[go: up one dir, main page]

WO2017049498A1 - 一种咪唑并吡啶类化合物与在制备pi3k抑制剂中的应用 - Google Patents

一种咪唑并吡啶类化合物与在制备pi3k抑制剂中的应用 Download PDF

Info

Publication number
WO2017049498A1
WO2017049498A1 PCT/CN2015/090433 CN2015090433W WO2017049498A1 WO 2017049498 A1 WO2017049498 A1 WO 2017049498A1 CN 2015090433 W CN2015090433 W CN 2015090433W WO 2017049498 A1 WO2017049498 A1 WO 2017049498A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
compound
imidazopyridine
compound according
pi3k
Prior art date
Application number
PCT/CN2015/090433
Other languages
English (en)
French (fr)
Inventor
刘忠
Original Assignee
前湾医药科技（深圳）有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 前湾医药科技（深圳）有限公司 filed Critical 前湾医药科技（深圳）有限公司
Priority to PCT/CN2015/090433 priority Critical patent/WO2017049498A1/zh
Publication of WO2017049498A1 publication Critical patent/WO2017049498A1/zh

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention belongs to the field of medicines, and in particular relates to an imidazopyridine compound and application thereof in preparing a PI3K inhibitor.
  • PI3K is a family of lipid kinases. According to their function and sequence homology, PI3K is divided into three types (I, II and III), of which the most comprehensive one is type I PI3K. Based on the difference between signaling pathway and regulatory proteins, type I PI3K can be further divided into IA type and IB type.
  • IA type PI3K includes PI3K ⁇ , PI3K ⁇ , and PI3K ⁇ , which exist as heterodimers, each heterodimer consisting of a catalytic subunit (p110 ⁇ , p110 ⁇ , or p110 ⁇ ) and a regulatory subunit, and its signal transduction is usually It is mediated by the receptor tyrosine kinase (RTK).
  • RTK receptor tyrosine kinase
  • the IB type PI3K gamma signal is mediated by a G protein-coupled receptor and consists of a p110 gamma catalytic domain that is linked to a regulatory subunit different from the IA subtype.
  • P13K plays an important role in the regulation of multiple cellular processes including cell cycle regulation, proliferation, survival, apoptosis and migration, and is an important component of the molecular mechanisms of diseases such as cancer, diabetes and immune inflammation.
  • I P13K The main P13K isoform in cancer is type I P13K.
  • IA type P13K is activated by RTK or Ras to generate phosphatidylinosnol-3,4,5-triphosphate (PIP3), which acts as a second messenger in the cell to activate the downstream target Akt. It plays an important regulatory role in tumor cell development, proliferation, survival and growth.
  • the two subtypes PI3K ⁇ and PI3K ⁇ are mainly expressed in immune-related cells and participate in the process of inflammatory response, and play a key regulatory role in acquired immunity and innate immune system.
  • P13K ⁇ plays an important role in B cell maturation, T cell activation, and neutrophil migration, and is involved in the activation of leukocytes associated with autoimmune diseases such as macrophages, dendritic cells, and NK T-cells.
  • B cell signaling in P13K ⁇ mutant mice has specific defects that result in B cell developmental disorders and reduced antibody responses following antigen stimulation.
  • P13K ⁇ is involved in the regulation of chemokine signal transduction, and its activity is crucial for T cell activation and differentiation.
  • P13K ⁇ regulates ROS production in neutrophils and regulates the migration of macrophages and neutrophils, which leads to macrophages and neutrophils towards the inflammatory site.
  • Recruitment disorders and T cell activation disorders Based on the close relationship between PI3K and inflammation and autoimmune diseases, PI3K has become a new target for the development of eye-catching anti-inflammatory drugs.
  • Another object of the present invention is to provide a process for producing the above imidazopyridine compounds.
  • a further object of the present invention is to provide the use of the above imidazopyridine compounds for the preparation of PI3K inhibitors.
  • An imidazopyridine compound which is a compound of formula I or a pharmaceutically acceptable salt thereof, and a solvent compound, enantiomer, diastereomer of said compound of formula I or a pharmaceutically acceptable salt thereof a construct, a tautomer or a mixture thereof in any ratio, including a racemic mixture;
  • Ar is a substituted or unsubstituted aryl or arylhetero group, and the substituted aryl or arylhetero group may be optionally substituted by one or more substituents independently selected from the group consisting of halogen, hydroxy and cyanogen. base;
  • R 1 is -H, halogen, hydroxy, cyano or C 2 -C 6 alkynyl
  • R 2 is -H or C 1 -C 6 alkyl
  • the aryl group means a carbocyclic hydrocarbon group having 6 to 14 ring carbon atoms and having at least one ring, wherein at least one ring is an aromatic ring, such as a phenyl group;
  • the heteroaryl group means a monocyclic aromatic hydrocarbon group having 6 ring atoms, such as a pyridyl group;
  • halogen or halogen means fluorine, chlorine, bromine or iodine
  • the hydroxyl group refers to an -OH group
  • the cyano group refers to a -CN group
  • the C 2 -C 6 alkynyl group means an alkynyl group having 2 to 6 carbon atoms, and examples of the alkynyl group include, but are not limited to, an ethynyl group, a 2-propynyl group and a 2-butynyl group;
