.7 mg, 0.267 mmol, 1.2 eq.) and p-toluenesulfonic acid (3.8 mg, 0.022 mmol) , 0.1 equivalent) was refluxed in 0.5 ml of toluene for 14 hours. After the end of the reaction was confirmed by LCMS, the residue was evaporated under reduced pressure to give residue, which was separated on a C18 reverse phase column by high-performance liquid chromatography (mobile phase: acetonitrile/water/0.5% ammonium bicarbonate, gradient elution 40% to 50%) % (volume ratio)), after evaporation of the volatile component under reduced pressure, the title compound (22 mg, yield 18.8%) was obtained by lyophilization.
光谱数据： Spectral data:
LC/MS (方法： UFLC): RT = 3.695 分钟； m/z = 530.1 [M+H]+ ; 总的运行时间为 7.00 分钟。 Ή NMR (400 MHz, CHLOROFORM-c/) δ 7.74 (s, 1H), 7.57 (s, 1H), 7.49 (s， 1H)， 7.31 (dd,J=4.8 8.8 Hz, 1H), 7.07 (t,J= 8.4 Hz, 1H), 6.86 (s, 1H), 6.09 (q,J= 6.8 Hz, 1H), 5.15 (s, 1H), 4.40-4.34 (m, 1H)， 3.90-3.85 (m, 2H), 3.24-3.18 (m, 2H), 2.67-2.64 (m, 2H), 2.46-2.44 (m, 2H)， 2.26-2.23 (m 2H), 2.12-2.07 (m, 2H)， 1.88 (d, J= 6.8 Hz, 3H). 实施例 87
Figure imgf000085_0001
LC/MS (method: UFLC): RT = 3.695 min; m/z = 530.1 [M+H] + ; NMR NMR (400 MHz, CHLOROFORM-c/) δ 7.74 (s, 1H), 7.57 (s, 1H), 7.49 (s, 1H), 7.31 (dd, J=4.8 8.8 Hz, 1H), 7.07 (t, J= 8.4 Hz, 1H), 6.86 (s, 1H), 6.09 (q, J= 6.8 Hz, 1H), 5.15 (s, 1H), 4.40-4.34 (m, 1H), 3.90-3.85 (m, 2H), 3.24-3.18 (m, 2H), 2.67-2.64 (m, 2H), 2.46-2.44 (m, 2H), 2.26-2.23 (m 2H), 2.12-2.07 (m, 2H), 1.88 (d, J = 6.8 Hz, 3H). Example 87
Figure imgf000085_0001
2-[4-[l-[6-氨基 -5-[(lR)-l-(2,6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基] P比唑 -4-基  2-[4-[l-[6-Amino-5-[(lR)-l-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl] P-pyrazole -4- base
小哌啶基] -N-甲基-乙酰胺  Small piperidinyl]-N-methyl-acetamide
步骤 A:
Figure imgf000085_0002
Step A:
Figure imgf000085_0002
2-[4-[1-[6-氨基 -5-[1-(2,6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基] P比唑 -4-基]  2-[4-[1-[6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]P-pyrazol-4-yl ]
- 哌啶基] -N-甲基-乙酰胺  - piperidinyl]-N-methyl-acetamide
操作步骤： Steps:
将 3- [ (2，6-二氯 -3-氟-苯基)乙氧基 ]-5-[4-(4-哌啶基)吡唑 -1-基] P比啶基 -2-胺 （30毫克， 0.067 毫摩尔，实施例 10)， 2-溴 -N-甲基-乙酰胺（13毫克， 0.087毫摩尔）， 碘化钠（1毫克， 0.0067 毫摩尔）和碳酸钾 （73毫克， 0.54毫摩尔）溶于乙醇 （3毫升）后在 80度下反应 12个小时。 然后冷却到室温， 将反应液用饱和食盐水（10 毫升）稀释， 并用乙酸乙酯 （10 毫升 *2)萃取. 合并的有机相用食盐水反洗一次， 再用硫酸钠干燥后旋干后得到粗品化合物。 此得到的粗品 采用用 HPLC纯化采用高效液相色谱在 C18反相柱上分离 (流动相： 乙腈 /水 /0.5%氨水， 梯度 洗脱 25%至 55% (体积比))， 得到目标化合物 （ 30毫克， 产率为 86%)。 步骤 B: 3-[(2,6-Dichloro-3-fluoro-phenyl)ethoxy]-5-[4-(4-piperidyl)pyrazol-1-yl]P-pyridyl-2- Amine (30 mg, 0.067 mmol, Example 10), 2-bromo-N-methyl-acetamide (13 mg, 0.087 mmol), sodium iodide (1 mg, 0.0067 mmol) and potassium carbonate (73) Mg, 0.54 mmol) was dissolved in ethanol (3 mL) and reacted at 80 °C for 12 hours. Then, it was cooled to room temperature, and the reaction mixture was diluted with brine (10 ml) and extracted with ethyl acetate (10 ml * 2). The combined organic phase was washed once with brine, dried over sodium sulfate and dried. The crude compound was obtained. The crude product thus obtained was subjected to HPLC purification by high performance liquid chromatography on a C18 reverse phase column (mobile phase: acetonitrile/water/0.5% aqueous ammonia, gradient elution 25% to 55% by volume) to obtain the target compound ( 30 mg, yield 86%). Step B:
操作步骤： Steps:
将化合物 2-[4-[1-[6-氨基 -5-[1-(2，6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基]吡唑 -4-基] -1-哌啶基] -N- 甲基-乙酰胺 (30毫克， 0.056毫摩尔)用 SFC手型拆分（ Chiralpak AD-3 50*4.6mm I.D., 3um 流 动相： 乙醇 (0.05% DEA)， C02 梯度 5% to 40%, 流速： 4mL/分钟） 浓缩得到目标化合物 2-[4-[1-[6-氨基 -5-[(lR)-l-(2,6-二氯 -3-氟-苯基)乙氧基 ]-3-吡啶基] P比唑 -4-基] -1-哌啶基] -N-甲基- 乙酰胺 (10毫克， 33%)和 2-[4-[1-[6-氨基 -5-[(lS)- (2,6-二氯 -3-氟-苯基)乙氧基 ]-3-B比啶基]吡唑 -4—基]小哌啶基] -N-甲基-乙酰胺 (11毫克， 两步产率为 34%)。 The compound 2-[4-[1-[6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazole-4- ]]-1-piperidinyl]-N-methyl-acetamide (30 mg, 0.056 mmol) was resolved by SFC hand (Chiralpak AD-3 50*4.6mm ID, 3um mobile phase: ethanol (0.05%) DEA), C0 2 gradient 5% to 40%, flow rate: 4 mL/min) Concentration to give the target compound 2-[4-[1-[6-amino-5-[(lR)-l-(2,6- Chloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]P-pyrazol-4-yl]-1-piperidinyl]-N-methyl-acetamide (10 mg, 33%) and 2-[4-[1-[6-Amino-5-[(lS)-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-Bpyridyl]pyrazole -4 -yl]piperidinyl] -N -methyl-acetamide (11 mg, 34% yield in two steps).
