TW202214621A

TW202214621A - Heterocyclic compounds with dual inhibition activity of phosphatidylinositol 3-kinase δ and γ and their medical use

Info

Publication number: TW202214621A
Application number: TW110126821A
Authority: TW
Inventors: 陳振華; 劉國標; 閆旭; 陳士柱; 杜佩金; 殷惠軍
Original assignee: 大陸商中國醫藥研究開發中心有限公司
Priority date: 2020-07-21
Filing date: 2021-07-21
Publication date: 2022-04-16
Also published as: CN114258393A; WO2022017371A1

Abstract

The present invention relates to heterocyclic compounds with dual inhibition activity of phosphatidylinositol 3-kinase [delta] and [gamma] and their medical use. Specifically, the present invention relates to a compound represented by general formula (I), its preparation method, pharmaceutical composition containing the same, and its use as phosphatidylinositol 3-kinase [delta] (PI3K[delta]) and phosphatidylinositol 3-kinase [gamma] (PI3K[gamma]) dual inhibitors for the prevention and/or treatment of respiratory diseases, especially asthma, chronic obstructive pulmonary disease, bronchitis and emphysema. The definition of each group in the general formula (I) is the same as the definition in the specification.

Description

具有磷脂醯肌醇3-激酶δ和γ的雙重抑制劑活性的雜環化合物及其醫藥用途 Heterocyclic compound with dual inhibitor activity of phosphatidylinositol 3-kinase delta and gamma and its medicinal use

本發明屬於醫藥技術領域，具體涉及一種雜環化合物、其製備方法及含有其的醫藥組成物，以及其作為磷脂醯肌醇3-激酶δ(PI3Kδ)和磷脂醯肌醇3-激酶γ(PI3Kγ)雙重抑制劑，在預防和/或治療呼吸系統疾病，特別是哮喘、慢性阻塞性肺病、支氣管炎、肺氣腫，更特別是哮喘和慢性阻塞性肺病中的用途。 The invention belongs to the technical field of medicine, and in particular relates to a heterocyclic compound, a preparation method thereof and a pharmaceutical composition containing the same, and its functions as phosphatidylinositol 3-kinase δ (PI3Kδ) and phosphatidylinositol 3-kinase γ (PI3Kγ) ) dual inhibitors for use in the prevention and/or treatment of respiratory diseases, in particular asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, more particularly asthma and chronic obstructive pulmonary disease.

磷脂醯肌醇3-激酶(phosphatidylinositol-3 kinase，PI3K)是一類位於細胞質中以磷脂醯肌醇作為受質的激酶。它可以識別來自受體酪胺酸激酶(receptor tyrosine kinase，RTK)、G蛋白偶聯受體(G-protein coupled receptor，GPCR)和Src樣蛋白偶聯酪胺酸激酶受體傳遞的信號，磷酸化磷脂醯肌醇3'位的羥基，產生磷脂醯肌醇-3-磷酸(phosphatidylinositol-3-phosphate，PIP)、磷脂醯肌醇-3,4-二磷酸(phosphatidylinositol-3,4-biphosphate，PIP2)和磷脂醯肌醇-3,4,5-三磷酸(phosphatidylinositol-3,4,5-triphosphate，PIP3)。PIP2和PIP3是細胞內重要的第二信使，可與細胞內的多種靶蛋白，如與Akt結合，藉由激酶級聯反應將信號逐級傳遞並放大，最終調節細胞的增殖、分化、代謝、凋亡等一系列活動(Huang等人，Science，2007，318(5857)，1744-1748)。 Phosphatidylinositol-3 kinase (PI3K) is a kind of kinase located in the cytoplasm and uses phosphatidylinositol as a substrate. It can recognize signals from receptor tyrosine kinase (RTK), G-protein coupled receptor (GPCR) and Src-like protein-coupled tyrosine kinase receptor, phosphorylation The hydroxyl group at the 3' position of phosphatidylinositol produces phosphatidylinositol-3-phosphate (PIP), phosphatidylinositol-3,4-diphosphate (phosphatidylinositol-3,4-biphosphate, PIP2) and phosphatidylinositol-3,4,5-triphosphate (PIP3). PIP2 and PIP3 are important second messengers in cells, which can bind to various target proteins in cells, such as Akt, through the kinase cascade reaction. It can be transmitted and amplified at the next stage, and finally regulate a series of activities such as cell proliferation, differentiation, metabolism, and apoptosis (Huang et al., Science, 2007, 318(5857), 1744-1748).

基於結構及對受質的選擇性不同，PI3K可分為I、II、III三類。I型PI3K又可分為IA和IB兩個亞型，其中IA型PI3K可接受來自多個上游的信號，如RTK和GPCR等；IB型的PI3K主要接受GPCR傳遞的信號(Vanhaesebroeck等人，J Mo Med，2016，94，5-11)。IA型的PI3K由一個催化亞基p110和一個調節亞基p85或其剪切變體組成。p110催化亞基由5個結構域組成：p85調節亞基結合結構域(p85 binding domain，P85 BD)，由α螺旋-β折疊組成的結構域，與調節亞基結合；Ras結合結構域(Ras binding domain，Ras BD)，由α螺旋-β折疊組成的結構域，與Ras蛋白結合；C2結構域，由2個4條鏈的反平行β片層構成，是與脂質膜結合的主要位點；螺旋區，由全α螺旋組成，作用未知；激酶催化結構域(kinase domain，KD)，由兩個亞結構域組成，每個亞結構域均是由α螺旋-β折疊組成的超二級結構，KD是PI3Ks發揮催化作用的核心區域，與ATP及脂質受質結合(Huang等人，Science，2007，318(5857)，1744-1748)。p85調節亞基由5個結構域組成：與p110催化亞基結合的結構域(inter Src-homology 2 domain，iSH2)及兩側的SRC同源結構域-N端SRC同源結構域(N-terminal Src-homology 2 domain，nSH2)和C端SRC同源結構域(C-terminal Src-homology 2 domain，cSH2)，N端的第三個SRC同源結構域(Src-homology 3 domain，SH3)和BC同源結構域(BCR homology domain，BH)。p85結構域的剪接變體p55α/p55γ和p50α僅由iSH2、nSH2和cSH2三個結構域組成。nSH2、iSH2和cSH2結構域可與催化亞基的5個結構域作用，發揮抑制催化活性的效果(Zhang等人，Mol Cell，2011，41(5)，567-78)。 PI3Ks can be divided into three categories: I, II, and III based on their structure and their selectivity for substrates. Type I PI3K can be divided into two subtypes, IA and IB, among which type IA PI3K can receive signals from multiple upstream, such as RTK and GPCR, etc.; type IB PI3K mainly accepts signals transmitted by GPCR (Vanhaesebroeck et al., J Mo Med, 2016, 94, 5-11). Type IA PI3Ks consist of a catalytic subunit p110 and a regulatory subunit p85 or its splice variants. The p110 catalytic subunit consists of five domains: the p85 regulatory subunit binding domain (p85 BD), a domain composed of α-helix-β folds, which binds to the regulatory subunit; the Ras binding domain (Ras binding domain, Ras BD), a domain composed of α-helix-β sheet, which binds to Ras protein; C2 domain, composed of two 4-chain anti-parallel β-sheets, is the main site for binding to lipid membranes ; Helical region, composed of whole α-helix, with unknown function; Kinase domain (KD), composed of two sub-domains, each sub-domain is a super-secondary composed of α-helix-β sheet Structurally, KD is the core region of PI3Ks for catalysis, binding to ATP and lipid substrates (Huang et al., Science, 2007, 318(5857), 1744-1748). The p85 regulatory subunit consists of 5 domains: the domain that binds to the p110 catalytic subunit (inter Src-homology 2 domain, iSH2) and the SRC homology domain on both sides-N-terminal SRC homology domain (N- terminal Src-homology 2 domain (nSH2) and C-terminal Src-homology 2 domain (cSH2), the third N-terminal SRC homology domain (Src-homology 3 domain, SH3) and BC homology domain (BCR homology domain, BH). The splice variants p55α/p55γ and p50α of the p85 domain consist of only three domains, iSH2, nSH2 and cSH2. The nSH2, iSH2 and cSH2 domains can interact with the five domains of the catalytic subunit to exert the effect of inhibiting catalytic activity (Zhang et al., Mol Cell, 2011, 41(5), 567-78).

根據催化亞基的不同，又可將IA類PI3Ks分為PI3Kα、PI3Kβ、PI3Kγ、PI3Kδ 4類。在哺乳動物體內，4種催化亞基p110α、p110β、p110δ和p110分別由4個基因(PIK3CA、IK3CB、PIK3CD、PI3KCG)進行編碼。調節亞基可與膜上的受體結合，募集PI3K至細胞膜附近並調節p110亞基的催化活性。調節亞基p85α(及其剪接變體p55α和p50α)、p85β和p55γ3個基因(PIK3R1、PIK3R2、PIK3R3)分別編碼。這些脂質激酶可以合成第二信使的形式參與下游信號活化及細胞功能調控。例如合成膜錨定的PIP3，PIP3與細胞內含有PH結構域的信號蛋白AKT和PDK1(phosphoinositide dependent kinase-1)結合，促使PDK1磷酸化AKT蛋白的Ser308導致AKT活化。活化的AKT藉由磷酸化多種酶、激酶和轉錄因子等下游因子，進而調節細胞的功能(Yuan等人，Oncogene，2008，27(41)，5497-5510)。 According to the different catalytic subunits, class IA PI3Ks can be further divided into four categories: PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ. In mammals, the four catalytic subunits p110α, p110β, p110δ and p110 are encoded by four genes (PIK3CA, IK3CB, PIK3CD, PI3KCG), respectively. The regulatory subunit can bind to receptors on the membrane, recruit PI3K to the vicinity of the cell membrane and modulate the catalytic activity of the p110 subunit. The regulatory subunit p85α (and its splice variants p55α and p50α), p85β and p55γ 3 genes (PIK3R1, PIK3R2, PIK3R3) are encoded respectively. These lipid kinases can participate in downstream signal activation and cell function regulation in the form of synthetic second messengers. For example, synthetic membrane-anchored PIP3 binds to the PH domain-containing signaling proteins AKT and PDK1 (phosphoinositide dependent kinase-1) in cells, prompting PDK1 to phosphorylate Ser308 of AKT protein, leading to AKT activation. Activated AKT regulates cellular functions by phosphorylating downstream factors such as various enzymes, kinases and transcription factors (Yuan et al., Oncogene, 2008, 27(41), 5497-5510).

目前針對I型PI3K的科學研究最多，對其瞭解也更加透徹。相比之下關於第II類和第III類PI3K功能的資訊相對較少。II類PI3K包括PI3K-C2α、PI3K-C2β、a-dPI3K-C2γ。PI3K-C2α和PI3K-C2γ是PIP3最具特徵性的兩種異構體，它們似乎有助於PIP3的囊泡生成，但由於缺乏選擇性抑制劑，很難對它們進行研究。III類PI3K包括Vps15和Vps34兩個成員，它們藉由PIP3的產生參與囊泡運輸、TLR信號轉導和自噬(Margaria等人，Biomolecules，2019，9(3),104)。PI3K通路受磷酸酶的嚴格調控，特別是磷酸酯酶與張力蛋白同源物(Phosphatase and tensin homolog，PTEN)，它是主要的內源性PI3K抑制劑，可以使PIP3去磷酸化形成PIP2，從而關閉PI3K的啟動(Carracedo等人，Oncogene，2008，27，5527-5541.；Worby等人，Annu Rev Biochem，2004，83，641-669；Worby等人，Pharmacol Ther，2004，156，59-68)。PTEN是一種腫瘤抑制因子，缺失常見於肺癌等癌症中，但目前已被認為是炎症和細胞增殖的重要調節因子。含有Src同源2結構域的肌醇59-磷酸酶(SHIP)也抑制PI3K信號轉導，主要存在於造血細胞，包括巨噬細胞(Backers等人，Adv Enzyme Regul，2003，43，15-28)。 At present, the scientific research on type I PI3K is the most, and the understanding of it is also more thorough. In contrast, relatively little information is available on the functions of class II and class III PI3Ks. Class II PI3Ks include PI3K-C2α, PI3K-C2β, a-dPI3K-C2γ. PI3K-C2α and PI3K-C2γ, the two most well-characterized isoforms of PIP3, appear to contribute to PIP3 vesicle production, but they are difficult to study due to the lack of selective inhibitors. Class III PI3Ks include two members, Vps15 and Vps34, which are involved in vesicular trafficking, TLR signaling and autophagy through the production of PIP3 (Margaria et al., Biomolecules, 2019, 9(3), 104). The PI3K pathway is tightly regulated by phosphatases, especially the phosphatase and tensin homolog (PTEN), which is the main endogenous PI3K inhibitor and can dephosphorylate PIP3 to form PIP2, thereby Turn off PI3K initiation (Carracedo et al., Oncogene, 2008, 27, 5527-5541.; Worby et al., Annu Rev Biochem, 2004, 83, 641-669; Worby et al., Pharmacol Ther, 2004, 156, 59-68 ). PTEN is a tumor suppressor, Deletions are common in cancers such as lung cancer, but are now recognized as important regulators of inflammation and cell proliferation. Src homology 2 domain-containing inositol 59-phosphatase (SHIP) also inhibits PI3K signaling, mainly in hematopoietic cells, including macrophages (Backers et al, Adv Enzyme Regul, 2003, 43, 15-28 ).

在IA類PI3K的四種亞型中，PI3Kα和β在許多組織中廣泛表達，並控制細胞增殖等基本過程，在胚胎上任何一種異構體的基因缺失都是致命的(Vanhaesebroeck等人，Blood，2005，106，1432-1440)。相比之下，PI3Kγ和δ在細胞分佈更受限，主要表達於白細胞之中並介導炎症反應，其基因缺失的小鼠不僅存活，而且炎症反應降低(Hannigan等人，Proc Natl Acad Sci U S A，2002，99，3603-3608；Hirsch等人，Science，2000，287，1049-1053；Yum等人，J Immunol，2001，167，6601-6608)。 Of the four isoforms of class IA PI3Ks, PI3Kα and β are widely expressed in many tissues and control fundamental processes such as cell proliferation, and genetic deletion of either isoform is lethal in embryos (Vanhaesebroeck et al., Blood , 2005, 106, 1432-1440). In contrast, PI3Kγ and δ have a more restricted cellular distribution, are mainly expressed in leukocytes and mediate inflammatory responses, and mice lacking their genes not only survive but also have reduced inflammatory responses (Hannigan et al., Proc Natl Acad Sci U S A , 2002, 99, 3603-3608; Hirsch et al, Science, 2000, 287, 1049-1053; Yum et al, J Immunol, 2001, 167, 6601-6608).

PI3K/AKT/mTOR通路在腫瘤的發生發展中起著至關重要的作用，臨床腫瘤患者中PI3K和PTEN具有較高的突變比例，可以以PI3K為靶點進行腫瘤類藥物開發。以往研究表明PI3Kδ和PI3Kγ是治療血液病的潛在靶點，Idelalisib的開發取得了顯著的成功，該藥物在治療慢性淋巴細胞白血病和非霍奇金淋巴瘤方面顯示出顯著的療效，現已獲准臨床使用(Furman等人，N Engl J Med，2014，370，997-1007；Miller等人，Clin Cancer Res，2015，21，1525-1529)。除了靶向PI3K途徑直接抑制腫瘤細胞生長外，PI3K抑制劑還可用於提高抗腫瘤免疫反應。在包括黑色素瘤、胸腺瘤、肺癌、乳腺癌和胰腺癌在內的一系列小鼠癌症模型中，抑制PI3Kδ可減弱Treg功能和腫瘤浸潤，同時使細胞毒性T細胞反應相對未受損害，從而增強抗腫瘤免疫力(Doisne等人，Cell Rep，2015，10，702-710)。在黑色素瘤、肺癌、胰腺癌和乳腺癌模型中，使用PI3Kγ抑制劑TG100-115和AS605240均可以減少腫瘤的生長和轉移。PI3Kγ信號是髓系細胞在生長因子和趨化因子的作用下，藉由整合素α4β1介導的黏附向腫瘤微環境募集所必需的。因此，抑制p110γ信號在減少全身腫瘤相關炎症和血管生成方面是有效的，而不影響髓系細胞的全身性數量(Schmid等人，Cancer Cell，2011，19，715-727)。 The PI3K/AKT/mTOR pathway plays a crucial role in the occurrence and development of tumors. PI3K and PTEN have a high mutation rate in clinical tumor patients, and PI3K can be used as a target for tumor drug development. Previous studies have shown that PI3Kδ and PI3Kγ are potential targets for the treatment of blood diseases. The development of Idelalisib has achieved remarkable success. The drug has shown remarkable efficacy in the treatment of chronic lymphocytic leukemia and non-Hodgkin lymphoma, and has now been approved for clinical use. used (Furman et al, N Engl J Med, 2014, 370, 997-1007; Miller et al, Clin Cancer Res, 2015, 21, 1525-1529). In addition to directly inhibiting tumor cell growth by targeting the PI3K pathway, PI3K inhibitors can also be used to enhance anti-tumor immune responses. In a range of mouse cancer models including melanoma, thymoma, lung, breast and pancreatic cancer, inhibition of PI3Kδ attenuated Treg function and tumor infiltration, while leaving cytotoxic T cell responses relatively unimpaired, thereby enhancing Antitumor immunity (Doisne et al, Cell Rep, 2015, 10, 702-710). The use of the PI3Kγ inhibitors TG100-115 and AS605240 both reduced tumor growth and metastasis in melanoma, lung, pancreatic and breast cancer models. PI3Kγ signaling is essential for myeloid cell growth Necessary for recruitment to the tumor microenvironment by integrin α4β1-mediated adhesion under the action of cytokines and chemokines. Thus, inhibition of p110γ signaling is effective in reducing systemic tumor-associated inflammation and angiogenesis without affecting systemic numbers of myeloid cells (Schmid et al., Cancer Cell, 2011, 19, 715-727).

此外越來越多的證據表明，PI3K藉由啟動炎症、皮質類固醇抵抗和細胞衰老等因素在包括類風濕性關節炎、過敏、哮喘、慢性阻塞性肺病(chronic obstructive pulmonary disease，COPD)和多發性硬化多種疾病中發揮關鍵作用(Marwick等人，Ther Adv Respir Dis，2010，4，19-34；Hirsch等人，Pharmacol Ther，2008，118，192-205；Marone等人，Biochim Biophys Acta，2008，1784，159-185；Rommel等人，Nat Rev Immunol，2007，7，191-201；Ruckle等人，Nat Rev Drug Discov，2006，5，903-91)。在其中尤其以包含哮喘和COPD的研究更為引人關注。全球哮喘防治創議對哮喘的定義為一種由多種細胞和細胞組分參與的氣道慢性炎症性疾病。慢性炎症與引起反復發作的喘鳴、呼吸急促、胸悶和咳嗽的氣道反應性有關。這些發作通常與肺內廣泛但不一的氣流阻塞有關，這種氣流阻塞常常自行緩解或經治療緩解。哮喘是兒童當中最常見的慢性疾病，並且也影響到數百萬成年人。而COPD則被定義為一種常見的可預防和治療的疾病，以持續性呼吸系統症狀和氣流受限為特徵，其通常由顯著暴露於有害顆粒或氣體引起的氣道和/或肺泡異常導致的。COPD的長期氣流受限特徵是由小氣道疾病(如阻塞性毛細支氣管炎)和肺實質破壞(肺氣腫)混合導致的，這兩種因素的相對促進作用因人而異。慢性炎症可引起結構改變、小氣道狹窄及肺實質破壞。小氣道丟失可促進氣流受限和黏液纖毛功能障礙，而後者是該病的特徵性表現。隨著疾病的發展，COPD患者可能會變得易於頻繁惡化，導致患者焦慮、健康狀況惡化、肺功能衰退並且死亡率增加。目前關於哮喘和COPD的一線療法包含長效β激動劑、長效毒蕈鹼拮抗劑和吸入皮質類固醇等。然而，這些藥物減少與疾病相關聯的症狀及惡化而不是靶向其分子和細胞基礎。因此，仍需進一步改進治療措施。 In addition, there is increasing evidence that PI3K is involved in rheumatoid arthritis, allergy, asthma, chronic obstructive pulmonary disease (COPD) and multiple Cirrhosis plays a key role in a variety of diseases (Marwick et al, Ther Adv Respir Dis, 2010, 4, 19-34; Hirsch et al, Pharmacol Ther, 2008, 118, 192-205; Marone et al, Biochim Biophys Acta, 2008, 1784, 159-185; Rommel et al, Nat Rev Immunol, 2007, 7, 191-201; Ruckle et al, Nat Rev Drug Discov, 2006, 5, 903-91). Among them, studies involving asthma and COPD are particularly interesting. Asthma is defined by the Global Initiative for Asthma as a chronic inflammatory disease of the airways involving a variety of cells and cellular components. Chronic inflammation is associated with airway responsiveness that causes recurrent episodes of wheezing, shortness of breath, chest tightness, and coughing. These episodes are usually associated with widespread but variable airflow obstruction in the lungs, which often resolves spontaneously or with treatment. Asthma is the most common chronic disease among children and also affects millions of adults. COPD is defined as a common preventable and treatable disease characterized by persistent respiratory symptoms and airflow limitation, usually caused by airway and/or alveolar abnormalities caused by significant exposure to noxious particles or gases. The chronic airflow limitation characteristic of COPD is caused by a mixture of small airway disease (eg, obstructive bronchiolitis) and lung parenchyma destruction (emphysema), the relative contribution of which varies from person to person. Chronic inflammation can cause structural changes, narrowing of the small airways, and destruction of the lung parenchyma. Small airway loss promotes airflow limitation and mucociliary dysfunction, which are characteristic features of the disease. As the disease progresses, patients with COPD may become prone to frequent exacerbations, leading to patient anxiety, health worsening, lung function declines, and mortality increases. Current first-line therapies for asthma and COPD include long-acting beta agonists, long-acting muscarinic antagonists, and inhaled corticosteroids. However, these drugs reduce symptoms and exacerbations associated with the disease rather than targeting its molecular and cellular basis. Therefore, further improvement of therapeutic measures is still required.

研究表明，非選擇性PI3K抑制劑LY294002吸入給藥可抑制致敏小鼠對變應原的過敏性炎症反應，降低嗜酸性粒細胞、Th2細胞因子和氣道高反應性(AHR)(Duan等人，2005，5，495-502)。對調節亞單位p85的顯性-負性抑制劑也得到了類似的結果，表明IA類PI3K參與其中，並可能決定從Th1細胞因子到Th2細胞因子的轉換(Myou等人，J Exp Med，2003，198，1573-1582)。更具體地說，PI3Kδ在IgE受體交聯後的肥大細胞脫顆粒中起關鍵作用，這種作用可被PI3Kδ選擇性抑制劑IC87114阻斷(Ali等人，J Immunol，2008，180，2538-2544；Kim等人，Trends Immunol，2008，29，493-501)。在哮喘小鼠模型中，氣管內給藥IC87114可抑制過敏反應、Th2細胞因子和AHR(Lee等人，2006a)。在煙麯黴的小鼠過敏性炎症模型中，PI3Kδ抑制劑抑制過敏反應，這一作用是藉由抑制內質網應激介導的，內質網應激在哮喘中增加，並導致NF-kB啟動(Lee等人，Thorax，2016，71：52-63)。PI3K還可能在增加犬氣道平滑肌的收縮性(Halayko等人，Am J Respir Cell Mol Biol，2004，31，266-275)和促進氣道平滑肌的增殖(如TGF-b等生長因子)方面發揮作用(Goldsmith等人，Am J Respir Cell Mol Biol，2006，34，247-254)。PI3K啟動在COPD中也很重要，COPD患者外周肺和巨噬細胞中以p-Akt表示的總PI3K活性顯著增加，並且PI3Kδ亞型的表達增加(Marwick等人，Am J Respir Crit Care Med，2009，179，542-548；To等人，Am J Respir Crit Care Med，2010，182，897-904)。在體外氧化應激增加外周血單核細胞和肺泡巨噬細胞中的p-Akt，這可以被PI3Kδ抑制劑阻止，但不能被PI3Kγ抑制劑阻止(Marwick等人，J Allergy Clin Immunol，2010，125，1146-1153)。PI3Kγ基因敲除小鼠表現出中性粒細胞遷移和啟動減少，T淋巴細胞和巨噬細胞功能受損(Medina-Tato等人，Immunology，2007，121，448-461)。此外，研究還表明PI3Kγ是介導趨化因子滴注後中性粒細胞重新聚集到肺中的關鍵信號通路(Thomas等人，Eur J Immunol，2015，35，1283-1291)。 Studies have shown that inhalation administration of the nonselective PI3K inhibitor LY294002 inhibits allergic inflammatory responses to allergens in sensitized mice and reduces eosinophils, Th2 cytokines, and airway hyperresponsiveness (AHR) (Duan et al. , 2005, 5, 495-502). Similar results were obtained for dominant-negative inhibitors of the regulatory subunit p85, suggesting that class IA PI3Ks are involved and may determine the switch from Th1 to Th2 cytokines (Myou et al., J Exp Med, 2003 , 198, 1573-1582). More specifically, PI3Kδ plays a key role in mast cell degranulation following IgE receptor cross-linking, which can be blocked by the PI3Kδ selective inhibitor IC87114 (Ali et al., J Immunol, 2008, 180, 2538- 2544; Kim et al, Trends Immunol, 2008, 29, 493-501). Intratracheal administration of IC87114 inhibits allergic responses, Th2 cytokines and AHR in a mouse model of asthma (Lee et al., 2006a). In a murine model of allergic inflammation in Aspergillus fumigatus, PI3Kδ inhibitors inhibit allergic responses, an effect mediated by inhibition of endoplasmic reticulum stress, which is increased in asthma and leads to NF-kB Initiation (Lee et al. Thorax, 2016, 71:52-63). PI3K may also play a role in increasing contractility of canine airway smooth muscle (Halayko et al., Am J Respir Cell Mol Biol, 2004, 31, 266-275) and in promoting the proliferation of airway smooth muscle (growth factors such as TGF-b) ( Goldsmith et al, Am J Respir Cell Mol Biol, 2006, 34, 247-254). PI3K priming is also important in COPD, with significantly increased total PI3K activity expressed as p-Akt in peripheral lung and macrophages of COPD patients, and increased expression of PI3Kδ isoforms (Marwick et al., Am J Respir Crit Care Med, 2009 , 179, 542-548; To et al, Am J Respir Crit Care Med, 2010, 182, 897-904). Oxidative stress increases peripherally in vitro p-Akt in blood monocytes and alveolar macrophages, which can be blocked by PI3Kδ but not PI3Kγ inhibitors (Marwick et al, J Allergy Clin Immunol, 2010, 125, 1146-1153). PI3Kγ knockout mice exhibit reduced neutrophil migration and priming, and impaired T lymphocyte and macrophage function (Medina-Tato et al., Immunology, 2007, 121, 448-461). In addition, studies have also shown that PI3Kγ is a key signaling pathway mediating neutrophil re-aggregation into the lung after chemokine instillation (Thomas et al., Eur J Immunol, 2015, 35, 1283-1291).

PI3Kδ還參與氧化應激後的糖皮質激素抵抗，這是藉由降低組蛋白脫乙醯化酶-2(HDAC2)介導的，PI3Kδ抑制劑可能藉由增加HDAC2的表達來逆轉COPD患者的糖皮質激素抵抗。用IC87114抑制PI3Kδ可以逆轉小鼠對香煙煙霧暴露的皮質類固醇抗藥性(To等人，Am J Respir Crit Care Med，2010，182，897-904)，並且PI3Kδ失活的小鼠在香煙煙霧暴露後不會產生皮質類固醇抗藥性，而PI3Kγ失活的動物正常發展為對皮質類固醇的抗藥性炎症(Marwick等人，Am J Respir Crit Care Med，2009，179，542-548)。COPD中PI3K的啟動也啟動了mTOR，藉由p70核糖體S6激酶(S6-kinase，S6K)的磷酸化來衡量，這在COPD患者肺組織和外周血單核細胞中有所增加(Mitani等人，Am J Respir Crit Care Med，2015，193，143-153)。S6K不僅能降低HDAC2，還能啟動JNK，增加c-jun，啟動AP-1，從而導致皮質激素抵抗。PI3K啟動還藉由啟動mTOR推動COPD肺中的細胞衰老和加速衰老，mTOR在加速衰老中發揮關鍵作用(Johnson等人，Nature，2013，493，338-345)。這會導致COPD患者肺部中關鍵的抗衰老分子sirtuin-1減少(Rajendrasozhan等人，Am J Respir Crit Care Med，2008，177，861-870)。同樣的PI3K-mTOR通路也可能導致與COPD相關的併發症，如缺血性心臟病、2型糖尿病、骨質疏鬆症、慢性腎臟疾病和癡呆(Barnes等人，Eur Respir J，2015，45，790-806)。 PI3Kδ is also involved in glucocorticoid resistance after oxidative stress, which is mediated by reducing histone deacetylase-2 (HDAC2), and PI3Kδ inhibitors may reverse glucose in COPD patients by increasing HDAC2 expression. Corticosteroid resistance. Inhibition of PI3Kδ with IC87114 reverses corticosteroid resistance in mice to cigarette smoke exposure (To et al., Am J Respir Crit Care Med, 2010, 182, 897-904), and PI3Kδ-inactivated mice after cigarette smoke exposure Corticosteroid resistance does not develop, whereas animals with PI3Kγ inactivation normally develop corticosteroid-resistant inflammation (Marwick et al., Am J Respir Crit Care Med, 2009, 179, 542-548). PI3K activation in COPD also initiates mTOR, as measured by phosphorylation of p70 ribosomal S6 kinase (S6-kinase, S6K), which is increased in COPD patient lung tissue and peripheral blood mononuclear cells (Mitani et al. , Am J Respir Crit Care Med, 2015, 193, 143-153). S6K not only reduces HDAC2, but also activates JNK, increases c-jun, and activates AP-1, resulting in corticosteroid resistance. PI3K priming also drives cellular senescence and accelerated senescence in COPD lungs by initiating mTOR, which plays a key role in accelerated senescence (Johnson et al., Nature, 2013, 493, 338-345). This leads to a decrease in the key anti-aging molecule sirtuin-1 in the lungs of COPD patients (Rajendrasozhan et al., Am J Respir Crit Care Med, 2008, 177, 861-870). The same PI3K-mTOR pathway may also contribute to COPD-related complications such as ischemic cardiac Heart disease, type 2 diabetes, osteoporosis, chronic kidney disease and dementia (Barnes et al, Eur Respir J, 2015, 45, 790-806).

PI3K參與哮喘和COPD所潛在的各種細胞過程的科學證據來源於抑制劑研究及基因靶向方法。在一些COPD患者中對諸如皮質類固醇的常規療法的抗性已被歸因於PI3K δ/γ途徑的上調。另外，PI3Kδ/γ的雙重抑制強烈地涉及氣道及其它自身免疫性疾病的過敏及非過敏性炎症作為干預策略。因此，針對PI3Kδ/γ信號傳導的抑制提供了一種旨在對抗免疫炎性反應的新手段。由於PI3Kδ和γ在介導諸如白細胞遷移和啟動以及肥大細胞脫粒的炎性細胞功能中發揮關鍵性作用，因此阻斷這些同種型同樣也可以是治療類風濕性關節炎的有效策略。鑒於這些同種型在免疫監控中確立的關鍵性，預期特異性地靶向δ和γ同種型的抑制劑將削弱在氣道炎症和類風濕性關節炎中所遇到的免疫應答的進展(William等人，Chemistry&Biology，17：123-134，2010；和Thompson等人，Chemistry&Biology，17：101-102，2010)。 Scientific evidence for the involvement of PI3K in various cellular processes underlying asthma and COPD comes from inhibitor studies and gene targeting approaches. Resistance to conventional therapies such as corticosteroids in some COPD patients has been attributed to upregulation of the PI3K delta/gamma pathway. In addition, dual inhibition of PI3Kδ/γ is strongly implicated in allergic and non-allergic inflammation of the airways and other autoimmune diseases as an intervention strategy. Thus, targeting the inhibition of PI3Kδ/γ signaling provides a new approach aimed at combating immune inflammatory responses. Since PI3Kδ and γ play critical roles in mediating inflammatory cell functions such as leukocyte migration and priming and mast cell degranulation, blocking these isoforms may also be an effective strategy for the treatment of rheumatoid arthritis. Given the established criticality of these isoforms in immune surveillance, inhibitors that specifically target the delta and gamma isoforms are expected to impair the progression of the immune response encountered in airway inflammation and rheumatoid arthritis (William et al. Human, Chemistry & Biology, 17: 123-134, 2010; and Thompson et al., Chemistry & Biology, 17: 101-102, 2010).

PI3K通路抑制劑在治療嚴重哮喘和慢性阻塞性肺疾病方面具有極大的潛力，因此有必要開發出新穎的PI3Kδ和PI3Kγ的雙重抑制劑，為呼吸系統疾病患者提供更多的臨床用藥選擇。 PI3K pathway inhibitors have great potential in the treatment of severe asthma and chronic obstructive pulmonary disease, so it is necessary to develop novel dual inhibitors of PI3Kδ and PI3Kγ to provide more clinical drug options for patients with respiratory diseases.

本發明人經過潛心研究，設計合成了一系列雜環化合物，其顯示出抑制磷脂醯肌醇3-激酶δ(PI3Kδ)和磷脂醯肌醇3-激酶γ(PI3Kγ)的雙重活性，可以被開發為治療和/或預防與PI3Kδ和PI3Kγ的活性相關的疾病的藥物，包括治療和/或預防呼吸系統疾病，如哮喘、慢性阻塞性肺病、支氣管炎、肺氣腫，特別是哮喘和慢性阻塞性肺病。 After intensive research, the inventors designed and synthesized a series of heterocyclic compounds, which show dual activities of inhibiting phosphatidylinositol 3-kinase delta (PI3Kδ) and phosphatidylinositol 3-kinase gamma (PI3Kγ), and can be developed Medications for the treatment and/or prevention of diseases associated with the activity of PI3Kδ and PI3Kγ, including Treatment and/or prevention of respiratory diseases such as asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, especially asthma and chronic obstructive pulmonary disease.