  • the C 1 -C 6 alkyl group means an alkyl group having 1 to 6 carbon atoms, and examples of the alkyl group include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, and iso Butyl, sec-butyl and tert-butyl;
  • the imidazopyridine compound is preferably a compound having a structure represented by A, B or C:
  • a pharmaceutically acceptable salt thereof and a solvent compound, enantiomer, diastereomer, or mutual compound of the compound having the structure represented by A, B or C or a pharmaceutically acceptable salt thereof Isomers or mixtures thereof in any ratio, including racemic mixtures;
  • the preparation method of the imidazopyridine compound comprises the following steps:
  • step (3) under alkaline conditions, the product 1 obtained in step (2) is subjected to a hydrolysis reaction to obtain a product 2;
  • step (6) under the action of the reducing agent L-tri-sec-butyl borohydride, the product 5 obtained in step (6) is subjected to a reduction reaction to obtain a product 6;
  • step (9) under basic conditions, the product 7 obtained in step (8) and chloroacetaldehyde cyclization reaction to obtain the product 8;
  • the product 8 obtained in the step (9) is taken off the tert-butylsulfinyl group to obtain the product 9;
  • Step (11) the product obtained is reacted with compound 10 containing a halogen, hydroxyl, cyano or C 2 ⁇ C 6 alkynyl group, to give compound 11, i.e. R 1 is halo, hydroxy, cyano or C 2 to C 6 alkynyl imidazopyridine compounds;
  • the synthetic route of the imidazopyridine compound is as follows:
  • the imidazopyridine compound is used in the preparation of a medicament for treating cancer, diabetes and/or immunoinflammatory;
  • the medicament may contain one or more pharmaceutically acceptable carriers, excipients or diluents;
  • the medicament includes various clinical pharmaceutical dosage forms, such as tablets, injections, liposome nanoparticles, controlled release agents, and the like;
  • a PI3K inhibitor comprising the above imidazopyridine compound
  • a medicament for treating a PI3K mediated disease comprising the above imidazopyridine compound
  • the compound of the present invention is selective for PI3K ⁇ , which is a selective inhibitor of PI3K ⁇ ; said "selective inhibitor of PI3K ⁇ " means that the compound binds or inhibits the affinity or potency of the PI3K ⁇ subtype compared to PI3K other
  • the subtype ie PI3K ⁇ , PI3K ⁇ or PI3K ⁇
  • the compounds of the invention may have a selectivity to PI3K ⁇ of at least about 400 fold, at least about 800 fold, or at least about 1000 fold.
  • the compounds of the invention may inhibit the activity of PI3K and may be useful in the preparation of diseases suitable for the treatment of PI3K activity, including, for example, inflammatory conditions, immunological disorders, cancer, and other diseases.
  • Methyl 2-amino-5-bromo-isonicotinate (10 g, 43.2 mmol) and 2,5-hexanedione (5.4 g, 47.5 mmol) were dissolved in 100 ml of toluene (toluene) and p-toluene was added.
  • step (2) The product obtained in the step (2) (8.4 g, 27.42 mmol) was dissolved in 40 ml of methanol (MeOH) and 10 ml of water, and sodium hydroxide (3.29 g, 82.25 mmol) was added and allowed to react at room temperature for 4 hours.
  • N-chlorosuccinimide (NCS, 24 mg, 0.18 mmol) was added, and the reaction was refluxed overnight and concentrated.
  • Biochemical analysis of PI3K kinase activity was performed using Promega's ADP-Glo technology.
  • the ADP-Glo kinase assay kit and PI3K ⁇ kinase were purchased from Promega, and PI3K ⁇ , PI3K ⁇ , and PI3K ⁇ kinase were purchased from Millipore Corporation. All experiments were performed in 384 well plates at room temperature.
  • the kinase mixture was diluted with kinase buffer including 50 mM HEPES (pH 7.5), 3 mM MgCl 2 , 100 mM NaCl, 1 mM EGTA, 0.03% CHAPS and 2 mM DTT.
  • the ATP/substrate mixture contained 5 ⁇ M PIP2/PS and 25 ⁇ M ATP.
  • Compounds to be tested (A, B and C) were dissolved in 100% DMSO and diluted to a final concentration with ddH 2 O. 2 ⁇ L of the diluted test compound and 4 ⁇ L of ATP/substrate mixture were added to each well of a 384-well assay plate. At the beginning of the reaction, 4 ⁇ L of the kinase mixture was added to each well.
  • the final reaction volume was 10 ⁇ L, the final concentration of PIP2/PS was 2 ⁇ M, and the final concentrations of PI3K ⁇ , PI3K ⁇ , PI3K ⁇ and PI3K ⁇ kinase were 0.2, 0.6, 0.25 and 0.4 nM, respectively, and the corresponding ATP final concentrations were 40, 40, 40 and 25 ⁇ M, respectively.
  • Add 10 ⁇ L of kinase ADP-Glo reagent to each well and incubate for 1 h. Then add 20 ⁇ L of kinase assay to each well. After incubation for 30 min, the luminescence readings were measured with Envision plate reader.
  • the inhibition rate of the compound was calculated and the IC 50 was calculated by XLFIT5 software. (50% inhibitory concentration) value.
  • the inhibition data of the measured compounds against PI3K kinase activity are shown in Table 1.
  • the results show that the compounds listed as selective inhibitors of PI3K ⁇ that PI3K ⁇ IC of at least 50 and lower than other subtypes of PI3K (i.e. PI3K ⁇ , PI3K ⁇ or PI3K ⁇ ) 400 times, such as a PI3K inhibitor compound, with For the treatment of diseases associated with PI3K activity, including, for example, inflammatory conditions, immune-based disorders, cancer, and other diseases.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