光谱数据： Spectral data:
LC/ S (方法： UFLC)： RT = 3.27分钟； m/z = 521.2 [M+H]+ ; 总的运行时间为 7.00分钟； 100%ee. LC/S (method: UFLC): RT = 3.27 min; m/z = 521.2 [M+H] + ; total run time is 7.00 min; 100% ee.
1H NMR (400 MHz, METHANOL-^) δ 7.76 (s, IH), 7.72 (s, IH), 7.53 (s, IH), 7.45 (dd, J= 4.8, 8.8 Hz, IH), 7.25 (t,J= 8.4 Hz, IH), 7.13 (d,J= 1.6 Hz, 1H)， 6.21 (q J= 6.4 Hz, IH), 5.00-4.95 (m, IH), 3.02 (s, 2H), 2.93-2.90 (m, 2H), 2.27 (s 3H), 2.31-2.25 (m, 2H), 1.95-1.86 (m, 5H), 1.79-1.69 (m, 2H).  1H NMR (400 MHz, METHANOL-^) δ 7.76 (s, IH), 7.72 (s, IH), 7.53 (s, IH), 7.45 (dd, J= 4.8, 8.8 Hz, IH), 7.25 (t, J= 8.4 Hz, IH), 7.13 (d, J= 1.6 Hz, 1H), 6.21 (q J= 6.4 Hz, IH), 5.00-4.95 (m, IH), 3.02 (s, 2H), 2.93-2.90 (m, 2H), 2.27 (s 3H), 2.31-2.25 (m, 2H), 1.95-1.86 (m, 5H), 1.79-1.69 (m, 2H).
表 1: ALK抑制剂的化合物 Table 1: Compounds for ALK inhibitors
Figure imgf000086_0001
基）甲酮
Figure imgf000086_0001
Ketone
2- [4 [4- [6-氨基 -5- [1- (2 6-二氯 2- [4 [4- [6-amino -5- [1- (2 6-dichloro)
- 3-氟-苯基）乙氧基 ]-3 -吡啶基]吡  - 3-fluoro-phenyl)ethoxy]-3-pyridyl]pyridyl
c,→0^F 559 唑 -1-基] c , → 0^ F 559 oxazol-1-yl]
哌啶- 1-羰基] -3-氧代 -丁腈  Piperidine- 1-carbonyl]-3-oxo-butyronitrile
2- [4- [4- [6-氨基- 5- [1- (2 6-二氯 2- [4- [4- [6-amino- 5- [1- (2 6- dichloride)
-3-氟 苯基）乙氧基 ]-3-吡啶基]吡 489 唑 -1-基]  -3-fluorophenyl)ethoxy]-3-pyridyl]pyrrole 489 azole-1-yl]
- 4 -哌啶基]乙腈  - 4 -piperidinyl]acetonitrile
2 [3 [4- [6-氨基- 5- [1- (2 6-二氯 2 [3 [4- [6-Amino- 5- [1-(2 6-dichloro)
_° -3-氟-苯基）乙氧基 ]-3-吡啶基]卩比 461 唑- 1 -基]  _°-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrene ratio 461 azole- 1 -yl]
氮杂环丁垸 -3-基]乙腈  Azetidin-3-yl]acetonitrile
3-[1-(2, 6-二氯 -3-氟-苯基）乙氧 3-[1-(2, 6-Dichloro-3-fluoro-phenyl)ethoxy
基] -5- [4- (4-哌啶基）吡唑 -1-基] 450 吡啶基 -2-胺  -5-[4-(4-piperidyl)pyrazole-1-yl]450 pyridyl-2-amine
^ ^
3- [ (1R) -1- (2, 6-二氯 -3-氟-苯基)  3- [ (1R) -1- (2, 6-Dichloro-3-fluoro-phenyl)
O 乙氧基] -5- [4- (4-哌啶基）吡唑 -1- 450 吡啶基 -2-胺  O ethoxy] -5-[4-(4-piperidinyl)pyrazole-1-450 pyridyl-2-amine
3 - [ (IS) 1 (2, 6 二氯- 3 氟 苯基） 乙氧基] -5- [4- (4-哌啶基）吡唑 -1- 450 基] 3 - [ (IS) 1 (2, 6 dichloro-3-fluorophenyl) ethoxy] -5- [4-(4-piperidyl)pyrazole-1-yl]
吡啶基 2 胺  Pyridyl 2 amine
3- [1- (2 6-二氯 -3-氟-苯基)乙氧 3- [1- (2 6-Dichloro-3-fluoro-phenyl) ethoxylate
Ό α 基] -5_[1 28 。^}r (1-甲基磺酰基 -4 哌啶 5 基）吡唑 -4-基]吡啶基 -2-胺 Ό α base] -5_[1 28 . ^}r (1-Methylsulfonyl-4 piperidinyl 5yl)pyrazol-4-yl]pyridinyl-2-amine
3- [1- (2, 6-二氯 -3-氟-苯基)乙氧 3- [1- (2, 6-Dichloro-3-fluoro-phenyl) ethoxylate
基] 5- [1- (1-乙烯磺酰基 -4-哌啶  5-[1-(1-vinylsulfonyl-4-piperidine)
。 540 基）  . 540 base)
吡唑- 4-基]吡啶基 -2-胺 3- [4- [4- [6-氨基 -5- [ (1R) -1- (2 6- 二氯- 3-氟-苯基）乙氧基 ]-3-吡啶 560 a- J(-_F 基]吡唑 -1-基] 1 哌啶基 ] 1, 1, 1- 三氟-丙 -2-酮 Pyrazole-4-yl]pyridin-2-amine 3-[4- [4- [6-Amino-5-[(1R)-1-(2 6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridine 560 a- J (- _ F. yl] pyrazol-1-yl] piperidin-1-yl] 1, 1, 1-trifluoromethyl - propan-2-one
2- [4- [4- [6-氨基 -5- [1- (2 6 -二氯  2- [4- [4- [6-amino -5- [1- (2 6 - dichloride)
-3-氟-苯基）乙氧基 ]-3-吡啶基]吡 569 唑 -1-基]  -3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrene 569 azole-1-yl]
-1-哌啶基]- N- (2-氯乙基）乙酰胺  -1-piperidinyl]-N-(2-chloroethyl)acetamide
2 - [4 [4 [6 氨基 -5- [1- (2, 6-二氯  2 - [4 [4 [6-amino-5- [1- (2, 6-dichloro)
- 3 -氟-苯基）乙氧基 ]-3-吡啶基] P比 547 唑 -1 基]  - 3 -fluoro-phenyl)ethoxy]-3-pyridyl] P ratio 547 azole -1 base]
-1-哌啶基]- N-环丙基-乙酰胺  -1-piperidinyl]-N-cyclopropyl-acetamide
(E)- 1- [4- [4- [6-氨基- 5- [1-(2 6- 二氯 -3-氟-苯基）乙氧基 ]-3-吡啶 518 基]吡唑 -1-基] -1-哌啶基]丁 -2-烯  (E)- 1-[4- [4- [6-Amino- 5- [1-(2 6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridine 518]pyrazole- 1-yl]-1-piperidinyl]but-2-ene
-1-酮  1-ketone
1-[4- [4- [6-氨基 5 [1 (2 6 二氯 1-[4- [4- [6-amino 5 [1 (2 6 dichloro)