因此，本發明的目的是提供一種通式(I)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽： Therefore, the object of the present invention is to provide a compound represented by the general formula (I) or its meso, racemate, enantiomer, diastereomer, or its mixture form, or its Medicinal salts:

其中， in,

X為O、S或NH； X is O, S or NH;

Y為N或CH； Y is N or CH;

A¹、A²、A³、A⁴和A⁵各自獨立地選自N或CH； A ¹ , A ² , A ³ , A ⁴ and A ⁵ are each independently selected from N or CH;

R¹各自獨立地選自氫、鹵素、胺基、硝基、氰基、羥基、巰基、側氧基、烷基、烷氧基、環烷基、雜環基、芳基、雜芳基、-C(O)R^a、-O(O)CR^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aR^b、-NR^aC(O)R^b、-S(O)_pR^a、-S(O)_pNR^aR^b、-NR^aS(O)_pNR^aR^b和-NR^aS(O)_pR^b，其中該烷基、烷氧基、環烷基、雜環基、芳基或雜芳基任選進一步被選自鹵素、胺基、硝基、氰基、側氧基、羥基、巰基、羧基、酯基、烷基、鹵烷基、烷氧基、鹵烷氧基、烯基、炔基、環烷基、雜環基、芳基和雜芳基的一個或多個基團取代；或者， R ¹ are each independently selected from hydrogen, halogen, amine, nitro, cyano, hydroxyl, mercapto, pendant oxy, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R ^a , -O(O)CR ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -NR ^a R ^b , -NR ^a C(O)R ^b , -S(O) _p R ^a , -S(O) _p NR ^a R ^b , -NR ^a S(O) _p NR ^a R ^b and -NR ^a S(O) _p R ^b , wherein the alkyl, alkane Oxy, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally further selected from halogen, amine, nitro, cyano, pendant oxy, hydroxyl, mercapto, carboxyl, ester, alkyl, One or more group substitutions of haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; or,

任意相鄰的兩個R¹與其連接的原子一起形成環烷基、雜環基、芳基或雜芳基，較佳雜芳基，更佳5或6員雜芳基，該環烷基、雜環基、芳基或雜芳基任選進一步被選自鹵素、胺基、硝基、氰基、側氧基、羥基、巰基、羧基、酯基、烷基、鹵烷基、烷氧基、鹵烷氧基、烯基、炔基、環烷基、雜環基、芳基和雜芳基的一個或多個基團取代； Any adjacent two R ¹ together with the atoms to which they are attached form a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, preferably a heteroaryl group, more preferably a 5- or 6-membered heteroaryl group, the cycloalkyl group, Heterocyclyl, aryl or heteroaryl optionally further selected from halogen, amine, nitro, cyano, pendant oxy, hydroxy, mercapto, carboxyl, ester, alkyl, haloalkyl, alkoxy , one or more group substitutions of haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R²選自氫、鹵素、烷基、烷氧基、鹵烷基或鹵烷氧基； R is selected from ^hydrogen , halogen, alkyl, alkoxy, haloalkyl or haloalkoxy;

R³選自-C(O)R^a、-C(O)NR^aR^b、-S(O)_pNR^aR^b、-S(O)_pR^a、-P(O)(R^a)₂、-S(NR^a)(O)R^b、-NR^aS(O)_pR^b-、-NR^aS(O)_pNR^aR^b、鹵素、環烷基、雜環基、芳基和雜芳基，其中該環烷基、雜環基、芳基或雜芳基任選進一步被選自鹵素、胺基、硝基、氰基、羥基、巰基、羧基、酯基、側氧基、烷基、鹵烷基、烷氧基、鹵烷氧基、烯基、炔基、環烷基、雜環基、芳基、雜芳基的一個或多個基團取代； R ³ is selected from -C(O)R ^a , -C(O)NR ^a R ^b , -S(O) _p NR ^a R ^b , -S(O) _p R ^a , -P(O)(R ^a ) ₂ , -S(NR ^a )(O)R ^b , -NR ^a S(O) _p R ^b -, -NR ^a S(O) _p NR ^a R ^b , halogen, cycloalkyl, heterocyclyl, Aryl and heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further selected from halogen, amine, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, pendant One or more group substitutions of oxy, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

R⁴選自烷基或環烷基，其中該烷基或環烷基任選進一步被選自鹵素、烷基、鹵烷基、烷氧基、鹵烷氧基、環烷基或雜環基的一個或多個基團取代； ^R4 is selected from alkyl or cycloalkyl, wherein the alkyl or cycloalkyl is optionally further selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl or heterocyclyl substituted with one or more groups;

R⁵選自氫、鹵素、烷基、烷氧基、鹵烷基或鹵烷氧基； R ⁵ is selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl or haloalkoxy;

R⁶選自氫、鹵素、烷基或鹵烷基； R ⁶ is selected from hydrogen, halogen, alkyl or haloalkyl;

R^a和R^b各自獨立地選自氫、鹵素、羥基、烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基，其中該烷基、烯基、炔基、環烷基、雜環基、芳基或雜芳基任選進一步被選自鹵素、胺基、硝基、氰基、羥基、巰基、羧基、酯基、側氧基、烷基、烷氧基、烯基、炔基、環烷基、雜環基、芳基、雜芳基的一個或多個基團取代；或者， R ^a and R ^b are each independently selected from hydrogen, halogen, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl , cycloalkyl, heterocyclyl, aryl or heteroaryl optionally further selected from halogen, amine, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, pendant oxy, alkyl, alkoxy substituted with one or more groups of alkenyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; or,

R^a和R^b與他們連接的氮原子一起形成含氮雜環基或含氮雜芳基，該含氮雜環基或含氮雜芳基任選進一步被選自鹵素、胺基、硝基、氰基、側氧基、羥基、巰基、羧基、酯基、烷基、烷氧基、鹵烷基、鹵烷氧基、烯基、炔基、環烷基、雜環基、芳基和雜芳基的一個或多個基團取代； R ^a and R ^b together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclyl or nitrogen-containing heteroaryl group optionally further selected from halogen, amine, nitro , cyano, pendant oxy, hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and One or more group substitutions of heteroaryl;

n為0、1、2或3； n is 0, 1, 2 or 3;

p為0、1或2。 p is 0, 1 or 2.

在一個較佳的實施方案中，根據本發明所述的通式(I)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其前藥、或其可藥用鹽，其為通式(II)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其前藥、或其可藥用鹽， In a preferred embodiment, the compound represented by the general formula (I) according to the present invention or its meso, racemate, enantiomer, diastereomer, or Its mixture form, or its prodrug, or its pharmaceutically acceptable salt, it is the compound represented by general formula (II) or its meso, racemate, enantiomer, diastereomer body, or a mixture thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof,

其中， in,

X為O或S； X is O or S;

A¹-A⁵、R¹、R²、R³、R⁴、R⁵、R⁶和n如通式(I)所定義。 A ¹ -A ⁵ , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and n are as defined in general formula (I).

在另一個較佳的實施方案中，根據本發明所述的通式(I)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽， In another preferred embodiment, the compound represented by the general formula (I) according to the present invention or its mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

其中， in,

A¹、A²、A³、A⁴和A⁵中最多有兩個為N，其餘為CH； At most two of A ¹ , A ² , A ³ , A ⁴ and A ⁵ are N, and the rest are CH;

較佳地，A¹、A²、A³、A⁴和A⁵中一個或兩個為N，其餘為CH； Preferably, one or two of A ¹ , A ² , A ³ , A ⁴ and A ⁵ are N, and the rest are CH;

更佳，A¹、A²、A³、A⁴和A⁵之一為N，其餘為CH。 More preferably, one of A ¹ , A ² , A ³ , A ⁴ and A ⁵ is N and the rest are CH.

在另一個較佳的實施方案中，根據本發明所述的通式(I)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽，其為通式(III)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽， In another preferred embodiment, the compound represented by the general formula (I) according to the present invention or its mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is the compound represented by the general formula (III) or its meso, racemate, enantiomer, diastereomer, or a mixture thereof, or its pharmaceutically acceptable salt,

其中， in,

X為O或S； X is O or S;

A¹、A²、A³、A⁴中最多有兩個為N，其餘為CH； At most two of A ¹ , A ² , A ³ and A ⁴ are N, and the rest are CH;

R¹、R²、R³、R⁴、R⁵和R⁶如通式(I)所定義。 R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined in general formula (I).

在另一個較佳的實施方案中，根據本發明所述的通式(I)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽，其為通式(IV)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽， In another preferred embodiment, the compound represented by the general formula (I) according to the present invention or its mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is the compound represented by the general formula (IV) or its meso, racemate, enantiomer, diastereomer, or its in the form of a mixture, or a pharmaceutically acceptable salt thereof,

其中， in,

較佳地，A¹、A²、A³、A⁴中一個或兩個為N，其餘為CH； Preferably, one or two of A ¹ , A ² , A ³ and A ⁴ are N, and the rest are CH;

更佳，A¹、A²、A³、A⁴之一為N，其餘為CH； More preferably, one of A ¹ , A ² , A ³ and A ⁴ is N, and the rest are CH;

其中，R¹、R²、R³、R⁴、R⁵和R⁶如通式(I)所定義。 wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined in the general formula (I).

在另一個較佳的實施方案中，根據本發明所述的通式(I)、(II)、(III)或(IV)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽， In another preferred embodiment, the compound represented by the general formula (I), (II), (III) or (IV) according to the present invention or its mesoform, racemate, para enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,

其中， in,

A¹為N，且A²、A³、A⁴為CH；或者， A ¹ is N, and A ² , A ³ , and A ⁴ are CH; or,

A²為N，且A¹、A³、A⁴為CH；或者， A ² is N, and A ¹ , A ³ , and A ⁴ are CH; or,

A⁴為N，且A¹、A²、A³為CH；或者， A ⁴ is N, and A ¹ , A ² , and A ³ are CH; or,

A¹和A³為N，且A²和A⁴為CH；或者， A ¹ and A ³ are N, and A ² and A ⁴ are CH; or,

A¹和A²為N，且A³和A⁴為CH。 A ¹ and A ² are N, and A ³ and A ⁴ are CH.

其中，條件是當A¹為N，A²、A³、A⁴為CH，且R¹選自

，R⁴選自

或

時，R³不是甲磺醯基、

或

。 wherein, the condition is that when A ¹ is N, A ² , A ³ , and A ⁴ are CH, and R ¹ is selected from

, R ⁴ is selected from

or

, R ³ is not methanesulfonyl,

or

.

在另一個較佳的實施方案中，根據本發明所述的通式(I)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽，其為通式(V)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽， In another preferred embodiment, the compound represented by the general formula (I) according to the present invention or its mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (V) or its meso, racemate, enantiomer, diastereomer, or its in the form of a mixture, or a pharmaceutically acceptable salt thereof,

(V)

其中，R¹、R²、R³、R⁴、R⁵和R⁶如請求項1所定義。 Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined in claim 1 .

在另一個較佳的實施方案中，根據本發明所述的通式(I)、(II)、(III)、(IV)或(V)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽， In another preferred embodiment, the compound represented by the general formula (I), (II), (III), (IV) or (V) according to the present invention or its meso, racemic Rotors, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,

其中， in,

R⁴選自C₁-C₆烷基，該C₁-C₆烷基任選進一步被選自C₃-C₁₀環烷基或3至10員雜環基的一個或多個基團所取代；較佳被選自C₃-C₈環烷基或3至8員雜環基的一個或多個基團所取代；進一步較佳被環丙基取代。 R ⁴ is selected from C ₁ -C ₆ alkyl, which is optionally further represented by _one or more groups selected from C ₃ -C ₁₀ cycloalkyl or 3 to ₁₀ membered heterocyclyl Substituted; preferably substituted by one or more groups selected from C3 _- C8 cycloalkyl or 3- to ₈ -membered heterocyclyl; further preferably substituted by cyclopropyl.

其中， in,

R¹選自鹵素、C₁-C₆烷基、C₁-C₆烷氧基、C₃-C₁₀環烷基、3至10員雜環基、C₆-C₁₀芳基、5至10員雜芳基、-NR^aR^b、-NR^aC(O)R^b和-NR^aS(O)_pR^b，其中該C₁-C₆烷基、C₁-C₆烷氧基、C₃-C₁₀環烷基、3至10員雜環基、C₆-C₁₀芳基、5至10員雜芳基任選進一步被選自鹵素、胺基、硝基、氰基、側氧基、羥基、巰基、羧基、酯基、烷基、鹵烷基、烷氧基、鹵烷氧基、烯基、炔基、環烷基、雜環基、芳基和雜芳基的一個或多個基團取代； R ¹ is selected from halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₁₀ cycloalkyl, 3- to 10-membered heterocyclyl, C ₆ -C ₁₀ aryl, 5 to 10-membered heteroaryl, -NR ^a R ^b , -NR ^a C(O) R ^b and -NR ^a S(O) _p R ^b , wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy group, C ₃ -C ₁₀ cycloalkyl, 3- to 10-membered heterocyclyl, C ₆ -C ₁₀ -membered aryl, 5- to 10-membered heteroaryl optionally further selected from halogen, amine, nitro, cyano , pendant oxy, hydroxyl, mercapto, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl substituted with one or more groups;

R^a和R^b各自獨立地選自氫、C₁-C₆烷基、C₃-C₁₀環烷基、3至10員雜環基、C₆-C₁₀芳基和5至10員雜芳基，其中該C₁-C₆烷基、C₃-C₁₀環烷基、3至10員雜環基、C₆-C₁₀芳基和5至10員雜芳基任選進一步被選自鹵素、胺基、硝基、氰基、羥基、巰基、羧基、酯基、側氧基、烷基、烷氧基、烯基、炔基、環烷基、雜環基、芳基、雜芳基的一個或多個基團取代；該C₃-C₁₀環烷基、3至10員雜環基、C₆-C₁₀芳基和5至10員雜芳基較佳C₃-C₈環烷基、3至6員雜環基、苯基和5至6員雜芳基；或者， R ^a and R ^b are each independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 3- to 10-membered heterocyclyl, C ₆ -C ₁₀ -membered aryl, and 5- to 10-membered heterocyclyl Aryl, wherein the C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 3 to 10 membered heterocyclyl, C ₆ -C ₁₀ aryl and 5 to 10 membered heteroaryl groups are optionally further selected From halogen, amine, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, pendant oxy, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, hetero One or more groups of aryl are substituted; the C ₃ -C ₁₀ cycloalkyl, 3 to 10 membered heterocyclyl, C ₆ -C ₁₀ aryl and 5 to 10 membered heteroaryl groups are preferably C ₃ -C ₈ -cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl; or,

R^a和R^b與他們連接的氮原子一起形成含5至7員，較佳5至6員氮雜環基，或5至10員，較佳5至6員含氮雜芳基，該含氮雜環基或含氮雜芳基任選進一步被選自鹵素、胺基、硝基、氰基、側氧基、羥基、巰基、羧基、酯基、烷基、烷氧基、鹵烷基、鹵烷氧基、烯基、炔基、環烷基、雜環基、芳基和雜芳基的一個或多個基團取代。 R ^a and R ^b together with the nitrogen atom to which they are attached form a 5- to 7-membered, preferably 5- to 6-membered, nitrogen-containing heterocyclyl group, or a 5- to 10-membered, preferably 5- to 6-membered, nitrogen-containing heteroaryl group, which contains The nitrogen heterocyclyl or nitrogen containing heteroaryl is optionally further selected from halogen, amine, nitro, cyano, pendant oxy, hydroxy, mercapto, carboxyl, ester, alkyl, alkoxy, haloalkyl , haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are substituted with one or more groups.

其中， in,

R¹選自3至10員雜環基，較佳5至7員單雜環基、5至7員螺雜環基或5至7員稠雜環基、C₆-C₁₀芳基、5至10員雜芳基，較佳5至6員雜芳基，更佳5員雜芳基； R ¹ is selected from a 3- to 10-membered heterocyclic group, preferably a 5- to 7-membered monoheterocyclic group, a 5- to 7-membered spiro heterocyclic group or a 5- to 7-membered fused heterocyclic group, a C ₆ -C ₁₀ aryl group, a 5- to 7-membered heterocyclic group to 10-membered heteroaryl, preferably 5- to 6-membered heteroaryl, more preferably 5-membered heteroaryl;

其中該雜環基、芳基、雜芳基任選進一步被選自鹵素、胺基、硝基、氰基、側氧基、羥基、巰基、羧基、酯基、烷基、鹵烷基、烷氧基、鹵烷氧基、烯基、炔基、環烷基、雜環基、芳基和雜芳基的一個或多個基團取代。 wherein the heterocyclyl, aryl, heteroaryl is optionally further selected from halogen, amine, nitro, cyano, pendant oxy, hydroxyl, mercapto, carboxyl, ester, alkyl, haloalkyl, alkane One or more groups of oxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are substituted.

其中， in,

R¹選自

、

、

、

、

、

。 R ¹ is selected from

,

.

在另一個較佳的實施方案中，根據本發明所述的通式(I)、(II)、(III)、(IV)或(V)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽，其中， In another preferred embodiment, the compound represented by the general formula (I), (II), (III), (IV) or (V) according to the present invention or its meso, racemic Rotors, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein,

R¹選自-NR^aR^b、-NR^aC(O)R^b和-NR^aS(O)_pR^b； R ¹ is selected from -NR ^a R ^b , -NR ^a C(O) R ^b and -NR ^a S(O) _p R ^b ;

R^a選自氫或C₁-C₆烷基； R ^a is selected from hydrogen or C ₁ -C ₆ alkyl;

R^b選自氫、C₁-C₆烷基、C₃-C₁₀環烷基較佳C₃-C₆環烷基。 R ^b is selected from hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, preferably C ₃ -C ₆ cycloalkyl.

其中， in,

R³選自-C(O)R^a、-C(O)NR^aR^b、-S(O)_pNR^aR^b、-S(O)_pR^a、-P(O)(R^a)₂、-S(NR^a)(O)R^b、-NR^aS(O)_pR^b-、鹵素、C₆-C₁₀芳基和5至10員雜芳基，其中該C₆-C₁₀芳基或5至10員雜芳基任選進一步被選自鹵素、胺基、硝基、氰基、羥基、巰基、羧基、酯基、側氧基、烷基、鹵烷基、烷氧基、鹵烷氧基、烯基、炔基、環烷基、雜環基、芳基、雜芳基的一個或多個基團取代； R ³ is selected from -C(O)R ^a , -C(O)NR ^a R ^b , -S(O) _p NR ^a R ^b , -S(O) _p R ^a , -P(O)(R ^a ) ₂ , -S(NR ^a )(O)R ^b , -NR ^a S(O) _p R ^b -, halogen, C ₆ -C ₁₀ aryl and 5- to 10-membered heteroaryl, wherein the C ₆ - C ₁₀ aryl or 5 to 10 membered heteroaryl optionally further selected from halogen, amine, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, pendant oxy, alkyl, haloalkyl, alkane One or more group substitutions of oxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

R^a和R^b各自獨立地選自氫、C₁-C₆烷基、C₃-C₆環烷基、3至8員雜環基、C₆-C₁₀芳基和5至10員雜芳基，其中該C₁-C₆烷基、C₃-C₆環烷基、3至8員雜環基、C₆-C₁₀芳基或5至10員雜芳基任選進一步被選自鹵素、胺基、硝基、氰基、羥基、巰基、羧基、酯基、側氧基、烷基、烷氧基、烯基、炔基、環烷基、雜環基、芳基、雜芳基的一個或多個基團取代；或者， R ^a and R ^b are each independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, 3- to 8-membered heterocyclyl, C ₆ -C ₁₀ -membered aryl, and 5- to 10-membered heterocyclyl Aryl, wherein the _C1 - _C6 alkyl, C3 _- _C6 cycloalkyl, 3- to 8-membered heterocyclyl, _C6 - _C10 -aryl or 5- to 10-membered heteroaryl is optionally further selected From halogen, amine, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, pendant oxy, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, hetero One or more groups of aryl groups are substituted; or,

R^a和R^b與他們連接的氮原子一起形成3至8員含氮雜環基或5至6員含氮雜芳基，該含氮雜環基或含氮雜芳基任選進一步被選自鹵素、胺基、硝基、氰基、側氧基、羥基、巰基、羧基、酯基、烷基、烷氧基、鹵烷基、鹵烷氧基、烯基、炔基、環烷基、雜環基、芳基和雜芳基的一個或多個基團取代； R ^a and R ^b together with the nitrogen atom to which they are attached form a 3- to 8-membered nitrogen-containing heterocyclic group or a 5- to 6-membered nitrogen-containing heteroaryl group, which is optionally further selected From halogen, amine, nitro, cyano, pendant oxy, hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl , heterocyclyl, aryl, and one or more group substitutions of heteroaryl;

p為1或2。 p is 1 or 2.

R³選自-S(O)_pR^a、-S(O)_pNR^aR^b、-NR^aS(O)_pR^b-、-C(O)R^a、-C(O)NR^aR^b、-P(O)(R^a)₂； R ³ is selected from -S(O) _p R ^a , -S(O) _p NR ^a R ^b , -NR ^a S(O) _p R ^b -, -C(O)R ^a , -C(O)NR ^a R ^b , -P(O)(R ^a ) ₂ ;

R^a選自氫、C₁-C₆烷基； R ^a is selected from hydrogen, C ₁ -C ₆ alkyl;

R^b選自氫、C₁-C₆烷基；或者， R ^b is selected from hydrogen, C ₁ -C ₆ alkyl; or,

R^a和R^b與他們連接的氮原子一起形成3至8員含氮雜環基，該含氮雜環基任選進一步被選自鹵素、羥基、C₁-C₆烷基、C₁-C₆烷氧基的一個或多個基團取代； R ^a and R ^b together with the nitrogen atom to which they are attached form a 3- to 8-membered nitrogen-containing heterocyclic group optionally further selected from halogen, hydroxy, C ₁ -C ₆ alkyl, C ₁ - One or more groups of C alkoxy groups are substituted _;

p為1或2。在另一個較佳的實施方案中，根據本發明所述的通式(I)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽，其為通式(VI)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽 p is 1 or 2. In another preferred embodiment, the compound represented by the general formula (I) according to the present invention or its mesomer, racemate, enantiomer, diastereomer, Or its mixture form, or its pharmaceutically acceptable salt, it is the compound represented by general formula (VI) or its meso, racemate, enantiomer, diastereomer, or its In the form of a mixture, or a pharmaceutically acceptable salt thereof

其中， in,

L選自-C(O)-、-S(O)_p-、-P(O)(R^a)-、-S(NR^a)(O)-、-NR^aS(O)_pR^b-； L is selected from -C(O)-, -S(O) _p- , -P(O)(R ^a )-, -S(NR ^a )(O)-, -NR ^a S(O) _p R ^b -;

R^b選自C₁-C₆烷基； R ^b is selected from C ₁ -C ₆ alkyl;

R⁷選自-NR^cR^d； R ⁷ is selected from -NR ^c R ^d ;

R^c和R^d各自獨立地選自氫、C₁-C₆烷基、C₃-C₆環烷基、3至8員雜環基、C₆-C₁₀芳基和5至10員雜芳基，其中該C₁-C₆烷基、C₃-C₆環烷基、3至8員雜環基、C₆-C₁₀芳基或5至10員雜芳基任選進一步被選自鹵素、胺基、硝基、氰基、羥基、巰基、羧基、酯基、側氧基、烷基、烷氧基、烯基、炔基、環烷基、雜環基、芳基、雜芳基的一個或多個基團取代；或者， R ^c and R ^d are each independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, 3- to 8-membered heterocyclyl, C ₆ -C ₁₀ -membered aryl, and 5- to 10-membered heterocyclyl Aryl, wherein the _C1 - _C6 alkyl, C3 _- _C6 cycloalkyl, 3- to 8-membered heterocyclyl, _C6 - _C10 -aryl or 5- to 10-membered heteroaryl is optionally further selected From halogen, amine, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, pendant oxy, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, hetero One or more groups of aryl groups are substituted; or,

R^c和R^d與他們連接的氮原子一起形成3至8員含氮雜環基或5至6員含氮雜芳基，該含氮雜環基或含氮雜芳基任選進一步被選自鹵素、胺基、硝基、氰基、側氧基、羥基、巰基、羧基、酯基、烷基、烷氧基、鹵烷基、鹵烷氧基、烯基、炔基、環烷基、雜環基、芳基和雜芳基的一個或多個基團取代； R ^c and R ^d together with the nitrogen atom to which they are attached form a 3- to 8-membered nitrogen-containing heterocyclic group or a 5- to 6-membered nitrogen-containing heteroaryl group, which is optionally further selected From halogen, amine, nitro, cyano, pendant oxy, hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl , heterocyclyl, aryl, and one or more group substitutions of heteroaryl;

較佳地， Preferably,

R^c和R^d各自獨立地選自氫、C₁-C₆烷基、C₃-C₆環烷基、3至8員雜環基，或者 R ^c and R ^d are each independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, 3- to 8-membered heterocyclyl, or

R^c和R^d與他們連接的氮原子一起形成3至8員含氮雜環基，該含氮雜環基任選進一步被選自鹵素、羥基、C₁-C₆烷基、C₁-C₆烷氧基、C₁-C₆鹵烷基、C₁-C₆鹵烷氧基的一個或多個基團取代； R ^c and R ^d together with the nitrogen atom to which they are attached form a 3- to 8-membered nitrogen-containing heterocyclic group optionally further selected from halogen, hydroxy, C ₁ -C ₆ alkyl, C ₁ - One or more groups of C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy are substituted;

p為1或2。 p is 1 or 2.

在另一個較佳的實施方案中，根據本發明所述的通式(I)、(II)、(III)、(IV)、(V)或(VI)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽， In another preferred embodiment, the compound represented by the general formula (I), (II), (III), (IV), (V) or (VI) according to the present invention or its meso isomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,

其中， in,

R⁷選自

、

、

、

、

，其任選進一步被選自鹵素、羥基、C₁-C₆烷基、C₁-C₆烷氧基、C₁-C₆鹵烷基、C₁-C₆鹵烷氧基的一個或多個基團取代； R ⁷ is selected from

,

, which is optionally further selected from one of halogen, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, or Multiple group substitutions;

R⁷進一步較佳

、

、

、

、

、

、

、

、

、

。 R ⁷ is further preferred

,

.

其中，R²選自氫、鹵素、C₁-C₆烷基、C₁-C₆烷氧基、C₁-C₆鹵烷基或C₁-C₆鹵烷氧基；較佳氫。 Wherein, R ² is selected from hydrogen, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl or C ₁ -C ₆ haloalkoxy; preferably hydrogen.

其中，R⁵選自氫、鹵素、C₁-C₆烷基、C₁-C₆烷氧基、C₁-C₆鹵烷基或C₁-C₆鹵烷氧基；較佳氫。 Wherein, R ⁵ is selected from hydrogen, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl or C ₁ -C ₆ haloalkoxy; preferably hydrogen.

其中，R⁶選自氫、鹵素、C₁-C₆烷基、或C₁-C₆鹵烷基；較佳C₁-C₆烷基。 Wherein, R ⁶ is selected from hydrogen, halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl; preferably C ₁ -C ₆ alkyl.

本發明的典型化合物，包括但不限於： Typical compounds of the present invention include, but are not limited to:

或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其前藥、或其可藥用鹽。

or a meso, racemate, enantiomer, diastereomer, or mixture thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

本發明進一步提供一種通式(III)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽的製備方法，其包括以下步驟： The present invention further provides a compound represented by the general formula (III) or a meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof The preparation method, it comprises the following steps:

在溶劑中，在加熱條件下，在鹼的存在下，在配體和催化劑的存在下，將化合物(Ie)與化合物(Ig)反應得到通式(III)的化合物； In a solvent, under heating conditions, in the presence of a base, in the presence of a ligand and a catalyst, the compound (Ie) is reacted with the compound (Ig) to obtain the compound of the general formula (III);

其中，該溶劑較佳為極性非質子溶劑如DMF； Wherein, the solvent is preferably a polar aprotic solvent such as DMF;

該加熱條件較佳在75℃-100℃的範圍內； The heating conditions are preferably in the range of 75°C-100°C;

該配體較佳空間位阻的三烷基膦，例如三第三丁基膦； The ligand is preferably a sterically hindered trialkylphosphine, such as tri-tert-butylphosphine;

該鹼較佳鹼金屬碳酸鹽，例如碳酸銫； The base is preferably an alkali metal carbonate, such as cesium carbonate;

該催化劑較佳過渡金屬，例如鈀； The catalyst is preferably a transition metal, such as palladium;

其中， in,

A¹-A⁴、X、R¹、R²、R³、R⁴、R⁵、R⁶如通式(III)所定義。 A ¹ -A ⁴ , X, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ are as defined in general formula (III).

本發明進一步提供一種通式(IV)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽的製備方法，其包括以下步驟： The present invention further provides a compound represented by the general formula (IV) or a meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof The preparation method, it comprises the following steps:

在溶劑中，在加熱條件下，在鹼的存在下，在配體和催化劑的存在下，將化合物(IVc)與化合物(Ig)反應得到通式(IV)的化合物； In a solvent, under heating, in the presence of a base, in the presence of a ligand and a catalyst, the compound (IVc) is reacted with the compound (Ig) to obtain the compound of the general formula (IV);

其中， in,

A¹-A⁴、R¹、R²、R³、R⁴、R⁵、R⁶如通式(IV)所定義。 A ¹ -A ⁴ , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ are as defined in general formula (IV).

本發明進一步提供一種通式(V)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽的製備方法，其包括以下步驟： The present invention further provides a compound represented by the general formula (V) or a meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof The preparation method, it comprises the following steps:

在溶劑中，在加熱條件下，在鹼的存在下，在配體和催化劑的存在下，將化合物(Vc)與化合物(Ig)反應得到通式(V)的化合物； In a solvent, under heating, in the presence of a base, in the presence of a ligand and a catalyst, the compound (Vc) is reacted with the compound (Ig) to obtain the compound of the general formula (V);

其中， in,

R¹、R²、R³、R⁴、R⁵、R⁶如通式(V)所定義。 R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ are as defined in general formula (V).

本發明進一步提供一種通式(VI)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽的製備方法，其包括以下步驟： The present invention further provides a compound represented by general formula (VI) or a meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof The preparation method, it comprises the following steps:

在溶劑中，在加熱條件下，在鹼的存在下，在配體和催化劑的存在下，將化合物(VIc)與化合物(VIg)反應得到通式(VI)的化合物； In a solvent, under heating conditions, in the presence of a base, in the presence of a ligand and a catalyst, the compound (VIc) is reacted with the compound (VIg) to obtain the compound of the general formula (VI);

其中， in,

R²、R⁵、R⁶、R⁷如通式(VI)所定義。 R ² , R ⁵ , R ⁶ , R ⁷ are as defined in general formula (VI).

本發明還涉及一種醫藥組成物，其包含根據本發明所述的通式(I)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其前藥、或其可藥用鹽和藥學上可接受的佐劑、稀釋劑或載體。 The present invention also relates to a pharmaceutical composition comprising the compound represented by the general formula (I) according to the present invention or its meso, racemate, enantiomer and diastereomer , or a mixture thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier.

本發明進一步涉及根據本發明所述的通式(I)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其前藥、或其可藥用鹽或含有其的醫藥組成物在製備磷脂醯肌醇3-激酶δ(PI3Kδ)和磷脂醯肌醇3-激酶γ(PI3Kγ)雙重抑制劑中的用途。 The present invention further relates to the compound represented by the general formula (I) according to the present invention or its meso, racemate, enantiomer, diastereomer, or a mixture thereof, or its prodrug, Use of a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same in the preparation of a dual inhibitor of phosphatidylinositol 3-kinase delta (PI3Kdelta) and phosphatidylinositol 3-kinase gamma (PI3Kgamma).

本發明還涉及根據本發明所述的通式(I)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其前藥、或其可藥用鹽或含有其的醫藥組成物在製備預防和/或治療與PI3Kδ和PI3Kγ的活性相關的疾病的藥物中的用途，該疾病較佳呼吸系統疾病，例如哮喘、慢性阻塞性肺病、支氣管炎、肺氣腫，較佳哮喘和慢性阻塞性肺病。 The present invention also relates to the compound represented by the general formula (I) according to the present invention or its meso, racemate, enantiomer, diastereomer, or a mixture thereof, or Use of its prodrug, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing it in the preparation of a medicament for preventing and/or treating a disease related to the activity of PI3Kδ and PI3Kγ, the disease is preferably a respiratory system disease, such as asthma, Chronic obstructive pulmonary disease, bronchitis, emphysema, preferably asthma and chronic obstructive pulmonary disease.

本發明還涉及一種醫藥組成物，其包含根據本發明所述的通式(I)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其前藥、或其可藥用鹽與另一種活性劑的組合，該另一種活性劑選自糖皮質激素受體激動劑(甾體性或非甾體性)、選擇性β2腎上腺素受體激動劑、抗毒蕈鹼劑、p38拮抗劑、黃嘌呤衍生物、和PDE4拮抗劑。 The present invention also relates to a pharmaceutical composition comprising the compound represented by the general formula (I) according to the present invention or its meso, racemate, enantiomer and diastereomer , or a mixture thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, in combination with another active agent selected from the group consisting of glucocorticoid receptor agonists (steroidal or non-steroidal), Selective beta2-adrenoceptor agonists, antimuscarinics, p38 antagonists, xanthine derivatives, and PDE4 antagonists.

本發明還涉及根據本發明所述的通式(I)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其前藥、或其可藥用鹽或含有其的醫藥組成物與另一種活性劑同時、分開或相繼使用在製備用於預防和/或治療PI3Kδ和PI3Kγ的活性相關的疾病的藥物中的用途；該疾病較佳呼吸系統疾病，例如哮喘、慢性阻塞性肺病、支氣管炎、肺氣腫，較佳哮喘和慢性阻塞性肺病；其中該另一種活性劑選自糖皮質激素受體激動劑(甾體性或非甾體性)、選擇性β2腎上腺素受體激動劑、抗毒蕈鹼劑、p38拮抗劑、黃嘌呤衍生物、和PDE4拮抗劑。 The present invention also relates to the compound represented by the general formula (I) according to the present invention or its meso, racemate, enantiomer, diastereomer, or a mixture thereof, or Use of a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, and another active agent simultaneously, separately or sequentially in the manufacture of a medicament for the prevention and/or treatment of a disease associated with the activity of PI3Kδ and PI3Kγ The disease is preferably a respiratory disease, such as asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, preferably asthma and chronic obstructive pulmonary disease; wherein the other active agent is selected from glucocorticoid receptor agonists (steroidal (steroidal or nonsteroidal), selective beta2-adrenergic agonists, antimuscarinics, p38 antagonists, xanthine derivatives, and PDE4 antagonists.

本發明還涉及根據本發明所述的通式(I)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其前藥、或其可藥用鹽或含有其的醫藥組成物，其用作磷脂醯肌醇3-激酶δ(PI3Kδ)和磷脂醯肌醇3-激酶γ(PI3Kγ)雙重抑制劑。 The present invention also relates to the compound represented by the general formula (I) according to the present invention or its meso, racemate, enantiomer, diastereomer, or a mixture thereof, or its prodrug, or A pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same, which is used as a dual inhibitor of phosphatidylinositol 3-kinase delta (PI3Kδ) and phosphatidylinositol 3-kinase gamma (PI3Kγ).

本發明還涉及根據本發明所述的通式(I)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其前藥、或其可藥用鹽或含有其的醫藥組成物，其用作藥物，該藥物用於預防和/或治療與PI3Kδ和PI3Kγ的活性相關的疾病，較佳呼吸系統疾病，例如哮喘、慢性阻塞性肺病、支氣管炎、肺氣腫，較佳哮喘和慢性阻塞性肺病。 The present invention also relates to the compound represented by the general formula (I) according to the present invention or its meso, racemate, enantiomer, diastereomer, or a mixture thereof, or A prodrug thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same, for use as a medicament for the prevention and/or treatment of diseases associated with the activity of PI3Kδ and PI3Kγ, preferably respiratory diseases such as asthma , chronic obstructive pulmonary disease, bronchitis, emphysema, preferably asthma and chronic obstructive pulmonary disease.

本發明還涉及根據本發明所述的通式(I)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其前藥、或其可藥用鹽或含有其的醫藥組成物，其用於與另一種活性劑同時、分開或相繼使用以預防和/或治療與PI3Kδ和PI3Kγ的活性相關的疾病，較佳呼吸系統疾病，例如哮喘、慢性阻塞性肺病、支氣管炎和肺氣腫，較佳哮喘和慢性阻塞性肺病，該另一種活性劑選自糖皮質激素受體激動劑(甾體性或非甾體性)、選擇性β2腎上腺素受體激動劑、抗毒蕈鹼劑、p38拮抗劑、黃嘌呤衍生物、和PDE4拮抗劑。 The present invention also relates to the compound represented by the general formula (I) according to the present invention or its meso, racemate, enantiomer, diastereomer, or a mixture thereof, or A prodrug thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same, for simultaneous, separate or sequential use with another active agent to prevent and/or treat diseases associated with the activity of PI3Kδ and PI3Kγ, preferably Respiratory diseases such as asthma, chronic obstructive pulmonary disease, bronchitis and emphysema, preferably asthma and chronic obstructive pulmonary disease, the other active agent is selected from glucocorticoid receptor agonists (steroidal or non-steroidal sex), selective beta2-adrenoceptor agonists, antimuscarinics, p38 antagonists, xanthine derivatives, and PDE4 antagonists.

本發明還涉及一種抑制磷脂醯肌醇3-激酶δ(PI3Kδ)和磷脂醯肌醇3-激酶γ(PI3Kγ)的方法，其包括向有需要的受試者施用抑制有效量的根據本發明所述的通式(I)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其前藥、或其可藥用鹽或含有其的醫藥組成物。 The present invention also relates to a method of inhibiting phosphatidylinositol 3-kinase delta (PI3Kdelta) and phosphatidylinositol 3-kinase gamma (PI3Kγ), comprising administering to a subject in need thereof an inhibitory effective amount of a compound according to the invention The compound represented by the general formula (I) or its meso, racemate, enantiomer, diastereomer, or its mixture form, or its prodrug, or its medicament Use salts or pharmaceutical compositions containing them.