提供了一种如式（I）所示的咪唑并吡啶类化合物或其药学上可接受的盐、溶剂化合物、对映异构体、非对映异构体、互变异构体或其任意比例的混合物，该类化合物可抑制PI3K的活性，因而可用于制备治疗与PI3K活性相关的疾病，例如炎性病症、免疫性病症、癌症等。

Description

一种咪唑并吡啶类化合物与在制备PI3K抑制剂中的应用 技术领域
本发明属于药物领域，具体涉及一种咪唑并吡啶类化合物与在制备PI3K抑制剂中的应用。
背景技术
PI3K是一个脂激酶家族。根据其功能和序列同源性，PI3K被分为三种类型(I、II和III)，其中了解最为全面的为I型PI3K。基于信号通路和调节蛋白的不同，I型PI3K又可以进一步分为IA型和IB型。IA型PI3K包括PI3Kα、PI3Kβ、和PI3Kδ，它们以异二聚体存在，每一个异二聚体由一个催化亚基(p110α、p110β、或p110δ)和一个调节亚基组成，其信号转导通常由受体络氨酸激酶(RTK)介导。而IB型PI3Kγ信号通过G蛋白偶联受体介导，并由能与不同于IA亚型的调节亚基联系的p110γ催化域组成。P13K在包括细胞周期调节、增殖、存活、凋亡和迁移等多个细胞过程的调节中起着重要作用，是癌症、糖尿病和免疫炎症等疾病的分子机理的重要组成部分。
PI3K基因突变和扩增在癌症中频繁发生以及PTEN在癌症中缺失等都提示PI3K与肿瘤发生的密切关系。由于PI3K位于多个重要信号转导通路的关键性信号位置，已成为抗癌药物研发的新靶点。在癌症中主要的P13K同工型为I型P13K。IA型P13K被RTK或Ras激活后催生成磷脂酰肌醇-3,4,5-三磷酸(phosphatidylinosnol-3,4,5-triphosphate，PIP3)，从而作为细胞内第二信使激活下游靶标Akt，对肿瘤细胞发展、增殖、存活和生长起着重要的调控作用。
PI3Kγ与PI3Kδ这两个亚型主要表达于免疫相关细胞中，并参与炎症应答进程，在获得性免疫和固有免疫系统中各自发挥着关键的调控作用。P13Kδ在B细胞成熟、T细胞激活、嗜中性粒细胞迁移中发挥着重要作用，并参与巨噬细胞、树突细胞和NK T-细胞等自身免疫疾病相关的白细胞的激活。P13Kδ突变型小鼠的B细胞信号传导具有特定缺陷，其导致B细胞发育障碍以及抗原刺激后的抗体反应降低。P13Kγ参与趋化因子信号转导调控，其活性对T细胞激活与分化至关重要。此外，P13Kγ在嗜中性粒细胞中调节ROS的生成，并调节巨噬细胞和嗜中性粒细胞的迁移，其缺失会导致巨噬细胞和嗜中性粒细胞朝向发炎位点 的募集障碍以及T细胞活化障碍。基于PI3K和炎症及自身免疫性疾病的密切关系，PI3K已成为令人瞩目的抗炎药物研发的新靶点。
发明内容
为了克服现有技术的不足和缺点，本发明的首要目的在于提供一种咪唑并吡啶类化合物。
本发明的另一目的在于提供上述咪唑并吡啶类化合物的制备方法。
本发明的再一目的在于提供上述咪唑并吡啶类化合物在制备PI3K抑制剂中的应用。
本发明的目的通过下述技术方案实现：
一种咪唑并吡啶类化合物，为式I化合物或其药学上可接受的盐，以及所述的式I化合物或其药学上可接受的盐的溶剂化合物、对映异构体、非对映异构体、互变异构体或其任意比例的混合物，包括外消旋混合物；
Figure PCTCN2015090433-appb-000001
其中，Ar为取代或未取代的芳基或者芳杂基，所述的取代的芳基或者芳杂基可任意地被一个或者多个独立地选自以下的取代基取代：卤素、羟基和氰基；
R1为-H、卤素、羟基、氰基或C2～C6炔基；
R2为-H或C1～C6烷基；
所述的芳基是指有一个环或者多个稠环组成的含有6～14个环碳原子的碳环烃基，其中至少一个环是芳族环，例如苯基；
所述的杂芳基是指具有6个环原子的单环芳族烃基，例如吡啶基；
所述的卤素或卤代是指氟、氯、溴或碘；
所述的羟基是指-OH基团；
所述的氰基是指-CN基团；
所述的C2～C6炔基是指具有2～6个碳原子的炔基，炔基的例子包括但不限于乙炔基、2-丙炔基和2-丁炔基；
所述的C1～C6烷基是指具有1～6个碳原子的烷基，烷基的例子包含但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基和叔丁基；
所述的咪唑并吡啶类化合物优选为具有A、B或C所示结构的化合物：
Figure PCTCN2015090433-appb-000002
或其药学上可接受的盐，以及所述的具有A、B或C所示结构的化合物或其药学上可接受的盐的溶剂化合物、对映异构体、非对映异构体、互变异构体或其任意比例的混合物，包括外消旋混合物；
所述的咪唑并吡啶类化合物的制备方法，包含如下步骤：
(1)在催化剂对甲苯磺酸的作用下，2-氨基-5-溴-异烟酸甲酯和2,5-己二酮反应，得到5-溴-2-(2,5-二甲基吡咯-1-基)-异烟酸甲酯；