-3-氟-苯基）乙氧基 ]-3-吡啶基]吡 532 唑 1 基] -1 哌啶基] -3-甲基-丁 -2 - 烯 -1-酮  -3-fluoro-phenyl)ethoxy]-3-pyridyl]pyridyl 532 azole 1 yl] -1 piperidinyl]-3-methyl-butan-2-ene-1-one
(E)-l-[4-[4-[6-氨基 -5-[1-(2, 6-
Figure imgf000089_0001
i 二氯 -3-氟-苯基）乙氧基 ]-3-吡啶 561 基]吡唑 -1-基] -1-哌啶基] -4- (二甲 基氨基）丁 -2-烯 -1-酮 (E)-l-[4-[4-[6-amino-5-[1-(2, 6-
Figure imgf000089_0001
i dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl 561 yl]pyrazol-1-yl]-1-piperidinyl]-4-(dimethylamino)but-2-ene 1-ketone
(E)-l-[4-[4-[6-氨基  (E)-l-[4-[4-[6-amino
-5- [ (IS) -1- (2 6-二氯 -3-氟-苯基）
Figure imgf000089_0002
乙氧基 ]-3-吡啶基]吡唑 1 基] 1- 561 哌啶基] "4- (二甲基氨基）丁 -2-烯 -5- [ (IS) -1- (2 6-Dichloro-3-fluoro-phenyl)
Figure imgf000089_0002
Ethoxy]-3-pyridyl]pyrazole 1 yl] 1- 561 piperidinyl] "4- (dimethylamino)but-2-ene
- 1 酮  - 1 ketone
(E)-l-[4-[4-[6-氨基  (E)-l-[4-[4-[6-amino
-5- [ (1R) -1- (2, 6-二氯 -3-氟-苯基） 乙氧基] -3-吡啶基]吡唑 -1-基] -1- 561 哌啶基] -4- (二甲基氨基）丁 -2-烯  -5- [(1R)-1-(2,6-Dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazol-1-yl]-1- 561 piperidinyl] -4- (dimethylamino)but-2-ene
- 1-酮  - 1-ketone
3 [(2 6 二氯苯基）甲氧 基] -5- [ 1- (4-哌啶基）吡唑 -4-基]吡 418
Figure imgf000089_0003
啶基 -2-胺 2 - [4- [4 [6-氨基- 5- [ (IR) 1- (2， 6- 二氯 -3-氟 苯基）乙氧基 ]-3-吡啶 536 基]吡唑 -1-基] -1-哌啶基]乙酸乙酯 3 [(2 6 Dichlorophenyl)methoxy] -5-[ 1-(4-piperidyl)pyrazol-4-yl]pyrazole 418
Figure imgf000089_0003
Pyridyl-2-amine 2-[4-[4 [6-Amino- 5-[(IR) 1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-3-pyridine 536]pyrazole-1- Acetyl]-1-piperidinyl]ethyl acetate
2- [4- [4- [6 -氨基- 5- [ (1R) -1- (2, 6- 二氯 -3-氟-苯基）乙氧基 ]-3-吡啶 535 ~Q 基]吡唑 1-基]- 1-哌啶基] -N， N-二 甲基-乙酰胺 2-[4- [4- [6-Amino- 5- [ (1R) -1- (2, 6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridine 535 ~ Q base] Pyrazole 1-yl]- 1-piperidinyl]-N, N-dimethyl-acetamide
1-[4-[4-[6-氨基 -5-[1- (2， 6-二氯 1-[4-[4-[6-amino-5-[1-(2,6-dichloride)
-3-氟-苯基）乙氧基 ]-3 -吡啶基]吡 535 -3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrr 535
、 σ ¾ 唑 -1-基] -1 哌啶基 ]-2- (二甲基氨 , σ 3⁄4 oxazol-1-yl] -1 piperidinyl]-2- (dimethylamine
基）乙酮  Ethyl ketone
1-[4-[4-[6-氨基 -5-[1 (2, 6-二氯 1-[4-[4-[6-amino-5-[1 (2,6-dichloro)
0 - 3-氟-苯基）乙氧基 ]-3 -吡啶基]吡  0 - 3-fluoro-phenyl)ethoxy]-3-pyridyl]pyridinium
Ί 521  Ί 521
唑- 1-基] -1-哌啶基 ]-2- (甲基氨基） 乙酮  Imidazole-1-yl]-1-piperidinyl]-2-(methylamino)ethanone
N- [2- [4_[4- [6-氨基 -5- [1- (2, 6-二 氯 -3 氟-苯基）乙氧基 ]-3-吡啶基] 549 吡唑 -1-基]" ·1-哌啶基 ]-2-氧代-乙 基]乙酰胺  N-[2-[4_[4-[6-amino-5-[1-(2,6-dichloro-3-phenyl)ethoxy]-3-pyridyl] 549 pyrazole-1- Base]" 1-piperidinyl]-2-oxo-ethyl]acetamide
Ν- [2- [4- [4- [6 氨基  Ν- [2- [4- [4- [6 amino group]
- 5- [ (1R)-1- (2， 6-二氯- 3-氟-苯基） 乙氧基 ]-3-吡啶基] 549 吡唑 -1-基]- 1-哌啶基 ]-2-氧代-乙 基]乙酰胺  - 5- [ (1R)-1-(2,6-Dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl] 549 pyrazol-1-yl]- 1-piperidinyl] -2-oxo-ethyl]acetamide
N-[2- [4- [4- [6-氨基  N-[2- [4- [4- [6-amino]
-5- [ (IS) -1- (2， 6-二氯- 3 氟-苯基） -5- [ (IS) -1- (2, 6-Dichloro-3-fluoro-phenyl)
\ ，"■■ < 尸 \ ,"■■ < corpse
乙氧基 ]-3 吡啶基] 549 吡唑 -1-基]- 1-哌啶基 ]-2-氧代-乙 基]乙酰胺  Ethoxy]-3 pyridyl] 549 pyrazole-1-yl]-1-piperidinyl]-2-oxo-ethyl]acetamide
^ [4- [4- [6 氨基 ^ [4- [4- [6 Amino]
°a a i 3-氨基 -1° aa i 3-amino-1
-J-r - 5-[1-(2, 6 -二氯 -3-氟-苯基)乙氧 521 基] -3-吡啶基] -J- r - 5-[1-(2, 6-dichloro-3-fluoro-phenyl)ethoxy 521 yl]-3-pyridyl]
吡唑 1-基]- 1-哌啶基]丙 -1-酮  Pyrazole 1-yl]- 1-piperidinyl]propan-1-one
4-氨基 -1- [4- [4- [6-氨基 4-amino-1- [4- [4- [6-amino]
- 5- [1- (2， 6 -二氯 -3-氟 苯基)乙氧 535 基]- 3-吡啶基]  - 5- [1- (2, 6 -Dichloro-3-fluorophenyl)ethoxy 535 yl]- 3-pyridyl]
吡唑 -1 基]- 1-哌啶基]丁 -1-酮 [4-[4-[6-氨基 5-[1-(2， 6-二氯 -3- 氟-苯基）乙氧基 ]-3-吡啶基]吡唑 561
Figure imgf000091_0001
- 1-基] Pyrazole-1 yl]- 1-piperidinyl]butan-1-one [4-[4-[6-Amino 5-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazole 561
Figure imgf000091_0001
- 1-base]
-1 哌啶基] -(4 哌啶基）甲酮  -1 piperidinyl]-(4 piperidinyl)methanone