本發明還涉及一種預防和/或治療與PI3Kδ和PI3Kγ的活性相關的疾病，較佳呼吸系統疾病，例如哮喘、慢性阻塞性肺病、支氣管炎、肺氣腫，較佳哮喘和慢性阻塞性肺病的方法，其包括向有需要的受試者施用預防或治療有效量的根據本發明所述的通式(I)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其前藥、或其可藥用鹽或含有其的醫藥組成物。 The present invention also relates to a prevention and/or treatment of diseases associated with the activity of PI3Kδ and PI3Kγ, preferably respiratory diseases such as asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, preferably asthma and chronic obstructive pulmonary disease A method comprising administering to a subject in need a prophylactically or therapeutically effective amount of the compound represented by the general formula (I) according to the present invention or its meso, racemate, enantiomer A isomer, a diastereomer, or a mixture thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.

本發明還涉及一種預防和/或治療與PI3Kδ和PI3Kγ的活性相關的疾病，較佳呼吸系統疾病，例如哮喘、慢性阻塞性肺病、支氣管炎、肺氣腫，較佳哮喘和慢性阻塞性肺病的方法，其包括向有需要的受試者同時、分開或相繼施用預防或治療有效量的根據本發明所述的通式(I)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其前藥、或其可藥用鹽或含有其的醫藥組成物以及另外一種活性劑，該另一種活性劑選自糖皮質激素受體激動劑(甾體性或非甾體性)、選擇性β2腎上腺素受體激動劑、抗毒蕈鹼劑、p38拮抗劑、黃嘌呤衍生物、和PDE4拮抗劑。 The present invention also relates to a prevention and/or treatment of diseases associated with the activity of PI3Kδ and PI3Kγ, preferably respiratory diseases such as asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, preferably asthma and chronic obstructive pulmonary disease A method comprising the simultaneous, separate or sequential administration to a subject in need of a prophylactically or therapeutically effective amount of the compound represented by the general formula (I) according to the present invention or its meso, racemate, Enantiomers, diastereomers, or mixtures thereof, or prodrugs thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them, and another active agent selected from sugars Corticosteroid receptor agonists (steroidal or non-steroidal), selective beta2 adrenergic receptor agonists, antimuscarinics, p38 antagonists, xanthine derivatives, and PDE4 antagonists.

按照本發明所屬領域的常規方法，本發明通式(I)所示的化合物可以與鹼或者酸生成藥學上可接受的鹼式加成鹽或酸式加成鹽。該鹼包括無機鹼和有機鹼，可接受的有機鹼包括二乙醇胺、乙醇胺、N-甲基葡糖胺、三乙醇胺、胺丁三醇等，可接受的無機鹼包括氫氧化鋁、氫氧化鈣、氫氧化鉀、碳酸鈉和氫氧化鈉等。該酸包括無機酸和有機酸，可接受的無機酸包括鹽酸、硫酸、硝酸、磷酸、氫溴酸等。可接受的有機酸包括乙酸、三氟乙酸、甲酸、抗環血酸等。 According to the conventional method in the field of the present invention, the compound represented by the general formula (I) of the present invention can form a pharmaceutically acceptable base addition salt or acid addition salt with a base or an acid. The base includes inorganic bases and organic bases. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, etc. Acceptable inorganic bases include aluminum hydroxide and calcium hydroxide. , potassium hydroxide, sodium carbonate and sodium hydroxide, etc. The acids include inorganic and organic acids, and acceptable inorganic acids include hydrochloric, sulfuric, nitric, phosphoric, hydrobromic, and the like. Acceptable organic acids include acetic acid, trifluoroacetic acid, formic acid, ascorbic acid, and the like.

含活性成分的醫藥組成物可以是適用於口服的形式，例如片劑、糖錠劑、錠劑、水或油混懸液、可分散粉末或顆粒、乳液、硬或軟膠囊，或糖漿劑或酏劑。可按照本領域任何已知製備藥用組成物的方法製備口服組成物，此類組成物可含有一種或多種選自以下的成分：甜味劑、矯味劑、著色劑和防腐劑，以提供悅目和可口的藥用製劑。片劑含有活性成分和用於混合的適宜製備片劑的無毒的可藥用的賦形劑。這些賦形劑可以是惰性賦形劑，如碳酸鈣、碳酸鈉、乳糖、磷酸鈣或磷酸鈉；造粒劑和崩解劑，例如微晶纖維素、交聯羧甲基纖維素鈉、玉米澱粉或藻酸；黏合劑，例如澱粉、明膠、聚乙烯吡咯烷酮或***膠；和潤滑劑，例如硬脂酸鎂、硬脂酸或滑石粉。這些片劑可以不包衣或可藉由掩蓋藥物的味道或在胃腸道中延遲崩解和吸收，因而在較長時間內提供緩釋作用的已知技術將其包衣。例如，可使用水溶性味道掩蔽物質，例如羥丙基甲基纖維素或羥丙基纖維素，或延長時間物質例如乙基纖維素、醋酸丁酸纖維素。 Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral administration, such as tablets, dragees, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Elixirs. Oral compositions may be prepared according to any method known in the art for the preparation of pharmaceutical compositions, such compositions may contain one or more ingredients selected from the group consisting of sweetening, flavoring, coloring, and preservative agents to provide an aesthetically pleasing and delicious medicinal preparations. Tablets contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients may be inert excipients such as calcium carbonate, sodium carbonate, Lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as microcrystalline cellulose, croscarmellose sodium, corn starch or alginic acid; binding agents, such as starch, gelatin, polyvinylpyrrolidone or acacia gums; and lubricants such as magnesium stearate, stearic acid, or talc. These tablets may be uncoated or they may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained release over an extended period of time. For example, water soluble taste masking materials such as hydroxypropyl methylcellulose or hydroxypropyl cellulose, or time prolonging materials such as ethyl cellulose, cellulose acetate butyrate can be used.

也可用其中活性成分與惰性固體稀釋劑例如碳酸鈣、磷酸鈣或高嶺土混合的硬明膠膠囊，或其中活性成分與水溶性載體例如聚乙二醇或油溶媒例如花生油、液體石蠟或橄欖油混合的軟明膠膠囊提供口服製劑。 Hard gelatin capsules are also available wherein the active ingredient is in admixture with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or in which the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oil vehicle such as peanut oil, liquid paraffin or olive oil. Soft gelatin capsules provide an oral preparation.

水混懸液含有活性物質和用於混合的適宜製備水混懸液的賦形劑。此類賦形劑是懸浮劑，例如羧基甲基纖維素鈉、甲基纖維素、羥丙基甲基纖維素、藻酸鈉、聚乙烯吡咯烷酮和***膠；分散劑或濕潤劑，可以是天然產生的磷脂例如卵磷脂，或烯化氧與脂肪酸的縮合產物，例如聚氧乙烯硬脂酸酯，或環氧乙烷與長鏈脂肪醇的縮合產物，例如十七碳亞乙基氧基鯨蠟醇(heptadecaethyleneoxy cetanol)，或環氧乙烷與由脂肪酸和己糖醇衍生的部分酯的縮合產物，例如聚環氧乙烷山梨醇單油酸酯，或環氧乙烷與由脂肪酸和己糖醇酐衍生的偏酯的縮合產物，例如聚環氧乙烷脫水山梨醇單油酸酯。水混懸液也可以含有一種或多種防腐劑例如尼泊金乙酯或尼泊金正丙酯、一種或多種著色劑、一種或多種矯味劑和一種或多種甜味劑，例如蔗糖、糖精或阿司帕坦。 Aqueous suspensions contain the active substances in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone and acacia; dispersing or wetting agents, which may be natural The resulting phospholipids such as lecithin, or the condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate, or the condensation products of ethylene oxide with long-chain fatty alcohols, such as heptadecaethyleneoxycetyl Heptadecaethyleneoxy cetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols, such as polyethylene oxide sorbitan monooleate, or ethylene oxide with fatty acids and hexitols Condensation products of anhydride-derived partial esters, such as polyethylene oxide sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propyl paraben, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or Spartan.

油混懸液可藉由使活性成分懸浮於植物油如花生油、橄欖油、芝麻油或椰子油，或礦物油例如液體石蠟中配製而成。油混懸液可含有增稠劑，例如蜂蠟、硬石蠟或鯨蠟醇。可加入上述的甜味劑和矯味劑，以提供可口的製劑。可藉由加入抗氧化劑例如丁羥茴醚或α-生育酚保存這些組成物。 Oily suspensions can be formulated by suspending the active ingredient in vegetable oils such as peanut oil, olive oil, sesame oil or coconut oil, or mineral oils such as liquid paraffin. The oily suspensions may contain thickening agents such as Such as beeswax, hard paraffin or cetyl alcohol. The aforementioned sweetening and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants such as butylated hydroxyanisole or alpha-tocopherol.

藉由加入水，適用於製備水混懸液的可分散粉末和顆粒可以提供活性成分和用於混合的分散劑或濕潤劑、懸浮劑或一種或多種防腐劑。適宜的分散劑或濕潤劑和懸浮劑如上所述。也可加入其他賦形劑例如甜味劑、矯味劑和著色劑。藉由加入抗氧化劑例如抗壞血酸保存這些組成物。 Dispersible powders and granules suitable for preparation of an aqueous suspension may provide the active ingredient with a dispersing or wetting agent, suspending agent or one or more preservatives for mixing by the addition of water. Suitable dispersing or wetting agents and suspending agents are those mentioned above. Other excipients such as sweetening, flavouring and colouring agents may also be added. These compositions are preserved by adding antioxidants such as ascorbic acid.

本發明的醫藥組成物也可以是水包油乳劑的形式。油相可以是植物油例如橄欖油或花生油，或礦物油例如液體石蠟或其混合物。適宜的乳化劑可以是天然產生的磷脂，例如大豆卵磷脂，和由脂肪酸和己糖醇酐衍生的酯或偏酯，例如山梨坦單油酸酯，和該偏酯和環氧乙烷的縮合產物，例如聚環氧乙烷山梨醇單油酸酯。乳劑也可以含有甜味劑、矯味劑、防腐劑和抗氧劑。可用甜味劑例如甘油、丙二醇、山梨醇或蔗糖配製的糖漿和酏劑。此類製劑也可含有緩和劑、防腐劑、著色劑和抗氧劑。 The pharmaceutical compositions of the present invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil such as olive or peanut oil, or a mineral oil such as liquid paraffin or mixtures thereof. Suitable emulsifiers may be naturally occurring phospholipids, such as soybean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of such partial esters and ethylene oxide , such as polyethylene oxide sorbitan monooleate. The emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Syrups and elixirs can be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, or sucrose. Such formulations may also contain a demulcent, a preservative, a coloring agent and an antioxidant.

本發明的醫藥組成物可以是無菌注射水溶液形式。可以使用的可接受的溶媒和溶劑有水、林格氏液和等滲氯化鈉溶液。無菌注射製劑可以是其中活性成分溶於油相的無菌注射水包油微乳。例如將活性成分溶於大豆油和卵磷脂的混合物中。然後將油溶液加入水和甘油的混合物中處理形成微乳。可藉由局部大量注射，將注射液或微乳注入患者的血流中。或者，最好按可保持本發明化合物恆定迴圈濃度的方式給予溶液和微乳。為保持這種恆定濃度，可使用連續靜脈內遞藥裝置。 The pharmaceutical compositions of the present invention may be in the form of sterile injectable aqueous solutions. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oily phase. For example, the active ingredient is dissolved in a mixture of soybean oil and lecithin. The oil solution is then processed into a mixture of water and glycerol to form a microemulsion. The injection solution or microemulsion can be injected into the bloodstream of the patient by local bolus injection. Alternatively, solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of the compound of the present invention. To maintain this constant concentration, a continuous intravenous drug delivery device can be used.

本發明的醫藥組成物可以是用於肌內和皮下給藥的無菌注射水或油混懸液的形式。可按已知技術，用上述那些適宜的分散劑或濕潤劑和懸浮劑配製該混懸液。無菌注射製劑也可以是在無毒腸胃外可接受的稀釋劑或溶劑中製備的無菌注射溶液或混懸液，例如在1,3-丁二醇中製備的溶液。此外，可方便地用無菌固定油作為溶劑或懸浮介質。為此目的，可使用包括合成甘油單或二酯在內的任何調和固定油。此外，脂肪酸例如油酸也可以製備注射劑。 The pharmaceutical compositions of the present invention may be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration. These may be according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above The suspension is formulated. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. In addition, sterile fixed oils are conveniently employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can also be used in the preparation of injectables.

可按用於直腸給藥的栓劑形式給予本發明化合物。可藉由將藥物與在普通溫度下為固體但在直腸中為液體，因而在直腸中會溶化而釋放藥物的適宜的無刺激性賦形劑混合來製備這些醫藥組成物。此類物質包括可哥脂、甘油明膠、氫化植物油、各種分子量的聚乙二醇和聚乙二醇的脂肪酸酯的混合物。 The compounds of the present invention may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid in the rectum and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights and mixtures of fatty acid esters of polyethylene glycols.

所屬技術領域具有通常知識者熟知，藥物的給藥劑量依賴於多種因素，包括但並非限定於以下因素：所用特定化合物的活性、病人的年齡、病人的體重、病人的健康狀況、病人的行被、病人的飲食、給藥時間、給藥方式、***的速率、藥物的組合等。另外，最佳的治療方式如治療的模式、通式化合物的日用量或可藥用的鹽的種類可以根據傳統的治療方案來驗證。 It is well known to those of ordinary skill in the art that the dosage of a drug to be administered depends on a variety of factors, including but not limited to the following factors: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient. , the patient's diet, administration time, administration mode, rate of excretion, combination of drugs, etc. In addition, the optimal treatment modality such as the mode of treatment, the daily dosage of the compound of the general formula, or the type of pharmaceutically acceptable salt can be verified according to conventional treatment regimens.

本發明可以含有通式(I)所示的化合物，及其藥學上可接受的鹽、水合物或溶劑化物作為活性成分，與藥學上可接受的載體或賦型劑混合製備成組成物，並製備成臨床上可接受的劑型。本發明的衍生物可以與其他活性成分組合使用，只要它們不產生其他不利的作用，例如過敏反應等。本發明化合物可作為唯一的活性成分，也可以與其它治療與酪胺酸激酶活性相關的疾病的藥物聯合使用。聯合治療藉由將各個治療組分同時、分開或相繼給藥來實現。 The present invention can contain the compound represented by the general formula (I) and its pharmaceutically acceptable salts, hydrates or solvates as active ingredients, mixed with pharmaceutically acceptable carriers or excipients to prepare a composition, and Prepared in a clinically acceptable dosage form. The derivatives of the present invention can be used in combination with other active ingredients as long as they do not produce other adverse effects such as allergic reactions and the like. The compounds of the present invention can be used as the sole active ingredient or in combination with other drugs for the treatment of diseases associated with tyrosine kinase activity. Combination therapy is accomplished by the simultaneous, separate or sequential administration of the individual therapeutic components.

[發明的詳細說明] [Detailed description of the invention]

除非有相反陳述，在說明書和申請專利範圍中使用的術語具有下述含義。 Unless stated to the contrary, terms used in the specification and claims have the following meanings.

術語“烷基”指飽和脂肪族烴基團，其為包含1至20個碳原子的直鏈或支鏈基團，較佳含有1至12個碳原子的烷基，更佳含有1至6個碳原子的烷基。非限制性實例包括甲基、乙基、正丙基、異丙基、正丁基、異丁基、第三丁基、第二丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各種支鏈異構體等。更佳的是含有1至6個碳原子的低級烷基，非限制性實施例包括甲基、乙基、正丙基、異丙基、正丁基、異丁基、第三丁基、第二丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的，當被取代時，取代基可以在任何可使用的連接點上被取代，該取代基較佳為一個或多個以下基團，其獨立地選自烷基、烯基、炔基、烷氧基、烷硫基、烷基胺基、鹵素、巰基、羥基、硝基、氰基、環烷基、雜環烷基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基、側氧基、羧基或羧酸酯基。 The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms Alkyl of carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl , 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl- 2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1 ,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl , 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethyhexyl Methylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl , 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4 -Ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3 -Ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof, etc. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, th Dibutyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl , 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2- Dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methyl pentyl, 2,3-dimethylbutyl, etc. Alkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, the substituents are preferably one or more of the following groups independently selected from the group consisting of alkanes group, alkenyl, alkynyl, alkoxy, alkylthio, alkylamine, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, pendant oxygen group, carboxyl group or carboxylate group.

術語“烯基”指由至少由兩個碳原子和至少一個碳-碳雙鍵組成的如上定義的烷基，例如乙烯基、1-丙烯基、2-丙烯基、1-、2-或3-丁烯基等。烯基可以是取代的或非取代的，當被取代時，取代基較佳為一個或多個以下基團，其獨立地選自烷基、烯基、炔基、烷氧基、烷硫基、烷基胺基、鹵素、巰基、羥基、硝基、氰基、環烷基、雜環烷基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基。 The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3 -Butenyl, etc. Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio , alkylamine, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio.

術語“炔基”指由至少由兩個碳原子和至少一個碳-碳三鍵組成的如上定義的烷基，例如乙炔基、丙炔基、丁炔基等。炔基可以是取代的或非取代的，當被取代時，取代基較佳為一個或多個以下基團，其獨立地選自烷基、烯基、炔基、烷氧基、烷硫基、烷基胺基、鹵素、巰基、羥基、硝基、氰基、環烷基、雜環烷基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基。 The term "alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, eg, ethynyl, propynyl, butynyl, and the like. Alkynyl groups can be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio , alkylamine, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio.

術語“環烷基”指飽和或部分不飽和單環或多環環狀烴取代基，環烷基環包含3至20個碳原子，較佳包含3至12個碳原子，更佳包含3至10個碳原子，進一步較佳包含3至8個碳原子，最佳包含3至6個碳原子。單環環烷基的非限制性實例包括環丙基、環丁基、環戊基、環戊烯基、環己基、環己烯基、環己二烯基、環庚基、環庚三烯基、環辛基等；多環環烷基包括螺環、稠環和橋環的環烷基。 The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 20 carbon atoms. 10 carbon atoms, more preferably 3 to 8 carbon atoms, most preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.

術語“螺環烷基”指5至20員的單環之間共用一個碳原子(稱螺原子)的多環基團，其可以含有一個或多個雙鍵，但沒有一個環具有完全共軛的π電子系統。較佳為6至14員，更佳為7至10員。根據環與環之間共用螺原子的數目將螺環烷基分為單螺環烷基、雙螺環烷基或多螺環烷基，較佳為單螺環烷基和雙螺環烷基。更佳為4員/4員、4員/5員、4員/6員、5員/5員或5員/6員單螺環烷基。螺環烷基的非限制性實例包括： The term "spirocycloalkyl" refers to a 5- to 20-membered monocyclic polycyclic group sharing one carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings are fully conjugated π electron system. Preferably it is 6 to 14 members, more preferably 7 to 10 members. According to the sharing of spiro atoms between rings The number divides the spirocycloalkyl group into a mono-spirocycloalkyl group, a double-spirocycloalkyl group or a poly-spirocycloalkyl group, preferably a mono-spirocycloalkyl group and a double-spirocycloalkyl group. More preferably 4-member/4-member, 4-member/5-member, 4-member/6-member, 5-/5-member or 5-/6-membered monospirocycloalkyl. Non-limiting examples of spirocycloalkyl include:

術語“稠環烷基”指5至20員，系統中的每個環與體系中的其他環共用毗鄰的一對碳原子的全碳多環基團，其中一個或多個環可以含有一個或多個雙鍵，但沒有一個環具有完全共軛的π電子系統。較佳為6至14員，更佳為7至10員。根據組成環的數目可以分為雙環、三環、四環或多環稠環烷基，較佳為雙環或三環，更佳為5員/5員或5員/6員雙環烷基。稠環烷基的非限制性實例包括： The term "fused cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more Multiple double bonds, but none of the rings have a fully conjugated pi electron system. Preferably it is 6 to 14 members, more preferably 7 to 10 members. According to the number of formed rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl. Non-limiting examples of fused cycloalkyl groups include:

術語“橋環烷基”指5至20員，任意兩個環共用兩個不直接連接的碳原子的全碳多環基團，其可以含有一個或多個雙鍵，但沒有一個環具有完全共軛的π電子系統。較佳為6至14員，更佳為7至10員。根據組成環的數目可以分為雙環、三環、四環或多環橋環烷基，較佳為雙環、三環或四環，更佳為雙環或三環。橋環烷基的非限制性實例包括： The term "bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two non-directly connected carbon atoms, which may contain one or more double bonds, but none of the rings has complete Conjugated pi electron system. Preferably it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

該環烷基環可以稠合於芳基、雜芳基或雜環烷基環上，其中與母體結構連接在一起的環為環烷基，非限制性實例包括茚滿基、四氫萘基、苯并環庚烷基等。環烷基可以是任選取代的或非取代的，當被取代時，取代基較佳為一個或多個以下基團，其獨立地選自烷基、烯基、炔基、烷氧基、烷硫基、烷基胺基、鹵素、巰基、羥基、硝基、氰基、環烷基、雜環烷基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基、側氧基、羧基或羧酸酯基。 The cycloalkyl ring can be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring linked to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthyl , benzo ring Heptyl, etc. Cycloalkyl can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamine, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio, heterocycloalkylthio, pendant oxy, carboxyl or carboxylate.

術語“雜環基”指飽和或部分不飽和單環或多環環狀烴取代基，其包含3至20個環原子，其中一個或多個環原子為選自氮、氧或S(O)_m(其中m是整數0至2)的雜原子，但不包括-O-O-、-O-S-或-S-S-的環部分，其餘環原子為碳。較佳包含3至12個環原子，其中1~4個是雜原子；最佳包含3至8個環原子，其中1~3個是雜原子；最佳包含5至7個環原子，其中1~2或1~3個是雜原子。單環雜環基的非限制性實例包括吡咯烷基、咪唑烷基、四氫呋喃基、四氫噻吩基、二氫咪唑基、二氫呋喃基、二氫吡唑基、二氫吡咯基、哌啶基、哌嗪基、嗎啉基、硫嗎啉基、高哌嗪基、吡喃基等，較佳1、2、5-噁二唑基、吡喃基或嗎啉基。多環雜環基包括螺環、稠環和橋環的雜環基。 The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) _m (where m is an integer from 0 to 2) heteroatoms, excluding ring moieties of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. Preferably it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; most preferably contains 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; and most preferably contains 5 to 7 ring atoms, of which 1 ~2 or 1~3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine group, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably 1, 2, 5-oxadiazolyl, pyranyl or morpholinyl. Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.

術語“螺雜環基”指5至20員的單環之間共用一個原子(稱螺原子)的多環雜環基團，其中一個或多個環原子為選自氮、氧或S(O)_m(其中m是整數0至2)的雜原子，其餘環原子為碳。其可以含有一個或多個雙鍵，但沒有一個環具有完全共軛的π電子系統。較佳為6至14員，更佳為7至10員。根據環與環之間共用螺原子的數目將螺雜環基分為單螺雜環基、雙螺雜環基或多螺雜環基，較佳為單螺雜環基和雙螺雜環基。更佳為4員/4員、4員/5員、4員/6員、5員/5員或5員/6員單螺雜環基。螺雜環基的非限制性實例包括： The term "spiroheterocyclyl" refers to a 5- to 20-membered monocyclic polycyclic heterocyclic group sharing one atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen or S(O ) _m (where m is an integer from 0 to 2) heteroatoms and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings have a fully conjugated pi electron system. Preferably it is 6 to 14 members, more preferably 7 to 10 members. According to the number of spiro atoms shared between rings, spiroheterocyclyl groups are classified into mono-spiroheterocyclyl, bis-spiro-heterocyclyl or poly-spiro-heterocyclyl, preferably mono-spiroheterocyclyl and bis-spiro-heterocyclyl . More preferably a 4-member/4-member, 4-member/5-member, 4-member/6-member, 5-/5-member or 5-/6-membered monospiroheterocyclyl. Non-limiting examples of spiroheterocyclyl include:

術語“稠雜環基”指5至20員，系統中的每個環與體系中的其他環共用毗鄰的一對原子的多環雜環基團，一個或多個環可以含有一個或多個雙鍵，但沒有一個環具有完全共軛的π電子系統，其中一個或多個環原子為選自氮、氧或S(O)_m(其中m是整數0至2)的雜原子，其餘環原子為碳。較佳為6至14員，更佳為7至10員。根據組成環的數目可以分為雙環、三環、四環或多環稠雜環基，較佳為雙環或三環，更佳為5員/5員或5員/6員雙環稠雜環基。稠雜環基的非限制性實例包括： The term "fused heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 20 members, each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more rings may contain one or more Double bonds, but none of the rings have a fully conjugated pi-electron system, where one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) _m (where m is an integer from 0 to 2), the remaining rings Atom is carbon. Preferably it is 6 to 14 members, more preferably 7 to 10 members. According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group . Non-limiting examples of fused heterocyclyl groups include:

術語“橋雜環基”指5至14員，任意兩個環共用兩個不直接連接的原子的多環雜環基團，其可以含有一個或多個雙鍵，但沒有一個環具有完全共軛的π電子系統，其中一個或多個環原子為選自氮、氧或S(O)_m(其中m是整數0至2)的雜原子，其餘環原子為碳。較佳為6至14員，更佳為7至10員。根據組成環的數目可以分為雙環、三環、四環或多環橋雜環基，較佳為雙環、三環或四環，更佳為雙環或三環。橋雜環基的非限制性實例包括： The term "bridged heterocyclyl" refers to a 5- to 14-membered polycyclic heterocyclic group of any two rings sharing two atoms that are not directly connected, which may contain one or more double bonds, but none of the rings has a complete common A pi-electron system of a yoke in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) _m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon. Preferably it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups include:

該雜環基環可以稠合於芳基、雜芳基或環烷基環上，其中與母體結構連接在一起的環為雜環基，其非限制性實例包括： The heterocyclyl ring can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which include:

和

等。

and

Wait.

雜環基可以是任選取代的或非取代的，當被取代時，取代基較佳為一個或多個以下基團，其獨立地選自烷基、烯基、炔基、烷氧基、烷硫基、烷基胺基、鹵素、巰基、羥基、硝基、氰基、環烷基、雜環烷基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基、側氧基、羧基或羧酸酯基。 Heterocyclyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamine, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio, heterocycloalkylthio, pendant oxy, carboxyl or carboxylate.

術語“芳基”指具有共軛的π電子體系的6至14員全碳單環或稠合多環(也就是共用毗鄰碳原子對的環)基團，較佳為6至10員，例如苯基和萘基。更佳苯基。該芳基環可以稠合於雜芳基、雜環基或環烷基環上，其中與母體結構連接在一起的環為芳基環，其非限制性實例包括： The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (ie, rings sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, eg Phenyl and naphthyl. More preferably phenyl. The aryl ring can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring linked to the parent structure is an aryl ring, non-limiting examples of which include:

芳基可以是取代的或非取代的，當被取代時，取代基較佳為一個或多個以下基團，其獨立地選自烷基、烯基、炔基、烷氧基、烷硫基、烷基胺基、鹵素、巰基、羥基、硝基、氰基、環烷基、雜環烷基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基、羧基或羧酸酯基。 Aryl may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio , alkylamine, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio, carboxyl or carboxylate.

術語“雜芳基”指包含1至4個雜原子、5至14個環原子的雜芳族體系，其中雜原子選自氧、硫和氮。雜芳基較佳為5至10員，含1至3個雜原子；更佳為5員或6員，含1至2個雜原子；較佳例如咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基等，較佳為咪唑基、噻唑基、吡唑基或嘧啶基、噻唑基；更佳吡唑基或噻唑基。該雜芳基環可以稠合於芳基、雜環基或環烷基環上，其中與母體結構連接在一起的環為雜芳基環，其非限制性實例包括： The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 members, containing 1 to 3 heteroatoms; more preferably 5 or 6 members, containing 1 to 2 heteroatoms; preferably such as imidazolyl, furanyl, thiophene base, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, thiazolyl, pyrazolyl or pyrimidinyl , thiazolyl; more preferably pyrazolyl or thiazolyl. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring linked to the parent structure is a heteroaryl ring, non-limiting examples of which include:

雜芳基可以是任選取代的或非取代的，當被取代時，取代基較佳為一個或多個以下基團，其獨立地選自烷基、烯基、炔基、烷氧基、烷硫基、烷基胺基、鹵素、巰基、羥基、硝基、氰基、環烷基、雜環烷基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基、羧基或羧酸酯基。 Heteroaryl groups can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamine, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio, heterocycloalkylthio, carboxyl or carboxylate.

術語“烷氧基”指-O-(烷基)和-O-(非取代的環烷基)，其中烷基的定義如上所述。烷氧基的非限制性實例包括：甲氧基、乙氧基、丙氧基、丁氧基、環丙氧基、環丁氧基、環戊氧基、環己氧基。烷氧基可以是任選取代的或非取代的，當被取代時，取代基較佳為一個或多個以下基團，其獨立地選自烷基、烯基、炔基、烷氧基、烷硫基、烷基胺基、鹵素、巰基、羥基、硝基、氰基、環烷基、雜環烷基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基、羧基或羧酸酯基。 The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. Alkoxy can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamine, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio, heterocycloalkylthio, carboxyl or carboxylate.

術語“鹵烷基”指被一個或多個鹵素取代的烷基，其中烷基如上所定義。 The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

術語“鹵烷氧基”指被一個或多個鹵素取代的烷氧基，其中烷氧基如上所定義。 The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

術語“羥烷基”指被一個或多個羥基取代的烷基，其中烷基如上所定義。 The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

術語“羥基”指-OH基團。 The term "hydroxy" refers to the -OH group.

術語“鹵素”指氟、氯、溴或碘。 The term "halogen" refers to fluorine, chlorine, bromine or iodine.

術語“胺基”指-NH₂。 The term "amino" refers to _-NH2 .

術語“氰基”指-CN。 The term "cyano" refers to -CN.

術語“硝基”指-NO₂。 The term "nitro" refers to _-NO2 .

術語“側氧基”指=O。 The term "pendant oxy" refers to =0.

術語“羧基”指-C(O)OH。 The term "carboxy" refers to -C(O)OH.

術語“巰基”指-SH。 The term "thiol" refers to -SH.

術語“酯基”指-C(O)O(烷基)或-C(O)O(環烷基)，其中烷基和環烷基如上所定義。 The term "ester" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.

術語“醯基”指含有-C(O)R基團的化合物，其中R為如上定義的烷基、環烷基、雜環基、芳基、雜芳基。 The term "aryl" refers to compounds containing a -C(O)R group, wherein R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl as defined above.

術語“磺醯基”指含有-S(O)₂R基團的化合物，其中R為如上定義的烷基、環烷基、雜環基、芳基、雜芳基。 The term "sulfonyl" refers to compounds containing a -S(O ₎ 2R group, wherein R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl as defined above.

術語“亞磺醯基”指含有-S(O)R基團的化合物，其中R為如上定義的烷基、環烷基、雜環基、芳基、雜芳基。 The term "sulfinyl" refers to compounds containing a -S(O)R group, wherein R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl as defined above.

術語“磷醯基”指含有-P(O)RR’基團的化合物，其中R和R’為如上定義的烷基、環烷基、雜環基、芳基、雜芳基。 The term "phosphoryl" refers to compounds containing a -P(O)RR' group, wherein R and R' are alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, as defined above.

“任選”或“任選地”意味著隨後所描述的事件或環境可以但不必發生，該說明包括該事件或環境發生或不發生的場合。例如，“任選被烷基取代的雜環基團”意味著烷基可以但不必須存在，該說明包括雜環基團被烷基取代的情形和雜環基團不被烷基取代的情形。 "Optional" or "optionally" means that the subsequently described event or circumstance can, but need not, occur, and that the description includes instances where the event or circumstance occurs or instances where it does not. For example, "optionally substituted with alkyl "Heterocyclic group" means that an alkyl group may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with the alkyl group and the case where the heterocyclic group is not substituted with the alkyl group.

“取代的”指基團中的一個或多個氫原子，較佳為最多5個，更佳為1~3個氫原子彼此獨立地被相應數目的取代基取代。不言而喻，取代基僅處在它們的可能的化學位置，所屬技術領域具有通常知識者能夠在不付出過多努力的情況下確定(藉由實驗或理論)可能或不可能的取代。例如，具有游離氫的胺基或羥基與具有不飽和(如烯屬)鍵的碳原子結合時可能是不穩定的。 "Substituted" means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those of ordinary skill in the art can determine (either experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amine groups or hydroxyl groups with free hydrogens may be unstable when bound to carbon atoms with unsaturated (eg, olefinic) bonds.

“醫藥組成物”表示含有一種或多種本文所述化合物或其生理學上/可藥用的鹽或前體藥物與其他化學組分的混合物，以及其他組分例如生理學/可藥用的載體和賦形劑。醫藥組成物的目的是促進對生物體的給藥，利於活性成分的吸收進而發揮生物活性。 "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as a physiological/pharmaceutically acceptable carrier and excipients. The purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.

“可藥用鹽”是指本發明化合物的鹽，這類鹽用於哺乳動物體內時具有安全性和有效性，且具有應有的生物活性。 "Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention, which are safe and effective when used in mammals, and possess the desired biological activity.

[本發明化合物的合成方法] [Synthesis method of the compound of the present invention]

為了完成本發明的目的，本發明採用如下合成方案製備本發明的通式(III)化合物。 In order to accomplish the purpose of the present invention, the present invention adopts the following synthetic scheme to prepare the compound of general formula (III) of the present invention.

