TW201016683A

TW201016683A - Preparing method of quinazoline derivatives and medicinal use thereof

Info

Publication number: TW201016683A
Application number: TW97141139A
Authority: TW
Inventors: Peng-Cho Tang; Jun Feng; Feng Feng; Lei Zhang; Jing-Quan Ye; Lin Wang; zhi-cheng Song; qian-feng Zhang; ya-xian Dang; Ye-Ying Lu; Ling Zong; Chi-Qiong Jin; Jie Zang; Ying Zhou
Original assignee: Shanghai Hengrui Pharm Co Ltd
Priority date: 2008-10-27
Filing date: 2008-10-27
Publication date: 2010-05-01

Abstract

The present invention relates to preparing methods of quinazoline derivates and medicinal use thereof. In other words, the present invention relates to novel quinazoline compounds of formulas (I), (II), (III), and their tautomers, enantiomers, racemates, and pharmaceutically acceptable salts, and their metabolites, and metabolic precursors or prodrugs, as well as their use as a therapeutic agent, in particular a protein kinase inhibitor, wherein each substituent in formulas (I), (II), (III) is defined as in the description.

Description

201016683 九、發明說明：【發明所屬之技術領域】本發明涉及一種新穎的喹唑啉類衍生物、其製備方法及含有該衍生物的藥物組合物以及其作為治療劑特別是作為酪胺酸激酶抑制劑的用途。【先前技術】細胞的信號傳導是一種基本的作用機制，在信號傳導過程中，來自細胞外的刺激被傳遞到細胞内部，進而調節 .不同細胞的進程。這些信號可調節多種生理反應，包:二眷胞增I、分化、壯和運鮮，它加不㈣類可溶性= 子形式存在，包括以旁分泌因子、自分泌因子和内分泌因子為主的生長因子。藉由與特定跨膜受體結合，生長因子配體將細胞外信號傳遞到細胞内信號途徑，從而引起個體 /細胞對細胞外信號的反應。很多信號傳遞過程是利用蛋白磷酸化的可逆過程，涉及到特定蛋白激酶和磷醯化酶。蛋白激酶（PKs)是對蛋白質的酪胺酸、絲胺酸、蘇胺酸 ❹殘基上的羥基的磷酸化起催化作用的酶。在信號傳導過程中，蛋白激酶和磷醯化酶的反向機制能夠平衡和調節俨號流三一個蛋白質磷酸化狀態能影響其構象、酶的活性、°細° 胞定位，蛋白激酶和磷酸酶的相應作用被修改，磷醯化在信號傳導中是-個重要的調節機制，在信號傳導過程甲的異常會導致細胞的非正常分化、轉形和生長。例如，细胞可藉由將其一部分腿轉形為致癌基因而成為癌細胞，酿胺酸激酶就是這樣的致癌基因所編碼的生長因子受體蛋 94389 7 201016683 白；酪胺酸激酶還可以突變為活化形式而導致多種人類細胞的變異，也可以說，過度表現的正常酿胺酸激酶可以引起不正常細胞增殖。酷·胺酸激S^(PKs)可以方便地分成兩類：蛋白酷胺酸激酶（PTKs)和絲胺酸一蘇胺酸激酶（STKs)。pTKs使蛋白質上的酪胺酸殘基磷酸化，STKs使蛋白質上的絲胺酸、蘇胺酸殘基磷酸化。酪胺酸激酶不僅可以是受體型（包括胞外區域、胞内區域和跨細胞膜區域）還可以是非受體型（包括全部胞内區域）。PTK活性的一個主要方面是它們涉及到作為糁麵胞表面蛋白生長因子受體。具有ρτκ活性的生長因子受體被稱為受體酪胺酸激酶（“RTKs”），在人類基因中90 種酪胺酸激酶被識別’其中約60種是受體型，約30種是非受體型’這些生長因子受體家族可進一步分為2〇種受體赂胺酸激酶亞族和10種非受體酪胺酸激酶亞族（R〇bins〇n 等，Oncogene, 2000，丛 5548-5557)。 RTKs亞族包括以下幾種：（1)EGF家族，如EGF，TGFa，鑛Neu和erbB等；（2)胰島素家族，包括胰島素受體、類胰島素生長因子I受體（IGF1)和胰島素受體相關性受體 (IRR)) ; (3) 111型家族，如血小板衍生生長因子受體 (PDGF，包括PDGFa和PDGFf受體）、幹細胞因子RTKs (SCF RTK，通常稱作C-Kit)、fms-相關酪胺酸激酶3(Flt3) 受體酪胺酸激酶和群落刺激因子1受體（CSF-1R)酪胺酸激酶等。它們在控制細胞生長及分化方面起著關鍵的作用，也是導致產生生長因子和細胞因子的細胞信號的關鍵傳遞 8 94389 201016683 者（參見 Schlessinger and Ullrich, 1 992，9, 383)。一部分非限制性激酶包括Abl, ARaf, ATK，ATM, bcr-abl, Blk, BRaf, Brk, Btk, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CHK, AuroraA, AuroraB, AuroraC, cfms, c-fms, c-Kit, c-Met, cRafl, CSF1R, CSK, c-Src, EGFR, ErbB2, ErbB3, ErbB4, ERK, ERK1, ERK2, Fak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, FLK-4, Fps, Frk, Fyn, GSK, gsk3a, gsk3b, Hck, Chk, Axl, Pim-1, Plh-1, IGF-1R, IKK, IKK1, IKK2, IKK3, INS-R, Φ Integrin-1inked kinase, Jak, JAK1, JAK2, JAK3, JNK, JNK, Lck, Lyn, MEK, MEK1, MEK2, p38, PDGFR, PIK, PKB1, PKB2, PKB3, PKC, PKCa, PKCb, PKCd, PKCe, PKCg, PKC1, PKCm, PKCz, PLK1, Polo-1 ike kinase, PYK2, tiei, tie2, TrkA, TrkB, TrkC, UL13, UL97, VEGF-R1, YEGF-R2, Yes 和Zap70等。人們認為PKs與中樞神經系統疾病如老年癡呆症（參見 Mandelkow, E. M.等.1992，314， 315; Sengupta，Α·等.#〇_/. Ce72. 5j’oc/3e/H· 1997， Ο 167,99)、痛感（參見 Yashpal，K. J. 1995，15， 3263-72)、炎症例如關節炎（參見Badger, J.尸 772er. 1996，279，1453)、牛皮癬（參見 Dvir，等，J. Ceii 1991，113，857)、骨骼疾病例如骨質疏鬆（參見 Tanaka 等，iVatiire，1996，383，528)、癌症（參見 Hunter andPines，CWil994, 79，573)、動脈硬化症（參見 Hajjar and Pomerantz, J· 1992，6，2933)、血栓症（參見 9 94389 201016683201016683 IX. OBJECTS OF THE INVENTION: TECHNICAL FIELD The present invention relates to a novel quinazoline derivative, a process for the preparation thereof, and a pharmaceutical composition containing the same, and as a therapeutic agent, particularly as tyrosine kinase The use of inhibitors. [Prior Art] Cellular signal transduction is a basic mechanism of action. During signal transduction, extracellular stimuli are transmitted to the interior of the cell, which in turn regulates the progression of different cells. These signals can regulate a variety of physiological responses, including: diploid cell I, differentiation, Zoster and fresh, it does not (4) soluble = sub-forms, including paracrine, autocrine and endocrine factors factor. By binding to a specific transmembrane receptor, the growth factor ligand transmits an extracellular signal to the intracellular signaling pathway, causing the individual/cell to respond to extracellular signals. Many signaling processes are reversible processes that utilize protein phosphorylation involving specific protein kinases and phosphonase. Protein kinases (PKs) are enzymes that catalyze the phosphorylation of hydroxyl groups on tyrosine, serine, and sulphonate residues of proteins. In the process of signal transduction, the reverse mechanism of protein kinase and phosphonase can balance and regulate the phosphating state. The phosphorylation state of a protein can affect its conformation, enzyme activity, cell localization, protein kinase and phosphoric acid. The corresponding role of the enzyme has been modified, and phosphorylation is an important regulatory mechanism in signal transduction. In the process of signal transduction, abnormality of A can lead to abnormal differentiation, transformation and growth of cells. For example, a cell can become a cancer cell by transforming a part of its leg into an oncogene, which is a growth factor receptor egg encoded by such an oncogene 94389 7 201016683 white; tyrosine kinase can also be mutated to The activation form leads to variation of a variety of human cells, and it can be said that excessive expression of normal tyrosine kinase can cause abnormal cell proliferation. The cool amine acid stimuli (PKs) can be conveniently divided into two classes: protein glutamate kinases (PTKs) and serine acid-threonine kinases (STKs). pTKs phosphorylate tyrosine residues on proteins, and STKs phosphorylate serine and threonine residues on proteins. Tyrosine kinases can be not only receptor types (including extracellular regions, intracellular regions, and transcellular membrane regions) but also non-receptor types (including all intracellular regions). A major aspect of PTK activity is that they are involved as a facial cell surface protein growth factor receptor. Growth factor receptors with ρτκ activity are called receptor tyrosine kinases (“RTKs”), and 90 tyrosine kinases are recognized in human genes. Of these, about 60 are receptor-type and about 30 are non-receptive. The body type 'the family of growth factor receptors can be further divided into two receptors, the glutamine kinase subfamily and the 10 non-receptor tyrosine kinase subfamilies (R〇bins〇n et al, Oncogene, 2000, plexus 5548 -5557). The RTKs subfamily includes the following: (1) EGF family, such as EGF, TGFa, mineral Neu and erbB, etc.; (2) insulin family, including insulin receptor, insulin-like growth factor I receptor (IGF1) and insulin receptor Related Receptors (IRR); (3) Family 111, such as platelet-derived growth factor receptor (PDGF, including PDGFa and PDGFf receptors), stem cell factor RTKs (SCF RTK, commonly referred to as C-Kit), fms - related tyrosine kinase 3 (Flt3) receptor tyrosine kinase and community stimulating factor 1 receptor (CSF-1R) tyrosine kinase and the like. They play a key role in controlling cell growth and differentiation, and are also a key driver of cellular signaling leading to the production of growth factors and cytokines 8 94389 201016683 (see Schlessinger and Ullrich, 1 992, 9, 383). A portion of the non-limiting kinases include Abl, ARaf, ATK, ATM, bcr-abl, Blk, BRaf, Brk, Btk, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CHK, AuroraA, AuroraB, AuroraC, cfms, c-fms, c-Kit, c-Met, cRafl, CSF1R, CSK, c-Src, EGFR, ErbB2, ErbB3, ErbB4, ERK, ERK1, ERK2, Fak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, FLK-4, Fps, Frk, Fyn, GSK, gsk3a, gsk3b, Hck, Chk, Axl, Pim-1, Plh-1, IGF-1R, IKK, IKK1, IKK2, IKK3, INS- R, Φ Integrin-1inked kinase, Jak, JAK1, JAK2, JAK3, JNK, JNK, Lck, Lyn, MEK, MEK1, MEK2, p38, PDGFR, PIK, PKB1, PKB2, PKB3, PKC, PKCa, PKCb, PKCd, PKCe, PKCg, PKC1, PKCm, PKCz, PLK1, Polo-1 ike kinase, PYK2, tiei, tie2, TrkA, TrkB, TrkC, UL13, UL97, VEGF-R1, YEGF-R2, Yes and Zap70, and the like. PKs are thought to be associated with central nervous system diseases such as Alzheimer's disease (see Mandelkow, EM et al. 1992, 314, 315; Sengupta, Α· et al. #〇_/. Ce72. 5j'oc/3e/H· 1997, Ο 167 , 99), pain (see Yashpal, KJ 1995, 15, 3263-72), inflammation such as arthritis (see Badger, J. corp. 772er. 1996, 279, 1453), psoriasis (see Dvir, et al., J. Ceii 1991) , 113, 857), bone diseases such as osteoporosis (see Tanaka et al, iVatiire, 1996, 383, 528), cancer (see Hunter and Pines, CWil994, 79, 573), atherosclerosis (see Hajjar and Pomerantz, J. 1992) , 6, 2933), thrombosis (see 9 94389 201016683)

Salari，仰凡S 1990, 263, 104)、代謝紊亂如糖尿病（參見 Borthwick, A. C.等.Biochem. Biophys. Res. Commun. 1995, 210, 738)、血管增生性疾病如血管生成（參見Strawn 等 1996，56，3540; Jackson 等 J. Pijan»· hp.Salari, Yang Fan S 1990, 263, 104), metabolic disorders such as diabetes (see Borthwick, AC et al. Biochem. Biophys. Res. Commun. 1995, 210, 738), vascular proliferative diseases such as angiogenesis (see Strawn et al 1996) ,56,3540; Jackson et al. J. Pijan»· hp.

Mer. 1998, 284，687)、自體免疫疾病和移植排斥反應（參見 Bolen and Brugge, Ann. Rev. Immunol. 1 997, 15, 371)、傳染病如病毒（參見 Littler，五.#atL/re 1992，358， 160)和真菌感染（參見 Lum，R. T. PCT Int Appl.，WO 9805335 A1 980212)等疾病的目標有密切的聯繫。 0 PTKs信號傳導過程中，特定生長因子（配體）之間在細胞外相互作用，隨後受體形成二聚體，瞬間内啟動蛋白激酶的内在活性，並進行磷醯化。内部信號傳導分子的結合位置產生，生成了與細胞質信號分子的複合物，促進各種細胞反應例如細胞***（增殖），對胞外微環境代謝作用的表現等。受體酪胺酸激酶罐醯化的結合位置也是與信號傳導分 β子SH2(與src同源）區域具有高度親和力的結合位置。很多與受體酪胺酸激酶相關的細胞内受質蛋白已被確定，可分為兩類：（1)有催化區受質（2)無催化區受質，但可作為結合體，且與某些有催化活性的分.子相關。受體或蛋白與受質SH 2區域相互作用的特異性是藉由靠近構酿化路胺酸 •殘基的胺基酸序列來確定的，SH2區域與碟醯化酷胺酸序列周圍的胺基酸序列與特定受體結合的差異性與受質磷醯化的差異性是一致的。蛋白酪胺酸激酶機能可藉由表現模 94389 10 201016683 式和配體可用性來確定’也可由特定受體啟動的下游區信號傳導路徑來確定。因此，磷醯化提供了一個重要可調節的步驟，此步驟可確定由特定受體啟動的信號傳導的選擇性和分化因子受體。受體酪胺酸激酶的非正常表現或突變可能導致不可控制的細胞增殖（如惡性腫瘤生長）或關鍵發展過程的缺失等。酪胺酸激酶，在大部分人類腫瘤，如白血病、乳腺癌、 ***癌、非小細胞肺癌（包括腺癌、肺鱗狀上皮細胞癌）、月腸癌（包括結腸癌、直腸癌和胃癌）、膀胱癌、食管癌、 _卵巢癌、胰腺癌等癌症中，都會出現突變或過度表現。藉由對人類腫瘤細胞進行檢測，路胺酸激酶廣泛性與關聯性進一步得到了確認。例如：在人類癌症包括肺癌、腦癌、頸癌、胃腸癌、乳腺癌、食管癌、卵巢癌、子宮癌、胯胱，癌和曱狀腺癌中，EGFR酪胺酸激酶會發生突變和過度表現。 “HER”或“Erb”受體酪胺酸激酶亞族包括EGFR， _ HER2，HER3和HER4。這些亞族由胞外糖基化配體結合區域、跨膜區域及可將蛋白質上的酪胺酸序列進行麟醯化的胞内細胞質催化區域所組成。受體酪胺酸激酶催化活性可藉由受體過度表現或配體誘導二聚合被啟動。HER2家族聚合體有同型二聚體和異型二聚體兩種形式。同型二聚化的一個例子是HERl(EGFR)與EGF家族配體（包括EGF，轉形生長因子a’betacellulin，與肝磷脂結合的EGF， ePiregulin)的聚合，四種HER酪胺酸激酶之間的異型二 11 94389 201016683 聚合可藉由與heregul in(也叫neuregul in)家族配體的結合被加速。雖然HER3的受體之一沒有酶活性，但HER2與 HER3，或HER3與HER4的異型二聚也可顯著地刺激酪胺酸激酶受體形成二聚體。在各種類型細胞中，受體過度表現可啟動HER2激酶的活性。受體同型二聚體和異型二聚體的啟動可將受體和其他細胞内蛋白質酪胺酸序列進行填醯化，隨後細胞内信號途徑如檄管相關蛋白激酶（MAP激酶）和磷脂醯肌醇（-3)激酶（PI3激酶）也被啟動，這些信號途徑的啟動促使細胞增殖，抑制細胞调亡。 Φ RTK另一個亞族包括胰島素受體（IR)，類胰島素生長因子-1受體（IGF-1R)，胰島素受體相關受體（IRR)。IR， IGF-1R與胰島素，IGF-1和IGF- Π相互作用，生成了由兩種完全胞外糖基化α亞基和兩個穿過細胞膜且含有酪胺酸激酶區域万亞基構成的異四聚體。 RTK第三個亞族是指血小板衍生生長因子受體（PDGFR) 家族，其中包括 PDGFRa，PDGFR/3，CSFIR，c-Kit 和Mer. 1998, 284, 687), autoimmune diseases and transplant rejection (see Bolen and Brugge, Ann. Rev. Immunol. 1 997, 15, 371), infectious diseases such as viruses (see Littler, V. #atL/) Re 1992, 358, 160) is closely related to the goals of diseases such as fungal infections (see Lum, RT PCT Int Appl., WO 9805335 A1 980212). 0 During PTKs signaling, specific growth factors (ligands) interact extracellularly, and then the receptor forms a dimer that initiates the intrinsic activity of the protein kinase and initiates phosphorylation. The binding site of the internal signaling molecule is generated to form a complex with the cytoplasmic signaling molecule, which promotes various cellular reactions such as cell division (proliferation) and the metabolism of the extracellular microenvironment. The binding site of the receptor tyrosine kinase can also be a binding site with a high affinity for the signal transduction β-SH2 (synchronous to src) region. Many intracellular receptor proteins associated with receptor tyrosine kinase have been identified and can be divided into two categories: (1) catalytic zone acceptor (2) catalytic zone-free substrate, but can be used as a combination, and Some catalytically active sub-related. The specificity of the interaction of the receptor or protein with the SH 2 region of the receptor is determined by the amino acid sequence close to the structuring of the glutamic acid residue, and the SH2 region is adjacent to the amine surrounding the carbamic acid sequence. The difference in binding of a base acid sequence to a specific receptor is consistent with the difference in the quality of the phosphate. The protein tyrosine kinase function can be determined by expressing the model 94389 10 201016683 and ligand availability to determine the downstream region signal conduction pathway that can also be initiated by a particular receptor. Thus, phosphorylation provides an important, regulatable step that determines the selectivity of signaling and the differentiation factor receptor that is initiated by a particular receptor. Abnormal expression or mutation of the receptor tyrosine kinase may result in uncontrolled cell proliferation (such as malignant tumor growth) or loss of critical developmental processes. Tyrosine kinase, in most human tumors such as leukemia, breast cancer, prostate cancer, non-small cell lung cancer (including adenocarcinoma, lung squamous cell carcinoma), colon cancer (including colon, rectal, and gastric) In cancers such as bladder cancer, esophageal cancer, _ovarian cancer, and pancreatic cancer, mutations or excessive manifestations may occur. The broadness and association of glutamate kinase has been further confirmed by detection of human tumor cells. For example, in human cancers including lung cancer, brain cancer, cervical cancer, gastrointestinal cancer, breast cancer, esophageal cancer, ovarian cancer, uterine cancer, sputum, cancer, and squamous cell carcinoma, EGFR tyrosine kinase is mutated and over-exposed. which performed. The "HER" or "Erb" receptor tyrosine kinase subfamily includes EGFR, _HER2, HER3 and HER4. These subfamilies consist of an extracellular glycosylation ligand binding region, a transmembrane region, and an intracellular cytoplasmic catalytic region that cleaves the tyrosine sequence on the protein. The receptor tyrosine kinase catalytic activity can be initiated by receptor overexpression or ligand induced dimerization. The HER2 family of polymers has both homodimers and heterodimers. An example of homodimerization is the polymerization of HER1 (EGFR) with the EGF family of ligands (including EGF, transforming growth factor a'betacellulin, heparin-binding EGF, ePiregulin), between four HER tyrosine kinases. Shape II 2 94389 201016683 Polymerization can be accelerated by binding to the heregul in (also known as neuregul in) family of ligands. Although one of the receptors for HER3 has no enzymatic activity, heterodimerization of HER2 with HER3, or HER3 and HER4, also significantly stimulates the formation of dimers of the tyrosine kinase receptor. In various cell types, receptor overexpression can activate HER2 kinase activity. The initiation of receptor homodimers and heterodimers can fill receptors and other intracellular protein tyrosine sequences, followed by intracellular signaling pathways such as fistula-associated protein kinases (MAP kinases) and phospholipid muscles. Alcohol (-3) kinase (PI3 kinase) is also initiated, and the initiation of these signaling pathways promotes cell proliferation and inhibits cell apoptosis. Another subfamily of Φ RTK includes the insulin receptor (IR), the insulin-like growth factor-1 receptor (IGF-1R), and the insulin receptor-associated receptor (IRR). IR, IGF-1R interacts with insulin, IGF-1 and IGF-Π to form a complete subcellular glycosylation of the alpha subunit and two tyrosine kinases containing the tyrosine kinase domain. Heterotetramer. The third subfamily of RTK refers to the platelet-derived growth factor receptor (PDGFR) family, including PDGFRa, PDGFR/3, CSFIR, c-Kit and

Oc-f ms。這些受體由含有各種類免疫球蛋白環糖基化胞外區域和一個胞内區域所組成，其中該胞内區域中酪胺酸激酶區被不相關的胺基酸序列阻斷。血小板衍生生長因子受體，如PDGFRa和PDGFRyS等也是跨膜酪胺酸激酶受體。當它們與配體相結合時，或形成同型二聚物（PDGF-AA, PDGF-BB)，或異型二聚物 (PDGF-AB)。隨後受體形成二聚體，酪胺酸激酶被活化，向下游區發信號來促進腫瘤生長。基因突變是受體不依賴於 12 94389 201016683 與配體結合而被啟動的原因，也是腫瘤生成的驅動力。在多種不同的腫瘤細胞株内，特別是***癌、結腸癌、卵巢癌、***癌、肉瘤和膠質瘤的細胞中，都發現能夠啟動 PDGFR生長因子一PDGF的表現，其中腦瘤，***癌（包括腺癌和骨轉移癌）惡性神經膠質過多症研究資料有研究價值。 c-Kit是PDGF受體家族的成員，當其與配體SCF(幹細胞因子）相結合時，活性被啟動。在各種不同的實體瘤中對 c-Kit表現模式進行了研究’在肉瘤，胃腸道膠質瘤 0 (GIST) ’精原細胞瘤和類癌瘤中，c_Kit有過量表現。[來見 Weber 等，J. Clin. Oncol. 22C14S)，9642 (2004)]。 GIST是一種非上皮細胞瘤，大多數存在於胃部，少數分佈於小腸’在食道中存在很少，也有分佈在肝、腹膜腔等部 -位。GIST源於Cajal間質細胞（ICC)，ICC可部分形成腸自主神經糸統’參與控制胃動力。大多數（5〇至產生疋由於c-Ki t基因發生突變，在消化道内，di 土/ _ CD117染色陽性的一般都為GIST，c-Kit突變能夠使其不依賴於SCF啟動便具有C-Kit機能，從而使細胞***率增加，導致基因體的不穩定。在畸變肥大細胞瘤、肥大細胞增生病、骨髓增生綜合症、蓴麻疹等疾病中，也可檢測到 c-Ki t的表現，在急性AML和惡性淋巴瘤中也有c-£i t的表現’在小細胞支氣管癌、精原細胞瘤、無性細胞瘤、睾丸、上皮内瘤樣變、黑素瘤、***癌、成神經細胞瘤、尤因肉瘤都有c-Kit表現（參見Sch^tte et al.， 13 94389 201016683 innovartis 3/2001.)。衆所周知，RET(rearranged during transfection)。致癌基因點遺傳突變是致癌的，患有多發性内分泌腺腫瘤症候群2(MEN 2)病人可能會導致患有嗜鉻細胞瘤、甲狀腺髓樣癌和甲狀旁腺腺瘤和增生等病症（見Oc-f ms. These receptors are composed of a variety of immunoglobulin-containing glycosylated extracellular regions and an intracellular region in which the tyrosine kinase domain is blocked by an unrelated amino acid sequence. Platelet-derived growth factor receptors such as PDGFRa and PDGFRyS are also transmembrane tyrosine kinase receptors. When they are combined with a ligand, either a homodimer (PDGF-AA, PDGF-BB), or a heterodimer (PDGF-AB) is formed. The receptor then forms a dimer, and the tyrosine kinase is activated to signal downstream regions to promote tumor growth. Gene mutations are responsible for the receptor being independent of 12 94389 201016683 and binding to ligands, and are also the driving force for tumorigenesis. In a variety of different tumor cell lines, especially breast cancer, colon cancer, ovarian cancer, prostate cancer, sarcoma and glioma cells, it was found to be able to initiate PDGFR growth factor-PDGF, including brain tumor, prostate cancer ( Research data on malignant gliosis including adenocarcinoma and bone metastases have research value. c-Kit is a member of the PDGF receptor family and is activated when it binds to the ligand SCF (dry cytokine). The c-Kit pattern was studied in a variety of different solid tumors. In sarcoma, gastrointestinal glioma 0 (GIST) s seminoma and carcinoid tumors, c_Kit was overexpressed. [See Weber et al., J. Clin. Oncol. 22C14S), 9642 (2004)]. GIST is a non-epithelial cell tumor, most of which is found in the stomach, and a few are distributed in the small intestine. There are few in the esophagus, and it is also distributed in the liver and peritoneal cavity. GIST is derived from Cajal interstitial cells (ICC), which can form part of the intestinal autonomic nervous system to participate in the control of gastric motility. Most of them (5〇 to produce 疋 due to c-Ki t gene mutation, in the digestive tract, di soil / _ CD117 staining is generally GIST, c-Kit mutation can make it independent of SCF start with C- Kit function, which leads to an increase in cell division rate, leading to instability of the genome. In the cases of distorted mast cell tumor, mast cell hyperplasia, myeloproliferative syndrome, urticaria, etc., the performance of c-Ki t can also be detected. There is also c-£it expression in acute AML and malignant lymphoma 'in small cell bronchial carcinoma, seminoma, dysgerminoma, testis, intraepithelial neoplasia, melanoma, breast cancer, neuroblasts Both tumor and Ewing sarcoma have c-Kit expression (see Sch^tte et al., 13 94389 201016683 innovartis 3/2001.) It is well known that RET (rearranged during transfection). Oncogene point genetic mutations are carcinogenic, Patients with multiple endocrine neoplasia syndrome 2 (MEN 2) may cause pheochromocytoma, medullary thyroid carcinoma, and parathyroid adenoma and hyperplasia (see

Huang et al.， Cancer Res· 60, 6223-6 (2000))。因胎肝激酶（FI k)受體亞族與pDGFR亞族很相似，有時被歸於該族。此亞族由含激酶***區域_受體胎肝激酶 (KDR/FLK-l，VEGFR2)、Flk-lR，Flk_4 和類仏3酪胺酸激酶UFlt-1)所組成。 _ 酪胺酸激酶生長因子受體家族的另外一個成員是纖維 _母細胞生長因子（FGF)受體亞族。此亞族由四個受體， FGFR1〜4、七個配體和FGF1-7組成。雖然目前尚未確定，仁些文體是由包含各種類免疫球蛋白環糖基化的一個胞卜區域和一個其中酪胺酸激酶序列被不相關的胺基酸序列所阻斯的胞内區域組成。酪胺酸激酶生長因子受體家族的另外一個成員是血管钃=j生長因子（VEGF)受體亞族。與pDGF相似，vegf是二 ^曰蛋白’但生物學功能和體内目標細胞特異性不同。特 ^疋VEGFR與血官生成有關，籍由抑制VEGFRs來抑制血卜成，正應用於臨床治療腫瘤，且取得了較好療效。VEGF 在各種惡性實體腫瘤中，如肺癌、乳腺癌、非霍奇金惡性瘤、卵巢癌、胰腺癌、惡性胸膜間皮瘤和黑素瘤有強烈表現，且與癌變進程相關，在白血球過多症和淋巴瘤中也有表現。除了其血管生成活性，VEGFR，VEGF配體也可 14 94389 201016683 以藉由在腫瘤細胞内直接藉由pr〇_survival性質促進腫瘤生長，PDGF也具有血管生成作用。新生血管生成的過程對於腫瘤持續生長起著關鍵作用，正常情況下，新生血管的生成在人的生理過程如胚胎生長、傷口癒合和女性生殖的各個過程都是非常重要的。然而，非預料或者病理學上的血管生成卻與疾病的一系列狀態相關，如糖尿病視網膜病、牛皮癬、癌症、類風濕性關節炎、動脈粥狀硬化、卡波濟（氏）肉瘤和血管瘤等。血管内皮細胞的生成啟動血管生成，具有刺激體内血管内皮細胞中的的生成活性一些多饗肽已經被確認，包括酸性、鹼性的纖維母細胞生長因子 (aFGF and bFGF)和血管内皮生長因子。由於VEGF受體的限制表現，其生長因子的活性與aFGF和bFGF活性相比，對内皮細胞相對來講具有特異性。最近的證據表明，vegf 在正常情況和病理學情況下的血管生成和血管滲透過程中，都是非常重要的刺激劑。vegf能夠誘導企管萌芽表型，匕誘導内皮細胞增瘦、蛋白酶的表現和遷移來促進毛 _細血管生成，從而形成超滲透、不成熟的血管網路，這是典型的病理學血管生成的典型特徵。人們期望拮抗vegf 活性在治療與血管生成作用或者血管滲透性相關的疾病如腫瘤特別是抑制腫瘤生長能夠有應用的價值。 FLT3(類Fms酪胺酸激酶）是酪胺酸激酶（pTdu型家族成員，在成人和幼兒急性髓細胞樣白血病（AML)、急性髓細胞樣白血病、骨髓增生異常綜合症等白血球過多症中， FLT3基因非正常表現。35%的急性趙細胞樣白血病病人的 94389 15 201016683 FLT3突變被啟動且預後不良，大多數的突變都有在近膜區域的結構内複製的現象，5—10%的病人天冬醯氨835發生點突變，FLT3的酪胺酸激酶活性被啟動，致使在配體缺失的情況下也有信號存在且發生增殖。據研究，有突變形式受體表現的患者治癒的幾率降低。總之，在人白血球過多症和骨髓增生異常綜合症中，FLT3突變都與腫瘤的發生相關。經證實肝細胞生長因子（HGF)受體（c-MET或HGFR)酪胺酸激酶與腫癟生成、增強細胞運動性、侵襲和轉移密切黌相關（參見 Ma，P.C 等（2003b). Cancer 22, 309-25; Maulik，G.等（2002b). Facto/· i?ev，13，41-59)。各種腫瘤包括小細胞肺癌（SCLC)中的過度表現或突變可啟動c-MET(HGFR)(參見Ma，P.C.等 (2003a)· Ca/3ceri?es, 63，6272-6281)。致癌基因c-Met編碼肝細胞生長因子受體，是具有酪胺酸激酶活性的細胞膜糖蛋白，對多種細胞增殖、分化具有 _重要的生理調節作用.c-met基因在許多惡性塍瘤中過表現，是甲狀腺濾泡上皮細胞癌變的重要因素，並與甲狀腺癌的病理分期、侵襲及轉移密切相關。關於 PKT 亞族，Plowman 等在 7(6): 334-339 (1994)中有更為詳細描述，該文獻作為一整體藉由引用結合到本文中。除了 PTKs以外，還存在另外的細胞酶家族，稱作受體酪胺酸激酶抑制劑，並在此使用後一名稱，縮寫為 16 94389 201016683 CTK 。CTKs本身缺少胞外區域和跨膜區域。目前，已經在 11 個亞族（Src，Frk，Btk，Csk，Abl，Zap70，Fes/Fps， Fak，Jak, Ack和LIMK)中已經雲定超過24種CTKs。在目前為止，Six亞族CTKs數目似乎最多，包括Src，Yes, Fyn，Huang et al., Cancer Res. 60, 6223-6 (2000)). Because the fetal liver kinase (FI k) receptor subfamily is very similar to the pDGFR subfamily, it is sometimes attributed to this family. This subfamily consists of a kinase-containing insertion region - receptor fetal liver kinase (KDR/FLK-1, VEGFR2), Flk-1R, Flk_4 and steroid-like tyrosinase UFlt-1). Another member of the tyrosine kinase growth factor receptor family is the fibro-maternal growth factor (FGF) receptor subfamily. This subfamily consists of four receptors, FGFR1~4, seven ligands and FGF1-7. Although it has not been determined at present, the genus is composed of a cellular region containing various types of immunoglobulin cycloglycosylation and an intracellular region in which the tyrosine kinase sequence is blocked by an unrelated amino acid sequence. Another member of the tyrosine kinase growth factor receptor family is the vascular 钃=j growth factor (VEGF) receptor subfamily. Similar to pDGF, vegf is a diterpene protein but differs in biological function from target cell specificity in vivo. Specifically, VEGFR is related to the formation of blood, and inhibits VEGFRs to inhibit blood stasis. It is used in clinical treatment of tumors and has achieved good results. VEGF is strongly expressed in various malignant solid tumors such as lung cancer, breast cancer, non-Hodgkin's malignant tumor, ovarian cancer, pancreatic cancer, malignant pleural mesothelioma, and melanoma, and is associated with the progression of cancer, in the case of leukemia And also in lymphoma. In addition to its angiogenic activity, VEGFR, VEGF ligands can also be used to promote tumor growth directly by pr〇_survival properties in tumor cells, and PDGF also has an angiogenic effect. The process of neovascularization plays a key role in the continued growth of tumors. Under normal conditions, the formation of new blood vessels is very important in human physiological processes such as embryo growth, wound healing and female reproduction. However, unanticipated or pathological angiogenesis is associated with a range of conditions, such as diabetic retinopathy, psoriasis, cancer, rheumatoid arthritis, atherosclerosis, Kaposi's sarcoma, and hemangioma. Wait. Vascular endothelial cell production initiates angiogenesis and has been shown to stimulate the production of vascular endothelial cells in vivo. Some polypeptides have been identified, including acidic, basic fibroblast growth factor (aFGF and bFGF) and vascular endothelial growth factor. . Due to the limited expression of VEGF receptors, the activity of growth factors is relatively specific to endothelial cells compared to aFGF and bFGF activities. Recent evidence suggests that vegf is a very important stimulator during angiogenesis and vascular infiltration in both normal and pathological conditions. Vegf can induce a budding phenotype, induce endothelial cell thinning, protease expression and migration to promote hairy-angiogenesis, thereby forming a super-osmotic, immature vascular network, which is typical of pathological angiogenesis. feature. It is expected that antagonizing vegf activity can be of value in the treatment of diseases associated with angiogenesis or vascular permeability, such as tumors, particularly tumor growth inhibition. FLT3 (Fms-like tyrosine kinase) is a member of the tyrosine kinase (pTdu family) in leukemia, such as adult and young children with acute myeloid leukemia (AML), acute myeloid leukemia, and myelodysplastic syndrome. FLT3 gene abnormal performance. 35% of patients with acute Zhao-like leukemia 94389 15 201016683 FLT3 mutation is initiated and the prognosis is poor, most of the mutations have a phenomenon of intrastructural replication in the membrane area, 5-10% of patients The point mutation of aspartate 835 was initiated, and the tyrosine kinase activity of FLT3 was initiated, resulting in the presence of a signal and proliferation in the absence of ligand. According to the study, patients with mutant form of receptor expression have a reduced chance of cure. In conclusion, in human leukemia and myelodysplastic syndromes, FLT3 mutations are associated with tumorigenesis. Hepatocyte growth factor (HGF) receptor (c-MET or HGFR) tyrosine kinase and tumor formation have been confirmed. Increased cell motility, invasion, and metastasis are closely related (see Ma, PC et al. (2003b). Cancer 22, 309-25; Maulik, G. et al. (2002b). Facto/· i?ev, 13 41-59). Overexpression or mutations in various tumors including small cell lung cancer (SCLC) can initiate c-MET (HGFR) (see Ma, PC et al. (2003a) Ca/3ceri?es, 63, 6272-6281) The oncogene c-Met encodes a hepatocyte growth factor receptor, a cell membrane glycoprotein with tyrosine kinase activity, which has important physiological regulation effects on various cell proliferation and differentiation. The c-met gene is in many malignant tumors. Over-expression is an important factor in the carcinogenesis of thyroid follicular epithelial cells and is closely related to the pathological stage, invasion and metastasis of thyroid cancer. Regarding the PKT subfamily, Plowman et al., 7(6): 334-339 (1994) For the detailed description, the document is incorporated herein by reference in its entirety. In addition to PTKs, there is an additional family of cellular enzymes called receptor tyrosine kinase inhibitors, and the latter name is used herein, abbreviated as 16 94389 201016683 CTK. CTKs themselves lack extracellular and transmembrane regions. Currently, they are already in 11 subfamilies (Src, Frk, Btk, Csk, Abl, Zap70, Fes/Fps, Fak, Jak, Ack and LIMK). More than 24 CTKs have been clouded. So far in front, Six subfamily seems the most number of CTKs, including Src, Yes, Fyn,

Lyn, Lck，Blk, Hck, Fgr 和 Yrk，且 Src 亞族酶與腫瘤生成有關。關於CTKs更為詳盡的描述，可參見iB〇;len， 1993’ 〇ncogen 8: 2025_2031，其全文包括任何附圖作為一整體提出’藉由引用結合到本文中。與CTKs相類似，絲胺酸-蘇胺酸激酶或，在細胞黌内佔據主導地位，雖然僅有幾種STK型受體激酶。STKs是最普遍的細胞溶質激酶，即它發揮其功能在部分細胞質中，而不是在細胞質胞器中。細胞溶質是細胞内一個區域，在此大夕數細胞中間代謝和生物合成活性發生；1如蛋白質是在細胞溶質核糖體上進行合成的。與過度增殖相關疾病如癌症等的特徵之一是對細胞傳導途徑進行破壞，細胞傳導途徑藉由細胞周期來控制進 _程。在真核細胞中，細胞周期與蛋白質的磷醯化有序的級聯反應（cascade)密切相關，在信號傳導的機制中，pKs很多豕族似乎在細胞***周期級聯中都起著關鍵的作用。關於癌症’提出兩個主要的假設解釋過度細胞增殖，該增殖驅動與已知由PK調節的功能相關的腫瘤發展。即，人們覺得惡性腫瘤生長是由於控制細胞***或增殖的機制被破壞弓|起的。致癌基因蛋白質產物能夠干擾調節細胞生長和增殖的信號傳導途徑，這些致癌基因的蛋白質產物包 94389 17 201016683 括上面討論的細胞外生長因子，跨膜生長因子ρτκ受體 (RTKs)，細胞質PTKs(CTKs)和細胞溶質STKs。人們期待著能夠合成具有抗腫瘤細胞增殖活性的抑制劑，希望能夠抑制PTKs、CTKs或者STKs中的一種或者多種，有效地治療和改善由PTKs、CTKs或者STKs以及血管生成作用誘導的超增殖生理蒼乱。【發明内容】為了克服現有技術的不足之處，本發明的目的在於提供一種通式I，II和ΠΙ所示的新穎的喹唑啉類化合物，參以及匕們的互變異構物、鏡像異構物、非鏡像異構物、消旋物和藥學上可接受的鹽，以及代謝產物和代謝前驅物或前藥。 R\ HNy R2Lyn, Lck, Blk, Hck, Fgr and Yrk, and Src subfamily enzymes are involved in tumorigenesis. For a more detailed description of CTKs, see iB〇; len, 1993' 〇ncogen 8: 2025_2031, the entire disclosure of which is incorporated herein by reference in its entirety. Similar to CTKs, serine-threonine kinases or dominate in cell rafts, although there are only a few STK-type receptor kinases. STKs are the most common cytosolic kinases, ie, they function in part of the cytoplasm, not in the cytoplasmic organelles. The cytosol is a region in the cell where metabolism and biosynthesis activity occur in the middle of the cell; 1 as the protein is synthesized on the cytosolic ribosome. One of the characteristics of diseases such as cancer associated with hyperproliferation is the destruction of the cell-mediated pathway, which is controlled by the cell cycle. In eukaryotic cells, the cell cycle is closely related to the phosphorylation cascade of proteins. In the signaling mechanism, many of the pKs seem to play a key role in the cell division cycle cascade. effect. Two major hypotheses are proposed for cancer to explain excessive cell proliferation, which drives tumor development associated with functions known to be regulated by PK. That is, it is believed that the growth of malignant tumors is caused by the mechanism that controls cell division or proliferation. Oncogene protein products can interfere with signaling pathways that regulate cell growth and proliferation. The protein product of these oncogenes contains 94389 17 201016683 including the extracellular growth factors discussed above, transmembrane growth factor ρτκ receptors (RTKs), and cytoplasmic PTKs (CTKs). ) and cytosol STKs. It is expected to be able to synthesize inhibitors with anti-tumor cell proliferation activity, and hope to inhibit one or more of PTKs, CTKs or STKs, effectively treat and improve hyperproliferative physiology induced by PTKs, CTKs or STKs and angiogenesis. Chaos. SUMMARY OF THE INVENTION In order to overcome the deficiencies of the prior art, it is an object of the present invention to provide novel quinazoline compounds of the formulae I, II and hydrazine, as well as their tautomers and mirror images. Constructs, non-image isomers, racemates and pharmaceutically acceptable salts, as well as metabolites and metabolic precursors or prodrugs. R\ HNy R2

Ν·Ν·

R1 e ⑴ (..) 其中： R1係選自烷基、雜環烷基雜％烧基、芳基或雜芳基可以進—步被__個或多個選自搞基:鹵素、芳基、羥基、胺基、炔基、烯基、氰基、硝基三氟甲基、#代苄基、雜環烷基、羧酸或羧酸酯的取代邊所取代；其中該芳基或雜芳基可以併成雙環，此雙環可》進一步被苄基或鹵代苄基所取代；或者R1為結構式：其中：方基或雜芳基、其中該烧基、 94389 18 201016683 B係選自芳基或雜芳基，其中該芳基或雜芳基可以進一步被一個或多個選自烷基、鹵素、芳基、羥基、胺基、炔基、烤基、氰基、硝基、二氟甲基、自代苄基、雜環院基、缓酸或羧酸酯的取代基所取代； T 係選自-〇(CH2)r-，-N(CH2)r-或-S(CH〇r ; L係選自芳基或雜芳基，其中該芳基或雜芳基可以進一步被一個或多個鹵素或烷基所取代； R2係選自氫原子、烷基、環烷基、三氟曱基、雜環烷基、芳基、雜芳基、芳烷基，其中該烷基、環烷基、雜環烷基、 ❹^'基、雜芳基、芳烧基進一步被一個或多個選***基、芳基、羥基、iS素、胺基、氰基、烷氧基、羥酸、羧酸酯或 -nr6r7的取代基所取代； R和R4係各自獨立地選自氫原子、烧基、三氟甲基、環院 -基、雜環烷基、芳基、羧酸酯、-S〇2R6、.-CH2C(=0)NR6R7、 -C〇0)NR6R7、-(CH2)nNR6R7 或-NC (=0) R6，其中該烷基、環烧基、雜環烷基進一步被一個或多個選自烷基、齒素、響三氣甲基、芳基、羥基、烷氧基、芳氧基、環烷基、雜環院基、雜芳基、雜環烷氧基、氰基、羧酸、羧酸酯、_s〇2R6、或~(CH2)nNR6R7的取代基所取代；同時，R3和R4 —起形成一個4至；8員環基；其中該5至8 員雜環内含有一個或多個N、0、S原子，並且4至8員雜環上進一步被一個或多個選自烷基、鹵素、芳基、雜芳基、鹵代烷基、齒代烷氧基、羥基、烷氧基、芳氧基、羰基、雜環烷基、羧酸、羧酸酯、=N-0R6或-NR6R7的取代基所取 19 94389 201016683 代； R5係選自氫原子、烷基、環烷基、-C〇0)0R6，其中該烷基或環烷基進一步被一個或多個選自烷基、羥基、烷氧基、氰基、-NR6R7、羧酸或羧酸酯所取代； R6和R7係分別選自氫原子、烷基、烯基、環烷基、雜環烷基、芳基或雜芳基，其中該烷基、烯基、環烷基、雜環炫基、芳基或者雜芳基進一步被一個或多個選自烷基、環烷基、鹵素、芳基、羥基、胺基、烷氧基、烯基、雜環烷基、經燒基、-S〇2R6、-C(=〇)R6、羧酸、羧酸酯或-NR6R7的取 •代基所取代；同時，R6和R7—起形成一個4至8員雜環基；其中該5至 8員雜環内含有一個或多個n、〇、s原子，並且4至8員雜環上進一步被一個或多個選自烷基、鹵素、芳基、雜芳 -基·、齒代芳基、鹵代烷氧基、胺基、.羥基、氰基、烷氧基、芳氧基、胺院基、羥院基、環烧基、雜環烧基、羰基、緩酸、羧酸酯、-C(=0)NR6R7、-NC (=0) R6、_s〇2R6、或_nr6r7 @的取代基所取代； η是0至6 ; r是0至2 〇具體地’本發明包括下述通式（1)表示的化合物或其R1 e (1) (..) wherein: R1 is selected from an alkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, which may be further substituted by __ or more selected from the group: halogen, aromatic Substituted with a substituted side of a hydroxy group, an amino group, an amino group, an alkynyl group, an alkenyl group, a cyano group, a nitrotrifluoromethyl group, a benzyl group, a heterocycloalkyl group, a carboxylic acid or a carboxylic acid ester; wherein the aryl group or The heteroaryl group may be combined into a bicyclic ring, which may be further substituted by a benzyl group or a halobenzyl group; or R1 is a structural formula: wherein: a aryl group or a heteroaryl group, wherein the alkyl group, 94389 18 201016683 B is selected Or aryl or heteroaryl, wherein the aryl or heteroaryl group may be further selected from one or more selected from the group consisting of alkyl, halogen, aryl, hydroxy, amine, alkynyl, alkoxy, cyano, nitro, Substituted by a substituent of a difluoromethyl group, a self-benzyl group, a heterocyclic compound, a slow acid or a carboxylate; T is selected from the group consisting of -〇(CH2)r-, -N(CH2)r- or -S( CH〇r; L is selected from an aryl or heteroaryl group, wherein the aryl or heteroaryl group may be further substituted by one or more halogen or alkyl groups; R2 is selected from a hydrogen atom, an alkyl group, a cycloalkyl group , trifluoromethyl, heterocyclic a aryl group, an aryl group, a heteroaryl group, an aralkyl group, wherein the alkyl group, the cycloalkyl group, the heterocycloalkyl group, the fluorenyl group, the heteroaryl group, and the aryl group are further selected from one or more selected from the group consisting of Substituted with an aryl group, a hydroxyl group, an iS element, an amine group, a cyano group, an alkoxy group, a hydroxy acid group, a carboxylic acid ester or a substituent of -nr6r7; R and R4 are each independently selected from a hydrogen atom, an alkyl group, and a trifluoro group. Methyl, cyclohexyl-based, heterocycloalkyl, aryl, carboxylate, -S〇2R6, .-CH2C(=0)NR6R7, -C〇0)NR6R7, -(CH2)nNR6R7 or -NC ( =0) R6, wherein the alkyl group, the cycloalkyl group, the heterocycloalkyl group are further selected from one or more selected from the group consisting of an alkyl group, a dentate, a tris-methyl group, an aryl group, a hydroxyl group, an alkoxy group, and an aryloxy group. Substituted by a substituent of a cycloalkyl group, a heterocyclic compound, a heteroaryl group, a heterocycloalkoxy group, a cyano group, a carboxylic acid, a carboxylic acid ester, _s〇2R6, or ~(CH2)nNR6R7; R4 together form a 4 to 8 membered ring group; wherein the 5 to 8 membered heterocyclic ring contains one or more N, 0, S atoms, and the 4 to 8 membered heterocyclic ring is further selected from one or more Alkyl, halogen, aryl, heteroaryl, haloalkyl, aldentate a substituent of a radical, a hydroxyl group, an alkoxy group, an aryloxy group, a carbonyl group, a heterocycloalkyl group, a carboxylic acid, a carboxylic acid ester, =N-0R6 or -NR6R7 taken from 19 94389 201016683; R5 is selected from a hydrogen atom, An alkyl group, a cycloalkyl group, -C〇0)0R6, wherein the alkyl group or cycloalkyl group is further selected from one or more selected from the group consisting of an alkyl group, a hydroxyl group, an alkoxy group, a cyano group, a -NR6R7, a carboxylic acid or a carboxylic acid. Substituted by an ester; R6 and R7 are each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, wherein the alkyl group, the alkenyl group, the cycloalkyl group, and the heterocyclic group Further, the aryl, aryl or heteroaryl group is further selected from one or more selected from the group consisting of alkyl, cycloalkyl, halogen, aryl, hydroxy, amine, alkoxy, alkenyl, heterocycloalkyl, alkyl, -S〇2R6, -C(=〇)R6, a carboxylic acid, a carboxylic acid ester or a substituent of -NR6R7; wherein R6 and R7 together form a 4 to 8 membered heterocyclic group; The 8-membered heterocyclic ring contains one or more n, 〇, s atoms, and the 4 to 8 membered heterocyclic ring is further selected from one or more selected from the group consisting of an alkyl group, a halogen, an aryl group, a heteroaryl group, and a tooth. Aryl, haloalkoxy, amine Base, hydroxyl group, cyano group, alkoxy group, aryloxy group, amine group, hydroxyl group, cycloalkyl group, heterocyclic group, carbonyl group, acid retardant, carboxylate, -C(=0)NR6R7, -NC (=0) Substituent of R6, _s〇2R6, or _nr6r7 @ is substituted; η is 0 to 6; r is 0 to 2 〇 Specifically, the present invention includes a compound represented by the following formula (1) Or

94389 20 (I) 201016683 其中·’ R係選***基、雜環炫基、芳基或雜芳基，其中該炫基、雜環炫基、芳基或雜芳基可以進一步被一個或多個選*** 基、函素、芳基、羥基、胺基、炔基、烯基、氰基、硝基、二氟甲基、鹵代苄基、雜環烷基、羧酸或羧酸酯的取代基所取代，其令該芳基或雜芳基可以併成雙環，此雙環可以進一步被一個苄基或鹵代苄基所取代；或者R1為結構式：其中： ❹B係選自芳基或雜芳基，其中該芳基或雜芳基可以進一步被一個或多個選自烷基、齒素、芳基、羥基、胺基、炔基、烯基、氰基、硝基、三氟甲基、齒代苄基、雜環烷基、羧酸或羧酸酯的取代基所取代； :T 係選自-〇(CH2)r-，-N(CH2)r-·或-S(CH2)r ; L係選自芳基或雜芳基，其中該芳基或雜芳基可以進一步被一個或多個鹵素或烷基所取代；鑄R2係選自氫原子、烷基、環烷基、三氟甲基、雜環烷基、芳基、雜芳基、芳烷基、其中該烷基、環烷基、雜環烷基、芳基、雜芳基、芳烷基進一步被一個或多個選自烷基、芳基、經基、鹵素、胺基、氰基、烧氧基、緩酸、羧酸酯或 -NR6R7的取代基所取代； R和R4係各自獨立地選自氫原子、烷基、三氟曱基、環烷基、雜環烷基、芳基、羧酸酯、_s〇2R6、-CH2C(=〇)nr6r7、 -C(=〇)NR6R7、-（CH2)nNR6R7 或~NC(=0)R6 ’ 其中該烷基、環 94389 21 201016683 烧基、雜環燒基進-步被-個或多個選***基、齒素、三氣甲基:芳基、經基、烧氧基、芳氧基、環烧基、雜環烧基、雜芳基、雜環燒氧基、氰基、幾酸、缓酸醋、_獅6、或_(CH2)nNR6R7的取代基所取代； f時’以和R4 一起形成-個4至8員環基；其中該5至8 員雜環内含有-個或多個N、〇、s原子，並且4至8員雜環上進一步被一個或多個選自烷基、商素、芳基、雜芳基、函代烷基、齒代烷氧基、羥基、烷氧基、芳氧基、羰基、雜環烷基、羧酸、羧酸酯、=N_〇R6或_NR6K7的取代基所取參代； R和R係分別選自氫原子、烷基、烯基、環烷基、雜環烷基、芳基或雜芳基，其中該烷基、稀基、環烷基、雜環烷基、芳基或者雜芳基進一步被一個或多個選自烷基、環烷 -基、齒素、芳基、羥基、胺基、烷氧基、烯基、雜環烷基、羥烷基、-S〇2R6、-C( = 0)R6、羧酸、羧酸酯或_NR6R7的取代基所取代； ⑩同時，R6和R7—起形成一個4至8員雜環基；其中該5至 8員雜環内含有一個或多個N、〇、s原子，並且4至8員雜環上進一步被一個或多個選自烷基、鹵素、芳基、雜芳基γ鹵代芳基、i代烷氧基、胺基、羥基、氰基、烷氧基、芳氧基、胺烷基、羥烷基、.環烷基、雜環烷基、羰基、羧酸、羧酸酯、-C(=〇)NR6R7、-NC(=0)R6、-s〇2R6、或-NR6R7 的取代基所取代； η是0至6 ; 94389 22 201016683 r是0至2。進一步’本發明包括下述通式（Π)表示的化合物或其94389 20 (I) 201016683 wherein R is selected from the group consisting of an alkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the thiol, heterocyclo, aryl or heteroaryl group may be further protected by one or more Selected from alkyl, aryl, aryl, hydroxy, amine, alkynyl, alkenyl, cyano, nitro, difluoromethyl, halobenzyl, heterocycloalkyl, carboxylic acid or carboxylic acid esters Substituted by a substituent which allows the aryl or heteroaryl group to form a bicyclic ring, which may be further substituted by a benzyl or halobenzyl group; or R1 is a structural formula: wherein: ❹B is selected from aryl Or a heteroaryl group, wherein the aryl or heteroaryl group may be further selected from one or more selected from the group consisting of alkyl, dentate, aryl, hydroxy, amine, alkynyl, alkenyl, cyano, nitro, trifluoro Substituted by a substituent of a methyl group, a dentate benzyl group, a heterocycloalkyl group, a carboxylic acid or a carboxylic acid ester; : T is selected from the group consisting of -〇(CH2)r-, -N(CH2)r-· or -S( CH2)r; L is selected from an aryl or heteroaryl group, wherein the aryl or heteroaryl group may be further substituted by one or more halogens or alkyl groups; the cast R2 is selected from the group consisting of a hydrogen atom, an alkyl group, and a cycloalkane. Base, trifluoro Or a heterocycloalkyl group, an aryl group, a heteroaryl group, an aralkyl group, wherein the alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, aralkyl group is further selected from one or more selected from Substituted by an alkyl group, an aryl group, a thiol group, a halogen group, an amine group, a cyano group, an alkoxy group, a buffer acid, a carboxylate or a substituent of -NR6R7; R and R4 are each independently selected from a hydrogen atom, an alkyl group , trifluoromethyl, cycloalkyl, heterocycloalkyl, aryl, carboxylate, _s〇2R6, -CH2C(=〇)nr6r7, -C(=〇)NR6R7, -(CH2)nNR6R7 or ~NC (=0)R6 ' wherein the alkyl group, ring 94389 21 201016683 alkyl group, heterocyclic group is further substituted with one or more selected from the group consisting of an alkyl group, a dentate, a trimethyl group: an aryl group, a thiol group, Substituents for alkoxy, aryloxy, cycloalkyl, heterocycloalkyl, heteroaryl, heterocycloalkyloxy, cyano, a few acid, a slow acid vinegar, _lion 6, or _(CH2)nNR6R7 Substituted; f when formed together with R4 - a 4 to 8 membered ring group; wherein the 5 to 8 membered heterocyclic ring contains - or more N, 〇, s atoms, and 4 to 8 membered heterocyclic rings Further selected from one or more selected from the group consisting of alkyl, commercial, aryl, heteroaryl, and Substituents for a base, a chitoalkoxy group, a hydroxyl group, an alkoxy group, an aryloxy group, a carbonyl group, a heterocycloalkyl group, a carboxylic acid, a carboxylic acid ester, =N_〇R6 or _NR6K7; R is each selected from a hydrogen atom, an alkyl group, an alkenyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, wherein the alkyl group, the dilute group, the cycloalkyl group, the heterocycloalkyl group, the aryl group or The heteroaryl group is further selected from one or more selected from the group consisting of alkyl, cycloalkyl-based, dentate, aryl, hydroxy, amine, alkoxy, alkenyl, heterocycloalkyl, hydroxyalkyl, -S〇2R6 Substituting -C(=0)R6, a carboxylic acid, a carboxylic acid ester or a substituent of _NR6R7; 10 simultaneously, R6 and R7 together form a 4 to 8 membered heterocyclic group; wherein the 5 to 8 membered heterocyclic ring Containing one or more N, 〇, s atoms, and further 4 or 8 membered heterocyclic rings are further selected from one or more selected from the group consisting of alkyl, halogen, aryl, heteroaryl γ halogenated aryl, i alkoxy Base, amine group, hydroxyl group, cyano group, alkoxy group, aryloxy group, amine alkyl group, hydroxyalkyl group, cycloalkyl group, heterocycloalkyl group, carbonyl group, carboxylic acid, carboxylate, -C(=〇 a substituent of NR6R7, -NC(=0)R6, -s〇2R6, or -NR6R7 ; [Eta] is from 0 to 6; 94389 22 201016683 r is 0 to 2. Further, the present invention includes a compound represented by the following formula (Π) or

其中： R係選***基、雜環燒基、芳基或雜芳基，其中該烧基、雜環烧基、芳基或雜芳基可以進一步被一個或多個選*** 參基、鹵素、芳基、羥基、胺基、炔基、烯基、氰基、硝基' 二氟甲基、齒代苄基、雜環烷基、羧酸或羧酸酯的取代基所取代，其甲該芳基或雜芳基可以併成雙環，此雙環可以進一步被苄基或函代苄基所取代；或者R1為結構式：其中： B係選自芳基或雜芳基，其中該芳基或雜芳基可以進一步 ❹被一個或多個選自烷基、齒素、芳基、羥基、胺基、炔基、烯基、氰基、硝基、三氟甲基、齒代苄基、雜環烷基、羧酸或羧酸酯的取代基所取代； T 係選自-0(CH2)r-，-N(CH2)r-或-S(CH〇r ; L係選自芳基或雜芳基，其中該芳基或雜芳基可以進一步被一個或多個齒素或烧基所取代； R2係選自氫原子、炫基、環燒基、三氟甲基、雜環燒基、芳基、雜芳基、芳烧基’其中該絲、職基、雜環烧基、 94389 23 201016683 芳基、雜芳基、芳烧基進一步被一個或多個選***基、芳基、羥基、鹵素、胺基、氰基、烷氧基、羧酸、羧酸酯或 -NR6R7的取代基所取代； R3係選自氫原子、烷基、三氟曱基、環烷基、雜環烷基、芳基、羧酸酯、-s〇2r6、-ch2c〇o)nr6r7、-c(=o)nr6r7、 -(CH〇nNR6R7或-NC(=0)R6，其中該烷基、環烷基、雜環烷基進一步被一個或多個選自烷基、鹵素、三氟甲基、芳基、羥基、烷氧基、芳氧基、環烷基、雜環烷基、雜芳基、雜環烷氧基、氰基、羧酸、羧酸酯、-S〇2R6、或-(CH2)nNR6R7 ©的取代基所取代； R5係選自氫原子、烷基、環烷基或-C(=0)0R6，其中該垸基或環烧基進一步被一個或多個選***基、經基、烧氧基、氰基、-NR6R7、羧酸或羧酸酯的取代基所取代； -R6和R7係分別選自氩原子、烷基、烯基、環烷基.、雜環烷基、芳基或雜芳基，其中該烧基、烯基、環烧基、雜環烧基、芳基或者雜芳基進一步被一個或多個選自烷基、環烷馨基、齒素、芳基、羧基、胺基、烧氧基、埽基、雜環烧基、經烧基、-SO2R6、-C(=0)R6、羰酸、羧酸酯或-NR6R7的取代基所取代；同時’R6和R7—起形成一個4至8員雜環基；其中該5至 8員雜環内含有一個或多個N、0、S原子，並且4至8員雜環上進一步被一個或多個選自烷基、鹵素、芳基、雜芳基、_代芳基、齒代烷氧基、胺基、羥基、氰基、烷氧基、芳氧基、胺燒基、羥烧基、環烧基、雜環烧基、徵基、叛 24 94389 201016683 酸、叛酸酯、-C(=〇)NR6R7、-NC(=0)R6、-SO2R6、或-NR6R7 的取代基所取代； η是0至6 ; r是0至2。進一步’本發明包括下述通式（III)表示的化合物或其Wherein: R is selected from the group consisting of an alkyl group, a heterocyclic alkyl group, an aryl group or a heteroaryl group, wherein the alkyl group, the heterocyclic alkyl group, the aryl group or the heteroaryl group may be further selected from one or more selected from the group consisting of a thiol group and a halogen. Substituted by a substituent of an aryl group, a hydroxyl group, an amine group, an alkynyl group, an alkenyl group, a cyano group, a nitro 'difluoromethyl group, a dentate benzyl group, a heterocycloalkyl group, a carboxylic acid or a carboxylic acid ester, The aryl or heteroaryl group may be combined into a bicyclic ring which may be further substituted by a benzyl or a functional benzyl group; or R1 is a structural formula: wherein: B is selected from an aryl group or a heteroaryl group, wherein the aryl group Or a heteroaryl group may be further deuterated by one or more selected from the group consisting of alkyl, dentate, aryl, hydroxy, amine, alkynyl, alkenyl, cyano, nitro, trifluoromethyl, dentylbenzyl, Substituted by a heterocycloalkyl, carboxylic acid or carboxylic acid ester substituent; T is selected from -0(CH2)r-, -N(CH2)r- or -S(CH〇r; L is selected from aryl Or a heteroaryl group, wherein the aryl or heteroaryl group may be further substituted by one or more dentants or alkyl groups; R2 is selected from the group consisting of a hydrogen atom, a leukoyl group, a cycloalkyl group, a trifluoromethyl group, and a heterocyclic ring. Base, aryl, miscellaneous a aryl group, wherein the silk, a group, a heterocyclic group, 94389 23 201016683 aryl, a heteroaryl group, an aryl group are further selected from one or more selected from the group consisting of an alkyl group, an aryl group, a hydroxyl group, a halogen, and an amine. Substituted by a substituent of a cyano group, a cyano group, an alkoxy group, a carboxylic acid, a carboxylic acid ester or -NR6R7; R3 is selected from a hydrogen atom, an alkyl group, a trifluoromethyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group , a carboxylate, -s〇2r6, -ch2c〇o)nr6r7, -c(=o)nr6r7, -(CH〇nNR6R7 or -NC(=0)R6, wherein the alkyl group, cycloalkyl group, heterocyclic ring The alkyl group is further selected from one or more selected from the group consisting of alkyl, halogen, trifluoromethyl, aryl, hydroxy, alkoxy, aryloxy, cycloalkyl, heterocycloalkyl, heteroaryl, heterocycloalkoxy Substituted by a substituent of a cyano group, a cyano group, a carboxylic acid, a carboxylic acid ester, -S〇2R6, or -(CH2)nNR6R7; R5 is selected from a hydrogen atom, an alkyl group, a cycloalkyl group or -C(=0) 0R6, wherein the fluorenyl or cycloalkyl group is further substituted with one or more substituents selected from the group consisting of an alkyl group, a thiol group, an alkoxy group, a cyano group, a -NR6R7, a carboxylic acid or a carboxylic acid ester; -R6 and R7 Are selected from the group consisting of argon atoms, alkyl groups, alkenyl groups, and cycloalkyl groups, respectively. a cycloalkyl, aryl or heteroaryl group, wherein the alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is further further selected from one or more selected from the group consisting of alkyl, cycloalkylene, A substituent of a dentate, an aryl group, a carboxyl group, an amine group, an alkoxy group, a fluorenyl group, a heterocyclic group, a pyridyl group, -SO2R6, -C(=0)R6, a carboxylic acid, a carboxylic acid ester or -NR6R7 Substituted; while 'R6 and R7 together form a 4 to 8 membered heterocyclic group; wherein the 5 to 8 membered heterocyclic ring contains one or more N, 0, S atoms, and 4 to 8 membered heterocyclic rings are further One or more selected from the group consisting of alkyl, halogen, aryl, heteroaryl, aryl, alkoxy, amino, hydroxy, cyano, alkoxy, aryloxy, amine alkyl, Hydroxyalkyl, cycloalkyl, heterocycloalkyl, levy, rebellion 24 94389 201016683 acid, oxalate, -C(=〇)NR6R7, -NC(=0)R6, -SO2R6, or -NR6R7 Substituted; η is 0 to 6; r is 0 to 2. Further, the present invention includes a compound represented by the following formula (III) or

參其中：Participate in:

Rl係選自烷基、雜環烷基、芳基或雜芳基，其中該烷基、雜環烷基、芳基或雜芳基可以進一步被一個或多個選自烷基、鹵素、芳基、羥基、胺基、炔基、烯基、氰基、硝基、 ―二氟甲基、鹵代苄基、雜環烷基、羧酸或羧酸酯所取代；其中該芳基或雜芳基可以併成雙環，此雙環可以進一步被节基或鹵代节基所取代； ❹或者R1為結構式：/B、r^ 其中：其中該芳基或雜芳基可以進一步鹵素、芳基、羥基、胺基、炔基、甲基、齒代苄基、雜環烷基、羧 B係選自芳基或雜芳基，其中拿被一個或多個選自烷基、鹵素、烯基、氰基、硝基、三氟〒基、酸或羧酸酯所取代； -N(CH2)r-4-S(CH2)r ；基，其中該芳基或雜芳基可 T 係選自-0(CH2)r-、-N(CH2)r-^ 以進一步 L係選自芳基或雜芳基，其中兮 94389 25 201016683 被一個或多個鹵素或烧基所取代； R3和R4係各自獨立地選自氫原子、烷基、三氟甲基、環烷基、雜環烷基、芳基、羧酸酯、-S〇2r6、-CH2(X=0)NR6R7、 -C(=0)NR6R7、-(CH2)nNR6R7 或-NC(=〇)R6，其中該烷基、環烷基、雜環烷基進一步被一個或多個選自烷基、函素、三氟曱基、芳基、羥基、烷氧基、芳氧基、環烷基、雜環烷基、雜芳基、雜環烷氧基、氰基、羧酸、羧酸酯、_S〇2r6、或-(CH2)nNR6R7的取代基所取代；同時’ R3和R4—起形成一個4至8員環基；其中該5至8 ❹員雜環内含有一個或多個N、0、S原子，並且4至8員雜環上進一步被一個或多個選自烷基、鹵素、芳基、雜芳基、鹵代烷基、齒代烷氧基、羥基、烷氧基、芳氧基、羰基、雜環烷基、羧酸、羧酸酯、=N-0R6或-NR6R7的取代基所取 .代；·· R6和R7係分別選自氩原子、烷基、烯基、環烷基、雜環烷基、芳基或雜芳基，其中該烷基、烯基、環烷基、雜環烷 ❹基、方基或者雜芳基進一步被一個或多個選***基、環烧基、齒素、芳基、羥基、胺基、烷氧基、烯基、雜環烷基、羥烷基、-S〇2R6、-C(=0)R6、羧酸、羧酸酯或-NR6R7的取代基所取代；同時，R6和R7—起形成一個4至8員雜環基；其中該5至 8貝雜環内含有·一·個或多個N、0、S原子’並且4至8員雜環上進一步被一個或多個選自烷基、鹵素、芳基、雜芳基、鹵代芳基、鹵代烷氧基、胺基、羥基、氰基、烷氧基' 26 94389 201016683 芳氧基、胺烷基、羥烷基、環烷基、雜環烷基、羰基、羧酸、羧酸酯、-C(=0)NR6R7、-NC (=〇) R6、-S〇2R6、或-NR6R7 的取代基所取代； η是0至6 ; τ是0至2 〇本發明的典型化合物包括如下化合物或它們藥學上可接受的鹽，但不限於這些：實施例結構名稱 1 ^Y〇^CXF Ο 1从Cl [3-氣-4-(3-氟-苄氧基）-苯基] -(6-"比咯-1-基-喹唑琳-4-基）-胺 2 °Το [3-氯-4-( 3-氟-苄氧基）-苯基] -(6-{2-[(2_甲磺醯基-乙胺基）-甲基]-0比洛_1_基卜喧·嗤琳-4-基）-胺 3 N-(l-.{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-喹唑啉-6-基}-111-吡咯-2_基甲基）-N’，N，-二乙基 -1,2-乙二胺 4 |ί#γ〇^ΧΧΡ 0 [3-氣-4-(3-氟-苄氧基）-苯基] ~(6-{2-[(2-嗎啉-4-基-乙胺基） ''甲基]-0比咯-1-基}-1#〇坐嚇·-4-基）-胺 5 <3. -^Y-Os^J^X-p [3-氣-4-(3-氣-苄氧基）-苯基] -(6-{3-[(2-曱續醯基-乙胺基）-甲基]-«比洛-1-基}-喧唾琳-4-基）-胺 6 。ί 立。j〇iF 1-{4-[3-氯-4-(3-氟-节氧基）_ 苯胺基]-喹唑琳-6-基}-4-三氟甲基-1H-吡咯-3-甲酸乙酯 94389 27 201016683 7 2-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-喧唾琳-6-基}-D比洛-1-甲酸第三丁酯 8 ^Y〇vjCXF [3-氯-4-(3-氟-节氧基）-苯基] -[6-(111-°比洛-2-基）-喧唾琳-4-基]-胺 9 ^ίγΟν^ΧΧρ [3-氯-4-(3-氟-苄氧基）-苯基] -[6-(1-曱基-1H-吡咯-2-基）-喹 β坐琳-4-基]-胺 10 .xx：^ 2-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-喹唑啉-6-基}-6, 7-二氫-2H-°比11 南[3, 4-。]°比洛-4-_ 11 1 从 N-(5-{4-[3-氣-4-(3-氟-苄氧基）-苯胺基]-喹唾啉-6-基}-111-吡咯-2-基甲基）-Ν’，Ν’ -二乙基 _1，2-乙二胺 12 P, fY0^O-^，_X-av-/l hA^ci [3-氣-4-(3-节氧基）-苯基] -(6-{5-[(2-甲磺醯基-乙胺基）-.甲基]-1H- °比洛-2-基}-啥°坐琳 -4-基）-胺 13 fjC〇v^F 1-{4-[3-氣-4-(3-氟-节氧基）-苯胺基]-喧吐嚇"-6-基}-4-(2-經基-乙基）-1Η-吡咯-3-曱酸-(2-二乙胺基-乙基）_胺 14 —\ ^ί?γ〇^ΧΧΡ ~/ /^=1 HN^^CI ^Nxx> N-(1-{4-[3-氣-4-(3-氟-苄氧基）-苯胺基]-喹唑啉-6-基}-111-吡咯-3-基甲基）-Ν’，Ν’ -二乙基 _1，2-乙二胺 15 ^VS^ hnXXci ^nO^n [3-氯-4-(3-氣-苄氧基）-苯基] -(6-{3-[(2-嗎啉-4-基-乙基胺基）-甲基]-〇比p各-1 ·~基}-啥〇坐琳 -4-基）-胺 28 94389 201016683 16 ΗΝ^Α〇| 2-{4-[3-氯-4-(3- IL -节氧基）-苯胺基]-啥峻淋-6-基}-5, 6-二氫-2H-環戊烧[(3]吼洛-4-酿I 17 / [1_{4-[3_氯-4-(3-氟-节氧基）-苯胺基]-喹唑啉-6-基}-4-(2-羥基-乙基）-1H_0比洛-3-基]-（4-甲基-娘啡-1-基）-甲嗣 18 9 < j〇C^ 1-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-喹唑啉-6-基}-4-(2-羥基-乙基）-1Η-吡咯-3-甲酸-（2-嗎淋_4：-基-乙基）-胺 19 °0^ ΗΝΧΧ：^ [6-(3-[1,4’ ]雙哌啶基-Γ-基甲基-°比哈-1-基）-喧唾琳-4-基] _[3-氯-4-(3-氟1-节氧基）-苯基] -胺 20 /-\ (^Y°^^'F ^ ΗΛ^α [3-氯-4-(3-象-节氧基）-苯基]-(6_{3-[ (2-0辰咬-.1-基-乙基胺基）-甲基]-吡咯-l-基}-喹唑啉-4-基）-胺 21 \-N /===1 HN*^^CI [3-氯-4-(3-氟-节氧基）-苯基] -[6-(3-二乙基胺基甲基-吡咯. -卜基）-喧唾淋-4-基]-胺 22 bl .XX：^ 2-[1-{4-[3-氣-4-(3-氟-节氧基）-苯胺基]-喹唑啉-6-基} -4-(4-甲基-哌畊-1-基曱基） -1H-吡咯-3-基]-乙醇 23 F. F ^^O-^XXp ΗΝΧϊα 〜N N-(l-{4-[3-氯-4-(3-氟-节氧基）-苯胺基]-喧唾琳-6-基}-4-三氟甲基-1H-吡咯-3-基曱基） _N’，’N’ _二乙基_1.，2_ 乙二胺 24 ° oCj 1-{4-[3-氣-4-(3- 节氧基）-苯胺基]-啥嗤琳-6-基}-4-(2-經基-乙基）-1Η-吡咯-3-甲酸-[2-(4-甲基-痕哄-1-基）-乙基]-胺 29 94389 201016683 25 Ql hnxi：^ °^nX5vn [l-{4-[3-氯-4-(3-氟-节氧基）-苯胺基]-喹唑啉-6-基}-4-(2-羥基·"乙基）_1H_ °比洛-3-基]-π底0定 -1-基-甲酮 26 HQ f\ o 1 ΗΝΧϊ, [1-{4-[3-氣-4-(3-氟-苄氧基）-苯胺基]-喧嗤琳-6-基}-4-(2-經基-乙基）-1Η-°比11 各-3-基]比略烧-1-基-甲酮 27 HO QI 。〜访 [1-{4-[3-氣-4-(3-氟-苄氧基）-苯胺基]-喹唑啉-6-基}-4-(2-羥基-乙基）·~1Η-ΤΙ比洛-3-基]-嗎琳 -4-基-甲酮 28 qJ jCC^ ^Ni〇vN 2-(1-{4-[3-氯-4-(3-氟-节氧基）-苯胺基]-喹嗤琳-6-基}-4-旅0定_1_基甲基_1H_0比嘻_3-基）-乙醇 29 Q1 .Χϊ：^ N"""Vn^w4n 2-(1-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-喹唑啉-6-基}-4-吡咯烷-1-基甲基-1H-吡咯-3-基）-乙醇 30 H〇 f^jl q! 2-(1-{4-[3-氯-4-(3-氟-节氧基）-苯胺基]-喧嗤琳-6-基}-4-嗎啉-4-基甲基-1H-吡咯-3-基）-乙醇 31 .1-{4-[3-氯-4_(3-氟-苄氧基）-苯胺基]-喹唑啉-6-基}-4-(2-羥基-乙基）-1Η-吡咯-3-甲酸-(2-吡咯烷-1-基-乙基）-胺 32 °^Nw 1-{4-[3-氯-4-(3-氟-节氧基）-苯胺基]-喹唑啉-6-基}-4-(2-羥基-乙基）-1Η-吡咯-3-曱酸-(2-旅咬-1-基-乙基）-胺 33 〇 } n FC HNXX„ F [3-氯-4-(3-氧-节氧基）-苯基]-(6-{3-[(2-嗎1#-4-基-乙胺基）-甲基]-4-三氟甲基-吡咯-1-基}-喧嗤#-4-基）-胺 30 94389 201016683 34 b / HN 人人 Cl [3-氯-4-(3-氟-节氧基）-苯基] _[6-(3-{[2_(4-甲基-派卩井-1-基）-乙胺基]-甲基卜4-三氟甲基 -〇比σ各-1-基）-喧°坐琳-4-基]-胺 35 Q ί HN^^a [3-氯-4-(3-氟-苄氧基）-苯基] -(6-{3-[(2-哌啶-1-基-乙胺基） -甲基]-4-三氟曱基-吡咯-1-基} 一啥唾琳-4-基）-胺 36 ? f\ NH F !>^ HN^^CI [3-氯-4-(3-氟-节氧基）-苯基] -(6-{3-[(2-甲氧基-乙胺基）-甲基]-4-三氟甲基-〇比嘻-l-基}-啥 β坐琳-4-基）-胺 37 0=Y〇 NH ^y〇^XXf ΗΝΛ^α Ft^NW [3-氯-4-( 3-敗-苄氧基）-苯基] -(6-{3-[(2-甲磺醯基-乙胺基）-甲基]_4-三氣曱基I-0比嘻-1-基}-啥。坐淋-4-基）-胺 38 o , f^°^CXF 4功 [3-氣-4-(3-氟* -节氧基）-苯基] -(6-{3-[(3-嗎啉-4-基-丙胺基） -甲基]-4-三氤甲基-吡咯-1-基} -啥峻淋-4-基）-胺 39 Q" ,NH F C HNXXC, F^N^a> [3-氣-4-(3-氟-节氧基）-苯基] -(6-{3-[(2-吡咯烷-1-基-乙胺基）-甲基]-4-三氟甲基-吡咯-l-基}—嗜嗤嘛-4-基)-胺 40 0 tw F 1 HNXX〇, #功 1-[(1-{4-[3-氯-4-(3-氟-节氧基）-苯胺基]-喧β坐淋-6-基}-4-三氟甲基-1Η-吡咯-3-基甲基）-胺基]-3-嗎啉-4-基-丙-2-醇 41 /4=〇 h〇4__/ a t：〇XiF F、HN^^CI 4-{[(1-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-啥°坐淋-6-基}-4-三氟甲基-1H-吼咯-3-基甲基）-胺基]-甲基}-1，1_二氧-六氫 -1 λ *6*-噻喃-4-醇 42 ^yO^jCXp K、 ΗΝΑΛα [3-氯-4-(3-氟-节氧基）-苯基] -[6_( 1Η_π比洛-3-基）_啥。坐琳_4_ 基]-胺 31 94389 201016683 43 rO ^以F iDvN [1-(3-氟苄基）-lH-吲唑-5-基] -(6_σ比洛_1-基-噎·σ坐琳-4~基）-胺 44 "JO /==, HM 人人Cl [3-氯-4-( D比咬-2-甲氧基）-苯基]-(6-D比嘻-1-基-喧°坐琳-4-基）-胺 45 [3-氯_4-(〇比0定-2-曱氧基）-苯基]-(6-吼洛-1-基-啥°坐琳-2-基）-胺 46 〇. 言1 以 Cl «xc； [3-氯-4-( 0比〇定-2-甲氧基）-苯基]-(6-{5-[(2-甲磺醯基-乙胺基）-甲基]-1Η-η比洛-2-基}-°|：0坐啉-4-基）-胺 47 .xx：^ 2-{4-[3-氣-4-(吡啶-2-甲氧基） -苯胺基]-喹唑啉-6-基}-6, 7-二氯-2H_°比喃[3，4-c]d比嘻-4-嗣 48 j〇cf ..X5vN (3-氣-4-氟-苯基）-(6-"比咯-1-喧°坐琳-4-基）-胺 49 jQC' ίχ x C] (3-氣-4-氟-苯基）-[6-(lH-比咯 -2-基）-喧嗤淋-4-基]-胺 50 J^jl 八 JOC F 0 nx> [3-氣-4-(3-氟-节氧基）-苯基] -(6-{4-[(2-嗎啉-4-乙胺基）-甲基]-1H-吼洛-2-基}-喧唾琳-4-基）-胺 51 ^-y〇^XXF )'Ok/JX以Cl [3-氣-4-(3-氟-节氧基）-苯基] -{6_[1_(2_ 二乙胺基乙基）_1H-〇比洛-3-基]-°|:°坐琳-4-基}-胺 52 GO、"众及 h*S〇6n [6-(5-[1，4’ ]二哌啶基-Γ -甲基 -1H- °比洛-3-基）-喧峻琳-4-基]-[3-氯-4-(3-氟-苄氧基）]-胺 32 94389 201016683 53 °=<ΝΗ _^==\ HN 人乂 Cl 1-{4-[3-氯-4-(o比〇定-2-甲氧基） -苯胺基]-喹唑啉-6-基}-4-(2_ 羥基）-1Η-吡咯-3-甲酸-(2-二乙胺基乙基）-甲醯胺 54 D 〇=<nh y^\ HN入入C丨 ko^ni〇vn 1-{4-[3_氯-4-(^比11 定-2-甲氧基） -苯胺基]-喹唑啉_6_基卜4--4-（2-經基）-1H- ϋ比洛-3-甲酸 (2-嗎啉-4-乙基）-曱醯胺 55 0JH ^°-Χ) η〇^ν^Λν 1-{4-[3-氯-4-(〇比〇定-2-甲氧基） -苯胺基]-喹唑啉-6-基} -4-4-(2-羥基）-1Η-吡嘻-3-甲酸 (2-甲氧基乙基）-甲醯胺 56 0 〇Hm fy°-X) }==^\ H0^NOvN 1-{4-[3-氯-4-(吼啶-2-甲氧基） -苯胺基]-啥17坐琳-6-基} -4-4-(2-羥基）-1Η-吡咯-3-甲酸 [2-(4-甲基-哌畊-1-基）-乙基]-醯胺 57 尸 $ joc^ 1-{4-[3-氣-4-(吡啶-2-甲氧基） -苯胺基]-啥°坐淋-6-基}-4-4-(2-經基）-1Η-°比哈-3-甲酸（3-嗎啉-4-丙基）-醯胺 58 o=P /T°^ )¾^ HN 人〆^Cl Η〇^ΝΊ〇φ 1-{4-[3-氯-4-(°比啶-2-甲氧基） -苯胺基]-啥°坐琳-6-基} 嗎琳-4-甲酮 59 rf^ )===^ HN^^^CI h〇V^N^n 1-{4-[3-氣-4-(吡啶-2-甲氧基） -苯胺基]-啥°坐琳-6-基} -4-4-(2-經基）-1Η-° 比洛-3-基]--(4-甲基-哌畊-1-基）-甲酮 60 0 _〇J〇 HNXXC, 1-{4-[3-氯-4-(吡啶-2-甲氧基） -苯胺基]-。坐淋-6-基} - 4-4-(2-羥基）-1Η-吡咯-3-基]-吡咯烧_1 -甲嗣 33 94389 201016683Rl is selected from an alkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, wherein the alkyl group, heterocycloalkyl group, aryl group or heteroaryl group may be further selected from one or more selected from the group consisting of alkyl, halogen and aromatic. Substituted with a hydroxy group, a hydroxyl group, an amino group, an alkynyl group, an alkenyl group, a cyano group, a nitro group, a difluoromethyl group, a halogenated benzyl group, a heterocycloalkyl group, a carboxylic acid or a carboxylic acid ester; The aryl group may be combined into a bicyclic ring which may be further substituted by a sulfhydryl group or a halogenated benzyl group; ❹ or R1 is a structural formula: /B, r^ wherein: wherein the aryl or heteroaryl group may be further halogen or aryl a hydroxyl group, an amino group, an alkynyl group, a methyl group, a dentylbenzyl group, a heterocycloalkyl group, or a carboxy group B, which is selected from an aryl group or a heteroaryl group, wherein one or more selected from the group consisting of an alkyl group, a halogen, and an alkenyl group Substituted with a cyano group, a nitro group, a trifluoromethyl group, an acid or a carboxylic acid ester; -N(CH2)r-4-S(CH2)r; a group wherein the aryl or heteroaryl group is T selected from -0(CH2)r-, -N(CH2)r-^ to further L-selected from an aryl or heteroaryl group, wherein 兮94389 25 201016683 is substituted by one or more halogen or alkyl groups; R3 and R4 are Each independently selected from the group consisting of hydrogen Sub, alkyl, trifluoromethyl, cycloalkyl, heterocycloalkyl, aryl, carboxylic acid ester, -S〇2r6, -CH2 (X=0)NR6R7, -C(=0)NR6R7, -( CH2)nNR6R7 or -NC(=〇)R6, wherein the alkyl group, cycloalkyl group, heterocycloalkyl group is further further selected from one or more selected from the group consisting of an alkyl group, a functional group, a trifluoromethyl group, an aryl group, a hydroxyl group, and an alkane a substituent of an oxy, aryloxy, cycloalkyl, heterocycloalkyl, heteroaryl, heterocycloalkoxy, cyano, carboxylic acid, carboxylic acid ester, _S〇2r6, or -(CH2)nNR6R7 Substituting; while 'R3 and R4' form a 4 to 8 membered ring group; wherein the 5 to 8 membered heterocyclic ring contains one or more N, 0, and S atoms, and the 4 to 8 membered heterocyclic ring is further One or more selected from the group consisting of alkyl, halogen, aryl, heteroaryl, haloalkyl, dentate alkoxy, hydroxy, alkoxy, aryloxy, carbonyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester The substituent of =N-0R6 or -NR6R7 is taken from the group; R6 and R7 are respectively selected from an argon atom, an alkyl group, an alkenyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group. Wherein the alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl Further further selected from one or more selected from the group consisting of alkyl, cycloalkyl, dentate, aryl, hydroxy, amine, alkoxy, alkenyl, heterocycloalkyl, hydroxyalkyl, -S〇2R6, -C ( =0) R6, a carboxylic acid, a carboxylic acid ester or a substituent of -NR6R7 is substituted; at the same time, R6 and R7 together form a 4- to 8-membered heterocyclic group; wherein the 5- to 8-shell heterocyclic ring contains One or more N, 0, S atoms' and further 4 or 8 membered heterocyclic rings are further selected from one or more selected from the group consisting of alkyl, halogen, aryl, heteroaryl, haloaryl, haloalkoxy, amine , hydroxy, cyano, alkoxy ' 26 94389 201016683 aryloxy, aminoalkyl, hydroxyalkyl, cycloalkyl, heterocycloalkyl, carbonyl, carboxylic acid, carboxylic acid ester, -C(=0)NR6R7 Substituted by a substituent of -NC (=〇) R6, -S〇2R6, or -NR6R7; η is 0 to 6; τ is 0 to 2 典型 Typical compounds of the invention include the following compounds or their pharmaceutically acceptable Salt, but not limited to these: Example structure name 1 ^Y〇^CXF Ο 1 from Cl [3- gas-4-(3-fluoro-benzyloxy)-phenyl]-(6-" 1-yl-quinazoline-4-yl)-amine 2 °Το [3-chloro-4-(3-fluoro-benzyloxy) -Phenyl]-(6-{2-[(2_methylsulfonyl-ethylamino)-methyl]-0) 洛_1_基布喧·嗤琳-4-yl)-amine 3 N -(l-.{4-[3-Chloro-4-(3-fluoro-benzyloxy)-anilino]-quinazolin-6-yl}-111-pyrrole-2-ylmethyl)-N ',N,-Diethyl-1,2-ethylenediamine 4 | ί#γ〇^ΧΧΡ 0 [3-Ga-4-(3-fluoro-benzyloxy)-phenyl] ~(6-{ 2-[(2-morpholin-4-yl-ethylamino) ''methyl]-0-pyrrol-1-yl}-1#〇,吓-4-yl)-amine 5 <3. -^Y-Os^J^Xp [3-Gas-4-(3-Gas-Benzyloxy)-phenyl]-(6-{3-[(2-曱 continued 醯-ethylamino)- Methyl]-«Bilo-1-yl}-喧琳琳-4-yl)-amine 6. ί立. j〇iF 1-{4-[3-Chloro-4-(3-fluoro-p-ethoxy)-anilino]-quinazoline-6-yl}-4-trifluoromethyl-1H-pyrrole-3 -ethyl formate 94389 27 201016683 7 2-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-anilino]-indole--6-yl}-D-pyr-l-carboxylic acid Third butyl ester 8 ^Y〇vjCXF [3-chloro-4-(3-fluoro-p-hydroxy)-phenyl]-[6-(111-°Pilo-2-yl)-喧Salina-4 -yl]-amine 9 ^ίγΟν^ΧΧρ [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1-indolyl-1H-pyrrol-2-yl)-quin Ββ琳-4-yl]-amine 10 .xx:^ 2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-anilino]-quinazoline-6-yl}- 6, 7-Dihydro-2H-° ratio 11 South [3, 4-. ]°Bilo-4-_ 11 1 from N-(5-{4-[3-Ga-4-(3-fluoro-benzyloxy)-anilino]-quinoxalin-6-yl}-111 -pyrrol-2-ylmethyl)-Ν',Ν'-diethyl-1,2-ethanediamine 12 P, fY0^O-^,_X-av-/l hA^ci [3-gas- 4-(3-hydroxy)-phenyl]-(6-{5-[(2-methylsulfonyl-ethylamino)-.methyl]-1H- °pyr-2-yl}-啥°坐琳-4-yl)-amine 13 fjC〇v^F 1-{4-[3-gas-4-(3-fluoro-oxy)-anilino]-喧吓吓 & -6 -yl}-4-(2-carbo-ethyl)-1Η-pyrrole-3-decanoic acid-(2-diethylamino-ethyl)-amine 14 —\ ^ί?γ〇^ΧΧΡ ~/ /^=1 HN^^CI ^Nxx> N-(1-{4-[3-Ga-4-(3-fluoro-benzyloxy)-anilino]-quinazolin-6-yl}-111 -pyrrol-3-ylmethyl)-Ν',Ν'-diethyl-1,2-ethanediamine 15 ^VS^ hnXXci ^nO^n [3-chloro-4-(3-gas-benzyloxy) -Phenyl]-(6-{3-[(2-morpholin-4-yl-ethylamino)-methyl]-anthracene p-1 -1 base}-啥〇坐琳- 4-yl)-amine 28 94389 201016683 16 ΗΝ^Α〇| 2-{4-[3-Chloro-4-(3- IL-ethoxy)-anilino]-啥峻淋-6-yl}- 5,6-Dihydro-2H-cyclopentan[(3]吼洛-4- Brewing I 17 / [1_{4-[3_Chloro-4-(3-fluoro-oxy)-anilinyl) ]-quinazoline-6-yl}-4-(2-hydroxy-ethyl)-1H-0biro-3-yl]-(4-methyl-infantyl-1-yl)-formamidine 18 9 &lt ; j〇C^ 1-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-anilino]-quinazolin-6-yl}-4-(2-hydroxy-ethyl) -1Η-pyrrole-3-carboxylic acid-(2-oxalin-4:-yl-ethyl)-amine 19 °0^ ΗΝΧΧ:^ [6-(3-[1,4' ]bispiperidinyl-oxime -ylmethyl-°Bha-1-yl)-喧喧琳-4-yl] _[3-chloro-4-(3-fluoro-1-hydroxyl)-phenyl]-amine 20 /-\ (^Y°^^'F ^ ΗΛ^α [3-chloro-4-(3-indolyl)-phenyl]-(6_{3-[ (2-0-bite-.1-yl) -ethylamino)-methyl]-pyrrole-l-yl}-quinazolin-4-yl)-amine 21 \-N /===1 HN*^^CI [3-chloro-4-( 3-fluoro-p-hydroxy)-phenyl]-[6-(3-diethylaminomethyl-pyrrole.-buyl)-indolyl-4-yl]-amine 22 bl .XX:^ 2-[1-{4-[3-Ga-4-(3-fluoro-p-hydroxy)-anilino]-quinazolin-6-yl}-4-(4-methyl-piped-1 -1H-pyrrol-3-yl]-ethanol 23 F. F ^^O-^XXp ΗΝΧϊα 〜N N-(l-{4-[3-chloro-4-(3-fluoro-section) Oxy)-anilino]-indolyl-6-yl}-4-trifluoromethyl-1H-pyrrol-3-ylindenyl) _N', 'N' _diethyl_1., 2_ B Amine 24 ° oCj 1-{4-[3-Ga-4-(3-hydroxy)-anilino]-indolyl-6-yl}-4-(2-trans-ethyl-ethyl)-1Η -pyrrole-3-carboxylic acid-[2-(4-methyl-indole-1-yl)-ethyl]-amine 29 94389 201016683 25 Ql hnxi:^ °^nX5vn [l-{4-[3-chlorine 4-(3-fluoro-p-hydroxy)-anilino]-quinazolin-6-yl}-4-(2-hydroxy·"ethyl)_1H_ °bi-3-yl]-π 0-1,4-yl-methanone 26 HQ f\ o 1 ΗΝΧϊ, [1-{4-[3- gas-4-(3-fluoro-benzyloxy)-anilino]-喧嗤琳-6- The base -4-(2-trans-ethyl-ethyl)-1 Η-° ratio 11 -3-yl] is slightly calcined 1-yl-ketone 27 HO QI . ~Access [1-{4-[3-Ga-4-(3-fluoro-benzyloxy)-anilino]-quinazolin-6-yl}-4-(2-hydroxy-ethyl)·~ 1Η-ΤΙ比洛-3-yl]-morphin-4-yl-ketone 28 qJ jCC^ ^Ni〇vN 2-(1-{4-[3-chloro-4-(3-fluoro-oxygen) ))-anilino]-quinoline-6-yl}-4-branches 0 1-1 _ ylmethyl_1H_0 嘻 _3- yl)-ethanol 29 Q1 .Χϊ:^ N""" Vn^w4n 2-(1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-anilino]-quinazolin-6-yl}-4-pyrrolidin-1-yl -1-1H-pyrrol-3-yl)-ethanol 30 H〇f^jl q! 2-(1-{4-[3-chloro-4-(3-fluoro-p-oxy)-anilino]-oxime嗤琳-6-yl}-4-morpholin-4-ylmethyl-1H-pyrrol-3-yl)-ethanol 31 .1-{4-[3-chloro-4_(3-fluoro-benzyloxy )-anilino]-quinazolin-6-yl}-4-(2-hydroxy-ethyl)-1Η-pyrrole-3-carboxylic acid-(2-pyrrolidin-1-yl-ethyl)-amine 32 °^Nw 1-{4-[3-Chloro-4-(3-fluoro-oxy)-anilino]-quinazolin-6-yl}-4-(2-hydroxy-ethyl)-1Η -pyrrole-3-decanoic acid-(2-Bride-1-yl-ethyl)-amine 33 〇} n FC HNXX F [3-chloro-4-(3-oxo-oxy)-phenyl ]-(6-{3-[(2-?1#-4-yl-ethylamino)-methyl]-4-trifluoromethyl-pyrrol-1-yl}-喧嗤#-4- )-amine 30 94389 201016683 34 b / HN ClCl [3-chloro-4-(3-fluoro-p-oxy)-phenyl] _[6-(3-{[2_(4-methyl-卩井-1-yl)-ethylamino]-methyl b 4-trifluoromethyl-indole ratio σ each-1-yl)-喧°坐琳-4-yl]-amine 35 Q ί HN^^ a [3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-{3-[(2-piperidin-1-yl-ethylamino)-methyl]-4- Trifluoromethyl-pyrrol-1-yl}-indolyl-3-yl)-amine 36 ? f\ NH F !>^ HN^^CI [3-chloro-4-(3-fluoro-oxygen) -Phenyl]-(6-{3-[(2-methoxy-ethylamino)-methyl]-4-trifluoromethyl-indenyl-l-yl}-啥β坐琳-4-yl)-amine 37 0=Y〇NH ^y〇^XXf ΗΝΛ^α Ft^NW [3-chloro-4-(3-a-benzyloxy)-phenyl]-(6-{3 -[(2-Methanesulfonyl-ethylamino)-methyl]_4-trimethylsulfonyl group I-0 is more than 嘻-1-yl}-oxime. Sodium-4-yl)-amine 38 o , f^°^CXF 4 work [3- gas-4-(3-fluoro*-hydroxyl)-phenyl]-(6-{3-[(3 -morpholin-4-yl-propylamino)-methyl]-4-trimethyl-pyrrol-1-yl}-anthracene-4-yl)-amine 39 Q" , NH FC HNXXC, F^ N^a> [3-Ga-4-(3-fluoro-p-hydroxy)-phenyl]-(6-{3-[(2-pyrrolidin-1-yl-ethylamino)-methyl] -4-trifluoromethyl-pyrrole-l-yl}-isophilic-4-yl)-amine 40 0 tw F 1 HNXX〇, #功1-[(1-{4-[3-chloro-4 -(3-Fluoro-p-hydroxy)-anilino]-喧β-sodium-6-yl}-4-trifluoromethyl-1Η-pyrrol-3-ylmethyl)-amino]-3-啉-4-yl-propan-2-ol 41 /4=〇h〇4__/ at: 〇XiF F, HN^^CI 4-{[(1-{4-[3-chloro-4-(3- Fluoro-benzyloxy)-anilino]-oxime-sodium-6-yl}-4-trifluoromethyl-1H-indol-3-ylmethyl)-amino]-methyl}-1, 1_Dioxo-hexahydro-1 λ *6*-thiopyran-4-ol 42 ^yO^jCXp K, ΗΝΑΛα [3-chloro-4-(3-fluoro-p-oxy)-phenyl]-[ 6_( 1Η_π 比洛-3-yl)_啥.坐琳_4_基]-amine 31 94389 201016683 43 rO ^ as F iDvN [1-(3-fluorobenzyl)-lH-indazol-5-yl] -(6_σBilo_1-yl-噎·σ坐琳-4~基)-amine 44 "JO /==, HM Renren Cl [3-chloro-4-(D-Bite-2-methoxy)-phenyl]-(6-D 嘻-1-yl-喧°坐琳-4-yl)-amine 45 [3-chloro- 4-(indole ratio 0-but-2-oxooxy)-phenyl]-(6-indol-1-yl -啥°坐琳-2-yl)-amine 46 〇. Word 1 with Cl «xc; [3-chloro-4-( 0 〇定-2-methoxy)-phenyl]-(6-{ 5-[(2-Methanesulfonyl-ethylamino)-methyl]-1Η-ηpyr-2-yl}-°|:0 oxalyl-4-yl)-amine 47 .xx:^ 2 -{4-[3-Ga-4-(pyridine-2-methoxy)-anilino]-quinazolin-6-yl}-6, 7-dichloro-2H_° than butyl [3,4- c]d 嘻-4-嗣48 j〇cf ..X5vN (3-gas-4-fluoro-phenyl)-(6-"birol-1-喧°坐琳-4-yl)-amine 49 jQC' ίχ x C] (3-Gas-4-fluoro-phenyl)-[6-(lH-pyrrol-2-yl)-indol-4-yl]-amine 50 J^jl 八JOC F 0 nx> [3-Ga-4-(3-fluoro-p-hydroxy)-phenyl]-(6-{4-[(2-morpholin-4-ethylamino)-methyl]-1H -吼罗-2-yl}-喧喧琳-4-yl)-amine 51 ^-y〇^XXF ) 'Ok/JX with Cl [3- gas-4-(3-fluoro- Oxy)-phenyl] -{6_[1_(2_diethylaminoethyl)_1H-indolobi-3-yl]-°|:°坐琳-4-yl}-amine 52 GO," And h*S〇6n [6-(5-[1,4' ]dipiperidinyl-fluorenyl-methyl-1H- °bi-3-yl)-喧峻琳-4-yl]-[ 3-Chloro-4-(3-fluoro-benzyloxy)]-amine 32 94389 201016683 53 °=<ΝΗ _^==\ HN Human 乂Cl 1-{4-[3-chloro-4-(o 〇定定-2-methoxy)-anilino]-quinazolin-6-yl}-4-(2-hydroxy)-1Η-pyrrole-3-carboxylic acid-(2-diethylaminoethyl)- Methionine 54 D 〇=<nh y^\ HN is incorporated into C丨ko^ni〇vn 1-{4-[3_chloro-4-(^~11-but-2-methoxy)-anilino ]-quinazoline_6_kib 4--4-(2-carbyl)-1H-indopol-3-carboxylic acid (2-morpholin-4-ethyl)-guanamine 55 0JH ^° -Χ) η〇^ν^Λν 1-{4-[3-Chloro-4-(indolyl-2-methoxy)-anilino]-quinazolin-6-yl}-4-4 -(2-hydroxy)-1Η-pyridin-3-carboxylic acid (2-methoxyethyl)-formamide 56 0 〇Hm fy°-X) }==^\ H0^NOvN 1-{4- [3-Chloro-4-(acridin-2-methoxy)-anilino]-indole 17-iso-6-yl}-4-4-(2-hydroxy)-1Η-pyrrole-3-carboxylic acid [ 2-(4-methyl-piped-1-yl)-ethyl]-nonylamine 57 corpse $ joc^ 1- {4-[3-Ga-4-(pyridine-2-methoxy)-anilino]-啥°Sit-6-yl}-4-4-(2-trans)-Η-°Bi 3-carboxylic acid (3-morpholin-4-propyl)-decylamine 58 o=P /T°^ ) 3⁄4^ HN Human 〆^Cl Η〇^ΝΊ〇φ 1-{4-[3-Chloro- 4-(°-pyridyl-2-methoxy)-anilino]-啥°Shenlin-6-yl}Merlin-4-ketone 59 rf^ )===^ HN^^^CI h〇V ^N^n 1-{4-[3-Ga-4-(pyridine-2-methoxy)-anilino]-啥°坐琳-6-yl} -4-4-(2-Ph-based) -1Η-°Bilo-3-yl]-(4-methyl-piped-1-yl)-methanone 60 0 _〇J〇HNXXC, 1-{4-[3-chloro-4-( Pyridine-2-methoxy)-anilino]-.坐-6-yl} - 4-4-(2-hydroxy)-1Η-pyrrol-3-yl]-pyrrole _1 - formazan 33 94389 201016683

61 O H0^nW 2-[l-{4-[3-氯-4-(吡啶-2-甲氧基）-苯胺基]-喹唑啉-6_基} -4-(4-曱基-哌畊-1-甲基）-1Η-吡咯-3-基]-乙醇 62 % .ΧΪ：^ HNn〇> [3-氯-4-(3-氟-节氧基）-苯基] -(6-{5-[(2-曱確酿基-乙胺基）-甲基]-1H-吡咯-3-基}-喹唑啉 -.4-基）-胺 63 ^〇jaF ^ λ [3-氣-4-(3-襄-苄氧基）-苯基] -(6-{5-[(3-嗎啡林-4-丙胺基）-甲基]-1H-吡咯-3-基}-喹唑啉 -4-基）-胺 64 ^Y〇-jCXF 0'〇^从’ i〇V [3-氣-4-(3-敗-苄氧基）苯基] -{6-[ 1-(2-吡咯烷-1-乙基）-1Η-〇比洛-3-基]-喧唾淋-4-基}-胺 65 ητ0^ρ N^—% /==. HN 人·人 Cl °OC> [3-氣-4-(3-氟-苄氧基）-苯基] -[6-(1-{3-[4-(3-氯苯基）-1*底哄 -卜基]-丙基卜1H-吡咯-3-基）-啥唾琳-4-基]-胺 66 Q S HN^°xx η〇^νό5ν 4-(2二羥乙基）-1-{4-[3-甲基-4-(6-甲基"比啶-3-氧基）-苯胺基]-喧唾琳-6-基}-111-0比嘻-3-甲酸 -(2-吡咯烷-1-乙基）-醯胺 67 Η,ΧΪο, rC^N N-（1-{4-[3-氯一4-(3-氟"·节氧基）-苯胺基]-啥嗤琳-6-基}-4-三氣甲基-1H-吼洛-3~~基）-2-甲基-丙烯醯胺 68 /1。力 ^/==η HN^^CI ho^nOvn [1-{4-[3-氯-4-(吡啶-2-甲氧基）_苯胺基]-喹唑啉-6-基} -4 -（2-經乙基）-1H-^比哈_3-基]-旅淀-1-甲酿I 34 94389 69 O X HN^^CI 2-(l-{4-[3-氯-4-(吡啶-2-曱氧基）-苯胺基]-喹唑啉-6-基}-4-娘淀-1-甲基-1Η_Π比嘻-3-基）-乙醇 70 Λ° )===1 ΗΝ 人乂 Cl 4-{[(1-{4-[3**氯-4-(3-氟-节氧基）-苯胺基]-喹唑啉-6-基}-111-吡咯-3-曱基）-胺基]-甲基} -1，1_二側氧基-六氮_1又*6*-嗔喃-4-醇 71 j； H1AXl -八必 4-(2-羥乙基）-1-{4-[3-甲基 -4-(6-甲基吼啶-3-氧基）-苯胺基]-喹唑啉-6-基}-111-吡咯3-甲酸（2-甲氧基乙基）-醯胺 72 Q 打。jC [1，4’ ]二哌啶基-Γ-基-(3-{4-[3-氯-4-(3-氟苄氧基）-苯胺基]-喧嗤琳-6-基}-°比洛-1-基）-甲酮 73 Η〇-^ΝΌνΝ 4-(2-羥乙基）-1-{4-[3-甲基 -4-(6-甲基°比啶-3-氧基）-苯胺 .基]-喧嗤琳-6-基}-111-0比嘻3-甲酸-(2-哌啶-1-乙基）-醯胺 74 〇ΚΝΗ fY0^) ΗΝ'^^α Η〇-^ΝΧ5νΝ 1-{4-[3-氯-4-(吡啶-2-甲氧基） -苯胺基]-啥°坐琳-6-基} -4-4-(2-羥乙基）-1Η-吡咯-3-甲酸（2-吡咯烷-1-乙基）-醯胺 75 孓 jOC^ H〇^W 1-{4-[3-氯-4-(吡啶-2-甲氧基） -苯胺基]-喧β坐琳-6-基}-4-(2-經乙基）_lH_ntb洛-3_甲酸_(2_派啶-1-乙基）-醯胺 76 fY0^) hn*^=^Nsci 2-(l-{4-[3-氯-4-(d比0定-2-曱氧基）-苯胺基]-啥嗤琳-6-基}-4-吡咯烷-1-甲基-1H-吡咯-3-基）-乙醇 35 94389 201016683 77 Ο A# {4-（2-經乙基）~*1-[4-(1-苯乙胺基）-喧嗤琳-6-基]-1H-Drt：嘻-3-基}-〇底咬-1-甲酮 78 0 A# {4-(2-羥乙基）-ι-[4-α-苯乙胺基）-喧唾味-6-基]-1Η-η比嘻-3-基}-吡咯烷-1-曱酮 79 4-(2-羥乙基）-1-[4-(1-苯基-乙胺基）-喧°坐淋-6-基]-1H-α比洛 _3_甲酸（2-二乙胺基乙基）-酿胺 80 σ° f ^jCX C ΗΝΧϊ〇, [3-氣-4-(3-氟-节氧基）-苯基] -[6-(3-{[(1，1-二氧-六氫-1 λ *6*-噻喃-4-甲基）-胺基]-甲基}-°比嘻-1-基）-啥°坐琳-4-基]-胺 81 Q 〇==c χχρ ^NTDvN 卜[4-(3-氯-4-氟-苯胺基）-喹唑啉-6-基]-4-(2-羥基-乙基）-1Η-吡咯-3-甲酸-(2-吡咯烷-1-乙基）-醯胺 82 o 4-(2-羥乙基）-1-{4-[3-甲基-4-(6-甲基-吼啶-3-氧基）-苯胺基]-喧°坐琳-6-基}-1Η-π比洛-3-甲酸（3-嗎啉-4-丙基）-醯胺 83 Η〇_^Νχ^ΛΝ 4-(2-羥乙基）-1-{4-[3-甲基-4-(6-甲基-0比咬-3-氧基）-苯胺基]-。坐琳-6-基}-1Η-°比洛-3-甲酸（2-嗎啉-4-乙基）-醯胺 36 94389 201016683 84 Ο 士 ΗΛ。议 ηο^Νί〇λν 4-(2-羥乙基）-1-{4-[3-曱基-4-(6-甲基-°比〇定-3-氧基）·~苯胺基]-喧唾琳-6-基}-iH-D比嘻-3-甲酸-(2-二乙胺基乙基）-醯胺 85 、。Ά [3-氣-4-(3-氟-节氧基）-苯基] -{6-[1-(2-甲氧基乙基）-1Η-吡 0各-3-基]-啥嗤淋-4-基}-胺 86 〇Ά H1 以Cl [3-氣-4-(3-|^_苄氧基）-苯基] -{6-[1-(2-嗎琳-4-乙基）-1H-0比洛-3-基]-喧嗤淋-4-基}-胺 87 一 α 5-{4-[3-氣-4-(3-氟-苄氧基）-苯胺基]-啥嗤琳-6基}-：^-°比洛 -2-甲酸（2-嗎啉-4-乙基）-醯胺 88 ρ Λ。^) Η0-\」==! ΗΝ^^-α 2-(l-{4-[3-氣-4-(吡啶-2-甲氧基）-苯胺基]-喹唑啉-6-基}-4-嗎琳-4-甲基-1Η_Π比洛-3_基）-乙醇 89 ο {4-(2-經乙基）-1-[4-(1-苯乙胺基）-喧嗤淋-6-基]-1Η-πΛ^-3-基}-嗎啉-4-甲酮 90 J 〇 Ν-/ {4-(2-經乙基）-1-[4-(1-苯乙胺基）_啥嗤淋—6_基]-1Η-°比哈-3-基}-(4-甲基-哌畊-1-基）-甲酮 91 ο H0^^0 2-{1-[4-(1-苯乙胺基）-喹唑啉 -6-基]-4-派淀_1_甲基-1Η-吼哈 - 3-基}_乙醉 37 94389 201016683 92 0 2-{1-[4-(1-苯乙胺基）-喧°坐淋 -6-基]-4-吡咯烷-1-甲基-1Η-吡咯-3-基}-乙醇 93 Q ΝΗ 4-(2-經乙基）-1-[4-(1-苯乙胺基）-啥。坐琳-6-基]-1Η-。比洛-3-曱酸（2_〇fcbp各焼《-1-基-乙基）-酿胺 94 0 ΝΗ 4-(2-經乙基）-卜[4-(1-苯乙胺基）-啥β坐琳—6-基]-l_H-π比嘻-3-甲酸（2-哌啶-1-乙基）-醯胺 95 ο7 \ ΝΗ h〇^Nx^o 4-(2-羥乙基）-1-[4-(1-苯乙胺基）-喧唾琳-6-基]-1Η-Β比洛-3-甲酸（2-甲氧基乙基）-醯胺 96 0 ，么 η〇^ν^!ό 4-(2-經乙基）-1~·[4-(1-苯乙胺基）_啥嗤琳_6_基]_1Η_Π比咯_3_ 甲酸（2-嗎啉-4-乙基）-醯胺 97 .〇 ΝΗ 4-(2-羥乙基）-1-[4-(1-苯乙胺基）-喧峻琳-6-基]-iH-n比洛-3-甲酸（3-嗎啉-4-丙基）-醯胺 98 〇 Ν-^ 2-{4-(4甲基哌畊-1-曱基）-1-[4-(1-苯乙胺基）-喹唑啉-6-基]-1H-吡咯-3-基}-乙醇 38 94389 201016683 99 Ο 0 ^〇jC) ηο-λ!% Η,Χϊο, [1,4’ ]二哌啶基-Γ-基-[1-{4-[3-氯-4_( 0比°定-2-甲氧基）-苯胺基]-啥嗤琳-6-基}-4-(2-經乙基）-1Η-吡咯-3-基]-甲酮 100 0 H0^n^〇 2-{4-嗎啉-4-甲基-1-[4-(1-苯乙胺基）-喧0坐琳-6-基]-1Η-0比11 各 -3-基}-乙醇 101 °=< ΓΤ ηο-λ/^ι hn^^ci 1-[4-(3-氯-4-氟-苯胺基）-喹唑 ^•^-基卜斗-^-經乙基）-；^-1^ 咯-3-甲酸（2-曱氧基乙基）-醯胺 102 ο 1 F ΗΟ-^ ηΛ ^ΝΌνΝ 1-[4-(3-氯-4-氟-苯胺基）-喹唑啉-6-基]-4-(2-羥乙基）-1Η-吡咯-3-甲酸（2-二乙胺基乙基）-醯胺 103 0 ΐ ρ ΝΗ ΗΟ-Ο^ ηΛ ^Νι〇νΝ 1 - [ 4-(3-氣-4-^ -苯胺基）-啥哇琳-6-基]-4-(2-經乙基）-1Η-°比咯-3-甲酸（2-哌啶-1-乙基）-醯胺 104 0 \ F ηΛ η,ΧΧο, 1-[4-(3-氣-4-敦-苯胺基）-喧唾. 琳-6_基]-4_(2-經乙基）- 1H_ π比咯-3-甲酸（2-嗎啉-4-乙基1)-醯胺 105 Ο ΝΗ Η0_^ ηΛ, 1-[4-(3-氯-4-氟-苯胺基）-啥唾淋-6-基]-4-(2-經乙基）-111-11比咯-3-甲酸[2-(4甲基哌畊-1-基）-乙基]-醯胺 39 94389 201016683 106 〇 F o=C XX [l-[ 4-(3-氯-4-氟-苯胺基）-啥唑啉-6-基]-4-(2-羥乙基）-1Η-吡咯-3-基]-嗎啉-4-曱酮 107 〇=<^ j3T ηο^Λ^ι hn^^ci ^NOvN [1-[4-(3-氯-4-氟-苯胺基）-喹唾琳-6-基]-4-(2-經乙基）-111-吡咯-3-基]-(4-甲基哌畊-1-基）-曱酮 108 0 NH H〇^ ηΛ [1-[4-(3-氣-4-氣-苯胺基）-唾。圭琳-6-基]-4-(2-經乙基）-111-吡咯-3-甲酸（3-嗎啉-4-丙基）-醯胺 109 〇 F °=( J〇( [1_[4—(3-氯-4- IL -苯胺基）-喧唑啉-6-基]-4-(2-羥乙基）-1Η-吡咯-3-基]-吡咯烷-1-甲酮 110 〇 F o=C XX HO—HN^^Ci [1-[4-(3-氯-4- |L_苯胺基）-啥〇坐琳-6-基]-4-(2-經乙基）-1Η-〇t匕哈-3_基]_0底咬_1-甲銅 111 V hnL "jCIf F )==i HN*^^CI 4-二曱胺基-丁-2-烯酸（1-{4-[3-氯-4-(3-氟-节氧基）-苯胺基]-喧嗤琳-6-基}-4-三氟甲基 -1H-吡咯-3-基）-醯胺 112 ' ^γθ-^C- 、""""^nV^Y^n {6-[3, 4-二-（二乙胺基甲基）-0比 '7各-1-基卜°1:°坐琳-4-基}-[3-氣 -4-(3-氟-苄氧基)-苯基]-胺 40 94389 201016683 113 Γ°> r Qj； J〇C [6-(3, 4-二-嗎琳-4-甲基0比洛 -1-基）-喹嗤琳-4-基]-[3-氣 -4-(3-就-节氧基）-苯基]-胺 114 η P rr。工 Q C ηΛ, 6-(3, 4-二-〇底0定-1-甲基〇比口各-l-基）-喹唑啉-4-基]-[3-氯-4-(3-氟-苄氧基）-苯基]-胺 115 一“、HN 人乂 Cl {6-[3, 4-二-(二甲基胺基甲基）〇比1ϊ|·-1-基]-啥唾琳-4-基}-[3-氯-4-(3-氟-节氧基）-苯基]-胺 116 0 NH ^y〇^CXF H0-\ ^NOvN 2-{1-{4-[3-氯-4-(3-氟节氧基） -苯胺基]-喹唑啉-6-基}-4-[(2-嗎啉-4-乙胺基）-甲基]-1H-吡咯 -3-基}-乙醇 117 ί 0j3^ ς .xx：r^F [3-氯-4-(3-氟-苄氧基）-苯基] -(6-{5-[(2-甲氧基-乙胺基）-甲基]-1H-D比洛-3-基}-啥°坐琳-4-基）_胺 118 〇 ς ,χχ：^ [3-氣-4-(3- I -节氧基）-苯基] -(6-{5-[(2-嗎啉-4-乙胺基）-甲基]-1H-D比洛_3-基}-嗤。圭嘛-4_ 基）-胺 119 χγ°^ VrTl Ηϊ Cl ^ n〇> [3-氯-4-(3- H -节氧基）-苯基] -[6-(1_曱磺醯基-1H-吡咯-3-基）-喧唾淋-4-基]-胺 41 94389 201016683 120 〇 F {： rx 2-{l-[4-(3-氯-4-氟苯胺基）-喹唾琳-6-基]-4-嗎琳-4-甲基-1H-吡咯-3-基}-乙醇 121 〇 {： j〇cF H〇-\/===] HN^^CI 2-{ 1-[4-(3-氯-4-氟-苯胺基）-喧嗤淋-6-基]-4-0底°定-1 -甲基 -1H-°比洛-3-基}-乙醇 122 〇 F C XI ηο-λ^τΗ hn^-^ci N 2-[1-[4-((3-氯-4-氟-苯胺基）-喹唑啉-6-基）-4-(4-甲基哌畊 -1-甲基）-1Η-吡咯-3-基]-乙醇 123 〈 XX Η〇-γ>=η HN^^CI 〜15^N 2-(1-{4-[3-氯-4-(3-氣-节氧基）-苯胺基]-喧唾琳-6-基}-4-二乙胺基曱基_1H_ 〇fcb洛-3-基）-乙醇 124 N- ^γ-Os^C- H0-\ )==1 唧人〆^Cl 2-(1-{4-[3-氯-4-(3-氟-节氧基）-苯胺基]-喹唑啉-6-基}-4-二甲胺基曱基-1H-吡咯-3-基）-乙醇 125 ^ Λ〇Χλ, H0^\ HN^^CI ^νυ^Λν w 4_( {[ 1-{4-[3-氣-4-(3-氟-节氧基）-苯胺基]-啥°坐琳-6-基} -4-(2-羥基乙基）-1Η-吡咯-3-甲基]-胺基} -甲基）_1，1-二側氧基 _六氮_1 λ *6*-嗔喃_4_醇 126 A。 n HO-J^ H^a _2-(1-{4-[3-氯-4-(3-氟-节氧基）-苯胺基]-喹唑啉-6-基} -4-{[(1，1-二側氧基-六氫-1 λ *6*-噻喃-4甲基）-胺基]-甲基} -1Η-吡咯-3-基）-乙醇 42 94389 201016683 127 NH ^y〇s^J〇Lf H〇-\ /=1 2-(l-{4-[3-氯-4-(3-敦-节氧基）-苯胺基]-喹唑啉-6-基}-4-[(2-甲磺醯基乙胺基）-甲基] -1H-吡咯-3-基}-乙醇 128 0_N^s' Hi^cl ^Nw [1-{4-[3-氯-4-(3-氟< 节氧基）-苯胺基]-喹唑啉-6-基}-4-(2-嗎琳-4-乙基）-1Η-π比嘻-3-基]-嗎琳-4-曱酮 129 Λ ηΛ [1-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-喧嗤淋-6-基}-4-(2-曱氧基乙基）-1Η-吡咯-3-基]-嗎啉 -4-甲 _ 130 〇J^ fY〇V^F ^N-\hn-^^ci [1-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-喹唑啉-6-基}-4-(2-二乙胺基乙基）-1Η-吡咯-3-基]-嗎琳-4-甲嗣 131 \-\ /=*» HN^^a 4功 [1-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]_喧°坐琳-6-基}-4-(2-二甲胺基乙基）_lH_ntb嘻_3-基]-嗎琳-4-甲酮 132 〇 rCrF Η0*Λ_^ HN·^^ 乂 x5n [1_{4-[1_(4-节基）-1Η-°引0坐 -5-胺基]-喧唾琳-6-基}-4-(2-羥乙基）-1Η-吡咯-3-基]-嗎啉 -4-甲酮 133 〇 rCr ΗΰΛ^ h,jCC'n 1-{4-[1-(4-氟-苄基）-1H 吲唑 -5-胺基]-喧°坐琳-6-基}-4-(2-羥乙基）-1Η-吡咯-3-基]-(4-甲基-哌畊-1-基）-甲酮 134 Ο ? r<T 1-{4-[1-(4-氟-节基）-1Η 11 弓丨0坐 -5-胺基]-喹嗤琳-6-基}-4-(2-羥乙基）-1Η-吡咯-3-甲酸（2-二乙胺基乙基）-醯胺 135 o \ XT ^^nVV^n 1-{4-[1-(4-氟苄基）-1Η 吲唑-5-胺基]-喧°坐琳-6-基}-4-(2-經乙基）-1Η-吡咯-3-甲酸（3-嗎啉-4-丙基）-醯胺 43 94389 20101668361 O H0^nW 2-[l-{4-[3-Chloro-4-(pyridine-2-methoxy)-anilino]-quinazolin-6-yl}-4-(4-fluorenyl) -Peptin-1-methyl)-1Η-pyrrol-3-yl]-ethanol 62% .ΧΪ:^ HNn〇> [3-chloro-4-(3-fluoro-p-oxy)-phenyl] -(6-{5-[(2-oxime-ethylamino)-methyl]-1H-pyrrol-3-yl}-quinazoline-.4-yl)-amine 63 ^〇jaF ^ λ [3-Gas-4-(3-襄-benzyloxy)-phenyl]-(6-{5-[(3-morphinyl-4-propylamino)-methyl]-1H-pyrrole-3 -yl}-quinazolin-4-yl)-amine 64 ^Y〇-jCXF 0'〇^ from 'i〇V [3- gas-4-(3-a-benzyloxy)phenyl]-{ 6-[ 1-(2-Pyrrolidin-1-ethyl)-1Η-dehydrazol-3-yl]-indenyl-4-yl}-amine 65 ητ0^ρ N^-% /==. HN human · human Cl °OC> [3- gas-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1-{3-[4-(3-chlorophenyl)-1 *Bottom-Bulk]-Propyl 1H-pyrrol-3-yl)-indolyl-4-yl]-amine 66 QS HN^°xx η〇^νό5ν 4-(2 dihydroxyethyl)- 1-{4-[3-Methyl-4-(6-methyl"bipyridyl-3-oxy)-anilino]-喧琳琳 -6-6-}}-111-0 嘻-3- Formic acid-(2-pyrrolidin-1-ethyl)-decylamine 67 Η, ΧΪο, rC^N N-(1-{4-[3-chloro-4-(3-fluoro" ))-anilino]-啥嗤琳-6-yl}-4-trimethylmethyl-1H-吼洛-3~~yl)-2-methyl-acrylamide 68 /1. Force ^/==η HN^^CI ho^nOvn [1-{4-[3-chloro-4-(pyridine-2-methoxy)-anilino]-quinazoline-6-yl} -4 -(2-ethyl)-1H-^比哈_3-基]-旅淀-1-甲酿 I 34 94389 69 OX HN^^CI 2-(l-{4-[3-chloro-4 -(pyridin-2-decyloxy)-anilino]-quinazolin-6-yl}-4-native-1-methyl-1Η_Π比嘻-3-yl)-ethanol 70 Λ° )== =1 ΗΝ Human 乂Cl 4-{[(1-{4-[3**chloro-4-(3-fluoro-hydroxy)-anilino]-quinazolin-6-yl}-111-pyrrole -3-indolyl)-amino]-methyl}-1,1_di-oxy-hexanitro-_1-*6*-indol-4-ol 71 j; H1AXl-八必4-(2 -hydroxyethyl)-1-{4-[3-methyl-4-(6-methylacridin-3-yloxy)-anilino]-quinazolin-6-yl}-111-pyrrole 3 - Formic acid (2-methoxyethyl)-guanamine 72 Q. jC [1,4' ]dipiperidinyl-fluorenyl-(3-{4-[3-chloro-4-(3-fluorobenzyloxy)-anilino]-indolyl-6-yl} -°Pilo-1-yl)-methanone 73 Η〇-^ΝΌνΝ 4-(2-hydroxyethyl)-1-{4-[3-methyl-4-(6-methyl-pyridyl- 3-oxy)-aniline.yl]-喧嗤琳-6-yl}-111-0 than hydrazine-3-carboxylic acid-(2-piperidin-1-ethyl)-nonylamine 74 〇ΚΝΗ fY0^) ΗΝ '^^α Η〇-^ΝΧ5νΝ 1-{4-[3-chloro-4-(pyridine-2-methoxy)-anilino]-啥°坐琳-6-yl} -4-4-( 2-Hydroxyethyl)-1Η-pyrrole-3-carboxylic acid (2-pyrrolidin-1-ethyl)-decylamine 75 孓jOC^ H〇^W 1-{4-[3-chloro-4-(pyridine -2-methoxy)-anilino]-indolyl β-yl-6-yl}-4-(2-ethyl)-lH_ntb-l-3-carboxylic acid _(2-pyridin-1-ethyl)-醯amine 76 fY0^) hn*^=^Nsci 2-(l-{4-[3-chloro-4-(d is 0-but-2-oxooxy)-anilino]-啥嗤琳-6- }}-4-pyrrolidin-1-yl-1H-pyrrol-3-yl)-ethanol 35 94389 201016683 77 Ο A# {4-(2-ethyl)~*1-[4-(1-benzene Ethylamino)-喧嗤琳-6-yl]-1H-Drt: 嘻-3-yl}-〇 bottom bite 1-ketone 78 0 A# {4-(2-hydroxyethyl)-ι-[ 4-α-phenethylamino)-hydrazin-6-yl]-1Η-η is more than indole-3-yl}-pyrrole 1-nonanone 79 4-(2-hydroxyethyl)-1-[4-(1-phenyl-ethylamino)-喧°坐-6-yl]-1H-αBilo_3_ Formic acid (2-diethylaminoethyl)-bristamine 80 σ° f ^jCX C ΗΝΧϊ〇, [3- gas-4-(3-fluoro-hydroxyl)-phenyl]-[6-(3 -{[(1,1-dioxo-hexahydro-1 λ *6*-thiopyran-4-methyl)-amino]-methyl}-° than 嘻-1-yl)-啥° sitting 4-yl]-amine 81 Q 〇==c χχρ ^NTDvN [4-(3-chloro-4-fluoro-anilino)-quinazolin-6-yl]-4-(2-hydroxy-B -1Η-pyrrole-3-carboxylic acid-(2-pyrrolidin-1-ethyl)-decylamine 82 o 4-(2-hydroxyethyl)-1-{4-[3-methyl-4- (6-Methyl-acridin-3-yloxy)-anilino]-喧°坐琳-6-yl}-1Η-πBilo-3-carboxylic acid (3-morpholin-4-propyl)- Indoleamine 83 Η〇_^Νχ^ΛΝ 4-(2-hydroxyethyl)-1-{4-[3-methyl-4-(6-methyl-0 butyl-3-oxy)-aniline base]-.坐琳-6-基}-1Η-°Bilo-3-carboxylic acid (2-morpholin-4-ethyl)-decylamine 36 94389 201016683 84 士士 ΗΛ. Ηο^Νί〇λν 4-(2-Hydroxyethyl)-1-{4-[3-indolyl-4-(6-methyl-°pyridine-3-oxy)·~anilinyl] - 喧琳 -6-6-yl}-iH-D than 嘻-3-carboxylic acid-(2-diethylaminoethyl)-decylamine 85. Ά [3-Gas-4-(3-fluoro-p-ethoxy)-phenyl]-{6-[1-(2-methoxyethyl)-1Η-pyridin-3-yl]-oxime嗤-4-yl}-amine 86 〇Ά H1 with Cl [3- gas-4-(3-|^-benzyloxy)-phenyl]-{6-[1-(2-?-lin-4 -ethyl)-1H-0bilo-3-yl]-indol-4-yl}-amine 87-α 5-{4-[3- gas-4-(3-fluoro-benzyloxy) -anilino]-啥嗤琳-6-yl}-:^-°Pilo-2-carboxylic acid (2-morpholin-4-ethyl)-decylamine 88 ρ Λ. ^) Η0-\"==! ΗΝ^^-α 2-(l-{4-[3-Ga-4-(pyridine-2-methoxy)-anilino]-quinazoline-6-yl }-4-Merlin-4-methyl-1Η_Π比洛-3_yl)-ethanol 89 ο {4-(2-Ethyl)-1-[4-(1-phenylethylamino)-oxime嗤-6-yl]-1Η-πΛ^-3-yl}-morpholin-4-methanone 90 J 〇Ν-/ {4-(2-ethyl)-1-[4-(1- Phenylethylamine)_啥嗤淋-6_基]-1Η-°Bha-3-yl}-(4-methyl-piped-1-yl)-methanone 91 ο H0^^0 2- {1-[4-(1-Phenylethylamino)-quinazolin-6-yl]-4-precipitate_1_methyl-1Η-吼哈- 3-基}_乙醉37 94389 201016683 92 0 2-{1-[4-(1-Phenylethylamino)-喧°坐-6-yl]-4-pyrrolidin-1-methyl-1Η-pyrrol-3-yl}-ethanol 93 Q ΝΗ 4-(2-Ethyl)-1-[4-(1-phenylethylamino)-indole. Sitting on Lin-6-based]-1Η-. Bilo-3-decanoic acid (2_〇fcbp each 焼"-1-yl-ethyl)-bristamine 94 0 ΝΗ 4-(2-ethyl-)-[4-(1-phenylethylamino) )-啥β坐琳-6-yl]-l_H-π than 嘻-3-carboxylic acid (2-piperidin-1-ethyl)-decylamine 95 ο7 \ ΝΗ h〇^Nx^o 4-(2- Hydroxyethyl)-1-[4-(1-phenylethylamino)-hydrazin-6-yl]-1Η-dehydrazol-3-carboxylic acid (2-methoxyethyl)-decylamine 96 0 , ηη〇^ν^!ό 4-(2-Ethyl)-1~·[4-(1-phenylethylamino)_啥嗤琳_6_基]_1Η_Π比咯_3_ formic acid ( 2-morpholin-4-ethyl)-nonylamine 97 .〇ΝΗ 4-(2-hydroxyethyl)-1-[4-(1-phenylethylamino)-喧峻琳-6-yl]- iH-n piroc-3-carboxylic acid (3-morpholin-4-propyl)-nonylamine 98 〇Ν-^ 2-{4-(4 methylpipen-1-yl)-1-[4 -(1-phenylethylamino)-quinazolin-6-yl]-1H-pyrrol-3-yl}-ethanol 38 94389 201016683 99 Ο 0 ^〇jC) ηο-λ!% Η,Χϊο, [1 , 4' ] Dipiperidinyl-fluorenyl-[1-{4-[3-chloro-4_(0-butoxy-2-methoxy)-anilino]-indolyl-6-yl} 4-(2-ethyl)-1Η-pyrrol-3-yl]-methanone 100 0 H0^n^〇2-{4-morpholin-4-methyl-1-[4-(1- Phenylethylamine)-喧0 sits 琳-6-yl]-1Η-0 ratio 11 each -3- }-Ethanol 101 °=< ΓΤ ηο-λ/^ι hn^^ci 1-[4-(3-Chloro-4-fluoro-anilino)-quinazoline^•^-基卜斗-^- Ethyl)-;^-1^ oleo-3-carboxylic acid (2-methoxyethyl)-decylamine 102 ο 1 F ΗΟ-^ ηΛ ^ΝΌνΝ 1-[4-(3-chloro-4-fluoro- Anilino)-quinazolin-6-yl]-4-(2-hydroxyethyl)-1Η-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-decylamine 103 0 ΐ ρ ΝΗ ΗΟ- Ο^ ηΛ ^Νι〇νΝ 1 - [ 4-(3-Ga-4-^-anilino)-啥wowolin-6-yl]-4-(2-ethyl)-1Η-° ratio- 3-carboxylic acid (2-piperidin-1-ethyl)-decylamine 104 0 \ F ηΛ η, ΧΧο, 1-[4-(3-气-4-敦-phenylamino)-喧s. Lin-6 _基]-4_(2-ethyl)- 1H_ πpyrrol-3-carboxylic acid (2-morpholin-4-ethyl 1)-decylamine 105 Ο Η Η0_^ ηΛ, 1-[4-(3 -chloro-4-fluoro-anilino)-indolyl-6-yl]-4-(2-ethyl)-111-11pyr-3-carboxylic acid [2-(4 methylpiped-1 -yl)-ethyl]-nonylamine 39 94389 201016683 106 〇F o=C XX [l-[ 4-(3-chloro-4-fluoro-anilino)-oxazoline-6-yl]-4- (2-hydroxyethyl)-1Η-pyrrol-3-yl]-morpholin-4-indanone 107 〇=<^ j3T ηο^Λ^ι hn^^ci ^NOvN [1-[4-(3 -chloro-4-fluoro-benzene Amino)-quinalin-6-yl]-4-(2-ethyl)-111-pyrrol-3-yl]-(4-methylpiped-1-yl)-fluorenone 108 0 NH H〇^ ηΛ [1-[4-(3-Ga-4-a-anilino)-saliva.圭琳-6-yl]-4-(2-ethyl)-111-pyrrole-3-carboxylic acid (3-morpholin-4-propyl)-decylamine 109 〇F °=( J〇( [1_ [4-(3-Chloro-4-IL-anilino)-oxazoline-6-yl]-4-(2-hydroxyethyl)-1Η-pyrrol-3-yl]-pyrrolidine-1-A Ketone 110 〇F o=C XX HO—HN^^Ci [1-[4-(3-chloro-4- |L_anilino)-啥〇坐琳-6-yl]-4-(2- Jing Ethyl)-1Η-〇t匕哈-3_基]_0Bottom bite_1-a copper 111 V hnL "jCIf F )==i HN*^^CI 4-diamylamino-but-2- Alkenoic acid (1-{4-[3-chloro-4-(3-fluoro-p-hydroxy)-anilino]-indolyl-6-yl}-4-trifluoromethyl-1H-pyrrole-3 -yl)-nonylamine 112 ' ^γθ-^C- ,""""^nV^Y^n {6-[3, 4-di-(diethylaminomethyl)-0 ratio '7 each-1-ylb °1: ° sitin-4-yl}-[3-gas-4-(3-fluoro-benzyloxy)-phenyl]-amine 40 94389 201016683 113 Γ°> r Qj; J〇C [6-(3, 4-di-morphin-4-methyl 0-l-l-yl)-quinoline-4-yl]-[3- gas-4-(3 - --oxyl)-phenyl]-amine 114 η P rr. work QC ηΛ, 6-(3, 4-di-fluorene base 0 -1-methyl oxime ratio -l- group)- Quinazolin-4-yl]-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-amine 115-, HN Human 乂Cl {6-[3, 4-di-(dimethylaminomethyl) oxime ratio 1ϊ|·-1-yl]-啥啥琳-4-yl}-[3-chloro-4-( 3-fluoro-hydroxyl)-phenyl]-amine 116 0 NH ^ y 〇 CXF H0-\ ^NOvN 2-{1-{4-[3-chloro-4-(3-fluoro- oxy) -anilino]-quinazolin-6-yl}-4-[(2-morpholin-4-ethylamino)-methyl]-1H-pyrrol-3-yl}-ethanol 117 ί 0j3^ ς . Xx: r^F [3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-{5-[(2-methoxy-ethylamino)-methyl]-1H -D 比洛-3-yl}-啥°坐琳-4-yl)_amine 118 〇ς ,χχ:^ [3-Ga-4-(3-I-hydroxyl)-phenyl]-( 6-{5-[(2-morpholin-4-ethylamino)-methyl]-1H-D bis-3-yl}-oxime. 圭-4_yl)-amine 119 χγ°^ VrTl Ηϊ Cl ^ n〇> [3-Chloro-4-(3-H-p-hydroxy)-phenyl]-[6-(1_oxasulfonyl-1H-pyrrol-3-yl)-hydrazine 4-yl]-amine 41 94389 201016683 120 〇F {: rx 2-{l-[4-(3-chloro-4-fluoroanilino)-quinalin-6-yl]-4-molin- 4-methyl-1H-pyrrol-3-yl}-ethanol 121 〇{: j〇cF H〇-\/===] HN^^CI 2-{ 1-[4-(3-chloro-4- Fluoro-anilino)-indole-6-yl]-4-0 bottom-deciding-1 -methyl-1H-°Pilo-3-yl}-ethanol 122 〇FC XI Ηο-λ^τΗ hn^-^ci N 2-[1-[4-((3-chloro-4-fluoro-anilino)-quinazolin-6-yl)-4-(4-methylpiperidine Plough-1-methyl)-1Η-pyrrol-3-yl]-ethanol 123 〈 XX Η〇-γ>=η HN^^CI 〜15^N 2-(1-{4-[3-chloro-4 -(3-gaso-oxy)-anilino]-indolyl-6-yl}-4-diethylaminoindenyl-1H_ 〇fcb-l-yl)-ethanol 124 N-^γ- Os^C- H0-\ )==1 唧人〆^Cl 2-(1-{4-[3-chloro-4-(3-fluoro-pethoxy)-anilino]-quinazoline-6 -yl}-4-dimethylaminoindolyl-1H-pyrrol-3-yl)-ethanol 125 ^ Λ〇Χλ, H0^\ HN^^CI ^νυ^Λν w 4_( {[ 1-{4- [3-Gas-4-(3-fluoro-p-hydroxy)-anilino]-啥°坐琳-6-yl}-4-(2-hydroxyethyl)-1Η-pyrrole-3-methyl] -amino}-methyl)_1,1-di-oxyl_hexanitro-1 λ *6*-nonyl-4-alol 126 A. n HO-J^ H^a _2-(1-{4-[3-chloro-4-(3-fluoro-oxy)-anilino]-quinazolin-6-yl} -4-{[ (1,1-di-oxy-hexahydro-1 λ *6*-thiopyran-4-methyl)-amino]-methyl} -1Η-pyrrol-3-yl)-ethanol 42 94389 201016683 127 NH ^y〇s^J〇Lf H〇-\ /=1 2-(l-{4-[3-Chloro-4-(3-d-n-hydroxy)-anilino]-quinazoline-6- }}-4-[(2-methylsulfonylethylamino)-methyl]-1H-pyrrol-3-yl}-ethanol 128 0_N^s' Hi^cl ^Nw [1-{4-[3 -Chloro-4-(3-fluoro<>oxyl)-anilino]-quinazolin-6-yl}-4-(2-morphin-4-ethyl)-1Η-π than 嘻-3 -基]-Merlin-4-indolone 129 Λ ηΛ [1-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-anilino]-indolyl-6-yl}- 4-(2-decyloxyethyl)-1Η-pyrrol-3-yl]-morpholine-4-methyl _ 130 〇J^ fY〇V^F ^N-\hn-^^ci [1-{ 4-[3-Chloro-4-(3-fluoro-benzyloxy)-anilino]-quinazolin-6-yl}-4-(2-diethylaminoethyl)-1Η-pyrrole-3 -基]-?琳-4-甲嗣131 \-\ /=*» HN^^a 4 work [1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-anilino ]_喧°坐琳-6-yl}-4-(2-dimethylaminoethyl)_lH_ntb嘻_3-yl]-molin-4-ketone 132 〇rCrF Η0*Λ_^ HN·^^乂x5n [1 _{4-[1_(4-pyrifosyl)-1Η-°#0--5-amino]-喧喧琳-6-yl}-4-(2-hydroxyethyl)-1Η-pyrrole-3 -yl]-morpholin-4-methanone 133 〇rCr ΗΰΛ^ h,jCC'n 1-{4-[1-(4-fluoro-benzyl)-1H oxazol-5-amino]-喧°坐琳-6-yl}-4-(2-hydroxyethyl)-1Η-pyrrol-3-yl]-(4-methyl-piped-1-yl)-methanone 134 Ο ? r<T 1 -{4-[1-(4-Fluoro-nodal)-1Η 11 丨0丨-5-amino]-quinoline-6-yl}-4-(2-hydroxyethyl)-1Η- Pyrrole-3-carboxylic acid (2-diethylaminoethyl)-guanamine 135 o \ XT ^^nVV^n 1-{4-[1-(4-fluorobenzyl)-1Η oxazol-5-amine基]-喧°坐琳-6-yl}-4-(2-ethyl)-1Η-pyrrole-3-carboxylic acid (3-morpholin-4-propyl)-decylamine 43 94389 201016683