3 -氨基 -1- [4 [4- [6-氨基  3-amino-1-[4 [4- [6-amino]
-5-[1 (2, 6-二氯 -3-氟-苯基）乙氧 基] -3-吡啶基] 549 吡唑 -1-基] -1-哌啶基 ]-3-甲基-丁  -5-[1 (2,6-Dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl] 549 pyrazol-1-yl]-1-piperidinyl]-3-methyl -Ding
-卜酮  -buprofen
[4_[4-[6-氨基 -5-[1-(2， 6 二氯 -3- 氟-苯基）乙氧基 ]-3 吡啶基]吡唑  [4_[4-[6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3pyridyl]pyrazole
533 533
-1-哌啶基] - (氮杂环丁垸 -3-基）甲 酮 -1-piperidinyl]-(azetidin-3-yl)methanone
(1-氨基环丁基) - [4- [4- [6-氨基  (1-aminocyclobutyl)-[4- [4- [6-amino]
-5- [1- (2， 6-二氯 -3-氟-苯基)乙氧 基] 547 -5- [1- (2, 6-Dichloro-3-fluoro-phenyl)ethoxy] 547
-3 -吡啶基]吡唑- 1-基] -1-哌啶基] 甲酮 -3 -pyridyl]pyrazole-1-yl]-1-piperidinyl]methanone
尸 1-[4-[4_[6-氨基 -5- [1-(2， 6-二氯 -3-氟-苯基）乙氧基 ]-3 -吡啶基]吡 唑 -1-基] 547 Corpse 1-[4-[4_[6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazol-1-yl] 547
-1-哌啶基] -2-甲基- 2- (甲基氨基） 丙 -1 酮 1-piperidinyl]-2-methyl-2-(methylamino)propan-1-one
[4- [4- [6 氨基 -5- [ (1R) - 1- (2， 6-二 氯 -3-氟-苯基）乙氧基 ]-3-吡啶基] 547
Figure imgf000091_0002
吡唑 -1-基] -1-哌啶基 ]-[(3R)_四氢 [4- [4-[6-Amino-5-[(1R)-1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl] 547
Figure imgf000091_0002
Pyrazol-1-yl]-1-piperidinyl]-[(3R)_tetrahydro
吡咯 -3-基]甲酮  Pyrrole-3-yl]methanone
[4- [4- [6-氨基- 5- [ (1R) 1- (2, 6_二 氯 -3-氟-苯基）乙氧基 ]-3-吡啶基] 547 吡唑 -1-基]- 1-哌啶基] - [ (3S) 四氢 吡咯 -3-基]甲酮 [4- [4-[6-Amino- 5-[(1R) 1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl] 547 pyrazole-1- ]]- 1-piperidinyl]-[(3S) tetrahydropyrrol-3-yl]methanone
[4- [4- [6-氨基 5 [(1R) -1- (2， 6-二 [4- [4- [6-amino 5 [(1R) -1- (2, 6-
o ~ 氯 -3 氟-苯基）乙氧基 ]-3-吡啶基] 563 o ~ chloro -3 fluoro-phenyl)ethoxy]-3-pyridyl] 563
吡唑 -1-基] -1-哌啶基] - [ (3S) -吗啉 Pyrazole-1-yl]-1-piperidinyl]-[(3S)-morpholine
3-基]甲酮  3-keto-ketone
2-氨基 -1 [4- [4- [6-氨基  2-amino-1 [4- [4- [6-amino]
-5 [ (1R) -1- (2, 6 二氯- 3 氟-苯基） 画 -5 [ (1R) -1- (2, 6 dichloro - 3 fluoro-phenyl)
Figure imgf000091_0003
乙氧基 ]-3-吡啶基] 575
Figure imgf000091_0003
Ethoxy]-3-pyridyl] 575
吡唑 1-基] -1-哌啶基 ]-3， 3, 3-三氟  Pyrazole 1-yl]-1-piperidinyl]-3, 3, 3-trifluoro
-丙 -1-酮 [4- [4- [6-氨基- 5 - [ (IR) -1- (2, 6 二 氯- 3-氟-苯基）乙氧基 ]-3-吡啶基] 561 吡唑- 1-基] -1-哌啶基] - [ (3S) -3 -哌 啶基]甲酮 -propan-1-one [4- [4-[6-Amino-5-[(IR)-1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl] 561 pyrazole- 1- -1-piperidinyl]-[(3S)-3-3 piperidinyl]methanone
[4- [4- [6-氨基- 5- [ (1R) -卜 (2, 6 二 氯 -3-氟-苯基）乙氧基 ] 3-吡啶基] 561 吡唑 -1-基] -1-哌啶基 ] [(3R)- 3-哌 啶基]甲酮  [4- [4- [6-Amino- 5-[(1R)-Bu(2,6-dichloro-3-fluoro-phenyl)ethoxy] 3-pyridyl] 561 pyrazol-1-yl] 1-(piperidinyl)[(3R)-3-piperidinyl]methanone
[4 - [4- [6-氨基- 5-[(lR)-l-(2, 6-二  [4 - [4- [6-Amino- 5-[(lR)-l-(2, 6-II)
P - 氯 -3-氟-苯基）乙氧基 ]-3-吡啶基] 563 吡唑 -1-基] -1-哌啶基] - [(2R) -吗啉  P - chloro-3-fluoro-phenyl)ethoxy]-3-pyridyl] 563 pyrazole-1-yl]-1-piperidinyl]-[(2R)-morpholine
-2-基]甲酮  -2-yl]methanone
[4-[4-[6-氨基-5_[(11 -1-(2,6-二 [4-[4-[6-Amino-5_[(11 -1-(2,6-II)
563 氯 3-氟-苯基）乙氧基 ]-3-吡啶基] 吡唑 -1-基] -1-哌啶基 ]- [(2S)-吗啉  563 chloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazole-1-yl]-1-piperidinyl]-[(2S)-morpholine
-2-基]甲酮  -2-yl]methanone
[4- [4- [6 -氨基 -5 - [ (1R) 1- (2, 6 二 氯 3-氟-苯基）乙氧基 ]-3-吡啶基] 547 吡唑 -1-基] -1 哌啶基 ]- [(2R) 四氢 吡咯 -2-基]甲酮 [4- [4- [6-Amino-5-[(1R) 1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl] 547 pyrazol-1-yl] -1 piperidinyl]-[(2R) tetrahydropyrrol-2-yl]methanone
[4-[4- [6-氨基- 5 [(1R) 1- (2, 6-二 氯 -3-氟 苯基）乙氧基 ] 3-吡啶基] 561[4-[4-[6-Amino- 5 [(1R) 1-(2,6-dichloro-3-fluorophenyl)ethoxy] 3-pyridyl] 561
° CI^T -F 吡唑 -1-基]- 1-哌啶基 ]-(2-哌啶基） ° CI ^ T - F pyrazol-1-yl] - 1-piperidinyl] - (2-piperidinyl)
甲酮  Ketone
(2S) -2-氨基 -1- [4 [4- [6-氨基 (2S) -2-amino-1- [4 [4- [6-amino]