當R³為-NR^aR^b時： When R ³ is -NR ^a R ^b :

步驟1：在溶劑中，在加熱條件下，在鹼的存在下，在配體和催化劑的存在下，將化合物(Ia)與R¹H反應得到化合物(Ib)；該反應在促進親核芳族置換的條件下進行；該溶劑典型地為極性非質子溶劑，如1,4-二噁烷；該加熱條件典型地在80℃進行，加熱可以藉由常規或微波方式進行，並且有利地，可以使用加壓系統以使反應能夠在溶劑沸點以上運行；合適的配體如二齒三取代膦，例如xantphos；合適的鹼如鹼金屬碳酸鹽，例如碳酸銫；合適的催化劑如過渡金屬，例如鈀； Step 1: In a solvent, under heating conditions, in the presence of a base, in the presence of a ligand and a catalyst, compound (Ia) is reacted with R ¹ H to obtain compound (Ib); this reaction promotes the nucleophilic aromatic The solvent is typically a polar aprotic solvent, such as 1,4-dioxane; the heating conditions are typically performed at 80°C, the heating can be performed by conventional or microwave means, and advantageously, A pressurized system can be used to enable the reaction to run above the boiling point of the solvent; suitable ligands such as bidentate trisubstituted phosphines, eg xantphos; suitable bases such as alkali metal carbonates, eg cesium carbonate; suitable catalysts such as transition metals, eg palladium;

步驟2：在溶劑中，在加熱條件下，在鹼的存在下，在配體和催化劑的存在下，將化合物(Ib)與化合物(Ih)反應得到化合物(Ic)；該反應在化合物的鹵素被胺基基團置換的條件下進行；該溶劑典型地為極性非質子溶劑，如DMF；該加熱條件典型地在125℃，加熱可以藉由常規或微波方式進行，並且有利地可以使用加壓系統以使反應能夠在溶劑沸點以上運行；合適的配體如二齒三取代膦，例如Ruphos，合適的鹼如鹼金屬碳酸鹽，例如碳酸鈉；合適的催化劑如過渡金屬，例如鈀； Step 2: In a solvent, under heating conditions, in the presence of a base, in the presence of a ligand and a catalyst, compound (Ib) is reacted with compound (Ih) to obtain compound (Ic); this reaction is in the halogen of the compound. Under conditions of displacement by amine groups; the solvent is typically a polar aprotic solvent, such as DMF; the heating conditions are typically at 125°C, heating can be carried out by conventional or microwave means, and can advantageously use pressurized system to enable the reaction to operate above the boiling point of the solvent; suitable ligands such as bidentate trisubstituted phosphines such as Ruphos, suitable bases such as alkali metal carbonates such as sodium carbonate; suitable catalysts such as transition metals such as palladium;

步驟3：在溶劑中，在加熱條件下，在鹼的存在下，將化合物(Id)與苄硫醇反應得到化合物(Ie)；合適的溶劑如1,4-二噁烷；合適的鹼如醇鈉，例如第三丁醇鈉；該加熱條件典型地為80℃； Step 3: Compound (Id) is reacted with benzyl mercaptan to obtain compound (Ie) in a solvent under heating in the presence of a base; a suitable solvent such as 1,4-dioxane; a suitable base such as Sodium alkoxide, such as sodium tert-butoxide; the heating conditions are typically 80°C;

步驟4：在溶劑中，化合物(Ie)與磺醯氯反應得到化合物(If)；合適的溶劑可以為混合溶劑，例如含有乙酸的水和乙腈的混合物；該反應溫度可以在-5℃與環境溫度之間； Step 4: In a solvent, compound (Ie) is reacted with sulfonyl chloride to obtain compound (If); a suitable solvent can be a mixed solvent, such as a mixture of water and acetonitrile containing acetic acid; the reaction temperature can be at -5°C and ambient temperature. between temperatures

步驟5：在溶劑中，在鹼的存在下，將化合物(Ie)與化合物HNR^aR^b反應得到化合物(Ig)；合適的溶劑例如二氯甲烷；該鹼典型地為有機鹼如三乙胺或無機鹼如碳酸銫；反應溫度可以在環境溫度與40℃之間)進行； Step 5: Compound (Ie) is reacted with compound HNR ^a R ^b in a solvent in the presence of a base to obtain compound (Ig); a suitable solvent such as dichloromethane; the base is typically an organic base such as triethylamine Or inorganic bases such as cesium carbonate; the reaction temperature can be between ambient temperature and 40 ° C);

步驟6：在溶劑中，在加熱條件下，在鹼的存在下，在配體和催化劑的存在下，將化合物(Ie)與化合物(Ig)反應得到通式(III)的化合物；該反應在促進芳基溴化物活化及其與活化的雙鍵反應(Heck反應)的條件下進行；該溶劑典型地為極性非質子溶劑如DMF；該加熱條件典型地在75℃-100℃的範圍內，加熱可以藉由常規或微波方式進行，並且有利地，可以使用加壓系統以使反應能夠在溶劑沸點以上運行；合適的配體如空間位阻的三烷基膦，例如三第三丁基膦；合適的鹼如鹼金屬碳酸鹽，例如碳酸銫；合適的催化劑如過渡金屬，例如鈀； Step 6: In a solvent, under heating conditions, in the presence of a base, in the presence of a ligand and a catalyst, compound (Ie) is reacted with compound (Ig) to obtain the compound of general formula (III); the reaction is in Under conditions that promote the activation of the aryl bromide and its reaction with the activated double bond (Heck reaction); the solvent is typically a polar aprotic solvent such as DMF; the heating conditions are typically in the range of 75°C to 100°C, Heating can be carried out by conventional or microwave means, and advantageously a pressurized system can be used to enable the reaction to operate above the boiling point of the solvent; suitable ligands such as sterically hindered trialkylphosphines, eg tri-tert-butylphosphine ; suitable bases such as alkali metal carbonates, such as cesium carbonate; suitable catalysts such as transition metals, such as palladium;

其中，Hal為鹵素； Wherein, Hal is halogen;

A¹-A⁴、X、R¹、R²、R⁴、R⁵、R⁶、R^a、R^b如通式(III)中所定義。 A ¹ -A ⁴ , X, R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ^a , R ^b are as defined in general formula (III).

進一步藉由實施例來理解本發明的化合物及其製備，這些實施例說明了一些製備或使用該化合物的方法。然而，要理解的是，這些實施例不限制本發明。現在已知的或進一步開發的本發明的變化被認為落入本文中描述的和要求保護的本發明範圍之內。 The compounds of the present invention and their preparation are further understood by the examples which illustrate some methods of making or using the compounds. However, it is to be understood that these examples are not limiting this invention. Variations of the invention now known or further developed are considered to fall within the scope of the invention described and claimed herein.

本發明化合物是利用便利的起始原料和通用的製備步驟來完成製備的。本發明給出了典型的或傾向性的反應條件，諸如反應溫度、時間、溶劑、壓力、反應物的莫耳比。但是除非特殊說明，其他反應條件也能採納。優化條件可能隨著具體的反應物或溶劑的使用而改變，但在通常情況下，反應優化步驟和條件都能得到確定。 The compounds of the present invention are prepared using convenient starting materials and general preparative procedures. Typical or biased reaction conditions are given herein, such as reaction temperature, time, solvent, pressure, molar ratio of reactants. But unless otherwise specified, other reaction conditions can also be adopted. Optimal conditions may vary with the specific reactants or solvent used, but in general, reaction optimization procedures and conditions can be determined.

另外，本發明中可能用到了一些保護基團來保護某些官能團避免不必要的反應。適宜於各種官能團的保護基以及它們的保護或脫保護條件已經為所屬技術領域具有通常知識者廣泛熟知。例如T.W.Greene和G.M.Wuts的《有機製備中的保護基團》(第3版，Wiley,New York,1999和書中的引用文獻)詳細描述了大量的保護基團的保護或脫保護。 Additionally, some protecting groups may be used in the present invention to protect certain functional groups from unwanted reactions. Suitable protecting groups for various functional groups and conditions for their protection or deprotection are well known to those of ordinary skill in the art. For example, "Protecting Groups in Organic Preparation" by T.W. Greene and G.M. Wuts (3rd Edition, Wiley, New York, 1999 and citations therein) describes in detail the protection or deprotection of numerous protecting groups.

化合物和中間體的分離和純化依據具體的需求採取適當的方法和步驟，例如過濾、萃取、蒸餾、結晶、管柱層析、製備薄層板色譜、製備高效液相色譜或上述方法的混合使用。其具體使用方法可參閱本發明描述的實例。當然，其他類似的分離和純化手段也是可以採用的。可以使用常規方法(包括物理常數和波譜資料)對其進行表徵。 Separation and purification of compounds and intermediates take appropriate methods and steps according to specific needs, such as filtration, extraction, distillation, crystallization, column chromatography, preparative thin layer plate chromatography, preparative high performance liquid chromatography or a combination of the above methods. . The specific use method can refer to the examples described in the present invention. Of course, other similar separation and purification means may also be employed. It can be characterized using conventional methods including physical constants and spectral data.

化合物的結構是藉由核磁共振(NMR)或/和質譜(MS)來確定的。NMR位移以10^-6(ppm)的單位給出。NMR的測定是用Brukerdps 300型核磁儀，測定溶劑為氘代二甲基亞碸(DMSO-d ₆)、氘代氯仿(CDCl₃)、氘代甲醇(CD₃OD)，內標為四甲基矽烷(TMS)。 The structures of the compounds were determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts are given in units of ^10-6 (ppm). NMR was measured by Brukerdps 300 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO- d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), and the internal standard was tetramethyl sulfoxide. Silane (TMS).

MS的測定用LC(Waters 2695)/MS(Quattro Premier xE)質譜儀(生產商：沃特世)(Photodiode Array Detector)。 For the measurement of MS, an LC (Waters 2695)/MS (Quattro Premier xE) mass spectrometer (manufacturer: Waters) (Photodiode Array Detector) was used.

製備液相色譜法使用lc6000高效液相色譜儀(生產商：創新通恒)。色譜管柱為DaisogelC18 10μm 100A(30mm×250mm)，流動相：乙腈/水。 Preparative liquid chromatography was performed using an lc6000 high performance liquid chromatograph (manufacturer: Chuangxin Tongheng). The chromatographic column is Daisogel C18 10 μm 100A (30 mm×250 mm), mobile phase: acetonitrile/water.

薄層層析矽膠板使用青島海洋化工GF254矽膠板，薄層色譜法(TLC)使用的矽膠板採用的規格是0.20mm~0.25mm，製備薄層層析分離純化產品採用的規格是0.5mm。 The thin layer chromatography silica gel plate uses Qingdao Ocean Chemical GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.20mm~0.25mm, and the specification used for the preparation of TLC separation and purification products is 0.5mm.

管柱層析一般使用青島海洋矽膠100~200目、200~300目和300~400目矽膠為載體。 Column chromatography generally uses Qingdao marine silica gel 100~200 mesh, 200~300 mesh and 300~400 mesh silica gel as the carrier.

本發明的已知的起始原料可以採用或按照本領域已知的方法來合成，或可購買自網化商城、北京偶合、Sigma、百靈威、易世明、上海書亞、上海伊諾凱、安耐吉化學、上海畢得等公司。 The known starting materials of the present invention can be synthesized by adopting or according to methods known in the art, or can be purchased from online shopping malls, Beijing Coupling, Sigma, Bailingwei, Yi Shiming, Shanghai Shuya, Shanghai Inokay, Anaiji Chemical, Shanghai Bide and other companies.

實施例中無特殊說明，反應能夠均在氮氣氛下進行。 There is no special description in the examples, and the reactions can all be carried out under nitrogen atmosphere.

氬氣氛或氮氣氛是指反應瓶連接一個約1L容積的氬氣或氮氣氣球。 Argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.

反應溶劑，有機溶劑或惰性溶劑各自表述為使用的該溶劑在所描述的反應條件下不參與反應，包括，如苯、甲苯、乙腈、四氫呋喃(THF)、二甲基甲醯胺(DMF)、氯仿、二氯甲烷、***、甲醇、氮-甲基吡咯碄酮(NMP)、吡啶等。實施例中無特殊說明，溶液是指水溶液。 Reaction solvent, organic solvent or inert solvent are each expressed as the solvent used that does not participate in the reaction under the described reaction conditions, including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), Chloroform, dichloromethane, ether, methanol, nitrogen-methylpyrrolidone (NMP), pyridine and the like. There is no special description in the examples, and the solution refers to an aqueous solution.

本發明中所描述的化學反應一般在常壓下進行。反應溫度在-78℃至200℃之間。反應時間和條件為，例如，一個大氣壓下，-78℃至200℃之間，大約1至24小時內完成。如果反應過夜，則反應時間一般為16小時。實施例中無特殊說明，反應的溫度為室溫，為20℃~30℃。 The chemical reactions described in the present invention are generally carried out under normal pressure. The reaction temperature is between -78°C and 200°C. The reaction time and conditions are, for example, between -78°C and 200°C under one atmosphere, Complete in about 1 to 24 hours. If the reaction is overnight, the reaction time is generally 16 hours. There is no special description in the examples, and the temperature of the reaction is room temperature, which is 20°C to 30°C.

實施例中的反應進程的監測採用薄層色譜法(TLC)，反應所使用的展開劑的體系有：A：二氯甲烷和甲醇體系，B：石油醚和乙酸乙酯體系，C：丙酮，溶劑的體積比根據化合物的極性不同而進行調節。 The monitoring of the reaction progress in the embodiment adopts thin layer chromatography (TLC), and the systems of the developing solvent used in the reaction are: A: dichloromethane and methanol system, B: petroleum ether and ethyl acetate system, C: acetone, The volume ratio of the solvent is adjusted according to the polarity of the compound.

純化化合物採用的管柱層析的沖提劑的體系和薄層色譜法的展開劑體系包括：A：二氯甲烷和甲醇體系，B：石油醚和乙酸乙酯體系，溶劑的體積比根據化合物的極性不同而進行調節，也可以加入少量的三乙胺和三氟乙酸等鹼性或酸性試劑進行調節。 The eluent system of column chromatography and the developing solvent system of thin layer chromatography used to purify the compound include: A: dichloromethane and methanol system, B: petroleum ether and ethyl acetate system, the volume ratio of the solvent is based on the compound It can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and trifluoroacetic acid.

除非另行定義，文中所使用的所有專業與科學用語與本領域熟練人員所熟悉的意義相同。此外，任何與所記載內容相似或均等的方法及材料皆可應用於本發明方法中。 Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described can be used in the methods of the present invention.

縮略語 abbreviation

μL=微升 μL = microliter

μM=微莫耳 μM = micromolar

NMR=核磁共振 NMR = nuclear magnetic resonance

Boc=第三丁氧基羰基 Boc = tertiary butoxycarbonyl

br=寬峰 br=broad peak

d=雙峰 d = double peak

δ=化學位移 δ=chemical shift

℃=攝氏度 °C = Celsius

dd=雙雙峰 dd = double double peak

DIPEA=二異丙基乙基胺 DIPEA=Diisopropylethylamine

DMAP=4-二甲胺基吡啶 DMAP=4-dimethylaminopyridine

DMF=N,N-二甲基甲醯胺 DMF= N,N -dimethylformamide

DMSO=二甲亞碸 DMSO=Dimethyl sulfoxide

DCM=二氯甲烷 DCM=dichloromethane

EA=乙酸乙酯 EA=ethyl acetate

HPLC=高效液相 HPLC = high performance liquid phase

Hz=赫茲 Hz = Hertz

IC₅₀=抑制50%活性的濃度 _IC50 = concentration that inhibits 50% activity

J=偶合常數(Hz) J=coupling constant (Hz)

LC-MS=液相色譜-質普聯用 LC-MS=liquid chromatography-mass spectrometry

m=多重峰 m=multiplet

M+H⁺=母體化合物質量+一質子 M+H ⁺ = mass of parent compound + one proton

mg=毫克 mg = milligrams

mL=毫升 mL = milliliters

mmol=毫莫耳 mmol = millimoles

mol=莫耳 mol=mol

Ms=甲磺醯基 Ms=Methylsulfonyl

MS=質譜 MS = Mass Spectrometry

MsCl=甲基磺醯氯 MsCl=methylsulfonyl chloride

m/z=質荷比 m/z = mass to charge ratio

NBS=N-溴琥珀醯亞胺 NBS=N-bromosuccinimide

nM=奈莫耳 nM=namol

PE=石油醚 PE = petroleum ether

ppm=每百萬分 ppm = parts per million

Pro=保護基 Pro=protecting group

Ruphos=2-二環己基膦-2',6'-二異丙氧基-1,1'-聯苯 Ruphos=2-Dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl

s=單峰 s=single peak

t=三重峰 t = triplet

t-buxphos=甲烷磺酸(2-二第三丁基膦基-2',4',6'-三異丙基-1,1'-聯苯基)(2'-胺基-1,1'-聯苯-2-基)鈀(II) t-buxphos=methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1, 1'-biphenyl-2-yl)palladium(II)

TBS-=第三丁基二甲基矽基 TBS-= tertiary butyldimethylsilyl

TEA=三乙胺 TEA = triethylamine

TFA=三氟乙酸 TFA = trifluoroacetic acid

THF=四氫呋喃 THF=tetrahydrofuran

Xantphos=4,5-雙二苯基膦-9,9-二甲基氧雜蒽。 Xantphos=4,5-bisdiphenylphosphine-9,9-dimethylxanthene.

製備實施例1：(S)-5-溴-2-(1-環丙基乙基)-7-(甲基磺醯基)異吲哚啉-1-酮(1d)的製備 Preparation Example 1: Preparation of (S)-5-bromo-2-(1-cyclopropylethyl)-7-(methylsulfonyl)isoindolin-1-one (1d)

步驟1：4-溴-2-(溴甲基)-6-氯苯甲酸甲酯(1a)的製備。 Step 1: Preparation of methyl 4-bromo-2-(bromomethyl)-6-chlorobenzoate (1a).

於室溫，將4-溴-2-氯-6-甲基苯甲酸甲酯(2.61g,10.0mmol)、四氯化碳(20mL)、過氧苯甲醯(121mg,0.500mmol)、NBS(1.78g,10.0mmol)加到反應瓶中，升溫至85℃攪拌反應15小時。反應結束後，加100mL水，加200mL二氯甲烷萃取，有機相用水洗滌一次，無水硫酸鈉乾燥，過濾，濾液減壓濃縮，得到3.3g無色油的標題產物，直接用於下一步，收率：98%。 At room temperature, methyl 4-bromo-2-chloro-6-methylbenzoate (2.61 g, 10.0 mmol), carbon tetrachloride (20 mL), benzyl peroxide (121 mg, 0.500 mmol), NBS (1.78 g, 10.0 mmol) was added to the reaction flask, the temperature was raised to 85° C. and the reaction was stirred for 15 hours. After the reaction, 100 mL of water was added, 200 mL of dichloromethane was added for extraction, the organic phase was washed once with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 3.3 g of the title product as colorless oil, which was directly used in the next step. The yield : 98%.

LCMS：m/z 339.90[M+H]⁺。 LCMS: m/z 339.90 [M+H] ⁺ .

步驟2：(S)-5-溴-7-氯-2-(1-環丙基乙基)異吲哚啉-1-酮(1b)的製備。 Step 2: Preparation of (S)-5-bromo-7-chloro-2-(1-cyclopropylethyl)isoindolin-1-one (1b).

於室溫，將4-溴-2-(溴甲基)-6-氯苯甲酸甲酯(3.39g,10.0mmol)、(S)-1-環丙基乙胺(1.21g,10.0mmol)、硼酸(618mg,10mmol)、碳酸鉀(4.14g,30mmol)、乙腈(20mL)加到反應瓶中，20℃攪拌反應15小時。反應結束後，抽濾，濾液減壓濃縮，殘餘物藉由矽膠管柱層析色譜法(沖提劑：石油醚：乙酸乙酯=5：1)純化，得到1.10g白色固體物的標題產物，收率：35.0%。 At room temperature, methyl 4-bromo-2-(bromomethyl)-6-chlorobenzoate (3.39 g, 10.0 mmol), (S)-1-cyclopropylethylamine (1.21 g, 10.0 mmol) , boric acid (618 mg, 10 mmol), potassium carbonate (4.14 g, 30 mmol), and acetonitrile (20 mL) were added to the reaction flask, and the reaction was stirred at 20° C. for 15 hours. After the reaction was completed, suction filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 5:1) to obtain 1.10 g of the title product as a white solid , yield: 35.0%.

LCMS：m/z 314.22[M+H]⁺。 LCMS: m/z 314.22 [M+H] ⁺ .

步驟3：(S)-5-溴-2-(1-環丙基乙基)-7-(甲硫基)異吲哚啉-1-酮(1c)的製備。 Step 3: Preparation of (S)-5-bromo-2-(1-cyclopropylethyl)-7-(methylthio)isoindolin-1-one (1c).

於室溫，將(S)-5-溴-7-氯-2-(1-環丙基乙基)異吲哚啉-1-酮(1.10g,3.50mmol)、甲硫醇鈉(0.73g,10mmol)、二噁烷(20mL)加到反應瓶中，90℃攪拌反應12小時。反應結束後，抽濾，濾液減壓濃縮，殘餘物藉由矽膠管柱層析色譜法(沖提劑：石油醚：乙酸乙酯=5：1)純化，得到0.80g黃色固體物的標題產物，收率：70.0%。 At room temperature, (S)-5-bromo-7-chloro-2-(1-cyclopropylethyl)isoindolin-1-one (1.10 g, 3.50 mmol), sodium methanethiolate (0.73 g, 10 mmol) and dioxane (20 mL) were added to the reaction flask, and the reaction was stirred at 90° C. for 12 hours. After the reaction was completed, suction filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 5:1) to obtain 0.80 g of the title product as a yellow solid , yield: 70.0%.

LCMS：m/z 326.22[M+H]⁺。 LCMS: m/z 326.22 [M+H] ⁺ .

步驟4：(S)-5-溴-2-(1-環丙基乙基)-7-(甲基磺醯基)異吲哚啉-1-酮(1d)的製備。 Step 4: Preparation of (S)-5-bromo-2-(1-cyclopropylethyl)-7-(methylsulfonyl)isoindolin-1-one (1d).

於室溫，將(S)-5-溴-2-(1-環丙基乙基)-7-(甲硫基)異吲哚啉-1-酮(0.80g,2.46mmol)、間氯過氧苯甲酸(0.846g,4.92mmol)、二氯甲烷(20mL)加到反應瓶中，20℃攪拌反應12小時。反應結束後，抽濾，濾液減壓濃縮，殘餘物藉由矽膠管柱層析色譜法(沖提劑：石油醚：乙酸乙酯=1：1)純化，得到0.40g黃色固體物的標題產物，收率：45.0%。 At room temperature, (S)-5-bromo-2-(1-cyclopropylethyl)-7-(methylthio)isoindolin-1-one (0.80 g, 2.46 mmol), m-chloro Peroxybenzoic acid (0.846 g, 4.92 mmol) and dichloromethane (20 mL) were added to the reaction flask, and the reaction was stirred at 20° C. for 12 hours. After the reaction was completed, suction filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 1:1) to obtain 0.40 g of the title product as a yellow solid , yield: 45.0%.

LCMS：m/z 358.22[M+H]⁺。 LCMS: m/z 358.22 [M+H] ⁺ .

製備實施例2：1-(6-((4-甲基噻唑-2-基)胺基)吡啶-2-基)吡咯烷-2-酮(2b)的製備 Preparation Example 2: Preparation of 1-(6-((4-methylthiazol-2-yl)amino)pyridin-2-yl)pyrrolidin-2-one (2b)

步驟1：1-(6-溴吡啶-2-基)吡咯烷-2-酮(2a)的製備。 Step 1: Preparation of 1-(6-bromopyridin-2-yl)pyrrolidin-2-one (2a).

於室溫，將2,6-二溴吡啶(24.0g,100mmol)、吡咯烷-2-酮(4.25g,50.0mmol)、二噁烷(250mL)加到反應瓶中，然後加入碳酸銫(65.0g,200mmol)、Pd(OAc)₂(1.12g,5.00mmol)、Xantphos(5.78g,10.0mmol)。氮氣氛下，於80℃攪拌反應6小時。反應結束後，抽濾，濾液減壓濃縮，殘餘物藉由矽膠管柱層析色譜法(沖提劑：石油醚：乙酸乙酯=5：1)純化，得到12.0g白色固體物的標題產物，收率：50.0%。 At room temperature, 2,6-dibromopyridine (24.0 g, 100 mmol), pyrrolidin-2-one (4.25 g, 50.0 mmol), and dioxane (250 mL) were added to the reaction flask, followed by cesium carbonate ( 65.0 g, 200 mmol), Pd(OAc) ₂ (1.12 g, 5.00 mmol), Xantphos (5.78 g, 10.0 mmol). The reaction was stirred at 80°C for 6 hours under nitrogen atmosphere. After the reaction was completed, suction filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 5:1) to obtain 12.0 g of the title product as a white solid , yield: 50.0%.

LCMS：m/z 241.19[M+H]⁺。 LCMS: m/z 241.19 [M+H] ⁺ .

步驟2：1-(6-((4-甲基噻唑-2-基)胺基)吡啶-2-基)吡咯烷-2-酮(2b)的製備。 Step 2: Preparation of 1-(6-((4-methylthiazol-2-yl)amino)pyridin-2-yl)pyrrolidin-2-one (2b).

於室溫，將1-(6-溴吡啶-2-基)吡咯烷-2-酮(2.40g,10mmol)、4-甲基噻唑-2-胺(1.14g,10.0mmol)、甲苯(15.0mL)DMF(1.00mL)加到反應瓶中，然後加入碳酸銫(6.50g,20.0mmol)、Pd(OAc)₂(112mg,0.50mmol)、Xantphos(578mg,1.00mmol)，於115℃攪拌反應5小時。反應結束後，抽濾，濾液減壓濃縮，殘餘物藉由矽膠管柱層析色譜法(沖提劑：石油醚：乙酸乙酯=1：1)純化，得到1.30g白色固體物的標題產物，收率：50.0%。 At room temperature, 1-(6-bromopyridin-2-yl)pyrrolidin-2-one (2.40 g, 10 mmol), 4-methylthiazol-2-amine (1.14 g, 10.0 mmol), toluene (15.0 mL) DMF (1.00 mL) was added to the reaction flask, then cesium carbonate (6.50 g, 20.0 mmol), Pd(OAc) ₂ (112 mg, 0.50 mmol), Xantphos (578 mg, 1.00 mmol) were added, and the reaction was stirred at 115° C. 5 hours. After the reaction was completed, suction filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 1:1) to obtain 1.30 g of the title product as a white solid , yield: 50.0%.

LCMS：m/z 275.19[M+H]⁺。 LCMS: m/z 275.19 [M+H] ⁺ .

製備實施例3：1-(4-((4-甲基噻唑-2-基)胺基)吡啶-2-基)吡咯烷-2-酮(3c)的製備 Preparation Example 3: Preparation of 1-(4-((4-methylthiazol-2-yl)amino)pyridin-2-yl)pyrrolidin-2-one (3c)

步驟1：4-溴-N-(4-溴吡啶-2-基)丁醯胺(3a)的製備。 Step 1: Preparation of 4-bromo-N-(4-bromopyridin-2-yl)butanamide (3a).

於-10℃，將4-溴吡啶-2-胺(5.02g,28.9mmol)、吡啶(3.51g,43.4mmol)、乙腈(50ml)加到反應瓶中，攪拌30分鐘，緩慢滴入4-溴丁醯氯(6.50g,34.7mmol)，保持該溫度攪拌2小時，緩慢升溫至15℃，繼續攪拌反應12小時。反應結束後，減壓濃縮，得到7.22g棕色固體物的標題產物，直接用於下一步。 At -10°C, 4-bromopyridin-2-amine (5.02g, 28.9mmol), pyridine (3.51g, 43.4mmol) and acetonitrile (50ml) were added to the reaction flask, stirred for 30 minutes, and slowly added dropwise 4- Bromobutyryl chloride (6.50 g, 34.7 mmol) was kept at the same temperature and stirred for 2 hours, slowly heated to 15° C., and the stirring reaction was continued for 12 hours. After the reaction was completed, it was concentrated under reduced pressure to obtain 7.22 g of the title product as a brown solid, which was used directly in the next step.

LCMS：m/z 322.91[M+H]⁺。 LCMS: m/z 322.91 [M+H] ⁺ .

步驟2：1-(4-溴吡啶-2-基)吡咯烷-2-酮(3b)的製備。 Step 2: Preparation of 1-(4-bromopyridin-2-yl)pyrrolidin-2-one (3b).

於室溫，將4-溴-N-(4-溴吡啶-2-基)丁醯胺(7.22g,28.9mmol)、碳酸銫(10.3g,31.8mmol)、DMF(50mL)加到反應瓶中，60℃攪拌反應15小時。反應結束後，向反應液中加入乙酸乙酯和水萃取，有機層減壓濃縮，殘餘物藉由矽膠管柱層析色譜法(沖提劑：石油醚：乙酸乙酯=3：1)純化，得到3.31g黃色固體物的標題產物，收率：35.6%。 At room temperature, 4-bromo-N-(4-bromopyridin-2-yl)butanamide (7.22g, 28.9mmol), cesium carbonate (10.3g, 31.8mmol), DMF (50mL) were added to the reaction flask The reaction was stirred at 60°C for 15 hours. After the reaction, ethyl acetate and water were added to the reaction solution for extraction, the organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 3:1) , to obtain 3.31 g of the title product as a yellow solid, yield: 35.6%.

LCMS：m/z 240.99[M+H]⁺。 LCMS: m/z 240.99 [M+H] ⁺ .

步驟3：1-(4-((4-甲基噻唑-2-基)胺基)吡啶-2-基)吡咯烷-2-酮(3c)的製備。 Step 3: Preparation of 1-(4-((4-methylthiazol-2-yl)amino)pyridin-2-yl)pyrrolidin-2-one (3c).

於室溫，將1-(4-溴吡啶-2-基)吡咯烷-2-酮(1.02g,4.21mmol)、4-甲基噻唑-2-胺(479mg,4.21mmol)、甲苯(45mL)、DMF(3mL)加到反應瓶中，然後加入碳酸銫(2.73g,8.42mmol)、Pd(OAc)₂(48.4mg,0.21mmol)、Xantphos(243mg,0.42mmol)，於115℃攪拌反應5小時。反應結束後，抽濾，濾液減壓濃縮，殘餘物藉由矽膠管柱層析色譜法(沖提劑：石油醚：乙酸乙酯=1：1)純化，得到620mg黃色固體物的標題產物，收率：53.7%。 At room temperature, 1-(4-bromopyridin-2-yl)pyrrolidin-2-one (1.02 g, 4.21 mmol), 4-methylthiazol-2-amine (479 mg, 4.21 mmol), toluene (45 mL) were combined ), DMF (3mL) was added to the reaction flask, then cesium carbonate (2.73g, 8.42mmol), Pd(OAc) ₂ (48.4mg, 0.21mmol), Xantphos (243mg, 0.42mmol) were added, and the reaction was stirred at 115°C 5 hours. After the reaction was completed, suction filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 1:1) to obtain 620 mg of the title product as a yellow solid, Yield: 53.7%.

LCMS：m/z 275.09[M+H]⁺。 LCMS: m/z 275.09 [M+H] ⁺ .

製備實施例4：(S)-5-(2-胺基-4-甲基噻唑-5-基)-2-(1-環丙基乙基)-7-(甲基磺醯基)異吲哚啉-1-酮(4c)的製備 Preparation Example 4: (S)-5-(2-amino-4-methylthiazol-5-yl)-2-(1-cyclopropylethyl)-7-(methylsulfonyl)iso Preparation of indolin-1-one (4c)

步驟1：N-(4-甲基噻唑-2-基)乙醯胺(4a)的製備。 Step 1: Preparation of N-(4-methylthiazol-2-yl)acetamide (4a).

於0℃，將4-甲基噻唑-2-胺(1.02g,8.78mmol)、乙醯氯(892mg,10.6mmol)、DCM(10ml)加到反應瓶中，攪拌20分鐘，然後加入三乙胺(2.71g,26.4mmol)，攪拌1小時，緩慢升溫至15℃，攪拌反應4小時。反應結束後，減壓濃縮，殘餘物藉由矽膠管柱層析色譜法(沖提劑：二氯甲烷：甲醇=20：1)純化，得到413mg褐色固體物的標題產物，收率：30.2%。 At 0°C, 4-methylthiazol-2-amine (1.02g, 8.78mmol), acetyl chloride (892mg, 10.6mmol), DCM (10ml) were added to the reaction flask, stirred for 20 minutes, then triethyl acetate was added Amine (2.71 g, 26.4 mmol) was stirred for 1 hour, slowly heated to 15°C, and the reaction was stirred for 4 hours. After the reaction was completed, it was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane: methanol = 20:1) to obtain 413 mg of the title product as a brown solid, yield: 30.2% .

LCMS：m/z 157.04[M+H]⁺。 LCMS: m/z 157.04 [M+H] ⁺ .

步驟2：(S)-N-(5-(2-(1-環丙基乙基)-7-(甲基磺醯基)-1-側氧基)異吲哚啉-5-基)-4-甲基噻唑-2-基)乙醯胺(4b)的製備。 Step 2: (S)-N-(5-(2-(1-Cyclopropylethyl)-7-(methylsulfonyl)-1-oxy)isoindolin-5-yl) - Preparation of 4-methylthiazol-2-yl)acetamide (4b).

於室溫，將(S)-5-溴-2-(1-環丙基乙基)-7-(甲基磺醯基)異吲哚啉-1-酮(1d)(1.02g,2.86mmol)、N-(4-甲基噻唑-2-基)乙醯胺(437mg,2.86mmol)、碳酸銫(437mg,2.86mmol)、Pd(OAc)₂(64.9mg,0.29mmol)、((t-bu)₃PH)BF₄(162mg,0.57mmol)、DMF(10mL)加到反應瓶中，100℃攪拌反應2小時。反應結束後，減壓濃縮，殘餘物藉由矽膠管柱層析色譜法(沖提劑：石油醚：乙酸乙酯=2：1)純化，得到770mg黃色固體物的標題產物，收率：62.2%。 At room temperature, (S)-5-bromo-2-(1-cyclopropylethyl)-7-(methylsulfonyl)isoindolin-1-one ( 1d ) (1.02 g, 2.86 g mmol), N-(4-methylthiazol-2-yl)acetamide (437 mg, 2.86 mmol), cesium carbonate (437 mg, 2.86 mmol), Pd(OAc) ₂ (64.9 mg, 0.29 mmol), (( t-bu) ₃ PH)BF ₄ (162 mg, 0.57 mmol) and DMF (10 mL) were added to the reaction flask, and the reaction was stirred at 100° C. for 2 hours. After the reaction was completed, it was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 2:1) to obtain 770 mg of the title product as a yellow solid, yield: 62.2 %.

LCMS：m/z 434.11[M+H]⁺。 LCMS: m/z 434.11 [M+H] ⁺ .

步驟3：(S)-5-(2-胺基-4-甲基噻唑-5-基)-2-(1-環丙基乙基)-7-(甲基磺醯基)異吲哚啉-1-酮(4c)的製備。 Step 3: (S)-5-(2-Amino-4-methylthiazol-5-yl)-2-(1-cyclopropylethyl)-7-(methylsulfonyl)isoindole Preparation of olin-1-one (4c).

於室溫，將(S)-N-(5-(2-(1-環丙基乙基)-7-(甲基磺醯基)-1-側氧基)異吲哚啉-5-基)-4-甲基噻唑-2-基)乙醯胺(770mg,1.77mmol)、3M鹽酸(20ml)、乙醇(20ml)混合，於70℃攪拌反應6小時。反應結束後，減壓濃縮，殘餘物藉由矽膠管柱層析色譜法(沖提劑：石油醚：乙酸乙酯=1：1)純化，得到312mg黃色固體物的標題產物，收率：45.1%。 At room temperature, (S)-N-(5-(2-(1-cyclopropylethyl)-7-(methylsulfonyl)-1-oxy)isoindoline-5- yl)-4-methylthiazol-2-yl)acetamide (770 mg, 1.77 mmol), 3M hydrochloric acid (20 ml), and ethanol (20 ml) were mixed, and the reaction was stirred at 70° C. for 6 hours. After the reaction was completed, it was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 1:1) to obtain 312 mg of the title product as a yellow solid, yield: 45.1 %.

LCMS：m/z 392.10[M+H]⁺。 LCMS: m/z 392.10 [M+H] ⁺ .

製備實施例5：(S)-7-(氮雜環丁烷-1-基磺醯基)-5-溴-2-(1-環丙基乙基)異吲哚啉-1-酮(5c)的製備 Preparation Example 5: (S)-7-(azetidin-1-ylsulfonyl)-5-bromo-2-(1-cyclopropylethyl)isoindolin-1-one ( 5c) Preparation

步驟1：(S)-7-(苄硫基)-5-溴-2-(1-環丙基乙基)異吲哚啉-1-酮(5a)的製備。 Step 1: Preparation of (S)-7-(benzylthio)-5-bromo-2-(1-cyclopropylethyl)isoindolin-1-one (5a).

於室溫，將(S)-5-溴-7-氯-2-(1-環丙基乙基)異吲哚啉-1-酮(313mg,1.00mmol)、苄硫醇(124mg,1.00mmol)、第三丁醇鈉(96.0mg,1.00mmol)、二噁烷(8mL)加到反應瓶中，80℃攪拌反應12小時。反應結束後，向反應液中加入二氯甲烷、水萃取，有機層減壓濃縮，得到561mg黃色油狀物的標題產物，直接用於下一步。 At room temperature, (S)-5-bromo-7-chloro-2-(1-cyclopropylethyl)isoindolin-1-one (313 mg, 1.00 mmol), benzylthiol (124 mg, 1.00 mmol), sodium tert-butoxide (96.0 mg, 1.00 mmol), and dioxane (8 mL) were added to the reaction flask, and the reaction was stirred at 80° C. for 12 hours. After the reaction was completed, dichloromethane was added to the reaction solution, followed by extraction with water, and the organic layer was concentrated under reduced pressure to obtain 561 mg of the title product as a yellow oil, which was directly used in the next step.

LCMS：m/z 402.04[M+H]⁺。 LCMS: m/z 402.04 [M+H] ⁺ .