136 0 l r<T ^Ni〇vN l-{4-[l-(4- l -节基）-lH— °引 °坐 -5-胺基]-喹唑啉-6-基}-4-(2-羥乙基）-1Η-吡咯-3-甲酸-(2-哌啶-1-乙基）-醯胺 137 Q j r〇T 卜{4-[1-(4-氟-苄基）-1Η-吲唑 -5-胺基]•喧ϋ坐琳-6-基}-4-(2-羥乙基）-1Η-吡咯-3-甲酸-(2-吡洛院-1-基-乙基）-酿胺 138 Q H0七，唧入人丨 1-(3-{4-[3-氯-4-(3-敗节氧基）-苯胺基]-喹唑啉-6-基}-°比咯-1-基）-3-嗎啉-4-丙-2-醇 139 P j〇CF 〜o6n 2-{1-[4-(3-氯-4-氟苯胺基）-喹唾淋-6-基]-4- °比哈烧-1-曱基 -1H-吡咯-3-基卜乙醇 140 r j〇cF ηο_Λ__/Η hn^^ci 2-{ 1-[4-(3_ 氣-4-敦-苯胺基）-喹唑啉-6-基]-4-二甲胺基甲基 -1H-吡咯-3-基}-乙醇 141 〇=\〇 r F r xx H〇--\h=\ 乂切N 2-{1-[4-((3_ 氯-4-氟-苯胺基）-喧^坐琳-6-基]-4-[(2-甲確醯基-乙胺基）-甲基]-1H-吡咯-3-基}-乙醇 142 P=o (OH NH ΗΟ-Λ^, HnO^CI 4-({[1-[4-(3-氯氣-_ 苯胺基）-喧嗤琳-6-基]-4-(2-經乙基）-1Η-吡咯-3-甲基]-胺基}-甲基）-M-二側氧基-六氫-1 λ*6* -隹11 南-4-醇 143 卢。 r rrF H〇-\>^ HN^^CI ^nX5vn 2-(1-[4-(3-氣-4-氟-苯胺基）-令。坐淋-6-基]-4-{[(1,1-二側氧基-六氫_1 λ *6*-垄喃-4-甲基）-胺基]-甲基}-1Η-吡咯-3-基）-乙醇 44 94389 201016683 144 〇 F J〇C 2-{l-[4-(3-氯4-氣-苯胺基）-啥唑啉-6-基]-4-二乙胺基甲基 -1H-吡咯-3-基}-乙醇 145 〇=s'° 〈NH |^γ0^Ό 2-{1-{4-[3-氯-4-(0比 °定-2-甲氧基）-苯胺基]-喹唑啉-6-基}-4-[(2_甲續酿基-乙胺基）-甲基] -1H-吡咯-3-基}-乙醇 146 NH H0^^lyO 2-{4-[(2-甲磺醯基-乙胺基）-甲基]-1-[4-(1-苯乙胺基）-喧：°坐淋 -6-基]_lH-Dit^-3-S}-乙醇 147 2-{4-二乙胺基甲基-l-[4-(l-苯乙胺基）-喹唑啉-6-基]-1H-吡咯 -3-基}-乙醇 148 fl HN 1-(3-{4-[3-氣-4-(3-氟-节氧基）-苯胺基]-喹唑啉-6-基}-吡咯-1-基）-3-[(1，1-二側氧基-六氮-1 λ *6*-嗟喃-4-甲基）-胺基]-丙-2-醇 149 H0-\ /==ϊ HN^^CI 2-(1-{4-[3-氯-4-（11 比°定-2-甲氧基）_苯胺基]-喹唑啉-6-基}-4-二乙胺基甲基- ΙΗ-η比洛-3-基）-乙醇 150 A ΗΝαο> [1-（3_說节基）-1Η_ °弓丨°坐_5_ 基]-[6-(1H-d比洛-3-基）-喧°坐琳 -4-基]-胺 151 厂L P ^ 2-(4-{[(1，1_二側氧基-六氫 -1又*6*-σ塞喃-4-曱基）-胺基]*~ 甲基}-l-{4-[1-(3 -氟节基）-111-,σ坐-5-胺基]-啥嗤琳-6-基} ~1Η-π比洛-3-基）-乙醇 152 、 2-(4-二甲胺基甲基_1-{4-[1-(3-氟苄基）-1Η-吲唑-5-胺基]-啥峻琳-6-基}-1Η-π*4 -3-基）-乙醇 45 94389 201016683136 0 l r<T ^Ni〇vN l-{4-[l-(4- l -])-lH- °#°-5-amino]-quinazoline-6-yl}-4 -(2-hydroxyethyl)-1Η-pyrrole-3-carboxylic acid-(2-piperidin-1-ethyl)-decylamine 137 Q jr〇T b {4-[1-(4-fluoro-benzyl) )-1Η-carbazole-5-amino]•喧ϋ坐琳-6-yl}-4-(2-hydroxyethyl)-1Η-pyrrole-3-carboxylic acid-(2-pyrrolin-1- Base-ethyl)-bristamine 138 Q H0 VII, indole 1-(3-{4-[3-chloro-4-(3-arginyloxy)-anilino]-quinazoline-6 -yl}-pyrrol-1-yl)-3-morpholin-4-propan-2-ol 139 P j〇CF 〜o6n 2-{1-[4-(3-chloro-4-fluoroanilinyl )-quinoline-6-yl]-4-°Habi--1-yl-1H-pyrrol-3-yl-ethanol 140 rj〇cF ηο_Λ__/Η hn^^ci 2-{ 1-[4 -(3_ gas-4-d-anilino)-quinazolin-6-yl]-4-dimethylaminomethyl-1H-pyrrol-3-yl}-ethanol 141 〇=\〇r F r xx H〇--\h=\ 乂切N 2-{1-[4-((3_ chloro-4-fluoro-anilino)-喧^坐琳-6-yl]-4-[(2-A Mercapto-ethylamino)-methyl]-1H-pyrrol-3-yl}-ethanol 142 P=o (OH NH ΗΟ-Λ^, HnO^CI 4-({[1-[4-(3- Chlorine-- anilino)-喧嗤琳-6-yl]-4-(2-ethyl)-1Η-pyrrole-3-methyl]-amine }-Methyl)-M-di- oxy-hexahydro-1 λ*6* -隹11 Nan-4-ol 143 L. r rrF H〇-\>^ HN^^CI ^nX5vn 2-( 1-[4-(3-Gas-4-fluoro-anilino)-----(6-yl)--4-{[(1,1-di-oxy-hexahydro_1 λ *6* - porphyrin-4-methyl)-amino]-methyl}-1Η-pyrrol-3-yl)-ethanol 44 94389 201016683 144 〇FJ〇C 2-{l-[4-(3-chloro-4- Gas-anilino)-oxazoline-6-yl]-4-diethylaminomethyl-1H-pyrrol-3-yl}-ethanol 145 〇=s'° 〈NH |^γ0^Ό 2-{ 1-{4-[3-Chloro-4-(0-butoxy-2-methoxy)-anilino]-quinazolin-6-yl}-4-[(2_甲后酿基-乙Amino)-methyl]-1H-pyrrol-3-yl}-ethanol 146 NH H0^^lyO 2-{4-[(2-methylsulfonyl-ethylamino)-methyl]-1-[ 4-(1-phenylethylamino)-oxime: °Shen-6-yl]_lH-Dit^-3-S}-ethanol 147 2-{4-diethylaminomethyl-l-[4- (l-Phenylethylamino)-quinazolin-6-yl]-1H-pyrrol-3-yl}-ethanol 148 fl HN 1-(3-{4-[3- gas-4-(3-fluoro - 节oxy)-anilino]-quinazolin-6-yl}-pyrrol-1-yl)-3-[(1,1-di- oxo-hexanitro-1 λ *6*- oxime) -4-methyl)-amino]-propan-2-ol 149 H0-\ /==ϊ HN^^CI 2-(1-{4-[3-chloro-4-( 11 约定-2-methoxy)-anilino]-quinazolin-6-yl}-4-diethylaminomethyl- ΙΗ-ηBilo-3-yl)-ethanol 150 A ΗΝαο> [1-(3_说节基)-1Η_ °弓丨°Sit_5_ 基]-[6-(1H-d 比洛-3-yl)-喧°坐琳-4-基]-amine 151 plant LP ^ 2-(4-{[(1,1_di-oxy-hexahydro-1-*6*-σ-propan-4-yl)-amino]*~ methyl}-l-{ 4-[1-(3-fluoronosyl)-111-, σ-s--5-amino]-啥嗤琳-6-yl} ~1Η-πpyr-3-yl)-ethanol 152, 2- (4-Dimethylaminomethyl-1-{4-[1-(3-fluorobenzyl)-1Η-indazole-5-amino]-啥junlin-6-yl}-1Η-π* 4 -3-yl)-ethanol 45 94389 201016683

153 °f A OCy 2-{l-{4-[l-(3-氟-苄基）-1Η-吲 °坐-5-胺基]-啥嗤淋-6-基}-4-[(2-甲磺醯基-乙胺基）-甲基] -1H-吡咯-3-基}-乙醇 154 N-j, HN^^^CI (3-氯-4-說-苯基）-[6-(1Η-°比口各 _3-基）-喧峻琳-4-基]-胺 155 fco S r\ HN H〇(N， Hi^CI ηοφ 1-(3-{4-[3_ 氯-4-(3- 1 -节氧基）-苯胺基]-喧嗤淋-6-基}-°比咯1-基）-3-(2-甲磺醯基-乙胺基）-丙-2-醇 156 y J〇 C%1 hn^c, w 2-{4-[3-氯-4-C3-氟-苄氧基）-苯胺基]-喹唑啉-6-基}-5, 6-二氫-2H-環戊烧并[c]D比11 各-4-晒 0-(2-二乙胺基乙基）-肟 157 0 / ,ΧΧ：^ w (2) 一 (Z)-2-{4-[3-氯-{4-[3-氯-4-(3-氟苄氧基）-苯胺基]-喹唑啉 _6-基卜5, 6-二氫-2H-環戊烧并 [c]°比洛-4-_ 0-(2-嗎琳-4-乙基）_將 158 ..夕 f Π Λ, ,xx« F (E) (E)-2-{4-[3_ 氯-{4_[3-氯-4-(3-氟苄氧基）-苯胺基]-喹唑啉 -6-基}-5, 6-二氫-2H-環戊烧并 [c]11 比嘻-4-_ 0-(2-嗎1#-4-乙基）-肟 159 Λ H(Axi [3-甲基-4-(6-曱基-吡啶-3-側氧基）-苯基]-[6-(1Η- 比咯-3-基）-喧峻淋-4-基]-胺 160 a。 xy°j^1f 〜α ϋ ct N-[2-(3-{4-[3-氯-4-(3-氟苄氧基）-苯胺基]-喹唑啉-6-基}-°比咯-1-基）-乙基]-甲磺醯胺 161 今 n HN ιΧ^ 4-{[3-(3-{4-[3-氯-4-(3-敗-节氧基）-苯胺基]-喹唑啉-6-基}-吡咯-1-基）-2-羥基-丙胺基]-甲基}-1，1-二側氧基-六氫-1λ 木6木-。塞。南-4 -醉 46 94389 201016683 162 9 广s=o h〇P 4-({[l-[4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-喧嗤琳_6-基]-4 -(2-羥乙基）-1H-吡咯-3-曱基]-胺基}-曱基）-1，1-二側氧基-六氮-1 λ *6*-喧喃-4-醇 163 (3-乙炔基苯基）-[6-(1Η-吼咯 -3-基）-喧唾琳-4-基]-胺 164 Λ-° W rQ ς身f ΗΝαα> 4-{[(4-{4-[1-(3-氟-节基）-1Η-°引α坐-5-基胺基]-喧°坐琳-6-基丨-ΙΗ-吡咯-2-基曱基）-胺基]-甲基}-1，1-二氧-六氮-1 λ *6*_ 嗟喃-4-醇 165 Ο^ψ ? r〇L ς身f [1-(3-氣-节基）-lH- D引 °坐-5-基]-(6-{5-[(2-甲確酿基-乙胺基）-甲基]-1H-吡咯-3-基}-喹唑琳-4-基）-胺 166 P。λ c淡f . [6-(5-{[(1，1-二氧-六氫-1λ *6*-噻喃-4-基甲基）-胺基]-甲基}-lH-Dfc11 各-3-基）-啥嗤淋-4-基]-[1-(3-敗-节基）-1H-d引〇坐 -5-基]-胺.. 167 0 - ^ν^Ον^ζ/Lp 4-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-喹唑啉-6-基}-1-(甲苯基-4-磺醯基）-1Η-吡咯-2-甲酸曱酯 168 〇°β~\ i〇vN 4-(3-{4_[3-氣-4-(3-氟-节氧基）-苯胺基]-喧嗤琳-6-基}-0比洛_1-基曱基）-1，1-二氧-六氫 -1又塞鳴-4-醇 169 rQ )'0^〇^Ν F {6-[1-(2-二乙胺基-乙基）-1Η-°比11 各-3*基]-啥°坐琳-4-基} -[1-(3-氟苄基）-1Η-吲唑-5-基] -胺 47 94389 201016683 170 8， [3-氯-4-(3-氟-苄氧基）-苯基] -{6-[(3R，8aR)-l-(六氫"比咯并 [2，l-c][l，4]噚噚畊基-3-基甲基）-1Η-πΛ洛-3-基]-喹唾琳-4-基}-胺 171 1 ^y〇^XXF C>^Na^X^cl [3-氯-4-(3-氟-节氧基）-苯基] -(6-{1-[2-(1- 曱基-吡咯烷-2-基）-乙基]-1Η-°比咯-3-基}-喹唑淋-4-基）-胺 172 Ηχχ产 4-(3-{4-[3-氣-4-(3-氧-节氧基）-苯胺基]-喧嗤琳-6-基}-〇比咯-1-基甲基）-哌啶-4-醇 173 jCC0^ Naa> [3-氯-4-(3-氟-节氧基）-苯基] - {6-[1-(3-旅淀-1·基-丙基） -1H-TI比嘻-3-基]-啥嗤琳_4-基}-胺 174 rQ 〇'〇^尸 F [1-(3-氟-苄基）-1Η-吲唑-5-基] -{6-[1-(2-嗎啉-4-基-乙基） -1Η-°比嘻-3-基]:唾琳-4-基}-胺 175 rQ F [1-(3_氣-节基）-1Η_α引°坐_5-基] -{6-[ 1-(2-吼咯烷-1-基-乙基） -1Η-°比洛-3-基]-啥嗤琳-4-基}-胺 176 ^Y〇v^CXF -^s-\ /=^1 唧人入 Cl [3-氯-4-(3- IL -节氧基）-苯基] -{6-[1-(2-曱磺醯基-乙基）-1Η-°比洛-3-基]-喧唾淋-4-基}-胺 177 〇 ^y°jCXf [3-氯-4-(3- IL -节氧基）-苯基] -(6-{1-[2-(四氫咬喃-2-基氧基）-乙基]-1H-0比洛-3-基}-啥〇坐啉-4-基）-胺 178 。飞 rQ l-(3-{4-[1_(3-|L -节基）-1Η-°引峻-5-基胺基]-啥唾琳-6-基}_〇比 π各-1-基）-3-嗎琳-4-基-丙-2-醇 48 94389 201016683153 °f A OCy 2-{l-{4-[l-(3-fluoro-benzyl)-1Η-吲° sit-5-amino]-啥嗤淋-6-yl}-4-[( 2-Methanesulfonyl-ethylamino)-methyl]-1H-pyrrol-3-yl}-ethanol 154 Nj, HN^^^CI (3-chloro-4-say-phenyl)-[6- (1Η-° ratio _3-base)-喧峻琳-4-yl]-amine 155 fco S r\ HN H〇(N, Hi^CI ηοφ 1-(3-{4-[3_ 氯- 4-(3- 1 -p-ethoxy)-anilino]-indole-6-yl}-°pyrrol-1-yl)-3-(2-methanesulfonyl-ethylamino)-propanyl- 2-alcohol 156 y J〇C%1 hn^c, w 2-{4-[3-chloro-4-C3-fluoro-benzyloxy)-anilino]-quinazoline-6-yl}-5 , 6-dihydro-2H-cyclopentan and [c]D ratio 11 each 4-tanning 0-(2-diethylaminoethyl)-肟157 0 / , ΧΧ:^ w (2) one ( Z)-2-{4-[3-Chloro-{4-[3-chloro-4-(3-fluorobenzyloxy)-anilino]-quinazoline-6-yl b 5,6-dihydrogen -2H-cyclopentan and [c]° pirox-4-_ 0-(2- morphine-4-ethyl) _ 158 .. 夕 f Π Λ, , xx « F (E) (E) -2-{4-[3_Chloro-{4_[3-chloro-4-(3-fluorobenzyloxy)-anilino]-quinazolin-6-yl}-5,6-dihydro-2H- Cyclopentene and [c]11 嘻-4-_ 0-(2-?1#-4-ethyl)-肟159 Λ H(Axi [3-methyl-4-(6-fluorenyl-pyridine) -3-sided oxy)-phenyl]- [6-(1Η-Butrol-3-yl)-indolyl-4-yl]-amine 160 a. xy°j^1f 〜α ϋ ct N-[2-(3-{4-[3- Chloro-4-(3-fluorobenzyloxy)-anilino]-quinazolin-6-yl}-pyrrol-1-yl)-ethyl]-methanesulfonamide 161 Today n HN ιΧ^ 4 -{[3-(3-{4-[3-chloro-4-(3-f-o-oxy)-anilino]-quinazolin-6-yl}-pyrrol-1-yl)-2- Hydroxy-propylamino]-methyl}-1,1-di-oxy-hexahydro-1λ, wood 6--. plug. south-4 - drunk 46 94389 201016683 162 9 wide s=oh〇P 4-({ [l-[4-[3-Chloro-4-(3-fluoro-benzyloxy)-anilino]-indolyl-6-yl]-4-(2-hydroxyethyl)-1H-pyrrole- 3-mercapto]-amino}-indenyl-1,1-di-oxy-hexanitro-1 λ*6*-indol-4-ol 163 (3-ethynylphenyl)-[6 -(1Η-吼rol-3-yl)-喧喧琳-4-yl]-amine 164 Λ-° W rQ ff fΗΝαα> 4-{[(4-{4-[1-(3-Fluorine - benzyl group -1Η-°αα-5-ylamino]-喧°坐琳-6-ylindole-purine-pyrrol-2-ylindenyl)-amino]-methyl}-1, 1-Dioxo-hexanitro-1 λ *6*_ 嗟 -4--4-ol 165 Ο^ψ ? r〇L f身 f [1-(3-气-节基)-lH- D引°Sit - 5-yl]-(6-{5-[(2-methyl-furyl-ethylamino)-methyl]-1H-pyrrol-3-yl}-quin Lin-4-yl) - amine 166 P. λ c light f . [6-(5-{[(1,1-dioxo-hexahydro-1λ *6*-thiopyran-4-ylmethyl)-amino]-methyl}-lH-Dfc11 Each -3-yl)-indole-4-yl]-[1-(3-fail-succinyl)-1H-d 〇 -5-5-yl]-amine.. 167 0 - ^ν^Ον ^ζ/Lp 4-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-anilino]-quinazolin-6-yl}-1-(methylphenyl-4-sulfonyl) )-1Η-pyrrole-2-carboxylic acid decyl ester 168 〇°β~\ i〇vN 4-(3-{4_[3-gas-4-(3-fluoro-p-oxy)-anilino]-喧嗤琳-6-基}-0 洛洛_1-yl fluorenyl-1,1-dioxy-hexahydro-1 and thiophene-4-ol 169 rQ )'0^〇^Ν F {6-[ 1-(2-diethylamino-ethyl)-1Η-° ratio 11 -3*yl]-啥°坐琳-4-yl}-[1-(3-fluorobenzyl)-1Η-吲Zyrid-5-yl]-amine 47 94389 201016683 170 8, [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-{6-[(3R,8aR)-l-(hexahydrogen "比比和[2,lc][l,4]噚噚耕-3-ylmethyl)-1Η-πΛ-3-yl]-quinalin-4-yl}-amine 171 1 ^ 〇^XXF C>^Na^X^cl [3-Chloro-4-(3-fluoro-oxy)-phenyl]-(6-{1-[2-(1- decyl-pyrrolidine) -2-yl)-ethyl]-1Η-°pyrrol-3-yl}-quinazolin-4-yl)-amine 172 4- 4-(3-{4-[3-气-4-( 3-oxo-oxygen ))-phenylamino]-indolyl-6-yl}-indolerol-1-ylmethyl)-piperidin-4-ol 173 jCC0^ Naa> [3-chloro-4-(3-fluoro-节oxy)-phenyl] - {6-[1-(3-joutin-1·yl-propyl)-1H-TI than 嘻-3-yl]-啥嗤琳_4-yl}-amine 174 rQ 〇'〇^尸F [1-(3-Fluoro-benzyl)-1Η-indazol-5-yl]-{6-[1-(2-morpholin-4-yl-ethyl)- 1Η-° than 嘻-3-yl]: salicylidene-4-yl}-amine 175 rQ F [1-(3_气-节基)-1Η_α引°坐_5-基] -{6-[ 1 -(2-pyrrolidin-1-yl-ethyl) -1Η-°Bilo-3-yl]-啥嗤琳-4-yl}-amine 176 ^Y〇v^CXF -^s-\ / =^1 唧 human into Cl [3-chloro-4-(3- IL-p-ethoxy)-phenyl]-{6-[1-(2-oxasulfonyl-ethyl)-1Η-° ratio洛-3-yl]-oxime-4-yl}-amine 177 〇^y°jCXf [3-chloro-4-(3- IL-hydroxyl)-phenyl] -(6-{1- [2-(Tetrahydromethane-2-yloxy)-ethyl]-1H-0bilo-3-yl}-hydrazin-4-yl)-amine 178. Flying rQ l-(3-{4-[1_(3-|L -])-1Η-°引峻-5-ylamino]-啥啥琳-6-yl}_〇 ratio π-1 -yl)-3-morphin-4-yl-propan-2-ol 48 94389 201016683

179 。 rQ F l-(3-{4-[l-(3-氟-苄基 ΜΗ-吲 0坐-5-基胺基]-喧.唾淋-6-基} -η比咯-1-基）-3-(2-甲磺醯基-乙胺基）-丙-2-醇 180 ^γ〇^Χλρ ΗΗ；ηα> 3-(3-{4—[3-氣-4-(3-敗-节氧基）-苯胺基]-喹唑啉-6-基}-°比咯-1-基）-丙烷-1，2-二醇三氟乙酸鹽 181 ^Y〇-vJ〇LF 〇Ί [3-氯-4-(3-氟-节氧基）-苯基] -{6-[1-(2- n辰咬-1-基-乙基） -1Η-°比洛-3-基]-喧°坐琳-4-基}-胺 182 ο、，上:及 Na€C> [3-氣-4-( 3-氟-节氧基）-苯基] -{6-[1-(3-嗎琳-4-基-丙基） -111-°比洛-3-基]-啥嗤琳-4-基}-胺 183 ^yOv^CXp 0(X_〇^cl 2-(3-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-喹唑啉-6-基}-吡咯-1-基）-1-嗎啉-4-基-乙酮 184 〇4-° n X HNxi, ΗΝΛα> . 4-{4-[3-氣-4-(3-氟-苄氧基）-苯胺基]-喧°坐琳-6-基}-1Η-π比洛 -2-甲酸-(2-曱磺醯基-乙基）-醯胺 185 NaCC> (S)-l-(3-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-喹唑啉-6-基}-吡咯-1-基）-3-嗎啉-4-基-丙-2-醇 186 (R)-l-(3-{4-[3-氯-4-(3-敗-节氧基）-苯胺基]-喹唑啉-6-基}-吡咯-1-基）-3-嗎啉-4-基-丙-2-醇 187 l-(3-{4-[3-氯-4-(3-氟-节氧基）-苯胺基]-啥唾琳-6-基}-°比口各-1-基）-3-(2,5-二氫11比洛-1-基）-丙-2-醇 188 (^) hnXIci °10> 1-(3-{4-[3-氯-4-(3-氟-节氧基）-苯胺基]-喧嗤琳-6-基}-°比洛-1-基）-3-β底咬-1-基-丙-2-醇 49 94389 201016683 189 j〇C^F l-(3-{4-[3-氯-4-(3-敦-节氧基）-苯胺基]-喧嗤琳-6-基} -D比洛-1-基）-3-二乙胺基-丙-2-醇 190 1-[1，4’ ]二哌啶基-Γ-基-2-(3-{4-[3-氯-4-(3-氟-节氧基）-苯胺基]-啥嗤琳-6-基}-D比洛-1-基）-乙嗣 191 /-°. ^^〇^XXF N-^H ^/==, HmAsAc| ι〇^ (S)-[3-氯-4-(3-氟-节氧基）-苯基]-[6-(1-嗎琳-3-基曱基-1Η-°比洛-3-基）-啥咬琳-4-基]-胺 192 很 2-(3-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-喧唾琳-6-基}-D比咯-1-基）-1-(4-甲基-哌畊-1-基）-乙酮 193 ΗΝΧΧ：^ 1-(3-{4-[3-氣-4-(3-氟-苄氧基）-苯胺基]-喧°坐淋-6-基} -0比咯-1-基）-3-(4-甲基-哌畊-1-基）-丙-2-醇 194 ρ. \ca， M ·. (R)-l-(3-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-喹唑琳-6-基}-吡咯-1-基）-3-[4-(2-甲磺醯基-乙胺基）-哌啶-1-基]-丙-2-醇 195 、 r〇L VVhX^’n F Naoc> 1_二乙胺基-3-(3-{4-[ 1-(3-氟-苄基）-1Η-0引峻-5-基胺基]-°|：β坐啉-6-基}-吡咯-1-基）-丙-2-醇 196 °^-i HN^c> 4-{4-[3-氯-4-(3-敗-节氧基）-苯胺基]-啥嗤琳 e-2-甲酸-(1，1-二氧-六氫-1 λ *6*-噻喃-4-基甲基）-醢胺 197 ^Y〇^XXF a [3-氣-4-(3-氟-节氧基）-苯基] -(6-{1-[2-(4-甲基-旅哄-1-基） -乙基]-1H-0比11 各-3-基}-啥〇坐琳 -4-基）-胺 198 0心'〇^广 {6_[1_(2_[1，4 ]二娘咬基-1’-基-乙基）-1Η-吡咯-3-基]-喹唑淋-4-基卜[3-氣-4-(3-氟-节氧基）-苯基]-胺 50 94389 201016683179. rQ F l-(3-{4-[l-(3-fluoro-benzyl ΜΗ-吲0-s--5-ylamino)-oxime. Salivary-6-yl}-n-pyrrol-1-yl )-3-(2-methylsulfonyl-ethylamino)-propan-2-ol 180 ^γ〇^Χλρ ΗΗ;ηα> 3-(3-{4-[3-气-4-(3- Phenoxy-p-hydroxy)-anilino]-quinazolin-6-yl}-pyrrol-1-yl)-propane-1,2-diol trifluoroacetate 181 ^Y〇-vJ〇LF 〇 Ί [3-Chloro-4-(3-fluoro-p-hydroxy)-phenyl]-{6-[1-(2- n-chenyl-1-yl-ethyl)-1Η-pilo-3 -基]-喧°坐琳-4-yl}-amine 182 ο,,上:和Na€C> [3- gas-4-(3-fluoro-hydroxyl)-phenyl] -{6- [1-(3-Molin-4-yl-propyl)-111-°Pilo-3-yl]-indolyl-4-yl}-amine 183 ^yOv^CXp 0(X_〇^cl 2-(3-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-anilino]-quinazolin-6-yl}-pyrrol-1-yl)-1-morpholine- 4-yl-ethanone 184 〇4-° n X HNxi, ΗΝΛα> . 4-{4-[3-Gas-4-(3-fluoro-benzyloxy)-anilino]-喧°坐琳-6 -yl}-1Η-πBilo-2-carboxylic acid-(2-oxasulfonyl-ethyl)-guanamine 185 NaCC> (S)-l-(3-{4-[3-chloro-4- (3-Fluoro-benzyloxy)-anilino]-quinazolin-6-yl}-pyrrol-1-yl)-3-morpholin-4-yl-propan-2-ol 186 (R)-l-(3-{4-[3-Chloro-4-(3-f-o-oxy)-anilino]-quinazolin-6-yl}-pyrrol-1-yl)-3 -morpholin-4-yl-propan-2-ol 187 l-(3-{4-[3-chloro-4-(3-fluoro-oxy)-anilino]-啥琳 -6 -6-6-yl }-° ratio -1-yl)-3-(2,5-dihydro-11-l-l-yl)-propan-2-ol 188 (^) hnXIci °10> 1-(3-{4 -[3-chloro-4-(3-fluoro-p-hydroxy)-anilino]-indolyl-6-yl}-°Pilo-1-yl)-3-β bottom bit-1-yl- Propan-2-ol 49 94389 201016683 189 j〇C^F l-(3-{4-[3-Chloro-4-(3-d-n-oxy)-anilino]-喧嗤琳-6-yl }-D-Bilo-1-yl)-3-diethylamino-propan-2-ol 190 1-[1,4' ]dipiperidinyl-fluorenyl-2-(3-{4-[ 3-Chloro-4-(3-fluoro-p-hydroxy)-anilino]-indolyl-6-yl}-D-l-l-yl)-acetamidine 191 /-°. ^^〇^XXF N-^H ^/==, HmAsAc| ι〇^ (S)-[3-chloro-4-(3-fluoro-oxy)-phenyl]-[6-(1-?-lin-3-曱 Η Η Η ° ° ° -3- -3- -3- -3- -3- -3- -3- 很很很 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- (3-{4-[3-chloro-4-(3-fluoro-benzyloxy) )-anilino]-indolyl-6-yl}-D-pyrrol-1-yl)-1-(4-methyl-piperidin-1-yl)-ethanone 193 ΗΝΧΧ:^ 1-(3 -{4-[3-Ga-4-(3-fluoro-benzyloxy)-benzene ]]-喧°坐淋-6-yl} -0-pyrrol-1-yl)-3-(4-methyl-piperidin-1-yl)-propan-2-ol 194 ρ. \ca, M · (R)-l-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-anilino]-quinazoline-6-yl}-pyrrol-1-yl) -3-[4-(2-Methanesulfonyl-ethylamino)-piperidin-1-yl]-propan-2-ol 195, r〇L VVhX^'n F Naoc> 1_diethylamino -3-(3-{4-[ 1-(3-Fluoro-benzyl)-1Η-0-lead-5-ylamino]-°|:β-sorry-6-yl}-pyrrole-1- ))-propan-2-ol 196 °^-i HN^c> 4-{4-[3-chloro-4-(3-f-o-oxy)-anilino]-啥嗤琳e-2- Formic acid-(1,1-dioxo-hexahydro-1 λ *6*-thiopyran-4-ylmethyl)-decylamine 197 ^Y〇^XXF a [3-gas-4-(3-fluoro-节oxy)-phenyl]-(6-{1-[2-(4-methyl-tour 哄-1-yl)-ethyl]-1H-0 ratio 11 -3-yl}-啥〇坐琳-4-基)-amine 198 0 heart '〇^广{6_[1_(2_[1,4 ] 娘娘基-1'-yl-ethyl)-1Η-pyrrol-3-yl]- Quinazoline-4-ylbu [3- gas-4-(3-fluoro-p-oxy)-phenyl]-amine 50 94389 201016683

199 η γΌ [1-(3-氟-苄基）-1Η-吲唑-5-基] -(6-{1-[2-(四氫α夫喃-2-基氧基）-乙基]-1Η-吡咯-3-基}-喹唑琳-4-基）-胺 200 1-[3-(3-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-喹唑啉-6-基}-°比洛-1-基）-丙基]-〇底〇定-4-醇 201 (R)l-[3-(3-{4-[3-氯-4-(3- H -苄氧基）-苯胺基]-喹唑啉-6-基}-σ比洛-1-基）-2-經基-丙基]-11 辰咬-4-醇 202 A:众 n^€C> (R)_l-(3-(4-(3-氯-4_( 3-氟-节氧基）苯胺基）喹唑啉-6-基）-1Η-吼咯-1-基）-3-((S)-2-(羥曱基）吡咯烷-1-基）丙-2-醇 203 0 〇Η j〇c。〜α八τ Cl (S)-l-[3-(3-{4-[3-氯-4-(3-氟 -苄氧基）-苯胺基]-喹唑啉-6-基}-吡咯-1-基）-2-羥-丙基]-哌咬-4-醇 204 Naoc> (S)-l-(3-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-喹唑啉-6-基}-°比哈-1-基）-3-環丙基胺基•丙 -2-醇 205 Ναο> ' (R)-l-[3-(3-{4-[3-氯-4-(3-氟 -苄氧基）-苯胺基]-喹唑啉-6-基}-π比洛-1-基）-2_經-丙基]_4_ 經甲基-旅咬-4-醇 206 -义，Η从 (R)-l-(3-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-喹唑啉-6-基}-吡咯-1-基）-3-甲氧基-丙-2-醇 207 Q\a Η1χχ:众 (S)-l-[l，4’ ]二哌啶基-Γ-基 -3-(3-{4-[3-氣-4-(3-氟-节氧基）-苯胺基]-喹唑啉-6-基}-°比洛_1 -基）_丙_2_醇 51 94389 201016683 208 HO % l-(3-{4-[3-氯-4-(3-氟-节氧基）-苯胺基]-喧嗤淋-6-基}-°比嘻_1_基）_3-[4_(2-經乙基）-〇底畊-1-基]-丙-2-醇 209 Naoc> 1-(3-{4-[3-氣-4-(3-氣-节氧基）-苯胺基]-啥°坐淋-6-基} -〇比咯-1-基）-3-(4-甲磺醯基-哌畊 -1-基）-丙-2-醇 210 ^Y〇vJ〇If [3-氯-4-(3-氟-苄氧基）-苯基] -{6-[ 1-(2-吡啶-2-基-乙基）胺 211 。術 1-(3-{4-[3_ 氯-4-(3- IL -节氧基）-苯胺基]-喧β坐琳—6-基}-〇比咯-1-基）-3-(1,1-二氧-六氫 -1又*6*-售喃-4-基胺基）-丙-2-醇 212 Na〇iN [3-氯-4-(3-氟-苄氧基）-苯基] -[6-(1-π比a定-2-基甲基-1H-0比n各 -3-基）-喧°坐琳-4-基]-胺 213 0A .. rO jO> F w Nn〇> (R)-l-(3-{4-[l-(3-氟-苄基） -111-1^丨唾-5-基胺基]」喧唾琳-6-基}-吡咯-1-基）-3-嗎啉-4-基-丙-2-醇 214 rO, F <s, (S)-l-(3-{4-[l-(3-氟-节基） -IH-i嗤-5-基胺基]-喧。坐琳-6-基}-11比嘻-1-基）-3-嗎淋-4-基-丙-2-醇 215 〇 rf'^F 〇〜fa 2-(3-{4-[3-氣.-4-(3-氟-节氧基）-苯胺基]-啥嗤琳-6-基} -〇比嘻-1-基）-1-11底唆-1-基-乙酮 216 2-(3-{4-[3-氣-4-(3-氟-苄氧基）-苯胺基]-啥嗤琳-6-基}_〇比咯-1-基）-Ν,Ν-二乙基-乙醯胺 217 2-(3-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-°Ι:σ坐淋-6-基}-π比咯-1-基）-Ν-環丙基-乙醯胺 52 94389 201016683 218 cl «CC^N 4-[(4-{4-[3-氣-4-(3-氟-苄氧基）-苯胺基]-喹唑啉-6-基}-111-吡咯-2-基甲基）-胺基]-哌啶-1-甲酸第三丁酯 219 〜口又〃，Hy人人丨 0 1-(3-{4-[3-氯-4-(3-氟-节氧基）-苯胺基]_啥°坐琳-6-基}-°比咯-1-基）-3-(2-哌啶-1-基-乙胺基）-丙-2-醇 220 、。〜 1-(3-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-嗅°坐琳-6-基}-〇比嘻-1-基）-3-（2-甲氧基-乙胺基） -丙-2-醇 221 h〇X〇^°^F ιΧ^Ν 1-(3-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-啥°坐琳-6-基}-〇比咯-1-基）-3-哌畊-1-基-丙-2-醇 222 rrB 又 c^oc0^ H0XJ 4-[3-(3-{4-[3_ 氯-4-(3-氟-苄氧基）-苯胺基]-喹唑啉-6-基}-吡咯-1-基）-2-羥-丙基胺基]-環己醇 223 八 /==1 m^^c\ "^ Nacc> HO N {1-[2-(3—{4-[3-氯-4-(3-氟-节氧基）-苯胺基]-喧β坐琳-6-基}-吡咯-1-基）-乙基]-°比咯炫-2-基}-甲醇 224 ^γΟ^Ο^ρ 0-0^、。 [3-氣-4-(3-氟-苄氧基）-苯基] -{6-[ 1-(2- σ比 σ定-4-基-乙基） - 1Η_ιτ比洛-3-基]-喧°坐琳-4-基}-胺 225 2-(3-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-喧σ坐琳-6-基} -〇比咯-1-基）-N-(l，l-二氧-六氫 -1 λ *6*-π塞喃-4-基）-乙酿胺 226 ^y〇^XXf /=η HN^^CI [3-氣-4-(3-氣-节氧基）-苯基] -[6-U-環丙基甲基-1H-吡咯-3-基）-喧唾琳-4-基]-胺 53 94389 201016683 227 cl 2-(3-{4-[3-氣-4-(3-氟-苄氧基）-苯胺基]_啥。坐嚇·_6-基}'-〇比嘻-1-基）-N-[(lr，4r)- (4-裡-環己基]-乙醯胺 228 ^y〇^XXf XrVf 2-(3-{4-[3-氯-4-(3-敗-节氧基）-苯胺基]-喧°坐琳-6-基}-0比洛_1_基）-1-(4-π比嘻烧-1 -基-n底。定-1-基）-乙_ 229 [3-氯-4-(3-氟-节氧基）-苯基] -{6-[1-(2-環丙基胺基-乙基） _111_11比洛_3-基]-啥°坐琳-4_基}-胺 230 [3-氯-4-(3-氟-节氧基）-苯基] -[6-(1-0比0定-4-基甲基-1H-0比洛 -3-基）-啥峻淋-4-基]-胺 231 ^Y〇^XXF 2-(3-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-喹唑啉-6-基}-°比 11 各-1-基）-1^-°底咬-4-基-乙酿胺 232 ^Y〇^〇LF HN^^a 9 Ναα> (8)-[3-氯-4-(3-敦-节氧基）-苯基]-[6_(1_ °比洛烧-3-基甲基 -111-°比洛-3-基）-〇|：°坐琳-4-基]-胺 233 H°^n XX〇J^F "^rc, 2-(3-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-喧°坐淋-6-基}-°比咯-1 -基）-1 - [ 4-(2-羥乙基）-哌畊-1-基]-乙酮 234 ^Y〇^XXF 1-(3-{4-[3-氣-4-(3-氟-节氧基）-苯胺基]-喧竣淋-6-基} - 〇t匕洛_1_基）-3-(4_π比洛烧基-派啶-1-基）-丙-2-醇 235 ^Y〇^xCXF [3-氯-4-(3-氟* -节氧基）-苯基] -(6-{1-[2-(1，1-二氧-六氩-1λ *6木-售喃-4-基胺基）-乙基]-111™ 〇比洛_3-基}_喧唾琳_4_基）-胺 236 ^γΟ^ΧΧρ vo^^i {4-[3-(3-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-喹唑啉-6-基}-D比洛-1-基）-2 -經-丙基]-派哄 -1-基}-環丙基-甲酮 54 94389 201016683 237 樣 α 1_(3~·{4-[3-氯-4-(3-氟-节氧基）-苯胺基]-喹唑啉-6-基}-°比咯-1-基）-3-(4-環丙基甲基-哌畊-1-基）-丙-2-醇 238 raxx> 2-(3-{4-[3-氣-4-(3-氟-苄氧基）-苯胺基]-喧°坐淋-6-基}-D比嘻-1-基）_1-旅哄-1-基-乙嗣 239 ^Y〇^〇LF Ν-{1-[3-(3-{4-[3-氣-4-(3-氟-苄氧基）-苯胺基]-喹唑啉-6-基} -〇比11 各-1 -基）-2-經-丙基]-η底唆 _4-基}-乙酿胺 240 H〇0勹旧XX力F [3-氯-4-(3-氟-节氧基）-苯基] -{6-[1-(2-哌畊-1-基-乙基）-1Η -π比嘻-3-基]-啥°坐琳-4-基}-胺 241 \Λ f〇L 〜F ι5ν 1-(3-{4-[1-(3-氟-苄基）-1Η-吲〇坐-5-基胺基]-啥°坐淋-6-基}-〇比咯-1-基）-3-(4-甲基-哌畊-1-基）-丙-2-醇 242 ΓΛα> 2-(3-{4-[3-氣-4-(3-氟-苄氧基）-苯胺基]-喹唑啉-6-基}-D比咯-1-基）-l-((3S，5R)-3, 5-二甲基-哌畊-1-基）-乙酮 243 N〇, "TO {_6-[1-(2-氮雜環庚-1-基-乙基）-1Η-°比11 各-3-基]-啥嗤琳-4-基}_[3_氯-4-(3-氟-节氧基苯基]-胺 244 hXC^ 2-(3-{4-[3-氯-4-(3-氟-节氧. 基）-苯胺基]-喧嗤琳-6-基}-°比咯-1-基）-N-(4-羥-1，1-二氧-六氮-1 λ *6*-嗟D南_4_基甲基）-乙醯胺 245 ^Y〇v^CXF 1-(3-{4-[3_ 氯-4-(3-氣-节氧基）-苯胺基]-啥°坐琳-6-基} -〇比咯-1-基）-3-(2-曱磺醯基-乙氧基）-丙-2-醇 55 94389 201016683 246 Ία产:及 N-{l-[2-(3-{4-[3-氣-4-(3-氟-苄氧基）-苯胺基]-喹唑啉-6-基}-吡咯-1-基）-乙醯基]-哌啶 -4-基}-乙醯胺 247 (^^-(^-{斗-^-氯-斗-^-貌-节氧基）-苯胺基]-喹唑啉-6-基Ια比洛 -1 - 基）-3_ [ (R)-2- °比嘻炫> -1-基曱基-吡咯烷-1-基]-丙-2-醇 248 6 A 1-[3-(3-{4-[1-(3-氟-苄基）-1H -π引嗤-5-基胺基]-喧峻淋—6-基} -〇比嘻-1-基）-2-經-丙基]-旅唆 -4-醇 249 J〇> 1-(1，1_二氧-六氮_1 λ *6*_°塞喃 -4-基胺基）-3-(3-{4-[1-(3-氟-苄基）-1Η-η引嗤-5-基胺基]-喧·1坐啉-6-基}-吡咯-1-基）-丙-2-醇 250 6 A ^XX^J 1-[1,4’]二哌啶基-Γ-基-3-(3-{4-[1-(3-氟-苄基）-1Η-吲唑 -5-基胺基]-喧°坐淋-6-基}-11比口各 -1-基）-丙-2-醇 251 ^ A ' “^NH ,ίί^τ^Ν 1-環丙基胺基-3-(3-{4-[l-(3-氟-苄基）-1Η-吲唑-5-基胺基]-啥。坐嚇· -6-基丨-0比n各-1-基）-丙 -2-醇 252 ^γ〇^θ^ρ 1-(3-{4-[3-氣-4-(3-氟-苄氧基）-苯胺基]-啥°坐琳-6-基}-0比咯-1-基）-3-(4-環丙基-哌畊-1-基）-丙-2-醇 253 ^s^〇^J^-X.F 2-(3-{4-[3-氣-4-(3-敦-节氧基）-苯胺基]-啥唾琳-6-基}-°比咯-1-基）-1-(4-環丙基曱基-哌哄-1_基）-乙晒 254 HO ν〇^Ν Ν^α> 1-(3-{4-[1-(3-氟-苄基）-1Η-吲〇坐-5-基胺基]-0!：11 坐琳-6-基}-°比咯-1-基）-3-[4-(2-羥乙基）-哌啶-1-基]-丙-2-醇 56 94389 201016683 255 HO 〇 A l-(3-{4-[l-(3-氟-苄基）-lH-吲。坐-5-基胺基]-喧唾琳-6-基}-〇比洛-1-基）-3-[4-(2-經乙基）-口辰哄-1-基]-丙-2-醇 256 HO、 1-(3-{4-[1-(3-氟-节基）-1Η-°引〇坐-5-基胺基]-喧°坐淋-6-基} - °比咯-1-基）-3-[(2-羥乙基）-甲基-胺基]-丙-2-醇 257 6 A 卜（3-{4-[1-(3-氟-节基）-1Η-π引。坐-5-基胺基]-喧唾淋-6-基}-σ比嘻_1_基）-3_派哄-1-基-丙-2-醇 258 ^ Λ 1-(3-{4-[1-(3-氟-节基）-1Η-° 引 °坐-5-基胺基]-喹。坐琳-6-基}-D比洛-1-基）-3-(4-嗎琳-4-基-派咬 -1-基）-丙-2-醇 259 1_(4-胺基-π底咬-1-基）-3-(3-{4-[3-氯-4-(3-氣-节氧基）-苯胺基]-啥嗤琳-6-基}-°比洛-1-基）-丙-2-醇 260 广Owl 1认 2-(3-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-喧嗤嚇_-6-基}-°比咯-1-基M-吡咯烷-1-基-乙酮 261 ^Y〇-^CXF Hf^cl raoi 2-(3-{4-[3-氯-4-(3-氟-节氧基）-苯胺基]-喧°坐琳-6-基}_〇比咯-1-基）-1-吡咯烷-1-基-乙酮 262 HN^>L hnXX：^f HN^ [3-氯-4-(3-氟-节氧基）-苯基] -{6-[5-0底咬-4-基胺基）-111-〇比嘻-3-基]-喧。坐琳-4-基}-胺 263 ^Y〇v-XXF (R)-[3-氯-4-(3-氟-节氧基）-苯基]-[6-(1-環氧丙烷基-2-基甲基-1Η- °比洛-3-基）-嗜唾琳-4-基]-胺 264 1-(3-{4-[3-氣-4-(3-氟-苄氧基）-苯胺基]-啥嗤琳-6-基}-°比嘻 _1_ 基）_3-((3S, 5R)-3, 5-二曱基-哌哄-1-基）-丙-2-醇 57 94389 201016683 265 气、 J〇C。众 2-(3-{4-[3-氣-4-(3-氟-节氧基）-苯胺基]-喧嗤琳-6-基}-〇比嘻-1_基）-1-(4-環丙基-派哄- I-基）-乙酮 266 4-{4-[3-氯-4-(3- 1 -苄氧基）-苯胺基]-喧°坐琳-6-基丨-ΙΗ-11比p各 -2-甲酸（2-二乙胺基-乙基）-醯胺 267 (4-胺基-哌啶-1-基）-(4-{4-[3-氯-4-(3-氟节.氧基）-苯胺基]-啥〇坐淋 _6-基}-lH-nft^ -2-基）-甲酮 268 (3R)-1-[3-(3-{4-[3-氯-4-(3-氟苄氧基）-苯胺基]-噎唑啉-6-基}-吼咯-1-基）-2-羥基-丙基]-吡咯烷-3-醇 269 0 ^γΟ^ζΧρ 、九从α 2-(3-{4-[3-氣-4-(3-說-节氧基）-苯胺基]-喹唑啉_6-基}-«比嘻_1-基）_N_(2_ 0比洛燒_1_基-乙基）-乙醯胺 270 /¾. HN^^CI (3-{4-[3-氯-4-(3-氟-节氧基）-苯胺基]-喧°坐琳-6-基}-°比p各-1-基）-乙腈 271 ^γΟν^ΧΧρ 1-(3-{4-[3-氣-4-(3-氟-苄氧基）-苯胺基]-喹唑啉-6-基}-吡咯-1-基）-3-[(2-羥基-乙基）-甲基-胺基]-丙-2-醇 272 0狐嘗 1-(3-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-喧°坐琳-6-基} -〇比洛-1 -基）-3-(4-嗎淋-4-基-派π定 -1-基）-丙-2-醇 273 ^γ-Ο^ΧΧρ [3-氯-4-(3-敦-节氧基）-苯基] -{6-[ 1-(3-乙基-環氧丙烷-3-基甲基）-1Η-。比洛-3-基]-啥〇坐琳 -4-基}-胺 58 94389 201016683 274 l-(3-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-喹。坐琳-6-基}-°比咯-1-基）-3-((10-3-二甲基胺基 -吡咯烷-1-基）-丙-2-醇 275 ^Y〇N^j〇LF 2-(3-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-唾唾琳-6-基}-π比咯-1-基）-N-(l-環丙基-哌啶-4-基）-乙醯胺 276 α 1-(3-{4-[3-氣—4_(3-敗—节氧基）-苯胺基]-啥嗤淋-6-基}-ϋ比洛—1-基）*~3_(1，1_ 二-1 嗟嗎琳-4-基）-丙-2-醇 277 1-(3-{4-[3-氯-4-(3-敦-节氧基）-苯胺基]-喹唑啉-6-基}-°比咯-1-基）-3-((R)-3-氟-吡咯烷 -1-基）-丙-2-醇 278 1-(3-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-啥嗤琳-6-基}-°比哈-1-基）_3_嗟n坐烧_3_基-丙-2-醇 279 [3-氯-4-( 3-氟-苄氧基）-苯基] _(6_{ 1-[2-(4_ 環丙基-n底口井-1-基）-乙基]-1Η-°比洛-3-基}-啥〇坐琳-4-基）-胺 280 ^Y〇v«j0> 1-[3-(3-{4-[3-氯-4-(3-氟苄氧基）-苯胺基]-喧°坐琳-6-基}-〇比嘻-1-基）_2_經基—丙基]-娘咬 -4-甲醯胺 281 'V A Ns^X5v 1-((3S，5R)-3, 5-二甲基-哌畊 -1-基）-3-(3-{4-[1-(3-氟-苄基）-1Η-π5丨嗤-5-基胺基]-喧°坐琳 -6-基}-吡咯-1-基）-丙-2-醇 282 "s a N^CC> 4-[3-(3-{4-[1-(3-氟-苄基）-1H -°弓丨峻-5-基胺基]-喧嗤琳-6-基}-°比洛-1-基）-2-經基-丙基]-哌畊-1-甲酸乙酯 59 94389 201016683199 η γΌ [1-(3-Fluoro-benzyl)-1Η-indazol-5-yl]-(6-{1-[2-(tetrahydroα-pentan-2-yloxy)-ethyl ]-1Η-pyrrol-3-yl}-quinazoline-4-yl)-amine 200 1-[3-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)- Anilino]-quinazolin-6-yl}-°Pilo-1-yl)-propyl]-〇〇〇定-4-ol 201 (R) l-[3-(3-{4-[ 3-Chloro-4-(3-H-benzyloxy)-anilino]-quinazolin-6-yl}-σpyr-l-yl)-2-yl-propyl]-11 -4-ol 202 A: a group of n^€C> (R)_l-(3-(4-(3-chloro-4_(3-fluoro-p-oxy)phenyl) quinazolin-6-yl) -1Η-吼rol-1-yl)-3-((S)-2-(hydroxyindenyl)pyrrolidin-1-yl)propan-2-ol 203 0 〇Η j〇c. ~α八τ Cl (S)-l-[3-(3-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-anilino]-quinazolin-6-yl}- Pyrrol-1-yl)-2-hydroxy-propyl]-piperidin-4-ol 204 Naoc> (S)-l-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy) ()-anilino]-quinazoline-6-yl}-°haha-1-yl)-3-cyclopropylamino-propan-2-ol 205 Ναο> ' (R)-l-[3 -(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-anilino]-quinazolin-6-yl}-πpyr-1-yl)-2_- Propyl]_4_ via methyl-Becker-4-ol 206-, from (R)-l-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-aniline ]]-quinazolin-6-yl}-pyrrol-1-yl)-3-methoxy-propan-2-ol 207 Q\a Η1χχ: public (S)-l-[l,4' ] Piperidinyl-fluorenyl-3-(3-{4-[3-gas-4-(3-fluoro-oxy)-anilino]-quinazoline-6-yl}-°Bilo_ 1 -yl)_propan-2-ol 51 94389 201016683 208 HO % l-(3-{4-[3-chloro-4-(3-fluoro-p-oxy)-anilino]-indole-6 -基}-°比嘻_1_基)_3-[4_(2-ethylidene)-indole-1-yl]-propan-2-ol 209 Naoc> 1-(3-{4-[ 3-ox-4-(3-a-hydroxy)-anilino]-啥°坐-6-yl}-indole-1-yl)-3-(4-methanesulfonyl-piperidin Plough-1-yl)-propan-2- Alcohol 210 ^Y〇vJ〇If [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-{6-[1-(2-pyridin-2-yl-ethyl)amine 211 . 1-(3-{4-[3_ chloro-4-(3- IL-p-ethoxy)-anilino]-喧β坐琳-6-yl}-indole-1-yl)-3- (1,1-dioxo-hexahydro-1 and *6*-furan-4-ylamino)-propan-2-ol 212 Na〇iN [3-chloro-4-(3-fluoro-benzyloxy) ))-phenyl]-[6-(1-π ratio a-but-2-ylmethyl-1H-0 to n--3-yl)-喧°坐琳-4-yl]-amine 213 0A . . rO jO> F w Nn〇> (R)-l-(3-{4-[l-(3-fluoro-benzyl)-111-1^丨丨-5-ylamino]] Lin-6-yl}-pyrrol-1-yl)-3-morpholin-4-yl-propan-2-ol 214 rO, F <s, (S)-l-(3-{4-[l -(3-fluoro-nodal)-IH-i嗤-5-ylamino]-oxime.Shenlin-6-yl}-11-indol-1-yl-3-indol-4-yl- Propan-2-ol 215 〇rf'^F 〇~fa 2-(3-{4-[3-Gas.-4-(3-Fluoro-ethoxy)-anilino]-啥嗤琳-6- }}-〇比嘻-1-yl)-1-11-end-1-yl-ethanone 216 2-(3-{4-[3- gas-4-(3-fluoro-benzyloxy)- Anilino]-indolyl-6-yl}-indole-1-yl)-indole, fluorene-diethyl-acetamide 217 2-(3-{4-[3-chloro-4-( 3-fluoro-benzyloxy)-anilino]-°Ι: σ-坐-6-yl}-πpyr-1-yl)-indole-cyclopropyl-acetamide 52 94389 201016683 218 cl «CC ^N 4-[(4-{4-[3-Ga-4-(3-Fluorine) -benzyloxy)-anilino]-quinazolin-6-yl}-111-pyrrol-2-ylmethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester 219 Hy human 丨0 1-(3-{4-[3-chloro-4-(3-fluoro-p-oxy)-anilino]_啥°坐琳-6-yl}-° ratior-1- 3-(2-piperidin-1-yl-ethylamino)-propan-2-ol 220. ~ 1-(3-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-anilino]-smell ° sits -6-yl}-〇嘻-1-yl)-3 -(2-methoxy-ethylamino)-propan-2-ol 221 h〇X〇^°^F ιΧ^Ν 1-(3-{4-[3-chloro-4-(3-fluoro- Benzyloxy)-anilino]-啥°坐琳-6-yl}-indole-1-yl)-3-piped-1-yl-propan-2-ol 222 rrB and c^oc0^ H0XJ 4-[3-(3-{4-[3_chloro-4-(3-fluoro-benzyloxy)-anilino]-quinazolin-6-yl}-pyrrol-1-yl)-2-hydroxy -propylamino]-cyclohexanol 223 八/==1 m^^c\ "^ Nacc> HO N {1-[2-(3-{4-[3-chloro-4-(3- Fluoro-p-hydroxy)-anilino]-indolyl β-yl-6-yl}-pyrrol-1-yl)-ethyl]-°pyrrol-2-yl}-methanol 224 ^γΟ^Ο^ρ 0-0^,. [3-Gas-4-(3-fluoro-benzyloxy)-phenyl]-{6-[ 1-(2- σ σ σ-4-yl-ethyl) - 1Η_ιτ比洛-3-yl ]-喧°坐琳-4-yl}-amine 225 2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-anilino]-喧σ sitting -6- -}-p-pyrrol-1-yl)-N-(l,l-dioxo-hexahydro-1 λ *6*-π-propan-4-yl)-ethanoamine 226 ^y〇^XXf / =η HN^^CI [3-Gas-4-(3-Gas-hydroxy)-phenyl]-[6-U-cyclopropylmethyl-1H-pyrrol-3-yl)-喧Salina 4-yl]-amine 53 94389 201016683 227 cl 2-(3-{4-[3-Ga-4-(3-fluoro-benzyloxy)-anilino]-啥. Sitting scared _6-yl} '-〇比嘻-1-yl)-N-[(lr,4r)-(4-里-Cyclohexyl)-acetamide 228 ^y〇^XXf XrVf 2-(3-{4-[3- Chloro-4-(3-f-o-oxy)-anilino]-喧° sitin-6-yl}-0-lolo-1_yl)-1-(4-π-pyrrol-1-yl) -n bottom. -1--1-)-B- 229 [3-chloro-4-(3-fluoro-p-oxy)-phenyl]-{6-[1-(2-cyclopropylamino)- Ethyl) _111_11 毕洛_3-基]-啥°坐琳-4_yl}-amine 230 [3-chloro-4-(3-fluoro-hydroxyl)-phenyl]-[6-(1 -0 比0-4-ylmethyl-1H-0 ratio -3-yl)-anthracene-4-yl]-amine 231 ^Y〇^XXF 2-(3-{4-[3- Chloro-4-(3-fluoro- Oxy))-anilino]-quinazoline-6-yl}-° ratio 11-1-yl)-1^-° bottom bit-4-yl-ethylamine 232 ^Y〇^〇LF HN^ ^a 9 Ναα> (8)-[3-Chloro-4-(3-d-hydroxyl)-phenyl]-[6_(1_ °pyrrol-3-ylmethyl-111-°Bilo -3-yl)-〇|:°坐琳-4-yl]-amine 233 H°^n XX〇J^F "^rc, 2-(3-{4-[3-chloro-4-( 3-fluoro-benzyloxy)-anilino]-喧°坐-6-yl}-°pyr-1-yl)-1 - [4-(2-hydroxyethyl)-piped-1- Ethyl]-ethanone 234 ^Y〇^XXF 1-(3-{4-[3-gas-4-(3-fluoro-oxy)-anilino]-indolyl-6-yl} - 〇 T匕洛_1_yl)-3-(4_πpyrrolidino-p-pyridin-1-yl)-propan-2-ol 235^Y〇^xCXF [3-chloro-4-(3-fluoro*-节oxy)-phenyl]-(6-{1-[2-(1,1-dioxo-hexa-argon-1λ *6-sodium-4-ylamino)-ethyl]-111TM 〇比洛_3-基}_喧喧琳_4_基)-amine 236 ^γΟ^ΧΧρ vo^^i {4-[3-(3-{4-[3-chloro-4-(3- Fluoro-benzyloxy)-anilino]-quinazolin-6-yl}-D-pyrid-1-yl)-2-trans-propyl]-pyridin-1-yl}-cyclopropyl- Ketone 54 94389 201016683 237 like α 1_(3~·{4-[3-chloro-4-(3-fluoro-oxy)-anilino]-quinazoline-6-yl}-° ratio Rol-1-yl)-3-(4-cyclopropylmethyl-pipedino-1-yl)-propan-2-ol 238 raxx> 2-(3-{4-[3-气-4-( 3-fluoro-benzyloxy)-anilino]-喧°Shen-6-yl}-D than 嘻-1-yl)_1-旅哄-1-基-乙嗣239 ^Y〇^〇LF Ν -{1-[3-(3-{4-[3-Gas-4-(3-fluoro-benzyloxy)-anilino]-quinazolin-6-yl}-〇 ratio 11 each-1 - ))-----propyl]- η 唆唆 4- 4- 4- 4- 4- 240 240 240 240 240 240 240 240 240 240 240 240 240 240 240 240 240 240 240 240 240 240 240 240 240 240 240 240 240 240 240 240 240 240 240 240 240 240 240 240 240 240 240 240 240 240 240 240 -{6-[1-(2-Peptin-1-yl-ethyl)-1Η-π is 嘻-3-yl]-啥°坐琳-4-yl}-amine 241 \Λ f〇 L~F ι5ν 1-(3-{4-[1-(3-Fluoro-benzyl)-1Η-吲〇?-5-ylamino]-啥°坐-6-基}-〇比-1-yl)-3-(4-methyl-pipedino-1-yl)-propan-2-ol 242 ΓΛα> 2-(3-{4-[3- gas-4-(3-fluoro- Benzyloxy)-anilino]-quinazolin-6-yl}-D-pyrrol-1-yl)-l-((3S,5R)-3, 5-dimethyl-piped-1-yl )-Ethylketone 243 N〇, "TO {_6-[1-(2-Azepan-1-yl-ethyl)-1Η-° ratio 11 -3-yl]-啥嗤琳-4 -yl}_[3_chloro-4-(3-fluoro-p-hydroxyphenyl)-amine 244 hXC^ 2-(3-{4-[3-chloro-4-(3-fluoro-oxygen). ))-anilino]-喧嗤琳-6-yl}- °Byr-1-yl)-N-(4-hydroxy-1,1-dioxo-hexanitro-1 λ *6*-嗟D South_4_ylmethyl)-acetamide 245 ^Y〇 V^CXF 1-(3-{4-[3_ chloro-4-(3- gas-hydroxy)-anilino]-啥°坐琳-6-yl}-〇比咯-1-yl)- 3-(2-oxasulfonyl-ethoxy)-propan-2-ol 55 94389 201016683 246 Ία production: and N-{l-[2-(3-{4-[3-gas-4-( 3-fluoro-benzyloxy)-anilino]-quinazolin-6-yl}-pyrrol-1-yl)-ethenyl]-piperidin-4-yl}-acetamide 247 (^^- (^-{斗-^-Chloro-bucket-^-morphology-oxyloxy)-anilino]-quinazoline-6-ylindole αBilo-1 -yl)-3_ [(R)-2- °比嘻炫>-1-ylmercapto-pyrrolidin-1-yl]-propan-2-ol 248 6 A 1-[3-(3-{4-[1-(3-fluoro-benzyl) -1H -π嗤嗤-5-ylamino]-喧峻淋-6-yl}-〇比嘻-1-yl)-2-per-propyl]-旅唆-4-ol 249 J〇&gt ; 1-(1,1_dioxy-hexanitro-1 λ *6*_°Sep-4-ylamino)-3-(3-{4-[1-(3-fluoro-benzyl) -1Η-η引嗤-5-ylamino]-喧·1 sitosporin-6-yl}-pyrrol-1-yl)-propan-2-ol 250 6 A ^XX^J 1-[1,4 ']Dipiperidinyl-fluorenyl-3-(3-{4-[1-(3-fluoro-benzyl)-1Η-indazol-5-ylamino]-喧° sitting--6- Base}-11 than each mouth - 1-yl)-propan-2-ol 251 ^ A ' "^NH , ίί^τ^Ν 1-cyclopropylamino-3-(3-{4-[l-(3-fluoro-benzyl) -1Η-indazole-5-ylamino]-oxime. Sit and -6-based 丨-0 to n-1-yl)-propan-2-ol 252 ^γ〇^θ^ρ 1-(3-{4-[3-气-4-(3- Fluoro-benzyloxy)-anilino]-啥°坐琳-6-yl}-0-pyrrol-1-yl)-3-(4-cyclopropyl-piped-1-yl)-propane-2 -Alcohol 253 ^s^〇^J^-XF 2-(3-{4-[3-Ga-4-(3-D--oxy)-anilino]-啥琳琳 -6-6-} °Byr-1-yl)-1-(4-cyclopropyldecyl-piperidin-1-yl)-ethyl 254 HO ν〇^Ν Ν^α> 1-(3-{4-[1 -(3-fluoro-benzyl)-1Η-吲〇 sitting-5-ylamino]-0!:11 坐琳-6-yl}-°pyr-1-yl)-3-[4-( 2-Hydroxyethyl)-piperidin-1-yl]-propan-2-ol 56 94389 201016683 255 HO 〇A l-(3-{4-[l-(3-Fluoro-benzyl)-lH-吲Sodium-5-ylamino]-喧琳 -6 -6-yl}-dehydrazol-1-yl)-3-[4-(2-ethyl)- phenazine-1-yl]- Prop-2-propanol 256 HO, 1-(3-{4-[1-(3-fluoro-)]-1Η-°〇〇-5-ylamino]-喧°坐-6-based } - °Byr-1-yl)-3-[(2-hydroxyethyl)-methyl-amino]-propan-2-ol 257 6 A Bu (3-{4-[1-(3- Fluorine-nodal group-1 Η-π 引. Sodium-5-ylamino]-喧淋 -6-6-} σ 嘻 _ _ _ _ _ _ _ _ - alcohol 258 ^ Λ 1-(3-{4-[1-(3-fluoro-section) Base) -1Η-° 引 °-5-ylamino]-quino. 坐琳-6-yl}-D-l-l-yl)-3-(4-morphin-4-yl-bite -1-yl)-propan-2-ol 259 1_(4-amino-π-bottom-1-yl)-3-(3-{4-[3-chloro-4-(3-gas-oxygen) ))-anilino]-啥嗤琳-6-yl}-°Pilo-1-yl)-propan-2-ol 260 broad Owl 1 recognize 2-(3-{4-[3-chloro-4- (3-fluoro-benzyloxy)-anilino]-indole -6-yl}-pyrrol-1-yl-M-pyrrolidin-1-yl-ethanone 261 ^Y〇-^CXF Hf ^cl raoi 2-(3-{4-[3-chloro-4-(3-fluoro-hydroxy)-anilino]-喧°坐琳-6-yl}_〇比r-1-yl) 1-pyrrolidin-1-yl-ethanone 262 HN^>L hnXX:^f HN^ [3-chloro-4-(3-fluoro-p-oxy)-phenyl] -{6-[5 -0 Bottom-4-ylamino)-111-indenyl-3-yl]-oxime.琳琳-4-yl}-amine 263 ^Y〇v-XXF (R)-[3-chloro-4-(3-fluoro-p-ethoxy)-phenyl]-[6-(1-epoxypropane Benzyl-2-ylmethyl-1Η-°Pilo-3-yl)-sinoyl-4-yl]-amine 264 1-(3-{4-[3- gas-4-(3-fluoro- Benzyloxy)-anilino]-indolyl-6-yl}-°~嘻_1_yl)_3-((3S, 5R)-3, 5-dimercapto-piperidin-1-yl)- Propan-2-ol 57 94389 201016683 265 gas, J〇C. 2-(3-{4-[3-Ga-4-(3-fluoro-oxy)-anilino]-indolyl-6-yl}-indenyl-1-yl)-1- (4-cyclopropyl-pyrene-I-yl)-ethanone 266 4-{4-[3-chloro-4-(3- 1 -benzyloxy)-anilino]-喧°坐琳-6 -Based-ΙΗ-11 ratio p--2-carboxylic acid (2-diethylamino-ethyl)-decylamine 267 (4-amino-piperidin-1-yl)-(4-{4-[ 3-Chloro-4-(3-fluoro.oxy)-anilino]-anthraquinone_6-yl}-lH-nft^-2-yl)-methanone 268 (3R)-1-[ 3-(3-{4-[3-Chloro-4-(3-fluorobenzyloxy)-anilino]-oxazoline-6-yl}-pyrrol-1-yl)-2-hydroxy-propyl ]]-pyrrolidin-3-ol 269 0 ^γΟ^ζΧρ, nine from α 2-(3-{4-[3-gas-4-(3-sayo-oxy)-anilino]-quinazoline Porphyrin_6-yl}-«比嘻_1-yl)_N_(2_0 比洛烧_1_yl-ethyl)-acetamide 270 /3⁄4. HN^^CI (3-{4-[3 -chloro-4-(3-fluoro-p-hydroxy)-anilino]-喧°坐琳-6-yl}-° ratio p-1-yl)-acetonitrile 271 ^γΟν^ΧΧρ 1-(3- {4-[3-Gas-4-(3-fluoro-benzyloxy)-anilino]-quinazolin-6-yl}-pyrrol-1-yl)-3-[(2-hydroxy-ethyl) )-Methyl-amino]-propan-2-ol 272 0 fox taste 1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-anilino]-oxime °坐琳-6-yl} - indolo-1 -yl)-3-(4-oxalin-4-yl-pyridin-1-yl)-propan-2-ol 273 ^γ-Ο^ ΧΧρ [3-Chloro-4-(3-d-hydroxyl)-phenyl]-{6-[ 1-(3-ethyl-epoxypropan-3-ylmethyl)-1Η-. Bilo-3-yl]-indole-4-yl}-amine 58 94389 201016683 274 l-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-anilinoyl ]-quino.Shen Lin-6-yl}-°pyrrol-1-yl)-3-((10-3-dimethylamino-pyrrolidin-1-yl)-propan-2-ol 275 ^ Y〇N^j〇LF 2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-anilino]-salivaline-6-yl}-π-pyrrole-1 -yl)-N-(l-cyclopropyl-piperidin-4-yl)-acetamide 276 α 1-(3-{4-[3- gas-4_(3-fail-oxyl)- Anilino]-indole-6-yl}-dehydrazol-1-yl)*~3_(1,1_di-1 嗟琳 -4--4-yl)-propan-2-ol 277 1-(3 -{4-[3-Chloro-4-(3-d-n-hydroxy)-anilino]-quinazolin-6-yl}-°pyrrol-1-yl)-3-((R)- 3-fluoro-pyrrolidin-1-yl)-propan-2-ol 278 1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-anilino]-啥嗤琳-6-yl}-°biha-1-yl)_3_嗟n sits _3_yl-propan-2-ol 279 [3-chloro-4-(3-fluoro-benzyloxy)-phenyl ] _(6_{ 1-[2-(4_cyclopropyl-n-bottom-1-yl)-ethyl]-1Η-°Bilo-3-yl}-啥〇坐琳-4-yl) -amine 280 ^Y〇v«j0> 1-[3-(3-{4-[3-chloro-4-(3-fluorobenzyloxy)-anilino]-喧°坐琳-6-yl} -〇比嘻-1- )_2_Phenyl-propyl]- Ninjabita-4-carboxamide 281 'VA Ns^X5v 1-((3S,5R)-3, 5-dimethyl-piped-1-yl)-3 -(3-{4-[1-(3-fluoro-benzyl)-1Η-π5丨嗤-5-ylamino]-喧°坐琳-6-yl}-pyrrol-1-yl)-propyl -2-ol 282 "sa N^CC> 4-[3-(3-{4-[1-(3-Fluoro-benzyl)-1H-°丨丨峻-5-ylamino]-喧嗤琳-6-基}-°Bilo-1-yl)-2-yl-propyl]-piperidine-1-carboxylic acid ethyl ester 59 94389 201016683

283 ιΟφ1 l-(3-{4_[ 1-(3-敗-节基）-1Η-α 引〇坐-5-基胺基]-喧°坐來-6-基}-°比嘻_1_基）-3-(2-甲氧基-乙胺基）-丙-2-醇 284 ί A . \〇η j〇Cn N-{(3R)-l-[3-(3-{4-[l-(3-氟-苄基）-1Η-吲唑-5-基胺基]-喹唑琳-6-基}-π比B各-1-基）-2-經基-丙基]-吡咯烷-3-基}-乙醢胺 285 1_(3-{4-[1-(3-敗-节基）-1H_0 引 °坐-5-基胺基]-喧°坐琳-6-基}-°比嘻-1-基）_3-[1，2, 3]三嗤-1-基-丙-2-醇 286 O' ^XIF 、NH 1-(3-{4-[1-(3-氟-苄基）-1Η-吲〇坐-5-基胺基]-喧。坐琳-6-基}-°比咯-1-基）-3-(2-嗎啉-4-基-乙胺基）-丙-2~醇 287 [1-(3-氟-苄基）-1Η-吲唑-5-基] -{6-[1-(3-嗎啉-4-基-丙基）-1Η -〇比嘻-3-基]-喧峻琳-4-基}-胺 288 ^γ.〇ΝχζΧρ ·.。默^5、α 4-[3-(3-{4-[3-氯-4-(3- IL 节氧基）-苯胺基]-喧嗤琳-6-基} -〇比洛-1-基）-2-經'基-丙基]底哄 -2-酿I 289 ^Y〇v^XF {6-[5-(4-胺基-哌啶-1-基甲基） -111-°比洛-3-基]-啥峻琳-4-基} _[3-氯-4-(3-敗-节氧基）-苯基] -胺 290 ^γ〇^ΧΧΡ ? /=^ HN^^CI 0人〇^ 2-(3-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-喧唾琳-6-基}-0比咯-1-基）-1-噻唑烷-3-基-乙酮 291 、°ϊ。 ΠΓ。^^ 1-[3-(3-{4-[3-氯-4-(3-氟苄氧基苯胺基卜喧°坐琳-6-基}-°比洛-1-基）-2-經基-丙基]-n底咬 -3-甲酸乙酯 292 9 /==1 H(；r*^人 Cl 〇P Nacc> 2-(3-{4-[3-氯·~4-(3-氣-节氧基）-苯胺基]-啥嗤琳-6-基}-π比洛 _1_)_1_(1，1_ 二氧 _1 λ*6*_0塞嗎啉-4-基）-乙酮 60 94389 201016683 293 O〇 Ναα> 2-(3-{4-[3-氯-4-(3-貌-苄氧基苯胺基]-喧1^淋-6-基}-11比洛-1-基）-1-( 4-嗎淋-4-基-旅唆 -卜基）-乙酮I 294 A 〇0NH hnj〇> [1-(3-氟-苄基）-1Η-吲唑-5-基] -[6-(1-嗎啉-2-基曱基-1H-吡咯 -3-基）-啥°坐琳-4-基]-胺 295 ^Y〇^CXF 一 y〇 °oiN 0 1-.[2-(3-{4-[3- 氯-4-(3-貌节氧基）-苯胺基]-喧峻琳_6-基} -D比咯-1-基）-乙醯基]-哌啶-4-甲酸乙酯 296 ^y〇^CXf 9 /=¾. HN^^a -γ〇 Να€φ 0 1-[ 2-(3-{4-[3-氯-4-(3-氟节氧基）-苯胺基]-啥。坐淋-6-基}_〇比咯-1-基）-乙醯基]-哌啶-4-甲醯胺 297 N-{(3R)-l-[3-(3-{4-[氯-4-(3-氟节氧基）-苯胺基]-啥唾琳_6-基1}-吡咯-1-基）-2-羥基-丙基] -吡咯烷-3-基}-甲醯胺 298 1-[3-(3-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-喹唑啉-6-基}-吡咯-1-墓）-2-羥基丙基]-哌啶 -4-甲酸乙酯 299 P A 1_(3-{4-[ 1-(3-氣节基）-1Η- π5| 〇坐-5-基胺基]-喧°坐琳-6-基}-〇比咯-1-基）-3-(4-吡啶-4-基甲基-哌畊-1-基）-丙-2-醇 300 Ϋ A 1_(3-{4-[1-(3-氟节基）-lEh D引〇坐-5-基胺基]-唾唾琳-6-基}-°比咯-1-基）-3-(4-吡啶-3-基甲基-哌啡-1-基）-丙-2-醇 301 A (S)-l-二乙胺基-3-(3-{4-[1-(3-氟-苄基）-1Η-吲唑-5-基胺基]-嗤唾淋-6-基}-D比B各-1-基）-丙-2-醇 302 A ^€C> 1-二乙胺基-3-(3-{4-[l-(3-氟苄基）-1Η-π5丨σ坐-5-基胺基]-喧。坐啉-6-基}-吡咯-1-基）-丙-2-醇 61 94389 201016683 303 /=¾ HN^^CI [3-氯-4-(3-氟节氧基）-笨基] -{6-[l-(2-甲胺基-乙基）-1Η-"比 p各-3-基]-°|：π坐1#-4-基}-胺 304 ^ A 。七 (6-{1-[4-(2-二乙胺基-乙基）-嗎琳-2-基曱基]-1Η- η比洛-3_ 基}-喹唑啉-4-基）-[1-(3-氟-苄基）-1Η-β引唾-5-基]-胺 305 〈。H hnQ, X^CI (4-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-喹唑啉-6-基}-1Η-吡咯 -2-基）-甲醇 306 H〇^ /=, ηνΛ^.0Ι 2-(3-{4-[3-氯-4-(3-氟-节氧基苯胺基]-啥°坐淋-6-基}-°比咯-1-基）-乙醇 307 K ^,〇jCXf w。’ (R)-2-(3-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-喹吐琳-6-基}-吡咯-1-基）-1-(3-二甲棊胺基-吡咯烷-1-基）-乙酮、 308 O^L ^γοΛρ ν〇^ (R)-N-{l-[2-(3-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-喹唑啉 -6-基}-吡咯-1-基）-乙醯基]-吡洛烧-3-基}-乙酿胺 309 ° Να€φ 1-(3-胺基-哌啶-1-基）-2-(3-{4-[3-氯-4-(3-氟-苄氧基）-苯基胺基]-喹°坐琳-6-基}-°比17各-1-基）-乙酮 310 Cs A C^nr0^" 1-(3-氟-苄基）-1Η-吲唑-5-基] -(6-{1-[4-(2-嗎啉-4-基-乙基） -嗎淋-2-基甲基]-1H-d比4-3-基}-喧。坐淋-4-基）-胺 311 〇4,〇 N^C0 [1-(3-氟-苄基）-1Η-吲唑-5-基] -{6-[ 1-(4-甲磺醯基-嗎啉-2-基甲基）-1Η_0比洛-3-基]-啥0坐淋 -4-基}-胺 312 °'f° 从 n „ h?x^'n 。七 [1-(3-氟-苄基）-1Η-吲唑-5-基] -(6-{1-[4-(2-甲磺醯基-乙基）-嗎啉-2-基甲基]-1H-吡咯-3-基} -啥唾淋-4-基）-胺 62 94389 201016683 313 \ A [1-(3-氟-苄基）-ιη-吲唑-5-基] -(6-{1-[4-(3-曱氧基-丙基）-嗎淋_2_基甲基]-1 Η- η比洛-3-基}-喹唑琳-4-基）-胺 314 〇 /=! 2-[2-(3-{4-[1-(3-氟-苄基）-lH -吲唑-5-基胺基]-喹唑啉-6-基} -吡咯-1-基甲基）-嗎啉-4-基]-乙醇附註：「哌畊」（piperazine)，為依國立編譯館的翻譯名詞所譯’此名稱另有譯為「哌嗪」的情形。其中，所述的鹽為上述化合物與選自以下的酸形成的鹽：蘋果酸、乳酸、馬來酸、鹽酸、甲續酸、對甲苯礦酸、 ©硫酸、磷酸、檸檬酸、酒石酸、乙酸或三氟乙酸。在本發明的另一個方面是一種藥物組合物，含有通式 (I)、（II)或（III)所示的化合物、其鹽或其前藥和藥學上可以接受的載體或賦形劑。在本發明的另一個方面是蛋白激酶催化活性的調節方法，包括使蛋白激酶與通式⑴、（⑴或（1⑴的化合物或 π接觸此蛋白激酶係選自受體酪胺酸激酶、非受體酪胺 ❾酸激酶和絲胺酸-蘇胺酸激酶。人从在本發明的另一個方面是通式⑴、（11)或⑴的化口物或鹽的製備方法，包括以下步驟：通式（I)化合物的製備方法，該方法包括以驟： (1) 94389 63 201016683283 ιΟφ1 l-(3-{4_[ 1-(3-Fail-knot)-1Η-α 〇 -5-5-ylamino]-喧° sit -6-based}-°比嘻_1 _))-3-(2-methoxy-ethylamino)-propan-2-ol 284 ί A . \〇η j〇Cn N-{(3R)-l-[3-(3-{4 -[l-(3-fluoro-benzyl)-1Η-oxazol-5-ylamino]-quinazoline-6-yl}-π ratio B-1-yl)-2-yl-propyl-propyl ]]-pyrrolidin-3-yl}-acetamidamine 285 1_(3-{4-[1-(3-)-phenyl]-1H_0 引 °-5-ylamino]-喧°坐琳-6-yl}-° ratio 嘻-1-yl)_3-[1,2,3]triter-1-yl-propan-2-ol 286 O' ^XIF , NH 1-(3-{4- [1-(3-Fluoro-benzyl)-1Η-吲〇?-5-ylamino]-oxime. Isolate-6-yl}-°pyr-1-yl)-3-(2-? Phenyl-4-yl-ethylamino)-propan-2-alcohol 287 [1-(3-fluoro-benzyl)-1Η-indazol-5-yl]-{6-[1-(3-morpholine) -4-yl-propyl)-1Η-〇比嘻-3-yl]-喧君琳-4-yl}-amine 288 ^γ.〇ΝχζΧρ ·.默^5,α 4-[3-(3-{4-[3-chloro-4-(3- IL-oxy)-anilino]-indolyl-6-yl}-indolebi-1 -yl)-2-yl-yl-propyl] underpin-2-broth I 289 ^Y〇v^XF {6-[5-(4-amino-piperidin-1-ylmethyl)-111 -°Bilo-3-yl]-啥峻琳-4-yl} _[3-chloro-4-(3-failino)-phenyl]-amine 290 ^γ〇^ΧΧΡ ? /= ^ HN^^CI 0人〇^ 2-(3-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-anilino]-喧喧琳-6-yl}-0 ratio -1-yl)-1-thiazolidin-3-yl-ethanone 291, °ϊ. Hey. ^^ 1-[3-(3-{4-[3-Chloro-4-(3-fluorobenzyloxyanilinyl) 坐°坐琳-6-yl}-°Pilo-1-yl)-2 -Phenyl-propyl]-n bottom bite 3-carboxylic acid ethyl ester 292 9 /==1 H(;r*^人Cl 〇P Nacc> 2-(3-{4-[3-chloro·~4 -(3-gaso-oxy)-anilino]-啥嗤琳-6-yl}-πBilo_1_)_1_(1,1_dioxo_1 λ*6*_0塞morpholine-4- Ethyl)-ethanone 60 94389 201016683 293 O〇Ναα> 2-(3-{4-[3-chloro-4-(3-pheno-benzyloxyanilino)-喧1^---6-yl}- 11-l-l-yl)-1-(4-oxalin-4-yl-tv-bu-ki)-ethanone I 294 A 〇0NH hnj〇> [1-(3-fluoro-benzyl) -1Η-oxazol-5-yl]-[6-(1-morpholin-2-ylindenyl-1H-pyrrol-3-yl)-啥°坐琳-4-yl]-amine 295 ^Y〇 ^CXF 一 y〇°oiN 0 1-.[2-(3-{4-[3- chloro-4-(3-phenoxy)-anilino]-喧君琳_6-yl} -D Ethyl pyrrol-1-yl)-ethenyl]-piperidine-4-carboxylate 296 ^y〇^CXf 9 /=3⁄4. HN^^a -γ〇Να€φ 0 1-[ 2-(3 -{4-[3-Chloro-4-(3-fluorooxy)-anilino]-oxime. Sodium-6-yl}-indole-1-yl)-ethinyl]-piperidine -4-carbamamine 297 N-{(3R)-l-[3-(3-{4-[chloro-4-(3-fluoro-oxy)-anilino]-啥啥_6-yl 1}-pyrrol-1-yl)-2-hydroxy-propyl]-pyrrolidin-3-yl}-formamide 298 1-[3-(3-{4-[3-chloro-4 -(3-Fluoro-benzyloxy)-anilino]-quinazolin-6-yl}-pyrrole-1-tomb)-2-hydroxypropyl]-piperidine-4-carboxylic acid ethyl ester 299 PA 1_( 3-{4-[ 1-(3-气气基)-1Η- π5| 〇-5-ylamino]-喧°坐琳-6-yl}-〇比咯-1-yl)-3 -(4-Pyridin-4-ylmethyl-pipedino-1-yl)-propan-2-ol 300 Ϋ A 1_(3-{4-[1-(3-Fluoro)-lEh D 〇 Sodium-5-ylamino]-salivaline-6-yl}-pyrrol-1-yl)-3-(4-pyridin-3-ylmethyl-piperidin-1-yl)-propanoid 2-Alcohol 301 A (S)-l-Diethylamino-3-(3-{4-[1-(3-fluoro-benzyl)-1Η-indazol-5-ylamino]-嗤嗤淋-6-yl}-D ratio B-1-yl)-propan-2-ol 302 A ^€C> 1-diethylamino-3-(3-{4-[l-(3-fluoro Benzyl)-1Η-π5丨σ sit-5-ylamino]-oxime. Seroton-6-yl}-pyrrol-1-yl)-propan-2-ol 61 94389 201016683 303 /=3⁄4 HN^^CI [3-Chloro-4-(3-fluoro-oxy)-styl] -{6-[l-(2-Methylamino-ethyl)-1Η-" than p)-3-yl]-°|: π sits 1#-4-yl}-amine 304^A. Hexa(6-{1-[4-(2-diethylamino-ethyl)-morphin-2-ylindenyl]-1Η- ηpiro-3_yl}-quinazolin-4-yl) -[1-(3-Fluoro-benzyl)-1Η-β-indol-5-yl]-amine 305 <. H hnQ, X^CI (4-{4-[3-chloro-4-(3-fluoro-benzyloxy)-anilino]-quinazolin-6-yl}-1Η-pyrrol-2-yl) -methanol 306 H〇^ /=, ηνΛ^.0Ι 2-(3-{4-[3-chloro-4-(3-fluoro-p-phenylanilide)-啥°坐-6-基}- °Byr-1-yl)-ethanol 307 K ^, 〇jCXf w. '(R)-2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-anilino ]-quinaline-6-yl}-pyrrol-1-yl)-1-(3-dimethylamido-pyrrolidin-1-yl)-ethanone, 308 O^L ^γοΛρ ν〇^ ( R)-N-{l-[2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-anilino]-quinazolin-6-yl}-pyrrole-1 -yl)-ethinyl]-pyrrolidin-3-yl}-ethylamine 309 ° Να€φ 1-(3-amino-piperidin-1-yl)-2-(3-{4- [3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quino-sodium-6-yl}-° ratio 17-1-yl)-ethanone 310 Cs AC^nr0 ^" 1-(3-Fluoro-benzyl)-1Η-indazol-5-yl]-(6-{1-[4-(2-morpholin-4-yl-ethyl)-Lin- 2-ylmethyl]-1H-d is more than 4-3-yl}-oxime. Sodium-4-yl)-amine 311 〇4, 〇N^C0 [1-(3-fluoro-benzyl)-1Η -carbazol-5-yl]-{6-[ 1-(4-methanesulfonyl-morpholin-2-ylmethyl)-1Η_0bilo-3-yl]-啥0 sit-4-yl }-amine 312 °'f° From n „ h?x^'n. Hepta[1-(3-fluoro-benzyl)-1Η-indazol-5-yl]-(6-{1-[4-(2-methylsulfonyl)- Ethyl)-morpholin-2-ylmethyl]-1H-pyrrol-3-yl}-indolyl-4-yl)-amine 62 94389 201016683 313 \ A [1-(3-Fluoro-benzyl) -ιη-carbazole-5-yl]-(6-{1-[4-(3-oximeoxy-propyl)-oxalin-2-ylmethyl]-1 Η-η比洛-3- 2-[2-(3-{4-[1-(3-Fluoro-benzyl)-lH-indazol-5-ylamine) ]]-quinazolin-6-yl}-pyrrol-1-ylmethyl)-morpholin-4-yl]-ethanol Note: "piperazine" (piperazine), translated by the translation terminology of the National Library 'This name is otherwise translated as "piperazine". Among them, the salt is a salt of the above compound and an acid selected from the group consisting of malic acid, lactic acid, maleic acid, hydrochloric acid, methyl acid, p-toluene Mineral acid, © sulfuric acid, phosphoric acid, citric acid, tartaric acid, acetic acid or trifluoroacetic acid. In another aspect of the invention, a pharmaceutical composition comprising a compound of the formula (I), (II) or (III), a salt thereof or a prodrug thereof, and a pharmaceutically acceptable carrier or excipient. In another aspect of the invention, a method for modulating the catalytic activity of a protein kinase comprises contacting a protein kinase with a compound of the formula (1), (1) or (1(1) or π, wherein the protein kinase is selected from the group consisting of a receptor tyrosine kinase, A tyrosine citrate kinase and a serine-threonine kinase. A method for preparing a hydration or salt of the formula (1), (11) or (1) in another aspect of the invention, comprising the steps of: A process for the preparation of a compound of formula (I), which comprises the steps of: (1) 94389 63 201016683

nhr6r7Nhr6r7

iBX, OMSOiBX, OMSO

HOHO

00

(lc) e (2)(lc) e (2)

nhrV ,NaBH(OAc)3nhrV , NaBH(OAc)3

(Id) R\(Id) R\

64 94389 (3) 20101668364 94389 (3) 201016683

(4)(4)

(5)(5)

一種通式（I I)化合物的製備方法，該方法包括以下步A method for preparing a compound of the formula (I I ), the method comprising the following steps

201016683201016683

-種通式un)化合物的製備方法，該方法包括驟： ’- A process for the preparation of a compound of the formula un), the process comprising:

❹發明的詳細説明下列用在說明書和權利要求書中的除非有相反陳述，術每具有下述含義。 ‘‘燒基”指飽和的脂族煙取代基，包括1至20個碳/ ^的直鏈和支鏈取代基。較佳含有丨至ig個碳原子_ 二三甲基、乙基、丙基〜基、正丁基、異丁基 ^ 、戊基等。更佳的是含有ι至4個碳原子的低& 烧基，例如甲基、乙基、丙基、2_丙基、正丁基、異丁違 94389 66 201016683 ^三°㈣可以是取代的或未取代的，當被取代取代基較佳為-個或多個，獨立地選㈣素、三纽 .^ ^ ^ 乳悉方基、方氧基、雜芳基、雜環烷基、雜方基、雜環燒氧基、氰基、硝基、-c(=0)R6、 -c(=〇)Nm(CH2)nNK6R7、—nc(=〇)r6r7 或 _s⑽6。 ¥烧基指3至8員全碳單環、全碳5員/6員或6 =貝^合環或多環稠合環（“稠合，，環系意味著系統中其母固％與體系中的其他環共用此鄰的一對碳原子）取代瘺一柄其中一個或多個環可以含有-個或多個雙鍵，但沒有 ❹:個^具有完全餘的以子純。㈣基的實例有環丙二：丁基、環戊基、環戊埽、環己烧、環己二稀、金剛 =%庚燒、#庚三料。環絲可以是取代或未取代的，二取代時’取代基較佳為—個或多個’獨立地選自低級基/素、三齒院基、輕基、低級燒氧基·、經炫基、芳 -二、方氧基、雜芳基、雜魏基、雜環燒氧基、氰基、硝 '-C(=〇)r ^-C(=〇)〇Re > -C(=0)NR6R^ -(CH0nNR6R^ 睿一 nc(=0)R6R7 或-S〇2R6。、婦基扎由至少兩個碳原子和至少一個碳_碳雙鍵其成的如上述定義的燒基。代表性實例包括但不限於乙稀二曰1丙烯基、2-丙缔基、卜，2_或3_丁婦基等。稀基可取代的或未取代的，#被取代時，取代基較佳為一個獨立地選自為自素、三i炫基、經基、低級烧氧二f基、芳氧基、雜芳基、雜環烧基、雜芳基、雜環烧 ^氰基、硝基、雜環烷氧基、氰基、硝基、-C(=〇)R6、 94389 67 201016683 ~(CH2)nNR6R7 -NC(=0)R6R7 ^ -CC=0)0R6 , -C(=〇)NR6R7 _S〇2R6。、炔基”指至少兩個碳原子和至少一個碳-碳三鍵組成的如上所定義的烷基。代表性實例包括但不限於乙炔基:1-丙炔基、2_丙炔基、卜，2_或3_丁炔基等。炔基可以疋取代的或未取代的，當被取代時，取代基較佳為一個或多H獨立地選㈣素、三㈣基、經基、低級燒氧基、芳基、芳氧基、雜芳基、雜環貌基、雜芳基、雜環烧基、雜環烷氧基、氰基、硝基、-c(=0)r6、_C(=0)0R6、_c(一0) ® NR6R7，-(CHOnNRY . -NC(=〇)R^^_S〇2R6 〇 “芳基’’指具有至少一個芳環結構的取代基，即且有共軛的π電子體系的芳環，包括碳環芳基、雜芳基和聯芳基。块基可以是取代的或絲代的，當被取代_，取代基較佳為.一個或多個’獨立地選自鹵素、.三齒烷基、羥基：硝基、氰基、I級烧氧基、㈣基、院基、雜芳基、雜環烷基、羧基、羧酸酯、雜環烷氧基、氰基、硝基、_C(=0)R6、 ❹ -C(=0)〇R6 . -C(=0)NRV > -(GHOnNRV > -NC(=〇)rV ,1 -S〇2R6。“雜芳基’，指具有]至3個雜原子作為環原子，其餘的環原子為碳的芳基，雜原子包括氧、硫和氮。所述環可以S 5 S或6員環。雜環芳基取代基的實例包括咬喃基、嘆吩基、吼咬基"比略、N_院基〇比口各基”密咬基"比哄基（pyrazine，為依國立編譯館的翻譯名詞所譯，^名稱另有譯為「㈣」的情形）ϋ基等。雜芳基可以是取的或未取代的’當被取代時，取代基較佳為—個或=個， 94389 68 201016683 獨立地選自函素、三輕基、經基、、氰基、低級院氧，、經烷基、烷基、芳基、雜環烷基、羧基、羧酸酯、雜 6環烷氧基、氰基、硝基、—C(=〇)r6、_c(=〇)〇r6、_c(=〇) NRR、-(CH2)nNR6R7、-NC(=〇)R6R74_s〇2R6。“雜環烷基” 指單環或稠環取代基，在環中，具有5至9個環原子，α 中一個或兩個環原子係選自氮、氧或s(〇)n(其中η是整數 0至2)的雜原子’其餘環原子為碳。這些環還可以具有一個或多個雙鍵。不過’這些環不具有完全共軛的、電子系統未取代的雜環炫基包括但不限.比洛烧基、旅咬子基、 © σ并:*馬琳基、硫代嗎琳基、高派哄其等、雜環燒基 .可以疋取代的或未取代的。块基可以是取代的或未取代、田被取代時，取代基較佳為一個或多個，獨立地選自齒素、低級燒基、經燒基、三齒燒基、經基、芳基、芳氧基、雜環燒基、、㈣酯、氰基、確基、㈣或-s 祕Ci=〇)〇R6、-C(=〇)NR6R7、—（CH2)nNR6R7、-NC(=0) φ 經基指-0Η取代基。矣_院氧基”指—〇_(炫基）和(未取代的環燒基）。代表性實例包括但不限於甲氧基、環丙氧基、環丁氧其、产（备其乳丞丁氧基以m“基戍氧基、％已氧基等。燒氧基可或Γ個^未取代的’當被取代時’取代基較佳為一個級烧氧基、4選自為烧基、齒素、三齒烧基、經基、低雜環烷、方減、雜芳基、雜觀基、雜芳基、雜衣虎基、氰基、石肖基、_C(=0)R6、_c(=〇)〇r6、一c(=〇)nr6r7、 94389 69 201016683 -(CH2)nNR6R7、-NC(=0)R6R7 或-S〇2R6。 “芳氧基”指-0-芳基和-0-雜芳基，芳基和雜芳基定義同上。代表性實例包括但不限於苯氧基、吡啶氧基、咬喃氧基、噻吩氧基、嘧啶氧基、吡哄氧基等及其衍生物。节基指-CH2-(芳基）。'. 鹵素”指氟、氯、溴或缺’較佳氟或氣。鹵代烧基，指院基被鹵素取代。代表性實例包括但 0 不限於三氟甲基、三溴曱基等經烧基”指烧基被經基取代。 © 胺烧基指烧基被胺基取代。 • 鹵代院氧基”指-〇-(鹵代烧基）。代表性實例包括但不限於三氟甲氧基、三溴甲氧基等。 ‘‘雜環烷氧基”指-〇-(雜環烷基）^ “鹵代苄基”指-CH2-(鹵代芳基）。 “三氟甲基，，指-cf3。确基指_N〇2。DETAILED DESCRIPTION OF THE INVENTION The following is used in the specification and claims, unless otherwise stated. ''Acrylate'' refers to a saturated aliphatic cigarette substituent comprising from 1 to 20 carbon/^ of straight and branched chain substituents. It preferably contains from ig to ig carbon atoms _ ditrimethyl, ethyl, propyl a group of a base, a n-butyl group, an isobutyl group, a pentyl group, etc. More preferably a lower & alkyl group having from 1 to 4 carbon atoms, such as a methyl group, an ethyl group, a propyl group, a 2-propyl group, n-Butyl, isobutylidene 94389 66 201016683 ^Three (4) may be substituted or unsubstituted, when the substituted substituent is preferably one or more, independently selected (tetra), three New Zealand. ^ ^ ^ milk Alkenyl, aryloxy, heteroaryl, heterocycloalkyl, heteroaryl, heterocycloalkyloxy, cyano, nitro, -c(=0)R6, -c(=〇)Nm(CH2 nNK6R7, -nc(=〇)r6r7 or _s(10)6. ¥烧基 refers to 3 to 8 members of full carbon single ring, all carbon 5 members / 6 members or 6 = shelled ring or polycyclic fused ring ("thick In addition, the ring system means that the % of the parent in the system shares a pair of carbon atoms of the neighbor with the other rings in the system.) One or more of the rings may contain one or more double bonds, but no ❹: A ^ has a complete rest with sub-pure. (4) Examples of the base are cyclopropane II: butyl, cyclopentyl, cyclopentanyl, cyclohexane, cyclohexane, diamond, %g, and #g. The loop filament may be substituted or unsubstituted, and the substituent is preferably one or more 'differently selected from the group consisting of lower base/prime, tridentate, light base, lower alkoxy, and dazzle. Base, aryl-di, aryloxy, heteroaryl, hetero- Wei, heterocyclic alkoxy, cyano, nitrate '-C(=〇)r ^-C(=〇)〇 Re > -C( =0) NR6R^ -(CH0nNR6R^Rio-nc(=0)R6R7 or -S〇2R6. A base group as defined above, which is composed of at least two carbon atoms and at least one carbon-carbon double bond. Representative examples include, but are not limited to, ethene propylene 1, 2-propyl phenyl, benzo, 2- or 3-butanyl, etc., dilute or unsubstituted, #substituted, substituted Preferably, the group is independently selected from the group consisting of a self-priming, a tri-, a thiol group, a lower alkoxy group, an aryloxy group, a heteroaryl group, a heterocyclic group, a heteroaryl group, and a heterocyclic group. Base, nitro, heterocycloalkoxy, cyano, nitro, -C(=〇)R6, 94389 67 201016683 ~(CH2)nNR6R7 -NC(=0)R6R7 ^ -CC=0)0R6 , -C (=〇)NR6R7 _S〇2R6. "alkynyl" means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond. Representative examples include, but are not limited to, ethynyl: 1-propynyl, 2-propynyl, , 2— or 3—butynyl, etc. The alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more H independently selected from the group consisting of (tetra), tri(tetra), perylene, and lower. Alkoxy, aryl, aryloxy, heteroaryl, heterocyclic, heteroaryl, heterocycloalkyl, heterocycloalkoxy, cyano, nitro, -c(=0)r6, _C (=0)0R6, _c(0) ® NR6R7, -(CHOnNRY . -NC(=〇)R^^_S〇2R6 〇 "Aryl" means a substituent having at least one aromatic ring structure, ie, An aromatic ring of a conjugated π-electron system, including a carbocyclic aryl group, a heteroaryl group, and a biaryl group. The block group may be substituted or substituted, and when substituted, the substituent is preferably one or more. 'Independently selected from halogen, tridentate alkyl, hydroxy: nitro, cyano, class I alkoxy, (tetra), indolyl, heteroaryl, heterocycloalkyl, carboxy, carboxylic acid ester, heterocyclic Alkoxy, cyano, nitro, _C(=0)R6, ❹-C (=0)〇R6 . -C(=0)NRV > -(GHOnNRV > -NC(=〇)rV ,1 -S〇2R6. "Heteroaryl" means having from 4 to 3 heteroatoms as a ring atom, the remaining ring atom is an aryl group of carbon, and the hetero atom includes oxygen, sulfur, and nitrogen. The ring may be a S 5 S or a 6-membered ring. Examples of the heterocyclic aryl substituent include a thiol group, a stilbene group. , 吼基 & 比比比比比比比比比比比比比比比比比比比比比比比比比比比比比比比比比比比比比比比比比比比比比比 py py py py py py py In the case of a fluorenyl group, etc. The heteroaryl group may be taken or unsubstituted. When substituted, the substituent is preferably one or =, 94389 68 201016683 independently selected from the group of elements, three light groups, Base, cyano group, lower house oxygen, alkyl, alkyl, aryl, heterocycloalkyl, carboxyl, carboxylate, hetero 6 cycloalkoxy, cyano, nitro, -C(=〇 R6, _c(=〇)〇r6, _c(=〇) NRR, -(CH2)nNR6R7, -NC(=〇)R6R74_s〇2R6. "Heterocycloalkyl" refers to a monocyclic or fused ring substituent, In the ring, there are 5 to 9 ring atoms, and one or two ring atoms in α are selected from nitrogen and oxygen. s(〇)n (where η is an integer 0 to 2) of the heteroatoms' remaining ring atoms are carbon. These rings may also have one or more double bonds. However, these rings are not fully conjugated, and the electronic system is not Substituted heterocyclic thiol groups include, but are not limited to, piroxicam, brigade bite group, © σ and: * Marlensky, thio-allinyl, high-pyrene, etc., heterocyclic alkyl. Or unsubstituted. The block group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more, independently selected from the group consisting of dentate, lower alkyl, calcined, tridentate, Or a aryl group, an aryloxy group, an aryloxy group, a heterocyclic alkyl group, a (tetra) ester, a cyano group, a decyl group, a (IV) or a s-Ci=〇)R6, -C(=〇)NR6R7, —(CH2)nNR6R7 , -NC(=0) φ is substituted by a base - 0Η.院_院 ” 指指院院院炫炫炫炫炫。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。院院院。 The alkoxy group has m "yloxy group, hexyloxy group, etc.. The alkoxy group may or may not be substituted. When it is substituted, the substituent is preferably one stage alkoxy group, and 4 is selected from Burning base, dentate, tridentate, mercapto, low heterocycloalkane, tetradecyl, heteroaryl, heteropoly, heteroaryl, misc, cyano, schwitz, _C(=0)R6 , _c(=〇)〇r6, a c(=〇)nr6r7, 94389 69 201016683 -(CH2)nNR6R7, -NC(=0)R6R7 or -S〇2R6. "Aryloxy" means-0-aryl And -0-heteroaryl, aryl and heteroaryl are as defined above. Representative examples include, but are not limited to, phenoxy, pyridyloxy, carboxyoxy, thienyloxy, pyrimidinyloxy, pyridoxy, and the like. And its derivatives. The radical refers to -CH2-(aryl). 'Halogen' means fluorine, chlorine, bromine or lack of 'preferred fluorine or gas. Halogenated alkyl, meaning the substituent is substituted by halogen. Representative examples Including but not limited to trifluoromethyl, tribromofluorenyl, etc. Substituted by a radical. © Aminealkyl refers to an alkyl group substituted by an amine group. • Halo-substituted oxy" refers to a hydrazine-(haloalkyl) group. Representative examples include, but are not limited to, trifluoromethoxy, tribromo Oxyl and the like. ''Heterocycloalkoxy" means -〇-(heterocycloalkyl)^ "Halobenzyl" means -CH2-(haloaryl). "Trifluoromethyl," means -cf3 Exactly refers to _N〇2.

氣基指-CN。胺基指_NH2。 “缓基”指-CO0)- “緩酸” #旨（燒基）C(=〇)〇jj “缓酸醋”指（烷基）C(=0)0(烷基） “可選”或“可選地”意味著隨後所描述地事件或環境可=但不必發生，該說明包括該事件或環境發生或不發生地％合。例如，“可選被烷基取代地雜環取代基，，意味 94389 70 201016683 著烷基可以但不必存在，該說明包括雜環取代基被烷基取代的情形和雜環取代基不被烷基取代的情形。藥物組合物”表示一種或多種本文所述化合物或其生理予上/藥學上可接受的鹽或前驅物藥物與其他化學組刀的混合物’其他組分例如生理學/藥學上可接受的載體和賦形劑。藥物組合物的目的是促進化合物對生物體的給藥。Gas base refers to -CN. Amine refers to _NH2. "Slow base" means -CO0)- "slow acid" #相(烧基)C(=〇)〇jj "slow acid vinegar" means (alkyl)C(=0)0(alkyl) "optional" Or "optionally" means that the event or environment described subsequently may = but need not occur, the description including the occurrence or non-occurrence of the event or environment. For example, "optionally substituted with an alkyl-substituted heterocyclic ring, meaning 94389 70 201016683 alkyl may but need not be present, the description includes the case where the heterocyclic substituent is substituted with an alkyl group and the heterocyclic substituent is not alkyl Substituted. "Pharmaceutical composition" means a mixture of one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or precursor thereof with other chemical knives' other components such as physiological/pharmaceutical Accepted carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to the organism.

為了疋成本發明的目的，本發明採用如下技術方案 ©以下步驟：.⑴ 本發明通式⑴所述的化合物或其鹽的製備方法，包括For the purpose of the invention, the present invention adopts the following technical scheme: The following steps: (1) A method for producing the compound of the formula (1) or a salt thereof of the present invention, including

94389 71 20101668394389 71 201016683

nhr6r7 NaBH(OAc):Nhr6r7 NaBH(OAc):

(le)(le)

(Id)(Id)

(3)(3)

(ig)(ig)

(4)(4)

72 94389 (5) 20101668372 94389 (5) 201016683

本發明通式（ii)所述的化合物或其鹽的製備方法，包括以下步驟： (1) 罄 (2)The preparation method of the compound of the formula (ii) or a salt thereof of the present invention comprises the following steps: (1) 罄 (2)

j MeONa, THF _P〇C，3'DMF h Γ\ ‘•-R1j MeONa, THF _P〇C, 3'DMF h Γ\ ‘•-R1

^ NaBH(OA〇,^ NaBH (OA〇,

,R1 NHReR7 d7 π-^ HN -^ R^N. Μ \,R1 NHReR7 d7 π-^ HN -^ R^N. Μ \

(Ha) 魯(Ha) Lu

本發明通式（m)所述的化合物或其鹽的製傷方法，括以下步驟包 94389 73 201016683The method for the injury of the compound of the formula (m) or a salt thereof of the present invention comprises the following steps: 94389 73 201016683

【實施方式】實施例化合物的結構是藉由核磁共振（NMR)或質譜（MS)來確定的。NMR位移（δ)以百萬分之一（ppm)為單位。NMR的測定是用Bruker AVANCE-400核磁儀，測定溶劑為氛代氯仿 (CDC13)、氘代二曱基亞砜（DMS0-D6)，内標為四曱基矽烷 (TMS)，化學位移是以10_6(ppm)為單位。 MS的測定用FINNIGAN LCQAd (ESI)質譜儀。激酶VEGFR平均抑制率的測定使用HTScan酶標儀 (Cell Signaling 公司）。激酶EGFR/HER — 2平均抑制率的測定用NovoStar酶標儀（德國BMG公司）。薄層矽膠使用煙臺黃海HSGF254或青島GF254矽膠板。管柱層析法一般使用煙臺黃海矽膠200〜300目矽膠為 74 94389 201016683 載體。 DMSO-D6 :氘代二甲基亞砜； CDC13 :氘代氯仿；製備實施例：實施例1 「3-氧-4-(g:·氟:苄氧基）-笨基1 一 (卜比吸一卜基一啥吨咏一4_ 基）-胺[Embodiment] The structure of the compound was determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). The NMR shift (δ) is in parts per million (ppm). The NMR was measured by a Bruker AVANCE-400 nuclear magnetic instrument. The solvent was determined to be chloroform (CDC13), deuterated dimethyl sulfoxide (DMS0-D6), and the internal standard was tetradecyl decane (TMS). The chemical shift was based on 10_6 (ppm) is the unit. The measurement of MS was performed using a FINNIGAN LCQAd (ESI) mass spectrometer. The average inhibition rate of the kinase VEGFR was measured using an HTScan plate reader (Cell Signaling). The average inhibition rate of the kinase EGFR/HER-2 was determined using a NovoStar plate reader (BMG, Germany). Thin layer silicone rubber is used in Yantai Yellow Sea HSGF254 or Qingdao GF254 rubber sheet. Column chromatography is generally carried out using Yantai Huanghai Silicone 200~300 mesh silicone as 74 94389 201016683 carrier. DMSO-D6: deuterated dimethyl sulfoxide; CDC13: deuterated chloroform; Preparation Example: Example 1 "3-oxo-4-(g:·fluoro:benzyloxy)-stupyl 1 Suction of one 基啥咏咏 4 4 4 4 4 4

第一步 2-氯-1-(3-氟-苄氧基）-4-硝基-苯至/皿下在250 mL茄形瓶中加入2-氯-4-硝基-苯鹼la (20.0 g ’ 115 mmol)，用 120 mL N，N-二曱基甲醯胺溶解原料’擾拌下加入無水碳酸卸（32.0 g，230 mmo 1 )，1 〇分鐘後加入間氟氯苄（24 g，126 mmol)，加熱至90°C反應1. 5 75 943B9 201016683 小時。薄層分析追蹤至原料消失，將反應液冷卻至室溫，倒入1000 mL水中攪拌30分鐘，減壓抽濾，用少量水洗固體，真空乾燥，得到標題產物氟-苄氧基卜4_ 硝基-苯lb (32. 3 g ,淡黃色固體）。產率：99. 5%。 MS m/z (ESI) ： 282[M+1] 第二步 3-氯-4-(3-氟-苄氧基）-苯胺鹽酸鹽在1000 mL三口瓶中加入2_氯―卜^—氟―苄氧基）_4_ 硝基-苯lb(38· 6 g，136. 9 mmol)，甩300 mL·甲醇溶解原 ❹料，攪拌下加入100 mL水，再加入鐵粉（32. 2 g，575 mmol) -和氯化銨（62. 4 g，1. 15 mol)，加熱回流6小時。薄層分析追蹤至原料消失，將反應液冷卻至室溫，用矽藻土減壓抽濾，減壓濃縮’用二氯甲烷（1〇〇 mLx3)萃取，合併有機 -相’用50 mL飽和氯化鈉溶液洗滌·，二氯甲烷層用無水硫 .酸鎂脫水’減壓濃縮，得到標題產物3-氯-4-(3-氟-节氧基）-苯胺鹽酸鹽lc (33.2 g，白色固體）。產率：84. 3%。 MS m/z (ESI) ： 252[M+1] 第三步 2-胺基-5-碘-苯甲酸甲酯在500 mL茄形瓶中加入2-胺基-苯曱酸曱酯id (23. 3 § ’ 154 mmol)，用鹽酸溶液（濃鹽酸16 mL，水200 mL) >谷解原料’在10C授摔下滴加氯化蛾（2 5 g，154 mmo 1)的鹽酸溶液（濃鹽酸28 mL，水100 mL)，室溫攪拌1小時，減壓抽濾，固體真空乾燥，得到標題產物2-胺基-5-碘-苯 76 94389 201016683 曱酸甲酯le (29 g，淡黃色固體）。產率：69. 〇%。 MS m/z (ESI) ： 278[M+ 1] 第四步 6-蛾-3 H-喧哇琳-4-酮氮氣下在250 mL拓形瓶中加入2 -胺基-5-埃-苯甲酸曱酉旨 le(13. 5 g ’ 48. 7 mmol)和甲酸銨（3. 5 g，55 mmol)，溶於75 mL甲醯胺中，攪拌下加熱至i8(rc反應L2小時。 TLC追蹤至原料消失’將反應液冷卻至室溫，放入冰箱冷凍，減壓抽濾’分別用15 mL曱醯胺和50 mL正己烷洗條， φ真空乾燥，得到標題產物6-碘-3H-喹唑啉-4-酮If (12 g， .白色固體）。產率：90. 9%。 MS m/z (ESI) ： 273[M+ 1] 第五步 [3-氯-4-(3-氟-苄氧基）-苯基.]-(6_鐵_啥峻琳_4_基）_胺氮氣下在500 mL茄形瓶中加入6-碘-3H-啥唑啉-4-酮 lf(25 g，91. 9 mmol)，溶於 300 mL 二氣亞颯和 5 虹 N，N- ❹一曱基曱酿胺的混合溶劑中，加熱回流至反應液透明。丁K 追蹤至原料消失，蒸出二氯亞颯，備用。氮氣下將備用中間體溶於400 mL異丙醇中，加入3_ 氯-4-(3-氟-苄基）-苯胺鹽酸鹽lc(12 g，5〇 4 _〇ι)，加熱回流3小時。薄層分析追蹤至原料消失，將反應液冷卻至室温，減壓抽濾，將所得固體用1〇〇mL乙酸乙酯和3〇乩氨水的混合溶劑溶解，室溫攪拌3〇分鐘，減壓抽濾，真空乾燥，得到標題產物[3-氯-4-(3-氟-苄氧基）_笨基]_(6_ 94389 77 201016683 破-啥唾琳_4~基）-胺lg (12 g，類白色固體）。產率： 51.7%。 MS m/z (ESI) : 506[M+ 1] 第六步 [3-氯-4-(3-氟-苄氧基）—苯基]_(6 -π比咯-1 -基-嗜嗤琳-4- 基）-胺氮氣下在250 mL茄形瓶中加入[3-氯-4-(3-氟-苄氧基）-苯基]-(6-碘-喹唑啉-4-基）-胺ig(6〇〇 mg，1.12 mmol)，無水碳酸鉀（650 mg，4. 7 mmol)，碘化亞銅（100 mg， © 0. 5 mmol)和吡咯（3 g ’ 44 mmol)，用25 mL曱苯溶解’攪 —拌下滴加 Ν，Ν’-二甲基-1，2-乙二胺（140 mg，1.6 mm〇l)，加熱回流攪拌過夜。薄層分析追蹤至原料消失，加入2〇以水和100 mL乙酸乙酯，矽藻土過濾，用2N鹽酸溶液調pH 至7，分液，有機相依次用水（50 mLx2)洗滌，再用無水硫 :酸鎂脫水，減壓抽濾，濾液減壓濃縮，用矽膠柱層析法純化所得殘餘物，得到標題產物[3_氯_4_(3_氟_苄氧基）一苯 ❿基]-(6-吡咯-1-基-喹唑啉_4—基）_胺j (5〇〇屻，淡黃色固體）。產率：95. 0% 〇、 MS m/z (ESI) ： 445[M+1] !HNMR (400MHz, DMSO-d,)： ^ 9. 73(s, 1H), 8. 59(t, 2fl) 8.14(dd，1H，风 2)，8. 03(d, 1H，J=2.4)，7,87(d, 1H，’ J=8.8), 7.76(dd, 1H, J=8.8), 7. 56(t, 2H), 7.4S(q, 1Εχ 7-32(q, 3H), 7. 18(m, 1H), 6. 39(t, 2H), 5. 27(s 實施例2 ’ ； 94389 78 201016683The first step of 2-chloro-1-(3-fluoro-benzyloxy)-4-nitro-benzene to / in a 250 mL eggplant bottle is added 2-chloro-4-nitro-benzene base la ( 20.0 g '115 mmol), dissolving the raw material with 120 mL of N,N-dimercaptomethylamine. Add the anhydrous carbonic acid to the mixture (32.0 g, 230 mmo 1 ), and add the fluorochlorobenzyl (1,4 min). g, 126 mmol), heated to 90 ° C reaction 1. 5 75 943B9 201016683 hours. The thin layer analysis was traced to the disappearance of the starting material, and the reaction solution was cooled to room temperature, poured into 1000 mL of water and stirred for 30 minutes, filtered under reduced pressure, and the solid was washed with a small amount of water and dried in vacuo to give the title product fluoro-benzyloxyb. - Benzene lb (32. 3 g, pale yellow solid). Yield: 99. 5%. MS m/z (ESI): 282 [M+1]. Step 2 3-chloro-4-(3-fluoro-benzyloxy)-phenylamine hydrochloride was added to a 1000 mL three-neck bottle. —Fluoro-benzyloxy)_4_nitro-benzenelb (38·6 g, 136.9 mmol), 甩300 mL·methanol dissolved raw material, 100 mL water was added with stirring, and iron powder was added (32. 2 g, 575 mmol) - and ammonium chloride (62. 4 g, 1.15 mol), heated to reflux for 6 hours. The thin layer analysis was traced to the disappearance of the starting material, and the reaction solution was cooled to room temperature, filtered under reduced pressure with celite, concentrated under reduced pressure, and extracted with dichloromethane (1 〇〇mL×3). The organic phase was combined and saturated with 50 mL. The sodium chloride solution was washed, and the methylene chloride layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give the title product, 3-chloro-4-(3-fluoro- hydroxy)-phenylamine hydrochloride lc (33.2 g , white solid). Yield: 84.3%. MS m/z (ESI): 252 [M + 1] Step 3 2-Amino-5-iodo-benzoic acid methyl ester in a 500 mL eggplant bottle with 2-amino-benzoic acid oxime ester id ( 23. 3 § ' 154 mmol), hydrochloric acid solution (25 mL of concentrated hydrochloric acid, 200 mL of water) > (Concentrated hydrochloric acid 28 mL, water 100 mL), stirred at room temperature for 1 hour, filtered under reduced pressure and dried in vacuo to give the title product 2-amino-5-iodo-benzene 76 94389 201016683 methyl decanoate le (29 g , light yellow solid). Yield: 69. 〇%. MS m/z (ESI): 278 [M+ 1] Step 4 6-Moth-3 H-Wowlin-4-one was added to a 250 mL tow bottle with 2-amino-5-ang-benzene. Formic acid hydrazine (13. 5 g '48. 7 mmol) and ammonium formate (3.5 g, 55 mmol), dissolved in 75 mL of carbamide, heated to i8 with stirring (rc reaction L2 hours. TLC Tracking until the disappearance of the raw materials' The reaction solution was cooled to room temperature, placed in a freezer and vacuum filtered. The strips were washed with 15 mL of guanamine and 50 mL of n-hexane, respectively, and dried under vacuum to give the title product 6-iodo-3H. - quinazolin-4-one If (12 g, . white solid). Yield: 90. 9%. MS m/z (ESI): 273 [M+ 1] Step 5 [3-chloro-4-( 3-Fluoro-benzyloxy)-phenyl.]-(6_铁_啥峻琳_4_yl)_amine 6-iodo-3H-oxazoline-4 was added to a 500 mL eggplant bottle under nitrogen - Keto lf (25 g, 91.9 mmol), dissolved in 300 mL of a mixture of 2 gas and 2,N-N-indole-based amines, heated to reflux until the reaction solution is transparent. After the disappearance of the starting materials, the dichlorohydrazine was distilled off and used. The spare intermediate was dissolved in 400 mL of isopropanol under nitrogen, and 3_chloro-4-(3-fluoro-benzyl)-phenylamine hydrochloride lc (12) was added. g, 5〇 4 _〇ι), heated under reflux for 3 hours. Thin layer analysis was followed until the disappearance of the starting material, the reaction solution was cooled to room temperature, filtered under reduced pressure, and the obtained solid was mixed solvent of 1 mL of ethyl acetate and 3? Dissolve, stir at room temperature for 3 minutes, filter under reduced pressure, and dry in vacuo to give the title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6_94389 77 201016683 Lin _4~yl)-amine lg (12 g, off-white solid). Yield: 51.7% MS m/z (ESI): 506 [M+ 1] Step 6 [3-chloro-4-(3- Fluoro-benzyloxy)-phenyl]-(6-πpyrrol-1-yl-isophilin-4-yl)-amine was added to a 250 mL eggplant vial under nitrogen [3-chloro-4-( 3-fluoro-benzyloxy)-phenyl]-(6-iodo-quinazolin-4-yl)-amine ig (6 mg, 1.12 mmol), anhydrous potassium carbonate (650 mg, 4. 7 mmol ), cuprous iodide (100 mg, © 0.5 mmol) and pyrrole (3 g '44 mmol), dissolved in 25 mL of hydrazine, stirred and mixed with hydrazine, Ν'-dimethyl-1, 2-Ethylenediamine (140 mg, 1.6 mm 〇l), stirred under heating and reflux overnight. Thin layer analysis was followed until the disappearance of the starting material, and 2 〇 was added with water and 100 mL of ethyl acetate. The pH of the hydrochloric acid solution was adjusted to 7, and the organic phase was washed with water (50 mL×2), then dried with anhydrous sulfur: magnesium sulfate, filtered under reduced pressure, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography. The title product [3_Chloro_4_(3_fluoro-benzyloxy)-phenylindenyl]-(6-pyrrol-1-yl-quinazoline-4-yl)-amine j (5 〇〇屻, Light yellow solid). Yield: 95. 0% 〇, MS m/z (ESI): 445 [M+1] "HNMR (400 MHz, DMSO-d,): ^ 9. 73 (s, 1H), 8. 59 (t, 2fl) 8.14 (dd, 1H, wind 2), 8. 03 (d, 1H, J = 2.4), 7, 87 (d, 1H, 'J = 8.8), 7.76 (dd, 1H, J = 8.8), 7. 56(t, 2H), 7.4S(q, 1Εχ 7-32(q, 3H), 7. 18(m, 1H), 6. 39(t, 2H), 5. 27(s Example 2 ' ; 94389 78 201016683

❿第一步 -2-曱磺醯-乙胺鹽酸鹽氮氣下在1〇〇 mL三口瓶中加入硼烷（4〇 mL， m〇l/L) ’室溫攪拌下滴加曱磺醯乙腈2a，室溫攪拌過夜。 -薄層分析追蹤至原料消失，向反應液中滴加曱醇至無氣泡 .產生為止，減壓濃縮除去甲醇。加入3〇 mL飽和的氯化氫曱醇溶液，加熱回流1小時，用30 mL二氯甲烷稀釋，減 ©壓抽濾’固體真空乾燥’得到標題.產物2-甲磺醯-乙胺鹽酸鹽2b(1.53 g，白色固體）。產率：67 4%。 MS m/z (ESI) ： 124[M+1] 第二步 ' 氯-4-(3-氟〜苄氧基）_苯胺基]_喹唑啉_6_基} -1Η-°比哈-2-曱醒：氣氣下’在500 mL三口瓶中加入本發明實施例1第五步中所得到的化合物[3_氯_4_(3_氟_苄氧基苯基]_(6_ 79 94389 201016683 碘-喹唑啉-4-基）-胺lg(l. 6 g，3. 17 mmol) ’再加入無水碳酸卸（1.7忌，13111111〇1)，蛾化亞銅（91〇11^，4.76 111111〇1)， 11比嘻-2-曱醛（1 g，10. 5 mmol) ’用200 mL甲笨溶解，挽拌下滴加 Ν，Ν’-二甲基-1，2-乙二胺（560 mg，6. 34 mmol)，加熱回流攪拌24小時。薄層分析追蹤至原料消失，將反應液冷卻至室溫’矽藻土過濾，用少量水洗滌有機相，減壓濃縮’用石夕膠管柱層析法純化所得殘餘物，得到標題產物 1-{4-[3 -氯-4-(3 -氟-节氧基）_苯胺基]-啥唾嘛_6_基} -1H-吡咯-2-曱醛2c(500 mg，淡黃色固體）。產率：33. 4%。 ❹ MS m/z (ESI) : 472[M+1] .!HNMR (400MHz, DMS0-d〇: (5 9.80(s, 1H), 9.60(s, 1H), 8.74(s, 1H), 8. 63(m, 1H), 8. 05(m, 1H), 7. 93(dd, 1H, J=8.8), 7.88(m, 1H), 7. 76(d, 1H, J=8.8), 7. 6〇Cm, 1H), • 7.50(m, 1H), 7. 35(m, 4H), 7.21(m, 1H), 6. 57(m, 1H), 5. 26(s, 2H) 第三步鲁[3-氯-4-(3-氟-苄氧基）-苯基]-(6-{2-[ (2-曱確醯基-乙胺基）-甲基]比嘻-l-基}-啥嗤琳-4-基）-胺氮氣下在5 0 mL茄形瓶中加入本發明實施例2第一步中所得到的化合物2-甲石黃醢-乙胺鹽酸鹽2b(70 mg，0.4 mmo 1)，加入5 mL四氫吱喃和5 mL曱醇的混合溶劑，授拌下加入三乙胺（0. 2 mL ’ 0. 6 mmol)，再加入卜μ-[3-氯 -4-(3-氟-苄氧基）-苯胺基]-啥嗤琳-6一基卜比洛-2-甲搭2c( 120 mg ’0· 25 mmol)，室溫攪拌30分鐘。薄層分析 80 94389 201016683❿Step 1-2-Hydrazinium-ethylamine hydrochloride Add borane (4〇mL, m〇l/L) to a 1〇〇mL three-necked flask under nitrogen. Add sulfonium sulfonate at room temperature with stirring. Acetonitrile 2a was stirred at room temperature overnight. - Thin layer analysis was traced until the disappearance of the starting material, and decyl alcohol was added dropwise to the reaction mixture until no bubbles were formed. The mixture was concentrated under reduced pressure to remove methanol. Add 3 mL of a saturated solution of guanidinium chloride, heat to reflux for 1 hour, dilute with 30 mL of dichloromethane, and reduce the pressure by vacuum filtration to give the title. Product 2-Methylsulfonyl-ethylamine hydrochloride 2b (1.53 g, white solid). Yield: 67 4%. MS m/z (ESI): 124 [M + 1]. Step 2 'chloro-4-(3-fluoro-benzyloxy)-anilinyl]-quinazoline_6_yl} -1Η-°Biha -2-Wake up: Add the compound obtained in the fifth step of Example 1 of the present invention [3_chloro_4_(3_fluoro_benzyloxyphenyl)_(6_) in a 500 mL three-necked flask under gas atmosphere 79 94389 201016683 Iodine-quinazolin-4-yl)-amine lg (1.6 g, 3.17 mmol) 'Addition of anhydrous carbonic acid unloading (1.7 bogey, 13111111〇1), moth copper (91〇11 ^, 4.76 111111〇1), 11 than 嘻-2-furaldehyde (1 g, 10. 5 mmol) 'Dissolve with 200 mL of sputum, add Ν, Ν'-dimethyl-1,2 - Ethylenediamine (560 mg, 6.34 mmol), stirred under reflux for 24 hours. Thin layer analysis was performed until the disappearance of the starting material, and the reaction mixture was cooled to room temperature. The mixture was filtered over Celite, and the organic phase was washed with a small amount of water. Concentration 'The residue obtained was purified by silica gel column chromatography to give the title product 1-{4-[3-chloro-4-(3-fluoro-oxy-oxy)-anilinyl]- 啥嘛 _6_ -1H-pyrrole-2-furaldehyde 2c (500 mg, pale yellow solid). Yield: 33.4%. ❹ MS m/z (ESI): 472[M+1] .HNMR (400 MHz, DMS0-d〇: (5 9.80(s, 1H), 9.60(s, 1H), 8.74(s, 1H), 8. 63(m, 1H), 8. 05(m, 1H), 7. 93(dd, 1H, J=8.8), 7.88(m, 1H ), 7. 76(d, 1H, J=8.8), 7. 6〇Cm, 1H), • 7.50(m, 1H), 7. 35(m, 4H), 7.21(m, 1H), 6. 57(m, 1H), 5. 26(s, 2H) The third step is [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-{2-[ (2-曱醯 - - 乙乙乙乙乙 - - - l l l l l l 在在在在在在在在在在在在在第一步第一步第一步第一步第一步第一步第一步第一步第一步第一步第一步第一步第一步第一步The compound obtained in the form of 2-methylgendrobium-ethylamine hydrochloride 2b (70 mg, 0.4 mmo 1) was added to a mixed solvent of 5 mL of tetrahydrofuran and 5 mL of decyl alcohol, and triethylamine was added under stirring. (0. 2 mL '0.6 mmol), then add b-[3-chloro-4-(3-fluoro-benzyloxy)-anilino]-啥嗤琳-6-kibbiolo-2 - Mole 2c (120 mg '0 · 25 mmol) and stir at room temperature for 30 minutes. Thin layer analysis 80 94389 201016683

吡咯-l-基}-喹唑啉-4_基）_胺2(12〇 mg，淡黃色固體）。產率：50%。 MS m/z (ESI) : 580[M+1] Φ !HNMR (400MHz, DMSO-c/O： δ 9.80(s, 1H), 8. 64(s, 1H), B.57(d, 1H, J=1.6), 8.06 (m, 2H), 7. 88Cd, 1H, J=8. 8), 7. 76(dd, 1H, J=9. 0), 7.48(q, 1H), 7. 32(m, 3H), 7. 18(m, 1H), 7. 08(s, 1H), 6.26(m, 2H), 5. 27(s, 2H), 3. 75(s, 2H), 3. 17(t, 2H), 2.89(d, 5H) .實施例3 [3~~氯- 4~~(3~~氟氧基）-苯胺基-啥g坐淋-6-某二liL-吡咯-2-盖甲某）-N’，Ν’ -二乙基-1，2-乙二胺Pyrrole-l-yl}-quinazolin-4-yl)amine 2 (12 mg, pale yellow solid). Yield: 50%. MS m/z (ESI): 580 [M+1] Φ.HNMR (400 MHz, DMSO-c/O: δ 9.80 (s, 1H), 8. 64 (s, 1H), B.57 (d, 1H) , J=1.6), 8.06 (m, 2H), 7. 88Cd, 1H, J=8. 8), 7. 76(dd, 1H, J=9. 0), 7.48(q, 1H), 7. 32(m, 3H), 7. 18(m, 1H), 7. 08(s, 1H), 6.26(m, 2H), 5. 27(s, 2H), 3. 75(s, 2H), 3. 17(t, 2H), 2.89(d, 5H). Example 3 [3~~Chloro-4~~(3~~fluorooxy)-anilino-啥g sitting -6- a certain liL -pyrrole-2-captomethyl)-N',Ν'-diethyl-1,2-ethanediamine

重複本發明實施例2第二步的反應，使用上述第二步中所得到的化合物卜{4-[3-氯-4-(3-氟-苄氧基）-苯胺基] '喹唑啉-6-基卜1H-吡咯-2-甲醛2c作原料，按照本發明實施例2第三步所述相同方式進行該原料與N，N-二乙基 81 94389 201016683 -1，2 -乙二胺的反應’用;έ夕膠管柱層析法純化所得殘餘物，則得到標題產物N-(l-{4-[3-氯-4-(3-氟-苄氧基）—苯胺基]-喹唑啉-6_基}-111-吡咯-2-基甲基）-ν’ r i -1,2-乙二胺3 (50mg，淺黃色固體）。產率：5%。 MS m/z (ESI) ： 573[M+ 1] ]HNMR (400MHz, DMSO-d〇 : (5 9.80(s, 1H), 8. 64(s, iH) B.60(d, 1H, J=1.6), 8.08 (m, 2H), 7. 88(d, 1H, J = 9 2) 7.77(dd, 1H, 1=9.0), 7.48(q, 1H), 7.31(m, 3H), 7. l8(m 1H), 7. 06(t, 1H), 6.22(d, 2H, J=2. 0), 5.26(s, 2H), ©3.71(s, 2H), 2.46(m, 2fl), 2.31(m, 5H), 1.91(s, 1H) .1.24(t, 6H) 實施例4 ·ί1^·-4-(3 二氟二^氧基）-苯基 1-(6-{2-「（2-噍啉-4-某一乙龜基）-甲基]-p比鳴·_1-|}-唾唾啦-4-基V脸The reaction of the second step of Example 2 of the present invention was repeated, using the compound obtained in the above second step, {4-[3-chloro-4-(3-fluoro-benzyloxy)-anilino]'quinazoline -6-Kip 1H-pyrrole-2-carbaldehyde 2c as a raw material, the raw material and N,N-diethyl 81 94389 201016683 -1,2-E 2 are carried out in the same manner as described in the third step of Example 2 of the present invention. The title compound N-(l-{4-[3-chloro-4-(3-fluoro-benzyloxy)-anilino] is obtained by chromatography. - quinazolin-6-yl}-111-pyrrol-2-ylmethyl)-ν' ri -1,2-ethanediamine 3 (50 mg, pale yellow solid). Yield: 5%. MS m/z (ESI): 573 [M+ 1]]HNMR (400 MHz, DMSO-d 〇: (5 9.80 (s, 1H), 8. 64 (s, iH) B.60 (d, 1H, J= 1.6), 8.08 (m, 2H), 7. 88(d, 1H, J = 9 2) 7.77(dd, 1H, 1=9.0), 7.48(q, 1H), 7.31(m, 3H), 7. L8(m 1H), 7. 06(t, 1H), 6.22(d, 2H, J=2. 0), 5.26(s, 2H), ©3.71(s, 2H), 2.46(m, 2fl), 2.31(m, 5H), 1.91(s, 1H) .1.24(t, 6H) Example 4 · ί1^·-4-(3 difluorodioxy)-phenyl 1-(6-{2- "(2-Porphyrin-4-Ethylthiol)-Methyl]-p is singular _1-|}-Saliva-4-yl V face

重複本發明實施例2第二步的反應，使用上述第二步中所得到的化合物1-{4-[3-氯氧基）_苯胺基]-喹唑啉-6-基}-111-吡咯—2_曱醛2c作原料，按照本發明實施例2第三步所述相同方式進行該原料與2_嗎淋_4_ 基〜乙胺的反應’㈣膠管柱層析法純化所得殘餘物，則得到標題產物[3-氯-4-(3-氟、节氧基卜苯基]_(6_{2_[(2_嗎啉-4-基-乙胺基)-甲基]1咯+基卜喹唑啉+基)一胺4 94389 82 201016683 (50 mg，淺黃色固體）。產率：23. 8%。 MS m/z (ESI) ： 586[M-f 1] 'HNMR (400MHz, DMSO-d〇： d 9. 86(s, 1H), 8. 65(s, 2H), 8.05(m, 2H), 7.87(m, 1H), 7. 75(dd, 1H, J=8. 8), 7 45(q 1H)，7.30(m，3H)，7. 18(m，1H)’ 7. 13(s，1H), 6 38(s, 1H), 6.27(s, 1H), 5.27(s, 2H), 3. 93(m, 2H), 3.4〇(m, 4H), 2. 87(m, 2H), 2. 35(t, 2H, J=2. 0), 2. 23(s 4H) 實施例5 li二氯-4-(3-氟-苄氧棊）-t基1_(6_丨3—fu—n酿基一乙 ®歷基）-甲基1-p比略-1_基}-°|·唾啦-4-基）-胺 5a $bThe reaction of the second step of Example 2 of the present invention was repeated, and the compound 1-{4-[3-chlorooxy)-anilino]-quinazolin-6-yl}-111- obtained in the above second step was used. Pyrrole-2-furfural 2c is used as a raw material, and the reaction of the raw material with 2_?_____ethylamine is carried out in the same manner as described in the third step of Example 2 of the present invention. , the title product [3-chloro-4-(3-fluoro, ethoxylated phenyl)_(6_{2_[(2_morpholin-4-yl-ethylamino)-methyl]1 </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; DMSO-d〇: d 9. 86(s, 1H), 8. 65(s, 2H), 8.05(m, 2H), 7.87(m, 1H), 7. 75(dd, 1H, J=8. 8), 7 45 (q 1H), 7.30 (m, 3H), 7. 18 (m, 1H)' 7. 13 (s, 1H), 6 38 (s, 1H), 6.27 (s, 1H), 5.27(s, 2H), 3. 93(m, 2H), 3.4〇(m, 4H), 2. 87(m, 2H), 2. 35(t, 2H, J=2. 0), 2. 23(s 4H) Example 5 li dichloro-4-(3-fluoro-benzyloxyindole)-tyl 1_(6_丨3—fu—n-bristyl-ethyl® yl)-methyl 1-p比比-1_基}-°|·sal-4-yl)-amine 5a $b

第一步 1H-吡咯-3-甲醛First step 1H-pyrrole-3-carbaldehyde

氣氣〇C下在250 inL痴形瓶中加入氮化納（1 51 g， 57 mmol)，溶解於80 mL四氫呋喃中，攪拌下滴加咄。各5a(4 g ’ 59 mmol)，室溫下攪拌30分鐘，0°C攪拌下滴加三異丙基氯矽炫（10 g，52 mmol)，反應45分鐘。薄層分析追蹤至原料消失，將反應液減壓濃縮，加入100 mL水和1 〇〇 mL 乙酸乙醋’乙酸乙醋層用5 0 mL水洗。減壓濃縮，備用。氮氣〇°C下將草醯氯（7. 24 g，46. 7 _〇1)溶解於240 mL 83 94389 201016683 一、甲烷中，攪拌下滴加N，N一二甲基甲醯胺（4.6 g，63 )的5此一氯甲貌溶液，〇 t：下授拌20分鐘。將備用中間體4於10 mL二氯甲烧t ’快速滴人反應液中，6〇〇c 下回流30分鐘，冷卻至〇t：，氮氣下過濾，固體用***洗務’真空乾燥備用。 —π將上述備用中間體溶於氫氧化鈉溶液（50 mL，5%)中，至ZfflL下撥拌4小時。薄層分析追蹤至原料消失，用二氯甲燒萃取（100 IDLX3)，合併有機相，用無水硫酸鎂脫水，過滤’滤液減壓濃縮，用石夕膠管柱層析法純化所得殘餘物， ©則得到標題產物1H一料一3一甲經5b(l 2〇g，褐色固體）。 -產率：31. 6%。第二步 1-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基喹唑啉_6_基 ~1珏-°比洛-3-甲藤使用本發明實施例i第五步中所得到的化合物氯 -4-(3-氟-苄氧基）-苯基]-(6—碘—喹唑啉基)_胺^作麕原料’按照本發明實施例i第六步所述相同方式進行該原料與1H—吼洛_3_甲盤5b的反應，用石夕膠管柱層析法純化所得殘餘物，則得到標題產物1-{4_[3__氣_4_(3_氟—— 基）-苯胺基]-喹唑啉-6-基}-1Η-吡咯—^田故c节氧哈d曱醛5c (250 ，淺黃色固體）。產率：47.0%。 MS m/z (ESI) ： 473[M+ 1] 第三步 [3-氯-4-(3-氟-苄氧基）-苯基]-(6-{3_[(2一曱磺醯基-乙 94389 84 201016683 胺基）-甲基]-B比B各-l-基}-喧嗤琳-4-基）__胺氣氣下在lOOmL莊形瓶ι中加入1-丨4〜[3-氯-4-(3-氟-：V氧基）-本胺基]-啥唾琳-6-基}-lH~π比洛—3_曱酸5c(50 mg’ 0· 1 ram〇l)和 2-曱磺醯-乙胺鹽酸鹽（4〇mg，〇 3mm〇1)，溶於10 mL四氫呋喃和0.2 mL曱醇的混合溶劑中，再加入三乙胺（0. 2 mL，10 mmol)，室溫攪拌30分鐘，加入氰基硼氫化鈉（40rog ’ 0.6mm〇l)，室溫攪拌4小時。薄層分析追蹤至原料消失’加入3 〇 mL乙酸乙酯和3 0 mL水，乙酸乙酯層用無水硫酸鎂脫水，過濾，濾液減壓濃縮，用石夕朦〇管柱層析法純化所得殘餘物，則得到標題產物[3_氯_4_(3_ •說-苄氧基）-苯基]-（6-{3-[(2-甲磺醢基-乙胺基）-甲基]- 11比洛-卜基}-喹唑啉-4-基）_胺5(20 mg，淡黃色固體），產率：34. 5%。 • MS m/z (ESI) ： 580[MH- 1] • (400MHz，DMSO-cW: d 9. 81(s，1H)，8. 59(t，2H)， 8.12(dd, 1H, J=9.0), 8.30 (d, 1H, J=2.8), 7. 86(d, 1H, ^J = 9.2), 7.77(dd, 1H, J=8. 8), 7. 50(m, 3H), 7. 33(m, 3H), 7. 19(m, 1H), 6.35(s, 1H), 5. 28(s, 2H), 3. 68(s, 2H), 3.34(m, 7H) 實施例6 1^{4-「3-氣-4-(^-||.-节氫甚、一黎胺某1-喹唑啉-6-某}-4-;IL曱基-1H- ^比p各-a -甲酸乙醋 85 94389 201016683Nitrile (1 51 g, 57 mmol) was added to a 250 inL immersed bottle under a gas 〇C, dissolved in 80 mL of tetrahydrofuran, and hydrazine was added dropwise with stirring. Each 5a (4 g '59 mmol) was stirred at room temperature for 30 minutes, and triisopropylchloropurine (10 g, 52 mmol) was added dropwise with stirring at 0 ° C for 45 minutes. The thin layer analysis was traced until the starting material disappeared, and the reaction solution was concentrated under reduced pressure, and then 100 mL of water and 1 〇〇 mL of ethyl acetate acetacetate ethyl acetate layer was washed with 50 mL of water. Concentrate under reduced pressure and set aside. The grass 醯 chlorine (7. 24 g, 46.7 _〇1) was dissolved in 240 mL of 83 94389 201016683 I. under methane, and N,N-dimethylformamide (4.6) was added dropwise with stirring. g, 63) 5 of this chloroform solution, 〇t: the next mixing for 20 minutes. The alternate intermediate 4 was refluxed in 10 mL of chloroform t-broth, and refluxed for 30 minutes at 6 ° C, cooled to 〇t: filtered, and the solid was washed with diethyl ether. - π The above-mentioned alternate intermediate was dissolved in a sodium hydroxide solution (50 mL, 5%), and stirred for 4 hours under ZfflL. Thin layer analysis was carried out until the disappearance of the starting material, extraction with methylene chloride (100 IDLX3), the organic phase was combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by chromatography on silica gel column chromatography. The title product 1H was obtained as a material, and then was taken from 5b (l 2 g, brown solid). - Yield: 31.6%. The second step 1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-anilinoquinazoline-6-yl~1珏-°Bilo-3-methyl vine using the embodiment of the invention i the compound chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-iodo-quinazolinyl)-amine obtained in the fifth step is used as a starting material according to the present invention. The reaction of the starting material with 1H-吼洛_3_甲盘5b is carried out in the same manner as described in the sixth step, and the obtained residue is purified by Shixi gum column chromatography to obtain the title product 1-{4_[3__气_ 4_(3_Fluoro-yl)-anilino]-quinazolin-6-yl}-1Η-pyrrole-^, c 故节节氧氧氧氧氧 250 250 5 5 ( (250, pale yellow solid). Yield: 47.0%. MS m/z (ESI): 473 [M+ 1]. Step 3 [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-{3_[(2- sulfonyl) -B 94389 84 201016683 Amino)-Methyl]-B is added to 1-100~ in the lOOmL bottle ι under the gas of B-l-yl}-喧嗤琳-4-yl)__amine [3-Chloro-4-(3-fluoro-:Voxy)-amino-amino]-啥琳 -6 -6-6-yl}-lH~πBilu-3_ decanoic acid 5c (50 mg' 0·1 Ram〇l) and 2-indolesulfonium-ethylamine hydrochloride (4〇mg, 〇3mm〇1), dissolved in a mixed solvent of 10 mL of tetrahydrofuran and 0.2 mL of decyl alcohol, and then added triethylamine (0. 2 mL, 10 mmol), stirred at room temperature for 30 minutes, sodium cyanoborohydride (40 rog '0.6mm 〇l) was added and stirred at room temperature for 4 hours. The thin layer analysis was traced to the disappearance of the starting material. '3 mL of ethyl acetate and 30 mL of water were added. The ethyl acetate layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained the title product [3_chloro_4_(3_•say-benzyloxy)-phenyl]-(6-{3-[(2-methylsulfonyl-ethylamino)-methyl] 5%。。。。。。。。。。。。。。。。。。。。。。。。。。。. • MS m/z (ESI): 580 [MH-1] • (400 MHz, DMSO-cW: d 9. 81 (s, 1H), 8. 59 (t, 2H), 8.12 (dd, 1H, J = 9.0), 8.30 (d, 1H, J=2.8), 7. 86(d, 1H, ^J = 9.2), 7.77(dd, 1H, J=8. 8), 7. 50(m, 3H), 7. 33(m, 3H), 7. 19(m, 1H), 6.35(s, 1H), 5. 28(s, 2H), 3. 68(s, 2H), 3.34(m, 7H) Example 6 1^{4-"3-Gas-4-(^-||.------------------------------ T-each-a-formic acid ethyl vinegar 85 94389 201016683