0 - 5- [(1R) - 1- (2 6 二氯- 3 氟-苯基） 606 乙氧基 ]-3-吡啶基]吡唑 -1-基] 1 哌啶基 ]-6- (二甲基氨基）己 -1 -酮  0 - 5- [(1R) - 1-(2 6 dichloro- 3 fluoro-phenyl) 606 ethoxy]-3-pyridyl]pyrazol-1-yl] 1 piperidinyl]-6- ( Dimethylamino)hex-1-one
(2S) -2-氨基 -1- [4- [4- [6-氨基  (2S) -2-amino-1- [4- [4- [6-amino]
-5 [(1R) - 1 -（2, 6-二氯- 3-氟 苯基） 587 乙氧基 ] 3-吡啶基]吡唑- 1-基] -1 哌啶基 ]-3-(1 Η^米唑 -4-基）丙 -1 酮  -5 [(1R) - 1 -(2,6-Dichloro-3-fluorophenyl) 587 ethoxy] 3-pyridyl]pyrazole-1-yl]-1 piperidinyl]-3-( 1 Η^Mizolyl-4-yl)propan-1 ketone
(2R) -2 氨基 -1- [4- [4- [6-氨基  (2R) -2 amino -1- [4- [4- [6-amino]
-5- [(1R)-1- (2 6 二氯 3-氟-苯基） n' ^ύτ乙氧基 ]-3-吡啶基]吡唑 -1-基] 1- 549 哌啶基 ]-3-甲基-丁 -1-酮 -5- [(1R)-1-(2 6 dichloro 3-fluoro-phenyl) n ' ^ύτ ethoxy]-3-pyridyl]pyrazol-1-yl] 1- 549 piperidinyl] -3-methyl-butan-1-one
Figure imgf000093_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
实施例 88: 动物实验方法和活性数据 雄性 SD大鼠 24小时内的药物代谢动力学试验共分为静脉和口服两组，每组 3只动物. 静 脉组取血时间点为给药前， 给药后 0.0833， 0.167， 0.5， 1， 2, 4， 8, 24小时； 口服组取血 时间点为给药前， 给药后 0.167， 0.5, 1， 2, 4， 8， 24小时。 采血完毕后， 利用 HPLC-MS/MS 进行生物分析， 报告化合物的血药浓度. 计算出的药物代谢动力学参数为静脉组动物的平均 清除率（Clp)， 平均表观分布容积（Vdss), 0-24h曲线下分布面积 (AUC) ， 0 24小时的平均滞 留时间（MRT), 半衰期 T1/2; 口服组动物在给药后的平均最大药物浓度（Cmax), 0_24h曲线下 分布面积 (AUC)， 0-24小时的平均滞留时间（MRT); 本次试验的平均相对生物利用度。 比格犬 24小时内的药物代谢动力学试验共分为静脉和口服两组，每组 3只动物. 静脉组 取血时间点为给药前， 给药后 0.033， 0.083， 0.25， 0.5， 1， 3， 6， 9， 24小时； 口服组取 血时间点为给药前， 给药后 0.083， 0.25， 0.5， 1， 3， 6， 9， 24小时。 采血完毕后， 利用 HPLOMS/MS进行生物分析， 报告化合物的血药浓度. 计算出的药物代谢动力学参数为静脉组 动物的平均清除率 (Clp)， 平均表观分布容积（Vdss), 0-24h曲线下分布面积 (AUC) ， 0 24小 时的平均滞留时间 (MRT)， 半衰期 T1/2; 口服组动物在给药后的平均最大药物浓度 (Cmax)， 0-24h曲线下分布面积（AUC)， 0-24小时的平均滞留时间（MRT)， 本次试验的平均相对生物利 用度。 化合物 18 对实验动物体内肿瘤增长的抑制作用： SCID鼠或裸鼠 （实验开始时 18 g左 右） 由软件随机分多组， 以达到组间体重均值接近， 并将偏差控制在允许范围内， 被注射 ALK 驱动的细胞株 （例如， 淋巴瘤 KARPAS299, 肺癌 NCI- H441) 成瘤。 口服给药， 每天一次， 共 7或 14天。 记录体重， 肿瘤体积。 肿瘤， 血液， 脑， 及眼睛取样通过 LC-MS/MS进行化合物 分析检测。 结果表明如图 1和图 2所示。 从图 1和图 2可以看出， 化合物 18具有良好的肿瘤 抑制作用并眼睛中化合物暴亮度比较低。 Example 88: Animal Experimental Methods and Activity Data The pharmacokinetic test of male SD rats within 24 hours was divided into two groups, intravenous and oral, with 3 animals in each group. The time of blood collection in the intravenous group was before administration. After the drug, 0.0833, 0.167, 0.5, 1, 2, 4, 8, 24 hours; the oral administration time was taken before administration, 0.167, 0.5, 1, 2, 4, 8, 24 hours after administration. After blood collection, bioassay was performed by HPLC-MS/MS to report the plasma concentration of the compound. The calculated pharmacokinetic parameters were the mean clearance rate (Clp) of the venous group, and the average apparent volume of distribution (Vdss). 0-24h distribution area under the curve (AUC), 0 24-hour mean retention time (MRT), half-life T1/2; mean maximum drug concentration (Cmax) after administration in the oral group, distribution area under the 0_24h curve (AUC) ), 0-24 hours mean residence time (MRT); average relative bioavailability of this trial. The pharmacokinetic test within 24 hours of Beagle dogs was divided into two groups, intravenous and oral, with 3 animals in each group. The time of blood collection in the intravenous group was before administration, 0.033, 0.083, 0.25, 0.5, 1 after administration. , 3, 6, 9, 24 hours; The time of blood in the oral group was 0.083, 0.25, 0.5, 1, 3, 6, 9, 24 hours before administration. After blood collection, HPLOMS/MS was used for bioassay to report the plasma concentration of the compound. The calculated pharmacokinetic parameters were the mean clearance rate (Clp) of the venous group, the average apparent volume of distribution (Vdss), 0- Distribution area under the 24h curve (AUC), mean retention time (MRT) at 0 24 hours, half-life T1/2; mean maximum drug concentration (Cmax) after administration in the oral group, distribution area