(2)在催化剂四(三苯基膦)钯的作用下，步骤(1)制得的5-溴-2-(2,5-二甲基吡咯-1-基)-异烟酸甲酯与Ar-B(OH)2进行suzuki反应，得到产物1；
(3)在碱性条件下，步骤(2)制得的产物1进行水解反应，得到产物2；
(4)在缩合剂EDCI的作用下，步骤(3)制得的产物2与N，O-二甲基羟胺盐酸盐进行缩合反应，制得产物3；
(5)步骤(4)制得的产物3与格式试剂R2MgBr反应，得到产物4；
(6)在催化剂钛酸四乙酯的作用下，步骤(5)制得的产物4与(R)-叔丁基亚磺酰胺进行催化缩合反应，得到产物5；
(7)在还原剂L-三仲丁基硼氢化锂的作用下，步骤(6)制得的产物5进行还原反应，得到产物6；
(8)步骤(7)制得的产物6与盐酸羟胺和三乙胺反应，得到产物7；
(9)在碱性条件下，步骤(8)制得的产物7与氯乙醛进行环化反应，得到产物8；
(10)在酸性条件下，步骤(9)制得的产物8脱掉叔丁基亚磺酰基，得到产物9；
(11)在DIPEA的作用下，步骤(10)制得的产物9与4-氨基-6-氯-吡啶-5-氰基反应，制得产物10，即为R1为-H的咪唑并吡啶类化合物；
(12)步骤(11)制得的产物10与含有卤素、羟基、氰基或C2～C6炔基的化合物进行反应，得到化合物11，即为R1为卤素、羟基、氰基或C2～C6炔基的咪唑并吡啶类化合物；
所述的咪唑并吡啶类化合物的合成路线如下所示：
Figure PCTCN2015090433-appb-000003
所述的咪唑并吡啶类化合物在制备PI3K抑制剂中的应用；
所述的咪唑并吡啶类化合物在制备治疗PI3K介导的疾病的药物中的应用；
优选的，所述的咪唑并吡啶类化合物在制备治疗癌症、糖尿病和/或免疫炎症药物中的应用；
所述的药物可含有一种或多种药学上可接受的载体、赋形剂或稀释剂；
所述的药物包括多种临床药物剂型，如片剂、注射液、脂质体纳米粒、控释剂等；
一种PI3K抑制剂，包含上述咪唑并吡啶类化合物；
一种治疗PI3K介导的疾病的药物，包含上述咪唑并吡啶类化合物；
本发明的化合物对PI3Kδ具有选择性，该化合物为PI3Kδ的选择性抑制剂；所述的“PI3Kδ的选择性抑制剂”，意指化合物结合或抑制PI3Kδ亚型的亲和力或效能相较于PI3K其它亚型(即PI3Kα、PI3Kβ或PI3Kγ)较大。本发明的化合物对PI3Kδ的选择性可为至少约400倍、至少约800倍或至少约1000倍。
本发明相对于现有技术具有如下的优点及效果：
本发明中的化合物可以抑制PI3K的活性，可以应用于制备适用于治疗与PI3K活性相关的疾病，包括(例如)炎性病症、免疫基病症、癌症以及其它疾病。
具体实施方式
下面结合实施例对本发明作进一步详细的描述，但本发明的实施方式不限于此。
实施例1
化合物A：(S)-4-氨基-6-【1-(3-氯-6-本机-咪唑并【1,2-a】吡啶-7-基)-乙基氨】-嘧啶-5-氰基，合成路线如下所示：
Figure PCTCN2015090433-appb-000004
(1)5-溴-2-(2,5-二甲基吡咯-1-基)-异烟酸甲酯
2-氨基-5-溴-异烟酸甲酯(10克，43.2毫摩尔)和2,5-己二酮(5.4克，47.5毫摩尔)溶解在100毫升甲苯(Toluene)中，加入对甲苯磺酸(TsOH，93毫克，0.43毫摩尔)后用分水器回流过夜。冷却至室温后浓缩干，残留物加入水中，室温搅拌15分钟，过滤得到棕色固体标题产物(12.05克)。收率：90.22％，MS(m/z)＝311.0[M+H]+312.1[M+2H]+。
(2)2-(2,5-二甲基-吡咯-1-基)-5-苯基-异烟酸甲酯
取步骤(1)所得产物(12.05克，38.98毫摩尔)，苯硼酸(7.13克，58.46毫摩尔)溶解在100毫升二氧六环(Dioxane)和5毫升水混合溶剂中，氮气保护条件下加入四(三苯基膦)钯(0.45克，0.39毫摩尔)和碳酸钾(10.77克，77.96毫摩尔)，100℃反应过夜，浓缩后通过柱层析分离得到棕色固体标题产物(8.4克)，收率：70.35％，MS(m/z)＝307.1[M+H]+。
(3)2-(2,5-二甲基-吡咯-1-基)-5-苯基-异烟酸
取步骤(2)所得产物(8.4克，27.42毫摩尔)溶解在40毫升甲醇(MeOH) 和10毫升水中，加入氢氧化钠(3.29克，82.25毫摩尔)，室温反应4小时。反应液用水稀释，用3摩尔/升盐酸调节pH至酸性，过滤后所得固体即为标题产物(6.2克)。收率：77.35％，MS(m/z)＝293.1[M+H]+。
(4)2-(2,5-二甲基-吡咯-1-基)-N-甲氧基-N-甲基-5-苯基-吡啶甲酰胺
取步骤(3)所得产物(6.2克，21.21毫摩尔)，N，O-二甲基羟胺盐酸盐(3.1克，31.81毫摩尔)和EDCI(4.88克，25.45毫摩尔)溶解在二氯甲烷(DCM)中，零度下加入三乙胺(Et3N，8.58克，84.84毫摩尔)，室温反应过夜，浓缩后通过柱层析分离得到棕色油状物(5.8克)，收率：81.57％，MS(m/z)＝336.1[M+H]+。