©第一步 4_二氣甲基-1 Η-π比嘻-3_曱酸乙酉旨氮氣下，將對曱苯磺醯基曱基異腈（〇. 975 g，5 mm〇1) 和（£)4,4,4-二氟丁坤酸乙醋（〇.84£，5 111111〇1)溶於8〇11^ 曱亞職和16 inL乙謎的混合溶劑中’室溫授掉下將甘滴加入氫化鈉（240 mg，6 mmol)的6 mL***懸濁液中，室溫攪摔15分鐘。薄層分析追蹤至原料消失，加入3〇mL水， ❿用***萃取（30 mLx3)，_合併有機相，用無水硫酸鎂脫水，過濾，濾液減壓濃縮，用矽膠管柱層析法純化所得殘餘物，則得到標題產物4-三氟甲基-1H-吡咯曱酸乙酯6b(64〇 mg ’淺黃色固體）。產率：61. 8%〆 MS m/z (ESI) ： 206[M- 1] 第二步使用本發明實施例1第五步中所得到的化合物[3_氯 -4-(3-氟-苄氧基）_苯基]-(6-碘-喹唑啉_4_基）_胺lg作 94389 86 201016683 原料’按照本發明實施例1第六步所述相同方式進行該原料與4-三氟曱基-1H_吡咯—3-甲酸乙酯6b的反應’得到標題化合物1-{4-[ 3-氯-4-(3-氟-苄氧基）-苯胺基]-喹唑啉 -6-基}-4-三氟曱基-1H-吡咯-3-曱酸乙酯6 (30 mg，淺黃色固體）。產率：51.4%。 MS m/z (ESI) : 585[M+ 1] 'HNMR (400MHz, DMSO-d〇: (5 8. 77(s, 2H), 8. 32(s, 1H), 8.27(s, 1H), 8.19(s, 1H), 8.00(d, 1H > J=4. 0), 7. 90(s, 1H), 7.72(dd, 1H, J=8.8), 7. 48(q, 1H), 7. 31(m, 3H), ©7.18(t, 1H), 5.26 (s, 2H), 4. 28(q, 2H), 1.31(t, 3H) -實施例7 2-{4-「3 -氣- 4-(¾一氟-卞乳基）-本胺某1-唾地啦基丨-吐咯-1-甲酴第三丁©Step 4_Dimethylmethyl-1 Η-π than 嘻-3_ 曱酉酉酉酉酉酉酉酉酉酉氮气氮气氮气氮气 975 975 975 975 975 975 975 975 975 975 975 975 975 975 975 975 (£) 4,4,4-difluorobutyric acid ethyl vinegar (〇.84£, 5 111111〇1) dissolved in 8〇11^ 曱 sub-job and 16 inL riddle mixed solvent 'room temperature The drops were added to a suspension of sodium hydride (240 mg, 6 mmol) in 6 mL of diethyl ether and stirred at room temperature for 15 min. Thin layer analysis was carried out until the disappearance of the starting material, 3 mL of water was added, and the mixture was extracted with diethyl ether (30 mL×3). The organic phase was combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography. The residue gave the title product 4-trifluoromethyl-1H-pyrroleic acid ethyl ester 6b (64 g. Yield: 61.8% 〆MS m/z (ESI): 206[M-1] The second step uses the compound obtained in the fifth step of Example 1 of the present invention [3_chloro-4-(3-fluoride) -Benzyloxy)-phenyl]-(6-iodo-quinazoline-4-yl)-amine lg as 94389 86 201016683 Starting material 'The raw material was carried out in the same manner as described in the sixth step of Example 1 of the present invention. Reaction of trifluoromethyl-1H-pyrrole-3-carboxylate 6b to give the title compound 1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-anilino]-quinazole Ethyl 6-yl}-4-trifluoromethyl-1H-pyrrole-3-furoate 6 (30 mg, pale yellow solid). Yield: 51.4%. MS m/z (ESI): 585 [M + 1] "HNMR (400 MHz, DMSO-d: (5 8. 77 (s, 2H), 8. 32 (s, 1H), 8.27 (s, 1H), 8.19(s, 1H), 8.00(d, 1H > J=4. 0), 7. 90(s, 1H), 7.72(dd, 1H, J=8.8), 7. 48(q, 1H), 7. 31(m, 3H), ©7.18(t, 1H), 5.26 (s, 2H), 4. 28(q, 2H), 1.31(t, 3H) - Example 7 2-{4-"3 - gas - 4-(3⁄4-fluoro-anthracene)---------------------

is y 第一步 94389 87 201016683 吡咯-1-甲酸第三丁酯在l〇〇mL蘇形瓶中加入吡咯（6.71g’1〇〇mm〇i)，二碳酸二第三丁醋咖^^麵叫^二甲胺基^ (4.89 g，40 mmol) ’用5〇 mL乙腈溶解，室溫擾掉過夜。薄層分=追蹤至原料消失，減壓濃縮，用石夕膠管柱層析法純化所得殘餘物，則得到標題產物吼咯甲酸第三丁酉匕 7a(12. 5 g，無色液體）。產率：85. 7%。第二步 1-甲酸第三丁酯-2-d比洛爛酸魯氬氣下，在250 mL三口瓶中加入比嘻~ι_甲酸第三丁 -酯 7a(10. 47 g，62. 6 mmol)，溶於 100 mL 四氫呋喃中， _78°C攪拌下滴加二異丙基胺基鋰（34mL，四氫呋喃溶液， 2. 0 m〇l/L)，-78°C反應2小時，滴加硼酸三甲酯（9 mL， • 81.4 mmol)’ -78°C反應1小時，升溫至-40。〇反應30分鐘。 -薄層分析追蹤至原料消失’將反應液倒入1〇0 mL冰水中，用1N鹽酸調pH至1，用乙酸乙酯萃取（1〇〇此><3)，合併 ❹有機相，有機相用200 mL飽和氯化鈉溶液洗滌，乙酸乙醋層用無水硫酸鎂脫水，過濾，濾液減壓濃縮，加入50 mL 正己烷’放入冰箱冷凍，減壓抽濾，真空乾燥，則得到標題產物1-甲酸第三丁酯-2-吡咯硼酸7b(6.94 g，淡黃色固體）。產率：52. 6%。 'HNMR (400MHz, DMS0-d〇 : (5 8. 02(s, 2H), 7.33(dd, 1H, J=2. 8), 6.43(dd, 1H, J=3. 2), 6. 22(t, 1H), 1.55(s, 9H) 第三步 88 94389 201016683 2 - {4-[3-氯- 4- (3 -氟-节氧基）-苯胺基]-啥唾琳基} 洛-1-甲酸第三丁酯重複實施例1第一步至第五步的反應，將得到的化人物[3-氯-4-(3-氟-苄氧基）-苯基]-(6-碘-喹唑琳—4〜義胺lg (2. 02 g，4 mmol)，卜（第三丁氧基羰基1Η—β比咯 -2-硼酸（1. ig，5· 2mmol) ’ 肆（三苯基膦）鈀（〇. 23g， 0. 2mmol)，碳酸鉀（1. 38g，lOmmol)溶於 25 mL N，N-二甲基甲酿胺和6 mL水的混合溶劑中，得到的混合物加熱到 70°C ’2小時後反應完畢。將反應液冷卻至室溫，倒入3〇〇mL 瘳冰水中，析出白色固體，攪拌十分鐘後，抽濾，產物在真空下乾燥’得到的固體進一步藉由管柱層析法，得到標題產物2-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-啥唾琳一6一基}-°比咯-1-曱酸第三丁酯7 (1.86 g，淺黃色固體）。產 •率：85. 7% 〇 MS m/z (ESI) ： 545[M+ 1] 'HNMR (400MHz, DMSO-^): ^ 9. 78(s, 1H), 8.61(s, 1H), ^8.58(s, 1H), 8.07(d, 1H, J=2. 0), 7. 85(dd, 1H, J=8. 6), 7.78(s, ,1H), 7.76(d, 1H), 7.46(m, 2H), 7.31(m, 3H), 7.18(t, 1H), 6.45(m, 1H), 6.38(t, 1H), 5. 26(s, 2H), 1.30(s, 9H) 實施例8 [3-氯-4-(3-氟-苄氳某）-笨基]-[ 啉-4-基1-胺 94389 89 201016683Is y first step 94389 87 201016683 pyrrole-1-carboxylic acid tert-butyl ester in l〇〇mL sigmoid flask to add pyrrole (6.71g '1〇〇mm〇i), dicarbonate two third vinegar vinegar ^^ The surface was called dimethylamino group (4.89 g, 40 mmol). It was dissolved in 5 mL of acetonitrile and was stirred overnight at room temperature. The thin layer was followed until the disappearance of the starting material, and the residue was purified under reduced pressure to give the titled product, the crude product of the title product, succinic acid, succinimide 7a (12.5 g, colorless liquid). Yield: 85.7%. In the second step, 1-butylic acid terephthalate-2-d is added to a 250 mL three-necked flask, and the third-butyl ester 7a (10.47 g, 62. 6 mmol), dissolved in 100 mL of tetrahydrofuran, add 2-isopropylamino lithium (34 mL, tetrahydrofuran solution, 2. 0 m〇l/L) with stirring at _78 ° C, and react at -78 ° C for 2 hours. Trimethyl borate (9 mL, • 81.4 mmol) was reacted at -78 ° C for 1 hour and warmed to -40. 〇React for 30 minutes. - Thin layer analysis was traced until the disappearance of the starting material'. The reaction solution was poured into 1 mL of ice water, adjusted to pH 1 with 1N hydrochloric acid, and extracted with ethyl acetate (1 〇〇><3), combined with hydrazine organic phase The organic phase was washed with 200 mL of saturated sodium chloride solution, the ethyl acetate layer was dehydrated with anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 50 mL of n-hexane was added to the refrigerator for freezing, vacuum filtration, and vacuum drying. The title product 1-carboxylic acid tert-butyl ester-2-pyrrole boronic acid 7b (6.94 g, pale yellow solid) was obtained. Yield: 52.6%. 'HNMR (400MHz, DMS0-d〇: (5 8. 02(s, 2H), 7.33(dd, 1H, J=2.8), 6.43(dd, 1H, J=3.2), 6. 22 (t, 1H), 1.55(s, 9H) Third step 88 94389 201016683 2 - {4-[3-Chloro-4-(3-fluoro-oxy)-anilino]-啥琳琳基洛1-1,3-carboxylic acid tert-butyl ester The reaction of the first step to the fifth step of Example 1 was repeated, and the obtained character [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6) was obtained. - Iodo-quinazoline - 4 to sense amine lg (2.02 g, 4 mmol), b (t-butoxycarbonyl 1 Η-β specific bromo-2-boronic acid (1. ig, 5 · 2 mmol) ' 肆(triphenylphosphine)palladium (〇. 23g, 0.2 mmol), potassium carbonate (1.38 g, 10 mmol) dissolved in a mixture of 25 mL of N,N-dimethylamine and 6 mL of water The mixture was heated to 70 ° C for 2 hours and the reaction was completed. The reaction solution was cooled to room temperature, poured into 3 mL of ice water, and a white solid was precipitated. After stirring for ten minutes, the mixture was filtered and dried under vacuum. The obtained solid was further subjected to column chromatography to give the title product 2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-anilinyl]-啥琳一一 6 6 - ° than 1,4-butyric acid tert-butyl ester 7 (1.86 g, shallow Color solid). Production rate: 85.7% 〇MS m/z (ESI): 545[M+ 1] 'HNMR (400MHz, DMSO-^): ^ 9.78(s, 1H), 8.61(s, 1H), ^8.58(s, 1H), 8.07(d, 1H, J=2. 0), 7. 85(dd, 1H, J=8. 6), 7.78(s, ,1H), 7.76(d , 1H), 7.46(m, 2H), 7.31(m, 3H), 7.18(t, 1H), 6.45(m, 1H), 6.38(t, 1H), 5. 26(s, 2H), 1.30( s, 9H) Example 8 [3-Chloro-4-(3-fluoro-benzidine)-styl]-[ phenyl-4-yl 1-amine 94389 89 201016683

在100 mL知形瓶中，加入本發明實施例7第三步中所得到的化合物2 ·~ β坐嚇· - 6 -基} - ί比略 3-氯-4-(3-氟-苄氧基）-苯胺基]-喹 -1-甲酸第三丁酯 7(1. 18 g，2. 17 -随〇1) ’溶於50 mL四氫呋喃中，加入甲醇鈉（936 mg，8. 66 ππηο 1)，至/JBL擾拌過夜。薄層分析追蹤至原料消失，將反應液倒入100 mL冰水中，用乙酸乙酯萃取（5〇 mLx3)，合併 .有機相，用無水硫酸鈉脫水，過濾，濾液減壓濃縮，加入 20 mL正己烷，放入冰箱冷凍，減壓抽濾，真空乾燥，則得到標題產物[3-氣-4-(3-氟-苄氧基）-苯基]-[6__ΠΗ_吨 ❹17各-2-基）-啥嗅淋-4-基]-胺8(0.65 g，淡綠色固體）。產率：80. 0%。 MS m/z (ESI) ： 445[M+1] 'HNMR (400MHz, DMS0-c?O： (5 8. 64(d, 1H, J=2. 〇), 8. 53(s 1H), 8. 14(dd, 1H, 1=8.4), 8. 05(d, 1H, J=2. 8), 7. 77(dd 2H, J=9.0), 7.49(q, 1H), 7. 33(m, 4H), 7. 19(m, 1H) 6.97(s, 1H), 6.78(s, 1H), 6. 22(s, 1H), 5. 27(s, 2H) 實施例9 94389 90 201016683In a 100 mL liter flask, the compound 2 obtained in the third step of Example 7 of the present invention was added, and the compound was subjected to 3-chloro-4-(3-fluoro-benzyl). Oxy)-anilino]-quinolin-1-carboxylic acid tert-butyl ester 7 (1.18 g, 2.17 - with 〇1) 'dissolved in 50 mL of tetrahydrofuran, added sodium methoxide (936 mg, 8.66 Ππηο 1), to /JBL disturbed overnight. Thin layer analysis was performed until the disappearance of the starting material. The reaction solution was poured into 100 mL of ice water, extracted with ethyl acetate (5 〇mL×3), and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Hexane, frozen in a freezer, vacuum filtered under reduced pressure and dried in vacuo to give the title product [3- -4-(4-fluoro-benzyloxy)-phenyl]-[6__ΠΗ_ ❹ 各各 -2- Base)-啥啥 -4--4-yl]-amine 8 (0.65 g, pale green solid). Yield: 80. 0%. MS m/z (ESI): 445 [M+1] "HNMR (400 MHz, DMS0-c?O: (5 8. 64 (d, 1H, J=2. 〇), 8. 53 (s 1H), 8. 14(dd, 1H, 1=8.4), 8. 05(d, 1H, J=2. 8), 7. 77(dd 2H, J=9.0), 7.49(q, 1H), 7. 33 (m, 4H), 7. 19(m, 1H) 6.97(s, 1H), 6.78(s, 1H), 6. 22(s, 1H), 5. 27(s, 2H) Example 9 94389 90 201016683

氬氣下’在10 mL蘇形瓶中加入本發明實施例8所得的化合物[3-氯-4-(3-氟-苄氧基）-苯基]_[6_(1H_吡咯—2_ 基）-喹唑啉-4-基]-胺8，溶於2 mL N，N-二甲基甲醯胺， '擾拌下加入氫化鈉（8 mg ’ 0. 337 mmol )，室溫擾拌1小時， .加入碘甲烷（32 mg，0.225 mmol)，室溫攪拌過夜。薄層分析追蹤至原料消失，將反應液倒入2 0 mL水中，用乙酸乙翁S旨萃取（25 mLx3)，合併有機相，用25mL飽和氯化鈉溶液洗滌，乙酸乙酯層用無水硫酸鎂脫水。過濾，濾液減壓漢縮，用矽膠管柱層析法純化所得殘餘物，則得到標題產物 [氯*~4-（3+-氣-节氧基）-苯基]-[β-(1 -曱基-1JJ-〇比洛一2_ 基）-喹唑啉-4-基]-胺9(35 mg，淡黃色固體）。產率： 34. 0% ° MS m/z (ESI) ： 459[M+ 1] !HNMR (400MHz，MSO-心）：5 9. 78(s，1H)，8. 59(s，1H)， 94389 91 201016683 8.53(s，1H)，8.04(d，1H，J = 2.4)，7.94(dd，1H，J = 8.4)， 7.81(d, 1H, J = 8.4), 7. 76(dd, 1H, J=9. 0), 7. 49(q, 1H), 7. 31(m, 3H), 7. 19(t, 1H), 6. 95(s, 1H), 6. 35(s, 1H), 6. 15(s, 1H), 5.27(s, 2H), 3. 75(s, 3H) 實施例10 2-{4-「3-氯-4-（3-就-爷氧基）-笨胺基1-喧峻琳-6-基} -6，7 -二氳-211-〇比口南「3，4-clp比洛-4-酮The compound [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6_(1H_pyrrole-2) group obtained in Example 8 of the present invention was added to a 10 mL sigma flask under argon. )-quinazolin-4-yl]-amine 8, dissolved in 2 mL of N,N-dimethylformamide, added with sodium hydride (8 mg '0. 337 mmol), stir at room temperature After 1 hour, iodomethane (32 mg, 0.225 mmol) was added and stirred at room temperature overnight. The thin layer analysis was traced to the disappearance of the starting material, and the reaction solution was poured into 20 mL of water, extracted with ethyl acetate (25 mL×3), the organic phase was combined, washed with 25 mL of saturated sodium chloride solution, and the ethyl acetate layer was treated with anhydrous sulfuric acid. Dehydration of magnesium. Filtration, the filtrate was reduced under reduced pressure, and the residue obtained was purified by silica gel column chromatography to give the title product [chloro*~4-(3+---------oxy-)-phenyl]-[β-(1 - mercapto-1JJ-debbiol-2-yl)-quinazolin-4-yl]-amine 9 (35 mg, pale yellow solid). Yield: 34. 0% ° MS m/z (ESI): 459 [M+ 1] !HNMR (400 MHz, MSO-min): 5 9.78 (s, 1H), 8. 59 (s, 1H), 94389 91 201016683 8.53(s,1H), 8.04(d,1H,J=2.4), 7.94(dd,1H,J=8.4), 7.81(d, 1H, J = 8.4), 7. 76(dd, 1H , J=9. 0), 7. 49(q, 1H), 7. 31(m, 3H), 7. 19(t, 1H), 6. 95(s, 1H), 6. 35(s, 1H), 6. 15(s, 1H), 5.27(s, 2H), 3. 75(s, 3H) Example 10 2-{4-"3-Chloro-4-(3-iso-yloxy) )--Amino-based 1-喧君琳-6-yl} -6,7-二氲-211-〇比口南"3,4-clp 比洛-4-ketone

第一步 6，7-二氮-211-11比鳴[3，4_〇]17比洛-4-嗣在100 mL三口瓶中，加入對甲苯磺醯基甲基異腈（5. 48 g，2 8. 0 5 mmo 1)，溶於2 0 mL四氣吱喃中，0 °C擾拌下滴加 1，8-二氮雙環[5. 4· 0]十一碳-7-烯（4. 2 mL ’ 28. 05 mmol)， 15分鐘後加入5,6 -二氫σ比喃酮10a(2.5 g，25.5 mmo 1) 92 94389 201016683 的20 mL四氫呋喃溶液，室溫攪拌2小時。薄層分析追蹤至原料消失，倒入150 mL飽和氯化鈉溶液中，室溫攪拌過夜。減壓濃縮除去四氫呋喃，用乙酸乙酯萃取（5〇 mLx5)，合併有機相’用無水硫酸鎂脫水。過濾，濾液減壓濃縮，用15 mL乙酸乙酯重結晶，得到標題產物6, 7_二氫_2H_吡喃[3’4-c]吡咯-4-酮l〇b(2.20 g，黃色固體）。產率： 76· 3% 〇 ^NMR (400MHz, DMSO-d〇: δ 11.70(s, 1Η), 7. 16(dd, 1H, J=2.8), 6.64(d, 1H, J = 0. 8), 2. 80(t, 2H), 2.71(t, 2H) ❹第二步 -2-{4-[3-氯-4-(3-氟-苄氧基苯胺基]-喹唑啉_6_基} -6, 7-二氫-2H-吡喃[3, 4-c]吡咯-4-酮氨氣下在250 mL茄形瓶中加入本發明實施例1第五步 .所得的化合物[3-氯=4-(3-氟—苄氧基苯基卜（6_碘._喹唑啉 4-基）-胺 ig(4. 31 g，8· 53 mm〇l)，再加入 6, 7-二氫 2H-吡喃[3, 4-c]吡咯-4-酮 i〇b(1. 52 g，u. 68 mm〇1)，書破化亞銅（840 mg，4.26 _丨）和賴卸（5·43 g，25·58 mmol)’洛於8〇 mL Ν，Ν-二甲基甲醯胺中，授拌下加入Ν，Ν，_ ，甲基-1，/一乙二胺（0·5虹，4·26 mmol)，加熱至68t:攪掉過仪。薄層分析追蹤至原料消失，將反應液倒入侧乩中擾拌下析出固體，減壓抽滤，固體用水洗滌（5〇 ’真空乾燥，則得到標題產物2_{4_[3一氯_4_(3_氟_ 二氧基）-苯胺基]_啥唾琳+基卜6, 7_二氩鲁吼喃 ’ 4 c]比咯4-酮1〇(3· 57 g，黃綠色固體）。產率：81. 3%。 94389 93 201016683 MS m/z (ESI) ： 515[M+ 1] !HNMR (400MHz, dUSO-de): δ 9. 81(s, 1H), 8. 74(d, 1H, J=2. 0), 8.61(s, 1H), 8.26(d, 1H, J=2. 0), 8. 23(dd, 1H, J=9.0), 8.02(d, 1H, J=2.8), 7. 90(d, 1H, J=：8. 8), 7.74(dd, 1H, J=8.8), 7.53(s, 1H), 7. 48(q, 1H), 7. 34(m, 3H), 7. 19(t, 1H), 5.28(s, 2H), 4.49(t, 2H, J = 5. 8), 2.91(t, 2H, J=5.8) 實施例11 N-(5-{4-[3-氧-4-(3-氟-苄氯盖苴胺基1-喹唑啾：=^：：^| ❹-1氏二°比咯-2-基甲某）-1^’ .1\1，-二7. 1-1. 2-乙二胺The first step of 6,7-diaza-211-11 than [[,4_〇]17 pirox-4-indole in a 100 mL three-necked bottle, adding p-toluenesulfonylmethyl isocyanide (5. 48 g,2 8. 0 5 mmo 1), dissolved in 20 mL of four gas sulphur, and added 1,8-diazabicyclo[5. 4·0]undec-7- at 0 °C. Alkene (4.2 mL ' 28. 05 mmol), after 15 minutes, add 5,6-dihydro-pyridinone 10a (2.5 g, 25.5 mmo 1) 92 94389 201016683 in 20 mL of tetrahydrofuran, stir at room temperature for 2 hours. . Thin layer analysis was traced until the starting material disappeared, poured into 150 mL of saturated sodium chloride solution, and stirred at room temperature overnight. The tetrahydrofuran was concentrated under reduced pressure and extracted with ethyl acetate (5 mL EtOAc). Filtration, the filtrate was concentrated under reduced pressure and crystallised eluted eluted eluted with 15 solid). Yield: 76·3% 〇^NMR (400MHz, DMSO-d〇: δ 11.70(s, 1Η), 7. 16(dd, 1H, J=2.8), 6.64(d, 1H, J = 0. 8 ), 2. 80(t, 2H), 2.71(t, 2H) ❹Step 2-2-{4-[3-Chloro-4-(3-fluoro-benzyloxyanilino)-quinazoline _ 6_7} 7-Dihydro-2H-pyrano[3,4-c]pyrrol-4-one is added to a 250 mL eggplant-shaped flask under the ammonia gas of the fifth step of the first embodiment of the present invention. a compound [3-chloro=4-(3-fluoro-benzyloxyphenyl)(6-iodo-quinazoline-4-yl)-amine ig (4.31 g, 8.53 mm〇l), Add 6,7-dihydro 2H-pyrano[3,4-c]pyrrol-4-one i〇b (1. 52 g, u. 68 mm〇1), book broken cuprous copper (840 mg, 4.26) _丨) and Lai unloading (5·43 g, 25.58 mmol) 'in 8 〇 mL Ν, Ν-dimethylformamide, add Ν, Ν, _, methyl-1, / Ethylenediamine (0·5 rainbow, 4·26 mmol), heated to 68t: stir off the instrument. Thin layer analysis followed until the disappearance of the raw materials, the reaction solution was poured into the side stalk and the solid was precipitated under the mixture. Filtration, solid washing with water (5 〇 'vacuum drying, then the title product 2_{4_[3-chloro_4_(3_fluoro_dioxy)-anilino]_啥啥琳+基卜6, 7_二Argon '' 4 c] 1,4- ketone 1 〇 (3·57 g, yellow-green solid). Yield: 81.3%. 94389 93 201016683 MS m/z (ESI): 515[M+ 1] !HNMR ( 400MHz, dUSO-de): δ 9. 81(s, 1H), 8. 74(d, 1H, J=2. 0), 8.61(s, 1H), 8.26(d, 1H, J=2. 0 ), 8. 23(dd, 1H, J=9.0), 8.02(d, 1H, J=2.8), 7. 90(d, 1H, J=:8. 8), 7.74(dd, 1H, J= 8.8), 7.53(s, 1H), 7. 48(q, 1H), 7. 34(m, 3H), 7. 19(t, 1H), 5.28(s, 2H), 4.49(t, 2H, J = 5. 8), 2.91 (t, 2H, J = 5.8) Example 11 N-(5-{4-[3-oxo-4-(3-fluoro-benzyl-chlorinamide-l-quinazoline)啾:=^::^| ❹-1 氏二°比咯-2-基甲)-1^' .1\1,-two 7. 1-1. 2-Ethylenediamine

-1H-D比咯-2-甲醛氨氣下在50 mL茄形瓶中加入本發明實施例8所得的化合物[3-氯-4-(3~•氟-苄氧基）_苯基]_[6_(1H_0比咯_2_ 基）土圭啉-4-基]-胺 go. 〇2 g ’ 2· 30 mmol) ’ 溶於 1〇 mL N，N-—甲基甲醯胺中，_15C>c攪拌下，加入三氯氧磷（〇. 3 mL 3· 45 mm〇1) ’室溫攪拌過夜。薄層分析追縱至原料消 94 94389 201016683 失，加入10 mL冰水，用IN氫氧化鈉溶液調pH至11，過濾，固體真空乾燥，則得到標題產物5-{4-[3-氯-4-(3-氟 _苄氧基苯胺基]-喹唑啉~6-基}-1H-吡咯-2-甲醛11a (0.686 g，墨綠色固體）粗產品。產率：63.1%。 MS m/z (ESI) ： 473[M+ 1] !HNMR (400MHz, DMSO-dO： ά I2.44(s, 1H), 9. 76(s, 1H), 9.56(s, 1H), 8.90(s, 1H), 8. 59(s, 1H), 8.40(d, 1H, J=9.2), 8.04(s, 1H), 7.81(d, 1H, J=8. 8), 7. 75(dd, 1H, J=8.8), 7.46(m, 1H), 7. 33(m, 3H), 7. 20(m, 2H), 7. 02(s, β 1H)，5. 28(s，2H) -第二步 1^-(5-{4-[3-氣-4-(3-氟-苄氧基）_苯胺基]—啥嗤淋-6- 基}-1H-d比咯-2-基甲基）-N’，N，-二乙基-1，2 -乙二胺 100 mL茄形瓶中加入5-{4-[3-氯-4-(-3-氟-苄氧基）--苯胺基]-喹唑啉-6-基}-111-吡咯-2-曱醛lla(294 mg，0.62 mmol)和 n，N-—乙基-1，2-乙二胺（139 mg，1. 2 mmol)，溶 ❾於10 mL四氫呋喃和〇. 2 mL曱醇的混合溶劑中，室溫攪拌 30为鐘’加入氰基獨氫化納（8〇呢，1.2 mmo 1 )，室溫擾掉4小時。薄層分析追蹤至原料消失，加入5〇水，用乙酸乙酯萃取（5〇x3)，合併有機相，乙酸乙酯層用無水硫酸鎂脫水，過濾，濾液減壓濃縮，用矽膠管柱層析法純化所得殘餘物，則得到標題產物卜（5_{4_[3_氯_4__(3_氟—苄氧基）-苯胺基]-喹唑啉基}_1H_吡咯_2_基甲基） N，N —乙基-1，2 -乙二胺11 (35 mg，黃色固體）。產率： 94389 95 201016683 10. 2%。 MS m/z (ESI) : 573[M+ 1] ^NMR (400MHz, DMSO-dO: ^ 11.82(s, 1H), 9. 84(s, 1H), 9.10(s, 1H), 8.55(s, 1H), 8. 26(s, 1H), 8. 14(d, 1H, J=8. 4), 7. 98(d, 1H, J = 8.4), 7. 75(d, 1H, J=8.4), 7.47(m, 1H), 7. 33(m, 3H), 7. 19(t, 1H), 6. 73(s, 1H), 6.19(s, 1H), 5.26(s, 2H), 2. 84(dd, 4H, J=13.8), 2.73(d, 4H, J=6. 8), 1.36(s, 1H), 1.26(s, 1H), 1.06(t, 6H, J=6. 6) β實施例12 -氯-4-(3-氟-苄氧基）-笨基甲確酿基歷基）-甲基]-1Η-°比洛-2-基}-啥畦吨-i-基）-胺-1H-D The compound obtained in Example 8 of the present invention [3-chloro-4-(3~•fluoro-benzyloxy)-phenyl] was added to a 50 mL eggplant-shaped flask under a molar ammonia-formaldehyde ammonia solution. _[6_(1H_0比咯_2_yl)Couguanolin-4-yl]-amine go. 〇2 g '2· 30 mmol) 'dissolved in 1〇mL of N,N-methylcarbamide, _15C>c was stirred, and phosphorus oxychloride (〇3 mL 3·45 mm〇1) was added. Thin layer analysis to the raw material to eliminate 94 94389 201016683 loss, add 10 mL of ice water, adjust the pH to 11 with IN sodium hydroxide solution, filter, solid vacuum drying, then the title product 5-{4-[3-chloro- 4-(3-Fluoro-benzyloxyanilino)-quinazoline~6-yl}-1H-pyrrole-2-carbaldehyde 11a (0.686 g, dark green solid) crude product. Yield: 63.1%. /z (ESI): 473[M+ 1] !HNMR (400MHz, DMSO-dO: ά I2.44(s, 1H), 9. 76(s, 1H), 9.56(s, 1H), 8.90(s, 1H), 8. 59(s, 1H), 8.40(d, 1H, J=9.2), 8.04(s, 1H), 7.81(d, 1H, J=8. 8), 7. 75(dd, 1H , J=8.8), 7.46(m, 1H), 7. 33(m, 3H), 7. 20(m, 2H), 7. 02(s, β 1H), 5. 28(s,2H) - The second step is 1^-(5-{4-[3-Ga-4-(3-fluoro-benzyloxy)-anilino]-indole-6-yl}-1H-d ratio -2- 5-{4-[3-chloro-4-(-3-fluoro-benzyloxy) was added to a 100 mL eggplant vial of methyl-)N-,2-diethyl-1,2-ethanediamine )--anilino]-quinazolin-6-yl}-111-pyrrole-2-furaldehyde lla (294 mg, 0.62 mmol) and n,N-ethyl-1,2-ethanediamine (139) Mg, 1. 2 mmol), dissolved in 10 mL of tetrahydrofuran and hydrazine. 2 mL of decyl alcohol in a mixed solvent, stirring at room temperature for 30 minutes Add cyanomonohydrogen (8 〇, 1.2 mmo 1 ), and dissipate for 4 hours at room temperature. Trace the trace to the disappearance of the starting material, add 5 〇 water, extract with ethyl acetate (5 〇 x 3), and combine the organic phases. The ethyl acetate layer is dehydrated with anhydrous magnesium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The obtained residue is purified by column chromatography to give the title product (5_{4_[3_chloro_4__(3_fluoro-) Benzyloxy)-anilino]-quinazolinyl}_1H_pyrrole-2-ylmethyl) N,N-ethyl-1,2-ethanediamine 11 (35 mg, yellow solid). </ RTI> <RTIgt; , 1H), 8.55(s, 1H), 8. 26(s, 1H), 8. 14(d, 1H, J=8. 4), 7. 98(d, 1H, J = 8.4), 7. 75(d, 1H, J=8.4), 7.47(m, 1H), 7. 33(m, 3H), 7. 19(t, 1H), 6. 73(s, 1H), 6.19(s, 1H ), 5.26(s, 2H), 2. 84(dd, 4H, J=13.8), 2.73(d, 4H, J=6. 8), 1.36(s, 1H), 1.26(s, 1H), 1.06 (t, 6H, J=6. 6) β Example 12 -Chloro-4-(3-fluoro-benzyloxy)-stupyl-based thiolatyl)-methyl]-1Η-°Bilo- 2-based}-xanthene-i-yl)-amine

甲績酿-乙胺鹽酸鹽2b的反應，得，用矽膠管柱層析法純化所The reaction of A-flavored-ethylamine hydrochloride 2b, obtained by purifying the column chromatography

唑啉—4—基）—胺12 (21 mg，黃色固體）。產率：9 1% -17比嘻-2 -基} -啥重複本發明實施例11第一步至第二步的反應，使用上述第一步中所得到的化合物5-{4-[3-氯-4-(3-氟-苄氧基）本胺基]-嗟嗤琳-6-基}-111-°比洛-2-曱酸11£作原料，按照本發明實施例11第二步所述相同方式進行該原料與2_ 94389 96 201016683 MS m/z (ESI) ： 580[M+1] ^NMR (400MHz, DMS0-d6): (5 11.90(s, 1H), 9. 86(s, 1H), 8.93(s, 1H), 8. 57(s, 1H), 8. 14(d, 2H), 7. 83(m, 2H), 7.48(q, 1H), 7. 32(q, 3H), 7. 20(t, 1H), 6. 82(s, 1H), 6.40(s, 1H), 5.28(s, 2H), 4.27(s, 2H), 3. 57(m, 2H), 3.39(m, 2H>, 3. 15(s, 3H) 實施例13 1-{4-「3-氣-4-(3 -氟-苄氧基）-笨胺暮啥峻琳-6-基} ：^-(2-羥基-乙基）-111-吡咯-3-甲酸-(2-二匕胺基-乙基）-©星Oxazoline-4-yl)-amine 12 (21 mg, yellow solid). Yield: 9 1% -17 to 嘻-2 -yl}-oxime The reaction of the first step to the second step of Example 11 of the present invention was repeated using the compound 5-{4-[3 obtained in the above first step. -Chloro-4-(3-fluoro-benzyloxy)-amino-amino]-indolyl-6-yl}-111-°Pilo-2-decanoic acid 11 £ as starting material, according to Example 11 of the present invention The starting material was carried out in the same manner as described in the two steps with 2_94389 96 201016683 MS m/z (ESI): 580 [M+1] ^NMR (400 MHz, DMS0-d6): (5 11.90 (s, 1H), 9.86 (s, 1H), 8.93(s, 1H), 8. 57(s, 1H), 8. 14(d, 2H), 7. 83(m, 2H), 7.48(q, 1H), 7. 32 (q, 3H), 7. 20(t, 1H), 6. 82(s, 1H), 6.40(s, 1H), 5.28(s, 2H), 4.27(s, 2H), 3. 57(m , 2H), 3.39 (m, 2H>, 3. 15(s, 3H) Example 13 1-{4-"3-Gas-4-(3-fluoro-benzyloxy)- phenoamine -6-yl} :^-(2-hydroxy-ethyl)-111-pyrrole-3-carboxylic acid-(2-diguanylamino-ethyl)-© star

氮氣下在25 mL祐形瓶中加入本發明實施例1〇第二— 所得的化合物2-U餐氯-4令氟_¥氧基）_苯胺基]_b 终6—基卜6, 7_二氫，，喃[3, Η]料+酮10(5(] mg，0.971mmol)，溶於2麵、二乙基-u—乙二胺中 =熱至85C擾拌過夜。薄層分析追蹤至原料消失液減壓濃縮，时膠管柱層析㉔化料殘餘物，再用h 94389 97 201016683 乙酸乙酯重結晶，則得到標題產物卜彳4-[3-氣-4-(3-氟-节氧基）-笨胺基]-啥°坐琳-6-基}-4-(2-經基-乙基）-1JJ-»比咯-3-曱酸-(2-二乙胺基-乙基）_胺13(274 mg，淡黃色固體）。產率：44.7% 〇 MS m/z (ESI) ： 631[M+ 1] JHNMR (400MHz, DMSO-d〇： <5 9.85(s, 1H), 8. 62(d, 1H, J-2. 0), 8. 59(s, 1H), 8.09 (dd, 1H, J=9. 0), 8. 00(dd, 2H, J=9. 0), 7.89(m, 2H), 7. 74(dd, 1H, J=9. 0), 7. 48(q, 1H) , 7.39(d, 1H, J = 2.0), 7. 33(q, 3H), 7. 19(t, 1H), 〇 5. 27(s, 2H), 4.82(s, 1H), 3. 66(s, 2H), 3.30(m, 3H), -2.90(ΐ, 2H, J=6.8), 2.53(m, 5H), 0. 99(t, 6H, J=7. 2) 實施例14 S二（l-{4-「3-氣-4-C3-氟-苄氧基）-芏胺某1-喹唑啉一β-其i '二 1Η-η比咯-3-基曱基）-Ν，，Ν，-二乙篡-1. 2-乙二胺In the 25 mL flask, the first embodiment of the present invention was added to a 25 mL flask. The resulting compound 2-U was prepared as a chloroform-4 fluoroacetic acid acetanilide] _b final 6-yl group 6, 7_ Dihydro, methane [3, oxime] material + ketone 10 (5 () mg, 0.971 mmol), dissolved in 2-sided, diethyl-u-ethylenediamine = hot to 85 C overnight overnight. Thin layer analysis The product was traced to the disappearance of the starting material under reduced pressure. The residue was purified by column chromatography eluting with EtOAc EtOAc EtOAc EtOAc Fluorine-nodaloxy)-phenylamino]-啥°坐琳-6-yl}-4-(2-trans-ethyl-ethyl)-1JJ-»bi--3-indole-(2-diethyl) Amino-ethyl)-amine 13 (274 mg, pale yellow solid). Yield: 44.7% 〇MS m/z (ESI): 631 [M+ 1] JHNMR (400 MHz, DMSO-d〇: <5 9.85 (s, 1H), 8. 62(d, 1H, J-2. 0), 8. 59(s, 1H), 8.09 (dd, 1H, J=9. 0), 8. 00(dd, 2H , J=9. 0), 7.89(m, 2H), 7. 74(dd, 1H, J=9. 0), 7. 48(q, 1H) , 7.39(d, 1H, J = 2.0), 7. 33(q, 3H), 7. 19(t, 1H), 〇 5.27(s, 2H), 4.82(s, 1H), 3. 66(s, 2H), 3.30(m, 3H) , -2.90(ΐ, 2H, J=6.8), 2.53(m, 5H), 0. 99(t, 6H, J=7.2) 14 S bis(l-{4-"3-Gas-4-C3-fluoro-benzyloxy)-decylamine 1- quinazoline-β- its i 'di- 1 Η-η-pyrrol-3-ylindole Base)-Ν,,Ν,-二乙篡-1. 2-Ethylenediamine

重複本發明實施例5第一步至第二步的反應，使用上述第二步中所得到的化合物1-{4-[3-氯-4-(3-氟-苄氧基） -苯胺基]-喹唑啉-6-基}-111-吡咯-3-曱醛5c作原料，按照本發明實施例5第三步所述相同方式進行該原料與N，N-二乙基-1，2-乙二胺的反應，用乙酸乙酯和正己烷重結晶，則得到標題產物N-(l-{4-[3-氯-4-(3-氟-苄氧基）_苯胺基]-喹唑啉-6-基}-111-吡咯-3-基甲基）-N’，N，-二乙基 98 94389 201016683 -1，2-乙二胺14(60 mg，黃色固體）。產率：43. 8%。 MS m/z (ESI) ： 573[M+1] ^NMR (400MHz, DMSO-dO： ά 8.60(s, 1H), 8. 58(s, 1H), 8.10(dd，1H，J=2.2)，8.19(d，1H, J=2.4)，7. 89(d，1H， J=8.8)，7.60(dd，1H，>2.4)，7.62(s，1H)，7.56(s，iH)， 7.48(q, 1H), 7. 32(m, 3H), 7. 18(t, 1H), 6. 51 (s, 1H), 5.27(s, 2H), 3.88(s, 2H), 2. 85(s, 2H), 2. 68(s, 4H), 2. 51(s, 2H), 1. 〇〇(t, 6H) 實施例15 ❹-4-(3-氟-苄氳某）-苯基1-(6-丨嗎啉-4-羞 ~基胺基）-甲基~1-°比洛-1-某}-者唾吸—4-美）-胺The reaction of the first step to the second step of Example 5 of the present invention was repeated, and the compound 1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-anilinyl group obtained in the above second step was used. ]-quinazoline-6-yl}-111-pyrrol-3-furaldehyde 5c as a starting material, the starting material and N,N-diethyl-1 are carried out in the same manner as described in the third step of Example 5 of the present invention. The reaction of 2-ethylenediamine is recrystallized from ethyl acetate and n-hexane to give the title product N-(l-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino] -quinazolin-6-yl}-111-pyrrol-3-ylmethyl)-N',N,-diethyl 98 94389 201016683 -1,2-ethylenediamine 14 (60 mg, yellow solid). Yield: 43.8%. MS m/z (ESI): 573 [M.sup.. , 8.19 (d, 1H, J = 2.4), 7. 89 (d, 1H, J = 8.8), 7.60 (dd, 1H, > 2.4), 7.62 (s, 1H), 7.56 (s, iH), 7.48(q, 1H), 7. 32(m, 3H), 7. 18(t, 1H), 6. 51 (s, 1H), 5.27(s, 2H), 3.88(s, 2H), 2. 85(s, 2H), 2. 68(s, 4H), 2. 51(s, 2H), 1. 〇〇(t, 6H) Example 15 ❹-4-(3-Fluoro-benzyl hydrazine) -Phenyl 1-(6-indolomorph-4-pyry-ylamino)-methyl~1-°Pilo-1-some}-salt- 4-mer)-amine

重複本發明實施例5第一步至第二步的反應，使用上述第二步中所得到的化合物1~{4-[3-氯-4_(3-氟-苄氧 ❹基）-苯胺基]-喹唑啉-6-基}-lH-吡咯-3-甲藤5c作原料，按知本發明實施例5第三步所述相同方式進行該原料與2一嗎淋-4-基-乙胺鹽酸鹽的反應，用乙酸乙酯重結晶所得固體，則得到標題產物[3-氯-4-(3-氟-苄氧基）-苯基]-(6_ {3-[(2-嗎啉-4-基-乙基胺基）-甲基]_吡咯-卜基卜喹唑啉 -4-基）-胺15 (20 mg，黃色固體）。產率：50%。 MS m/z (ESI) ： 587[M+ 1] !HNMR (400MHz, dUSO-de)： δ 8. 60(d, 1H, J = l. 6), 8. 55(s, 99 94389 201016683 1H), 8.09(dd, 1H, J = 9. 2), 8. 02(d, 1H, J = 2. 0), 7. 84(d, 1H, 1 = 9.2), 7.76(dd, 1H, J = 8. 8), 7. 56(d, 2H), 7. 46(q, 1H), 7. 30(m, 3H), 7. 18(t, 1H), 6. 39(s, 1H), 5. 24(s, 2H), 3.56(s, 4H), 2. 77(t, 2H), 2. 46(t, 2H), 2. 35(s, 4H), 1.82(s, 2H) 實施例16 2-{4-「3-氣-4-(3-氟-苄氧基）-笨胺基卜喹唑啉-6-基} _5，6_二氮_211_環戍烧[(3]15比洛_4_闕The reaction of the first step to the second step of Example 5 of the present invention was repeated, and the compound 1~{4-[3-chloro-4_(3-fluoro-benzyloxyindenyl)-anilinyl group obtained in the above second step was used. ]-quinazoline-6-yl}-lH-pyrrole-3-methyl vine 5c as a raw material, the raw material and 2 chloropyrim-4-yl-B are carried out in the same manner as described in the third step of the present invention. Reaction of the amine hydrochloride, the obtained solid was crystallized from ethyl acetate to give the title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6_{3-[(2- Morpholin-4-yl-ethylamino)-methyl]-pyrrole-bukibrazolin-4-yl)-amine 15 (20 mg, yellow solid). Yield: 50%. MS m/z (ESI): 587 [M+ 1] <RTI ID=0.0>> , 8.09(dd, 1H, J = 9. 2), 8. 02(d, 1H, J = 2. 0), 7. 84(d, 1H, 1 = 9.2), 7.76(dd, 1H, J = 8. 8), 7. 56(d, 2H), 7. 46(q, 1H), 7. 30(m, 3H), 7. 18(t, 1H), 6. 39(s, 1H), 5. 24(s, 2H), 3.56(s, 4H), 2. 77(t, 2H), 2. 46(t, 2H), 2. 35(s, 4H), 1.82(s, 2H) Example 16 2-{4-"3-Gas-4-(3-fluoro-benzyloxy)- phenylaminoquinazolin-6-yl} _5,6-diaza_211_cyclic oxime [( 3]15 Billo _4_阙

第一步 5，6_二氮_2Η~·環戊炫[c]%b^§·-4 -晒在0°C下於50 mL三口瓶中加入對曱苯磺醯基異乙腈 (2. 56 g，13. 1 mmo 1 )，溶於12mL四氫°夫喃，滴加入1，8-二氮雜二環[5, 4, 0]十一碳-7-烯（2. 0 g，13. 4 mmol)，0°C 攪拌15分鐘。滴加入環戊浠-2-_ 16a( 1. 0 g’ 11. 9 mmol)，室温攪拌2小時。薄層分析追蹤至原料消失，倒入50 mL 100 94389 0201016683First step 5,6_Dinitrogen 2Η~·Cyclopentyl[c]%b^§·-4 - Add p-phenylsulfonyl isoacetonitrile in a 50 mL three-neck bottle at 0 °C (2 56 g,13. 1 mmo 1 ), dissolved in 12 mL of tetrahydrofuran, and added 1,8-diazabicyclo[5,4,0]undec-7-ene (2.0 g) , 13. 4 mmol), stir at 0 ° C for 15 minutes. Cyclopentanyl-2- 16a (1.0 g' 11. 9 mmol) was added dropwise and stirred at room temperature for 2 hr. Thin layer analysis traced to disappearance of raw materials, poured into 50 mL 100 94389 0201016683

白色固體）。產率：52%。縮蒸除四氫呋喃，用乙酸乙醋萃用無水硫酸鎂脫水’過濾，遽液析法純化所得殘餘物，則得到標 c>比咯-4-酮 16b(749 MS m/z (ESI) ： 122[M+1] lHNMR(4_Hz，DMS〇-㈨mms，1H)，7.16(dd，1H， J = 2.8), 6.64(d, 1H, J = 0.8), 2. 80(t, 2H), 2.71(t, 2H) 第二步 ❹2-{4-[3-氣-4-(3-氟-苄氧基）_苯胺基]_喹唑啉_6_基} -5，6 - —風- 2H -環戍烧[c]w比哈-4 -酮重複本發明實施例1第一步至第五步的反應，使用上 •述第五步中所得到的化合物[3_氣_4_(3_氟_苄氧基）一笨基]-(6-碘-喹唑啉-4-基）-胺lg作原料，按照本發明實施例1第六步所述相同方式進行該原料與5, 6_二氫_2jj—環戊院[c ] η比洛-4-酮16b的反應’用二氣甲烷重結晶，則得到 ❹標題產物2-{4-[3-氣-4-(3-氟-苄氧基）_苯胺基]-喹唑啉 -6-基}-5,6-二氫-211-環戊烷[^]吡咯-4-酮16(21111^，白色固體）。產率：42. 3%。 MS m/z (ESI) ： 499[M+1] 'HNMR (400MHz, DMS0-JO： δ 9. 79(s, 1H), 8. 75(d, m J = 2.4), 8.62(s, 1H), 8.22(dd, 1H, J = 9. 0), 8. 02(d, 2H), 7.90(d，lH)，7.75(dd，1H’ J=8.8)，7.50(m，2H)，7.35(m, 3H), 7.18(t, 1H), 5.28(s, 2H), 2. 97(t, 2H), 2. 83(q, 94389 101 201016683 2H) 實施例17White solid). Yield: 52%. The residue was purified by trituration with EtOAc (EtOAc) eluting with EtOAc EtOAc EtOAc (EtOAc) [M+1] lHNMR (4_Hz, DMS〇-(9) mms, 1H), 7.16 (dd, 1H, J = 2.8), 6.64 (d, 1H, J = 0.8), 2. 80(t, 2H), 2.71 ( t, 2H) The second step ❹2-{4-[3-Ga-4-(3-fluoro-benzyloxy)-anilino]-quinazoline_6_yl} -5,6 --wind - 2H - Cyclone[c]w than Haha-4-ketone repeats the reaction of the first step to the fifth step of Example 1 of the present invention, using the compound obtained in the fifth step of the above [3_气_4_(3 _Fluoro-benzyloxy)-phenyl]-(6-iodo-quinazolin-4-yl)-amine lg is used as a starting material, and the raw material is carried out in the same manner as described in the sixth step of Example 1 of the present invention. 6_Dihydro-2jj-cyclopentanol [c] η-pyr-4-one 16b reaction 'recrystallized from di-methane to give the title product 2-{4-[3- gas-4-(3 -Fluoro-benzyloxy)-anilino]-quinazolin-6-yl}-5,6-dihydro-211-cyclopentane[^]pyrrol-4-one 16 (21111^, white solid). Yield: 42.3% MS m/z (ESI): 499 [M+1] 'HNMR (400 MHz, DMS0-JO: δ 9. 79 (s, 1H), 8. 75(d, m J = 2.4), 8.62(s, 1H), 8.22(dd, 1H, J = 9. 0), 8. 02(d, 2H), 7.90(d , lH), 7.75 (dd, 1H' J = 8.8), 7.50 (m, 2H), 7.35 (m, 3H), 7.18 (t, 1H), 5.28 (s, 2H), 2. 97 (t, 2H) ), 2. 83(q, 94389 101 201016683 2H) Example 17

l.-iii [ 3—氟—芊氣某茉胺某·|_喹唑啉-6_某} -~d笔義1二比略-3-某甲某-ρ底哄~~1-甚、-L.-iii [ 3 - fluoro-helium gas a certain sulphate · | _ quinazoline-6 _ a certain } - ~ d pen meaning 1 two than slightly -3- a certain - ρ bottom 哄 ~ ~ 1- very ,-

jaF 重複本發明實施例10第一步至第二步的反應，使用上述第二步中所得到的化合物2-{4-[3-氯-4-(3-氟-苄氧基） -苯胺基]-喹唑啉_6_基卜6, 7_二氫_2H_吡喃[3,4_c]吡咯 .-4-酮10作原料’按照本發明實施例13所述相同方式進、行該原料與1 一甲基-哌畊的反應，用矽膠管柱層析法純化所付殘餘物’得到標題產物[1 _{4- [ 3-氣-4-(3-氟-节氧基）_本胺基]-啥唾琳-6-基}-4-(2-經基-乙基）_ih-d比洛 ❺-3 -基]-(4 -曱基辰卩井-1-基）-甲_ 17 (366 mg，淺黃色固體）。產率：77. 7%。 MS m/z (ESI) ： 615[M+1] ]HNMR (400MHz, DMSO-c?〇: 5 9. 77(s, 1H), 8.58(s, 2H), 8.16(dd, 1H, J = 9.0), 8.01(d, „1H, J=2.8), 7. 86(d, 1H, J = 8.8), 7.73(dd, 1H, J=9. 0), 7. 66(d, ih, j = 2. 0), 7.48(q, 2H), 7. 34(q, 3H), 7. 19(t, 1H), 5. 28(s, 2H), 4.69(t, 1H, J = 1.2), 3.58(t, 6H), 2. 69(t, 2H, J = 3. 2), 94389 102 201016683 2. 33(s, 4H), 2.21(s, 3H) 實施例18jaF The reaction of the first step to the second step of Example 10 of the present invention is repeated, and the compound 2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-aniline obtained in the above second step is used. a quinazoline-6-yl b,6-dihydro-2H-pyran[3,4_c]pyrrole-4-one 10 as a starting material 'in accordance with the same manner as described in Example 13 of the present invention The reaction of the starting material with 1-methyl-piperidine was carried out by purifying the residue by hydrazine column chromatography to give the title product [1 _{4-[ 3- gas-4-(3-fluoro- ethoxy) )_本胺基]-啥啥琳-6-yl}-4-(2-Ph-ethyl-ethyl)_ih-d 比洛❺-3-yl]-(4 -曱基辰卩井-1- Base)-A-17 (366 mg, pale yellow solid). Yield: 77.7%. MS m/z (ESI): 615 [M+1]]HNMR (400 MHz, DMSO-c?: 5 9. 77 (s, 1H), 8.58 (s, 2H), 8.16 (dd, 1H, J = 9.0), 8.01(d, „1H, J=2.8), 7. 86(d, 1H, J = 8.8), 7.73(dd, 1H, J=9. 0), 7. 66(d, ih, j = 2. 0), 7.48(q, 2H), 7. 34(q, 3H), 7. 19(t, 1H), 5. 28(s, 2H), 4.69(t, 1H, J = 1.2) , 3.58(t, 6H), 2. 69(t, 2H, J = 3. 2), 94389 102 201016683 2. 33(s, 4H), 2.21(s, 3H) Example 18

重複本發明實施例10第一步至第二步的反應，使用上述第二步中所得到的化合物2-{4-[3-氯-4-(3-氟-苄氧基） -苯胺基]-啥唑琳-6-基}_6,7-二氫-2Η-β比喃[3, 4_<3]°比咯 -4-酮10作原料’按照本發明實施例13所述相同方式進行該原料與2-嗎啉-4-基-乙胺的反應.，用矽膠管枉層析^法純化所得殘餘物，則得到標題產物1-{4-[3—氯(3氣苄氧基）-苯胺基]-喹唑啉-6-基卜4-(2-羥基/乙基）1Η比，：炎黃色固咯-3-曱酸-(2-嗎啉-4-基-乙基）-胺18(50 、體）。產率：13. 3%。 MS m/z (ESI) ： 645ΓΜ+ 1] 1 τ、 8 64(d，1Η， WNMRUOOMHz，DMSO-A): 5 9.87(s，lH)， 7.41(s, 1H), 4.83(s, 1H), 2>g〇(t, 2H), J=1.6)，8.59(s, 1H)，8.10(d, 1H)，8. 02(山 2H), 7. 75(dd, 1H, J=8. 8), 7.48(q, 1H), 7. 33(q, 3H), 7. 19(t, 1H), 5. 27(s, 2H), 3. 65(t, 2H), 3.60(t, 4H), 3.38(ra, 2H), 94389 103 201016683 2.45(m, 6H) 實施例19 [Q.__(3-[ 1，支丄^哌啶基_ι’ _基甲某比也-卜基）一唼唑说 :±1棊_]-[3：：J^-(3-氟-节氣基芏其]•胺The reaction of the first step to the second step of Example 10 of the present invention was repeated, and the compound 2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-anilinyl group obtained in the above second step was used. ]- oxazolidin-6-yl}_6,7-dihydro-2Η-β than silane [3, 4_<3]° pyrol-4-one 10 as a starting material 'in the same manner as described in Example 13 of the present invention The reaction of the starting material with 2-morpholin-4-yl-ethylamine is carried out. The obtained residue is purified by hexane chromatography to give the title product 1-{4-[3-chlorobenzene -)-anilino]-quinazoline-6-yl b 4-(2-hydroxy/ethyl) 1 fluorene ratio, inflammatory yellow solid-tert--3-decanoic acid-(2-morpholin-4-yl-B Base)-amine 18 (50, body). Yield: 13.3%. MS m/z (ESI): 645 ΓΜ + 1] 1 τ, 8 64 (d, 1 Η, WNMRUOO MHz, DMSO-A): 5 9.87 (s, lH), 7.41 (s, 1H), 4.83 (s, 1H) , 2>g〇(t, 2H), J=1.6), 8.59(s, 1H), 8.10(d, 1H), 8. 02(Mountain 2H), 7. 75(dd, 1H, J=8. 8), 7.48(q, 1H), 7. 33(q, 3H), 7. 19(t, 1H), 5. 27(s, 2H), 3. 65(t, 2H), 3.60(t, 4H), 3.38 (ra, 2H), 94389 103 201016683 2.45(m, 6H) Example 19 [Q.__(3-[ 1, 丄丄哌哌哌哌哌 _ _ 卜卜卜卜卜卜) carbazole says: ±1棊_]-[3::J^-(3-fluoro-gas 芏 ] ])•amine

重複本發明實施例5第一步至第二步的反應，使用上述第二步中所得到的化合物卜U-[3-氯-4-(3-氟-苄氧基） ® -苯胺基]-喹唑啉-6-基卜1H_吡咯_3_甲醛5c作原料，按照本發明實施例5第三步所述相同方式進行該原料與4—哌咬基娘咬的反應，用乙酸乙酯重結晶所得固體，則得到標 •題產物[6_(3-[1，4,]雙哌啶基-1’-基甲基比咯-卜基）_喹唑啉-4-基]-[3-氣-4-(3-氟-苄氧基）—苯基]-胺19 (6〇 mg ’淺褐色固體）。產率：60. 1%。 MS m/z (ESI) ： 625[M+ 1] ⑩1HNMR(400MHz，DMSO-A): 5 8.61(d，1H，J=2.0)，8.55(s 1H), 8.12(dd, 1H, J = 8.8), 8. 03(d, 1H, J = 2. 8), 7. 85(d, 1H, J = 9.2), 7.76(dd, 1H, J = 8.8), 7.50(m, 3H), 7. 32(q, 3H), 7. 18(t, 1H), 6.31(s, 1H), 5. 26(s, 2H), 3. 43(s, 2H), 2. 50(m, 5H), 1.70(m, 4H), 1.40(ra, 10H) 實施例20 [3-氣-4_-(3-氟-苄氧基）-苯基]-(6-丨3-「（2-哌啶基胺基）-甲基1_p比嘻-1-基} - p奎p坐蛛_4-基）-胺 94389 104 201016683The reaction of the first step to the second step of Example 5 of the present invention was repeated, and the compound obtained in the above second step, U-[3-chloro-4-(3-fluoro-benzyloxy) ® -anilino] was used. - quinazoline-6-ylpyr 1H_pyrrole_3_formaldehyde 5c as a raw material, the reaction of the raw material with 4-piperidine bitumen is carried out in the same manner as described in the third step of Example 5 of the present invention, using acetic acid The solid obtained by recrystallization of the ester gave the title product [6_(3-[1,4,]bispiperidinyl-1'-ylmethylpyrrole-bry)-quinazolin-4-yl]- [3-Gas-4-(3-fluoro-benzyloxy)-phenyl]-amine 19 (6 〇 mg 'light brown solid). Yield: 60. 1%. MS m/z (ESI): 625 [M + 1] <RTI ID=0.0>>&&&&&&&&&&&&&&&& , 8. 03(d, 1H, J = 2. 8), 7. 85(d, 1H, J = 9.2), 7.76(dd, 1H, J = 8.8), 7.50(m, 3H), 7. 32 (q, 3H), 7. 18(t, 1H), 6.31(s, 1H), 5. 26(s, 2H), 3. 43(s, 2H), 2. 50(m, 5H), 1.70 (m, 4H), 1.40 (ra, 10H) Example 20 [3- gas-4_-(3-fluoro-benzyloxy)-phenyl]-(6-indole3-"(2-piperidinylamine) Base)-methyl 1_p is more than 嘻-1-yl} - p-quine p-spidula _4-yl)-amine 94389 104 201016683

重複本發明實施例5第一步至第二步的反應，使用上述第二步中所得到的化合物1-{4-[3-氯-4-(3-氟-苄氧基） -苯胺基]-喹唑啉-6-基}-111-吡咯-3-甲醛5c作原料，按照本發明實施例5第三步所述相同方式進行該原料與2-哌 °定-1 -基-乙胺的反應’用乙酸乙酯重結晶所得固體，則得到標題產物[3-氣- 4-(3-氟-节氧基）-苯基]-(6_{3-[(2-娘啶-1-基-乙基胺基）-曱基]-吡咯_1-基}_喹唑啉_4_基）一胺 20(48 mg，黃色固體）。產率：46. 7%。 MS m/z (ESI) : 585[M+ 1] • 'HNMR (400MHz, DMSO-d〇: 5 8. 58(t, 2H), 8.11(dd, 1H, \ J = 8.8), 8.02(d, 1H, J = 2. 4), 7. 86(d, 1H, J = 9. 2), 7.76(dd，1H，J=8.8), 7.52(m，2H)，7.46(t，1H), 7.32(q， 3H), 7. 18(t, 1H), 6.36(s, 1H), 5. 26(s, 2H), 3. 70(s, © 2H), 2.70(t, 2H), 2.35(m, 6H), 1.50(m, 6H) 實施例21The reaction of the first step to the second step of Example 5 of the present invention was repeated, and the compound 1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-anilinyl group obtained in the above second step was used. ]-quinazolin-6-yl}-111-pyrrole-3-carbaldehyde 5c as a starting material, the starting material and 2-piperidine-1 -yl-B are carried out in the same manner as described in the third step of Example 5 of the present invention. Reaction of the amine 'The solid obtained by recrystallization from ethyl acetate gave the title product [3- gas-4-(3-fluoro-hydroxy)-phenyl]-(6_{3-[(2----- 1-Methyl-ethylamino)-indenyl]-pyrrole-1-yl}-quinazoline-4-yl)monoamine 20 (48 mg, yellow solid). Yield: 46.7%. MS m/z (ESI): 585 [M + 1]: "HNMR (400 MHz, DMSO-d〇: 5 8. 58 (t, 2H), 8.11 (dd, 1H, \ J = 8.8), 8.02 (d, 1H, J = 2. 4), 7. 86(d, 1H, J = 9. 2), 7.76(dd,1H,J=8.8), 7.52(m,2H),7.46(t,1H), 7.32 (q, 3H), 7. 18(t, 1H), 6.36(s, 1H), 5. 26(s, 2H), 3. 70(s, © 2H), 2.70(t, 2H), 2.35( m, 6H), 1.50 (m, 6H) Example 21

多-1-基）-喹唑呲-4-篡卜脸Poly-1-yl)-quinazolin-4-篡b face

重複本發明實施例5第一步至第二步的反應，使用上 105 94389 201016683 述第二步中所得到的化合物[3_氯_4〜（3—氟〜苄& -苯胺基]-喹唑啉-6-基}-111-吡咯-3-甲醛5c作原料乳，）照本發明實施例5第三步所述相同方式進行該原料與2按基胺的反應’用乙酸乙酯重結晶所得固體，則得到乙物[3-氯-4-(3-氟-节氧基苯基H6_{3_[(2、呢唆二= 產乙基胺基）-甲基]-吡咯-1-基卜喹唑啉_4_基）_胺2 mg，黃色固體）。產率：63. 1%。 5〇 MS m/z (ESI) ： 630[M+ 1 ] HNMR (400MHz，DMSO-de): 5 8.63(s’ 1H)，8.58(s ijj) ❹ 8.14(dd，1H，J=9.2)’ 8.04(d，1H)，7.88(d，1H，j=8 8)’ 7.77(dd，1H，J=8.8)，7.64(s，1H)，7.57(s，1H)，7,48(， 1H)，7.32(m’ 3H)，7. 18(t，1H)，6.42(s，1H)，5. 27(sq’ 2H)，3.84(s，2H)，2.79(d’ 3H，J=5.2)，1.92(s，1H)’ 1.12(m, 6H) ’ ’ - ,· 實施例22 苄氧基）-笑胺某1-喹唑喊^^ Q二4一（t-甲羞:二0底基）-1Η-吼略-3-基1-乙醇The reaction of the first step to the second step of Example 5 of the present invention was repeated, using the compound obtained in the second step of 105 94389 201016683 [3_chloro-4~(3-fluoro-benzyl-ampic-anilinyl)- Quinazoline-6-yl}-111-pyrrole-3-carbaldehyde 5c as raw material milk,) The reaction of the starting material with 2 base amine was carried out in the same manner as described in the third step of Example 5 of the present invention. The solid obtained is recrystallized to give ethyl [3-chloro-4-(3-fluoro-pethoxyphenyl)H6_{3_[(2, 唆2 = ethylamino)-methyl]-pyrrole- 1-kibquinazoline-4-yl)-amine 2 mg, yellow solid). Yield: 63. 1%. 5 〇 MS m/z (ESI): 630 [M+ 1 ] HNMR (400 MHz, DMSO-de): 5 8.63 (s' 1H), 8.58 (s ijj) ❹ 8.14 (dd, 1H, J=9.2)' 8.04 (d,1H), 7.88(d,1H,j=8 8)' 7.77(dd,1H,J=8.8), 7.64(s,1H),7.57(s,1H),7,48(,1H) , 7.32 (m' 3H), 7. 18 (t, 1H), 6.42 (s, 1H), 5. 27 (sq' 2H), 3.84 (s, 2H), 2.79 (d' 3H, J = 5.2) , 1.92(s,1H)' 1.12(m, 6H) ' ' - ,· Example 22 Benzyloxy)- laughing amine Some 1-quinazole shouting ^^ Q two 4 one (t-jia shame: two zero bottom Base)-1Η-吼略-3-yl 1-ethanol

在50 mL莊形瓶中加入四氫鋁鋰（26 mg，〇. 68 _〇1)， 94389 106 201016683Add lithium tetrahydrogenate (26 mg, 〇. 68 _〇1) to a 50 mL bottle, 94389 106 201016683

乙基）-1Η-吡 ⑴ mg，〇· 27 咯-3-基]-(4-甲基-哌哄-ι_ '基）-甲酮 17(166 mmol)的5 mL四氳呋喃溶液，加熱回流4小時。薄層分析追蹤至原料消失，將反應液冷卻至室溫，加入1 mL無水甲醇，過濾，濾液減壓濃縮，用矽膠管柱層析法純化所得殘餘物’則得到標題產物2-[1-{4-[3-氣-4-(3-氟-节氧基）〜苯胺基]-喹唑啉-6-基}-4-(4-曱基-哌畊-1-基甲基）一吡咯-3-基]-乙醇22 (72 mg，黃色固體）。產率：45%。 ® MS m/z (ESI) ： 601[M+l] ]HNMR (400MHz, MSO-de): δ 9. 76(s, 1H), 8. 52(d, 2H) 8.11(d，1H，J=8.4)，8.01(s，1H)，7_83(d，1H’ J=8.8)’ ' 7.74(d，1H，J=8.0)，7.40(m，6H)，7.19(t，1H)，5.27(s’ • 2H), 5.03(s, 1H), 3.61(s, 2H), 3. 32(m, 2H), 2. 67(s， 2H), 2.35(m, 8H), 2.21(s, 3H) ’ 實施例23 _ 1(1 「3-氣-4-(3-氟-苄氧基）-茉胺基卜崦^林_6_其^ 二4-三氟甲基-1H-吡咯-3-基甲某）-Ν’，Ν’ -二Λ 二胺Ethyl)-1Η-pyridyl (1) mg, 〇·27-r--3-yl]-(4-methyl-piperidin-ι_ 'yl)-methanone 17 (166 mmol) in 5 mL of tetrahydrofuran, heated Reflux for 4 hours. The thin layer analysis was followed until the disappearance of the starting material, the reaction solution was cooled to room temperature, 1 mL of anhydrous methanol was added, filtered, and the filtrate was concentrated under reduced pressure, and the residue obtained was purified by column chromatography to give the title product 2-[1- {4-[3-Ga-4-(3-fluoro-hydroxy)~-anilino]-quinazolin-6-yl}-4-(4-indolyl-piped-1-ylmethyl) Monopyrrol-3-yl]-ethanol 22 (72 mg, yellow solid). Yield: 45%. ® MS m/z (ESI): 601 [M+l] ]HNMR (400MHz, MSO-de): δ 9. 76(s, 1H), 8. 52(d, 2H) 8.11(d,1H,J = 8.4), 8.01 (s, 1H), 7_83 (d, 1H' J = 8.8) ' ' 7.74 (d, 1H, J = 8.0), 7.40 (m, 6H), 7.19 (t, 1H), 5.27 ( s' • 2H), 5.03(s, 1H), 3.61(s, 2H), 3. 32(m, 2H), 2. 67(s, 2H), 2.35(m, 8H), 2.21(s, 3H Example ' _ 1 (1 "3-Gas-4-(3-fluoro-benzyloxy)-mosamine-based 崦崦 _ _ _ _ ^ ^ 4-trifluoromethyl-1H-pyrrole - 3-yl-methyl)-Ν',Ν'-di-diamine

^4389 107 201016683^4389 107 201016683

第一步 (H4-m(3n氧基）_苯胺基] -4-三氟甲基-lΗ-吡咯-3-基）-曱醇First step (H4-m(3noxy)-anilino]-4-trifluoromethyl-lΗ-pyrrol-3-yl)-nonanol

Ο “在50 mL祐形瓶加人卜{4_[3_氯_4_(3_氣‘节氧基）一苯胺基]基卜4_三氟甲基鲁㈣+甲酸乙醋 6(250 mg，0.40 mmol) ’溶於15 ‘四氫呋喃中攪拌下滴加入四氫鋁鋰(4〇 mg，！ mm〇1)的5以四氫呋喃溶液， 4(TC授拌過夜。薄層分析追縱至原料消失，加入μ無水曱醇’㈣n減壓濃縮，用謂管柱層析法純化所得殘餘物，則得到標題產物（1_{4_[3_氯_4_(3—氟1氧基）_ 苯胺基]-喹唑啉-6-基卜4_三氟曱基_1H—吡咯_3_基）一曱醇 23a(177mg，！色固體）。產率：76.3%。 MS m/z (ESI) : 543[M+1] 第二步 (l-{4-[3-氣-4-(3-氟-苄氧基卜苯胺基]_喹唑啉_6_基} 4二氣曱基-1Η-η比洛一3-基）-曱酸在100 mL茄形瓶加入鄰碘醯苯甲酸（185 mg，0.66 mmol)’溶於i〇mL二甲亞砜中，滴加入（卜{4_[3_氣一4 (3_ 氟-苄氧基）-苯胺基]-喹唑啉_6_基卜4_三氟甲基—1H_吡咯 108 94389 201016683 -3-基）-甲醇 23a(177 mg，0, 33 mmol)的 5 inL 二甲亞砜溶液，室溫攪拌過夜。薄層分析追蹤至原料消失，將反廡液倒入30 inL冰水中，減壓抽濾，固體用二氣甲烷重結^，則得到標題產物（1-{4-[3-氯-4-(3-氟-苄氧基苯胺基]_ 喹唑啉-6-基卜4-三氟甲基-1H-吡咯基）一甲醛23b(n9 mg，黃色固體）。產率：70. 0%。 MS m/z (ESI) ： 541[M+1] 第三步 N-(l-{4-[3-氣-4-(3-氟-苄氧基）-苯胺基]-喹唑啉_6_ 基}-4-三氟甲基-1H-吡咯-3-基甲基）-n’，N，-二乙美y 2一乙二胺土’ 在25 mL茄形瓶加入（i-{4-[3-氯-4-(3-氟〜苄氧基）_ 苯胺基]-喹唑啉-6-基}-4-三氟曱基-1H_吡咯_3_基）_甲醛 23b(40 mg，0.075 mmol)和 N，N-二乙基r 丞乙二胺（10 mg，0.08mm〇l) ’溶於5inL二氯甲烷中，反應3小時後， ❹ 加入三乙醯氧基硼氫化鈉（32 mg，0.15咖〇1)。室溫攪拌 3—天。薄層分析追蹤至原料消失，加入2〇虮飽和2化鈉溶液，用二氯甲烷萃取（2〇mLx3)，合併有機相，用無水硫酸鎂脫水，過濾，濾液減壓濃縮，用矽膠管柱層析法純^ 所得殘餘物，則得到標題產物N_(卜{4__[3_氯_4〜（3—氟一苄氧基）-笨胺基]-喹唑啉-6-基卜4-三氟曱基_；^_比咯_3_其甲基二乙基《2-乙二胺23(22 mg，黃色固體^ 產率：51. 2%。 MS m/z (ESI) ： 641[M+1] 94389 109 201016683 ^NMR (400MHz, DMS0-d〇： 5 9.85(s, 1H), 8. 70(s, 1H), 8.60(s, 1H), 8.20(d, 1H, J=8. 8), 8. 03(d, 2H, J = 15.2), 7.89(d, 1H, J = 8.0), 7.75(d5 1H, J=7. 2), 7. 65(s, 1H), 7.49(m, 1H), 7. 30(m, 3H), 7.19(t, 1H), 5. 27(s, 2H), 3.74(s, 2H), 2.67(d, 2H, J=5. 6), 2. 55(s, 4H), 1.23(s, 2H), 0.95(t, 6H) 實施例24 氧-4-(3- _ - 基）_ 芄胺 i ]_ 喹唑啉篡} 二4一（2-經棊-乙基:各审醯-[2_(4-甲基-哌卩 °基）-乙基Ί-胺Ο “In a 50 mL bottle, add {4_[3_Chloro_4_(3_ qi'oxy)-anilino) phenyl 4_trifluoromethyl ru (4) + formic acid vinegar 6 (250 mg , 0.40 mmol) 'Dissolved in 15 'tetrahydrofuran with the addition of lithium tetrahydrogen aluminum (4 〇 mg, ! mm 〇 1) in a solution of 5 in tetrahydrofuran, 4 (TC) overnight. Thin layer analysis to trace disappearance The title product (1_{4_[3_chloro-1-oxy)-anilino] is obtained by adding the anhydrous decyl alcohol '(iv) n under reduced pressure and purifying the residue by column chromatography. - quinazoline-6-ylbu-4_trifluoromethyl-1H-pyrrole-3-yl)-sterol 23a (177 mg, color solid). Yield: 76.3%. MS m/z (ESI): 543[M+1] The second step (l-{4-[3-gas-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl} 4 diazide-yl-1 -η比洛一3-基)-decanoic acid was added to o-iodobenzoic acid (185 mg, 0.66 mmol) in a 100 mL eggplant-shaped flask, dissolved in i〇mL dimethyl sulfoxide, and added dropwise (Bu {4_[ 3_Gas-4 (3_Fluoro-benzyloxy)-anilino]-quinazoline_6_ kib-4-trifluoromethyl-1H_pyrrole 108 94389 201016683-3-yl)-methanol 23a (177 mg , 0, 33 mmol) of 5 inL dimethyl The sulfone solution was stirred at room temperature overnight. The thin layer analysis was followed until the disappearance of the starting material. The ruthenium was poured into 30 inL of ice water, filtered under reduced pressure, and the solid was re-suppleed with di-methane to give the title product (1-{4 -[3-chloro-4-(3-fluoro-benzyloxyanilino)-quinazoline-6-ylbu 4-trifluoromethyl-1H-pyrrolyl)-formaldehyde 23b (n9 mg, yellow solid) Yield: 70. 0% MS m/z (ESI): 541 [M+1] Step 3 N-(l-{4-[3- gas-4-(3-fluoro-benzyloxy) -anilino]-quinazoline_6_yl}-4-trifluoromethyl-1H-pyrrol-3-ylmethyl)-n',N,-di-ethyl y 2-ethylenediamine soil' at 25 mL mL-shaped flask is added (i-{4-[3-chloro-4-(3-fluoro-benzyloxy)-anilino]-quinazolin-6-yl}-4-trifluoromethyl-1H_ Pyrrole _3_yl)-formaldehyde 23b (40 mg, 0.075 mmol) and N,N-diethyl ruthenium ethylenediamine (10 mg, 0.08 mm 〇l) 'dissolved in 5 inL dichloromethane, reacted for 3 hours Afterwards, 三 added sodium triethoxysulfonate (32 mg, 0.15 curry 1). Stir at room temperature for 3 days. Trace analysis followed until the disappearance of the starting material, adding 2 〇虮 saturated sodium solution, using dichloro Methane extraction (2〇mLx3), combined organic phase, with anhydrous sulfur The magnesium sulfate is dehydrated, filtered, and the filtrate is concentrated under reduced pressure, and the residue obtained is purified by silica gel column chromatography to give the title product N-(b{4__[3_chloro_4~(3-fluoro-benzyloxy)-笨胺 ] - - - ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 : 51. 2%. MS m/z (ESI): 641 [M+1] 94389 109 s. , 8.20(d, 1H, J=8. 8), 8. 03(d, 2H, J = 15.2), 7.89(d, 1H, J = 8.0), 7.75(d5 1H, J=7.2), 7. 65(s, 1H), 7.49(m, 1H), 7. 30(m, 3H), 7.19(t, 1H), 5. 27(s, 2H), 3.74(s, 2H), 2.67( d, 2H, J=5. 6), 2. 55(s, 4H), 1.23(s, 2H), 0.95(t, 6H) Example 24 Oxy-4-(3- _yl)- decylamine i ]_ quinazolinium 二 2 4 (2-pyridinium-ethyl: each review - [2_(4-methyl-piperidinyl)-ethyl hydrazine-amine

- 重複本發明實施例第一步至第二步的反應，使用上述第二步中所得到的化合物2-U-[3-氯-4_(3-氟-苄氧基） -苯胺基]-喹唑啉-6·基卜6,7-二氫_2H_吡喃[3 4_c]吡咯 _ -4-酮1〇作原料，按照本發明實施例13所述相同方式進 =該原料與2_(4_甲基-哌哄—丨—基）—乙胺的反應，用矽膠管柱層析法純化所得殘餘物，則得到標題產物卜{4-[3一氯 -4-(3-氟-苄氧基）_苯胺基喹唑啉_6_基卜4_(2_羥基一乙基）-1Η-吡咯-3_甲酸_[2一（4—曱基一哌畊_丨_基）一乙基]一胺 24(512 mg，淡黃色固體）。產率：5〇 4%。 MS m/z (ESI) ： 658[M+ 1] HNMR (400MHz, DMS0-cf〇： ^ 9.86(s, 1H), 8. 63(s, lH), ]]〇 943^9 201016683 8.59(s，1H)，8.1〇(dd，1H，J = 9.2)，8.01(dd，2H，J = 8. 〇)， 7.89(m, 2H), 7. 75(dd, 1H, J = 9. 0), 7. 48(q, 1H), 7.40(d, 1H), 7.33(q, 3H), 7. 19(t, 1H), 5. 28(s, 2H), 4. 82(s, 1H), 3.66(t, 2H), 3.35(2H), 2. 90(t, 2H), 2. 40(m, 10H), 2. 16(s, 3H) 實施例25 1_1-{4-[3-氧-1(3-氟-苄氫篡）_茉胺基1_崦唑啉：^：：^1 二j-(2-經基-乙臬）-1 H-叫咯-3-某i-哌啶篡-甲乳 ❿- repeating the reaction of the first to second steps of the examples of the present invention, using the compound 2-U-[3-chloro-4_(3-fluoro-benzyloxy)-anilino]- obtained in the above second step Quinazoline-6·kib 6,7-dihydro-2H-pyran[3 4_c]pyrrole-4-one 1 oxime as a starting material, in the same manner as described in Example 13 of the present invention = the raw material and 2_ (4-Methyl-piperidine-hydrazinyl)-ethylamine reaction, the residue obtained is purified by silica gel column chromatography to give the title product: {4-[3-chloro-4-(3-fluoro) -benzyloxy)-anilinoquinazoline_6_ylbu-4_(2-hydroxyethyl)-1Η-pyrrole-3_carboxylic acid _[2-(4-indolyl-piperidin-丨-yl) Monoethyl]monoamine 24 (512 mg, pale yellow solid). Yield: 5 〇 4%. MS m/z (ESI): 658 [M + 1] HNMR (400 MHz, DMS0-cf:::::::::::::::::::::::::::::::::::::::::::::::::::::::: 1H), 8.1 〇 (dd, 1H, J = 9.2), 8.01 (dd, 2H, J = 8. 〇), 7.89 (m, 2H), 7. 75 (dd, 1H, J = 9. 0), 7. 48(q, 1H), 7.40(d, 1H), 7.33(q, 3H), 7. 19(t, 1H), 5. 28(s, 2H), 4. 82(s, 1H), 3.66(t, 2H), 3.35(2H), 2. 90(t, 2H), 2. 40(m, 10H), 2. 16(s, 3H) Example 25 1_1-{4-[3-Oxygen -1(3-Fluoro-benzylhydroquinone)_Molylamine 1_oxazoline: ^::^1 Two j-(2-trans-acetamido)-1 H-called -3-some i- Piperidine-mercapto

：:

重複本發明實施例10第一步至第二步的反應，使用上 •述第二步中所得到的化合物2-{4-[3-氯-4-(3-氟-苄氧基） -本胺基]-喧11 坐琳-6-基}-6, 7-二氫- 2Η-°ϋ喃[3, 4-c ] °比哈 -4-酮10作原料，按照本發明實施例13所述相同方式進行該原料與哌啶的反應，用矽膠管柱層析法純化所得殘餘 ❹物，則得到標題產物[卜{4-[3-氣-4-(3-氟-苄氧基）_苯胺基]-喹唑啉-6-基}-4-(2-羥基-乙基）一 1H_吡咯基卜哌啶-卜基-甲酮25(15〇 mg，淡黃色固體）。產率：^土⑽。 MS m/z (ESI) ： 600[M+ 1] · °。 ]HNMR (400MHz，DMSO-cW: (5 8 57〔ς 〇 ,The reaction of the first step to the second step of Example 10 of the present invention was repeated, and the compound 2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-] obtained in the second step described above was used. The present invention is according to the present invention. The present invention is based on the present invention. The present invention is in the form of a starting material according to the present invention. The reaction of the starting material with piperidine is carried out in the same manner as in the above manner, and the obtained residue is purified by silica gel column chromatography to obtain the title product [b{4-[3- gas-4-(3-fluoro-benzyloxy). ))-anilino]-quinazolin-6-yl}-4-(2-hydroxy-ethyl)- 1H-pyrrolylpiperidine-bupropion-methanone 25 (15 mg, pale yellow solid) . Yield: ^ soil (10). MS m/z (ESI): 600 [M+ 1]. ]HNMR (400MHz, DMSO-cW: (5 8 57 [ς 〇 ,

8. 15(dd 1H J = 9.2)，8.01(d’ 1H’ J = 2.8)， 7 86(d, ih ’ 7.73(dd，1H，J=9.〇)，7.63(d，1H，J=2 4)，7 46(m 2 ’ 7.32(,, 3H), 7.18(t, 1H), 5. 27(s, 2H), 3.58(^ 6H)， 94389 111 201016683 2-67(t, 2H), 1.64(d, 2H), 1.51(s, 4H) 實施例2 6 氤-苄氣某笨胺某1-崦崦姑-6-基} zi·-（2-經基二^基）一1H_吡咯-3一基ι_吡略悛_卜某-曱酮8. 15 (dd 1H J = 9.2), 8.01 (d' 1H' J = 2.8), 7 86 (d, ih ' 7.73 (dd, 1H, J=9.〇), 7.63 (d, 1H, J= 2 4), 7 46(m 2 ' 7.32(,, 3H), 7.18(t, 1H), 5. 27(s, 2H), 3.58(^ 6H), 94389 111 201016683 2-67(t, 2H) , 1.64(d, 2H), 1.51(s, 4H) Example 2 6 氤-Benzene gas Some of the stupid amines 1-崦崦gu-6-yl} zi·-(2-trans-diyl)- 1H _pyrrole-3-based ι_pyrrole _b-anthone

重複本發明實施例1〇第一步至第二步的反應，使用上魯述第二步中所得到的化合物2-{4-[3-氯-4-(3-氟-苄氧基） -苯胺基]-喹唑啉_6_基卜6, 7_二氫-2H-吡喃[3,4-c]吡咯一4 一酮10作原料，按照本發明實施例13所述相同方式進行該原料與吡咯烷的反應，用矽膠管柱層析法純化所得殘 '餘物’則传到標題產物[1_丨4-[3_氯-4-(3-氟-节氧基）_苯 —基]-啥。坐琳-6—基}-4-(2-經基-乙基比洛_3_基]_ 〇比0各烧-1-基-甲酮26(596 mg，淡黃色固體）。產率：52 4%。 MS m/z (ESI) ： 586[M+ 1 ] ]HNMR (400MHz, DMS0-d〇： 5 9.76(s, 1H), 8. 58(s, 2H), B.18(dd, 1H, J = 9.2), 8.01(d, 1H, J = 2.4), 7. 87(d, 1H, J = 8.8), 7.81(d, 1H, J=2.0), 7. 73(dd, 1H, j = 6.4), 7.48(q, 1H), 7. 43(s, 1H), 7.33(q, 3H), 7. l8(t, 1H), 5.28(s, 2H), 4.79(1, 1H), 3.62(m, 4H), 3.47(m, 2H), 2.80(t, 2H), 1.88(s, 4H) 實施例27 3-氯-4-(3 -氟-爷氣基）-笨胺基]隻琳_6-基} 94389 112 201016683 _4-基-甲酮The reaction of the first step to the second step of Example 1 of the present invention was repeated, and the compound 2-{4-[3-chloro-4-(3-fluoro-benzyloxy) obtained in the second step of the above description was used. -anilino]-quinazoline-6-ylbu-6,7-dihydro-2H-pyrano[3,4-c]pyrrole-4-oneone 10 as a starting material in the same manner as described in Example 13 of the present invention The reaction of the starting material with pyrrolidine is carried out, and the residue 'residue' obtained by purifying the column chromatography is passed to the title product [1_丨4-[3_chloro-4-(3-fluoro-oxy). _Benzyl-based]-啥.坐琳-6-yl}-4-(2-trans-ethyl-ethyl pyrrole_3_yl]- 〇 0 0 each -1-yl-ketone 26 (596 mg, pale yellow solid). Yield : 52 4%. MS m/z (ESI): 586 [M+ 1 ] ]HNMR (400 MHz, DMS0-d〇: 5 9.76 (s, 1H), 8. 58 (s, 2H), B.18 (dd , 1H, J = 9.2), 8.01(d, 1H, J = 2.4), 7. 87(d, 1H, J = 8.8), 7.81(d, 1H, J=2.0), 7. 73(dd, 1H , j = 6.4), 7.48(q, 1H), 7. 43(s, 1H), 7.33(q, 3H), 7. l8(t, 1H), 5.28(s, 2H), 4.79(1, 1H ), 3.62(m, 4H), 3.47(m, 2H), 2.80(t, 2H), 1.88(s, 4H) Example 27 3-Chloro-4-(3-fluoro-aryl)-stupylamine基]琳琳_6-基} 94389 112 201016683 _4-keto-ketone

重複本發明實施例10第-步至第二步的反應，使用上述第二步中所得到的化合物2-{4-[3-氯—4_(3_氟_爷氣某） -苯胺基]-喹唑啉+基} —6,7一二氫，1喃[3,4_。]吡： _4-酮10作原料，按照本發明實施例13所述相同方式進行該原料與嗎琳的反應’用梦膠管柱層析法純化所得殘餘物，則得到標題產物[1-{4-[3-氯-4-(3-氟-苄氧基）_苯胺基]-喹唑啉-6-基}-4-(2-羥基-乙基）-1Η_吡咯_3_基卜嗎琳-4-基-甲酮27(695 mg，淡黃色固體）。產率：59 5%。 MS m/z (ESI) ： 602[M+ 1] 'HNMR (400MHz, DMSO-d〇： d 9. 77(s, 1H), 8. 66(s 2H), 8. 17(s, 1H), 8.02(d, 2H, J=2.4), 7. 74(dd, 1H, J=8.8), 7. 69(d, 1H, J=2.4), 7.48(m, 2H), 7. 33(q, 3H), 7. 20(t, ❹ 1H), 5.28(s, 2H), 4.69(t，2H)，3.59(s, 4H), 2 70(t, 4H), 1.99(s, 2H) 實施例28 2-(1-{4-[3-氧-1_-(-3~~1-苄氳某）-茉胺基~1-气逢啉_6_基} -4-p底0定-1-基曱基-1Η~η比够基）一乙醇The reaction of the first step to the second step of the tenth embodiment of the present invention is repeated, and the compound 2-{4-[3-chloro-4_(3_fluoro_yellow)-anilino group obtained in the above second step is used. -quinazoline +yl}-6,7-dihydrogen, 1 silane [3,4_. Pyridine: 4-ketone 10 was used as a starting material, and the reaction of the starting material with morphine was carried out in the same manner as in Example 13 of the present invention. The residue obtained by purification of the gel column chromatography was used to obtain the title product [1-{4]. -[3-chloro-4-(3-fluoro-benzyloxy)-anilino]-quinazolin-6-yl}-4-(2-hydroxy-ethyl)-1Η-pyrrole_3_yl b Phyto-4-yl-methanone 27 (695 mg, pale yellow solid). Yield: 59 5%. MS m/z (ESI): 602 [M + 1] "HNMR (400 MHz, DMSO-d: d 9. 77 (s, 1H), 8. 66 (s 2H), 8. 17 (s, 1H), 8.02(d, 2H, J=2.4), 7. 74(dd, 1H, J=8.8), 7. 69(d, 1H, J=2.4), 7.48(m, 2H), 7. 33(q, 3H), 7. 20(t, ❹ 1H), 5.28(s, 2H), 4.69(t, 2H), 3.59(s, 4H), 2 70(t, 4H), 1.99(s, 2H) 28 2-(1-{4-[3-Oxy-1_-(-3~~1-benzyl 氲)-Mosyl-1~1- phenanthroline _6_ base} -4-p bottom 0- 1-mercapto-1Η~η ratio enough) ethanol

28 113 94389 20101668328 113 94389 201016683

HOHO

氬氣刀下在1 〇mL茄形瓶中加入2此四氫吱喃，再加入四虱鋁鋰（16mg’ Ο·42ππη〇1)，室溫攪拌下滴加入[卜{4_ ❹Add 2 tetrahydrofuran to a 1 〇mL eggplant bottle under an argon knife, and add tetrakilium aluminum lithium (16 mg' Ο·42ππη〇1), and add it at room temperature with stirring [Bu{4_ ❹

[3-氯-4-(3-氟-苄氧基）_苯胺基]_喹唑啉_6_基卜4_(2一羥基-乙基）-1Η-吡咯-3 一基]一哌啶η 一基一甲酮25(5〇邶，〇〇8 mmol)的2 mL四氫呋喃溶液，加熱回流攪拌3小時。薄層 :析追蹤至原料消失，加入含水四氫吱喃猝滅反應，減壓 /辰縮石夕膠柱層析法純化所得殘餘物，則得到標題產物2-(1-{4-[3-氯-4-(3-氟-苄氧基）_苯胺基]_喹唑啉刊一基卜4-哌啶-丨-基甲基_1H_吡咯_3_基）_乙醇28(32邶，淡黃色固體）。產率：65. 6%。 MS m/z (ESI) ： 58β[Μ+ 1] HNMR (400MHz, DMS0-d〇: δ 10. 12(s, 1Η), 8.81(s 1H) 8.57(s’ 110, 8.11(d，2H)，7 86(t，2H)，7..76(s’ ⑻’ 7.55(3, 1H), 7.47(q, 1H), 7. 33(ra, 3H), 7.19(t, ifl)! 5.27(s, 2H), 3.97(s, 2H), 3. 68(t, 2H), 2. 73(t, 2H) 1-71(8, 4H), 1.52(s, 2H), i.24(s, 4H) ’ ’ 實施例29[3-Chloro-4-(3-fluoro-benzyloxy)-anilino]-quinazoline-6-ylbu-4_(2-hydroxy-ethyl)-1Η-pyrrole-3-yl]-piperidine A solution of η-yl-one ketone 25 (5 〇邶, 〇〇 8 mmol) in 2 mL of THF was stirred and stirred for 3 hr. Thin layer: the trace is traced to the disappearance of the starting material, and the reaction is quenched by the addition of aqueous tetrahydrofuran. The residue obtained is purified by decompression/column gel column chromatography to obtain the title product 2-(1-{4-[3 -Chloro-4-(3-fluoro-benzyloxy)-anilino]-quinazoline-one-bub-4-piperidine-fluorenyl-methyl-1H-pyrrole_3_yl)-ethanol 28 (32 Oh, light yellow solid). Yield: 65.6%. MS m/z (ESI): 58β [Μ+ 1] HNMR (400 MHz, DMS0-d〇: δ 10. 12 (s, 1 Η), 8.81 (s 1H) 8.57 (s' 110, 8.11 (d, 2H) ,7 86(t,2H),7..76(s' (8)' 7.55(3, 1H), 7.47(q, 1H), 7. 33(ra, 3H), 7.19(t, ifl)! 5.27( s, 2H), 3.97(s, 2H), 3. 68(t, 2H), 2. 73(t, 2H) 1-71(8, 4H), 1.52(s, 2H), i.24(s , 4H) ' ' Example 29

94389 114 201016683 Ο ΗΝ94389 114 201016683 Ο ΗΝ

2929

〆〇、、CI 使用本發明實施例26所得化合物— 氣-4-(3- 氟-苄氧基）-苯胺基]-喹唑啉-6-基}-4-( 2-羥基-乙基） -1H-吡咯-3-基]-吡咯烷-卜基-甲酮26按照本發明實施例 28所述相同方式進行該原料與四氫鋁鐘的反應，用石夕勝管柱層析法純化所得殘餘物，則得到標題產物2-〇-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-喹唑啉_6_基卜4_吡洛燒 1-基曱基-1Η-0比嘻-3_基）-乙醇29 (55 mg，淡黃色固體）。產率：28. 2%。 MS m/z (ESI) ： 572[M+ 1] .JHNMR (400MHz, DMSO-dO： (5 10.〇9(s, 1H), 8. 75(S) lH) 8. 56(s, 1H), 8. 10(m, 2H), 7. 84(m, 2H), 7.67(s, 1H), 7.48(m, 2H), 7. 32(m, 3H), 7. 18(t, 1H), 5. 27(s, 2H), 3.80(s，2H), 3.64(t，2H)’ 2.89(s, 4H), 2. 71(q, 2H) ⑩ U2(s，4H) ’ ’ 實施例30 lz_U-U-[3-氧-4-(3-氣-苄l基）-茉胺某崦二4 -嗎淋_4 -基甲基-1Η_Ρ比哈-3-基）一匕醇〆〇, CI, using the compound obtained in Example 26 of the present invention - gas-4-(3-fluoro-benzyloxy)-anilino]-quinazolin-6-yl}-4-(2-hydroxy-ethyl -1H-pyrrol-3-yl]-pyrrolidine-bupropion-methanone 26 The reaction of the starting material with the tetrahydrogen aluminum clock was carried out in the same manner as described in Example 28 of the present invention, using Shi Xisheng column chromatography. The obtained residue was purified to give the title product: 2-[upsil]-{4-[3-chloro-4-(3-fluoro-benzyloxy)-anilinyl]-quinazoline -6- br. 1-Mercapto-1-Η-0 to 嘻-3_yl)-ethanol 29 (55 mg, pale yellow solid). Yield: 28.2%. MS m/z (ESI): 572 [M+ 1]. JHNMR (400 MHz, DMSO-dO: (5 10. 〇9(s, 1H), 8. 75(S) lH) 8. 56(s, 1H) , 8. 10(m, 2H), 7. 84(m, 2H), 7.67(s, 1H), 7.48(m, 2H), 7. 32(m, 3H), 7. 18(t, 1H) , 5. 27(s, 2H), 3.80(s, 2H), 3.64(t, 2H)' 2.89(s, 4H), 2. 71(q, 2H) 10 U2(s,4H) ' ' 30 lz_U-U-[3-oxo-4-(3-a-benzyl-l-yl)-mosamate 崦2 4 -Olin- 4 -ylmethyl-1Η_Ρ比哈-3-yl)-sterol

QQ

30 /〇、、α 使用本發明貫施例2 7所得化合物[1 _丨4 - [ 3 -氣-4 - ( 3 _ 94389 115 201016683 氣乳基）_本胺基]-啥唾琳-6-基}-4-(2-經基-乙基） -1H-吡咯-3-基]-嗎啉-4-基-甲酮27按照本發明實施例28 所述相同方式進行該原料與四氫鋁鋰的反應，用矽膠管柱層析法純化所得殘餘物’則得到標題產物2-(i-{4-[3-氯 4 (3-氣氧基）-苯胺基]—啥嗤淋_6-基}-4-嗎琳-4-基甲基-1HH3-基）-乙醇3〇 (115呢，淡黃色固體）。產率：58. 9%。 MS ra/z (ESI) ： 588[M+ 1] !HNMR (400MHz, DMSO-dO： <5 9. 93(s, 1H), 8. 63(s, 1H), 8.55(s, 1H), 8.09(d, 1H, J=9.2), 8. 05(d, 1H, J=2.4), 7.83(d, 1H, J=8.8), 7. 79(dd, 1H, J=9. 0), 7. 53(s, 1H), 7.46(m, 2H), 7. 32(m, 3H), 7. 19(t, 1H), 5. 26(s, 2H), -3.65(m, 6H), 3. 53(s, 2H), 2. 70(t, 2H, J=2. 6), 2. 59(s, 4H) 實施例3130 /〇, ,α using the compound obtained in Example 27 of the present invention [1 _丨4 - [ 3 - gas-4 - ( 3 _ 94389 115 201016683 gas-milk base) - the present amine group] - 啥琳琳 -6 -yl}-4-(2-trans-ethyl-ethyl)-1H-pyrrol-3-yl]-morpholin-4-yl-methanone 27 was carried out in the same manner as described in Example 28 of the present invention. The reaction of lithium aluminum hydride was purified by column chromatography on silica gel column chromatography to give the title product 2-(i-{4-[3-chloro 4 (3-oxy)-anilinyl]- _6-yl}-4-morphin-4-ylmethyl-1HH3-yl)-ethanol 3 hydrazine (115, pale yellow solid). Yield: 58.9%. MS ra/z (ESI): 588 [M+ 1] "HNMR (400 MHz, DMSO-dO: <5 9.93 (s, 1H), 8. 63 (s, 1H), 8.55 (s, 1H), 8.09(d, 1H, J=9.2), 8. 05(d, 1H, J=2.4), 7.83(d, 1H, J=8.8), 7. 79(dd, 1H, J=9. 0), 7. 53(s, 1H), 7.46(m, 2H), 7. 32(m, 3H), 7. 19(t, 1H), 5. 26(s, 2H), -3.65(m, 6H) , 3. 53(s, 2H), 2. 70(t, 2H, J=2. 6), 2. 59(s, 4H) Example 31

基）-胺Amine

重複本發明實施例1〇第一步至第二步的反應，使用上述第二步中所得到的化合物2-{4-[3-氯-4-(3-氟-苄氧基） -苯胺基]-喹唑啉_6_基卜6,7_二氫_2H_吡喃[3,4_c]吡咯 116 94389 201016683 -4-酮10作原料’按照本發明實施例13所述相同方式進行該原料與2-吡咯院-1-基-乙胺的反應’用矽膠管柱層析法純化所得殘餘物’則得到標題產物卜{4-[3-氣-4-(3-氟 -苄氧基）-苯胺基]-喹唑琳-6-基}-4-(2-羥基-乙基）-ih-吡咯-3-曱酸-(2-吡咯烷-1-基-乙基）_胺31(42〇 mg，黃褐色固體）。產率：38. 5%。 MS ra/z (ESI) ： 629[M+ 1] 'HNMR (400MHz, MS0-de)：d 9.75(s, 1H), 8. 63(s, 1H), 8.56(s, 1H), 8.09(dd, 1H, J=9.2), 8. 02(d, 2H, J=l. 6), ®7.91(m, 2H), 7. 74(dd, 1H, J=8. 8), 7. 48(q, 1H), 7.40(d, 1H, J = 2.0), 7.33(q, 3H), 7. 19(t, 1H), 5. 28(s, 2H), 4. 70(s, 1H), 3. 64(m, 2H), 3.35(m, 2H), 2. 9〇(t, 2H), 2. 55(m, 6H), 1. 68(m, 4H) 實施例32 _龜< -4-(3-氣-卞氧基）-苯胺某i —啥峻u_基} -4-(2-亀基二吡座二甲酸一（2-哌咜μ-芊-7早、 0 ζΜ.The reaction of the first step to the second step of Example 1 of the present invention was repeated, and the compound 2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-aniline obtained in the above second step was used. ] quinazoline _6_ kib 6,7-dihydro 2H-pyran [3,4_c]pyrrole 116 94389 201016683 -4- ketone 10 as starting material 'in the same manner as described in Example 13 of the present invention Reaction of the starting material with 2-pyrrolidin-1-yl-ethylamine 'purification of the obtained residue by hydrazine column chromatography' gave the title product: {4-[3- s. Oxy)-anilino]-quinazoline-6-yl}-4-(2-hydroxy-ethyl)-ih-pyrrole-3-decanoic acid-(2-pyrrolidin-1-yl-ethyl) _ Amine 31 (42 〇 mg, tan solid). Yield: 38. 5%. MS ra/z (ESI): 629 [M + 1] "HNMR (400 MHz, MS0-de):d: 9.75 (s, 1H), 8. 63 (s, 1H), 8.56 (s, 1H), 8.09 (dd , 1H, J=9.2), 8. 02(d, 2H, J=l. 6), ®7.91(m, 2H), 7. 74(dd, 1H, J=8. 8), 7. 48( q, 1H), 7.40(d, 1H, J = 2.0), 7.33(q, 3H), 7. 19(t, 1H), 5. 28(s, 2H), 4. 70(s, 1H), 3. 64(m, 2H), 3.35(m, 2H), 2. 9〇(t, 2H), 2. 55(m, 6H), 1. 68(m, 4H) Example 32_Turtle< -4-(3-Gas-decyloxy)-aniline, i, 啥 u u_基} -4-(2-mercaptodipyridyldicarboxylic acid mono(2-piperidinium μ-芊-7 early, 0 Hey.

〇jaF〇jaF

Cl 重複本發明實施例10第一步至第二步的反應，使用上述第二步中所得到的化合物2-{4-[3-氣-4-(3-氟-苄氧基） -苯胺基]-喹唑啉-6-基}-6, 7-二氫_2H_吡喃[3, 4_c]吡咯 -4-酮10作原料，按照本發明實施例丨3所述相同方式進 94389 117 201016683 行該原料與2-哌啶-1-基-乙胺的反應，用矽膠管柱層析法純化所得殘餘物，則得到標題產物卜{4-[3-氯-4-(3-氟-卞氧基）-苯胺基]-喧唾琳基卜4-(2_經基-乙基比咯-3-曱酸-(2-哌啶-1-基-乙基）_胺32(546 mg ’黃褐色固體）。產率：43. 4%。 MS m/z (ESI) ： 643[M-f 1] ]HNMR (400MHz, DMS0-d〇： ^ 9. 85(s, 1H), 8. 63(d, 1H, J=2.0), 8.59(s, 1H), 8.1〇(dd, 1H, J=9. 2), 8.01(m, 2H), 7.89(m, 2H), 7.74(dd, 1H, J = 8. 8), 7.48(q, 1H), 7.40(d, ® 1H, J = 1.6), 7.33(q, 3H), 7.20(t, 1H), 5. 27(s, 2H), 4-83(s, 1H), 3.66(t, 2H, 1 = 2.4), 3. 35(t, 2H), 2. 90(t, 2H, J=2.8), 2.42(m, 6H), 1.52(m, 6H) 實施例33 -1 氯-4-(3-氟-苄氣基）-芏其噁啉-4-基 ^基甲某]-4-三氟曱某-τ>比來—1一基丨_哇〇生说-4-基脸Cl Repeat the reaction of the first step to the second step of Example 10 of the present invention, using the compound 2-{4-[3- gas-4-(3-fluoro-benzyloxy)-aniline obtained in the above second step. , quinazolin-6-yl}-6,7-dihydro-2H-pyrano[3,4-c]pyrrol-4-one 10 as a starting material, in the same manner as described in Example 3 of the present invention, into 94389 117 201016683 The reaction of the starting material with 2-piperidin-1-yl-ethylamine is carried out, and the obtained residue is purified by silica gel column chromatography to give the title product (4-[3-chloro-4-(3-) Fluoro-nonyloxy)-anilino]-indolyl 4-(2-trans-ethyl-pyrrol-3-indole-(2-piperidin-1-yl-ethyl)-amine 32 (546 mg 'yellow solid). Yield: 43.4%. MS m/z (ESI): 643[Mf 1] ]HNMR (400 MHz, DMS0-d〇: ^ 9. 85 (s, 1H), 8. 63(d, 1H, J=2.0), 8.59(s, 1H), 8.1〇(dd, 1H, J=9. 2), 8.01(m, 2H), 7.89(m, 2H), 7.74( Dd, 1H, J = 8. 8), 7.48(q, 1H), 7.40(d, ® 1H, J = 1.6), 7.33(q, 3H), 7.20(t, 1H), 5. 27(s, 2H), 4-83(s, 1H), 3.66(t, 2H, 1 = 2.4), 3. 35(t, 2H), 2. 90(t, 2H, J=2.8), 2.42(m, 6H ), 1.52 (m, 6H) Example 33 -1 Chloro-4-(3-fluoro-benzyl)-indole -4-基^基甲某]-4-Trifluoromethane--τ> 比来—1一基丨_哇〇生说-4-基脸

重複本發明實施例23第一步至第二步的反應，使用上述第二步中所得到的化合物（1-{4-[3-氣-4-(3-氟-苄氧基） ''苯胺基]-喹唑啉-6-基}-4_三氟曱基_ijj_吡咯_3-基）一甲駿23b作原料，按照本發明實施例23第三步所述相同方式進行該原料與2-嗎啉-4-基-乙胺的反應，用矽膠管柱層析法純化所得殘餘物，則得到標題產物[3-氯-4-(3-氟-苄 94389 ]18 201016683 氧基）-苯基]-(6-{3-[ (2-嗎琳-4-基-乙胺基）-甲基]-4-三氟甲基比11 各-l-基}-啥唾琳-4-基）—胺33(86 mg，淡黃色固體）。產率：71. 0%。 MS m/z (ESI) ： 655[M+ 1] 】HNMR(400MHz，DMS0-d〇: 6 9.85(s，1H)，8.70(s，1H), 8.61(s, 1H), 8. 19(d, 1H, J = 9. 6), 8. 07(s, 1H), 8. 〇2(s, 1H), 7. 91(d, 1H, J=8.8), 7. 74(d, 1H, J=6. 8), 7. 68(s, 1H), 7.49(q, 1H), 7. 33(m, 3H), 7. 19(t, 1H), 5. 28(s, 2H), 3.80(s, 2H), 3.58(s, 4H), 3. 31(s, 4H), 2. 77(s, ® 2H), 2. 39(s, 2H) 實施例34 11^-4-(3-氟-苄氧皋）-笨基1-「6_(^一{「？_^4-甲基-畈叫The reaction of the first step to the second step of Example 23 of the present invention was repeated, and the compound (1-{4-[3- gas-4-(3-fluoro-benzyloxy)'' obtained in the above second step was used. Anilino]-quinazolin-6-yl}-4_trifluoromethyl _ijj_pyrrole-3-yl)-methyl thiophene 23b is used as a starting material in the same manner as described in the third step of Example 23 of the present invention. The reaction of the starting material with 2-morpholin-4-yl-ethylamine was purified by EtOAc EtOAc EtOAc EtOAc EtOAc Base)-phenyl]-(6-{3-[(2-morphin-4-yl-ethylamino)-methyl]-4-trifluoromethyl ratio 11-l-yl}-啥Lin-4-yl)-amine 33 (86 mg, pale yellow solid). Yield: 71.0%. MS m/z (ESI): 655 [M+ 1]] HNMR (400 MHz, DMS0-d: 6 9.85 (s, 1H), 8.70 (s, 1H), 8.61 (s, 1H), 8. 19 (d) , 1H, J = 9. 6), 8. 07(s, 1H), 8. 〇2(s, 1H), 7. 91(d, 1H, J=8.8), 7. 74(d, 1H, J=6. 8), 7. 68(s, 1H), 7.49(q, 1H), 7. 33(m, 3H), 7. 19(t, 1H), 5. 28(s, 2H), 3.80(s, 2H), 3.58(s, 4H), 3. 31(s, 4H), 2. 77(s, ® 2H), 2. 39(s, 2H) Example 34 11^-4-( 3-fluoro-benzyloxindole)-stupid 1-"6_(^一{"?_^4-methyl-畈

重複本發明實施例23第一步至第二步的反應，使用上述第二步中所得到的化合物氣-4-(3-氟-苄氧基） ''笨胺基]-喹唑啉_6_基卜4_三氟曱基_1H一吡咯_3_基）_甲輕23b作原料，按照本發明實施例23第三步所述相同方式進行該原料與2-(4-曱基底哄-1-基）-乙胺的反應，用石夕膠管柱層析法純化所得殘餘物，則得到標題產物[3〜氣 4 (3-說-苄氧基）—苯基]一[6_(3一 {[2-(4 -曱基-旅卩井-1~基） 119 94389 201016683 -乙胺基]-曱基}-4-三氟曱基-吡咯-1 一基）一喹唑啉_4_基]_ 胺34(88 mg，淡黃色固體）。產率：71· 5% ° MS m/z (ESI) ： 668[M+ 1] ]HNMR (400MHz, DMS〇-d〇: δ 9. 87(s, 1H), 8. T3(s, 1H), 8.61(s, 1H), 8.18(dd, 1H, J=8. 8), 8.07(s, 1H), B.03(s, 1H), 7.91(d, 1H, J=8.8), 7. 77(d, 1H, J = 2. 8), 7.71(s, 1H), 7. 48(m, 1H), 7.31(m, 3H), 7. 18(t, 1H), 5. 28(s, 2H), 3.83(s, 2H), 3. 83(s, 2H), 2. 44(m, 6H), 2. 20(s, 3H), 2.09(s, 4H) ®實施例35 LI-氯-4-(3-氩-苄 y 某 W6- 版基）-甲某1-4- =事甲其-地政-1-1}-喹唑The reaction of the first step to the second step of Example 23 of the present invention was repeated, using the compound gas 4-(3-fluoro-benzyloxy) ''m-amino]-quinazoline obtained in the above second step. 6_Kibu 4_trifluoromethyl-1H-pyrrole_3_yl)_methyl light 23b as a raw material, the raw material and the 2-(4-anthracene substrate) were carried out in the same manner as described in the third step of Example 23 of the present invention. The reaction of the indole-1-yl)-ethylamine was purified by chromatography on silica gel column chromatography to give the title product [3~[s. (3-{[2-(4-曱基-旅卩井-1~基) 119 94389 201016683 -ethylamino]-mercapto}-4-trifluoromethyl-pyrrole-1-yl)-quinazoline Porphyrin_4_yl]-amine 34 (88 mg, pale yellow solid). Yield: 71· 5% ° MS m/z (ESI): 668 [M+ 1] ]HNMR (400 MHz, DMS〇-d〇: δ 9. 87 (s, 1H), 8. T3 (s, 1H) , 8.61(s, 1H), 8.18(dd, 1H, J=8. 8), 8.07(s, 1H), B.03(s, 1H), 7.91(d, 1H, J=8.8), 7. 77(d, 1H, J = 2. 8), 7.71(s, 1H), 7. 48(m, 1H), 7.31(m, 3H), 7. 18(t, 1H), 5. 28(s , 2H), 3.83(s, 2H), 3. 83(s, 2H), 2. 44(m, 6H), 2. 20(s, 3H), 2.09(s, 4H) ® Example 35 LI- Chloro-4-(3-argon-benzyl y, a W6-version)-A 1-4- = 甲甲-地政-1-1}-quinazoline

35 重複本發明實施例23第一步至第二步的反應，使用上35 repeating the reaction of the first step to the second step of the embodiment 23 of the present invention, using

述第二步中所得到的化合物（1_{4-[3_氯-4-(3-氟_苄氧基） -苯胺基]-喹唑啉_6_基卜4_三氟甲基_1H—吡咯-3-基）-甲醛23b作原料，按照本發明實施例23第三步所述相同方式進行該原料與2_哌啶―卜基―乙胺的反應，用矽膠管杈層 f法純化所得殘餘物’則得到標題產物[3-氯-4-(3~氣〜苄，基）-苯基]—(6—{3_[(2+定+基-乙胺基）_甲基]+三鼠甲基吼H一基卜啥唾琳_4_基）一胺35(邮M，淡固體）。產率：71.7%。、 94389 120 201016683 MS m/z (ESI) : 653[M+ 1] !HNMR (400MHz, DMSO-dO： 5 9.86(s, 1H), 8. 74(s, 1H), 8.62(s, 1H), 8. 17(dd, 1H, J=8. 4), 8. 〇8(s, 1H), 8. 04(m, 1H), 7.92(d, 1H, J = 9.2), 7. 76(m, 2H), 7.47(q, 1H), 7.32(q, 3H), 7. 19(t, 1H), 5.28(s, 2H), 3. 84(s, 2H), 2.87(s, 2H), 2. 66(m, 6H), 1.61(s, 4H), 1.44(s, 2H) 實施例36 L3-氯-4-(3-氟-芊氧基）-茉某1 -jlzia-[(2二氧棊-乙胺基）-甲基1-4-三_甲基-吡咯-卜基上淋基）一胺The compound obtained in the second step (1_{4-[3-chloro-4-(3-fluoro-benzyloxy)-anilino]-quinazoline_6_ylbu-4_trifluoromethyl_ 1H-pyrrol-3-yl)-carboxaldehyde 23b is used as a starting material, and the reaction of the starting material with 2-piperidinyl-ethylamine is carried out in the same manner as described in the third step of Example 23 of the present invention. Purification of the obtained residue to give the title product [3-chloro-4-(3~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Base] + three mouse methyl 吼 H - kibu 啥啥 _ _ _ 4 _ base) a amine 35 (mail M, light solid). Yield: 71.7%. , 94389 120 201016683 MS m/z (ESI): 653[M+ 1] !HNMR (400MHz, DMSO-dO: 5 9.86 (s, 1H), 8. 74 (s, 1H), 8.62 (s, 1H), 8. 17(dd, 1H, J=8. 4), 8. 〇8(s, 1H), 8. 04(m, 1H), 7.92(d, 1H, J = 9.2), 7. 76(m , 2H), 7.47(q, 1H), 7.32(q, 3H), 7. 19(t, 1H), 5.28(s, 2H), 3. 84(s, 2H), 2.87(s, 2H), 2. 66(m, 6H), 1.61(s, 4H), 1.44(s, 2H) Example 36 L3-Chloro-4-(3-fluoro-indolyloxy)-Momo 1 -jlzia-[(2 Dioxin-ethylamino)-methyl1-4-tri-methyl-pyrrole-diyl-monoamine

重複本發明實施例23第一步至第二步的反應，使用上述第二步中所得到的化合物（卜{4-[3_氯-4-(3-氟-苄氧基） -苯胺基]-啥唾琳一6_基}-4-三氟甲基—比略-3-基）-曱醛23b作原料，按照本發明實施例23第三步所述相同方馨式進行該原料與2一甲氧基-乙胺的反應，用矽膠管柱層析法純化所得殘餘物，則得到標題產物氯_4_(3_氟〜苄氧基）-苯基]々々-[(之-甲氧基-乙胺基卜甲基卜卜三氣甲基-吡咯-1-基卜喹唑啉_4_基）_胺36(78邶，淡黃色固體）。產率：70. 3%。 MS m/z (ESI) ： 600[M+ 1] ]ΗΝΜΚ (400MHz, DMSO-dO： 5 S.66(d, 1H), 8. 59(s, iH), 8.17(dd, 1H, J=9.0), 8.03(s, 1H), 8. 00(d, 1H, J=2.8), 94389 12] 201016683 7. 89(d, 1H, J=8.8), 7. 73(dd, 1H, J=8. 8), 7. 64(s, 1H), 7.46(q, 1H), 7.31(q, 3H), 7. 18(t, 1H), 5. 26(s, 2H), 3. 76(s, 2H), 3.45(s, 2H), 3. 25(s, 3H), 2. 78(t, 2H) 實施例37 二苄氣基）-茇篡歷棊三氟甲某略―卜基卜喹嚴The reaction of the first step to the second step of Example 23 of the present invention was repeated, and the compound obtained in the above second step (Bu {4-[3-chloro-4-(3-fluoro-benzyloxy)-anilinyl) was used. ]-啥琳一一 6 _ _ -4- -4- -4- -4- -4- -4- -4- -4- -4- -4- -4- -4- 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 The residue obtained by purifying with 2-methyl-ethylamine was purified by silica gel column chromatography to give the title product chloro-4-[(3-fluoro-benzyloxy)-phenyl]indole-[ -Methoxy-ethylaminobupromethane tris-methyl-pyrrol-1-ylbuquinazoline-4-yl)-amine 36 (78 邶, pale yellow solid). Yield: 70.3%. MS m/z (ESI): 600 [M+ 1] ] ΗΝΜΚ (400 MHz, DMSO-dO: 5 S.66 (d, 1H), 8. 59 (s, iH), 8.17 (dd, 1H, J=9.0 ), 8.03(s, 1H), 8. 00(d, 1H, J=2.8), 94389 12] 201016683 7. 89(d, 1H, J=8.8), 7. 73(dd, 1H, J=8 8), 7. 64(s, 1H), 7.46(q, 1H), 7.31(q, 3H), 7. 18(t, 1H), 5. 26(s, 2H), 3. 76(s , 2H), 3.45(s, 2H), 3. 25(s, 3H), 2. 78(t, 2H) Example 37 Dibenzyl gas group) - 茇篡棊棊棊棊棊 ― 卜Quasi-rigorous

重複本發明實施例23第一步至第二步的反應，使用上述第二步中所得到的化合物（1-{4-[3-氯-4-(3-氟-苄氧基） -苯胺基]-喹唑啉_6_基}_4_三氟甲*_1H_吡咯_3_基）-曱酸23b作原料’按照本發明實施例.23第三步所述相同方式進行該原料與2-甲磺醯基-乙胺的反應，用矽膠管柱層析法純化所得殘餘物，則得到標題產物[3-氯_4-(3~氟〜苄肇氧基）-苯基]-(6一{3_[(2一甲磺醯基_乙胺基）一甲基卜4〜三氟曱基1-吡咯-卜基卜喹唑啉_4_基）_胺37(5〇 mg，淡黃色固體）。產率：41. 7%。、 MS m/z (ESI) : 648[M+ 1] jHNMR (400MHz, DMS0-d〇： ^ 8.66(d, 1H), 8. 60(s, iH)5 8.17(dd, 1H, J = 8.8), 8. 04(s, 1H), 8.01(d, 1H, J=2.4)5 7.90(d，1H，J=8.8)，7.73(dd，1H，J = 9.0)，7.63(s, 1H),’ 7.47(q，1H)，7.31(m，3H)，7.18(t，1H), 5.26(s，2H) 94389 122 201016683 3.74(s, 2H), 3.42(s, 2H), 3. 29(t, 2H, J = 2. 8), 3.01(t, 3H) 實施例38 一氯氟-苄氣某袈某Wfi-丨3-「〔3-嗎啉览棊）-甲義上^-三氟甲基-吡略篡卜喹唑啉-4-基脍The reaction of the first step to the second step of Example 23 of the present invention was repeated, and the compound (1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-aniline obtained in the above second step was used. The base]-quinazoline-6-yl}_4_trifluoromethyl*_1H_pyrrole_3_yl)-nonanoic acid 23b is used as a raw material. The raw material is subjected to the same manner as described in the third step of the embodiment of the present invention. The reaction of 2-methanesulfonyl-ethylamine is purified by column chromatography to give the title product [3-chloro- 4-(3~fluoro-benzyloxy)-phenyl]- (6-{3_[(2-Methanesulfonyl-ethylamino)-methyl b 4~Trifluoromethyl 1-pyrrole-bupybuquinazoline-4-yl)-amine 37 (5 〇 mg , light yellow solid). Yield: 41.7%. , MS m/z (ESI): 648 [M+ 1] jHNMR (400 MHz, DMS0-d〇: ^ 8.66 (d, 1H), 8. 60(s, iH)5 8.17 (dd, 1H, J = 8.8) , 8. 04(s, 1H), 8.01(d, 1H, J=2.4)5 7.90(d,1H,J=8.8), 7.73(dd,1H,J=9.0), 7.63(s, 1H), ' 7.47(q,1H), 7.31(m,3H), 7.18(t,1H), 5.26(s,2H) 94389 122 201016683 3.74(s, 2H), 3.42(s, 2H), 3. 29(t , 2H, J = 2. 8), 3.01(t, 3H) Example 38 Chlorofluoro-Benzyl Benzene A certain Wfi-丨3-"[3-morpholine]-methodone--trifluoro Methyl-pyrrolidinoquinazolin-4-ylindole

重複本發明實施例23第一步至第二步的反應，使用上 ®述第二步中所得到的化合物（1-{4_[3_氯_4—(3-氟-苄氧基） -苯胺基]-喹唑啉—6_基}一4-三氟甲基一 1H-吡咯-3-基）-甲駿23b作原料，按照本發明實施例23第三步所述相同方式進行該原料與3-嗎琳-4-基-丙胺的反應’用矽膠管柱層 :析法純化所得殘餘物’則得到標題產物[3-氯_4__(3_氣—节氧基）-苯基]-(6-{3 - [(3-嗎喻-4-基-丙胺基）-甲基]r：氟甲基-吡咯-1-基卜喹唑啉-4-基）-胺38(70 mg，淡黃色糝固體）。產率：56. 9%。、 MS m/z (ESI) ： 669[M+ 1] ^NMR (400MHz, DMSO-JO: <5 9. 94(s, 1H), 8. 78(s, 1H) 8.62(s, 1H), 8.17(dd, 1H, J = 8. 8), 8. 13(s, 1H), 8. 〇5(m 1H)，7.92(d，1H，J = 9.2)，7.84(s，1H), 7.77(m，1H) 7.48(q, 1H), 7. 32(q, 3H), 7. 19(t, 1H), 5. 26(s, 2H) 3.92(s, 2H), 3.54(t, 4H), 2. 84(s, 2H), 2. 37(t, 6H) 1.72(t, 2H) ’ 94389 123 201016683 實施例39The reaction of the first step to the second step of Example 23 of the present invention was repeated, using the compound obtained in the second step of the above (1-{4_[3_chloro-4-(3-fluoro-benzyloxy)-) Anilino]-quinazoline-6-yl}-4-trifluoromethyl-1H-pyrrol-3-yl)-methyljun 23b is used as a starting material in the same manner as described in the third step of Example 23 of the present invention. Reaction of the starting material with 3-morphin-4-yl-propylamine 'Using a ruthenium tube column: purification of the resulting residue' to give the title product [3-chloro_4__(3_qi- ethoxy)-phenyl ]-(6-{3 - [(3-isomethyl-4-propylamino)-methyl]r: fluoromethyl-pyrrol-1-ylquinazolin-4-yl)-amine 38 ( 70 mg, pale yellow 糁 solid). Yield: 56.9%. , MS m/z (ESI): 669 [M+ 1] NMR (400 MHz, DMSO-JO: <5 9. 94 (s, 1H), 8.78 (s, 1H) 8.62 (s, 1H), 8.17(dd, 1H, J = 8. 8), 8. 13(s, 1H), 8. 〇5(m 1H), 7.92(d,1H,J = 9.2), 7.84(s,1H), 7.77 (m,1H) 7.48(q, 1H), 7. 32(q, 3H), 7. 19(t, 1H), 5. 26(s, 2H) 3.92(s, 2H), 3.54(t, 4H) ), 2. 84(s, 2H), 2. 37(t, 6H) 1.72(t, 2H) ' 94389 123 201016683 Example 39

躁暴三氟甲基-吡略-i-某卜喹唑啉一4-某yHurricane trifluoromethyl-pyridyl-i-a certain quinazoline-4-some y

重複本發明實施例23第一步至第二步的反應，使用上 •述第二步中所得到的化合物（1_{4-[3-氯-4-(3-氟-苄氧基） -苯胺基]-喹唑啉_6_基卜4_三氟甲基_1H_吡咯_3_基）_曱盤23b作原料’按照本發明實施例23第三步所述相同方式進行該原料與2-吡咯烷-1-基-乙胺的反應，用矽膠管柱 •層析法純化所得殘餘物’則得到標題產物[3-氯-4-(3-1-苄氧基）-苯基]-(6-{3-[(2-吼咯烧-1-基-乙胺基）一甲基]. -4-三氟曱基-吡咯_丨—基卜喹唑啉_4_基）_胺39(6〇mg，淡黃色固體）。產率：50. 4%。 φ MS m/z (ESI) ： 639[M+ 1] ]HNMR (400MHz, DMSO-dO： 5 10.〇l(s, 1H), 8. 84(s, 1H) 8-61(s, 1H), 8.21(d, 1H, J = 8. 8), 8. 10(m, 2H), 7. 87(m, 3H), 7.47(q, 1H), 7.32(m, 3H), 7.21(t, 1H), 5. 27(s, 2H), 3.80(s, 2H), 2.89(m, 8H), 1.84(m, 4H) 實施例40 11[(1-{4-[3-氣-4-(3-氟-苄氲某）-装胺基1-喹唑设^^^ 二I-二氟曱基-lH-^bp各-3-基甲某v胺基1-3-嗎吸__ 94389 124 201016683 丙-2-醇The reaction of the first step to the second step of Example 23 of the present invention was repeated, and the compound (1_{4-[3-chloro-4-(3-fluoro-benzyloxy)) obtained in the second step described above was used. Anilino]-quinazoline-6-ylbu- 4-trifluoromethyl-1H-pyrrole_3_yl)_anthracene 23b as a starting material 'The raw material was carried out in the same manner as described in the third step of Example 23 of the present invention. Reaction with 2-pyrrolidin-1-yl-ethylamine, purification of the residue by hydrazine column chromatography to give the title product [3-chloro-4-(3-1-benzyloxy)-benzene ]]-(6-{3-[(2-indole-1-yl-ethylamino)-methyl].-4-Trifluoromethyl-pyrrole-丨-pybuquinazoline_4_ Amine 39 (6 mg, pale yellow solid). Yield: 50. 4%. φ MS m/z (ESI): 639[M+ 1] ]HNMR (400MHz, DMSO-dO: 5 10.〇l(s, 1H), 8. 84(s, 1H) 8-61(s, 1H) , 8.21(d, 1H, J = 8. 8), 8. 10(m, 2H), 7. 87(m, 3H), 7.47(q, 1H), 7.32(m, 3H), 7.21(t, 1H), 5. 27(s, 2H), 3.80(s, 2H), 2.89(m, 8H), 1.84(m, 4H) Example 40 11[(1-{4-[3-气-4- (3-Fluoro-benzyl hydrazine)-Amine-l-quinazoline set ^^^ Di-I-difluoroindolyl-lH-^bp each -3-yl-methyl-a-amino group 1-3- _ 94389 124 201016683 propan-2-ol

重複本發明實施例23第一步至第二步的反應，使用上述第二步中所得到的化合物（1_{4_[3_氯-4-(3-氟-苄氧基） -苯胺基]-啥唾琳-6-基丨-4-三氟甲基-1Η-1 2比p各-3-基）-甲搭23b作原料，按照本發明實施例23第三步所述相同方式進行該原料與1-胺基-3-嗎啉-4-基-丙-2-醇的反應’用擊矽膠管柱層析法純化所得殘餘物，則得到標題產物氣-4-(3-氟-苄氧基）-苯胺基]-喹唑啉-6-•基} -4-三氟甲基-1H-吡咯-3-基曱基）-胺基]-3-嗎琳-4-基、丙 -2-醇40(70 mg，淡黃色固體）。產率：55· 1%。、MS m/z (ESI) ： 685[M+ 1] 'HNMR (400MHz, DMS0-c?6): d 9. 98(s, 1H), 8. 80(s, 1H), 8.61(s, 1H), 8.17(ra, 2H), 8. 06(s, 1H), 7.91(d, 1H, Q J=8.8), 7. 79(m, 2H), 7.48(q, 1H), 7. 32(m, 3H), 7.l9(t, 1H), 5. 27(s, 2H), 4.80(s, 1H), 3. 87(s, 3H), 3. 53(m, 4H), 2.84(m, 1H), 2. 67(m, 1H), 2. 33-2.42(m, 6H) 實施例41 i二{[(1-丨4-「3-氩-4-(3-氟-苄氣某装胺基]-喹崠基j-4-三氤曱基-1H-吡咯-3-基甲某V胺基1-甲某Ui 1 125 1 一六I一1入氺6氺一〇塞〇南一4一1^· 2 94389 201016683The reaction of the first step to the second step of Example 23 of the present invention was repeated, and the compound obtained in the above second step (1_{4_[3_chloro-4-(3-fluoro-benzyloxy)-anilinyl] was used. - 啥琳 -6 -6-yl 丨-4-trifluoromethyl-1 Η -1 2 than p -3- yl)-Met 23b as a starting material, in the same manner as described in the third step of Example 23 of the present invention Reaction of the starting material with 1-amino-3-morpholin-4-yl-propan-2-ol. The obtained residue was purified by column chromatography, to afford title product: -benzyloxy)-anilino]-quinazolin-6-yl}-4-trifluoromethyl-1H-pyrrol-3-ylindenyl)-amino]-3-morphin-4-yl , propan-2-ol 40 (70 mg, pale yellow solid). Yield: 55.1%. MS m/z (ESI): 685 [M+ 1] 'HNMR (400 MHz, DMS0-c?6): d 9. 98 (s, 1H), 8. 80 (s, 1H), 8.61 (s, 1H) ), 8.17(ra, 2H), 8. 06(s, 1H), 7.91(d, 1H, QJ=8.8), 7. 79(m, 2H), 7.48(q, 1H), 7. 32(m , 3H), 7.l9(t, 1H), 5. 27(s, 2H), 4.80(s, 1H), 3. 87(s, 3H), 3. 53(m, 4H), 2.84(m , 1H), 2. 67(m, 1H), 2. 33-2.42(m, 6H) Example 41 i bis{[(1-丨4-"3-argon-4-(3-fluoro-benzyl) A certain amine]-quinolyl j-4-tridecyl-1H-pyrrol-3-yl-methyl V-amino group 1-A certain Ui 1 125 1 one six I one into the 氺 6 氺 one 〇〇南一4一1^· 2 94389 201016683

aa

F 重複本發明實施例23第一步至第二步的反應’使用上述第二步中所得到的化合物（1 -丨4-[3-氯-4-(3-氟-苄氧基） -苯胺基]-喹唑啉-6-基卜4-三氟甲基-1H-吡咯-3-基）-甲搭23b作原料’按照本發明實施例23第三步所述相同方式進行該原料與4-胺基甲基-1，1-二氧-六氫__丨λ *6*_噻嗔--醇的反應’用㈣管柱層析法純化所得殘餘物，到標題產物4-{[(卜{4-[3-氯-4-(3-氟-节氧基）一+基卜4-三氣甲基―各i基甲基胺基土]: 甲基卜1’卜二氧-六氫·1λ.嗔痛_4_醇41(1〇7呢，淡黃色固體）。產率：82. 3%。 MS m/z (ESI) ： 704[M+ 1 ] HNMR (400MHz, DMSO-de) ： (5 9. 84(s 1H") « cn^ » llly, 〇-69(s 1H) ^ 8.2G(dd，1H’ 风 8)，8 G6(s iH) 8 〇2(d，馨 1H’ J-2.8)’ 7.90(d，1H’ J=9.2)，7.73(dd，1H，j = 8 8) 7.65(s，1H)，7.48(m，1H)，7.33(q，3H)，7 2〇 · ’ 5.28(s, 2H), 4.78(s, 1H), 3.76(s, 2H), 3. I8(mi 2H)， 2.95(m, 2H)’ 2.60(s，2H), 1.98(m，4H) 實施例42 喹唑F. The reaction of the first step to the second step of Example 23 of the present invention was repeated. 'The compound obtained in the above second step (1 -丨4-[3-chloro-4-(3-fluoro-benzyloxy)-) was used. Anilino]-quinazolin-6-ylbu-4-trifluoromethyl-1H-pyrrol-3-yl)-mole 23b as starting material 'The raw material was carried out in the same manner as described in the third step of Example 23 of the present invention. Reaction with 4-aminomethyl-1,1-dioxo-hexahydro__丨λ *6*-thiazide-alcohol' The residue obtained by (4) column chromatography is purified to the title product 4- {[(Bu{4-[3-chloro-4-(3-fluoro-p-oxy)-)-yl- 4-trimethyl--- each i-methylamine-based soil]: methyl b 1' Dioxo-hexahydro·1λ. Anthraquinone_4_ol 41 (1〇7, pale yellow solid). Yield: 82.3% MS m/z (ESI): 704 [M+ 1 ] HNMR (400 MHz , DMSO-de) : (5 9. 84(s 1H") « cn^ » llly, 〇-69(s 1H) ^ 8.2G(dd,1H' wind 8), 8 G6(s iH) 8 〇2 (d, 馨1H' J-2.8)' 7.90(d,1H' J=9.2), 7.73(dd,1H,j = 8 8) 7.65(s,1H), 7.48(m,1H),7.33(q ,3H),7 2〇· ' 5.28(s, 2H), 4.78(s, 1H), 3.76(s, 2H), 3. I8(mi 2H), 2.95(m, 2H)' 2.60(s,2H ), 1.98 (m, 4H) Example 42 quinazole

Hi.氟-4-(3-氟二节氣甚)_笨基卜「6一琳-4-基1-胺 94389 126 201016683Hi.Fluorine-4-(3-fluoro-2 节气气)_ Stupid base "6-lin-4-yl 1-amine 94389 126 201016683

1β 氮氣下在5 0 inL莊形瓶中’將[3 -氣-氣氧基）-苯基]-(6-碘-喹唑啉-4-基）-胺 lg(255 mg，〇.505 mmo1)， 1_(三異丙基石夕）-1Η-η比略-3-棚酸（269 mg’ i·01 mmo1)，肆（三苯基膦）鈀（2. 3 mg，0. 02 mmol)，碳酸鉀（138邶，1 mmol)溶於6 mL N，N-二甲基甲醯胺和1.5 mL水的混合溶劑中’得到的混合物加熱到7(Tc ’ 2小時後反應完畢反應液冷卻至室溫，倒入1 〇〇mL冰水中，析出白色固體，攪拌十分鐘後，抽濾，產物在真空下乾燥，得到的固體進 -步藉由管柱層析法’得到標題產物[3〜氣、4_(3务节氧基）-苯基]-[6-(1Η-«比略-3-基）+坐淋、4、基]一胺42 (138 馨mg，黃色固體）。產率：61.7%。 MS m/z (ESI) ： 445[M+ 1] (400MHz，DMS0-d6): 5 U. 〇9(s，1H)，9.68(s， W’8.56(d，1H，J = 1.2)，8.50(S，1H)，8 〇_，1Η， J=7.6)，8.〇3(d’1H，J = U)，7.H (dd，1H，J=8.8)， 7.70(d，1H，J=8.8)，7.46(m，2H)，7.33(n]，3H)，719(t， 1H)’ 6.98(m，1H)，6. 70(d，1H，J=h6)，5 27(s，2H) 實施例43 · 94389 127 201016683 1-(3-基）-胺引-5-基 Μ6：：吡咯-1 -'[3-Gas-oxyl)-phenyl]-(6-iodo-quinazolin-4-yl)-amine lg (255 mg, 〇.505) in a 50 inL bottle under 1β nitrogen Mmo1), 1_(triisopropyl shixi)-1Η-η ratio -3- benzyl acid (269 mg' i·01 mmo1), hydrazine (triphenylphosphine) palladium (2.3 mg, 0.02 mmol) ), potassium carbonate (138 邶, 1 mmol) was dissolved in 6 mL of a mixed solvent of N,N-dimethylformamide and 1.5 mL of water. The resulting mixture was heated to 7 (Tc' 2 hours after the reaction was completed. After cooling to room temperature, it was poured into 1 mL of ice water, and a white solid was precipitated. After stirring for ten minutes, it was filtered with suction, and the product was dried under vacuum, and the obtained solid was obtained by column chromatography to give the title product. 3~ gas, 4_(3 hydroxy)-phenyl]-[6-(1Η-«比略-3-yl)+sodium, 4,yl]monoamine 42 (138 mg, yellow solid) Yield: 61.7% MS m/z (ESI): 445 [M+ 1] (400 MHz, DMS0-d6): 5 U. 〇9(s, 1H), 9.68 (s, W'8.56 (d, 1H) , J = 1.2), 8.50 (S, 1H), 8 〇 _, 1 Η, J = 7.6), 8. 〇 3 (d'1H, J = U), 7.H (dd, 1H, J = 8.8) , 7.70 (d, 1H, J = 8.8), 7.46 (m, 2H), 7.33 (n), 3H) 719(t, 1H)' 6.98(m,1H), 6.70(d,1H,J=h6),5 27(s,2H) Example 43 · 94389 127 201016683 1-(3-yl)-amine引-5-基Μ6::pyrrole-1 -

Cn.Cn.

HNHN

43 43a 第一步 r<\办F功 ΪΙ； Cn1 43b43 43a First step r<\F-function ΪΙ; Cn1 43b

43 第一步 ® [1-(3-氟苄基）-1 u-吲唑-5-基]-(6-碘喹唑啉基）_胺重複本發明實施例1第一步至第四步的反應，將第四步所得的化合物6_碘_3H_喹唑啉_4_酮lf(1〇运，％ 7 -mmol)，在氮氣下加入到5〇〇 mL茄形瓶中溶於以匕二氣亞砜和3 mL N，N-二曱基甲醯胺的混合溶劑中，加熱回流至反應液透明。攪拌6小時後，薄層分析追蹤原料|肖失，蒸出二氯亞砜，備用。氮氣下將備用中間體溶於250 mL異丙醇中，加入卜 (3-氟节基）]Hm5_胺 43a(8 85 g，36 7 μ⑷加 =流過夜。薄層分析絲至原料消失，將反應液冷卻至室溫，減壓抽濾，將所得固體用5〇社乙酸乙酯洗滌，將滤餅加入到氨水（200 mL，1〇〇mL氨水加剛此水）和乙酸乙醋的混合溶劑中溶解，室溫攪拌ίο分鐘，減麼抽減，直空乾燥，得到標題產物[卜（3一氟节基）_1Η_π引唾_5_基]普破喹唑啉-4-基脸/10 )胺43b (13 g ’類白色固體）。產率： φ 94389 】28 201016683 71.8%。 MS m/z (ESI) ·· 496[M+1] 第二步 [3-氣-4-(吡啶-2-曱氧基）-笨基]_(6—吡咯_i-基-喹唑啉 -4-基）-胺氮氣下在100 mL茄形瓶中加入[ι_(3-氟苄基）-ih-吲唑-5-基]-(6-碘喹唑啉-4-基）-胺 43b(100 mg，0. 2 mmol) ’ 磷酸鉀（127 mg，〇· 6 mm〇i)，碘化亞銅（57 mg， 0.3mmol)和吡咯（20 mg，0.3 mm〇l)，用 5 raL N，N-二甲基 ❾甲醯胺溶解，攪拌下滴加N，N’-二曱基-i，2-乙二胺（26 mg，0.29 ππηοΐ)，加熱回流攪拌過夜。薄層分析追蹤至原料消失^倒入50 roL冰水中’過滤、，得到墨綠色固體進一步藉由管柱層析法分離純化得到標題產物[3盘 -2-甲氧基)-苯基]-(6-料_卜基一啥唾琳、$ 4夕，43 First Step® [1-(3-Fluorobenzyl)-1 u-indazol-5-yl]-(6-iodoquinazolinyl)-amine repeats the first to fourth embodiments of the present invention In the reaction of the step, the compound 6_iodo_3H_quinazoline_4_one lf (1 〇, % 7 -mmol) obtained in the fourth step is added to a 5 〇〇 mL eggplant bottle under nitrogen. In a mixed solvent of hydrazine disulfoxide and 3 mL of N,N-dimercaptocarbamide, the mixture was heated to reflux until the reaction liquid was transparent. After stirring for 6 hours, the thin layer analysis traced the raw materials, lost, and distilled off thionyl chloride for use. The spare intermediate was dissolved in 250 mL of isopropanol under nitrogen, and then added to the (3-fluoronodo)]Hm5-amine 43a (8 85 g, 36 7 μ (4) plus = flow overnight. The thin layer was analyzed to remove the material. The reaction solution was cooled to room temperature, suction-filtered under reduced pressure, and the obtained solid was washed with ethyl acetate. The filter cake was added to aqueous ammonia (200 mL, 1 mL of ammonia water plus water) and ethyl acetate. Dissolve in a mixed solvent, stir at room temperature for ίο min, reduce or decrease, and dry in a straight space to obtain the title product [Bu (3-fluoro-fluorenyl)_1 Η _ _ _ _ _ _ _ ] 破喹唑唑唑基基基基/10) Amine 43b (13 g 'white solid). Yield: φ 94389 】28 201016683 71.8%. MS m/z (ESI) ·· 496[M+1] The second step [3- gas-4-(pyridin-2-yloxy)-phenyl]_(6-pyrrole-i-yl-quinazoline [0-(3-Fluorobenzyl)-ih-indazol-5-yl]-(6-iodoquinazolin-4-yl) was added to a 100 mL eggplant vial under nitrogen. -amine 43b (100 mg, 0.2 mmol) 'potassium phosphate (127 mg, 〇·6 mm〇i), cuprous iodide (57 mg, 0.3 mmol) and pyrrole (20 mg, 0.3 mm 〇l), After dissolving with 5 raL of N,N-dimethylformamide, N,N'-dimercapto-i,2-ethylenediamine (26 mg, 0.29 ππηοΐ) was added dropwise with stirring, and the mixture was stirred under reflux overnight. The thin layer analysis was traced to the disappearance of the starting material and poured into 50 roL of ice water to be filtered, and the dark green solid was obtained, which was further purified by column chromatography to give the title product [3-disc-2-methoxy)-phenyl]- (6-Materials _ _ _ 啥啥、、、, $ 4 eve,

(30 mg，淡黃色固體）。產率：3〇%。土 J胺W MS m/z (ESI) ： 435[M+1] 8· 7Us, 1H), 8· ^(dd, 1H, 1H, J = 8. 8)’ 7. 11(m，3H)，馨 HNMR (400MHz，DMSO-de): (5 9.98(s 1U) 8.53(s, 1H), 8.25(s, 1H), 8. 18(s, 1H), J = 9. 2)， 7. 87(d, 1H, J = 9. 2)， 7. 79(廿 7. 74(m, 1H), 7. 61(ra, 2H), 7. 38(m, 1H) 6.38(m, 2H) ’ 實施例44(30 mg, light yellow solid). Yield: 3〇%. Soil J amine W MS m/z (ESI): 435 [M+1] 8·7Us, 1H), 8·^(dd, 1H, 1H, J = 8. 8)' 7. 11(m,3H) , H HNMR (400MHz, DMSO-de): (5 9.98(s 1U) 8.53(s, 1H), 8.25(s, 1H), 8. 18(s, 1H), J = 9. 2), 7. 87(d, 1H, J = 9. 2), 7. 79(廿7. 74(m, 1H), 7. 61(ra, 2H), 7. 38(m, 1H) 6.38(m, 2H) 'Example 44

94389 129 20101668394389 129 201016683

-Ο 第一步Η»Ν_-Ο Step 1ΗΝΝΝ

,α°^ 第一步 ❾3-氣-4-(吡啶-2-曱氧基）-苯胺在250mL莊形瓶中加入2-(2-氯-4-硝基—苯氧基甲基） -口比啶 44a(9.5g，35.9mmol) ’ 1〇〇此甲醇，氯化敍 .(19. 17g，359mmol)和50 mL水，所得的混合物加熱回流3 ]、日ΤΓ後反應元畢。冷卻反應液至室溫，過渡，母液減壓下濃縮’得到的殘留物加入80 mL水，用二氯甲烷萃取所得混合液（100 mLx3) ’有機相用無水硫酸鈉脫水，過渡，渡 _液濃縮後得到本標題產物3-氯-4-(吡啶-2-甲氧基）-苯胺 44b(8· 7 g，黃色固體），100%。純度：98. 13%。第二步乳-4-(〇比0定-2-曱氧基）-苯基]-(6 -喊喧0坐琳_4 -基）-胺重複本發明實施例1第一步至第四步的反應，將第四步所得的化合物6-续坐琳-4-酮lf(5g’18.3mmol) 溶於50 mL二氯亞礙和0.5 mL N，N-二曱基曱醯胺的混合溶劑中，加熱回流至反應液透明。攪拌6小時後，薄層分 130 94389 201016683 析追蹤至原料消失，蒸出二氯亞砜，備用虹異丙醇中，加入3,α°^ first step ❾3-gas-4-(pyridin-2-yloxy)-phenylamine 2-(2-chloro-4-nitro-phenoxymethyl) was added to a 250 mL bottle Oral pyridine 44a (9.5 g, 35.9 mmol) '1 〇〇甲醇 methanol, chlorinated (19. 17 g, 359 mmol) and 50 mL of water, the resulting mixture was heated to reflux 3], after the reaction time. The reaction solution was cooled to room temperature, and the mixture was concentrated under reduced pressure. The residue obtained was added to 80 mL of water, and the mixture was extracted with dichloromethane (100 mL×3). The organic phase was dried over anhydrous sodium sulfate. After concentration, the title product 3-chloro-4-(pyridin-2-methoxy)-phenylamine 44b (8·7 g, yellow solid) Purity: 98. 13%. The second step of the first step to the first embodiment of the present invention is the second step of the emulsion - 4 (〇 0 0 曱曱曱曱 )) - phenyl] - (6 - 喧喧坐坐 _ _ _ _ _ _ yl)-amine repeat In a four-step reaction, the compound 6-supplied 4-ketone lf (5g '18.3mmol) obtained in the fourth step is dissolved in 50 mL of dichloro sulphate and 0.5 mL of N,N-didecyl decylamine. In the mixed solvent, the mixture was heated to reflux until the reaction liquid was transparent. After stirring for 6 hours, the thin layer was divided into 130 94389 201016683 and the trace disappeared until the starting material disappeared. The thionyl chloride was distilled off, and the spare rainbow isopropanol was added.