步驟2：(S)-6-溴-2-(1-環丙基乙基)-3-側氧異吲哚啉-4-磺醯氯(5b)的製備。 Step 2: Preparation of (S)-6-bromo-2-(1-cyclopropylethyl)-3-oxoisoindoline-4-sulfonyl chloride (5b).

於0℃，將(S)-7-(苄硫基)-5-溴-2-(1-環丙基乙基)異吲哚啉-1-酮(561mg,1.00mmol)、冰醋酸(1.8mL)、乙腈(8ml)、水(0.3ml)加到反應瓶中攪拌10分鐘，加入磺醯氯(405mg,3.00mmol)，攪拌反應1小時，緩慢升溫至15℃，繼續攪拌1小時。反應結束後，減壓濃縮，殘餘物加入二氯甲烷，依次用飽和碳酸氫鈉溶液、飽和氯化鈉溶液洗滌，有機層減壓濃縮，得到571mg黃色油狀物的標題產物，直接用於下一步。 (S)-7-(benzylthio)-5-bromo-2-(1-cyclopropylethyl)isoindolin-1-one (561 mg, 1.00 mmol), glacial acetic acid ( 1.8mL), acetonitrile (8ml), water (0.3ml) were added to the reaction flask and stirred for 10 minutes, sulfonyl chloride (405mg, 3.00mmol) was added, the reaction was stirred for 1 hour, the temperature was slowly raised to 15°C, and stirring was continued for 1 hour. After the reaction was completed, concentrated under reduced pressure, dichloromethane was added to the residue, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution in turn, and the organic layer was concentrated under reduced pressure to obtain 571 mg of the title product as a yellow oil, which was directly used in the next step. step.

LCMS：m/z 377.95[M+H]⁺。 LCMS: m/z 377.95 [M+H] ⁺ .

步驟3：(S)-7-(氮雜環丁烷-1-基磺醯基)-5-溴-2-(1-環丙基乙基)異吲哚啉-1-酮(5c)的製備。 Step 3: (S)-7-(azetidin-1-ylsulfonyl)-5-bromo-2-(1-cyclopropylethyl)isoindolin-1-one (5c) preparation.

於室溫，將(S)-6-溴-2-(1-環丙基乙基)-3-側氧異吲哚啉-4-磺醯氯(571mg,1.00mmol)、氮雜環丁烷(571mg,10.0mmol)、三乙胺(202mg,2.00mmol)、DCM(8mL)加到反應瓶中，在氮氣氛下，於40℃攪拌反應12小時。反應結束後，減壓濃縮，殘餘物藉由矽膠管柱層析色譜法(沖提劑：石油醚：乙酸乙酯=1：1)純化，得到265mg白色固體物的標題產物，收率66.05%。 At room temperature, (S)-6-bromo-2-(1-cyclopropylethyl)-3-oxoisoindoline-4-sulfonyl chloride (571 mg, 1.00 mmol), azetidine Alkane (571 mg, 10.0 mmol), triethylamine (202 mg, 2.00 mmol), DCM (8 mL) were added to the reaction flask, and the reaction was stirred at 40° C. for 12 hours under nitrogen atmosphere. opposite After the reaction was completed, it was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 1:1) to obtain 265 mg of the title product as a white solid, yield 66.05% .

LCMS：m/z 399.03[M+H]⁺。 LCMS: m/z 399.03 [M+H] ⁺ .

製備實施例6：N-(6-溴吡啶-2-基)環丙烷甲基磺胺(6b)的製備 Preparation Example 6: Preparation of N-(6-bromopyridin-2-yl)cyclopropanemethylsulfonamide (6b)

步驟1：N-(6-溴吡啶-2-基)環丙烷磺胺(6a)的製備。 Step 1: Preparation of N-(6-bromopyridin-2-yl)cyclopropanesulfonamide (6a).

於室溫，將6-溴吡啶-2-胺(1.71g,10mmol)、吡啶(20mL)、環丙基磺醯氯(1.40g,10.0mmol)加到反應瓶中，氮氣氛下，於60℃攪拌反應12小時。反應結束後，抽濾，濾液減壓濃縮，殘餘物藉由矽膠管柱層析色譜法(沖提劑：石油醚：乙酸乙酯=5：1)純化，得到1.38g白色固體物的標題產物，直接用於下一步，收率：50.0%。 At room temperature, 6-bromopyridin-2-amine (1.71 g, 10 mmol), pyridine (20 mL), and cyclopropylsulfonyl chloride (1.40 g, 10.0 mmol) were added to the reaction flask, under nitrogen atmosphere, at 60 The reaction was stirred for 12 hours. After the reaction was completed, suction filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 5:1) to obtain 1.38 g of the title product as a white solid , used directly in the next step, yield: 50.0%.

LCMS：m/z 276.96[M+H]⁺。 LCMS: m/z 276.96 [M+H] ⁺ .

步驟2：N-(6-溴吡啶-2-基)環丙烷甲基磺胺(6b)的製備。 Step 2: Preparation of N-(6-bromopyridin-2-yl)cyclopropanemethylsulfonamide (6b).

於室溫，將N-(6-溴吡啶-2-基)環丙烷磺胺(275mg,1.00mmol)、THF(10mL)，NaH(120mg,3.00mmol)加到反應瓶中，滴加碘甲烷(426mg,3.00mmol)，氮氣氛下，於40℃攪拌反應12小時。反應結束後，抽濾，濾液減壓濃縮，殘餘物藉由管柱層析色譜法(沖提劑：石油醚：乙酸乙酯=5：1)純化，得到125mg白色固體物的標題產物，收率：50.0%。 At room temperature, N-(6-bromopyridin-2-yl)cyclopropanesulfonamide (275 mg, 1.00 mmol), THF (10 mL), NaH (120 mg, 3.00 mmol) were added to the reaction flask, and iodomethane ( 426 mg, 3.00 mmol), and the reaction was stirred at 40° C. for 12 hours under nitrogen atmosphere. After the reaction was completed, suction filtration, and the filtrate was concentrated under reduced pressure Condensed, the residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 5:1) to obtain 125 mg of the title product as a white solid, yield: 50.0%.

LCMS：m/z 291.96[M+H]⁺。 LCMS: m/z 291.96 [M+H] ⁺ .

製備實施例7：(S)-5-溴-2-(1-環丙基乙基)-7-(噻唑-2-基)異吲哚啉-1-酮(7e)的製備 Preparation Example 7: Preparation of (S)-5-bromo-2-(1-cyclopropylethyl)-7-(thiazol-2-yl)isoindolin-1-one (7e)

步驟1：4-溴-2-碘-6-甲基苯甲酸(7a)的製備。 Step 1: Preparation of 4-bromo-2-iodo-6-methylbenzoic acid (7a).

於室溫，將4-溴-2-甲基苯甲酸(8.60g,40.0mmol)、碘苯二乙酸(15.5g,48.0mmol)、DMF(200mL)加到反應瓶中，然後加入碘(12.2g,48.0mmol)、Pd(OAc)₂(448mg,2.00mmol，在氮氣氛下，於100℃攪拌反應10小時。反應結束後，向反應瓶中加入100ml甲基第三丁基醚稀釋，加入250ml Na₂SO₃溶液，緩慢滴入20ml濃鹽酸，收集有機層，向其中加入30ml 10%的NaOH溶液，緩慢滴入濃鹽酸至pH為2，收集有機層，濃縮得到11.1g磚紅色油狀液體的標題產物，直接用於下一步。 At room temperature, 4-bromo-2-methylbenzoic acid (8.60 g, 40.0 mmol), iodobenzenediacetic acid (15.5 g, 48.0 mmol), DMF (200 mL) were added to the reaction flask, followed by iodine (12.2 g, 48.0 mmol), Pd(OAc) ₂ (448 mg, 2.00 mmol, under a nitrogen atmosphere, the reaction was stirred at 100 ° C for 10 hours. After the reaction was completed, 100 ml of methyl tertiary butyl ether was added to the reaction flask to dilute, add 250ml Na ₂ SO ₃ solution, slowly drip 20ml concentrated hydrochloric acid, collect the organic layer, add 30ml 10% NaOH solution to it, slowly drip concentrated hydrochloric acid to pH 2, collect the organic layer, and concentrate to obtain 11.1g of brick red oil. The title product as a liquid was used directly in the next step.

LCMS：m/z 340.86[M+H]⁺。 LCMS: m/z 340.86 [M+H] ⁺ .

步驟2：4-溴-2-碘-6-甲基苯甲酸甲酯(7b)的製備。 Step 2: Preparation of methyl 4-bromo-2-iodo-6-methylbenzoate (7b).

於室溫，將4-溴-2-碘-6-甲基苯甲酸(11.1g,32.7mmol)、碘甲烷(11.6g,81.8mmol)、碳酸鉀(9.11g,65.4mmol)、DMF(500ml)加到反應瓶中，10℃攪拌反應12小時。反應結束後，抽濾，濾液減壓濃縮，殘餘物藉由矽膠管柱層析色譜法(沖提劑：石油醚：乙酸乙酯=20：1)純化，得到9.72g黃色油狀物的標題產物，收率：86.2%。 At room temperature, 4-bromo-2-iodo-6-methylbenzoic acid (11.1 g, 32.7 mmol), iodomethane (11.6 g, 81.8 mmol), potassium carbonate (9.11 g, 65.4 mmol), DMF (500 ml) were mixed ) was added to the reaction flask, and the reaction was stirred at 10°C for 12 hours. After the reaction was completed, suction filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 20:1) to obtain 9.72 g of the title as a yellow oil. Product, yield: 86.2%.

LCMS：m/z 354.88[M+H]⁺。 LCMS: m/z 354.88 [M+H] ⁺ .

步驟3：4-溴-2-(溴甲基)-6-碘苯甲酸甲酯(7c)的製備。 Step 3: Preparation of methyl 4-bromo-2-(bromomethyl)-6-iodobenzoate (7c).

於室溫，將4-溴-2-碘-6-甲基苯甲酸甲酯(3.54g,10.0mmol)、四氯化碳(30mL)、過氧苯甲醯(121mg,0.50mmol)、NBS(1.78g,10.0mmol)加到反應瓶中，升溫至80℃攪拌反應15小時。反應結束後，加100mL水、200mL二氯甲烷萃取，有機相用水洗滌一次，無水硫酸鈉乾燥，過濾，濾液減壓濃縮，得到5.12g淡黃色油狀物的標題產物，直接用於下一步。 At room temperature, methyl 4-bromo-2-iodo-6-methylbenzoate (3.54 g, 10.0 mmol), carbon tetrachloride (30 mL), benzyl peroxide (121 mg, 0.50 mmol), NBS (1.78 g, 10.0 mmol) was added to the reaction flask, the temperature was raised to 80° C. and the reaction was stirred for 15 hours. After the reaction, 100 mL of water and 200 mL of dichloromethane were added for extraction. The organic phase was washed once with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 5.12 g of the title product as a pale yellow oil, which was directly used in the next step.

LCMS：m/z 434.78[M+H]⁺。 LCMS: m/z 434.78 [M+H] ⁺ .

步驟4：(S)-5-溴-2-(1-環丙基乙基)-7-碘異吲哚啉-1-酮(7d)的製備。 Step 4: Preparation of (S)-5-bromo-2-(1-cyclopropylethyl)-7-iodoisoindolin-1-one (7d).

於室溫，將4-溴-2-(溴甲基)-6-碘苯甲酸甲酯(5.12g,9.50mmol)、(S)-1-環丙基乙胺(1.16g,9.50mmol)、硼酸(588mg,9.50mmol)、碳酸鉀(3.94g,28.5mmol)、乙腈(30mL)加到反應瓶中，20℃攪拌反應15小時。反應結束後，抽濾，濾液減壓濃縮，殘餘物藉由矽膠管柱層析色譜法(沖提劑：石油醚：乙酸乙酯=10：1)純化，得到1.91g黃色固體物的標題產物，收率：49.6%。 At room temperature, methyl 4-bromo-2-(bromomethyl)-6-iodobenzoate (5.12 g, 9.50 mmol), (S)-1-cyclopropylethylamine (1.16 g, 9.50 mmol) , boric acid (588 mg, 9.50 mmol), potassium carbonate (3.94 g, 28.5 mmol), and acetonitrile (30 mL) were added to the reaction flask, and the reaction was stirred at 20° C. for 15 hours. After the reaction was completed, suction filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 10:1) to obtain 1.91 g of the title product as a yellow solid , yield: 49.6%.

LCMS：m/z 405.92[M+H]⁺。 LCMS: m/z 405.92 [M+H] ⁺ .

步驟5：(S)-5-溴-2-(1-環丙基乙基)-7-(噻唑-2-基)異吲哚啉-1-酮(7e)的製備。 Step 5: Preparation of (S)-5-bromo-2-(1-cyclopropylethyl)-7-(thiazol-2-yl)isoindolin-1-one (7e).

於室溫，將(S)-5-溴-2-(1-環丙基乙基)-7-碘異吲哚啉-1-酮(405mg,1.00mmol)、2-(三丁基錫烷基)噻唑(374mg,1.00mmol)、二噁烷(5mL)加到反應瓶中，然後加入碳酸鉀(276mg,2.00mmol)、Pd(PPh₃)₄(58.4mg,0.05mmol)，80℃攪拌反應12小時。反應結束後，減壓濃縮，殘餘物藉由矽膠管柱層析色譜法(沖提劑：石油醚：乙酸乙酯=5：1)純化，得到132mg黃色固體物的標題產物，收率：36.5%。 At room temperature, (S)-5-bromo-2-(1-cyclopropylethyl)-7-iodoisoindolin-1-one (405 mg, 1.00 mmol), 2-(tributylstannyl) ) Thiazole (374mg, 1.00mmol) and dioxane (5mL) were added to the reaction flask, then potassium carbonate (276mg, 2.00mmol), Pd(PPh ₃ ) ₄ (58.4mg, 0.05mmol) were added, and the reaction was stirred at 80°C 12 hours. After the reaction was completed, it was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 5:1) to obtain 132 mg of the title product as a yellow solid, yield: 36.5 %.

LCMS：m/z 363.01[M+H]⁺。 LCMS: m/z 363.01 [M+H] ⁺ .

實施例1：(S)-2-(1-環丙基乙基)-5-(4-甲基-2-((2-(2-側氧吡咯烷-1-基)吡啶-4-基)胺基)噻唑-5-基)-7-(甲基磺醯基)異吲哚啉-1-酮(1)的製備 Example 1: (S)-2-(1-cyclopropylethyl)-5-(4-methyl-2-((2-(2-oxypyrrolidin-1-yl)pyridine-4- Preparation of yl)amino)thiazol-5-yl)-7-(methylsulfonyl)isoindolin-1-one (1)

步驟1：(S)-2-(1-環丙基乙基)-5-(4-甲基-2-((2-(2-側氧吡咯烷-1-基)吡啶-4-基)胺基)噻唑-5-基)-7-(甲基磺醯基)異吲哚啉-1-酮(1)的製備。 Step 1: (S)-2-(1-Cyclopropylethyl)-5-(4-methyl-2-((2-(2-oxopyrrolidin-1-yl)pyridin-4-yl) )amino)thiazol-5-yl)-7-(methylsulfonyl)isoindolin-1-one (1).

於室溫，將1-(4-((4-甲基噻唑-2-基)胺基)吡啶-2-基)吡咯烷-2-酮(3c)(138mg,0.50mmol)、(S)-5-溴-2-(1-環丙基乙基)-7-(甲基磺醯基)異吲哚啉-1-酮(1d)(179mg,0.50mmol)、DMF(1mL)加到反應瓶中，然後加入碳酸銫(325mg,1.00mmol)、Pd-118(CAS：95408-45-0)(10.4mg,0.02mmol)，80℃攪拌反應2小時。反應結束後，減壓濃縮，殘餘物用製備液相色譜法分離(色譜管柱型號：Daisogei 30mm*250mm，C18，10um，100A，流動相：乙腈/水，梯度：30%-80%)，得37.1mg黃色固體狀標題化合物，收率13.5%。 At room temperature, 1-(4-((4-methylthiazol-2-yl)amino)pyridin-2-yl)pyrrolidin-2-one (3c) (138 mg, 0.50 mmol), (S) -5-Bromo-2-(1-cyclopropylethyl)-7-(methylsulfonyl)isoindolin-1-one (1d) (179 mg, 0.50 mmol), DMF (1 mL) were added to In the reaction flask, cesium carbonate (325 mg, 1.00 mmol) and Pd-118 (CAS: 95408-45-0) (10.4 mg, 0.02 mmol) were added, and the reaction was stirred at 80° C. for 2 hours. After the reaction, concentrated under reduced pressure, and the residue was separated by preparative liquid chromatography (chromatographic column model: Daisogei 30mm*250mm, C18, 10um, 100A, mobile phase: acetonitrile/water, gradient: 30%-80%), 37.1 mg of the title compound was obtained as a yellow solid in a yield of 13.5%.

LCMS：m/z 552.17[M+H]⁺。 LCMS: m/z 552.17 [M+H] ⁺ .

¹H NMR(300MHz,DMSO-d ₆)δ 10.95(s,1H),8.48(s,1H),8.23-8.22(d,1H),8.03-7.98(d,2H),7.65-7.63(d,1H),4.71(s,1H),4.02-3.97(t,2H),3.64-3.60(s,4H),2.61-2.56(t,2H),2.50-2.46(s,3H),2.08-2.01(t,2H),1.32-1.14(t,5H),0.62-0.57(s,1H),0.44-0.42(m,2H),0.28-0.26(m,1H)。 ¹ H NMR (300MHz, DMSO- d ₆ ) δ 10.95(s,1H), 8.48(s,1H), 8.23-8.22(d,1H), 8.03-7.98(d,2H), 7.65-7.63(d, 1H), 4.71(s, 1H), 4.02-3.97(t, 2H), 3.64-3.60(s, 4H), 2.61-2.56(t, 2H), 2.50-2.46(s, 3H), 2.08-2.01( t, 2H), 1.32-1.14 (t, 5H), 0.62-0.57 (s, 1H), 0.44-0.42 (m, 2H), 0.28-0.26 (m, 1H).

實施例2：(S)-7-氯-2-(1-環丙基乙基)-5-(4-甲基-2-((6-(2-側氧吡咯烷-1-基)吡啶-2-基)胺基)噻唑-5-基)異吲哚啉-1-酮(2)的製備 Example 2: (S)-7-Chloro-2-(1-cyclopropylethyl)-5-(4-methyl-2-((6-(2-oxypyrrolidin-1-yl) Preparation of Pyridin-2-yl)amino)thiazol-5-yl)isoindolin-1-one (2)

步驟1：(S)-7-氯-2-(1-環丙基乙基)-5-(4-甲基-2-((6-(2-側氧吡咯烷-1-基)吡啶-2-基)胺基)噻唑-5-基)異吲哚啉-1-酮(2)的製備。 Step 1: (S)-7-Chloro-2-(1-cyclopropylethyl)-5-(4-methyl-2-((6-(2-oxopyrrolidin-1-yl)pyridine) Preparation of -2-yl)amino)thiazol-5-yl)isoindolin-1-one (2).

於室溫，將(S)-5-溴-7-氯-2-(1-環丙基乙基)異吲哚啉-1-酮(1b)(30.0mg,0.100mmol)、1-(6-((4-甲基噻唑-2-基)胺基)吡啶-2-基)吡咯烷-2-酮(2b)(32.0mg,0.100mmol)、DMF(1.00mL)加到反應瓶中，然後加入碳酸銫(65.0mg,0.200mmol)、Pd(OAc)₂(2.24mg,0.010mmol)、((t-bu)₃PH)BF₄(5.80mg,0.02mmol)，100℃攪拌反應2小時。反應結束後，減壓濃縮，殘餘物用製備液相色譜法分離(色譜管柱型號：Daisogei 30mm*250mm，C18，10um，100A，流動相：乙腈/水，梯度：30%-80%)，得5.90mg黃色固體狀標題化合物，收率11.6%。 At room temperature, (S)-5-bromo-7-chloro-2-(1-cyclopropylethyl)isoindolin-1-one (1b) (30.0 mg, 0.100 mmol), 1-( 6-((4-Methylthiazol-2-yl)amino)pyridin-2-yl)pyrrolidin-2-one (2b) (32.0 mg, 0.100 mmol), DMF (1.00 mL) were added to the reaction flask , and then added cesium carbonate (65.0mg, 0.200mmol), Pd(OAc) ₂ (2.24mg, 0.010mmol), ((t-bu) ₃ PH)BF ₄ (5.80mg, 0.02mmol), and the reaction was stirred at 100 ° C for 2 Hour. After the reaction, concentrated under reduced pressure, and the residue was separated by preparative liquid chromatography (chromatographic column model: Daisogei 30mm*250mm, C18, 10um, 100A, mobile phase: acetonitrile/water, gradient: 30%-80%), 5.90 mg of the title compound was obtained as a yellow solid with a yield of 11.6%.

LCMS：m/z 508.15[M+H]⁺。 LCMS: m/z 508.15 [M+H] ⁺ .

¹H NMR(300MHz,DMSO-d ₆)δ 11.49(s,1H),7.85(s,1H),7.82(s,1H),7.62(s,1H),7.49(t,1H),6.78(d,1H),4.58(s,2H),4.23(t,2H),3.60(t,1H),2.60(t,2H),2.46(s,3H),2.11(s,2H),1.32(d,3H),1.10-1.22(m,1H),0.59-0.63(m,1H),0.40-0.47(m,2H),0.25-0.33(m,1H)。 ¹ H NMR (300MHz, DMSO- d ₆ ) δ 11.49(s,1H), 7.85(s,1H), 7.82(s,1H), 7.62(s,1H), 7.49(t,1H), 6.78(d ,1H),4.58(s,2H),4.23(t,2H),3.60(t,1H),2.60(t,2H),2.46(s,3H),2.11(s,2H),1.32(d, 3H), 1.10-1.22 (m, 1H), 0.59-0.63 (m, 1H), 0.40-0.47 (m, 2H), 0.25-0.33 (m, 1H).

實施例3：(S)-2-(1-環丙基乙基)-5-(4-甲基-2-((6-(2-側氧吡咯烷-1-基)吡嗪-2-基)胺基)噻唑-5-基)-7-(甲基磺醯基)異吲哚啉-1-酮(3)的製備 Example 3: (S)-2-(1-Cyclopropylethyl)-5-(4-methyl-2-((6-(2-oxopyrrolidin-1-yl)pyrazine-2 Preparation of -yl)amino)thiazol-5-yl)-7-(methylsulfonyl)isoindolin-1-one (3)

步驟1：(S)-2-(1-環丙基乙基)-5-(4-甲基-2-((6-(2-側氧吡咯烷-1-基)吡嗪-2-基)胺基)噻唑-5-基)-7-(甲基磺醯基)異吲哚啉-1-酮(3)的製備。 Step 1: (S)-2-(1-Cyclopropylethyl)-5-(4-methyl-2-((6-(2-oxopyrrolidin-1-yl)pyrazine-2- Preparation of yl)amino)thiazol-5-yl)-7-(methylsulfonyl)isoindolin-1-one ( 3 ).

於室溫，將1-(6-溴-吡嗪-2-基)吡咯烷-2-酮(60.2mg,0.25mmol)(根據製備實施例2步驟1製備，將2,6-二溴吡啶替換為2,6-二溴吡嗪)、(S)-5-(2-胺基-4-甲基噻唑-5-基)-2-(1-環丙基乙基)-7-(甲基磺醯基)異吲哚啉-1-酮(4c)(88.9mg,0.23mmol)、碳酸鈉(79.5mg,0.75mmol)、Ruphos(35.0mg,0.075mmol)、Ruphos Pd G2(58.3mg,0.075mmol)、DMF(5mL)加到反應瓶中，125℃攪拌反應3小時。反應結束後，減壓濃縮，殘餘物用製備液相色譜法分離(色譜管柱型號：Daisogei 30mm*250mm，C18，10um，100A，流動相：乙腈/水，梯度：30%-80%)，得52.2mg黃色固體狀標題化合物，收率41.1%。 At room temperature, 1-(6-bromo-pyrazin-2-yl)pyrrolidin-2-one (60.2 mg, 0.25 mmol) (prepared according to Preparation Example 2, Step 1, 2,6-dibromopyridine replaced with 2,6-dibromopyrazine), (S)-5-(2-amino-4-methylthiazol-5-yl)-2-(1-cyclopropylethyl)-7-( Methylsulfonyl)isoindolin-1-one (4c) (88.9mg, 0.23mmol), sodium carbonate (79.5mg, 0.75mmol), Ruphos (35.0mg, 0.075mmol), Ruphos Pd G2 (58.3mg , 0.075 mmol) and DMF (5 mL) were added to the reaction flask, and the reaction was stirred at 125° C. for 3 hours. After the reaction, concentrated under reduced pressure, and the residue was separated by preparative liquid chromatography (chromatographic column model: Daisogei 30mm*250mm, C18, 10um, 100A, mobile phase: acetonitrile/water, gradient: 30%-80%), 52.2 mg of the title compound was obtained as a yellow solid in a yield of 41.1%.

LCMS：m/z 552.17[M+H]⁺。 LCMS: m/z 552.17 [M+H] ⁺ .

¹H NMR(400MHz,DMSO-d ₆)δ 11.95(s,1H),9.05(s,1H),8.14(s,1H),8.06-8.04(d,2H),4.71(s,2H),4.20-4.17(t,2H),3.66-3.62(s,4H),2.60-2.50(t,2H),2.46(s,3H),2.15-2.11(m,2H),1.33-1.31(d,3H),1.16(m,1H),0.58(m,1H),0.42(m,2H),0.27(m,1H)。 ¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.95(s, 1H), 9.05(s, 1H), 8.14(s, 1H), 8.06-8.04(d, 2H), 4.71(s, 2H), 4.20 -4.17(t, 2H), 3.66-3.62(s, 4H), 2.60-2.50(t, 2H), 2.46(s, 3H), 2.15-2.11(m, 2H), 1.33-1.31(d, 3H) , 1.16 (m, 1H), 0.58 (m, 1H), 0.42 (m, 2H), 0.27 (m, 1H).

實施例4：(S)-2-(1-環丙基乙基)-5-(4-甲基-2-((6-(2-側氧吡咯烷-1-基)吡啶-2-基)胺基)噁唑-5-基)-7-(甲基磺醯基)異吲哚啉-1-酮(4)的製備 Example 4: (S)-2-(1-cyclopropylethyl)-5-(4-methyl-2-((6-(2-oxypyrrolidin-1-yl)pyridine-2- Preparation of oxazol-5-yl)-7-(methylsulfonyl)isoindolin-1-one (4)

與實施例1的製備方法相同，除了用1-(6-((4-甲基噁唑-2-基)胺基)吡啶-2-基)吡咯烷-2-酮(根據製備實施例2步驟2製備，將4-甲基噻唑-2-胺替換為4-甲基噁唑-2-胺)代替1-(4-((4-甲基噻唑-2-基)胺基)吡啶-2-基)吡咯烷-2-酮(3c)，製得標題化合物。 The preparation method was the same as that of Example 1, except that 1-(6-((4-methyloxazol-2-yl)amino)pyridin-2-yl)pyrrolidin-2-one (according to Preparation Example 2) was used. Prepared in step 2, replacing 4-methylthiazol-2-amine with 4-methyloxazol-2-amine) instead of 1-(4-((4-methylthiazol-2-yl)amino)pyridine- 2-yl)pyrrolidin-2-one (3c) to give the title compound.

LCMS：m/z 536.65[M+H]⁺。 LCMS: m/z 536.65 [M+H] ⁺ .

¹H NMR(300MHz,DMSO-d ₆)δ 10.96(s,1H),8.21(s,1H),8.07(s,1H),7.95(d,1H),7.85(t,1H),7.68(d,1H),4.75(s,2H),4.05(t,2H),3.64(s,4H),2.60(t,2H),2.49(s,3H),2.02(s,2H),1.20(d,3H),1.18-1.20(m,1H),0.59-0.63(m,1H),0.44(m,2H),0.30(m,1H)。 ¹ H NMR (300MHz, DMSO- d ₆ ) δ 10.96(s, 1H), 8.21(s, 1H), 8.07(s, 1H), 7.95(d, 1H), 7.85(t, 1H), 7.68(d ,1H),4.75(s,2H),4.05(t,2H),3.64(s,4H),2.60(t,2H),2.49(s,3H),2.02(s,2H),1.20(d, 3H), 1.18-1.20 (m, 1H), 0.59-0.63 (m, 1H), 0.44 (m, 2H), 0.30 (m, 1H).

實施例5：(S)-7-(氮雜環丁烷-1-基磺醯基)-2-(1-環丙基乙基)-5-(4-甲基-2-((6-(2-側氧吡咯烷-1-基)吡啶-2-基)胺基)噻唑-5-基)異吲哚啉-1-酮(5)的製備 Example 5: (S)-7-(azetidin-1-ylsulfonyl)-2-(1-cyclopropylethyl)-5-(4-methyl-2-((6 Preparation of -(2-oxypyrrolidin-1-yl)pyridin-2-yl)amino)thiazol-5-yl)isoindolin-1-one (5)

與實施例1的製備方法相同，除了用(S)-7-(氮雜環丁烷-1-基磺醯基)-5-溴-2-(1-環丙基乙基)異吲哚啉-1-酮(5c)代替(S)-5-溴-2-(1-環丙基乙基)-7-(甲基磺醯基)異吲哚啉-1-酮(1d)，以及用1-(6-((4-甲基噻唑-2-基)胺基)吡啶-2-基) 吡咯烷-2-酮(2b)代替1-(4-((4-甲基噻唑-2-基)胺基)吡啶-2-基)吡咯烷-2-酮(3c)，製得標題化合物。 The preparation method was the same as that of Example 1, except that (S)-7-(azetidin-1-ylsulfonyl)-5-bromo-2-(1-cyclopropylethyl)isoindole was used Lin-1-one ( 5c ) in place of (S)-5-bromo-2-(1-cyclopropylethyl)-7-(methylsulfonyl)isoindolin-1-one ( 1d ), and 1-(6-((4-methylthiazol-2-yl)amino)pyridin-2-yl)pyrrolidin-2-one ( 2b ) instead of 1-(4-((4-methylthiazole) -2-yl)amino)pyridin-2-yl)pyrrolidin-2-one ( 3c ) to give the title compound.

LCMS：m/z 593.19[M+H]⁺。 LCMS: m/z 593.19 [M+H] ⁺ .

¹H NMR(300MHz,DMSO-d ₆)δ 11.53(s,1H),7.98-7.95(d,2H),7.87-7.85(d,1H),7.74-7.70(t,1H),6.78-6.76(d,1H),4.66(s,2H),4.24-4.22(t,2H),3.92(t,4H),3.60(t,1H),2.57(t,2H),2.51-2.50(d,3H),2.07-1.99(t,4H),1.31-1.29(d,3H),0.85(s,1H),0.58(s,1H),0.42(m,2H),0.27(m,1H)。 ¹ H NMR (300MHz, DMSO- d ₆ ) δ 11.53(s,1H), 7.98-7.95(d,2H), 7.87-7.85(d,1H), 7.74-7.70(t,1H), 6.78-6.76( d, 1H), 4.66(s, 2H), 4.24-4.22(t, 2H), 3.92(t, 4H), 3.60(t, 1H), 2.57(t, 2H), 2.51-2.50(d, 3H) , 2.07-1.99(t, 4H), 1.31-1.29(d, 3H), 0.85(s, 1H), 0.58(s, 1H), 0.42(m, 2H), 0.27(m, 1H).

實施例6：(S)-2-(1-環丙基乙基)-5-(4-甲基-2-((4-(2-側氧吡咯烷-1-基)吡啶-2-基)胺基)噻唑-5-基)-7-(甲基磺醯基)異吲哚啉-1-酮(6)的製備 Example 6: (S)-2-(1-cyclopropylethyl)-5-(4-methyl-2-((4-(2-oxopyrrolidin-1-yl)pyridine-2- Preparation of (6) amino)thiazol-5-yl)-7-(methylsulfonyl)isoindolin-1-one

與實施例3的製備方法相同，除了用1-(2-溴吡啶-2-基)吡咯烷-2-酮(根據製備實施例3步驟1和2製備，將4-溴吡啶-2-胺替換為2-溴吡啶-4-胺)代替1-(6-溴-吡嗪-2-基)吡咯烷-2-酮，製得標題化合物。 The preparation method was the same as that of Example 3, except that 1-(2-bromopyridin-2-yl)pyrrolidin-2-one (prepared according to steps 1 and 2 of Preparation Example 3, 4-bromopyridin-2-amine was used Substitute 2-bromopyridin-4-amine) in place of 1-(6-bromo-pyrazin-2-yl)pyrrolidin-2-one to give the title compound.

LCMS：m/z 552.17[M+H]⁺。 LCMS: m/z 552.17 [M+H] ⁺ .

¹H NMR(400MHz,DMSO-d ₆)δ 11.43(s,1H),8.28-8.27(d,1H),8.02(s,2H),4.45(s,1H),7.29-7.27(m,1H),4.70(s,2H),3.83-3.66(t,2H),3.63-3.62(s,4H),2.50-2.49(t,2H),2.44(s,3H),2.09-2.05(t,2H),1.32-1.18(m,3H),1.16-1.12(t,1H),0.58(m,1H),0.40(m,2H),0.28-0.26(m,1H)。 ¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.43(s,1H), 8.28-8.27(d,1H), 8.02(s,2H), 4.45(s,1H), 7.29-7.27(m,1H) ,4.70(s,2H),3.83-3.66(t,2H),3.63-3.62(s,4H),2.50-2.49(t,2H),2.44(s,3H),2.09-2.05(t,2H) , 1.32-1.18(m, 3H), 1.16-1.12(t, 1H), 0.58(m, 1H), 0.40(m, 2H), 0.28-0.26(m, 1H).

實施例7：(S)-N-(6-((5-(2-(1-環丙基乙基)-7-(甲基磺醯基)-1-異吲哚啉-5-基)-4-甲基噻唑-2-基)胺基)吡啶-2-基)環丙烷(7)的製備 Example 7: (S)-N-(6-((5-(2-(1-cyclopropylethyl)-7-(methylsulfonyl)-1-isoindolin-5-yl )-4-methylthiazol-2-yl)amino)pyridin-2-yl)cyclopropane (7) preparation

與實施例3的製備方法相同，除了用N-(6-溴吡啶-2-基)環丙烷磺胺(6a)代替1-(6-溴-吡嗪-2-基)吡咯烷-2-酮，製得標題化合物。 The preparation method was the same as in Example 3, except that N-(6-bromopyridin-2-yl)cyclopropanesulfonamide (6a) was used instead of 1-(6-bromo-pyrazin-2-yl)pyrrolidin-2-one , the title compound was obtained.

LCMS：m/z 588.58[M+H]⁺。 LCMS: m/z 588.58 [M+H] ⁺ .

¹H NMR(300MHz,DMSO-d ₆)δ 11.44(s,1H),10.44(s,1H),8.04-8.00(m,2H),7.68-7.62(m,1H),6.77-6.75(m,1H),6.67-6.65(m,1H),4.72(s,2H),3.63-3.59(m,4H),3.33(s,1H),2.50(s,3H),1.35-0.86(m,12H),0.61-0.57(m,2H),0.47-0.41(m,2H),0.28-0.26(m,1H)。 ¹ H NMR (300MHz, DMSO- d ₆ ) δ 11.44(s, 1H), 10.44(s, 1H), 8.04-8.00(m, 2H), 7.68-7.62(m, 1H), 6.77-6.75(m, 1H), 6.67-6.65(m, 1H), 4.72(s, 2H), 3.63-3.59(m, 4H), 3.33(s, 1H), 2.50(s, 3H), 1.35-0.86(m, 12H) ,0.61-0.57(m,2H),0.47-0.41(m,2H),0.28-0.26(m,1H).