(5)1-【2-(2,5-二甲基-吡咯-1-基)-5-苯基-吡啶-4-基】乙酮
取步骤(4)所得产物(5.8克，17.29毫摩尔)溶解在40毫升干燥四氢呋喃(THF)中，0℃下加入甲基溴化镁(MeMgBr，12.68毫升，38.04毫摩尔)。室温反应3小时，饱和氯化铵水溶液淬灭后用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥后浓缩，柱层析分离得到棕色固体标题产物(3.0克)，收率：59.76％，MS(m/z)＝291.1[M+H]+。
(6)(R)-2-甲基-丙烷-2-亚磺酸{1-【2-(2,5-二甲基-吡咯-1-基)-5-苯基-吡啶-4-基】亚乙级}-酰胺
取步骤(5)所得产物(3.0克，10.33毫摩尔)和(R)-叔丁基亚磺酰胺(1.5克，12.39毫摩尔)溶解在20毫升干燥四氢呋喃(THF)中，加入钛酸四乙酯(Ti(OEt)4)。回流反应过夜，反应液冷却至室温，乙酸乙酯稀释后倒入水中，过滤，浓缩干后柱层析分离得到黄色油状物标题产物(3.5克)，收率：86.10％，MS(m/z)＝394.2[M+H]+。
(7)(R)-{(S)-1-【2-(2,5-二甲基-吡咯-1-基)-5-苯基-吡啶-4-基】-乙基}-2-甲基丙烷-2-亚磺酰胺
取步骤(6)所得产物(3.5克，8.89毫摩尔)溶解在30毫升干燥四氢呋喃(THF)中，-78℃加入L-三仲丁基硼氢化锂(L-selectride，17.78毫摩尔)，-78℃反应2小时，饱和氯化铵水溶液淬灭，乙酸乙酯萃取，有机相用饱和食盐水洗涤后，无水硫酸钠干燥，浓缩后通过柱层析分离得到黄色油状物标题产物(3.0克)，收率：85.22％，MS(m/z)＝396.2[M+H]+。
(8)(R)-【(S)-1-(2-氨基-5-苯基-吡啶-4-基)-乙基】-2-甲基丙烷-2-亚磺酰胺
取步骤(7)所得产物(3.0克，7.58毫摩尔)和盐酸羟胺(7.91克，75.8 毫摩尔)溶解在20毫升乙醇(EtOH)和20毫升水中，加入三乙胺(Et3N，7.67克，75.8毫摩尔)，回流反应过夜，冷却至室温，乙酸乙酯稀释后倒入水中，有机相分离后浓缩，柱层析分离得到黄色油状物标题产物(1.1克)，收率：45.7％，ee％＝99.5％，MS(m/z)＝318.1[M+H]+。
(9)(R)-【(S)-1-(6-苯基-咪唑并【1,2-a】吡啶-7-基)-乙基】-2-甲基丙烷-2-亚磺酰胺
取步骤(8)所得产物(1.1克，3.46毫摩尔)和氯乙醛(3.4克，17.33毫摩尔)溶解在20毫升乙醇(EtOH)中，加入碳酸氢钠(2.32克，27.68毫摩尔)，回流反应过夜，浓缩，柱层析分离得到标题产物(0.85克)，收率：72.03％，MS(m/z)＝342.2[M+H]+。
(10)(S)-1-(6-苯基-咪唑并[1,2-a]吡啶-7-基)-乙基胺
取步骤(9)所得产物(0.85克，2.49毫摩尔)溶解在10毫升乙酸乙酯(EA)和5毫升甲醇(MeOH)混合溶液中，加入5毫升4M HCl乙酸乙酯溶液，室温反应1小时，浓缩得到标题灰色标题产物(0.8克)，收率：100％，MS(m/z)＝238.1[M+H]+。
(11)(S)-4-氨基-6-[1-(6-苯基-咪唑并[1,2-a]吡啶-7-基)-乙基氨]-嘧啶-5-氰基
取步骤(10)所得产物(80毫克，0.29毫摩尔)和4-氨基-6-氯-吡啶-5-氰基(67毫克，0.43毫摩尔)溶解在正丁醇(n-BuOH)中，加入二异丙基乙胺(DIPEA，112毫克，0.87毫摩尔)，120℃反应过夜，反应液冷却至室温后柱层析分离得到白色固体标题产物(64毫克)，收率：62.13％，MS(m/z)＝356.1[M+H]+.。
(12)(S)-4-氨基-6-[1-(3-氯-6-苯基-咪唑并[1,2-a]吡啶-7-基)-乙基氨]-嘧啶-5-氰基
取步骤(11)所得产物(64毫克，0.18毫摩尔)溶解在5毫升氯仿中，加入N-氯代丁二酰亚胺(NCS，24毫克，0.18毫摩尔)，回流反应过夜，浓缩后柱层析分离得到白色固体标题产物(47毫克)，收率：66.98％，MS(m/z)＝390.1[M+H]+；1H NMR(400MHz,cdcl3)δ8.03(s,1H),7.91(s,1H),7.63(s,1H),7.55(s,1H),7.51-7.49(m,2H),7.47-7.45(m,1H),7.43-7.41(m,1H),5.43–5.36(m,2H),5.29(s,2H),1.36(d,J＝6.5,3H)。
实施例2
化合物B：(S)-4-氨基-6-[1-(3-氯-6-吡啶-2-咪唑并[1,2-a]吡啶-7-)-乙胺]嘧啶 -5-氰基，合成路线如下所示：
Figure PCTCN2015090433-appb-000005