苯基]-(6-碘喹唑啉-4-基胺44c (8 g，類白色固體）^ 氮氣下將備用中間體溶於16〇 mL異氯_4-(吡啶-2-甲氧基）_苯胺44b(4 25 產率：89. 6%。 ® MS m/z (ESI) ： 489[M+ 1] HNMR (400MHz, DMS0-d〇： δ 9. 78(s, 1H), 8. 60(d, 3H), 8.16(d, 1H, J = 9.2), 8. 04(m, 1H), 7. 89(m, 2H), 7. 76(d, .1H, J=9.2), 7. 59(m, 3H), 7.38(t, 1H), 7.31(d, 1H, J=8.8), 6.38(s, 2H), 5. 31(s, 2H) 第三步 [3_氯-4-(吼啶-2-曱氧基）_苯基]_(6_„比咯―卜基―喹唑啉馨-2-基）-胺氮氣下在100 mL茄形瓶中加入[3-氯-4-(吡啶-2-曱氧基）_ 本基]-(6-破喧唾淋-4-基）-胺 44c(l. 95 g，4 mmol)，鱗酸钟（2.55 g，12 mmol)，硪化亞銅（2.28 g，12 mmol) 和0比咯（11 mL，160 mmol)，用25 mL N，N-二曱基甲醯胺溶解，攪拌下滴加N，N，-二曱基-1，乙二胺（1. 3 mL，12 mmol)’加熱回流攪拌4小時後反應完畢。將反應液冷卻至室溫，倒入1 〇〇 mL冰水中，過濾，得到黑色固體，進一步 131 94389 201016683 藉由管柱層析法分離純化，得到標題產物[3_氯_4_(吡啶 -2-曱氧基）-苯基]-(6-吼嘻-1-基—喹唑啉〜2_基）一胺44 (1. 3 g，白色固體）。產率：76%。 MS m/z (ESI) : 428[M+1] ]HNMR (400MHz, DMSO-d〇: (5 9. 78(s, 1H), 8. 60(d, 3H), 8. 16(d，1H，J = 9.2)，8.04(m，1H), 7.89(m，2H)，7. 76(d 1H，J = 9.2)，7.59(m，3H)，7.38(t，1H)，7. 31(d，1H: J=8.8)，6. 38(s，2H)，5.31(s，2H) ’ 實施例45Phenyl]-(6-iodoquinazolin-4-ylamine 44c (8 g, off-white solid)^ Dissolve the intermediate in 16 mL of isochloro- 4-(pyridine-2-methoxy) under nitrogen ) phenylaniline 44b (4 25 yield: 89.6%) MS m/z (ESI): 489 [M+ 1] HNMR (400 MHz, DMS0-d〇: δ 9.78 (s, 1H), 8. 60(d, 3H), 8.16(d, 1H, J = 9.2), 8. 04(m, 1H), 7. 89(m, 2H), 7. 76(d, .1H, J=9.2), 7. 59(m, 3H), 7.38(t, 1H), 7.31(d, 1H, J=8.8), 6.38(s, 2H), 5. 31(s, 2H) Step 3 [3_Chlorine- 4-(Acridine-2-decyloxy)-phenyl]-(6_„Bisole-buki-quinazolin-2-yl)-amine was added to a 100 mL eggplant bottle under nitrogen [3- Chloro-4-(pyridin-2-yloxy)-benyl]-(6-deuteril-4-yl)-amine 44c (1.95 g, 4 mmol), succinic acid (2.55 g, 12 mmol), cuprous halide (2.28 g, 12 mmol) and 0 pyrrole (11 mL, 160 mmol), dissolved in 25 mL of N,N-dimercaptocarbamide, and N,N was added dropwise with stirring. - Dimercapto-1, ethylenediamine (1.3 mL, 12 mmol)' After heating and refluxing for 4 hours, the reaction was completed. The reaction solution was cooled to room temperature, poured into 1 mL of ice water and filtered to give a black Solid, further 131 9438 9 201016683 Separation and purification by column chromatography to give the title product [3_chloro_4_(pyridin-2-yloxy)-phenyl]-(6-fluoren-1-yl-quinazoline~2 _ base) monoamine 44 (1.3 g, white solid). Yield: 76%. MS m/z (ESI): 428[M+1]]HNMR (400 MHz, DMSO-d〇: (5 9. 78(s, 1H), 8. 60(d, 3H), 8. 16(d,1H,J = 9.2), 8.04(m,1H), 7.89(m,2H), 7.76(d 1H, J = 9.2), 7.59 (m, 3H), 7.38 (t, 1H), 7. 31 (d, 1H: J = 8.8), 6. 38 (s, 2H), 5.31 (s, 2H) ' 45

-2-基）-胺-2-yl)-amine

第一步 2-{4-[3_氟_4 -（σ比咬—2 -甲氧基）-苯胺基]-啥唾琳一6_基卜吡嘻-1 -曱酸第三丁醋重複實施例44第一步至第二步的反應，將得到的化合物[3-氣-比咬一2_曱氧基）—苯基]一（6一破噎唾啉-4-基胺44c (1· 95 g，4 _〇〇，卜（第三丁氧基羰基）-ιη~吡咯 94389 132 201016683 -2-硼酸 7b(l.l g，5.2 mm〇i)，肆（三苯基膦）鈀（〇23 g，〇· 2 mmol)，石反酸卸（1.38 g，10 觀〇1)溶於 25 mL· n，N-二甲基甲醒胺和6 mL水的混合溶劑中，得到的混合物加熱到 70 C，2小％後反應完畢。將反應液冷卻至室溫，倒入 mL冰水中，析出白色固體，攪拌十分鐘後抽濾，產物在 ^空下乾燥，得到的固體進一步藉由管柱層析法，得到標題產物2-{4-[3-氯-4-(吼咬-2-甲氧基）-苯胺基卜喧嗤嚇 -6-基卜吡咯一卜甲酸第三丁酯45a(2〇g，黃色固體），產率：95%。 ® MS m/z (ESI) ： 529[M+1] 第二步 [3-氯-4-(吼啶-2 一甲氧基）_苯基]_(6一吼咯4_基_喹唑 -_2-基）-胺將上述步驟得到的化合物2_{4_[3_氯_4_(吡啶_2一甲氧基）-苯胺基]-喹唑啉_6_基卜吡咯_丨_甲酸第三丁酯溶解於55 mL無水四氫咬喃中，得到的黃色溶液用冰水浴 _冷卻至（TC ’加入甲醇納（1.728 g，16mmol)，將反應液逐漸升至室溫，3小時後反應完畢，反應液呈深紅色。將得到的反應液倒入飽和氣化鈉水溶液中，析出固體過濾，得到的黃色固體在真空下乾燥後，進一步藉由管柱層析法分離純化，得到標題產物[3_氣_4_(吡啶_2〜曱氧2)一苯基]-(6-吡咯-1-基-喹唑啉—2-基）一胺45(115 g，^色固體），產率68%。 MS m/z (ESI) : 428[M+1] 94389 133 201016683 JHNMR (400MHz, DMS0-d〇： ^ li.38(s, 1H), 9. 67(s, 1H), 8.65(s, 1H), 8.61(d, 1H), 8. 53(s, 1H), 8. 14(d, 1H, J = 9.2), 8.06(m, 1H), 7. 88(t, 1H), 7. 76(m, 2H), 7.60(d, 1H, J = 7.6), 7.38(t, 1H), 7.31(d, 1H, J=9. 2), 6. 97(s, 1H), 6.77(s, 1H) , 6.22(s, 1H) , 5.31(s, 2H) 實施例46 U-氧-4-("比咬-2-甲惠一笨基Ί_(β_·[5_「（2-曱碏醯基-胺基）-曱基比》色二2-基卜崦嘁啉-4-基）-胺The first step 2-{4-[3_fluoro_4 -(σ ratio bite-2-methoxy)-anilino]-啥琳一一 6 _ _ _ _ _ _ _ _ 第三第三第三第三第三The reaction of the first step to the second step of Example 44 was repeated, and the obtained compound [3-gas-specific bite 2- methoxyl group]-phenyl]-(6-breaking succinyl-4-ylamine 44c) (1·95 g, 4 〇〇, 卜 (t-butoxycarbonyl)-ιη~pyrrole 94389 132 201016683 -2-boronic acid 7b (ll g, 5.2 mm〇i), ruthenium (triphenylphosphine) palladium (〇23 g, 〇· 2 mmol), stone anti-acid unloading (1.38 g, 10 Guanlan 1) dissolved in a mixed solvent of 25 mL·n,N-dimethylmethamine and 6 mL of water. The mixture was heated to 70 C, and the reaction was completed after 2% by volume. The reaction solution was cooled to room temperature, poured into mL ice water, and a white solid was precipitated. After stirring for ten minutes, suction filtration was carried out, and the product was dried under air, and the obtained solid was further borrowed. By column chromatography, the title product 2-{4-[3-chloro-4-(bite-2-methoxy)-anilinylpyrazine-6-ylpyrrole-benzoic acid was obtained. Butyl ester 45a (2 〇g, yellow solid), yield: 95%. MS m/z (ESI): 529[M+1] Step 2 [3-chloro-4-(acridin-2 Monomethoxy)-phenyl]-(6-fluorenyl 4_yl-quinazolyl-2-yl)-amine The compound obtained in the above step 2_{4_[3_chloro_4_(pyridine-2-methoxy) Tert-)-anilino]-quinazoline_6_ pyopyrrol-indole-carboxylic acid tert-butyl ester was dissolved in 55 mL of anhydrous tetrahydroanthracene, and the obtained yellow solution was cooled to (TC 'added methanol) with ice water bath. Nano (1.728 g, 16 mmol), the reaction solution was gradually warmed to room temperature, and after 3 hours, the reaction was completed, and the reaction mixture was dark red. The obtained reaction mixture was poured into a saturated aqueous solution of sodium carbonate, and the solid was filtered to give a yellow color. After the solid was dried under vacuum, it was further purified by column chromatography to give the title product [3_ gas_4_(pyridine-2~~~~~~~~~~~~~~~~~~~~~~ Quinazoline-2-yl)-amine 45 (115 g, color solid), yield 68%. MS m/z (ESI): 428[M+1] 94389 133 201016683 JHNMR (400MHz, DMS0-d〇 : ^ li.38(s, 1H), 9. 67(s, 1H), 8.65(s, 1H), 8.61(d, 1H), 8. 53(s, 1H), 8. 14(d, 1H , J = 9.2), 8.06(m, 1H), 7. 88(t, 1H), 7. 76(m, 2H), 7.60(d, 1H, J = 7.6), 7.38(t, 1H), 7.31 (d, 1H, J=9. 2), 6. 97(s, 1H), 6. 77(s, 1H) , 6.22(s, 1H) , 5.31(s, 2H) Example 46 U-Oxygen-4-("Bite 2-Bei Huiyi Stupid Ί_(β_·[5_"( 2-mercapto-amino)-indenyl ratio chromo-2- 2-carbobolin-4-yl)-amine

第一步 5-{4-[3-氯-4-(。比啶一2_甲氧基）_苯胺基]_喹唑啉_6_基} _ -1H-0比洛-2-甲齡。氣氣^ ’將10 mL N, N-二曱基曱醯胺用冰浴冷卻至 C力入一氣敦膦（〇. ，〇. 98丽〇1)，混合液升至室概，攪拌半小時。得到的溶液冷卻至（TC，加入實施例45 所付到的化合物[3_氣_4-(吡啶-2-曱氧基)-苯基]-(6—吡咯1基-喹唑啉_2 —基）_胺45，混合液在室溫下攪拌4小時反應完畢後，加入1QmL冰水，並用1N氫氧化鈉溶液調整pH=U °用二氯曱烷和甲醇混合溶劑（60 mLx5)進行萃 94389 134 201016683 取。有機相在減塵下濃縮，所得的殘留物在室溫下放置過伏，有頁色固體析出，過濾，得到標題產物5_丨4_[3_氯_4_ (吡啶-2-甲氧基）-苯胺基]-喹唑啉_6_基卜1H一吡咯_2_曱醛46a(120 mg ’黃色固體），產率4〇%。 MS m/z (ESI) ： 456[M+1] HNMR (400MHz, DMS0-d〇： δ 12.59(s, 1H), 11.20(s, 1H) 9.60(s, 1H), 9.25(s, 1H), 8.86(s, 1H), 8. 62(d, 1H, J=4.4), 8.58(d, 1H, J=8.8), 8. 〇〇(s> iH), 7.91(m, 2H), 7.72(d, 1H, J = 8.8), 7.61(d, 1H, J=7. 6), 7. 38(m, 2H), 7. 20(s, 1H), 7. 14(s, 1H), 5. 36(s, 2H) 第二步 [3-氯-4-(叱啶-2-甲氧基）-苯基]一（6一{5_[(2_甲磺醯基_ 乙胺基）-曱基]-1H-吡咯-2-基}-喹唑啉_4_基）_胺將2-曱磺醯-乙胺鹽酸鹽2b(3〇 mg，〇186 mmQl)，二乙胺（0.038 mL，0.275 mmol)溶於5mL·二氣曱烧中，完全溶解後加入上述步驟所得的化合物5_{4_[3_氣_4_(吡 _咬-2-曱氧基）-苯胺基]-喹唑啉一基丨一1H_吡咯-2_曱駿 46a(50 mg，0.11 mmol)，攪拌6小時後，加入三乙醯氧基棚氫化納（61 rag，0.286 mmol)。所得的混合液在室溫下攪拌過夜’反應完畢。用TLC層析分離產物，得到標題產物[3-氯-4-〇比啶-2_甲氧基）-苯基]-(6一{5_[(2-甲磺醯基 -乙胺基）-曱基]-1H-吡咯-2-基}_喹唑啉_4_基）-胺46(46 mg，黃色固體），產率74. 0%。 MS m/z (ESI) ： 564[M+1] 94389 135 201016683 JHNMR (400MHz, DMSO-d〇: (5 11.92(s, 1H), 9. 84(s, 1H), 9.04(s, 1H), 8.61(s, 1H), 8.55(s, 1H), 8. 23(s, 1H), 8. 15(d, 1H, J = 8.8), 7. 90(m, 2H), 7. 77(d, 1H, J=8.4), 7.61(d, 1H, J=7.6), 7. 38(t, 1H), 7. 30(d, 1H, J=9. 2), 6.77(s, 1H), 6.29(s, 1H), 5.36(s, 2H), 4. 12(s, 2H), 3.51(t, 2H), 3. ll(s, 3H), 3. 06(t, 2H) 實施例47 2-{4-[3 -氣-4-(°比咬-2 -甲氧基）~苯胺基~|-喧《坐琳-6-基} -6, 7-二氬- 2!1-〇比喃「3, 4-〇:1口比洛-4-_First Step 5-{4-[3-Chloro-4-(.pyridyl-2-yloxy)-anilino]-quinazoline_6_yl} _ -1H-0Bilo-2-A age. Air gas ^ '10 mL of N, N-didecyl decylamine was cooled to C by force in an ice bath (一., 〇. 98 〇1), the mixture was added to the room and stirred for half an hour. . The resulting solution was cooled to (TC, the compound [3_qi_4-(pyridin-2-yloxy)-phenyl]-(6-pyrrole-1-yl-quinazoline-2) added in Example 45 was added. —基)_amine 45, the mixture was stirred at room temperature for 4 hours, after completion of the reaction, 1QmL of ice water was added, and the pH was adjusted to U ° with 1N sodium hydroxide solution with a mixed solvent of dichloromethane and methanol (60 mL×5). Extraction 94389 134 201016683 Take. The organic phase is concentrated under dust reduction, and the residue obtained is placed at room temperature under a volt, a solid is precipitated and filtered to give the title product 5_丨4_[3_chloro_4_ (pyridine- 2-methoxy)-anilino]-quinazoline-6-ylbu- 1H-pyrrole-2_furfural 46a (120 mg 'yellow solid), yield 4%. MS m/z (ESI): 456[M+1] HNMR (400MHz, DMS0-d〇: δ 12.59(s, 1H), 11.20(s, 1H) 9.60(s, 1H), 9.25(s, 1H), 8.86(s, 1H), 8. 62(d, 1H, J=4.4), 8.58(d, 1H, J=8.8), 8. 〇〇(s>iH), 7.91(m, 2H), 7.72(d, 1H, J = 8.8 ), 7.61(d, 1H, J=7. 6), 7. 38(m, 2H), 7. 20(s, 1H), 7. 14(s, 1H), 5. 36(s, 2H) The second step [3-chloro-4-(acridin-2-methoxy)-phenyl]-(6-{5_[(2_methylsulfonyl)ethylamine - mercapto]-1H-pyrrol-2-yl}-quinazoline-4-yl)-amine 2-oxasulfonyl-ethylamine hydrochloride 2b (3 〇 mg, 〇186 mm Ql), diethylamine (0.038 mL, 0.275 mmol) dissolved in 5 mL·digas smolder, completely dissolved and added to the compound obtained in the above step 5_{4_[3_气_4_(pyridine-2-oxooxy)-anilino] - quinazoline-based hydrazine-1H_pyrrole-2_曱jun 46a (50 mg, 0.11 mmol), after stirring for 6 hours, triethyloxy hydride sodium hydride (61 rag, 0.286 mmol) was added. The solution was stirred at room temperature overnight. The reaction was completed. The product was isolated by chromatography to afford the title product [3-chloro-4-indolepyridin-2-yloxy)-phenyl]-(6-{5_[( 2-methanesulfonyl-ethylamino)-indenyl]-1H-pyrrol-2-yl}-quinazoline-4-yl)-amine 46 (46 mg, yellow solid), yield 74. 0% MS m/z (ESI): 564[M+1] 94389 135 201016683 JHNMR (400MHz, DMSO-d〇: (5 11.92(s, 1H), 9. 84(s, 1H), 9.04(s, 1H ), 8.61(s, 1H), 8.55(s, 1H), 8. 23(s, 1H), 8. 15(d, 1H, J = 8.8), 7. 90(m, 2H), 7. 77 (d, 1H, J=8.4), 7.61(d, 1H, J=7.6), 7. 38(t, 1H), 7. 30(d, 1H, J=9. 2), 6.77(s, 1H ), 6.29(s, 1H), 5.36( s, 2H), 4. 12(s, 2H), 3.51(t, 2H), 3. ll(s, 3H), 3. 06(t, 2H) Example 47 2-{4-[3 - gas -4-(° than bite-2-methoxy)~aniline~|-喧 "Sitlin-6-yl} -6, 7-di-argon - 2!1-〇比喃"3, 4-〇 : 1 port bilo-4-_

10b10b

4747

Cl 在100 mL茄形瓶中，依次加入[3-氯-4-(吡啶-2-曱氧基）-苯基]-(6-破啥唾淋-4-基）-胺 44c(l. 95 g，4 mmol)， 6,7-二氩-2^吡喃并[3,4-。]吡咯-4-酮1〇1>(713 11^，5.2 mmo 1)，罐酸钟（2· 55.g’ 12 romo 1)，峨化亞銅（〇· 76 g，4 mmo 1) 和25 mL N，N-二曱基曱醯胺，混合物在攪拌下加入n，n，_ 一甲基1,2-乙一胺（〇·44 mL ’ 4 mmol)’加熱反應液到 7〇°C ’攪拌過夜。冷卻反應液，倒入1〇〇 ml冰水中，綠色固體析出，抽濾，得到的固體藉由管栓層折有墨刀離純 94389 136 201016683 化，得到的標題產物2-U-[3-氯-4-(吡啶-2-甲氧基）-苯胺基]-喹唑啉-6-基卜6, 7-二氫-2H-吡喃[3,4-c]吡咯-4-酮47(0· 9 g ’類白色固體），產率45. 2%。 MS m/z (ESI) ： 498 [M+ 1 ] HNMR(400MHz，DMSO-cW: (5 9.83(s，1H)，8.75(s，1H), 8.61(m，2H)，8.24(t，2H)，8.〇3(s，ih)，7.89(m，2H)， 7. 73(d, 1H, J=8.8), 7. 60(d, 1H, J=7. 6), 7. 54(s, 1H), 7.38(t, 1H), 7.32(d, 1H, J = 8. 8), 5.32(s, 2H) , 4. 48(t, 2H), 2. 91(t, 2H) 瘳實施例48 (3.二基-4-氟苯基）-(6-吡咯-i-喹吔喻某胳Cl In a 100 mL eggplant-shaped flask, [3-chloro-4-(pyridin-2-yloxy)-phenyl]-(6-deutero-4-yl)-amine 44c (1. 95 g, 4 mmol), 6,7-diar-2^pyrano[3,4-. Pyrrole-4-one 1〇1> (713 11^, 5.2 mmo 1), pot acid clock (2·55.g' 12 romo 1), cuprous telluride (〇· 76 g, 4 mmo 1) and 25 mL of N,N-didecylguanamine, the mixture was stirred with n, n, _ monomethyl 1,2-ethylamine (〇·44 mL '4 mmol)' to heat the reaction solution to 7 ° C 'Stirring overnight. The reaction solution was cooled, poured into 1 ml of ice water, and a green solid was precipitated and suction filtered, and the obtained solid was obtained by the tube plug layer and the ink knife was separated from the pure 94389 136 201016683 to obtain the title product 2-U-[3- Chloro-4-(pyridine-2-methoxy)-anilino]-quinazolin-6-yl b 6,7-dihydro-2H-pyrano[3,4-c]pyrrol-4-one 47 2%。 (0·9 g 'white solid), yield 45.2%. MS m/z (ESI): 495 [M+1] HNMR (400 MHz, DMSO-cW: (5 9.83 (s, 1H), 8.75 (s, 1H), 8.61 (m, 2H), 8.24 (t, 2H) , 8. 〇 3 (s, ih), 7.89 (m, 2H), 7. 73 (d, 1H, J = 8.8), 7. 60 (d, 1H, J = 7.6), 7. 54 ( s, 1H), 7.38(t, 1H), 7.32(d, 1H, J = 8. 8), 5.32(s, 2H) , 4. 48(t, 2H), 2. 91(t, 2H) 瘳Example 48 (3. Diyl-4-fluorophenyl)-(6-pyrrole-i-quinoline

第一步 (3-氣-4-氟苯基）-(6-碳-啥唾琳—4-基）一胺重複本發明實施例1第五所述的實驗步驟，不同的是以實施例1第四步所得的化合物6_碘_311_喹唑啉_4_酮lf 作原料，按照本發明實施例1第五步所述的相同方式使得該原料與3-氣-4-氟-苯胺的反應，得到標題化合物（3_氣 -4-氟苯基）-(6-碘-喹唑啉—4—基胺48&(15呢，黃色固 94389 137 201016683 體），產率56%。 MS m/z (ESI) ： 400 [M+ 1 ] 第二步 (3-氣-4-氟苯基）-(6--比咯_ι_喹唑啉__4_基）_胺在100 mL茄形瓶中，將上述步驟所得的化合物（3_氯 -4-氟苯基）-(6-碘-喹唑啉-4-基）-胺 48a(2 g，5 mmol)，磷酸鉀（3. 18 g，l5mmol)，碘化亞銅（〇. 95g，5mmol)溶解於40mLN，N-二曱基曱醯胺中，混合物在攪拌下加入N, N，_ 一甲基-1，2-乙二胺（0.55 mL’ 5 mmol)，加熱反應液到 ® 6 5 C，擾拌過夜。將反應液倒入6 〇〇 mL水中，有黃綠色固體析出’抽濾’得到的固體藉由管柱層析法分離純化，得到的標題產物（3-氣-4-氟苯基）-(6-«比咯啥唑啉_4_基） -胺48(0· 9 g黃色固體），產率53%。 MS m/z (ESI) ： 339 [M+ 1] jHNMR (400MHz, DMSO-^): (5 9.89(s, 1H), 8. 64(d, 2H), 8. 19(m, 2H), 7.91(d, 1H, J = 9. 2), 7. 85(m, iH), 7. 59(t, φ 2H), 7. 50(m, 1H), 6. 39(t, 2H) 實施例49 ~~里氟-笨某）-「6-(1Η·~ρ比洛-2-基^哇喊-4_基卜脸The first step (3-afluoro-4-fluorophenyl)-(6-carbon-indolyl-4-yl)monoamine repeats the experimental procedure described in the fifth embodiment of the present invention, except that the examples are The compound 6_iodo_311_quinazoline-4-ketone lf obtained in the fourth step is used as a raw material, and the raw material is made into 3-gas-4-fluoro- in the same manner as described in the fifth step of Example 1 of the present invention. The reaction of aniline gave the title compound (3 _ -4- fluorophenyl)-(6-iodo-quinazolin-4-ylamine 48 & (15, yellow solid 94389 137 201016683), yield 56% MS m/z (ESI): 400 [M+ 1 ] The second step (3- gas-4-fluorophenyl)-(6--pyrrole_ι_quinazoline__4_yl)-amine at 100 In a mL eggplant-shaped flask, the compound obtained in the above step (3-chloro-4-fluorophenyl)-(6-iodo-quinazolin-4-yl)-amine 48a (2 g, 5 mmol), potassium phosphate (3. 18 g, l5 mmol), cuprous iodide (〇. 95 g, 5 mmol) was dissolved in 40 mL of N,N-didecylguanamine, and the mixture was added with N,N,_methyl-1, with stirring. 2-Ethylenediamine (0.55 mL '5 mmol), heat the reaction mixture to ® 6 5 C, and stir overnight. Pour the reaction into 6 mL of water and precipitate with a yellow-green solid. The solid obtained by filtration was separated and purified by column chromatography to give the title product (3- s. 4-fluorophenyl)-(6-«b-oxazoline-4-yl)-amine 48 (0) · 9 g of yellow solid), yield 53%. MS m/z (ESI): 339 [M+ 1] jHNMR (400 MHz, DMSO-^): (5 9.89 (s, 1H), 8. 64 (d, 2H) ), 8. 19(m, 2H), 7.91(d, 1H, J = 9. 2), 7. 85(m, iH), 7. 59(t, φ 2H), 7. 50(m, 1H ), 6. 39(t, 2H) Example 49 ~~ lye-stupid)-"6-(1Η·~ρ比洛-2-基^哇叫-4_基卜脸

94389 138 20101668394389 138 201016683

第一步 2-{4-[3-氯-4-氟-苯胺基]-喹唑啉-6-基卜吡咯—卜甲酸第三丁酯重複實施例48第一步的反應，將得到的化合物（3_氯 -4-氟苯基）-(6-碘-喹唑啉-4-基胺48a(16〇 g，4 mmol)，卜（第三丁氧基羰基）-1H_吡咯—2_硼酸7b(1.丨运， ❹5. 2 mmol)，肆（三苯基膦）鈀（0. 23 g，〇· 2丽〇1)，碳酸鉀 (1.38 g，10 mmol)溶於25 mL N，N-二甲基甲醯胺和6社水的混合溶劑中，得到的混合物加熱到7(rc，2小時後反 .應完畢。將反應液冷卻至室溫，倒入3〇〇 mL冰水中，白色固體，授拌十分鐘後’抽濾，產物在真空下乾燥到的固體進-步藉由管柱層析法，得到標題產物氯-4-氟-苯胺基]-喹唑啉_6__基}吡咯_丨_曱酸第三 ⑩49a(1.49g，黃色固體）產率：85%。 — 酯 MS m/z (ESI ) ： 439[M+1] 第二步 [(3 -氯-4-氟-苯基胺 °比嘻-2-基）-喧。坐琳基] 將上述步驟得到的化合物2音[3一氣氣一笨十坐淋-6-基卜叫+甲酸第三丁 g| 溶解於土無水四氫蝴，得到的黃色溶液用冰水浴冷卻至丨 94389 139 201016683 加入甲醇鈉（1.46 g，13 mmol)，將反應液逐漸升至室溫，3 小時後反應完畢’反應液呈深紅色。將得到的反應液倒入飽和氣化鈉水溶液中，析出固體，過濾’得到的黃色固體在真空下乾燥後，進一步藉由管柱層析法分離純化，得到標題化合物（3-氣-4-氟-苯基）_[6_(1h_吡咯_2_基）_喹唑啉-4-基]-胺49(767邺，淡黃色固體），產率67%。 MS m/z (ESI) ： 339[M+ 1] 膽（40〇MHZ，DMS〇i):5ll.4l(s，1H)，9 79(s，iH) 8.65(3, 1H), 8.58(s, 1H), 8.2l(d, 1H, J = 6.8)> 15(； ®1H，>8.G)，7.86(m，1H)’U()(d，1H，I=8.8)，7.48(t ’ m，6.98(S，1H)，6.78(t，1H)，6 24(q，1H) ’ 實施例50 [3-氣-4-(3-氟-苄氧基）-茉色1 ΤΓ77Π7 嗎啉-4-^jgThe first step of 2-{4-[3-chloro-4-fluoro-anilino]-quinazolin-6-ylpyrrole-benzoic acid tert-butyl ester repeats the reaction of the first step of Example 48, which will be obtained. Compound (3-chloro-4-fluorophenyl)-(6-iodo-quinazolin-4-ylamine 48a (16 g, 4 mmol), b (t-butoxycarbonyl)-1H-pyrrole- 2_boric acid 7b (1. 丨, ❹ 5. 2 mmol), hydrazine (triphenylphosphine) palladium (0.23 g, 〇·2 〇 1), potassium carbonate (1.38 g, 10 mmol) dissolved in 25 In a mixed solvent of mL N,N-dimethylformamide and 6 water, the obtained mixture was heated to 7 (rc, after 2 hours, the reaction was completed. The reaction solution was cooled to room temperature and poured into 3 Torr. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Porphyrin_6__yl}pyrrole_丨_decanoic acid third 1049a (1.49 g, yellow solid) Yield: 85%. — ester MS m/z (ESI): 439 [M+1]. -Chloro-4-fluoro-phenylamine ° 嘻-2-yl)-喧. sit Linji] The compound obtained in the above step 2 sound [3 a gas, a stupid ten sitting -6-kib called + Acid tributyl g | dissolved in soil anhydrous tetrahydrogen butterfly, the obtained yellow solution was cooled to 丨94389 139 201016683 with ice water bath, sodium methoxide (1.46 g, 13 mmol) was added, and the reaction solution was gradually warmed to room temperature, 3 hours later. After the reaction is completed, the reaction solution is dark red. The obtained reaction solution is poured into a saturated aqueous solution of sodium carbonate to precipitate a solid, and the obtained yellow solid is dried under vacuum and further purified by column chromatography. The title compound (3- gas-4-fluoro-phenyl)-[6-(1h-pyrrole-2-yl)-quinazolin-4-yl]-amine 49 (767 邺, pale yellow solid), yield 67 MS m/z (ESI): 339 [M+ 1] biliary (40 〇 MHZ, DMS 〇i): 5 ll. 4l (s, 1H), 9 79 (s, iH) 8.65 (3, 1H), 8.58 (s, 1H), 8.2l(d, 1H, J = 6.8)>15(;®1H,>8.G), 7.86(m,1H)'U()(d,1H,I=8.8 ), 7.48 (t ' m, 6.98 (S, 1H), 6.78 (t, 1H), 6 24 (q, 1H) ' Example 50 [3- gas-4-(3-fluoro-benzyloxy)- Jasmine 1 ΤΓ77Π7 morpholine-4-^jg

Ai~yAi~y

94389 140 201016683 [3-氣-4-(3-氟苄氧基）_苯基]_[6_(1_三異丙基矽基—^一 °比嘻-2-基）-喹唾琳_4_基]一胺將本發明實施8所得的化合物[3_氯_4_(3_氟_苄氧其） -苯基]-[6-UH-吡咯基）_喹唑啉_4_基]_胺8(225吨二 0.5mm〇。！）溶解於i〇mL四氫咳痛中，溶解後在乾冰浴冷卻至一78C，加入二異丙基胺鋰（〇 5 mL，〇·5助丨），攪拌 20分鐘後升至室溫反應1〇分鐘後，繼續冰浴冷卻至〜π C，加入二異丙基矽氯（195 mg，1 mmol)，1小時後反應完畢。在反應液中加水猝滅反應，減壓下蒸出四氫呋喃，殘留物用乙酸乙酯（1〇〇 mLx3)萃取反應液，合併的有機相用無水硫酸鈉脫水，過濾，濾液減壓下濃縮，殘留物進一步藉由管柱層析法分離純化’得到本標題產物[3_氯_4_(3一 •氟苄氧基）-苯基]-[6-(1_三異丙基石夕燒基-1H-吡咯一2一基）-喹唑琳-4-基]-胺50a(145 mg，黃色固體），產率： 48.3%。 ' MS m/z (ESI) ： 601 [M+ 1 ] ❹第二步 5-丨4-[3-氣-4-(3-氟苄氧基）-苯胺基]_喹唑啉_6_基卜卜三異丙基石夕基-1Η-°比洛-3-曱酸· 將5 —inL Ν,Ν - 一曱基曱酿胺在冰浴條件下，冷卻至〇 C後，加入二氣氧碟（26 mg’ 0..17 mmo 1)，升溫至室严，授拌1小時後再冷卻至〇°C ’加入上述步驟所得的化合物 [3-氯-4-(3-氟苄氧基）-苯基]-[6-(ι_三異丙基石夕燒基 -1H-吡咯-2-基）-喹唑啉-4-基]-胺 50a(67 mg，0.11 94389 141 201016683 mmol) ’所得的混合物在室溫下攪拌過夜反應完畢。反應液中滴加5%氮氧化鈉溶液，調整ρΗ=ι丨，用乙酸乙酯（1〇〇虬 x3)萃取反應液，合併的有機相用無水硫酸鈉脫水，過濾，遽液減壓下濃縮，所得的殘留物藉由管柱層析法進一步分離純化’得到本標題產物5_丨4_[3_氯_4_(3_氟苄氧基）一苯胺基]啥坐琳_6-基}-i-三異丙基石夕基_ih_0比洛_3_曱醒: 50b(36 mg’黃色固體），產率：68%。 MS m/z (ESI) ： 473 [M+ 1] 第三步 ❺[3-氣-4-(3-氟-节氧基）_苯基]_(6_{4_[(2_嗎琳+乙胺基）-曱基]-1Η-°比略-2-基}-喧嗤琳_4-基）-胺將上述步驟所得的化合物5_{4_[3_氯_4_(3_氟苄氧 •基）-苯胺基]-喹唑啉-6-基M-三異丙基矽基_1H_吡咯一 3一曱醛50b(36 mg，〇. 〇76 mmol)溶解於5 mL四氫呋喃中，攪拌下滴加2-嗎啉-4-基-乙胺（15 mg’ 〇114 mm〇1)，分批加入三乙醯氧基硼氫化鈉（127 mg，〇 6则，所得的 ❹混合物液加熱回流3小時後反應完畢。反應液在減壓下蒸乾，所得的殘留物進一步藉由管柱層析法分離純化，得到標題產物[3_氣+ (3-氟-节氧基）-笨基]_(6_{4_[(2 +乙胺基卜甲基]鲁料+基卜♦㈣—4_基）^ 50(37 rag ’黃色固體），產率：83. 1%。 MS m/z (ESI) : 587 [M+ 1] ]HNMR (400MHz, CDCls): c5 10.17(s, iH), 8. 67(s, 1H) 8.〇9(s, 1H), 7.96(d, 1H, J = 8. 8), 7. 89(s, 1H), 7.82(^ 94389 142 201016683 2H), 7.64(d, 1H, J=8.8), 7. 35(m, 1H), 7. 25(m, 2H), 7.02(m, 1H), 6.96(d, 1H, J = 8. 8), 6. 13(s, 1H), 6. 12(s, 1H), 5.14(s, 2H), 3.91(s, 2H), 3. 64(t, 4H), 2. 80(t, 2H), 2.50(t, 2H), 2.20(t, 4H) 實施例51 [3-氧氧臬）一苳其i_{6一「hQ一二乙胺基乙甚） -1衫-°比嘻~~3-基]-啥咏啦暮丨-胺94389 140 201016683 [3-Actyl-4-(3-fluorobenzyloxy)-phenyl]_[6_(1_Triisopropyldecyl-^1° than 嘻-2-yl)-quinoline _ 4-amino]monoamine The compound obtained in the practice of the present invention 8 [3-chloro-4-[(3-fluoro-benzyloxy)-phenyl]-[6-UH-pyrrolyl]-quinazoline-4-yl ]_amine 8 (225 tons of two 0.5mm 〇.!) dissolved in i〇mL tetrahydrocough, dissolved, cooled to a 78C in a dry ice bath, added lithium diisopropylamide (〇 5 mL, 〇·5 After stirring for 20 minutes, the mixture was allowed to react to room temperature for 1 minute, and then cooled to ~π C in an ice bath, and diisopropylphosphonium chloride (195 mg, 1 mmol) was added. After 1 hour, the reaction was completed. The reaction mixture was quenched with EtOAc EtOAc (EtOAc m. The residue is further purified by column chromatography to give the title product [3_chloro_4_(3-fluorobenzyloxy)-phenyl]-[6-(1_triisopropyl) -1H-pyrrole-2-yl)-quinazoline-4-yl]-amine 50a (145 mg, yellow solid), yield: 48.3%. ' MS m/z (ESI): 601 [M+ 1 ] ❹Step 2 5-丨4-[3-Ga-4-(3-fluorobenzyloxy)-anilino]-quinazoline_6_yl卜卜三isopropyl石夕基-1Η-°Bilo-3-decanoic acid · 5 - inL Ν, Ν - 曱曱曱曱 amine in ice bath, cooled to 〇 C, add dioxine Dish (26 mg '0..17 mmo 1), warm to room temperature, stir for 1 hour, then cool to 〇 °C 'Add the compound obtained in the above step [3-chloro-4-(3-fluorobenzyloxy) )-Phenyl]-[6-(ι_triisopropyl sulphate-1H-pyrrol-2-yl)-quinazolin-4-yl]-amine 50a (67 mg, 0.11 94389 141 201016683 mmol) The resulting mixture was stirred at room temperature overnight to complete the reaction. A 5% sodium nitrite solution was added dropwise to the reaction mixture, and ρΗ=ι丨 was adjusted, and the reaction mixture was extracted with ethyl acetate (1××3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and evaporated. Concentration, the residue obtained is further separated and purified by column chromatography to obtain the title product 5_丨4_[3_chloro_4_(3_fluorobenzyloxy)-anilinyl]啥坐琳_6-yl }-i-triisopropyl shiji _ih_0 bil _3_ awake: 50b (36 mg 'yellow solid), yield: 68%. MS m/z (ESI): 473 [M+ 1] The third step ❺[3- gas-4-(3-fluoro-hydroxyl)-phenyl]_(6_{4_[(2_?琳+乙) Amino)-fluorenyl]-1Η-°bi-2-yl}-喧嗤琳_4-yl)-amine The compound obtained in the above step 5_{4_[3_chloro_4_(3_fluorobenzyloxy) • phenyl)-anilino]-quinazolin-6-yl M-triisopropyldecyl-1H-pyrrole-3-oxanal 50b (36 mg, 〇. mmol76 mmol) was dissolved in 5 mL of tetrahydrofuran. 2-morpholin-4-yl-ethylamine (15 mg' 〇114 mm〇1) was added dropwise with stirring, and sodium triethyl sulfonium borohydride (127 mg, 〇6) was added in portions. After heating under reflux for 3 hours, the reaction was completed. The reaction mixture was evaporated to dryness mjjjjjjjjjjjjjjjjj _(6_{4_[(2 + ethylaminomethyl) ruthenium + keb ♦ (4) - 4 yl) ^ 50 (37 rag 'yellow solid), yield: 83.1% MS m / z (ESI): 587 [M+ 1] ]HNMR (400MHz, CDCls): c5 10.17(s, iH), 8. 67(s, 1H) 8.〇9(s, 1H), 7.96(d, 1H, J = 8. 8), 7. 89(s, 1H), 7.82(^ 94389 142 201016683 2H), 7.64(d, 1H, J=8.8), 7. 35 (m, 1H), 7. 25(m, 2H), 7.02(m, 1H), 6.96(d, 1H, J = 8. 8), 6. 13(s, 1H), 6. 12(s, 1H), 5.14(s, 2H), 3.91(s, 2H), 3. 64(t, 4H), 2. 80(t, 2H), 2.50(t, 2H), 2.20(t, 4H) 51 [3-Oxygen oxime] 苳 i i i i i i i i i i i i i i i i i i i i i i 胺胺胺胺胺胺胺胺胺胺胺胺胺胺胺胺

將本發明實施42所得的化合物[3-氣-4-(3-氟-苄氧基）-苯基]-[6-(1Η-»比咯-3-基）-喹唑啉-4-基]-胺42 (70 mg ’ 0· 157mmol)溶解於5 mL N，N-二曱基甲醯胺中，溶液在冰浴冷卻下，加入氫化鈉（16mg，0 4mm〇1)，混合液升至室溫，攪拌30分鐘後，加入（2-溴乙基）—二乙胺氫溴酸鹽（62 mg ’ 0. 236 mmol)，加熱反應液至6〇°c，攪拌2小 ⑩時後反應完畢，加水猝滅反應。反應液用乙酸乙酯（1 〇〇社 x3)萃取，合併的有機相用無水硫酸鈉脫水，過濾，濾液減壓下濃縮所得的殘留物進一步藉由管柱層析法分離純化，得到本標題產物[3-氯-4-(3-氟-苄氧基）_苯基]_ί6_π_ (2-二乙胺基乙基吡略_3—基]_喹唑啉基卜胺η (40 mg，黃色固體），產率·· 46. 8%。 MS m/z (ESI) ： 544 [M-f 1 ] ]HNMR (400MHz, CDsOD): (5 8. 40(s, 1H), 7. 85(d, 1H) 94389 143 201016683 7. 70(s’ 1H)，7. 34(d，1H, j 4H)，7. 03(m，3H)，6.7〇(s， 2H), 4. 02(t, 2H), 2. 63(t, 6H) ， =8.8)，7.27(m，1H)，7.11(m’ U)，6.48(s，1H)，4.72(s’ 2H)，2.42(q，4H)，〇. 79(t 實施例52 £_6 - (5 - [ 1, 4? ] — 〇f 咬美-1，_ 田甘 Ί_Γ' 吡咯-3-i 土基The compound obtained in the practice of the present invention 42 [3-gas-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-»b-r-but-3-yl)-quinazoline-4- Base]-amine 42 (70 mg '0·157 mmol) was dissolved in 5 mL of N,N-dimercaptocaramine. The solution was cooled in an ice bath and sodium hydride (16 mg, 0 4 mm 〇1) was added. After warming to room temperature and stirring for 30 minutes, (2-bromoethyl)-diethylamine hydrobromide (62 mg '0. 236 mmol) was added, and the reaction mixture was heated to 6 ° C, and stirred for 2 hours and 10 hours. After the reaction is completed, the reaction is quenched by adding water. The reaction mixture was extracted with ethyl acetate (1 mL), and the combined organic phase was dried over anhydrous sodium sulfate. [3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]_ί6_π_(2-diethylaminoethylpyrrol-3-yl)-quinazolinylamine η (40 mg, Yellow solid), Yield · 46.8% MS m/z (ESI): 544 [Mf 1 ] ]HNMR (400MHz, CDsOD): (5 8. 40(s, 1H), 7. 85(d , 1H) 94389 143 201016683 7. 70(s' 1H), 7. 34(d,1H, j 4H), 7. 03(m,3H), 6.7〇(s, 2H), 4. 02(t, 2H), 2. 63(t, 6H) , =8.8), 7.27(m,1H), 7.11(m' U), 6.48(s,1H), 4.72(s' 2H), 2.42(q,4H) , 〇. 79(t Example 52 £_6 - (5 - [ 1, 4? ] — 〇f 咬美-1, _ 田甘Ί_Γ' pyrrole-3-i soil base

•暴丨〜1- ·ί4-[3-氯-4-(3_氟苄氧基）_苯胺基]-喹唑啉異丙基矽-1H-。比咯—2_甲酸• violent ~ 1- · ί4-[3-chloro-4-(3_fluorobenzyloxy)-anilino]-quinazoline Isopropyl hydrazine-1H-. Bis- 2_carboxylic acid

b重複本發明實施例5G第二步所述的實驗步驟 =述第一步所得的化合物[3.4—(3—氣1氧基J f H6:(1hh3_基）-㈣琳+基卜胺42a作為原貫5G第二步所述的方式，進行該原料與三氯氧，-一甲基甲醯胺的反應，得到本標題產物氣-4-(3-氟苄氧基）-苯胺基]-喹唑啉_6_基卜卜三異丙基矽1H吡咯-2-甲醛52a(35mg’黃色固體），產率：56 〇%。 MS m/z (ESI) ： 473[M+ 1] · 94389 144 201016683 第二步重複本發明實施例50第三步所述的實驗步驟，不同是以上述實驗所得的化合物3-{4-[3-氯—4-(3_氟苄氡' -苯胺基]-喹唑啉_6-基}-1-三異丙基矽-1H—吡咯〜2—甲 52a作原料’按照本發明實施例5〇第三步所述的相同方式使得該原料與[1，4,]二°底啶的反應’得到標題化合二 [6-（5-[1，4’ ]二哌啶基-1’ -曱基_ΐΗ-吡咯-3-基）-喹唑啉 -4-基]-[3-氯-4-(3-氟-苄氧基）-]-胺52(1〇〇111§，白色固體），產率68. 0%。 ® MS m/z (ESI) ： 625 [M+ 1] HNMR (400MHz, DMSO-cf〇： δ 11.12(s, 1H), 9.91(s> ijj) 8.62(s, 1H), 8.59(s, 1H), 8. 18(d, 1H, J = 8. 8), 8. 14(s, ' 1H)，7. 86(d, 1H, J=8. 8)，7· 80(d, 1H，J=8. 8)，7· 55(m 1H), 7.40(m, 2H), 7. 25(t, 1H), 6. 85(s, 1H), 6. 60(s, 1H), 5.33(s, 2H), 3.65(s, 2H), 2. 96(m, 2H), 2. 74(m, 2H), 2.05(m, 1H), 2. 02(m, 2H), 1.82(ra, 2H), 1.3〇-i.6〇 .(m， 10H) 實施例53 1~ {4-「3-氣-4-〇比咬-2-曱氣基笨胺基1-啥n坐说-β一芊} 二4-(2 -雜暮）-lH-pfcp各-3-甲酸-二乙胺基乙某甲酿脸b Repeat the experimental procedure described in the second step of Example 5G of the present invention = the compound obtained in the first step [3.4 - (3-gas 1 oxy J f H6: (1hh3_yl)-(tetra) lin + kebamine 42a The reaction of the starting material with trichloroox,-monomethylformamide is carried out in the manner described in the second step of the original 5G to obtain the title product -4-(3-fluorobenzyloxy)-anilino] - quinazoline _6_ kib-triisopropyl hydrazine 1H pyrrole-2-carbaldehyde 52a (35 mg 'yellow solid), yield: 56 〇% MS m/z (ESI): 473 [M+ 1] 94389 144 201016683 The second step repeats the experimental procedure described in the third step of Example 50 of the present invention, except that the compound obtained in the above experiment is 3-{4-[3-chloro-4-(3-fluorobenzidine)-aniline a quinazoline-6-yl}-1-triisopropylhydrazine-1H-pyrrole~2-a 52a as a starting material 'in the same manner as described in the fifth step of Example 5 of the present invention [1,4,] Reaction of dipyridinium' gave the title compound [6-(5-[1,4']dipiperidinyl-1'-indolyl-ΐΗ-pyrrol-3-yl)-quin Oxazolin-4-yl]-[3-chloro-4-(3-fluoro-benzyloxy)-]-amine 52 (1 〇〇 111 §, white solid), yield 68. 0%. / z (ESI): 625 [M+ 1] H NMR (400 MHz, DMSO-cf 〇: δ 11.12 (s, 1H), 9.91 (s> ijj) 8.62 (s, 1H), 8.59 (s, 1H), 8. 18 (d, 1H, J = 8. 8), 8. 14(s, ' 1H), 7.86(d, 1H, J=8. 8), 7·80(d, 1H, J=8. 8 ),7·55(m 1H), 7.40(m, 2H), 7. 25(t, 1H), 6. 85(s, 1H), 6. 60(s, 1H), 5.33(s, 2H) , 3.65(s, 2H), 2. 96(m, 2H), 2. 74(m, 2H), 2.05(m, 1H), 2. 02(m, 2H), 1.82(ra, 2H), 1.3 〇-i.6〇.(m, 10H) Example 53 1~ {4-"3-Gas-4-〇 ratio biting-2-曱 gas base 笨-amino group 1-啥n sitting-β一芊} 2- 4-(2-heteroquinone)-lH-pfcp each 3-carboxylic acid-diethylamine B

94389 145 20101668394389 145 201016683

α --- 第一步將2-{4-[3-氯-4-(吡啶-2-甲氧基）-苯胺基]-喹唑啉 -6-基卜6, 7-二氫_2H_吡喃[3, 4-c]吡咯_4_酮 47(100 mg， 0·2 mmol)和1此N，N-二乙基-1,2-乙二胺加入10 mL茄形瓶中，混合物加熱至90°C，攪拌過夜，反應完畢。反應液在減壓下濃縮，得到的殘留物用乙酸乙酯溶解後，再加 ®入環己院’有大量白色固體析出，過濾，得到的固體用少量甲醇溶解，用TLC板進一步分離純化，得到黃色固體，真空乾燥得到標題產物卜{4-[3-氯-4-0比啶-2-甲氧基）-苯胺基]-喹唑啉-6-基}-4-(2-羥基）-1Η-吡咯-3-曱酸-(2-二乙胺基乙基）-甲醯胺53(110 mg，黃色固體），產率： 89.5%。 MS m/z (ESI) ： 615 [M+1] ⑩]HNMR(400MHz，DMSO-心）：（5 l〇.25(s，1H)，8.91(s，1H)， 8.61(m, 2H), 8.42(s, 2H), 8. 13(d, 2H, J=7. 2), 7. 89(m, 3H), 7. 60(d, 1H, J=7. 6), 7. 53(s, 1H), 7. 38(m, 1H), 7.30(d, 1H, J=8.8), 5.31(s, 2H), 4. 70(s, 1H), 3. 64(m, 4H), 3.22(m, 6H), 2.91(t, 2H), 1.27(t, 6H) 實施例54 l-{4-[3-氣-4-(°比0定-2-甲氣基）-笨胺基]-唾岭啦-6-基} -4--4-(2-經基）-1Η-°比洛-3 -甲酸- (2-嗎基）-甲酿 146 94389 -0 201016683 Οα --- The first step is 2-{4-[3-chloro-4-(pyridine-2-methoxy)-anilino]-quinazoline-6-yl b,6-dihydro-2H _pyran[3,4-c]pyrrole-4-one 47 (100 mg, 0·2 mmol) and 1 N,N-diethyl-1,2-ethanediamine in a 10 mL eggplant bottle The mixture was heated to 90 ° C, stirred overnight and the reaction was completed. The reaction mixture was concentrated under reduced pressure, and the obtained residue was dissolved in ethyl acetate, and then added to the mixture, and a large amount of white solid was precipitated. The solid was dissolved in a small amount of methanol and further purified by TLC. A yellow solid is obtained which is dried in vacuo to give the title product <RTI ID=0.0############################################################## -1Η-pyrrole-3-decanoic acid-(2-diethylaminoethyl)-carboxamide 53 (110 mg, yellow solid), yield: 89.5%. MS m/z (ESI): 615 [M+1] 10]HNMR (400 MHz, DMSO-min): (5 l 〇.25 (s, 1H), 8.91 (s, 1H), 8.61 (m, 2H) , 8.42(s, 2H), 8. 13(d, 2H, J=7.2), 7. 89(m, 3H), 7. 60(d, 1H, J=7. 6), 7. 53 (s, 1H), 7. 38(m, 1H), 7.30(d, 1H, J=8.8), 5.31(s, 2H), 4. 70(s, 1H), 3. 64(m, 4H) , 3.22(m, 6H), 2.91(t, 2H), 1.27(t, 6H) Example 54 l-{4-[3-gas-4-(° ratio 0--2-methyl group)-stupid Amino]-salt-6-yl}-4--4-(2-carbyl)-1Η-°Bilo-3-formic acid-(2-meryl)-broiler 146 94389 -0 201016683 Ο

重複本發明實施例53第一步所述的實驗步驟，不同的是以實施例47所得的化合物2-{4-[3-氯-4-(吡啶-2-甲氧基）-苯胺基]-喹唑啉-6-基}-6, 7-二氫-2H-吡喃[3, 4~^>比咯-4-酮47作原料，按照本發明實施例53第一步所述的相同方式使得該原料與2-嗎啉-4-基-乙胺的反應，得到標題化合物卜{4-[3-氣-4-(吡啶-2-曱氧基）-苯胺基;μ喹唑啉-6-基}-4-(2-羥基）-1Η-吡咯-3-曱酸-(2-嗎啉-4-乙基） • -甲醯胺54(110 mg，黃色固體），產率：87. 3%。 .MS m/z (ESI) ： 629 [M+ 1] WNMRUoomhz，DMS0_d6): 5 9 97(s，1H)，8 74(s，ih) 8.60(m，2H)，8.09(m，3H)，7 89(m，3H)，7.79(d, ih’ ©>8.8)，7.60(d，1H，J=8.〇)，7 45(s，ih)，7 38(七，ih)| 7-30(d, 1H, J = 8.8), 5.31(s, 2H), 4. 81(s, 1H), 3. 64(m 8H), 3. 17(m, 6H), 2. 89(t, 2H) ’ 實施例55 94389 147 201016683The experimental procedure described in the first step of Example 53 of the present invention was repeated, except that the compound obtained in Example 47 was 2-{4-[3-chloro-4-(pyridine-2-methoxy)-anilino] -quinazolin-6-yl}-6,7-dihydro-2H-pyran [3, 4~^> pyrrol-4-one 47 as a starting material, according to the first step of Example 53 of the present invention The reaction of the starting material with 2-morpholin-4-yl-ethylamine in the same manner gave the title compound {4-[3- gas-4-(pyridin-2-yloxy)-anilinyl; Oxazolin-6-yl}-4-(2-hydroxy)-1Η-pyrrole-3-decanoic acid-(2-morpholin-4-ethyl)-carbamidine 54 (110 mg, yellow solid), Yield: 87.3%. .MS m/z (ESI): 629 [M+ 1] WNMRUoomhz, DMS0_d6): 5 9 97 (s, 1H), 8 74 (s, ih) 8.60 (m, 2H), 8.09 (m, 3H), 7 89(m,3H), 7.79(d, ih' ©>8.8), 7.60(d,1H,J=8.〇), 7 45(s,ih),7 38(seven,ih)| 7- 30(d, 1H, J = 8.8), 5.31(s, 2H), 4. 81(s, 1H), 3. 64(m 8H), 3. 17(m, 6H), 2. 89(t, 2H) 'Example 55 94389 147 201016683

NHNH

HOHO

e重複本發明實施例53第-步所述的實驗步驟，疋以實施例47所得的化合物2_{4,一氯+ (吡啶： J]〇t 洛+ _ 47作原料，按照本發明實施例53第同方式使得該原料與2_甲氧基乙胺的反應，得到〇物1-{4-[3-氯-4-(吡啶-2-甲氧基）__苯胺基]-喹唑啉 -6-基}-4-(2-羥基）-111-吡咯-3-曱酸-(2-甲氧基乙基）-曱醯胺55(110 mg，黃色固體），產率：87 3%。 ' MS m/z (ESI) ： 571 [Μ- 1] HNMR (400MHz, DMS0-d6)： δ 10. 〇〇(s, 1H), 8. 72(s, 1H), 8.68(d, 2H), 8.18(d, 1H, J=9. 2), 8. 13(s, 1H), 8. 09(m, 2H), 8.00(m, 2H), 7.97(d, 1H, J=8. 0), 7.67(d, 1H, Q J = 8.0), 7.46(m, 2H), 7. 39(d, 1H, J=9.2), 5. 39(s, 2H), 4.85(s, 1H), 3.72(t, 2H), 3. 52(m, 2H), 3.47(m, 2H), 3.37(s，3H)，2.97(t，2H) 實施例5 6e repeating the experimental procedure described in the first step of Example 53 of the present invention, using the compound 2_{4, monochloro+(pyridine:J]〇tlo+_47 obtained in Example 47 as a raw material, according to an embodiment of the present invention In the same manner, the reaction of the starting material with 2-methoxyethylamine afforded the compound 1-{4-[3-chloro-4-(pyridine-2-methoxy)-anilino]-quinazole Phenyl-6-yl}-4-(2-hydroxy)-111-pyrrole-3-decanoic acid-(2-methoxyethyl)-guanamine 55 (110 mg, yellow solid), yield: 87 3%. ' MS m/z (ESI): 571 [Μ-1] HNMR (400MHz, DMS0-d6): δ 10. 〇〇(s, 1H), 8. 72(s, 1H), 8.68(d , 2H), 8.18(d, 1H, J=9. 2), 8. 13(s, 1H), 8. 09(m, 2H), 8.00(m, 2H), 7.97(d, 1H, J= 8. 0), 7.67(d, 1H, QJ = 8.0), 7.46(m, 2H), 7. 39(d, 1H, J=9.2), 5. 39(s, 2H), 4.85(s, 1H ), 3.72(t, 2H), 3. 52(m, 2H), 3.47(m, 2H), 3.37(s, 3H), 2.97(t, 2H) Example 5 6

Ll{4-「3-氮-4-(吡啶-2-甲筚其、-y胺11-喹唑U-基} 二4--4-(2-經基）-1 Η-°比略-3-甲酿-[2-(4 -甲基_派啡~~1-D 二乙基- SH胺 148 94389 201016683Ll{4-"3-Aza-4-(pyridine-2-carboxamide, -y-amine 11-quinazolyl U-yl}] 2- 4-(2-carbyl)-1 Η-° ratio -3-甲酿-[2-(4-methyl-pyrone~~1-D diethyl-SHamine 148 94389 201016683

重複本發明實施例53第一步所述的實驗步驟，不同的疋以貫施例4 7所得的化合物2 - {4 - [ 3 -氯_ 4 - (°比咬-2 -甲氧基）-苯胺基]-喹唑啉-6-基}-6, 7-二氫-2H-吡喃[3, 4-c]吡略-4-酮47作原料，按照本發明實施例53第一步所述的相同方式使得該原料與2-(4-曱基-哌畊-1-基）-乙胺的反應’付到標題化合物1_{4_[3_氯_4_(D比咬_2 -甲氧基）-苯胺基]-喹唑啉-6-基}-4-(2-羥基）-1Η-吡咯-3-甲酸-[2-(4-曱基-哌畊-1 一基）一乙基]-醯胺56(90 mg，黃色固體）， •產率：88%。 MS m/z (ESI) ： 643 [M+ 1] 'HNMR (400MHz, DMSO-dO： ¢5 10.11(s, 1H), 8. 89(s, 1H), 8-〇6(m, 2H), 8. 25(s, 1H), 8. 13(m, 2H), 7. 90(m, 4H), 〇 ^60(d, 1H, J=7.6), 7.49(s, 1H), 7. 37(t, 1H), 7. 26(d, 1H, J = 9.2), 5.31(s, 2H), 4. 82(s, 1H), 3. 65(t, 2H), 3.26(m, 2H), 2. 89(t, 2H), 2.67(m, l〇H), 2.41(s, 3H) 實施例57 氮-4-〔吡啶-2-甲氣基茉胺基]-喹唑啉-6-基} 149 94389 201016683The experimental procedure described in the first step of Example 53 of the present invention was repeated, and the different compounds obtained by the application of Example 4 7 - {4 - [3 -chloro-4-(-)-bito-2-methoxy) -anilino]-quinazolin-6-yl}-6,7-dihydro-2H-pyran[3,4-c]pyr-4-one 47 as starting material, according to Example 53 of the present invention In the same manner as described in the step, the reaction of the starting material with 2-(4-mercapto-piperidin-1-yl)-ethylamine is paid to the title compound 1_{4_[3_氯_4_(D ratio bite_2 -methoxy)-anilino]-quinazolin-6-yl}-4-(2-hydroxy)-1Η-pyrrole-3-carboxylic acid-[2-(4-mercapto-piped-1-yl) Monoethyl]-nonylamine 56 (90 mg, yellow solid), • Yield: 88%. MS m/z (ESI): 643 [M+ 1] "HNMR (400 MHz, DMSO-dO: ¢5 10.11 (s, 1H), 8. 89 (s, 1H), 8-〇6 (m, 2H), 8. 25(s, 1H), 8. 13(m, 2H), 7. 90(m, 4H), 〇^60(d, 1H, J=7.6), 7.49(s, 1H), 7. 37 (t, 1H), 7. 26(d, 1H, J = 9.2), 5.31(s, 2H), 4. 82(s, 1H), 3. 65(t, 2H), 3.26(m, 2H) , 2. 89(t, 2H), 2.67(m, l〇H), 2.41(s, 3H) Example 57 Nitro-4-[pyridine-2-carbazyl]-quinazoline-6 -基} 149 94389 201016683

重複本發明實施例53第一步所述的實驗步驟，不同的疋以實施例47所得的化合物2-{4-[3-氯-4-(吡啶-2-甲氧基）-苯胺基]-喹唑啉_6_基卜6 7 —二氫-2h_吡喃[3 4 c]吡咯-4-酮47作原料，按照本發明實施例53第一步所述的相同方式使得該原料與3_嗎琳基-丙胺的反應，得到榨〇題化合物丨令絲基] 琳6基}-4-(2-髮基）-ΐΗ-η比洛-3-甲酸-（3_嗎嚇*-4-丙基）醯胺57(90 mg，黃色固體），產率 MS m/z (ESI) ： 640 [Μ- l] HNMR (4〇〇ΜΗζ, DMS0-de)： ^ 10. l〇(s, 1H), 8. 84(s, 1H), 8-59(d, 2H), 8.21(s, 1H), 8. 10(m, 2H), 8. 02(s, 1H), 7-88(m, 2H), 7.83(d, 1H, J=8. 0), 7. 60(d, 1H, J = 7. 6), 〇 7-49(s, 1H), 7.38(t, 1H), 7. 29(d, 1H, J=8. 8), 5.31(s, 2H)> 4.86(s, 1H), 3.62(m, 6H), 3.36(m, 2H), 3. 25(m, 2H)» 2.89(t, 2H), 2.21(m, 4H), 1.71(m, 2H) 實施例58The experimental procedure described in the first step of Example 53 of the present invention was repeated, and the compound obtained in Example 47 was obtained as the compound 2-{4-[3-chloro-4-(pyridine-2-methoxy)-anilino]. -quinazoline_6_yl b 6 7 -dihydro-2h-pyran[3 4 c]pyrrol-4-one 47 as a starting material, in the same manner as described in the first step of Example 53 of the present invention Reaction with 3_morphinyl-propylamine to obtain the scorpion compound 丨丝 ] 琳琳琳 -4- -4- -4- -4- -4- -4- -4- -4- -4- -4- -4- -4- -4- -4- -4- -4- -4- -4- -4- -4- -3- -3- -3- -3- -3- -3- -3- -3- -3- *-4-propyl) decylamine 57 (90 mg, yellow solid), yield MS m/z (ESI): 640 [Μ- l] HNMR (4 〇〇ΜΗζ, DMS0-de): ^ 10. l 〇(s, 1H), 8. 84(s, 1H), 8-59(d, 2H), 8.21(s, 1H), 8. 10(m, 2H), 8. 02(s, 1H), 7-88(m, 2H), 7.83(d, 1H, J=8. 0), 7. 60(d, 1H, J = 7. 6), 〇7-49(s, 1H), 7.38(t , 1H), 7. 29(d, 1H, J=8. 8), 5.31(s, 2H)> 4.86(s, 1H), 3.62(m, 6H), 3.36(m, 2H), 3. 25(m, 2H)» 2.89(t, 2H), 2.21(m, 4H), 1.71(m, 2H) Example 58

•ίϋζίΐτ氯-4-(吡啶二2-甲氣基）-笨胺基卜喹唑啉-6-篡} 羥基咯-3-基 μ嗎嚇二UA 150 94389 201016683• ίϋζίΐτ chloro-4-(pyridinedi-2-carbyl)-phenylaminoquinazoline-6-篡} hydroxy-l-yl-yl μ 吓吓 UA 150 94389 201016683

重複本發明實施例53第一步所述的實驗步驟’不同的是以實施例47所得的化合物2-{4-[3-氯_4-(吡啶-2-甲氧基）-苯胺基]-喹唑啉-6-基}-6, 7_二氫-2H—吡喃[3, 4-c]吡咯-4-酮47作原料，按照本發明實施例53第一步所述的相同方式使得該原料與嗎啉的反應，得到標題化合物1-H-[3-氣-4-(吡啶-2-曱氧基）-苯胺基]-喳唑啉-6-基}-4-®(2-經基）-1Η-πΛ^-3-基]-嗎被-4-甲酮 58(230 mg，白色固體），產率：98. 2% 〇 MS m/z (ESI) ： 584 [Μ- 1] .'HNMR (400MHz, DMSO-dO： 5 9. 77(s, 1H), 8. 59(m, 3H), 8. 17(d, 1H, 1=10.4), 8.02(s, 1H), 7. 88(m, 2H), 7. 73(d, 1H, J=8. 0), 7.68(s, 1H), 7. 60(d, 1H, J=7. 2), 7.45(s, 1H)，7.38(t，1H)，7.32(d, 1H, J=9.2), 5.31(s，2H)， 69(t, 1H), 3.57(m, 8H), 3. 17(m, 2H), 2. 7〇(t, 2H) 實施例5ΘThe experimental procedure described in the first step of Example 53 of the present invention was repeated, except that the compound obtained in Example 47 was 2-{4-[3-chloro-4-(pyridine-2-methoxy)-anilino] -quinazolin-6-yl}-6,7-dihydro-2H-pyrano[3,4-c]pyrrol-4-one 47 as the starting material, the same as described in the first step of Example 53 of the present invention The reaction of the starting material with morpholine gives the title compound 1-H-[3- gas-4-(pyridin-2-yloxy)-anilino]-oxazolin-6-yl}-4-® (2-carbyl)-1Η-πΛ^-3-yl]-is-4-ketone 58 (230 mg, white solid), yield: 98. 2% 〇MS m/z (ESI): 584 [Μ-1] .HNMR (400MHz, DMSO-dO: 5 9. 77(s, 1H), 8. 59(m, 3H), 8. 17(d, 1H, 1=10.4), 8.02(s , 1 (H), 7. 7.45(s, 1H), 7.38(t,1H), 7.32(d, 1H, J=9.2), 5.31(s,2H), 69(t, 1H), 3.57(m, 8H), 3. 17( m, 2H), 2. 7〇(t, 2H) Example 5Θ

Iil4-[3-氣-4-(吡啶-2-曱氧基）-笨胺某 Κ2-羥基）-1Η-吡咯-3-基]-(4-甲某-哌 0 XI: H0-Iil4-[3-Ga-4-(pyridin-2-yloxy)-moleamine Κ2-hydroxy)-1Η-pyrrol-3-yl]-(4-methyl-pipeline 0 XI: H0-

59 重複本發明實施例53第一步所述的實驗步驟，不同的 94389 151 201016683 是以實施例47所得的化合物2-{4-[3-氯-4-(吡啶曱氧基）-苯胺基]-喹唑啉-6-基}-6, 7-二氫-2H-吡喃[3, 4_c]吡咯-4-酮47作原料，按照本發明實施例53第一步所述的相同方式使得該原料與1-甲基哌畊的反應，得到標題化合物卜{4-[3-氯-4-(吡啶-2-甲氧基）-苯胺基]一喹唑啉_6_ 基}-4-(2-羥基）-iH-吼咯-3-基]-(4-甲基-哌哄y 一基）-甲酮59(100 mg，棕色油狀物），產率：95%。 MS m/z (ESI) ： 599 [M+ 1] HNMR(400MHz，DMSO-A): 5 9.77(s，1H)，8. 60(m，3H) 8.17(d，1H，J=8.8)，8.02(s，1H)，7. 88(m，2H), 7.73(d’ 1H, J=6.4), 7.65(s, 1H), 7.60(d, 1H, J=8. 0), 7<45(s， 1H), 7.38(t，1H), 7.32(d, 1H, J=9. 2)，5. 31(S，2H)’ '4.69(s，1H)，3.60(m，6H)，2.69(t，2H)，2. 33(t，4H)’ .2.21(s, 3H) ’ ’ 實施例60 idi二L3-氯-4二1吡啶-2-甲氣基茉胺基1-喹^^^^ © 羥基）-1H-咐.咯-3-基1-吡鳴烷-1-甲酮59 The experimental procedure described in the first step of Example 53 of the present invention was repeated, and the different 94389 151 201016683 was the compound 2-{4-[3-chloro-4-(pyridinyloxy)-anilinyl obtained in Example 47. ]-quinazolin-6-yl}-6,7-dihydro-2H-pyrano[3,4-c]pyrrol-4-one 47 as a starting material in the same manner as described in the first step of Example 53 of the present invention The reaction of the starting material with 1-methylpiperidine gave the title compound {4-[3-chloro-4-(pyridine-2-methoxy)-anilino]-quinazoline-6-yl}-4 -(2-Hydroxy)-iH-indol-3-yl]-(4-methyl-piperidinyl-yl)-methanone 59 (100 mg, brown oil), yield: 95%. MS m/z (ESI): 592 [M+ 1] H NMR (400 MHz, DMSO-A): 5 9.77 (s, 1H), 8.60 (m, 3H) 8.17 (d, 1H, J = 8.8), 8.02 (s, 1H), 7. 88 (m, 2H), 7.73 (d' 1H, J = 6.4), 7.65 (s, 1H), 7.60 (d, 1H, J = 8. 0), 7 < 45 ( s, 1H), 7.38(t,1H), 7.32(d, 1H, J=9. 2), 5. 31(S,2H)' '4.69(s,1H), 3.60(m,6H),2.69 (t, 2H), 2. 33(t, 4H)' .2.21(s, 3H) ' ' Example 60 idi di L3-chloro-4di 1 pyridin-2-methyl sulfamoyl 1-quino^ ^^^ © hydroxy)-1H-咐.rr-3-yl 1-pyridin-1-one

重複本發明實施例5 3第一步所述的實驗步驟，τ θ 也不同的曱氧疋以實施例47所得的化合物2-{4-[3-氣-4-(吡唆、2 基）-笨胺基]-喹唑啉-6-基卜6, 7-二氫-2H-吡喃[3 4 口各-4-_ 47作原料，按照本發明實施例53第一弗纪所述的 94389 152 201016683 相同方式使得該原料與吡咯烷的反應，得到標題化合物 1 一U-[3-氯〜4-(吡啶-2-甲氧基）-苯胺基]-喹唑啉_6_基} -4-(2-羥基）-ih-吡洛—3-基]-吡咯烷-1-甲酮6〇(i7〇 mg，灰色固體），產率95%。 MS m/z (ESI) ： 570 [M+ 1] !HNMR (400MHz, DMSO-d〇: δ 9. 78(s, 1H), 8. 59(m, 3H) 8.18(d, 1H, J=8.4), 8.01(s, 1H), 7. 89(t, 2H), 7.81(s, 1H), 7. 72(d，1H，J=7.2), 7.60(d，1H，J=7.6), 7.42(s， 1H)，7.36(t’ 1H)，7.32(d，1H，J=8.8)，5.31(s，2H)， ® 4.78(s, 1H), 3.62(t, 4H), 3. 52(t, 2H), 2. 79(t, 2H), 1.88(s, 4H) 實施例61 2-「1-{4-[3二氯-4^(吡啶-2-甲氧基）一茉胺基1 —崦4咐^ 基}-4-(4-曱基-哌畔-l-甲某吡略- 3-基1 -乙醇The experimental procedure described in the first step of Example 5 of the present invention was repeated, and the compound obtained in Example 47 was obtained as the compound obtained in Example 47. 2-{4-[3-Ga-4-(pyridinium, 2-yl) - phenylamino]-quinazoline-6-yl b,6-dihydro-2H-pyran [3 4 port each 4-47] as a starting material, according to Example 53 of the present invention 94389 152 201016683 The reaction of the starting material with pyrrolidine in the same manner gave the title compound 1 - U-[3-chloro~4-(pyridine-2-methoxy)-anilino]-quinazoline-6-yl -4-(2-Hydroxy)-ih-pyrrole-3-yl]-pyrrolidin-1-one 6 oxime (i7 mg, gray solid), yield 95%. MS m/z (ESI): 570 [M+1].HNMR (400 MHz, DMSO-d: δ 9. 78 (s, 1H), 8. 59 (m, 3H) 8.18 (d, 1H, J=8.4 ), 8.01(s, 1H), 7. 89(t, 2H), 7.81(s, 1H), 7. 72(d,1H,J=7.2), 7.60(d,1H,J=7.6), 7.42 (s, 1H), 7.36 (t' 1H), 7.32 (d, 1H, J = 8.8), 5.31 (s, 2H), ® 4.78 (s, 1H), 3.62 (t, 4H), 3. 52 ( t, 2H), 2. 79(t, 2H), 1.88(s, 4H) Example 61 2- "1-{4-[3 Dichloro-4^(pyridine-2-methoxy)-monomethylamine Base 1 —崦4咐^ base}-4-(4-mercapto-piperazine-l-methylpyrrol-3-yl-1-ethanol

在25 mL祐形瓶中加入氳化鋁鋰（44呢，和4mL四氫呋喃，室溫下攪拌，逐漸滴加化合物氯4 (0比咬2甲氧基）_苯胺基]_喧唾琳_6一基卜4_(2__經 94389 153 201016683 基）-1 Η-0比p各-3-基]--(4-甲基_π辰哄-1-基）-甲酮59 (130 mg，0. 385 mmol)的3 mL四氫呋喃溶液，溶液中有大量氣泡產生，並有粘稠狀固體產生，反應液呈黃色。將反應液加熱至50°C ’攪拌2小時後反應完畢，用冰浴冷卻反應液，慢慢滴加甲醇’反應液呈澄清透明。用減壓柱沖洗，濃縮反應液’得到的固體進一步藉由TLC板分離純化，得到標題產物2-[卜{4-[3-氯-4-(吡咬-2-甲氧基）-苯胺基]-喹唑啉-6-基}-4-(4-曱基-哌畊-1-曱基）_in-吡咯-3-基]-乙醇61(70 mg，黃色固體），產率：55. 6%。 ® MS m/z (ESI) ： 585 [M+ 1] !HNMR (400MHz, MSO-de): δ 9. 99(s, 1H), 8.61(m, 3H), 8.05(d, 2H), 7.88(t, 1H), 7.81(t, 2H), 7. 59(d, 1H, .J=7. 6), 7. 46(d, 2H), 7. 39(t, 1H), 7. 29(d, 1H, J=9. 2), 5.30(s, 2H), 3.78(m, 4H), 2. 73(t, 2H), 2. 23(m, 8H), 2. ll(s, 3H) 實施例62 鬱1--.氟一 4-(3-.盞^节氧基）-笨基]-(6_(5_r(2_甲磺醯某咬基）-甲基咯-3-基卜喹唑啉基）_胺Add lithium aluminum telluride (44?, and 4 mL of tetrahydrofuran) to a 25 mL flask, and stir at room temperature to gradually add the compound chlorine 4 (0 to bite 2 methoxy) to the aniline group. A kibu 4_(2__ via 94389 153 201016683 base)-1 Η-0 ratio p -3-yl]--(4-methyl-π 哄哄-1-yl)-methanone 59 (130 mg, 0. 385 mmol) of 3 mL of tetrahydrofuran solution, a large amount of bubbles were generated in the solution, and a viscous solid was produced, and the reaction solution was yellow. The reaction solution was heated to 50 ° C. After stirring for 2 hours, the reaction was completed, and an ice bath was used. The reaction solution was cooled, and methanol was slowly added dropwise. The reaction mixture was clear and transparent. The solid obtained by rinsing with a vacuum column was concentrated and purified by a TLC plate to obtain the title product 2-[Bu{4-[3- Chloro-4-(pyridyl-2-methoxy)-anilino]-quinazolin-6-yl}-4-(4-indolyl-piperidin-1-yl)_in-pyrrole-3- Base]-ethanol 61 (70 mg, yellow solid), yield: 55. 6%. MS m/z (ESI): 585 [M+ 1] !HNMR (400 MHz, MSO-de): δ 9. 99 ( s, 1H), 8.61(m, 3H), 8.05(d, 2H), 7.88(t, 1H), 7.81(t, 2H), 7. 59(d, 1H, .J=7. 6), 7 46(d, 2H), 7. 39(t, 1H), 7. 2 9(d, 1H, J=9. 2), 5.30(s, 2H), 3.78(m, 4H), 2. 73(t, 2H), 2. 23(m, 8H), 2. ll(s , 3H) Example 62 1- 1--.Fluoro-4-(3-.盏^ 氧基oxy)-styl]-(6_(5_r(2_methylsulfonate))-methyl-3- -kibquinazolinyl)amine

重複本發明實施例52第二步所述的實驗步驟，不同的是以上述實驗所得的化合物3-丨4-[3-氯-4-(3-氟苄氧基）本胺基]-啥唾琳_6_基卜1_三異丙比嘻甲盤 94389 154 201016683 52a作原料，按照本發明實施例52第二步所述的相同方式使得該原料與2-曱磺醯基乙胺的反應，得到標題化合物 [3-氯-4-(3-氟苄氧基）-苯基]-(6-{5-[(2-曱磺醯基-乙胺基）-甲基]-1H-吡咯-3-基}-喹唑啉-4-基胺62(10 mg，黃色固體），產率8. 5%。 MS m/z (ESI) ： 580 [M+ 1] !HNMR (400MHz, DMS0-de)： d 11.15(s, 1H), 9.91(s, 1H), 8.70(s, 1H), 8.49(s, 1H), 8. 08(d, 1H, J=8. 8), 7. 83(d, 1H, J=9.2), 7.69(d, 1H, J=8. 8), 7.51(s, 1H), 7. 47(t, ® 1H), 7. 32(m, 3H), 7.20(t, 1H), 6. 88(s, 1H), 6. 74(s, 1H), 5.26(s, 2H), 3.86(s, 2H), 3. 24(t, 2H), 2. 95(s, 3H), 2. 92(t, 2H) . 實施例6 3 .氟-苄氳篡Λ-笨其]-f6-{5-_「C3二嗎啡林气胺基）-甲篡]-1 Η-吡哈-3-基丨-啥唑成-4-基胺The experimental procedure described in the second step of Example 52 of the present invention was repeated, except that the compound obtained in the above experiment was 3-indole 4-[3-chloro-4-(3-fluorobenzyloxy)amino-amino]-oxime唾琳_6_基布1_三isopropyl比嘻甲盘94389 154 201016683 52a as a raw material, in the same manner as described in the second step of Example 52 of the present invention, the raw material and 2-nonylsulfonylethylamine Reaction to give the title compound [3-chloro-4-(3-fluorobenzyloxy)-phenyl]-(6-{5-[(2-oxasulfonyl-ethylamino)-methyl]-1H -pyrrol-3-yl}-quinazolin-4-ylamine 62 (10 mg, yellow solid), mp. 8. MH. MS m/z (ESI): 580 [M+ 1] !HNMR (400 MHz, DMS0-de): d 11.15(s, 1H), 9.91(s, 1H), 8.70(s, 1H), 8.49(s, 1H), 8. 08(d, 1H, J=8. 8), 7 83(d, 1H, J=9.2), 7.69(d, 1H, J=8. 8), 7.51(s, 1H), 7. 47(t, ® 1H), 7. 32(m, 3H) , 7.20(t, 1H), 6. 88(s, 1H), 6. 74(s, 1H), 5.26(s, 2H), 3.86(s, 2H), 3. 24(t, 2H), 2 95(s, 3H), 2. 92(t, 2H) . Example 6 3. Fluoro-benzyl hydrazine-stupid]-f6-{5-_"C3 dimorphine oxalyl)-A篡]-1 Η-pyha-3-yl hydrazine-carbazole to 4-ylamine

重複本發明實施例52第二步所述的實驗步驟，不同的是以上述實驗所得的化合物3_μ_[3-氯-4-(3-氟苄氧基） -苯胺基]-喹唑啉—6_基卜卜三異丙基矽-1H-吡咯-2-甲醛 52a作原料，按照本發明實施例52第二#所述的相同方式使得該原料與3-嗎啉-4-基-丙胺的反應’得到標題化合物 [3-氯-4-(3-氟-苄氧基）_苯基]_(6-{5-[(3-嗎啡林-4-丙 155 94389 201016683 胺基）-甲基]-1Η-σ比洛-3-基}-喧峻嚇·-4-基）_胺63(20 mg，黃色固體），產率35. 0%。 MS m/z (ESI) ： 601 [M+ 1] !HNMR (400MHz, DMSO-dO： δ 11.10(s, 1H), 9. 90(s, 1H), 8.53(d, 2H), 8. 08(s, 1H), 8. 10(d, 1H, J=8. 4), 7. 81(d, 1H), 7.73(d, 1H, J=8.4), 7.47(m, 1H), 7. 30(m, 3H), 7. 18(t, 1H), 6.80(s, 1H), 6.46(s, 1H), 5. 26(s, 2H), 3.86(s, 2H), 3.59(t, 2H), 3. 48(t, 2H), 2. 33(t, 4H), 2.24(t, 4H), 1.57(m, 2H) ❹實施例64 13 -氣- 4- (3 -氟-爷氧基）笨基~|-{6-「1~~(2 - 0比洛炫~~卜基— Α基）~~ 1H ~~g比哈-3 ~~基]-啥嗤淋-4 -基}-胺The experimental procedure described in the second step of Example 52 of the present invention was repeated, except that the compound obtained by the above experiment was 3-[3-chloro-4-(3-fluorobenzyloxy)-anilino]-quinazoline-6. _Kibubu triisopropyl hydrazine-1H-pyrrole-2-carbaldehyde 52a as a starting material, the starting material and 3-morpholin-4-yl-propylamine were obtained in the same manner as described in Example #24 of the present invention. Reaction' gave the title compound [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-{5-[(3-morphinelin-4-propan-155 94389 201016683 Amino)-A 0%。。 Η σ σ σ σ σ -3- -3- -3- -3- -3- -3- 63 63 63 63 63 63 63 63 63 63 63 63 63. MS m/z (ESI): 601 [M+1].HNMR (400 MHz, DMSO-dO: δ 11.10 (s, 1H), 9. 90 (s, 1H), 8.53 (d, 2H), 8. 08 ( s, 1H), 8. 10(d, 1H, J=8. 4), 7. 81(d, 1H), 7.73(d, 1H, J=8.4), 7.47(m, 1H), 7. 30 (m, 3H), 7. 18(t, 1H), 6.80(s, 1H), 6.46(s, 1H), 5. 26(s, 2H), 3.86(s, 2H), 3.59(t, 2H ), 3. 48(t, 2H), 2. 33(t, 4H), 2.24(t, 4H), 1.57(m, 2H) ❹Example 64 13 - Gas - 4- (3-Fluoro-Oxygen Base) Stupid base ~|-{6-"1~~(2 - 0 比洛炫~~卜基-Α基)~~ 1H ~~g比哈-3~~基]-啥嗤淋-4 - Amine

重複本發明實施51所述的實驗步驟，不同的是以實施輪例42所得的化合物[3-氯-4-(吡啶-2-曱氧基）-苯基]_(6-吡咯-卜基-喹唑啉-4-基）-胺42作為原料，按照實施例51 所述的方式，進行該原料與1-(2-氯乙基）-吡咯烷的反應，得到本標題產物[3-氯-4-(3-氟-苄氧基）苯基]-{6-[1_ (2-吡咯烷-1-基-乙基）_1H-吡咯—3-基]-喹唑啉-4-基}-胺 (30 mg，黃色固體），產率：35.9%。 MS m/z (ESI) ： 542[M+ 1] !HNMR (400MHz, DMS0-c?6): 5 8. 65(s, 1H), 8. 02(m, 2H), 156 94389 201016683 7. 91(d，1H，J=8.4)，7. 81(m，2H), 7.52(d，1H，J = 8.8)， 7. 32(m, 1H), 7. 20(m, 2H), 7. 04(m, 2H), 6. 90(d, 1H, J=9.2), 6.70(s, 1H), 6.49(s, 1H), 5. 09(s, 2H), 4.01(t, 2H), 2.86(t, 2H), 2. 54(m, 4H), 1.77(m, 4H) 實施例65 「3 -氣- 4-(3 -氟节氧基）-笨基l-「6-(l-{3-「4-(3 -氣笨基）-σ底畊-1-基]-丙基}-1Η-^^-3-基）-啥唾淋-4-基]-胺The experimental procedure described in Example 51 of the present invention was repeated, except that the compound [3-chloro-4-(pyridin-2-yloxy)-phenyl]-(6-pyrrole-bry) obtained in Example 42 was carried out. - quinazolin-4-yl)-amine 42 as a starting material, the reaction of the starting material with 1-(2-chloroethyl)-pyrrolidine was carried out as described in Example 51 to give the title product. Chloro-4-(3-fluoro-benzyloxy)phenyl]-{6-[1_(2-pyrrolidin-1-yl-ethyl)_1H-pyrrole-3-yl]-quinazoline-4- Base}-amine (30 mg, yellow solid), yield: 35.9%. MS m/z (ESI): 542 [M+ 1] "HNMR (400 MHz, DMS0-c?6): 5 8. 65 (s, 1H), 8. 02 (m, 2H), 156 94389 201016683 7. 91 (d, 1H, J = 8.4), 7.81 (m, 2H), 7.52 (d, 1H, J = 8.8), 7. 32 (m, 1H), 7. 20 (m, 2H), 7. 04(m, 2H), 6. 90(d, 1H, J=9.2), 6.70(s, 1H), 6.49(s, 1H), 5. 09(s, 2H), 4.01(t, 2H), 2.86(t, 2H), 2. 54(m, 4H), 1.77(m, 4H) Example 65 "3-Gas- 4-(3-fluorohethoxy)-styl-l-"6-(l -{3-"4-(3-indolyl)-σ bottom cultivating-1-yl]-propyl}-1Η-^^-3-yl)-indolyl-4-yl]-amine

重複本發明實施51所述的實驗步驟，不同的是以實施例42所得的化合物[3-氯-4-(吡啶-2-甲氧基）-苯基]-(6-吡咯-1-基-喹唑啉-4-基）-胺42作為原料，按照實施例51 所述的方式，進行該原料與1-(3=氯苯基）-4-(3-氯丙基）-哌哄的反應，得到本標題產物[3-氣-4-(3-氟苄氧基）-苯基] -[6-(1-{3-[4-(3-氣苯基）-哌畊-1-基]-丙基}-111-吼咯 ⑩-3-基）-喹唑啉-4-基]-胺（32 mg，黃色固體），產率： 20.9%。 MS m/z (ESI) ： 681[M+ 1] ^I^MR UOOMHz，DMSO-A): (5 9.67(s，1H)，8.52(d，2H)， 8.03(m, 2H), 7. 70(d, 1H, J=8. 8), 7.46(d, 1H, J = 10.8), 7.34(m, 2H), 7. 29(m, 3H), 7. 19(in, 2H), 6. 92(m, 3H), 6.77(d, 1H, J=6.4), 6. 67(s, 1H), 5.21(s, 2H), 4. 01(t, 2H), 3.28(t, 4H), 3. 20(t, 4H), 2. 33(t, 2H), 1. 98(t, 157 94389 201016683 2H) 實施例66The experimental procedure described in Example 51 of the present invention was repeated, except that the compound obtained in Example 42 [3-chloro-4-(pyridine-2-methoxy)-phenyl]-(6-pyrrol-1-yl) -quinazolin-4-yl)-amine 42 as a starting material, the starting material and 1-(3=chlorophenyl)-4-(3-chloropropyl)-piperazine were carried out in the same manner as described in Example 51. The reaction gave the title product [3-Ga-4-(3-fluorobenzyloxy)-phenyl]-[6-(1-{3-[4-(3-phenylphenyl)-piped- 1-yl]-propyl}-111-nonyl 10-3-yl)-quinazolin-4-yl]-amine (32 mg, yellow solid), yield: 20.9%. MS m/z (ESI): 681 [M+ 1] </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; (d, 1H, J=8. 8), 7.46(d, 1H, J = 10.8), 7.34(m, 2H), 7. 29(m, 3H), 7. 19(in, 2H), 6. 92(m, 3H), 6.77(d, 1H, J=6.4), 6.67(s, 1H), 5.21(s, 2H), 4. 01(t, 2H), 3.28(t, 4H), 3. 20(t, 4H), 2. 33(t, 2H), 1. 98(t, 157 94389 201016683 2H) Example 66

Lr(2-經乙基）-i-{4-「3~ 甲基- 4~(6-與基~|-啥°坐琳-β-基丨- IH-p比嘻_3-乙基）-酿胺氫基）-笨略炫-1 _基-Lr(2-ethylidene)-i-{4-"3~methyl-4~(6- and yl~|-啥°坐琳-β-based oxime- IH-p than 嘻3-3-ethyl )--Amine Hydrogenyl)- Stupid Hyun-1 _Base-

⑩（6-碘-喹唑啉_4_基）_[3_甲基_4_(6_10(6-iodo-quinazoline_4_yl)_[3_methyl_4_(6_

-苯基]-胺. A吡啶~3-側氧J f複本發明實施们第五步所述的實驗步不第四步所得的化合物Μ，+坐… Η作原枓’按照本發明實施例i第五方得該原料與3一甲基 k的相Π万式便 C ^ , Χβ ξ. 土啶~3一側氧基）-苯胺的-Phenyl]-amine. A pyridine ~3-side oxygen J f complex The experimental step described in the fifth step of the practice of the invention is not the compound obtained in the fourth step Μ, + sit ... Η 枓枓按照 according to the embodiment of the invention i, the fifth party has the same material as the 3-methyl k, C ^ , Χβ ξ. 啶 ~ ~ 3 side oxy) - aniline

反應ϋ “題化合物（6H -4-(6-甲基-吡啶_3 土； Ld V基側氧基）-本基]-胺66a(1〇g，灰白 94389 158 201016683 固體），產率65% 〇 MS m/z (ESI) ： 469[M+ 1] 第二步 2-{4-[3-甲基~4-(6-曱基-吼啶_3_側氧基）_苯胺基]_喹唑啉-6-基}-6, 7-二氫-2H-吡喃并[3, 4-c]吡咯_4_酮在250 mL茄形瓶中，將上述步驟所得的化合物（6_碘_ 喹唑啉-4-基H3-甲基-4-(6-甲基-吡啶—3-側氧基）_苯基] -胺 66a(11. 7 g’ 25則1〇1)，6,7-二氫-2H-吼喃并[3,4-c] 吡略-4-酮 47b(3. 6g ’ 26. 25 mmol)，磷酸鉀（15. 92 g， ® 25mmol)，蛾化亞銅（4.775 g，25mmol)溶解於 80 mL N，N- 二甲基甲醯胺中，混合物在攪拌下滴加N，N，_二甲基―丨，2— 乙二胺（2· 18 g，25 mmol)，加熱反應液到8〇。〇，攪拌過 .夜。將反應液倒入250 mL冰水中，有黃色固體析出，抽濾，得到的固體用300 mL· ·甲醇洗滌，得到的固體在真空下乾燥，得到本標題產物2-{4-[3-甲基-4-(6-甲基-吡啶一3_側氧基）-苯胺基]-喹唑啉-6-基卜6, 7_二氫__2H— B比喃并響[3,4-c]吡咯-4-酮66b(ll. 59 g，黃色固體），產率97. 〇6%。 MS m/z (ESI) ： 478 [M+ 1 ] 第三步 4-(2-羥乙基）-1-{4-[3-甲基-4-(6-甲基〇比啶-3-氧基）一笨胺基]-喹唑啉-6-基}-皿-吡咯-3-甲酸-(2-吡咯烷_卜基〜乙基）-酿胺將2-U-[3-曱基-4-(6-甲基-吼啶一3一氧苯胺基]一喹唑啉-6-基}-6, 7-二氫-2H-吡喃并[3, 4_c]吡咯_4_酮 94389 159 201016683 66b(120 mg，0.25 mmol)和 2 mL 2-吡咯燒基-1_基_ 乙胺加入10 mL茄形瓶中，混合物加熱至9〇〇c，攪拌過夜，反應元畢。反應液在減壓下濃縮，得到的殘留物用乙酸乙醋溶解後，再加入環己烷，有大量白色固體析出，過遽，得到的固體用少量甲醇溶解，用TLC板分離純化，得到黃色固體’真空乾燥得到標題產物4-(2 -經乙基）-丨~{4-[3-甲基-4-(6-甲基吼啶-3-氧基）-苯胺基]-喹唑啉_6_基卜1H_ 吡咯-3-甲酸-(2-吡咯烷-1-基-乙基）-醞胺66(17 mg，淺黃色固體），產率：97. 0%。鲁 MS m/z (ESI) : 592 [M+ 1] 'HNMR (400MHz, DMS0-d〇: δ 9. 89(s, 1H), 8. 68(s, 1H), 8.58(s, 1H), 8. 19(s, 1H), 8. 09(m, 3H), 7.91(d, 1H, J=8. 8), 7. 78(s, 1H), 7. 73(dd, 1H, J=8.4), 7.42(s, 1H), 7.24(m, 2H), 6. 99<d, 1H, J=8. 8), 4. 85(s, 1H), 3； 65(t, 2H), 3.41(m, 2H), 2. 90(t, 2H), 2. 67(m, 6H), 2.45(s, 3H), 2.23(s, 3H), 1.74(m, 4H) ❹實施例67 MLτ{4-[3-氯-4-(3-氟芊氳某）-笨胺某1-喹唑嗽-fi_篡1 -4-三氟甲基-11}-〇比略-3-基）-2-甲基-丙埽醯脸Reaction ϋ "The title compound (6H -4-(6-methyl-pyridine_3 soil; Ld V-based side oxy)-benyl]-amine 66a (1 〇g, gray 94389 158 201016683 solid), yield 65 % 〇MS m/z (ESI) : 469[M+ 1] Step 2 2-{4-[3-Methyl~4-(6-fluorenyl-acridine_3_sideoxy)-anilino] _ quinazolin-6-yl}-6, 7-dihydro-2H-pyrano[3,4-c]pyrrole-4-one in a 250 mL eggplant-shaped flask, the compound obtained in the above step (6 _ Iodine_ quinazolin-4-yl H3-methyl-4-(6-methyl-pyridine-3-octyloxy)-phenyl]-amine 66a (11. 7 g' 25 then 1〇1) ,6,7-dihydro-2H-indolo[3,4-c]pyr-4-one 47b (3.6 g ' 26. 25 mmol), potassium phosphate (15.92 g, ® 25 mmol), Copper molybdenum (4.775 g, 25 mmol) was dissolved in 80 mL of N,N-dimethylformamide, and the mixture was added dropwise with N,N,_dimethyl-indole, 2-ethylenediamine (2). · 18 g, 25 mmol), heat the reaction solution to 8 Torr. 〇, stir overnight. The reaction solution was poured into 250 mL of ice water, a yellow solid was precipitated, suction filtered, and the obtained solid was washed with 300 mL··Methanol. , the obtained solid is dried under vacuum to obtain the title product 2-{4-[3-A -4-(6-Methyl-pyridyl-3-ytoxy)-anilino]-quinazoline-6-yl b6,7-dihydro__2H-B is more ambiguous [3,4-c Pyrrole-4-one 66b (ll. 59 g, yellow solid), yield 97. 〇 6%. MS m/z (ESI): 478 [M+ 1] Step 3 4-(2-hydroxyethyl) 1-{4-[3-methyl-4-(6-methylindolepyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-dish-pyrrole-3-carboxylic acid -(2-pyrrolidine-buyl~ethyl)-bristamine 2-U-[3-mercapto-4-(6-methyl-acridin-3-oxoanilinyl)-quinazoline-6 -yl}-6,7-dihydro-2H-pyrano[3,4_c]pyrrole_4-one 94389 159 201016683 66b (120 mg, 0.25 mmol) and 2 mL 2-pyrrole-1-based Ethylamine was added to a 10 mL eggplant-shaped flask, the mixture was heated to 9 ° C, stirred overnight, and the reaction was completed. The reaction solution was concentrated under reduced pressure, and the obtained residue was dissolved in ethyl acetate. A large amount of a white solid was precipitated, and the obtained solid was dissolved in a small amount of methanol, and then purified and purified by chromatography to afford a yellow solid, which was dried in vacuo to give the title product 4-(2-ethyl-ethyl)- 丨~{4-[3- Methyl-4-(6-methylacridin-3-yloxy)-anilino]-quinazoline_6_ 0%。 Ib 1H_ pyrrole-3-carboxylic acid-(2-pyrrolidin-1-yl-ethyl)-decylamine 66 (17 mg, pale yellow solid), yield: 97.0%.鲁MS m/z (ESI): 592 [M+ 1] 'HNMR (400MHz, DMS0-d〇: δ 9. 89(s, 1H), 8. 68(s, 1H), 8.58(s, 1H), 8. 19(s, 1H), 8. 09(m, 3H), 7.91(d, 1H, J=8. 8), 7. 78(s, 1H), 7. 73(dd, 1H, J= 8.4), 7.42(s, 1H), 7.24(m, 2H), 6. 99<d, 1H, J=8. 8), 4. 85(s, 1H), 3; 65(t, 2H), 3.41(m, 2H), 2. 90(t, 2H), 2. 67(m, 6H), 2.45(s, 3H), 2.23(s, 3H), 1.74(m, 4H) ❹Example 67 MLτ {4-[3-Chloro-4-(3-fluoroindole)-stupylamine 1-quinazolium-fi_篡1 -4-trifluoromethyl-11}-indole-3-yl )-2-methyl-propionate face

160 94389 201016683160 94389 201016683

oxOx

第一步 4, 4, 4-三氟-丁-2-烯酸 • 在100 mL茄形瓶中加入4, 4, 4-三氟-丁-2-稀酸乙酯 67a(56 g，〇. 33 mmol)，曱酸（46g，1 mmol)和 1 瓜L 濃硫酸，得到的混合液加熱至8(TC，攪拌過夜，反應完畢。停止加熱，在常溫下蒸餾，收集40至8(TC的餾分，得到本 ❹標題產物4, 4, 4-三氟-丁-2-烯酸67b(24 g，白色固體），產率51. 9%。 MS m/z (ESI) ： 139 [M-l] 第二步 4, 4, 4-三氟-丁-2-烯酸苄酯在1 000 mL茄形瓶中加入4, 4, 4-三氟-丁-2-烯酸67b (26· 5 g，〇· 18 mol) ’ 1-(3-二甲胺基丙基）-3-乙基碳二亞胺鹽酸鹽（54 g’ 0. 27 mo 1)’ 1-經基苯并三唾（3.85 g， 161 94389 201016683 0. 27mol) ’ 三乙胺（46g，〇.45mol)，和 400 mL 四氫°夫0南，所得的混合物在室溫下攪拌1小時後加入苄醇（29.2 g，〇. 27mol)，攪拌過夜，反應完畢。在反應液中加入冰水猝滅反應’用乙酸乙酯（4〇〇 mLx3)萃取，有機相用無水硫酸納脫水，過濾，濾液濃縮，得到的殘留物進一步藉由管柱層析法分離純化，得到本標題產物4, 4, 4-三氟-丁-2-晞酸苄醋67c(2. 95 g，黃色油狀液體），產率：7. 7%。 MS m/z (ESI) ： 579 [M-l] 第三步 ❹4-三氟甲基-in-"比洛-3-甲酸节酯將對甲苯磺醯甲基異腈（2.73g，14.1mm〇l)溶解於25 mL四氫呋喃中，冰浴冷卻至〇<t，氮氣下，加入二環 • [5’4, 〇]_1，8~ 二氮-7_ 壬烯（2. 15 g，14. lmmol)，攪拌 30 分鐘後加入4,4,4-三氟-丁 _2_烯酸苄酯.67c(2 95g， 12. 7mmol)’得到的混合物攪拌過夜，反應完畢。在反應液中加入40mL冰水猝滅反應，用二氯曱烷（1〇〇mLx3)萃取，髻合併的有機相用無水硫酸鎂脫水，過濾，濃縮，得到的殘留物進-步藉由管㈣析法分離純化，得到本標題產物4— 三亂甲基-lH-η比嘻_3_甲酸节酯67d(L 938运，黃色固體產率：56. 7% 〇 MS m/z (ESI) : 268 [M-l] 第四步 4-三氟曱基-1H~吡洛一3-甲酸在25 mL祐形瓶中，冰洛條件下，加入上述步驟所得 94389 162 201016683 的化合物4-三氟甲基_1 Η-吡咯-3-甲酸苄酯67d( 120 mg， 0. 445mmol)和3 mL三氟醋酸，攪拌30分鐘後撤去冰浴，室溫下攪拌過夜’反應完畢。將反應液倒入5〇 mL冰水中，用乙酸乙酯（200 mlx3)萃取，有機相用無水硫酸鈉脫水，過濾、’滤液濃縮’得到的殘留物進一步藉由管柱層析法分離純化，得到本標題產物4-三氟曱基-1H-吼哈-3-甲酸6 7e (3. 39 g，黃色固體），產率：52. 6%。 MS m/z (ESI) ： 180 [M+l] 第五步 ❹l-{4-[3-氯-4-(3-氟苄氧基）-苯胺基]-喹唑啉-6_基卜4_ 三氟甲基-1 Η-0比嘻-3-甲酸將上述步驟所得的化合物4_三氟甲基-1 H-nit洛-3-甲 _ 酸（2. 14 g’ 12 mmol)，[3-氯-4-(3-氟-苄氧基）-苯基]—(6_ 碘-喹唑琳-4-基）-胺 lg (6. 〇7 g，12 mmol)，磷酸鉀（10. 19 g ’ 48 mmo 1)，埃化亞銅（3.44 g，18 mmo 1)和4-三氟曱基 -1H-比咯-3-甲酸（2.14 g，12 mmol)和 5 mL N，N-二曱基馨甲醯胺溶解，攪拌下滴加N，N’_二曱基—12-乙二胺（16 g，18 mmol) ’加熱回流攪拌過夜。將反應液加入到i5〇 mL 冰水中，有黃色固體析出，抽濾，得到的黃色固體不經分離直接進行下一步反應（5〇〇 mg，淡黃色固體）。 MS m/z (ESI) ： 445[M-fl] 第六步 l-{4-[4-(3-氟苄氧基）-3_氯苯胺基]-喹唑啉_6__基}_4_三氟甲基-111-吼略-3-疊氮基-甲酮 94389 163 201016683 ，上述步驟所得的化合物卜{4-[3-氯-4-(3-氟苄氧 .基）本胺基]-喹唑啉基卜4_三氟甲基一吡咯_3_甲酸 67f(278 mg ’ 〇. 5mmol)，三乙胺（76 mg，〇 75mm〇1)溶解於2 mL四氫呋喃中，攪拌下加入疊氮基磷酸二苯酯 mg’ 0. 55mmol) ’所得的混合物在室溫下攪拌7小時後反應凡畢反應液用乙酸乙酯（3〇mLx3)萃取，合併的有機相依次用70 mL水，30 niL飽和食鹽水洗滌，無水硫酸鈉脫水，過濾，減壓下濃縮有機相，所得的殘留物進一步藉由管柱層析法分離純化，得到本標題產物氟苄氧，）-3-氯苯胺基]-喹唑啉_6_基卜4_三氟甲基_1H_吡咯_3_ 疊氮基-甲酮67g(l〇l mg ,黃色固體），產率：35%。 MS m/z (ESI) ： 581 [M+l] .第七步 (1 {4-[3-氯-4-(3-氟苄氧基）-苯胺基]一喹嗤淋_6_基}_4一 —亂甲基比嘻-3-基）-胺基甲酸第三丁酯將上述步驟所得的化合物1_{4_[4_(3_氟苄氧基）_3一馨氯苯胺基]-喹唑啉-6-基卜4-三氟甲基-1Η_吡咯_3_疊氮基 -甲酮67g(l· 37 g，2. 35mmol)溶於75 mL·甲苯，在外浴溫度為13(TC下，加熱所得的黃色混懸液，3小時後加入第三丁醇（15 mL·，159 mmol)，繼續回流2小時後，在45t下攪拌過夜’蒸乾反應液’所得的殘留物丨4_[3_氯_4_(3一氣节氧基）-苯胺基]-喹唑啉-6-基卜4-三氟甲基_11}_„比哈一基）-胺基甲酸第三丁醋67h(1.6 g，黃色固體）不經分離直接進行下一步反應。 94389 164 201016683 MS m/z (ESI) : 628 [M+l] 第八步 [6-(3-胺基-4-三氟甲基-吡咯―卜基）—喹唑啉一4_基]_[3_ 氯-4-(3-氟节氧基）-苯基]-胺氮氣下’在50 mL茄形瓶中，將上述步驟所得的化合物（1·~{4-[3虱4-(3-氟卞氧基）-苯胺基]__啥唾琳_6__基} -4-二氟甲基-111-°比洛-3-基）-胺基甲酸第三丁酯67h(219 mg，0.35 mmol)溶解於20 mL二氯甲烷，得到的溶液在冰浴冷卻下逐漸滴加5 mL三氟醋酸，室溫下攪拌5小時後 ®反應完畢。將反應液在減壓下濃縮蒸去溶劑，得到的固體在乾燥皿中乾燥’得到本標題產物[6-(3-胺基-4-三氟甲基比咯-1-基）-喹唑啉—4-基]-[3-氯-4-(3-氟苄氧基）-苯基] •-胺67i(100 mg，黃色固體），產率：54. 3% MS m/z (ESI) ： 528 [M+l] 第九步 N~(l-{4-[3-氣-4-(3-氟苄氧基）-苯胺基]-喹唑啉-6-基} _ -4-三氟曱基-1H-吡咯-3-基）-2-甲基-丙烯醯胺將上述步驟所得的化合物[6-(3-胺基-4-三氟甲基比 11 各-1-基）-喹唑啉_4_基卜[3__氯-4-(3-氟苄氧基）-苯基]-胺 67i(200 mg ’ 〇· 379 mmol)，三乙胺（〇. 4 mL，〇. 758 mmol) 溶解於15 mL二氯甲烧中，混合物在丙酮乾冰浴冷卻下加入2-甲基-丁烯醯氯（〇. j mL，〇. 379 mmol)，攪拌4小時後有固體析出。所得的固體藉由TLC板進行分離純化，用乙酸乙酯進行沖洗，得到本標題產物N-(1 -{4- [ 3-氯-4- 165 94389 201016683 (3-氟苄氧基）-苯胺基]-啥0坐琳-6-基}-4-三氣甲哈-3-基）-2-曱基-丙稀酿胺（49 mg，黃色阳 ^ 只巴固體）， 21. 7% ° 產率 MS m/z (ESI) : 596[M+1]First step 4, 4, 4-Trifluoro-but-2-enoic acid • Add 4, 4, 4-trifluoro-butan-2-ethyl ester 67a (56 g, 〇 in a 100 mL eggplant vial) 33 mmol), citric acid (46 g, 1 mmol) and 1 melon L concentrated sulfuric acid, the resulting mixture was heated to 8 (TC, stirred overnight, the reaction was completed. Stop heating, distill at room temperature, collect 40 to 8 (TC The fraction obtained from the title product, 4, 4, 4-trifluoro-but-2-enoic acid 67b (24 g, white solid), yield 51.9%. MS m/z (ESI): 139 [Ml The second step 4, 4, 4-trifluoro-but-2-enoic acid benzyl ester in a 1 000 mL eggplant-shaped flask was added 4, 4, 4-trifluoro-but-2-enoic acid 67b (26·5) g,〇· 18 mol) ' 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (54 g' 0. 27 mo 1)' 1-Phenylbenzotriene Saliva (3.85 g, 161 94389 201016683 0. 27mol) 'Triethylamine (46g, 〇.45mol), and 400 mL of tetrahydrofuran, the resulting mixture was stirred at room temperature for 1 hour and then added to benzyl alcohol (29.2 g, 〇. 27mol), stirred overnight, the reaction is completed. Add the ice water to the reaction solution to quench the reaction 'extracted with ethyl acetate (4 〇〇 mL x 3), the organic phase with anhydrous sodium sulfate Dehydration, filtration, and concentration of the filtrate. The obtained residue was purified and purified by column chromatography to give the title product 4, 4, 4-trifluoro-butyl-2-decanoic acid benzyl acetate 67c (2. 95 g, Yellow oily liquid), Yield: 7.7% MS m/z (ESI): 579 [Ml] The third step ❹ 4-trifluoromethyl-in-"Bilo-3-carboxylic acid ester ester will be Toluene sulfonium methyl isocyanide (2.73g, 14.1mm 〇l) was dissolved in 25 mL of tetrahydrofuran, cooled to 〇<t in an ice bath, and added to the ring under nitrogen. [5'4, 〇]_1, 8~ Dinitro-7-decene (2.15 g, 14.1 mmol), stirred for 30 minutes, then added 4,4,4-trifluoro-but-2-enoic acid benzyl ester. 67c (2 95 g, 12. 7 mmol) The obtained mixture was stirred overnight, and the reaction was completed. The reaction mixture was stirred and evaporated, evaporated, evaporated, evaporated, The residue was separated and purified by the tube (4) separation method to obtain the title product 4-tris-methyl-lH-n than 嘻_3_carboxylic acid ester 67d (L 938, yellow solid yield: 56. 7% 〇MS m/z (ESI): 268 [Ml] Step 4 4-Trifluoromethane -1H~Pylo-3-carboxylic acid in a 25 mL flask, under the conditions of ice-cold, add 94389 162 201016683 compound 4-trifluoromethyl-1 Η-pyrrole-3-carboxylate 67d ( 120 mg, 0. 445 mmol) and 3 mL of trifluoroacetic acid. After stirring for 30 minutes, the ice bath was removed and stirred at room temperature overnight. The reaction mixture was poured into 5 mL of ice water, extracted with ethyl acetate (200 ml×3), and the organic phase was dried over anhydrous sodium sulfate, and the residue obtained by filtration and concentration of the filtrate was further purified by column chromatography. 6%。 The title product was obtained as the title product: 4-trifluoromethyl-1H-puro-3-carboxylic acid 6 7e (3. 39 g, yellow solid). MS m/z (ESI): 180 [M+l] Step 5 ❹ l-{4-[3-chloro-4-(3-fluorobenzyloxy)-anilino]-quinazoline-6-yl 4_Trifluoromethyl-1 Η-0 to 嘻-3-carboxylic acid The compound obtained in the above step 4-trifluoromethyl-1 H-nitlo-3-methyl-acid (2. 14 g' 12 mmol), [3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-iodo-quinazoline-4-yl)-amine lg (6. 〇7 g, 12 mmol), potassium phosphate ( 10. 19 g '48 mmo 1), cuprousin (3.44 g, 18 mmo 1) and 4-trifluorodecyl-1H-pyrrol-3-carboxylic acid (2.14 g, 12 mmol) and 5 mL N, The N-dimercaptoinamide was dissolved, and N,N'-didecyl-12-ethylenediamine (16 g, 18 mmol) was added dropwise with stirring. The reaction solution was poured into i.sub.5 mL of ice water, and a yellow solid was precipitated, and filtered, and the obtained yellow solid was directly subjected to the next reaction (5 〇〇 mg, pale yellow solid). MS m/z (ESI): 445 [M-fl]. Step 6 l-{4-[4-(3-fluorobenzyloxy)-3-chloroanilinyl]-quinazoline_6__ base}_4 _Trifluoromethyl-111-吼3--3-azido-methanone 94389 163 201016683 , the compound obtained in the above step, {4-[3-chloro-4-(3-fluorobenzyloxy)ylamine ] quinazolinyl 4_trifluoromethyl-pyrrole_3_carboxylic acid 67f (278 mg '〇. 5mmol), triethylamine (76 mg, 〇75mm〇1) dissolved in 2 mL of tetrahydrofuran, stirred Addition of azide diphenyl phosphate mg' 0. 55 mmol) 'The resulting mixture was stirred at room temperature for 7 hours, then the reaction mixture was extracted with ethyl acetate (3 mL mL), and the combined organic phases were sequentially used. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; -Chloroanilino]-quinazoline_6_ kib-4-trifluoromethyl-1H-pyrrole_3_ azido-methanone 67 g (10 mg, yellow solid), yield: 35%. MS m/z (ESI): 581 [M+l]. Step 7 (1 {4-[3-chloro-4-(3-fluorobenzyloxy)-anilinyl]-quinoline _6_yl }_4一- disordered methylidene-3-yl)-aminocarboxylic acid tert-butyl ester The compound obtained in the above step 1_{4_[4_(3_fluorobenzyloxy)_3-mono-chloroanilino]-quin Oxazolin-6-ylbu 4-trifluoromethyl-1Η-pyrrole_3_azido-methanone 67g (1.33 g, 2.35 mmol) was dissolved in 75 mL·toluene at an external bath temperature of 13 ( The resulting yellow suspension was heated at TC. After 3 hours, the third butanol (15 mL·, 159 mmol) was added. After refluxing for 2 hours, the residue obtained by evaporation of the reaction mixture was stirred overnight at 45 Torr. 4_[3_Chloro_4_(3-gas oxy)-anilino]-quinazoline-6-ylbu 4-trifluoromethyl_11}_„Biha-based)-Aminocarbamic acid tert-butyl Vinegar 67h (1.6 g, yellow solid) was directly subjected to the next reaction without isolation. 94389 164 201016683 MS m/z (ESI): 628 [M+l] Step 8 [6-(3-Amino-4-III) Fluoromethyl-pyrrole-byl)-quinazoline-4-yl]-[3_chloro-4-(3-fluorooxy)-phenyl]-amine under nitrogen in a 50 mL eggplant-shaped flask, The compound obtained in the above step (1·~{4-[3 4-(3-Fluorodecyloxy)-anilino]__啥啥琳_6__基}-4-Difluoromethyl-111-°Pilo-3-yl)-tert-butyl ester 67h (219 mg, 0.35 mmol) was dissolved in 20 mL of dichloromethane, and the resulting solution was gradually added dropwise with 5 mL of trifluoroacetic acid under ice-cooling. After stirring at room temperature for 5 hours, the reaction was completed. The solvent was evaporated to dryness, and the obtained solid was dried in a dry dish to give the title product [6-(3-amino-4-trifluoromethylpyrrol-1-yl)-quinazoline-4-yl] -[3-Chloro-4-(3-fluorobenzyloxy)-phenyl]--amine 67i (100 mg, yellow solid), yield: 54. 3% MS m/z (ESI): 528 [M +l] ninth step N~(l-{4-[3- gas-4-(3-fluorobenzyloxy)-anilino]-quinazolin-6-yl} _ -4-trifluoromethyl -1H-pyrrol-3-yl)-2-methyl-propenylamine The compound obtained in the above step [6-(3-amino-4-trifluoromethyl ratio 11-1-yl)-quinazoline Porphyrin_4_ kib [3__chloro-4-(3-fluorobenzyloxy)-phenyl]-amine 67i (200 mg ' 〇 · 379 mmol), triethylamine (〇. 4 mL, 〇. 758 Ment) dissolved in 15 mL of methylene chloride, the mixture was added to 2-methyl-butene oxime under cooling in an acetone dry ice bath (Square. J mL, square. 379 mmol), stirred for 4 hours after the solid has precipitated. The resulting solid was isolated and purified by EtOAc (EtOAc) eluting elute基]-啥0坐琳-6-yl}-4-three gas methylha-3-yl)-2-mercapto-acrylic amine (49 mg, yellow yang ^ aba solid), 21. 7% ° Yield MS m/z (ESI): 596 [M+1]

^NMR (400MHz, DMSO-dO: 5 9. 87(s, 1H), 9 8.69(s’ 1H)，8.62(s，1H)，8.24(d，1H，Κ8. 8) (S，U)， 1H)，8.01(s，1H)，7.91(d，1H，J=8.8)，7·的 8. 1〇(s， 7.73(d，1H，J = 8.8)，7.48(q，1H)，7.33(m，3H) (S，1H)， 1H)，5.82(s，1H)，5.52(s，1H)，5.28(s,外、，2〇(V Φ3Η) X 實施例68 [l-{4_[3-氯-4-（吡啶-2-甲氧基）-茉胺② 基}-4-(2-經乙基基底咬〜^NMR (400MHz, DMSO-dO: 5 9. 87(s, 1H), 9 8.69 (s' 1H), 8.62 (s, 1H), 8.24 (d, 1H, Κ8. 8) (S, U), 1H), 8.01 (s, 1H), 7.91 (d, 1H, J = 8.8), 7. 1 〇 (s, 7.73 (d, 1H, J = 8.8), 7.48 (q, 1H), 7.33 (m, 3H) (S, 1H), 1H), 5.82 (s, 1H), 5.52 (s, 1H), 5.28 (s, outside, 2 〇 (V Φ3 Η) X Example 68 [l-{4_ [3-Chloro-4-(pyridin-2-methoxy)-mosilamine 2 base}-4-(2-biton ethyl base bite~

6868

〇重複本發明實施例53第一步所述的實檢步驟是以實施例47所得的化合物2_丨4_[3_氯_4〜（呪—，不同的基）-苯胺基]-喹唑啉刊-基}-6, 7-二氫-2Η-^嘀^ 甲氡咯-4-酮47作原料，按照本發明實施例53第〜步4〜c]吡相同方式使得該原料與哌啶的反應，得到襟題f [1-{ 4-[3-氯-4-〇比啶一2-甲氧基）-苯胺基]-喹"坐琳-e-基} -4-(2-羥乙基）-11^11比洛_3_基]_派啶-1-甲酮68(1〇0 mg’灰色固體），產率95%。 94389 166 201016683 MS m/z (ESI) ： 584 [M+l] 'HNMR (400MHz, DMSO-c/O： δ 9. 88(s, 1H), 8.61(m, 3H), 8.17(d, 1H, J=8.8), 8.05(s, 1H), 7. 88(m, 2H), 7. 76(d, 1H, J=8.8), 7.67(s, 1H), 7. 60(d, 1H, J=7.6), 7.48(s, 1H), 7.38(t, 1H), 7.31Cd, 1H, J=8.4), 5.31(s, 2H), 4. 71(s, 1H), 3.56(m, 6H), 2. 68(t, 2H), 1. 52-1. 64(m, 6H) 實施例69 2-（1-{4-[3-氣-4 -（〇比σ定-2-曱氧基）_苯胺基]一喧唾琳- 6-®基}-4-哌啶-1-甲基-1H-吡咯-3-基）-乙醇The repeated detection step described in the first step of Example 53 of the present invention is the compound 2_丨4_[3_chloro-4~(呪-, different base)-anilino]-quinazole obtained in Example 47.啉刊 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - The reaction of pyridine gives the title [1-{4-[3-chloro-4-indenylpyridin-2-methoxy)-anilino]-quino"sitting-e-yl}-4-( 2-Hydroxyethyl)-11^11 pirin-3-yl]-pyridin-1-one ketone 68 (1 〇 0 mg 'gray solid), yield 95%. </ RTI> <RTIgt; , J=8.8), 8.05(s, 1H), 7. 88(m, 2H), 7. 76(d, 1H, J=8.8), 7.67(s, 1H), 7. 60(d, 1H, J=7.6), 7.48(s, 1H), 7.38(t, 1H), 7.31Cd, 1H, J=8.4), 5.31(s, 2H), 4.71(s, 1H), 3.56(m, 6H) ), 2. 68(t, 2H), 1. 52-1. 64(m, 6H) Example 69 2-(1-{4-[3-Gas-4 -(〇比σ定-2-曱) Oxy))-anilino]-indolyl- 6-yl}-4-piperidin-1-methyl-1H-pyrrol-3-yl)-ethanol

重複本發明實施例61第一步所述的實驗步驟，不同的是以實施例68所得的化合物[1-{4-[3-氯-4-(吡唆-2-甲氧基）-苯胺基]-喹唑啦-6-基}-4-(2-經乙基）-111-«比洛__3__ ❹基]-娘咬-1-甲酮68作原料，按照本發明實施例Μ第— 步所述的相同方式使得該原料與氫化紹鐘反應，得到標題化合物2-(1-{4-[3-氯-4-(吡啶-2-甲氧基）-苯胺基]―啥嗤琳-6-基}-4-°底咬-1-曱基-1Η-σ比嘻-3-基）-乙醇69(150 mg，棕色固體），產率：40%。 MS m/z (ESI) ： 570 [M+l] ^NMR (400MHz, DMSO-c/e): <5 10.07(s, 1H), 8.79(s l{j) 8. 60(t，2H), 8.10(q，2H)，7. 90(t，2H), 7.80(t, 2H)’ 94389 167 201016683 7. 59(t, 2H), 7.38(t, 1H), 7. 30(d, 1H, J=8. 8), 5.31(s, 2H), 4. 14(s, 2H), 3. 69(t, 2H), 3. 00(t, 4H), 2. 75(t, 2H), 1.66(m, 6H) 實施例70 izU(l-{4-「3-U-(3-氟-苄1基）_茉胺基μ喹唑嗷二 1Η-°比洛-3-!基）-胺基基丨—丨·卜二侧氣篡—亡备一1又氺6氺一 g塞p南一 0The experimental procedure described in the first step of Example 61 of the present invention was repeated, except that the compound [1-{4-[3-chloro-4-(pyridin-2-methoxy)-aniline obtained in Example 68 was obtained. ]]-quinazolin-6-yl}-4-(2-ethyl)-111-«Bilo__3__ fluorenyl]-negant-1-ketone 68 as a starting material, in accordance with an embodiment of the invention The starting material was reacted with hydrogenation to give the title compound 2-(1-{4-[3-chloro-4-(pyridine-2-methoxy)-anilinyl]-oxime in the same manner as described in the first step.嗤琳-6-基}-4-° bottom bite 1-mercapto-1Η-σ than 嘻-3-yl)-ethanol 69 (150 mg, brown solid), yield: 40%. MS m/z (ESI): 570 [M+l] NMR (400 MHz, DMSO-c/e): <5 10.07 (s, 1H), 8.79 (sl{j) 8. 60 (t, 2H) , 8.10(q,2H), 7. 90(t,2H), 7.80(t, 2H)' 94389 167 201016683 7. 59(t, 2H), 7.38(t, 1H), 7. 30(d, 1H , J=8. 8), 5.31(s, 2H), 4. 14(s, 2H), 3. 69(t, 2H), 3. 00(t, 4H), 2. 75(t, 2H) , 1.66 (m, 6H) Example 70 izU(l-{4-"3-U-(3-fluoro-benzyl 1 yl)-mosamine-based quinazodazole 2 Η-°Bilo-3-! )-Amino-based 丨-丨·卜二侧气篡-亡一一一氺6氺一g塞普南一 0

NHNH

70 .XX：, 重複本發明實施例5第一步至第三步所述的實驗 •驟，不同的是以實施例5第二步所得的化合物丨—{4 ’ -4-(3-氟-苄氧基·)-苯胺基]-啥咬琳基卜氣 - Q 〜醛5c作原料，按照本發明實施例5第三步所述、甲式使得該原料與4-氨甲基-1，1 -二侧氧基〜丄^、同方 _噻喃-4-醇反應，得到本標題產物4-{[(卜丨4气3」λ 氟-苄氧基）-苯胺基]-喹唑啉氯4〜（3-基]·'甲基}-1，1-二側氧基-六氫嘆略、/ 土）私r 公网〜4：〜7 (\ Γ mg ’黃色固體），產率：67.2%。 UC9° MS m/z (ESI) ： 637[M+1] 'HNMR (400MHz, MSO-ds): δ 9.42(s, 1H), g 99 8. 92(s，1H), 8. 38(dd，1H’ J=8.8)，8. 〇5(d，1H (S，1H)， 8.01(d，1H，J=2.4)，7.94(s，1H)，7.85(t ih、，J=9.2)，入 7.79(dd, 94389 168 201016683 1H, J = 9.2), 7.48(m, 1H), 7. 35(m, 3H), 7. 20(t, 1H), 6.62(s, 1H), 5.25(s, 2H), 4. 〇9(S) 2H), 3. 19(m, 2H), 3.07(m, 4H), 2. 06(ra, 4H) 實施例71 甲基啶-3-氣臬茇棊卜-曱酸一甲氣基乙某v 醯胺70 .XX:, repeating the experiment described in the first step to the third step of the fifth embodiment of the present invention, the difference is the compound obtained in the second step of the embodiment 5 - {4 ' -4- (3-fluoro -Benzyloxy))-anilino]-啥琳基基 - - Q 〜 aldehyde 5c as a raw material, according to the third step of the fifth embodiment of the present invention, the formula is made with 4-aminomethyl-1 , 1 -di-terminated oxy-oxime^, isomerized with thiopyran-4-ol to give the title product 4-{[(卜丨4 gas 3"λ fluoro-benzyloxy)-anilino]-quinazoline Porphyrin chloride 4~(3-yl)·'methyl}-1,1-di- oxy-hexahydro-sinus, / soil) private r public network ~4:~7 (\ Γ mg 'yellow solid), Yield: 67.2%. UC9° MS m/z (ESI): 637[M+1] 'HNMR (400MHz, MSO-ds): δ 9.42 (s, 1H), g 99 8. 92 (s, 1H), 8. 38 (dd ,1H' J=8.8), 8. 〇5(d,1H (S,1H), 8.01(d,1H,J=2.4), 7.94(s,1H),7.85(t ih,,J=9.2) , into 7.79 (dd, 94389 168 201016683 1H, J = 9.2), 7.48 (m, 1H), 7. 35 (m, 3H), 7. 20 (t, 1H), 6.62 (s, 1H), 5.25 ( s, 2H), 4. 〇9(S) 2H), 3. 19(m, 2H), 3.07(m, 4H), 2. 06(ra, 4H) Example 71 Methyl pyridine-3- gas 臬茇棊卜-曱酸一甲气基乙v 醯amine

重複本發明實施例66第一步至第三步的實驗步驟，不 .同的是以第二步所得的化合物將2~{4-[3-甲基-4-(6-甲基-吼啶-3-侧氧基）-苯胺基]-喹唑啉__6_基丨_6, 7—二氮 -2H-吡喃并[3,4-c]吡咯-4-酮66b作原料，按照本發明實施例66第三步所述的相同方式使得該原料與2-甲氧基乙 g胺的反應，得到標題化合物4-(2-羥乙基）-1-{4-[3-甲基 -4-(6-甲基吡啶-3-氧基）-苯胺基]-喹唑啉-6-基}-1Η-吡咯-3-甲酸（2-甲氧基乙基）-醯胺71(15 mg，黃色固體），產率：8% ^ MS m/z (ESI) ： 553 [M+l] !HNMR (400MHz, DMS0-d〇： (5 9.86(s, 1H), 8. 69(s, 1H), 8.58(s, 1H), 8. 19(s, 1H), 8. 08(t, 2H), 8.00(s, 1H), 7. 91(d, 1H, J=8. 4), 7. 78(s, 1H), 7.71(d, 1H, J=8. 4), 169 94389 201016683 7.41(s, 1H), T.25(m, 2H), 7. 00(d, 1H, J = 8. 4), 4. 80(t, 1H), 3.66(q, 2H), 3.44(t, 2H), 3. 39(t, 2H), 3. 29(s, 3H), 2. 90(t, 2H), 2.45(s, 3H), 2. 24(s, 3H) 實施例72 1X4’ 1二哌啶基二21^^{4-「3-氯二_4-(3-氟苄氧基）-苯版基]一0坐琳-6-暮卜1H-吼咬—9-其甲獅The experimental steps of the first step to the third step of the embodiment 66 of the present invention are repeated, and the same compound obtained by the second step is 2~{4-[3-methyl-4-(6-methyl-oxime). Pyridin-3-yloxy)-anilino]-quinazoline__6_ylindole-6,7-diaza-2H-pyrano[3,4-c]pyrrol-4-one 66b as a raw material, The reaction of the starting material with 2-methoxyethyl gamine was carried out in the same manner as described in the third step of Example 66 to give the title compound 4-(2-hydroxyethyl)-1-{4-[3- Methyl-4-(6-methylpyridin-3-yloxy)-anilino]-quinazolin-6-yl}-1Η-pyrrole-3-carboxylic acid (2-methoxyethyl)-decylamine 71 (15 mg, yellow solid), Yield: 8% mp. MS m/z (ESI): 553 [M+l].HNMR (400 MHz, DMS0-d〇: (5 9.86 (s, 1H), 8. 69(s, 1H), 8.58(s, 1H), 8. 19(s, 1H), 8. 08(t, 2H), 8.00(s, 1H), 7. 91(d, 1H, J=8 4), 7. 78(s, 1H), 7.71(d, 1H, J=8.4), 169 94389 201016683 7.41(s, 1H), T.25(m, 2H), 7. 00(d , 1H, J = 8. 4), 4. 80(t, 1H), 3.66(q, 2H), 3.44(t, 2H), 3. 39(t, 2H), 3. 29(s, 3H) , 2. 90(t, 2H), 2.45(s, 3H), 2. 24(s, 3H) Example 72 1X4' 1 Dipiperidinyl 2 21^^{4-"3-Chloro-2- (3- Fluorobenzyloxy)-phenyl quinone] one 0 sitting -6- 暮 1 1H-bite - 9- its lion

72a 7 ^^-以-氣-居-㈡-氟苄氧基^苯胺基卜喹唑啉^ —基卜^一吡咯-2-甲酸 .第一步重複本發明實施11第一步的實驗步驟，將實施例11 ®第一步所得的化合物5-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]''嗜唾琳基卜1H-吡咯-2-曱醛lla(283 mg，0. 6 mmol) 洛解於5 mL四氫呋喃中，分批加入6 mL 1. 5N高錳酸鉀溶液’授摔5小時後反應完畢。在反應液中加入飽和亞硫酸納溶液’過濾，濾液用乙酸乙酯（100 mLx3)萃取，合併的有機1相依次用50 mL飽和氯化鈉溶液洗滌，無水硫酸鈉脫水’過滤’濾液減壓下濃縮，得到本標題產物5-{4-[3-氯一4-(3-氟苄氧基）一苯胺基]—喹唑啉_6_基卜1Η_Π比咯一2—曱 170 94389 201016683 酸72a(265 mg ’黃色固體），產率90. 4%。 MS m/z (ESI) ： 489 [M+l] 第二步 5-{4-[3-氣-4-(3-氟苄氧基）-苯胺基]-喹唑啉-6基卜 0比嘻-2-甲酸（2-嗎琳-4-乙基）-醯胺將上述實驗所得的化合物5-{4-[3-氯-4-(3-氟节氧基）-苯胺基]-喹唑啉-6-基卜1H-吡咯-2-曱酸72a(49 mg， 0. 1 mmo 1)’ 二氯亞硬（6〇 mg，0.5 mmo 1)溶解於 5 mL 二氯甲烷中，加熱回流1小時後冷卻至室溫，加入[U，]二旅 ®啶（33. 6 mg ’ 0.2 mmol)的5 mL二氯甲烷溶液，所得的混合液在室溫下攪拌2小時後反應完畢。減壓下濃縮溶劑，得到的殘留物藉由TLC板分離純化，得到本標題產物 • 5-丨4—[3_氯氟苄氧基）-苯胺基]-喹唑啉-6基丨-in- 吼咯-2-曱酸（2-嗎啉-4-乙基）-醯胺72(12 mg，白色固體），產率：18. 8°/0 〇 MS m/z (ESI) ： 639 [M+-1] ❹1HNMR (400MHz，CDCl〇: 5 9'2〇(s，1H)，8.71(s，1H)， 7.92(d, 3H, J=9.2), 7. 85(m, 2H), 7. 53(d, 1H, 1=8.8), 7.35Cm, 1H), 7. 22(m, 2H), 7. 02(t, 1H), 6. 96(d, 1H, J=8.8), 6.88(s, 1H), 6. 38(s, 1H), 5. 16(s, 2H), 2. 53(m, 4H), 2.19(m, 4H), 2. 00(m, 1H), 1.48(m, 8H), 1.34(m, 2H) ，實施例7 3 4_(2-經乙_基）-1-.{4-[3-曱基-4-(6-甲基°比°定.-3-氣某）-笼 94389 171 20101668372a 7 ^^---gas-homo-(di)-fluorobenzyloxy^anilinoquinazoline^-pyridyl-pyrrole-2-carboxylic acid. The first step is repeated in the first step of the present invention. The compound obtained in the first step of Example 11 ® 5-{4-[3-chloro-4-(3-fluoro-benzyloxy)-anilino]''sindolyl 1H-pyrrole-2- Furfural lla (283 mg, 0.6 mmol) was dissolved in 5 mL of tetrahydrofuran, and 6 mL of 1. 5N potassium permanganate solution was added in batches. After 5 hours, the reaction was completed. Adding saturated sodium sulfite solution to the reaction solution, the filtrate was extracted with ethyl acetate (100 mL×3), and the combined organic phase 1 was washed successively with 50 mL of saturated sodium chloride solution and dehydrated with anhydrous sodium sulfate. Concentration to give the title product 5-{4-[3-chloro-4-(3-fluorobenzyloxy)-anilino]-quinazoline _6_ kib 1 Η Π Π 咯一 2 94 94 94 94 94 94389 201016683 4%。 Acid 72a (265 mg 'yellow solid), yield 90.4%. MS m/z (ESI): 489 [M+l]. Step 2 5-{4-[3- </RTI> 4-(3-fluorobenzyloxy)-anilinyl]-quinazoline-6. The compound obtained by the above experiment, 5-{4-[3-chloro-4-(3-fluoro-oxy)-anilino], is a compound obtained by the above experiment. -quinazoline-6-ylpyr 1H-pyrrole-2-furic acid 72a (49 mg, 0.1 mmo 1)' Dichlorocholine (6 mg, 0.5 mmo 1) was dissolved in 5 mL of dichloromethane After heating under reflux for 1 hour, it was cooled to room temperature, and a solution of [U,]Bila® pyridine (33.6 mg, 0.2 mmol) in 5 mL of dichloromethane was added, and the mixture was stirred at room temperature for 2 hours. Finished. The solvent was concentrated under reduced pressure, and the residue was purified m t t t t t t t t - 吼曱曱曱曱曱 2- 2- 2- 曱 72 72 72 72 72 72 72 18 18 18 18 18 18 18 18 18 18 18 639 639 639 639 639 639 639 639 639 639 639 639 639 639 639 639 [M+-1] ❹1H NMR (400 MHz, CDCl 〇: 5 9 '2 〇 (s, 1H), 8.71 (s, 1H), 7.92 (d, 3H, J = 9.2), 7. 85 (m, 2H), 7. 53(d, 1H, 1=8.8), 7.35Cm, 1H), 7. 22(m, 2H), 7. 02(t, 1H), 6. 96(d, 1H, J=8.8), 6.88(s, 1H), 6. 38(s, 1H), 5. 16(s, 2H), 2. 53(m, 4H), 2.19(m, 4H), 2. 00(m, 1H), 1.48(m, 8H), 1.34(m, 2H), Example 7 3 4_(2-B-yl)-1-.{4-[3-mercapto-4-(6-methyl°°°定.-3-气某)-Cage 94389 171 201016683

重複本發明實 /王矛二步所i十、驟，不同的是以實施例66所得的化合物2〜丨4 ^的實驗步 (6-曱基-吡啶-3-側氧基）-苯胺基]一口啥唑啉〜基 ❿氫-2H-吡喃并[3, 4-c]吡咯-4-酮66b作片粗^ ，？— 杳始存丨Μ兹-牛祕、中μ, 原料’按照本發明實施例66第二步所述的相同方式使得該原料與哌啶一 1 基-乙胺的反應’得到標題化合物4-(2-羚7甘、 \ G 基）~1一{4-「3- •曱基一4-(6-曱基吡啶―3-氧基）一苯胺基μ喹唑啉一6一 } .-1Η-吡咯-3-曱酸-（2-哌啶一Γ_乙基）一醯胺73(42 ，固體），產率：15.7%。 8 MS m/z (ESI) : 604 [M-l] 8. 73(s，1H)， 8.〇9(m，1H)， "8· 8), 7. 44(s, 3肩(t，2H)， 2-34(m, 2H), Θ ^NMR (400MHz, DMSO-d〇： <5 9. 93(s, 1H), 8.58(s，1H), 8.19(s，1H)，8.11(s，1H)， 7.90(m, 2H), 7. 76(s, 1H), 7. 75(dd, 1H, j 1H), 7. 23(m, 2H), 7. 〇〇(d, 1H, J=B. 8), 3.58(q，2H)，2.89(t，2H)，2.45(m，6H)， 2.27(m, 4H), 1.50(m, 6H) 實施例74 唾啦-fi- 1-{4-[3-氯-4-0比文^2-甲氫篡）-I吃 94389 172 201016683 基} - 4-4〇經乙基）-111-°比味-3-甲酸（2-咐)洛院-1-基-乙基）-醯胺Repeat the steps of the present invention, except that the compound (2-fluorenyl-pyridin-3-yloxy)-anilino group of the compound 2~丨4 ^ obtained in Example 66 was obtained. ] A oxazoline~ylhydrazine hydrogen-2H-pyrano[3,4-c]pyrrol-4-one 66b as a tablet ^? - 杳丨Μ - 牛牛牛牛牛牛牛牛牛牛原料原料原料原料原料原料原料原料原料原料原料原料原料原料原料原料原料原料按照按照按照按照按照按照按照按照按照按照按照按照按照按照按照按照(2-Antelope 7 Gan, \ G base) ~1 - {4-"3- • fluorenyl- 4-(6-mercaptopyridine-3-oxy)-anilino-quinazoline- 6-}. -1 Η-pyrrole-3-decanoic acid-(2-piperidinium oxime-ethyl) decylamine 73 (42, solid), Yield: 15.7%. 8 MS m/z (ESI): 604 [Ml] 8. 73(s,1H), 8.〇9(m,1H), "8· 8), 7. 44(s, 3 shoulders (t, 2H), 2-34(m, 2H), Θ ^NMR (400 MHz, DMSO-d 〇: <5 9.93 (s, 1H), 8.58 (s, 1H), 8.19 (s, 1H), 8.11 (s, 1H), 7.90 (m, 2H), 7. 76(s, 1H), 7. 75(dd, 1H, j 1H), 7. 23(m, 2H), 7. 〇〇(d, 1H, J=B. 8), 3.58(q, 2H), 2.89 (t, 2H), 2.45 (m, 6H), 2.27 (m, 4H), 1.50 (m, 6H) Example 74 saliva-fi- 1-{4-[3-chloro-4- 0 比文^2-methylhydroquinone)-I eat 94389 172 201016683 base} - 4-4 〇ethyl)-111-° flavonoid-3-carboxylic acid (2-咐)洛院-1-基-乙Amine

重複本發明實施例53第一步所述的實驗步驟，不同的是以實施例47所得的化合物2-{4-[3-氯-4-(吡啶-2-曱氧基：-苯胺基卜啥嗤琳^-基丨^-二氫-?!!-1^^!^，^…1^ 咯-4-酮47作原料，按照本發明實施例53第一步所述的 ®相同方式使得該原料與2-吡咯烷-卜基-乙胺的反應，得到標題化合物1-{4-[3-氯-4-(吡啶-2-曱氧基）-苯胺基]-喹唾淋-6-基}-4-4-(2-羥乙基）-1Η-σ比洛_3-甲酸（2-σ比17各烧 • -1-基-乙基）-酿胺.74(140 mg，黃色固體.）’產率.4〇.〇%。 MS m/z (ESI) ： 611 [M-l] !HNMR (400MHz, DMSO-c/〇: δ 9. 99(d, 1H, J=12.8), 8.85(d, ίΗ, J=12.8), 8. 61(d, 2H, J=6. 0), 8. 44(m, 1H), q8.31(s, 1H), 8.13(t, 2H), 7. 88(t, 3H), 7. 60(d, 1H, J=8.0), 7.50(d, 1H, J=5.2), 7.38(t, 1H), 7.30(d, 1H, J=9.2), 5.31(s, 2H), 4. 73(s, 1H), 3. 58Cm, 6H), 3. 09(m, 4H), 2. 91(t, 2H), 1. 96(m, 4H) 實施例75 l-{4-[3-氯- 4-(°比σ定-2-甲氧基）_苯胺基]一啥唾琳-6-基} -4-（2-羥乙基）-1Η-吡咯-3-曱酸_(2-σ底啶_1—乙基）-醯胺 173 94389 201016683The experimental procedure described in the first step of Example 53 of the present invention was repeated, except that the compound obtained in Example 47 was 2-{4-[3-chloro-4-(pyridin-2-yloxy:-anilinyl)啥嗤琳^-基丨^-Dihydro-?!!-1^^!^,^...1^ -4--4-ketone 47 as a starting material, in the same manner as described in the first step of Example 53 of the present invention The reaction of the starting material with 2-pyrrolidine-bu-ethylamine afforded the title compound 1-{4-[3-chloro-4-(pyridin-2-yloxy)-phenylamino]-quinal- 6-yl}-4-4-(2-hydroxyethyl)-1Η-σ-Bilo_3-carboxylic acid (2-σ ratio 17 calcination • -1-yl-ethyl)-bristamine.74 (140 Mg, yellow solid.) 'yield. 4 〇. 〇%. MS m/z (ESI): 611 [Ml] !HNMR (400 MHz, DMSO-c/〇: δ 9. 99 (d, 1H, J= 12.8), 8.85(d, ίΗ, J=12.8), 8. 61(d, 2H, J=6. 0), 8. 44(m, 1H), q8.31(s, 1H), 8.13(t , 2H), 7. 88(t, 3H), 7. 60(d, 1H, J=8.0), 7.50(d, 1H, J=5.2), 7.38(t, 1H), 7.30(d, 1H, J=9.2), 5.31(s, 2H), 4. 73(s, 1H), 3. 58Cm, 6H), 3. 09(m, 4H), 2. 91(t, 2H), 1. 96( m, 4H) Example 75 l-{4-[3-Chloro-4-(° ratio sigma-2-methoxy)-anilino]-indolyl-6-yl}-4-(2- Hydroxyethyl -1Η- pyrrole-3 Yue acid _ (2-σ bottom piperidine _1- ethyl) - 173 Amides 94389201016683