under the curve 0-24h (AUC) ), 0-24 hours mean residence time (MRT), the average relative bioavailability of this trial. Compound 18 inhibits tumor growth in experimental animals: SCID mice or nude mice (about 18 g at the beginning of the experiment) were randomly divided into groups by software to achieve close to the mean body weight between groups, and the deviation was controlled within the allowable range. The ALK-driven cell line (for example, lymphoma KARPAS299, lung cancer NCI-H441) was injected into the tumor. Oral administration, once a day for 7 or 14 days. Record body weight, tumor volume. Tumor, blood, brain, and eye samples were analyzed by LC-MS/MS for compound analysis. The results are shown in Figures 1 and 2. As can be seen from Fig. 1 and Fig. 2, compound 18 has a good tumor suppressing effect and the compound in the eye has a relatively low brightness.

Claims

权 利 要 求 书 Claim
1. 由通式 （I) 或 （π)表示的化合物， 其对映体和： l 对映体或其可药用的盐， A compound represented by the formula (I) or (π), an enantiomer thereof and: an enantiomer or a pharmaceutically acceptable salt thereof,
Figure imgf000097_0001
其中：
Figure imgf000097_0001
among them:
Ar 选自通式 （III)  Ar is selected from the general formula (III)
Figure imgf000097_0002
式中， A A , A^A5各自独立地足 C或者 N， 吋， 其上无取代基取代；
Figure imgf000097_0002
Wherein AA , A^A 5 are each independently C or N, 吋, which is substituted without a substituent;
一个饱和的或不饱和的 CI- C8碳链， 芳基， 杂环烷基或杂芳基： 这些碳链， 芳基， 杂环 垸基和杂芳基的碳或氮原 /·上的氢原/ · ί任选被烷基， 环烷基， 垸氧基， 环烷 基， 氨基， C , 酰¼基或 μΐ素所取代；  a saturated or unsaturated CI-C8 carbon chain, aryl, heterocycloalkyl or heteroaryl: hydrogen of these carbon chains, aryl, heterocyclic fluorenyl and heteroaryl carbon or nitrogen The original / · ί is optionally substituted by an alkyl group, a cycloalkyl group, a decyloxy group, a cycloalkyl group, an amino group, a C group, an acyl group or a stilbene;
其中， A还可以冋 Q或 R,;形成 3 8元的芳基或杂芳基； Wherein, A may also be Q or R ; forming a 38-membered aryl or heteroaryl group;
和 各自独立地为式 （IV) 或 （V) 表示的基闭：  And base closures of formula (IV) or (V), respectively:
Figure imgf000097_0003
Figure imgf000097_0003
IV V 其屮， Q是 CO或 S( ;  IV V, Q is CO or S ( ;
其中， R,， R2， R3， R„ R5， R6， R7， R8, R9， R,„, RIb Rl2， Rl3 , 和 Y各自独立表示 ¾， 氘， 氨基， 卤素， 羟基， 羧基， 硝基， 氰基， （C2-C6) 烯基， （C2- C6) 炔基， 三 ¾甲基， 二' 甲 t基， (Π- C.6) 烷基， (C1-C6) 垸 m¾， (C3-C10) 环烷基， 其屮的烷基， 烷¼基或环 浣基上可进一歩仟选被： 氘， 卤素， ¼基， 羟基， 羧基， 硝基， 基， （C I C6 )烷基， （C卜 C6 ) 烷氧基所取代； 其中， 1¾还" 以足芳基或杂芳基； Wherein R, R 2 , R 3 , R „ R 5 , R 6 , R 7 , R 8 , R 9 , R, „, R Ib R l2 , R l3 , and Y each independently represent 3⁄4, 氘, amino , halogen, hydroxy, carboxy, nitro, cyano, (C2-C6) alkenyl, (C2-C6) alkynyl, tris-methyl, bis-methyl, (Π-C.6) alkyl, (C1-C6) 垸m3⁄4, (C3-C10) cycloalkyl, anthracene alkyl, alkyl or ring The sulfhydryl group may be further selected as: hydrazine, halogen, 1⁄4 group, hydroxy group, carboxyl group, nitro group, group, (CI C6 ) alkyl group, (CBu C6) alkoxy group; wherein, 13⁄4 Alkaryl or heteroaryl;
其中， 还可以同 Q或 Mt形成 3-8元的芳基或杂芳基： Among them, it is also possible to form a 3-8 membered aryl or heteroaryl group with Q or M t :
所述芳基或 ¾芳基的碳或氮原子上的氢原子可任选被烷基， 环烷基， 垸氧基， 环烷氧基， H 基， CN， 酰 (基， 卤素所取代； 其中， Xl ; X X:„ X^P Χ「,各 fi独立地足 C， N, 0， S; 3为 C或者 N时， 其上 nj被氘， 卤素， 氨基， 羟基， 硝基， 氰基， （CI- C6 ) 垸基， （C卜 C6 ) 垸氧基所^代。 The hydrogen atom on the carbon or nitrogen atom of the aryl or 3 aryl group may be optionally substituted by an alkyl group, a cycloalkyl group, a decyloxy group, a cycloalkoxy group, a H group, a CN, an acyl group, a halogen group; Wherein, X l ; XX: „ X^P Χ ", each fi is independently C, N, 0, S; 3 is C or N, on which nj is deuterated, halogen, amino, hydroxyl, nitro, cyanide Base, (CI-C6) sulfhydryl, (CBuC6) 垸oxy group.