(1)(S)-4-氨基-6-[1-(-6-吡啶-2-咪唑并[1,2-a]吡啶-7-)-乙胺]嘧啶-5-氰基
将(S)-1-(6-吡啶-2-咪唑并[1,2-a]吡啶-7-)乙胺盐酸盐(购买自苏州岚云医药科技有限公司)(100毫克，0.36毫摩尔)和4-氨基-6-氯-5-氰基嘧啶(85毫克，0.55毫摩尔)加入到正丁醇(n-BuOH，5毫升)中，加入二异丙基乙胺(DIPEA，93毫克，0.72毫摩尔)，加热回流反应过夜。反应结束后，冷却至室温，减压蒸除溶剂，残留物通过柱层析分离，得到白色固体产物(100毫克)，收率：71.07％；MS(m/z)＝357.1[M+H]+。
(2)(S)-4-氨基-6-[1-(3-氯-6-吡啶-2-咪唑并[1,2-a]吡啶-7-)-乙胺]嘧啶-5-氰基
将(S)-4-氨基-6-[1-(-6-吡啶-2-咪唑并[1,2-a]吡啶-7-)-乙胺]嘧啶-5-氰基(100毫克，0.28毫摩尔)和N-氯代丁二酰亚胺(NCS，38毫克，0.28毫摩尔)加入到氯仿(5毫升)中，回流反应2小时。反应结束后，冷却至室温，减压蒸除溶剂，残留物通过柱层析分离，得到白色固体产物标题产物(75毫克)，收率：68.53％；MS(m/z)＝391.1[M+H]+。1H NMR(400MHz,cdcl3)δ8.90-8.88(m,1H),8.52(d,J＝8.0,1H),8.14(s,1H),8.07(d,J＝0.5,1H),7.92-7.88(m,1H),7.73(s,1H),7.63-7.61(m,1H),7.59(s,1H),7.43-7.40(m,1H),5.82-5.75(m,1H),5.27(s,2H),1.19(d,J＝7.1,3H).
实施例3
化合物C：(S)-4-氨基-5-[1-(3-氟-6-吡啶-2-基-咪唑并[1,2-a]吡啶-7-基)-乙基氨]-嘧啶-5-氰基，合成路线如下所示：
Figure PCTCN2015090433-appb-000006
将(S)-4-氨基-6-[1-(6-吡啶-2-基-咪唑并[1,2-a]吡啶-7-)-乙氨]-嘧啶-5-氰基(30毫克，0.08毫摩尔，实施例2制备)溶解在5毫升氯仿中，加入N-氟代双苯磺酰胺(NCS，27毫克，0.08毫摩尔)，回流反应过夜，浓缩后柱层析分离得到白色固体产物(10毫克)，收率：31.73％，MS(m/z)＝375.1[M+H]+；1H NMR(400MHz,cdcl3)δ8.87(dd,J＝4.9,0.9,1H),8.50(d,J＝7.3,1H),8.13(s,1H),7.92(s,1H),7.89-7.85(m,1H),7.63(d,J＝1.5,1H),7.58(d,J＝7.8,1H),7.44–7.38(m,1H),7.21(d,J＝7.1,1H),5.77-5.71(m,1H),5.36(s,2H),1.17(d,J＝7.1,3H)。
实施例4 PI3K酶活性测定
采用Promega公司的ADP-Glo技术进行PI3K激酶活性生化分析。ADP-Glo激酶检测试剂盒和PI3Kβ激酶购自Promega公司，PI3Kα、PI3Kδ、PI3Kγ激酶购自Millipore公司。所有实验均在室温下于384孔板中完成。激酶混合物用激酶缓冲液进行稀释，激酶缓冲液包括50mM HEPES(pH 7.5)，3mM MgCl2，100mM NaCl，1mM EGTA，0.03％CHAPS和2mM DTT。ATP/底物混合物含有5μM PIP2/PS和25μM ATP。待测化合物(A、B和C)用100％DMSO溶解，并用ddH2O稀释至终浓度。将2μL稀释待测化合物和4μL ATP/底物混合物加入384孔分析板各孔内。反应开始时，每孔加入4μL激酶混合物。反应终体积为10μL，PIP2/PS终浓度为2μM，PI3Kα、PI3Kβ、PI3Kδ和PI3Kγ激酶终浓度分别为0.2、0.6、0.25和0.4nM，对应的ATP终浓度分别为40、40、40和25μM。每孔加入10μL的激酶ADP-Glo试剂后孵育1h，然后每孔加入20μL激酶检测剂，孵育30min后用Envision酶标仪检测发光读数，计算化合物对激酶的抑制率，并用XLFIT5软件计算出IC50(50％抑制浓度)值。测定的化合物对PI3K激酶活性的抑制数据列于表1。结果表明所列化合物为PI3Kδ的选择性抑制剂，其对PI3Kδ的IC50与对PI3K其它亚型(即PI3Kα、PI3Kβ或PI3Kγ)相比至少低400倍，此类化合物可以作为PI3K抑制剂，用于治疗与PI3K活性相关的疾 病，包括(例如)炎性病症、免疫基病症、癌症以及其它疾病。
表1待测化合物对PI3K激酶活性的抑制结果分析
Figure PCTCN2015090433-appb-000007
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。