重複本發明實施例53第·—步所述的實驗步驟，不同的是以實施例47所得的化合物2-{4-[3-氯-4-(吡啶-2〜甲氧基）-苯胺基]-喹唑啉-6-基卜6, 7_二氳-2H-吡喃[3, 4-c]吡嘻-4-酿I 47作原料，按照本發明實施例53第一步所述的相同方式使得該原料與2-哌啶-1-基-乙胺的反應，得到標 ®通化合物1-{4-[3-氯-4-(°比°定-2-甲氧基）_苯胺基]-啥唾啉-6-基}-4-(2-羥乙基）-iH-吡咯_3-甲酸-（2-0辰啶-1-乙基）-醯胺75(70 mg，棕色固體），產率56.0%。 .MS m/z (ESI) ： 625 [M-l] !HNMR (400MHz, dUSO-de)： δ l〇.〇7(s, 1H), 8. 89(s, 1H), 8.60(d, 1H, J=7.6), 8. 29-8. 45(m, 2H), 8. 14(m, 2H), 7. 89(t, 3H), 7. 60(d, 1H, J=8. 〇), 7. 52(d, 1H), 7. 37(t, © 1H), 7.30(d, 1H, J=9.2), 5.31(s, 2H), 4.74(s, 1H), 3.65(m, 4H), 2. 98-3. 16(m, 4H), 2.91(t, 4H), 2. 78(m, 6H) 實施例76 ^(1-{4-「3-氯-4-(°比咬-2-甲氳基）-笨胺基1-啥邱坤^_ 羞丄-4-吡咯烷-1-甲基-ijj 一吡咯-3-基）-乙醢 174 94389 201016683The experimental procedure described in the first step of Example 53 of the present invention was repeated, except that the compound obtained in Example 47 was 2-{4-[3-chloro-4-(pyridine-2~methoxy)-anilinyl. ]-quinazoline-6-yl b 6,7-dioxa-2H-pyrano[3,4-c]pyridin-4-furan I 47 as a starting material, according to the first step of Example 53 of the present invention In the same manner, the reaction of the starting material with 2-piperidin-1-yl-ethylamine gives the standard compound 1-{4-[3-chloro-4-(° ratio = 2-methoxy) _anilinyl]-hydrazin-6-yl}-4-(2-hydroxyethyl)-iH-pyrrole_3-formic acid-(2-0-decyl-1-ethyl)-decylamine 75 (70 Mg, brown solid), yield 56.0%. .MS m/z (ESI): 625 [Ml] !HNMR (400MHz, dUSO-de): δ l〇.〇7(s, 1H), 8. 89(s, 1H), 8.60(d, 1H, J=7.6), 8. 29-8. 45(m, 2H), 8. 14(m, 2H), 7. 89(t, 3H), 7. 60(d, 1H, J=8. 〇) , 7. 52(d, 1H), 7. 37(t, © 1H), 7.30(d, 1H, J=9.2), 5.31(s, 2H), 4.74(s, 1H), 3.65(m, 4H ), 2. 98-3. 16(m, 4H), 2.91(t, 4H), 2. 78(m, 6H) Example 76 ^(1-{4-"3-chloro-4-(° ratio)咬-2-甲氲基)-笨胺胺1-啥邱坤^_ Shame-4-pyrrolidine-1-methyl-ijj-pyrrol-3-yl)-acetamidine 174 94389 201016683

重複本發明實施例61第一步所述的實驗步驟，不同的是以實施例6 0所得的化合物-{4 - [ 3 -氯-4 - (σ比咬-2 ~甲氧基）-苯胺基]-喹唑啉-6-基}-4--4-(2-羥基）-1Η-吡咯基]-吡咯烷-1-甲酮6Ό作原料，按照本發明實施例61第一步所述的相同方式使得該原料與氫化鋁鋰反應，得到標題化合物2-(1-{4-[3-氯-4-(吡啶-2-甲氧基）-苯胺基]-®喹唑啉-6-基}-4-吡咯烷-1-甲基-1H-吡咯-3-基）-乙醇76 (30 mg，棕色固體），產率：44%。 MS m/z (ESI) ： 556 [M+l] • JHNMR (400MHz, dUSO-de): δ 9. 88(s, 1H), 8. 58(d, 3H), 8.11(d, 1H, J=7； 6), 8. 04(s, 1H), 7. 88(m, 2H), 7. 76(d, 1H, J=6.8), 7.60(d, 2H), 7.44(s, 1H), 7. 37(t, 1H), 7. 31(d, 1H, J=9.2), 5. 31(s, 2H), 3.85(s, 2H), 3. 65(t, 02H), 2.90(m, 4H), 2.71(t, 2H), 1.83(m, 4H) 實施例77 {4-(2-羥乙基）-1-「4-(1-苯乙胺基）-啥°去被-6-某]-彳11-0比嘻-3 -基}-派°定-1~甲酮The experimental procedure described in the first step of Example 61 of the present invention was repeated, except that the compound obtained in Example 60 was -{4 - [3-chloro-4-(sigma ratio-2~methoxy)-aniline a quinazoline-6-yl}-4--4-(2-hydroxy)-1 Η-pyrrolyl]-pyrrolidine-1-methyl ketone 6 oxime as a starting material, according to the first step of Example 61 of the present invention The starting material is reacted with lithium aluminum hydride in the same manner to give the title compound 2-(1-{4-[3-chloro-4-(pyridine-2-methoxy)-anilino]-quinazoline- 6-yl}-4-pyrrolidin-1-yl-1H-pyrrol-3-yl)-ethanol 76 (30 mg, brown solid), yield: 44%. MS m/z (ESI): 556 [M+l]: JHNMR (400 MHz, dUSO-de): δ 9. 88 (s, 1H), 8. 58 (d, 3H), 8.11 (d, 1H, J =7; 6), 8. 04(s, 1H), 7. 88(m, 2H), 7. 76(d, 1H, J=6.8), 7.60(d, 2H), 7.44(s, 1H) , 7. 37(t, 1H), 7. 31(d, 1H, J=9.2), 5. 31(s, 2H), 3.85(s, 2H), 3. 65(t, 02H), 2.90( m, 4H), 2.71(t, 2H), 1.83 (m, 4H) Example 77 {4-(2-hydroxyethyl)-1-"4-(1-phenylethylamino)-啥° -6-某]-彳11-0 than 嘻-3-基}-派°定-1~methanone

175 94389 77175 94389 77

第一步 (6-蛾-喹唑琳-4-基）-(1-苯乙基）-胺重複本發明實施例1第五所述的實驗步驟，不同的是以實施例1第四步所得的化合物6-碘-3H-喹唑啉-4-_ if 作原料，按照本發明實施例1第五步所述的相同方式使得該原料與1-苯基乙胺的反應，得到標題化合物（6_碘_喹唑 ❾琳4基）-(1-本乙基）-胺77a(9g’黃色固體），產率gg%。 MS m/z (ESI) ： 376[M+1] 第二步 • 2-[4-(1-苯乙胺基）-喹唑啉_6 —基]_6,7_二氫_2]1_〇比喃并 [3, 4-c]n比17各-4-酮、在100 mL茄形瓶中，將上述步驟所得的化合物（6_碘一啥嗤淋一4一基）一（1一苯乙基）_胺 77a(2.3 g，6.13 mmol)， ❾ 6, 7-二氫-2H-吡喃并[3, 4-c]吡咯-4-酮 l〇b(l. 〇93g，7. 97 mmol) ’ 磷酸鉀（3. 9 g，18. 4mmol)，碘化亞銅（2. 33 g，10. 26 職〇1)溶解於25 mL N，N-二甲基曱醯胺中，攪拌下滴加 Ν’N 一曱基 1，2-乙一胺（〇· 897 g，1 〇. 26 mmol)，加熱反應液到70t，攪拌過夜。將反應液倒入1〇〇冰水中，有白色固體析出’抽濾，得到的固體用300 mL甲醇洗滌，固體在真空下乾燥，得到本標題產物2-[4-(1-苯乙胺基）-喹唑啉-6-基]-6, 7-二氫-2H-吡喃并[3, 4-c]吡咯-4-酮 94389 176 201016683 77b(2.2 g，黃色固體），產率95. 7%。 MS m/z (ESI) : 385 [M+1] 第三步 % {4-(2-經乙基）-l-[4-(l-苯乙胺基）-喹唾琳基]、u 嘻- 基}·-旅咬-1-甲嗣將2-[4-(1-苯乙胺基）-喹唑琳-6-基]-6, 7-二&The first step (6-moth-quinazolin-4-yl)-(1-phenethyl)-amine repeats the experimental procedure described in the fifth embodiment of the present invention, except that the fourth step of the first embodiment The obtained compound 6-iodo-3H-quinazoline-4-if is used as a starting material, and the title compound is obtained by reacting the starting material with 1-phenylethylamine in the same manner as described in the fifth step of Example 1 of the present invention. (6-Iodo-quinazoline 4-)-(1-ethylethyl)-amine 77a (9 g 'yellow solid), yield gg%. MS m/z (ESI): 376 [M+1]. Step 2: 2-[4-(1-phenylethylamino)-quinazoline_6-yl]_6,7-dihydro-2]1 _ 〇喃喃 [3, 4-c]n than 17 -4- ketone, in a 100 mL eggplant bottle, the compound obtained in the above step (6 iodine 啥嗤一 4 4 4 ) ) ) 1-monophenyl)-amine 77a (2.3 g, 6.13 mmol), ❾ 6, 7-dihydro-2H-pyrano[3,4-c]pyrrol-4-one l〇b (l. 〇93g , 7.97 mmol) 'Potassium phosphate (3.9 g, 18.4 mmol), cuprous iodide (2.33 g, 10.26 grade 1) dissolved in 25 mL of N,N-dimethylhydrazine In the amine, Ν'N-mercapto 1,2-ethylamine (〇·897 g, 1 〇. 26 mmol) was added dropwise with stirring, and the reaction mixture was heated to 70t and stirred overnight. The reaction solution was poured into 1 hr of ice water, and a white solid was separated and filtered, and the obtained solid was washed with 300 mL of methanol, and the solid was dried under vacuum to give the title product 2-[4-(1-phenylethylamine) - quinazolin-6-yl]-6,7-dihydro-2H-pyrano[3,4-c]pyrrol-4-one 94389 176 201016683 77b (2.2 g, yellow solid), yield 95 .7%. MS m/z (ESI): 385 [M+1]. Step 3 % {4-(2-ethyl-ethyl)-l-[4-(l-phenylethylamino)-quinalinyl], u嘻-基}·-Brigade bite-1-carboside 2-[4-(1-phenylethylamino)-quinazoline-6-yl]-6, 7-di &

乳、2H ml 過口比喃并[3, 4-c]°tb嘻-4-酮 77b(300 mg，〇. 78 mmol)和攪掉 °底咬加入至10 mL莊形瓶中，混合物加熱至6 5， 0 夜，反應完畢。反應液在減壓下濃縮，得到的殘留物酸乙酯溶解後，再加入環己烧’有大量白色固體析出過滤、’得到的固體用少量甲醇溶解’用TLC板分離純化，得到黃色固體，真空乾燥得到標題產物{4-(2~經乙基）―卜 [4-(1-苯乙胺基）-喹唑啉-6-基]-1H-吡咯-3 —基}_旅唆曱酮77(360 mg，淺黃色固體），產率：·98. 6%。 MS m/z (ESI) ： 470 [M+1] ]HNMR (400MHz, DMSO-dO： 8. 56(s, 1H), 8. 48(d, 2H, φ J=6. 8), 8.07(s, 1H), 7.83(s, 1H), 7. 78(s, iH), 7. U(m, 3H)，7.33(t，2H), 7.23(t, 1H)，5.64(ffi，1H), 4. 71(s， 1H)，3.68(m，6H)，2.67(t，2H)，1.63(d，3H，J=6 4)， 1.24(t, 6H) 實施例78 {.4-( 2-赵乙某）-i -「4-(i -笨乙胺基）-喧唾被〜立^基i _ i江一0比嘻-3-基丨比洛欲-1-甲酮 94389 177 201016683Milk, 2H ml was transpired with [3, 4-c]°tb嘻-4-ketone 77b (300 mg, 〇. 78 mmol) and the bottom bite was added to a 10 mL bottle and the mixture was heated. At 6 5, 0 nights, the reaction is complete. The reaction mixture was concentrated under reduced pressure, and the obtained residue ethyl acetate was dissolved, and then the mixture was stirred and then filtered, and the solid was separated and filtered, and the obtained solid was dissolved in a small amount of methanol. Drying under vacuum gave the title product {4-(2~ethyl)-[[4-(1-phenylethylamino)-quinazolin-6-yl]-1H-pyrrole-3-yl}} Ketone 77 (360 mg, pale yellow solid), yield: 98.6%. MS m/z (ESI): 470 [M+1]]HNMR (400 MHz, DMSO-dO: 8. 56 (s, 1H), 8. 48 (d, 2H, φ J = 6.8), 8.07 ( s, 1H), 7.83(s, 1H), 7. 78(s, iH), 7. U(m, 3H), 7.33(t,2H), 7.23(t, 1H), 5.64(ffi,1H) , 4. 71 (s, 1H), 3.68 (m, 6H), 2.67 (t, 2H), 1.63 (d, 3H, J = 6 4), 1.24 (t, 6H) Example 78 {.4-( 2-赵乙)) -i - "4-(i - stupid ethylamine) - 喧被 is ~ 立 ^ 基 i _ i 江一0 than 嘻-3-基丨比洛欲-1-methanone 94389 177 201016683

步至第二步所述的實驗步重複本發明實施例77第一驟，不同的是以實施例77所得的化合物2_[4_(卜苯乙胺基）-喹唑啉-6-基]-6,7-二氫-2H-吡喃并[3,4_c]吡咯_4一酮77b作原料，按照本發明實施例77第三步所述的相同方式使得該原料與吡咯烷的反應，得到標題化合物{4_(2_ •赵乙基）-1-[4-(1-苯乙胺基）-喧嗤琳_6_基]_1{[-0比咯-3-基}-°比洛烧-1-甲酮78(42mg，黃色固體），產率：95%。 MS m/z (ESI) ： 456 [M+l] .^NMR (400MHz, DMSO-dO： 5 8.65(s, 2H), 8.4〇(s, 1H), 8.1〇(d, 1H, J=8.4), 7. 83(s, 1H),· 7. 76(d, 1H, J=8.4), 7.46(m, 3H), 7. 32(t, 2fl), 7.21(t, 1H), 5. 64(m, 1H), 4. 81(s, 1H), 3.61(m, 4H), 3.46(m, 2H), 2. 78(t, 2H), ^ 1. 86(m, 4H), 1. 64(d, 3H, J=6. 8) 實施例79 羥乙基）-1-「4-Π-笨某-乙胺基）-唼衅嗾-ft-基1-1H-生洛-3-曱酸（2-二乙胺基乙某）-醯胺Steps to the first step described in the second step are repeated in the first step of Example 77 of the present invention, except that the compound obtained in Example 77 is 2-[4_(phenylphenethyl)-quinazolin-6-yl]- 6,7-Dihydro-2H-pyrano[3,4_c]pyrrole-4-one ketone 77b is used as a starting material to react the starting material with pyrrolidine in the same manner as described in the third step of Example 77 of the present invention. The title compound {4_(2_ • Zhao ethyl)-1-[4-(1-phenylethylamino)-喧嗤琳_6_yl]_1{[-0-r-but-3-yl}-°Biro- 1-Methylketone 78 (42 mg, yellow solid), yield: 95%. MS m/z (ESI): 456 [M+l]. NMR (400 MHz, DMSO-dO: 5 8.65 (s, 2H), 8.4 〇 (s, 1H), 8.1 〇 (d, 1H, J=8.4 ), 7. 83(s, 1H), · 7. 76(d, 1H, J=8.4), 7.46(m, 3H), 7. 32(t, 2fl), 7.21(t, 1H), 5. 64(m, 1H), 4. 81(s, 1H), 3.61(m, 4H), 3.46(m, 2H), 2. 78(t, 2H), ^ 1. 86(m, 4H), 1 64(d, 3H, J=6. 8) Example 79 Hydroxyethyl)-1-"4-anthracene-phenoxy-ethylamino)-oxime-ft-yl-1-1H-shengluo- 3-decanoic acid (2-diethylaminoethyl)-guanamine

79 178 94389 201016683 重複本發明實施例77第一步至第三步所述的實驗步驟，不同的是以實施例77所得的化合物2-[4-(i —笨乙胺基）-喹唑啉-6-基]-6, 7-二氫-2H-吡喃并[3, 4-c]吡咯一4_ 酮77b作原料，按照本發明實施例77第三步所述的相同方式使得該原料N，N-二乙基-1，2-乙二胺的反應，得到標題化合物{4-(2-羥乙基）-1~[4-(1-苯基_乙胺基）-喹唑啉 -6-基]-1H-吡咯-3-甲酸（2-二乙胺基乙基）-醯胺79(5〇 mg，黃色固體），產率：26%。 MS m/z (ESI) ： 501[M+1] ❹1HNMR (400MHz，DMS0-c?e): d 8.82(s，1H)，8. 75(d，1H， J=7.2), 8.41(m, 3H), 8. 03(d, 1H, J=8.8), 7. 78(d, 1H, J=8.8), 7. 50(m, 3H), 7. 32(t, 2fl), 7.21(t, 1H), 5. 64(m, .1H), 4. 76(s, 1H), 3.64(t, 2H), 3. 58(m, 2H), 3. 13(m, 6H)，2.91(t，2H)，1.66(d, 3H，J=7.2)，1. 24(t，6H) 實施例80 「3-氯-4-(3-氟苄氧基）-笨基1-「643_{「(：1>1：::;^-六氤 φ -1入木6*-嗟唾-4-甲基）-胺基1-甲某丨出也p坐嚇 -4-基1-胺79 178 94389 201016683 The experimental procedure described in the first step to the third step of Example 77 of the present invention was repeated, except that the compound obtained in Example 77 was 2-[4-(i-i-ethylamino)-quinazoline. -6-yl]-6,7-dihydro-2H-pyrano[3,4-c]pyrrole-4-one 77b is used as a starting material in the same manner as described in the third step of Example 77 of the present invention. Reaction of N,N-diethyl-1,2-ethanediamine to give the title compound {4-(2-hydroxyethyl)-1~[4-(1-phenyl-ethylamino)-quinazole Phenyl-6-yl]-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-decylamine 79 (5 mg, yellow solid), yield: 26%. MS m/z (ESI): 501 [M+1] ❹1HNMR (400 MHz, DMS0-c?e): d 8.82 (s, 1H), 8.75 (d, 1H, J = 7.2), 8.41 (m, 3H), 8. 03(d, 1H, J=8.8), 7. 78(d, 1H, J=8.8), 7. 50(m, 3H), 7. 32(t, 2fl), 7.21(t , 1H), 5. 64(m, .1H), 4. 76(s, 1H), 3.64(t, 2H), 3. 58(m, 2H), 3. 13(m, 6H), 2.91( t, 2H), 1.66 (d, 3H, J = 7.2), 1. 24 (t, 6H) Example 80 "3-chloro-4-(3-fluorobenzyloxy)-stupyl 1-"643_{ "(:1>1:::;^-Six 氤φ-1 into wood 6*-嗟sal-4-methyl)-Amino 1-A sputum is also p-spotted 4-yl 1-amine

重複本發明實施例5第一步至第三少所述的實驗步驟，不同的是以實施例5第二步所得的化合物1一丨4-[3 一氯 -4-(3-氟-苄氧基）-苯胺基]-喹唑啉-6_基卜1H -11比11 各甲 94389 179 201016683 酸1 5c作原料，按照本發明實施例$第三夕戶斤述的相同方式使得該原料與C-(l，1-二側氧基-六氫-1又*6*-噻喃〜4-基）-甲胺的反應，得到標題化合物[3_氯_4-(3-氟苄氡基）一苯基]-[6-(3-{[(1，1-二氧-六氫-1 λ *6*-雀喃甲基）-胺基]-甲基}-吡咯-1-基）-喹唑啉-4-基]-胺80(53 mg，黃色固體），產率40. 7%。 MS m/z (ESI) ： 621 [M+l] !HNMR (400MHz, dUSO-de)： δ 9. 85(s, 1H), 8· 62(s, 1H) 8.57(s, 1H), 8. 12(dd, 1H, J=8. 8), 8. 04(d, 1H, j=2 4) ❹ 7.86(d, 1H，J=8.8)，7.77(dd，1H，J=8.8)，7. 54(s，2H) 7.47(q，1H)’ 7.32(m，3H)，7.19(t，1H)’ 6.39(s，1H) 5.27(s，2H)，3.71(s，2H)，3.08(m，4H)，2.58(m，2H) .2.11(m, 2H), 1.80(m, 1H), 1.62(m, 2H) 實施例81 1 -「4-(3-氯-4-氟笨胺基）_啥唾被-6-某"|_4The experimental procedure of the first step to the third less invention of Example 5 of the present invention is repeated, except that the compound obtained in the second step of Example 5 is mono- 4-[3-chloro-4-(3-fluoro-benzyl) Oxy)-anilino]-quinazoline-6-yl b 1H -11 to 11 each A 94389 179 201016683 acid 1 5c as a starting material, in the same manner as the third embodiment of the present invention makes the raw material Reaction with C-(l,1-di-oxy-hexahydro-1-*6*-thiopyran-4-yl)-methylamine gave the title compound [3_chloro- 4-(3-fluorobenzyl) Indenyl)-phenyl]-[6-(3-{[(1,1-dioxo-hexahydro-1 λ *6*-flanmethyl)-amino]-methyl}-pyrrole-1 - ))-quinazolin-4-yl]-amine 80 (53 mg, yellow solid), yield 40.7%. MS m/z (ESI): 621 [M+l].HNMR (400MHz, dUSO-de): δ 9. 85(s, 1H), 8·62(s, 1H) 8.57(s, 1H), 8 12(dd, 1H, J=8. 8), 8. 04(d, 1H, j=2 4) ❹ 7.86(d, 1H, J=8.8), 7.77(dd,1H,J=8.8), 7. 54(s,2H) 7.47(q,1H)' 7.32(m,3H),7.19(t,1H)' 6.39(s,1H) 5.27(s,2H),3.71(s,2H),3.08 (m, 4H), 2.58 (m, 2H) 2.11 (m, 2H), 1.80 (m, 1H), 1.62 (m, 2H) Example 81 1 - "4-(3-chloro-4-fluoro] Amino)_啥啥被-6-某"|_4

-1H-吡咯-3‘甲酸-C2-吡咯烷-卜乙基）—醯胺-1H-pyrrole-3 'formic acid-C2-pyrrolidine-ethyl}-decylamine

94389 180 201016683 第一步 2-[4-(3-氯-4-氟-苯胺基）-喹唑啉_6_基]_6,7_二氫_2{1一 π比喃[3, 4-(：]°比嘻-4-_ 在100 mL茄形瓶中，依次加入（3_氯_4 一氟苯基）_(6 一碘-喹唑啉-4-基）-胺 lg(l〇〇mg，0.25mm〇l)，6, 7_二氫_2H_ 吡喃并[3,4-c]吼嘻 + 酮 i〇b(44.6 mg，〇·33 _υ，碟酸鉀（159· 2 mg，0. 75 mmol)，碘化亞銅（57· lmg，〇. 3 麵〇1) 溶解於2mLN，N-二甲基甲醯胺中，攪拌下滴加N，N，一二甲基-1，2-乙二胺（26. 3 mg’ 0. 3 mmol)，加熱反應液到 7〇t：，攪拌過夜。將反應液倒入40mL冰水中，有白色固體析出，抽濾，得到的固體用300 mL曱醇洗滌，固體在真空下乾燥，得到本標題產物2-[4-(3-氯-4-氣-苯胺基唑: • -6-基]-6,7-二氫-2H-吡喃[3,4-c]吡咯酮 81a(1〇22 .S，黃色固體）’產率·100%。 MS m/z (ESI) : 409 [M+1] 第二步 © ^[4-(3-氯-4-氟苯胺基）-喹唑啉基卜4_(2_羥基—乙基〉 -1H-吡咯-3-甲酸一（2_吡咯烷_卜乙基）_醯胺土將2 [4 (3-氯-4-氣-本胺基）—喧嗤琳_6_基]_6,7_二氫-2H-吨喃[3,4-c>比嘻-4, 81a⑴〇 mg，〇 25 _υ —口 2-吡咯烷一卜基一乙胺（〇 6niL，〇 25龍〇1)加入至ι〇汕东形瓶中’混合物加熱至9(rc，授掉過夜，反應完畢。反應液在減壓下濃縮，得到的殘留物用乙酸乙醋溶解後，再裒己烷有大量白色固體析出，過濾，得到的固體用 94389 181 201016683 少量甲醇溶解，用TLC板分離純化，得到黃色固體，真空乾燥得到標題產物1-[4-(3-氯-4-氟苯胺基）-喹唑啉一6_ 基]-4-(2-羥基-乙基）-1Η-吡咯-3-甲酸-(2-吡咯烷-1-乙基）-醯胺81(25 mg，黃色固體），產率：31.87%。 MS m/z (ESI) ： 524 [M+l] !HNMR (400MHz, DMS0-c/6): δ 10.24(s, 1H), 8. 97(s, 1H), 8.64(s, 1H), 8.56(s, 1H), 8. 35(m, 2H), 8. 15(d, 1H, J=8.8), 8.06(m, 1H), 7. 92(d, 1H, J=9.2), 7. 56(s, 1H), ^7.47(t, 1H), 4.73(s, 1H), 3.71(t, 2H), 3. 63(q, 2H), ®3.43(m, 2H), 2.91(t, 2H), 2. 50(m, 4H), 1.85(m, 4H) 實施例82 i (2 經一甲 u_(6一甲基比啶一氣某 • 基」-1H-吡咯-3-1麼-(3-嗎嗷_払呙I、 -醯胺94389 180 201016683 First step 2-[4-(3-chloro-4-fluoro-anilino)-quinazoline-6-yl]_6,7-dihydro-2{1-π-pyran[3, 4 -(:]° 嘻-4-_ In a 100 mL eggplant bottle, (3_chloro-4-tetrafluorophenyl)_(6-iodo-quinazolin-4-yl)-amine lg ( L〇〇mg, 0.25mm〇l),6,7_dihydro-2H_pyrano[3,4-c]indole+ketone i〇b (44.6 mg, 〇·33 υ, potassium silicate (159) · 2 mg, 0.75 mmol), cuprous iodide (57·lmg, 〇. 3 〇1) dissolved in 2mL of N,N-dimethylformamide, and added N, N, one or two with stirring Methyl-1,2-ethanediamine (26.3 mg <0.3 mmol), the reaction mixture was heated to 7 〇t:, and stirred overnight. The reaction solution was poured into 40 mL of ice water, and a white solid was precipitated. The obtained solid was washed with 300 mL of decyl alcohol, and the solid was dried under vacuo to give the title product 2-[4-(3-chloro-4- s-anilinazole: -6-yl)-6,7- Dihydro-2H-pyrano[3,4-c]pyrrolidone 81a (1〇22.S, yellow solid), yield, 100%. MS m/z (ESI): 409 [M+1] Step © ^[4-(3-Chloro-4-fluoroanilino)-quinazolinyl b 4_(2-hydroxy-ethyl)-1H-pyrrole-3-carboxylic acid one (2_ 1 [4 (3-chloro-4-gas-amino-amino)-喧嗤琳_6_yl]_6,7-dihydro-2H-tonan [3,4] -c> 嘻-4, 81a(1)〇mg, 〇25 _υ-mouth 2-pyrrolidine-p-ethylamine (〇6niL, 〇25龙〇1) is added to the 〇汕〇汕东形瓶' mixture heated to 9 (rc, the reaction was completed overnight, the reaction was completed. The reaction mixture was concentrated under reduced pressure, and the obtained residue was dissolved in ethyl acetate, and then a large amount of white solid was precipitated from hexane, and filtered, and the obtained solid was used with a small amount of 94389 181 201016683 The residue was purified by EtOAc (EtOAc) elute Ethyl)-1Η-pyrrole-3-carboxylic acid-(2-pyrrolidin-1-ethyl)-decylamine 81 (25 mg, yellow solid), yield: 31.87%. MS m/z (ESI): 524 [M+l] !HNMR (400MHz, DMS0-c/6): δ 10.24(s, 1H), 8. 97(s, 1H), 8.64(s, 1H), 8.56(s, 1H), 8. 35(m, 2H), 8. 15(d, 1H, J=8.8), 8.06(m, 1H), 7. 92(d, 1H, J=9.2), 7. 56(s, 1H), ^ 7.47(t, 1H), 4.73(s, 1H), 3.71(t, 2H), 3. 63(q, 2H), ®3.43(m, 2H ), 2.91(t, 2H), 2. 50(m, 4H), 1.85(m, 4H) Example 82 i (2 via a methyl i-(6-methyl-pyridinyl-1)-H-pyrrole -3-1么-(3-?嗷_払呙I, - guanamine

82 ^複本發明實施例66第-步至第三步的實驗步驟，可同的是二第二步所得的化合物將2-{4令f基+ (6_，基比疋側氧基）一苯胺基]-喹唑啉-6-基}-6, 7-二童并[3’ 4~C] Π比洛一4一嗣’作原料，按照本發明拿脸Μ θ =步所述的相同方式使得該原料與3—嗎啉-4 —这 ' ‘、、，得到標題化合物4-(2-羥乙基）_1_{4_[3_甲邊 94389 182 201016683 -4-(6 -曱基〇比°定-3-氧基）-苯胺基]-噎唾淋_6-基}-1[|-1»比嘻-3 -甲酸-(3-嗎淋-4-丙基）-醯胺82(20 mg，黃色固體），產率：8. 6% 〇 MS m/z (ESI) ： 621 [M+l] !HNMR (400MHz, DMSO-d〇： <5 9. 87(s, 1H), 8. 69(s iH) 8.58(s, 1H), 8.19(s, 1H), 8. 10(d, 1H, J=8. 8), 8 〇〇(lI1 2H), 7. 91(d, 1H, 1=8.8), 7. 78(s, 1H), 7. 72(d 1H J=8.8)，7. 42(s，1H)，7. 25(m，2H)，7. 〇〇(d, iH, J=8 8)82 ^ The experimental steps of the first step to the third step of the inventive example 66, the same as the compound obtained in the second step, the 2-{4 order f group + (6_, carbitol oxime) aniline ]]-quinazoline-6-yl}-6, 7-two tong[3' 4~C] Π 洛一 4 4 4 4 作作作作按照按照按照按照按照按照按照按照 θ θ θ θ In a manner such that the starting material is combined with 3-morpholine-4, this gives the title compound 4-(2-hydroxyethyl)_1_{4_[3_甲边94389 182 201016683 -4-(6 -曱基〇 °定定-3-oxy)-anilino]-噎噎 _6-yl}-1[|-1» than 嘻-3-formic acid-(3-hept-4-propyl)-guanamine 82 (20 mg, yellow solid), Yield: 8.6% 〇MS m/z (ESI): 621 [M+l] !HNMR (400MHz, DMSO-d〇: <5 9. 87(s, 1H), 8. 69(s iH) 8.58(s, 1H), 8.19(s, 1H), 8. 10(d, 1H, J=8. 8), 8 〇〇(lI1 2H), 7. 91 (d, 1H, 1=8.8), 7. 78(s, 1H), 7. 72(d 1H J=8.8), 7. 42(s,1H), 7. 25(m,2H), 7. 〇〇(d, iH, J=8 8)

4. 84(t，1H)，3.58-3.66(m，8H)，2. 89(t，2H) 2 45( ® 3H)，2. 36(s，6H)，2. 24(s，3H)，2. 14(t，2H) S 實施例834. 84(t,1H), 3.58-3.66(m,8H), 2.89(t,2H) 2 45( ® 3H), 2. 36(s,6H), 2. 24(s,3H) , 2. 14(t, 2H) S Example 83

4-(2-羥乙某）-1-U-「3-甲基-4-(6-兮苯胺基1-喹唑啉-6-基卜1H-吡咯-3-甲 -醯胺4-(2-hydroxyethyl)-1-U-"3-methyl-4-(6-indoleanilide-1-quinazolin-6-ylbu-1H-pyrrole-3-methyl-decylamine

重複本發明實施例66第一步至第三步的實同的是以第二步所得的化合物將2〜{4-[3—曱美步驟’不基_吡啶-3-侧氧基）-苯胺基]-喹唑啉〜基4~(6〜甲 _2H-°比喃并[3,4-c]吡咯-4-酮66b作原料，如，7 —氫施例66第三步所述的相同方式使得該原料虚难明實 -乙胺的反應，得到標題化合物4_(2_羥 4基 0暴）〜卜{4〜[3〜甲 94389 183 201016683 基_4-(6-曱基〇比唆-3_氧基）-苯胺基]-嗜0圭琳、g 〇比洛-3_曱.酸-(2-嗎琳-4-乙基）-酿胺83(1q 體），產率：5. 4%。基}，1H-黃色固 MS m/z (ESI) ： 608 [M+l] ^NMR (400MHz, DMSO-dO： ά 9. 85(s, 1H), 8 Rd ，·b6(s 8.58(s，1H)，8.19(s，1H)，8.09(d，1H，j=9.2) 1H)，7.91(m，2H)，7.77(s，1H)，7.72U，1H’ 7.41(s，1H)，7.25(m，2H)，7.00(d，1H，8)’ 1H), 3. 58-3. 66(m, 8H), 2. 90(t, 2H), ’ 1H), •〇〇(s, "9.2), •82(t, 〇 2.24(s, 3H) 實施例84 4-(2-羥乙基）-1-{4-「3-甲基-4-(6 .45 (in， 9H), 乙苯胺基]-喧°坐嘛-6-基}-1Η-°比鳴~-3-甲西^^ 某醯胺Repeating the first step to the third step of the embodiment 66 of the present invention, the compound obtained in the second step is 2~{4-[3 - comparable to the step 'nonyl-pyridin-3-yloxy)- Anilino]-quinazoline~yl 4~(6~A_2H-° pyrano[3,4-c]pyrrol-4-one 66b as a starting material, eg, 7-hydrogen, example 66, third step In the same manner as described, the reaction of the starting material is simplistic-ethylamine, and the title compound 4_(2_hydroxy 4 group 0 violent)~b{4~[3~甲94389 183 201016683 _4-(6-曱) 〇〇唆 _ _ _ _ _ _ _ _ _ _ 圭圭圭圭圭圭圭圭圭圭圭圭圭圭圭酸酸酸酸酸酸酸酸酸酸酸酸酸酸酸酸酸酸酸, yield: 5.4%., NMR, m.p. Rd , · b6 (s 8.58 (s, 1H), 8.19 (s, 1H), 8.09 (d, 1H, j = 9.2) 1H), 7.91 (m, 2H), 7.77 (s, 1H), 7.72 U, 1H' 7.41(s,1H), 7.25(m,2H), 7.00(d,1H,8)' 1H), 3. 58-3. 66(m, 8H), 2. 90(t, 2H), ' 1H), •〇〇(s, "9.2), •82(t, 〇2.24(s, 3H) Example 84 4-(2-Hydroxyethyl)-1-{4-"3-methyl -4-(6 .45 (in, 9H), ethylanilino] -喧°Sit 6-6-base}-1Η-°比鸣~-3-甲西^^ A certain amine

，複本發明實施例66第-步至第三步的實驗步驟，不同的是以第二步所得的化合物將2-{4-[3-甲基一4_(6_甲基—吡啶_3_氧）~苯胺基]-喹唑啉_6-基}-6,7-1氫-2H—比喃并[3, 4-c]«*比咯-4-酮66b作原料，按照本發明實施例66 第三步所述的相同方式使得該原料與N，N-二乙基-1，2-乙二胺的反應’得到標題化合物4-(2-羥乙基）-i-{4-[3-曱 184 94389 201016683 基-4-(6-曱基吡啶-3-氧基>-苯胺基]-喹唑啉-6-基}-111-吡咯-3-曱酸-(2-乙胺基乙基）-醢胺84(36 mg，黃色固體），產率：15%。 MS m/z (ESI) ： 592 [M-l] !HNMR (400MHz, DMS0-c?6): 5 9. 98(s, 1H), 8.81(s, 1H), 8.58(s, 1H), 8.09-8.19(m, 4H), 7.78-7.91(m, 3H), 7.48(s, 1H), 7.24(s, 2H), 6. 99(d, 1H, J=8. 0), 4. 79(s, 1H), 3.65(t, 2H), 3.40(t, 2H), 2. 74-2. 90 (m, 8H), 2.45(s, 3H), 2.23(s, 3H), 1. 08(t, 6H) ®實施例85 13-氣-4-(3-氟苄氧基）-笨基]-丨6-「1-Γ2-甲氧基乙基） -11!-11比口各-3-基1-哇11>坐嘛-4_基}-胺The experimental procedure of the first step to the third step of the embodiment 66 of the invention is repeated, except that the compound obtained in the second step is 2-{4-[3-methyl-4_(6-methyl-pyridine_3_) Oxygen)-anilino]-quinazoline-6-yl}-6,7-1-hydrogen-2H-pyrano[3,4-c]«*pyrol-4-one 66b as a starting material, according to the invention Example 66 The reaction of the starting material with N,N-diethyl-1,2-ethanediamine was carried out in the same manner as described in the third step to give the title compound 4-(2-hydroxyethyl)-i-{4. -[3-曱184 94389 201016683 -4-(6-decylpyridin-3-oxy)-anilino]-quinazolin-6-yl}-111-pyrrole-3-decanoic acid-(2 -ethylaminoethyl)-decylamine 84 (36 mg, mp. 9. 98(s, 1H), 8.81(s, 1H), 8.58(s, 1H), 8.09-8.19(m, 4H), 7.78-7.91(m, 3H), 7.48(s, 1H), 7.24( s, 2H), 6. 99(d, 1H, J=8. 0), 4. 79(s, 1H), 3.65(t, 2H), 3.40(t, 2H), 2. 74-2. 90 (m, 8H), 2.45(s, 3H), 2.23(s, 3H), 1. 08(t, 6H) ® Example 85 13-Gas-4-(3-fluorobenzyloxy)-styl] -丨6-"1-Γ2-methoxyethyl) -11!-11 than each mouth -3- group 1-wow 11> sit well-4_ } - amine

重複本發明實施51所述的實驗步驟，不同的是以實施 ❾例42所得的化合物[3-氯-4-〇比咬-2-甲氧基）_苯基]_(6一吡咯-1-基-喹唑啉-4-基）-胺42作為原料，按照實施例51 所述的方式’進行該原料與1-氣-2-甲氧基乙烷的反應，得到本標題產物[3-氯-4-(3-氟苄氧基）一苯基]_{6_[1_(2一甲氧基乙基）-1Η-吡咯-3-基]-喹唑啉一4 一基卜胺85 Q 〇〇 mg，黃色固體），產率：20%。 MS m/z (ESI) ： 503[M+1] !HNMR (400MHz, DMSO-d6)： ^ 9. 87(s, 1H), 8 65(s, 1H), 94389 185 201016683 8.49(3, 1H), 8.07(s, 1H), 8. 04(d, lHj J=8. 8), 7. 80(d, 1H), 7. 69(d, 1H, J=8.8), 7.48(m, 2H), 7.31(m, 3H), 7. 18(t，1H), 6.89(t，1H)，6_70(s，1H)，5.27(s，2H)， 4.1〇(t, 2H), 3.66(t, 2H), 3.28(s, 3H) 實施例86 基]--嚙啉 _4_乙基）二111-°比洛-3-基}-啥峰啦_4_基丨_胺The experimental procedure described in Example 51 of the present invention was repeated, except that the compound obtained in Example 42 was subjected to the compound [3-chloro-4-indole ratio 2-methoxy)-phenyl]-(6-pyrrole-1). -Base-quinazolin-4-yl)-amine 42 as a starting material, the reaction of the starting material with 1- gas-2-methoxyethane was carried out in the manner described in Example 51 to give the title product. -Chloro-4-(3-fluorobenzyloxy)-phenyl]_{6_[1_(2-methoxyethyl)-1Η-pyrrol-3-yl]-quinazoline-4 ethenylamine 85 Q 〇〇mg, yellow solid), yield: 20%. MS m/z (ESI): 503 [M+1] "HNMR (400 MHz, DMSO-d6): </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; ), 8.07(s, 1H), 8. 04(d, lHj J=8. 8), 7. 80(d, 1H), 7. 69(d, 1H, J=8.8), 7.48(m, 2H ), 7.31(m, 3H), 7. 18(t,1H), 6.89(t,1H),6_70(s,1H), 5.27(s,2H), 4.1〇(t, 2H), 3.66(t , 2H), 3.28(s, 3H) Example 86, hydrazinyl-4-yl}

86 重複本發明實施51所述的實驗步驟，不同的是以實施例42所知的化合物[3-氯一4-（σ比咬一甲氧盖裳美1一一吡咯-卜基―喹唑啉_4_基）_胺42作為原料，按照實施例Η 所述的方式，進行該原料與氯乙基）_嗎啉鹽酸鹽的反應，得到本標題產物[3-氯-4-(3-氟苄氧基）_苯基]_{6一 [1-(2-嗎琳-4-乙基各-3-基]-啥唾琳一4-基卜胺（6 mg，黃色固體）86，產率：7.2°/。。 MS m/z (ESI) ： 559 [M+l] 7-92(d, 1H), 7.23(m，2H), 6. 52(m，1H)， 2.75(t, 2H), !HNMR (400MHz, CDC13): (5 8. 70(s, 1H), 7.83(m, 3H), 7.54(m, 2H), 7. 34(m, 1H), 7. 09(s, 1H), 6.99(m, 2H), 6. 77(m, 1H), 5.14(s, 2H), 4. 03(t, 2H), 3. 71(t, 4H), 2.49(t, 4H) 實施例87 94389 186 201016683 — 笨胺篡 1-啐 ) HLzlzi^(2-嗎一86 Repeat the experimental procedure described in Example 51 of the present invention, except that the compound is known in Example 42 [3-chloro-4-(σ ratio bite one methoxy cape shangmei 1-1 pyrazole-buji-quinazoline) The title compound [3-chloro-4-() is obtained by reacting the starting material with chloroethyl)-morpholine hydrochloride in the same manners as described in Example. 3-fluorobenzyloxy)-phenyl]_{6-[1-(2-morphin-4-ethyl-3-yl)-indole- 4-indolyl (6 mg, yellow solid 86, Yield: 7.2 ° /. MS m / z (ESI): 559 [M+l] 7-92 (d, 1H), 7.23 (m, 2H), 6. 52 (m, 1H), 2.75(t, 2H), !HNMR (400MHz, CDC13): (5 8. 70(s, 1H), 7.83(m, 3H), 7.54(m, 2H), 7. 34(m, 1H), 7 . 09(s, 1H), 6.99(m, 2H), 6. 77(m, 1H), 5.14(s, 2H), 4. 03(t, 2H), 3. 71(t, 4H), 2.49 (t, 4H) Example 87 94389 186 201016683 — stupid amine 篡 1-啐) HLzlzi^(2-?

〇/ 重複本發明實施例72第一步至第二步的〇同的是以實施例72第-步所得的化合物5、^步驟’不 (3-氟苄氧基）-苯胺基]一啥唾琳_6_基卜iH—吨氯4〜 72a作為原料，按照實施例72第二步所述的方弋.2〜甲酸 •原料與2-嗎啉-4-基-乙胺的反應，得到本標題1物進行該 [3-氣-4 -（3-氟苄氧基）-苯胺基]-喹唑啉_6基丨邝5〜{4〜 -2-曱酸-(2-嗎啉-4-乙基）-醯胺87(20邮，么▲ 曰色固ft、產率：33%。瑕）， φ MS m/z (ESI) ： 601 [M+l] !HNMR (400MHz, DUSO-de): (5 11.85(s, 1H) q Ql^ ’ j(s，im 8.64(s, 1H), 8.56(s, 1H), 8. 04(s, 1H), 7 Qo, Λ〇/ Repeating the first step to the second step of Example 72 of the present invention is the same as the compound obtained in the first step of Example 72, and the step 'N-(3-fluorobenzyloxy)-anilino)唾琳_6_基卜iH-ton of chlorine 4~72a as a raw material, according to the reaction of the square 弋.2~carboxylic acid• raw material and 2-morpholin-4-yl-ethylamine described in the second step of Example 72, Obtaining the title 1 to carry out the [3- gas-4-(3-fluorobenzyloxy)-anilino]-quinazoline-6-indole-5~{4~-2-decanoic acid-(2-? Porphyrin-4-ethyl)-decylamine 87 (20 mail, ▲ ▲ color solid ft, yield: 33%. 瑕), φ MS m/z (ESI): 601 [M+l] !HNMR (400MHz , DUSO-de): (5 11.85(s, 1H) q Ql^ ' j(s,im 8.64(s, 1H), 8.56(s, 1H), 8. 04(s, 1H), 7 Qo, Λ

y3(d, 1H J=8.4), 7. 78(m, 2H), 7. 47(q, 1H), 7. 30(m ’ ，Η)，7· 十 1H)，7. 06(s，1H)，6. 98(s，1H)，6.36(s，1H) 5 2H)，3.26(t，2H)，3.20(s，4H)，2.29(t，2H、 n’26(S’ 、 λ 2.2l(s 4H) 、s，實施例88 94389 187 201016683 2-(1 -丨4-..[lz氧二(吡啶一2_甲氣基）_菜胺基]_喹唑呲基}-4-嗎並二基-Iff-吡咯-3-篡Va醉Y3(d, 1H J=8.4), 7. 78(m, 2H), 7. 47(q, 1H), 7. 30(m ' , Η), 7·10 1H), 7. 06(s, 1H), 6.98 (s, 1H), 6.36 (s, 1H) 5 2H), 3.26 (t, 2H), 3.20 (s, 4H), 2.29 (t, 2H, n'26 (S', λ 2.2l(s 4H), s, Example 88 94389 187 201016683 2-(1 -丨4-..[lz Oxygen (Pyridin-2-yl)]-anilinyl]-quinazoline} 4-?-diyl-Iff-pyrrole-3-篡Va drunk

重複本發明實施例61第一步所述的實驗步驟，不同的是以實施例58所得的化合物1-{4-[3-氯-4-0比咬~2-甲氧基）-苯胺基]-喹唑啉-6-基}-4--4-(2-羥基）-1Η-吡哈-3-基]-嗎淋-4-甲酮58作原料，按照本發明實施例61第一 ®步所述的相同方式使得該原料與氫化鋁鋰反應，得到標題化合物2-(1-{4-[3-氯-4-(吡啶-2-曱氧基）-苯胺基]一啥〇坐琳-6-基}-4-嗎琳-4-曱基-1Η-°比洛-3-基）-乙醇88(3〇 .mg，棕色固體），產率：44%。 MS m/z (ESI) ： 556 [M+l] !HNMR (400MHz, DMSO-dO： (5 9.82(s, 1H), 8.61(d, 1H, J=4. 4), 8.54(s, 2H), 8. ll(d, 1H, J=8. 8), 8. 02(s, 1H), φ7. 89(t, 1H), 7. 83(d, 1H, J=8. 8), 7. 74(d, 1H, J=8. 8), 7.60(d, 1H, J=7. 6), 7.44(s, 1H), 7. 38(m, 2H), 7. 31(d, 1H, J=8.8), 5.31(s, 2H), 3. 63(t, 2H), 3. 58(s, 4H), 3.36Cs, 2H), 2.68(t, 3H), 2.42 (s, 4H) 實施例89 {4-(2-羥乙基）-1-「4-Π-苳已胺基）_噎°坐U-基]-1H-吡洛-3-基鳴甲_ 188 94389 201016683The experimental procedure described in the first step of Example 61 of the present invention was repeated, except that the compound obtained in Example 58 was 1-{4-[3-chloro-4-0-bito~2-methoxy)-anilinoyl. ]-quinazolin-6-yl}-4--4-(2-hydroxy)-1Η-pyha-3-yl]-nor--4-ketone 58 as a starting material, according to Example 61 of the present invention The starting material is reacted with lithium aluminum hydride in the same manner as described in the Step to give the title compound 2-(1-{4-[3-chloro-4-(pyridin-2-yloxy)-anilinyl]. 〇琳 -6-6-yl}-4-Merin-4-mercapto-1 Η-°Bilo-3-yl)-ethanol 88 (3 〇. mg, brown solid), yield: 44%. MS m/z (ESI): 556 [M+l].HNMR (400 MHz, DMSO-dO: (5 9.82 (s, 1H), 8.61 (d, 1H, J=4. 4), 8.54 (s, 2H) ), 8. ll(d, 1H, J=8. 8), 8. 02(s, 1H), φ7. 89(t, 1H), 7. 83(d, 1H, J=8. 8), 7. 74(d, 1H, J=8. 8), 7.60(d, 1H, J=7.6), 7.44(s, 1H), 7. 38(m, 2H), 7. 31(d, 1H, J=8.8), 5.31(s, 2H), 3. 63(t, 2H), 3. 58(s, 4H), 3.36Cs, 2H), 2.68(t, 3H), 2.42 (s, 4H Example 89 {4-(2-Hydroxyethyl)-1-"4-indolyl-fluorenylamino)_噎°Suit-U-yl]-1H-pyro-3-yl-sounding _ 188 94389 201016683

重複本發明實施例77第一步至第三步所述的實驗步驟’不同的是以實施例77所得的化合物2-[4-（ 1_本乙胺基）-喹唑淋_6-基]-6, 7-二氫-2H-吡喃并[3, 4-c] °比咯-4-酮77b作原料，按照本發明實施例77第三步戶斤述的相同方式使得該原料與嗎淋的反應，得到標題化合物{4-(2-羥乙基）_1-[4-(1-苯乙胺基）-喧唾琳_6__基]比咯_3-基} ® -嗎淋-4-曱酮89(110 mg ’黃色固體），產率：30%。 MS m/z (ESI) ： 472[M+1] 'HNMR (400MHz, DMS0- ¢/0: δ 8. 57(s, 1H), 8. 51(d, 1H, .J=7. 6), 8.40(s, 1H), 8. 08(d, 1H, J=8.4), 7. 77(d, 1H, J=8. 8), 7. 67(s, 1H), 7. 45(m, 3H), 7. 33(t, 2H), 7. 23(t, 1H), 5.64(m, 1H), 4. 70(t, 1H), 3. 60(s, l〇H), 2. 69(t, 2H), 1.63(d, 3H, J=6.8) ❹實施例90 {4-(2-羥乙基）-卜「4-(1-苯乙胺甚V崦地1Π ^ 路基丨-（4-甲基-a底啡~~1-基甲酮The experimental procedure described in the first step to the third step of Example 77 of the present invention was repeated. The difference is the compound 2-[4-(1-aminoethyl)-quinazoline-6-based obtained in Example 77. -6,7-dihydro-2H-pyrano[3,4-c] ° than keto-4-one 77b as a starting material, in the same manner as in the third step of Example 77 of the present invention The reaction with praline gives the title compound {4-(2-hydroxyethyl)_1-[4-(1-phenylethylamino)- 喧琳 _ _ _ _ _ _ _ _ _ _ _ _ _ _吗曱曱 ketone 89 (110 mg 'yellow solid), yield: 30%. MS m/z (ESI): 472 [M+1] "HNMR (400 MHz, DMS0- ¢/0: δ 8. 57 (s, 1H), 8. 51 (d, 1H, .J=7. 6) , 8.40(s, 1H), 8. 08(d, 1H, J=8.4), 7. 77(d, 1H, J=8. 8), 7. 67(s, 1H), 7. 45(m , 3H), 7. 33(t, 2H), 7. 23(t, 1H), 5.64(m, 1H), 4. 70(t, 1H), 3. 60(s, l〇H), 2 69(t, 2H), 1.63(d, 3H, J=6.8) ❹Example 90 {4-(2-Hydroxyethyl)-b "4-(1-phenylethylamine V 崦 Π 1Π ^ Subgrade丨-(4-methyl-a-bottomin~~1-ketone

重複本發明實施例77第一步至第驟，不同的是以實施例7 7所得的化合冻 94389 189 201016683 0比，黃色固基）-喹唑啉-6-基]-6, 7-二氫-2H-吡喃并[3, 4〜C]B比咯酿I 77b作原料，按照本發明實施例77第三步所述的相方式使得該原料與1-曱基哌畊的反應，得到標題化人同 {4-(2-羥乙基）-1-[4-(1-苯乙胺基）-喹唑啉基卜物咯-3-基}-(4-甲基-哌哄一 1-基）_曱酮9〇(13〇體），產率：34%。 MS m/z (ESI) ： 485[M+1] 'HNMR (400MHz, DMSO- c/6) ： 5 8. 62(s, 1H), 7. 89(s lH) 7.87(d, 1H), 7. 69(dd, 1H, J=8. 8), 7.48(d, 2H), 7 35^ ©2H)，7.28(d，1H)，7. 15(s, 1H), 7.03(s，1H)， 1H)，5.70(m，1H)，3.78(m, 6H)，3.48(s, 1H)，2 80(t 2H)，2.48(t，4H)，2.33(s，3H)，1.73(d，3H，J=6.8)’ 實施例91 ·The first step to the first step of the present invention 77 are repeated, except that the compound obtained by the embodiment 7 7 is 94389 189 201016683 0 ratio, yellow solid) quinazolin-6-yl]-6, 7-di Hydrogen-2H-pyrano[3,4~C]B is used as a raw material for broiling I 77b, and the reaction of the raw material with 1-mercaptopiped is carried out according to the phase mode described in the third step of Example 77 of the present invention. Obtaining the title of human with {4-(2-hydroxyethyl)-1-[4-(1-phenylethylamino)-quinazolinylpyrrol-3-yl}-(4-methyl-piperidin哄 1-yl) ketone 9 〇 (13 〇), yield: 34%. MS m/z (ESI): 495 [M+1] "HNMR (400 MHz, DMSO-c/6): 5 8. 62 (s, 1H), 7. 89 (s lH) 7.87 (d, 1H), 7. 69(dd, 1H, J=8. 8), 7.48(d, 2H), 7 35^ ©2H), 7.28(d,1H), 7.15(s, 1H), 7.03(s,1H) ), 1H), 5.70 (m, 1H), 3.78 (m, 6H), 3.48 (s, 1H), 2 80 (t 2H), 2.48 (t, 4H), 2.33 (s, 3H), 1.73 (d , 3H, J = 6.8) 'Example 91 ·

胺基）二啥g坐琳-6-基1 -4- p麻冷一卜 -1 H-口比洛-3-基}-乙醇Amino) diterpene sylvestre-6-yl 1 -4-p 麻冷一卜 -1 H-mouth bilo-3-yl}-ethanol

91 在25 mL茄形瓶中加入氳化鋁鋰（36啤，〇. 957龍〇1) 3 mL四氫夫南至/jnL下攪拌，逐漸滴加化合物{4-(2- 和 94389 190 201016683 羥乙基）-l-[4-(l-苯乙胺基）-喹唑啉-6-基]-1H-吡咯-3~ 基卜派定-1-甲酮77(150 mg，0.319 mmol)的3 mL四氫u夫喃溶液，溶液中有大量氣泡產生，並有粘稠狀固體產生，反應液呈黃色。將反應液加熱至50°C，攪拌4小時後反應完畢’用冰浴冷卻反應液，慢慢滴加曱醇，反應液呈澄清透明。用減壓柱沖洗，濃縮反應液，得到的固體進一步藉由TLC板分離純化，得到標題產物2-{1-[4~(1_苯乙胺基）-喹唑啉-6-基]-4-哌啶-1-曱基-1H-吡咯-3-基卜乙醇91 (40 mg，黃色固體），產率：27. 5%。 ® MS m/z (ESI) ： 456[M+1] *HNMR (400MHz, DMS0-d6): ^ 8. 79(s, 1H), 8. 75(s, 1H), 8.39(s, 1H), 8.01(d, 1H, J=8.4), 7. 78(d, 2H, J=6. 8), 7.50(m, 3H), 7.31(t, 2H), 7.22(t, 1H), 5. 64(m, 1H), 4.07(s, 2H), 3.67(q, 2H), 3.17(m, 4H), 3.11(t, 2H), 1.74(s, 4H), 1.65(d, 3H, J=6. 8), 1.43(m, 2H) 實施例92 ❹基）一喹唑啉-6一某·μ4—吡晓烷4-甲某 -1Η-°比洛-3-基丨-乙辞 091 Add lithium aluminum telluride (36 beer, 〇. 957 〇 1) to a 25 mL eggplant bottle. Stir under 3 mL of tetrahydrofuran to /jnL, gradually add the compound {4-(2- and 94389 190 201016683) Hydroxyethyl)-l-[4-(l-phenylethylamino)-quinazolin-6-yl]-1H-pyrrole-3~ kipidine-1-enketone 77 (150 mg, 0.319 mmol A 3 mL tetrahydrofuran solution, a large amount of bubbles are generated in the solution, and a viscous solid is produced, and the reaction solution is yellow. The reaction solution was heated to 50 ° C and stirred for 4 hours, and the reaction was completed. The reaction solution was cooled with an ice bath, and decyl alcohol was slowly added dropwise, and the reaction mixture was clear and transparent. The title compound (2-{1-[4~(1-phenylethylamino)-quinazolin-6-yl]- was obtained by chromatography. 4-piperidin-1-yl-1H-pyrrol-3-ylbuethanol 91 (40 mg, yellow solid), yield: 27.5%. ® MS m/z (ESI): 456[M+1] *HNMR (400MHz, DMS0-d6): ^ 8. 79(s, 1H), 8. 75(s, 1H), 8.39(s, 1H) , 8.01(d, 1H, J=8.4), 7. 78(d, 2H, J=6. 8), 7.50(m, 3H), 7.31(t, 2H), 7.22(t, 1H), 5. 64(m, 1H), 4.07(s, 2H), 3.67(q, 2H), 3.17(m, 4H), 3.11(t, 2H), 1.74(s, 4H), 1.65(d, 3H, J= 6. 8), 1.43 (m, 2H) Example 92: mercapto)-quinazoline-6-m-μ4-pyridane 4-methyl-1-pyran-3-yl---

重複本發明貫施例91第一步所述的實驗步驟，不同的是以實施例78所得的化合物{4-(2-羥乙基）_i-[4-(l-苯乙胺基）-喹唑啉-6-基]-1 η-吡咯-3-基}-吡咯烷-1 -曱酮 191 94389 201016683 78作原料，按照本發明實施例90第一步所述的相同方式使得該原料與氫化銘鐘反應，得到標題化合物2~ {[在〜 (1-苯乙胺基）-啥唾琳-6-基]_4-π比u各院-1 -甲基·~ 1 Η-η比落 -3-基}-乙醇92(60 mg，黃色固體），產率：31%。 MS m/z (ESI) · 442 [M+l] ^NMR (400MHz, DMS0- de) ： δ 8. 91(s, 1H), 8. 82(s, Hj) 8. 34(s, 1H), 8.00(dd, 1H, J = 8. 8), 7. 88(s, 1H), 7. 77(d, 1H, J=8.8), 7.51(m, 3H), 7.31(t, 2H), T.21(t, lH)5 5.64(m, 1H), 4. 20(s, 2H), 3. 66(t, 2H), 3. 29(m, 4H), ® 2.74(t, 2H), 1.94(s, 4H), 1.66(d, 3H, 7=6.8) 實施例93 —~~(2 -1½乙基）-l-「4-(l -笨乙胺基）~~τφΡ坐嚇^-6 -基叫、 ' 查-3-甲酸-(2-吡咯烷-1-某-乙基醢胗The experimental procedure described in the first step of Example 91 of the present invention was repeated, except that the compound obtained in Example 78 was {4-(2-hydroxyethyl)-i-[4-(l-phenylethylamino)- Quinazoline-6-yl]-1 η-pyrrol-3-yl}-pyrrolidine-1-anone 191 94389 201016683 78 as a starting material, in the same manner as described in the first step of Example 90 of the present invention The reaction with hydrogenation of the bell gives the title compound 2~ {[in ~(1-phenylethylamino)-啥琳 -6 -6-yl]_4-π than u 院-1 - methyl·~ 1 Η-η L--3-yl}-ethanol 92 (60 mg, yellow solid), yield: 31%. MS m/z (ESI) · 442 [M+l] NMR (400 MHz, DMS0- de) : δ 8. 91 (s, 1H), 8. 82 (s, Hj) 8. 34 (s, 1H) , 8.00 (dd, 1H, J = 8. 8), 7. 88(s, 1H), 7. 77(d, 1H, J=8.8), 7.51(m, 3H), 7.31(t, 2H), T.21(t, lH)5 5.64(m, 1H), 4. 20(s, 2H), 3. 66(t, 2H), 3. 29(m, 4H), ® 2.74(t, 2H) , 1.94(s, 4H), 1.66(d, 3H, 7=6.8) Example 93 —~~(2 -11⁄2 ethyl)-l-“4-(l-muteethylamino)~~τφΡ ^-6 -Based, 'Check-3-carboxylic acid-(2-pyrrolidine-1-one-ethyl hydrazine

重複本發明實施例77第一步至第三步所述的實驗步驟’不同的是以實施例77所得的化合物2-[4-(1-苯乙胺基）-喧唾啉-6-基]-6, 7-二氫-2H-吡喃并[3, 4-c]吡咯-4-同77b作原料’按照本發明實施例77第三步所述的相同方式使得該原料與2-吡咯烷基基-乙胺的反應，得到標題化合物4-(2-羥乙基）-1-[4-(i-苯乙胺基）一喹唑啉-6-基]-1H-吡咯-3-甲酸-(2-吡咯烷—^―基―乙基醯胺g3(5〇 192 94389 201016683 mg，黃色固體），產率：32%。 MS m/z (ESI) ： 490[M+1] 8-4〇Cm, 3H), 7. 48(m，3H), 4-75(s, 1H), 2*9〇(t, 2H), ]HNMR (400MHz, DMS0- : δ 8.81(m, 2H), 8.04(d, 1H, J=8.8), 7.78((1, 1H, J=8. 8), 7.32(t, 2H), 7. 22(t, 1H), 5. 64(m, 1H), 3.64(t, 2H), 3. 57(q, 2H), 3. 22(m, 6H), 1.93(s, 4H), 1. 65(d, 3H, J=7. 2) 實施例94The experimental procedure described in the first step to the third step of Example 77 of the present invention was repeated. The difference is the compound 2-[4-(1-phenylethylamino)-indenyl-6-yl obtained in Example 77. ]-6,7-Dihydro-2H-pyrano[3,4-c]pyrrole-4-with 77b as starting material 'in the same manner as described in the third step of Example 77 of the present invention, the starting material is 2- Reaction of pyrrolidinyl-ethylamine to give the title compound 4-(2-hydroxyethyl)-1-[4-(i-phenylethylamino)-quinazolin-6-yl]-1H-pyrrole- 3-carboxylic acid-(2-pyrrolidine-yl-ethyl decylamine g3 (5〇192 94389 201016683 mg, yellow solid), yield: 32%. MS m/z (ESI): 490 [M+1 8-4〇Cm, 3H), 7. 48(m,3H), 4-75(s, 1H), 2*9〇(t, 2H), ]HNMR (400MHz, DMS0- : δ 8.81(m) , 2H), 8.04(d, 1H, J=8.8), 7.78((1, 1H, J=8. 8), 7.32(t, 2H), 7. 22(t, 1H), 5. 64(m , 1 (H, 6H), 3. Example 94

2-無乙基-苯 )-啥〇圭 1 -1Η 屮嘻-3-曱酸- (2 -a底咬-1-乙基）-醯脸2-No ethyl-benzene )-啥〇圭 1 -1Η 屮嘻-3-曱-acid - (2 -a bottom bite-1-ethyl)-醯脸

重複本發明實施例77第一步至第三步所述的實驗步驟’不同的是以實施例77所得的化合物2〜[4_(1_苯乙胺级基）-喹唑啉-6-基]-6’ 7-二氫—2H-吡喃并[3,4-c]吡咯-4-酮77b作原料，按照本發明實施例77第三步所述的相同方式使得該原料與2-哌啶基~1__基-乙胺的反應，得到標題化合物4-(2-經乙基）-1-[4~(1_苯乙胺基）一咬《坐1#-6-基]-1H-吡咯-3-甲酸-(2-哌啶乙基）一醯胺94(50 mg，黃色固體），產率：25% 〇 MS m/z (ESI) ： 513[M+1] ^NMR (400MHz, dlSO-de) ： δ 8. 82(s, 1H), 8. 76(d, 1H, 193 94389 201016683 J二6_0)，8.45(m，3H)，8.04(d’ 1H，J = 7.6)，7.79(d，lH J = 8.0)，7. 51(m，3H)，7. 31(t，2H)，7.22(t，1H)，5.64(m 1H), 4.75(s, 1H), 3.64(t, 4H), 3.49(m, 2H), 3. 2〇(t 2H), 2.90(t, 4H), 1.82(m, 4H), 1.66(d, 3H, J=6. 〇) 1.23(m, 2H) ’ 實施例Θ5 4-(2:¾:基笨乙胺基）-喹吔呲-fi-其UitT .. " 一 ' 咯-3-甲酸-(2-甲氳篡λ基）-醯胺The experimental procedure described in the first step to the third step of Example 77 of the present invention was repeated. The difference is the compound 2~[4_(1-phenylethylamine)-quinazoline-6-yl obtained in Example 77. ]-6' 7-Dihydro-2H-pyrano[3,4-c]pyrrol-4-one 77b as a starting material, which is obtained in the same manner as described in the third step of Example 77 of the present invention. Reaction of piperidinyl~1_-yl-ethylamine to give the title compound 4-(2-ethylethyl)-1-[4~(1-phenylethylamino)-biting "Sit 1#-6-yl] -1H-pyrrole-3-carboxylic acid-(2-piperidinylethyl)-indolamine 94 (50 mg, yellow solid), yield: 25% 〇MS m/z (ESI): 513 [M+1] NMR (400MHz, dlSO-de) : δ 8. 82(s, 1H), 8. 76(d, 1H, 193 94389 201016683 J 2 6_0), 8.45 (m, 3H), 8.04 (d' 1H, J = 7.6), 7.79 (d, lH J = 8.0), 7. 51 (m, 3H), 7. 31 (t, 2H), 7.22 (t, 1H), 5.64 (m 1H), 4.75 (s, 1H) , 3.64(t, 4H), 3.49(m, 2H), 3. 2〇(t 2H), 2.90(t, 4H), 1.82(m, 4H), 1.66(d, 3H, J=6. 〇) 1.23(m, 2H) 'Examples Θ5 4-(2:3⁄4: phenylethylamino)-quinoline-fi-its UitT.. "-'----3-carboxylic acid-(2-formamidine Λ-based)-nonylamine

95 重複本發明實施例77第一步至第三步所述的實驗步驟，不同的是以實施例77所得的化合物2-[4-(1-笨己胺基）-喹唑啉-6-基]-6, 7-二氫-2Η-吡喃并[3,4-c]吡咯、4、酮77b作原料’按照本發明實施例77第三步所述的相同方式使得該原料與2-曱氧基乙胺的反應，得到樣題化合物 ❿4-(2-羥乙基）-1-[4-(1-笨乙胺基）-喹唑啉一6_基]-1H-吡咯-3-甲酸-(2-曱氧基乙基）-醯胺95(50 mg，黃色固體），產率：28%。 MS m/z (ESI) ： 460[M+1] 'HNMR (400MHz, DMSO- ： δ 8. 76(d, 1H, J=7. 2), 8.68(s, 1H), 8.44(s, 1H), 8. 09(s, 1H), 8. 02(t, 2H), 7.81(d, 1H, J=8.8), 7.47(d, 2H, J=7. 6), 7.40(s, 1H>, 7.33(t, 2H), 7. 23(t, 1H), 5. 66(m, 1H), 4. 80(s, 1H), 194 94389 201016683 3.64(t, 2H), 3.45(t, 2H), 3.39(t, 2H), 3. 27(s, 3H), 2.89(t, 2H), 1.64(d, 3H, J = 6. 8) 實施例96 4. (2_[~4-(1-笨乙胺基）-喧°坐啦-6-基1-1!1-〇比 f ^^2-嗎啉-4-乙某）-醯胺95 The experimental procedure described in the first step to the third step of Example 77 of the present invention was repeated, except that the compound obtained in Example 77 was 2-[4-(1-stupylamino)-quinazoline-6-. a group of -6,7-dihydro-2-indole-pyrano[3,4-c]pyrrole, 4, ketone 77b as a starting material 'in the same manner as described in the third step of Example 77 of the present invention, the starting material is 2 - a reaction of methoxyethylamine to give the title compound ❿4-(2-hydroxyethyl)-1-[4-(1-othylethylamino)-quinazoline-6-yl]-1H-pyrrole-3 - formic acid-(2-decyloxyethyl)-guanamine 95 (50 mg, yellow solid), yield: 28%. MS m/z (ESI): 460 [M+1] "HNMR (400 MHz, DMSO-: δ 8. 76 (d, 1H, J=7.2), 8.68 (s, 1H), 8.44 (s, 1H) ), 8. 09(s, 1H), 8. 02(t, 2H), 7.81(d, 1H, J=8.8), 7.47(d, 2H, J=7. 6), 7.40(s, 1H> , 7.33(t, 2H), 7. 23(t, 1H), 5. 66(m, 1H), 4. 80(s, 1H), 194 94389 201016683 3.64(t, 2H), 3.45(t, 2H ), 3.39(t, 2H), 3. 27(s, 3H), 2.89(t, 2H), 1.64(d, 3H, J = 6. 8) Example 96 4. (2_[~4-(1) - stupid ethylamine)-喧°Sit-6-based 1-1!1-〇 ratio f ^^2-morpholin-4-ethyl)-guanamine

重複本發明實施例77第一步至第三步所述的實驗步驟’不同的是以實施例77所得的化合物2-[4-0-苯乙胺基）-喹唑啉-6-基]-6, 7-二氫-2H-吡喃并[3, 4-c]e比咯-4-•酮77b作原料’按照本發明實施例77第三梦所述的相同方式使得該原料與的.2-嗎啉、4-基-乙胺反應，得到標題化合物4-(2-羥乙基）-1-[4-(1-苯乙胺基）_喹唑啉-6-基] -1H-吡咯-3-曱酸-(2-嗎啉-4~乙基）_醯胺96(85 mg，黃色 ❺固體），產率·· 42. 5%。 MS m/z (ESI) ： 515[M+1] JHNMR (400MHz, MS0- de)： δ 8.66(m, 2H), 8.41(s, iH)5 8.00(m，3H), 7. 76(d，1H), 7. 47(d, 2H，J=7. 6), 7-39(s， 1H)，7.33(t，2H)，7.19(1;，if})，5.62(瓜，lH)，4. 7〇(s， 1H)，3.64(m，8H)，2.89(t，2H), 2.54(m，6H)，1.64(d， 3H, J=6. 8) 實施例97 195 94389 201016683 卜「4-(i-笨乙胺基）-喹唑啾邊1-3-甲蹲二£3-嗎啉-4-丙基）-醯胺The experimental procedure described in the first step to the third step of Example 77 of the present invention was repeated, except that the compound obtained in Example 77 was 2-[4-0-phenethylamino)-quinazolin-6-yl] -6,7-Dihydro-2H-pyrano[3,4-c]e than pyren-4-one ketone 77b as a starting material 'in the same manner as described in the third dream of Example 77 of the present invention Reaction of 2-morpholine and 4-yl-ethylamine to give the title compound 4-(2-hydroxyethyl)-1-[4-(1-phenylethylamino)-quinazolin-6-yl] -1H-pyrrole-3-decanoic acid-(2-morpholin-4~ethyl)-decylamine 96 (85 mg, yellow yttrium solid), yield 42.5%. MS m/z (ESI): 515 [M+1] MH.sup.sssssssssssssssssssssssssssssss , 1H), 7. 47(d, 2H, J=7. 6), 7-39(s, 1H), 7.33(t, 2H), 7.19(1;, if}), 5.62 (melon, lH) , 4. 7 〇 (s, 1H), 3.64 (m, 8H), 2.89 (t, 2H), 2.54 (m, 6H), 1.64 (d, 3H, J = 6. 8) Example 97 195 94389 201016683卜"4-(i-ethylideneethylamino)-quinazoline 1-3-methyl hydrazine 2 -morpholin-4-propyl)-guanamine

重複本發明實施例77第一步至第三步所述的實驗步驟，不同的是以實施例77所得的化合物2-[4-(1-笨乙/ ❹基）-喹唑啉-6-基]—6,7_二氫—2H_吡喃并[3,4_c]吡咯、= 酮77b作原料，按照本發明實施例77第三步所述的相同方式使得該原料與的2-嗎啉，4-基-丙胺反應，得到標題化合物4-(2-羥乙基）-1-[4-(卜苯乙胺基）_喹唑啉__6_基] .HH-吡咯-3-甲酸-(2-嗎啉-4~丙基）-醯胺97(86 mg，黃色固體），產率：42%。 MS m/z (ESI) ： 529[M+1] 'HNMR (400MHz, DMSO- d〇: ά 8. 88(s, 2H), 8. 39(s, 2H), O 8.12(s, 1H), 8.04(d, 1H, J=8.4), 7.77(d, 1H, J=8. 8), ^•51(m, 3H), 7. 31(t, 2H), 7. 21(t, 1H), 5. 64(m, 1H), 4. 83(s, 1H), 3. 70(m, 6H), 3. 33Cm, 2H), 2.89(m, 6H), 2.54(m, 2H), 1.84(m, 2H), 1.67(d, 3H, J=6. 8) 實施例98 1z!4-(4甲基旅哄-1-曱基一「4_(i 一茉已胺基）—喹唑呲 zl-基哈-3-基丨-乙醇 196 94389 201016683The experimental procedure described in the first step to the third step of Example 77 of the present invention was repeated, except that the compound obtained in Example 77 was 2-[4-(1-stupyl/indenyl)-quinazoline-6-. a group of -6,7-dihydro-2H-pyrano[3,4_c]pyrrole, = ketone 77b as a starting material, in the same manner as described in the third step of Example 77 of the present invention, the starting material is 2-? The title compound 4-(2-hydroxyethyl)-1-[4-(Phenylethylamino)-quinazoline __6-yl].HH-pyrrole-3- Formic acid-(2-morpholin-4~propyl)-decylamine 97 (86 mg, yellow solid), yield: 42%. MS m/z (ESI): 529 [M+1] "HNMR (400 MHz, DMSO- d 〇: ά 8. 88 (s, 2H), 8. 39 (s, 2H), O 8.12 (s, 1H) , 8.04(d, 1H, J=8.4), 7.77(d, 1H, J=8. 8), ^•51(m, 3H), 7. 31(t, 2H), 7. 21(t, 1H ), 5. 64(m, 1H), 4. 83(s, 1H), 3. 70(m, 6H), 3. 33Cm, 2H), 2.89(m, 6H), 2.54(m, 2H), 1.84(m, 2H), 1.67(d, 3H, J=6. 8) Example 98 1z! 4-(4 methyl 哄哄曱一一「「 4 4 4 4 4 4 4 4 Zolazole zl-kiha-3-ylindole-ethanol 196 94389 201016683

重複本發明實施例91第一步所述的實驗步驟，不同的是以實施例90所得的化合物{4-(2-羥乙基）-1-[4-(1-苯乙胺基）-啥0坐淋-6-基]-1H-〇比咯-3-基}· _(4_曱基-旅口井_ 1 __ 基）-曱酮90作原料’按照本發明實施例91第一步所述的相同方式使得該原料與氫化鋁鋰反應，得到標題化合物 2-{4-(4甲基哌哄-1-甲基）— -苯乙胺基）一喹唑啉 -6-基]-1H-吼咯-3-基卜乙醇98(9〇mg，黃色固體），產率： 91%。 MS m/z (ESI) ： 471 [M+l] -JHNMR (400MHz, DMSO-de)： s 8.68(s, 1H), 8. 62(s, 1H), 8. 37(s, 1H), 8. 01(dd, 1H, J=8.8), 7. 73(d, 1H, J=8. 8), 7.47(m, 4H), 7. 32(t, 2H), 7.22(t, 1H), 5. 64(m, 1H), 3.63(t, 2H), 3.52(s, 2H), 2. 85(m, 4H), 2. 67(m, 6H), • 1. 65(d，3H, J=6. 8) 實施例99 「1，4’ ]二座:咬基-1’ -基-「1二j4一「3_氪_4一（吐啶_2_曱氳甚、 -苯胺基]-喹唑啉^-基}-；!^?-羥乙基）~1H-吡咯-3-篡卜The experimental procedure described in the first step of Example 91 of the present invention was repeated, except that the compound obtained in Example 90 was {4-(2-hydroxyethyl)-1-[4-(1-phenylethylamino)-啥0坐淋-6-yl]-1H-indolerol-3-yl}·_(4_曱基-旅口井_ 1 __ base)-fluorenone 90 as a raw material 'according to Example 91 of the present invention The starting material was reacted with lithium aluminum hydride in the same manner as described in one step to give the title compound 2-{4-(4methylpiperazin-1-methyl)-phenylethylamino)-quinazoline-6- -1H-Chloro-3-ylbuethanol 98 (9 mg, yellow solid), yield: 91%. MS m/z (ESI): 471 [M+l] -JHNMR (400MHz, DMSO-de): s 8.68 (s, 1H), 8. 62 (s, 1H), 8. 37 (s, 1H), 8. 01(dd, 1H, J=8.8), 7. 73(d, 1H, J=8. 8), 7.47(m, 4H), 7. 32(t, 2H), 7.22(t, 1H) , 5. 64(m, 1H), 3.63(t, 2H), 3.52(s, 2H), 2. 85(m, 4H), 2. 67(m, 6H), • 1. 65(d,3H , J=6. 8) Example 99 "1,4'] two seats: bite base -1 ' - base - "1 two j4 one" 3_氪_4 one (piperidine_2_曱氲甚, - Anilino]-quinazoline^-yl}-;!^?-hydroxyethyl)~1H-pyrrole-3-indole

94389 197 201016683 重複本發明實施例53第一步所述的實驗步驟，不同的是以實施例47所得的化合物2-{4〜[3_氯_4_(吡啶-2-甲氧基）-苯胺基]-喹唑啉-6-基}-6, 7〜二氫_2H_吡喃[3, 4-c]吡咯-4-詷47作原料，按照本發明實施例53第一步所述的相同方式使得該原料與[1，4，]二哌啶的反應，得到標題化合物[1，4,]二哌啶基-Γ -基-[卜{4_[3_氯_4_(吡啶_2_甲氧基）-苯胺基]-喹唑啉-6-基}-4〜（2—羥乙基）_1H_吡咯_3_ 基]-甲酮99(120 mg，黃色固體），產率：43%。 MS m/z (ESI) ： 667[M41] ® ^NMR (400MHz, DMSO-dO： 10. 2〇(s, 1H)j 8. 90(s, 1H), 8.6Kd，1H，J=4.4)，8.58(S，1H)，8 15(m 2H)， 7 88(m， 4H), 7.60(d, 1H, J=8.0), 7. 55(Sj 1H), 7. 38Ct, 1H), U9(d，1H，： = 8_8)，5.31(s，2H)，4.71(t，1H)，3 6〇(q， • 2HX 3：39(mj 4HX 2.93U, 5H), 2.69(tj 2H)> L82(m> 6H), 1. 69(m, 4H) 實施例100 0 ^喹唑啉 _6_某 Ί ~1Η-吡咯-3-基} - λ94389 197 201016683 The experimental procedure described in the first step of Example 53 of the present invention was repeated, except that the compound obtained in Example 47 was 2-{4~[3_chloro-4-yl(pyridine-2-methoxy)-aniline a quinazoline-6-yl}-6,7-dihydro-2H-pyran[3,4-c]pyrrole-4-indole 47 as a starting material, according to the first step of Example 53 of the present invention The reaction of the starting material with [1,4,]dipiperidine in the same manner gave the title compound [1,4,]dipiperidinyl-indole-yl-[b{4_[3_chloro_4_(pyridine_ 2-(methoxy)-anilino]-quinazolin-6-yl}-4~(2-hydroxyethyl)_1H_pyrrole_3_yl]-methanone 99 (120 mg, yellow solid), yield : 43%. MS m/z (ESI): 667 [M41] NMR (400 MHz, DMSO-dO: 10. 2 〇 (s, 1H)j 8. 90 (s, 1H), 8.6 Kd, 1H, J = 4.4) , 8.58(S,1H),8 15(m 2H), 7 88(m, 4H), 7.60(d, 1H, J=8.0), 7. 55(Sj 1H), 7. 38Ct, 1H), U9 (d,1H,: = 8_8), 5.31(s,2H), 4.71(t,1H),3 6〇(q, • 2HX 3:39(mj 4HX 2.93U, 5H), 2.69(tj 2H)&gt ; L82 (m > 6H), 1. 69 (m, 4H) Example 100 0 ^ quinazoline _6_ Ί ~1Η-pyrrol-3-yl} - λ

100 重複本發明實施例91第一步所述的實驗㈣，不同的是以實施例89所得的化合物{4、（2，乙基）+ [4_(卜苯乙胺基基卜嗎以―曱綱⑽ 94389 198 201016683 作原料，按照本發明實施例91第一步所述的相同方式使得該原料與氫化鋁鋰反應，得到標題化合物{4_嗎啉_4_曱基-l-[4-(l-苯乙胺基）-啥唾琳-6-基；]—1H—吡洛_3_基}一乙醇100(95mg，黃色固體），產率：85%。 MS m/z (ESI) ： 458 [M+l] !HNMR (400MHz, DMSO-c?〇 : δ 8. 79(s, 1H) 8 7〇(s 1H) 8. 41 (s，1H)，8. 01 (d，1H，J=8 · 8 )，7 7 7 ( d i jj J = 8 8 ) 7. 69(s，1H)，7.49(d，3H)’ 7.32(t，2H)，7.22(t，1H)’ 5. 65(m，1H)，3. 97(s，2H)，3. 78(m，. 4fj) 3 66(t 2H), ®3.02(m, 4H), 2,74(ts 2H), 1.65(d, 3H, J=6. 0) 實施例101 l-[4_-(3-氯-4-氟-苯胺基）-喹唑咐二6_某卜絲―。一羥乙基） .-1Η-°比洛-3-甲酸- (2 -甲氧基乙臬100 The experiment (IV) described in the first step of Example 91 of the present invention was repeated, except that the compound obtained in Example 89 was {4, (2, ethyl) + [4_(phenylphenethylamino) (10) 94389 198 201016683 As a starting material, the starting material was reacted with lithium aluminum hydride in the same manner as described in the first step of Example 91 of the present invention to give the title compound {4_morpholine_4_mercapto-l-[4- (l-Phenylethylamino)-indolyl-6-yl;]-1H-pyrrole-3-yl}-ethanol 100 (95 mg, yellow solid), yield: 85%. MS m/z (ESI) ) : 458 [M+l] !HNMR (400MHz, DMSO-c?〇: δ 8. 79(s, 1H) 8 7〇(s 1H) 8. 41 (s,1H), 8. 01 (d, 1H, J=8 · 8 ), 7 7 7 ( di jj J = 8 8 ) 7. 69(s,1H), 7.49(d,3H)' 7.32(t,2H), 7.22(t,1H)' 5. 65(m,1H), 3.97(s,2H), 3.78(m,.4fj) 3 66(t 2H), ®3.02(m, 4H), 2,74(ts 2H), 1.65 (d, 3H, J=6. 0) Example 101 l-[4_-(3-Chloro-4-fluoro-anilino)-quinazolium quinone 6 _ _ _ _ hydroxyethyl). -1Η-°Bilo-3-carboxylic acid-(2-methoxyethyl hydrazine

重複本發明實施例81第一步至第二步所述的實驗步驟，不同的是以實施例81第一步所得的化合物2-[4-(3-氯-4-氟-苯胺基）-喹唑啉-6-基]_6, 7_二氫—2H-吡喃 [3, 4-c]吡咯-4-酮81a作原料，按照本發明實施例81第二步所述的相同方式使得該原料與2_曱氧基乙胺的反應’得到標題化合物1-[4-(3 -氯-4-氟-苯胺基坐嚇· -6-基]-4-(2-羥乙基）-111-吡洛~3~甲酸—（2-甲氧基乙基）-酿胺101(130 mg ’黃色固體）’產率：6〇%。. 199 94389 201016683 MS m/z (ESI) ： 484[M+1] 8.79(s， 8. l〇(d， 7.45(m， 3-4〇(m, 'HNMR (400MHz, DMS0- : δ 10.14(s, 1H), 1H), 8. 25(dd, 1H, J=6. 8), 8. 19(d, 1H, J=2. 〇) 1H, J=9.2), 8. 01(t, 1H), 7. 89-7. 94(m, 2H), 2H), 4.80(s, 1H), 3.67(t, 2H), 3. 46(t, 2H), 2H), 3.29(s, 3H), 2. 90(t, 2H) 實施例102The experimental procedure described in the first step to the second step of Example 81 of the present invention was repeated, except that the compound obtained in the first step of Example 81 was 2-[4-(3-chloro-4-fluoro-anilino)- Quinazoline-6-yl]_6,7-dihydro-2H-pyrano[3,4-c]pyrrol-4-one 81a is used as a starting material in the same manner as described in the second step of Example 81 of the present invention. Reaction of the starting material with 2-methoxyethylamine to give the title compound 1-[4-(3-chloro-4-fluoro-anilininosin-6-yl)-4-(2-hydroxyethyl) -111-Pylo-~3~carboxylic acid-(2-methoxyethyl)-nitramine 101 (130 mg 'yellow solid) 'yield: 6 〇%.. 199 94389 201016683 MS m/z (ESI): 484[M+1] 8.79(s, 8. l〇(d, 7.45(m, 3-4〇(m, 'HNMR (400MHz, DMS0- : δ 10.14(s, 1H), 1H), 8. 25 (dd, 1H, J=6. 8), 8. 19(d, 1H, J=2. 〇) 1H, J=9.2), 8. 01(t, 1H), 7. 89-7. 94( m, 2H), 2H), 4.80(s, 1H), 3.67(t, 2H), 3. 46(t, 2H), 2H), 3.29(s, 3H), 2. 90(t, 2H) Example 102

‘ 重複本發明實施例81第一步至第二步所述 •驟，不同的是以實施例81第一步所得的化合物2__[4_(3_ 氯_4_氟-苯胺基）-喹唑啉-6-基]-6, 7-二氫-211-吼喃 [3, 4-c]吡咯-4-酮81a作原料，按照本發明實施例81第 .二步所述的相同方式使得該原料與N，N-二乙基-1,2-乙二胺的反應，得到標題化合物1-[4-(3-氣—4-氟-苯胺基）-喹唑啉-6-基]-4-(2-羥乙基吡咯曱酸_(2—二乙胺基乙基）-醯胺102(100 mg，黃色固體），產率：43. 29%。 MS m/z (ESI) ： 526[M+1] ^NMR (400MHz, DMSO-dO： 5 l〇.l6(Sj 1H)> 8<89(s, 1H), 8.64(s, 1H), 8.46(s, 1H), 8. 32(ffi, 2H), 8 13(d, 1H, J=8.0), 8.02(m, 1H), 7. 92(d, IH, J=8. 8)! 7 52(s, 1H), 94389 200 201016683 ^ 7.41(t, 1H), 4.74(s, 1H), 3. 65(m, 4H), 3. 17(m, 4H), 2.91(t, 4H), 1.53-1.80(m, 6H) 實施例103 -lH-g比咯-3-甲酸-(2-哌啶-1-乙其'Repeating the first step to the second step of the present invention 81, except that the compound obtained in the first step of Example 81 is 2__[4_(3_chloro-4-[fluoro-anilino)-quinazoline -6-yl]-6,7-dihydro-211-furan [3,4-c]pyrrol-4-one 81a as a starting material, in the same manner as described in the second step of Example 81 of the present invention Reaction of the starting material with N,N-diethyl-1,2-ethanediamine afforded the title compound 1-[4-(3--(4-fluoro-anilinyl)-quinazolin-6-yl]- 4-(2-Hydroxyethylpyrroleic acid _(2-diethylaminoethyl)-decylamine 102 (100 mg, yellow solid), yield: 43. 29%. MS m/z (ESI): 526[M+1]^NMR (400MHz, DMSO-dO: 5 l〇.l6(Sj 1H)>8<89(s, 1H), 8.64(s, 1H), 8.46(s, 1H), 8 32(ffi, 2H), 8 13(d, 1H, J=8.0), 8.02(m, 1H), 7. 92(d, IH, J=8. 8)! 7 52(s, 1H), 94389 200 201016683 ^ 7.41(t, 1H), 4.74(s, 1H), 3. 65(m, 4H), 3. 17(m, 4H), 2.91(t, 4H), 1.53-1.80(m, 6H Example 103 - lH-g than azole-3-carboxylic acid-(2-piperidine-1-ethylidene

❿ 重複本發明實施例81第一步至第二步所述的實驗步驟，不同的是以實施例81第一氯-4-氟-苯胺基）-喹唾琳-6 步所得的化合物2-[4-(3-—基]-6, 7-二氫-2H-吡喃 [3,4-c>比洛-4-綱81a作原料’按照本發明實施例81第重复 Repeat the experimental procedure described in the first step to the second step of Example 81 of the present invention, except that the compound 2 obtained in the first step of Example 81, first chloro-4-fluoro-anilino)-quinalin-6 [4-(3--yl)-6,7-dihydro-2H-pyran [3,4-c>Bilo-4-class 81a as starting material] according to Example 81 of the present invention

.-醯胺103(154 mg，黃色固體），產率：65. 。 MS m/z (ESI) ： 537[M+1] ^NMR (400MHz, DMSO-W： (5 10. ι6(δ, 1H), 8.91(s, 1H) 8.61(s, 1H), 8.50(s, 1H), 8. 39(t, 1H), 8.31(dd, 1H, J=6.8)，8.10(dd，1H，J=8, 8)，8.〇i(m，1H)，7 87(d，1H >9.2)，7.54(s，1H)，7.42(t，1H), 4.8〇(s，1H)，3·’67α 2H), 3.60(q, 2H), 3. 19(m, 6H), 2.91(t, 2H), 1 25(t 94389 201 201016683 實施例104 1 -「4-( 3 -氣-4-氟-笨胺基）-啥0坐嘛其1 -4~ιΧ^惠 -1Η-°比鳴~-3-甲酸-（2-嗎嘛-4-乙基）-酿胳 0.-decylamine 103 (154 mg, yellow solid), yield: 65. MS m/z (ESI): 537 [M+1] NMR (400 MHz, DMSO-W: (5 10. ι6 (δ, 1H), 8.91 (s, 1H) 8.61 (s, 1H), 8.50 (s , 1H), 8. 39(t, 1H), 8.31(dd, 1H, J=6.8), 8.10(dd,1H,J=8, 8), 8.〇i(m,1H),7 87( d, 1H > 9.2), 7.54 (s, 1H), 7.42 (t, 1H), 4.8 〇 (s, 1H), 3 · '67α 2H), 3.60 (q, 2H), 3. 19 (m, 6H), 2.91(t, 2H), 1 25(t 94389 201 201016683 Example 104 1 - "4-(3- gas-4-fluoro-stanoamine)-啥0 sitting its 1 -4~ιΧ^惠-1Η-°比鸣~-3-carboxylic acid-(2-?--4-ethyl)-broiler 0

HKHK

104 ：重複本發明實施例81第一步至第· 二步所述的實驗步驟，不同的是以實施例81第一步所得的化合物2-[4-(3-®氣-4-氟-苯胺基）-啥唾琳-6~基]_6, 二氫-2H- η比喃 [3, 4-c]吼洛-4-嗣81a作原料，按照本發明實施例81第 ,一步所述的相同方式使得該原料與2_嗎啉_^_基_乙胺的反應，得到標題化合物1-[4-(3、氯+氣_苯胺基）_喧唾琳务基]-4-(2-經乙基）-iH-轉乙基) -醯胺104(128 mg，黃色固體），產率：53 92%。 MS m/z (ESI) ： 540[M+1] O !HNMR (400MHz, DMS0-c?6)： ^ 3fi iAr 、〇 i0. "(s，1H), 8.82(s，1H) 8. 63(s, 1H), 8. 28(dd, 1H t-r 〇、 5 J-6.8)，8.22(s, 1H), 8. 12(dd，lH，J=5.2)，8.02(s 7n" U)，7. 94(m，2H)，7. 46(t 2H)，4. 81 (s，1H)，3. 66(m，6H) q 、 0ί1λ 3.42(m, 4H), 2. 90(t, 2H), 2.50(m, 4H) 實施例105 94389 202 201016683104: The experimental procedure described in the first step to the second step of Example 81 of the present invention was repeated, except that the compound obtained in the first step of Example 81 was 2-[4-(3-® gas-4-fluoro- An anilino)-indolyl-6-yl]-6, dihydro-2H-n-pyrano[3,4-c]indole-4-indole 81a as a starting material, according to the embodiment 81 of the present invention In the same manner, the reaction of the starting material with 2-morpholine-ethylamine-ethylamine afforded the title compound 1-[4-(3, chloro-gas-anilinyl) 喧喧琳 ] -4- -4- 2-Ethyl)-iH-transethyl)-decylamine 104 (128 mg, yellow solid), yield: 53. MS m/z (ESI): 540 [M+1] O.HNMR (400MHz, DMS0-c?6): ^ 3fi iAr, 〇i0. "(s,1H), 8.82(s,1H) 8. 63(s, 1H), 8. 28(dd, 1H tr 〇, 5 J-6.8), 8.22(s, 1H), 8. 12(dd,lH,J=5.2),8.02(s 7n" U) , 7. 94 (m, 2H), 7. 46 (t 2H), 4. 81 (s, 1H), 3. 66 (m, 6H) q , 0ί1λ 3.42 (m, 4H), 2. 90 (t , 2H), 2.50 (m, 4H) Example 105 94389 202 201016683

重複本發明實施例81第一步至笛__ 驟，不同的是以實施例81第-步所得的一化合所物述2的二氯-4-氟-苯胺基）-喧唾淋+基卜6,厂二氫比喃馨 [3’4一C]料一4, 81a作原料，按照本發明實施例81第二步所述的相同方式使得該原料與2_(4_甲基—哌哄_丨_基） -乙胺的反應，得到標題化合物氟_苯胺基） -喹嗅啉-6-基]-4-(2-羥乙基）-ih-吡咯_3_甲酸一[2_(4甲基派D井-1-基）-乙基]-醢胺 105(90 mg，黃色固體），產率：69. 4%。 MS m/z (ESI) ： ·553[Μ+1] ^NMR (400MHz, DMSO- ¢/0: <5 10.05(s, 1H), 8 72(s, 1H), 8.64(s, 1H), 8.22(dd, 1H, J=6. 8), 8. 13(dd, 1H, J=5. 2), q 8.07(s, 1H), 7.90(m, 3H), 7.49(t, 1H), 7. 43(s, 1H), 4.81(s, 1H), 3.65(t, 2H), 3. 35(m, 12H), 2. 89(t, 2H), 2.30(t, 3H) 實施例106 Π-「4-(3-氯-4-氟-策胺基上3唑啉-6-某1-4-Γ2-羥乙基） -1^-吡咯-3-某1-嗎啉-4-^^1 203 94389 201016683The first step of the present invention was repeated in the first step of the present invention to the flute, except that the dichloro-4-fluoro-anilino-anilinium-based group of the compound of the present invention was obtained in the same manner as in the step 81 of the first embodiment.卜6, plant dihydrogen cyclamate [3'4-C] material-4, 81a as raw material, in the same manner as described in the second step of Example 81 of the present invention, the raw material and 2_(4_methyl-per pipe哄_丨_yl)-Ethylamine reaction to give the title compound fluoro-anilino)-quinolinol-6-yl]-4-(2-hydroxyethyl)-ih-pyrrole_3_carboxylic acid-[2_ 4%。 (4 methyl group D well-1-yl)-ethyl]-decylamine 105 (90 mg, yellow solid), yield: 69.4%. MS m/z (ESI): 553 [Μ +1] NMR (400 MHz, DMSO- ¢/0: <5 10.05 (s, 1H), 8 72 (s, 1H), 8.64 (s, 1H) , 8.22(dd, 1H, J=6. 8), 8. 13(dd, 1H, J=5. 2), q 8.07(s, 1H), 7.90(m, 3H), 7.49(t, 1H) , 7. 43(s, 1H), 4.81(s, 1H), 3.65(t, 2H), 3. 35(m, 12H), 2. 89(t, 2H), 2.30(t, 3H) 106 Π-"4-(3-Chloro-4-fluoro-amino-triazoline-6- 1-4-Γ2-hydroxyethyl)-1^-pyrrole-3-some 1-morpholine- 4-^^1 203 94389 201016683

106 重複本發明實施例8ί第一步至第二步所述的實驗步驟，不同的是以實施例81第一步所得的化合物2_[4_(3_ 氯-4-氟-苯胺基）-喹唑啉-6-基]-6, 7-二氫—2Η-吡喃 [3, 4-c]吡咯-4-酮81a作原料，按照本發明實施例81第二步所述的相同方式使得該原料與嗎啉的反應，得到標題化合物[1-[4-(3-氯-4-氟-苯胺基）-喧唾琳_6-其]1 ®羥乙基）-1Η-°比咯-3-基]-嗎啉-4-甲酮i〇6(158 龙出运，黃色固體），產率：72. 3%。 MS m/z (ESI) ： 496[M+1] 2H), 2H), !HNMR (400MHz, DMS0- : (5 10.〇7(s, 1H), 8 67(d 8. 21(s, 2H), 7. 90(t，2H)，7.73(s, ih)，7.49(s 4.68(s, 1H), 3.22(m, 10H), 2. 70(t, 2H) 實施例10 7 Q |~1-|~4-(1:氧-4-氟-苯胺基）-喹复來-6-某卜^：：£^^ -111-0比洛~~3-基1-(4-甲基派哄-1~基）-^西同 Ο106 Repeat the experimental procedure described in the first step to the second step of the present invention, except that the compound obtained in the first step of Example 81 is 2_[4_(3_chloro-4-fluoro-anilino)-quinazoline Phenyl-6-yl]-6,7-dihydro-2-indole-pyrano[3,4-c]pyrrol-4-one 81a is used as a starting material in the same manner as described in the second step of Example 81 of the present invention. The reaction of the starting material with morpholine gives the title compound [1-[4-(3-chloro-4-fluoro-anilino)-喧琳 _ _6-]] 1 hydroxyethyl)-1 Η-° ratio- 3- 。。。。。。。。。。。。。。。。。。。. MS m/z (ESI): 496 [M+1] 2H), 2H), NMR (400 MHz, DMS0-: (5 10. 〇7 (s, 1H), 8 67 (d 8. 21 (s, 2H), 7. 90(t, 2H), 7.73(s, ih), 7.49 (s 4.68(s, 1H), 3.22(m, 10H), 2. 70(t, 2H) Example 10 7 Q | ~1-|~4-(1: Oxy-4-fluoro-anilino)-quino-complex-6-abu^::£^^ -111-0Bilo~~3-base 1-(4- Methyl 哄-1~基)-^西同Ο

107107

hAI 重複本發明實施例81第-步至第二步所述驟，不同的是以實施例81第一步所得的化合物' 氯-4-氟-苯胺基）-啥峻琳-6~基7— _ & (3 」b’ / 一虱、2H〜吡喃 94389 204 201016683 [3, 4-c]吡咯-4-酮81a作原料’按照本發明實施例8i第一步所述的相同方式使得該原料與4~甲基-旅卩井的反應，得到標題化合物[1-[4-(3-氣-4-氟-笨胺基）_喹唑啉-6-基]-4-(2-羥乙基）-111-°比洛-3-基]~(4_甲基哌畊-卜基）-甲酮107(184 mg，黃色固體）’產率：82 〇8%。 MS m/z (ESI) ： 509[M+1] ^NMR (400MHz, DMS0- : 5 9. 97(s, 1H), 8. 64(d, 2H), 8.18(d, 2H, J=9.2), 7. 89(d, 2H, J = 8. 8), 7. 70(s, 1H), 7.48(m, 2H), 4. 69(s, 1H), 3. 63(m, 6H), 2. 70(t, 2H), ® 2. 44(m, 4H), 2. 28(s, 3H) 實施例108 .[_1-[4-(3-氧-4-氟-._苯蓋基」-喹唑蛛二6_基卜4_(2_羥乙基）The hAI repeats the steps described in the first step to the second step of the present invention, except that the compound obtained in the first step of the example 81 is a compound of the formula 'chloro-4-fluoro-anilinyl group-啥Junlin-6~7 — _ & (3 ′b′ / 虱, 2H~pyran 94389 204 201016683 [3, 4-c]pyrrol-4-one 81a as a starting material 'in the same manner as described in the first step of Example 8i of the present invention The reaction of the starting material with a 4-methyl-browning well afforded the title compound [1-[4-(3-carb-4-fluoro-phenylamino)-quinazolin-6-yl]-4-( 2-Hydroxyethyl)-111-°Pilo-3-yl]~(4-methylpiped-bry)-methanone 107 (184 mg, yellow solid). Yield: 82 〇 8%. m/z (ESI): 509 [M+1] NMR (400 MHz, DMS0-: 5 9. 97 (s, 1H), 8. 64 (d, 2H), 8.18 (d, 2H, J = 9.2) , 7. 89(d, 2H, J = 8. 8), 7. 70(s, 1H), 7.48(m, 2H), 4. 69(s, 1H), 3. 63(m, 6H), 2. 70(t, 2H), ® 2. 44(m, 4H), 2. 28(s, 3H) Example 108. [_1-[4-(3-Oxo-4-fluoro-._benzene cap) "-quinazoline two 6_ kib 4_(2_hydroxyethyl)

重複本發明實施例81第一步至第二步所述的實驗步驟，不同的是以實施例81第一步所得的化合物2_[4—(3_ 氯-4-氟-笨胺基）_喹唑啉_卜基]_6, 了_二氫-2JJ_吡喃 [3, 4-c]吡咯-4-酮81a作原料，按照本發明實施例81第二步所述的相同方式使得該原料與3_嗎啉_4_基_丙胺的反應’得到標題化合物[1_[4_(3_氣_4_氟_笨胺基）_喹唑啉 -6-基]-4-(2-羥乙基）-ih-吡咯曱酸-(3-嗎啉-4-丙基） 205 94389 201016683 -酿胺108(146 mg，黃色固體），產率：59.9%。 MS m/z (ESI) ： 554[M+1] ]HNMR (400MHz, MSO-de) : δ 10. 13(s, 1H), 8. 82Γ v · ^v,s, 1H), 8.62(s, 1H), 8.26(d, 1H, J=4. 8), 8. 20(s, 1H), g li(d 1H，J=8.8)，8.02(m’ 1H), 7.92(m, 2H)，7.45(t，2H)’ 4.80(s，1H)，3.74(m，6H)，3.27(m, 4H)，2.87(t 2H)’ 2. 61(m, 4H), 1. 76(m, 2H) ’ ’ 實施例109 Ο [1-[4-(3-氯-4-氟-苯胺基）-啥唑被-6—某 1-^1- -1Η-口比洛-3-基]-0比洛烧-1 -〒酿The experimental procedure described in the first step to the second step of Example 81 of the present invention was repeated, except that the compound obtained in the first step of Example 81 was 2-[4-(3-chloro-4-fluoro-phenylamino)-quinoline. Oxazoline- _ _6, _dihydro-2JJ_pyran[3,4-c]pyrrol-4-one 81a as a starting material, which is obtained in the same manner as described in the second step of Example 81 of the present invention. Reaction with 3_morpholine_4_yl-propylamine' gave the title compound [1_[4_(3_气_4_Fluoro-phenylamino)-quinazolin-6-yl]-4-(2-hydroxyl Ethyl)-ih-pyrrolidino-(3-morpholin-4-propyl) 205 94389 201016683 - Amine amine 108 (146 mg, yellow solid), yield: 59.9%. MS m/z (ESI): 554 [M+1]]HNMR (400 MHz, MSO-de): δ 10. 13 (s, 1H), 8. 82 Γ v · ^v, s, 1H), 8.62 (s , 1H), 8.26(d, 1H, J=4. 8), 8. 20(s, 1H), g li(d 1H, J=8.8), 8.02(m' 1H), 7.92(m, 2H) , 7.45(t,2H)' 4.80(s,1H), 3.74(m,6H), 3.27(m, 4H), 2.87(t 2H)' 2. 61(m, 4H), 1. 76(m, 2H) ' ' Example 109 Ο [1-[4-(3-Chloro-4-fluoro-anilino)-carbazole is -6-a 1-^1- -1Η-portpirin-3-yl] -0 比洛烧-1 - Brewing

109 ·.重複本發明實施例81第一步.至第二步所述的實驗步驟，不同的是以實施例81第一步所得的化合物2_[4—(3— 氯-4-氟-笨胺基）-喹唑啉基]_6, 7_二氫_2Η_吡喃钃[3, 4-c]吡咯-4-酮81a作原科，按照本發明實施例81第二步所述的相同方式使得該原料與吡咯烷的反應，得到標題化合物Π-[4-(3-氯-4-氟—苯胺基）_喹唑啉_6_基]_4_ (2-羥乙基）-lH-吡咯-3-基μ吡咯烷_卜曱酮1〇9(190 mg，黃色固體 >，產率：67. 4°/〇。 MS m/z (ESI) ： 480[M+1] !HNMR (400MHz, DMS0-c?〇： ^ i〇> i2(s, 1H), 8. 75(s, 1H), 8. 63(s, 1H), 8. 23(m, 2H), 7. 89(m, 3H), 7.48(t, 2H), 206 94389 201016683 3.48(m, 2H)， 2.79(t，2H)， 4. 80(s, 1H), 3. 65(m, 4H), 1.87(m, 4H) 實施例110109. Repeat the experimental procedure described in the first step of the present invention 81 to the second step, except that the compound obtained in the first step of Example 81 is 2_[4-(3-chloro-4-fluoro-stupid) Amino)-quinazolinyl]-6,7-dihydro-2-indole-pyrano[3,4-c]pyrrol-4-one 81a as the original subject, according to the second step of Example 81 of the present invention The reaction of the starting material with pyrrolidine in the same manner gave the title compound Π-[4-(3-chloro-4-fluoro-anilino)-quinazoline-6-yl]_4_(2-hydroxyethyl)-lH -pyrrol-3-ylpyrrolidine-doprone 1〇9 (190 mg, yellow solid >, yield: 67. 4°/〇. MS m/z (ESI): 480 [M+1] HNMR (400MHz, DMS0-c?〇: ^ i〇> i2(s, 1H), 8. 75(s, 1H), 8. 63(s, 1H), 8. 23(m, 2H), 7 . . . (m, 2H), 1.87 (m, 4H) Example 110

_1!1-0比略~-3-基1-旅°定-1-甲酮_1!1-0 ratio slightly ~-3-based 1-Brigade °-1-ketone

重複本發明實施例81第一步至第二步所述的實驗步 ©驟，不同的是以實施例81第一步所得的化合物2_[4_(3_ 氯-4-氟-苯胺基）-喧°坐嚇 -6-基]-6, 7-二氫-2H- τ»比啥 [3,4-c]n比嗜*-4_酮81a作原料，按照本發明實施例μ第二步所述的相同方式使得該原料與旅咬的反應，得到標題化合物[1_[4-(3-氯-4-氟-苯胺基）-啥嗤琳-6-基]-4-(2-經乙基）-1Η-σ比咯_3-基]-派咬-1-甲_ 110(200 mg，黃色固體），產率·· 68·⑽。 g MS m/z (ESI) ： 494[M+1] !HNMR (400MHz, DMSO- c/O： (5 9. 91(s, 1H), 8. 63(s, 2H), 8.19(m, 2H), 7. 89(id, 2H), 7. 65(s, 1H), 7. 48(m, 2H), 4. 69(t, 1H), 3.57(m, 6H), 2. 68(t, 2H), 1. 64(m, 2H), 1.53(m, 4H) 實施例111 4-二甲胺基-丁- 嫌酸-〇-{ 4-「3-氯-4-(3 -氟-苄氳某）-笨胺基Ί -音°坐嚇-6-基丨-4-三氟曱基-1Η-°比鳴~-3-基）-醯胺 207 94389 201016683The experimental procedure described in the first step to the second step of the present invention was repeated, except that the compound obtained in the first step of Example 81 was obtained as the compound 2_[4_(3_chloro-4-fluoro-anilino)-oxime. ° 吓-6-yl]-6,7-dihydro-2H- τ» than 啥[3,4-c]n than the *-4-4 ketone 81a as a raw material, according to the embodiment of the present invention μ second step In the same manner as described, the reaction of the starting material with the brittle bite gives the title compound [1_[4-(3-chloro-4-fluoro-anilino)-indolyl-6-yl]-4-(2- Ethyl)-1 Η-σ ratio _3-3-]]-bite-1-methyl _ 110 (200 mg, yellow solid), yield 68·(10). g MS m/z (ESI): 494 [M+1].HNMR (400 MHz, DMSO-c/O: (5 9. 91 (s, 1H), 8. 63 (s, 2H), 8.19 (m, 2H), 7. 89(id, 2H), 7. 65(s, 1H), 7. 48(m, 2H), 4. 69(t, 1H), 3.57(m, 6H), 2. 68( t, 2H), 1. 64(m, 2H), 1.53(m, 4H) Example 111 4-Dimethylamino-butylic acid-〇-{4-"3-chloro-4-(3 - Fluoro-benzyl hydrazine)-stupidylaminopurine--sounds-scarred--6-based fluorene-4-trifluoromethyl-1Η-° than syllabic ~-3-yl)-nonylamine 207 94389 201016683

基卜胺 67i(150mg，0.284 mmol)，0.2mL 二異丙基乙胺，切 mmol)，4-二曱胺基-丁-2-烯酸（52 mg，0. 雙（2-侧氧基-3-曙嗤烧基）次填醯氯（86. 56. 74 mg > 〇. 341 〇· 312 mmol)溶於 25 mL二氯甲烷中，室溫下授拌過夜，反應完畢。用TLC 層析分離產物，得到標題產物4-二曱胺基-丁-2-烯酸-(1- {4-[3-氣-4-(3-氟-苄氧基）-苯胺基]-喹唑琳-6-基}-4-三氟曱基-1Η-°比咯-3-基）_醯胺111(32 mg，黃色固體），產. 率：17· 6% 〇 MS m/z (ESI) ： 640[M+1] ❹1HNMR(400MHz，DMSO-A): (5 10.〇5(s，1H)，9.71(s，1H)， 8.79(s，1H)，8.60(s，1H)，8.21(dd，1H，J=8. 8)，8. 12(d， 2H, J = 9. 6), 8.04(s, 1H), 7. 90(d, 1H, J=8. 8), 7. 77(dd, 1H, J=9.2), 7.48(q, 1H), 7. 32(m, 3H), 7. 19(m, 1H), 6. 78(m, 1H), 6. 63(d, 1H), 5. 27(s, 2H), 3. 55(m, 2H), 2. 47(s, 6H) 實施例112 {6-「3, 4-二-(二乙胺基甲某吡咯-1二基1-喹4嗾-A-其} 208 94389 201016683 ::13-氯-4-(3-氣二^氣某装某]_胺Kebamine 67i (150 mg, 0.284 mmol), 0.2 mL diisopropylethylamine, cut in mmol), 4-diamido-but-2-enoic acid (52 mg, 0.曙嗤曙嗤 ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) The product was isolated by chromatography to give the title product 4-diamino-buty-2-enoic acid-(1-{4-[3-carb-4-(3-fluoro-benzyloxy)-anilinyl]-quin Zolazine-6-yl}-4-trifluoromethyl-1Η-pyrrol-3-yl)-decylamine 111 (32 mg, yellow solid), yield. Yield: 17·6% 〇MS m/z (ESI): 640 [M+1] ❹1H NMR (400 MHz, DMSO-A): (5 10. 〇5 (s, 1H), 9.71 (s, 1H), 8.79 (s, 1H), 8.60 (s, 1H) ), 8.21 (dd, 1H, J = 8.8), 8. 12 (d, 2H, J = 9. 6), 8.04(s, 1H), 7. 90(d, 1H, J=8. 8 ), 7. 77(dd, 1H, J=9.2), 7.48(q, 1H), 7. 32(m, 3H), 7. 19(m, 1H), 6. 78(m, 1H), 6 63(d, 1H), 5. 27(s, 2H), 3. 55(m, 2H), 2. 47(s, 6H) Example 112 {6-"3, 4-II-(二乙Aminopyrrole-1diyl-1-quinoline-4-anthracene-A-yl} 208 94389 201016683::13-chloro-4-(3-gas 2^气一装某)_amine

第一步 • 1-{4-[3-氯_4-(3-氟-苄氧基）-苯胺基]-喹唑啉__6__基} -1H-吼咯-3, 4-二羧基二乙酯在250 mL茄形瓶中，依次加入實施例1第五步所得化合物[3-氯-4-(3-氟-苄氧基）_苯基]_(6_碘-喹唑啉-4__基） -胺 lg (7. 10 g ’ 〇. 〇14 mol)，1Η-°比17各-3, 4-二甲酸二乙嗚醋（2. 97 g，0. 014 m〇l)，碟酸钟（8. 92 g，0. 042 mol)，碟化亞銅（2. 76 g，〇· 〇i4 m〇l)，n，N，-二甲基-1，2-乙二胺（1. 23 g ’ 0. 014 mol)和 100 mL N，N-二甲基甲醯胺，所得的混合液在氮氣保護下加熱至，擾拌過夜，反應完畢。將反應液倒入1 〇〇〇 mL水中，授拌，過滤，固體進一步藉由管柱層析法分離純化，得到本標題產物1-{4-[3-氯一4-(3-氟-苄氧基）-苯胺基]—喹唑啉_6_基卜1H_吡咯_3, 4_ —羧基一乙酯112a (3. 3g’黃色固體），產率·· 4〇%。 209 943S9 201016683 MS m/z (ESI) : 588[M-1] 第二步 (l~{4-[3-氯-4-(3-氟苄氧基）-苯胺基]-喹唑啉_6_基卜4_ 經基甲基-1 Η-0比嘻-3-基）-曱醇在250 mL茄形瓶中，將氫化鋁鋰（581 mg，i5. 3mm〇1) 溶解於75 mL四氫呋喃令，所得的溶液在冰浴條件下，冷卻至0°C，攪拌下加入上述步驟所得化合物氯_4— (3-氟-苄氧基）-苯胺基]-喹唑啉_6_基}_1Η_Π比咯-3, 4一二缓基一乙酉旨112a(1.5 g’ 2.55 mmo 1)，保持冰浴反應2小 ®時後反應完畢。在反應液中滴加7. 5 mL水，7. 5 mL 1N氣氧化納溶液，授拌下加入1 〇〇 mL乙酸乙酯，石夕蒸土過濾，用2 0 0 mL·乙酸乙酯洗滌，濾液依次用飽和氯化鈉溶液洗滌，無水硫酸鈉脫水，過濾，濾液減壓下濃縮，得到本化合物（1_{4-[3_氯-4_(3_氣节氧基）-苯胺基]—喧·唾琳_6__美j -4-羥基曱基-1H-吡咯-3-基）-曱醇112b(黃色固體）不經分離直接進行下一步反應。 φ MS m/z (ESI) ： 503[M-1] 第三步卜{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-喹唑啉_6_基} -1Η_ο比哈-3，4_二甲經· 在250 mL霖形瓶中，將鄰填酿苯甲酸（2.86 g， 10. 2mmol))溶解於50 mL二曱基亞砜中，攪拌下加入上述步驟所得的化合物（1-{4-[3-氯-4-C3-氟苄氧基）-苯胺基] -啥Τ»坐琳-6-基}-4-羥基曱基-ijj-n比哈-3-基）-甲醇 94389 210 201016683 (1. 287g ’ 2. 55mmol)的25 mL二甲基亞礙溶液，所得的混合液在室溫下攪拌2小時，反應完畢。將反應液倒入5〇〇 mL 冰水中，用乙酸乙酯（250 mLx4)萃取，有機相用飽和碳酸氫鈉溶液洗滌，飽和氯化鈉溶液洗滌，無水硫酸鈉脫水，過濾’減壓下濃縮，得到的殘留物藉由管柱層析法進一步分離純化’得到本標題產物1 -{4-[3-氯-4-(3-氟-节氧基） -本胺基]-喧〇坐琳-6-基}-111-0比略-3, 4-二甲酸：U2c(760 mg，黃色固體），產率：59. 4%。 MS m/z (ESI) ： 499[M-1] ®第四步 {6-[3, 4-一 -(二乙胺基甲基）-σ比嘻-1-基]-啥0坐淋_4一基} ' -[3-氯-4-(3-氟-苄氧基）-苯基]—胺 • 將上述步驟所得的化合物1-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-喹唑啉-6-基}-111-吡咯-3,4.-二甲醛112〇 (100 Μ ’ 0.2 mmol)溶解於5 mL二氯甲烷中，攪拌下加入二乙胺（44 mg，0. 6 mmol)，繼續攪拌6小時後，加入三乙 ❹醯氧基硼氫化（170 mg，0.8匪〇1)，攪拌過夜，反應完畢。在反應液中加入5 mL飽和氯化鈉溶液，1 mL飽和碳酸氫鈉溶液，二氯甲烷（20 mLx3)萃取，有機相用飽和氯化鈉溶液洗滌，無水硫酸鈉脫水，過濾，濃縮，得到的殘留物進一步藉由TLC板分離純化，得到本標題產物{6_[3,4_二 -(二乙胺基甲基）-吡咯-1-基]-喹唑啉一4_基丨—[3一氯一4一 (3-氣-节氧基）-苯基]-胺112(73 mg，黃色固體），產 59. 4% ° 94389 211 201016683 MS m/z (ESI) ： 615[M+1] , 1 ίί), 78(s, 沱丽R (400MHz，DMS0- cW:占 10.04(s，、« 〇7(d, 1H, 1H)，8.59(s，1H)，8.14(dd，1H，J=8.8)，^ 7 47(q, 1H), J=2.4)，7. 90(d，1H，J=9.2>，7. 83(m，3H)，7· / 〇 93(s, 4H), 7.32(m, 3H), 7. 19(t, 1H), 5. 27(s, 2H)，3* 2. 91(q, 8H), 1. 14(t, 12H) 實施例113 Γ6-(3,4-二-嗎啉-4-甲基吡咯-1-基晻也基]「3 氯-4-(3-氟-苄氣基）-笨基胺© 〇First Step • 1-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-anilino]-quinazoline __6__yl} -1H-Pyro-3,4-dicarboxyl Diethyl ester in a 250 mL eggplant-shaped flask, the compound [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-iodo-quinazoline) obtained in the fifth step of Example 1 was sequentially added. -4__基)-amine lg (7. 10 g ' 〇. 〇14 mol), 1Η-° ratio 17-3,4-dicarboxylic acid diethyl vinegar (2. 97 g, 0. 014 m〇l ), disc acid clock (8. 92 g, 0. 042 mol), disc bronze (2. 76 g, 〇·〇i4 m〇l), n, N,-dimethyl-1,2-B The diamine (1. 23 g '0. 014 mol) and 100 mL of N,N-dimethylformamide were added, and the resulting mixture was heated under a nitrogen atmosphere, and the mixture was stirred overnight to complete the reaction. The reaction solution was poured into 1 mL of water, mixed, filtered, and the solid was further purified by column chromatography to give the title product 1-{4-[3-chloro- 4-(3-fluoro- Benzyloxy)-anilino]-quinazoline _6_ kib 1H_pyrrole_3, 4_-carboxyethyl ester 112a (3.3 g of a yellow solid), yield ··4%. 209 943S9 201016683 MS m/z (ESI): 588 [M-1] Step 2 (1~{4-[3-chloro-4-(3-fluorobenzyloxy)-anilino]-quinazoline _ 6_基卜4_ benzylmethyl-1 Η-0 嘻-3-yl)-nonanol Lithium aluminum hydride (581 mg, i5. 3mm 〇1) was dissolved in 75 mL in a 250 mL eggplant bottle Tetrahydrofuran, the resulting solution was cooled to 0 ° C under ice-cooling, and the compound obtained in the above step was added with stirring to give the compound chloro-4-(3-fluoro-benzyloxy)-anilino]-quinazoline -6-based }_1Η_Π比咯-3, 41-2 缓基一乙酉第112a (1.5 g' 2.55 mmo 1), the reaction was completed after maintaining the ice bath reaction 2 hours. To the reaction solution, 7.5 mL of water, 7.5 mL of 1N gas oxidized sodium solution was added dropwise, and 1 〇〇mL of ethyl acetate was added thereto, and the mixture was filtered and washed with 200 mL of ethyl acetate. The filtrate is washed successively with a saturated sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to give the compound (1_{4-[3_chloro-4_(3_ gas oxy)-anilinyl] —喧·唾琳_6__美j -4-hydroxyindolyl-1H-pyrrol-3-yl)-nonanol 112b (yellow solid) was directly subjected to the next reaction without isolation. φ MS m/z (ESI) : 503 [M-1] The third step is {4-[3-chloro-4-(3-fluoro-benzyloxy)-anilino]-quinazoline_6_yl } -1Η_ο比哈-3,4_Dimensional· Dissolve o-filled benzoic acid (2.86 g, 10. 2 mmol) in 50 mL of decyl sulfoxide in a 250 mL lump bottle with stirring Adding the compound obtained in the above step (1-{4-[3-chloro-4-C3-fluorobenzyloxy)-anilino]-indole» sits -6-yl}-4-hydroxyindolyl-ijj- nBihar-3-yl)-methanol 94389 210 201016683 (1. 287 g ' 2.55 mmol) of 25 mL of dimethyl sulphur solution, the resulting mixture was stirred at room temperature for 2 hours and the reaction was completed. The reaction mixture was poured into 5 mL of ice water and extracted with ethyl acetate (250 mL×4). The organic phase was washed with saturated sodium hydrogen carbonate solution, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and filtered , the obtained residue is further separated and purified by column chromatography to obtain the title product 1 -{4-[3-chloro-4-(3-fluoro-hydroxy)-amino-]-琳-6-基}-111-0 比略-3, 4-dicarboxylic acid: U2c (760 mg, yellow solid), yield: 59.4%. MS m/z (ESI): 499[M-1] ® fourth step {6-[3, 4-一-(diethylaminomethyl)-σ than 嘻-1-yl]-啥0 sitting _4-yl} '-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-amine • The compound obtained in the above step 1-{4-[3-chloro-4-(3) -Fluoro-benzyloxy)-anilino]-quinazolin-6-yl}-111-pyrrole-3,4.-diformaldehyde 112 〇 (100 Μ '0.2 mmol) was dissolved in 5 mL of dichloromethane. Diethylamine (44 mg, 0.6 mmol) was added with stirring. After stirring for 6 hrs, triethyl ethoxy hydride (170 mg, 0.8 匪〇 1) was added and stirred overnight. 5 mL of saturated sodium chloride solution, 1 mL of saturated sodium hydrogencarbonate solution, and dichloromethane (20 mL×3) were added to the reaction mixture, and the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was further purified by a TLC plate to give the title product: [6_[3,4-di-(diethylaminomethyl)-pyrrol-1-yl]-quinazoline- 4-ylindole-[ 3-chloro-4-iso-(3-carbo-oxy)-phenyl]-amine 112 (73 mg, yellow solid), yield 59. 4% ° 94389 211 201016683 MS m/z (ESI): 615 [M +1] , 1 ίί), 78(s, brilliant R (400MHz, DMS0- cW: 10.04(s, , « 〇7(d, 1H, 1H), 8.59(s,1H), 8.14(dd, 1H, J=8.8), ^ 7 47(q, 1H), J=2.4), 7.90 (d, 1H, J=9.2>, 7.83(m, 3H), 7· / 〇93( s, 4H), 7.32(m, 3H), 7. 19(t, 1H), 5. 27(s, 2H), 3* 2. 91(q, 8H), 1. 14(t, 12H) Example 113 6-(3,4-Di-morpholine-4-methylpyrrol-1-ylxanthyl) "3 chloro-4-(3-fluoro-benzyl)-stupylamine © 〇

、ci 重複本發明實施例112第一步至第四少所述的實驗步驟，不同的是以第三步所得的化合物1二{4-[3-氯"*4-(3~氟 ❹ -苄氧基）-苯胺基]-喹唑啉-6_基}-lH-吡咯_3, 4-二甲駿 112c作原料’按照本發明實施例112第四步所式使得該原料與嗎啉的反應，得到標題化合、相同方嗎琳-4-曱基〇比π各-1 -基）—嗤嗤琳_4_基]〜[3 (3, 4-二〜苄氧基）-苯基]-胺113(73mg’黃色固體），▲氣氟 59. 4% MS m/z (ESI) ： 616[M+1] !H NMR (400MHz, MSO-de)： δ 9. 78(s, 1H) 8. 14(dd，1H，J=9.2)，8.00(d，1H，>2.4)’ 8.54(m，2H)， >8.8)，7.73(dd，1H，J=8.8)，7.47(m，3H)’ 7.83(d，1H， 7. 19(t，1H)，5.28(s，2H)，3.58(s 8H) ，7*33(m，3H) ，，3.44(s，4H)，’ 94389 212 201016683 2.41(s, 8H) 實施例114The ci repeats the experimental steps described in the first step to the fourth less invention of the present invention, except that the compound 1 obtained in the third step is {2-[3-chloro"*4-(3~fluorene) -Benzyloxy)-anilino]-quinazolin-6-yl}-lH-pyrrole_3, 4-dimethyljun 112c as a starting material 'According to the fourth step of Example 112 of the present invention, is the raw material made? The morphological reaction of the morpholine gives the title compound, the same aryl 曱曱曱曱〇 π π -1 - - - -1 -1 -1 -1 -1 _ _ _ _ 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 Phenyl]-amine 113 (73 mg 'yellow solid), ▲ gas fluoride 59.4% MS m/z (ESI): 616 [M+1] !H NMR (400 MHz, MSO-de): δ 9.78 ( s, 1H) 8. 14 (dd, 1H, J = 9.2), 8.00 (d, 1H, > 2.4) ' 8.54 (m, 2H), > 8.8), 7.73 (dd, 1H, J = 8.8) , 7.47(m,3H)' 7.83(d,1H, 7. 19(t,1H), 5.28(s,2H),3.58(s 8H) ,7*33(m,3H) ,,3.44(s, 4H), '94389 212 201016683 2.41(s, 8H) Example 114

6 ~~ ( 3，4 ~ — ~~ 娘咬 _ 1 -甲基p比略-1 -基）-_ -4-(3-|t苄氯某）-笨基1-脸6 ~~ ( 3,4 ~ — ~~ Ninja bite _ 1 -Methyl p is slightly -1 -yl)-_ -4-(3-|tbenzyl chloride) - Stupid 1-face

114 重複本發明實施例112第一步至第四布w步所述的警认卜驟’不同的是以第三步所得的化合物卜丨4〜[3〜氣貫驗步甲醛苄氧基）-苯胺基]-喧唾琳_6-基}_；^-«»比洛—3 4 (3氟 112c作原料，按照本發明實施例Π2第四步所述的一 _ -式使得該原料與哌啶的反應’得到標題化合物6_( 3 4同方 0底啶-1-甲基吡咯-1-基）-喹唑啉-4-基]一[3一氯、4 一 " ^ k d 一氣爷氧基）-苯基]-胺114(100 mg，黃色固體），產枭· 胆^压千· 78. 1%。 MS m/z (ESI) ： 640 [M+l] 'H NMR (400MHz, DMSO- de): δ 10.〇〇rs iHv 〇 5 8· 72(s 〇 1H), 8.58(s, 1H), 8. 13(dd, 1H, J=8. 8), 8. 〇5(s 7.88(d，1H，J=8.4)，7.72(m, 3H)，7.48(q，1H) 7, jH)114 repeating the first step to the fourth step w of the embodiment of the present invention, the alert is different from the compound obtained in the third step, dip 4~[3~ gas-testing stepaldehyde benzyloxy) - anilino]- 喧琳 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 4 4 (3 fluoro 112c as a raw material, according to the embodiment of the invention Π 2 described in the fourth step of the _ - Reaction with piperidine' gave the title compound 6-(3 4-iso-n-oxaridin-1-methylpyrrol-1-yl)-quinazolin-4-yl]-[3-chloro, 4- " ^ kd氧基 oxy)-phenyl]-amine 114 (100 mg, yellow solid), calving 胆胆压压 · 78 78. 1%. MS m/z (ESI): 640 [M+l] "H NMR (400 MHz, DMSO-de): δ 10.〇〇rs iHv 〇5 8·72(s 〇1H), 8.58(s, 1H), 8. 13(dd, 1H, J=8. 8), 8. 〇5(s 7.88(d,1H,J=8.4), 7.72(m, 3H), 7.48(q,1H) 7, jH)

，’ · d 3 (IQ 3H), 7. 19(t, 1H), 5.27(s, 2H), 3.86(s, 4H) 〇 / ’’乙.83(s 8H), 1.63(s, 8H), 1. 53(s, 4H) 實施例115 ~~[-3，4-一 -( 一甲基胺基甲基）°比略 -1 -基-吟4 二[3-氯-4-Γ3-氟芊氳某茉基1-胺 94389 213 201016683, ' · d 3 (IQ 3H), 7. 19(t, 1H), 5.27(s, 2H), 3.86(s, 4H) 〇 / ''B.83(s 8H), 1.63(s, 8H) , 1. 53(s, 4H) Example 115 ~~[-3,4-I-(monomethylaminomethyl) ° ratio-1 -yl-吟4 bis[3-chloro-4-Γ3 - Fluoroquinone, a certain methyl group, 1-amine 94389 213 201016683

115 重二本發明實施例112第一步至第四步所述的實驗步驟？：的疋以第三步所得的化合物[3'氣_4例 -苄巩基）-苯胺基]-喹唑啉—6_基}_11}—吡咯二甲+ 112c作原料，按照本發明實施例112第四步所述的式使得該原料與二曱胺的反應，得到標題化合物丨6气3 * 一-(一甲基胺基曱基）吡咯-1-基]-喹唑啉__4一基卜[3 一 ~4-(3-氟苄氧基）-苯基]一胺115(4〇mg，黃色固體友乳 35.7%。率： MS rn/z (ESI) ： 560 [M+l] NMR (400MHz, DMSO- de) ： δ 10.59(s, 1H), 9. 24(s -1H), 8.60(s, 1H), 8.22(d,-lH, J=2. 4), 8. 14(ddj ^ J=8.8), 8.05(s, 2H), 7. 97(dd，1H，J=8.8)，7.9i(d J=8. 8)，7.48(q, 1H), 7. 31(m, 3H), 7. 16(t， D 5.27(s, 2H), 4. 28(s, 4H), 2. 66(s, 12H) ’ 實施例116 -「3_風》~~4-(3~~敗午氣基）-笨胺基1-啥吨咏二基上二^-[ (2-嗎淋-4-乙胺基）-甲基~[-1Η-ρ比洛-3-某115 is the experimental procedure described in the first step to the fourth step of the embodiment 112 of the present invention? The compound obtained in the third step is a raw material obtained by the third step [3' gas_4 - benzylidene)-anilino]-quinazoline-6-yl}_11}-pyrrole dimethyl + 112c, which is used according to the present invention. The reaction of the starting material with diamine was carried out by the method described in the fourth step of Example 112 to give the title compound 丨6 gas 3*-(monomethylaminopurinyl)pyrrol-1-yl]-quinazoline__4 A kibu [3 - 4-(3-fluorobenzyloxy)-phenyl]-amine 115 (4 〇 mg, yellow solid friend milk 35.7%. Rate: MS rn / z (ESI): 560 [M+ l] NMR (400MHz, DMSO-de): δ 10.59(s, 1H), 9. 24(s -1H), 8.60(s, 1H), 8.22(d, -lH, J=2. 4), 8 14(ddj ^ J=8.8), 8.05(s, 2H), 7. 97(dd,1H,J=8.8), 7.9i(d J=8. 8), 7.48(q, 1H), 7. 31(m, 3H), 7. 16(t, D 5.27(s, 2H), 4. 28(s, 4H), 2. 66(s, 12H) ' Example 116 - "3_风》~~ 4-(3~~败午气基)- 笨胺啥啥啥啥啥啥 ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ 洛洛洛洛洛洛-3-some

94389 214 116 20101668394389 214 116 201016683

徽2-(H4-[3-氯-4-(3-氟$氧基）_苯胺基卜㈣啭+基} 醫-4-羥甲基-1H-吡咯-3-基）一乙醇在5〇〇mL單口燒瓶中，將氫化鋁鋰（1.48g，38.8mm〇l) •溶解於1。50汕四氫呋喃中，將反應液在冰浴條件下，冷卻至〇至5°C，攪拌下分批加入實施例1〇所得的化合物2_丨4_ [3-氯-4-(3-氟-苄氧基）-苯胺基]_喹唑琳_6_基丨_6,7_二氫-2H-吡喃[3,4-c]吡咯-4_酮 1〇(1〇g，19 4麗〇1)，所得的混合液在室溫下攪拌下3小時後反應完畢。用1〇〇乩鬱四氫呋喃和50 mL水的混合溶劑猝滅反應。將反應液中倒入150 mL水和150 mL乙酸乙酯中進行分液，用乙酸乙酯 (100 mLx3)進一步萃取水層’合併的有機相依次用飽和氣化納溶液洗滌，無水硫酸鈉脫水，過濾，濾液減壓下濃縮，得到的固體用5 mL乙酸乙酯洗務，得到本標題產物2~(1、 {4-[3_氯-.4-(3 -氣节氧基）-苯胺基]-啥β坐琳-6_基}-.4~趣甲基-1Η-吡咯-3-基）-乙醇U6a(5. 23g，灰色固體），產率：52. 1%。 215 94389 201016683 MS m/z (ESI) ： 519[M+1] 第二步卜{4-[3-氯-4-(3-氟苄氧基）-苯胺基]-喹唑啉—6—基） - 4-(2-羥乙基）-111-吡咯-3-甲醛在50 mL單口燒瓶中’將鄰碘醯基苯曱酸（54〇 mg， 1. 93mmol)溶解於5 mL二甲基亞颯中，擾拌下逐滴加入將上述步驟所得的化合物2-(1-{4-[3-氯-4-(3-氟苄氧基）_ 苯胺基]-喹唑啉-6-基}-4-羥甲基-1H-吡咯-3-基）-乙醇 116a(lg ’1.93 mmol)的3 mL二曱基亞砜溶液，所得的反 ®應液在室溫下攪拌1小時後，反應完畢。將反應液加入到 150 mL 5%碳酸氫鈉溶液中’有固體析出，過濾，真空下乾燥’得到本標題產物卜{4-[3-氯-4-(3-氟苄氧基）-苯胺基]-啥嗤琳-6-基}-4-(2-經乙基）-iH-吼嘻-3-甲經116b -(l.lg，土黃色固體）粗產品，不經分離直接進行下一步反應。 MS m/z (ESI) ： 518[M+1] .第三步 2-{1-{4-[3-氯-4-(3-氟苄氧基）-苯胺基]_喹唑啉_6_ 基卜4-[C2-嗎啉-4-乙胺基）-甲基卜1H_吡咯_3_基卜乙醇將上述步驟所得的粗品1_{4_[3_氯_4_(3_氟苄氧基） -苯胺基]-喹唑啉-6-基}-4-(2-羥乙基）-ih-吡咯-3-曱醛 116b(500 mg，0. 71 mmol)溶解於 20 mL 二氯甲烧中，授拌下加入2-嗎啉-4-基-乙胺（185 mg，142賴〇1)，室溫下擾拌3小時後加入三乙醯氧基硼氫化鈉（3〇〇 mg， 94389 216 201016683 1.42mmo 1) ’所得的混合液在室溫下攪拌過夜，反應完畢。在反應液中加入5 mL飽和碳酸氫鈉溶液和5 mL飽和氯化鈉溶液，用二氯甲烷（1〇〇 mLx3)萃取反應液，合併的有機相用飽和氯化鈉溶液洗滌，無水硫酸鈉脫水，過濾，濾液減座濃縮，得到的固體進一步藉由TLC板進行分離純化，得到本標題產物2-{1-{4-[3-氯-4-(3-氟苄氧基）-苯胺基]-喹唑啉-6-基}-4-[(2-嗎啉-4-乙胺基）-甲基]-11^吡咯-3-基卜乙醇116(90 mg，黃色固體），產率：20%。 MS m/z (ESI) ： 632[M+1] 〇 ^NMR (400MHz, DMSO-^) : 5 9. 75(s, 1H), 8. 52(s, 1H), 8.48(s, 1H), 8. 〇6(d, lfl), 7. 99(s, 1H), 7.81(d, 1H, 1=8.8), 7.71(d, 1H), 7.45(m, 2H), 7.31(m, 4H), 7. 15(t, 1H), 5.25(s, 2H), 3. 60(s, 4H), 3. 54(t, 4H), 2. 65(m, 4H), 2.39(t, 2H), 2. 33(t, 4H) 實施例117 「3-氯-4-(3-氟苄氫某V策基f篡-乙胺基） ❹-甲基]一1H-0比洛-3-某}-啥0坐嚇Emblem 2-(H4-[3-chloro-4-(3-fluoro-oxy)-anilinobu (tetra) 啭+yl} 医-4-hydroxymethyl-1H-pyrrol-3-yl)-ethanol in 5 In a 〇〇mL single-necked flask, lithium aluminum hydride (1.48 g, 38.8 mm 〇l) was dissolved in 1.50 汕 tetrahydrofuran, and the reaction solution was cooled to ° to 5 ° C under ice bath, and stirred. The compound obtained in Example 1 was added in batches. 2_丨4-[3-chloro-4-(3-fluoro-benzyloxy)-anilino]-quinazoline _6_ylindole_6,7-dihydro- 2H-pyrano[3,4-c]pyrrole-4-one 1 hydrazine (1 〇g, 19 4 〇1), and the resulting mixture was stirred at room temperature for 3 hours and then the reaction was completed. The reaction was quenched with a mixed solvent of 1 郁 tetrahydrofuran and 50 mL of water. The reaction mixture was poured into 150 mL of water and 150 mL of ethyl acetate, and the aqueous layer was further extracted with ethyl acetate (100 mL×3). The combined organic phases were washed successively with saturated sodium carbonate solution and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained solid was washed with ethyl acetate (5 mL) to give the title product 2~(1, {4-[3-chloro-. 。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。. 215 94389 201016683 MS m/z (ESI): 519[M+1] The second step {4-[3-chloro-4-(3-fluorobenzyloxy)-anilino]-quinazoline-6- - 4-(2-Hydroxyethyl)-111-pyrrole-3-carbaldehyde In a 50 mL single-necked flask, 'o-iododecyl benzoic acid (54 〇 mg, 1.93 mmol) was dissolved in 5 mL of dimethyl 2-(1-{4-[3-chloro-4-(3-fluorobenzyloxy)-anilino]-quinazoline-6 obtained by the above procedure was added dropwise under stirring. -Based on a solution of 4-hydroxymethyl-1H-pyrrol-3-yl)-ethanol 116a (lg '1.93 mmol) in 3 mL of dimethyl sulfoxide, and the resulting solution was stirred at room temperature for 1 hour. After that, the reaction is completed. The reaction solution was added to 150 mL of 5% sodium hydrogencarbonate solution, and the solid was precipitated, filtered, and dried under vacuum to give the title product (4-[3-chloro-4-(3-fluorobenzyloxy)-aniline). ]]-啥嗤琳-6-yl}-4-(2-ethyl)-iH-indole-3-methyl 116b-(l.lg, khaki solid) crude product, directly without isolation The next step is to react. MS m/z (ESI): 518 [M+1]. Step 3 2-{1-{4-[3-chloro-4-(3-fluorobenzyloxy)-anilinyl]-quinazoline 6_ kib 4-[C2-morpholin-4-ethylamino)-methyl b 1H_pyrrole_3_ kibuethanol The crude product obtained in the above step 1_{4_[3_chloro_4_(3_fluorobenzyl) Oxyphenyl)-anilino]-quinazolin-6-yl}-4-(2-hydroxyethyl)-ih-pyrrol-3-furaldehyde 116b (500 mg, 0.71 mmol) dissolved in 20 mL In the chloroformylation, 2-morpholin-4-yl-ethylamine (185 mg, 142 lysine 1) was added with stirring, and after stirring for 3 hours at room temperature, sodium triethoxy borohydride (3 加入) was added. 〇mg, 94389 216 201016683 1.42mmo 1) 'The resulting mixture was stirred at room temperature overnight and the reaction was completed. 5 mL of saturated sodium bicarbonate solution and 5 mL of saturated sodium chloride solution were added to the reaction mixture, and the reaction mixture was extracted with dichloromethane (1 mL mL), and the combined organic phases were washed with saturated sodium Dehydration, filtration, and concentration reduction of the filtrate, the obtained solid was further purified by a TLC plate to obtain the title product 2-{1-{4-[3-chloro-4-(3-fluorobenzyloxy)-aniline ]-quinazoline-6-yl}-4-[(2-morpholin-4-ethylamino)-methyl]-11^pyrrol-3-ylbuethanol 116 (90 mg, yellow solid) Yield: 20%. MS m/z (ESI): 632 [M+1] NMR (400 MHz, DMSO-^): 5 9. 75 (s, 1H), 8. 52 (s, 1H), 8.48 (s, 1H) , 8. 〇6(d, lfl), 7. 99(s, 1H), 7.81(d, 1H, 1=8.8), 7.71(d, 1H), 7.45(m, 2H), 7.31(m, 4H ), 7. 15(t, 1H), 5.25(s, 2H), 3. 60(s, 4H), 3. 54(t, 4H), 2. 65(m, 4H), 2.39(t, 2H ), 2. 33(t, 4H) Example 117 "3-Chloro-4-(3-fluorobenzylhydrogen V-based ketone-ethylamino) ❹-methyl]-1H-0 piroxa-3 - Some}-啥0 sitting scared

重複本發明實施例52第一步至第二步所述的實驗步驟’不同的是以實施例52第一步所得的化合物3-{4_[3-氯-4-(3-氟苄氧基）-苯胺基]-噎唾琳-6_基}-1-三異丙基 94389 217 201016683The experimental procedure described in the first step to the second step of Example 52 of the present invention was repeated. The difference is the compound 3-{4_[3-chloro-4-(3-fluorobenzyloxy) obtained in the first step of Example 52. )-anilino]-噎噎琳-6_yl}-1-triisopropyl 94389 217 201016683

/ 〜wV仰pj々％便得該原料與應，得到標題化合物[3—氯__4-(3-款 {5 [(2甲氧基-乙胺基）_甲基卜1H_吡咯一基卜喹唑淋按照本發明實施例52第 F與2-甲氧基乙胺的反 -氟V氧基）-苯基]-(6一 4基）胺117(55 mg，黃色固體），產率gi g%。 MS m/z (ESI) ： 532 [M+l] !H NMR (400MHz, DMSO- ： (5 10. 94(s, 1H), 9. 67(s, 1H) 8.54(s, 1H), 8.44(s, 1H), 8.03(m, 2H), 7. 75(m, 2H), 7.47(m, 1H), 7.31(m, 3H), T.20(m, 1H), 6.80(t, 1H), 6.44(t, 1H), 5.27(s, 2H), 3.87(s, 2H), 3. 39(t! 2H)! 3. 19(s, 3H), 2.68(t, 2H) 實施例118 [3'氰~ir(3-氟卞氧D：·丰棊]~H{5—「（2-嗎味_4_乙脸基）-甲基]二各-3-基}-啥〇坐嘛-4-芊/~wV 仰pj々%, the starting material is obtained, and the title compound [3-chloro-_4-(3-款{5[(2methoxy-ethylamino)]methyl) 1H_pyrrole-based is obtained. Biquinazoline according to Example 52 of the invention, F and 2-methoxyethylamine, trans-fluoro-Voxy)-phenyl]-(6-tetrayl)amine 117 (55 mg, yellow solid) Rate gi g%. MS m/z (ESI): 532 [M+l]. NMR (400 MHz, DMSO-: (5 10. 94 (s, 1H), 9. 67 (s, 1H) 8.54 (s, 1H), 8.44 (s, 1H), 8.03(m, 2H), 7. 75(m, 2H), 7.47(m, 1H), 7.31(m, 3H), T.20(m, 1H), 6.80(t, 1H ), 6.44(t, 1H), 5.27(s, 2H), 3.87(s, 2H), 3. 39(t! 2H)! 3. 19(s, 3H), 2.68(t, 2H) Example 118 [3'Cyanide~ir(3-fluoroantimony D:·丰棊]~H{5—“(2-?味_4_乙脸基)-Methyl]diyl-3-yl}-啥〇 Sitting -4-芊