2. 如权利要求 1所述的化合物， 其优选为通式 （VI )和 （VII ) 表示的化合物， 其对映体和 非对映体或其可药用的盐， The compound according to claim 1, which is preferably a compound represented by the formulae (VI) and (VII), an enantiomer thereof and a diastereomer thereof or a pharmaceutically acceptable salt thereof,
Figure imgf000098_0001
Figure imgf000098_0001
式中， Ar， Μ,, Q， R6， Rs, Χ, , X2， X3， X4， X5和 Y的定义如权利要求 1所述。 Wherein Ar, Μ, Q, R 6 , R s , Χ, X 2 , X 3 , X 4 , X 5 and Y are as defined in claim 1.
3. 如权利要求 1-2任一所述的化合物， 其对映体和非对映体或其可药用的盐， 3. A compound according to any one of claims 1-2, an enantiomer thereof and a diastereomer thereof, or a pharmaceutically acceptable salt thereof,
其中： Ar为取代的苯基或吡啶， 优选为取代的苯基。 Wherein: Ar is a substituted phenyl or pyridine, preferably a substituted phenyl group.
4. 如权利要求 1-3任一所述的化合物， 其对映体和非对映体或其可药用的盐， 4. A compound according to any one of claims 1 to 3, an enantiomer thereof and a diastereomer thereof, or a pharmaceutically acceptable salt thereof,
、 X - 其中： 为吡唑基， 优选为
Figure imgf000098_0002
更优选为 , X - wherein: is pyrazolyl, preferably
Figure imgf000098_0002
More preferably
Figure imgf000099_0001
Figure imgf000099_0001
5. 如权利要求 1 4任一所述的化合物， 其对映体和非对映体或其可药用的盐， 5. A compound according to any one of claims 1 to 4, an enantiomer thereof and a diastereomer thereof, or a pharmaceutically acceptable salt thereof,
其中所述的化合物由下列结构式 （VIII) 或 （IX) 表示： The compound described therein is represented by the following structural formula (VIII) or (IX):
Figure imgf000099_0002
其中： Ar， Re, R8, Q，M1和 Y的定义如权利要求 1所述。
Figure imgf000099_0002
Wherein: Ar, Re, R 8 , Q, M 1 and Y are as defined in claim 1.
6. 如权利要求 5所述的化合物， 其对映体和非对映体或其可药用的盐， 其中 Υ优选为 ¼基。 6. A compound according to claim 5, an enantiomer thereof and a diastereomer thereof, or a pharmaceutically acceptable salt thereof, wherein hydrazine is preferably a benzyl group.
7. 如权利要求 5或 6所述的化合物， 其对映体和非对映体或其可药用的盐， Ar优选为苯基 或取代的苯基， 其中苯基上取代基各自独立地为氘， 氨基， 卤素， 羟基， 羧基， 硝基， 氰基，The compound according to claim 5 or 6, the enantiomer and the diastereomer thereof or a pharmaceutically acceptable salt thereof, Ar is preferably a phenyl group or a substituted phenyl group, wherein the substituents on the phenyl group are each independently Is an anthracene, an amino group, a halogen, a hydroxyl group, a carboxyl group, a nitro group, a cyano group,
(C2-C6)烯基， （C2-C6) 炔基， 二: ¾甲基， 二氣甲 基， （C C6) 烷基， （ -C6)烷氧 基或 （C3-C10) 环烷基； 其中的垸基， 烷氧基或环垸基上的取代基团可进 -歩任选被下列基 团所取代： 氘， 素， ί基， ¾基， 羧基， 硝基， 1基， (C1-C6)烷基， (C1-C6)垸氧基。 (C2-C6) alkenyl, (C2-C6) alkynyl, di: 3⁄4 methyl, dioxomethyl, (C C6) alkyl, (-C6)alkoxy or (C3-C10) cycloalkyl The substituent group on the fluorenyl, alkoxy or cycloalkyl group may be optionally substituted with the following groups: hydrazine, aryl, yl, 3⁄4, carboxy, nitro, 1 group, ( C1-C6)alkyl, (C1-C6)decyloxy.
8. 如权利要求 1 7任一所述的化合物， 其对映体和非对映体或其可药用的盐， 8. A compound according to any one of claims 1 to 7, an enantiomer and a diastereomer thereof, or a pharmaceutically acceptable salt thereof,
其中所述的化合物由下列结构式 （X) 或 （XI) 所表达： The compound described therein is expressed by the following structural formula (X) or (XI):
Figure imgf000099_0003
Figure imgf000099_0003
其中： Ar, R6， 和 Y的定义如权利要求 1所述。 Wherein: Ar, R 6 , and Y are as defined in claim 1.
9. 如权利要求 8所述的化合物， 其对映体和非对映体或其可药用的盐， 其中： R6优选为甲胺
Figure imgf000100_0001
The compound according to claim 8, the enantiomer and the diastereomer thereof or a pharmaceutically acceptable salt thereof, wherein: R 6 is preferably methylamine
Figure imgf000100_0001
基或 基。  Base or base.
10. 如权利要求 8或 9所述的化合物， 其对映体和非对映体或其可药用的盐， 其中： R«优选 为甲基。  The compound according to claim 8 or 9, the enantiomer and diastereomer thereof or a pharmaceutically acceptable salt thereof, wherein: R« is preferably a methyl group.
11如权利要求 8— 10中任一项所述的化合物，其对映体和非对映体或其可药用的盐，其中： Y 优选为氨基。  The compound according to any one of claims 8 to 10, which is an enantiomer and a diastereomer thereof, or a pharmaceutically acceptable salt thereof, wherein: Y is preferably an amino group.