Claims (10)

  1. 一种咪唑并吡啶类化合物，其特征在于为式I化合物或其药学上可接受的盐，以及所述的式I化合物或其药学上可接受的盐的溶剂化合物、对映异构体、非对映异构体、互变异构体或其任意比例的混合物，包括外消旋混合物；
    Figure PCTCN2015090433-appb-100001
    其中，Ar为取代或未取代的芳基或者芳杂基；
    R1为-H、卤素、羟基、氰基或C2～C6炔基；
    R2为-H或C1～C6烷基。
  2. 根据权利要求1所述的咪唑并吡啶类化合物，其特征在于：
    所述的取代的芳基或者芳杂基可任意地被一个或者多个独立地选自以下的取代基取代：卤素、羟基和氰基。
  3. 根据权利要求1或2所述的咪唑并吡啶类化合物，其特征在于：
    所述的芳基为苯基。
  4. 根据权利要求1或2所述的咪唑并吡啶类化合物，其特征在于：
    所述的杂芳基为吡啶基。
  5. 根据权利要求1所述的咪唑并吡啶类化合物，其特征在于：
    所述的C2～C6炔基为乙炔基、2-丙炔基或2-丁炔基。
  6. 根据权利要求1所述的咪唑并吡啶类化合物，其特征在于：
    所述的C1～C6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。
  7. 根据权利要求1所述的咪唑并吡啶类化合物，其特征在于：
    所述的咪唑并吡啶类化合物为具有A、B或C所示结构的化合物：
    Figure PCTCN2015090433-appb-100002
    或其药学上可接受的盐，以及所述的具有A、B或C所示结构的化合物或其药学上可接受的盐的溶剂化合物、对映异构体、非对映异构体、互变异构体或其任意比例的混合物，包括外消旋混合物。
  8. 权利要求1～7任一项所述的咪唑并吡啶类化合物在制备PI3K抑制剂中的应用。
  9. 权利要求1～7任一项所述的咪唑并吡啶类化合物在制备治疗PI3K介导的疾病的药物中的应用。
  10. 根据权利要求9所述的咪唑并吡啶类化合物在制备治疗PI3K介导的疾病的药物中的应用，其特征在于：
    所述的药物可含有一种或多种药学上可接受的载体、赋形剂或稀释剂。
PCT/CN2015/090433 2015-09-23 2015-09-23 一种咪唑并吡啶类化合物与在制备pi3k抑制剂中的应用 WO2017049498A1 (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/CN2015/090433 WO2017049498A1 (zh) 2015-09-23 2015-09-23 一种咪唑并吡啶类化合物与在制备pi3k抑制剂中的应用

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2015/090433 WO2017049498A1 (zh) 2015-09-23 2015-09-23 一种咪唑并吡啶类化合物与在制备pi3k抑制剂中的应用

Publications (1)

Publication Number Publication Date
WO2017049498A1 true WO2017049498A1 (zh) 2017-03-30