重複本發明實施例52第一步至第二步所述的實驗步驟，不同的是以實施例52第一步所得的化合物丨4_[卜 94389 218 201016683 氯-4-(3-氟苄氧基）_苯胺基]-喹唑啉基卜卜三異丙基石夕-lH-nfc11 各-2-甲駿52a作原料，按照本發明實施例52第二步所述的相同方式使得該原料與2-嗎琳-4-基-乙胺的反應，得到標題化合物[3-氯-4-(3-氟苄氧基）-苯基]-(6-{5-[(2-嗎啉-4-乙胺基）-曱基]-in-吡咯_3一基卜喹唑啉 -4-基）-胺118(26 mg，黃色固體），產率：48. 5%。 MS m/z (ESI) : 587IM+1] ]H NMR (400MHz, CDC13): (510.60(s, 1H), 8.61(s, 1H), 7. 71(m, 4H), 7. 44(d, 1H, J=8.8), 7. 33(m, 1H), 7. 20(m, ®2H), 7.16Cm, 1H), 6. 87(d, 1H, J=8. 8), 6. 76(s, 1H), 6.28(s, 1H), 5. 〇7(s, 2H), 3.87(s, 2H), 3. 71(t, 4H), 2.50(m, 8H) 實施例119 [3一氧二4-(3—氟至苯基甲碏醯篡 -1H- 口比洛 -3-基）-喹唑啉-4-基卜胗The experimental procedure described in the first step to the second step of Example 52 of the present invention is repeated, except that the compound obtained in the first step of Example 52 is _4_[Bu 94389 218 201016683 chloro-4-(3-fluorobenzyloxy) _ phenylamino]-quinazolinylbubtriisopropyl sulphate-lH-nfc11 each -2-methyljun 52a as a starting material, in the same manner as described in the second step of Example 52 of the present invention, the raw material and 2 Reaction of morphin-4-yl-ethylamine to give the title compound [3-chloro-4-(3-fluorobenzyloxy)-phenyl]-(6-{5-[(2-morpholin-4) Ethylamino)-indenyl]-in-pyrrole-3-ylquinazolin-4-yl)-amine 118 (26 mg, yellow solid). MS m/z (ESI): 587 </ RTI> </ RTI> </ RTI> NMR (400 MHz, CDC 13): (510.60 (s, 1H), 8.61 (s, 1H), 7. 71 (m, 4H), 7. 44 (d) , 1H, J=8.8), 7. 33(m, 1H), 7. 20(m, ®2H), 7.16Cm, 1H), 6. 87(d, 1H, J=8. 8), 6. 76(s, 1H), 6.28(s, 1H), 5. 〇7(s, 2H), 3.87(s, 2H), 3.71(t, 4H), 2.50(m, 8H) Example 119 [ 3-oxo-2-4-(3-fluoro-phenylformamidine-1H-portpirin-3-yl)-quinazoline-4-yldiphenyl

-[6-(1-甲磺醯基— 施例51所述的相同方式使得該原料與甲磺醯 ^到標題化合物[3-氯-4-(3-氟苄氧基）-苯基] 艮醯基W-11比洛-3-基）-啥唑琳—4-基]-胺119 94389 219 201016683 (26 1^，黃色固體），產率：48.5%。 MS m/z (ESI) ： 523[M+1] ^ NMR (400MHz, DMS0-： <5 10. 24(s, 1H), 9. 04(s, 1H), 8.94(s, 1H), 8.19(d, 1H, J = 8. 8), 8. 14(s, 1H), 7. 86(s, 1H), 7. 75(d, 1H, J=8. 4), 7. 48(d, 1H, J=6. 0), 7. 39(m, 1H), 7.30(m, 5H), 7.81(m} 1H), 5. 27(s, 2H), 3. 55(s, 3H) 實施例120-[6-(1-Methanesulfonyl--the same procedure as described in Example 51 to give the title material to the title compound [3-chloro-4-(3-fluorobenzyloxy)-phenyl] Mercapto W-11 pirazol-3-yl)-carbazol- 4-yl]-amine 119 94389 219 201016683 (26 1^, yellow solid), yield: 48.5%. MS m/z (ESI): 523 [M+1] NMR (400 MHz, DMS0-: <5 10.24 (s, 1H), 9. 04 (s, 1H), 8.94 (s, 1H), 8.19(d, 1H, J = 8. 8), 8. 14(s, 1H), 7. 86(s, 1H), 7. 75(d, 1H, J=8. 4), 7. 48( d, 1H, J=6. 0), 7. 39(m, 1H), 7.30(m, 5H), 7.81(m} 1H), 5. 27(s, 2H), 3. 55(s, 3H Embodiment 120

-~~ί-1 ~~[4-_(_3-氣-4-氟苯胺基）-啥峻琳-基~|_4-鳴嘛- 4~~甲一基-lH-pfc^-3-基 1- Λ _-~~ί-1 ~~[4-_(_3-气-4-fluoroanilino)-啥峻琳-基~|_4-鸣--4~~甲基基-lH-pfc^-3- Base 1 - Λ _

在25 mL茄形瓶中加入氫化鋁鋰L 31瓜邮 =3 mL四氫呋喃，冰浴冷卻下逐漸滴加化合物[^4-( 乳-4'氟-苯胺基）_啥嗤琳+基]+ (2_經乙基hh_0比 :3:基]，琳_4-甲㈣6⑽，，ο.· 的“LAdd lithium aluminum hydride L 31 melon = 3 mL of tetrahydrofuran to a 25 mL eggplant bottle, and gradually add the compound [^4-(milk-4'fluoro-anilino)_啥嗤琳+基]+ under ice cooling. (2_ via ethyl hh_0 ratio: 3: base), Lin _4-A (four) 6 (10),, ο. · "L

將反應液在室溫下_4小時後反應完畢 ^反應液在減壓下濃縮，得到板進仃分離純化，得簡題產叫叩各氯―4物氣用笨T 94389 220 201016683 基）-喹唑啉-6-基]-4-嗎啉-4-甲基-1H-吡咯-3-基卜乙醇 120(54 mg，黃色固體），產率：85. 54%。 MS m/z (ESI) ： 482[M+1] !H NMR (400MHz, DMS0-^ 9. 88(s, 1H), 8. 6〇(s, ih) 8.53(s, 1H), 8. 18(m, 2H), 7. 86(d, 2H, J=8. 4), 7.4g(m 1H), 7.42(d, 2H), 4. 90(s, 1H), 3. 62(m, 6H), 3. 37(m 2H), 2. 69(t, 2H), 2. 43(m, 4H) 實施例121 2-{lz..U-(_3-氯二_4-氟苯胺某 V喹唑啉—6-基 1-4-©基-1H-吡咯-3-基卜乙醢The reaction solution is allowed to react at room temperature for _4 hours. The reaction solution is concentrated under reduced pressure to obtain a plate for separation and purification, and the product is called 叩氯氯氯 ― ― 94 94 94 94 94 94 94 94 94 94 94 94 94 94 94 94 94 94 94 94 94 94 94 94 </RTI> quinazolin-6-yl]-4-morpholin-4-methyl-1H-pyrrol-3-yl-b-ethanol 120 (54 mg, yellow solid). MS m/z (ESI): 482 [M+1] "H NMR (400 MHz, DMS0-^ 9. 88 (s, 1H), 8. 6 〇 (s, ih) 8.53 (s, 1H), 8. 18(m, 2H), 7. 86(d, 2H, J=8.4), 7.4g(m 1H), 7.42(d, 2H), 4. 90(s, 1H), 3. 62(m , 6H), 3. 37(m 2H), 2. 69(t, 2H), 2. 43(m, 4H) Example 121 2-{lz..U-(_3-chlorodi-4-fluoroaniline a certain quinazoline-6-yl1-4--yl-1H-pyrrol-3-ylbu-pyridinium

重複本發明實施例120第一步所述的實驗步驟，不同的是以實施例110最終所得的化合物[；[_[4-(3-氯—4—氟一苯胺基）-喹唑啉-6-基]-4-(2-羥乙基）-lH-吡咯-3-基]一哌 ❾啶-1-甲酮110作原料，按照本發明實施例12〇第一步所述的相同方式使得該原料與氫化鋁鋰的反應，得到標題化合物2-{1-[4-(3-氯-4-氟苯胺基）-喹唑啉-6_基]_4—哌啶 -1-甲基-1Η-°比洛-3-基卜乙醇121(57 mg ’黃色固體），產率：78· 13%。 MS m/z (ESI) ： 480[M+1] !H NMR (400MHz, MSO-de) ： δ 9. 90(s, 1H), 8.55(^, 2H) 8.15(m，2H)，7.83(d，2H，J = 8.8)，7.46(t，IH), 7. 39(d’ 94389 221 201016683 2H, J = 10.0), 5.20(s, 1H), 3. 62(m, 2H), 3. 29(s, 2H), 2.67(t, 2H), 2.38(m, 4H), 1.49(m, 4H), 1.41(ra, 2H) 實施例122 2-「l-「4-((3-氣-4-氟笨胺基）-喹唑啉-6-基1-4-(4-甲基哌畊-1-甲基）-1Η-吡咯-3-基1-乙醇The experimental procedure described in the first step of Example 120 of the present invention was repeated, except that the compound [;[_[4-(3-chloro-4-fluoroanilino)-quinazoline] finally obtained in Example 110 was 6-yl]-4-(2-hydroxyethyl)-lH-pyrrol-3-yl]-piperidin-1-one ketone 110 as a starting material, the same as described in the first step of Example 12 of the present invention The reaction of the starting material with lithium aluminum hydride afforded the title compound 2-{1-[4-(3-chloro-4-fluoroanilinyl)-quinazolin-6-yl]-4-piperidine-1- Base-1Η-°Pilo-3-kib ethanol 121 (57 mg 'yellow solid), yield: 78·13%. MS m/z (ESI): 480 [M+1] <RTI ID=0.0>> d, 2H, J = 8.8), 7.46(t, IH), 7. 39 (d' 94389 221 201016683 2H, J = 10.0), 5.20(s, 1H), 3. 62(m, 2H), 3. 29(s, 2H), 2.67(t, 2H), 2.38(m, 4H), 1.49(m, 4H), 1.41(ra, 2H) Example 122 2-"1-"4-((3- 4-fluoroaminoamino)-quinazolin-6-yl1-4-(4-methylpipen-1-methyl)-1Η-pyrrol-3-yl 1-ethanol

122 v 重複本發明實施例120第一步所述的實驗步驟，不同的是以實施例107最終所得的化合物[1-[4-(3-氯-4-氟-苯胺基）_啥°坐琳-6-基]-4_(2-經乙基比咯-3-基] -(4-曱基哌畊-卜基）-曱酮107作原料，按照本發明實施例120第一步所述的相同·方式使得該原料與氫化鋁鋰的反應，得到標題化合物2-[1-[4-((3 -氯-4-氟苯胺基）-喧。坐嚇·-6_基）-4-(4-甲基旅哄-1-甲基）-1Η_πΛ洛-3-基]-乙醇 φ 122(40 mg，黃色固體），產率：45. 7°/〇。 MS m/z (ESI) ： 480[M+I] !H NMR (400MHz, DMS0-(5 9. 90(s, 1H), 8. 59(d, 2H), 8.18(d, 2H), 8. 13Cd, 1H, J=8. 8), 7. 86(d, 2H, J=8. 8), 7.48(t, 1H), 7. 38(d, 2H), 5. 00(s, lfi), 3. 62(s, 2H), 3.33(s, 2H), 2.67(t, 2H), 2.42(m, 8H), 2. 15(s, 3H) 實施例123 2-(1-{4-「3 -氯- 4- (3 -氟节氧基）-笨胺基喧口坐淋-6-基} 222 94389 201016683122 v The experimental procedure described in the first step of Example 120 of the present invention was repeated, except that the compound [1-[4-(3-chloro-4-fluoro-anilino)) was finally obtained in Example 107. Lin-6-yl]-4_(2-ethylpyrrol-3-yl)-(4-mercaptopiperidin-bu)-indolone 107 as a starting material, according to the first step of Example 120 of the present invention The same reaction was carried out to obtain the title compound 2-[1-[4-((3-chloro-4-fluoroanilino)-oxime. 4-(4-Methyl 哄-1-methyl)-1Η_πΛ -3--3-yl]-ethanol φ 122 (40 mg, yellow solid), yield: 45. 7° / 〇. MS m/z ( ESI): 480[M+I] !H NMR (400MHz, DMS0-(5 9. 90(s, 1H), 8. 59(d, 2H), 8.18(d, 2H), 8. 13Cd, 1H, J=8. 8), 7. 86(d, 2H, J=8. 8), 7.48(t, 1H), 7. 38(d, 2H), 5. 00(s, lfi), 3. 62 (s, 2H), 3.33(s, 2H), 2.67(t, 2H), 2.42(m, 8H), 2. 15(s, 3H) Example 123 2-(1-{4-"3-Chlorine - 4-(3 -Fluoro- oxy)-stupyl-based 喧口坐淋-6-基} 222 94389 201016683

-4-二乙胺基重複本發明實施例116第一步至第三步所述的實驗步驟，不同的是以實施例116第二步所得的化合物1-{4-[3-氣-4-(3--說卡氧基）-苯胺基]-嗜唾琳_6__基卜4-（2-經乙基）-1Η-吡咯-3-甲醛116b作原料，按照本發明實施例116 第二步所述的相同方式使得該原料與二乙胺的反應，得到 ®標題化合物2-(1-{4-[3-氯-4-(3-氟苄氧基）_苯胺基]一啥唑淋-6-基}-4-二乙胺基曱基-lH-η比洛-3-基）-乙醇123 (14 mg，黃色固體），產率：5%。 MS m/z (ESI) ： 674[M+1] JH NMR (400MHz, DMSO-dO : (5 9. 77(s, 1H), 8. 54(s,· 1H), 8. 50(s, 1H), 8.11(dd, 1H, J = 8.8), 8. 01(s, 1H), 7. 83(d, 1H, J=8.8), 7. 74(dd, 1H, J-8. 8), 7. 47(m, 1H), Q 7.42(s, 1H), 7. 35(m, 4H), 7. 19(t, 1H), 5. 27(s, 2H), 3.62(t, 2H), 3.42(s, 2H), 2. 68(t, 2H), 2. 53(q, 4H), 1.02(t, 6H) 實施例124 2-(l-{4-「3-氣-4-Γ3-氤苄氣基茉胺基1_-喹唑啉 -4-二甲胺基甲基-1 H-p比洛-3_基）-乙酵 223 94389 201016683-4-Diethylamine repeats the experimental steps described in the first to third steps of Example 116 of the present invention, except that the compound 1-{4-[3-gas-4 obtained in the second step of Example 116 -(3--Ethyloxy)-anilino]-salivaline_6__ kib 4-(2-ethyl)-1 Η-pyrrole-3-carbaldehyde 116b as starting material, according to Example 116 of the present invention The reaction of the starting material with diethylamine in the same manner as described in the second step gave the title compound 2-(1-{4-[3-chloro-4-(3-fluorobenzyloxy)-anilino] Carbazole-6-yl}-4-diethylaminoindolyl-lH-npylo-3-yl)-ethanol 123 (14 mg, yellow solid), yield: 5%. MS m/z (ESI): 674 [M+1] MH.sup.. NMR (400 MHz, DMSO-dO: (5 9. 77 (s, 1H), 8. 54 (s, · 1H), 8. 50 (s, 1H), 8.11 (dd, 1H, J = 8.8), 8. 01(s, 1H), 7. 83(d, 1H, J=8.8), 7. 74(dd, 1H, J-8. 8) , 7. 47(m, 1H), Q 7.42(s, 1H), 7. 35(m, 4H), 7. 19(t, 1H), 5. 27(s, 2H), 3.62(t, 2H ), 3.42(s, 2H), 2. 68(t, 2H), 2. 53(q, 4H), 1.02(t, 6H) Example 124 2-(l-{4-"3-gas-4 -Γ3-氤benzyl carbyl ylamino 1_-quinazoline-4-dimethylaminomethyl-1 Hp bilo-3_yl)-ethyl yeast 223 94389 201016683

124 重複本發明實施例116第一步至第r:步所述的實驗步驟，不同的是以實施例116第二步所得的化合物1 - {4*~ [ 3-氯-4-( 3--氟苄氧基）-苯胺基]-喹唑琳_6_基卜4-(2-羥乙基）-1Η-吡咯-3-曱醛116b作原料，按照本發明實施例116 第三步所述的相同方式使得該原料與二曱胺的反應，得到標題化合物2-(1-{4-[3-氯-4-(3-氟苄氧基）_苯胺基]一喧 ®唑淋-6-基}-4-二甲胺基甲基-1H~吡嘻-3-基）-乙醇124 (122 mg，黃色固體），產率：38.5%。 MS m/z (ESI) ： 546[M+1] ^NMR (400MHz, MS0-de) ： δ 9. 77(s, 1H), 8. 54(s, lH) 8.51(d, 1H, J=2.4)，8.10(dd, 1.H)，8..〇i(d，ih·· J=2 4) 7.83(d，1H，J=8.8)，7.74(dd，1H，J=8.8)，7 48(m，1H)’ 7.43(d，1H)，7. 35(m，4H)，7. 29(t，1H)，5.27(s 2H) φ 5.10(s, 1H), 3.61(t, 2H), 3.28(s, 2H), 2. 66(t 2H) 2.19(s, 6H) ，，實施例125 4-({[l二{4—-_.[3-_氣-4-(3-氣 y 氧 -4-（2二經基乙基）-1 Η-17比嘻-3-甲某卜胺甚丨二1 土侧氣基-六氮-1 Λ *6* -嗔°南"~4-醇 94389 224 201016683The experiment steps described in the first step to the r: step of the embodiment 116 of the present invention are repeated, except that the compound 1 - {4*~ [ 3-chloro-4-( 3-) obtained in the second step of the embodiment 116 is obtained. -fluorobenzyloxy)-anilino]-quinazoline _6_ kib 4-(2-hydroxyethyl)-1 Η-pyrrole-3-furaldehyde aldehyde 116b as a starting material, according to Example 116 of the present invention The reaction of the starting material with diamine is carried out in the same manner to give the title compound 2-(1-{4-[3-chloro-4-(3-fluorobenzyloxy)-anilino]-indolyl azole. -6-yl}-4-dimethylaminomethyl-1H~pyridin-3-yl)-ethanol 124 (122 mg, yellow solid), yield: 38.5%. MS m/z (ESI): 546 [M+1] NMR (400 MHz, MS0-de): δ 9. 77 (s, 1H), 8. 54 (s, lH) 8.51 (d, 1H, J= 2.4), 8.10(dd, 1.H), 8..〇i(d,ih·· J=2 4) 7.83(d,1H,J=8.8), 7.74(dd,1H,J=8.8), 7 48(m,1H)' 7.43(d,1H), 7.35(m,4H), 7.29(t,1H), 5.27(s 2H) φ 5.10(s, 1H), 3.61(t, 2H), 3.28(s, 2H), 2. 66(t 2H) 2.19(s, 6H) , , Example 125 4-({[l 2{4—-_.[3-_气-4-( 3- gas y oxy-4-(2 di-diethyl)-1 Η-17 嘻-3-methyl amide 丨丨 2 1 soil side gas-hexanitro-1 Λ *6* -嗔° South "~4-alcohol 94389 224 201016683

重複本發明實施例116第一步至第三步所述的實驗步驟’不同的是以實施例116第二步所得的化合物卜{4-[ 3-氯-4-(3--氟苄氧基）__苯胺基]_喹唑啉_6_基卜4_(2_羥乙基）-111-吼嘻~3~甲醛116b作原料，按照本發明實施例116 第三步所述的相同方式使得該原料與4-氨曱基-1，1 —二侧氧基-六氫-1 λ 噻喃-4-醇的反應，得到標題化合物 ❹4-U [卜U-[3-氯-4-(3-氟苄氧基）-苯胺基]-喹唑啉_6__基} -4-(2-羥基乙基）-ih-吡咯-3-曱基]-胺基}-甲基）4，卜二侧氧基-六氫-1又*6*-噻喃-4-醇125(103 mg，黃色固體），產率：31. 3%。 MS m/z (ESI) ： 680[M+1] - !H NMR (400MHz, DMS0-: ά 9. 77(s, 1H), 8. 55(s, 1H) 8.50(s, 1H), 8. 10(d, 1H, J=9. 6), 8.01(s, 1H), 7. 84(d φ 1H, J = 8.8), T.75(dd, 1H, J=8. 8), 7.49(m, 1H), 7. 43(s 1H), 7. 36(m, 4H), 7. 20(m, 1H), 5.27(s, 2H), 3. 64(t 2H), 3.58(s, 2H), 3. 10(m, 4H), 2. 67(t, 2H), 2. 5〇(m> 2H), 2.10(m, 2H), 1. 6d(m, 2H) 實施例126 2-(l-{4-「3 -氯- 4-(3 -氟爷氧基）-茉胺某-嗜唾喊- i -4-{「（l，1_二侧氣基-六氫·~1 λ *6*-嗟喃-4曱篡吟早1 _ 甲基卜1Η-吡咯-3-基乙醇 94389 225 201016683The experimental procedure described in the first step to the third step of the embodiment 116 of the present invention is repeated. The difference is that the compound obtained in the second step of the embodiment 116 is {4-[ 3-chloro-4-(3--fluorobenzyloxy). Base) __anilino]-quinazoline_6_ kib 4_(2-hydroxyethyl)-111-吼嘻~3~formaldehyde 116b as a starting material, the same as described in the third step of Example 116 of the present invention The reaction of the starting material with 4-aminomethyl-1,1-di-oxy-hexahydro-1 λ thiopyran-4-ol gives the title compound ❹4-U [Bu U-[3-chloro-4] -(3-fluorobenzyloxy)-anilino]-quinazoline_6__yl}-4-(2-hydroxyethyl)-ih-pyrrole-3-indenyl]-amino}-methyl) 4重量。 The bis-oxo-hexahydro-1 and *6*-thiopyran-4-ol 125 (103 mg, yellow solid), yield: 31.3%. MS m/z (ESI): 680 [M+1] - "H NMR (400 MHz, DMS0-: ά 9. 77(s, 1H), 8. 55(s, 1H) 8.50(s, 1H), 8 10(d, 1H, J=9. 6), 8.01(s, 1H), 7. 84(d φ 1H, J = 8.8), T.75(dd, 1H, J=8. 8), 7.49 (m, 1H), 7. 43(s 1H), 7. 36(m, 4H), 7. 20(m, 1H), 5.27(s, 2H), 3. 64(t 2H), 3.58(s , 2H), 3. 10(m, 4H), 2. 67(t, 2H), 2. 5〇(m> 2H), 2.10(m, 2H), 1. 6d(m, 2H) Example 126 2-(l-{4-"3-Chloro-4-(3-fluoro-yloxy)-mosamine--salvation-i -4-{"(l,1_di-side gas-hexahydrogen ·~1 λ *6*-嗟嗟-4曱篡吟早1 _ Methylbu-1Η-pyrrol-3-ylethanol 94389 225 201016683

126 重複本發明實施例116第一步至第三步所述的實驗步驟，不同的是以實施例116第二步所得的化合物丨—丨^^ — 氯-4-(3--氟苄氡基）-苯胺基卜喹唑啉_6_基卜羥乙基）-1Η-吡咯-3-曱醛116b作原料，按照本發明實施例ιΐ6 第二步所述的相同方式使得該原料與(1，1 _二侧氧基_ ©六氫_1又嗔喃-4-基）-甲胺的反應，得到^題化合物 2-(1-{4-[3-氯-4-(3-氟苄氧基）-苯胺基；|_喹唑啉-6_基} -4-{[(1，1-二側氧基-六氫-1 λ *6*-嗔喃-4-曱基）_胺基]_ 曱基卜1Η-吡咯-3-基）-乙醇126(115 mg，黃色固體），產率：35. 8% 〇 MS m/z (ESI) ： 664[M+1] !H NMR (400MHz, DMSO-de)： 5 9. 82(s, 1H), 8. 55(m 2H) ⑩ 8.10(d，1H，J=8.8)，8.03(d, 1H，J=2.4)，7.86(d, 1H， J=8.8)，7.77(dd，1H，J=7.2)，7.53(m，2H)，7.39(s，in)， 7. 35(m, 3H), 7. 19(m, 1H), 5.27(s, 2H), 3. 74(s? 2H), 3.66(t, 2H), 3.18(m, 3H), 2.97(d, 2H), 2.7l(m, 4H), 2. 00(m, 4H) 實施例127 2-Π-{4-「3_氯-Klrlg氧基）-苯胺篡卜喹唑呲斗―其} 酿棊HU-甲基比略一3_甚哼 94389 226 201016683126 The experimental procedure described in the first step to the third step of the embodiment 116 of the present invention is repeated, except that the compound obtained in the second step of the embodiment 116 is 丨-丨^^-chloro-4-(3--fluorobenzidine). Alkaloid--anilinoquinazoline-6-yl-hydroxyethyl)-1 -pyrrole-3-furaldehyde 116b as a starting material, in the same manner as described in the second step of the present invention, the starting material 1,1 _ di-sideoxy_ ©hexahydro-1-indol-4-yl)-methylamine reaction, the compound of the formula 2-(1-{4-[3-chloro-4-(3-) Fluorobenzyloxy)-anilino;|_quinazolin-6-yl}-4-{[(1,1-di-oxy-hexahydro-1 λ *6*-pyran-4-yl) ) _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ !H NMR (400MHz, DMSO-de): 5 9. 82(s, 1H), 8. 55(m 2H) 10 8.10 (d, 1H, J = 8.8), 8.03 (d, 1H, J = 2.4) , 7.86 (d, 1H, J = 8.8), 7.77 (dd, 1H, J = 7.2), 7.53 (m, 2H), 7.39 (s, in), 7. 35 (m, 3H), 7. 19 ( m, 1H), 5.27(s, 2H), 3.74(s? 2H), 3.66(t, 2H), 3.18(m, 3H), 2.97(d, 2H), 2.7l(m, 4H), 2. 00 (m, 4H) Example 127 2-Π-{4-"3_Chlorine -Klrlg oxy)-aniline oxime quinazozole - its} brewing 棊HU-methyl ratio slightly 3_ 哼 94389 226 201016683

127 重複本發明實施例116第-步至第三步所述的實驗步驟，不同的是以實施例116第二步所得的化合物卜{4_[3_ 氯-4-(3--氟苄氧基）-苯胺基]—喹唑啉_6_基卜4_(2_羥乙基）-1Η-吡咯-3-甲醛116b作原料，按照本發明實施例116 第二步所述的相同方式使得該原料與2 -甲確酿基乙胺的 ®反應’得到標題化合物2-(1-{4-[3-氯-4-(3-氟节氧基）_ 苯胺基]-啥嗤琳-6-基}-4-[(2-曱石黃醢基乙胺基）一曱基] -111-11比洛-3-基}-乙醇127(97 111呈，黃色固體），產率： 32. 1% 〇 MS m/z (ESI) ： 624[M+1] !H NMR (400MHz, DMS0-d〇: 5 9. 77(s, 1H), 8. 55(m, 1H), 8.51(s, 1H), 8.10(dd, 1H, J=9. 6), 8. 01 (d, 1H, J=2.8), φ 7.85(d, 1H, J = 8. 8), 7.76(dd, 1H, J=8. 8), 7.49(m, 2H), 7.37(m, 4H), 7. 19(m, 1H), 5.27(s, 2H), 3.65(t, 4H), 3.28(m, 2H), 3. 02(m, 2H), 2.68(t, 2H), 2.51(t, 3H) 實施例128 [1-丨4-「3-氯-4-(3-氟苄氧基）-苯胺某1-啥咬琳-6-某} -4-(2_嗎1#-4-乙基）-1及-°比嘻-3-基1-嗎散-4-甲臟 94389 227 201016683127 The experimental procedure described in the first step to the third step of the embodiment 116 of the present invention is repeated, except that the compound obtained in the second step of the embodiment 116 is {4_[3_chloro-4-(3--fluorobenzyloxy). )-anilino]-quinazoline_6_ylbu 4-(2-hydroxyethyl)-1Η-pyrrole-3-carbaldehyde 116b as a starting material, in the same manner as described in the second step of Example 116 of the present invention Reaction of the starting material with 2-ethylglycolate® to give the title compound 2-(1-{4-[3-chloro-4-(3-fluoro-oxy)-phenylamino]-啥嗤琳-6 -基}-4-[(2-曱石黄醢基ethylamino)-indenyl]-111-11pyr-3-yl}-ethanol 127 (97 111 as a yellow solid), yield: 32. % 〇MS m/z (ESI) : 624[M+1] !H NMR (400MHz, DMS0-d〇: 5 9. 77(s, 1H), 8. 55(m, 1H), 8.51(s, 1H), 8.10(dd, 1H, J=9. 6), 8. 01 (d, 1H, J=2.8), φ 7.85(d, 1H, J = 8. 8), 7.76(dd, 1H, J =8. 8), 7.49(m, 2H), 7.37(m, 4H), 7. 19(m, 1H), 5.27(s, 2H), 3.65(t, 4H), 3.28(m, 2H), 3. 02(m, 2H), 2.68(t, 2H), 2.51(t, 3H) Example 128 [1-丨4-"3-Chloro-4-(3-fluorobenzyloxy)-aniline 1 -啥咬琳-6-某} -4-(2_?1#-4-ethyl)-1 and -°比嘻-3- 1- 4-scattered it dirty 94389227 201 016 683

甲％1 2-[l-{4-[3-氯-4-(3、氟节氧基）一苯胺基]一啥嗤琳 ._6-基}-4-(嗎啉-4_羰基）基]—乙醋在50mL蘇形瓶中，將[H4〜[3一氯+ (3_氣_节氧基） -苯胺.基]琳+基}_4_(2—__乙基）]Hm 基]-嗎琳-4-基-甲_ 27(500屻，〇· 83麵υ溶解於2〇乩四虱咬喃中，料下加人〇.23 mL三乙胺，所得的混合液 ©在冰浴冷卻下逐漸滴加曱確酿氯（議心^咖㈣的5 虹四氫吱喃溶液，反應液在室溫下擾掉i小時後反應完，。將反應液加人到5〇mL水中，有黃色㈣析出，過滤，得到的固體在真空下錢’得到本標題產物甲績酸^[卜 ί4-[3-氣-4-(3-氟苄氧基）_苯胺基]—喹唑啉_6_基卜4_ (嗎啉-4-羰基）-lH-吡咯-3-基]-乙酯^83(500 mg，黃色固體），產率：90%。 MS m/z (ESI) ： 681[M+1] 94389 228 201016683 第二步 [l-{4-[3-氣-4-(3-氟苄氧基）_苯胺基]-喹唑啉-6~基} -4-（2-嗎啉-4-乙基吡咯-3-基]-嗎啉-4-曱酮在25 mL茄形瓶中，將上述步驟所得的化合物甲碲峻 2-[1-{4-[3-氣-4-(3-氟苄氧基）_苯胺基]_喹唑啉_6〜基} -4-(嗎啉-4-羰基）-ih~吡咯一 3_基]_乙酉旨128a(8〇 %，〇· 118 mmol)溶解於2 mL [1，4]二氧六環中，混合液在欖拌下加入1 mL嗎啉，加熱反應液至7(rc，反應4小時反應完畢。反應液冷卻至室溫，滴加到5〇址水中，析4 白色固體’過濾、’所得的粗品進—步藉由TLC板進行分離純化，得到本標題產物^氧基>苯胺 •基]-喹唑啉-6-基卜4-(2-嗎啉-4-乙基）— 1H_吡咯〜3—基]一嗎啉-4-甲酮128(50 mg ’黃色固體），產率：64%。 MS m/z (ESI) ： 672[M+1] 'H NMR (400MHz, DMSO-5 9.8〇(s, iH), 9. 〇〇Cs 1H) 8.60(s, 1H), 8.20(d, 2H), 7. 90(m> 7. 80(s, 1H), ❹ 7.47(m，1H), 7. 32 (m’ 3H)，7.19 (m，1H〉，5. 28(s，2H)， 3.97(s，2H)，3.81(s，2H)，3.67(s，8H)，3.48(s 2H)， 3.40(s, 2H), 3. 14(s, 2H), 3. 〇4(s, 2H) 實施例129 [l-{4r[_3-氧-4-(3.-1..苄氧基）-笔龙^基^喹唑被^^ 氧基乙基)二111「°比洛-3-是_]^啉一4一甲酮 94389 229 201016683 ΟA1% 1-[l-{4-[3-chloro-4-(3,fluorohexyloxy)-phenylamino]-indenyl._6-yl}-4-(morpholin-4-carbonyl) Base] - Ethyl vinegar in a 50mL sigma bottle, [H4~[3 chloro + (3_ _ _ 氧基 oxy) - aniline. yl] lin + yl} _4_ (2 - _ ethyl)] Hm Base]-Molin-4-yl-A_ 27 (500 屻, 〇 · 83 υ υ dissolved in 2 〇乩虱虱 , , , , , , , 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 Under the cooling of the ice bath, gradually add 5 chlorotetrahydrofuran solution of chlorinated chlorine (resolving the heart of the coffee), and the reaction solution is disturbed at room temperature for 1 hour, and the reaction is completed. Add the reaction solution to 5 〇. In the water of mL, yellow (4) is precipitated, filtered, and the obtained solid is obtained under vacuum to obtain the title product, the acid of the title product, [bü4-[3- gas-4-(3-fluorobenzyloxy)-anilino]- Quinazoline _6_ kib 4_(morpholine-4-carbonyl)-lH-pyrrol-3-yl]-ethyl ester ^83 (500 mg, yellow solid), yield: 90%. MS m/z ( ESI): 681[M+1] 94389 228 201016683 Second step [l-{4-[3-Ga-4-(3-fluorobenzyloxy)-anilino]-quinazoline-6-yl} 4-(2-morpholin-4-ethylpyrrol-3-yl)-morpholin-4-indanone in a 25 mL eggplant-shaped bottle, the above steps The compound obtained is methyl 2-[1-{4-[3-gas-4-(3-fluorobenzyloxy)-anilino]-quinazoline-6-yl}-4-(morpholine-4) -carbonyl)-ih~pyrrole-3_yl]_ethyl hydrazine 128a (8〇%, 〇·118 mmol) was dissolved in 2 mL of [1,4] dioxane, and the mixture was added to 1 mL under the mixture. Morpholine, the reaction solution was heated to 7 (rc, reaction was completed for 4 hours. The reaction solution was cooled to room temperature, added dropwise to 5 Å of water, and 4 white solids were filtered, and the resulting crude product was passed through a TLC plate. Is isolated and purified to obtain the title product: oxy > aniline yl]-quinazoline-6-yl b 4-(2-morpholin-4-ethyl)-1H_pyrrole~3-yl] Phenan-4-one ketone 128 (50 mg 'yellow solid), yield: 64%. MS m/z (ESI): 672[M+1] 'H NMR (400 MHz, DMSO-5 9.8 〇(s, iH) ), 9. 〇〇Cs 1H) 8.60(s, 1H), 8.20(d, 2H), 7. 90(m> 7. 80(s, 1H), ❹ 7.47(m,1H), 7. 32 ( m' 3H), 7.19 (m, 1H>, 5.28 (s, 2H), 3.97 (s, 2H), 3.81 (s, 2H), 3.67 (s, 8H), 3.48 (s 2H), 3.40 ( s, 2H), 3. 14(s, 2H), 3. 〇4(s, 2H) Example 129 [l-{4r[_3-oxy-4-(3.-1..benzyloxy)- Pen dragon ^ base ^ quinazole ^^ oxyethyl) di 111 "° _ Bulow -3- is] a ^ methanone morpholine-4 94389 229 201016683 Ο

〇aF〇aF

129 Ν，重複本發明實施例128®-步至第二步所述的實驗步驟’不同的是以實施例128第-步所得的化合物甲續酸2 — [1-{4-[3-氣-4-(3-氟¥氧基）-苯胺基卜㈣琳+基Μ — (嗎啉-4-羰基)-1Η-吡咯-3-基卜乙酉曰t ma作原料，按昭本發明實施例128第二步所述的相同方式使得該原料與甲、醇鈉的反應，得到標題化合物Π_η^3_1_4_(3__ ❿基）-苯胺基]-啥㈣-6-基卜4-(2-甲氧基乙基）鲁吨略 -3-基]-嗎啉-4-曱酮129(25mg，黃色固體），產率：3 MS m/z (ESI) ： 617[M+1] 。。 !H NMR (400MHz, DMSO- de) ： δ l〇 i〇rc; 1lT、。 '1H), 8；〇9((s；；：；； ?8·：^ 3H), 7.50U, 2H), 7.30U, 3H), 7. l8(t, 1Ηχ 5> ； 2H), 3.62(3, 8H), 3. 53(t, 2H), 3.27(s, 3H) 2 78 ❿ 2H) ’ U，實施例130 Π-{4-.Ι3_-Α-4-氟苄氧基 -4-(2-二.乙—胺碁比咯~^ Ο129 Ν, repeating the experimental procedure described in the embodiment 128®-step to the second step of the present invention, the difference is the compound obtained in the first step of the embodiment 128, the methyl 2-(1-{4-[3-gas -4-(3-Fluoroacetoxy)-anilinobu (tetra) linyl + hydrazine - (morpholine-4-carbonyl)-1 Η-pyrrol-3-yl acetamidine t ma as raw material, according to the invention The reaction of the starting material with sodium and sodium alkoxide in the same manner as described in the second step of Example 128 gave the title compound Π_η^3_1_4_(3__ decyl)-anilino]-indole (tetra)-6-ylbu 4-(2- Ethoxyethyl) ruthen-3-yl]-morpholin-4-indolone 129 (25 mg, yellow solid), yield: 3 MS m/z (ESI): 617[M+1]. . !H NMR (400MHz, DMSO-de): δ l〇 i〇rc; 1lT,. '1H), 8; 〇9((s; ;:;; ?8·:^ 3H), 7.50U, 2H), 7.30U, 3H), 7. l8(t, 1Ηχ 5>; 2H), 3.62 (3, 8H), 3. 53(t, 2H), 3.27(s, 3H) 2 78 ❿ 2H) ' U, Example 130 Π-{4-.Ι3_-Α-4-fluorobenzyloxy-4 -(2-二.乙-胺碁比咯~^ Ο

重複本發明實施例128第一步至第二舟、、夕所述的實 94389 230 201016683 驟，不同的是以實施例128第一步所得的化合物甲磺酸 2 [1-{4-[3 -氯-4-(3 -氣节氧基）-苯胺基]坐琳—6 —基} -4-(嗎啉-4-羰基）-1Η-吡咯-3-基]-乙酯128a作原料，按照本發明實施例128第二步所述的相同方式使得該原料與二乙胺的反應，得到標題化合物[1-{4-[3-氯-4-(3-氟苄氧基）-苯胺基]-喹唑啉-6-基}-4-(2-二乙胺基乙基）4 H_吡咯-3-基]-嗎啉-4-甲酮130(40 mg，黃色固體），產率：48%。 MS m/z (ESI) : 657[M+1] !H NMR (400MHz, DMSO-： d 9. 80(s, 1H), 9. 00(s, 1H) ® 8· 62(s， 1H)， 8. 20(d, 1H, J=1 0. 〇), 8. 14(s, 1H) 7. 92(m, 3H), 7. 90(s, 1H), 7. 47(m, 1H), 7.32 (m, 3H), 7. 19(m, 1H), 5. 28(s, 2H), 3. 67(s, 8H), 3. 50(t, 2H), 3. 19(q, 4H), 2. 96(t, 2H), 1.26(t, 6H) 實施例131 [1-{4-「3-氯-4_-(3-氟苄氣某）-笨胺基]_唾嗤啦-6-某} -1-(2-二甲胺基乙基）-1Η-」比咯-3-篡1-嗎呲-4 一甲酾The first step to the second boat of the present invention was repeated, and the actual product was 94389 230 201016683, except that the compound obtained in the first step of Example 128 was methanesulfonic acid 2 [1-{4-[3 -Chloro-4-(3- gas oxy)-anilino]- lysine-6-yl}-4-(morpholin-4-carbonyl)-1Η-pyrrol-3-yl]-ethyl ester 128a as raw material Reaction of the starting material with diethylamine in the same manner as described in the second step of Example 128 of the present invention afforded the title compound [1-{4-[3-chloro-4-(3-fluorobenzyloxy)- Anilino]-quinazolin-6-yl}-4-(2-diethylaminoethyl)4H-pyrrol-3-yl]-morpholin-4-methanone 130 (40 mg, yellow solid) , Yield: 48%. MS m/z (ESI): 657 [M+1] "H NMR (400 MHz, DMSO-: d 9. 80 (s, 1H), 9. 00 (s, 1H) ® 8· 62 (s, 1H) , 8. 20(d, 1H, J=1 0. 〇), 8. 14(s, 1H) 7. 92(m, 3H), 7. 90(s, 1H), 7. 47(m, 1H ), 7.32 (m, 3H), 7. 19(m, 1H), 5. 28(s, 2H), 3. 67(s, 8H), 3. 50(t, 2H), 3. 19(q , 4H), 2. 96(t, 2H), 1.26(t, 6H) Example 131 [1-{4-"3-Chloro-4_-(3-fluorobenzyl)-phenylamino]_sal嗤啦-6-某}-1-(2-dimethylaminoethyl)-1Η-"pyrrol-3-篡1-?呲-4 one formazan

重複本發明實施例128第一步至第二步所述的實驗步驟，不同的疋以實施例12 8第一步所得的化合物甲績酸 2-[1-{4-[3-氯-4-(3-氟苄氧基）-苯胺基]—喹唑啉_6_基} -4-(嗎琳-4-幾基）-1Η-啦咯-3-基]-乙酯128a作原料，按照本發明實施例128第二步所述的相同方式使得該原料與 94389 231 201016683 二甲胺的反應，得到標題化合物[l-{4-[3-氯-4-(3-氟苄氧基）-苯胺基]-喹唑啉-6-基}-4-(2-二甲胺基乙基）-1Η-°比咯-3-基]-嗎啉-4-甲酮131(180 mg，黃色固體），產率： 65% ° MS m/z (ESI) ： 630[M+1] NMR (400MHz, DMSO- cf〇 : 5 9. 80(s, 1H), 8. 60(d, 2H, J = 9.2), 8.13(dd, 1H, J = 9. 2), 8. 00(d, 1H, J=2. 0), 7. 84(d, 1H, J=8.8), 7. 73(dd, 1H, J=8.8), 7. 66(d, 1H, J = 1.6), 7.46(m, 2H), 7. 30(m, 3H), 7. 18(t, 1H), 5. 26(s, ®2H), 3.60(s, 8H), 2. 66(ΐ, 2H), 2. 44(t, 2H), 2. 17(s, 6H) 實施例132 「l-{4-「1-(4-氣节基）_1H-P弓卜坐_5 -胺基-喧口坐琳-6-基} -4-(2-經乙基）-lH-g比洛-3-基1-嗎琳-4-曱酮The experimental procedure described in the first step to the second step of Example 128 of the present invention was repeated, and the compound obtained in the first step of Example 12 was treated with 2-[1-{4-[3-chloro-4]. -(3-Fluorobenzyloxy)-anilino]-quinazoline-6-yl}-4-(Merlin-4-yl)-1Η-l-r--3-yl]-ethyl ester 128a as raw material Reaction of the starting material with 94389 231 201016683 dimethylamine in the same manner as described in the second step of Example 128 of the present invention afforded the title compound [l-{4-[3-chloro-4-(3-fluorobenzyloxy) -phenylamino]-quinazolin-6-yl}-4-(2-dimethylaminoethyl)-1 Η-pyrrol-3-yl]-morpholine-4-ketone 131 (180 Mg, yellow solid), Yield: 65% ° MS m/z (ESI): 630[M+1] NMR (400MHz, DMSO- cf〇: 5 9. 80 (s, 1H), 8. 60 (d , 2H, J = 9.2), 8.13(dd, 1H, J = 9. 2), 8. 00(d, 1H, J=2. 0), 7. 84(d, 1H, J=8.8), 7 73(dd, 1H, J=8.8), 7. 66(d, 1H, J = 1.6), 7.46(m, 2H), 7. 30(m, 3H), 7. 18(t, 1H), 5. 26(s, ®2H), 3.60(s, 8H), 2. 66(ΐ, 2H), 2. 44(t, 2H), 2. 17(s, 6H) Example 132 "l-{ 4-"1-(4-气气基)_1H-P 弓坐_5 -Amino-喧口坐琳-6-yl} -4-(2-ethyl) -lH-g piro-3-yl 1-morphin-4-indanone

132N 232 94389 201016683132N 232 94389 201016683

第一步 [1-(4-氟节基）-i β坐-5-基]-(6-蛾喧°坐琳_4_基）-胺 ® 重複本發明實施例1第五步所述的實驗步驟，不同的是以實施例1第四步所得的化合物6-碘-3H-喹唑啉-4-酮 If作原料’按照本發明實施例1第五步所述的相同方式使該原料與1-(4-氟节基引峻_5-胺的反應，得到標題化合物[1-(4-氟苄基）-ih-吲嗤-5-基]-(6-碘-喹唑啉-4-基）-胺132a(13 g，灰白色固體），產率71.8%。 MS m/z (ESI) ： 496[M+1] ❹第一少 2-(4-{3-[2-(4-氟苄基u-4—乙烯基_2Η_π比唑_3_基]一烯丙胺基}啥坐琳6-基）-6,7-二氫-2Η-η比喃[3,4-c]n比口各 -4-明在250乩茄形瓶中，將上述步驟所得的化合物[1-(4-氟节基）-則丨唾-5-基]_(6_蛾_啥㈣_4_基）_胺132&(5 g lOmmol) 6,7 一氳-2H-吼喃并[3,4一c]o比嘻_4_酉同融 (1.78 g，13 _1)，磷酸鉀(6.37 g，3〇丽〇1)，碘化亞 94389 233 201016683 銅（2.86 g，15mmGl)溶解於5Q mL Ν，Ν_:ψ基甲醯胺中，混合物在攪拌下加入Ν，Ν，-二f基-L2—乙二胺（132 g， 15ΠΠΠ01)，加熱反應液到65。〇，攪拌過夜。將反應液倒入 250 mL冰水中，有墨綠色固體析出’抽濾，得到的固體用 300 niL甲醇洗滌，固體在真空下乾燥，得到本標題產物 2-(4-{3-[2-(4-氟苄基D-4-乙烯基_2H_o比唑_3_基]一烯丙胺基}-喹唑啉-6-基）_6,7_二氫_2H—吡喃[3,4_c]吡咯 -4-酮132b(5.1g，墨綠色固體），不經分離直接進行下一步反應。 ® MS m/z (ESI) ： 478 [M+l] 第三步 .[1 {4 [ 1-(4-氟苄基）-iu-吲唾胺基]-喧嗤琳一基}-4-(2-羥乙基）-1H-吡咯-3-基]-嗎啉_4_甲酮將2-(4-{3-[2-(4-氟苄基1)-4-乙烯基 -2H-°比唆-3- 基]-烯丙胺基卜喹唑啉-6-基）_6, 7一二氫_2Η_π比喃[3,4_c]The first step [1-(4-fluoro)]-iβ-spin-5-yl]-(6-mothene _4_yl)-amine® is repeated as described in the fifth step of Example 1 of the present invention. The experimental procedure differs from the compound 6-iodo-3H-quinazolin-4-one If obtained in the fourth step of Example 1 as the starting material in the same manner as described in the fifth step of Example 1 of the present invention. Reaction of the starting material with 1-(4-fluoronodal benzyl 5-amine to give the title compound [1-(4-fluorobenzyl)-ih-indol-5-yl]-(6-iodo-quinazoline) Phenyl-4-yl)-amine 132a (13 g, off-white solid), yield 71.8%. MS m/z (ESI): 496[M+1] ❹ first less 2-(4-{3-[2 -(4-fluorobenzyl u-4-vinyl 2 Η_π-biazole _3_yl]-allylamino} 啥琳 6-yl)-6,7-dihydro-2 Η-η than butyl [3, 4-c]n is a compound of the above-mentioned step in the 250-liter eggplant-shaped bottle, and the compound obtained in the above step [1-(4-fluoro-based)-] 丨 -5-5-yl]_(6_Moth _啥(四)_4_基)_amine 132&(5 g lOmmol) 6,7 a 氲-2H-吼并[3,4 a c]o than 嘻_4_酉同融 (1.78 g, 13 _1), Potassium phosphate (6.37 g, 3 〇〇 1), iodide sub-94389 233 201016683 copper (2.86 g, 15 mm Gl) dissolved in 5Q mL Ν, Ν _: mercaptocarbamide, mixed Add hydrazine, hydrazine, -di-f-yl-L2-ethylenediamine (132 g, 15 ΠΠΠ 01) with stirring, and heat the reaction mixture to 65 ° C. Stir overnight. Pour the reaction solution into 250 mL of ice water with dark green Solid precipitation was filtered off with suction, the obtained solid was washed with 300 <RTI ID=0.0></RTI> </RTI> <RTIgt; Benzene_3_yl]-allylamino}}-quinazolin-6-yl)_6,7-dihydro-2H-pyran[3,4_c]pyrrol-4-one 132b (5.1 g, dark green solid ), proceed to the next reaction without isolation. ® MS m/z (ESI): 478 [M+l] Step 3. [1 {4 [ 1-(4-Fluorobenzyl)-iu-吲吲胺4-(4-hydroxyethyl)-1H-pyrrol-3-yl]-morpholine_4_methanone 2-(4-{3-[2-(4) -fluorobenzyl 1)-4-vinyl-2H-° than 唆-3-yl]-allylaminoquinazolin-6-yl)_6, 7-dihydro-2Η_πpyran[3,4_c]

吡咯-4-酮 132b(150 mg，0· 3 mmol)和 1 mL 嗎啉加入 1〇 mL ❾茄形瓶中，混合物加熱至12(rc，攪拌過夜，反應完畢。反應液在減壓下濃縮，得到的殘留物用二氯曱烷萃取，有機相在減壓下濃縮，得到的固體進一步藉由11^板分離純化，得到黃色固體，真空乾燥得到標題產物— d 氟苄基）-1Η-吲唑-5-胺基]-喹唑啉—6_基卜4_(2_羥乙基） -1H-吡咯-3-基]-嗎啉-4-甲酮132(27 mg，淺黃色固體），產率：15%。 MS m/z (ESI) ： 592 [M+l] 234 94389 201016683 9. 〇6(m, J = 8.8)， 7.63(s， 4.77(s, !H NMR C400MHz, DMS0- de) ： d 10.49(s> 1R) 1H), 8.51(s, 1H), 8.31(s, 1H), 8. 18(dd, 2H 7.92(s, 1H), 7.88(m, 2H), 7. 76(d, 1H, J=8 ^ 1H), 7.38(m, 1H), 7. 10(m, 3H), 5. 72(s, 2H) 1H), 3.62(m, 10H), 2.71(t, 2H) ’ 實施例133Pyrrole-4-one 132b (150 mg, 0.3 mmol) and 1 mL of morpholine were added to a 1 mL mL eggplant flask, and the mixture was heated to 12 (rc, stirred overnight, the reaction was completed. The reaction was concentrated under reduced pressure. The residue obtained is extracted with dichloromethane and EtOAc (EtOAc m. Oxazol-5-amino]-quinazoline-6-ylbu-4_(2-hydroxyethyl)-1H-pyrrol-3-yl]-morpholin-4-methanone 132 (27 mg, pale yellow solid ), Yield: 15%. MS m/z (ESI): 592 [M+l] 234 94389 201016683 9. 〇6(m, J = 8.8), 7.63(s, 4.77(s, !H NMR C400MHz, DMS0- de) : d 10.49( s> 1R) 1H), 8.51(s, 1H), 8.31(s, 1H), 8. 18(dd, 2H 7.92(s, 1H), 7.88(m, 2H), 7. 76(d, 1H, J=8 ^ 1H), 7.38 (m, 1H), 7. 10(m, 3H), 5. 72(s, 2H) 1H), 3.62(m, 10H), 2.71(t, 2H) ' 133

▽ Ν· 133 ί複本發明實施例132第-步至第三步的實驗步驟，不同的是以第二步所得的化合物將2-(4-{3-[2-(4-氟苄基1)-4-乙烯基-2Η-吡唑-3-基]-烯丙胺基卜喹唑啉_6 —基） -6,7-二氫-211-°比喝[3,4-(：]°比洛-4-酿）1321)作原料，按照 ❿本發明實施例13 2第二步所述的相同方式使得該原料與1 -甲基°底啡的反應’得到標題化合物1 - {4-.[ 1 - (4_氟节基） -1H吲°圭-5-胺基]-喧°坐琳-6-基}-4-(2-羧乙基）_1Η-β比洛 -3-基]-(4-甲基-〇底啡-1-基）-曱酮133(10 mg，黃色固體），產率：5. 5% 〇 MS m/z (ESI) : 6G5 [M+1] !H NMR (400MHz, DMSO- ： § 10.30(s, 1H), 8. 75(s, 1H), 8.52(s, 1H), 8.31(s, 1H), 8. 12(m, 2H), 7. 86Cm, 235 94389 201016683 1H), 7. 76(m, 3H), 7. 52(s, 1H), 7.49(m, 1H), 7. 07(m, 3H), 5.72(s, 2H), 4. 76(s, 1H), 3. 59(m, 6H), 2. 70(s, 2H), 2. 51(m, 4H), 2.21(m, 3H) 實施例134 1-{4-[1-(4-氟苄基）-111-°引。坐-5-胺某1-唾峻琳-6-基} -4-(2-羥乙基）-1 H-吡咯-3-甲酸-(2-二胺某乙某）-醯胺▽ Ν · 133 复 The experimental procedure of the first step to the third step of the embodiment 132 of the invention, the difference is that the compound obtained in the second step is 2-(4-{3-[2-(4-fluorobenzyl 1) )-4-vinyl-2Η-pyrazol-3-yl]-allylaminoquinazoline-6-yl)-6,7-dihydro-211-° than drink [3,4-(:] °Bilo-4-brew) 1321) as a starting material, the reaction of the starting material with 1-methyl-pereptin is obtained in the same manner as described in the second step of the present invention, in the same manner as in the second step of the invention, to obtain the title compound 1 - {4 -.[ 1 - (4_Fluoro]yl-1H吲°圭-5-Amino]-喧°坐琳-6-yl}-4-(2-carboxyethyl)_1Η-βBilo-3 -yl]-(4-methyl-indextrin-1-yl)-fluorenone 133 (10 mg, yellow solid), yield: 5. 5% 〇MS m/z (ESI): 6G5 [M+ 1] !H NMR (400MHz, DMSO- : § 10.30(s, 1H), 8. 75(s, 1H), 8.52(s, 1H), 8.31(s, 1H), 8. 12(m, 2H) , 7. 86Cm, 235 94389 201016683 1H), 7. 76(m, 3H), 7. 52(s, 1H), 7.49(m, 1H), 7. 07(m, 3H), 5.72(s, 2H ), 4. 76(s, 1H), 3. 59(m, 6H), 2. 70(s, 2H), 2. 51(m, 4H), 2.21(m, 3H) Example 134 1-{ 4-[1-(4-Fluorobenzyl)-111-°. Sodium-5-amine-1-Silverin-6-yl}-4-(2-hydroxyethyl)-1 H-pyrrole-3-carboxylic acid-(2-diamine-ethyl)-guanamine

重複本發明實施例132第一步至第三步的實驗步驟，不同的是以第二步所得的化合物將2-(4-{3-[2-(4-氟节基1)-4-乙烯基-2Η-σΛβ坐-3-基]-烯丙胺基}-唉唾淋_6_基）二氳_2Η-ϋ比喃[3,4ι]α比σ各-4-酿I 132b作原料，按照本發明實施例132第三步所述的相同方式使得該原料與 N，N-二乙基-1，2-乙二胺的反應，得到標題化合物 ❹1-{4-[1-(4_氟苄基）-1Η-π$α坐-5-胺基]-喧哇琳-6-基}一4一 (2-經乙基）-1Η-π比洛-3-曱酸- (2-二乙胺基乙基）-酿胺 134(40 mg，黃色固體），產率：21. 5%。 MS m/z (ESI) ： 621 [M+l] !H NMR (400MHz, DMSO- de): δ 10.28(s, 1H), 9. 00(s 1H), 8.54(s, 1H), 8.33(m, 1H), 8. 32(s, 1H), 8. 17(m, 1H), 8.13(dd, 1H, J=9.2), 7. 89(m, 2H), 7. 77(d, 1H, J=9. 2), 7. 59(s, 1H), 7. 38(m, 1H), 7. ll(m, 3H), 5. 72(s, 94389 236 201016683 2H)，4.80(s，1H)，3.66(t，2H)，3.45(t，2H), 2.91(m 8H), 1.10(s, 6H) 實施例135 1-{4-[1-(4-氟苄某）-1H-碎丨吐-5-胺基1-电^啦_^—早 -4-(2-經乙基）-1Η-η比洛-3-甲酸二（3-嗎淋-4:^基）一酿#The experimental steps of the first step to the third step of the embodiment 132 of the present invention are repeated, except that the compound obtained in the second step is 2-(4-{3-[2-(4-fluoro)1)-4- Vinyl-2Η-σΛβ sit-3-yl]-allylamino}-唉淋 _6_ base) 氲 2氲-ϋ 喃喃 [3,4ι]α ratio σ each-4- brewing I 132b The starting material is reacted with N,N-diethyl-1,2-ethanediamine in the same manner as described in the third step of Example 132 of the present invention to give the title compound ❹1-{4-[1-( 4-fluorobenzyl)-1Η-π$α sit-5-amino]-喧wowolin-6-yl}- 4-(2-ethyl)-1Η-πpyr-3-carboxylic acid- (2-Diethylaminoethyl)-nitramine 134 (40 mg, yellow solid), yield: 21.5%. MS m/z (ESI): 621 [M+l] <EMI> NMR (400 MHz, DMSO-de): δ 10.28 (s, 1H), 9. 00 (s 1H), 8.54 (s, 1H), 8.33 ( m, 1H), 8. 32(s, 1H), 8. 17(m, 1H), 8.13(dd, 1H, J=9.2), 7. 89(m, 2H), 7. 77(d, 1H , J=9. 2), 7. 59(s, 1H), 7. 38(m, 1H), 7. ll(m, 3H), 5. 72(s, 94389 236 201016683 2H), 4.80(s , 1H), 3.66 (t, 2H), 3.45 (t, 2H), 2.91 (m 8H), 1.10 (s, 6H) Example 135 1-{4-[1-(4-fluorobenzyl)-1H - 碎丨吐-5-Amino 1-Electric ^啦_^- Early 4-(2-Ethyl)-1Η-ηBilo-3-carboxylic acid Di(3-Moridine-4:^ base)一酿#

重複本發明實施例132第一步至第三步的實驗步驟，不同的是以第二步所得的化合物將2-(4-{3-[2-(4-氟爷基1)-4-乙烯基-2H-吡唑-3-基]-烯丙胺基}-喹唑啉_6_基） ❹ -6,7-二氫-211-吡喃[3,4-〇]吡咯-4-酮13213作原料，按照本發明實施例132第三步所述的相同方式使得該原料與3一嗎啉-4-丙胺的反應’得到標題化合物i-{4-[1-(4-氟苄基） -1H-吲唑-5-胺基]-喹唑啉-6-基卜4-(2-羥乙基）-1Η-吡咯 ❹-3-曱酸（3-嗎琳-4-丙基）-醯胺135(20 mg，黃色固體），產率：10. 3%。 MS m/z (ESI) : 649 [M+1] JH NMR (400MHz, DMSO- de) ： § 10. 19(s, 1H), 8. 90(s, 1H), 8.35(s, 1H), 8.26(s, 1H), 8. 17(s, 1H), 7. 98(s, 1H), 7. 96(dd, 1H, J=8. 8), 7. 74(m, 2H), 7. 58(d, 1H, J=8. 8), 7.41(s, 1H), 7.19(m, 1H), 6. 92(m, 3H), 5. 54(s, 2H), 4. 69(s, 1H), 3. 48(m, 8H), 3. 07(m, 2H), 2.71(m, 237 94389 201016683 2H), 2.20(m, 6H) 實施例136The experimental steps of the first step to the third step of the embodiment 132 of the present invention are repeated, except that the compound obtained in the second step is 2-(4-{3-[2-(4-fluoroaryl 1)-4- Vinyl-2H-pyrazol-3-yl]-allylamino}-quinazoline-6-yl) -6-6,7-dihydro-211-pyrano[3,4-indolyl]pyrrole-4- Ketone 13213 was used as the starting material, and the reaction of the starting material with 3-morpholine-4-propylamine was carried out in the same manner as described in the third step of Example 132 of the present invention to give the title compound i-{4-[1-(4-fluorobenzyl). -1H-carbazole-5-amino]-quinazoline-6-ylbu 4-(2-hydroxyethyl)-1Η-pyrrole-3-indole (3-Merlin-4-propanol 3%。 The guanamine 135 (20 mg, yellow solid), yield: 10.3%. MS m/z (ESI): 649 [M+1]JH NMR (400 MHz, DMSO-de): § 10. 19 (s, 1H), 8. 90 (s, 1H), 8.35 (s, 1H), 8.26(s, 1H), 8. 17(s, 1H), 7. 98(s, 1H), 7. 96(dd, 1H, J=8. 8), 7. 74(m, 2H), 7 58(d, 1H, J=8. 8), 7.41(s, 1H), 7.19(m, 1H), 6. 92(m, 3H), 5. 54(s, 2H), 4. 69( s, 1H), 3. 48(m, 8H), 3. 07(m, 2H), 2.71(m, 237 94389 201016683 2H), 2.20(m, 6H) Example 136

重複本發明實施例132第一步至第三步的實， ❷不同的是以第二步所得的化合物將2_([{3七=步=: 基1)-4-乙烯基-2H-吡唑-3-基]-烯丙胺基}_喹唑啉_6_基） .二氫-2Η-Π比喃[3,4-c]n比嘻-4-酮132b作原料，按照本發明實施例132第三步所述的相同方式使得該原料與2_ 哌啶-1-乙胺的反應，得到標題化合物l-{4-[1-.(4-氟节基） - 1H-吲唑-5-胺基]-喹唑啉-6-基}-4_(2-羥乙基）-lH 哈 -3-曱酸-(2-哌啶-1-乙基）-醯胺136(17 mg，黃色固體）’ ❺產率：8%。 MS m/z (ESI) ： 633 [M+l] !H NMR (400MHz, DMSO- de) ： δ 10.07(s, 1H), 8. B〇(s, 1H)，8.54(s, 1H), 8.26(s，2H)，8.17(瓜，1H)，8.11(dd， 1H, J=8.8), 7.91(d, 1H, J=8. 8), 7.76(s, 2H), 7.47(s, 1H), 7.38(ra, 1H), 7. ll(m, 3H), 5. 72(s, 2H), 4. B〇(s, 1H), 3.67(t, 2H), 3.55(m, 2H), 3. l〇(m, 4H), 2. 92(m, 4H), 1. 72(s, 4H), 1. 44(m, 2H) 94389 238 201016683 實施例137 1 -{4-f 1-(4_氣十基）_1H- °引嗅-5 -胺基]-邊0办嚇^ 一土—蒸丄 -4-(2-羥乙基）-1Η-°比鳴~-3-甲酸-(^-g比鳴炫二醯胺Repeating the first step to the third step of the embodiment 132 of the present invention, the difference is that the compound obtained in the second step will be 2_([{3七=step=: base 1)-4-vinyl-2H-pyridyl Zin-3-yl]-allylamino}_quinazoline-6-yl). Dihydro-2-indole-pyridinium [3,4-c]n is compared to indole-4-one 132b as a starting material, in accordance with the present invention Reaction of the starting material with 2-piperidin-1-ethylamine in the same manner as described in the third step of Example 132 gave the title compound l-{4-[1-.(4-fluorohexyl)-1H-carbazole. 5-5-amino]-quinazolin-6-yl}-4-(2-hydroxyethyl)-lH-ha-3-decanoic acid-(2-piperidin-1-ethyl)-decylamine 136 (17 Mg, yellow solid) '❺ yield: 8%. MS m/z (ESI): 633 [M+l]. NMR (400 MHz, DMSO-de): δ 10.07 (s, 1H), 8. B〇(s, 1H), 8.54 (s, 1H), 8.26(s,2H), 8.17 (melon, 1H), 8.11 (dd, 1H, J=8.8), 7.91(d, 1H, J=8. 8), 7.76(s, 2H), 7.47(s, 1H ), 7.38(ra, 1H), 7. ll(m, 3H), 5. 72(s, 2H), 4. B〇(s, 1H), 3.67(t, 2H), 3.55(m, 2H) , 3. l〇(m, 4H), 2. 92(m, 4H), 1. 72(s, 4H), 1. 44(m, 2H) 94389 238 201016683 Example 137 1 -{4-f 1 -(4_气十基)_1H- °引闻-5-Amino]-Bone 0 scare ^ One soil - steamed 丄-4-(2-hydroxyethyl)-1Η-° 比鸣~-3- Formic acid-(^-g ratio

重複本發明實施例132第一步至第三步的實驗步驟’ 不同的是以第二步所得的化合物將2-(4-{3-[2-(4-氟苄 ❿基）-4-乙烯基_211-°比《坐-3-基]-婦丙胺基卜β坐淋-6-基） -6,7-二氫-211-吡喃[3,4-(；]吡哈-4-酮1321)作原料，按照本發明實施例132第三步所述的相同方式使得該原料與2- 吡咯烷-1-基-乙胺的反應，得到標題化合物^{441-(4-氟苄基）-.1Η-吲唑-5-胺基]~喹唑琳_6_基}_4_(2_羥乙基）-1Η-吡咯-3-曱酸-(2-吡咯烷_卜基_乙基醯胺137 8.6%。 ^ 10.08(s, !H), 8. 18(s, 2H), 7.48(s, 3H), 5. 72(s, 2H), 3. 10(m, 1H), 8.84(s, 1H), 8. 10(m, 1H>, 7.39(s, 2H), 4. 80(s, 4H), 2.93(m, (16 mg，黃色固體），產率： ,MS m/z (ESI) : 619 [M+1] !H NMR (400MHz, DMSO- de) 1H), 8.54(s, 1H), 8.28(s, 1Ή), 7. 91(d, 1H), 7. 78(m, 1H), 7. 39(m, 1H), 7. ll(m, 1H), 3. 67(m, 2H), 3. 54(m, 4H), 1.91(m, 4H) 實施例138 94389 239 201016683 1_(3-{4-「3-氯-4-(3-氟芊氫某>)-笨胺羞丄〜啥唑说-6-基}_ 口比口各-1-基）-3-嗎嚇·_4-而-The experimental procedure of the first step to the third step of the embodiment 132 of the present invention is repeated. The difference is that the compound obtained in the second step is 2-(4-{3-[2-(4-fluorobenzyl)-4-. Vinyl _211-° than "sit-3-yl"-female propyl basal beta -6-yl) -6,7-dihydro-211-pyran [3,4-(;]pyha- 4-ketone 1321) was used as a starting material, and the title compound was obtained by the reaction of the starting material with 2-pyrrolidin-1-yl-ethylamine in the same manner as described in the third step of Example 132. Fluorobenzyl)-.1Η-carbazole-5-amino]~ quinazoline _6_yl}_4_(2-hydroxyethyl)-1Η-pyrrole-3-decanoic acid-(2-pyrrolidine-b _ethyl decylamine 137 8.6%. ^ 10.08 (s, !H), 8. 18 (s, 2H), 7.48 (s, 3H), 5. 72 (s, 2H), 3. 10 (m, 1H), 8.84(s, 1H), 8. 10(m, 1H>, 7.39(s, 2H), 4. 80(s, 4H), 2.93 (m, (16 mg, yellow solid), yield: , MS m/z (ESI): 619 [M+1] !H NMR (400MHz, DMSO- de) 1H), 8.54 (s, 1H), 8.28 (s, 1 Ή), 7. 91 (d, 1H) , 7. 78(m, 1H), 7. 39(m, 1H), 7. ll(m, 1H), 3. 67(m, 2H), 3. 54(m, 4H), 1.91(m, 4H) Example 138 94389 239 201016683 1_(3-{4-"3-chloro-4-(3-fluoroindole hydrogen)>-stupidamine shy~carbazole said -6-基}_ mouth ratio -1-base) -3- 吓 _ _ 4- and -

第一步 ® [3-氯-4-(3-氟苄氧基）-苯基]-[6-(1-環氧乙烷基曱基 -1H-吡咯-3-基）-喹唾啉-4-基]-胺 . 將本發明實施42所得的化合物[3-氯-4-(3-氟-苄氧基）-苯基]~·[6-(1Η-σ比咯-3-基）-啥吐喊-4-基]-胺42 (447 mg，1· 〇〇7 mmol)溶解於5 mL· Ν，Ν-二甲基甲醯胺中，溶液在冰浴冷卻下’加入氫化納（16 mg ’ 0. 4随〇 1)’混合液升至室溫’攪拌30分鐘後，加入2-氯甲基環氧乙烷（125 mg， ® 1.351 mmol)，加熱反應液至6(TC，攪拌2小時後反應完畢’加水猝滅反應。反應液用乙酸乙酯（1〇〇 mLx3)萃取，合併的有機相用無水硫酸鈉脫水，過濾，濾液減壓下濃縮，所得的殘留物進一步藉由管柱層析法分離純化，得到本標題產物[3-氯-4-(3-氟苄氧基）-苯基]_[6_g_環氧乙烷基甲基-1H-吡咯-3-基）-喹唑啉-4-基]-胺138a(2〇〇 mg，黃色固體），產率：39. 8%。 MS m/z (ESI) ： 501 [M+l] 94389 240 201016683 第二步 1-(3-{4-[3-氯-4-(3-氟苄氧基）_苯胺基]-喹唑啉-6-基卜 σ比洛-1-基）-3-嗎琳一4-丙-2-醇將嗎啉（35 mg，〇. 402醜〇1)溶解於〇. 5 mL N，N-二甲基甲醯胺，在冰浴條件下，冷卻至〇〇c，加入氫化鈉（7mg， 0. 175 mmol)，室溫下攪拌2〇分鐘後加入上述步驟所得的化合物[3-氯-4-(3-氟¥氧基）_苯基]_[6_(1_環氧乙烷基曱基-1H-吡咯-3-基）-喹唑啉一4_基]一胺138a(68mg，〇 136 mmol)的〇. 5 mL· N，二曱基曱醯胺的溶液，室溫下攪拌過 ®夜，所得的混合液藉由TLC板進一步分離純化，得到本標題產物[3-氯-4-(3-氟苄氧基）-苯基；μ[6_(卜環氧乙烷基曱基-1Η-°比咯-3-基）-喹唑啉-4-基]-胺138(36 mg，黃色固體）’產率：45%。 MS m/z (ESI) ： 588 [M+l] 'H NMR (400MHz, DMSO-: δ 9. 70(s, 1H), 8. 50(s, 1H), 8. 02(s, 1H), 7.71(m, 2H), 7.42(m, 1H), 7.40(t, 1H), 響 7.33(m，3H), 7. 19(t, 2H)，6.87(m，2H)，6.64(m，1H)， 5.27(s, 2H), 4. 10(m, 1H), 4. 00(m, m), 3. 85Cm, 1H), 3.61(ra, 4H), 2.40(m, 2H), 2. 19(m, 4H) 實施例139 2-{ l-[4-(3-氣-4-氟笨胺基）-啥嗤咏-ft-某1-4-°比哈炫-i-甲基-1H-吡略-3-某卜乙醇 94389 241 201016683First Step® [3-Chloro-4-(3-fluorobenzyloxy)-phenyl]-[6-(1-oxiranylmercapto-1H-pyrrol-3-yl)-quinoline 4-yl]-amine. The compound obtained in the practice of the present invention 42 [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]~·[6-(1Η-σ ratior-3- Base)-啥啥 -4--4-yl]-amine 42 (447 mg, 1· 〇〇7 mmol) was dissolved in 5 mL·Ν, Ν-dimethylformamide, and the solution was added under ice cooling. Sodium hydride (16 mg '0.4 with 〇1)' mixture was allowed to warm to room temperature. After stirring for 30 minutes, 2-chloromethyloxirane (125 mg, ® 1.351 mmol) was added and the reaction mixture was heated to 6 (TC, after 2 hours of stirring, the reaction was completed.) The reaction mixture was quenched with water. The mixture was extracted with ethyl acetate (1 mL mL), and the combined organic phases were dried over anhydrous sodium sulfate, filtered and evaporated Further purification by column chromatography gave the title product [3-chloro-4-(3-fluorobenzyloxy)-phenyl]-[6_g_oxiranylmethyl-1H-pyrrole -3-yl)-quinazolin-4-yl]-amine 138a (2 mg, yellow solid), yield: 39.8%. MS m/z (ESI): 501 [M+l] 94389 240 201016683 Step 2 1-(3-{4-[3-chloro-4-(3-fluorobenzyloxy)-anilino]-quinazole Porphyrin-6-ylpyrazine-l-l-yl)-3-morphin-4-propan-2-ol is dissolved in morpholine (35 mg, 〇. 402 ugly 1). 5 mL N,N - dimethylformamide, cooled to 〇〇c under ice-cooling, sodium hydride (7 mg, 0. 175 mmol), and stirred at room temperature for 2 hrs. 4-(3-fluoroacetoxy)-phenyl]-[6-(1_oxiranylhydrazino-1H-pyrrol-3-yl)-quinazoline-4-yl]monoamine 138a ( 68 mg, 〇136 mmol) of 〇. 5 mL·N, dimethyl decylamine solution, stirred at room temperature for </ RTI> overnight, and the resulting mixture was further separated and purified by TLC. Chloro-4-(3-fluorobenzyloxy)-phenyl; μ[6_(ethylene oxide sulfhydryl-1Η-pyrrol-3-yl)-quinazolin-4-yl]-amine 138 (36 mg, yellow solid) 'yield: 45%. MS m/z (ESI): 588 [M+l] "H NMR (400 MHz, DMSO-: δ 9. 70 (s, 1H), 8. 50 (s, 1H), 8. 02 (s, 1H) , 7.71(m, 2H), 7.42(m, 1H), 7.40(t, 1H), 7.33(m,3H), 7. 19(t, 2H), 6.87(m,2H), 6.64(m, 1H), 5.27(s, 2H), 4. 10(m, 1H), 4. 00(m, m), 3. 85Cm, 1H), 3.61(ra, 4H), 2.40(m, 2H), 2 19(m, 4H) Example 139 2-{ l-[4-(3-Ga-4-fluorophenylamino)-啥嗤咏-ft- 1-4-° 比哈炫-i-甲Base-1H-pyrrol-3-one ethanol 94389 241 201016683

重複本發明實施例120第一步所述的實驗步驟，不同的是以實施例109最終所得的化合物[1_[4-(3-氯_4-氟-苯胺基）-喧0坐琳-6-基]-4-(2-經乙基）-iH-11比哈基]比咯烷-1-甲酮109作原料，按照本發明實施例120第一步所述的相同方式使得該原料與氫化銘鋰的反應，得到標題鑛化合物2-{1-[4-(3-氯-4-氟苯胺基）-喹唑啉__6—基]—4_吼咯烷-1-甲基-1H-吡咯-3-基卜乙醇139(62 mg，黃色固體），產率：71. 16%。 MS m/z (ESI) ： 466[M+1] ']HNMR (400MHz, DMSO- ： (5 9.90(s, 1H), 8. 52(d 2H) 8.14(d，2H), 7.80(m，2H)，7·46(ιη，1H), 7.42(s，1Η)’ 7.33(s，1H)，5.10(s，1H)’ 3.61(t，2H)，3.46(s，2H)’ ❿ 2.66(t，2H)，2.50(m，4H)，1.70(s，4H) 實施例140 2-{1-[4-Cg-氯-4-氟苯胺某）-喹唑淋-6-某1-』--甲胗其甲基-1H-吡咯-3-基卜乙薛The experimental procedure described in the first step of Example 120 of the present invention was repeated, except that the compound [1_[4-(3-chloro-4-fluoro-anilino)-喧0坐琳-6 finally obtained in Example 109 was obtained. -yl]-4-(2-ethyl)-iH-11bihaki]pyrrolidine-1-one 109 as a starting material in the same manner as described in the first step of Example 120 of the present invention Reaction with hydrogenated lithium to obtain the title mineral compound 2-{1-[4-(3-chloro-4-fluoroanilino)-quinazoline__6-yl]-4-pyrrolidin-1-methyl -1H-pyrrol-3-yl-ethanol 139 (62 mg, yellow solid), yield: 71. 16%. MS m/z (ESI): 466 [M+1] </RTI> NMR (400 MHz, DMSO-: (5 9.90 (s, 1H), 8. 52 (d 2H) 8.14 (d, 2H), 7.80 (m, 2H),7·46(ιη,1H), 7.42(s,1Η)' 7.33(s,1H),5.10(s,1H)' 3.61(t,2H), 3.46(s,2H)' ❿ 2.66( t, 2H), 2.50 (m, 4H), 1.70 (s, 4H) Example 140 2-{1-[4-Cg-chloro-4-fluoroaniline)-quinazoline-6-some 1-" --Metformin methyl-1H-pyrrol-3-yl b

94389 242 20101668394389 242 201016683

第一步 2-{l-[4-(3-氯-4-氟苯胺基）_喹唑啉_6一基]_4_羥甲基 -111-吼洛-3-基}-乙醇在50 mL茄形瓶中’將20 mL四氫呋喃冰浴條件下冷卻至0至5°C，攪拌下加入氫化鋁鋰（18. 6mg，〇 49mm〇1)，隨後分批加入實施例81第一步所得的產物2_[4-(3-氯-4-•氟-苯胺基）-喹唑啉-6-基]-6,7-二氫-2H-响喃[3,4-c>tb 咯-4-酮81a(100 mg，0.245 mmol)，在冰浴條件下繼續攪拌30分鐘後反應完畢。在溶液中加入〇. lmL水和〇.丨此 20%氫氧化鈉溶液，抽濾、，依次用5〇 mL四氩吱嚼洗務濾餅， ;慮液中加入2 0 mL二氯甲烧有固體析出，抽濾，固體真空 ⑩乾燥，得到本標題產物2-{1-[4-(3-氯-4-氟苯胺基）-喹唑啉-6-基]-4-羥曱基-1H-吡咯-3-基}-乙醇I40a(65mg，黃色固體），產率：64. 1%。 MS m/z (ESI) ： 413[M+1] 第二步 l-[4-(3-氯-4-氟苯胺基）-喹唑啉_6_基]_4_(2_羥基_乙基） -1H-d比洛-3-曱搭將鄰蛾醯基本曱酸（44. 1 mg，〇· 157 mmol)溶解於3 mL 94389 243 201016683 二甲亞砜中，攪拌下加入上述步驟所得的化合物2_U_ [4-(3-氯-4-氟苯胺基）一喹唑啉_6_基]羥甲基η一吡咯 3-基}-乙醇140a (65 mg，0.157 mmol )，室温下授拌2小時後反應完畢。將反應液倒入1 〇〇 mL 5%碳酸氫納溶液中，攪拌5分鐘後，用乙酸乙酯（1〇〇 mLx3)萃取反應液，合併的有機相在減壓下濃縮，得到的殘留物進一步藉由管柱層析法为離純化，得到本標題產物卜[4_ (3-氯氟苯胺基）-喹唑啉-6-基]-4-(2-羥基-乙基）-iH-吡咯-3-甲醛 140b(32 mg，黃色固體），產率：51. 9%。 _ MS m/z (ESI) : 411[M+1] 第三步 • 2-{l-[4-(3-氯-4-氟苯胺基）-喹唑啉-6-基]-4-二甲胺基甲基-1H-吡咯-3-基}-乙醇在50mL茄形瓶中將上述步驟所得的化合物氯氣苯胺基）-喧^坐琳-6 —基]_4_(2_經基-乙基）比嘻-3-甲盤 140b(80 mg , 0. 195 mmol)溶解於 5 mL· 二氣甲 _院中，攪拌下加入二甲胺（0.2 mL，0.389 mmol)和三乙醯氧基硼氫化鈉（165 mg，0. 389 mmol)，所得的混合液在室溫下擾拌過夜，反應完畢。將反應液中加入5 mL碳酸氫納和5 mL飽和氯化納水溶液，分層後’水層用二氯曱院 (5 0 mLx3 )萃取，合併的有機相用無水硫酸鈉脫水，過滤，濾液減壓下濃縮，得到的殘留物進一步藉由TLC板進行分離純化，得到本標題產物2-{1-[4-(3-氯-4-氟苯胺基）-啥嗤啉-6-基]-4-二甲胺基甲基-1H-吡咯-3-基}-乙醇140 94389 244 201016683 (70 mg，黃色固體），產率：40. 9%。 MS m/z (ESI) ： 438[M-1] ^NMR (400MHz, DMS0- 5 9.00(s, 1H), g 62(s 1H) 8.35(m, 1H), 8. 12(m, 1H), 8. 05(m, 1H), 7 92(m 2H) 7.65(d, 2H), 7. 44(t, 1H), 5. 10(s, 1H), 4 17(s 2H) 3.67(t, 2H), 2. 78(s, 6H), 2. 72(t, 2H) ’ 實施例141 gr{l-f4-((3-氣_-j-氟苯胺基）-喹唑^^〜4一「（2—甲石善藤基-乙胺基）-甲基比嘻，3-基}-乙The first step 2-{l-[4-(3-chloro-4-fluoroanilino)-quinazoline-6-yl]_4-hydroxymethyl-111-indol-3-yl}-ethanol in 50 In a mL eggplant-shaped flask, the mixture was cooled to 0 to 5 ° C in an ice bath of 20 mL of tetrahydrofuran, and lithium aluminum hydride (18.6 mg, 〇49 mm 〇1) was added with stirring, and then the first step of Example 81 was added in portions. The product 2_[4-(3-chloro-4-•fluoro-anilino)-quinazolin-6-yl]-6,7-dihydro-2H-ring [3,4-c>tb- 4-ketone 81a (100 mg, 0.245 mmol) was stirred for 30 min. Add 〇.lmL water and 〇.丨20% sodium hydroxide solution to the solution, suction filtration, and then wash the filter cake with 5 〇mL of tetra argon, and add 20 mL of dichloromethane to the solution. Solid precipitated, suction filtered, and dried in vacuo to give the title product 2-{1-[4-(3-chloro-4-fluoroanilinyl)-quinazolin-6-yl]-4-hydroxyindole 1%。 -1H-pyrrol-3-yl}-ethanol I40a (65 mg, yellow solid), yield: 64.1%. MS m/z (ESI): 413 [M + 1]. Step 2 -[4-(3-chloro-4-fluoroanilinyl)-quinazoline-6-yl]_4_(2-hydroxyl-ethyl -1H-d piroxime 曱将邻邻邻 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 44 Compound 2_U_[4-(3-Chloro-4-fluoroanilino)-quinazoline-6-yl]hydroxymethyl η-pyrrol-3-yl}-ethanol 140a (65 mg, 0.157 mmol), mixed at room temperature The reaction was completed after 2 hours. The reaction solution was poured into 1 mL of a 5% sodium hydrogencarbonate solution, and after stirring for 5 minutes, the reaction mixture was extracted with ethyl acetate (1 mL mL), and the combined organic phases were concentrated under reduced pressure to give residue. Further purification by column chromatography gave the title product [4_(3-chlorofluoroanilino)-quinazolin-6-yl]-4-(2-hydroxy-ethyl)-iH- Pyrazole-3-carbaldehyde 140b (32 mg, yellow solid), yield: 51.9%. _ MS m/z (ESI): 411 [M+1] Step 3 • 2-{l-[4-(3-Chloro-4-fluoroanilino)-quinazolin-6-yl]-4- Dimethylaminomethyl-1H-pyrrol-3-yl}-ethanol The compound obtained in the above step was subjected to the above-mentioned compound, chloroaniline, hydrazine, hydrazine-6-yl- Ethyl) was dissolved in 5 mL·2 gas in a hospital, and dimethylamine (0.2 mL, 0.389 mmol) and triethylene oxide were added with stirring. Sodium borohydride (165 mg, 0. 389 mmol) was obtained and the mixture was stirred overnight at room temperature. 5 mL of sodium bicarbonate and 5 mL of saturated aqueous sodium chloride solution were added to the reaction mixture, and the layers were separated, and the aqueous layer was extracted with dichlorohydrazine (50 mL×3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. Concentration under reduced pressure, and the obtained residue was purified and purified to afford the title product 2-{1-[4-(3-chloro-4-fluoroanilinyl)- porphyrin-6-yl] -4-dimethylaminomethyl-1H-pyrrol-3-yl}-ethanol 140 94389 244 201016683 (70 mg, yellow solid), yield: 40.9%. MS m/z (ESI): 438 [M-1] NMR (400 MHz, DMS0 - 5 9.00 (s, 1H), g 62 (s 1H) 8.35 (m, 1H), 8. 12 (m, 1H) , 8. 05(m, 1H), 7 92(m 2H) 7.65(d, 2H), 7. 44(t, 1H), 5. 10(s, 1H), 4 17(s 2H) 3.67(t , 2H), 2. 78(s, 6H), 2. 72(t, 2H) 'Example 141 gr{l-f4-((3-Gas--j-fluoroanilino)-quinazoline^^~ 4"(2-methyl sylvestre-ethylamino)-methyl hydrazine, 3-yl}-B

重複本發明實施例140第一步至第三步的實驗步驟，不同的是以第二步所得的化合物1-[4-(3-氣-4-氟苯胺基） —喧唑啉-6-基]-4-(2-羥基-乙基）-1Η-吡咯-3-甲醛140b 鑄作為原料，進行該原料與2-曱磺醯基乙胺的反應，得到本標題產物2-{1-[4-((3-氯-4-氟苯胺基）-喹唑琳-6-基） -4-[(2-曱磺酿基-乙胺基）-曱基]-1H-吡咯-3-基]-乙醇 141(67 mg，黃色固體），產率：33. 3%。 MS 瓜/z (ESI) : 518[M+1] 'H NMR (400MHz, DMSO- 5 10.24(s, 1H), 8. 90(s, !H), 8.61(s, 1H), 8.29(m, 1H), 8.11(m, 1H), 7. 98(m, 1H), 7.90(m, 1H), 7. 70(s, 1H), 7. 53(m, 1H), 7. 49(m, 245 94389 201016683 1H), 3.90(s, 2H), 3.66(t, 2H), 3. 50(m, 2H), 3. 25〇n, 2H), 3. 10(s, 3H), 2. 70(m, 2H) 實施例142 一某卜4一〇一趂广基）-1H-d比落-3-甲甚1_蚣箕田苴、，， ^ 妝秦二侧氳某-亡急一1 Λ氺6氺一p塞口去一4一 _The experimental steps of the first step to the third step of the embodiment 140 of the present invention are repeated, except that the compound obtained in the second step is 1-[4-(3-(a)-4-fluoroanilino)-oxazoline-6- 4-[2-hydroxy-ethyl]-1Η-pyrrole-3-carbaldehyde 140b is cast as a raw material, and the reaction of the starting material with 2-nonylsulfonylethylamine is carried out to obtain the title product 2-{1- [4-((3-Chloro-4-fluoroanilino)-quinazoline-6-yl)-4-[(2-oxasulfonic acid-ethylamino)-indenyl]-1H-pyrrole-3 3%。 The base - ethanol 141 (67 mg, a yellow solid), yield: 33.3%. MS melon/z (ESI): 518 [M+1] 'H NMR (400 MHz, DMSO- 5 10.24 (s, 1H), 8. 90 (s, !H), 8.61 (s, 1H), 8.29 (m) , 1H), 8.11(m, 1H), 7. 98(m, 1H), 7.90(m, 1H), 7. 70(s, 1H), 7. 53(m, 1H), 7. 49(m , 245 94389 201016683 1H), 3.90(s, 2H), 3.66(t, 2H), 3. 50(m, 2H), 3. 25〇n, 2H), 3. 10(s, 3H), 2. 70(m, 2H) Example 142 A certain 4 4 〇趁趁 ) ) -1 -1 -1 -1 -1 -1 -3- -3- -3- -3- -3- -3- -3- -3- -3- -3- -3- -3- , , , , , , , , , , , , 妆妆妆妆妆妆妆妆妆1 Λ氺 6 氺 a p plug to a 4 _

重複本發明實施例140第一步至第三步的實驗步驟， •不同的是以第二步所得的化合物η4_(3_氯_4_氟苯胺基）喹嗤嚇6基]-4-(2-羥基-乙基）-ijj-吼嘻-3_甲搭140b 作為原料，進行該原料與4-氨曱基，卜二氧_六氫 -1又*6*-噻喃-4-醇的反應，得到本標題產物^({[卜“ 一 (3-氯-4-氟苯胺基）-喹唑琳_6_基]_4_(2_羥乙基）_1H一吼響咯-3-曱基]-胺基卜曱基）一l i一二侧氧基_六氫一i噻喃-4-醇142(76 mg，黃色固體），產率：34. 8%。 MS m/z (ESI) ： 574[M+1] !HNMR (400MHz, DMSO-de)： δ 10.29(s, 1H), 8. 85(s, 1H), 8.64(s, 1H), 8.31(dd, 1H, J=6. 4), 8. 12(dd, 1H, >9.2), 8.00(m, 1H), 7.91(d, 1H, J = 9. 2), 7. 80(m, 1H), 7. 56(m, 1H), 7.49(t, 1H), 5.78(s, 1H), 4. 08(s, 2H), 3. 67(t, 2H), 3. 19(m, 4H), 3. 〇6(m, 2H), 2. 71(ts 2H), 2. 16(m, 246 94389 201016683 實施例143 J貝!1氧基-六氮-1 Λ *6木-嗓ρ南—4~ 略-3-基）-乙薛The experimental steps of the first step to the third step of the embodiment 140 of the present invention are repeated, and the difference is that the compound η4_(3_chloro_4_fluoroanilino) obtained in the second step is scared to 6 base]-4-( 2-hydroxy-ethyl)-ijj-吼嘻-3_Mate 140b as a raw material, the starting material and 4-aminoindenyl, dioxo-hexahydro-1 and *6*-thiopyran-4-ol The reaction gave the title product ^({[卜"-(3-chloro-4-fluoroanilino)-quinazoline_6_yl]_4_(2_hydroxyethyl)_1H-吼咯 -3-曱 ] ] ] ] 一一一一一一一一一一一一一 MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS : 574[M+1] !HNMR (400MHz, DMSO-de): δ 10.29(s, 1H), 8. 85(s, 1H), 8.64(s, 1H), 8.31(dd, 1H, J=6 4), 8. 12 (dd, 1H, > 9.2), 8.00 (m, 1H), 7.91 (d, 1H, J = 9. 2), 7. 80 (m, 1H), 7. 56 ( m, 1H), 7.49(t, 1H), 5.78(s, 1H), 4. 08(s, 2H), 3. 67(t, 2H), 3. 19(m, 4H), 3. 〇6 (m, 2H), 2. 71 (ts 2H), 2. 16 (m, 246 94389 201016683 Example 143 J: 1 oxy-hexanitro-1 Λ *6 wood-嗓ρ南—4~ 略3-base)-Bei Xue

鬌重複本發明實施例140第-步至第三步的實驗步驟，不同的是以第二步所得的化合物卜[4_(3_氯_4_氟笨胺基） .-喹唑啉-6-基]-4-(2-羥基-乙基）_1Η_吡咯_3_甲醛丨斗此作為原料，進行該原料與C-(1，卜二氧_六氫_1又杆*_噻喃 -4-基）-曱胺的反應，得到本標題產物2_(1_[4_(3_氯一4一氟苯胺基）-喹唑啉^-基卜扣几“卜二侧氧基/六氫 -1λ木6木-噻喃-4-甲基）-胺基]一甲基}_1H_吡咯_3_基卜乙 ❹醇143(24 mg，黃色固體），產率：n. 1%。广胺基）_喹唑鬼某·^心丨卜〗〗-一歷基1 ~~ Ψ基} -1Η -咐, MS m/z (ESI) ： 558[M+1] ]HNMR (400MHz, MSO-de)： δ 1〇>29(Sj 1H), 8.85(s 1R) 8.64(s, 1H), 8.31(dd, 1H, J=6.4), 8. 12(dd, 1H J = 9 2) 8.00(m, 1H), 7.91(d, 1H, J=9. 2), 7. 80(ffi, lH), 7.56(,, 1H), 7. 49(t, 1H), 5.78(s, 1H), 4. 08(s, 2H), 3. 67(t, 2H), 3.19(m，4H)，3.06(ra，2H), 2.71(t，2H), 2 16(m’ 4H) ， ·， 94389 247 201016683 實施例144 _2-{l-[4-(3-氯 4-氟-苯胺基）-啥唾啦-fi-基 1-4-二^ 甲基-1H-吡咯-3-篡卜乙醇鬌 Repeat the experimental steps of the first step to the third step of the embodiment 140 of the present invention, and the difference is the compound obtained in the second step [4_(3_chloro_4_fluoroamino)-quinazoline-6 -yl]-4-(2-hydroxy-ethyl)_1Η_pyrrole_3_formaldehyde oxime as a raw material, and the raw material is carried out with C-(1, dioxo hexahydro _1 argon * thiopyran The reaction of -4-yl)-nonylamine gives the title product 2_(1_[4_(3_chloro-4-tetrafluoroanilino)-quinazoline^-yl b. -1λ木6木-thiopyran-4-methyl)-amino]monomethyl}_1H_pyrrole_3_ kibitol 143 (24 mg, yellow solid), yield: n. Aminoamine) _ quinazolidone · ^ heart 丨〗〖 - a calendar base 1 ~ ~ Ψ }} -1 Η - 咐, MS m / z (ESI): 558 [M + 1] ] HNMR (400MHz, MSO-de): δ 1〇>29(Sj 1H), 8.85(s 1R) 8.64(s, 1H), 8.31(dd, 1H, J=6.4), 8. 12(dd, 1H J = 9 2 ) 8.00(m, 1H), 7.91(d, 1H, J=9. 2), 7. 80(ffi, lH), 7.56(,, 1H), 7. 49(t, 1H), 5.78(s, 1H), 4. 08(s, 2H), 3. 67(t, 2H), 3.19(m,4H), 3.06(ra,2H), 2.71(t,2H), 2 16(m' 4H) , ·, 94389 247 201016683 Example 144 _2-{l-[4-(3-chloro 4-fluoro-anilino)-hydrazino-fi-yl 1-4-di^methyl-1H-pyrrole-3-indole ethanol

重複本發明實施例140第一步至第三步的實驗步驟，不同的是以第二步所得的化合物1-[4-(3-氯-4-氟苯胺基） -喹唑啉-6-基]-4-(2-羥基-乙基）-ih-吡咯-3-甲醛l4〇b ®作為原料，進行該原料與二乙胺的反應，得到本標題產物 2-{1-[4-(3-氯4-氟-苯胺基>-喹唾琳基]—4-二乙胺美甲基-1H-吡咯-3-基}-乙醇144(98 mg，黃色固體），產率： 54.9%。 MS m/z (ESI) ： 468[M+1] !HNMR (400MHz, DMSO- de)： <5 10.63(s, 1H), 9. 13(s, iH) 8.62(s, 1H), 8.40(m, 1H), 8. 14(m, 2H), 8. 10(s, lg)The experimental procedure of the first step to the third step of the embodiment 140 of the present invention is repeated, and the difference is the compound 1-[4-(3-chloro-4-fluoroanilino)-quinazoline-6- obtained in the second step. 4-[2-hydroxy-ethyl)-ih-pyrrole-3-carbaldehyde l4〇b® as a starting material, the reaction of the starting material with diethylamine is carried out to obtain the title product 2-{1-[4- (3-Chloro-4-fluoro-anilino)-quinoline- 4-diethylamine-methyl-1H-pyrrol-3-yl}-ethanol 144 (98 mg, yellow solid). 54.9% MS m/z (ESI): 468 [M+1] <5NMR (400 MHz, DMSO-de): <5 10.63 (s, 1H), 9. 13 (s, iH) 8.62 (s, 1H) ), 8.40(m, 1H), 8. 14(m, 2H), 8. 10(s, lg)

錄 7. 90(d，1H，J-8. 8)，7. 68(s，1H)，7. 46(t，IH), 4, 14(S 2H), 3. 70(t, 2H), 3. 19(ra, 4H), 2. 73(t, 2H), 1. 32(m, 6H) ，實施例145 氯-4-(°比啶-2-甲氣基）一装胺基1-喹吔嵫 _基}-4二lij-甲磺醯基-乙骇基）-甲某吡咯-3-其卜Λ 94389 248 201016683Record 7.90 (d, 1H, J-8. 8), 7. 68 (s, 1H), 7. 46 (t, IH), 4, 14 (S 2H), 3. 70 (t, 2H) , 3. 19(ra, 4H), 2. 73(t, 2H), 1. 32(m, 6H), Example 145 chloro-4-(°-pyridyl-2-carbyl)-loaded amine 1-quinoline-yl}-4dilij-methanesulfonyl-ethenyl)-methylpyrrole-3-intermediate 94389 248 201016683

145 N145 N

第一步 .2-(l-{4-[3-氯-4-(吡啶一2 一甲氧基）_苯胺基基幾甲基乙醇坐琳+ 145 魯在50乩茄形瓶中，將氫化鋁鋰（220 mg，5. 86 inmol) 溶解於15 mL四氫呋喃中，所得的溶液在冰浴條件下，冷卻至-5°C ’攪拌下分批加入實施例47所得的最終化合物馨2_{4_[3-氯-4-（吡啶-2-甲氧基）-苯胺基]-喹唑啉_6一基} -6,7-二氩-2^°比喃[3,4-〇]°比'1各_4-酮 47(1.45 运，2.93 mmol)，攪拌30分鐘後反應完畢。在反應液中加入1 mL 水，1 mL飽和氫氧化納溶液，過滤反應液，母液在減塵下濃縮，得到本標題產物2-(1-{4-[3_氯-4-(n比啶-2-曱氧基） -苯胺基]-喹唑啉-6-基}-4_羥曱基-1Η_σ比咯_3一基）-乙醇 145a(381 mg，黃色固體），產率：33%。 MS m/z (ESI) ： 502[M+1] 249 94389 201016683 第二步 2-(1-{4-[3-氯-4-(吡啶-2-曱氧基）-苯胺基]-喹唑啉_6-基}-4-(2-經乙基）-1Η-π比嘻-3-曱搭在25 mL茄形瓶中，將鄰碘醯基苯曱酸（93 mg，0. 32 mmol)溶解於5 mL二甲基亞砜中，攪拌下逐滴加入上述步驟所得的化合物2-(1-{4-[3-氯-4-(吡淀-2-甲氧基）-苯胺基]-喹唑啉-6-基}-4-羥曱基-1H-吼咯-3-基）-乙醇 145a(147 mg，〇· 29mmol)的2 mL二曱基亞礙溶液，攪拌過夜’反應完畢。將反應液倒入1 〇〇 mL水中，有固體生成， ❹抽濾，得到本標題產物2-(1-{4-[3-氯-4-(π比唆-2_曱氧基） -苯胺基]-喹唑啉-6-基}-4-(2-羥乙基）-ΐΗ-吡咯-3-甲醛 • 145b(80mg’黃色固體），產率：55%。 MS m/z (ESI) ： 500[M+1] 第三步 2-{1-{4-[3-氯-4-(吼啶-2-曱氧基）_苯胺基]_喹唑啉基卜4-[(2-曱磺醯基-乙胺基）一曱基]一1H_吡咯_3_基卜乙 .醇將上述步驟所得的化合物2—(卜{4_[3_氣_4_(吡啶 -2-甲氧基）-苯胺基]-喹唑啉_6_基卜4—(2_羥乙基）_lH〜吡咯-3-甲醛145b(30 mg，〇· 〇6 mm〇l)溶解於1〇 mL甲醇中，攪拌下加入2-甲磺醯基乙胺鹽酸鹽（19 mg，〇. 12咖〇1)，室溫下攪拌3小時後加人三乙酿氧基魏化納（25 4呢，〇· 12 mmol)，所得的混合液在室溫下攪拌過夜，反應完畢。反應液在減壓下濃縮，得到的固體進一步藉由tlc板進行 94389 250. 201016683 分離純化，得到本標題產物2-U-{4-[3-氯-4-(吡啶-2-甲氧基）-苯胺基]-喹唑啉-6-基}-4-[ (2-甲磺醯基-乙胺基）-曱基]-1H-吡咯-3-基}-乙醇145(50 mg，黃色固體），產率： 31%。 MS m/z (ESI) ： 608[M+1] ^NMR (400MHz, DMS〇-d〇: 5 10. 17(s, 1H), 8. 80(s, 1H), 8.61(d, 1H, J=4.4), 8.55(s, IH), 8. 13(s, 1H), 8. 07(d, 1H, J=9.2), 7.88(m, 3H), 7. 67(s, 1H), 7. 60(d, 1H, J = 7. 6), 7.53 (s, 1H), 7.37 (t, 1H), 7.30 (d, 1H, ®J=8.8 ), 5.30 (s, 2H), 3.81(s, 2H), 3. 65(t, 2H), 3.44(t, 2H), 3. 15(t, 2H), 3. 09(s, 3H), 2. 69(t, 2H) 實施例146 2-{4-「（2-曱磺醯基-乙胺基）-甲基1-卜「4-(卜笨乙胺基）-喧口坐琳-6-基1-1 H-口比嘻-3-基}-乙醇 0，xs°The first step. 2-(l-{4-[3-chloro-4-(pyridyl-2-methoxy))-anilino-methylethanol sitin + 145 Lu in a 50-orange eggplant bottle, will Lithium aluminum hydride (220 mg, 5.86 inmol) was dissolved in 15 mL of tetrahydrofuran, and the resulting solution was cooled to -5 ° C under ice-cooling conditions. The final compound obtained in Example 47 was added in portions. 4_[3-chloro-4-(pyridine-2-methoxy)-anilino]-quinazoline-6-yl} -6,7-di-argon-2^° ratio [3,4-〇] ° ° _ 4- ketone 47 (1.45 transport, 2.93 mmol), stirring for 30 minutes, the reaction is completed. Add 1 mL of water, 1 mL of saturated sodium hydroxide solution to the reaction solution, filter the reaction solution, the mother liquor is dust reduction Concentration to give the title product 2-(1-{4-[3_chloro-4-(n-pyridin-2-yloxy)-anilino]-quinazolin-6-yl}-4_hydroxy曱 Η σ σ σ σ σ σ σ _ 乙醇乙醇乙醇乙醇乙醇乙醇乙醇乙醇乙醇乙醇乙醇 381 381 381 381 381 381 381 381 381 381 381 381 381 381 381 381 381 381 381 381 381 381 381 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- (1-{4-[3-Chloro-4-(pyridin-2-yloxy)-anilino]-quinazoline-6-yl}-4-(2-ethyl)-1Η-π ratio嘻-3-曱 in a 25 mL eggplant-shaped bottle with o-iododecyl benzoic acid (93 mg, 0. 32 mmol) was dissolved in 5 mL of dimethyl sulfoxide, and the compound 2-(1-{4-[3-chloro-4-(pyridin-2-methoxy) obtained in the above step was added dropwise with stirring. 2-diphenylthiol solution of -anilino]-quinazolin-6-yl}-4-hydroxyindole-1H-indol-3-yl)-ethanol 145a (147 mg, 〇·29 mmol) After stirring overnight, the reaction was completed. The reaction solution was poured into 1 mL of water, and a solid was formed, which was filtered with suction to give the title product 2-(1-{4-[3-chloro-4-(π-唆-唆- 2_decyloxy)-anilino]-quinazolin-6-yl}-4-(2-hydroxyethyl)-indole-pyrrole-3-carbaldehyde• 145b (80 mg 'yellow solid), yield: 55 MS m/z (ESI): 500 [M+1] Step 3 2-{1-{4-[3-chloro-4-(acridin-2-yloxy)-anilino]-quin Oxazolinyl 4-[(2-oxasulfonyl-ethylamino)-indenyl]- 1H_pyrrole_3_yl b. Alcohol The compound obtained in the above step 2 - (Bu {4_[3_ Gas_4_(pyridine-2-methoxy)-anilino]-quinazoline_6_yl b-4-(2-hydroxyethyl)_lH~pyrrole-3-carbaldehyde 145b (30 mg, 〇·〇6 Mm〇l) was dissolved in 1 mL of methanol, and 2-methanesulfonylethylamine hydrochloride (19 mg, 〇. 12 咖〇1) was added with stirring. After stirring at temperature for 3 hours the addition of a sodium triacetate brewing Jiwei oxide (254 does, square · 12 mmol), the resulting mixture was stirred at room temperature overnight, the reaction is complete. The reaction mixture was concentrated under reduced pressure, and the obtained solid was further purified and purified by EtOAc EtOAc EtOAc EtOAc EtOAc --anilino]-quinazolin-6-yl}-4-[(2-methylsulfonyl-ethylamino)-indenyl]-1H-pyrrol-3-yl}-ethanol 145 (50 mg, Yellow solid), Yield: 31%. MS m/z (ESI): 608 [M+1] NMR (400 MHz, DMS 〇-d〇: 5 10. 17 (s, 1H), 8. 80 (s, 1H), 8.61 (d, 1H, J=4.4), 8.55(s, IH), 8. 13(s, 1H), 8. 07(d, 1H, J=9.2), 7.88(m, 3H), 7. 67(s, 1H), 7. 60(d, 1H, J = 7. 6), 7.53 (s, 1H), 7.37 (t, 1H), 7.30 (d, 1H, ® J=8.8), 5.30 (s, 2H), 3.81 ( s, 2H), 3. 65(t, 2H), 3.44(t, 2H), 3. 15(t, 2H), 3. 09(s, 3H), 2. 69(t, 2H) Example 146 2-{4-"(2-oxasulfonyl-ethylamino)-methyl-1-b "4-(b]ethylamino)-喧口坐琳-6-yl 1-1 H-port ratio嘻-3-yl}-ethanol 0,xs°

251 94389 201016683 第一步 2-{4-羥甲基-1 一[4-(1 一苯乙胺基）_喹0坐啉_6_基卜ih_吡咯 -3-基}-乙醇在50 mL茄形瓶中，將氫化鋁鋰（197 mg，5. 2咖〇1) 洛解於15 mL四氫吱喃中，所得的溶液在冰浴條件下，a 卻至-5°C，攪拌下分批加入實施例77第二步所得的化合物 2-{4-[3-氯-4-(吡啶-2-甲氧基）-苯胺基卜喹唑啉一6一基}-6, 7-二氫-2Η-π比喃[3, 4-c] °比嘻-4-酮 77b(l g，26 mmol)，攪拌30分鐘後反應完畢。在反應液中加入」社脅水，1 mL飽和氫氧化鈉溶液，過濾反應液，母液在減壓下濃縮，得到本標題產物2-{4-羥甲基-l-[4-(l-苯乙胺基）一 •喹唑啉-6-基]-in-吡咯-3-基卜乙醇146a(480mg，類白色固體），產率：47% 〇 MS m/z (ESI)·： 389[M+1] 第二步 4-(2-羥乙基— —笨基—乙胺基）_喹唑啉_6_基] _ -1H-吡咯-3-甲醛在25 mL茄形瓶中，將鄰碘醯基苯曱酸（415 mg，1. 48 mmol)溶解於5 mL二曱基亞砜中，攪拌下逐滴加入上述步驟所得的化合物2-{4-羥甲基-l-[4-(l-苯乙胺基）-喹唑琳-6-基]-1H-吡咯-3-基卜乙醇 146a(480 mg，1. 23 mmol) 的4 mL二甲基亞颯溶液，攪拌過夜，反應完畢。將反應液倒入100 mL水中，有固體生成，抽濾，得到本標題產物 4-(2-羥乙基）-i-[4-(1-苯基-乙胺基）-喹唑啉-6-基]-1H- 252 94389 201016683 吡略-3-甲醛146b(400 mg，黃色固體），產率：84%。 MS m/z (ESI) ： 387[M+1] 第三步 2-{4-[(2-曱磺醯基-乙胺基）_曱基]^ — [^〜（卜苯乙胺基）一喹唑啉-6-基]- 1H-吡咯-3-基卜乙醇將上述步驟所得的化合物4-(2-經乙墓）-i_[4-(1-苯基-乙胺基）-喹唑啉-6-基]-1H-吡咯—3—曱醛i46b(90 mg Φ 0· 233 mmol)溶解於20 mL二氯曱烷中，择拌下加入2-甲石基乙胺鹽酸鹽（74 mg，0.466 mmo 1 )，三乙胺（0.066 mL，0.466 mmol)，室溫下攪拌4小時後加入三乙醯氧基硼致化納（99 mg，0.466 mmo 1 )，所得的混合液在室溫下擾拌 .過夜，反應完畢。反應液在減壓下濃縮，得到的固體進一步藉由TLC板進行分離純化，得到本標題產物2_丨4-[(2— 甲磺醯基乙胺基）-甲基]一卜[^-(卜苯乙胺基）一喹唑啉刊一基]-1H-吡咯-3-基}-乙醇146(30 mg，黃色固體），產率： 26% 〇湯 MS m/z (ESI) : 494{M+1] !HNMR (400MHz, DMS0-cf〇： δ 8.80(s, 1H), 8. 7〇(s, 1H) 8. 4(s, 1H), 7. 98(d, 1H, J=9.2), 7.80(d, 2H, J=8. 8), 7.50(d, 3H, J=6.8), 7.32(t, 2H), 7.23(t, 1H), 5.65^ 1H), 4.09(s, 2H)，3.67(t, 4H)，3.41(t, 2H)，3.i5(s，’ 3H), 2. 74(t, 2H), 1.65(d, 3H, J=7.2) 實施例147251 94389 201016683 Step 2 2-{4-Hydroxymethyl-1-[4-(1-phenylethylamino)- quinoxadolo-6-yl-ibu-pyrrol-3-yl}-ethanol in 50 In the mL eggplant bottle, lithium aluminum hydride (197 mg, 5.2 curry 1) was dissolved in 15 mL of tetrahydrofuran, and the resulting solution was stirred in an ice bath, a to -5 ° C, stirring. The compound obtained in the second step of Example 77 was added in portions, 2-{4-[3-chloro-4-(pyridine-2-methoxy)-anilinoquinazoline-6-yl}-6, 7 -Dihydro-2-indole-π-pyran[3,4-c] ° than hydrazin-4-one 77b (lg, 26 mmol), and the reaction was completed after stirring for 30 minutes. The reaction liquid was added with 1 mL of saturated sodium hydroxide solution, and the reaction liquid was filtered, and the mother liquid was concentrated under reduced pressure to give the title product 2-{4-hydroxymethyl-l-[4-(l- Phenylethylamino)-quinazolin-6-yl]-in-pyrrol-3-yl-ethanol 146a (480 mg, off-white solid), yield: 47% 〇MS m/z (ESI)·: 389 [M+1] The second step 4-(2-hydroxyethyl-phenyl)-quinazoline-6-yl] _-1H-pyrrole-3-carbaldehyde in a 25 mL eggplant bottle , o-iododecyl benzoic acid (415 mg, 1.48 mmol) was dissolved in 5 mL of dimethyl sulfoxide, and the compound 2-{4-hydroxymethyl-l- obtained in the above step was added dropwise with stirring. [4-(l-Phenylethylamino)-quinazoline-6-yl]-1H-pyrrol-3-ylbuethanol 146a (480 mg, 1.23 mmol) in 4 mL of dimethyl hydrazine solution, Stir overnight and the reaction is complete. The reaction solution was poured into 100 mL of water, and solid was formed and filtered to give the title product 4-(2-hydroxyethyl)-i-[4-(1-phenyl-ethylamino)-quinazoline- 6-yl]-1H- 252 94389 201016683 Pyrol-3-carbaldehyde 146b (400 mg, yellow solid), yield: 84%. MS m/z (ESI): 387 [M+1]. Step 3 2-{4-[(2-oxasulfonyl-ethylamino)-indolyl]^ — [^~(phenylphenylamine) - quinazoline-6-yl]- 1H-pyrrol-3-yl-ethanol The compound obtained in the above step 4-(2-B-tomb)-i_[4-(1-phenyl-ethylamino) -quinazolin-6-yl]-1H-pyrrole-3-furfural i46b (90 mg Φ 0· 233 mmol) dissolved in 20 mL of dichloromethane, and added with 2-methylglycolamine salt Acid salt (74 mg, 0.466 mmo 1 ), triethylamine (0.066 mL, 0.466 mmol), stirred at room temperature for 4 hrs, then added triethyl ethoxy hydride boron (99 mg, 0.466 mmo 1 ). The mixture was stirred at room temperature overnight and the reaction was completed. The reaction mixture was concentrated under reduced pressure, and the obtained solid was further purified and purified to afford the title product 2 丨 4-[(2-methanesulfonylethylamino)-methyl] (Phenylethylamino)-quinazoline-yl]-1H-pyrrol-3-yl}-ethanol 146 (30 mg, yellow solid), yield: 26% broth MS m/z (ESI): 494{M+1] !HNMR (400MHz, DMS0-cf〇: δ 8.80(s, 1H), 8. 7〇(s, 1H) 8. 4(s, 1H), 7. 98(d, 1H, J=9.2), 7.80(d, 2H, J=8. 8), 7.50(d, 3H, J=6.8), 7.32(t, 2H), 7.23(t, 1H), 5.65^ 1H), 4.09( s, 2H), 3.67(t, 4H), 3.41(t, 2H), 3.i5(s, '3H), 2. 74(t, 2H), 1.65(d, 3H, J=7.2) 147

94389 253 201016683 二1H-吡咯-3-篡丨-r,蟀94389 253 201016683 二1H-pyrrole-3-篡丨-r,蟀

重複本發明實施例146第一步至第三步所述的實驗驟’不同的是以實施例146第二步化合物4__(2〜羥步 -1-[4-(卜苯基-乙胺基）-啥唑啉-6-基]_1Η__吼吹基） ’ 〜甲酸： n比略 146b作原料’按照本發明實施例146第三步所述的相5 式使得該原料與二乙胺的反應，得到標題化合物2—丨參乙胺基甲基苯乙胺基）-喧唾琳__6_基]— -3-基}-乙醇147(35 mg，黃色固體），產率：74%。 MS m/z (ESI) ： 444[M+1] ^NMR (400MHz, DMSO-dO : 5 10.〇〇(s, 1H), 8. 93(s 8.43(s，1H)，8.04(d, 1H，J=9. 2)，7.93(s，1H)，7 8〇(d， 1H，J=8.8)，7.60(s，1H)，7. 53(d, 2H，J=7. 2)，7.31(t’ 2H)，7. 22(m，1H)，5.65(m，ih)，5.5〇(s, 1H), 4. l6(s’ ❹ 2H), 3.67(t，2H)，3.16(s，4H)，2.72(1:，2H)，l.67(d 3H, J=7. 2), L 30(q, 6H) ’ 實施例148 lzL3-.iir[a·-氧-4-(3-氟1^基）_茉胺基 >喹唑呲早} 生咯-上碁1ζ·3-[α 1-二级^基-六氤-l又冰6木-嘍某）-胺基]-丙_2-醇 94389 254 201016683The experiment described in the first step to the third step of the embodiment 146 of the present invention is repeated. The difference is that the compound of the second step of the embodiment 146 is 4__(2~hydroxyl-1-[4-(phenyl-ethylamino) - oxazoline-6-yl]_1 Η _ _ 吼 ) ) 〜〜〜 carboxylic acid: n ratio 146b as a raw material 'in accordance with the third step of the third step of the embodiment of the invention 146 to make the raw material and diethylamine Reaction, the title compound 2 - hydrazine ethylaminophenylethylamino)- hydrazine __6-yl]--3-yl}-ethanol 147 (35 mg, yellow solid), yield: 74% . MS m/z (ESI): 444 [M+1] NMR (400 MHz, DMSO-dO: 5 10. s (s, 1H), 8. 93 (s 8.43 (s, 1H), 8.04 (d, 1H, J=9. 2), 7.93 (s, 1H), 7 8 〇 (d, 1H, J = 8.8), 7.60 (s, 1H), 7. 53 (d, 2H, J = 7. 2) , 7.31 (t' 2H), 7. 22 (m, 1H), 5.65 (m, ih), 5.5 〇 (s, 1H), 4. l6 (s' ❹ 2H), 3.67 (t, 2H), 3.16 (s, 4H), 2.72 (1:, 2H), 1.67 (d 3H, J = 7.2), L 30 (q, 6H) ' Example 148 lzL3-.iir[a·-oxy-4 -(3-Fluoro 1^yl)-monomethylamino> quinazolyl early} raw sputum-upper 碁1ζ·3-[α 1-secondary base-six-l-l and ice 6 wood-喽) -amino]-propan-2-ol 94389 254 201016683

重複本發明實施例138第一步至第二步的實驗步驟，不同的是以實施例138第一步所得的化合物[3_氯_4_(3一氟苄氧基）-苯基]-[6-(1_環氧乙烷基曱*_1Η_β比咯_3_基） _喹唑啉-4-基]-胺138a作為原料，按照實施例138第二步所述的實驗方式，進行該原料與c_(1，卜二氧_六氩 # -Ιλ氺6*-噻喃-4-基）-曱胺的反應，得到本標題產物1-(3_ {4-[3-氯-4-(3-氟节氧基）-苯胺基]_喹唑啉_6_基}^比咯 -1-基）_3-[(1，1-二側氧基—六氫4 λ *6木_噻喃_4_甲基）一胺基]-丙-2-醇148(34 mg，黃色固體）’產率：52.3%。 'MS m/z (ESI) : 664[M+1] !HNMR (400MHz, DMS0-d〇： (5 9. 80(s, 1H), 8.61(s, 1H), 8.49(s, 1H), 8.05(m, 2H), 7. 80(dd, 1H), 7.71(d, 1H, ^ J=8.8), 7.45(m, 2H), 7. 33(m, 3H), 7. 28(t, 1H), 6. 89(t, 1H), 6.70(t, 1H), 5.60(s, 1H), 5. 27(s, 2H), 4. l〇(d, 2H), 3.98(m, . 1H), 3. 03(m, 4H), 2.70(m, 4H), 1. 7〇(m> 1H), 1.30(m, 4H) 實施例149 2-〇-{4了[3-氯二4-〇比啶-2-曱氳基、_黎胳基~]-喹唑呲^_ 基}~~4_二_^ 胺基曱基-1^-°比也-3-甚:、一乙醇 255 94389 201016683The experimental procedure of the first step to the second step of Example 138 of the present invention was repeated, except that the compound obtained in the first step of Example 138 [3_chloro-4-(3-fluorobenzyloxy)-phenyl]-[ 6-(1_Ethylene oxide 曱*_1Η_β ratio _3_yl) _ quinazolin-4-yl]-amine 138a as a starting material, according to the experimental method described in the second step of Example 138, The reaction of the starting material with c_(1,b dioxo-6 argon #-Ιλ氺6*-thiopyran-4-yl)-decylamine gives the title product 1-(3_{4-[3-chloro-4- (3-fluorohexyloxy)-anilino]-quinazoline-6-yl}^pyr-1-yl)_3-[(1,1-di-oxy-hexahydro 4 λ *6 wood _ Thio-4-methyl)-amino]-propan-2-ol 148 (34 mg, yellow solid) yield: 52.3%. 'MS m/z (ESI): 664[M+1] !HNMR (400MHz, DMS0-d〇: (5 9. 80(s, 1H), 8.61(s, 1H), 8.49(s, 1H), 8.05(m, 2H), 7. 80(dd, 1H), 7.71(d, 1H, ^ J=8.8), 7.45(m, 2H), 7. 33(m, 3H), 7. 28(t, 1H), 6. 89(t, 1H), 6.70(t, 1H), 5.60(s, 1H), 5. 27(s, 2H), 4. l〇(d, 2H), 3.98(m, . 1H), 3. 03(m, 4H), 2.70(m, 4H), 1. 7〇(m> 1H), 1.30(m, 4H) Example 149 2-〇-{4[3-chlorodi 4-〇啶曱氲曱氲曱氲、、 _ _ ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] 胺胺胺胺胺胺胺胺胺One ethanol 255 94389 201016683

重複本發明實施例145第一步至第三步所逃的實驗步驟’不同的是以實施例145第二步化合物— 一氯 -4-(〇比咬-2-曱氧基）-苯胺基]-啥0坐琳-6-基}-4-(2-經乙基）-1Η-吡咯-3-曱醛145b作原料，按照本發明實施例145 第三步所述的相同方式使得該原料與二乙胺的反應，得到標題化合物2-(1-丨4_[3 -氯_4~(π比淀-2-曱氧基）-本胺基] ® -喹唑啉-6-基}-4-二乙胺基曱基-1Η-吡咯-3-基）—乙醇 149(50 mg，黃色固體），產率：30%。 MS m/z (ESI) ： 559[M+1] » !HNMR (400MHz, DMSO- : d 11.12(s, 1H), 10. 〇8(s, 1H), 8.72(s, 1H), 8.48(s, 1H), 8. 23(s, 1H), 8. 17(s, 1H), 8.11(d, 1H, J-8.4), 7. 72(m, 3H), 7.49(s, 1H), 7.37(q, 1H), 7. 10(m, 3H), 6. 89(s, 1H), 6. 74(s, 1H), q 5. 72(s, 2H) 實施例.15 0 ]~1-〔3_氤苄基）-111-吲唑-5-基11^:门11-吡咯-3-_^·^!!^· 说-4_基1-胺The experimental procedure of the first step to the third step of the 145th embodiment of the present invention is repeated. The difference is that the compound of the second step of the embodiment 145 - monochloro-4-(indenyl-2-oxooxy)-anilino ]-啥0坐琳-6-yl}-4-(2-ethyl)-1Η-pyrrole-3-furaldehyde 145b as a starting material, in the same manner as described in the third step of the embodiment 145 of the present invention The reaction of the starting material with diethylamine gives the title compound 2-(1-丨4_[3-chloro-4-[~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ }-4-Diethylaminomercapto-1Η-pyrrol-3-yl)-ethanol 149 (50 mg, yellow solid), yield: 30%. MS m/z (ESI): 559 [M+1] <RTI ID=0.0>>&&&&&&&&&&&&&&&&&&&& s, 1H), 8. 23(s, 1H), 8. 17(s, 1H), 8.11(d, 1H, J-8.4), 7. 72(m, 3H), 7.49(s, 1H), 7.37(q, 1H), 7. 10(m, 3H), 6. 89(s, 1H), 6. 74(s, 1H), q 5. 72(s, 2H) Example.15 0 ]~ 1-[3_氤benzyl)-111-oxazol-5-yl 11^: Gate 11-pyrrole-3-_^·^!!^· Said-4_yl 1-amine

94389 256 20101668394389 256 201016683

氣氣下在50 mL茄形瓶中，將氟苄基）_1H_吲唑 -5-基]-(6-破啥哇啉-4_ 基）_ 胺 43b (25〇呢，0.505 mmol) ’ 1-(三異丙基矽）_1H_吡咯_3_硼酸（269呢’ 1. 〇i mmol)，肆（三笨基膦）鈀（2. 3 mg，〇. 〇2 mm〇1)，碳酸鉀（138 mg，1 mmol)溶於6 mL· N，N-二曱基甲醯胺和1. 5 mL水的 ®混合溶劑中，得到的混合物加熱到7〇。〇，2小時後反應完畢。將反應液冷卻至室溫，倒入1〇〇mL冰水中，析出白色固體，攪拌十分鐘後，抽濾，產物在真空下乾燥，得到的固體進一步藉由管柱層析法，得到標題產物氟苄基） -1H-吲唑-5-基]-[6-C1H-吡咯-3_基）_喹唑啉基]二胺 150(130 mg，黃色固體），產率：59. 3%。 MS m/z (ESI) ： 435[M+1] q JHNMR (400MHz, DMS0-d〇： ^ i〇.27(s, 1H), 8. 86(s, 1H), 8.51(s, 1H), 8.27(s, 1H)，8.17(s, 1H)，8.07((1, iff J=8.8)，7. 87(m，1H)，7. 76(s，3H)，7. 56(s，1H)，7.39(q 1H), 7. 07(m, 3H), 5. 71(s, 2H), 3. 99(s, 2H), 3. 67(m 2H), 2. 73(m, 2H), 2. 62Cm, 6H) 實施例151 2-(4-{ 側氧基-六虱-1 A 一喧喘一甲甚、一胺其甲基}二1=1.4-[1-(3-1节基hjj-吲唑—5一胺甚 94389 257 201016683 二6-基}-111-^^_3_某）— 乙醇Under a gas atmosphere, in a 50 mL eggplant-shaped flask, fluorobenzyl)_1H_indazol-5-yl]-(6-deuteroside-4-yl)-amine 43b (25 〇, 0.505 mmol) ' 1 -(triisopropylhydrazine)_1H_pyrrole_3_boric acid (269?' 1. 〇i mmol), hydrazine (triphenylphosphine) palladium (2.3 mg, 〇. 〇2 mm〇1), carbonic acid Potassium (138 mg, 1 mmol) was dissolved in 6 mL of N,N-dimercaptocarhamamine and 1.5 mL of water in a mixture of solvents, and the resulting mixture was heated to 7 Torr. Hey, the reaction was completed after 2 hours. The reaction solution was cooled to room temperature, poured into 1 mL of ice water, and a white solid was precipitated. After stirring for ten minutes, the mixture was filtered, and the product was dried under vacuum. The obtained solid was further purified by column chromatography to give the title product. Fluorobenzyl)-1H-indazol-5-yl]-[6-C1H-pyrrole-3-yl)-quinazolinyl]diamine 150 (130 mg, yellow solid), yield: 59. 3% . MS m/z (ESI): 435 [M + 1] q JHNMR (400 MHz, DMS0-d〇: ^ i〇.27 (s, 1H), 8. 86 (s, 1H), 8.51 (s, 1H) , 8.27(s, 1H), 8.17(s, 1H), 8.07((1, iff J=8.8), 7. 87(m,1H), 7.76(s,3H), 7.56(s, 1H), 7.39 (q 1H), 7. 07 (m, 3H), 5. 71 (s, 2H), 3. 99 (s, 2H), 3. 67 (m 2H), 2. 73 (m, 2H), 2. 62Cm, 6H) Example 151 2-(4-{ oxo-hexa-1-a 喧一一甲、、、一一一一一一一一一一一 = = = = = = = = = = -1 base hjj-carbazole-5-amine even 94389 257 201016683 di 6-yl}-111-^^_3_ a) - ethanol

2 (1 {4 [1 (3~氟苄基）_1H_吲唑_5_胺基卜喹唑啉基 -4-羥甲基-1H-吡咯_3_基）_乙醇在250 mL$形瓶中，將氫化链鐘（34〇呢，52丽〇1) _ Γ解於。5G mL四氫ϋ夫喃中，所得的溶液在冰浴條件下，冷部至-5 C，搜拌下分批加入實施Μ 132第二步所得的化合物 2-(4-{3-[2-(4-氟¥基 1)_4_乙烯基-2Η-吡唑-3-基]- 烯丙胺基}-喹唑啉-6—基）_6, 7_二氫_2{1_吡喃[3,44]吡咯 -4-酮132b(2. 26 g ’ 4. 48 mmol) ’擾拌3小時後反應完畢。在反應液中加入50 mL四氫呋喃和水（體積比為1 ·· 1)的混合溶劑猝滅反應，加入100 mL乙酸乙酯，授拌，有固體生成，矽藻土過濾，濾液用乙酸乙酯（100 mLx3)萃取，合併 258 94389 201016683 的有機相在減壓下蒸乾，得到本標題產物— 氟苄基）-1Η-吲唑-5-胺基]-喹唑琳-6-基卜4-經甲基_1H_ π比洛-3-基）-乙醇151a(1.713 g，黃色固體），產率. 75.19%。。第二步卜{4-[1-(3_氟节基嗅-5-胺基]_喹唑啉_6_基} -4-(2-經乙基）-1Η-0比洛-3-甲醒· 在50mL茄形瓶中，將鄰碘醯基苯甲酸（99〇吨，3 54 丽〇1)溶解於20 mL二曱基亞砜中，攪拌下逐滴加入上述步驟所得的化合物2-(1-{4-[1-(3-氟苄基）_1H_吲唑胺基]-喧嗤淋-6-基}-4-羥甲基-1H-吡咯-3_基）_乙醇15la .(1.713 g，3. 37 mmol)的5 mL二曱基亞砜溶液，攪拌過夜，反應完畢。將反應液倒入100 mL 5%碳酸氫鈉溶液和5〇乩乙酸乙酯，有固體生成，抽濾，得到本標題產.物^{4^ 一 (3-氟苄基）-lH-吲唑-5-胺基]-喹唑啉基卜4_(2_羥乙基）-1Η-吡咯-3-甲醛151b(4.5 g，黃色固體），產物不經 ❹分離直接進行下一步反應。 MS m/z (ESI) ： 507[M+1] 第三步 2 (4-{[(1，1-二側氧基-六氫_ι χ *6*-嗟喃_4_甲基）_胺基] -甲基}-1-{4-[1-(3-氟苄基）-lH-吲唑_5_胺基]一喹唑啉 -6-基}-1Η-η比嘻-3-基）-乙醇將上述步驟所得的化合物丨_氟苄基一吲唑-5-胺基]-喹唑啉邻-基}-4-(2-羥乙基）-ih-吡咯_3_ 94389 259 201016683 曱醛151b(500 mg，0. 493 mmol)溶解於20 mL二氣甲烧中，授掉下加入C_(l, 1-一氧-六氮_1 λ *6*-π塞喃-4-基）_甲胺 (161 mg，0.987 mmol)，室溫下攪拌4小時後加入三乙醯氧基硼氫化鈉（209 mg，0.987 mmol)，所得的混合液在室溫下攪拌過夜，反應完畢。反應液在減壓下濃縮，得到的固體進一步藉由TLC板進行分離純化，得到本標題產物2_ (4-{[(1，1-二側氧基-六氫-1又*6*-嗔喃-4-甲基）-胺基]一曱基}-1-{4-[ 1-(3-氟节基）-iH-吲唾-5-胺基]-啥唾琳-6— 基丨-ΙΗ-吼洛-3-基）-乙醇151(80 mg，黃色固體），產率：鬱 24· 9%。 MS m/z (ESI) ： 654[M+1] !HNMR (400MHz, DMSO-de)： δ ll.l〇(s, 1H), 9. 80(s, 1H), 8.56(d, 2H), 8.21(dd, 1H, J=6.8), 8.11(d, 1H, J=8. 8), 7. 87(m, - 1H), 7. 73(d, 1H, J = 8. 4)，- 7. 47(m， 2H), 6. 91(s > 1H), 6. 71(s, 1H) 實施例152 © 1-(4-二甲胺基曱基-l-{4-「l-(3-羞i 基)二基]-啥峻嘴-6-基]·-1 H-b比哈-3-某巧2 (1 {4 [1 (3~fluorobenzyl)_1H_carbazole_5_aminoquinazolinyl-4-hydroxymethyl-1H-pyrrole_3_yl)-ethanol in 250 mL$ In the bottle, the hydrogenated chain clock (34 〇, 52 〇 1) _ is dissolved. In 5G mL of tetrahydrofurfuran, the obtained solution was added to the compound 2-(4-{3-[2) obtained in the second step of Μ132 in batches under ice bath conditions, to the cold portion to -5 C. -(4-fluoro¥yl 1)_4_vinyl-2Η-pyrazol-3-yl]-allylamino}-quinazolin-6-yl)_6,7-dihydro-2{1_pyran [3,44]pyrrol-4-one 132b (2.66 g ' 4.48 mmol) 'The reaction was completed after 3 hours of scramble. The reaction mixture was quenched by adding a mixed solvent of 50 mL of tetrahydrofuran and water (1··1 by volume), 100 mL of ethyl acetate was added, and a solid was formed, and the mixture was filtered, and the filtrate was filtered. (100 mL x 3) extraction, combined with 258 94389 201016683, the organic phase was evaporated to dryness under reduced pressure to give the title product - fluorobenzyl)-1 Η-carbazol-5-amino]- quinazoline-6- keb - by methyl-1H_πbilo-3-yl)-ethanol 151a (1.713 g, yellow solid), yield: 75.19%. . The second step is {4-[1-(3_fluorohexyl s--5-amino)-quinazoline-6-yl}-4-(2-ethyl)-1Η-0 piroxa-3 -Awakening · In a 50mL eggplant-shaped bottle, o-iodohydrazinobenzoic acid (99 〇 ton, 3 54 〇 1) was dissolved in 20 mL of dimethyl sulfoxide, and the compound obtained in the above step was added dropwise with stirring. 2-(1-{4-[1-(3-fluorobenzyl)_1H-indazolamino]-indole-6-yl}-4-hydroxymethyl-1H-pyrrole-3_yl) Ethanol 15 la. (1.713 g, 3.37 mmol) in 5 mL of dimethyl sulfoxide solution, stirred overnight, and the reaction was completed. Pour the reaction solution into 100 mL of 5% sodium bicarbonate solution and 5 〇乩 ethyl acetate. The solid is formed and suction filtered to give the title product: </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 1Η-pyrrole-3-carbaldehyde 151b (4.5 g, yellow solid), the product was taken directly to the next reaction without hydrazine. MS m/z (ESI): 507 [M+1] The third step 2 (4-{[ (1,1-di-oxy-hexahydro- ι χ *6*-嗟 __4_methyl)-amino]-methyl}-1-{4-[1-(3-fluorobenzyl) -lH-carbazole_5_amino]-quinazoline-6-yl}-1Η-η than indole-3-yl)-ethanol The compound obtained in the above step is 丨_Fluorobenzyl-oxazole-5-amino]-quinazoline o-yl}-4-(2-hydroxyethyl)-ih-pyrrole_3_ 94389 259 201016683 Furfural 151b (500 mg, 0. 493 Ment) dissolved in 20 mL of methane, and added C_(l, 1-oxo-hexanitro-1 λ *6*-π-propan-4-yl)-methylamine (161 mg, 0.987) After stirring for 4 hours at room temperature, sodium triethoxysulfonate hydride (209 mg, 0.987 mmol) was added, and the mixture was stirred at room temperature overnight, and the reaction was completed. The solid was further isolated and purified by a TLC plate to give the title product: 2-(4-{[(1,1-di- oxy-hexahydro-1 -6*-pyran-4-yl)-amine Alkyl}-yl}-1-{4-[1-(3-fluoronodo)-iH-indole-5-amino]-啥琳 -6 - 丨-ΙΗ-吼洛-3- Base)-ethanol 151 (80 mg, yellow solid), yield: s. 24 9%. MS m/z (ESI): 654[M+1] !HNMR (400 MHz, DMSO-de): δ ll.l 〇(s, 1H), 9. 80(s, 1H), 8.56(d, 2H), 8.21(dd, 1H, J=6.8), 8.11(d, 1H, J=8. 8), 7. 87 (m, - 1H), 7. 73(d, 1H, J = 8. 4), - 7. 47(m, 2H), 6. 91(s > 1H), 6. 71(s, 1H) Example 152 © 1-(4-two Methylamino fluorenyl-l-{4-"1-(3-hei i)diyl]-啥啥嘴-6-yl]·-1 H-b than ha -3-

重複本發明實施例151第一步至第三少/斤述的只驗步驟’不同的是以實施例151第二步化合物ρμ-ΠΥ3-氟 260 94389 201016683 苄基）-1Η-吲唑-5-胺基]-喹唑啉_6_基卜4 —(2_羥乙基） _1H-吡咯-3-甲醛151b作原料，按照本發明實施例151第三步所述的相同方式使得該原料與二甲胺的反應，得到標題化合物2-(4-二曱胺基甲基—ρμ一π_(3_氟苄基）_1Η_ 吲唑-5-胺基]-喹唑啉-6-基卜1Η一吡咯_3_基）_乙醇152 (6〇111莒，黃色固體），產率：35%。 MS m/z (ESI) ： 536[M+1] ^NMR (400MHz, DMSO-de)： d l〇.27(s, 1H), 8. 86(s, 1H) 8.51(s, 1H), 8.27(s, 1H), 8. 17(s, 1H), 8. 07(d, 1H, J=8.8)’ 7. 87(m’ 1H)，7.76(S’3H)，7.56(s, 1H), 7. 39(q， 1H), 7. 07(m, 3H), 5.71(s, 2H), 3. 99(s, 2H), 3. 67(m, 2H), 2.73(m, 2H), 2. 62(m, 6H) ’ 實施例153 二Ll.-(_g_-氟苄基）-1Ητ^〇坐-5^胺篡 i —啐唑啉其}Repeat the first step of the first embodiment of the present invention to the third less than the second test step. The difference is that the compound of the second step of the embodiment 151 is ρμ-ΠΥ3-fluoro 260 94389 201016683 benzyl)-1 Η-carbazole-5. -Amino]-quinazoline-6-yl b 4-(2-hydroxyethyl) _1H-pyrrole-3-carbaldehyde 151b as a starting material, which is obtained in the same manner as described in the third step of Example 151 of the present invention. Reaction with dimethylamine to give the title compound 2-(4-didecylaminomethyl-ρμ-π_(3-fluorobenzyl)_1Η-oxazol-5-amino]-quinazoline-6-yl 1 Ηpyrrole_3_yl)-ethanol 152 (6〇111莒, yellow solid), yield: 35%. MS m/z (ESI): 536 [M+1] NMR (400 MHz, DMSO-de): dl s.27 (s, 1H), 8. 86 (s, 1H) 8.51 (s, 1H), 8.27 (s, 1H), 8. 17(s, 1H), 8. 07(d, 1H, J=8.8)' 7. 87(m' 1H), 7.76(S'3H), 7.56(s, 1H) , 7. 39(q, 1H), 7. 07(m, 3H), 5.71(s, 2H), 3. 99(s, 2H), 3. 67(m, 2H), 2.73(m, 2H) , 2. 62(m, 6H) 'Example 153 L L.-(_g_-fluorobenzyl)-1Ητ^〇 sitting-5^amine 篡i-oxazoline

重複本發明實施例151第一步至第三步所述的實驗步驟，不同的是以實施例151第二步化合物一氟苄基）-1H''吲唑-5-胺基]-喹唑啉-6-基}-4-(2-羥乙基） -1H-吡咯-3-甲醛151b作原料，按照本發明實施例i5i第三步所述的相同方式使得該原料與2_甲磺醯基乙胺的反 94389 261 201016683 應，得到標題化合物2-{1-{4-[1-(3-氟苄基）〜1η〜π51嗅胺基]-啥〇坐琳-6-基}-4-[(2-甲績酿基-乙胺基）甲 -1H-吡咯-3-基卜乙醇153(35 mg，黃色固體），產盎.〇基] 展年.37%。 MS m/z (ESI) ： 614 [M+l] !HNMR (400MHz, DMSO-d〇: ά 10.24(s, 1H), 8 e〇}(s，1H) 8.50(s, 1H), 8.27(s, 1H), 8.16(s, 1H), 8. 〇6(d ^ 、u， 1H) 7. 80(m，3H)，7. 67(s，1H)，7.53(s，1H)，7.37(q ’ 3.44(t，2H)，3. 16(t，2H)，3.08(s，3H)，2.69Q )， ❹實施例154 2H)The experimental procedure described in the first step to the third step of Example 151 of the present invention was repeated, except that the compound of Example 151, the first step of the compound, monofluorobenzyl)-1H''oxazol-5-amino]-quinazoline Phenyl-6-yl}-4-(2-hydroxyethyl)-1H-pyrrole-3-carbaldehyde 151b as a starting material, which is made in the same manner as described in the third step of Example i5i of the present invention. The anti-94389 261 201016683 of mercaptoethylamine should give the title compound 2-{1-{4-[1-(3-fluorobenzyl)~1η~π51 olamine base]-啥〇坐琳-6-yl} -4-[(2-Acryl-ethylamino)methyl-1H-pyrrol-3-ylbuethanol 153 (35 mg, yellow solid), y. MS m/z (ESI): 614 [M+l].HNMR (400 MHz, DMSO-d: ά 10.24 (s, 1H), 8 e〇} (s, 1H) 8.50 (s, 1H), 8.27 ( s, 1H), 8.16(s, 1H), 8. 〇6(d ^, u, 1H) 7. 80(m,3H), 7.67(s,1H),7.53(s,1H),7.37 (q ' 3.44 (t, 2H), 3. 16 (t, 2H), 3.08 (s, 3H), 2.69Q), ❹ Example 154 2H)

重複本發明實施例150的實驗步驟，不间的e 氯-4-氟本基）-(6-蛾-啥β坐琳_4_基）-胺48a作為原料參照實施例150所述的方法，進行該原料與ι_(三異丙其發 7. 07(m，3H)，5.71(s，2H)，3.80(s，2H)，3.65(t =)， -1H-吡咯-3-硼酸的反應，得到本標題產物（3_氣_4_氟苯基）-[6-(1Η-吡咯-3-基）-喹唑啉-4-基]-胺154(25 mg，棕色固體），產率：10%。， MS m/z (ESI) ： 339[M+1] ^NMR (400MHz, DMSO- cf〇： δ 11.10(s, 1H), 9.80(s, 1H), 8.56(d, 2H), 8.21(dd, 1H, J = 6. 8), 8.11(d, 1H, J=8.8), 7. 87(m, 1H), 7. 73(d, 1H, J = 8. 4), 7.47(m, 2H), 6.91(s, 262 94389 201016683 1H), 6.71(s, 1H) 實施例155 ^啉-6_ 基卜座1：各1-基甲磺醯棊二乙胺甚 hThe experimental procedure of Example 150 of the present invention was repeated, and the method described in Example 150 was carried out as the starting material of e-chloro-4-fluorobenzyl)-(6-moth-[beta]-[beta]-[beta]-yl)-amine 48a. , the raw material and ι_(triisopropyl ketone 7.07 (m, 3H), 5.71 (s, 2H), 3.80 (s, 2H), 3.65 (t =), -1H-pyrrole-3-boronic acid The reaction afforded the title product (3_m.s..sup..sup..sup..sup..sup. Yield: 10%., MS m/z (ESI): 339[M+1] NMR (400 MHz, DMSO- cf 〇: δ 11.10 (s, 1H), 9.80 (s, 1H), 8.56 (d, 2H), 8.21 (dd, 1H, J = 6. 8), 8.11(d, 1H, J=8.8), 7. 87(m, 1H), 7. 73(d, 1H, J = 8. 4) , 7.47 (m, 2H), 6.91 (s, 262 94389 201016683 1H), 6.71 (s, 1H) Example 155 ^ -6 -6 -6 基 Block 1: each 1-methylmethanesulfonate diethylamine