實施例8：(S)-5-(2-((1H-吡咯并[2,3-b]吡啶-6-基)胺基)-4-甲基-噻唑-5-基)-2-(1-環丙基乙基)-7-(甲基磺醯基)異吲哚啉-1-酮(8)的製備 Example 8: (S)-5-(2-((1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-4-methyl-thiazol-5-yl)-2- Preparation of (1-cyclopropylethyl)-7-(methylsulfonyl)isoindolin-1-one (8)

與實施例3的製備方法相同，除了用6-溴-1H-吡咯并[2,3-b]吡啶代替1-(6-溴-吡嗪-2-基)吡咯烷-2-酮，製得標題化合物。 The preparation method was the same as that of Example 3, except that 6-bromo-1H-pyrrolo[2,3-b]pyridine was used instead of 1-(6-bromo-pyrazin-2-yl)pyrrolidin-2-one to prepare The title compound was obtained.

LCMS：m/z 508.14[M+H]⁺。 LCMS: m/z 508.14 [M+H] ⁺ .

¹H NMR(300MHz,DMSO-d ₆)δ 11.58(s,1H),11.46(s,1H),8.04(s,2H),7.91-7.88(m,1H),7.21-7.19(m,1H),6.84-6.81(m,1H),6.38-6.36(m,1H),4.72(s,2H),3.63-3.59(m,4H),2.50(s,3H),1.33-1.15(m,4H),0.62-0.59(m,1H),0.46-0.39(m,2H),0.28-0.26(m,1H)。 ¹ H NMR (300MHz, DMSO- d ₆ ) δ 11.58(s,1H), 11.46(s,1H), 8.04(s,2H), 7.91-7.88(m,1H), 7.21-7.19(m,1H) ,6.84-6.81(m,1H),6.38-6.36(m,1H),4.72(s,2H),3.63-3.59(m,4H),2.50(s,3H),1.33-1.15(m,4H) ,0.62-0.59(m,1H),0.46-0.39(m,2H),0.28-0.26(m,1H).

實施例9：(S)-2-(1-環丙基乙基)-5-(4-甲基-2-((6-(噁唑-2-基)吡啶-2-基)胺基)噻唑-5-基)-7-(甲基磺醯基)異吲哚啉-1-酮(9)的製備 Example 9: (S)-2-(1-cyclopropylethyl)-5-(4-methyl-2-((6-(oxazol-2-yl)pyridin-2-yl)amino ) Preparation of thiazol-5-yl)-7-(methylsulfonyl)isoindolin-1-one (9)

與實施例3的製備方法相同，除了用2-(6-溴吡啶-2-基)噁唑(根據製備實施例2步驟1製備，將吡咯烷-2-酮替換為噁唑)代替1-(6-溴-吡嗪-2-基)吡咯烷-2-酮，製得標題化合物。 The preparation method was the same as that of Example 3, except that 2-(6-bromopyridin-2-yl)oxazole (prepared according to Step 1 of Preparation Example 2, substituting oxazole for pyrrolidin-2-one) was used instead of 1- (6-Bromo-pyrazin-2-yl)pyrrolidin-2-one to give the title compound.

LCMS：m/z 536.13[M+H]⁺。 LCMS: m/z 536.13 [M+H] ⁺ .

¹H NMR(300MHz,DMSO-d ₆)δ 11.81(s,1H),8.28(s,1H),8.14-8.06(m,2H),7.94-7.89(t,1H),7.70-7.67(m,1H),7.49(s,1H),7.20-7.17(d,1H),4.74(s,2H),3.67-3.61(t,4H),2.51-2.48(m,3H),1.34-1.31(m,3H),1.23(s,1H),0.61(s,1H),0.46-0.43(t,2H),0.29-0.27(m,1H)。 ¹ H NMR (300MHz, DMSO- d ₆ ) δ 11.81(s,1H), 8.28(s,1H), 8.14-8.06(m,2H), 7.94-7.89(t,1H), 7.70-7.67(m, 1H), 7.49(s, 1H), 7.20-7.17(d, 1H), 4.74(s, 2H), 3.67-3.61(t, 4H), 2.51-2.48(m, 3H), 1.34-1.31(m, 3H), 1.23(s, 1H), 0.61(s, 1H), 0.46-0.43(t, 2H), 0.29-0.27(m, 1H).

實施例10：(S)-2-(1-環丙基乙基)-5-(4-甲基-2-((4-(2-側氧吡咯烷-1-基)嘧啶-2-基)胺基)噻唑-5-基)-7-(甲基磺醯基)異吲哚啉-1-酮(10)的製備 Example 10: (S)-2-(1-cyclopropylethyl)-5-(4-methyl-2-((4-(2-oxopyrrolidin-1-yl)pyrimidine-2- Preparation of (10)

與實施例3的製備方法相同，除了用1-(2-氯嘧啶-4-基)吡咯烷-2-酮(根據製備實施例2步驟1製備，將2,6-二溴吡啶替換為2-氯-4-溴嘧啶)代替1-(6-溴-吡嗪-2-基)吡咯烷-2-酮，製得標題化合物。 The preparation method was the same as that of Example 3, except that 1-(2-chloropyrimidin-4-yl)pyrrolidin-2-one (prepared according to Step 1 of Preparation Example 2) was used, and 2,6-dibromopyridine was replaced by 2 -chloro-4-bromopyrimidine) in place of 1-(6-bromo-pyrazin-2-yl)pyrrolidin-2-one to give the title compound.

LCMS：m/z 553.17[M+H]⁺。 LCMS: m/z 553.17 [M+H] ⁺ .

¹H NMR(300MHz,DMSO-d ₆)δ 11.85(s,1H),8.52-8.50(m,1H),8.05(s,2H),7.87-7.85(m,1H),4.72(s,2H),4.13-4.10(t,2H),3.64-3.60(s,4H),2.60(t,2H),2.45(s,3H),2.13-2.08(t,2H),1.30-1.17(m,3H),0.83(t,1H),0.46(m,1H),0.46-0.42(m,2H),0.28-0.26(m,1H)。 ¹ H NMR (300MHz, DMSO- d ₆ ) δ 11.85(s,1H), 8.52-8.50(m,1H), 8.05(s,2H), 7.87-7.85(m,1H), 4.72(s,2H) ,4.13-4.10(t,2H),3.64-3.60(s,4H),2.60(t,2H),2.45(s,3H),2.13-2.08(t,2H),1.30-1.17(m,3H) ,0.83(t,1H),0.46(m,1H),0.46-0.42(m,2H),0.28-0.26(m,1H).

實施例11：(S)-N-(6-((5-(2-(1-環丙基乙基)-7-(甲基磺醯基)-1-異吲哚啉-5-基)-4-甲基噻唑-2-基)胺基)吡啶-2-基)-甲磺醯胺(11)的製備 Example 11: (S)-N-(6-((5-(2-(1-cyclopropylethyl)-7-(methylsulfonyl)-1-isoindolin-5-yl )-4-methylthiazol-2-yl)amino)pyridin-2-yl)-methanesulfonamide (11) preparation

與實施例3的製備方法相同，除了用N-(6-溴吡啶-2-基)甲磺醯胺(根據製備實施例6步驟1製備，將環丙基磺醯氯替換為甲磺醯氯)代替1-(6-溴-吡嗪-2-基)吡咯烷-2-酮，製得標題化合物。 The preparation method was the same as that of Example 3, except that N-(6-bromopyridin-2-yl)methanesulfonamide (prepared according to Preparation Example 6, Step 1) was used, and cyclopropylsulfonyl chloride was replaced by methanesulfonyl chloride ) in place of 1-(6-bromo-pyrazin-2-yl)pyrrolidin-2-one to give the title compound.

LCMS：m/z 562.12[M+H]⁺。 LCMS: m/z 562.12 [M+H] ⁺ .

¹H NMR(300MHz,DMSO-d ₆)δ 11.44(s,1H),10.55(s,1H)8.055(s,1H),8.00(s,1H),7.62(m,1H),6.75-6.72(m,1H)6.57-6.55(m,1H),4.73(s,2H),3.643.60(m,4H),3.40(s,3H),2.46(s,3H),1.18-1.15(m,3H),1.14-1.12(t,1H),0.44-0.42(m,1H),0.42(m,2H),0.28-0.26(m,1H)。 ¹ H NMR (300MHz, DMSO- d ₆ ) δ 11.44(s, 1H), 10.55(s, 1H) 8.055(s, 1H), 8.00(s, 1H), 7.62(m, 1H), 6.75-6.72( m,1H)6.57-6.55(m,1H),4.73(s,2H),3.643.60(m,4H),3.40(s,3H),2.46(s,3H),1.18-1.15(m,3H) ), 1.14-1.12(t, 1H), 0.44-0.42(m, 1H), 0.42(m, 2H), 0.28-0.26(m, 1H).

實施例12：(S)-5-(2-((6-(1H-咪唑-1-基)吡啶-2-基)胺基)-4-甲基-噻唑-5-基)-2-(1-環丙基乙基)-7-(甲基磺醯基)異吲哚啉-1-酮(12)的製備 Example 12: (S)-5-(2-((6-(1H-imidazol-1-yl)pyridin-2-yl)amino)-4-methyl-thiazol-5-yl)-2- Preparation of (1-cyclopropylethyl)-7-(methylsulfonyl)isoindolin-1-one (12)

與實施例3的製備方法相同，除了用2-溴-6-(1H-咪唑-1-基)吡啶(根據製備實施例2步驟1製備，將吡咯烷-2-酮替換為咪唑)代替1-(6-溴-吡嗪-2-基)吡咯烷-2-酮，製得標題化合物。 The preparation method was the same as in Example 3, except that 2-bromo-6-(1H-imidazol-1-yl)pyridine (prepared according to Step 1 of Preparation Example 2, replacing pyrrolidin-2-one with imidazole) was used in place of 1 -(6-Bromo-pyrazin-2-yl)pyrrolidin-2-one to prepare the title compound.

LCMS：m/z 535.15[M+H]⁺。 LCMS: m/z 535.15 [M+H] ⁺ .

¹H NMR(300MHz,DMSO-d ₆)δ 11.85(s,1H),8.61(s,1H),8.07-7.92(m,3H),7.89(m,1H),7.38(m,1H),7.15(m,1H),7.04-7.01(m,1H),4.74(s,2H),3.65(m,4H),2.45(s,3H),1.33-1.31(m,3H),1.18(t,1H),0.45-0.42(m,1H),0.42(m,2H),0.29-0.27(m,1H)。 ¹ H NMR (300MHz, DMSO- d ₆ ) δ 11.85(s,1H), 8.61(s,1H), 8.07-7.92(m,3H), 7.89(m,1H), 7.38(m,1H), 7.15 (m,1H),7.04-7.01(m,1H),4.74(s,2H),3.65(m,4H),2.45(s,3H),1.33-1.31(m,3H),1.18(t,1H) ), 0.45-0.42(m, 1H), 0.42(m, 2H), 0.29-0.27(m, 1H).

實施例13：(S)-N-(2-(1-環丙基乙基)-6-(4-甲基-2-((6-(2-側氧吡咯烷-1-基)吡啶-2-基)胺基)噻唑-5-基)-3-異吲哚啉-4-基)甲磺醯胺(13)的製備 Example 13: (S)-N-(2-(1-cyclopropylethyl)-6-(4-methyl-2-((6-(2-oxopyrrolidin-1-yl)pyridine Preparation of -2-yl)amino)thiazol-5-yl)-3-isoindolin-4-yl)methanesulfonamide (13)

步驟1：(S)-N-(5-(2-(1-環丙基乙基)-7-(甲基磺醯胺基)-1-異吲哚啉-5-基)-4-甲基噻唑-2-基)乙醯胺(13a)的製備。 Step 1: (S)-N-(5-(2-(1-Cyclopropylethyl)-7-(methylsulfonamido)-1-isoindolin-5-yl)-4- Preparation of methylthiazol-2-yl)acetamide (13a).

於室溫，將(S)-N-(5-(7-氯-2-(1-環丙基乙基)-1-異吲哚啉-5-基)-4-甲基噻唑-2-基)乙醯胺(根據製備實施例4步驟2製備，只將原料1d替換為1b)(389mg,1.00mmol)、甲基磺醯胺(285mg,3mmol)、DMF(10.0mL)加到反應瓶中，然後加入第三丁醇鈉(288mg,3mmol)、t-buxphos(84.0mg,0.200mmol)、醋酸鈀(22.4mg,0.100mmol)，140℃攪拌反應7小時。反應結束後，抽濾，濾液減壓濃縮，殘餘物藉由管柱層析色譜法(沖提劑：石油醚：乙酸乙酯=5：1)純化，得到0.220黃色固體物的標題產物，收率：50.0%。 At room temperature, (S)-N-(5-(7-chloro-2-(1-cyclopropylethyl)-1-isoindolin-5-yl)-4-methylthiazole-2 -yl) acetamide (prepared according to Preparation Example 4, step 2, only replacing starting material 1d with 1b) (389 mg, 1.00 mmol), methylsulfonamide (285 mg, 3 mmol), DMF (10.0 mL) were added to the reaction Into the bottle, sodium tert-butoxide (288 mg, 3 mmol), t-buxphos (84.0 mg, 0.200 mmol), and palladium acetate (22.4 mg, 0.100 mmol) were added, and the reaction was stirred at 140° C. for 7 hours. After the reaction was completed, suction filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 5:1) to obtain 0.220 g of the title product as a yellow solid. Rate: 50.0%.

LCMS：m/z 449.12[M+H]⁺。 LCMS: m/z 449.12 [M+H] ⁺ .

步驟2：(S)-N-(6-(2-胺基-4-甲基噻唑-5-基)-2-(1-環丙基乙基)-3-異吲哚啉-4-基)甲磺醯胺(13b)的製備。 Step 2: (S)-N-(6-(2-Amino-4-methylthiazol-5-yl)-2-(1-cyclopropylethyl)-3-isoindoline-4- yl) methanesulfonamide (13b).

於室溫，將(S)-N-(5-(2-(1-環丙基乙基)-7-(甲基磺醯胺基)-1-異吲哚啉-5-基)-4-甲基噻唑-2-基)乙醯胺(110mg,0.25mmol)、3M鹽酸(20ml)、乙醇(20ml)混合，於70℃攪拌反應6小時。反應結束後，減壓濃縮，得到100mg黃色固體物的標題產物，直接用於下一步，收率：95.1%。 At room temperature, (S)-N-(5-(2-(1-cyclopropylethyl)-7-(methylsulfonamido)-1-isoindolin-5-yl)- 4-Methylthiazol-2-yl)acetamide (110 mg, 0.25 mmol), 3M hydrochloric acid (20 ml), and ethanol (20 ml) were mixed, and the reaction was stirred at 70° C. for 6 hours. After the reaction was completed, concentrated under reduced pressure to obtain 100 mg of the title product as a yellow solid, which was directly used in the next step, yield: 95.1%.

LCMS：m/z 407.10[M+H]⁺。 LCMS: m/z 407.10 [M+H] ⁺ .

步驟3：(S)-N-(2-(1-環丙基乙基)-6-(4-甲基-2-((6-(2-側氧吡咯烷-1-基)吡啶-2-基)胺基)噻唑-5-基)-3-異吲哚啉-4-基)甲磺醯胺(13)的製備。 Step 3: (S)-N-(2-(1-cyclopropylethyl)-6-(4-methyl-2-((6-(2-oxopyrrolidin-1-yl)pyridine- Preparation of 2-yl)amino)thiazol-5-yl)-3-isoindolin-4-yl)methanesulfonamide (13).

於室溫，將1-(6-溴吡啶-2-基)吡咯烷-2-酮(60.1mg,0.25mmol)、(S)-N-(6-(2-胺基-4-甲基噻唑-5-基)-2-(1-環丙基乙基)-3-異吲哚啉-4-基)甲磺醯胺(98.56mg,0.25mmol)、DMF(2.00mL)加到反應瓶中，然後加入碳酸鈉(79mg,0.750mmol)、Ruphos(35.0mg,0.075mmol)、2ndRuphos-Pd(29.0mg,0.0375mmol)，於125℃攪拌反應3小時。反應結束後，減壓濃縮，殘餘物用製備液相色譜法分離(色譜管柱型號：Daisogei 30mm*250mm，C18，10um，100A，流動相：乙腈/水，梯度：30%-80%)，得11.0mg黃色固體狀標題化合物，收率8.00%。 At room temperature, 1-(6-bromopyridin-2-yl)pyrrolidin-2-one (60.1 mg, 0.25 mmol), (S)-N-(6-(2-amino-4-methyl) Thiazol-5-yl)-2-(1-cyclopropylethyl)-3-isoindolin-4-yl)methanesulfonamide (98.56 mg, 0.25 mmol), DMF (2.00 mL) were added to the reaction To the bottle, sodium carbonate (79 mg, 0.750 mmol), Ruphos (35.0 mg, 0.075 mmol), 2nd Ruphos-Pd (29.0 mg, 0.0375 mmol) were then added, and the reaction was stirred at 125° C. for 3 hours. After the reaction, concentrated under reduced pressure, and the residue was separated by preparative liquid chromatography (chromatographic column model: Daisogei 30mm*250mm, C18, 10um, 100A, mobile phase: acetonitrile/water, gradient: 30%-80%), 11.0 mg of the title compound was obtained as a yellow solid in a yield of 8.00%.

LCMS：m/z 567.18[M+H]⁺。 LCMS: m/z 567.18 [M+H] ⁺ .

¹H NMR(300MHz,DMSO-d ₆)δ 11.44(s,1H),7.84-7.81(m,1H),7.71-7.68(m,1H),7.45(s,1H),7.34(s,1H),6.74-6.71(m,1H),4.72(s,2H),4.22-4.18(m,2H),3.31(s,1H),3.22(s,3H),2.59-2.56(m,2H),2.40(s,3H),2.07-2.05(m,2H),1.29-1.21(m,3H),1.20-1.10(m,1H),0.61-0.57(m,1H),0.47-0.41(m,2H),0.28-0.26(m,1H)。 ¹ H NMR (300MHz, DMSO- d ₆ ) δ 11.44(s,1H), 7.84-7.81(m,1H), 7.71-7.68(m,1H), 7.45(s,1H), 7.34(s,1H) ,6.74-6.71(m,1H),4.72(s,2H),4.22-4.18(m,2H),3.31(s,1H),3.22(s,3H),2.59-2.56(m,2H),2.40 (s,3H),2.07-2.05(m,2H),1.29-1.21(m,3H),1.20-1.10(m,1H),0.61-0.57(m,1H),0.47-0.41(m,2H) ,0.28-0.26(m,1H).

實施例14：(S)-2-(1-環丙基乙基)-5-(4-甲基-2-((6-(2-側氧吡咯烷-1-基)吡啶-2-基)胺基)噻唑-5-基)-7-(噻唑-2-基)異吲哚啉-1-酮(14)的製備 Example 14: (S)-2-(1-Cyclopropylethyl)-5-(4-methyl-2-((6-(2-oxopyrrolidin-1-yl)pyridine-2- Preparation of yl)amino)thiazol-5-yl)-7-(thiazol-2-yl)isoindolin-1-one (14)

與實施例2的製備方法相同，除了用(S)-5-溴-2-(1-環丙基乙基)-7-(噻唑-2-基)異吲哚啉-1-酮(7e)代替(S)-5-溴-7-氯-2-(1-環丙基乙基)異吲哚啉-1-酮(1b)，製得標題化合物。 The preparation method was the same as that of Example 2, except that (S)-5-bromo-2-(1-cyclopropylethyl)-7-(thiazol-2-yl)isoindolin-1-one (7e ) in place of (S)-5-bromo-7-chloro-2-(1-cyclopropylethyl)isoindolin-1-one (1b) to give the title compound.

LCMS：m/z 557.17[M+H]⁺。 LCMS: m/z 557.17 [M+H] ⁺ .

¹H NMR(300MHz,DMSO-d ₆)δ 11.47(s,1H),8.30(s,1H),7.98(s,1H),7.93(s,1H),7.83(t,2H),7.71(t,1H),6.78-6.75(d,1H),4.66(s,2H),4.28-4.23(t,2H),3.65-3.60(t,1H),2.62-2.57(t,2H),2.46(s,3H),2.13-2.09(t,2H),1.32-1.30(d,3H),1.17(s,1H),0.42(s,1H),0.41(s,2H),0.28-0.26(m,1H)。 ¹ H NMR (300MHz, DMSO- d ₆ ) δ 11.47(s, 1H), 8.30(s, 1H), 7.98(s, 1H), 7.93(s, 1H), 7.83(t, 2H), 7.71(t ,1H),6.78-6.75(d,1H),4.66(s,2H),4.28-4.23(t,2H),3.65-3.60(t,1H),2.62-2.57(t,2H),2.46(s ,3H),2.13-2.09(t,2H),1.32-1.30(d,3H),1.17(s,1H),0.42(s,1H),0.41(s,2H),0.28-0.26(m,1H) ).

實施例15：(S)-N-(6-((5-(2-(1-環丙基乙基)-7-(甲基磺醯基)-1-異吲哚啉-5-基)-4-甲基噻唑-2-基)胺基)吡啶-2-基)N-甲基環丙烷磺醯胺(15)的製備 Example 15: (S)-N-(6-((5-(2-(1-cyclopropylethyl)-7-(methylsulfonyl)-1-isoindolin-5-yl )-4-methylthiazol-2-yl)amino)pyridin-2-yl)N-methylcyclopropanesulfonamide (15) preparation

與實施例3的製備方法相同，除了用N-(6-溴吡啶-2-基)環丙烷甲基磺胺(6b)代替1-(6-溴-吡嗪-2-基)吡咯烷-2-酮，製得標題化合物。 The preparation method was the same as in Example 3, except that N-(6-bromopyridin-2-yl)cyclopropanemethylsulfonamide (6b) was used instead of 1-(6-bromo-pyrazin-2-yl)pyrrolidine-2 - ketone to give the title compound.

LCMS：m/z 602.15[M+H]⁺。 LCMS: m/z 602.15 [M+H] ⁺ .

¹H NMR(300MHz,DMSO-d ₆)δ 11.70(s,1H),8.04-8.00(m,2H),7.68-7.62(m,1H),7.02-6.94(m,2H),4.72(s,2H),3.63-3.59(m,4H),3.46(s,3H),2.77(s,1H),2.50(s,3H),1.65-1.00(m,9H),0.61-0.57(m,1H),0.47-0.41(m,2H),0.28-0.26(m,1H)。 ¹ H NMR (300MHz, DMSO- d ₆ ) δ 11.70(s, 1H), 8.04-8.00(m, 2H), 7.68-7.62(m, 1H), 7.02-6.94(m, 2H), 4.72(s, 2H), 3.63-3.59(m, 4H), 3.46(s, 3H), 2.77(s, 1H), 2.50(s, 3H), 1.65-1.00(m, 9H), 0.61-0.57(m, 1H) ,0.47-0.41(m,2H),0.28-0.26(m,1H).

實施例16：(S)-2-(1-環丙基乙基)-5-(4-甲基-2-((6-(5-側氧-4-氮雜螺[2.4]庚-4-基)吡啶-2-基)胺基)噻唑-5-基)-7-(甲基磺醯基)異吲哚啉-1-酮(16)的製備 Example 16: (S)-2-(1-Cyclopropylethyl)-5-(4-methyl-2-((6-(5-oxo-4-azaspiro[2.4]heptyl- Preparation of 4-yl)pyridin-2-yl)amino)thiazol-5-yl)-7-(methylsulfonyl)isoindolin-1-one (16)

與實施例3的製備方法相同，除了用4-(6-溴吡啶-2-基)-4-氮雜螺[2.4]庚烷-5-酮(根據製備實施例2步驟1製備，將2,6-二溴吡啶替換為5-側氧-4-氮雜螺[2.4]庚烷)代替1-(6-溴-吡嗪-2-基)吡咯烷-2-酮製得標題化合物。 The preparation method is the same as that of Example 3, except that 4-(6-bromopyridin-2-yl)-4-azaspiro[2.4]heptan-5-one (prepared according to step 1 of Preparation Example 2, 2 , 6-dibromopyridine was replaced by 5-oxo-4-azaspiro[2.4]heptane) instead of 1-(6-bromo-pyrazin-2-yl)pyrrolidin-2-one to obtain the title compound.

LCMS：m/z 578.18[M+H]⁺。 LCMS: m/z 578.18 [M+H] ⁺ .

¹H NMR(300MHz,DMSO-d ₆)δ 11.59(s,1H),8.05-8.03(m,2H),7.83-7.77(t,1H),7.06-7.03(m,1H),6.84-6.81(m,1H),4.72(s,2H),3.64-3.60(s,4H),2.51(t,2H),2.45(s,3H),2.18(t,2H),1.33(s,3H),1.07(s,1H),1.03(m,2H),0.72-0.68(m,2H),0.60(s,1H),0.44-0.42(m,2H),0.28-0.27(m,1H)。 ¹ H NMR (300MHz, DMSO- d ₆ ) δ 11.59 (s, 1H), 8.05-8.03 (m, 2H), 7.83-7.77 (t, 1H), 7.06-7.03 (m, 1H), 6.84-6.81 ( m, 1H), 4.72(s, 2H), 3.64-3.60(s, 4H), 2.51(t, 2H), 2.45(s, 3H), 2.18(t, 2H), 1.33(s, 3H), 1.07 (s, 1H), 1.03 (m, 2H), 0.72-0.68 (m, 2H), 0.60 (s, 1H), 0.44-0.42 (m, 2H), 0.28-0.27 (m, 1H).

實施例17：(S)-2-(1-環丙基乙基)-5-(4-甲基-2-((6-(噻唑-2-基)吡啶-2-基)胺基)噻唑-5-基)-7-(甲基磺醯基)異吲哚啉-1-酮(17)的製備 Example 17: (S)-2-(1-Cyclopropylethyl)-5-(4-methyl-2-((6-(thiazol-2-yl)pyridin-2-yl)amino) Preparation of Thiazol-5-yl)-7-(methylsulfonyl)isoindolin-1-one (17)

與實施例3的製備方法相同，除了用2-(6-溴吡啶-2-基)噻唑(根據製備實施例2步驟1製備，將2,6-二溴吡啶替換為噻唑)代替1-(6-溴-吡嗪-2-基)吡咯烷-2-酮，製得標題化合物。 The preparation method was the same as that of Example 3, except that 2-(6-bromopyridin-2-yl)thiazole (prepared according to Step 1 of Preparation Example 2, replacing 2,6-dibromopyridine with thiazole) was used instead of 1-( 6-Bromo-pyrazin-2-yl)pyrrolidin-2-one to give the title compound.

LCMS：m/z 552.11[M+H]⁺。 LCMS: m/z 552.11 [M+H] ⁺ .

實施例18：2-((S)-1-環丙基乙基)-5-(4-甲基-2-((6-(2-側氧-3-氮雜雙環[3.1.0]己-3-基)吡啶-2-基)胺基)噻唑-5-基)-7-(甲基磺醯基)異吲哚啉-1-酮(18)的製備 Example 18: 2-((S)-1-Cyclopropylethyl)-5-(4-methyl-2-((6-(2-oxo-3-azabicyclo[3.1.0] Preparation of hex-3-yl)pyridin-2-yl)amino)thiazol-5-yl)-7-(methylsulfonyl)isoindolin-1-one (18)

與實施例3的製備方法相同，除了用4-(6-溴吡啶-2-基)-氮雜雙環[3.1.0]己-5-酮(根據製備實施例2步驟1製備，將2,6-二溴吡啶替換為氮雜雙環[3.1.0]己-5-酮)代替1-(6-溴-吡嗪-2-基)吡咯烷-2-酮，製得標題化合物。 The preparation method was the same as that of Example 3, except that 4-(6-bromopyridin-2-yl)-azabicyclo[3.1.0]hexan-5-one (prepared according to Step 1 of Preparation Example 2, 2, Substituting 6-dibromopyridine with azabicyclo[3.1.0]hex-5-one) instead of 1-(6-bromo-pyrazin-2-yl)pyrrolidin-2-one afforded the title compound.

LCMS：m/z 564.17[M+H]⁺。 LCMS: m/z 564.17 [M+H] ⁺ .

¹HNMR(300MHz,DMSO-d ₆)δ 11.52(s,1H),8.09-8.05(m,2H),7.70-7.68(m,2H),6.74-6.71(m,1H),4.73(s,2H),4.31(s,1H),4.18(d,1H),3.65(s,4H),2.50-2.46(m,3H),1.33-1.31(m,3H),1.23(s,4H),0.80(s,1H),0.60(s,1H),0.44(s,2H),0.29(s,1H)。 ¹ HNMR (300MHz, DMSO- d ₆ ) δ 11.52(s, 1H), 8.09-8.05(m, 2H), 7.70-7.68(m, 2H), 6.74-6.71(m, 1H), 4.73(s, 2H) ),4.31(s,1H),4.18(d,1H),3.65(s,4H),2.50-2.46(m,3H),1.33-1.31(m,3H),1.23(s,4H),0.80( s, 1H), 0.60 (s, 1H), 0.44 (s, 2H), 0.29 (s, 1H).

實施例19：(S)-2-(1-環丙基乙基)-7-(二甲基磷醯基)-5-(4-甲基-2-((6-(2-側氧吡咯烷-1-基)吡啶-2-基)胺基)噻唑唑-5-基)異吲哚啉-1-酮(19)的製備 Example 19: (S)-2-(1-Cyclopropylethyl)-7-(dimethylphosphoryl)-5-(4-methyl-2-((6-(2-oxygen Preparation of pyrrolidin-1-yl)pyridin-2-yl)amino)thiazolazol-5-yl)isoindolin-1-one (19)

步驟1：(S)-5-溴-2-(1-環丙基乙基)-7-(二甲基磷醯基)異吲哚啉-1-酮(19a)的製備。 Step 1: Preparation of (S)-5-bromo-2-(1-cyclopropylethyl)-7-(dimethylphosphoronyl)isoindolin-1-one (19a).

於室溫，將(S)-5-溴-2-(1-環丙基乙基)-7-碘代異吲哚啉-1-酮(7d)(204mg,0.504mmol)、二甲基磷氧化物(1.18g,15.1mmol)、乙腈(5mL)加到反應瓶中，然後加入磷酸三鉀(129mg,0.605mmol)、Pd(dppf)Cl₂(37.4mg,0.051mmol)、Xantphos(35.3mg,0.061mmol)，60℃攪拌反應12小時。反應結束後，減壓濃縮，殘餘物藉由管柱層析色譜法(沖提劑：二氯甲烷：甲醇=20：1)純化，得到122mg棕色固體物的標題產物，收率：68.2%。 At room temperature, (S)-5-bromo-2-(1-cyclopropylethyl)-7-iodoisoindolin-1-one (7d) (204 mg, 0.504 mmol), dimethyl Phosphorus oxide (1.18 g, 15.1 mmol), acetonitrile (5 mL) were added to the reaction flask, followed by tripotassium phosphate (129 mg, 0.605 mmol), Pd(dppf)Cl ₂ (37.4 mg, 0.051 mmol), Xantphos (35.3 mg, 0.061 mmol), and the reaction was stirred at 60°C for 12 hours. After the reaction was completed, it was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: dichloromethane: methanol = 20: 1) to obtain 122 mg of the title product as a brown solid, yield: 68.2%.

LCMS：m/z 356.03[M+H]⁺。 LCMS: m/z 356.03 [M+H] ⁺ .

步驟2：(S)-2-(1-環丙基乙基)-7-(二甲基磷醯基)-5-(4-甲基-2-((6-(2-側氧吡咯烷-1-基)吡啶-2-基)胺基)噻唑唑-5-基)異吲哚啉-1-酮(19)的製備。 Step 2: (S)-2-(1-Cyclopropylethyl)-7-(dimethylphosphoryl)-5-(4-methyl-2-((6-(2-oxopyrrole) Preparation of alk-1-yl)pyridin-2-yl)amino)thiazolazol-5-yl)isoindolin-1-one (19).

與實施例2的製備方法相同，除了用(S)-5-溴-2-(1-環丙基乙基)-7-(二甲基磷醯基)異吲哚啉-1-酮代替(S)-5-溴-7-氯-2-(1-環丙基乙基)異吲哚啉-1-酮(1b)，製得標題化合物。 The preparation method was the same as that of Example 2, except that (S)-5-bromo-2-(1-cyclopropylethyl)-7-(dimethylphosphoronyl)isoindolin-1-one was used instead of (S)-5-Bromo-7-chloro-2-(1-cyclopropylethyl)isoindolin-1-one (1b) to give the title compound.

LCMS：m/z 550.20[M+H]⁺。 LCMS: m/z 550.20 [M+H] ⁺ .

¹H NMR(400MHz,DMSO-d ₆)δ 11.50(s,1H),8.19-8.16(m,1H),7.85(t,2H),7.74-7.70(m,1H),6.78-6.76(m,1H),4.66(s,2H),4.23-4.21(s,2H),3.60(s,1H),2.51-2.50(m,2H),2.43(s,3H),2.09(t,2H),1.86(d,4H),1.52(t,3H),1.17-1.13(m,2H),1.10(s,1H),0.59(s,1H),0.43-0.27(m,2H),0.26-0.25(m,1H)。 ¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.50(s, 1H), 8.19-8.16(m, 1H), 7.85(t, 2H), 7.74-7.70(m, 1H), 6.78-6.76(m, 1H), 4.66(s, 2H), 4.23-4.21(s, 2H), 3.60(s, 1H), 2.51-2.50(m, 2H), 2.43(s, 3H), 2.09(t, 2H), 1.86 (d,4H),1.52(t,3H),1.17-1.13(m,2H),1.10(s,1H),0.59(s,1H),0.43-0.27(m,2H),0.26-0.25(m , 1H).

實施例20：(S)-5-(2-((6-(1H-咪唑-1-基)吡啶-2-基)胺基)-4-甲基-噻唑-5-基)-7-(氮雜環丁烷-1-基磺醯基)-2-(1-環丙基乙基)異吲哚啉-1-酮(20)的製備 Example 20: (S)-5-(2-((6-(1H-imidazol-1-yl)pyridin-2-yl)amino)-4-methyl-thiazol-5-yl)-7- Preparation of (azetidin-1-ylsulfonyl)-2-(1-cyclopropylethyl)isoindolin-1-one (20)

步驟1：(S)-N-(5-(7-(氮雜環丁烷-1-基磺醯基)-2-(1-環丙基乙基)-1-氧基異吲哚啉-5-基)-4-甲基噻唑-2-基)乙醯胺(20a)的製備。 Step 1: (S)-N-(5-(7-(azetidin-1-ylsulfonyl)-2-(1-cyclopropylethyl)-1-oxyisoindoline Preparation of -5-yl)-4-methylthiazol-2-yl)acetamide (20a).

與製備實施例4的步驟2相同，除了用(S)-7-(氮雜環丁烷-1-基磺醯基)-5-溴-2-(1-環丙基乙基)異吲哚啉-1-酮(5c)代替(S)-5-溴-2-(1-環丙基乙基)-7-(甲基磺醯基)異吲哚啉-1-酮(1d)，製得標題化合物。 Same as step 2 of Preparative Example 4, except using (S)-7-(azetidin-1-ylsulfonyl)-5-bromo-2-(1-cyclopropylethyl)isoindium Indolin-1-one (5c) in place of (S)-5-bromo-2-(1-cyclopropylethyl)-7-(methylsulfonyl)isoindolin-1-one (1d) , the title compound was obtained.

LCMS：m/z 475.14[M+H]⁺。 LCMS: m/z 475.14 [M+H] ⁺ .

步驟2：(S)-5-(2-胺基-4-甲基噻唑-5-基)-7-(氮雜環丁烷-1-基磺醯基)-2-(1-環丙基乙基)異吲哚啉-1-酮(20b)的製備。 Step 2: (S)-5-(2-Amino-4-methylthiazol-5-yl)-7-(azetidin-1-ylsulfonyl)-2-(1-cyclopropane Preparation of ethyl)isoindolin-1-one (20b).