Family

ID=58385606

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2015/090433 WO2017049498A1 (zh) 2015-09-23 2015-09-23 一种咪唑并吡啶类化合物与在制备pi3k抑制剂中的应用

Country Status (1)

Country Link
WO (1) WO2017049498A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107793394A (zh) * 2017-08-03 2018-03-13 上海厚璞生物科技有限公司 一种生产选择性pi3k抑制剂的系列关键中间体

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0710870A (ja) * 1993-06-23 1995-01-13 Asahi Glass Co Ltd 新規アミノピリジン誘導体およびその塩
CN101677569A (zh) * 2007-04-17 2010-03-24 雷诺维思公司 2-氰基苯基稠合杂环化合物及其组合物和用途
US20120035153A1 (en) * 2007-10-12 2012-02-09 Astex Therapeutics Limited Bicyclic heterocyclic compounds as protein tyrosine kinase inhibitors
US20130005721A1 (en) * 2009-09-23 2013-01-03 Panmira Pharmaceuticals, Llc Indolizine inhibitors of 5-lipoxygenase
CN105130984A (zh) * 2015-09-23 2015-12-09 前湾医药科技（深圳）有限公司 一种咪唑并吡啶类化合物与在制备pi3k抑制剂中的应用

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0710870A (ja) * 1993-06-23 1995-01-13 Asahi Glass Co Ltd 新規アミノピリジン誘導体およびその塩
CN101677569A (zh) * 2007-04-17 2010-03-24 雷诺维思公司 2-氰基苯基稠合杂环化合物及其组合物和用途
US20120035153A1 (en) * 2007-10-12 2012-02-09 Astex Therapeutics Limited Bicyclic heterocyclic compounds as protein tyrosine kinase inhibitors
US20130005721A1 (en) * 2009-09-23 2013-01-03 Panmira Pharmaceuticals, Llc Indolizine inhibitors of 5-lipoxygenase
CN105130984A (zh) * 2015-09-23 2015-12-09 前湾医药科技（深圳）有限公司 一种咪唑并吡啶类化合物与在制备pi3k抑制剂中的应用

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107793394A (zh) * 2017-08-03 2018-03-13 上海厚璞生物科技有限公司 一种生产选择性pi3k抑制剂的系列关键中间体

Similar Documents

Publication Publication Date Title
KR101541086B1 (ko) 피롤로피리미딘 화합물 및 그 용도
KR101571720B1 (ko) 신규 Syk 억제제로서의 치환된 피리도피라진
CN103582643B (zh) 蛋白激酶抑制剂
JP6664414B2 (ja) ＩＧＦ−１Ｒ／ＩＲ阻害薬としての新規５，８−ジメチル−９−フェニル−５，８−ジヒドロ−６Ｈ−ピラゾロ［３，４−ｈ］キナゾリン−２−イル）−（１Ｈ−ピラゾール−３−イル）−アミン及び誘導体
CN102675286B (zh) 一类吲唑类化合物及其制备方法、用途和药物组合物
NZ522989A (en) Quinazoline ditosylate salt compounds
JP2009535388A (ja) ピラゾール誘導体、及びそのｐｉ３ｋ阻害薬としての使用
TW200401640A (en) Substituted 3-amino-thieno[2,3-b]pyridine-2-carboxylic acid amide compounds and processes for preparing and their uses
MX2007000116A (es) Pirimidinas 2,4,6-trisustituidas como inhibidores de fosfotidilinositol (pi) 3-cinasa y su uso en el tratamiento de cancer.
TW200528447A (en) Novel imidazole derivatives and their use as pharmaceutical agents
US20120208810A1 (en) Novel 1,2,3,4-tetrahydro-pyrimido(1,2-a)pyrimidin-6-one derivatives, preparation thereof, and pharmaceutical use thereof
GB2603386A (en) Dihydro-pyrrolo-pyrimidine selective JAK2 inhibitor
JP7587887B2 (ja) Ｊａｋキナーゼ阻害剤としての小分子化合物及びその用途
US20220008386A1 (en) Tosylacetate based compounds and derivatives thereof as phgdh inhibitors
CN105837574B (zh) N‑(3‑哌啶基)‑芳香胺衍生物及其制备方法和用途
KR102264189B1 (ko) Pi3k 억제제인 피라졸로피리미딘 화합물 및 이의 용도
EP3134405B1 (en) Heteroaromatic compounds and their use as dopamine d1 ligands
CN113105434A (zh) 新型cdk4/6抑制剂及其制备方法和应用
WO2017049498A1 (zh) 一种咪唑并吡啶类化合物与在制备pi3k抑制剂中的应用
TW200403247A (en) An optically active pyridine derivative and a medicament containing the same
CA2946990A1 (en) Heterocyclic compounds and their use as dopamine d1 ligands
CN105130984B (zh) 一种咪唑并吡啶类化合物与在制备pi3k抑制剂中的应用
CN116731020A (zh) 一种egfr抑制剂及其制备方法和用途
US11021479B2 (en) Pyridoquinazoline derivatives useful as protein kinase inhibitors
WO2022068860A1 (zh) 一种吡咯并杂环类衍生物的晶型及其制备方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15904385

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15904385

Country of ref document: EP

Kind code of ref document: A1