H\ nroJ^F 155 重複本發明實施例138第一步至第二步的實驗步驟，不同的是以實施例138第一步所得的化合物[3_氯_4_(3_ 氣节氧基）-笨基]-[6-(卜環氧乙院基甲基_1{1一〇比略+基） -喹唑啉-4-基]-胺138a作為原料，按照實施例138第二 .步所述的實驗方式，進行該原料與2_甲磺醯基乙胺的反應，得到本標題產物苄氧基）_苯胺基]-喹唑啉-6-基}-吡咯.1-基）_3_(2_曱磺醯基_乙胺基）. -丙-2-醇155(17 mg，黃色固體），產率：27. 9%。 MS m/z (ESI) ： 624[M+1] φ HNMR (400MHz, DMSO-cfe): (5 9. 69(s, 1H), 8. 52(d, 2H), 8.02(d, 2H), 7.78(dd, 1H), 7. 70(d, 1H, J=8. 8), 7. 49(q, 1H), 7.41(s, 1H), 7. 32(m, 3H), 7. 19(t, 1H), 6.88(s, 1H), 6.66(s, 1H), 5.27(s, 2H), 5.10(d, 1H), 4. 03(d, 2H), 3.80(m, 1H), 3. 23(m, 2H), 3.15(t, 2H), 3. 02(s, 3H), 2.95(t, 2H) 實施例156 1ιιΐ4·~「3-氣-4-(3-氟苄氧基）-苯胺基i-喹唑蛛-6-某1 94389 263 201016683 -5, 6-二氫-2H-環戊烧并f cl °比洛-4-g同二q、（2-二乙胺基4 基）-蔣HjrroJ^F 155 The experimental procedure of the first step to the second step of Example 138 of the present invention was repeated, except that the compound obtained in the first step of Example 138 [3_chloro_4_(3_gas oxy)- Stupid base]-[6-(b-epoxide-based methyl-1)-quinazoline-4-yl]-amine 138a as a starting material, according to Example 138, second step In the experimental manner, the reaction of the starting material with 2-methanesulfonylethylamine is carried out to obtain the title product benzyloxy)-anilino]-quinazolin-6-yl}-pyrrole.1-yl)_3_ (2_ oxasulfonyl-ethylamine). -propan-2-ol 155 (17 mg, yellow solid), yield: 27.9%. MS m/z (ESI): 624 [M+1] φ HNMR (400 MHz, DMSO-cfe): (5 9. 69 (s, 1H), 8. 52 (d, 2H), 8.02 (d, 2H) , 7.78(dd, 1H), 7. 70(d, 1H, J=8. 8), 7. 49(q, 1H), 7.41(s, 1H), 7. 32(m, 3H), 7. 19(t, 1H), 6.88(s, 1H), 6.66(s, 1H), 5.27(s, 2H), 5.10(d, 1H), 4. 03(d, 2H), 3.80(m, 1H) , 3. 23(m, 2H), 3.15(t, 2H), 3. 02(s, 3H), 2.95(t, 2H) Example 156 1 ιιΐ4·~ "3-Ga-4-(3-fluorobenzyl) Oxy)-anilino i-quinazoline-6-some 1 94389 263 201016683 -5, 6-dihydro-2H-cyclopentan and f cl ° pir-4-g identical to q, (2-two Ethylamine 4 base)-Jiang

156 第一步 5, 6-二氫-2H-環戊院并[c]°比嘻-4-1^-〇〜（2_二乙胺基乙基） -躬· 在50 inL茄形瓶中’將5,6-二氫環戍烧[c]D比哈 -4-酮 16b(200 mg，1·65 mmol)，0-(2、二乙胺基乙基）-0羥胺鹽酸鹽（474 mg，2. 31mmol)溶解於2〇 mL乙醇中，授摔下加入醋酸納（406 mg’ 4. 95 mmol)，所得的混合液加熱回流4小時，反應完畢。溶液冷卻至室溫，過遽，遽液減壓下濃縮，得到的殘留物藉由管柱層析法進一步分離純化，得到本標題產物5,6-二氫_211_環戊烷并[c]吡咯_4_酮 -0-(2-二乙胺基乙基）-肟156a(155 mg，黃色固體），產率： 40% MS m/z (ESI) ： 254[M+1] 94389 264 201016683 第二步 2-{4-[3-氯-4-(3-氟苄氧基）-苯胺基]-喹唑啉_6—基} -5’ 6-二氫-2H-環戊烷并[c]吡咯_4_酮-〇_(2-二乙胺基乙基）-躬' 在50 mL茄形瓶中’依次加入上述步驟所得的化合物 5, 6-二氫-2H-環戊烷并[c]吡咯_4一酮〇_(2_二乙胺基乙基） -肟 156a(70 mg ’ 0. 3mmol)，（3-氯-4-氟苯基）-(6-碘-喹唑啉-4-基）-胺 lg(i52 mg，〇· 3mmol)，磷酸鉀（191 mg， 0. 9 mmol) ’碘化亞銅（57mg，〇. 3 mmol)，N，N，-二曱基-1，2-乙二胺（26 mg，〇. 3mmol)溶解於3mL N，N-二甲基甲醯胺中，混合物在氮氣保護下’加熱到7(pc，攪拌過夜。將反應液倒入100 mL冰水中’用乙酸乙酯（3〇 mLx3)萃取，合併的有機相依次用飽和氯化鈉洗滌，無水硫酸鈉脫水，過濾’ 濾液減壓下濃縮，得到的殘留物用TLC板，固體在真空下乾燥，得到本標題產物2-{4-[3-氯-4-(3-氟苄氧基）-苯胺基]-喹唑啉-6-基}-5, 6-二氫-2H-環戊烷并[c]吡咯-4-酮鲁-0-(2-二乙胺基乙基）-蔣（46 mg，黃色固體），產率： 25. 3% 〇 MS m/z (ESI) ： 614[M+1] 'HNMR (400MHz, DMSO- cf6) ： δ 10. 13(s, 1H), 8. 92(s, 1H), 8.60(s, 1H), 8.17(m, 3H), 7. 88(d, 2H, J=9. 2), 7.47(m, 1H), 7. 43(s, 1H), 7.32(m, 2H), 7. 28(d, 1H, J=9. 2), 7. 19(t, 1H), 5.27(s, 2H), 4.40(t, 2H), 3. 14(m, 2H), 3.05(q, 2H), 2. 90(t, 2H), 1.26(m, 10H) 265 94389 201016683 實施例157 ii-[3-氯-4-C3二敦苄氳篡苯胺基1-喹唾琳-L基丨ϋ三氯-?J-環c 1吡略-4-酮-0-(2~ 嗎 - 4 -乙蠢156 First step 5, 6-dihydro-2H-cyclopentanol and [c]° than 嘻-4-1^-〇~(2_diethylaminoethyl)-躬· in a 50 inL eggplant bottle Medium '5,6-dihydrocycloindole [c]D than ha-4-ketone 16b (200 mg, 1.65 mmol), 0-(2, diethylaminoethyl)-hydroxylamine hydrochloride The salt (474 mg, 2.31 mmol) was dissolved in 2 mL of ethanol, and sodium acetate (406 mg ' 4. 95 mmol) was added and the mixture was heated and refluxed for 4 hours, and the reaction was completed. The solution was cooled to room temperature, and the residue was concentrated under reduced pressure. The residue obtained was purified and purified by column chromatography to give the title product 5,6-dihydro-211-cyclopentane. Pyrrole_4-ketone-0-(2-diethylaminoethyl)-indole 156a (155 mg, yellow solid), yield: 40% MS m/z (ESI): 254[M+1] 94389 264 201016683 Step 2 2-{4-[3-Chloro-4-(3-fluorobenzyloxy)-anilino]-quinazoline-6-yl} -5' 6-dihydro-2H-cyclopentyl Alkano[c]pyrrole_4-keto-oxime-(2-diethylaminoethyl)-躬' In a 50 mL eggplant-shaped flask, the compound obtained in the above step, 5,6-dihydro-2H-, was added in sequence. Cyclopenta[c]pyrrole_4-one oxime 〇(2-diethylaminoethyl)-indole 156a (70 mg '0.3 mmol), (3-chloro-4-fluorophenyl)-(6 -iodo-quinazolin-4-yl)-amine lg (i52 mg, 〇·3 mmol), potassium phosphate (191 mg, 0.9 mmol), cuprous iodide (57 mg, 〇. 3 mmol), N, N,-Dimercapto-1,2-ethanediamine (26 mg, 〇. 3 mmol) was dissolved in 3 mL of N,N-dimethylformamide, and the mixture was heated to 7 (pc, stirred under nitrogen). Overnight. Pour the reaction into 100 mL of ice water. (3 〇mLx3), the combined organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, filtered, evaporated, evaporated, evaporated. 2-{4-[3-Chloro-4-(3-fluorobenzyloxy)-anilino]-quinazolin-6-yl}-5,6-dihydro-2H-cyclopentane[c] Pyrrole-4-onelu-O-(2-diethylaminoethyl)-Jiang (46 mg, yellow solid), Yield: 25. 3% 〇MS m/z (ESI): 614[M+1 'HNMR (400MHz, DMSO- cf6) : δ 10. 13(s, 1H), 8. 92(s, 1H), 8.60(s, 1H), 8.17(m, 3H), 7. 88(d, 2H, J=9. 2), 7.47(m, 1H), 7. 43(s, 1H), 7.32(m, 2H), 7. 28(d, 1H, J=9. 2), 7. 19 (t, 1H), 5.27(s, 2H), 4.40(t, 2H), 3. 14(m, 2H), 3.05(q, 2H), 2. 90(t, 2H), 1.26(m, 10H 265 94389 201016683 Example 157 ii-[3-Chloro-4-C3 didonium benzalkonium 1-quinoxaline-L-based ruthenium trichloride-?J-cycloc 1pyr-4-one- 0-(2~? - 4 - stupid

16b16b

(Z) 157(Z) 157

157a157a

157 第一步 5,6-二氩-211-環戊烷并[〇]吡咯_4_酮_〇_(2_嗎啉—4_乙基) -肟在50 mL茄形瓶中’將5,6_二氫一2H_環戊烷[c]吡咯 ❹-4-酮 16b(200 mg，1.65 _1)，〇_(2_嗎琳_4_ 乙基）_經胺鹽酸鹽（507mg，2.31mmol)溶解於2〇mL乙醇中，攪拌下加入醋酸鈉（406 mg，4.95職〇1)，所得的混合液加埶回流 6小時’反應完畢。溶液冷卻至室溫，過遽，減壓下濃縮，得到的殘留物藉由管柱層析法進一步分離純化，得到本標題產物5, 6-二氫-2H-環戊燒并[c]料_4_綱_〇_(2 一嗎: -4-乙基）-肟157a(328 mg，白色固體），產率：8〇% MS m/z (ESI) ： 250 [M+1] 94389 266 201016683 第二步 (Z) 2-{4-[3-氯-4-(3-氟苄氧基）-苯胺基]-喹唑啉-6_基} -5, 6-二氫-2H-環戊烷并[c]吡咯-4-酮-0-(2-嗎啉-4-乙基）一肟在50 mL茄形瓶中’依次加入上述步驟所得的化合物 5, 6-二氫-2H-環戊烷并[c]吡咯-4-酮-0-(2-嗎琳-4-乙基） -肟 157a (100 mg，0. 4 mmol)，（3-氯-4-氟苯基）-(6-碘-喹唑啉-4-基）-胺 lg (203 mg，0. 4 mmol)，填酸卸（255 mg， 1. 2 mmol)，碘化亞銅（76 mg，0. 4mmol)，N，N，-二曱基-1，2-切乙二胺（35 mg ’ 0. 4mniol)溶解於3 mL N，N-二曱基甲醯胺中，混合物在氮氣保護下，加熱到7〇艺，攪拌20小時後 •反應完畢。將反應液倒入100 mL冰水中，用乙酸乙酯（30 mL X 3 )萃取’合併的有機相依次用飽和氯化納洗務，無水硫酸鈉脫水，·過濾，減壓下濃縮，得到的殘留物用HPLC進一步分離純化’得到本標題產物（Z)2-{4-[3-氯-4-(3-氟苄氧基）-苯胺基]-喹唑啉-6-基卜5, 6-二氫-2H-環戊烷并[C]吡 ❺嘻-4-酮-0-(2-嗎啭-4-乙基）-將157(80 mg，黃色固體），產率：32%。 MS m/z (ESI) ： 628[M+1] !HNMR (400MHz, MSO-de): δ 9. 82(s, 1H), 8. 62(d, 2H), 8.13(d, 1H, J=8.4), 8. 02(s, 1H), 7.87(d, 1H, J=9. 2), 7. 74(d, 2H, J=8.0), 7.46(q, 1H), 7. 30(m, 4H), 7. 18(t, 1H), 5.26(s, 2H), 4. 19(t, 2H), 3. 55(t, 4H), 3. 03(t, 2H), 2.89(t, 2H), 2. 67(t, 2H), 2.48(m, 4H) 267 94389 201016683 實施例158 氲基）-笑胺某卜喹157 First step 5,6-Di-argon-211-cyclopenta[〇]pyrrole_4_one_〇_(2_morpholine-4_ethyl)-肟 in a 50 mL eggplant-shaped bottle 5,6-Dihydro-2H-cyclopentane [c]pyrrole-4-one 16b (200 mg, 1.65 _1), 〇_(2_?琳_4_ethyl)_amine hydrochloride (507mg , 2.31 mmol) was dissolved in 2 mL of ethanol, sodium acetate (406 mg, 4.95) was added with stirring, and the resulting mixture was refluxed for 6 hours to complete the reaction. The solution was cooled to room temperature, dried, and concentrated under reduced pressure. The residue obtained was purified and purified by column chromatography to give the title product 5, 6-dihydro-2H-cyclopentane and [c] _4_纲_〇_(2 I: -4-ethyl)-肟157a (328 mg, white solid), Yield: 8〇% MS m/z (ESI): 250 [M+1] 94389 266 201016683 Second step (Z) 2-{4-[3-Chloro-4-(3-fluorobenzyloxy)-anilino]-quinazolin-6-yl}-5,6-dihydro-2H -cyclopenta[c]pyrrol-4-one-0-(2-morpholin-4-ethyl)-indole in a 50 mL eggplant-shaped flask' sequentially added the compound obtained in the above step, 5,6-dihydrogen -2H-cyclopenta[c]pyrrol-4-one-0-(2-morphin-4-ethyl)-indole 157a (100 mg, 0.4 mmol), (3-chloro-4-fluoro Phenyl)-(6-iodo-quinazolin-4-yl)-amine lg (203 mg, 0.4 mmol), acid-depleted (255 mg, 1. 2 mmol), cuprous iodide (76 mg , 0. 4mmol), N, N,-dimercapto-1,2-cut ethylenediamine (35 mg '0.4mniol) was dissolved in 3 mL of N,N-dimercaptocarhamamine, the mixture was under nitrogen Under protection, heat to 7 〇 art, stir for 20 hours • The reaction is completed. The reaction mixture was poured into 100 mL of ice water and extracted with ethyl acetate (30 mL×3). The combined organic phases were washed successively with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was further purified by HPLC to give the title product (Z) 2-{4-[3-chloro-4-(3-fluorobenzyloxy)-anilinyl]-quinazoline-6-yl b. 6-Dihydro-2H-cyclopenta[C]pyridin-4-one-0-(2-indol-4-ethyl)- 157 (80 mg, yellow solid), yield: 32 %. MS m/z (ESI): 628 [M+1].HNMR (400 MHz, MSO-de): δ 9. 82 (s, 1H), 8. 62 (d, 2H), 8.13 (d, 1H, J =8.4), 8. 02(s, 1H), 7.87(d, 1H, J=9. 2), 7. 74(d, 2H, J=8.0), 7.46(q, 1H), 7. 30( m, 4H), 7. 18(t, 1H), 5.26(s, 2H), 4. 19(t, 2H), 3. 55(t, 4H), 3. 03(t, 2H), 2.89( t, 2H), 2. 67(t, 2H), 2.48(m, 4H) 267 94389 201016683 Example 158 thiol)- laughing amine quinquin

嗎琳-4-乙某_琳-4-乙

(E) 158 必重複本發明實施例157第一步至第二步的實驗步驟， ❹對第二步的粗產品進行HpLC製備分離得到本標題產物 (£)-2-{4-[3-氯-{4-[3-氣-4-(3-氟节氧基）_苯胺基]-喹 °坐琳-6-基}-5, 6-二氫-2H-環戊烧并[c]吼略_4_酮-〇-(2-嗎啉-4-乙基）-肟158(60 mg ’黃色固體），產率24%。 MS -m/z (ESI) ： 628[M+1 ] JHNMR (400MHz, . DMS0- (5 9. 69(s, 1H), 8. 59(d, 2H), 8.14(d, 1H, J=8. 8), 8.01(s, 1H), 7. 82(d, 1H, J=8. 8), ❹ 7.74(s, 2H)，7. 47(q, 1H)，7. 33(m，4H)，7. 18(t, 1H)， 5.25(s, 2H), 4. 16(t, 2H), 3. 58(t, 4H), 3. 04(t, 2H), 2.82(t, 2H), 2.61(t, 2H), 2.50(m, 4H) 實施例159 , [3-甲基-4-(6-甲基-吡啶-3-侧氣某）-笑篡1-「1。11-吡咯 - 3-基）-喧唾啦-4_基1-胺 268 94389 201016683(E) 158 The experimental procedure of the first step to the second step of the embodiment 157 of the present invention must be repeated, and the crude product of the second step is subjected to HpLC preparation to obtain the title product (£)-2-{4-[3- Chloro-{4-[3-gas-4-(3-fluorohexyloxy)-anilino]-quino-isoline-6-yl}-5,6-dihydro-2H-cyclopentan and [c吼 _4_keto-oxime-(2-morpholin-4-ethyl)-indole 158 (60 mg 'yellow solid), yield 24%. MS - m / z (ESI): 628 [M+1] JHNMR (400 MHz, . DMS0- (5 9. 69 (s, 1H), 8. 59 (d, 2H), 8.14 (d, 1H, J = 8. 8), 8.01(s, 1H), 7. 82(d, 1H, J=8. 8), ❹ 7.74(s, 2H), 7. 47(q, 1H), 7.33(m, 4H), 7.18(t, 1H), 5.25(s, 2H), 4. 16(t, 2H), 3. 58(t, 4H), 3. 04(t, 2H), 2.82(t, 2H), 2.61 (t, 2H), 2.50 (m, 4H) Example 159, [3-methyl-4-(6-methyl-pyridin-3- ss.). 11-pyrrole-3-yl)-hydrazino-4-yl 1-amine 268 94389 201016683

重複本發明實施例150的實驗步驟，不同的是以（6一碘 -喹唑啉—4-基）-[3-曱基-4-(6-甲基-吡啶一3-侧氧基）-苯基]-胺66a作為原料，按照實施例150所述的方式’進行該原料與1-(三異丙基矽）-1Η-吡咯-3-硼酸的反應’得到本標題產物（3-氯-4-氟苯基）-[6-(1Η-吡咯-3-基）-喹唑啉 -4-基]-胺159(30 mg，棕色固體），產率：21%。 ® MS m/z (ESI) ： 408[M+1] ^NMR (400MHz, DMSO-dO： (5 8.51(s, 1H), 8.41(s, 1H), 8.10(m, 2H), 7.70(d, 1H, J=8. 8), 7. 67(s, 1H), 7. 59(dd, 1H, J=8.8), 7.35(s, 1H), 7. 27(m, 2H), 7. 98(d, 1H, • J=8.8), 6.84(1, 1H), 6.70(t, 1H), 2. 49(s, 3H), 2. 25(s, 3H) 實施例160 Q N-[{_4-[3-氣-4-(3-氟苄氧基）-苯胺基1-啥嗤嚇 -6- 基}-p比洛-1-基）-乙某-甲4酿胺一The experimental procedure of Example 150 of the present invention was repeated, except that (6-iodo-quinazolin-4-yl)-[3-indolyl-4-(6-methyl-pyridyl-3-o-oxy) -Phenyl]-amine 66a as a starting material, the reaction of the starting material with 1-(triisopropylhydrazin)-1?-pyrrole-3-boronic acid was carried out in the manner described in Example 150 to give the title product (3- Chloro-4-fluorophenyl)-[6-(1Η-pyrrol-3-yl)-quinazolin-4-yl]-amine 159 (30 mg, brown solid), yield: 21%. ® MS m/z (ESI): 408 [M+1] NMR (400 MHz, DMSO-dO: (5 8.51 (s, 1H), 8.41 (s, 1H), 8.10 (m, 2H), 7.70 (d) , 1H, J=8. 8), 7. 67(s, 1H), 7. 59(dd, 1H, J=8.8), 7.35(s, 1H), 7. 27(m, 2H), 7. 98(d, 1H, • J=8.8), 6.84(1, 1H), 6.70(t, 1H), 2. 49(s, 3H), 2. 25(s, 3H) Example 160 Q N-[ {_4-[3-Gas-4-(3-fluorobenzyloxy)-anilino-1-indole-6-yl}-p-Bylo-1-yl)-Ethyl-A-4

重複本發明貫施51所述的實驗步驟，不同的是以實施例42所付的化合物[3-氯-4-(。比咬-2-甲氧基）_苯基]_(6_ 吡咯-1-基-喹唑啉-4-基）_胺42作為原料，按照實施例51 94389 269 201016683 所述的方式，進行該原料與N 應.，得到本標題產物N- [ 2- ( 3 苯胺基]-啥°坐琳-6-基}-°比鳴· (114 mg，黃色固體），產率: MS m/z (ESI) ： 566[M+1] !HNMR (400MHz, DMSO-d6): c 8.51(s, 1H), 8.04(m, 2H), 7. 31(m, 4H), 7. 20(t, 1H), 5.28(s, 2H), 4.04(t, 2H), ®實施例161 (2~溴·'乙基）-甲磺醯胺的反氯-4-(3-氟苄氧基）- 1一基）-乙基]-甲磺醯胺160 44%。 9· 76(s，1H)，8· 55(s，1H), 7*74^ 2H), 7.48(m, 2H), 6-95(t, 1H), 6.69(t, 1H), 3.38(t，2H)，2.83(s, 3H) 喹唑啉-6· 处二侧氳某. 古氫-1 λ *6*-°宴喃-4-醇 HN)The experimental procedure described in Example 51 of the present invention was repeated except that the compound of Example 42 was [3-chloro-4-(. butyl-2-methoxy)-phenyl]-(6-pyrrole- 1-Base-quinazolin-4-yl)-amine 42 was used as a starting material, and the title compound was obtained from N to [2-(3-aniline) as described in Example 51 94389 269 2010. Base]-啥°坐琳-6-yl}-°biming·(114 mg, yellow solid), Yield: MS m/z (ESI): 566[M+1] !HNMR (400MHz, DMSO-d6 ): c 8.51(s, 1H), 8.04(m, 2H), 7. 31(m, 4H), 7. 20(t, 1H), 5.28(s, 2H), 4.04(t, 2H), ® Example 161 (2-Chloro-ethyl)-methanesulfonamide, transchloro-4-(3-fluorobenzyloxy)-1-yl)-ethyl]-methanesulfonamide 160 44%. 9· 76(s,1H),8· 55(s,1H), 7*74^ 2H), 7.48(m, 2H), 6-95(t, 1H), 6.69(t, 1H), 3.38( t,2H), 2.83(s, 3H) quinazoline-6· at the two side 氲.. Ancient hydrogen-1 λ *6*-° feastan-4-ol HN)

161 N ^ _重複本發明實施例138第—步至第二步的實驗步驟，不同的是以實施例138第一步所得的化合物[3_氯一 ^节氧基）-笨基]-[^-(卜環氧乙烷基甲基—Μ—比咯_3_基）〜喹唑啉-4-基]-胺138a作為原料，按照實施例138第二步所述的實驗方式，進行該原料與二氧—六氫入6塞喃-4-基）-甲胺的反應，得到本標題產物4_ (3 {4 [3-亂-4-(3-敗苄氧基）-苯胺基]_啥唾琳_6_基} 比咯-1-基）-2一羥基_丙胺基]_甲基卜丨，卜二側氧基—六氫 94389 270 201016683 -1入嗟喃-4-醇161(30 mg’黃色固體），產率：44 2%。 MS m/z (ESI) ： 680[M+1] !HNMR (400MHz, DMSO- de): δ 9. 77(s, 1H), 8. 59(s 1H)，8. 50(s，1H)，8.04(m, 2H)，7. 76(m, 2H)，7. 48(m 2H), 7.33(m, 3H), 7. 19(t, 1H), 6. 90(m, 2H), 6. 63(s 1H), 5.27(s, 2H), 4. 06(m, 4H), 3. 79(m, 1H), 3. 23(m 2H), 3. 18(m, 4H), 2. 01(m, 4H) 實施例162 4-({[1~~[4-[3-氣-4-(3-氟苄氣基）-装胺基~|~疮^坐__^;^ 1 ❹-4-(2-羥乙基）-1Η-吡咯-3-甲基1-胺基卜甲氧基-六胤-1 A木6木-嗟喃-4-醇161 N ^ _ repeats the experimental procedure of the first step to the second step of the embodiment 138 of the present invention, except that the compound obtained in the first step of the embodiment 138 is [3-chloro-oxyloxy]-styl]-[ ^-(Ethylene oxide methyl-oxime-pyrrolyl-3-yl)-quinazolin-4-yl]-amine 138a was used as a starting material in the same manner as described in the second step of Example 138. The reaction of the starting material with dihydro-hexahydro 6-propan-4-yl)-methylamine gives the title product 4_(3{4[3-ran-4-(3- benzyloxy)-phenylamino) ] 啥啥琳 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Alcohol 161 (30 mg 'yellow solid), yield: 44 2%. MS m/z (ESI): 650 [M+1] "HNMR (400 MHz, DMSO-de): δ 9. 77 (s, 1H), 8. 59 (s 1H), 8. 50 (s, 1H) , 8.04(m, 2H), 7.76(m, 2H), 7.48(m 2H), 7.33(m, 3H), 7. 19(t, 1H), 6. 90(m, 2H), 6. 63(s 1H), 5.27(s, 2H), 4. 06(m, 4H), 3. 79(m, 1H), 3. 23(m 2H), 3. 18(m, 4H), 2. 01(m, 4H) Example 162 4-({[1~~[4-[3-Ga-4-(3-fluorobenzyl))-Amine~|~疮^坐__^ ;^ 1 ❹-4-(2-hydroxyethyl)-1Η-pyrrole-3-methyl 1-amino-p-methoxy-hexa-1-A-wood 6-anthrace-4-ol

重複本發明實施例151第一步至第三步所述的實驗步 ❹驟，不同的是以實施例151第二步化合物i-{4-[1-(3-氣卞基）-1Η-α引〇坐-5-胺基]-啥坐琳- β- 基}_4-(2-經乙基）曱趁151b作原料，按照本發明實施例I。第三步所述的相同方式使得該原料與4-氨甲基-二氧_ 六氫-1又*6*-噻喃-4-醇的反應，得到標題化合物[({[i一 [4_[3 -氯4-(3 -氟节氧基）-苯胺基]-喧^坐琳_6_基]一4_(2_ 羥乙基）-1Η-吡咯-3-曱基]-胺基}-曱基）4,卜二侧氧基— 六氫-1又*6*-噻喃-4-醇162(125 mg，黃色固體），產率： 94389 271 201016683 37· 8%。 MS m/z (ESI) ： 670 [M+l] WNMRMOOMHz，DMSO-cW: 6 9.89(s，1H)，8.56(s 8.49(s，1H)，8.21(s，1H)，8.17(s，1H)’ 8.1〇(dd，lH) 7.83(m，1H)’ 7.76(m，1H)’ 7. 72(糾，lfl)，7.45(s，1H) 7.38(m，2H)，7. 07(m，3H)，5.72(s，2H)，4.75(s，2h) 3.63(t，4H)，3. 15(m，2H)，2.94〇d，2H)’ 2*67(t，2h) 2. 59(s，2H)，1.98(m，4H) 實施例163 ® (3-乙炔基笨基）-「6-ΠΗ-吡咯-3-某1 n.The experimental steps described in the first step to the third step of the embodiment 151 of the present invention are repeated, except that the compound i-{4-[1-(3- gas fluorenyl)-1Η- in the second step of the embodiment 151 is α -5 -5 - - -5 -5 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - The reaction of the starting material with 4-aminomethyl-dioxy-hexahydro-1 and *6*-thiopyran-4-ol in the same manner as described in the third step gave the title compound [({[i[[ [3-Chloro-4-(3-fluorohethoxy)-anilino]-喧^坐琳_6_yl]-4_(2-hydroxyethyl)-1Η-pyrrole-3-indenyl]-amino} - fluorenyl) 4, bis-oxo- hexahydro-1 and *6*-thiopyran-4-ol 162 (125 mg, yellow solid), yield: 94389 271 201016683 37·8%. MS m/z (ESI): 670 [M+l] WNMRMOO MHz, DMSO-cW: 6 9.89 (s, 1H), 8.56 (s 8.49 (s, 1H), 8.21 (s, 1H), 8.17 (s, 1H) ) 8.1〇(dd,lH) 7.83(m,1H)' 7.76(m,1H)' 7. 72(correct, lfl), 7.45(s,1H) 7.38(m,2H), 7. 07(m , 3H), 5.72 (s, 2H), 4.75 (s, 2h) 3.63 (t, 4H), 3. 15 (m, 2H), 2.94 〇 d, 2H) ' 2 * 67 (t, 2h) 2. 59(s, 2H), 1.98 (m, 4H) Example 163 ® (3-ethynylphenyl)-"6-indole-pyrrole-3- some 1 n.

163163

❹第一步 (3-乙炔基-苯基）-(β-埃-啥唾琳一4-基）胺重複本發明實施例1第五步所述的實驗步驟，不向是以實施例1第四步所得的化合物6-碘-3Η-喹唑啉的 If作原料，按照本發明實施例丨第五步所述的相鲷得該原料與3-乙炔基-苯胺的反應，得到標題化合物（3一乙炔基-苯基）-(6-碘-喹唑啉-4-基）-胺163a(2g，灰白色固體），產率65%。 272 94389 201016683 MS m/z (ESI) ： 372[M+1] 第二步 (3-乙炔基-苯基）-[6-(lH-吡咯-3-基）-喹唑啉-4-基μ胺重複本發明實施例150的實驗步驟，不同的是以（6_ 碘-喹唑啉-4-基）-(3-乙炔基苯基）-胺163a作為原料，按照實施例150所述的方式，進行該原料與ι_(三異丙基矽）-1Η-吡咯-3-硼酸的反應，得到本標題產物（3_乙炔基_ 苯基）-[6-(1Η-吡咯-3-基）-喹唑啉_4_基卜胺163(1〇 mg，白色固體），產率：5. 7%。 ❹ MS m/z (ESI) : 311[M+1]The first step (3-ethynyl-phenyl)-(β-A-pyrylin-4-yl)amine repeats the experimental procedure described in the fifth step of Example 1 of the present invention, which is not the embodiment 1 The compound 6-iodo-3Η-quinazoline obtained in the fourth step is used as a starting material, and the starting material is reacted with 3-ethynyl-aniline according to the phase in the fifth step of the present invention to obtain the title compound. (3-Ethynyl-phenyl)-(6-iodo-quinazolin-4-yl)-amine 163a (2 g, off-white solid), yield 65%. 272 94389 201016683 MS m/z (ESI): 372[M+1] Step 2 (3-ethynyl-phenyl)-[6-(lH-pyrrol-3-yl)-quinazolin-4-yl The amide is repeated in the experimental procedure of Example 150 of the present invention, except that (6-iodo-quinazolin-4-yl)-(3-ethynylphenyl)-amine 163a is used as a starting material, as described in Example 150. In the same manner, the reaction of the starting material with ι_(triisopropylhydrazine)-1Η-pyrrole-3-boronic acid affords the title product (3-ethynyl-phenyl)-[6-(1Η-pyrrol-3-yl). 。。。。。。。。。。。。。。。。。。。。。。。。。. ❹ MS m/z (ESI) : 311[M+1]

Wl^MRMOOMHz，DMS0-d〇: 5 8.51(s’ 1H)，8.44(s，1H)， 8. 09(d，1H, J=8.8), 7. 95(s，1H)，7.80(d，1H，J=8.4), 7.71(d, 1H, J=8.4), 7. 38(t, 2H), 7.27(d, 1H, J = 7. 6), 6.83(s, 1H), 6.70(s, 1H), 3.30(s, 1H) · 實施例164 4-{「（4-{4-[l-__(3-氟-节基)二 1H-吲吔Ί其昤某[-♦唑啉 ❹-6-基卜1H-吡咯-2-基甲基^胺基1—甲其卜l i一二氧一六氲 —1入氺Θ氺一4 _ 一4一醇Wl^MRMOOMHz, DMS0-d〇: 5 8.51(s' 1H), 8.44(s,1H), 8. 09(d,1H, J=8.8), 7. 95(s,1H), 7.80(d, 1H, J=8.4), 7.71(d, 1H, J=8.4), 7. 38(t, 2H), 7.27(d, 1H, J = 7. 6), 6.83(s, 1H), 6.70(s , 1H), 3.30(s, 1H) · Example 164 4-{"(4-{4-[l-__(3-Fluoro-nod))1H-吲吔Ί[吲吔Ί-[oxazoline] ❹-6-kib 1H-pyrrol-2-ylmethylamine 1-methylpyrifidyl di-oxo-hexa- 1 氺Θ氺 4 4 _ 1-4 ol

94389 273 20101668394389 273 201016683

.4-溴甲搭氬氣下，將 1Η-吡咯-2-甲醛 164a (3. 04g，32 mmol) 溶於150 mL四氫呋喃中’乾冰_丙酮浴冷卻至_7〇。〇，分批加入N-溴琥珀醯亞胺（5· 62 g，32 mm〇i)，保持_78°c攪拌1小時反應完畢。加入1 〇〇 mL水和1 〇〇 mL正己烧，溫 ⑩度升至室溫’抽濾，濾液水相藉由正己烷（1〇〇 mLx3)萃取，合併的有機相依次用飽和氯化鈉溶液洗滌，無水硫酸鈉脫水，過濾，減壓下濃縮，殘留物中加入3〇 mL正己烷和四氫呋喃的混合溶劑（正己烧：四氫呋喊=2〇 : 1)，在室溫下攪拌1小時，有固體析出，過濾，濾餅用正己烷洗滌 3次，得到4-溴-1H-吡咯_2_甲醛164b (2. 2 g，棕色固體），產率：40%。 MS m/z (ESI) ： 174[M+1] 94389 274 201016683 第二步 4-溴-2-甲醯基吡咯甲酸第三丁酯將 4-濞--η比嘻-2-甲酸 164b(l g，5. 78 mmol)溶於 50mL乙腈中，攪拌下依次加入二碳酸二第三丁酯（i.89g， 8. 67 mmol)和 4-二曱胺基口比淀（353 mg，2. 89 mmol)，溶. 4-Bromomethyl argon was dissolved in 1 mL of azole-carbaldehyde 164a (3.04 g, 32 mmol) in 150 mL of tetrahydrofuran. 〇, N-bromosuccinimide (5·62 g, 32 mm〇i) was added in portions, and the reaction was completed by stirring at _78 ° C for 1 hour. Add 1 〇〇mL of water and 1 〇〇mL of hexane, and raise the temperature to 10 °C by room temperature. The aqueous phase of the filtrate is extracted with n-hexane (1 〇〇mL×3). The combined organic phases are sequentially saturated with sodium chloride. The solution was washed, dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and a mixture of 3 mL of n-hexane and tetrahydrofuran was added to the residue (n-hexane: tetrahydrofuran = 2 〇: 1), and stirred at room temperature 1 The solid was precipitated, filtered, and the filter cake was washed three times with n-hexane to give 4-bromo-1H-pyrrole-2-carbaldehyde 164b (2.2 g, brown solid), yield: 40%. MS m/z (ESI): 174 [M+1] 94389 274 201016683 The second step 4-bromo-2-carboxylpyrrolecarboxylic acid tert-butyl ester 4-濞--η than 嘻-2-carboxylic acid 164b ( Lg, 5.78 mmol) was dissolved in 50 mL of acetonitrile, and dibutyl succinate diacetate (i.89 g, 8.67 mmol) and 4-diamine hydrazide port (353 mg, 2. 89 mmol), dissolved

液在室溫下授拌30分鐘反應完畢。反應液在減壓下濃縮，殘留物中加入50 mL正己烷和四氫呋喃混合溶劑（正己烷：四氫吱喃=20 : 1)和50 mL水，分液，有機相依次用水，飽和氣化鈉溶液溶液洗滌，無水硫酸鈉脫水，過濾，減壓下濃縮’得到4-溴-2-甲醯基吡咯-1-甲酸第三丁酯164c (1. 2 g，棕黃色固體），產率：7⑽。 .MS m/z (ESI) ： 274[Μ+1] 第三步 2-甲醯基-4-(4, 4, 5, 5-四甲基-[l，..3, 2]二氧雜硼雜戊環一2-基）-»比略-1-曱酸第三丁酯氬氣下，將4-溴-2-甲醯基吡咯_ι_甲酸第三丁酯164c 傷（200 mg’ 0. 73 mmol)，聯硼酸頻那醇酯（28〇 mg，l j 咖〇1)，四（三苯基）膦鈀（60 mg，〇. 073 mm〇l)，醋酸鉀（216 mg， 2.2 mm〇l)溶於10 mL四氫呋喃中，混合液加熱至8〇ΐ，回流過夜。反應液在減壓下濃縮，所得的殘留物藉由矽膠管柱層析法進行分離純化，得到2_甲醯基_4_(4,4,5,5一四甲基-[1，3,2]二氧雜硼雜戊環_2_基）_吡咯曱酸第三丁酿164d(45 mg，黃色固體），產率：ι9%。 MS m/z (ESI) : 322 [M+1] 94389 275 201016683 第四步 4-{4-[l-(3-氟卞基引0坐-5-基胺基]_啥嗤琳_6_基} ~ 1Η -0比嘻-2 -甲酸在100 inL痴形瓶中’加入化合物2-甲醯基-4_ (4, 4, 5, 5-四甲基- [1，3, 2]二氧雜蝴雜戊環基）_π比洛 -卜甲酸第三丁酯164d(584 mg，1.82mm〇l)，[卜（4一氟节基）-1Η-吲唑-5-基]-(6-碘-喹唑啉-4-基胺i32a (5〇〇 mg，1. 82 mmol)，碳酸卸（lg ’ 4. 56minol)，30 mL N N-二甲基甲醯胺和7mL水的混合溶劑，氮氣保護下加入四（三苯 ❹基）膦Ιβ(31 Omg ’ 0· 182mmol) ’混合液加熱至7〇至75¾，用薄層層析追蹤反應進程，4小時後反應完畢。將反應液倒入250 mL冰水中’有固體析出’抽滤，濾、餅藉由石夕膠管柱層析法進一步分離純化，得到4- {4- [ 1 -(3-氟节基）-1JJ-••吲唑-5-基胺基]-喹唑啉-6-基}-111-吡咯-2-甲經164e (168 mg，黃色固體），產率20%。 MS m/z (ESI) ： 322 [M+l] 鲁1HNMR (400MHz，CD30D-A):6 12.48(s，lH), 9.89(s, 1H), 9. 60(s, 1H), 8. 82(s, 1H), 8. 48(s, 1H), 8. 20(m, 3H), 7. 96(s, 1H), 7. 75(m, 3H), 7. 64(s, 1H), 7. 35(m, 1H), 7. 06(m, 3H), 5.72(s, 2H) 第五步 4-{[(4-{4-[1-(3-氟-苄基）-111-吲唑-5-基胺基]-喹唑啉 -6-基}-111-吼咯-2-基甲基）-胺基]-曱基卜1，i-二氧-六氫塞喃-4 -醇 94389 276 201016683 氮氣下’在l〇〇mL茄形瓶中加入4-{4~[i-(3-氟苄基） -1H-吲唑-5-基胺基]-喹唑啉_6—基卜1H_吡咯_2—甲醛 164e(120 mg，〇. 259 mmol)和 4-氨甲基1 一二氧-六氳 -1 又 *6 氺-噻喃-4-醇（84 mg ’ 0. 466 mmol)，溶於 6 mL 二氯甲烷中，室溫攪拌6小時後加入三（乙醯氧基）硼氫化鈉 (165 mg，0.78 mmol)，室溫攪拌過夜。在反應液中加入5 mL飽和礙酸氫納溶液，萃取，分層，有機相減壓下濃縮，得到的殘留物進-步藉由㈣管柱層析法（二氯甲燒：甲醇 =10 : 1)分離純化，得到本標題產物咎氟一 _节基）-ιη-·+基胺基]基卜1{1_料小基甲基）-胺基]-曱基}-1，卜二氧一六氮—J λ *6*_b塞喃—4一醇 164 (25 mg ’黃色固體）’產率：15 4%。 MS m/z (ESI) ： 626[M+1] MMR(4G0MHz，CD3〇D-d〇: (H1.15(；S，1H)，9>93(uH) 8. 69 (s，1H)，8.44 (s，1H)，8.25 (S，1H)，8·17 (s jH) 8.06 (d, 1H, J=8.8Hz), 7.76 (s, 1H), 7. 69 (d； 1R；The solution was stirred at room temperature for 30 minutes and the reaction was completed. The reaction solution was concentrated under reduced pressure, and 50 mL of a mixture solvent of n-hexane and tetrahydrofuran (n-hexane: tetrahydrofuran = 20:1) and 50 mL of water were added to the residue, and the organic phase was sequentially washed with water and saturated sodium carbonate. The solution solution was washed, dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated, 7 (10). .MS m/z (ESI) : 274 [Μ+1] Step 3 2-Methyl group-4-(4, 4, 5, 5-tetramethyl-[l,..3, 2]diox 4-bromo-2-carboxyrylpyrrole_t-butylic acid tert-butyl ester 164c under argon under arborazolium-2-yl)-»bile-1-pyruic acid tert-butyl ester (200 Mg' 0. 73 mmol), pinacol borate (28 〇 mg, lj curry 1), tetrakis(triphenyl)phosphine palladium (60 mg, 〇. 073 mm 〇l), potassium acetate (216 mg) , 2.2 mm 〇l) was dissolved in 10 mL of tetrahydrofuran, and the mixture was heated to 8 Torr and refluxed overnight. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified and purified by silica gel column chromatography to afford 2-carbazyl- 4-(4,4,5,5-tetramethyl-[1,3, 2] Dioxaborolan-2-yl)-pyrrolidine tributyl 164d (45 mg, yellow solid), yield: ι 9%. MS m/z (ESI): 322 [M+1] 94389 275 201016683 The fourth step 4-{4-[l-(3-fluoroanthryl-dosin-s--5-ylamino)_啥嗤琳_6 _基} ~ 1Η -0 than 嘻-2 - formic acid in the 100 inL immersed bottle 'Add compound 2-methylmercapto-4_ (4, 4, 5, 5-tetramethyl-[1,3, 2] Dioxacyclopentanyl)_πBilo-b-butylic acid tert-butyl ester 164d (584 mg, 1.82 mm 〇l), [Bu (4-fluoro-fluorenyl)-1 Η-oxazol-5-yl]- (6-iodo-quinazolin-4-ylamine i32a (5 〇〇 mg, 1.82 mmol), carbonic acid unloading (lg ' 4. 56 minol), 30 mL N N-dimethylformamide and 7 mL water The mixed solvent was added with tetrakis(triphenylphosphonium)phosphonium Ιβ (31 Omg '0·182 mmol)' mixture under nitrogen to heat to 7 〇 to 752⁄4, and the progress of the reaction was followed by thin layer chromatography, and the reaction was completed after 4 hours. The reaction solution was poured into 250 mL of ice water, and the solid was precipitated and filtered. The mixture and the cake were further separated and purified by Shixi rubber column chromatography to obtain 4-{4-[1-(3-fluoro-nodal)- 1JJ-••oxazol-5-ylamino]-quinazolin-6-yl}-111-pyrrole-2-methyl via 164e (168 mg, yellow solid), yield 20%. MS m/z ( ESI) : 322 [M+l] Lu 1HNMR (400MHz, CD30D -A): 6 12.48(s,lH), 9.89(s, 1H), 9. 60(s, 1H), 8. 82(s, 1H), 8. 48(s, 1H), 8. 20( m, 3H), 7. 96(s, 1H), 7. 75(m, 3H), 7. 64(s, 1H), 7. 35(m, 1H), 7. 06(m, 3H), 5.72(s, 2H) Step 5 4-{[(4-{4-[1-(3-Fluoro-benzyl)-111-oxazol-5-ylamino]-quinazoline-6-yl }-111-Chloro-2-ylmethyl)-amino]-mercapto 1,1-di-dioxo-hexahydropyran-4-ol 94389 276 201016683 Under nitrogen, 'in l〇〇mL eggplant-shaped bottle 4-{4~[i-(3-fluorobenzyl)-1H-indazol-5-ylamino]-quinazoline-6-ylbu-1H-pyrrole-2-formaldehyde 164e (120 mg, 259. 259 mmol) and 4-aminomethyl 1 dioxo-6 氲-1 and *6 氺-thiopyran-4-ol (84 mg '0. 466 mmol), dissolved in 6 mL of dichloromethane. After stirring at room temperature for 6 hours, sodium tris(ethyloxy)borohydride (165 mg, 0.78 mmol) was added and stirred at room temperature overnight. 5 mL of saturated sodium hydrogensulfate solution was added to the reaction solution, extracted, and the layers were separated, and the organic phase was concentrated under reduced pressure. The residue obtained was purified by column chromatography (dichloromethane: methanol = 10 : 1) Isolation and purification, to obtain the title product, fluorinated fluoro- _ benzyl)- ιη-· + ylamino] yl 1 1 1 1 1 1 1 1 1 1 1 1 1 1 Dioxo-hexanitro-J λ *6*_b-propan-4-ol 164 (25 mg 'yellow solid') Yield: 15 4%. MS m/z (ESI): 626 [M+1] MMR (4G0MHz, CD3〇Dd〇: (H1.15(;S,1H),9>93(uH) 8. 69 (s,1H),8.44 (s,1H), 8.25 (S,1H),8·17 (s jH) 8.06 (d, 1H, J=8.8Hz), 7.76 (s, 1H), 7. 69 (d; 1R;

J=8.8Hz)，7.48 (s，1H)，7.38(m，1H)，7.08 (m，3H) 6.75(3, 1H), 5.72(s, 2H), 3. 91 (s, 2H), 3. 52 (m, ΐΗ)5 3.19 (m, 4H), 3.00 (m, 2H), 2.02 (m> 4H) ’ 實施例165 ’ [卜（3-氟-节坐-5-基]_(6_{卜[(2—曱續酿基—乙胺基）-甲基]洛-3-基}~喹。坐咐—4-基）_胺 94389 277 201016683J = 8.8 Hz), 7.48 (s, 1H), 7.38 (m, 1H), 7.08 (m, 3H) 6.75 (3, 1H), 5.72 (s, 2H), 3. 91 (s, 2H), 3 52 (m, ΐΗ) 5 3.19 (m, 4H), 3.00 (m, 2H), 2.02 (m> 4H) 'Example 165 ' [Bu (3-fluoro-segment-5-yl]_(6_ {卜[(2—曱酿 — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — —

氮氣下’在100 mL茄形瓶中加入4-{4-[l-(3-氟苄基） 1H °引唾基胺基]-啥〇坐琳-6-基}-1Η-吼嘻-2-曱越 164e(100 mg，〇. 216 mmol)、2-甲磺醯基乙胺鹽酸鹽（1〇〇 mg，0.43 mmol)和三乙胺（〇·2 mL，5 随〇1)，溶於 6 乩二氯甲烷中，室溫攪拌6小時後加入三（乙醯氧基）珊氫化鈉（137 mg，〇. 648 mm〇i)，室溫攪拌過夜。在反應液中加入5 mL飽和碳酸氫鈉溶液，萃取，分層，有機相減壓下濃縮，得到的殘留物進一步藉由矽膠管柱層析法（二氯甲烷：甲醇=10 : 1)分離純化，得到本標題產物[丨—^—氟-苄基） -1H-吲唑-5-基]_(6一{5_[(2_甲磺醯基_乙胺基子基] -1H-吡咯-3-基卜喹唑啉_4_基）_胺165(3〇呢，黃色"固體），產率：24. 4%。 φ MS m/z (ESI) ： 570[M+1] 'HNMR (400MHz, CD30D-cf〇： 511.32 (s, 1H), i〇〇5 (s 1H), 8.71 (s, 1H), 8.45 (s, 1H), 8.26 (s, 1H) 8 17 (s, 1H), 8.05 Cd, 1H, J=8. 8Hz), 7. 77 (s, 1H), 7. 7〇 (d 1H，J=8. 8Hz)，7. 56(s, 1H)，7.37(s，1H)，7.〇7(m，3II)， 6· 80 (s’ 1H)，5· 72 (s，2H)，4. 04 (s，2H)，3. 20 (s，2H) 3. 10 (s，3H), 3. 05 (m，2H) 實施例166 94389 278 201016683 16 -(5 -{[(1，1-二氧-六氣-1又*6*-嘆喃-4-某甲其胺基] ~~甲基}-1Η~ο比洛-3~基）-啥°坐嚇-4_基1-「1-(^ -氟._节基）. - 1H~口引口坐-5-基1-胺Adding 4-{4-[l-(3-fluorobenzyl) 1H °-sialylamino]-啥〇坐琳-6-yl}-1Η-吼嘻- in a 100 mL eggplant bottle under nitrogen 2-曱 164e (100 mg, 216. 216 mmol), 2-methanesulfonylethylamine hydrochloride (1 〇〇 mg, 0.43 mmol) and triethylamine (〇·2 mL, 5 with 〇1) Dissolved in 6 乩 dichloromethane, stirred at room temperature for 6 hours, then added tris(ethyloxy)sodium hydride (137 mg, 648. 648 mm 〇i) and stirred at room temperature overnight. 5 mL of a saturated sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was separated, and the organic layer was concentrated under reduced pressure. The obtained residue was further separated by chromatography (methylene chloride: methanol = 10:1). Purification to obtain the title product [丨-^-fluoro-benzyl)-1H-indazole-5-yl]-(6-{5_[(2_methylsulfonyl)ethylamino]-1H-pyrrole -3- Benzene quinazoline _4 yl) amide 165 (3 ,, yellow "solid), yield: 24. 4%. φ MS m/z (ESI): 570 [M+1] 'HNMR (400MHz, CD30D-cf〇: 511.32 (s, 1H), i〇〇5 (s 1H), 8.71 (s, 1H), 8.45 (s, 1H), 8.26 (s, 1H) 8 17 (s , 1H), 8.05 Cd, 1H, J=8. 8Hz), 7. 77 (s, 1H), 7. 7〇 (d 1H, J=8. 8Hz), 7. 56(s, 1H), 7.37 (s, 1H), 7. 〇 7 (m, 3II), 6 · 80 (s' 1H), 5 · 72 (s, 2H), 4. 04 (s, 2H), 3. 20 (s, 2H ) 3. 10 (s, 3H), 3. 05 (m, 2H) Example 166 94389 278 201016683 16 -(5 -{[(1,1-dioxo-6 gas-1 and *6*- spur -4-A certain amino group] ~~Methyl}-1Η~ο比洛-3~基)-啥° sits scared-4_ base 1-"1-(^-fluoro._节基). - 1H~ mouth mouth sitting -5-yl 1-amine

氣氣下’在100 mL莊形瓶.中加入4-{4-[1-(3 -氟节基） -1H-吲唑-5-基胺基]-喹唑啉-6-基}-1Η-吡洛-2-甲醛 © 164e(200 mg，0. 46 mmol)和 C-(l，1-二侧氧基—六氫 -1 又 *6*-噻喃-4-基）-甲胺鹽酸鹽（18〇 mg，〇· 9〇 mm〇1)，溶於10 mL二氯甲烷中，室溫攪拌6小時後加入三（乙醯氧基）硼氫化鈉（275 mg ’ 1.3 mmol)，室溫攪拌過夜。在反應液中加入5 mL飽和碳酸氫鈉溶液，萃取,.，分層，有機相減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化（二氯曱烷：曱醇=15 : 1)，得到本標題產物[卜^一 ❹氟-¥基）-111-。引嗤-5-基]-（6-{5-[(2~曱項醯基一乙胺基）一甲基]-1Η-吼嘻-3-基卜啥嗤琳-4-基）-胺166(58 mg，黃色固體），產率：22%。 MS m/z (ESI) ： 610[M+1] !HNMR (400MHz, CD30D-ci〇: (5 11.25 (S, 1H), 9. 92 (s, 1H) 8.69(s, 1H), 8.45(s, 1H), 8. 24 (s, 1H), 8. 17 (s, 1H), 8. 06 (d, 1H, J=8. 8Hz)，7. 75 (s，in)， 7 7i (d jjj J=8.8Hz)，7. 53(s，1H)’ 7. 38(m，1H)，7.〇8(m，3H)，6.80 94389 279 201016683 (s，1H)，5. 72 (s，2H)，4· 02 (s，2H)，3. 10 (m，4H)，2. 75 (m，2H)，2.15 (m，2H)，2.02 (m，1H)，1.682 (m，2H) 實施例167 4-{4二[3二氧氧某基It 喹唾^ 一 1- 曱务棊酿基）~11]-〇比叹-9.-甲酸甲酷Add 4-{4-[1-(3-fluorogangyl)-1H-indazol-5-ylamino]-quinazoline-6-yl}- in a 100 mL bottle. 1Η-pyrrol-2-carbaldehyde © 164e (200 mg, 0.446 mmol) and C-(l,1-di-oxy-hexahydro-1 and *6*-thiopyran-4-yl)- Amine hydrochloride (18 mg, 〇·9〇mm〇1), dissolved in 10 mL of dichloromethane, stirred at room temperature for 6 hrs, then sodium tris(ethyloxy) borohydride (275 mg '1.3 mmol ), stirred at room temperature overnight. 5 mL of a saturated sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was separated, and the organic layer was concentrated under reduced pressure. The residue obtained was further separated and purified by silica gel column chromatography (dichloromethane: decyl alcohol) =15 : 1), the title product [Bu ❹ ❹ ❹ - - - - - - - - - - - - - - -嗤-5-yl]-(6-{5-[(2~曱-醯-yl-ethylamino)-methyl]-1 Η-吼嘻-3- 啥嗤啥嗤 -4- -4-yl)- Amine 166 (58 mg, yellow solid), yield: 22%. MS m/z (ESI): 610 [M+1] "HNMR (400 MHz, CD30D-ci〇: (5 11.25 (S, 1H), 9. 92 (s, 1H) 8.69 (s, 1H), 8.45 ( s, 1H), 8. 24 (s, 1H), 8. 17 (s, 1H), 8. 06 (d, 1H, J=8. 8Hz), 7. 75 (s,in), 7 7i ( d jjj J=8.8Hz), 7. 53(s,1H)' 7. 38(m,1H),7.〇8(m,3H),6.80 94389 279 201016683 (s,1H),5.72 ( s, 2H), 4· 02 (s, 2H), 3. 10 (m, 4H), 2. 75 (m, 2H), 2.15 (m, 2H), 2.02 (m, 1H), 1.682 (m, 2H) Example 167 4-{4 bis[3 dioxooxyl quinones quinones ^ 1- 曱棊 ) ~) ~ 11] - 〇叹 -9. - formic acid cool

2,2，2-二乳~1-(1|{-17比洛-2-基）_乙辆將吡咯（1.4 mL，20mmol)和三氯乙醯氯（2.4虹， 21.4mmol)分別溶於12mL***中，攪拌下將吡咯的***溶液滴加至二氯乙醯氯的***溶液中，室溫下撥拌1】時後，反應完畢。在反應液中加入30 „^1〇%碳酸鉀溶液/分液，有機相在減壓下濃縮，得到的粗品藉由矽膠管柱層析法進一步分離純化，得到卩^^-三氯-丨气^-吡咯—^基）— 乙_ 167a C3.79g’灰色固體）’產率：89.6%。 MS ra/z (ESI) : 213[M+1] 第二步 94389 280 201016683 2, 2, 2-二氯-1-(4-蛾比洛-2-基）-乙酮將氯化破（〇. 91 mL，18. 2mmol)溶於15 mL二氯甲烷中’緩忮滴加到2,2,2-三氯-1-(111-吡略-2-基）-乙酮167& (3.79g, 17.8mmol)的30mL二氯甲烷溶液中，室溫下攪拌 2小時’加入1 〇%碳酸鈉溶液淬滅反應，分液’有機相依次藉由水，飽和氯化鈉溶液洗滌，無水硫酸鈉脫水，過濾，減壓下濃縮’得到的殘留物用乙酸乙酯和正己烷重結晶，得到2, 2, 2-三氯-i-(4-織-iH-n比嘻-2-基）-乙酮167b (5.152g，灰色固體），產率；85.5%。 ❹ MS m/z (ESI) : 339[M+1] 第三步 .4-碘-1 Η-吡咯-2-甲酸甲酯將曱醇鈉（436 mg，8. 07mmol)溶於1〇 mL甲醇中，所得的溶液逐漸滴加到2, 2, 2-三氯-1-(4-碘-1H-吡咯-2-基） -乙酮167b (2. 276g ’ 6· 72mmol)15 mL·曱醇中，室溫下攪拌1小時後反應完畢。將反應液減壓下濃縮，加入100m]L ❹水和100 mL甲基第三丁基醚，分液，有機相依次藉由水，餘和氯化納溶液洗務’無水硫酸納脫水，過濾，減壓下濃縮，得到4-碘-1H-吡咯-2-甲酸曱酯I67c(l. 353 g，灰色固體），產率：80. 2%。 MS m/z (ESI) : 252[M+1] 第四步 4-蛾-1-(甲苯-4-績酿基）-ΐΗ-π比洛-2-甲酸甲醋將4-碘-1Η-吡咯-2-甲酸甲酯167c(1.353 g，5.4随〇1) 94389 281 201016683 溶於5 mL二氯甲烷中，攪拌下依次加入三乙胺（1.65 mL， 11. 88mmol)，4-二甲胺基吡啶（62 mg，0. 5mmol)和對甲苯石黃醯氯（1.13g，5. 94mmo 1)，混合液在室溫下擾拌16小時，反應完畢。加入1N HC1淬滅反應，分液，有機相依次用飽和碳酸氫納（100 mLx3)洗滌，飽和氯化納溶液（iQo虹以）洗蘇’無水硫酸納脫水，過濾，減壓下濃縮，得到的粗品進一步藉由曱基第三丁基醚重結晶，得到4-碘-1-(甲苯 -4-磺醯基）-1Η-吡咯-2-曱酸甲酯167d(1.834 g，淡黃色固體），產率：83. 9%。〇 MS m/z (ESI) ： 406[M+1] 第五步 4-(4, 4, 5, 5-四甲基-[1，3, 2]二氧雜硼雜戊環_2-基） -1-(曱苯-4-續醢基）-1Η-°比略-2-曱酸甲醋 -·將4-碘-1-(曱苯-4-磺醯基)-ih-吡咯一2_甲酸甲酯 167d(288 mg，0. 7mmol)，雙聯頻哪醇硼酸酯（235 mg， 0. 91 mmol)和醋酸钾（210 mg，2. 1 mmol)溶於 N，N-二甲基甲簪醯胺中，攪拌下加入二氯[M，—二茂鐵磷酸]鈀的imL二氯甲烷溶液中，混合液加熱至80°c，18小時後反應完畢。將反應液中加入1 〇〇 mL水和1〇〇 mL***，過濾，分液，有機相依次用100 mL水，1〇〇 mL飽和氯化鈉溶液洗滌，無水硫酸鈉脫水，過濾，減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化，得到標題產物4_(4,4, 5’ 5-四甲基-[1，3, 2]二氧雜硼雜戊環_2_基甲苯磺醯基）-1Η-吡咯-2-甲酸甲酯i67e(l〇5mg，無色固體）， 94389 282 201016683 產率：37%。 MS m/z (ESI) ： 406[M+1] 第六步 4-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-喹唑啉-6-基} -1-(甲苯基-4-磺醯基）-1Η-吡咯-2-甲酸甲酯將4-(4, 4, 5, 5-四甲基-[1，3, 2]二氧雜硼雜戊環-2-基）-1-(甲苯-4-磺醯基）-lH-吡咯-2-甲酸甲醋167e(l〇5 mg，0. 26mmol)，[3-氯-4-(3-氟-苄氧基）-苯基]-(6-碘-喹唑啉-4-基）-胺 lg(i3〇 mg，〇. 26mmol)，碳酸鉀（93. 9 ❺mg，0. 65mm〇l)和四三苯基膦鈀（45 mg，〇. 〇26mm〇1)溶於6 mL N，N-二甲基曱醯胺和2乩水的混合溶劑中，反應液加熱至55°C攪拌過夜。過濾反應液，濾液用乙酸乙酯萃取，合併的有機相依次藉由水，飽和氯化鈉溶液洗滌，無水硫 .酸納脫水，過遽，減壓下濃縮.，得到的殘留物藉由石夕膠管L 柱層析法進一步分離純化，得到4_{4_[3_氯_4_(3—氟—苄氧基）-苯胺基]-嗟唾琳-6-基卜卜（曱苯基_4_續釀基）替 •料-2-甲酸甲酯167(58 mg，淺黃色固體），產率：32δ%。 MS m/z (ESI) : 657[Μ+1] ΧΗ NMR (400 MHz, CDC1-3)： 5 8< 72 (δί 1H)> 8> 〇9 (d?] =2.4Hz, 1H), 8.06 (s, 1H), 7.93 (d> j = 2. 0Hz, 2H) 7.91 (s, 2H), 7.89 (d, J = 2. 4Hz, 1H), 7.81 (s, 1H) 7.60(dd, J = 1.6Hz, 1H), 7. 41 (d, J = 2. 0Hz, 1H) 7 (br，3H), 7.23(br，2H)，7.〇〇(m，2H)，515(s 3.74 (s，3H)，2.43 (s，3H) ’ ’ 94389 283 201016683 實施例1682,2,2-di-milk~1-(1|{-17bi-l-yl)_ B-pyrrol (1.4 mL, 20 mmol) and trichloroethane chloride (2.4 rainbow, 21.4 mmol) The mixture of pyrrole and diethyl ether was added dropwise to a solution of dichloroacetamidine in diethyl ether in 12 mL of diethyl ether. After stirring at room temperature, the reaction was completed. 30 „1〇% potassium carbonate solution/liquid fraction was added to the reaction liquid, and the organic phase was concentrated under reduced pressure, and the obtained crude product was further separated and purified by hydrazine column chromatography to obtain 卩^^-trichloro-hydrazine. Gas ^-pyrrole-yl)-B_167a C3.79g 'gray solids' yield: 89.6%. MS ra/z (ESI): 213[M+1] second step 94389 280 201016683 2, 2, 2-Dichloro-1-(4-moprobi-2-yl)-ethanone chlorinated (〇.91 mL, 18.2 mmol) dissolved in 15 mL of dichloromethane. , 2,2-trichloro-1-(111-pyrrol-2-yl)-ethanone 167 & (3.79 g, 17.8 mmol) in 30 mL of dichloromethane, stirred at room temperature for 2 hrs. The sodium carbonate solution was quenched, and the organic phase was separated by water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was recrystallized from ethyl acetate and n-hexane. , 2, 2, 2-trichloro-i-(4-woven-iH-n-pyrimidin-2-yl)-ethanone 167b (5.152 g, m.p.), yield: 85.5%. ❹ MS m/ z (ESI): 339 [M+1] Step 3. 4-Iodo-1 Η-pyrrole-2-carboxylic acid methyl ester sodium decyl hydride (436 mg, 8. 07 mmol) The obtained solution was gradually added dropwise to 2,2,2-trichloro-1-(4-iodo-1H-pyrrol-2-yl)-ethanone 167b (2. 276 g '6·72 mmol) in 1 mL of methanol. In 15 mL·nonanol, the reaction was completed after stirring at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and 100 m]L of water and 100 mL of methyl-tert-butyl ether were added, and the organic phase was sequentially taken. It is dehydrated from water, residual sodium chloride solution, anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 4-iodo-1H-pyrrole-2-carboxylic acid oxime ester I67c (l. 353 g, gray solid). Rate: 80. 2%. MS m/z (ESI): 252 [M+1] Step 4 4-Moth-1-(Toluene-4-Chloryl)-ΐΗ-πBilo-2-carboxylic acid A Vinegar 4-Iso-1Η-pyrrole-2-carboxylic acid methyl ester 167c (1.353 g, 5.4 with 〇1) 94389 281 201016683 Dissolved in 5 mL of dichloromethane, and then added triethylamine (1.65 mL, 11. 88 mmol), 4-dimethylaminopyridine (62 mg, 0.5 mmol) and p-toluene xanthine chloride (1.13 g, 5.94 mmo 1), the mixture was stirred at room temperature for 16 hours, and the reaction was completed. 1N HC1 quenching reaction, liquid separation, organic phase washed with saturated sodium bicarbonate (100 mL×3), saturated sodium chloride The liquid (iQo rainbow) is dehydrated by sodium sulphate anhydrous, filtered, and concentrated under reduced pressure, and the obtained crude product is further recrystallized from decyl-tert-butyl ether to give 4-iodo-1-(toluene-4-sulfonate) Methyl decyl-pyridole-2-furic acid 167d (1.834 g, pale yellow solid), yield: 83.9%. 〇MS m/z (ESI): 406 [M+1] Step 5 4-(4, 4, 5, 5-Tetramethyl-[1,3, 2]dioxaborolane-2- Base) -1-(indolyl-4-thinyl)-1Η-° ratio -2- carboxylic acid methyl vinegar-- 4-iodo-1-(indolyl-4-sulfonyl)-ih- Pyrrole-2-methyl formate 167d (288 mg, 0.7 mmol), bis-pinacol borate (235 mg, 0.91 mmol) and potassium acetate (210 mg, 2.1 mmol) dissolved in N, N-dimethylformamide was added to an imL dichloromethane solution of dichloro[M,-ferrocenephosphoric acid]palladium under stirring, and the mixture was heated to 80 ° C. After 18 hours, the reaction was completed. Add 1 mL of water and 1 mL of diethyl ether to the reaction solution, filter and separate the layers. The organic phase was washed with 100 mL of water and 1 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated. Concentration, the residue obtained was further separated and purified by silica gel column chromatography to give the title product 4-(4,4,5' 5-tetramethyl-[1,3,2]dioxaborolane. Methyl 2-_2-toluenesulfonyl)-1Η-pyrrole-2-carboxylate i67e (10 mg, colorless solid), 94389 282 201016683 Yield: 37%. MS m/z (ESI): 406 [M+1]. Step 6 4-{4-[3-chloro-4-(3-fluoro-benzyloxy)-anilinyl]-quinazoline-6-yl }-1-(Tolyl-4-sulfonyl)-1Η-pyrrole-2-carboxylic acid methyl ester 4-(4, 4, 5, 5-tetramethyl-[1,3, 2]dioxa Borapentan-2-yl)-1-(toluene-4-sulfonyl)-lH-pyrrole-2-carboxylic acid methyl vinegar 167e (10 mg, 0.26 mmol), [3-chloro-4- (3-Fluoro-benzyloxy)-phenyl]-(6-iodo-quinazolin-4-yl)-amine lg (i3 〇 mg, 〇. 26 mmol), potassium carbonate (93. 9 ❺mg, 0. 65mm〇l) and tetrakistriphenylphosphine palladium (45 mg, 〇.26mm〇1) are dissolved in 6 mL of a mixed solvent of N,N-dimethyl decylamine and 2 hydrazine, and the reaction solution is heated to 55. Stir at °C overnight. The reaction solution was filtered, and the filtrate was extracted with ethyl acetate. The combined organic phases were washed successively with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and dried under reduced pressure. Further separation and purification by E-column L-column chromatography to obtain 4_{4_[3_chloro_4_(3-fluoro-benzyloxy)-anilino]-嗟嗟琳 -6- kib (曱 phenyl _4 _ continuation of the base material -2- carboxylic acid methyl ester 167 (58 mg, pale yellow solid), yield: 32 δ%. MS m/z (ESI): 657 [Μ+1] ΧΗ NMR (400 MHz, CDC 1-3): 5 8 < 72 (δί 1H)>8> 〇9 (d?] = 2.4 Hz, 1H), 8.06 (s, 1H), 7.93 (d> j = 2. 0Hz, 2H) 7.91 (s, 2H), 7.89 (d, J = 2. 4Hz, 1H), 7.81 (s, 1H) 7.60(dd, J = 1.6Hz, 1H), 7. 41 (d, J = 2. 0Hz, 1H) 7 (br,3H), 7.23(br,2H),7.〇〇(m,2H),515(s 3.74 ( s, 3H), 2.43 (s, 3H) ' ' 94389 283 201016683 Example 168

第一步 1-侧氧基-6-硫代-螺[2. 5]辛燒氮氣下，在冰浴冷卻下，將三曱基氧硫化碘（13. 5 g , ❿ 61 mmol)和氩化鈉（2.46 g，6. 15 mm〇1)溶於 6〇社二曱基亞颯中，混合液在室溫下授摔！小時後，滴加四氣嗟喃-4-酮168&(6.79§’60酿〇1)的80mL二甲基亞砜溶液，溫度控制不高於15它，攪拌1〇分鐘後自然升至室溫，3 小時後反應完畢。把反應液倒入35〇mL冰水中，用***萃取（40G mLx3)，合併的有機相依次藉由飽和氯化鈉溶液洗滌，無水硫酸鈉脫水，過濾，減壓下濃縮，得到卜側氡美 6硫代-螺[2. 5]辛烷168b(7· 〇9g，白色固體），產率： 94389 284 201016683 92%。 MS m/z (ESI) ： 131[M+1] 第二步 1-側氧基-6-硫代-螺[2. 5]辛烧6, 6-二氧化物將1-侧氧基-6-硫代-螺[2.5]辛烷168b(7g，53.8 mmol)溶於1〇〇 mL乙腈中，攪拌下加入5〇 mL水，攪拌5 分鐘後依次加入臭氧（99 g，161 mmo 1)和礙酸鈉（51 g，0.48 mol)’室溫下攪拌1小時後反應完畢。在反應液中加入3〇〇 mL二氯甲烷，攪拌30分鐘’過濾，濾餅用二氯甲烷洗滌 © (150mLx2) ’濾液在減壓下濃縮，得到粗品卜側氧基_6_硫代-螺[2. 5]辛烷6, 6-二氧化物168c (7. 48 g，黃色固體），產物不經分離直接進行下一步反應。 MS m/z (ESI) ： 163[M+1] 第三步 4-(3-{4-[3-氣-4-(3-氟-苄氧基）-苯胺基]—喹唑啉_6_基} 比洛-1-基甲基）-1，1-二氧-六氫-1 A *6*-嗟喃-4-醇 φ 將[3-氯-4—(3-氟-苄氧基）-苯基]-[6-(1Η-吡咯-3-基） -喹唑啉-4-基]-胺 42(89 mg，0. 2 mmol)和氫化鈉（24 mg， 0. 6 mmol)溶於2 mL N，N-二甲基曱醯胺中，室溫下擾掉 30分鐘後加入1-侧氧基-6-硫代-螺[2. 5]辛烷6, 6-二氧化物168c(40 mg，0.24 mmol) ’室溫下攪拌i.5小時後反應完畢。在反應液中加入100 mL水’水相用乙酸乙酯（i〇〇 x3)萃取’合併的有機相依次藉由飽和氯化鈉溶液洗滌，無水硫酸納脫水，過遽’減壓下濃縮，得到的殘留物藉由珍 94389 285 201016683 膠管柱層析法進一步分離純化，得到標題產物4-(3-{4-[3_氯-4-(3-氟-苄氧基）-苯胺基]-喹唑啉-6-基}-啦咯-1-基甲基）-1，1-二氧-六氳噻喃-4-醇168(40 mg，黃色固體），產率：33%。 MS m/z (ESI) ： 608[M+1] !H NMR(400 MHz , DMSO-d6): (5 9. 726 (s, 1H), 8. 535 (s, 1H), 8. 503 Cs, 1H), 8. 031 (d, J=8. 4 Hz, 2H), 7. 726 (t, J=8.4Hz, 2H), 7.484 (d, J=6. 4Hz, 1H), 7. 407 (s, 1H), 7. 322 (m, 3H), 7. 190 (s, 1H), 6. 907 (s, 1H), 6. 679 (s, 〇 1H), 5. 274 (s, 2H), 5. 256 (s, 1H), 3. 994 (s, 2H), 3. 181 (m, 2H), 3.008 (d, J=12. 8Hz, 2H), 2.005 (d, J=7. 6Hz, 2H), 1. 831 (d，J=13. 6Hz，2H) 實施例169 {6-「1-(2-二乙胺基-乙基）-1!1-口比?各-3-基~|-1#〇坐淋-4-基} -「l-(3-氟苄基）-1Η-吲唑-5-基1-胺In the first step, 1-oxo-6-thio-spiro[2.5.], under argon-burning nitrogen, tridecyloxysulfuric acid iodine (13.5 g, ❿61 mmol) and argon were cooled in an ice bath. Sodium (2.46 g, 6.15 mm 〇1) is dissolved in 6 〇曱曱 , , , , , , , , , ! ! !! After an hour, add 40 mL of dimethyl sulfoxide solution of Tetraxanthone-4-one 168 & (6.79 § '60 〇 1), the temperature control is not higher than 15 it, and after stirring for 1 自然, it naturally rises to the room. After warming, the reaction was completed after 3 hours. The reaction mixture was poured into 35 mL of ice water and extracted with diethyl ether (40 g mL×3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 6 thio-spiro[2.5]octane 168b (7·〇9g, white solid), yield: 94389 284 201016683 92%. MS m/z (ESI): 131 [M+1], Step 2, 1-oxo-6-thio-spiro[2. 5]octane, 6,6-dioxide 6-Thio-spiro[2.5]octane 168b (7 g, 53.8 mmol) was dissolved in 1 mL of acetonitrile, and 5 mL of water was added with stirring. After stirring for 5 minutes, ozone (99 g, 161 mmo 1) was added in sequence. The reaction was completed after stirring for 1 hour at room temperature with sodium sulphate (51 g, 0.48 mol). 3 〇〇 mL of dichloromethane was added to the reaction mixture, and the mixture was stirred for 30 minutes to filter. The filter cake was washed with dichloromethane (150 mL×2). The filtrate was concentrated under reduced pressure to give crude s. Spirulina [2.5] octane 6,6-dioxide 168c (7. 48 g, yellow solid). The product was taken to the next step without isolation. MS m/z (ESI): 163 [M + 1]. Step 3 4-(3-{4-[3- </RTI> 4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline 6_基}Bilo-1-ylmethyl)-1,1-dioxo-hexahydro-1 A *6*-indol-4-ol φ [3-chloro-4-(3-fluoro- Benzyloxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinazolin-4-yl]-amine 42 (89 mg, 0.2 mmol) and sodium hydride (24 mg, 0) 6 mmol) was dissolved in 2 mL of N,N-dimethyl decylamine, and after being disturbed for 30 minutes at room temperature, 1-sided oxy-6-thio-spiro[2.5]octane 6 was added. 6-Dioxide 168c (40 mg, 0.24 mmol) 'The reaction was completed after stirring for 5 hours at room temperature. 100 mL of water was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (i〇〇x3). The combined organic phases were washed sequentially with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue obtained was further separated and purified by column chromatography, </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> - quinazolin-6-yl}-l-r-yl-1-ylmethyl)-1,1-dioxo-hexathiopyran-4-ol 168 (40 mg, yellow solid), yield: 33%. MS m/z (ESI): 608 [M+1] "H NMR (400 MHz, DMSO-d6): (5 9. 726 (s, 1H), 8. 535 (s, 1H), 8. 503 Cs , 1H), 8. 031 (d, J=8. 4 Hz, 2H), 7. 726 (t, J=8.4Hz, 2H), 7.484 (d, J=6. 4Hz, 1H), 7. 407 (s, 1H), 7. 322 (m, 3H), 7. 190 (s, 1H), 6. 907 (s, 1H), 6. 679 (s, 〇1H), 5. 274 (s, 2H ), 5. 256 (s, 1H), 3. 994 (s, 2H), 3. 181 (m, 2H), 3.008 (d, J=12. 8Hz, 2H), 2.005 (d, J=7. 6 Hz, 2H), 1. 831 (d, J = 13.6 Hz, 2H) Example 169 {6-"1-(2-Diethylamino-ethyl)-1! 1-port ratio? -基~|-1#〇坐淋-4-yl} - "l-(3-fluorobenzyl)-1Η-indazol-5-yl 1-amine

將{6-[卜（2-二乙胺基-乙基）-1Η-吡咯-3-基]-喹唑啉 -4-基}-[]·-(3-氟节基）-1Η-π引唾-5-基]-胺 150(434 mg， 286 94389 201016683 lmmol)溶於6 mL的N，N-二曱基曱醯胺中，冰浴冷卻至 0C ’加入氫化納（200 mg，5 mmol)，攪拌30分鐘。另取2-溴-N，N-二乙基乙胺氫溴酸鹽（287 mg， mmol)的2 mL N，N-二甲基甲醯胺溶液，加入氫化鈉（44吨， 1. 83 mmol)，在0°C下攪拌30分鐘後，將溶液加入上述放入反應液中，所得的溶液在0°c下攪拌3〇分鐘後反應完畢。將反應液倒入40 mL·冰水中，分液，水層用乙酸乙醋 (25 mLx4)萃取’合併的有機相依次藉由飽和氯化鈉溶液 (10 mLx2)洗務，無水硫酸納脫水，過濾、，減壓下濃縮，得 ❹到的殘留物藉由製備型薄層層析板分離純化，得到標題產物{6 [1 (2 —乙胺基 ''乙基）比哈-3 -基]-啥t»坐琳-4 - 基卜[卜（3-氟苄基）-1Η-吲唑-5-基]-胺169(300 mg，黃色固體），產率56. 3%。 MS m/z (ESI) : 534[M+1] !HNMR (400MHz, dUSO-d6)： δ 9. 84(s, 1H), 8. 82(s, 1H), 8.46(s, 1H), 8.25(s, 1H), 8. 18(s, lfl), 8. 05(d, 1H, ^J=8.4), 7. 75(s, 2H), 7. 72(d, 1H, J=8. 4), 7. 47(s, 1H), 7.40(dd， 1H, J=7. 2, J=14), 7.13(dd, 3H, J=8.4, J=19.2), 6.93(s, 1H), 6. 69(s, 1H), 5. 72(s, 2H), 4. 01(brs, 2H), 2.81(brs, 2H), 2. 55(br s, 4H), 〇. 97(s, 6H) 實施例170 「3-氣-4-(3-氟-苄氧基）-装甚 ~|-{fi-「〔3R，8aR)-l-〔六氤吡络共[2，l-c]「l，4]!%!%啡基-t3-基甲基比鳴>-3_基 287 94389 201016683 ϋ琳-4-篡卜脸{6-[Bu(2-diethylamino-ethyl)-1Η-pyrrol-3-yl]-quinazolin-4-yl}-[]·-(3-fluoro-fiephthyl)-1Η- π 唾 -5-5-yl]-amine 150 (434 mg, 286 94389 201016683 lmmol) was dissolved in 6 mL of N,N-didecyl decylamine, cooled to 0C in an ice bath and added with sodium hydride (200 mg, 5 mmol), stir for 30 minutes. Another 2-bromo-N,N-diethylethylamine hydrobromide (287 mg, mmol) in 2 mL of N,N-dimethylformamide was added and sodium hydride (44 ton, 1.83) was added. After stirring at 0 ° C for 30 minutes, the solution was added to the above reaction solution, and the resulting solution was stirred at 0 ° C for 3 minutes and the reaction was completed. The reaction solution was poured into 40 mL of ice water, and the aqueous layer was separated and extracted with ethyl acetate (25 mL×4). The combined organic phases were washed successively with saturated sodium chloride solution (10 mL×2) and dehydrated with anhydrous sodium sulfate. Filtration, and concentration under reduced pressure, and the residue obtained was purified by preparative thin-layer chromatography chromatography to give the title product (6 [1 (2-ethylamino) 。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。. MS m/z (ESI): 534 [M+1] "HNMR (400 MHz, dUSO-d6): δ 9. 84 (s, 1H), 8. 82 (s, 1H), 8.46 (s, 1H), 8.25(s, 1H), 8. 18(s, lfl), 8. 05(d, 1H, ^J=8.4), 7. 75(s, 2H), 7. 72(d, 1H, J=8 4), 7. 47(s, 1H), 7.40(dd, 1H, J=7.2, J=14), 7.13(dd, 3H, J=8.4, J=19.2), 6.93(s, 1H ), 6. 69(s, 1H), 5. 72(s, 2H), 4. 01(brs, 2H), 2.81(brs, 2H), 2. 55(br s, 4H), 〇. 97( s, 6H) Example 170 "3-Gas-4-(3-fluoro-benzyloxy)-packaged ~|-{fi-"[3R,8aR)-l-[六氤pyridine complex [2, Lc]"l,4]!%!% cyano-t3-ylmethylbiperene>-3_yl 287 94389 201016683 ϋ琳-4-篡卜脸

β第一步 (3只，8沾）-3-(氯甲基）-六氫-1}}~11比哈[2，1-<:][1,4] . 將環氧氯丙烷17〇a (157 ml, 2 mol)加入乾燥的圓底燒瓶中，冰浴冷卻20分鐘後滴加D-脯氨醇l7〇b (20 g, 〇. 2 mol) ’在40°C反應0.5小時。蒸掉過量環氧氯丙烷。冰浴下滴加濃硫酸（60 ml)，在150-1801：下反應1. 5小時。將反應液倒入冰水（200 ml)中以淬滅反應，用氨水調節溶液 ⑩pH值為8 ’正己烷/乙酸乙酯（1/1，300 ml)萃取，水相用乙酸乙酯（200 mlx3)萃取，合併有機相，用飽和氯化銅溶液（100 ml)洗滌有機相，用無水硫酸鎂脫水，過濾，減壓濃縮濾、液，用梦膠柱層析法純化所得殘餘物，得到標題產物（3匕8&1〇-3-(氯曱基）-六氫-111-11比洛[2，1-〇][1，4]嗜啡 170c (6. 882 g，棕色油狀液體），產率19. 8%。 MS m/z (ESI) : 585 [M+1] 弟二步 94389 288 201016683 [3-氣-4-(3-氟-苄氧基）_苯基]— {6_[(3R，8aR)-i-(六氫。比嘻并[2, l-c][l，4]Pf畊基-3-基甲基）-111-°比咯-3-基μ喧唑琳-4-基卜胺 ! 在25 mL的單口燒瓶中，將[3_氯_4_(3_氟-苄氧基）〜苯基]-[6-(1Η-吡咯-3-基）-喹唑啉-4-基]-胺42 (444 mg ’ 1 mmol)溶於6 mL N，N-二曱基曱醯胺中，在冰浴條件下’冷卻至〇°C，加入氫化鋼（120 mg，3 mmol)，擾拌 30分鐘後加入（3R，8aR)-3-(氯曱基）-六氫-1H- η比咯 [2, 1-c] [1，4]噚啡 170c (211 mg，1. 2 mmol)，室溫下攪 ©拌4小時反應完畢。反應液減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化（二氯甲烷：甲醇=40: 1)，得到本標題產物[3-氯-4-(3-氟-苄氧基）-苯基]-{6-(3R，8aR)-l-(六氫《比嘻并[2, i-c][i，4]噚哄基-3-基曱基） 111-°比洛-3-基]-喹峻琳-4-基}-胺17〇(511^，黃色固體），產率·· 6. 5%。 MS m/z (ESI) : 585[M+1] ^ ^ NMR(400 MHz , DMS0-d6) ： δ 9.67 s, 1H), 8. 8 (s, 1H), 8.5 (s, 1H), 8.03 (d, J=8.8Hz, 2H), 7.76 (dd, J=2Hz, 1H), 7.70 (d, J=8.4Hz, 1H), 7.5 (m, 2H), 7.36(m, 3H), 7.2 (s, 1H), 6.93 (s, 1H), 6.60 (s, 1H), 5.27 (s, 2H), 4.0 (m, 1H), 3.62 (t, J = 12Hz, 2H), 3.51 (s, 2H), 3.0 (br, 1H)’ 2.31 (m, 1H), 2.1 (br，3H)，1.4-1.6 (瓜，2H), 1. 1237 (m, 2H) 實施例171 289 94389 201016683 U-羞-4-(3-氟·羞基）-苯基卜（6_[卜「2-n—甲篡—吡吹 &二,g-基）-乙基1-_1H-吡略-3-基卜喹唑啉-4-某脸β first step (3, 8 dip)-3-(chloromethyl)-hexahydro-1}}~11 Biha [2,1-<:][1,4] . Epichlorohydrin 17〇a (157 ml, 2 mol) was added to a dry round bottom flask, and after cooling for 20 minutes in an ice bath, D-prolinol l7〇b (20 g, 〇. 2 mol) was added dropwise to react at 40 ° C. hour. Excess epichlorohydrin was distilled off. 5小时。 The ice bath was added dropwise concentrated sulfuric acid (60 ml), reacted at 150-1801: 1.5 hours. The reaction solution was poured into ice water (200 ml) to quench the reaction, and the pH of the solution 10 was adjusted to 8 '-hexane/ethyl acetate (1/1,300 ml), and the aqueous phase was extracted with ethyl acetate. The organic phase was extracted with a saturated aqueous solution of copper chloride (100 ml), dried over anhydrous magnesium sulfate, filtered, filtered and evaporated. Title product (3匕8&1〇-3-(chloroindolyl)-hexahydro-111-11 piroxi[2,1-〇][1,4] morphine 170c (6. 882 g, brown oil Liquid), yield 19.8%. MS m/z (ESI): 585 [M+1] 2nd step 94389 288 201016683 [3- gas-4-(3-fluoro-benzyloxy)-phenyl] — {6_[(3R,8aR)-i-(hexahydro. 嘻[2, lc][l,4]Pf phenyl-3-ylmethyl)-111-°pyr-3-yl μ Oxazolidin-4-ylpamine! [3_Chloro_4_(3_fluoro-benzyloxy)~phenyl]-[6-(1Η-pyrrol-3-yl) in a 25 mL single-necked flask )-quinazolin-4-yl]-amine 42 (444 mg '1 mmol) dissolved in 6 mL of N,N-didecylguanamine, cooled to 〇 ° C under ice bath, hydrogenation Steel (120 mg, 3 mmol) with 30 points After adding (3R,8aR)-3-(chloroindolyl)-hexahydro-1H-ηpyr[2,1-c][1,4] morphine 170c (211 mg, 1.2 mmol), room The reaction mixture was stirred for 4 hours under warming. The reaction mixture was concentrated under reduced pressure. The obtained residue was purified and purified by methylene chloride column chromatography (dichloromethane:methanol = 40:1) to give the title product. -chloro-4-(3-fluoro-benzyloxy)-phenyl]-{6-(3R,8aR)-l-(hexahydro"[嘻,[2, ic][i,4]fluorenyl -3-ylindenyl) 111-°bilo-3-yl]-quinolin-4-yl}-amine 17〇 (511^, yellow solid), yield ·· 6. 5% MS m/ z (ESI): 585[M+1]^^ NMR (400 MHz, DMS0-d6): δ 9.67 s, 1H), 8. 8 (s, 1H), 8.5 (s, 1H), 8.03 (d, J=8.8Hz, 2H), 7.76 (dd, J=2Hz, 1H), 7.70 (d, J=8.4Hz, 1H), 7.5 (m, 2H), 7.36(m, 3H), 7.2 (s, 1H) ), 6.93 (s, 1H), 6.60 (s, 1H), 5.27 (s, 2H), 4.0 (m, 1H), 3.62 (t, J = 12Hz, 2H), 3.51 (s, 2H), 3.0 ( Br, 1H)' 2.31 (m, 1H), 2.1 (br, 3H), 1.4-1.6 (melon, 2H), 1. 1237 (m, 2H) Example 171 289 94389 201016683 U-Shame-4-(3 -Fluoric group]-Phenyl b (6_[Bu"2-n-methano-pyrazine&2, g-group )-Ethyl 1-_1H-pyrrol-3-ylquinazoline-4-one face

Ο 在25 mL的單口燒瓶中，將[3_氯_4_(3_氟_苄氧基）_ 苯基]-[6-C1H-吡咯-3-基）-喹唑啉_4-基]-胺42(1〇〇 mg , 0· 22 mmol)溶於6 mL N，N-二曱基曱醯胺中，在冰浴條件下，冷卻至0°C，加入氫化鈉（27 mg，l 13職〇1)，攪拌 30分鐘後加入2-(2-氯乙基曱基吡咯烷鹽酸鹽〈5〇 mg，0.27 mmol)，室溫下攪拌4小時反應完畢。反應液減壓下浪縮，得到的殘留物藉由矽膠管柱層析法進一步分離 φ純化（二氯甲烷：甲醇M0U)，得到本標題產物[3 一氯_4_(3一氣-节氧基）-苯基]-(6-{1-[2-(卜甲基_σ比咯烧_2_基）_乙基]-1Η-吡咯-3-基卜喹唑啉-4-基胺171(27 mg，淡黃色固體），產率：78%。 MS m/z (ESI) ： 558[M+1] lH^R(400MHz，DMS〇-d6): d 9.67(s，1H)，8.8 (s，1H)， 8.5 (s, 1H), 8. 03 (d, J=8. 8Hz, 2H), 7.76 (dd, J=2Hz, 1H), 7.70 (d, J=8. 4Hz, 1H), 7. 5(m, 2H), 7.36 (m, 3H), 94389 290 201016683 7. 2 (s，1H)，6. 93 (s，1Η)，6·60 (s，1H)，5.27 (s，2H)， 3.97 (m，2H)，2.08 (m，3H)，1.66 (m，2H)，1.24-1.30 (m, 7H) 實施例172 4-(3-{4-「3 -氣- 4- (3-氟氧基）-笨胺某-唾嗅蛛早·I -吡咯-1-基甲基）-哌啶-4-醇[ [3_Chloro_4_(3_Fluoro-benzyloxy)_phenyl]-[6-C1H-pyrrol-3-yl)-quinazoline-4-yl] in a 25 mL single-necked flask -Amine 42 (1 〇〇 mg, 0·22 mmol) was dissolved in 6 mL of N,N-didecyl decylamine, cooled to 0 ° C under ice-bath, and sodium hydride (27 mg, l 13) 1), after stirring for 30 minutes, 2-(2-chloroethyl-decylpyrrolidine hydrochloride <5 mg, 0.27 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was reduced under reduced pressure, and the obtained residue was purified by EtOAc EtOAc EtOAc EtOAc EtOAc )-phenyl]-(6-{1-[2-(p-methyl-σ-pyrrolin-2-yl)-ethyl]-1Η-pyrrol-3-ylbuquinazolin-4-ylamine 171 ( 27 mg, pale yellow solid), yield: 78%. MS m/z (ESI): 558[M+1] lH^R (400 MHz, DMS 〇-d6): d 9.67 (s, 1H), 8.8 ( s,1H), 8.5 (s, 1H), 8. 03 (d, J=8. 8Hz, 2H), 7.76 (dd, J=2Hz, 1H), 7.70 (d, J=8. 4Hz, 1H) , 7. 5(m, 2H), 7.36 (m, 3H), 94389 290 201016683 7. 2 (s, 1H), 6.93 (s, 1Η), 6·60 (s, 1H), 5.27 (s , 2H), 3.97 (m, 2H), 2.08 (m, 3H), 1.66 (m, 2H), 1.24-1.30 (m, 7H) Example 172 4-(3-{4-"3 - gas - 4 - (3-Fluorooxy)-stupylamine-Salmonella early I-pyrrol-1-ylmethyl)-piperidin-4-ol

❿卜側氧基-6-氫雜-螺[2. 5]辛烷-6-甲酸第三丁酯在冰鹽浴冷卻下，將100mL二甲基亞砜逐漸滴加到三甲基氧硫化碘（4〇g，〇. 18 m〇1)和氫化鈉（7 48 g，〇 18助u 的混合物令，滴加過程中，保持溫度在〇至代滴加4-侧氧基-娘咬一卜甲酸第三丁醋(以.“，〇 η =)的100 mL二？基亞赌液，滴加完畢後逐漸升至二水在室溫下攪拌3切，反應完畢嘯反應液倒人⑽‘ 承求中，用***萃敌 ^ 卒取合併的有機相依次用無水硫酸鈉脫 94389 291 201016683第三侧 ethoxy-6-hydrohetero-spiro[2.5]octane-6-carboxylic acid tert-butyl ester, 100 mL of dimethyl sulfoxide gradually added dropwise to trimethyl oxysulfide under ice-cooling bath cooling Iodine (4〇g, 〇. 18 m〇1) and sodium hydride (7 48 g, 〇18 help u mixture, during the addition process, keep the temperature in the 〇 to the drop add 4-side oxy-Nitney bite A solution of formic acid terpene vinegar (with "", 〇η =) of 100 mL of dimethyl ketone, after the addition is completed, gradually rise to dihydrate and stir at room temperature for 3 cuts. (10) In the pursuit, extract the combined organic phase with diethyl ether and remove the organic phase with sodium sulfate in sequence. 94389 291 201016683

水，過濾，減壓下濃縮，得到化合物卜侧氧基_6_氮雜_螺 [2. 5]辛烷-6-曱酸第三丁酯i72b(32g，黃色固體），產率： 83. H MS m/z (ESI) ·* 214[M+1] 第二步 4-(3-{4-[3-氯-4-(3-氟-苄氧基）_苯胺基]-喹唑啉_6_基j 比略-1-基甲基）-4-經基-派咬—1-甲酸第三丁酯在50 mL的燒瓶中，將[3-氯-4-(3-氟-苄氧基）-苯基] -[6-(1Η-吡咯-3-基）-喹唑啉-4-基]-胺 42(223 mg，〇. 5 © mmol)溶於10 mL無水N，N-二甲基甲醯胺中，在冰浴條件下’冷卻至0°C，加入氫化鈉（60 mg，1. 5 mmol)，攪拌30 分鐘後加入卜側氧基-6-氮雜-螺[2.5]辛烷-6-曱酸第三丁酯172b(50 mg ’ 0· 27 mmol)，室溫下攪拌1小時反應完畢。反應液減壓下濃縮’得到的殘留物藉由矽膠管柱層析法進一步分離純化（二氯曱烷：曱醇=40 : 1)，得到本標題產物4-(3-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-喹唑啉 -6-基}-吡咯-卜基甲基）-4-羥基-哌啶-1-曱酸第三丁酯 172c(193 mg，淡黃色固體），產率·· 58. 7%。 MS m/z (ESI) ： 659[M+1] 第三步 4-(3-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-啥吐淋-6-基} -α比哈-1-基甲基）_〇底唆-4-醇將4-(3-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-啥《坐琳-6-基卜吡咯-1-基甲基）-4-羥基-哌咬-1-曱酸第三丁酯 292 94389 201016683 172c(90 mg，〇. 137 mmol)溶於 25 mL 二氯甲烷中，在冰浴條件下，冷卻至0 °C，逐漸滴加三氟乙酸（25 mL， 1.38mol)，升至室溫，攪拌40分鐘後反應完畢。將反應液在減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化，得到標題產物4~(3-{4-[3~氯-4-(3-氟-苄氧基）-苯胺基]-喧峻琳-6-基}-吼咯—基甲基）_哌唆__4一醇二氣乙.酸鹽172(92 mg ’貫綠色固體），產率：1〇〇%。 MS m/z (ESI) ： 559[M+1] 4 NMR (400 MHz， DMS0_d6): (Π〇. 742 (s， 1H)， 8 733 (s ❹ 1H)，8.687 (s，lH)，8.598 (d，J=12HZ，ih)，8.340 (d J=9. 2Hz, 1H), 8.194 (d, J=8. 8Hz, 1H), 7. 942 (s 1H) 7.784 (d’ J-8.4Hz, 1H), 7.690 (t, J=4.4Z，iH)，7.491 (m，3H)，7.201 (t，J=8.8Hz，1H)，6.926 (s，1H)，5 308 (s, 1H), 5.173 (d, J=12Hz, 1H), 3. 059 (d, J=4. 8Hz, 2H) 1.708 (t，J = 11.4Hz，2H), 1·584 (d, j=13 6Hz ’ 1.342 (s, 2H) ’ 實施例173 [3-氣-4-(3-氟_苄氧基」-苯基]~{6-「〗—「3_哌啶_1_芋—内某比咯-3-基Ί-喹唑啉-4-基}-脍Water, filtered, and concentrated under reduced pressure to give compound s. s. _ 6 _ _ _ s s s s s s s s s s s s s s s s s s s s s s s s s s s H MS m/z (ESI) ·* 214[M+1] Step 2 4-(3-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-anilino]-quin Oxazoline _6_yl j than s-l-ylmethyl)-4-yl-pyro-1-carboxylic acid tert-butyl ester in a 50 mL flask, [3-chloro-4-(3- Fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinazolin-4-yl]-amine 42 (223 mg, 〇. 5 © mmol) dissolved in 10 mL anhydrous In N,N-dimethylformamide, it was cooled to 0 ° C under ice bath conditions, sodium hydride (60 mg, 1.5 mmol) was added, and after stirring for 30 minutes, the oxo-6-nitrogen was added. Hetero-spiro[2.5]octane-6-decanoic acid tert-butyl ester 172b (50 mg '0·27 mmol) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue obtained was further purified and purified by hexane column chromatography (dichloromethane: decyl alcohol = 40:1) to give the title product 4-(3-{4-[3 -Chloro-4-(3-fluoro-benzyloxy)-anilino]-quinazolin-6-yl}-pyrrole-buylmethyl)-4-hydroxy-piperidine-1-decanoic acid tert-butyl Ester 172c (193 mg, pale yellow solid), yield 58.7%. MS m/z (ESI): 659 [M+1]. Step 3 4-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-anilinyl]-oxime-- 4-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-aniline 4-(yl)-α-ha-l-ylmethyl) Base]-啥 "Shen Lin-6-Kippyrrole-1-ylmethyl)-4-hydroxy-piperidine-1-decanoic acid tert-butyl ester 292 94389 201016683 172c (90 mg, 〇. 137 mmol) The mixture was cooled to 0 ° C in 25 mL of dichloromethane, and then trifluoroacetic acid (25 mL, 1.38 mol) was gradually added dropwise, and the mixture was warmed to room temperature. After stirring for 40 minutes, the reaction was completed. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified and purified to give the title product 4~(3-{4-[3~chloro-4-(3-fluoro-benzyloxy) ))-anilino]-喧junlin-6-yl}-fluorenyl-ylmethyl)-piperazine__4-alcohol dioxate 172 (92 mg 'trans-green solid), yield: 1 〇〇%. MS m/z (ESI): 559 [M+1] 4 NMR (400 MHz, DMS0_d6): (Π〇. 742 (s, 1H), 8 733 (s ❹ 1H), 8.687 (s,lH),8.598 (d, J=12HZ, ih), 8.340 (d J=9. 2Hz, 1H), 8.194 (d, J=8. 8Hz, 1H), 7. 942 (s 1H) 7.784 (d' J-8.4Hz , 1H), 7.690 (t, J=4.4Z, iH), 7.491 (m, 3H), 7.201 (t, J = 8.8 Hz, 1H), 6.926 (s, 1H), 5 308 (s, 1H), 5.173 (d, J=12Hz, 1H), 3. 059 (d, J=4. 8Hz, 2H) 1.708 (t, J = 11.4Hz, 2H), 1·584 (d, j=13 6Hz ' 1.342 ( s, 2H) 'Example 173 [3-Ga-4-(3-Fluoro-benzyloxy)-phenyl]~{6-"〗-"3_Piperidine_1_芋- Within a certain ratio - 3-ylindole-quinazolin-4-yl}-oxime

173 Ν 94389 293 201016683173 Ν 94389 293 201016683

將化合物[3-氯-4-(3-氟-苄氧基）-苯基]-[6-( 1H-"比嘻基）_啥嗤淋-4-基卜胺42(111 mg，0.25 mmol)和氫化鈉（65. 3 mg，1.25 mmol)溶於5 mL N，N-二甲基甲醯胺中’至溫下授摔30分鐘後加入1-(3 -氯丙基旅唆鹽酸鹽 (70. 5 mg，0. 3 mmol)，加熱至50°C，2小時後反應完畢。在反應液中加入10 〇 mL水和10 0 mL，分液，水相用乙酸 ❿乙酯（100 mLx3)萃取，合併的有機相依次藉由飽和氣化納溶液洗滌，無水硫酸鈉脫水，過濾，減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化，得到標題產物[3-氯-4-(3-氟-苄氧基）-苯基]-{6-[ 基一丙基）-1Η-吡咯-3-基]-喹唑琳-4-基卜胺173(3〇吨，紅色固體），產率·· 21. 1% 〇 MS m/z (ESI) ： 570[M+1] ^ !H NMR (400 MHz, DMSO-de)： 5 9.68 (s, 1H), 8 53 (s, 1H)，8.50 (s，1H)，8.05 (s，1H)，8.03 (d，j = 8 8Hz， 1H)，7. 76 (d，J = 8. 8Hz，lH)，7.70 (d，J = 8.8Hz，1H)， 7.50 (t, J = 8.8Hz, 1H), 7.43 (s, 1H), 7.33 (m, 3H), 7.19 (t，J = 8.8Hz’ 1H)，6.89 (s，1H)，6.66 (s’ 1H)， 5.27 (s，2H)，3.96 (t，J = 6.8Hz，2H)，2,33 (br 4H)， 2.23 (br，2H)，1.92 (m，2H)，1.52 (br，4H)，l 3l (br， 2H) 94389 294 201016683 實施例174 「卜（3-1-m-lH-吲唑-5-基基）-1 H:pjb p各二3-基1 -啥唑被-4-某丨-脍The compound [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1H-"bi-yl)-indole-4-ylbumin 42 (111 mg, 0.25 mmol) and sodium hydride (65. 3 mg, 1.25 mmol) were dissolved in 5 mL of N,N-dimethylformamide, and then added to 1-(3-chloropropyl tour) for 30 minutes. Hydrochloride (70. 5 mg, 0.3 mmol), heated to 50 ° C, after 2 hours, the reaction was completed. Add 10 mL of water and 100 mL to the reaction solution, and separate the liquid. The ester (100 mL×3) was extracted, and the combined organic phases were washed successively with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue obtained was further separated and purified by hydrazine column chromatography. The title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-{6-[yl-propyl)-1Η-pyrrol-3-yl]-quinazoline-4-yl Amine 173 (3 Torr, red solid), yield · 21.1% 〇MS m/z (ESI): 570[M+1] ^ !H NMR (400 MHz, DMSO-de): 5 9.68 ( s, 1H), 8 53 (s, 1H), 8.50 (s, 1H), 8.05 (s, 1H), 8.03 (d, j = 8 8Hz, 1H), 7. 76 (d, J = 8. 8Hz , lH), 7.70 (d, J = 8.8Hz, 1H), 7.50 (t , J = 8.8Hz, 1H), 7.43 (s, 1H), 7.33 (m, 3H), 7.19 (t, J = 8.8Hz' 1H), 6.89 (s, 1H), 6.66 (s' 1H), 5.27 (s, 2H), 3.96 (t, J = 6.8 Hz, 2H), 2, 33 (br 4H), 2.23 (br, 2H), 1.92 (m, 2H), 1.52 (br, 4H), l 3l ( Br, 2H) 94389 294 201016683 Example 174 "Bu (3-1-m-lH-carbazole-5-yl)-1 H:pjb p each di-3-yl-1-carbazole is -4- 丨-脍

174 將{6-[1-(2-二乙胺基-乙基）-1H_吡咯-3—基喹唑啉 -4-基}-[ 1-(3-氟苄基）-1Η-吲唑-5-基]-胺 150 (434 mg， 1 mmol)溶於6 mL的N，N-二曱基甲醯胺中，冰浴冷卻至 0°C，加入氫化鈉（200 mg ’ 5 mmol)，攪拌30分鐘。另取4-(2_溴乙基1)-嗎啉氫溴酸鹽（3〇2 mg，1. 1随〇1；) 的2 niL N，N_ —甲基甲酿胺溶液’加入氯化納（44 mg，1.83 mmol)，在G°C下攪拌30分鐘後，將溶液加入上述放入反應液中，所得的溶液在0°C下攪拌2小時後反應完畢。將反應液倒入100 mL冰水中，分液，水層用乙酸乙酯（25 mLx4) 萃取’合併的有機相依次藉由飽和氯化鈉溶液洗滌，無水硫酸鈉脫水’過濾，減壓下濃縮，得到的殘留物藉由製備型薄層層析板分離純化，得到標題產物[〗_(3_氟_节基） -1H-吲唑-5-基]-{6-[1-(2-嗎啉-4-基-乙基）_ih-吡咯-3-94389 295 201016683 基]-喹唑啉-4-基卜胺174(300mg，黃色固體），產率54.8%。 MS m/z (ESI) ： 548[M+1] !HNMR (400MHz, CD30D-d〇 : 5 9. 84 (s, 1H), 8.61 (s, 1H) 8.45 (s, 1H), 8.23 (s, 1H), 8.17 (s, 1H), 8.05 (d, 1H, J=8.8Hz), 7.75 (s, 2H), 7. 71 (d, 1H, J=8. 8Hz), 7.46 (s, 1H), 7. 38 (m, 1H), 7.08 (m, 3H), 6. 93 (s, 1H), 6.68 (s, 1H), 5. 72 (s, 2H), 4. 07 (m, 2H), 3. 58 (m, 4H), 2. 71 (m, 2H), 2.45 (m, 4H) 實施例175 ❿「l-(3-氟-苄基）-1Η-吲唑-5-基Μ6-|Ί-(2-吡咯烷-1-某〜乙基）-1Η-吡咯-3-基1-崦唑啉-4-基}-胺174 {6-[1-(2-Diethylamino-ethyl)-1H-pyrrole-3-ylquinazolin-4-yl}-[ 1-(3-fluorobenzyl)-1Η-吲Oxazol-5-yl]-amine 150 (434 mg, 1 mmol) was dissolved in 6 mL of N,N-didecylcarbamide, cooled to 0 ° C in ice bath and sodium hydride (200 mg < ), stirring for 30 minutes. Another 2-(2-bromoethyl 1)-morpholine hydrobromide salt (3〇2 mg, 1.1 with 〇1;) of 2 niL N,N_-methylcaraamine solution 'added chlorination After the mixture was stirred at G ° C for 30 minutes, the solution was added to the above reaction solution, and the resulting solution was stirred at 0 ° C for 2 hours and then the reaction was completed. The reaction solution was poured into 100 mL of ice water, and the aqueous layer was separated and evaporated with ethyl acetate (25 mL×4). The combined organic phases were washed sequentially with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The residue obtained is isolated and purified by preparative thin-layer chromatography chromatography to give the title product [ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ -morpholin-4-yl-ethyl)_ih-pyrrole-3-94389 295 201016683 yl]-quinazolin-4-ylbumin 174 (300 mg, yellow solid), yield 54.8%. MS m/z (ESI): 548[M+1] !HNMR (400MHz, CD30D-d〇: 5 9. 84 (s, 1H), 8.61 (s, 1H) 8.45 (s, 1H), 8.23 (s , 1H), 8.17 (s, 1H), 8.05 (d, 1H, J=8.8Hz), 7.75 (s, 2H), 7. 71 (d, 1H, J=8. 8Hz), 7.46 (s, 1H) ), 7. 38 (m, 1H), 7.08 (m, 3H), 6. 93 (s, 1H), 6.68 (s, 1H), 5. 72 (s, 2H), 4. 07 (m, 2H) ), 3. 58 (m, 4H), 2. 71 (m, 2H), 2.45 (m, 4H) Example 175 ❿ "l-(3-Fluoro-benzyl)-1 - oxazol-5-yl Μ6-|Ί-(2-pyrrolidin-1-one~ethyl)-1Η-pyrrol-3-yl 1-oxazolin-4-yl}-amine

將{6-[卜（2-二乙胺基-乙基）_1Η-吡咯-3-基]-喹唑啉 -4-基卜[1-(3-氟苄基）-1Η-吲唑-5-基]-胺 150(434 mg，1 mmol)溶於6 mL的N，N-二曱基甲醢胺中，冰浴冷卻至0°C，加入氫化鈉（200 mg，5 mmo 1)，擾拌30分鐘後’加入；氯乙基）-吡咯烷鹽酸鹽（187 mg，1. 1 mmol)，室溫下攪拌 30分鐘後，加熱至5(TC，1.5小時後反應完畢。將反應液 296 94389 201016683 倒入100 mL冰水中，有固體析出，過濾，將濾餅溶於100 mL乙酸乙酯中，藉由無水硫酸鈉脫水，過濾濃縮，得到的殘留物進一步藉由HPLC製備型層析分離，得到標題產物 [1-(3 -氣-节基）-1Η -°引 σ坐_5_基]-{6-[ 1-(2_π比p各烧-1-基-乙基）-1Η-吡咯-3-基]-喹唑啉-4-基卜胺175(700 mg，淡黃色固體），產率40%。 MS m/z (ESI) ： 532[M+1] ^NMR (400MHz, CD30D-d〇: 5 9. 87 (s, 1H), 8. 65 (s, 1H), 8. 45 (s, 1H), 8. 24 (s, 1H), 8. 17 (s, 1H), 8. 03 (d, 1H, © J=8.8Hz), 7.75 (s, 2H), 7. 71 (d, 1H, J=8. 8Hz), 7.51 (s, 1H), 7.38 (m, 1H), 7. 08 (m, 3H), 6.96 (s, 1H), 6.72 (s, 1H), 5. 72 (s, 2H), 4. 18 (m, 2H), 3. 10 (m, 2H), 2. 75 (m, 4H), 1. 77 (m, 4H) 實施例176 「3 -氯- 4-(3-1-爷氣基）-笨基l-{6-「1-(2 -甲確醯基-乙基比嘻-3 -基-喧口坐琳―4.-基}-胺{6-[Bu(2-diethylamino-ethyl)_1Η-pyrrol-3-yl]-quinazolin-4-yl b[1-(3-fluorobenzyl)-1Η-carbazole- 5-yl]-amine 150 (434 mg, 1 mmol) was dissolved in 6 mL of N,N-didecylcarbamide, cooled to 0 ° C in ice bath, and sodium hydride (200 mg, 5 mmo 1) After stirring for 30 minutes, 'add; chloroethyl)-pyrrolidine hydrochloride (187 mg, 1.1 mmol), stir at room temperature for 30 minutes, then heat to 5 (TC, 1.5 hours later, the reaction is complete. Reaction liquid 296 94389 201016683 Pour into 100 mL of ice water, solid precipitated, filter, dissolve the filter cake in 100 mL of ethyl acetate, dehydrate with anhydrous sodium sulfate, and concentrate by filtration, and the residue obtained is further prepared by HPLC. Chromatographic separation gave the title product [1-(3- gas-synthesis)-1Η-° σ _5_ yl]-{6-[ 1-(2_π ratio p each -1-yl-ethyl -1Η-pyrrol-3-yl]-quinazolin-4-ylbumin 175 (700 mg, pale yellow solid), yield 40%. MS m/z (ESI): 532[M+1] NMR (400MHz, CD30D-d〇: 5 9. 87 (s, 1H), 8. 65 (s, 1H), 8. 45 (s, 1H), 8. 24 (s, 1H), 8. 17 ( s, 1H), 8. 03 (d, 1H, © J=8.8Hz), 7.75 (s, 2H), 7. 71 (d, 1 H, J=8. 8Hz), 7.51 (s, 1H), 7.38 (m, 1H), 7. 08 (m, 3H), 6.96 (s, 1H), 6.72 (s, 1H), 5. 72 ( s, 2H), 4. 18 (m, 2H), 3. 10 (m, 2H), 2. 75 (m, 4H), 1. 77 (m, 4H) Example 176 "3-Chloro- 4- (3-1-Yeqi base)- Stupid base l-{6-"1-(2-methyl-decyl-ethyl-pyridin-3-yl-喧口坐琳-4.-yl}-amine

176 〇W/〇〇wp /S、CI q'P °^P OH — 176a 297 94389 201016683176 〇W/〇〇wp /S, CI q'P °^P OH — 176a 297 94389 201016683

第一步曱磺酸2-甲磺醯基乙酯將2 -曱確醯基乙醇（248mg，2 mmol)溶於10 mL無水二氯甲烧中，授拌下加入**比咬（316 mg，4mmo 1)，將溶液冷卻至0°C，加入甲確酿氯（344 mg，3 mmol )，混合液升〇至室溫，攪拌2小時反應完畢。將反應液減壓下濃縮，在殘留物中加入15 mL水，用乙酸乙酯萃取，合併的有機相依次藉由飽和氯化鈉溶液洗滌（10 mLx2)，無水硫酸鈉脫水，過濾’減壓下濃縮，得到甲磺酸2-甲磺醯基乙酯176a (240 mg ’淡黃色固體），產率：60%。 MS m/z (ESI) ： 203[M+1] 第二步 ❾[3 -氯_4_(3 -氟-卞氧基）-苯基]甲續酿基〜乙基） -1Η-Ρ比洛>3-基]-啥唾琳-4-基}-胺In the first step, 2-methanesulfonyl sulfonate is dissolved in 2 mL of anhydrous dichloromethane. The mixture is mixed with dimethyl oxalate (316 mg, 2 mmol). , 4mmo 1), the solution was cooled to 0 ° C, added to the chlorine (344 mg, 3 mmol), the mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc)EtOAc. Concentration to give 2-methanesulfonyl methanesulfonate 176a (240 mg 'yellow yellow solid), yield: 60%. MS m/z (ESI): 203 [M+1] s. [3 - chloro- 4-(3 - fluoro- decyloxy)-phenyl]methyl </ br>洛>3-yl]-啥啥琳-4-yl}-amine

在25 mL的單口燒瓶中，將[3-氯-4-(3-氟-苄氧基）一苯基]-[6-C1H-吡咯-3-基）-喹唑啉-4-基]-胺42(89 mg， 0·2 mmol)溶於3 mL N，N-二甲基甲醢胺中，在冰浴條件下’冷卻至0°C ’加入氫化鈉（24 mg，1 mmol )，攪拌分鐘後逐漸滴加甲磺酸2-甲磺醯基乙酯（49 mg，〇. 24 mmol) ’室溫下攪拌4小時反應完畢。反應液中加入10mL 298 94389 201016683 水，用乙酸乙酯萃取（1 〇 mLx4)，合併的有機相依次藉由飽和氯化鈉溶液洗滌，無水硫酸鈉脫水，過濾，減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化（二氯曱烷：曱醇=5 ·· 2)，得到本標題產物[3_氯一4_(3__氣―苄氧基）-苯基]-{6-[卜（2-甲磺醯基-乙基）_1H-吼咯一基卜喹唑啉-4-基卜胺176 (60 mg，淡黃色固體），產率：54%。 MS m/z (ESI) ： 551[M+l] !H NMRC400 MHz , DMSO-de)： (5 9. 70 (s, 1H), 8. 55 (s, iH) 8. 50 (s，1H)，8. 05 (m，1H)，8. 02 (m，1H)，7. 73 (m，2H): Φ 7. 52 (m, 2H), 7. 34 (m, 3H), 7. 19 (m, 1H), 7. 01 (s, 1H)> 6.72(s，1H)’ 5.27 (s, 2H), 4.40 (t，2H)，3.72 (t’ 2H)， 2.82 (s, 3H) ， « 實施例177 [3 一羞二4 - (3-氟_-卞氣某）-茉基~]-(6-丨1 —「2-(四鱼,.ρ去p南基氧基）-乙基1-111-咐1吸-3-某丨-嗟嗤啦-4-基）-胺[3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-C1H-pyrrol-3-yl)-quinazolin-4-yl] in a 25 mL single-necked flask -Amine 42 (89 mg, 0. 2 mmol) was dissolved in 3 mL of N,N-dimethylformamide, and then cooled to <0>C under ice bath to add sodium hydride (24 mg, 1 mmol) After stirring for a while, 2-methanesulfonyl methanesulfonate (49 mg, 〇. 24 mmol) was gradually added dropwise. The reaction was completed by stirring at room temperature for 4 hours. 10 mL of 298 94389 201016683 water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (1 〇mL×4). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was further separated and purified by hydrazine column chromatography (dichloromethane: decyl alcohol = 5 ·· 2) to give the title product [3_chloro-4-[(3__ s-benzyloxy)-phenyl] -{6-[Bu(2-methanesulfonyl-ethyl)-lH-indole-yl-buquinazolin-4-yl-p- ylamine 176 (60 mg, pale-yellow solid), yield: 54%. MS m/z (ESI): 551 [M+l].H NMRC 400 MHz, DMSO-de): (5 9. 70 (s, 1H), 8. 55 (s, iH) 8. 50 (s, 1H) ), 8. 05 (m, 1H), 8. 02 (m, 1H), 7. 73 (m, 2H): Φ 7. 52 (m, 2H), 7. 34 (m, 3H), 7. 19 (m, 1H), 7. 01 (s, 1H)> 6.72(s,1H)' 5.27 (s, 2H), 4.40 (t,2H), 3.72 (t' 2H), 2.82 (s, 3H ), « Example 177 [3 A shy two 4 - (3-Fluoro_-卞气) - Molybdenum ~]-(6-丨1 - "2-(four fish, .ρ to p-Southernoxy) )-Ethyl 1-111-咐1 吸-3-某丨-嗟嗤啦-4-yl)-amine

將[3-氯-4-(3-氟-苄氧基）-苯基]-[6-(111-°比咯-3-基） -喹峻啉-4-基]-胺 42 (120 mg，0.27 mmol)和氫化鈉（32. 4 299 94389 201016683[3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(111-°pyrol-3-yl)-quinucolin-4-yl]-amine 42 (120 Mg, 0.27 mmol) and sodium hydride (32. 4 299 94389 201016683

下攪拌30分鐘後加入2__(2 0. 3 mmol)，室溫下攪拌3〇 H N，N-二甲基甲醯胺中，室溫 ~凜乙氧基）-四氫《比喃（7 0 mg，分鐘後反應完畢。在反應液中After stirring for 30 minutes, add 2__(2. 3 mmol), stir at room temperature, 3 〇HN, N-dimethylformamide, room temperature ~ 凛 ethoxy)-tetrahydro "pyran (7 0 After the reaction is completed in mg, the reaction solution is completed.

啉-4-基）-胺177(190 mg，黃色固體），產率：55. 2%。 Φ MS m/z (ESI) ： 573[M+1] ]H NMR (400 MHz, DMS0-d6): (5 9.69 (s, 1H), 8.54 (s, • 1H)，8.50 (s，1H)，8. 05 (s, 1H), 8.03 (d，J = 8.8Hz， ^ 1H), 7.76 (d, J = 8.8Hz, 1H), 7.70 (d, J = 8. 8Hz, 1H), 7.50 (t, J = 8.8Hz, 1H), 7.43 (s, 1H), 7.33 (m, 3H), 7. 19(t, J = 8.8Hz, 1H), 6.93 (s, 1H), 6. 67 (s, 1H), 5. 27 (s, 2H), 4. 57(br, 1H), 4. 14 (br, 2H), 3. 90 (br, ❹ 1H)，3.70 (br, 1H)，3.57 (m，2H)，2.90 (br，1H)，2.74 (br, 1H), 1. 38 (br, 4H) 實施例178 l-(3-{j-[l-(3-氟-苄基）-1Η-吲唑ί!腚某·μ喹唑啉_6-基}_p比格-1 -基）- 3 -嗎1^ - 4 -基-丙-2 -拜·2%。 phenyl-4-yl)-amine 177 (190 mg, yellow solid), yield: 55.2%. Φ MS m/z (ESI): 573[M+1] ]H NMR (400 MHz, DMS0-d6): (5 9.69 (s, 1H), 8.54 (s, • 1H), 8.50 (s, 1H) , 8. 05 (s, 1H), 8.03 (d, J = 8.8Hz, ^ 1H), 7.76 (d, J = 8.8Hz, 1H), 7.70 (d, J = 8. 8Hz, 1H), 7.50 ( t, J = 8.8Hz, 1H), 7.43 (s, 1H), 7.33 (m, 3H), 7. 19(t, J = 8.8Hz, 1H), 6.93 (s, 1H), 6. 67 (s , 1H), 5. 27 (s, 2H), 4. 57(br, 1H), 4. 14 (br, 2H), 3. 90 (br, ❹ 1H), 3.70 (br, 1H), 3.57 ( m, 2H), 2.90 (br, 1H), 2.74 (br, 1H), 1. 38 (br, 4H) Example 178 l-(3-{j-[l-(3-fluoro-benzyl)- 1Η-carbazole ί!腚μ·μ quinazoline _6-yl}_pbig-1 -yl)- 3 -?1^ - 4 -yl-propyl-2 -by

94389 178 300 Φ 20101668394389 178 300 Φ 201016683

178 第一步 Ο ⑩ [1-(3-氟-苄基）_1Η-吲唑-5-基]-[6_(1-環氧乙基曱基 ~111-咐>略-3-基）-〇|:«1坐琳-4~基]_胺在100 mL茄形瓶中，將{6_ [卜（2-二乙胺基-乙基）-iH- D比洛-3-基]-喹唑啉-4-基卜[i-(3_氟苄基）-1Η-吲唑-5-基] -胺150(1.3 g，3 mmol)溶於30 mL的N，N-二甲基曱酿胺中’冰浴冷卻至〇°C ’加入氫化鈉（1 g ’ 6. 6 mmol)，擾掉 30分鐘後，室溫下加入環氧氯丙烷（〇 42lDL，5.35mm〇丨）， 2小時後反應完畢。將反應液倒入1〇〇mL冰水中 * 5 Ml *8^ 析出，得到[1-(3-氟-苄基）-11]-吲哇_5-基]~[6、（115〇基甲基-1H-料-3-基）十坐嘴+奸胺ma(i〜環氧乙色固體），產物不經分離直接進行下一步反應。· MS m/z (ESI) ： 491[M+1] 〜 HNMR (400MHz, CD30D-d〇: 5 8 r〇 , 1UN 0 、 · (s，lH)，8. i6 Γ 1 Π o nc r r, ou、 n „ ^ s> 1H), M〇(s, 1H), 8.06(s, 2H), 7. g9 ^ 1H? J=g>(d，爪 J=8.8Hz)，7.65(d，1H，Μ.·)，7 )，？. ^8. SH2), 7.34(,, 1H), 7.20(S} ^ 〇 9039 Cd, ih, 94389 301 201016683 6. 92 (d，1H，J=9· 6Hz)，6. 80 (s，1Η)，6· 62 (s，1H)，5. 63 (s, 2H)，4. 29 (m，1H)，3. 98 (m，1H)，3· 33 (m，1H)，2. 9〇 (m, 1H), 2.56 (m, 1H) 第二步 l_(3-{4-[l-(3 -氟-苄基）-1Η-σ引吐-5-基胺基]-啥唾琳〜基}-吡咯-1-基）-3-嗎啉-4-基-丙-2-醇在1〇〇 mL茄形瓶中，將[i-(3-氟-苄基）-lH-吲唑〜基]-[6-(1-環氧乙基甲基-ΐΗ-α比哈-3 -基）-喧》坐淋-4-基] 胺178a (1.8 g，3. 67mmol)溶於40 mL曱醇中，檀拌下 ®加入嗎琳（510 mg，5.87mmo 1 )，反應液加熱回流過夜。將反應液在減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化，得到本標題產物卜（3勺氟一苄 .基）-1Η-吲唑-5-基胺基]-喹唑啉_6_基}_吡咯_丨_基）_3_ = 啉-4-基-丙-2-醇178(600 mg，黃色固體），產率：35⑽。 MS m/z (ESI) ： 578[M+1] ' 4NMR (400MHz，CD30D-d〇: 59.82 (s，1H)，8 6〇(s, 1H)， ❹ 8.44 (s’ 1H)’ 8.23 (s’ 1H)，8.17 (s，1H)，8 〇3 (d，1H， J=8.8Hz)’ 7.73(m，3H)’ 7.43(s，1H)，7.38(m，lH)，7 l〇 (m, 3H), 6.88(s, 1H), 6. 67 (s, 1H), 5. 72 (s, 2H)! 4'96 (s, 1H), 3. 97 (m, 3H), 3. 61 (m, 4H), 2. 43 (m, 4H) 2 26 (m, 2H) 5 實施例17 9 (3 - U - [ 基卜喹唑基卜吼丙 _2-醇 94389 302 201016683178 First step Ο 10 [1-(3-Fluoro-benzyl)_1Η-indazol-5-yl]-[6_(1-epoxyethyl decyl~111-咐> s3-yl) -〇|:«1坐琳-4~基]_amine in a 100 mL eggplant-shaped bottle, {6_[Bu (2-diethylamino-ethyl)-iH-D is more than benzyl-3-yl] -quinazolin-4-yl b[i-(3-fluorobenzyl)-1Η-indazol-5-yl]-amine 150 (1.3 g, 3 mmol) dissolved in 30 mL of N,N-dimethyl Add sodium hydride (1 g '6 6 mmol) to the base amine in the 'ice bath to 〇 ° C ', and after disturbing for 30 minutes, add epichlorohydrin (〇42lDL, 5.35mm〇丨) at room temperature. After 2 hours, the reaction was completed. Pour the reaction solution into 1 mL of ice water * 5 Ml *8^ to give [1-(3-fluoro-benzyl)-11]-吲w_5-yl]~[6,(115〇基Methyl-1H-form-3-yl) ten sitting mouth + acetonide ma (i~epoxy ethoxy solid), the product was directly subjected to the next reaction without isolation. MS m/z (ESI): 491 [M+1] ~ HNMR (400 MHz, CD30D-d〇: 5 8 r〇, 1UN 0 , · (s, lH), 8. i6 Γ 1 Π o nc rr, Ou, n „ ^ s> 1H), M〇(s, 1H), 8.06(s, 2H), 7. g9 ^ 1H? J=g>(d, claw J=8.8Hz), 7.65(d,1H) ,Μ.·),7),?. ^8. SH2), 7.34(,,1H), 7.20(S} ^ 〇9039 Cd, ih, 94389 301 201016683 6. 92 (d,1H,J=9· 6 Hz), 6. 80 (s, 1 Η), 6.62 (s, 1H), 5. 63 (s, 2H), 4. 29 (m, 1H), 3. 98 (m, 1H), 3· 33 (m,1H), 2. 9〇(m, 1H), 2.56 (m, 1H) The second step l_(3-{4-[l-(3-fluoro-benzyl)-1Η-σ induces spit -5-ylamino]-啥啥琳~yl}-pyrrol-1-yl)-3-morpholin-4-yl-propan-2-ol in a 1 mL mL eggplant bottle, [i- (3-fluoro-benzyl)-lH-carbazole~yl]-[6-(1-epoxyethylmethyl-anthracene-α-haha-3-yl)-oxime-sodium-4-yl] The amine 178a (1.8 g, 3.67 mmol) was dissolved in 40 mL of methanol, and the mixture was mixed with lanolin (510 mg, 5.87 mmo 1 ), and the reaction solution was heated to reflux overnight. The residue was further separated and purified by ruthenium column chromatography to obtain the title product (3). Fluorobenzylidene-l-indole-5-ylamino]-quinazoline-6-yl}_pyrrole_丨_yl)_3_ = phenyl-4-yl-propan-2-ol 178 (600 Mg, yellow solid), Yield: 35 (10). MS m/z (ESI): 578[M+1] ' 4 NMR (400 MHz, CD30D-d: 59.82 (s, 1H), 8 6 〇 (s, 1H) , ❹ 8.44 (s' 1H)' 8.23 (s' 1H), 8.17 (s, 1H), 8 〇 3 (d, 1H, J = 8.8Hz) ' 7.73(m,3H)' 7.43(s,1H) , 7.38 (m, lH), 7 l〇(m, 3H), 6.88(s, 1H), 6. 67 (s, 1H), 5. 72 (s, 2H)! 4'96 (s, 1H) , 3. 97 (m, 3H), 3. 61 (m, 4H), 2. 43 (m, 4H) 2 26 (m, 2H) 5 Example 17 9 (3 - U - [ quinazolinyl卜吼丙_2-ol 94389 302 201016683

179 1179 1

在100 mL莊形瓶中’將[1-(3-氟-苄基）-1Η-吲唑-5-基]-[6-(1-環氧乙基甲基_1H_吡咯_3_基）_喹唑啉_4_基]一'1-(3-Fluoro-benzyl)-1Η-indazol-5-yl]-[6-(1-epoxyethylmethyl-1H_pyrrole_3_) in a 100 mL bottle Base)_quinazoline_4_yl]

胺178a(134 g ’ 〇. 27 mmol)溶於10 mL甲醇中，授拌下加入2-曱確醯基乙胺鹽酸鹽呵，0. 47mmol)和〇. 3 mL三乙胺，反應液加熱回流過夜。將反應液在減壓下濃縮，得到的殘留物藉由石夕膠管柱層析法進一步分離純化，得到本標題產物卜（3-{4-[1-(3-氟-苄基）-1Η-吲唑-5-基胺基]-喹唑啉-6-基卜吡咯-1-基）-3-(2-甲磺醯基-乙胺基）-丙 - 2-醇179(29 mg，黃色固體），產率：17.5%。 MS m/z (ESI) ： 614[M+1] q ^NMR (400MHz, CD30D-^) ： <5 9. 96 (s, 1H), 8. 69 (s, 1H), 8.44 (s, 1H), 8.24 (s, 1H), 8.17 (s, 1H), 8.04 (d, 1H, J=8.8Hz), 7.76 (s, 2H), 7.69 (d, 1H, J = 8.8Hz), 7.48 (s, 1H), 7.38 (m, 1H), 7.08 (m, 3H), 6. 90 (s, 1H), 6.72 (s, 1H), 5. 72 (s, 2H)，4. l〇 (m，3H), 3. 39 (m，4H), 3. 12 (m, 3H), 2.91 (m, 2H) 實施例180 3-(3-·(4-「3-氯-4-(3-氤-芊氣某）-笨膦基J-_喧唑啉-6-某1 303 94389 201016683 二吼咯-1-篡ν丙烷_；!. 2_二酵The amine 178a (134 g ' 〇. 27 mmol) was dissolved in 10 mL of methanol, and the mixture was stirred and added with 2-ethylidene ethylamine hydrochloride, 0. 47 mmol) and 〇. 3 mL of triethylamine. Heat to reflux overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was further purified and purified by chromatography, to give the title product (3-{4-[1-(3-fluoro-benzyl)-1? -oxazol-5-ylamino]-quinazolin-6-ylpyrrolidin-1-yl)-3-(2-methanesulfonyl-ethylamino)-propan-2-ol 179 (29 mg , yellow solid), yield: 17.5%. MS m/z (ESI): 614 [M + 1] <RTI ID=0.0>>>> 1H), 8.24 (s, 1H), 8.17 (s, 1H), 8.04 (d, 1H, J=8.8Hz), 7.76 (s, 2H), 7.69 (d, 1H, J = 8.8Hz), 7.48 ( s, 1H), 7.38 (m, 1H), 7.08 (m, 3H), 6. 90 (s, 1H), 6.72 (s, 1H), 5. 72 (s, 2H), 4. l〇(m , 3H), 3. 39 (m, 4H), 3. 12 (m, 3H), 2.91 (m, 2H) Example 180 3-(3-·(4-"3-chloro-4-(3-氤-芊气某)- Stupid phosphino group J-_oxazoline-6-some 1 303 94389 201016683 dimerole-1-篡νpropane _;!. 2_ two leaven

在100 mL茄形瓶中，將[1-(3-氟-苄基）-1Η-吲唑-5-•基]-[6-(1-環氧乙基曱基_；^-吡咯-3-基）-喹唑啉-4-基]-胺 178a(130 g，0.25 mmol)溶於 1〇 mL 二氧六環中，搜拌下加入1 mL三氟醋酸和1 mL水，將反應液加熱至80。(：， 2小時後反應完畢。將反應液在減壓下濃縮，得到的殘留 •物藉由矽膠管柱層析法進一步分離純化（二氯甲烷：曱醇 • -20 · 1) ’得到本標題產物3-(3-{4-[3-氣-4-(3-氟-苄氧基笨胺基]-喧咬琳-6-基比各-1-基）-丙烧-i，2-二醇三氟乙酸鹽180(158 mg ’黃色固體），產率：1〇〇%。 φ MS m/z (ESI) ： 519[M+1] NMR (400 MHz, CD30D-de) 8.60 (s，1H)，8.58 (s， 1H), 8.19 (d, 1H), 7.71 (d, 1H), 7.60 (d, 1H), 7.41 (m, 1H), 7. 32 (d, 1H), 7. 29 (m, 1H), 7. 15 (d, 1H), 7. 05 (m，1H)6. 86 (s, 1H), 6. 80 (s, 1H), 5. 24 (s, 2H), 4.15 (d, 1H), 3.95 (d, 1H), 3.90 (m, 1H), 3.66 (s, 1H),3.51 (d, 2H) 實施例181 304 94389 201016683 [3-氯-4-(3-氟-苄氡基）-芏篡-(2-派啶-卜基-乙基）-lH-piip各-3-基坐啦-4-美卜胺[1-(3-Fluoro-benzyl)-1Η-indazole-5-•yl]-[6-(1-epoxyethyl fluorenyl _;^-pyrrole- in a 100 mL eggplant-shaped flask 3-yl)-quinazolin-4-yl]-amine 178a (130 g, 0.25 mmol) was dissolved in 1 mL of dioxane, and 1 mL of trifluoroacetic acid and 1 mL of water were added to the reaction. The liquid is heated to 80. (: After 2 hours, the reaction was completed. The reaction solution was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (dichloromethane: methanol: -20 · 1) The title product 3-(3-{4-[3- gas-4-(3-fluoro-benzyloxyamino)-indole-6-ylpyr-1-yl)-propan-i, 2-diol trifluoroacetate 180 (158 mg 'yellow solid), yield: 1% φ MS m/z (ESI): 519 [M+1] NMR (400 MHz, CD30D-de) 8.60 (s, 1H), 8.58 (s, 1H), 8.19 (d, 1H), 7.71 (d, 1H), 7.60 (d, 1H), 7.41 (m, 1H), 7. 32 (d, 1H), 7. 29 (m, 1H), 7. 15 (d, 1H), 7. 05 (m, 1H) 6.86 (s, 1H), 6. 80 (s, 1H), 5. 24 (s, (H, 1H) (3-fluoro-benzylindenyl)-indole-(2-p-pyridinyl-ethyl-ethyl)-lH-piip-3-yl-iso-4-amibamine

w 將[3-氯-4-(3-氟-苄氧基）-苯基]-[6-UH-吼咯-3-基） -噎:唾淋-4-基]-胺 42(230 mg，0.5 mmol)和氫化納（113 mg，2.5 mmol)溶於10 mL N，N-二甲基甲醯胺中，室溫下攪拌30分鐘後加入1-(2-氣乙基）-哌啶鹽酸鹽（70. 5 mg， 0. 3 mmol)，加熱至50°C，2小時後反應完畢。在反應液中加入200 mL水和200 mL，分液，水相用乙酸乙酯（2〇〇 x3)萃取，合併的有機相依次藉由飽和氯化鈉溶液洗滌，無 ❾水硫酸鈉脫水，過濾’減壓下濃縮，得到的殘留物藉由石夕膠管柱層析法進一步分離純化，得到標題產物[3_氣_4_(3__ 氟-苄氧基）-苯基]-{6-[1-(3-哌啶-1-基-丙基）_111_11比略 -3-基]-喹唑淋-4-基}-胺181(65 mg’桔黃色固體），產率： 21%。 MS m/z (ESI) ： 557[M+1] ]H NMR (400 MHz, CD30D-ci6) ： 5 9. 68 (s, 1H), 8.53 (s 1H)，8.50 (s，1H)，8.05 (s，1H)，8.02 (d，J = 8.8Hz 94389 305 201016683 1H), 7. 85 (d, j 7. 54 (t，J = 8. 7. 19 (t, J - 8 5. 27 (s, 2H), 3 4H), 1.51 (m, 實施例182 =8.8Hz, 1H), 7.69 (d, J = 8. 8HZ> iH), 8Hz, 1H), 7.42 (s, 1H), 7.32 (ra, 8Hz，1H)’ 6· 92 (s，1H)，6. 65 (s，1H)’ •96 (br, 2H), 2.70 (br, 2H), 2. 42 (br! 4H), 1.20 (m, 2H) ’ Γ 3- H -4-( 基）-lH-p比疼二3 一氧基）-毛基 l-{6-「卜（3-嗎^二基]-喹唑啉-4-其丨-眩w [3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-UH-indol-3-yl)-indole: salivyl-4-yl]-amine 42 (230 Mg, 0.5 mmol) and sodium hydride (113 mg, 2.5 mmol) dissolved in 10 mL of N,N-dimethylformamide, stirred at room temperature for 30 min and then added 1-(2-ethylethyl)-piper The pyridine hydrochloride (70. 5 mg, 0.3 mmol) was heated to 50 ° C and the reaction was completed after 2 hours. 200 mL of water and 200 mL were added to the reaction mixture, and the liquid phase was extracted with ethyl acetate (2 〇〇 x 3). The combined organic phases were washed successively with saturated sodium chloride solution and dehydrated without sodium sulfate. Filtration was concentrated under reduced pressure, and the obtained residue was further purified and purified by silica gel column chromatography to give the title product [3_ gas_4_(3__fluoro-benzyloxy)-phenyl]-{6-[ 1-(3-piperidin-1-yl-propyl)-111_11 bis-3-yl]-quinazolin-4-yl}-amine 181 (65 mg of orange solid). Yield: 21%. MS m/z (ESI): 557 [M+1]]H NMR (400 MHz, CD30D-ci6): 5 9. 68 (s, 1H), 8.53 (s 1H), 8.50 (s, 1H), 8.05 (s, 1H), 8.02 (d, J = 8.8Hz 94389 305 201016683 1H), 7. 85 (d, j 7. 54 (t, J = 8. 7. 19 (t, J - 8 5. 27 ( s, 2H), 3 4H), 1.51 (m, Example 182 = 8.8 Hz, 1H), 7.69 (d, J = 8. 8HZ> iH), 8Hz, 1H), 7.42 (s, 1H), 7.32 ( Ra, 8Hz, 1H)' 6· 92 (s,1H),6. 65 (s,1H)' •96 (br, 2H), 2.70 (br, 2H), 2. 42 (br! 4H), 1.20 (m, 2H) ' Γ 3- H -4-(yl)-lH-p is more than 2 methoxy)-hair base l-{6-"Bu(3-?^diyl)-quinazoline -4-there is 丨-dizziness

182182

將化合物[3-氯-4-(3-1-节氡基）一苯基H6_(1h”比 ❾洛-3-基）-噎η坐琳+基]—胺42(654 mg，148咖⑴溶於 5 mLN，N-二甲基甲醯胺中，在乾冰乙醇浴冷卻下加入氫化鈉（176 rag，4· 43 mmol)，攪拌30分鐘後加入4__(3_溴丙基卜嗎琳⑽了心^麵…升至室溫授掉過夜^應液在減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進二步分離純化，得到標題產物[3-氣_4_(3_氟-苄氧0基）_苯基"] -{6-[1-(3-嗎啉-4-基_丙基）-1}1-吡咯-3_基]_喹唑啉一4_ 基卜胺182(110 mg，淡黃色固體），產率· 13%。 94389 306 201016683 MS m/z (ESI) ： 572[M+1] ]H NMR (400 MHz, CD30D-d〇： δ 9. 67 (s, 1H), 8. 8 (s, 1H) 8.5 (s, 1H), 8.03 (d, J=8. 8Hz, 2H), 7.76 (dd, J = 2Hz 1H)，7. 70 (d, J=8. 4Hz，1H), 7. 5 (m, 2H), 7· 36 (m，3H) 7.2 (s, 1H), 6.93 (s, 1H), 6.60 (s, 1H), 5. 27 (s, 2H), 4.0 (t, J = 14Hz, 2H), 3.67 (m, 4H), 2.51 (m, 4H), 2.27 (m, 2H), 1. 9 (m, 2H) 實施例183The compound [3-chloro-4-(3-1-penteryl)-phenyl H6_(1h" is more than indole-3-yl)-噎η坐琳+yl]-amine 42 (654 mg, 148 coffee) (1) Dissolve in 5 mL of N,N-dimethylformamide, add sodium hydride (176 rag, 4.43 mmol) under cooling in an ice-cold ethanol bath, stir for 30 minutes, then add 4__(3_bromopropyl b-line (10) The surface of the heart is raised to room temperature and allowed to stand overnight. The solution is concentrated under reduced pressure, and the residue obtained is separated and purified by hydrazine column chromatography to give the title product [3- gas_4_( 3_fluoro-benzyloxycarbonyl]phenyl]-{6-[1-(3-morpholin-4-yl-propyl)-1}1-pyrrole-3-yl]-quinazoline 4- 4 benzylamine 182 (110 mg, pale yellow solid), yield: 13%. 94389 306 201016683 MS m/z (ESI): 572[M+1] ]H NMR (400 MHz, CD30D-d〇: δ 9. 67 (s, 1H), 8. 8 (s, 1H) 8.5 (s, 1H), 8.03 (d, J=8. 8Hz, 2H), 7.76 (dd, J = 2Hz 1H), 7. 70 (d, J=8. 4Hz, 1H), 7. 5 (m, 2H), 7· 36 (m, 3H) 7.2 (s, 1H), 6.93 (s, 1H), 6.60 (s, 1H) , 5. 27 (s, 2H), 4.0 (t, J = 14Hz, 2H), 3.67 (m, 4H), 2.51 (m, 4H), 2.27 (m, 2H), 1. 9 (m, 2H) Example 183

1-(3-{4-「3二氧-4-(3-氟氧基）-笨胺某i —晻唑啾— 芊} -°比嘻-1-基）-1-嗎淋-4-某-λ獅1-(3-{4-"3 dioxo-4-(3-fluorooxy)-stupylamine i - oxazolium oxime - 芊} -° than 嘻-1-yl)-1-? - some - λ lion

αχ • 183 將[3-氯-4-(3-氟-苄氧基）_苯基]_[6_(1Η_β比咯_3_ 基）-啥°坐啦-4-基]-胺42(1〇〇 mg ’ 0. 225 mmol)和氫化納 (27 mg ’ 0.675 mmol)溶於 10 mL Ν,Ν-二曱基甲醯胺中，室溫下攪拌30分鐘後加入2-氯_卜嗎啉-4-基-乙酮（44 mg’ 0.27 mmol) ’攪拌30分鐘後反應完畢。在反應液中加入100 mL飽和氯化鈉溶液淬滅反應，水相用乙酸乙酯萃取 (100 raLx3) ’合併的有機相依次藉由水（100 mLx3)洗滌， 307 94389 201016683 飽和氯化鈉溶液洗滌，無水硫酸鈉脫水，過濾’減壓下濃端’得到的殘留物藉由韓管㈣析法進-梦分泰] 得到標題產物2-(3-{4-[3-氯-4-(3-象-爷氣參）一 183(5〇〜喹唑啉-6-基卜》比咯-1-基）嗎啉一4一赛一 ^ ®g，黃色固體），產率：38. 9%。 53 (s ’ 7 T6 MS m/z (ESI) ： 573[M+1] !H NMR (400 MHz, CD30D-d〇： <5 9. 69 (s » lH)， *Αχ• 183 [3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]_[6_(1Η_β比咯_3_yl)-啥°坐-4-yl]-amine 42 (1 〇〇mg '0. 225 mmol) and sodium hydride (27 mg '0.675 mmol) dissolved in 10 mL of hydrazine, hydrazine-dimercaptocarbamide, stirred at room temperature for 30 minutes, then added 2-chloro-morpholine 4--4-Ethyl Ketone (44 mg '0.27 mmol) 'The reaction was completed after stirring for 30 minutes. The reaction mixture was quenched by adding 100 mL of saturated sodium chloride solution, and the aqueous phase was extracted with ethyl acetate (100 raLx3). The combined organic phases were washed sequentially with water (100 mL×3), 307 94389 201016683 saturated sodium chloride solution Washing, dehydration with anhydrous sodium sulfate, filtration of the residue obtained under the 'concentrated end under reduced pressure' by the Han tube (four) analysis method into the dream - the title product 2-(3-{4-[3-chloro-4- (3-icon-Yangqi ginseng)-183 (5〇~quinazolin-6-yl b)pyr-l-yl)morpholine-4-1 赛一^®g, yellow solid), yield: 38 . 9%. 53 (s ' 7 T6 MS m/z (ESI) : 573 [M+1] !H NMR (400 MHz, CD30D-d〇: <5 9. 69 (s » lH), *