將(S)-N-(5-(7-(氮雜環丁烷-1-基磺醯基)-2-(1-環丙基乙基)-1-氧基異吲哚啉-5-基)-4-甲基噻唑-2-基)乙醯胺(322mg,0.679mmol)、氫氧化鋰(164mg，6.79mmol)、甲醇(10ml)、水(2ml)加到反應瓶中，60℃攪拌反應8小時。反應結束後，減壓濃縮，殘餘物藉由矽膠管柱層析色譜法(沖提劑：二氯甲烷：甲醇=20：1)純化，得到124mg黃色固體物的標題產物，收率：42.3%。 (S)-N-(5-(7-(azetidin-1-ylsulfonyl)-2-(1-cyclopropylethyl)-1-oxyisoindoline-5 -yl)-4-methylthiazol-2-yl)acetamide (322mg, 0.679mmol), lithium hydroxide (164mg, 6.79mmol), methanol (10ml), water (2ml) were added to the reaction flask, 60 The reaction was stirred for 8 hours. After the reaction was completed, it was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane: methanol = 20: 1) to obtain 124 mg of the title product as a yellow solid, yield: 42.3% .

LCMS：m/z 433.13[M+H]⁺。 LCMS: m/z 433.13 [M+H] ⁺ .

步驟3：(S)-5-(2-((6-(1H-咪唑-1-基)吡啶-2-基)胺基)-4-甲基-噻唑-5-基)-7-(氮雜環丁烷-1-基磺醯基)-2-(1-環丙基乙基)異吲哚啉-1-酮(20)的製備。 Step 3: (S)-5-(2-((6-(1H-imidazol-1-yl)pyridin-2-yl)amino)-4-methyl-thiazol-5-yl)-7-( Preparation of azetidin-1-ylsulfonyl)-2-(1-cyclopropylethyl)isoindolin-1-one (20).

與實施例3的製備方法相同，除了用2-溴-6-(1H-咪唑-1-基)吡啶代替1-(6-溴-吡嗪-2-基)吡咯烷-2-酮，以及用(S)-5-(2-胺基-4-甲基噻唑-5-基)-7-(氮雜環丁烷-1-基磺醯基)-2-(1-環丙基乙基)異吲哚啉-1-酮(20b)代替(S)-5-(2-胺基-4-甲基噻唑-5-基)-2-(1-環丙基乙基)-7-(甲基磺醯基)異吲哚啉-1-酮(4c)，製得標題化合物。 Prepared in the same manner as in Example 3, except that 2-bromo-6-(1H-imidazol-1-yl)pyridine was used instead of 1-(6-bromo-pyrazin-2-yl)pyrrolidin-2-one, and with (S)-5-(2-amino-4-methylthiazol-5-yl)-7-(azetidin-1-ylsulfonyl)-2-(1-cyclopropylethyl) yl)isoindolin-1-one (20b) in place of (S)-5-(2-amino-4-methylthiazol-5-yl)-2-(1-cyclopropylethyl)-7 -(Methylsulfonyl)isoindolin-1-one (4c) to prepare the title compound.

LCMS：m/z 576.18[M+H]⁺。 LCMS: m/z 576.18 [M+H] ⁺ .

¹H NMR(300MHz,DMSO-d ₆)δ 11.85(s,1H),8.62(s,1H),8.05-8.04(m,2H),7.97-7.90(m,2H),7.38-7.36(m,1H),7.15(s,1H),7.04-7.01(m,1H),4.69(s,2H),3.98-3.93(m,4H),3.65(m,1H),2.46(s,3H),2.11-2.06(m,2H),1.32-1.29(m,3H),1.23(m,1H),0.46(m,1H),0.43(m,2H),0.41(m,1H)。 ¹ H NMR (300MHz, DMSO- d ₆ ) δ 11.85(s,1H), 8.62(s,1H), 8.05-8.04(m,2H), 7.97-7.90(m,2H), 7.38-7.36(m, 1H), 7.15(s, 1H), 7.04-7.01(m, 1H), 4.69(s, 2H), 3.98-3.93(m, 4H), 3.65(m, 1H), 2.46(s, 3H), 2.11 -2.06(m, 2H), 1.32-1.29(m, 3H), 1.23(m, 1H), 0.46(m, 1H), 0.43(m, 2H), 0.41(m, 1H).

實施例21：(S)-2-(1-環丙基乙基)-7-((3-羥基氮雜環丁烷-1-基)磺醯基)-5-(4-甲基-2-((6-(2-氧吡咯烷-1-基)吡啶-2-基)胺基)噻唑基-5基)異吲哚啉-1-酮(21)的製備 Example 21: (S)-2-(1-Cyclopropylethyl)-7-((3-hydroxyazetidin-1-yl)sulfonyl)-5-(4-methyl- Preparation of 2-((6-(2-Oxypyrrolidin-1-yl)pyridin-2-yl)amino)thiazolyl-5yl)isoindolin-1-one (21)

步驟1：(S)-5-溴-2-(1-環丙基乙基)-7-((3-羥基氮雜環丁烷-1-基)磺醯基)異吲哚啉-1-酮(21a)的製備。 Step 1: (S)-5-Bromo-2-(1-cyclopropylethyl)-7-((3-hydroxyazetidin-1-yl)sulfonyl)isoindoline-1 - Preparation of ketone (21a).

於室溫，將(S)-6-溴-2-(1-環丙基乙基)-3-側氧異吲哚啉-4-磺醯氯(5b)(500mg,1.33mmol)、氮雜環丁烷-3-醇(1.47g,13.3mmol)、碳酸銫(865mg,2.66mmol)、DCM(5mL)加到反應瓶中，在氮氣氛下，於40℃攪拌反應12小時。反應結束後，減壓濃縮，殘餘物藉由矽膠管柱層析色譜法(沖提劑：石油醚：乙酸乙酯=2：1)純化，得到263mg白色固體物的標題產物，收率47.8%。 At room temperature, (S)-6-bromo-2-(1-cyclopropylethyl)-3-oxoisoindoline-4-sulfonyl chloride (5b) (500 mg, 1.33 mmol), nitrogen Hetetan-3-ol (1.47 g, 13.3 mmol), cesium carbonate (865 mg, 2.66 mmol), DCM (5 mL) were added to the reaction flask, and the reaction was stirred at 40° C. for 12 hours under nitrogen atmosphere. After the reaction was completed, it was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 2:1) to obtain 263 mg of the title product as a white solid, yield 47.8% .

LCMS：m/z 415.02[M+H]⁺。 LCMS: m/z 415.02 [M+H] ⁺ .

步驟2：(S)-2-(1-環丙基乙基)-7-((3-羥基氮雜環丁烷-1-基)磺醯基)-5-(4-甲基-2-((6-(2-氧吡咯烷-1-基)吡啶-2-基)胺基)噻唑基-5基)異吲哚啉-1-酮(21)的製備。 Step 2: (S)-2-(1-Cyclopropylethyl)-7-((3-hydroxyazetidin-1-yl)sulfonyl)-5-(4-methyl-2 - Preparation of ((6-(2-oxopyrrolidin-1-yl)pyridin-2-yl)amino)thiazolyl-5yl)isoindolin-1-one (21).

與實施例1的製備方法相同，除了用1-(6-((4-甲基噻唑-2-基)胺基)吡啶-2-基)吡咯烷-2-酮(2b)代替1-(4-((4-甲基噻唑-2-基)胺基)吡啶-2-基)吡咯烷-2-酮(3c)，以及用(S)-5-溴-2-(1-環丙基乙基)-7-((3-羥基氮雜環丁烷-1-基)磺醯基)異吲哚啉-1-酮(21a)代替(S)-5-溴-2-(1-環丙基乙基)-7-(甲基磺醯基)異吲哚啉-1-酮(1d)，製得標題化合物。 The preparation method was the same as in Example 1, except that 1-(6-((4-methylthiazol-2-yl)amino)pyridin-2-yl)pyrrolidin-2-one (2b) was used instead of 1-( 4-((4-Methylthiazol-2-yl)amino)pyridin-2-yl)pyrrolidin-2-one (3c), and (S)-5-bromo-2-(1-cyclopropane) ethyl)-7-((3-hydroxyazetidin-1-yl)sulfonyl)isoindolin-1-one (21a) instead of (S)-5-bromo-2-(1 -Cyclopropylethyl)-7-(methylsulfonyl)isoindolin-1-one (1d) to prepare the title compound.

LCMS：m/z 609.19[M+H]⁺。 LCMS: m/z 609.19 [M+H] ⁺ .

¹H NMR(300MHz,DMSO-d ₆)δ 11.54(s,1H),7.99-7.95(m,2H),7.87-7.84(m,1H),7.75-7.70(m,1H),6.78-6.76(m,1H),5.72-5.70(m,1H),4.67(s,2H),4.36-4.31(m,1H),4.26-4.21(m,2H),4.11-4.05(m,2H),3.70-3.59(m,3H),2.62-2.57(m,2H),2.45(s,3H),2.11-2.06(m,2H),1.31-1.29(m,3H),1.16-1.13(m,1H),0.59(m,1H),0.44-0.38(m,2H),0.27-0.25(m,1H)。 ¹ H NMR (300MHz, DMSO- d ₆ ) δ 11.54 (s, 1H), 7.99-7.95 (m, 2H), 7.87-7.84 (m, 1H), 7.75-7.70 (m, 1H), 6.78-6.76 ( m, 1H), 5.72-5.70(m, 1H), 4.67(s, 2H), 4.36-4.31(m, 1H), 4.26-4.21(m, 2H), 4.11-4.05(m, 2H), 3.70- 3.59(m,3H), 2.62-2.57(m,2H), 2.45(s,3H), 2.11-2.06(m,2H), 1.31-1.29(m,3H), 1.16-1.13(m,1H), 0.59 (m, 1H), 0.44-0.38 (m, 2H), 0.27-0.25 (m, 1H).

實施例22：(S)-2-(1-環丙基乙基)-5-(4-甲基-2-((6-(2-側氧吡咯烷-1-基)吡啶-2-基)胺基)噻唑-5-基)-7-(吡咯烷-1-基磺醯基)異吲哚啉-1-酮(22)的製備 Example 22: (S)-2-(1-Cyclopropylethyl)-5-(4-methyl-2-((6-(2-oxopyrrolidin-1-yl)pyridine-2- Preparation of (22)

與實施例2的製備方法相同，除了用(S)-5-溴-2-(1-環丙基乙基)-7-(吡咯烷-1-基磺醯基)異吲哚啉-1-酮(根據製備實施例5製備，將步驟3的氮雜環丁烷替換為吡咯烷)代替(S)-5-溴-7-氯-2-(1-環丙基乙基)異吲哚啉-1-酮(1b)，製得標題化合物。 The preparation method was the same as that of Example 2, except that (S)-5-bromo-2-(1-cyclopropylethyl)-7-(pyrrolidin-1-ylsulfonyl)isoindoline-1 was used -ketone (prepared according to Preparation Example 5, replacing azetidine in step 3 with pyrrolidine) in place of (S)-5-bromo-7-chloro-2-(1-cyclopropylethyl)isoindium indolin-1-one (1b) to give the title compound.

LCMS：m/z 607.21[M+H]⁺。 LCMS: m/z 607.21 [M+H] ⁺ .

¹H NMR(300MHz,DMSO-d ₆)δ 11.55(s,1H),7.95-7.93(m,2H),7.87-7.84(m,1H),7.75-7.70(m,1H),6.78-6.76(m,1H),4.64(s,2H),4.26-4.21(m,2H),3.64-3.59(m,1H),3.42-3.39(m,4H),2.62-2.57(m,2H),2.45(s,3H),2.10-2.06(m,2H),1.76(s, 4H),1.30-1.28(m,3H),1.15(s,1H),0.61-0.58(m,1H),0.41-0.39(m,2H),0.26-0.24(m,1H)。 ¹ H NMR (300MHz, DMSO- d ₆ ) δ 11.55 (s, 1H), 7.95-7.93 (m, 2H), 7.87-7.84 (m, 1H), 7.75-7.70 (m, 1H), 6.78-6.76 ( m, 1H), 4.64(s, 2H), 4.26-4.21(m, 2H), 3.64-3.59(m, 1H), 3.42-3.39(m, 4H), 2.62-2.57(m, 2H), 2.45( s,3H),2.10-2.06(m,2H),1.76(s,4H),1.30-1.28(m,3H),1.15(s,1H),0.61-0.58(m,1H),0.41-0.39( m, 2H), 0.26-0.24 (m, 1H).

實施例23：2-((S)-1-環丙基乙基)-7-((3-羥基吡咯烷-1-基)磺醯基)-5-(4-甲基-2-((6-(2-側氧吡咯烷-1-基)吡啶-2-基)胺基)噻唑-5-基)異吲哚啉-1-酮(23)的製備 Example 23: 2-((S)-1-Cyclopropylethyl)-7-((3-hydroxypyrrolidin-1-yl)sulfonyl)-5-(4-methyl-2-( Preparation of (6-(2-oxypyrrolidin-1-yl)pyridin-2-yl)amino)thiazol-5-yl)isoindolin-1-one (23)

與實施例1的製備方法相同，除了用1-(6-((4-甲基噻唑-2-基)胺基)吡啶-2-基)吡咯烷-2-酮(2b)代替1-(4-((4-甲基噻唑-2-基)胺基)吡啶-2-基)吡咯烷-2-酮(3c)，以及用5-溴-2-((S)-1-環丙基乙基)-7-((3-羥基吡咯烷-1-基)磺醯基)異吲哚啉-1-酮(根據製備實施例5製備，將步驟3的氮雜環丁烷替換為3-羥基吡咯烷)代替(S)-5-溴-2-(1-環丙基乙基)-7-(甲基磺醯基)異吲哚啉-1-酮(1d)，製得標題化合物。 The preparation method was the same as in Example 1, except that 1-(6-((4-methylthiazol-2-yl)amino)pyridin-2-yl)pyrrolidin-2-one (2b) was used instead of 1-( 4-((4-Methylthiazol-2-yl)amino)pyridin-2-yl)pyrrolidin-2-one (3c), and 5-bromo-2-(((S)-1-cyclopropane) ylethyl)-7-((3-hydroxypyrrolidin-1-yl)sulfonyl)isoindolin-1-one (prepared according to Preparation Example 5, replacing the azetidine of step 3 with 3-Hydroxypyrrolidine) instead of (S)-5-bromo-2-(1-cyclopropylethyl)-7-(methylsulfonyl)isoindolin-1-one (1d), prepared title compound.

LCMS：m/z 623.20[M+H]⁺。 LCMS: m/z 623.20 [M+H] ⁺ .

¹H NMR(300MHz,DMSO-d ₆)δ 11.85(s,1H),7.97-7.92(m,2H),7.86-7.84(m,1H),7.71(m,1H),6.77-6.75(m,1H),5.02(s,1H),4.63(s,2H),4.24(s,3H),3.60-3.58(m, 5H),2.61-2.58(m,2H),2.43(s,3H),2.09(m,2H),2.06(m,2H),1.30(m,3H),1.28(m,1H),0.46(m,1H),0.40(m,2H),0.21(m,1H)。 ¹ H NMR (300MHz, DMSO- d ₆ ) δ 11.85 (s, 1H), 7.97-7.92 (m, 2H), 7.86-7.84 (m, 1H), 7.71 (m, 1H), 6.77-6.75 (m, 1H), 5.02(s, 1H), 4.63(s, 2H), 4.24(s, 3H), 3.60-3.58(m, 5H), 2.61-2.58(m, 2H), 2.43(s, 3H), 2.09 (m, 2H), 2.06 (m, 2H), 1.30 (m, 3H), 1.28 (m, 1H), 0.46 (m, 1H), 0.40 (m, 2H), 0.21 (m, 1H).

實施例24：(S)-7-(氮(S)-2-(1-環丙基乙基)-5-(4-甲基-2-((6-(2-側氧吡咯烷-1-基)吡啶-2-基)胺基)噻唑-5-基)-7-(嗎啉磺醯基)異吲哚啉-1-酮(24)的製備 Example 24: (S)-7-(Nitrogen(S)-2-(1-cyclopropylethyl)-5-(4-methyl-2-((6-(2-oxopyrrolidine- Preparation of 1-yl)pyridin-2-yl)amino)thiazol-5-yl)-7-(morpholinosulfonyl)isoindolin-1-one (24)

與實施例1的製備方法相同，除了用1-(6-((4-甲基噻唑-2-基)胺基)吡啶-2-基)吡咯烷-2-酮(2b)代替1-(4-((4-甲基噻唑-2-基)胺基)吡啶-2-基)吡咯烷-2-酮(3c)，以及用(S)-5-溴-2-(1-環丙基乙基)-7-(嗎啉磺醯基)異吲哚啉-1-酮(根據製備實施例5製備，將步驟3的氮雜環丁烷替換為嗎啉)代替(S)-5-溴-2-(1-環丙基乙基)-7-(甲基磺醯基)異吲哚啉-1-酮(1d)，製得標題化合物。 The preparation method was the same as in Example 1, except that 1-(6-((4-methylthiazol-2-yl)amino)pyridin-2-yl)pyrrolidin-2-one (2b) was used instead of 1-( 4-((4-Methylthiazol-2-yl)amino)pyridin-2-yl)pyrrolidin-2-one (3c), and (S)-5-bromo-2-(1-cyclopropane) (S)-5 (S)-5 -Bromo-2-(1-cyclopropylethyl)-7-(methylsulfonyl)isoindolin-1-one (1d) to give the title compound.

LCMS：m/z 623.20[M+H]⁺。 LCMS: m/z 623.20 [M+H] ⁺ .

¹H NMR(300MHz,DMSO-d ₆)δ 11.55(s,1H),7.98(s,2H),7.87-7.84(m,1H),7.75-7.70(m,1H),6.78-6.76(m,1H),4.66(s,2H),4.27-4.22(m,2H),3.64-3.62(m,1H), 3.59-3.54(m,4H),3.25(s,4H),2.62-2.57(m,2H),2.45(s,3H),2.11-2.06(m,2H),1.31-1.29(m,3H),1.23(m,1H),0.58(m,1H),0.42-0.39(m,2H),0.27-0.25(m,1H)。 ¹ H NMR (300MHz, DMSO- d ₆ ) δ 11.55(s, 1H), 7.98(s, 2H), 7.87-7.84(m, 1H), 7.75-7.70(m, 1H), 6.78-6.76(m, 1H), 4.66(s, 2H), 4.27-4.22(m, 2H), 3.64-3.62(m, 1H), 3.59-3.54(m, 4H), 3.25(s, 4H), 2.62-2.57(m, 2H), 2.45(s, 3H), 2.11-2.06(m, 2H), 1.31-1.29(m, 3H), 1.23(m, 1H), 0.58(m, 1H), 0.42-0.39(m, 2H) ,0.27-0.25(m,1H).

實施例25：(S)-2-(1-環丙基乙基)-7-((3,3-二氟氮雜環丁烷-1-基)磺醯基)-5-(4-甲基-2-((6-(2-側氧吡咯烷-1-基)吡啶-2-基)胺基)噻唑-5-基)異吲哚啉-1-酮(25)的製備 Example 25: (S)-2-(1-Cyclopropylethyl)-7-((3,3-difluoroazetidin-1-yl)sulfonyl)-5-(4- Preparation of methyl-2-((6-(2-oxypyrrolidin-1-yl)pyridin-2-yl)amino)thiazol-5-yl)isoindolin-1-one (25)

與實施例2的製備方法相同，除了用(S)-5-溴-2-(1-環丙基乙基)-7-((3,3-二氟氮雜環丁烷-1-基)磺醯基)異吲哚啉-1-酮(根據製備實施例5製備，將步驟3的氮雜環丁烷替換為3,3-二氟氮雜環丁烷)代替(S)-5-溴-7-氯-2-(1-環丙基乙基)異吲哚啉-1-酮(1d)，製得標題化合物。 The preparation method was the same as that of Example 2, except that (S)-5-bromo-2-(1-cyclopropylethyl)-7-((3,3-difluoroazetidin-1-yl) was used ) sulfonyl)isoindolin-1-one (prepared according to Preparation Example 5, substituting 3,3-difluoroazetidine for azetidine in step 3) instead of (S)-5 -Bromo-7-chloro-2-(1-cyclopropylethyl)isoindolin-1-one (1d) to prepare the title compound.

LCMS：m/z 629.17[M+H]⁺。 LCMS: m/z 629.17 [M+H] ⁺ .

¹H NMR(300MHz,DMSO-d ₆)δ 11.55(s,1H),8.00-7.98(m,2H),7.86-7.83(m,1H),7.74-7.71(m,1H),6.77-6.74(m,1H),4.68(s,2H),4.57-4.48(m,4H),4.25-4.20(m, 2H),3.61(m,1H),2.61-2.55(m,2H),2.44(s,3H),2.11-2.04(m,2H),1.30-1.28(m,3H),1.22(m,1H),0.61-0.58(m,1H),0.41-0.40(m,2H),0.26-0.24(m,1H)。 ¹ H NMR (300MHz, DMSO- d ₆ ) δ 11.55 (s, 1H), 8.00-7.98 (m, 2H), 7.86-7.83 (m, 1H), 7.74-7.71 (m, 1H), 6.77-6.74 ( m, 1H), 4.68(s, 2H), 4.57-4.48(m, 4H), 4.25-4.20(m, 2H), 3.61(m, 1H), 2.61-2.55(m, 2H), 2.44(s, 3H), 2.11-2.04(m, 2H), 1.30-1.28(m, 3H), 1.22(m, 1H), 0.61-0.58(m, 1H), 0.41-0.40(m, 2H), 0.26-0.24( m, 1H).

實施例26：(S)-2-(1-環丙基乙基)-7-(((3-氟-3-甲基氮雜環丁烷-1-基)磺醯基)-5-(4-甲基-2-((6-(2-側氧吡咯烷-1-基)吡啶-2-基)胺基)噻唑-5-基)異吲哚啉-1-酮(26)的製備 Example 26: (S)-2-(1-Cyclopropylethyl)-7-(((3-fluoro-3-methylazetidin-1-yl)sulfonyl)-5- (4-Methyl-2-((6-(2-oxypyrrolidin-1-yl)pyridin-2-yl)amino)thiazol-5-yl)isoindolin-1-one (26) preparation

與實施例2的製備方法相同，除了用(S)-5-溴-2-(1-環丙基乙基)-7-((3-氟-3-甲基氮雜環丁烷-1-基)磺醯基)異吲哚啉-1-酮(根據製備實施例5製備，將步驟3的氮雜環丁烷替換為3-氟-3-甲基氮雜環丁烷)代替(S)-5-溴-7-氯-2-(1-環丙基乙基)異吲哚啉-1-酮(1d)，製得標題化合物。 The preparation method was the same as that of Example 2, except that (S)-5-bromo-2-(1-cyclopropylethyl)-7-((3-fluoro-3-methylazetidine-1 was used -yl)sulfonyl)isoindolin-1-one (prepared according to Preparation Example 5, replacing the azetidine of step 3 with 3-fluoro-3-methylazetidine) instead of ( S)-5-Bromo-7-chloro-2-(1-cyclopropylethyl)isoindolin-1-one (1d) to give the title compound.

LCMS：m/z 625.20[M+H]⁺。 LCMS: m/z 625.20 [M+H] ⁺ .

¹H NMR(300MHz,DMSO-d ₆)δ 11.55(s,1H),7.98-7.95(m,2H),7.85-7.82(m,1H),7.73-7.70(m,1H),6.76-6.73(m,1H),4.66(s,2H),4.24-4.19(m,2H),4.14-4.05(m,4H),3.65-3.62(m,1H),2.60-2.55(m,2H),2.43(s,3H),2.09-2.04(m,2H),1.53-1.45 (m,3H),1.29-1.27(m,3H),1.13(m,1H),0.51-0.48(m,1H),0.39-0.37(m,2H),0.14-0.12(m,1H)。 ¹ H NMR (300MHz, DMSO- d ₆ ) δ 11.55 (s, 1H), 7.98-7.95 (m, 2H), 7.85-7.82 (m, 1H), 7.73-7.70 (m, 1H), 6.76-6.73 ( m, 1H), 4.66(s, 2H), 4.24-4.19(m, 2H), 4.14-4.05(m, 4H), 3.65-3.62(m, 1H), 2.60-2.55(m, 2H), 2.43( s,3H),2.09-2.04(m,2H),1.53-1.45(m,3H),1.29-1.27(m,3H),1.13(m,1H),0.51-0.48(m,1H),0.39- 0.37 (m, 2H), 0.14-0.12 (m, 1H).

實施例27：(S)-7-((2-氧雜-6-氮雜螺[3.3]庚-6-基)磺醯基)-2-(1-環丙基乙基)-5-(4-甲基-2-((6-(2-側氧吡咯烷-1-基)吡啶-2-基)胺基)噻唑-5-基)異吲哚啉-1-酮(27)的製備 Example 27: (S)-7-((2-oxa-6-azaspiro[3.3]hept-6-yl)sulfonyl)-2-(1-cyclopropylethyl)-5- (4-Methyl-2-((6-(2-oxypyrrolidin-1-yl)pyridin-2-yl)amino)thiazol-5-yl)isoindolin-1-one (27) preparation

與實施例2的製備方法相同，除了用(S)-7-((2-氧雜-6-氮雜螺[3.3]庚-6-基)磺醯基)-5-溴-2-(1-環丙基乙基)異吲哚啉-1-酮(根據製備實施例5製備，將步驟3的氮雜環丁烷替換為2-氧雜-6-氮雜螺[3.3]庚烷)代替(S)-5-溴-7-氯-2-(1-環丙基乙基)異吲哚啉-1-酮(1d)，製得標題化合物。 The preparation method was the same as that of Example 2, except that (S)-7-((2-oxa-6-azaspiro[3.3]hept-6-yl)sulfonyl)-5-bromo-2-( 1-Cyclopropylethyl)isoindolin-1-one (prepared according to Preparation Example 5, replacing the azetidine of step 3 with 2-oxa-6-azaspiro[3.3]heptane ) in place of (S)-5-bromo-7-chloro-2-(1-cyclopropylethyl)isoindolin-1-one (1d) to give the title compound.

LCMS：m/z 635.20[M+H]⁺。 LCMS: m/z 635.20 [M+H] ⁺ .

¹H NMR(300MHz,DMSO-d ₆)δ 11.54(s,1H),7.95-7.92(m,2H),7.85-7.83(m,1H),7.73-7.68(m,1H),6.76-6.74(m,1H),4.64(s,2H),4.55(s,4H),4.25-4.20(m,2H), 4.14(s,4H),3.60(m,1H),2.61-2.56(m,2H),2.43(s,3H),2.11-2.06(m,2H),1.29-1.21(m,3H),1.15(m,1H),0.57(m,1H),0.40-0.38(m,2H),0.26-0.24(m,1H)。 ¹ H NMR (300MHz, DMSO- d ₆ ) δ 11.54 (s, 1H), 7.95-7.92 (m, 2H), 7.85-7.83 (m, 1H), 7.73-7.68 (m, 1H), 6.76-6.74 ( m, 1H), 4.64(s, 2H), 4.55(s, 4H), 4.25-4.20(m, 2H), 4.14(s, 4H), 3.60(m, 1H), 2.61-2.56(m, 2H) ,2.43(s,3H),2.11-2.06(m,2H),1.29-1.21(m,3H),1.15(m,1H),0.57(m,1H),0.40-0.38(m,2H),0.26 -0.24(m, 1H).

實施例28：(S)-2-(1-環丙基乙基)-7-((3-甲氧基氮雜環丁烷-1-基)磺醯基)-5-(4-甲基-2-((6-(2-側氧吡咯烷-1-基)吡啶-2-基)胺基)噻唑-5-基)異吲哚啉-1-酮(28)的製備 Example 28: (S)-2-(1-Cyclopropylethyl)-7-((3-methoxyazetidin-1-yl)sulfonyl)-5-(4-methyl) Preparation of yl-2-((6-(2-oxypyrrolidin-1-yl)pyridin-2-yl)amino)thiazol-5-yl)isoindolin-1-one (28)

與實施例2的製備方法相同，除了用(S)-5-溴-2-(1-環丙基乙基)-7-((3-甲氧基氮雜環丁烷-1-基)磺醯基)異吲哚啉-1-酮(根據製備實施例5製備，將步驟3的氮雜環丁烷替換為3-甲氧基氮雜環丁烷)代替(S)-5-溴-7-氯-2-(1-環丙基乙基)異吲哚啉-1-酮(1d)，製得標題化合物。 The preparation method was the same as that of Example 2, except that (S)-5-bromo-2-(1-cyclopropylethyl)-7-((3-methoxyazetidin-1-yl) was used Sulfonyl)isoindolin-1-one (prepared according to Preparation Example 5, substituting azetidine in step 3 for 3-methoxyazetidine) instead of (S)-5-bromo -7-Chloro-2-(1-cyclopropylethyl)isoindolin-1-one (1d) to give the title compound.

LCMS：m/z 623.20[M+H]⁺。 LCMS: m/z 623.20 [M+H] ⁺ .

¹H NMR(300MHz,DMSO-d ₆)δ 11.56(s,1H),7.99-7.96(m,2H),7.87-7.84(m,1H),7.75-7.70(m,1H),6.78-6.75(m,1H),4.67(s,2H),4.24(s,2H),4.11(s,3H),3.78(s, 2H),3.61(s,1H),3.12(s,3H),2.59-2.57(m,2H),2.45(s,3H),2.08(s,2H),1.31-1.29(m,3H),1.15(s,1H),0.59(s,1H),0.41(s,2H),0.25(s,1H)。 ¹ H NMR (300MHz, DMSO- d ₆ ) δ 11.56 (s, 1H), 7.99-7.96 (m, 2H), 7.87-7.84 (m, 1H), 7.75-7.70 (m, 1H), 6.78-6.75 ( m, 1H), 4.67(s, 2H), 4.24(s, 2H), 4.11(s, 3H), 3.78(s, 2H), 3.61(s, 1H), 3.12(s, 3H), 2.59-2.57 (m, 2H), 2.45(s, 3H), 2.08(s, 2H), 1.31-1.29(m, 3H), 1.15(s, 1H), 0.59(s, 1H), 0.41(s, 2H), 0.25(s, 1H).

生物學測試 biological test

試驗例1：本發明化合物對PI3K的抑制活性 Test Example 1: Inhibitory activity of the compounds of the present invention on PI3K

磷酸肌醇3-激酶(PI3K)是由細胞內能夠磷酸化磷脂醯環己六醇的肌醇環3號位置羥基基團的相關信號傳導酶組成的一個家族，其參與細胞存活、生長、代謝和血糖穩態等多種功能的調控。可利用商業化激酶檢測試劑盒對其活性進行測定。本實施採用購自於普洛麥格公司的ADP-Glo^TM檢測試劑盒進行化合物對重組人PI3K活性的檢測。 Phosphoinositide 3-kinase (PI3K) is a family of related signaling enzymes that can phosphorylate the hydroxyl group at position 3 of the inositol ring of phosphatidylinositol in cells, and is involved in cell survival, growth, and metabolism. and regulation of various functions such as blood glucose homeostasis. Its activity can be measured using commercial kinase assay kits. In this implementation, the ADP-Glo ^TM detection kit purchased from Promega was used to detect the activity of recombinant human PI3K by compounds.

(1)溶液製備 (1) Solution preparation

①配製1X實驗緩衝液，其中包含50mM HEPES(西格瑪奧德里奇公司，H3375)PH7.5，3mM MgCl₂(西格瑪奧德里奇公司，M1028)，1mM EGTA(西格瑪奧德里奇公司，E3889)，0.03% CHAPS(西格瑪奧德里奇公司，C9426)，100mM NaCl(西格瑪奧德里奇公司，S5886)，2mM DTT(Merk，CB233155)。 ① Prepare 1X assay buffer containing 50 mM HEPES (Sigma-Aldrich, H3375) pH 7.5, 3 mM MgCl ₂ (Sigma-Aldrich, M1028), 1 mM EGTA (Sigma-Aldrich, E3889), 0.03 % CHAPS (Sigma-Aldrich, C9426), 100 mM NaCl (Sigma-Aldrich, S5886), 2 mM DTT (Merk, CB233155).

②配製2.5X脂質緩衝液，其中包含62.5mM HEPES PH7.5，1.25mM EGTA。 ② Prepare 2.5X lipid buffer containing 62.5mM HEPES PH7.5, 1.25mM EGTA.

③配製2.5 X PI3K激酶工作溶液： ③ Prepare 2.5 X PI3K kinase working solution:

PI3Kα(英傑生命技術有限公司，PV4788)：利用1X實驗緩衝液將儲備液稀釋至625ng/mL，即工作濃度為250ng/mL。 PI3Kα (Invitrogen Life Technology Co., Ltd., PV4788): The stock solution was diluted to 625 ng/mL with 1X assay buffer, ie the working concentration was 250 ng/mL.

PI3Kβ(英傑生命技術有限公司，PV5374)：利用1X實驗緩衝液將儲備液稀釋至625ng/mL，即工作濃度為250ng/mL。 PI3Kβ (Invitrogen Biotechnology Co., Ltd., PV5374): The stock solution was diluted to 625 ng/mL with 1X assay buffer, i.e., the working concentration was 250 ng/mL.

PI3Kγ(英傑生命技術有限公司，PV4786)：利用1X實驗緩衝液將儲備液稀釋至3.75μg/mL，即工作濃度為1.5μg/mL。 PI3Kγ (Invitrogen Biotechnology Co., Ltd., PV4786): The stock solution was diluted to 3.75 μg/mL with 1X assay buffer, i.e., the working concentration was 1.5 μg/mL.

PI3Kδ(英傑生命技術有限公司，PV6451)：利用1X實驗緩衝液將儲備液稀釋至625ng/mL，即工作濃度為250ng/mL。 PI3Kδ (Invitrogen Biotechnology Co., Ltd., PV6451): The stock solution was diluted to 625 ng/mL with 1X assay buffer, i.e., the working concentration was 250 ng/mL.

④2.5 X基質工作液： ④2.5 X matrix working solution:

PIP：3PS：利用2.5X脂質緩衝液將PIP：3PS儲備液(普洛麥格公司，V1701)稀釋至0.02mg/mL。 PIP:3PS: PIP:3PS stock solution (Promega, V1701) was diluted to 0.02 mg/mL with 2.5X lipid buffer.

ATP：利用2.5X脂質緩衝液將ATP儲備液(普洛麥格公司，V915B)稀釋至20μM。 ATP: ATP stock solution (Promega, V915B) was diluted to 20 [mu]M with 2.5X lipid buffer.

隨後將PIP：3PS及ATP溶液等比例混合，即它們的工作濃度分別為0.01mg/mL和10μM。 The PIP:3PS and ATP solutions were then mixed in equal proportions, ie their working concentrations were 0.01 mg/mL and 10 μM, respectively.

⑤測試化合物工作液製備：測試化合物利用DMSO溶解為初始濃度為100μM的儲備液，並利用DMSO為稀釋液以3倍梯度進行稀釋，共10個濃度。各濃度溶液再次利用1X實驗緩衝液進行20倍稀釋。 ⑤ Preparation of test compound working solution: The test compound was dissolved in DMSO into a stock solution with an initial concentration of 100 μM, and was diluted with DMSO as a dilution solution with a 3-fold gradient, with a total of 10 concentrations. Each concentration solution was again diluted 20-fold with 1X assay buffer.

(2)活性篩選 (2) Activity screening

利用移液器將2.5X PI3K激酶工作溶液加入到384孔板(珀金埃爾默公司，6008280)中，2μL/孔。隨後向各孔中加入1μL不同濃度的化合物溶液。同時設立1% DMSO作為陰性對照，100μM已知PI3K抑制劑(GSK2126458(Selleck公司，S2658)作為陽性對照。將384孔板置於微孔板搖床(其林貝爾公司，QB-9002)上振搖30s使孔內溶液充分混合，並將反應物於25℃孵育15分鐘。孵育結束後，向各孔中加入2μL 2.5X基質工作液，密封384孔板後於25℃孵育60分鐘。反應結束後，向各孔中加入5μL ADP-Glo試劑(普洛麥格公司，V9102)，密封384 孔板後於25℃繼續孵育40分鐘。隨後向各孔加入10μL激酶檢測試劑，將384孔板密封，於25℃孵育40分鐘。利用多功能酶標儀(珀金埃爾默公司，Envision 2104)進行資料獲取。 2.5X PI3K kinase working solution was added to a 384-well plate (PerkinElmer, 6008280) using a pipette at 2 μL/well. 1 [mu]L of compound solutions at various concentrations were then added to each well. At the same time, 1% DMSO was set up as a negative control, and 100 μM of a known PI3K inhibitor (GSK2126458 (Selleck, S2658)) was used as a positive control. The 384-well plate was placed on a microplate shaker (Qilin Bell, QB-9002). Shake for 30 s to fully mix the solution in the well, and incubate the reaction at 25°C for 15 minutes. After the incubation, add 2 μL of 2.5X matrix working solution to each well, seal the 384-well plate and incubate at 25°C for 60 minutes. The reaction is over Then, add 5 μL of ADP-Glo reagent (Promega, V9102) to each well, seal 384 The plate was then incubated at 25°C for 40 minutes. 10 μL of kinase detection reagent was then added to each well, and the 384-well plate was sealed and incubated at 25° C. for 40 minutes. Data acquisition was performed using a multi-plate reader (PerkinElmer, Envision 2104).