12. 如权利要求 8— 11中任一项所述的化合物， 其对映体和非对映体或其可药用的盐， 其中: Ar优选为苯基或取代的苯基， 其中苯基上取代基各自独立地为氘， 氨基， 卤素， 羟基， 羧 基， 硝基， 氛基， (C2-C6) 烯基， (C2-C6) 炔基， 二氟 Ψ基， 二氟屮氧基， (C1-C6) 烷 基， （C1-C6) 垸氧基， （C3-C10) 环烷基， 其中的垸棊， 烷氧基或环烷基上的取代基团可 任选被 F列基闭所取代：気， 卤'素，氨 ，羟 ffi， 羧基，硝基， 氰基， （C1-C6)烷基， （C1-C6) 烷氧 ffi。  The compound according to any one of claims 8 to 11, which is an enantiomer and a diastereomer thereof, or a pharmaceutically acceptable salt thereof, wherein: Ar is preferably a phenyl group or a substituted phenyl group, wherein phenyl group The upper substituents are each independently hydrazine, amino, halogen, hydroxy, carboxy, nitro, aryl, (C2-C6) alkenyl, (C2-C6) alkynyl, difluoroindolyl, difluorodecyloxy, (C1-C6) alkyl, (C1-C6) decyloxy, (C3-C10) cycloalkyl, wherein the hydrazine, alkoxy or cycloalkyl substituent group may be optionally substituted by F group Substituted for substitution: hydrazine, halogen ', ammonia, hydroxyffi, carboxyl, nitro, cyano, (C1-C6) alkyl, (C1-C6) alkoxy ffi.
13. 由下列结构式表示的化合物， 其对映体和非对映体或其可药用的盐 13. A compound represented by the following structural formula, an enantiomer thereof and a diastereomer thereof or a pharmaceutically acceptable salt thereof
Figure imgf000100_0002
001
Figure imgf000100_0002
001
Figure imgf000101_0001
Figure imgf000101_0001
88Z000/M0ZN3/X3d 98t9 / 0Z OAV TOT 88Z000/M0ZN3/X3d 98t9 / 0Z OAV TOT
Figure imgf000102_0001
Figure imgf000102_0001
88Z000/M0ZN3/X3d 98t9 / 0Z OAV
Figure imgf000103_0001
88Z000/M0ZN3/X3d 98t9 / 0Z OAV
Figure imgf000103_0001
88Z000/M0ZN3/X3d 98t9 / 0Z OAV 88Z000/M0ZN3/X3d 98t9 / 0Z OAV
Figure imgf000104_0001
Figure imgf000104_0001
14. 一种药物组合物， 包括一种惰性载体和权利要求 1 - 13屮任一项所述的化合物， 其对映 体和非对映体或其可药用的盐， 优选权利要求 13的化合物。 A pharmaceutical composition comprising an inert carrier and a compound according to any one of claims 1 to 13, an enantiomer and a diastereomer thereof, or a pharmaceutically acceptable salt thereof, preferably according to claim 13. Compound.
15. 一种用于治疗或抑制癌症或其他疾病的方法， 所述方法包括给需要的患者有效剂量的如 权利要求 1 - 1 3仟一项所述的化合物，其对映体和非对映体或其可药用的盐，或权利要求 1 4的 组合物， 所述癌症或其他疾病包括， 但不限于， 非小细胞 UNG肺癌 （NSCLC ) ， 间变性大细胞 淋巴瘤 （ALCL ) ， 祌经母细胞瘤， 以及其他抑制 ALK激酶活性对病人冇益处的疾病。 15. A method for treating or inhibiting cancer or other disease, the method comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 - 13, enantiomers and diastereoisomers Or a pharmaceutically acceptable salt thereof, or a composition according to claim 14, wherein the cancer or other diseases include, but are not limited to, non-small cell UNG lung cancer (NSCLC), anaplastic large cell lymphoma (ALCL), sputum Transblastoblasts, as well as other diseases that inhibit the benefit of ALK kinase activity in patients.
16. 如权利要求 15所述的方法， 其中所述癌症优选为肝癌。  16. The method of claim 15, wherein the cancer is preferably liver cancer.
17. 如权利要求 16所述的方法， 其中所述肝癌优选为亚洲患者的肝癌。  17. The method of claim 16, wherein the liver cancer is preferably liver cancer of an Asian patient.
18. 如权利要求 15所述的方法， 其中所述癌 为非小细胞肺癌 ( NSCLC ) 。  18. The method of claim 15, wherein the cancer is non-small cell lung cancer (NSCLC).
19. 如权利要求 15所述的方法， 其中所述癌症为 I'nj变性大细胞淋巴瘤 。 19. The method of claim 15, wherein the cancer is I'nj degenerative large cell lymphoma.
20. 如权利要求 1 5所述的方法， 其中所述癌症为神经母细胞瘤。  20. The method of claim 15, wherein the cancer is a neuroblastoma.
21. 一种抑制在患者体内 A1J (活性的方法， 包括给予所述患者有效剂量的如权利要求 1 - 13 屮任一项所述的化合物， 其对映体和非对映体或其可药用的盐， 。  A method for inhibiting A1J (activity in a patient, comprising administering to the patient an effective amount of the compound according to any one of claims 1 to 13, an enantiomer and a diastereomer thereof or a pharmaceutically acceptable drug thereof Salt used,
22. 一种药物， 它包括一种惰性载体和权利要求 1 - 13中任意一项所述的化合物，其对映体 和非对映体或其可药用的盐作为活性成分， 优选权利要求 13的化合物。 22. A medicament comprising an inert carrier and a compound according to any one of claims 1 to 13, an enantiomer and a diastereomer thereof, or a pharmaceutically acceptable salt thereof, as an active ingredient, preferably a claim 13 compounds.
23. 权利要求 1 13任一项所述的化合物、其对映体和非对映体或其可药用的盐在制备治疗癌 症或其他疾病的药物中的用途， 其中所述癌 f;或其他疾病包括， 似不限丁， 非小细胞 U\G肺 癌 （NSCLC ) ， 间变性大细胞淋巴瘤 （ALCL ) ， 祌经母细胞瘤， 以及其他抑制 ALK激酶活性对 病人冇益处的疾病。 23. The use of a compound according to any one of claims 1 to 13, an enantiomer thereof and a diastereomer thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer or other diseases, wherein said cancer f; Other diseases include, but not limited to, non-small cell U\G lung cancer (NSCLC), anaplastic large cell lymphoma (ALCL), sputum mesenchyblastoma, and other diseases that inhibit the benefit of ALK kinase activity in patients.
24. 如权利要求 23所述的用途， 其中癌症为肝癌。 24. The use of claim 23, wherein the cancer is liver cancer.
25. 如权利要求 24所述的用途， 其中所述肝癌优选为亚洲忠者的肝癌。 25. The use according to claim 24, wherein the liver cancer is preferably liver cancer of an Asian loyal.
26. 如权利要求 23所述的用途， 其中所述癌 ϋί'「；为非小细胞肺癌 ( SCLC) 。 26. The use of claim 23, wherein the cancer is non-small cell lung cancer (SCLC).
27. 如权利要求 23所述的方法， 其中所述癌症为间变性大细胞淋巴瘤 （Al£l.) 。 27. The method of claim 23, wherein the cancer is an anaplastic large cell lymphoma (Al£l.).
28. 如权利要求 23所述的方法， 其中所述癌症为神经母细胞瘤。 28. The method of claim 23, wherein the cancer is a neuroblastoma.
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