其中抑制率按以下公式進行計算： The inhibition rate is calculated according to the following formula:

所獲得資料利用軟體(GraphPad軟體公司，GraphPad prism 6.0)進行統計分析，以化合物的濃度Log值為橫座標，抑制率%為縱座標，採用非線性擬合(劑量回應-變化斜率)計算IC₅₀值。結果如下表1所示。 The obtained data were analyzed by software (GraphPad software company, GraphPad prism 6.0), with the concentration Log value of the compound as the abscissa, the inhibition rate % as the ordinate, and nonlinear fitting (dose response-slope of change) was used to calculate _IC50 value. The results are shown in Table 1 below.

本試驗例提供了本發明化合物1-28對各種PI3K同種型的體外酶學活性數據。使用前面描述的方法可以獲得表1中收集的資料，該表提供了對化合物在抑制PI3Kα、β、γ和δ活性中的活性的瞭解。相對於PI3Kα和PI3Kβ，這些化合物一般對PI3Kδ和γ具有選擇性。 This test example provides in vitro enzymatic activity data for compounds 1-28 of the invention against various PI3K isoforms. The data collected in Table 1, which provides insight into the activity of compounds in inhibiting PI3K alpha, beta, gamma and delta activity, can be obtained using the methods previously described. These compounds are generally selective for PI3Kδ and γ over PI3Kα and PI3Kβ.

試驗例2：本發明化合物對PI3K α、PI3K γ和PI3Kδ的細胞學選擇性抑制活性 Test Example 2: Cytologically selective inhibitory activity of the compounds of the present invention on PI3Kα, PI3Kγ and PI3Kδ

(1)PI3K α選擇性抑制測試 (1) PI3K α selective inhibition test

C2C12小鼠肌母細胞中由IGF1蛋白引導的AKT磷酸化僅由p110α介導。基於此，可以用於評估化合物對於PI3Kα的特異性抑制行為(Won Jun Lee，Molecules and Cells，2009，28(5)，495-499)。 IGF1 protein-directed AKT phosphorylation in C2C12 mouse myoblasts is mediated only by p110α. Based on this, it can be used to evaluate the specific inhibitory behavior of compounds on PI3Kα (Won Jun Lee, Molecules and Cells, 2009, 28(5), 495-499).

具體實施方案如下：將C2C12細胞(美國典型培養物保藏中心，ATCC^® CRL-1772^TM)培養於含有10%胎牛血清(Invitrogen，10099141)以及青黴素和鏈黴素(Gibco公司，15140-122)的DMEM培養基(Gibco，11995-073)中。開始測試時，利用多道移液器(賽默飛世爾科技有限公司，836-4049)將C2C12細胞以 30,000細胞/孔的密度接種至384孔板(珀金埃爾默公司，6007680)。500轉/分鐘離心30秒後置於37℃，5%CO₂濕式培養箱(賽默飛世爾科技有限公司，BBD6220)中孵育2小時。隨後利用聲波移液器(Labcyte公司，Echo 550)將不同濃度的化合物(起始終濃度為30μM，3倍梯度稀釋，共計10個濃度)加入到培養板之中，30nL/孔，並在上述培養條件下繼續孵育30分鐘。隨後向各孔中加入2μL 4倍濃度的IGF-1(200ng/mL，R&D Systems公司，291-G1-200)，500轉/分鐘離心30秒後置於37℃，5%CO₂濕式培養箱中孵育20分鐘。隨後向各孔加入試劑盒(AlphaLISA SureFire Ultra p-AKT1/2/3(Thr 308)試劑盒，珀金埃爾默公司，ALSU-PAKT-A500)所提供2X裂解液2μL，並將細胞培養板置於水準搖床上振搖10分鐘。向各孔中加入5μL試劑盒所提供的受體混合液，1000轉/分鐘離心1分鐘，接著加入5μL試劑盒所提供的供體混合液，1000轉/分鐘離心1分鐘。將細胞培養板移至25℃環境避光孵育2小時。利用多功能酶標儀(珀金埃爾默公司，Envision 2104)讀取AlphaLISA信號資料。 The specific embodiment is as follows: C2C12 cells (American Type Culture Collection, ATCC ^® CRL-1772 ^™ ) were cultured in cells containing 10% fetal bovine serum (Invitrogen, 10099141) and penicillin and streptomycin (Gibco, 15140-122). in DMEM medium (Gibco, 11995-073). To begin testing, C2C12 cells were seeded into 384-well plates (PerkinElmer, 6007680) at a density of 30,000 cells/well using a multichannel pipette (Thermo Fisher Scientific, Inc., 836-4049). After centrifugation at 500 rpm for 30 seconds, the cells were incubated in a 37°C, 5% CO ₂ wet incubator (Thermo Fisher Scientific Co., Ltd., BBD6220) for 2 hours. Then, using a sonic pipette (Labcyte, Echo 550), different concentrations of compounds (starting at 30 μM, 3-fold serial dilution, a total of 10 concentrations) were added to the culture plate, 30 nL/well, and incubated in the above-mentioned culture. Continue to incubate for 30 minutes under conditions. Then, 2 μL of 4-fold concentration of IGF-1 (200 ng/mL, R&D Systems, 291-G1-200) was added to each well, centrifuged at 500 rpm for 30 seconds, and then placed at 37°C, 5% CO ₂ for wet culture Incubate in the box for 20 minutes. Then 2 μL of 2X Lysis Buffer provided by the kit (AlphaLISA SureFire Ultra p-AKT1/2/3 (Thr 308) kit, PerkinElmer, ALSU-PAKT-A500) was added to each well, and the cell culture plates were Shake on a horizontal shaker for 10 minutes. Add 5 μL of the acceptor mixture provided by the kit to each well, centrifuge at 1000 rpm for 1 minute, then add 5 μL of the donor mixture provided by the kit, and centrifuge at 1000 rpm for 1 minute. Move the cell culture plate to 25°C and incubate in the dark for 2 hours. AlphaLISA signal data were read using a multi-plate reader (PerkinElmer, Envision 2104).

(2)PI3K γ選擇性抑制測試 (2) PI3K γ selective inhibition test

RAW264.7小鼠巨噬細胞中由C5a引導的AKT磷酸化僅由p110γ介導。基於此，可以用於評估化合物對於PI3Kγ的特異性抑制行為(Montserrat Camps等人，Nature Medicine，2005，11(9)，936-943)。 C5a-directed AKT phosphorylation in RAW264.7 mouse macrophages is mediated only by p110γ. Based on this, it can be used to assess the specific inhibitory behavior of compounds on PI3Kγ (Montserrat Camps et al., Nature Medicine, 2005, 11(9), 936-943).

具體實施方案如下：將Raw264.7細胞(美國典型培養物保藏中心，ATCC^® TIB-71^TM)培養於含有10%胎牛血清(Invitrogen，10099141)以及青黴素和鏈黴素(Gibco公司，15140-122)的RPMI 1640培養基(Invitrogen，A10491-01)中。開始測試時，利用多道移液器(賽默飛世爾科技有限公司，836-4049)將Raw264.7細胞以30000細胞/孔的密度接種至384孔板(珀金埃爾默公司，6007680)。500轉 /分鐘離心30秒後置於37℃，5%CO₂濕式培養箱(賽默飛世爾科技有限公司，BBD6220)中孵育2小時。隨後利用聲波移液器(Labcyte公司，Echo 550)將不同濃度的化合物(起始終濃度為1000nM，3倍梯度稀釋，共計10個濃度)加入到培養板之中，30nL/孔，並在上述培養條件下繼續孵育30分鐘。隨後向各孔中加入2μL 4倍濃度的C5a(320ng/mL，西格瑪奧德里奇公司，204902)，500轉/分鐘離心30秒後置於37℃，5%CO₂濕式培養箱中孵育5分鐘。隨後向各孔加入試劑盒(AlphaLISA SureFire Ultra p-AKT1/2/3(Thr 308)試劑盒，珀金埃爾默公司，ALSU-PAKT-A500)所提供2X裂解液2μL，並將細胞培養板置於水準搖床上振搖10分鐘。向各孔中加入5μL試劑盒所提供的受體混合液，1000轉/分鐘離心1分鐘，接著加入5μL試劑盒所提供的供體混合液，1000轉/分鐘離心1分鐘。將細胞培養板移至25℃環境避光孵育2小時。利用多功能酶標儀(珀金埃爾默公司，Envision 2104)讀取AlphaLISA信號資料。 The specific embodiment is as follows: Raw264.7 cells (American Type Culture Collection, ATCC ^® TIB-71 ^™ ) were cultured in cells containing 10% fetal bovine serum (Invitrogen, 10099141) and penicillin and streptomycin (Gibco, 15140- 122) in RPMI 1640 medium (Invitrogen, A10491-01). At the start of the assay, Raw264.7 cells were seeded into 384-well plates (PerkinElmer, 6007680) at a density of 30,000 cells/well using a multichannel pipette (Thermo Fisher Scientific, Inc., 836-4049). . After centrifugation at 500 rpm for 30 seconds, the cells were incubated in a 37°C, 5% CO ₂ wet incubator (Thermo Fisher Scientific Co., Ltd., BBD6220) for 2 hours. Then, using a sonic pipette (Labcyte, Echo 550), different concentrations of compounds (the initial concentration was 1000 nM, 3-fold serial dilution, a total of 10 concentrations) were added to the culture plate, 30 nL/well, and incubated in the above-mentioned culture. Continue to incubate for 30 minutes under conditions. Subsequently, 2 μL of 4-fold concentration of C5a (320 ng/mL, Sigma-Aldrich, 204902) was added to each well, centrifuged at 500 rpm for 30 s, and then incubated at 37°C in a 5% CO ₂ wet incubator for 5 s. minute. Then 2 μL of 2X Lysis Buffer provided by the kit (AlphaLISA SureFire Ultra p-AKT1/2/3 (Thr 308) kit, PerkinElmer, ALSU-PAKT-A500) was added to each well, and the cell culture plates were Shake on a horizontal shaker for 10 minutes. Add 5 μL of the acceptor mixture provided by the kit to each well, centrifuge at 1000 rpm for 1 minute, then add 5 μL of the donor mixture provided by the kit, and centrifuge at 1000 rpm for 1 minute. Move the cell culture plate to 25°C and incubate in the dark for 2 hours. AlphaLISA signal data were read using a multi-plate reader (PerkinElmer, Envision 2104).

(3)PI3Kδ選擇性抑制測試 (3) PI3Kδ selective inhibition test

利用抗人IgM刺激Raji細胞所造成的B細胞受體的信號傳導僅受PI3K δ所調控，因此可以用於評估化合物對於PI3Kδ的特異抑制行為(Liu等人，Oncotarget，2016，7(33)：53515)。 B cell receptor signaling by anti-human IgM stimulation of Raji cells is only regulated by PI3Kδ, and thus can be used to assess the specific inhibitory behavior of compounds on PI3Kδ (Liu et al., Oncotarget, 2016, 7(33): 53515).

具體實施方案如下：將Raji細胞(美國典型培養物保藏中心，ATCC^® CCL-86^TM)培養於含有10%胎牛血清(Invitrogen，10099141)以及青黴素和鏈黴素(Gibco，15140-122)的RPMI 1640培養基(Invitrogen，A10491-01)中。開始測試時，利用多道移液器(賽默飛世爾科技有限公司，836-4049)將Raji細胞以60000細胞/孔的密度接種至384孔板(珀金埃爾默公司，6007680)。500轉/分鐘離心30秒後置於37℃，5%CO₂濕式培養箱中孵育2小時。隨後利用聲波移液器 (Labcyte公司，Echo 550)將不同濃度的化合物(起始終濃度為1000nM，3倍梯度稀釋，共計10個濃度)加入到培養板之中，30nL/孔，並在上述培養條件下繼續孵育30分鐘。隨後向各孔中加入2μL4倍濃度的山羊抗人IgM(12μg/mL，傑克遜免疫研究實驗有限公司，109-006-129)，500轉/分鐘離心30秒後置於37℃，5%CO₂濕式培養箱中孵育10分鐘。隨後向各孔加入試劑盒(AlphaLISA SureFire Ultra p-AKT1/2/3(PS 473)試劑盒，珀金埃爾默公司，ALSU-PAKT-B500)所提供2X裂解液2μL，並將細胞培養板置於水準搖床上振搖10分鐘。向各孔中加入5μL試劑盒所提供的受體混合液，1000轉/分鐘離心1分鐘，接著加入5μL試劑盒所提供的供體混合液，1000轉/分鐘離心1分鐘。將細胞培養板移至25℃環境避光孵育2小時。利用多功能酶標儀(珀金埃爾默公司，Envision 2104)讀取AlphaLISA信號資料。 Specific embodiments are as follows: Raji cells (American Type Culture Collection, ATCC® CCL-86 ^™ ⁾ were cultured in cells containing 10% fetal bovine serum (Invitrogen, 10099141) and penicillin and streptomycin (Gibco, 15140-122). in RPMI 1640 medium (Invitrogen, A10491-01). To begin testing, Raji cells were seeded into 384-well plates (PerkinElmer, 6007680) at a density of 60,000 cells/well using a multichannel pipette (Thermo Fisher Scientific, Inc., 836-4049). After centrifugation at 500 rpm for 30 s, place in a 37°C, 5% CO ₂ wet incubator for 2 h. Then, using a sonic pipette (Labcyte, Echo 550), different concentrations of compounds (the initial concentration was 1000 nM, 3-fold serial dilution, a total of 10 concentrations) were added to the culture plate, 30 nL/well, and incubated in the above-mentioned culture. Continue to incubate for 30 minutes under conditions. Subsequently, 2 μL of 4-fold concentration of goat anti-human IgM (12 μg/mL, Jackson Immunoresearch Experiment Co., Ltd., 109-006-129) was added to each well, centrifuged at 500 rpm for 30 seconds, and then placed at 37°C, 5% CO ₂ . Incubate in a wet incubator for 10 min. Then 2 μL of 2X Lysis Buffer provided by the kit (AlphaLISA SureFire Ultra p-AKT1/2/3 (PS 473) kit, PerkinElmer, ALSU-PAKT-B500) was added to each well, and the cell culture plates were Shake on a horizontal shaker for 10 minutes. Add 5 μL of the acceptor mixture provided by the kit to each well, centrifuge at 1000 rpm for 1 minute, then add 5 μL of the donor mixture provided by the kit, and centrifuge at 1000 rpm for 1 minute. Move the cell culture plate to 25°C and incubate in the dark for 2 hours. AlphaLISA signal data were read using a multi-plate reader (PerkinElmer, Envision 2104).

所獲得資料利用軟體(GraphPad軟體公司，GraphPad prism 6.0)進行統計分析，以化合物的濃度Log值為橫座標，抑制率%為縱座標，採用非線性擬合(劑量回應-變化斜率)計算IC₅₀值。化合物針對不同亞型PI3K細胞水準抑制結果如下表2所示。 The obtained data were analyzed by software (GraphPad software company, GraphPad prism 6.0), with the concentration Log value of the compound as the abscissa, the inhibition rate % as the ordinate, and nonlinear fitting (dose response-slope of change) was used to calculate _IC50 value. The results of compound inhibition against different subtypes of PI3K cell levels are shown in Table 2 below.

資料結果表明本發明化合物在細胞水準具有特異性抑制PI3Kγ/δ的能力。 The data results show that the compounds of the present invention have the ability to specifically inhibit PI3Kγ/δ at the cellular level.

試驗例3：本發明化合物在SD大鼠體內藥物代謝動力學評價分別精確稱取實施例5、實施例12、實施例15、實施例18、實施例26、實施例27和實施例28化合物各4mg置於15mL離心管中，加入400μL DMSO充分震盪使供試品完全溶解，隨後加入4mL PBS緩衝鹽溶液以及3.6mL PEG400，充分混勻至化合物完全溶解狀態，此時供試品為濃度0.5mg/mL的溶液。 Test Example 3: Pharmacokinetic evaluation of the compounds of the present invention in SD rats The compounds of Example 5, Example 12, Example 15, Example 18, Example 26, Example 27 and Example 28 were accurately weighed 4mg was placed in a 15mL centrifuge tube, 400μL DMSO was added to fully shake to completely dissolve the test product, then 4mL PBS buffered saline solution and 3.6mL PEG400 were added, and the mixture was fully mixed until the compound was completely dissolved. At this time, the concentration of the test product is 0.5mg /mL solution.

雄性SD大鼠(北京維通利華實驗動物中心)，6-8週齡，飼養環境：溫濕度：溫度20~26℃，相對濕度40~70%RH；換氣次數：

15次/小時；動物照度：15-20Lx。適應性飼養3天後，於實驗前禁食過夜。給藥前稱重體重，尾部編號。按表3所列方式進行給藥。 Male SD rats (Beijing Weitong Lihua Experimental Animal Center), 6-8 weeks old, rearing environment: temperature and humidity: temperature 20~26℃, relative humidity 40~70%RH; ventilation times:

15 times/hour; animal illumination: 15-20Lx. After 3 days of adaptive feeding, they were fasted overnight before the experiment. Body weight was weighed before administration and tail numbered. Dosing was performed in the manner listed in Table 3.

受試物的灌胃給藥劑量為3mg/kg，靜脈給藥劑量為1mg/kg。分別於給藥後0.00、0.083、0.25、0.50、1.00、2.00、4.00、6.00和8.00h進行血液樣本採集。動物採用吸入麻醉(異氟烷，河北一品製藥有限公司，C002151205)，麻醉參數：流速：1.0L/min，氧氣壓力：0.1MPa，溶度：4.5%，麻醉用時：3分鐘。麻醉後眼眶採血，每隻動物每個時間點採血量為500μL，將血液收集至已編號的一次性使用抗凝管(抗凝劑為肝素鈉，0.5mg/管)中，搖晃混勻。3500rpm 離心，離心10分鐘，取上層血漿，轉移至1.5mL離心管之中，凍存到-80℃冰箱內直至測試。取血漿樣品50μL於1.5mL離心管中，加入400μL含有5ng/mL鹽酸維拉帕米(內標)的乙腈工作液，渦旋1分鐘充分混勻，10000rpm離心10分鐘。移取上清液0.2mL，用0.22μM有機膜(AS081320-T，Agela Technologies)過濾後，加入進樣小瓶中，經LC/MS(Waters，Waters UPLC I Class、TQ-S micro)分析得出血藥濃度，並藉由DAS軟體3.3.0分析藥物代謝動力學參數。 The oral administration dose of the test substance was 3 mg/kg, and the intravenous dose was 1 mg/kg. Blood samples were collected at 0.00, 0.083, 0.25, 0.50, 1.00, 2.00, 4.00, 6.00 and 8.00 h after administration, respectively. Animals were under inhalation anesthesia (Isoflurane, Hebei Yipin Pharmaceutical Co., Ltd., C002151205), anesthesia parameters: flow rate: 1.0L/min, oxygen pressure: 0.1MPa, solubility: 4.5%, anesthesia time: 3 minutes. Orbital blood was collected after anesthesia, and the blood volume of each animal was 500 μL at each time point. The blood was collected into a numbered single-use anticoagulant tube (the anticoagulant was heparin sodium, 0.5 mg/tube), and the blood was shaken and mixed. 3500rpm Centrifuge, centrifuge for 10 minutes, take the upper plasma, transfer it to a 1.5mL centrifuge tube, and store it in a -80°C refrigerator until testing. Take 50 μL of plasma sample into a 1.5 mL centrifuge tube, add 400 μL of acetonitrile working solution containing 5 ng/mL verapamil hydrochloride (internal standard), vortex for 1 minute to mix well, and centrifuge at 10,000 rpm for 10 minutes. Pipette 0.2 mL of the supernatant, filter it with a 0.22 μM organic membrane (AS081320-T, Agela Technologies), and add it to the injection vial. The blood was analyzed by LC/MS (Waters, Waters UPLC I Class, TQ-S micro). drug concentration, and the pharmacokinetic parameters were analyzed by DAS software 3.3.0.

按下列公式計算絕對生物利用度： Calculate absolute bioavailability according to the following formula:

絕對生物利用度F=(AUC_PO×D_IV)/(AUC_IV×D_PO)×100%(AUC為血藥濃度-時間曲線下面積，D為給藥劑量，PO為灌胃給藥，IV為靜脈注射給藥)。 Absolute bioavailability F=(AUC _PO ×D _IV )/(AUC _IV ×D _PO )×100% (AUC is the area under the plasma concentration-time curve, D is the dose, PO is the intragastric administration, IV for intravenous administration).

本發明化合物給藥後藥物代謝動力學試驗資料見表4。 The pharmacokinetic test data of the compounds of the present invention after administration are shown in Table 4.

本發明化合物靜脈給予SD大鼠後有較好的體內藥物代謝動力學性質，口服給藥無吸收或生物利用度較小。 The compounds of the present invention have good pharmacokinetic properties in vivo after intravenous administration to SD rats, but have no absorption or low bioavailability after oral administration.

Claims

一種通式(I)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽， A compound represented by the general formula (I) or a meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

其中， in,

X為O、S或NH； X is O, S or NH;

Y為N或CH； Y is N or CH;

R¹各自獨立地選自氫、鹵素、胺基、硝基、氰基、羥基、巰基、側氧基、烷基、烷氧基、環烷基、雜環基、芳基、雜芳基、-C(O)R^a、-O(O)CR^a、-C(O)OR^a、-C(O)NR^aR^b、-NR^aR^b、-NR^aC(O)R^b、-S(O)_pR^a、-S(O)_pNR^aR^b、-NR^aS(O)_pNR^aR^b和-NR^aS(O)_pR^b，其中該烷基、烷氧基、環烷基、雜環基、芳基或雜芳基任選進一步被選自鹵素、胺基、硝基、氰基、側氧基、羥基、巰基、羧基、酯基、烷基、鹵烷基、烷氧基、鹵烷氧基、烯基、炔基、環烷基、雜環基、芳基和雜芳基的一個或多個基團取代； R ¹ are each independently selected from hydrogen, halogen, amine, nitro, cyano, hydroxyl, mercapto, pendant oxy, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R ^a , -O(O)CR ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -NR ^a R ^b , -NR ^a C(O)R ^b , -S(O) _p R ^a , -S(O) _p NR ^a R ^b , -NR ^a S(O) _p NR ^a R ^b and -NR ^a S(O) _p R ^b , wherein the alkyl, alkane Oxy, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally further selected from halogen, amine, nitro, cyano, pendant oxy, hydroxyl, mercapto, carboxyl, ester, alkyl, One or more group substitutions of haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

n為0、1、2或3； n is 0, 1, 2 or 3;

p為0、1或2。 p is 0, 1 or 2.

如請求項1所述的通式(I)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽，其為通式(II)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽， The compound represented by the general formula (I) according to claim 1, or its meso, racemate, enantiomer, diastereomer, or its mixture form, or its pharmaceutically acceptable Use salt, which is the compound represented by the general formula (II) or its mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof ,

其中， in,

X為O或S X is O or S

A¹-A⁵、R¹、R²、R³、R⁴、R⁵、R⁶和n如請求項1所定義。 A ¹ -A ⁵ , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and n are as defined in claim 1 .

如請求項1或2所述的通式(I)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽， The compound represented by the general formula (I) according to claim 1 or 2, or a meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a form thereof pharmaceutically acceptable salt,

其中， in,

如請求項1至3中任一項所述的通式(I)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽，其為通式(III)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽， The compound represented by the general formula (I) according to any one of claims 1 to 3 or a meso, racemate, enantiomer, diastereomer, or a mixture thereof form, or a pharmaceutically acceptable salt thereof, which is the compound represented by the general formula (III) or its meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

其中， in,

X為O或S； X is O or S;

R¹、R²、R³、R⁴、R⁵和R⁶如請求項1所定義。 R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined in claim 1 .

如請求項1至4中任一項所述的通式(I)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽，其為通式(IV)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽， The compound represented by the general formula (I) according to any one of claims 1 to 4 or a meso, racemate, enantiomer, diastereomer, or a mixture thereof form, or a pharmaceutically acceptable salt thereof, which is the compound represented by the general formula (IV) or its meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

其中， in,

如請求項1至5中任一項所述的通式(I)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽，其中， The compound represented by the general formula (I) according to any one of claims 1 to 5 or a meso, racemate, enantiomer, diastereomer, or a mixture thereof form, or a pharmaceutically acceptable salt thereof, wherein,

如請求項1至6中任一項所述的通式(I)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽， The compound represented by the general formula (I) according to any one of claims 1 to 6 or a meso, racemate, enantiomer, diastereomer, or a mixture thereof form, or a pharmaceutically acceptable salt thereof,

其中，條件是當A¹為N，A²、A³、A⁴為CH，且R¹選自

，R⁴選自

或

時，R³不是甲磺醯基、

或

, R ⁴ is selected from

or

, R ³ is not methanesulfonyl,

or

.

如請求項1至7中任一項所述的通式(I)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽，其為通式(V)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽， The compound represented by the general formula (I) according to any one of claims 1 to 7 or a meso, racemate, enantiomer, diastereomer, or a mixture thereof form, or a pharmaceutically acceptable salt thereof, which is the compound represented by the general formula (V) or its meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

如請求項1至8中任一項所述的通式(I)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽，其中， The compound represented by the general formula (I) according to any one of claims 1 to 8 or a meso, racemate, enantiomer, diastereomer, or a mixture thereof form, or a pharmaceutically acceptable salt thereof, wherein,

如請求項1至9中任一項所述的通式(I)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽，其中， The compound represented by the general formula (I) according to any one of claims 1 to 9 or a meso, racemate, enantiomer, diastereomer, or a mixture thereof form, or a pharmaceutically acceptable salt thereof, wherein,

如請求項1至10中任一項所述的通式(I)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽，其中， The compound represented by the general formula (I) according to any one of claims 1 to 10 or a meso, racemate, enantiomer, diastereomer, or a mixture thereof form, or a pharmaceutically acceptable salt thereof, wherein,

如請求項1至11中任一項所述的通式(I)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽，其中， The compound represented by the general formula (I) according to any one of claims 1 to 11 or a meso, racemate, enantiomer, diastereomer, or a mixture thereof form, or a pharmaceutically acceptable salt thereof, wherein,

R¹選自

、

、

、

、

、

。 R ¹ is selected from

,

.

如請求項1至13中任一項所述的通式(I)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽，其中， The compound represented by the general formula (I) according to any one of claims 1 to 13 or a meso, racemate, enantiomer, diastereomer, or a mixture thereof form, or a pharmaceutically acceptable salt thereof, wherein,

R^a和R^b與他們連接的氮原子一起形成3至8員含氮雜環基或5至6員含氮雜芳基，該含氮雜環基或含氮雜芳基任選進一步被選自鹵素、胺基、硝基、氰基、側氧基、羥基、巰基、羧基、酯基、烷基、烷氧基、鹵烷基、鹵烷氧基、烯基、炔基、環烷基、雜環基、芳基和雜芳基的一個或多個基團取代；p為1或2； R ^a and R ^b together with the nitrogen atom to which they are attached form a 3- to 8-membered nitrogen-containing heterocyclic group or a 5- to 6-membered nitrogen-containing heteroaryl group, which is optionally further selected From halogen, amine, nitro, cyano, pendant oxy, hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl , heterocyclyl, aryl, and heteroaryl are substituted with one or more groups; p is 1 or 2;

較佳地， Preferably,

R^a和R^b與他們連接的氮原子一起形成3至8員含氮雜環基，該含氮雜環基任選進一步被選自鹵素、羥基、C₁-C₆烷基、C₁-C₆烷氧基的一個或多個基團取代；p為1或2。 R ^a and R ^b together with the nitrogen atom to which they are attached form a 3- to 8-membered nitrogen-containing heterocyclic group optionally further selected from halogen, hydroxy, C ₁ -C ₆ alkyl, C ₁ - One or more groups of C ₆ alkoxy are substituted; p is 1 or 2.

如請求項1至14中任一項所述的通式(I)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽，其為通式(VI)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽 The compound represented by the general formula (I) according to any one of claims 1 to 14 or a meso, racemate, enantiomer, diastereomer, or a mixture thereof form, or a pharmaceutically acceptable salt thereof, which is the compound represented by the general formula (VI) or its meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof

其中， in,

R^b選自C₁-C₆烷基； R ^b is selected from C ₁ -C ₆ alkyl;

R⁷選自-NR^cR^d； R ⁷ is selected from -NR ^c R ^d ;

R^c和R^d各自獨立地選自氫、C₁-C₆烷基、C₃-C₆環烷基、3至8員雜環基、C₆-C₁₀芳基和5至10員雜芳基，其中該C₁-C₆烷基、C₃-C₆環烷基、3至8員雜環基、C₆-C₁₀ 芳基或5至10員雜芳基任選進一步被選自鹵素、胺基、硝基、氰基、羥基、巰基、羧基、酯基、側氧基、烷基、烷氧基、烯基、炔基、環烷基、雜環基、芳基、雜芳基的一個或多個基團取代；或者， R ^c and R ^d are each independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, 3- to 8-membered heterocyclyl, C ₆ -C ₁₀ -membered aryl, and 5- to 10-membered heterocyclyl Aryl, wherein the _C1 - _C6 alkyl, C3 _- _C6 cycloalkyl, 3- to 8-membered heterocyclyl, _C6 - _C10 -aryl or 5- to 10-membered heteroaryl is optionally further selected From halogen, amine, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, pendant oxy, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, hetero One or more groups of aryl groups are substituted; or,

較佳地， Preferably,

p為1或2。 p is 1 or 2.

如請求項1至15中任一項所述的通式(I)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽， The compound represented by the general formula (I) according to any one of claims 1 to 15 or a meso, racemate, enantiomer, diastereomer, or a mixture thereof form, or a pharmaceutically acceptable salt thereof,

其中， in,

R⁷選自

、

、

、

、

,

R⁷進一步較佳

、

、

、

、

、

、

、

、

、

。 R ⁷ is further preferred

,

.

如請求項1至16中任一項所述的通式(I)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽， The compound represented by the general formula (I) according to any one of claims 1 to 16 or a meso, racemate, enantiomer, diastereomer, or a mixture thereof form, or a pharmaceutically acceptable salt thereof,

如請求項1至17中任一項所述的通式(I)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽， The compound represented by the general formula (I) according to any one of claims 1 to 17 or a meso, racemate, enantiomer, diastereomer, or a mixture thereof form, or a pharmaceutically acceptable salt thereof,

如請求項1至19中任一項所述通式(I)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽，其中該化合物選自： The compound represented by the general formula (I) according to any one of claims 1 to 19 or the form of meso, racemate, enantiomer, diastereomer, or mixture thereof , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

一種通式(III)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽的製備方法，其包括以下步驟： A compound represented by general formula (III) or a method for preparing a meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, It includes the following steps:

在溶劑中，在加熱條件下，在鹼的存在下，在配體和催化劑的存在下，將化合物(Ic)與化合物(Ig)反應得到通式(III)的化合物； In a solvent, under heating, in the presence of a base, in the presence of a ligand and a catalyst, the compound (Ic) is reacted with the compound (Ig) to obtain the compound of the general formula (III);

其中， in,

A¹-A⁴、X、R¹、R²、R³、R⁴、R⁵、R⁶如請求項4所定義。 A ¹ -A ⁴ , X, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ are as defined in claim 4.

一種醫藥組成物，其包含如請求項1至20中任一項所述的通式(I)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽和藥學上可接受的佐劑、稀釋劑或載體。 A pharmaceutical composition comprising a compound represented by general formula (I) as described in any one of claims 1 to 20 or a meso, racemate, enantiomer, diastereomer Isomers, or mixtures thereof, or pharmaceutically acceptable salts thereof and pharmaceutically acceptable adjuvants, diluents or carriers.

一種如請求項1至20中任一項所述的通式(I)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽或如請求項22所述的醫藥組成物在製備磷脂醯肌醇3-激酶δ(PI3Kδ)和磷脂醯肌醇3-激酶γ(PT3Kγ)雙重抑制劑中的用途。 A compound represented by general formula (I) as described in any one of claims 1 to 20 or a meso, racemate, enantiomer, diastereomer, or its In the preparation of dual inhibitors of phosphatidylinositol 3-kinase delta (PI3Kdelta) and phosphatidylinositol 3-kinase gamma (PT3Kgamma) in the form of a mixture, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as claimed in claim 22 use.

一種如請求項1至20中任一項所述的通式(I)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽或如請求項22所述的醫藥組成物在製備預防和/或治療與PI3Kδ和PI3Kγ的活性相關的疾病的藥物中的用途，該疾病較佳呼吸系統疾病，例如哮喘、慢性阻塞性肺病、支氣管炎、肺氣腫，較佳哮喘和慢性阻塞性肺病。 A compound represented by general formula (I) as described in any one of claims 1 to 20 or a meso, racemate, enantiomer, diastereomer, or its Use of a mixture form, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described in claim 22, in the preparation of a medicine for preventing and/or treating a disease related to the activity of PI3Kδ and PI3Kγ, preferably a respiratory system disease, For example asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, preferably asthma and chronic obstructive pulmonary disease.

一種醫藥組成物，其包含如請求項1至20中任一項所述的通式(I)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽與另一種活性劑的組合，該另一種活性劑選自糖皮質激素受體激動劑(甾體性或非甾體性)、選擇性β2腎上腺素受體激動劑、抗毒蕈鹼劑、p38拮抗劑、黃嘌呤衍生物、和PDE4拮抗劑。 A pharmaceutical composition comprising a compound represented by general formula (I) as described in any one of claims 1 to 20 or a meso, racemate, enantiomer, diastereomer Isomers, or mixtures thereof, or pharmaceutically acceptable salts thereof in combination with another active agent selected from the group consisting of glucocorticoid receptor agonists (steroidal or non-steroidal), selective Beta2 adrenergic agonists, antimuscarinics, p38 antagonists, xanthine derivatives, and PDE4 antagonists.

一種如請求項1至20中任一項所述的通式(I)所示的化合物或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽或如請求項21所述的醫藥組成物與另一種活性劑同時、分開或相繼使用在製備用於預防和/或治療PI3Kδ和PI3Kγ的活性相關的疾病的藥物中的用途；該疾病較佳呼吸系統疾病，例如哮喘、慢性阻塞性肺病、支氣管炎、肺氣腫，較佳哮喘和慢性阻塞性肺病；其中該另一種活性劑選自糖皮質激素受體激動劑(甾體性或非甾體性)、選擇性β2腎上腺素受體激動劑、抗毒蕈鹼劑、p38拮抗劑、黃嘌呤衍生物、和PDE4拮抗劑。 A compound represented by general formula (I) as described in any one of claims 1 to 20 or a meso, racemate, enantiomer, diastereomer, or its A mixture form, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as claimed in claim 21 and another active agent for simultaneous, separate or sequential use in the preparation of a medicament for the prevention and/or treatment of diseases associated with the activity of PI3Kδ and PI3Kγ Use in; the disease preferably respiratory disease, such as asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, preferably asthma and chronic obstructive pulmonary disease; wherein the another active agent is selected from glucocorticoid receptor agonists (steroidal or non-steroidal), selective beta2 adrenergic receptor agonists, antimuscarinic agents, p38 antagonists, xanthine derivatives, and PDE4 antagonists.