Cd，J=2Hz, 1H)，7.70(d，J = 8.4Hz lH)，— /e lH) 鳴 ’ 66 (s， 7· 32 (m，3H)，7. 19 (m, 1H)，6. 94 (s，lH)，b. 45 (br 5.27 (s，2H)，4.06 (m’ 2H)，3.58 〇n，4I°’ · 1H) (5 8.50 (s，1H)，8.03 (d，j=8.8Hz，^)(^ 2H)， 4H) 6^· 實施例184 {4 -「3 -氣-4-(3 -氟-节氣基）-事料二111-°比洛-2-甲酸（2-甲確酿某：-&基敵藤〇4'°Cd, J=2Hz, 1H), 7.70 (d, J = 8.4Hz lH), — /e lH) 鸣 ' 66 (s, 7· 32 (m, 3H), 7. 19 (m, 1H), 6 94 (s,lH),b. 45 (br 5.27 (s,2H),4.06 (m' 2H),3.58 〇n,4I°' · 1H) (5 8.50 (s,1H),8.03 (d, j=8.8Hz,^)(^ 2H), 4H) 6^· Example 184 {4 - "3-Gas-4-(3-fluoro-gas-based)-those two 111-°Bilo-2 - Formic acid (2-A is indeed brewed: -& base enemy vine 4'°

184N184N

308 201016683308 201016683

2’ 2, 2-三氯吼咯_2_基）_甲酮第一步 ^x^C23*8 ^ 5 345 100 ®L Ζ,ΗΨ =::斗緩慢滴加到氯乙醯氣⑷“…一 ❹中’滴加過程中有熱量放出，用冰⑽ 反應液在室溫下麟h5小時後，用也 ='::=80，_(30g’217mmol)_4 ^ 滴加70畢後有機相經由無水硫酸納脫水 .減[下浴掉溶劑，殘留物用正己烧溶解，三氣-卜（1H-吡咯-2-A)田*π 10, 5 -體），產率：75.6%。…甲嗣184a(55.4g，灰白色固第二步 _ 2’ 2’ 2-二氯-1-(4-碘-iH_吡咯_2_基）一甲酮，2,2 一氣 1 (ijj-n 比洛 _2_ 基）_ 甲酮 ΐ8“（32 1 ^⑸酿^溶於⑽乩重蒸的二氯甲院中’授摔下滴加氣化硤（25 g，153.8随〇1)的8〇乩二氯甲烧溶液，滴加完畢後，反應液在室溫下麟2小時後，加入1〇〇虹1〇% 石厌酸鉀>谷液淬滅反應，分液，有機相依次用1〇〇此！ N亞硫酸納溶液# 100 mL水和飽和氣化納溶液洗條，無水硫酸鈉脫水，過濾，減壓下濃縮’得到粗品2,2,2_三氯 94389 309 201016683 白色固體）產物碘_1H一吡咯-2~基）-甲酮 184b (50. 78g，不經分離直接進行下一步反應。第三步 4-碘-1H-吡咯-2-甲酸甲醋將粗品2,2’2-三氯一卜(4_碘，藝⑽.78g)溶於25〇mL 基）〜甲輒 :叫，咖_40句醇溶^:加加完^ 至派下攪拌1小時反應完畢。將反應液在減留物用f基第三丁趟和水分液，有機相依: /辰縮侍到粗品4-碘-1H-吡咯-2-曱酸甲酯184ΰ (29. 435g ’灰白色固體）’產物不經分離直接進行下一反應。 y 第四步 1-(甲本-4-石黃酿基比嘻-2-曱酸甲醋將粗品4-碘-1H-吡咯-2-甲酸甲酯184c (29. 4g)溶於 _ 180 mL二氯甲烷中’攪拌下依次加入三乙胺（26 g，258 mmo 1)、4-一甲胺基〇比〇定（1.43g，11.7 mmol )和對甲基苯續醯氣（24. 6 g ’ 129 mmol)，混合液在室溫下攪拌過夜。在反應液中加入1N鹽酸溶液淬滅反應，有機相依次經由飽和碳_酸氫納溶液、飽和氣化納溶液洗蘇，無水硫酸鈉脫水，過濾，減壓下濃縮，得到的殘留物用矽膠管柱層析法分離純化（正己烷和乙酸乙酯=4 : 1)，得到1-(曱苯-4-磺醯基） -1H-吡咯-2-曱酸曱酯184d(22. 87g，白色固體）。 310 94389 201016683 MS m/z (ESI) ： 405[M+1] 第五步 4-(4, 4, 5, 5-四曱基- [1，3, 2]二氧雜硼雜戊環-2-基） -1_(曱苯-4-確酿基）-1 H_η比D各-2-曱酸甲醋將1-(甲苯-4-確醢基）-1Η-。比嘻-2-曱酸甲酯I84d (4. 05 g，10 mmol)、雙聯頻那醇硼酸酯（3· 43 g，13 mmol )、二氯[1，Γ-二茂鐵碌酸]把（746 mg，1 mmol)和醋酸針（3 g ’ 30 mmol)溶於30 mL N，N-二甲基甲醯胺中，於氣氣氛下’加入1 mL重蒸的二氣曱烷中，將反應液加熱至8(rc，攪拌18小時後反應完畢。將反應液在減壓下濃縮，得到的殘質用***溶解，過濾，除去不溶物，有機相依次經由i N 鹽酸溶液、水和飽和氯化鈉溶液洗滌，無水硫酸鈉脫水， •過濾，減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化（正己烷：乙酸乙酯=1〇 : n，得到4-(4 4, 5,5-四曱基-[1，3,2]二氧雜硼雜戊環一2_基）一1_(曱苯_4_ 磺醯基）-1Η-吡咯一2一甲酸甲酯184e(3 〇3g，白色固體）， ❹產率·· 74. 7%。 MS m/z (ESI) : 406[M+1] 第六步 4 {4 氣4-(3-氟-苄氧基苯胺基卜喹唑啉刊_基} 1 (曱笨基-4~曱石黃醢基比π各-2-曱酸甲酿 I、將“4,4’5,5-四甲基-[1，3,2]二氧雜；雜戊環_2_ 土 -1-(曱苯-4-磺醯基）_1H—吡咯_2 一曱酸甲酯i84e(2. 91 S’ 7.1 _1)和[3_氣_4_(3_n氧基）_苯基]峨“奎 94389 311 201016683 唾琳-4-基）-胺 lg(3· 53 g，7· 1 mmol)溶於 30 mL N，N-二曱基曱醯胺中，攪拌下加入肆（三苯基膦）鈀（〇. 82 g，〇· 71 mmol)和碳酸鉀（2.59 g，Π· 75 mmol)，加入 10 mL水，有白色不溶物析出’加熱反應液至6〇°c，24小時後反應完畢。反應液中加入1〇〇 mL水和1〇〇 mL乙酸乙酯，分液，有機相依次用水洗滌’飽和氯化鈉溶液洗滌，無水硫酸鈉脫水’過滤，減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化（正己烷：乙酸乙酯=1 : 1 )，得到 4-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-喹唑啉-6—基}一卜 ® (甲苯基-4-甲續醯基）-lH-«比略-2-甲酸甲酯184f (3. 45 g，黃色固體），產率：73. 9%。 MS m/z (ESI ) ： 657[M+1] 第七步 4-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-喹唾啉-6-基} _1Η_ο比哈_2_曱酸將4-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-啥唾嚇參-6 -基卜1-(曱苯基-4-曱確酸基）-1Η-β比嘻-2-曱酸曱g旨 184f (350 mg，0. 53 mmol)和一水合氫氧化鐘（224 mg，5. 3 mmo 1)加入到微波反應瓶中，加入4 mL甲醇和2 mL水，1 〇〇 °C下，微波反應2小時。將反應液倒入1 〇 mL水中，用1 n 鹽酸調整pH值=6，過濾，得到4-{4-[3-氯-4-(3-氟-节氧基）-苯胺基]-喹唑啉-6-*}-1Η-吡咯-2-曱酸I84g(248 mg，黃色固體），產率：95%。 MS m/z (ESI) : 489[M+1] 94389 312 201016683 JH NMR (400MHz, DMS0-d6): <5 12. 09 (s, 1H), 11.90 (s, 1H), 9.63 (s, 1H), 8.62 (s, 1H), 8.51 (s, 1H), 8.37 (s, 1H), 8. 04 (m, 2H), 7. 79 (in, 1H), 7. 60 (ra, 1H), 7. 49 (m, 1H), 7.32 (m, 4H), 7.19 (m, 1H), 5.27 (s, 2H) 第八步 4-{4-[ 3-氯-4-(3-氟-苄氧基）-苯胺基]-喹唑啉-6-基} -1H-W比嘻-2-甲酸（2-曱績醯基-乙基）-醢胺將4-{4-[3 -氣-4-(3 -氟-苄氧基）-苯胺基]-喧唾琳 -6-基}-111-0比口各-2-甲酸 184g(49 mg，0.1 mmol)和 2-曱 ®績醯基乙胺鹽酸鹽（103 mg’ 0.8 mmo 1)溶於8 mL無水二氯曱烷中，攪拌下加入N，N-二異丙基乙胺（1〇3 mg，0.8 mmol) 和雙（二侧氧基-3-嗜唾院基）次鱗酿氯（1 〇2 mg，〇. 4 mmo 1)’室溫下2小時反應完畢。將反應液在減壓下濃縮，得到的殘留物藉由碎膠管柱層析法進一步分離純化（二氯曱院.曱醇=8. 1)，得到標題產物4-{4-[3 -氣- 4- (3 -氣-苄氧基）-苯胺基]-喹吐啉-6-基}-111-"比咯-2-甲酸（2_甲確 ❹醯基-乙基）-醯胺184(21 mg，黃色固體），產率：4%。 MS m/z (ESI) ： 595[M+1] NMR (400 MHz, CD30D-c/6):5 11.86 (s, 1H) 9 74 (s 1H), 8.65 (s, 1H), 8.53 (s, 1H), 8.37 (s, 1H) g 〇4 (m，2 H )，7. 7 6 (m，2 H )，7. 6 0 ( m，1H)，7. 4 9 ( m，i jj ) 7 3 2 (m，4H)，7. 19 (m，1H)，5· 27 (s，2H), 3. 68 (t，J=6 8Hz 2H)，3.38 (t，J = 6.8Hz，2H)，3.06 (s，3H) 實施例185 94389 313 201016683 -6-基卜吡咯-1-甚、。& ^ 啉-4_l：：LgJ：2一醇2' 2, 2-Trichloropyrrole_2_yl)-methanone first step ^x^C23*8 ^ 5 345 100 ®L Ζ,ΗΨ =:: bucket slowly added to the chloroacetam (4) ...in the middle of the 'drip process, there is heat release, use ice (10) reaction solution at room temperature for 5 hours, then use ==::=80, _(30g'217mmol)_4 ^ The phase was dehydrated by anhydrous sodium sulfate. [The solvent was removed from the bath, and the residue was dissolved in n-hexane, tris-b (1H-pyrrole-2-A) field *π 10,5-body), yield: 75.6%. ... formazan 184a (55.4g, off-white solid second step _ 2' 2' 2-dichloro-1-(4-iodo-iH_pyrrole_2-yl)-methanone, 2,2 one gas 1 (ijj- n 毕洛_2_基)_ ketone oxime 8" (32 1 ^ (5) brewing ^ dissolved in (10) 乩 re-steamed dichlorohydrazine in the hospital's drop of gasification 硖 (25 g, 153.8 with 〇 1) 8 〇乩 Dichloromethane solution, after the addition is completed, the reaction solution is incubated at room temperature for 2 hours, then added 1 〇〇 rainbow 1%% potassium analate > gluten solution quenching reaction, liquid separation, organic dependence Use 1 〇〇 this! N sulphite solution # 100 mL water and saturated gasification solution solution, dehydrated with anhydrous sodium sulfate, filtered, concentrated under reduced pressure Product 2,2,2_trichloro 94389 309 201016683 white solid) product iodine_1H-pyrrole-2~yl)-methanone 184b (50. 78 g, the next reaction is carried out without isolation. The third step 4-iodine -1H-pyrrole-2-carboxylic acid methyl vinegar The crude product 2,2'2-trichloro-b (4_iodine, art (10).78g) is dissolved in 25〇mL base)~甲辄:叫,咖_40句醇Dissolve ^: Add the addition ^ until the reaction is stirred for 1 hour. The reaction solution was treated with f-based tributylhydrazine and a water solution in the residue, and the organic phase was added to the crude 4-iodo-1H-pyrrole-2-carbamic acid methyl ester 184 (29. 435 g 'gray white solid) 'The product was directly subjected to the next reaction without isolation. y The fourth step 1-(Aben-4-Dellow-branched than 嘻-2-decanoic acid methyl vinegar to dissolve the crude 4-iodo-1H-pyrrole-2-carboxylic acid methyl ester 184c (29. 4g) in _ 180 Triethylamine (26 g, 258 mmo 1), 4-methylamino hydrazine (1.43 g, 11.7 mmol) and p-methylbenzene oxime (24. 6 g '129 mmol), the mixture was stirred at room temperature overnight. The reaction was quenched by adding 1N hydrochloric acid solution to the reaction mixture, and the organic phase was successively washed with saturated sodium hydrogencarbonate solution and saturated sodium carbonate solution. The sodium was dehydrated, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane and ethyl acetate = 4:1) to give 1-(phenylbenzene-4-sulfonyl)- 1H-pyrrole-2-decanoate 184d (22.87g, white solid). 310 94389 201016683 MS m/z (ESI): 405[M+1] Step 5 4-(4, 4, 5, 5 -tetradecyl-[1,3,2]dioxaborolan-2-yl)-1-(indolyl-4-anthracene)-1 H_η ratio D each -2-carboxylic acid methyl vinegar 1-(Toluene-4-dedecyl)-1Η-. Compared with methyl 嘻-2-decanoate I84d (4. 05 g, 10 mmol), bis-pinacol borate (3·43 g, 13 Mm (ol), dichloro[1, fluorene-ferrocene] (746 mg, 1 mmol) and acetic acid needle (3 g '30 mmol) dissolved in 30 mL of N,N-dimethylformamide After adding 1 mL of the re-distilled dioxane under a gas atmosphere, the reaction mixture was heated to 8 (rc, and the reaction was completed after stirring for 18 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in diethyl ether. Filtration, removal of insolubles, organic phase washed sequentially with i N hydrochloric acid solution, water and saturated sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue obtained was further purified by hydrazine column chromatography. Separation and purification (n-hexane:ethyl acetate = 1 〇: n to give 4-(4 4,5,5-tetradecyl-[1,3,2]dioxaborolan-2-yl) Methyl methoxide 184e (3 〇 3g, white solid), ❹ yield·· 74. M+1] Step 6 4 {4 Gas 4-(3-Fluoro-benzyloxyanilinoquinazoline journal _ yl} 1 (曱笨基-4~ 曱石黄醢基比π各-2-曱酸I brewed I, will be "4,4'5,5-tetramethyl-[1,3,2] dioxa; heteropentane-2_ soil-1-(indolyl-4-sulfonyl) )_1H-pyrrole_2 methyl decanoate i84e (2. 91 S' 7.1 _1) and [3_gas_4_(3_noxy)_phenyl] 峨 "Quie 94389 311 201016683 Salina-4-yl) -Amine lg (3·53 g, 7.1 mmol) is dissolved in 30 mL of N,N-didecylguanamine, and ruthenium (triphenylphosphine)palladium (〇. 82 g, 〇·71) is added with stirring. Methyl) and potassium carbonate (2.59 g, Π·75 mmol), 10 mL of water was added, and white insolubles were precipitated. 'The reaction mixture was heated to 6 ° C. After 24 hours, the reaction was completed. 1 mL of water and 1 mL of ethyl acetate were added to the reaction mixture, and the organic phase was washed with water, washed with saturated sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Further separation and purification by hydrazine column chromatography (n-hexane:ethyl acetate = 1 : 1) gave 4-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino] -quinazoline-6-yl}ib® (tolyl-4-methylindoleyl)-lH-«bidi-2-methylcarboxylate 184f (3. 45 g, yellow solid), yield: 73 . 9%. MS m/z (ESI): 657 [M+1] Step 7 4-{4-[3-chloro-4-(3-fluoro-benzyloxy)-anilinyl]-quinoxalin-6-yl } _1Η_ο比哈_2_曱酸 4-{4-[3-chloro-4-(3-fluoro-benzyloxy)-anilino]-啥啥吓 -6-6-kib 1-(indene benzene曱-4-曱 acid group)-1Η-β is added to 嘻-2-曱曱旨 184f (350 mg, 0. Into a microwave reaction flask, 4 mL of methanol and 2 mL of water were added, and the reaction was carried out for 2 hours at 1 °C under microwave. Pour the reaction solution into 1 mL of water, adjust the pH to 6 with 1 n hydrochloric acid, and filter to give 4-{4-[3-chloro-4-(3-fluoro-p-oxy)-anilino]-quin Oxazoline-6-*}-1Η-pyrrole-2-furic acid I84g (248 mg, yellow solid), yield: 95%. MS m/z (ESI): 489 [M+1] 94389 312 201016683 JH NMR (400MHz, DMS0-d6): <5 12. 09 (s, 1H), 11.90 (s, 1H), 9.63 (s, 1H), 8.62 (s, 1H), 8.51 (s, 1H), 8.37 (s, 1H), 8. 04 (m, 2H), 7. 79 (in, 1H), 7. 60 (ra, 1H) , 7. 49 (m, 1H), 7.32 (m, 4H), 7.19 (m, 1H), 5.27 (s, 2H) Step 8 4-{4-[ 3-chloro-4-(3-fluoro- Benzyloxy)-anilino]-quinazolin-6-yl}-1H-W than hydrazine-2-carboxylic acid (2-fluorenyl-ethyl)-decylamine 4-{4-[3 - Gas-4-(3-fluoro-benzyloxy)-anilino]-indolyl-6-yl}-111-0 specific -2-carboxylic acid 184 g (49 mg, 0.1 mmol) and 2-indole® Dimethylaminoamine hydrochloride (103 mg ' 0.8 mmo 1) was dissolved in 8 mL of anhydrous dichloromethane, and N,N-diisopropylethylamine (1 〇 3 mg, 0.8 mmol) was added with stirring. The bis (two-sided oxy-3-saliva) secondary squamous chlorine (1 〇 2 mg, 〇. 4 mmo 1) was completed at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified and purified by EtOAc EtOAc EtOAc EtOAc - 4-(3- gas-benzyloxy)-anilino]-quinoxaline-6-yl}-111-"bibromo-2-carboxylic acid (2-methyl-decyl-ethyl)-oxime Amine 184 (21 mg, yellow solid), yield: 4%. MS m/z (ESI): 595 [M+1] NMR (400 MHz, CD30D-c/6): 5 11.86 (s, 1H) 9 74 (s 1H), 8.65 (s, 1H), 8.53 (s , 1H), 8.37 (s, 1H) g 〇4 (m, 2 H ), 7. 7 6 (m, 2 H ), 7. 6 0 ( m, 1H), 7. 4 9 ( m, i jj 7 3 2 (m, 4H), 7. 19 (m, 1H), 5 · 27 (s, 2H), 3. 68 (t, J = 6 8Hz 2H), 3.38 (t, J = 6.8Hz, 2H), 3.06 (s, 3H) Example 185 94389 313 201016683 -6-Kippyrrole-1-V. & ^ porphyrin-4_l::LgJ: 2-alcohol

185185

〇aF〇aF

第一步 (S)-[3-氣-4-(3~氟〜苄氣篡、 -1H- Q 乳基）-本基]~[6-U-環氧乙基曱基 1H-吡咯-3-基）~喹唑啉_4_基]_胺First step (S)-[3-Ga-4-(3~Fluoro-benzyl hydrazine, -1H-Q milyl)-benyl]~[6-U-epoxyethyl decyl 1H-pyrrole- 3-yl)~quinazoline_4_yl]-amine

在lOOmL祐形瓶中，將[3_氯一 4_(3务节氧基苯基] -[6-UHH3-基）—㈣琳+基卜胺42 (459呢，丄〇34 nnnoU溶於5ffii^N’N_二甲基f酿胺中，冰浴冷卻至代，加入氫化鈉（96 mg，2.4 _〇1)，攪拌3〇分鐘後，室温下加入（R)-2-氣甲基環氧乙烷（148 mg，h6咖〇1)，1小時後反應完畢。將反應液倒入100 mL冰水中，用乙酸乙酯（1〇〇 mLx3)萃取，合併的有機相依次經由水（1〇〇mLx3)洗滌，飽和氣化鈉溶液（100 rnL)洗滌，無水硫酸鈉脫水，過濾，減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離 314 94389 201016683 純化（梯度沖提：二氯甲烷：甲醇= 15〇 : 1，l〇〇 : υ，得到 (S)-[3-氣-4-(3-氟-苄氧基）-苯基]_[6_(1_環氧乙基甲基 -1H-吡咯-3-基）-喹唑啉-4-基;I-胺185a(24〇 mg，黃色固體），產率：70%。 MS m/z (ESI) ： 501[M+1] 】HNMR(400 MHz，DMSO-M): d n.100(s，1H)，8 319 (s’ 1H)，7.902 (s，1H)，7.846 (s，1H)，7.539 (s，1H ), 7.480 (s, 1H), 7.323 (m, 2H), 7. 251 (s, 1H), 7.115 (s, 2H), 7.020 (s, 1H), 6.838 (s, 1H), 6.497 (s, 1H), 5.209 (s, 2H), 4.492 (d, /=12. 8Hz, 1H), 4. 118(m, 1H), 3.189 (s, 1H), 2.837 (s, 1H), 2.651 (s, 1H) 第二步 .(s)-1_(3-{4-[3-氣-4-(3-氟-苄氧基）—苯胺基喹唑啉 -6-基}-°比洛-1-基）-3-嗎琳-4-基-丙-2-醇在100mL茄形瓶中，將（S)一[3_氣_4_(3一氟_苄氧基）一笨基]-[6-(1-環氧乙基曱基-1JJ-吼嘻-3-基）-喧唾琳_4_ ❹基]-胺 185a(240 mg’ 0. 48 mmol)和嗎啉（69 mg, 0. 793 ramol) 溶於10 mL無水曱醇中，加熱回流過夜。將反應液在減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化（梯度沖提：二氣甲烷：甲醇=60 : 1，50 : 1，40 : 1)，得到本標題產物（SM-(3-{4-[3-氯-4-(3-氟-苄氧基）一苯胺基]-噎嗤琳-6-基卜吡咯+基）_3_嗎啉_4_基_丙_2_醇 185(170 mg ’ 黃色固體），產率：60.3%。 MS m/z (ESI) · 588[M+1] 94389 315 201016683 !H NMR (400 MHz, CD30D-d〇: (5 9. 70 (s, 1H), 8.54 (s, 1H), 8.50 (s, 1H), 8.05 (s, 1H), 8.02 (s, 1H), 7.76 (dd, J = 8. 8Hz 2. 4Hz, 1H), 7.70 (d, J = 8. 8Hz, 1H), 7.49 (m, 1H), 7.42(s, 1H), 7. 32 (m, 3H), 7. 19 (t, J = 8. 4Hz, 1H), 6.88(s,lH), 6.66(s, 1H), 5. 27 (s, 2H), 4. 06 (dd, J = 13.6Hz 3.6Hz, 1H), 3.96 (m, 1H), 3.87 (m, 1H), 3.61 (in, 4H), 2. 42 (m, 4H), 2. 28 (m, 2H) 實施例186 (R)-l-(3-{4-「3 -氯- 4- (3 -氟-爷氧基）-笨胺基1-嗜°坐嚇 ® -6-基卜吡咯-卜基）-3-嗎啉-4-基-丙-2-醇In a 100 mL flask, [3_chloro-4-(3)-hydroxyphenyl]-[6-UHH3-yl)-(tetra)lin+pyramine 42 (459, 丄〇34 nnnoU dissolved in 5ffii ^N'N_Dimethylf-brown amine, cooled to the next in ice bath, add sodium hydride (96 mg, 2.4 _〇1), stir for 3 minutes, then add (R)-2-methylmethyl at room temperature Ethylene oxide (148 mg, h6 curry 1), the reaction was completed after 1 hour. The reaction solution was poured into 100 mL of ice water and extracted with ethyl acetate (1 mL mL 3). 1 〇〇mLx3) Wash, wash with saturated sodium carbonate solution (100 rnL), dehydrate with anhydrous sodium sulfate, filter and concentrate under reduced pressure. The residue obtained is further separated by hydrazine column chromatography. 314 94389 201016683 Purification (gradient Extraction: dichloromethane: methanol = 15 〇: 1, l 〇〇: υ, (S)-[3- gas-4-(3-fluoro-benzyloxy)-phenyl]_[6_(1 _Epoxyethylmethyl-1H-pyrrol-3-yl)-quinazolin-4-yl; I-amine 185a (24 mg, yellow solid), yield: 70%. MS m/z (ESI) ) : 501[M+1] 】HNMR (400 MHz, DMSO-M): d n.100 (s, 1H), 8 319 (s' 1H), 7.902 (s, 1H), 7.846 ( s,1H), 7.539 (s,1H), 7.480 (s, 1H), 7.323 (m, 2H), 7. 251 (s, 1H), 7.115 (s, 2H), 7.020 (s, 1H), 6.838 (s, 1H), 6.497 (s, 1H), 5.209 (s, 2H), 4.492 (d, /=12. 8Hz, 1H), 4. 118(m, 1H), 3.189 (s, 1H), 2.837 (s, 1H), 2.651 (s, 1H) Step 2. (s)-1_(3-{4-[3-Gas-4-(3-fluoro-benzyloxy)-anilinoquinazoline- 6-yl}-°Pilo-1-yl)-3-morphin-4-yl-propan-2-ol in a 100 mL eggplant-shaped flask, (S)-[3_gas_4_(3-fluoro _Benzyloxy)-styl]-[6-(1-epoxyethylmercapto-1JJ-indol-3-yl)-喧Salina_4_ fluorenyl]-amine 185a (240 mg' 0. 48 mmol) and morpholine (69 mg, 0. 793 ramol) were dissolved in 10 mL of anhydrous decyl alcohol and heated to reflux overnight. The reaction mixture was concentrated under reduced pressure and the residue obtained was further purified by silica gel column chromatography. Separation and purification (gradient elution: di-methane: methanol = 60: 1, 50: 1, 40: 1) gave the title product (SM-(3-{4-[3-chloro-4-(3-fluoro) -benzyloxy)monophenylamino]-indolyl-6-ylpyrrole+yl)_3_morpholine_4_yl-propan-2-ol 185 (170 mg 'yellow solid), yield: 60.3% . MS m/z (ESI) · 588 [M+1] 94389 315 201016683 !H NMR (400 MHz, CD30D-d〇: (5 9. 70 (s, 1H), 8.54 (s, 1H), 8.50 (s , 1H), 8.05 (s, 1H), 8.02 (s, 1H), 7.76 (dd, J = 8. 8Hz 2. 4Hz, 1H), 7.70 (d, J = 8. 8Hz, 1H), 7.49 (m , 1H), 7.42(s, 1H), 7. 32 (m, 3H), 7. 19 (t, J = 8. 4Hz, 1H), 6.88(s,lH), 6.66(s, 1H), 5 . 27 (s, 2H), 4. 06 (dd, J = 13.6Hz 3.6Hz, 1H), 3.96 (m, 1H), 3.87 (m, 1H), 3.61 (in, 4H), 2. 42 (m , 4H), 2. 28 (m, 2H) Example 186 (R)-l-(3-{4-"3-Chloro-4-(3-fluoro-yloxy)- phenylamino 1- °坐惊® -6-kibpyrrole-buki)-3-morpholin-4-yl-propan-2-ol

186 第一步 (R)-[3 -氣-4-(3 -氟-节氧基）-苯基]-[6-（1-環氧乙基曱基 -1H-吡咯-3-基）-喹唑啉-4-基]-胺在100 mL茄形瓶中，將[3-氯-4-(3-氟-苄氧基）-苯基] 316 94389 201016683 -[6-( 1H-吡咯-3-基）-喹唑啉-4-基]-胺 42 (561 mg，1. 264 mmol)溶於5 mL的N，N-二曱基曱酿胺中，冰浴冷卻至〇。匚，加入氫化鈉（112 mg，2. 8 mmol)，攪拌30分鐘後，室溫下加入（S)-2-氯曱基環氧乙烷（uo mg，2. 054 mmol)，1小時後反應完畢。將反應液倒入100mL冰水中，用乙酸乙酯 (100 mLx3)萃取，合併的有機相依次經由水洗滌，飽和氯化鈉溶液洗滌，無水硫酸納脫水，過濾，減壓下濃縮，得到的殘留物藉由石夕膠管柱層析法進一步分離純化（梯度沖提：二氣甲烷：曱醇= 150:1，1〇〇:1)，得到（r)_[ 3-氯一 4-(3- 氟-苄氧基）-苯基]-[6-(1-環氧乙基甲基-1Η_Π比咯_3_基）_ 喹唑啉-4-基]-胺186a (317 mg，黃色固體），產率：50. 2%。 MS ra/z (ESI) ： 501[M+1] !H NMR (400 MHz , MS0-d6): 5 11.100 (s, 1H), 8.319 (s, 1H), 7. 902 (s, 1H), 7. 846 (s, 1H), 7. 539 (s, 1H ), 7.480 (s, 1H), 7.323 (m, 2H), 7. 251 (s, 1H), 7.115 (s, 2H), 7.020 (s, 1H), 6.838 (s, 1H), 6.497 (s, 1H), Q 5. 209 (s, 2H), 4. 492 (d, J=12. 8Hz, 1H), 4. 118 (m, 1H), 3.189 (s, 1H), 2.837 (s, 1H), 2.651 (s, 1H) 第二步 (R)-1-(3-{4-[3-氣-4-(3-氟-苄氧基）-苯胺基]-喹唑啉 -6-基}-°比11 各-1-基）-3-嗎琳-4-基-丙-2-醇在100 niL力S形瓶中’將（R)-[3 -氯-4-(3 -氟-节氧基）-苯基]-[6-（1-環氧乙基曱基- iH-吡咯-3-基）-喹唑啉-4-基]-胺 186a (315 mg’ 0.702 mmol)和嗎琳（87 mg，1 mmol) 317 94389 201016683 ，加熱回流過夜。將反應液在減壓186 First step (R)-[3-Galy-4-(3-fluoro-oxy)-phenyl]-[6-(1-epoxyethylmercapto-1H-pyrrol-3-yl) -quinazolin-4-yl]-amine in a 100 mL eggplant-shaped flask, [3-chloro-4-(3-fluoro-benzyloxy)-phenyl] 316 94389 201016683 -[6-( 1H- Pyrrol-3-yl)-quinazolin-4-yl]-amine 42 (561 mg, 1. 264 mmol) was dissolved in 5 mL of N,N-didecylamine amine and cooled to hydr.匚, adding sodium hydride (112 mg, 2. 8 mmol), stirring for 30 minutes, then adding (S)-2-chloroindenyl oxirane (uo mg, 2.054 mmol) at room temperature, 1 hour later The reaction is completed. The reaction solution was poured into 100 mL of ice water and extracted with ethyl acetate (100 mL×3). The combined organic phases were washed with water, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The material was further separated and purified by Shixi rubber column chromatography (gradient elution: di-methane: decyl alcohol = 150:1, 1 〇〇:1) to obtain (r)_[3-chloro-4-(3) - fluoro-benzyloxy)-phenyl]-[6-(1-epoxyethylmethyl-1Η_Π比咯_3_yl)_quinazolin-4-yl]-amine 186a (317 mg, yellow 2%。 Yield: 50.2%. MS ra/z (ESI): 501 [M+1] "H NMR (400 MHz, MS0-d6): 5 11.100 (s, 1H), 8.319 (s, 1H), 7. 902 (s, 1H), 7. 846 (s, 1H), 7. 539 (s, 1H), 7.480 (s, 1H), 7.323 (m, 2H), 7. 251 (s, 1H), 7.115 (s, 2H), 7.020 ( s, 1H), 6.838 (s, 1H), 6.497 (s, 1H), Q 5. 209 (s, 2H), 4. 492 (d, J=12. 8Hz, 1H), 4. 118 (m, 1H), 3.189 (s, 1H), 2.837 (s, 1H), 2.651 (s, 1H) The second step (R)-1-(3-{4-[3-gas-4-(3-fluoro- Benzyloxy)-anilino]-quinazoline-6-yl}-° ratio 11-1-yl)-3-morphin-4-yl-propan-2-ol in a 100 niL force S-shaped bottle '(R)-[3-Chloro-4-(3-fluoro-oxy)-phenyl]-[6-(1-epoxyethylindolyl-iH-pyrrol-3-yl)-quin Oxazolin-4-yl]-amine 186a (315 mg '0.702 mmol) and morphine (87 mg, 1 mmol) 317 94389 201016683, heated to reflux overnight. The reaction solution is under reduced pressure

層柯法進一步分離純 ’ 4 0 : 1)，得到本標苄氧基）-苯胺基]一邊 -丙-2-醇 186(271 溶於10 niL無水甲醇中下濃縮，化（梯度沖提：二氣甲燒：曱醇: 題產物 00-1-(3-{4-[3-氣-4-(3-氟Further separation of pure '40:1) to obtain the standard benzyloxy)-anilino]-propan-2-ol 186 (271 dissolved in 10 niL of anhydrous methanol, concentrated (gradient elution: Dioxane: sterol: Product 00-1-(3-{4-[3-Ga-4-(3-Fluorine)

mg，黃色固體），產率：65. 8%。 MS m/z (ESI) ： 588[M+1] 4 NMR (400 MHz，CD30D-dU9.7〇 (s，iH)，8·54 (s， 1H)，8.50 (s，1H)’ 8.05 (s，1H)，δ 〇2 (s，’iH)，7 76 (dd，J=8. 8Hz 2. 4Hz, 1H), 7.70 (d，J=8 8Hz’，1H)，7·49 (m，1H)，7.42 (s’ 1H)，7.32 (m，3H)，7 (t j=8 4Hz， 1H)，6.88(S’1H)，6.66(s，1H)，5.27(s，2H)，’4 〇6(dd， J=13.6Hz 3.6Hz，1H)’ 3. 96 (m，iH)，3 87 (m，1H)，3 6i (m，4 H)，2. 4 2 (m，4 H )，2. 2 8 (ni，2 ) 實施例187Mg, yellow solid), yield: 65.8%. MS m/z (ESI): 588 [M+1] 4 NMR (400 MHz, CD30D-dU 9.7 s (s, iH), 8.54 (s, 1H), 8.50 (s, 1H) ' 8.05 ( s,1H),δ 〇2 (s,'iH),7 76 (dd,J=8. 8Hz 2. 4Hz, 1H), 7.70 (d,J=8 8Hz',1H),7·49 (m , 1H), 7.42 (s' 1H), 7.32 (m, 3H), 7 (tj = 8 4Hz, 1H), 6.88 (S'1H), 6.66 (s, 1H), 5.27 (s, 2H), ' 4 〇6(dd, J=13.6Hz 3.6Hz, 1H)' 3. 96 (m, iH), 3 87 (m, 1H), 3 6i (m, 4 H), 2. 4 2 (m, 4 H), 2. 2 8 (ni, 2 ) Example 187

〇 -吡咯-1-基）-3-(2,5二^^咯-1-^：1丙_2一醇〇-pyrrol-1-yl)-3-(2,5二^^or-1-^:1 propan-2-ol

943^9 187 318 201016683 第一步 [3-氣-4-(3-氟-苄氧基）-苯基]一[6_(卜環氧乙基曱基— 吼B各-3-基）-啥唾琳-4-基]-胺在100mL茄形瓶中，將[3-氣_4_(3_氟-苄氧基卜笨基] -[6-(1Η-吡咯-3-基）-喹唑啉-4-基]-胺 42(890 mg，2 nmol) 溶於10 mL N，N-二曱基曱醯胺中，冰浴冷卻至，加入氫化鈉（176 mg，4. 4 mmol)，攪拌3〇分鐘後，室溫下加入 2氯曱基環乳乙烧（300 mg, 3.2 mmol)，1小時後反應完 ❹畢。將反應液倒入1〇〇 mL冰水中，用乙酸乙酯u〇〇 mLx3) 萃取，合併的有機相依次經由水〇〇 mLx3)洗滌，飽和氯化鈉溶液（100 mLx3)洗滌，無水硫酸鈉脫水，過濾，減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純 .化，得到[3-氯-4-(3-氟-苄氧基）_苯基]_[6_(卜環氧乙基甲基-1H-吡咯-3-基）-喹唑啉-4-基]一胺187a (7〇〇 mg，黃色固體），產率：70%。 MS m/z (ESI) ： 501[M+1] Q ]H NMR (400 MHz, DMS0-d6)： 5ll.l〇〇(s, iH), 8. 319 (s, 1H)，7.902 (s，1H), 7.846 (s，1H)，7.539 (s, 1H), 7.480943^9 187 318 201016683 First step [3- gas-4-(3-fluoro-benzyloxy)-phenyl]-[6_(epoxyethyl fluorenyl- 吼B-3-yl)- In a 100 mL eggplant-shaped flask, [3-gas_4_(3_fluoro-benzyloxybuphenyl)-[6-(1Η-pyrrol-3-yl)- Quinazolin-4-yl]-amine 42 (890 mg, 2 nmol) was dissolved in 10 mL of N,N-didecylamine, cooled to ice, and sodium hydride (176 mg, 4. 4 mmol After stirring for 3 minutes, 2 chloropyridyl lactoacetate (300 mg, 3.2 mmol) was added at room temperature, and after 1 hour, the reaction was completed. The reaction solution was poured into 1 mL of ice water with acetic acid. Ethyl acetate u〇〇mLx3) was extracted, and the combined organic phases were washed successively with water 〇〇mLx3), washed with saturated sodium chloride solution (100 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Further separation and purification by hydrazine column chromatography gave [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6_(b-epoxyethylmethyl-1H-pyrrole- 3-yl)-quinazolin-4-yl]monoamine 187a (7 mg, yellow solid), yield: 70%. MS m/z (ESI): 501 [M+1] Q]H NMR (400 MHz, DMS0-d6): 5ll.l (s, iH), 8. 319 (s, 1H), 7.902 (s , 1H), 7.846 (s, 1H), 7.539 (s, 1H), 7.480

Cs, 1H), 7.323 (m, 2H), 7. 251 (s, 1H), 7.115 (s, 2H), 7-〇20(s, 1H), 6.838 (s, 1H), 6.497 (s, 1H), 5. 209 (s, 2H)，4.492 (d，>12. 8Hz，1H), 4.118 (m, 1H)，3.189 (s， 1H)，2. 837 (s，1H)，2· 651 (s，1H) 第二步 1-(3-{4-[3-氣-4-(3-氟-苄氧基）-笨胺基卜喹唑啉_6_基） 319 94389 201016683 -咐哈-1-基）-3-(2, 5-二氫吡咯]—基）_丙_2一酵在1〇0 ‘茄形瓶中，將[3-氯-4-(3-氟-苄氧基）一苯基]-[6-(1-環氧乙基曱基-1H-吡咯一基）_喹唑啉一基]-胺 187a(1.8g，3.67mra〇l)和 2,5_ 二氫 _1H_ 吡咯（41 5 mg，0.6 mmol)溶於1〇 mL無水甲醇中，加熱回流3小時後，反應完畢。將反應液在減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化，得到本標題產物卜（3_丨4_ [3-氯~4-(3-氟-苄氧基）-苯胺基]_喹唑啉_6_基卜1|比咯_1_ 基）-3-(2,5-二氫吡咯-1-基）-丙_2一醇187〇1〇呢，黃色固體），產率：64. 4%。 MS m/z (ESI) ： 570[M+1] NMR (400 MHz, CD30D-c/〇： <5 9. 704 (s, 1H), 8.544 .(s, 1H), 8.496 (s, 1H), 8.035 (t, J = 6. 4Hz, 2H), 7 753 (m, 1H), 7.704 (d, J=13.6Hz, 1H), 7.475 (t, J = 7Hz, 1H) 7.421 (s, 1H) , 7.322 (m, 3H), 7.205 (d, J = 9. 6Hz, 1H), 6. 880 (s, 1H), 6. 656 (s, 1H), 5. 813 (s, 2H), 5. 274 (s, 〇 2H), 4.997 (d, J=4. 4Hz, 1H), 4.08 (d, J = 13.6Hz, 1H) 3.884 (m, 2H), 3.492 (m, 4H), 2.557 (d, J=5. 6Hz, 2H) 實施例188 氧-4丑3.·-氟-免_氧基）-苯胺基1-喹唑啉^_早二p比略基）-3_p底咬-1-基-丙-2 -醇Cs, 1H), 7.323 (m, 2H), 7. 251 (s, 1H), 7.115 (s, 2H), 7-〇20(s, 1H), 6.838 (s, 1H), 6.497 (s, 1H ), 5. 209 (s, 2H), 4.492 (d, > 12.8 Hz, 1H), 4.118 (m, 1H), 3.189 (s, 1H), 2. 837 (s, 1H), 2· 651 (s, 1H) The second step 1-(3-{4-[3- gas-4-(3-fluoro-benzyloxy)-phenylaminoquinazoline-6-yl) 319 94389 201016683 -咐[Halk-1-yl)-3-(2,5-dihydropyrrole]-yl)-propan-2-one in a 1〇0' eggplant-shaped flask, [3-chloro-4-(3-fluoro- Benzyloxy)-phenyl]-[6-(1-epoxyethylmercapto-1H-pyrrole-yl)-quinazoline-yl]-amine 187a (1.8 g, 3.67 mra〇l) and 2, 5_ Dihydro-1H_pyrrole (41 5 mg, 0.6 mmol) was dissolved in 1 mL of anhydrous methanol and heated to reflux for 3 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was further purified and purified by hexane column chromatography to give the title product (3_丨4_[3-chloro~4-(3-fluoro-benzyloxy) )-anilino]-quinazoline_6_ylbu-1|pyrolo-1_yl)-3-(2,5-dihydropyrrol-1-yl)-propan-2-ol 187〇1〇, 4%。 Yield: 64. 4%. MS m/z (ESI): 570 [M+1] NMR (400 MHz, CD30D-c/〇: <5 9. 704 (s, 1H), 8.544. (s, 1H), 8.496 (s, 1H ), 8.035 (t, J = 6. 4Hz, 2H), 7 753 (m, 1H), 7.704 (d, J=13.6Hz, 1H), 7.475 (t, J = 7Hz, 1H) 7.421 (s, 1H ), 7.322 (m, 3H), 7.205 (d, J = 9. 6Hz, 1H), 6. 880 (s, 1H), 6. 656 (s, 1H), 5. 813 (s, 2H), 5 274 (s, 〇2H), 4.997 (d, J=4. 4Hz, 1H), 4.08 (d, J = 13.6Hz, 1H) 3.884 (m, 2H), 3.492 (m, 4H), 2.557 (d , J=5. 6Hz, 2H) Example 188 Oxygen-4 ugly 3.·-Fluoro-free oxy)-anilino-1-quinazoline^_Early dip-rhoki)-3_p bottom bite-1 -yl-propan-2-ol

94389 320 20101668394389 320 201016683

在100 mL茄形瓶中，將[3-氣-4~(3-^_苄氧基）-苯基]-[6-(1-環氧乙基曱基-1H-*»比略-3-基）-啥唑琳-4-基]-胺 187a(150 mg’ 0.3 mmol)和 D底咬（51. 1 mg，0. 6 mmol) 溶於10 mL無水甲醇中，加熱回流3小時反應完畢。將反 ❹應液在減壓下濃縮’得到的殘留物藉由；e夕膠管柱層析法進一步分離純化’得到本標題產物1-(3-{4-[3-•氯-4-(3-氣- 苄氧基）-苯胺基]-喹唑啉-6-基卜吡咯-卜基彡-^派咬一卜基-丙-2-醇188(135 mg ’黃色固體），產率：77%。 -MS m/z (ESI) ： 586[M+1] .JH NMR (400 MHz, CD30D-de) ： d 9. 700 (s, 1H), 8. 536 (s 1H), 8.496 (s, 1H), 8.037 (m, 2H), 7.765 (in, 1H), 7.703 (d, J = 8.8Hz, 1H), 7. 484 (s, 1H), 7.413 (s, 1H) O 7.322 (m, 3H), 7.193 (t, J = 8. 6 Hz, 1H) , 6.870 (s! 1H)，6.653 (s，1H)’ 5.273 (s，2H)，4.863 (s，1H): 4.042 (m，1H)，3.930 (s，1H)，3.852 (m，1H)，2.377 (s 4H)，2.208 (m，2H)，1.522 (m，4H)，1.393 (m，2H) 實施例189 _°_比p各-1-基）-3-二乙胺I二丙—2-酵 94389 321 189 201016683In a 100 mL eggplant-shaped flask, [3-gas-4~(3-^-benzyloxy)-phenyl]-[6-(1-epoxyethyl decyl-1H-*) is slightly more than - 3-yl)-oxazolidin-4-yl]-amine 187a (150 mg '0.3 mmol) and D bottom bit (51. 1 mg, 0.6 mmol) dissolved in 10 mL anhydrous methanol and heated to reflux for 3 h The reaction is completed. The ruthenium solution was concentrated under reduced pressure to obtain a residue obtained by further separation and purification by e-chelating column chromatography to obtain the title product 1-(3-{4-[3-•chloro-4-( 3-oxo-benzyloxy)-anilino]-quinazoline-6-ylpyrrole-bryzine-^-pyrazine-propan-2-ol 188 (135 mg 'yellow solid), yield : 77%. -MS m/z (ESI): 586[M+1] .JH NMR (400 MHz, CD30D-de): d 9. 700 (s, 1H), 8. 536 (s 1H), 8.496 (s, 1H), 8.037 (m, 2H), 7.765 (in, 1H), 7.703 (d, J = 8.8Hz, 1H), 7. 484 (s, 1H), 7.413 (s, 1H) O 7.322 ( m, 3H), 7.193 (t, J = 8. 6 Hz, 1H), 6.870 (s! 1H), 6.653 (s, 1H)' 5.273 (s, 2H), 4.863 (s, 1H): 4.042 (m , 1H), 3.930 (s, 1H), 3.852 (m, 1H), 2.377 (s 4H), 2.208 (m, 2H), 1.522 (m, 4H), 1.393 (m, 2H) Example 189 _°_ Ratio p-1-yl)-3-diethylamine I dipropene 2-alternate 94389 321 189 201016683

在100 mL茄形瓶中，將[3 —氯_4_(3_氟一苄氧基）_苯 ❺基]-[6-(1-%氧乙基曱基_1Η_吡咯_3_基）_喹唑啉_4_基]一胺 187a(150 mg ’ 〇. 3 ®mol)和乙二胺（43. 9 mg，0· 6 mmol) 洛於10 mL無水曱醇中，加熱回流3小時反應完畢。將反應液在減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進 ' 一步分離純化，得到本標題產物1-(3-{4-[3-氯-4-(3〜氟〜专氧基）-本胺基]-喧唾琳-6-基} -η比洛-卜基）_3_二乙鞍義 -丙-2-醇189 (120 mg，黃色固體），產率：7〇%。土 MS m/z (ESI) ： 574[M+1] ❹1H NMR (400 MHz’ CD30D-A): δ 9. 699 (s，1H)，8. 539 ( 1H), 8.495 (s, 1H), 8.034 (t, J=6. 4Hz, 2H), 7.752 1H)，7.703 (d, J = 8.8Hz, 1H), 7.485 (d, j=7 2Hz llj) 7. 4 2 6 (s, 1H), 7. 3 2 3 (m，3 H )，7. 19 4 ( s，1H ) 6 8 8 4 ( 1H), 6. 656 (s, 1H), 5. 274 (s, 2H), 4. 078 (d, J=12Hz 1H), 3. 829 (s, 2H), 2. 509 (br, 4H), 2 351 (s 2H) 0.968 (t, J = 7.2Hz, 6H) ’ 實施例190 94389 322 201016683[3-Chloro_4_(3_fluoro-benzyloxy)-phenylindoleyl]-[6-(1-% oxyethylindolyl-1Η_pyrrole_3_yl) in a 100 mL eggplant-shaped flask _ quinazoline _4_ yl] monoamine 187a (150 mg '〇. 3 ® mol) and ethylenediamine (43. 9 mg, 0.6 mmol) in 10 mL of anhydrous decyl alcohol, heated to reflux 3 The hour reaction is completed. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by EtOAc EtOAc EtOAc. ~Special oxy)-amino-amino]- 喧琳 -6 -6-yl}-n-bi-bu-ki)_3_diethyl-sodium-propan-2-ol 189 (120 mg, yellow solid), yield : 7〇%. Soil MS m/z (ESI): 574 [M+1] ❹1H NMR (400 MHz 'CD30D-A): δ 9. 699 (s, 1H), 8. 539 (1H), 8.495 (s, 1H), 8.034 (t, J=6. 4Hz, 2H), 7.752 1H), 7.703 (d, J = 8.8Hz, 1H), 7.485 (d, j=7 2Hz llj) 7. 4 2 6 (s, 1H), 7. 3 2 3 (m,3 H ), 7. 19 4 ( s,1H ) 6 8 8 4 ( 1H), 6. 656 (s, 1H), 5. 274 (s, 2H), 4. 078 (d, J=12Hz 1H), 3. 829 (s, 2H), 2. 509 (br, 4H), 2 351 (s 2H) 0.968 (t, J = 7.2Hz, 6H) ' Example 190 94389 322 201016683

第一步 • l-[1，4’]二哌啶基-1’-基-2-氯-乙酮將4-哌啶基哌啶（9〇 mg，〇· 54賴〇1)溶於1〇乩四氫。夫喃中’♦加入二乙胺（1〇8 mg，L 〇7丽〇1)，冰浴冷卻至〇 °c，攪拌下加入氯乙醯氯（67 mg，〇 59 mm〇1)，攪拌加 ©分鐘後反應完畢。在反應液中加入1〇mL水，減壓下蒸去四氫呋喃，得到的溶液用乙酸乙酯萃取（5〇mLx3)，合併的有機相依次經由水洗滌，無水硫酸鈉脫水，過濾，減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化 (一氯甲烷.甲醇=1 : 1)，得到化合物卜U，4’ ]二哌啶基 -1’-基-2-氯-乙酮（65 mg，黃色油狀液體），產率·· 50%。 MS m/z (ESI) : 245[M+1] 第二步 323 94389 201016683 1 [1’4 ] 一喻 D定基-1’-基-2-(3-{4-[3-氣-4-(3-氟-苄氧基苯胺基]''喹唑啉-6-基}-吡咯-1-基）-乙酮將化合物[3-氣-4-(3-氟-苄氧基）-苯基]-[6_(iH-η比哈一3_基啥嗤啉-4-基]-胺42(80 mg，0.18 mm〇i)和氫化納（21· 6 mg，〇· 54 mmol)溶於 10 mL N，N-二甲基甲酿胺中’室溫下授拌30分鐘後加入1-[1，4’]二娘π定基基-2-氯-乙嗣190a (53 mg，0. 216 mmol)，授拌30分鐘後反應完畢。在反應液中加入100 mL飽和氯化納溶液淬滅反應，水相用乙酸乙酯萃取（100 mLx3)，合併的有機相依次 ®經由水（100 mLx3)洗滌，飽和氯化鈉溶液洗滌（1〇〇 mLx3)，無水硫酸鋼脫水，過滤，減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化’得到標題產物1-[1，4’ ] .二哌啶基-1’ -基-2-(3-{4_[3-氯-4-(3-氟-苄氡基）-苯胺基]-喧唾淋-6-基卜β比哈-1-基）-乙_ 190(40 mg，黃色固體），產率：34%。 MS m/z (ESI) ： 653[M+1] q ]H NMR (400 MHz, CD30D-d〇: (5 9. 71 (s, 1H) , 8.54 (s, 1H) =8.50 (s, 1H), =8.02 (m, 2H) , 7.77 (dd, J=2.4Hz, 1H) , 7.71 (d , J=8.4Hz , 1H) , 7.48 (m, 1H) , 7.31 (m，4H)，7. 19 (m，1H)’ 6. 82 (s，1H)，6. 66 (s，1H)， 5. 27 (s, 2H) , 4. 95 (d, J=4Hz, 2H), 4. 14 (d, J = 12. 8Hz , 1H), 3.83 (d, J = 13.6Hz, 1H), 3.15 (m, 3H), 2.84 (t, J = 10.8Hz, 1H) , 2.24 (br, 1H), 1.86(t, J = 12.4Hz, 2H), 1.68 (br，4H)，1.39 (m，3H) 324 94389 201016683 實施例191 基-111-°比洛-3-某）-啥吔被—4-某]一脸First step • l-[1,4']Dipiperidinyl-1'-yl-2-chloro-ethanone dissolves 4-piperidylpiperidine (9〇mg, 〇·54赖〇1) 1 〇乩 tetrahydrogen. ♦ 中 ' ♦ Add diethylamine (1 〇 8 mg, L 〇 7 〇 1), cool to 〇 °c in an ice bath, add chloroacetic acid chloride (67 mg, 〇 59 mm 〇 1) with stirring, stir After adding % minutes, the reaction is completed. 1 〇 mL of water was added to the reaction mixture, and tetrahydrofuran was evaporated under reduced pressure. The obtained solution was extracted with ethyl acetate (5 〇mL×3), and the combined organic phases were washed with water, dried over anhydrous sodium sulfate, filtered and evaporated. After concentration, the residue obtained was further separated and purified by hydrazine column chromatography (chloromethane.methanol = 1 : 1) to give the compound U,4']dipiperidinyl-1'-yl-2-chloro - Ethyl ketone (65 mg, yellow oily liquid), yield · 50%. MS m/z (ESI): 245 [M+1] The second step 323 94389 201016683 1 [1'4 ] A D-based-1'-yl-2-(3-{4-[3-gas-4 -(3-Fluoro-benzyloxyanilino)''quinazolin-6-yl}-pyrrol-1-yl)-ethanone compound [3- gas-4-(3-fluoro-benzyloxy) -phenyl]-[6_(iH-η比哈3-3-ylporphyrin-4-yl]-amine 42 (80 mg, 0.18 mm〇i) and sodium hydride (21.6 mg, 〇·54 mmol) Dissolved in 10 mL of N,N-dimethylamine, and allowed to mix for 30 minutes at room temperature, then add 1-[1,4'] succinyl π-decyl-2-chloro-acetamidine 190a (53 mg 0. 216 mmol), the reaction was completed after 30 minutes of mixing. The reaction was quenched by adding 100 mL of saturated sodium chloride solution, and the aqueous phase was extracted with ethyl acetate (100 mL×3). Washing with water (100 mL×3), washing with saturated sodium chloride solution (1〇〇mLx3), dehydration of anhydrous sulfuric acid steel, filtration, concentration under reduced pressure, and the residue obtained is further separated and purified by gel column chromatography. The product 1-[1,4' ].dipiperidinyl-1'-yl-2-(3-{4_[3-chloro-4-(3-fluoro-benzylindolyl)-anilino]-pyrene淋-6-基卜β比哈-1-yl)-B_190 (40 mg , yellow solid), Yield: 34%. MS m/z (ESI): 653[M+1] q]H NMR (400 MHz, CD30D-d〇: (5 9. 71 (s, 1H) , 8.54 (s, 1H) = 8.50 (s, 1H), = 8.02 (m, 2H), 7.77 (dd, J = 2.4 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.48 (m, 1H) ), 7.31 (m, 4H), 7. 19 (m, 1H)' 6. 82 (s, 1H), 6. 66 (s, 1H), 5. 27 (s, 2H) , 4. 95 (d , J=4Hz, 2H), 4. 14 (d, J = 12. 8Hz , 1H), 3.83 (d, J = 13.6Hz, 1H), 3.15 (m, 3H), 2.84 (t, J = 10.8Hz , 1H), 2.24 (br, 1H), 1.86 (t, J = 12.4Hz, 2H), 1.68 (br, 4H), 1.39 (m, 3H) 324 94389 201016683 Example 191 Base - 111-°Bilo - 3-some)-啥吔被——4-某]一脸

^.OH H02CT’、NH2^.OH H02CT', NH2

191 第一步191 first step

191c191c

191d 191丨191d 191丨

42 191 ❾第一步 2-苄胺基-3-經基丙酸在100 mL的三口燒瓶中，加入L_絲胺酸（4. 1 mmol)和2M氫氧化鈉溶液（2〇 mL，h 6g)，攪拌下滴加苯甲醛（8. 3 g，80 ramol.)，授拌】5分鐘後，冰浴冷卻至5^本加入硼氫隸（G. 86g ’ 22麵1)，室溫下㈣2小時反完畢。用***洗滌反應液，在冰浴冷卻τ，用漠鹽酸調 ρΗ-6. 5，抽;慮，得到2—节胺基_3_經基丙酸⑼a(4· 〇5忌， 94389 325 201016683 白色固體），產率：51.9%。 MS m/z (ESI) : 196[M+1] 第二步 4-苄基_5-侧氧基-嗎啉一3一甲酸將2-爷胺基-3-羥基丙酸i91a(7 2 g，36 mm〇i)溶於50 mL四氫呋喃中’冰浴冷卻至，加入5°c的飽和碳酸納溶液（15. 4 g’ 11 ram〇i )，滴加完畢後加入氣乙醯氯（7. 2 mL，60romol) ’攪拌3小時反應完畢。反應液中加入1〇mL 50%氫氧化鈉溶液，攪拌1〇分鐘後用正己烷萃取（2〇 mLx 2)，水相冷卻至οχ：，用濃鹽酸調整pH<2，在_2〇t>c下放置 6小時，過濾，得到的固體真空乾燥，得到4_苄基_卜侧氧基嗎琳-3-甲酸I91b(6.6 g，白色固體），產率：76%。 MS m/z (ESI) ： 234[M-1] 第三步 (R)_(4-苄基嗎琳-3-基）-甲醇將4-苄基-5-側氧基-嗎啉-3-曱酸191b(1〇g，42 5 〇 mmol)溶於l〇mL曱苯中，氬氣氛下，冰浴冷卻下加入紅鋁溶液（65 mL，0.21 mol) ’反應液在室溫下攪拌24小時反應完畢。在反應液中滴加乙醇，直至無氣泡生成，用2M 氫氧化鈉溶液調整PH=12，加入10〇虬水，分液，水相用 2N鹽酸溶液洗滌三次，用2M氫氧化鈉溶液調整pH__8，用乙酸乙醋萃取（50 mLx3) ’合併的有機相用無水硫酸鈉脫水’過遽’減壓下濃縮’得到⑻替节基嗎啉_3—基)_甲醇191c(8 g’黃色油狀液體），產率：86於 94389 326 201016683 MS m/z (ESI) : 208[M+1] 第四步 (S)_(4 ^基嗎嚇·_3_基）-曱確酸曱酉旨將（R)-(4-苄基嗎啉-3-基）-曱醇191c(1〇35 g，5 mmol)和口比啶（790 mg ’ 10 mmol)溶於20 mL二氯甲院中，在冰浴條件下，冷卻至〇°c，逐漸滴加罕磺醯氣（859 mg， 7.5 mmol)，室溫下攪拌過夜。在反應液中加入5〇社水，減壓下旋乾溶劑，用乙酸乙酯萃取（5〇 mLx3)，合併的有機相依次經由飽和氯化鈉溶液洗滌，無水硫酸鈉脫水，過濾， ®減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化（正己烧.乙酸乙酯=1 : 1)，得到（S)_(4-苄基嗎琳 -3-基）-曱磺酸曱酯191d (1. 4 g，無色油狀液體），產率： 98%。 MS m/z (ESI) ： 286[M+1] 第五步 (S)-(嗎啦-3-基）-曱續酸甲酯 Q 將（SM4-苄基嗎啉-3-基）-曱磺酸曱酯l91d (285 mg，1 mmol)溶於15 mL乙醇中’加入50 mg Pd/C，抽真空’充入虱氣’室溫下攪拌2小時反應完畢。過滤反應液’ 濾液在減壓下濃縮，得到（S)-(嗎啉-3-基）-曱磺酸曱酯 191e(185 mg，淡黃色油狀液體），產率：95%。 MS m/z (ESI) ： 195[M+1] 第六步 (R)-[3-氯- 4- (3 -鼠-卞氧基）-苯基]-[6_(1-嗎琳-3_基甲 327 94389 201016683 基-1H-吡咯-3~基）-喹唑啉_4_基]一胺將[3-氯~4-(3-氟-苄氧基）-苯基]-[6-(111-°比咯-3-基啥峻淋基]-胺42 (222 mg，0. 5 mmol)和氫化鈉（60 mg ’ 2· 5mmo1)溶於6 mL N，N-二甲基曱醯胺中，攪拌30分鐘德加入(嗎啉-3-基）-曱磺酸甲酯191e (116 mg，0. 6 mmol)’反應液在室溫下攪拌2小時反應完畢。在反應液中加入15 mL水和20 mL乙酸乙酯，水相用乙酸乙酯萃取（20 mLx3) ’合併的有機相依次經由飽和氯化鈉溶液洗滌，無水硫酸納脫水’過濾，減壓下濃縮，得到的殘留物藉由矽膠 ®管挺層析法進一步分離純化（梯度沖提：二氯甲烷：曱醇 =40 : 1 ’ 20 : 1)，得到（r)-[3-氯-4_(3-氟-苄氧基）-苯基；| -[6-(卜嗎啉-3-基甲基-111-吡咯-3-基）-喹唑啉-4-基]-胺 .191(105 mg，淡黃色固體），產率：89%。 MS in/z (ESI) ： 544[M+1] !H NMR (400 MHz, CD30D-d〇： (5 9. 69 (s, 1H), 8.54 (s, 1H), 8.50 (s, 1H), 8.04 (m, 2H), 7.75 (m, 2H), 7.47 q (m, 1H), 7. 40 (m, 1H), 7. 30 (m, 3H), 7. 19 (m, 1H), 6.88 (s, 1H), 6.68 (s, 1H), 5.27 (s, 2H), 3.88 (m, 2H), 3.62 (m, 2H), 3.36(m, 1H), 3. 13 (m, 1H), 3.03 (m, 1H), 2.80 (m, 1H), 2.72 (ηι, 1H) 實施例192 2-(3-{4-[3 -氮-4-(3 -氟-苄氡基）-笨胺基1-啥唾嘴-fi—其} -p比洛-1-基）-1-(4-甲基_p底1^~1-基）-乙酮 94389 328 20101668342 191 ❾Step 1 2-Benzylamino-3-transpropionic acid In a 100 mL three-necked flask, add L-serine (4.1 mmol) and 2M sodium hydroxide solution (2 mL, h 6g), add benzaldehyde (8.3 g, 80 ramol.), stir, stir for 5 minutes, then cool to 5^ by adding ice to the boron hydride (G. 86g '22 face 1), room temperature The next (four) 2 hours reversed. The reaction solution was washed with diethyl ether, and the τ was cooled in an ice bath, and the mixture was adjusted to pH -6. 5 with a hydrochloric acid to give a 2-amino group _3_ cyanopropionic acid (9) a (4· 〇 5 bogey, 94389 325 201016683 White solid), Yield: 51.9%. MS m/z (ESI): 196 [M + 1] Step 2 4-benzyl-5-side-oxy-morpholine-3-carboxylic acid 2-arylamino-3-hydroxypropionic acid i91a (7 2 g, 36 mm〇i) dissolved in 50 mL of tetrahydrofuran. Cool down to ice bath, add 5 °c saturated sodium carbonate solution (15.4 g '11 ram〇i), add ethylene chlorinated chlorine after the addition. 7. 2 mL, 60romol) 'Stirring for 3 hours is complete. 1 〇mL 50% sodium hydroxide solution was added to the reaction solution, stirred for 1 hr, extracted with n-hexane (2 〇 mL x 2), and the aqueous phase was cooled to οχ: pH was adjusted with concentrated hydrochloric acid < 2, at _2 〇 t > The mixture was allowed to stand for 6 hours, and filtered, and the obtained solid was dried in vacuo to give 4- benzyl-di- oxy- s----------- MS m/z (ESI): 234 [M-1] (3) (V)-(4-benzyl-n-phenyl-3-yl)-methanol 4-benzyl-5-s-oxy-morpholine 3-decanoic acid 191b (1〇g, 42 5 〇mmol) was dissolved in 1〇mL of benzene. Under argon atmosphere, red aluminum solution (65 mL, 0.21 mol) was added under ice cooling. The reaction solution was at room temperature. The reaction was completed after stirring for 24 hours. Add ethanol to the reaction solution until no bubbles are formed. Adjust the pH to 12 with 2M sodium hydroxide solution, add 10 〇虬 water, separate the liquid, wash the aqueous phase three times with 2N hydrochloric acid solution, adjust pH__8 with 2M sodium hydroxide solution. Extracted with ethyl acetate (50 mL×3) 'The combined organic phases are dehydrated with anhydrous sodium sulfate'. The mixture is concentrated under reduced pressure to give (8) succinyl morpholine-3-yl)-methanol 191c (8 g' yellow oil Liquid), yield: 86 at 94389 326 201016683 MS m/z (ESI): 208 [M+1] The fourth step (S) _ (4 ^ 吗吓 _ _ 3 _ base) - 曱曱酉曱酉In order to dissolve (R)-(4-benzylmorpholin-3-yl)-nonanol 191c (1〇35 g, 5 mmol) and pyridine (790 mg '10 mmol) in 20 mL of dichloroform In an ice bath, it was cooled to 〇 ° C, and sulphur sulfonium (859 mg, 7.5 mmol) was gradually added dropwise, and stirred at room temperature overnight. 5 〇〇〇在在 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 The mixture was concentrated under reduced pressure, and the residue obtained was further purified and purified by hexane column chromatography (yield, ethyl acetate = 1 : 1) to give (S)-(4-benzyl- phenin-3-yl)- Ethyl sulfonate 191d (1.4 g, colorless oily liquid), Yield: 98%. MS m/z (ESI): 286 [M + 1] Step 5 (S)-(??-3-yl)- </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> (SM4-benzylmorpholin-3-yl)- Ethyl sulfonate l91d (285 mg, 1 mmol) was dissolved in 15 mL of ethanol 'Add 50 mg of Pd/C, vacuumed 'filled with helium' and stirred at room temperature for 2 hours. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give (S)-(morpholin-3-yl)- sulfonic acid decyl ester 191e (185 mg, pale yellow oily liquid), yield: 95%. MS m/z (ESI): 195 [M + 1] Step 6 (R)-[3-chloro-4-(3-money-decyloxy)-phenyl]-[6_(1-? 3_基甲327 94389 201016683 yl-1H-pyrrole-3~yl)-quinazoline-4-yl]monoamine [3-chloro~4-(3-fluoro-benzyloxy)-phenyl]- [6-(111-°pyr-3-ylindole]-amine 42 (222 mg, 0.5 mmol) and sodium hydride (60 mg '2.5 mmo1) dissolved in 6 mL N,N-II In the methyl decylamine, the reaction mixture was stirred for 30 minutes and the methyl (morpholine-3-yl)-sulfonic acid methyl ester 191e (116 mg, 0.6 mmol) was stirred at room temperature for 2 hours. 15 mL of water and 20 mL of ethyl acetate were added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (20 mL×3). The combined organic phases were washed sequentially with saturated sodium chloride solution, dried over anhydrous sodium sulfate and filtered. The residue obtained is further separated and purified by gelatin® tube chromatography (gradient elution: dichloromethane: methanol = 40: 1 '20: 1) to obtain (r)-[3-chloro-4_( 3-fluoro-benzyloxy)-phenyl;|-[6-(Bumorpholin-3-ylmethyl-111-pyrrol-3-yl)-quinazolin-4-yl]-amine.191( 105 mg, pale yellow solid), yield: 89%. MS in /z (ESI ) : 544[M+1] !H NMR (400 MHz, CD30D-d〇: (5 9. 69 (s, 1H), 8.54 (s, 1H), 8.50 (s, 1H), 8.04 (m, 2H) ), 7.75 (m, 2H), 7.47 q (m, 1H), 7. 40 (m, 1H), 7. 30 (m, 3H), 7. 19 (m, 1H), 6.88 (s, 1H) , 6.68 (s, 1H), 5.27 (s, 2H), 3.88 (m, 2H), 3.62 (m, 2H), 3.36(m, 1H), 3. 13 (m, 1H), 3.03 (m, 1H) ), 2.80 (m, 1H), 2.72 (ηι, 1H) Example 192 2-(3-{4-[3-Aza-4-(3-fluoro-benzylindolyl)- phenylamino 1-pyrene Mouth-fi-the}-p-l-l-yl)-1-(4-methyl-p-bottom 1^~1-yl)-ethanone 94389 328 201016683

2-氯-1-(4-甲基-哌啡-丨一基）一乙酮將卜曱基哌畊（2 g ’ 2〇 mm〇i)溶於6〇 mL四氫呋嘀在乾冰乙醇浴冷卻至-7〇t，授掉下逐漸滴加氣乙_ (2. 26 g，30 mmol)，滴加完畢在冰浴冷卻下攪拌分鐘後反應完畢。在反應液中加入2〇乩水，減壓下蒸去:氫〇呋喃，得到的溶液用二氯曱烷萃取（1〇〇，合併的= 機相依次經由水洗滌，無水硫酸鈉脫水，過濾，減壓下濃縮’得到的殘留物藉由矽膠管柱層析法進一步分離純化（二氯甲烷：甲醇=1 : 1)，得到2-氣-i-(4-曱基-哌畊-1-基）_ 乙酮192a (500 mg，黃色固體），產率：2〇%。 MS m/z (ESI) ： 1T7[M+1] 第二步 2-(3-{4-[3-氣-4-(3-氟-苄氧基）_苯胺基卜喹唑啉-6_基} 94389 329 201016683 -°比p各-1-基）-1-(4-甲基-旅畊-1-基）-乙酮將化合物[3-氯-4-(3-氟-苄氧基）-苯基]_ [ 6_( iH-o比咯-3-基）-喹唑啉-4-基]-胺 42(200 mg，0.45 mmol)和氫化鈉（54 mg ’ 1. 35 mmol)溶於10 mL N，N-二曱基甲酿胺中’室溫下搜拌30分鐘後加入2 -氣-1-(4-曱基-娘d井-1- 基）-乙酮192a (95 mg ’ 0. 54 mmol) ’反應液加熱至5〇°c， 2小時後反應完畢。在反應液中加入loo mL飽和氣化鈉溶液淬滅反應’水相用乙酸乙酯萃取（1〇〇 mLx3)，合併的有機相依次經由水（100 mLx3)洗滌，飽和氣化鈉溶液洗務 ❹（100 mLx3)，無水硫酸鈉脫水，過濾，減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化，得到標題產物2-(3-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-喹唑啉 -6-基}-吡咯-1-基）-1-(4-甲基-哌哄-1-基）-乙酮192(85 mg，黃色固體），產率：32. 3%。 MS m/z (ESI) ： 586[M+1] Ή NMR (400 MHz, CD30D-d〇： <5 9. 70 (s, 1H), 8.54 (s, ❹ 1H) 8.49 (s, 1H), 8.03 (d, J=8Hz, 2H), 7.76 (d, J=8.4Hz, 1H), 7.70 (d, J=8. 8Hz, 1H), 7.48 (m, 1H), 7.41 (s, 1H), 7.33 (m, 3H), 7.19 (t, J=8Hz, 1H), 6.88 (s, 1H), 6.65 (s, 1H), 5.27 (s, 2H), 4.97 (s, 2H), 3.49 (m, 4H), 2.36 (m, 2H), 2.29 Cm, 2H), 2.21 Cs, 3H) 實施例193 l-(3-{4-[3-氣-4-(3-氟-苄氣某）脸篡1-喹唑啉-β-其} 比洛-1-基）-3-(4 -甲基-喻叫-1-甚）-¾- 2-醇 330 94389 2010166832-Chloro-1-(4-methyl-piperidin-yl-yl)-ethanone diazepam (2 g '2〇mm〇i) dissolved in 6〇mL tetrahydrofuran in a dry ice ethanol bath To -7 〇t, gradually add gas _ (2. 26 g, 30 mmol), and the reaction is completed after stirring for an additional minute in an ice bath. 2 Torr of water was added to the reaction solution, and the hydrazine furan was distilled off under reduced pressure. The obtained solution was extracted with dichloromethane (1 〇〇, combined = machine phase washed sequentially with water, dried over anhydrous sodium sulfate, filtered The residue obtained by concentrating under reduced pressure was further separated and purified by methylene chloride column chromatography (dichloromethane:methanol = 1 : 1) to give 2- gas-i-(4-mercapto-piperidine-1 -yl) ketone 192a (500 mg, yellow solid), yield: 2%. MS m/z (ESI): 1T7[M+1] Step 2 2-(3-{4-[3- Gas-4-(3-fluoro-benzyloxy)-anilinoquinazoline-6-yl} 94389 329 201016683 -° ratio p-1-yl)-1-(4-methyl-bred tillage - 1-[1]-)-ethanone compound [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(iH-opyrol-3-yl)-quinazoline-4- Base]-amine 42 (200 mg, 0.45 mmol) and sodium hydride (54 mg ' 1.35 mmol) dissolved in 10 mL of N,N-dimercaptoamine. Add at room temperature for 30 minutes and add 2 - Gas-1-(4-indolyl-nivine d-1-yl)-ethanone 192a (95 mg '0.54 mmol) 'The reaction solution was heated to 5 ° C. After 2 hours the reaction was completed. Add loo mL saturated sodium vapor solution to the liquid to quench The reaction 'aqueous phase was extracted with ethyl acetate (1 〇〇 mL×3), the combined organic phases were washed successively with water (100 mL×3), saturated sodium carbonate solution (100 mL×3), dehydrated with anhydrous sodium sulfate, filtered, reduced Concentration under reduced pressure, the residue obtained was further purified by silica gel column chromatography to give the title product 2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino ]-quinazolin-6-yl}-pyrrol-1-yl)-1-(4-methyl-piperidin-1-yl)-ethanone 192 (85 mg, yellow solid), yield: 32. 3% MS m/z (ESI): 586 [M+1] NMR (400 MHz, CD30D-d〇: <5 9. 70 (s, 1H), 8.54 (s, ❹ 1H) 8.49 (s , 1H), 8.03 (d, J=8Hz, 2H), 7.76 (d, J=8.4Hz, 1H), 7.70 (d, J=8. 8Hz, 1H), 7.48 (m, 1H), 7.41 (s , 1H), 7.33 (m, 3H), 7.19 (t, J=8Hz, 1H), 6.88 (s, 1H), 6.65 (s, 1H), 5.27 (s, 2H), 4.97 (s, 2H), 3.49 (m, 4H), 2.36 (m, 2H), 2.29 Cm, 2H), 2.21 Cs, 3H) Example 193 l-(3-{4-[3- gas-4-(3-fluoro-benzyl) a) 篡1-quinazoline-β-其} Pilo-1-yl)-3-(4-methyl-Yu-yi-1-)-3⁄4- 2-alcohol 330 94389 201016683

ΗΝΧΪΗΝΧΪ

將[3-氣-4-(3-氟-节氧基）_苯基]_[6_(卜環氧乙基甲基-1Η-料+基）-啥唾琳_4_基]_胺 187a〇53mg，〇 3〇6 mmol)溶於15 mL曱醇中，攪拌下加入卜甲基哌畊（48呵， 0.48 mmol)，加熱回流7小時後反應完畢。反應液在減壓下濃縮’得到的殘留物藉由矽膠管柱層析法進一步分離純化（梯度沖提：二氣甲燒：曱醇=5〇 : 1，20: 1)，得到本標題產物1-(3-{4-[3-氣-4-(3-氟-苄氧基）-苯胺基]-喹唑啉-6-基}-吡咯-卜基）-3-(4-甲基-哌哄-1-基）-丙-2-醇 193(120 mg ’ 黃色固體），產率：65. 2%。 Q MS m/z (ESI) ： 601[M+1] JH NMR (400 MHz, CD30D-d〇: 5 9. 68 (s, 1H), 8.52 (s, 1H), 8.48(s, 1H), 8.02(m, 2H), 7.75 (d, J = 8. 8Hz, 1H), 7.69(d, J=8.8Hz, 1H), 7. 47 (q, J = 7. 2Hz, 1H), 7. 39 (s, 1H), 7. 31 (id, 3H), 7. 18 (t, J=8. 4Hz, 1H), 6. 85 (s, 1H), 6.64(s, 1H), 5.26(s, 2H), 4. 89 (s, 1H), 4.02 (m, 1H), 3.92 (m, 1H), 3.84 (in, 1H), 2.41 (dr, 4H), 2.33 (dr, 4H), 2.22 (m, 5H) 331 94389 201016683 實施例194 (R)-l~~(3-{4-「3 -氣-4-(3-氟-爷氣基）-笨胺基]-喧唾啦 -6-基卜吡咯-1-基）-3-「4-〔2-甲磺醯基-L胺基）-哌啶-1-某1-丙-2-酵[3-Gas-4-(3-fluoro-hydroxyl)-phenyl]-[6_(b-epoxyethylmethyl-1Η-material+yl)-啥啥琳_4_yl]-amine 187a 〇 53 mg, 〇 3 〇 6 mmol) was dissolved in 15 mL of decyl alcohol, and then added with methyl peptin (48 ̄, 0.48 mmol) under stirring, and the reaction was completed after heating under reflux for 7 hours. The reaction mixture was concentrated under reduced pressure. The obtained residue was further purified and purified by silica gel column chromatography (gradient elution: dioxin: decyl alcohol = 5 〇: 1, 20: 1) to give the title product. 1-(3-{4-[3-Gao-4-(3-fluoro-benzyloxy)-anilino]-quinazolin-6-yl}-pyrrole-bu)-3-(4-A 2%。 Benzyl-pyridin-1-yl)-propan-2-ol 193 (120 mg 'yellow solid), yield: 65.2%. Q MS m/z (ESI): 601 [M+1] JH NMR (400 MHz, CD30D-d: 5 9. 68 (s, 1H), 8.52 (s, 1H), 8.48 (s, 1H), 8.02(m, 2H), 7.75 (d, J = 8. 8Hz, 1H), 7.69(d, J=8.8Hz, 1H), 7. 47 (q, J = 7. 2Hz, 1H), 7. 39 (s, 1H), 7. 31 (id, 3H), 7. 18 (t, J=8. 4Hz, 1H), 6. 85 (s, 1H), 6.64(s, 1H), 5.26(s, 2H), 4. 89 (s, 1H), 4.02 (m, 1H), 3.92 (m, 1H), 3.84 (in, 1H), 2.41 (dr, 4H), 2.33 (dr, 4H), 2.22 (m , 5H) 331 94389 201016683 Example 194 (R)-l~~(3-{4-"3-gas-4-(3-fluoro-yenyl)-phenylamino]-喧啦 -6-6- Kebyrrol-1-yl)-3-"4-[2-methylsulfonyl-L-amino)-piperidine-1-one 1-prop-2-enzyme

第一步 ❹4-(2-曱確醯基-乙胺基）-略啶-1-曱酸第三丁酯將2-甲磺醯基乙胺鹽酸鹽（527 mg，3. 25 mmol)溶於重蒸的四氫呋喃溶液中，加入4 mL三乙胺，室溫下授拌1 小時後加入4-側氧基-旅啶-1-甲酸第三丁酯i94a(525 mg’ 2. 5 mmol) ’繼續攪拌1小時後加入三（乙醯氧基）硼氫化鈉（1· 96 g，15 mm〇l)，室溫下攪拌1小時後反應完畢。在反應液中加入30 mL水淬滅反應，減壓下蒸掉四氫味嚼，水相用乙酸乙酯萃取（5〇mLx3)，合併的有機相經由無水硫 94389 332 201016683 酸納脫水，過濾，減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化（正己烷：乙酸乙酯=1 :丨），得到 4-(2-甲磺醯基1-乙胺基）-哌啶―卜曱酸第三丁酯19扑 (567 mg ’類白色固體），產率·· 73. 9%。 MS m/z (ESI) ： 307[M+] 第二步 (2-甲磺醯基-乙基）-哌啶_4_基胺三氟乙酸鹽將4-(2-甲磺醯基1-乙胺基哌啶甲酸第三丁酯 194b(567 mg，1·85 ramol)溶於 15 mlj 二氯甲烷中，攪拌下濟加6 mL三氟乙酸，室溫下攪拌！小時，反應完畢。將反應液在減壓下濃縮，殘留物藉由矽膠管柱層析法分離純化（乙酸乙酯：曱醇=3 : 1)，得到（2-甲磺醯基-乙基）一哌啶，-4-基胺三氟乙酸鹽194c(835 mg’黃色固體），產率：91%。 MS m/z (ESI) ： 208[M+1] 第三步 (R)-l-(3-{4-[3-氣-4-(3-氟-苄氧基）-苯胺基]-喹唑啉 ❹-6-基}-吡咯-卜基）-3-[4-(2-甲磺醯基-乙胺基）-哌啶_1β 基]-丙-2-醇在100 mL茄形瓶中’將（R)-[3-氯-4-(3-氟-苄氧基）_ 本基]_[6_(1-壞氧乙基曱基-1Η-°比洛-3 -基喧嗤琳-4 -基] -胺186a(244 mg ’ 0· 5 mmol)溶於30 mL甲醇中，授拌下依次加入三乙胺（0. 5 mL，2· 5 mmol )和（2-甲續酿基-乙基）_ 〇底唆-4-基胺三氟乙酸鹽194c(432 mg，1 mmol )，混合液加熱回流反應過夜。將反應液在減壓下濃縮，得到的殘留 94389 201016683 物藉由矽膠管柱層析法進一步分離純化（二氯甲烷：曱醇 =8 : 1)，得到本標題產物（R)-；l-(3-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]奎0坐琳_6 -基}-D比p各_1_基）_3-[4-(2 -曱石黃醯基-乙胺基）-哌啶-卜基]-丙-2-醇194 (186 mg，黃色固體），產率：29%。 MS m/z (ESI) ： 707[M+] !H NMR (400 MHz, CD30D-d〇: 5 9. 72 (s, 1H), 8.55 (s, 1H), 8.50(s, 1H), 8.05(s, 1H), 8. 03 (d, J = 8. 8Hz, 1H), 7.77 (d, J= .8Hz, 1H), 7.71 (d, J = 8. 8Hz, 1H), 7.48 ® (t, J = 8. 8Hz, 1H), 7. 42 (s, 1H), 7. 31 (m, 3H), 7. 19 (t, J = 8.8Hz, 1H), 6.89(s, 1H), 6. 68 (s, 1H), 5. 27 (s, 2H), 4.06 (t, J = 12.8Hz, 1H), 3.94 (s, 1H), 3.85 (m, 1H), .3.08 (br, 9H), 2.57 (br, 1H), 2.40 (br, 5H), 1.18 (t, J = 7.2Hz, 4H) 實施例195 1-二乙胺基-3-（3-{4 -「1-（3-氟-节基）- 1H-P引峻-5-基胺基"I ❹-喧口坐琳-6-基口比嘻-1-基）-丙-2~醉First step ❹ 4-(2-曱醯 --ethylamino)-l-pyridine-1-carboxylic acid tert-butyl ester 2-methanesulfonylethylamine hydrochloride (527 mg, 3.25 mmol) Dissolve in a re-distilled tetrahydrofuran solution, add 4 mL of triethylamine, and mix for 1 hour at room temperature. Add 4-tert-oxy-bendidine-1-carboxylic acid tert-butyl ester i94a (525 mg' 2. 5 mmol After stirring for 1 hour, sodium tris(ethyloxy)borohydride (1·96 g, 15 mm·l) was added, and the reaction was completed after stirring at room temperature for 1 hour. The reaction mixture was quenched by the addition of 30 mL of water, and the tetrahydrogen was evaporated under reduced pressure. The aqueous phase was extracted with ethyl acetate (5 〇mL×3), and the combined organic phases were dehydrated with anhydrous sulfur 94389 332 201016683. Concentration under reduced pressure, the residue obtained was further purified by hexane column chromatography (hexane: ethyl acetate = 1 : hexane) to give 4-(2-methylsulfonyl 1-ethylamine) - piperidine-di-tert-butyl citrate 19 puff (567 mg 'white-like solid), yield 73.9%. MS m/z (ESI): 307 [M+]. Step 2 (2-Methanesulfonyl-ethyl)-piperidine-4-aminoamine trifluoroacetate 4-(2-methylsulfonyl 1- Ethylaminopiperidinecarboxylic acid tert-butyl ester 194b (567 mg, 1.85 ramol) was dissolved in 15 ml of dichloromethane, and 6 mL of trifluoroacetic acid was added thereto with stirring, and stirred at room temperature for an hour. The reaction mixture was concentrated under reduced pressure and the residue was purified and purified eluted eluted eluted eluted eluted eluted eluted eluted eluted 4-Hydrylamine trifluoroacetate 194c (835 mg 'yellow solid), yield: 91%. MS m/z (ESI): 208[M+1] Step 3 (R)-l-(3-{ 4-[3-Gas-4-(3-fluoro-benzyloxy)-anilino]-quinazolinin-6-yl}-pyrrole-bu)-3-[4-(2-methanesulfonate) -(E)-[3-chloro-4-(3-fluoro-benzyloxy)-benz in a 100 mL eggplant-shaped vial of ethyl-ethylamino)-piperidine-1β-yl]-propan-2-ol Base]_[6_(1-badoxyethylmercapto-1Η-°Bilo-3-ylindol-4-yl)-amine 186a (244 mg '0.5 mmol) dissolved in 30 mL of methanol Adding triethylamine (0.5 mL, 2.5 mmol) and (2-methyl-bromo-ethyl) _ 〇唆-4-ylamine three in sequence Fluorine acetate 194c (432 mg, 1 mmol), the mixture was heated and refluxed overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was obtained. Hydroxide = 8 : 1), the title product (R)-; l-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-anilino] quinine 0 sits _ 6-yl}-D ratio p__1_yl)_3-[4-(2-valve-xanthyl-ethylamino)-piperidine-buyl]-propan-2-ol 194 (186 mg, yellow solid ), Yield: 29%. MS m/z (ESI): 707 [M+] NMR (400 MHz, CD30D-d: 5 9. 72 (s, 1H), 8.55 (s, 1H), 8.50 (s, 1H), 8.05(s, 1H), 8. 03 (d, J = 8. 8Hz, 1H), 7.77 (d, J= .8Hz, 1H), 7.71 (d, J = 8. 8Hz, 1H), 7.48 ® (t, J = 8. 8Hz, 1H), 7. 42 (s, 1H), 7. 31 (m, 3H), 7. 19 (t, J = 8.8Hz, 1H), 6.89 (s, 1H), 6. 68 (s, 1H), 5. 27 (s, 2H), 4.06 (t, J = 12.8Hz, 1H), 3.94 (s, 1H), 3.85 (m, 1H), .3.08 (br, 9H), 2.57 (br, 1H), 2.40 (br, 5H), 1.18 (t, J = 7.2 Hz, 4H) Example 195 1-Diethylamino-3-(3-{4 - "1-(3-Fluoro-nodal)- 1H-P 引峻-5-ylamino" "I ❹-喧口坐6-port than hee l-yl) - propan -2 ~ drunk

334 94389 201016683 在100 mL茄形瓶中，加入2 mL二乙胺和2 mL曱醇，攪拌下加入[1-(3-氟-苄基）-1Η-吲唑-5-基]-[6-(1-環氧乙基甲基-1H-吡咯-3-基）-喹唑啉-4-基]-胺178a (150 mg ’ 0. 283 mmol)，將反應液加熱至50°C反應過夜。將反應液在減壓下濃縮’得到的殘留物藉由製備型薄層層析板進行分離純化，得到本標題產物1-二乙胺基-3-(3~{4-[1-(3-氟-苄基）-111-°引》坐-5-基胺基]坐琳- 6-基}-。比略 -1-基）-丙-2-醇195(92 mg，黃色固體），產率：56. 8%。 MS m/z (ESI) ： 564[M+1] !HNMR (400MHz, CD30D-d〇: (5 9.91 (s, 1H), 8.71 (s, 1H), 8.45 (s, 1H), 8.25 (s, 1H), 8.17 (s, 1H), 8.03 (d, ih, J=8.8Hz), 7.7 6(s, 2H), 7.70 (d, 1H, J=8.8Hz), 7.52 (s, 1H), 7.38(m, 1H), 7. 08 (m, 3H), 6. 93 (s, 1H), 6.74 (s, 1H), 5. 72(s, 2H), 4. 08 (m, 3H), 3. 18 (m, 4H), 3. 〇〇 (m, 2H), 1.22 (m, 6H) 實施例196 Φ 4-{4-「3-氣-4-(3-氟-苄1某、-苄眩臬1-喹°坐淋-6-某} -1H-吡咯e-2-甲酸Π. 1-二你丨fi其-六氤-1 基甲基）-醯胺334 94389 201016683 In a 100 mL eggplant-shaped flask, add 2 mL of diethylamine and 2 mL of decyl alcohol, and add [1-(3-fluoro-benzyl)-1 Η-oxazol-5-yl]-[6] with stirring. -(1-Epoxyethylmethyl-1H-pyrrol-3-yl)-quinazolin-4-yl]-amine 178a (150 mg '0. 283 mmol), the reaction was heated to 50 ° C overnight. The reaction mixture was concentrated under reduced pressure. The obtained residue was purified by preparative thin-layer chromatography to give the title product 1-diethylamino-3-(3~{4-[1-(3) -Fluoro-benzyl)-111-°Indole-5-ylamino]Chenlin-6-yl}-.pyridin-1-yl)-propan-2-ol 195 (92 mg, yellow solid) , yield: 56.8%. MS m/z (ESI): 564[M+1] !HNMR (400MHz, CD30D-d〇: (5 9.91 (s, 1H), 8.71 (s, 1H), 8.45 (s, 1H), 8.25 (s , 1H), 8.17 (s, 1H), 8.03 (d, ih, J=8.8Hz), 7.7 6(s, 2H), 7.70 (d, 1H, J=8.8Hz), 7.52 (s, 1H), 7.38(m, 1H), 7. 08 (m, 3H), 6. 93 (s, 1H), 6.74 (s, 1H), 5. 72(s, 2H), 4. 08 (m, 3H), 3. 18 (m, 4H), 3. 〇〇(m, 2H), 1.22 (m, 6H) Example 196 Φ 4-{4-"3-Gas-4-(3-fluoro-benzyl 1) -Benzyl sorghum 1-quino-sodium -6-some} -1H-pyrrole e-2-carboxylic acid oxime. 1-II you 丨fi--hexa-1-methyl-amine

335 94389 201016683335 94389 201016683

將4-{4-[3-氣-4-(3-氟-苄氧基）_苯胺基]_喹唑啉 -6-基}-111-吡咯-2-曱酸 184g(122 mg，〇.25 賴〇1)和 c_ (1，1-一側氧基-六氫一1 λ *6*-噻喃-4-基）-甲胺鹽酸鹽（75 mg，0· 375 mmol)溶於1〇 mL無水二氯甲烷中，攪拌下加入 0Ν，Ν-二異丙基乙胺（129 mg，1 mmol)和雙（二側氧基·3_^ 唑烷基）次磷醯氯（127 mg’ 0. 5 mmol)，室溫下反應2小時。將反應液在減壓下、濃縮，得到的殘留物藉由石夕膠管柱層析法進一步分離純化（梯度沖提：二氣甲烷：甲醇=5〇 :丨，3〇 : 1)，付到^示產物4-{4-[3-氯-4-(3 -氟-节氧基）_苯胺基]-喹唑啉-6-基}-111-吡咯e-2-甲酸（1，卜二側氧基_六氫-1 λ *6*-噻喃-4-基曱基）-醯胺196 (12 mg’黃色固體），產率：7. 6%。 Q MS m/z (ESI) ： 634[M+1] Ή NMR (400 MHz, CD30D-d6) ： <5 11. 93 (s, 1H), 9.68 (s 1H)，8.63 (s，1H)，8.48 (s，1H)，8.13 (d，J = 9.2Hz，1H)， 8.0 (s, 1H), 7.70 (m, 2H), 7.60 (s, 1H), 7.45 (m, 1H), 7. 28 (m, 4H), 7. 16 (m, 1H), 5. 25 (s, 2H), 3. 21 (ra, 2H), 3.10 (m，4H), 2.05 (m, 2H), 1.80 (m，1H) 1.68 (m, 2H) 實施例197 [3-氣-4-(3-氟-—苄氧基）.-苯基1-(6-{1-|~2-(4~甲其-命叫 94389 336 201016683 -1-基）-乙基]-1Η-°比口各-3-基}-喹峋4-{4-[3-Ga-4-(3-fluoro-benzyloxy)-anilino]-quinazolin-6-yl}-111-pyrrole-2-furic acid 184 g (122 mg, hydrazine) .25 lysine 1) and c_ (1,1-one oxy-hexahydro-1 λ *6*-thiopyran-4-yl)-methylamine hydrochloride (75 mg, 0·375 mmol) In 1 mL of anhydrous dichloromethane, 0 Ν, Ν-diisopropylethylamine (129 mg, 1 mmol) and bis(di- oxy- 3 oxazolidinyl)phosphonium chloride (127) were added with stirring. Mg' 0. 5 mmol), reacted at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was further separated and purified by chromatography on silica gel column chromatography (gradient elution: di-methane: methanol = 5 〇: 丨, 3 〇: 1), ^Products 4-{4-[3-chloro-4-(3-fluoro-oxy)-anilino]-quinazolin-6-yl}-111-pyrrole e-2-carboxylic acid (1, 6%。 The oxy-hexahydro-1 λ *6*-thiopyran-4-ylindenyl)-nonylamine 196 (12 mg 'yellow solid), yield: 7.6%. Q MS m/z (ESI): 634[M+1] NMR (400 MHz, CD30D-d6): <5 11. 93 (s, 1H), 9.68 (s 1H), 8.63 (s, 1H) , 8.48 (s, 1H), 8.13 (d, J = 9.2 Hz, 1H), 8.0 (s, 1H), 7.70 (m, 2H), 7.60 (s, 1H), 7.45 (m, 1H), 7. 28 (m, 4H), 7. 16 (m, 1H), 5. 25 (s, 2H), 3. 21 (ra, 2H), 3.10 (m, 4H), 2.05 (m, 2H), 1.80 ( m,1H) 1.68 (m, 2H) Example 197 [3- gas-4-(3-fluoro--benzyloxy).-phenyl 1-(6-{1-|~2-(4~A) Its - life is called 94389 336 201016683 -1-yl)-ethyl]-1Η-° than the mouth of each -3-yl}-quinoquinone

192192

197197

°-j〇LF 將卜二乙胺基-3-(3-{4-[1-(3-氟_苄基）_1H—吲唑 -5-基胺基]-喹唑啉-6-基}-吡咯-1-基）_丙—醇195(197 mg，0 · 3 3 7 mmo 1) >谷於1 〇 mL四氩°夫°^中，冰浴冷卻至〇加入氫化鋁鋰（38 mg ’ 1 mmol) ’攪拌1〇分鐘後反應完畢。在反應液中加入十水合硫酸鈉淬滅反應，過濾反應=，濾餅用甲醇洗滌，濾液在減壓下濃縮，得到的殘留物藉由ς 膠管柱層析法進一步分離純化（二氯甲烷：甲醇：氨水=ι〇 : 1 : Id)，得到標題產物[恥氣_4_(3_氟_苄氧基）__苯基]_ (6-{1-[2-(4-甲基-哌哄η、基）一乙基]_1H_〇比咯_3_基卜喹唑啉-4-基）-胺197(55rag，黃色固體），產率：26%。 MS m/z (ESI) ： 572[M+1] NMR (400 MHz，CD30D-A) :(5 9. 70 (s，1H)，8.54 (s， lH)8.49(s, 1H), 8.03(d, j=8Hz, 2H), 7. 76 (d, J=8. 4Hz, 1H)，7. 70 (d, J=8. 8Hz，1H)，7. 48 (m, 1H), 7. 41 (s，1H)， 7. 33 (ra，3H)，7. 19 (t，J=8Hz，1H)，6.88 (s，1H)，6 65 (s’ 1H)，5.27 (s，2H)，4.04 (m，2H)，2.68 (m，2H)，3.46 337 94389 201016683 (m, 4H), 2. 32 (m, 4H), 3. 15 (s, 3H) 實施例198°-j〇LF will be diethylamino-3-(3-{4-[1-(3-fluoro-benzyl)_1H-indazol-5-ylamino]-quinazolin-6-yl }-pyrrol-1-yl)-propanol 195 (197 mg, 0 · 3 3 7 mmo 1) > Valley in 1 〇 mL of tetra argon, cooled in an ice bath to 〇 add lithium aluminum hydride ( 38 mg '1 mmol) 'The reaction was completed after stirring for 1 minute. The reaction mixture was quenched by the addition of sodium sulfate decahydrate, and the mixture was filtered. The filtrate was washed with methanol and the filtrate was concentrated under reduced pressure. Methanol: Ammonia = ι〇: 1 : Id), the title product [Shame_4_(3_Fluoro-benzyloxy)__phenyl]_(6-{1-[2-(4-methyl-) Piperazine η, yl)-ethyl]_1H_indole _3_ quinquinazolin-4-yl)-amine 197 (55 rag, yellow solid), yield: 26%. MS m/z (ESI): 572 [M+1] NMR (400 MHz, CD30D-A): (5 9. 70 (s, 1H), 8.54 (s, lH) 8.49 (s, 1H), 8.03 ( d, j=8Hz, 2H), 7. 76 (d, J=8. 4Hz, 1H), 7. 70 (d, J=8. 8Hz, 1H), 7. 48 (m, 1H), 7. 41 (s, 1H), 7. 33 (ra, 3H), 7. 19 (t, J=8Hz, 1H), 6.88 (s, 1H), 6 65 (s' 1H), 5.27 (s, 2H) , 4.04 (m, 2H), 2.68 (m, 2H), 3.46 337 94389 201016683 (m, 4H), 2. 32 (m, 4H), 3. 15 (s, 3H) Example 198

喹鱼,被二4-棊j-「3-氣-4-(3-氟-苄氧基）-苯基1_吃Quinoa, eaten by di 4-棊j-"3-gas-4-(3-fluoro-benzyloxy)-phenyl 1_

198198

〇aF 將 1-[1，4,]二哌啶基-1’ -基-2-(3-{4-[3~氣~4-(3- - 氟-苄氧基）-苯胺基]-喹唑啉-6-基}-吡咯-卜基）—乙綱 _ 190(220 mg，〇. 337 mmol)溶於10 mL四氫呋喃中，冰洛冷卻至0°C ’加入氫化鋁裡（38 mg，1 mmol)，攪拌1〇分鐘後反應完畢。在反應液中加入十水合碳酸鈉淬滅反應，〇過濾反應液，濾餅用甲醇洗滌，濾液在減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化（二氯曱烷：曱醇：氨水=10 : 1: Id) ’得到標題產物{6_[卜（2_[ 1，4’ ] 二0底0定基-1 -基-乙基）-1Η-βΛπ各-3-基]-喧嗤琳基}- [3-氣-4-(3-氟-苄氧基> 苯基]-胺ι98(72呢，黃色固體），產率：33. 5%。 MS m/z (ESI ) ： 640[M+1] ]H NMR (400 MHz, CD30D-JO ： 5 9. 69 (s, 1H), 8.53 (s, 338 94389 201016683 1H)，8.50 (s，1H)，8.03 (m，2H)，7· 77 (dd’ J = 2 4Hz 1H)，7.70 (d，J = 8. 4Hz，1H)，7.43 (m，2H), 7.30 (m，3^ 7.19(m，1H)，6.91 (s，1H)，6.65(s，ih)，5.27 (s 2h) 4.03(t，J=6.8Hz，2H)，2.96(d，J=6.4Hz，2H)，2 66 (t J = 6.4Hz, 2H), 2.44 (br, 4H), 2.21 (br, 1H), i 98 (m 2H), 1.69 (d，J=6.0Hz, 2H)，1.44 (m，8H) 實施例199 [1-(3-氟-苄A1-1H-吲唑二棊 — (四〇aF 1-[1,4,]dipiperidinyl-1'-yl-2-(3-{4-[3~gas~4-(3--fluoro-benzyloxy)-anilino] - quinazolin-6-yl}-pyrrole-bry)-ethyl _ 190 (220 mg, 〇. 337 mmol) dissolved in 10 mL of tetrahydrofuran, cooled to 0 ° C. Mg, 1 mmol), the reaction was completed after stirring for 1 minute. The reaction solution was quenched by the addition of sodium carbonate decahydrate, and the reaction mixture was filtered, the filter cake was washed with methanol, and the filtrate was concentrated under reduced pressure, and the residue obtained was further separated and purified by silica gel column chromatography (dichloropurine) Alkane: decyl alcohol: ammonia water = 10 : 1: Id) 'Get the title product {6_[Bu(2_[ 1,4' ] 00 base 0-decyl-1 -yl-ethyl)-1Η-βΛπ each-3- ] [ 气基 } - - - 3- MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS /z (ESI): 640[M+1] ]H NMR (400 MHz, CD30D-JO: 5 9. 69 (s, 1H), 8.53 (s, 338 94389 201016683 1H), 8.50 (s, 1H), 8.03 (m, 2H), 7· 77 (dd' J = 2 4Hz 1H), 7.70 (d, J = 8. 4Hz, 1H), 7.43 (m, 2H), 7.30 (m, 3^ 7.19(m, 1H), 6.91 (s, 1H), 6.65 (s, ih), 5.27 (s 2h) 4.03 (t, J = 6.8 Hz, 2H), 2.96 (d, J = 6.4 Hz, 2H), 2 66 (t J = 6.4 Hz, 2H), 2.44 (br, 4H), 2.21 (br, 1H), i 98 (m 2H), 1.69 (d, J = 6.0 Hz, 2H), 1.44 (m, 8H) Example 199 [1-(3-Fluoro-benzyl A1-1H-carbazole dioxime - (four

0某癱基）-乙基]-1Η-°比洛-3-基丨-啥吨兔^4—某）0 瘫 )))-ethyl]-1Η-°Bilu-3-yl丨-啥吨兔^4—a)

QQ

°^V-N°^V-N

0 將二乙胺基-乙基»比咯_3_基]〜啥唾琳 -4-基卜[1_(3-氟苄基）-1Η-°引嗤-5-基]-胺i5〇(ii9 〇. 276 mmol)溶於1 mL N，N-二曱基曱醯胺中，冰浴冷卻至〇。(：，加入氫化鈉（100 mg ’ 0. 8mmol) ’攪拌30分鐘後，加入2-(2-漠乙氧基）-四氫呋喃（25 mg ’ 〇· 359mmol)，30分鐘後反應完畢。將反應液倒入5 0 mL冰水中，有固體析出，過滤’滤餅藉由石夕膠管柱層析法分離純化，得到標題產物 [1 -（3-氟-苄基）-1Η-吲唑-5-基]-(6-{1-[2-(四氫呋喃 __2_ 94389 339 201016683 基氧基）-乙基]-1Η-°比π各_3 -基}'-喧〇坐琳-4 -基）-胺199 (86. 9mg，黃色固體），產率：56%。 MS m/z (ESI) ： 563[M+1] ]HNMR (400MHz, CD30D-d〇: (5 9. 86 (s, 1H), 8. 62 (s, 1H), 8.46 (s, 1H), 8.23 (s, 1H), 8.18 (s, 1H), 8.04 (d, 1H, J = 8.8Hz)，7.73 (m，3H), 7.46 (s，1H)，7.38 (m，1H)， 7. 09 (in, 3H), 6. 93 (s, 1H), 6. 69 (s, 1H), 5. 72 (s, 2H), 4. 57 (m, 1H), 4. 14 (m, 2H), 3. 91 (m, 1H), 3. 71 (m, 1H), 1^3.59 (m, 1H), 3.39 (m, 1H), 1.63 (m, 6H) 實施例200 l-「3-(3-丨4-「3-氣-4-(3-氟-苄氣基）-笨胺基1-喹唑啉-6-基卜吡咯-卜基）-丙基1-哌啶-4-醇0 will diethylamino-ethyl»比咯_3_基]~啥啥琳-4-基卜[1_(3-fluorobenzyl)-1Η-°嗤-5-yl]-amine i5〇 (ii9 〇. 276 mmol) was dissolved in 1 mL of N,N-didecylguanamine and cooled to hydrazine in an ice bath. (:, adding sodium hydride (100 mg '0.8 mmol)' After stirring for 30 minutes, 2-(2- ethoxyethoxy)-tetrahydrofuran (25 mg ' 〇 · 359 mmol) was added, and the reaction was completed after 30 minutes. The liquid was poured into 50 mL of ice water, and a solid precipitated. The filtered cake was separated and purified by chromatography on silica gel column chromatography to give the title product [1 -(3-fluoro-benzyl)-1?-indazole-5. -yl]-(6-{1-[2-(tetrahydrofuran__2_94389 339 201016683 methoxy)-ethyl]-1Η-° ratio π each _3 -yl}'-喧〇坐琳-4 -yl -amine 199 (86. 9 mg, yellow solid), yield: 56%. MS m/z (ESI): 563[M+1]]HNMR (400 MHz, CD30D-d〇: (5 9.86 (s , 1H), 8. 62 (s, 1H), 8.46 (s, 1H), 8.23 (s, 1H), 8.18 (s, 1H), 8.04 (d, 1H, J = 8.8Hz), 7.73 (m, 3H), 7.46 (s, 1H), 7.38 (m, 1H), 7. 09 (in, 3H), 6. 93 (s, 1H), 6. 69 (s, 1H), 5. 72 (s, 2H), 4. 57 (m, 1H), 4. 14 (m, 2H), 3. 91 (m, 1H), 3. 71 (m, 1H), 1^3.59 (m, 1H), 3.39 ( m, 1H), 1.63 (m, 6H) Example 200 l-"3-(3-丨4-"3-Gas-4-(3-fluoro-benzyl)-phenylamino-1-quinazoline -6-kibpyrrole-buki)-propyl 1-piperidin-4-ol

第一步 4-經基底咬_1_曱酸第三丁西旨 340 94389 201016683 將化合物4-側氧基-哌啶—〗田；取足卜甲酸第三丁酯200a (10g，0· 05mmol)溶於30 mL甲醇中，與妯τ 1 τ畔r ’攪拌下加入二氯化鈷溶液（6.53g ’ 0.05麵丨），分批加入硼氫化鈉（3化， 0.1函D’攪捽1小時後反應完畢。反應液，滤液在減壓下濃縮，得到的殘留物藉切膠管柱層析法進一步分離純化’得到化合物4 -經基-痕哈1田办& 签瓜哫一1—甲酸第三丁酯200b (9g，淡黃色固體），產率：9〇%。 MS m/z (ESI) ： 202[M+1] ϋ 第二步哌啶-4-醇三氟醋酸鹽將化合物4-羥基-哌啶—卜甲酸第三丁醋2〇〇b(ig， 4.98mmol)溶於15 mL三氟乙酸溶液中，冰浴冷卻至，授拌2小時後反應完畢，下濃縮反應液，所得的產物The first step 4 - through the substrate bite _1 _ citrate third butyl 340 94389 201016683 will be the compound 4-side oxy-piperidine - 〗〖; take the butyl butyl terephthalate 200a (10g, 0. 05mmol Soluble in 30 mL of methanol, add cobalt dichloride solution (6.53g '0.05 丨) with 妯τ 1 τ, r ' stirring, add sodium borohydride in batches (3, 0.1 letter D' 捽 1 After the reaction is completed, the reaction solution and the filtrate are concentrated under reduced pressure, and the obtained residue is further separated and purified by a gel column chromatography to obtain a compound 4 - a base-marked ha 1 field office & Third butyl formate 200b (9g, pale yellow solid), yield: 9%. MS m/z (ESI): 202[M+1] ϋ The second step of piperidin-4-ol trifluoroacetate The compound 4-hydroxy-piperidine-benzoic acid tributyl vinegar 2〇〇b (ig, 4.98mmol) was dissolved in 15 mL of trifluoroacetic acid solution, cooled to an ice bath, and the reaction was completed after 2 hours of mixing. Liquid, the resulting product

σ辰0定-4-醇三氟酷酸鹽200c (Άηη m ^ A 孤心Uc C500 ，黃色固體）不經分離直接進行下一步反應。第三步 1-(3-溴丙基）-旅咬—4-醇將化合物哌啶-4-醇三氟醋酸鹽2〇〇c(5〇〇邶， 2.33mm〇l)溶於1〇 mL二氣甲烷中，攪拌下加入13一二溴丙烷（2.82g，13. 95酬〇1)，冰浴冷卻至〇t：，逐滴加入三乙胺（705mg ’ 6· 98随〇1)，攪拌！小時後反應完畢，有固= 生成。過濾反應液，濾液在減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化（二氯甲烷：甲醇=4〇: 1)，侍到化合物1-(3-溴丙基）-哌啶_4_醇2〇〇d(672邶， 943 S9 341 201016683 淡貫色油狀液體），產物不經分離直接進行下一 + MS m/z (ESI) ： 222[M+1] 第四步卜[3-(3-U餐氯+ (3U氧基胺基]寺坐琳+ 基}-σ比17各-1-基）-丙基]辰咬-醇 …在25 mL的單口燒瓶中，將[3_氣_[(3_氣_节氧基）_ 本基]-[6-(1Η-吡咯-3-基）-喹唑啉_4_基]_胺42(445邶， 1 mmol)溶於6 mL N，N-二甲基甲醯胺中，在冰浴 ◎冷卻至Ot ’加入氫化納（72呢，3醜〇1)，授掉3〇分鐘後逐漸滴加1-(3-溴丙基）-哌啶_4_醇（672 mg，2咖〇1)的 lmL三乙胺溶液，室溫下授拌4小時反應完畢。反應液減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離 .純化（二氯甲炫·：甲醇=4: 1 )，得到本標題產物卜[3_ (3_(4一 [3-氯-4-(3-氟-苄氧基 >苯胺基卜喹唑啉_6_基卜吼咯—卜基）-丙基]-派啶-4-醇200(10 mg，淡黃色固體），產率： 1.7%。 Q MS ra/z (ESI) ： 587[M+1] !H NMR (400 MHz, CD30D-d〇： (5 9. 67 (s, 1H), 8. 8 (s, 1H) 8.5 (s, 1H), 8.03 (d, J=8.8Hz, 2H), 7.76 (dd, J=2Hz, 1H), 7.70 (d, J=8. 4Hz, 1H), 7.5 (m, 2H), 7.36 (m, 3H), 7.2 (s, 1H), 6.93 (s, 1H), 6.60 (s, 1H), 5.27 (s, 2H), 4.08 (m, 1H), 3.89 (m, 4H), 3.50 (m, 4H), 1.2 (m, 6H) 實施例201σ辰0定-4-ol trifluorocurate 200c (Άηη m ^ A orphan Uc C500, yellow solid) was directly subjected to the next reaction without isolation. The third step 1-(3-bromopropyl)-Brigade bite-4-alcohol The compound piperidin-4-ol trifluoroacetate 2〇〇c (5〇〇邶, 2.33mm〇l) is dissolved in 1〇 In mL two-gas methane, 13-dibromopropane (2.82 g, 13.95 〇1) was added with stirring, and cooled to 〇t: by ice bath, and triethylamine (705 mg '6·98 with 〇1) was added dropwise. , stirring! After the hour, the reaction is completed and there is solid = generation. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified and purified by methylene chloride column chromatography (dichloromethane:methanol = 4 〇: 1) to afford 1-(3-bromopropyl) - piperidine _4-alcohol 2 〇〇 d (672 邶, 943 S9 341 201016683 lightly colored oily liquid), the product was directly subjected to the next + MS m/z (ESI): 222 [M+1 ] The fourth step is [3-(3-U meal chlorine + (3U oxyamino) temple sitin + base}-σ ratio 17-1-yl)-propyl] chen bite-alcohol... in 25 mL In a single-mouth flask, [3_gas_[(3_气_节oxy)_benyl]-[6-(1Η-pyrrol-3-yl)-quinazoline-4-yl]-amine 42 (445 邶, 1 mmol) dissolved in 6 mL of N,N-dimethylformamide, cooled to Ot in ice bath ◎ Add sodium hydride (72, 3 ugly 1), after 3 minutes A solution of 1-(3-bromopropyl)-piperidine-4-ol (672 mg, 2 curry 1) in 1 mL of triethylamine was gradually added dropwise, and the reaction was completed at room temperature for 4 hours. Concentration, the residue obtained was further separated by hydrazine column chromatography. Purification (dichloromethane: methanol = 4:1) gave the title product [3_(3_(4-[3-chloro-4] -(3-fluoro-benzyl Base > Anilinoquinazoline_6_ kibbrozol-bu)-propyl]-pyridin-4-ol 200 (10 mg, pale yellow solid), yield: 1.7%. Q MS ra /z (ESI) : 587[M+1] !H NMR (400 MHz, CD30D-d〇: (5 9. 67 (s, 1H), 8. 8 (s, 1H) 8.5 (s, 1H), 8.03 (d, J=8.8Hz, 2H), 7.76 (dd, J=2Hz, 1H), 7.70 (d, J=8. 4Hz, 1H), 7.5 (m, 2H), 7.36 (m, 3H), 7.2 (s, 1H), 6.93 (s, 1H), 6.60 (s, 1H), 5.27 (s, 2H), 4.08 (m, 1H), 3.89 (m, 4H), 3.50 (m, 4H), 1.2 (m, 6H) Example 201

94389 342 20101668394389 342 201016683

第一步first step

201 N201 N

〇jar β 在1〇〇汕茄形瓶中，將（RM3-氯-4-(3-氟-苄氧基）-苯基]-[6-(l-環氧乙基甲基_1H_吡咯_3_基）_喹唑啉_4_ 基]-胺186a(250mg’0.5mmOl)和4-羥基哌啶（50mg， 0.5 mmol)溶於10mL無水曱醇中，加熱回流過夜。將反應 .液在減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化（梯度沖提：二氣甲烷：曱醇=1〇 :丨），得到本標題產物（R)l-[3-(3-{4-[3-氯-4-(3-氟-苄氧基）_苯胺基] _喹唑啉-6-基}-吡咯-1-基）-2-羥基-丙基]-哌啶_4_醇〇 201(105 mg，黃色固體），產率：35%。 MS m/z (ESI) ： 602[M+1] !Η NMR (400 MHz，CD30D-d6): 5 9. 67 (s，1H)，8 8 (s 1H)， 8.5 (s, 1H), 8.03 (d, J = 8.8Hz, 2H), 7.76 (dd, J=2Hz, 1H), 7.70 (d, J=8.4Hz, 1H), 7.5 (m, 2H), 7.36 (m, 3H), 7. 2 (s, 1H), 6. 93 (s, 1H), 6. 60 (s, 1H)，5 27 (s 2H) 5.0 (br，1H)，3.9-4.4 (m，3H)，3.5 (id, 1H)，3.4 (m， 1H)，3. 1 (m，2H)，1. 9 (br, 2H)，l. 7 (br，2H)，l 26 (m， 94389 343 201016683 4H) 實施例202 (R)-l-(3-(4-(3 -氯- 4-(3 -氟节氧基）苯啤基）啥唾被—其、 -1Η-ρϋρ各-1-基）-3-((S)-2-(經甲基比吸烧一 1-基）雨 _2_ 0〇jar β in a 1 〇〇汕 eggplant bottle, (RM3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(l-epoxyethylmethyl_1H_ Pyrrole-3-yl)-quinazoline-4-yl]-amine 186a (250 mg '0.5 mm Ol) and 4-hydroxypiperidine (50 mg, 0.5 mmol) were dissolved in 10 mL of anhydrous methanol and heated to reflux overnight. The liquid was concentrated under reduced pressure, and the obtained residue was further purified and purified by silica gel column chromatography (gradient elution: methane methane: decyl alcohol = 1 〇: 丨) to give the title product (R) l-[ 3-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-anilino]-quinazolin-6-yl}-pyrrol-1-yl)-2-hydroxy-propyl Base]-piperidine-4-enol 201 (105 mg, yellow solid), yield: 35%. MS m/z (ESI): 602[M+1] Η NMR (400 MHz, CD30D-d6) : 5 9. 67 (s,1H),8 8 (s 1H), 8.5 (s, 1H), 8.03 (d, J = 8.8Hz, 2H), 7.76 (dd, J=2Hz, 1H), 7.70 ( d, J=8.4Hz, 1H), 7.5 (m, 2H), 7.36 (m, 3H), 7. 2 (s, 1H), 6. 93 (s, 1H), 6. 60 (s, 1H) , 5 27 (s 2H) 5.0 (br, 1H), 3.9-4.4 (m, 3H), 3.5 (id, 1H), 3.4 (m, 1H), 3. 1 (m, 2H), 1. 9 ( Br, 2H), l. 7 (br, 2H), l 26 (m, 94389 343 2010 16683 4H) Example 202 (R)-l-(3-(4-(3-Chloro-4-(3-fluorooxy)phenyl)-salt--, -1Η-ρϋρ-1 -yl)-3-((S)-2-(methyl-to-burn-one-base) rain_2_ 0

202 OH202 OH

第二步Second step

202b 202a202b 202a

202 第一步 ^ (S)-2-羥甲基-11比哈烧-1-曱酸第三丁酉旨將氫化紹链（759 mg，20 mmol)溶於20 mL四氫吱喃溶液中’加熱回流15分鐘後冷卻至室溫’加入L-脯胺酸（1. 15 g ’ 10 mmo 1)的10 mL四氫呋喃溶液，加熱回流3小時後反應結束。反應液降至室溫，加入3 0 mL飽和氯化銨溶液，水相用乙酸乙酯萃取（20 mLx3)，合併的有機相經由飽和氯化納谷液洗務’無水硫酸鈉脫水’過遽，減墨下濃縮，殘質中加入碳酸氫納（840 mg ’ 10 mmol)授拌5分鐘後加入二 344 94389 201016683 碳酸二第三丁酯（3.485 g，16 mmol)，混合液在室溫下攪拌24小時反應完畢。將反應液用2N鹽酸調整pH=7，水相用乙酸乙酯萃取（20 mLx3)，合併的有機相經由飽和氯化鈉溶液洗務，無水硫酸納脫水，過滤，減壓下濃縮’得到（S) - 2 -羥甲基-吡咯烷-1-曱酸第三丁酯202a(2. 57 g，無色油狀液體）。 MS m/z (ESI) ： 202[M+1] 第二步打（S)-吡咯烷-2-基甲醇在50 mL三口燒瓶中，加入（S)-2-經甲基-π比洛烧-1-甲酸第三丁酯 202a( 100. 6 mg，0.5 mmol)溶於 20 mL 二氯曱烷中，冰浴冷卻至〇°C，加入三氟乙酸（2.2 mL，28 mmo 1)’室溫下授拌1. 5小時’反應完畢。將反應液在減壓下濃縮’得到化合物（S)-吡咯烷-2-基曱醇202b不經分離直接進行下一步反應。 MS m/z (ESI) ： 102[M+1] ❸第三步 (R)-l-(3-(4-(3-氣-4-(3-氟苄氧基）苯胺基）喹唑啉_6_ 基）_1Η-η比咯-1-基）-3-((S)-2-(羥甲基）π比咯烷_卜基）丙 -2-醇在100 mL茄形瓶中，將（R)-[3_氣_4_(3_氟_苄氧基苯基]-[6-(1-環氧乙基曱基-in-吡咯_3_基喹唑啉基]-胺 186a(150 mg，0.3 mmol)和（s)一吡咯烷 _2-基曱醇 202b(25.3mg，0.25 mmol)溶於12 mL無水甲醇中，加入j 94389 345 201016683 仏二乙胺加熱回流6小時反應完畢。將反應液在減麗下濃縮，得到的殘留物藉由石夕膠管柱層析法進一步分離純化（梯度沖提.二氣曱烷：曱醇=50:1)，得到本標題產 (4-(3-氯-4-(3-氟苄氧基）苯胺基）喹唑啉_6_基）_1H〜n比咯 -卜基）-3-((S)-2-(羥曱基）吡咯烷一卜基）丙_2_醇2〇2(28 mg，黃色固體），產率：18. 6%。 MS m/z (ESI) ： 602[M+1] 'H NMR (400 MHz, CD30D-d6)： δ 9. 935 (s, 1H), 8. 686 (s202 First Step ^(S)-2-Hydroxymethyl-11-Habib--1-decanoic acid T-butyr is prepared by dissolving hydrogenated chain (759 mg, 20 mmol) in 20 mL of tetrahydrofuran solution. After heating under reflux for 15 minutes, it was cooled to room temperature. A solution of L-proline (1. 15 g '10 mmo 1) in 10 mL of tetrahydrofuran was added, and the mixture was heated to reflux for 3 hr. The reaction solution was cooled to room temperature, 30 mL of a saturated ammonium chloride solution was added, the aqueous phase was extracted with ethyl acetate (20 mL×3), and the combined organic phases were washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. Concentrate under reduced ink, add sodium bicarbonate (840 mg '10 mmol) to the residue for 5 minutes, then add two 344 94389 201016683 dibutyl butyl carbonate (3.485 g, 16 mmol), and mix the mixture at room temperature. The reaction was completed in 24 hours. The reaction mixture was adjusted to pH=7 with 2N hydrochloric acid, and the aqueous phase was extracted with ethyl acetate (20 mL×3). The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. S) - 2 -Hydroxymethyl-pyrrolidine-1-decanoic acid tert-butyl ester 202a (2.57 g, colorless oily liquid). MS m/z (ESI): 202 [M+1] s (s)-pyrrolidin-2-ylmethanol in a 50 mL three-necked flask, (S)-2-methyl-pyrrol The tributyl ketone 1-carboxylate 202a (100. 6 mg, 0.5 mmol) was dissolved in 20 mL of dichloromethane, cooled to 〇 ° C, and added trifluoroacetic acid (2.2 mL, 28 mmo 1). The reaction was completed at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure to give the compound (S)-pyrrolidin-2-ylfurfuryl alcohol 202b directly to the next reaction without isolation. MS m/z (ESI): 102 [M + 1] ❸ Step 3 (R)-l-(3-(4-(3- </RTI> <RTIgt; Porphyrin_6_yl)_1Η-ηpyr-1-yl)-3-((S)-2-(hydroxymethyl)πpyrrolidinyl)propan-2-ol in a 100 mL eggplant-shaped bottle , (R)-[3_Gas_4_(3_Fluoro-benzyloxyphenyl]-[6-(1-epoxyethylindenyl-in-pyrrole_3-quinazolinyl)- Amine 186a (150 mg, 0.3 mmol) and (s)-pyrrolidine-2-yl sterol 202b (25.3 mg, 0.25 mmol) were dissolved in 12 mL of anhydrous methanol and then added to j 94389 345 201016683 仏 diethylamine heated to reflux 6 After the completion of the reaction, the reaction mixture was concentrated under reduced concentration, and the obtained residue was further separated and purified by gradient chromatography (gradient elution: dioxane: decyl alcohol = 50:1) to obtain the title. (4-(3-Chloro-4-(3-fluorobenzyloxy)anilino)quinazoline-6-yl)_1H~npyr-bu-ki)-3-((S)-2-( Hydroxymercapto)pyrrolidine-diyl)propan-2-alcohol 2〇2 (28 mg, yellow solid), yield: 18.6%. MS m/z (ESI): 602[M+1] 'H NMR (400 MHz, CD30D-d6): δ 9. 935 (s, 1H), 8. 686 (s

D 1H)，8.483 (s，1H)，8.094 (s，1H)，8.035 (d，J=8.8HZ ^ 1H), 7.830 (d, J = 8.4Hz, 1H), 7.685 (d, J=8. 4Hz, 1¾) 7.480 (m, 2H), 7.317 (m，3H), 7.190 (t，J=8.4Hz，ih) 6.870 (s, 1H), 6.707 (s, 1H), 5.271 (s, 2H), 5.048 (s .IH), 4.606 (s，1H)，4.118 (d，J = 12.8Hz，1H)，3.795 (m， • 2H)，3.417 (t，J = 5.2Hz，2H)，2.717 (m，1H)，2.456 (d， J=6Hz，2H)，2.316 (m，1H)，2.221 (t，J=8.4H,z，iH)， 1.792 (m, 1H), 1.629 (t, J = 24Hz, 2H), 1.536 (d, J=6HZ> 〇 1H) 實施例203 (^)-1-「3-(3-{4-「3-氣-4-(3-氟-苄氣基）-装胺基卜^^ 啦_6-基比嘻-基）- 2 -經基-丙基]-口底p定-4-醇D 1H), 8.438 (s, 1H), 8.094 (s, 1H), 8.035 (d, J = 8.8HZ ^ 1H), 7.830 (d, J = 8.4Hz, 1H), 7.685 (d, J=8. 4Hz, 13⁄4) 7.480 (m, 2H), 7.317 (m, 3H), 7.190 (t, J=8.4Hz, ih) 6.870 (s, 1H), 6.707 (s, 1H), 5.271 (s, 2H), 5.048 (s .IH), 4.606 (s,1H), 4.118 (d, J = 12.8Hz, 1H), 3.795 (m, • 2H), 3.417 (t, J = 5.2Hz, 2H), 2.718 (m, 1H), 2.456 (d, J=6Hz, 2H), 2.316 (m, 1H), 2.221 (t, J=8.4H, z, iH), 1.792 (m, 1H), 1.629 (t, J = 24Hz, 2H), 1.536 (d, J=6HZ> 〇1H) Example 203 (^)-1-"3-(3-{4-"3-Gas-4-(3-fluoro-benzyl)-loading Amine base ^^ 啦_6-kibido-yl)- 2 -trans-propyl-propyl]-endo-p--4-ol

346 94389 203 201016683346 94389 203 201016683

203 在lOOmL茄形瓶中，將（SM3 一氣_4_(3_氟_苄氧基）_ 苯基]-[6-U-環氧乙基甲基_1H_吡咯_3_基）_喹唑啉_4_ 基]-胺185a(250 mg，0.5職〇1)和4_羥基哌啶（5〇呢， 0.5棚〇1)溶於l〇mL無水曱醇中，加熱回流過夜。將反應 &液在減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化（梯度沖提··二氯曱烷：曱醇=1〇 :丨），得到本標題產物（S)-l-[3-(3-{4-[3-氣-4-(3-氟-苄氧基）_苯胺基]-啥唾啦-6-基卜吼嘻-1-基）-2_羥基-丙基]_哌啶_4_醇 203(105 mg，黃色固體），產率：35%。 MS m/z (ESI) ： 602[M+1] ]H NMR (400 MHz, CD30D-A): (5 9. 67 (s，1H)，8. 8 (s 1H) 8. 5 (s, 1H), 8. 03 (d, J=8. 8Hz, 2H), 7. 76 (dd J=2Hz 〇 1H), 7.70 (d，J=8.4Hz, 1H), 7.5 (m, 2H), 7 3β (m SR) 7.2(s，1H)，6.93(s’ 1H)，6.60(s，ih)，5 27(s 2H)’ 4.1 (m, 2H), 3.9 (br, 1H), 3.55 (s, 1H) % a r , 入 3.4 (m，in), 3.05 (s, 4H),2.5 (m, 2H), 1.85 (br, 2H) i qc /i A. 55 (br, 2H) 實施例204203 In a lOOmL eggplant-shaped flask, (SM3 gas _4_(3_fluoro_benzyloxy)_phenyl]-[6-U-epoxyethylmethyl-1H_pyrrole_3_yl)-quine Oxazoline-4-yl]-amine 185a (250 mg, 0.5 〇1) and 4-hydroxylidine (5 〇, 0.5 shed 1) were dissolved in 1 mL of anhydrous decyl alcohol and heated to reflux overnight. The reaction & solution was concentrated under reduced pressure, and the obtained residue was further purified and purified by silica gel column chromatography (gradient elution·dichloromethane: decyl alcohol = 1 〇: 丨) to give the title product (S)-l-[3-(3-{4-[3-Gas-4-(3-fluoro-benzyloxy)-anilino]-indole-salt-6-yldipyridin-1-yl 2-hydroxy-propyl]-piperidine-4-ol 203 (105 mg, yellow solid), yield: 35%. MS m/z (ESI): 602 [M+1]]H NMR (400 MHz, CD30D-A): (5 9. 67 (s, 1H), 8. 8 (s 1H) 8. 5 (s, 1H), 8. 03 (d, J=8. 8Hz, 2H), 7. 76 (dd J=2Hz 〇1H), 7.70 (d, J=8.4Hz, 1H), 7.5 (m, 2H), 7 3β (m SR) 7.2 (s, 1H), 6.93 (s' 1H), 6.60 (s, ih), 5 27 (s 2H)' 4.1 (m, 2H), 3.9 (br, 1H), 3.55 (s , 1H) % ar , 3.4 (m, in), 3.05 (s, 4H), 2.5 (m, 2H), 1.85 (br, 2H) i qc /i A. 55 (br, 2H) Example 204

94389 347 20101668394389 347 201016683

204204

在100 mL茄形瓶中’將（S)-[3-氯-4-(3-氟-苄氧基）-苯基]-[6-(1-環氧乙基甲基_1H_吡咯_3_基）一喹唑啉_4_基] '胺 185a(216mg’ 〇·4 mmo 1)和環丙胺（〇. 1 mL，〇. 8 mmo 1) 溶於20 mL無水甲醇中，加熱回流過夜。將反應液在減壓下濃縮’得到的殘留物藉由石夕耀L管柱層析法進一步分離純化（梯度沖提：二氯甲烷：甲醇=1(^ 1)，得到本標題產物 (5)-1-(3-{4-[3-氣-4-(3-氟-苄氧基）-苯胺基]-喹唑啉 - 6-基卜吡咯—1-基）_3_環丙基胺基-丙-2_醇2〇4 (202'(S)-[3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1-epoxyethylmethyl-1H_pyrrole in a 100 mL eggplant-shaped flask _3_yl)-quinazoline_4_yl] 'amine 185a (216mg' 〇·4 mmo 1) and cyclopropylamine (〇. 1 mL, 〇. 8 mmo 1) dissolved in 20 mL of anhydrous methanol, heated Reflux overnight. The reaction mixture was concentrated under reduced pressure. The obtained residue was further purified and purified by EtOAc (EtOAc: EtOAc:MeOH: )-1-(3-{4-[3-Ga-4-(3-fluoro-benzyloxy)-anilino]-quinazoline-6-ylpyrrole-l-yl)_3_cyclopropyl Amino-propan-2-ol 2〇4 (202

，黃色固體），產率：83. 8%。 MS m/z (ESI) ： 558[M+1] 】H NMR (400 MHz, CD30D-A)H74 (s，1H)，8.56 (s， 1H)，8.49 (s，1H)，8.03 (s，1H)，8.02 (d，J = 8.8Hz， !H), 7. 77 (d, J = 8. 8Hz, 1H), 7. 70 (d, J = 8. 8Hz, 1H), ^•48 (t, J = 8.8Hz, 1H), 7.43 (s, 1H), 7. 33 (in, 3H), ^.16 (t, J = 8.8Hz, 1H), 6.88 (s, 1H), 6.71 (s, 1H), 5.27 (s, 2H), 4.06 (t, J = 12.8Hz, 1H), 3.94 (s, 1H), 348 94389 201016683 3·85 (m，1H)’ 2.69 (m，2H)，2 23 (br，1H)，0.43 (m， 4H) 實施例205 氣苄氫篡、-笨胺基上一？一鞀基-丙篡一镟甲某一哌啶 M-8%。 The yield was 83.8%. MS m/z (ESI): 558 [M+1]] H NMR (400 MHz, CD30D-A) H74 (s, 1H), 8.56 (s, 1H), 8.49 (s, 1H), 8.03 (s, 1H), 8.02 (d, J = 8.8Hz, !H), 7. 77 (d, J = 8. 8Hz, 1H), 7. 70 (d, J = 8. 8Hz, 1H), ^•48 ( t, J = 8.8Hz, 1H), 7.43 (s, 1H), 7. 33 (in, 3H), ^.16 (t, J = 8.8Hz, 1H), 6.88 (s, 1H), 6.71 (s , 1H), 5.27 (s, 2H), 4.06 (t, J = 12.8Hz, 1H), 3.94 (s, 1H), 348 94389 201016683 3·85 (m,1H)' 2.69 (m,2H),2 23 (br, 1H), 0.43 (m, 4H) Example 205 Gas benzyl hydroquinone, - stupid amine on the first? A sulfhydryl-propionyl-purine-a piperidine M-

P第一步 205 〇 1_氧雜_6 一氮雜~螺[2.5]辛院三氟乙酸鹽將1-氧雜、6、氮雜_螺[2.5]辛燒— ： 205a(509 mg，2 刊，馱弟一丁适曰 g z.39mmol)溶於 2〇()社二氣浴條件下，冷卻至〇卩，士 λ ζ τ _ & r，在冰 q π 此二氟乙酸，室溫下授掉 3〇为鐘’反應完畢。將反應液在減壓下濃縮，狀液體粗品卜氧雜I氮雜-螺[2.5]辛烧三氣乙= 2〇5b ,產物不經分離直接進行下一步反應。夂风 94389 349 201016683 第二步 (RM-[3-(3-{4-[3-氯-4-(3-氟-苄氧基）_苯胺基卜喹唑啉基卜吡咯-1-基）-2-羥基-丙基羥曱基一哌啶醇在100 mL茄形瓶中，將（r)-[3-氣_4_(3_氟_苄氧基）_ 笨暴]-[6-(1-環氧乙基甲基-in-。比嘻-3一基）_噎唑淋基] -胺 186a (154 mg，0. 3 mmol)溶於 25 mL 甲醇中，攪拌下依次加入1-氧雜-6-氮雜-螺[2.5]辛烷三氟乙酸鹽205b ^(0.1 mL’ 0.8 mmol)和碳酸鉀（41.4 mg，0. 3mmol)，力口熱 ❿回流4小時，反應完畢。將反應液在減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化（梯度沖提：二氯甲烷：曱醇=20: 1)，得到本標題產物（R)-i-[3-(3-U-tt ‘氣-4-(3 -氟-节氧基）-苯胺基]-喧嗤琳-6-基}-°比嘻-1-基） -2-經基-丙基]-4-經曱基- π底淀-4-醇205(632 mg，黃色固體），產率：41. 2°/。。 MS m/z (ESI) ： 632[M+1] ^ ]H NMR (400 MHz, CD30D-d6) ： <5 9. 76 (s, 1H), 8.56 (s ^ 1H), 8.49 (s, 1H), 8.04 (s, 1H), 8.02 (d, J = 8. 8Hz, 1H)，7· 78 (d，J = 8. 8Hz，1H)，7. 70 (d，J = 8. 8Hz，1H)， 7.47 (t, J = 8.8Hz, 1H), 7.45 (s, 1H), 7.32 (m, 3H), 7.20 (t, J = 8.8Hz, 1H), 6.87 (s, 1H), 6.66 (s, 1H), 5.27 (s, 2H)，4.56 (br, 1H) 4.06 (t, J = 12.8Hz, 1H)， 3.94 (s’ 1H)，3.85 (m，1H)，3.52 (s，2H)，3.43 (br, 4H), 3.18(t, J = 6.0Hz, 2H), 1. 38 (d, J = 12.8Hz, 2H), 94389 350 201016683 1. 25 (d, J = 9. 6Hz, 2H) 實施例206P first step 205 〇1_oxax_6 aza-spiro[2.5] Xinyuan trifluoroacetate salt 1-oxa, 6, aza-spiro[2.5] octyl - - 205a (509 mg, 2 Journal, 驮弟一丁适曰g z.39mmol) dissolved in 2〇() under the condition of two gas bath, cooled to 〇卩,士λ ζ τ _ & r, in ice q π this difluoroacetic acid, At room temperature, 3 〇 is given as the clock' reaction is completed. The reaction liquid was concentrated under reduced pressure, and the crude liquid was obtained as a crude product, oxabenzene, sulphur, snail, sulphur, sulphur, sulphur, sulphur, sulphur, sulphur, sulphur, sulphur, sulphur, sulphur, sulphur Hurricane 94389 349 201016683 Second step (RM-[3-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-anilinoquinazolinylpyrrole-1-yl) )-2-hydroxy-propyl hydroxydecyl-piperidinol in a 100 mL eggplant-shaped flask, (r)-[3-gas_4_(3_fluoro-benzyloxy)_ violent]-[6 -(1-Epoxyethylmethyl-in-. than 嘻-3-yl)-oxazolidine-amine 186a (154 mg, 0.3 mmol) dissolved in 25 mL of methanol and then added with stirring 1-oxa-6-aza-spiro[2.5]octane trifluoroacetate 205b ^ (0.1 mL ' 0.8 mmol) and potassium carbonate (41.4 mg, 0.3 mmol), and refluxed for 4 hours. The reaction mixture is concentrated under reduced pressure, and the obtained residue is further purified and purified by chromatography (chromate elution: methylene chloride: decyl alcohol = 20:1) to give the title product (R) -i-[3-(3-U-tt 'gas-4-(3-fluoro-p-ethoxy)-anilino]-indolyl-6-yl}-° than 嘻-1-yl) -2 - propyl-propyl]-4-carboxylidene- π-propan-4-ol 205 (632 mg, yellow solid), yield: 41. 2 ° /. MS m / z (ESI): 632 [ M+1] ^ ]H NMR (400 MHz, CD30D-d6): <5 9. 76 (s, 1H), 8.56 (s ^ 1H), 8.49 (s, 1H) , 8.04 (s, 1H), 8.02 (d, J = 8. 8Hz, 1H), 7· 78 (d, J = 8. 8Hz, 1H), 7. 70 (d, J = 8. 8Hz, 1H) , 7.47 (t, J = 8.8Hz, 1H), 7.45 (s, 1H), 7.32 (m, 3H), 7.20 (t, J = 8.8Hz, 1H), 6.87 (s, 1H), 6.66 (s, (H, 1H) (br, 4H), 3.18(t, J = 6.0Hz, 2H), 1. 38 (d, J = 12.8Hz, 2H), 94389 350 201016683 1. 25 (d, J = 9. 6Hz, 2H) Example 206

206 ‘ 在1〇0虹茄形瓶中，將（S)-[3-氯-4-(3-氟一苄氧基卜 .苯基]普（卜環氧乙基f基鲁鱗_3_基）_料琳+基] -胺 185a (150 mg，〇.3 mmol)和 4_ 甲基辰哄+ 基胺（38 mg，0.33麵〇溶於20 mL無水甲醇中，加熱回流反應3 g小時。將反應液在減壓下濃縮，得到的殘留物藉由梦膠管柱層析法進一步分離純化（二氯甲烷：曱醇=5〇 : 〇，得到本標題產物（R)-l-(3-{4-[3-氯-4-(3-氟-苄氧基）_苯胺基] 啥峻琳-6-基比p各-1-基）-3-曱氧基-丙_2-醇206 (76 mg，黃色固體），產率：47. 6%。 MS m/z (ESI) ： 533[M+1] ]H NMR (400 MHz, CD30D-d〇: 5 9. 69 (s, 1H), g 54 (s 1H)，8.50 (s，1H)，8.05 (s，1H)，8.03 (d，J = 8.8Hz 94389 35】 201016683206' In a 1〇0 rainbow egg-shaped bottle, (S)-[3-chloro-4-(3-fluoro-benzyloxybu-phenyl)-p-epoxyethyl-f-rule scale_3 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ The reaction mixture was concentrated under reduced pressure, and the obtained residue was further purified and purified by methylene chloride column chromatography (dichloromethane: decyl alcohol = 5 〇: 〇 to give the title product (R)-l-( 3-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-anilino] 啥君琳-6-kibbi p-1-yl)-3-decyloxy-propan-2- - alcohol 206 (76 mg, yellow solid), yield: 47. 6%. MS m/z (ESI): 533[M+1]]H NMR (400 MHz, CD30D-d〇: 5 9. 69 ( s, 1H), g 54 (s 1H), 8.50 (s, 1H), 8.05 (s, 1H), 8.03 (d, J = 8.8Hz 94389 35) 201016683

1H), 7. 77 (d, J = 8. 8Hz, 1H), 7. 70 (d, J = g 〇H ΰΠ2, \ϊ\\ 7. 50 (t, J _ 8. 8Hz, 1H), 7. 43 (s, 1H), 7. 33 (m ， 7. 19 (t, J = 8.8Hz，1H)，6.87 (s，1H)，6.66 (s’ 3H)’ 5. 27 (s，2H)，5. 20 (d, J = 4. 8Hz，1H)，4. (t )’ 12.8Hz, 1H), 3.94(S, lH), 3.85 (m, 1H), 3 31 r ，：= 3. 36(m, 2H) . 1 (s’ 3H)，實施例207 0 (S)-l-「l，4’ 底发，-基苄氧基苯胺基卜琳-6-篡卜咐U-其 '〜円1H), 7. 77 (d, J = 8. 8Hz, 1H), 7. 70 (d, J = g 〇H ΰΠ2, \ϊ\\ 7. 50 (t, J _ 8. 8Hz, 1H), 7. 43 (s, 1H), 7. 33 (m , 7. 19 (t, J = 8.8Hz, 1H), 6.87 (s, 1H), 6.66 (s' 3H)' 5. 27 (s, 2H ), 5. 20 (d, J = 4. 8Hz, 1H), 4. (t )' 12.8Hz, 1H), 3.94(S, lH), 3.85 (m, 1H), 3 31 r ,:= 3 36(m, 2H) . 1 (s' 3H), Example 207 0 (S)-l-"l,4' base,-benzylbenzyl aniline phenylamine -6-篡b咐U- Its '~円

QQ

OXOX

在100 mL茄形瓶中，將（S)-[3-氯-4-(3-氟〜苄氧苯基]-[6-(1-環氧乙基甲基_1H—吡咯_3_基）—喹唑啉 -胺 185a(100 mg，〇. 2 賴〇1)和 4-旅咬基旅咬（43 mg 〇 mmol)溶於20 mL無水甲醇中，加熱回流5小時後反應二4 畢。將反應液在減壓下濃縮，得到的殘留物藉由矽膠= 層析法進一步分離純化（梯度沖提··二氣甲烷：$醇=^卜 5 : 1)，得到本標題產物以兴卜门“”二哌啶基-^-基勺一 94389 352 201016683 (3-{4-[3-氣-4-(3 -氟-苄氧基）-苯胺基]-喧。坐琳_6__美j 0比洛-1 -基）-丙-2-醇207(73 mg ’淡黃色固體），產率：54%。 MS m/z (ESI) ： 669[M+1] ]H NMR (400 MHz, CD30D-d〇: <5 9. 70 (s, 1H), 8.54 (s 1H) =8.49 (s，1H)，=8.03 (d，J = 8Hz，2H)，7.76 (d J = 8.4Hz，1H)，7.70 (d，J=8.8Hz，1H)，7.48 (m，ijj) 7.41 (s，1H)，7.33 (m，3H)，7.19 (t，J=8Hz，1H)，6 88 (s, 1H), 6.65 (s, 1H), 5.27 (s, 2H), 4.88 (m, 1H), 4 〇2 ^ (m, 1H), 3.87 (m, 2H), 2.90 (m, 2H), 2.42 (m, 4H), 2 21 U (m, 3H), 1.94 (m, 2H), 1.64 (m, 2H), 1.36 (m, gH) 實施例208 1-(3-{4-「3-氣-4-(3-氟>-苄氧基）-笨胺基~|-啥〇坐嘛—6_旱} • -°比略-1-基）-3-[4-(2-經基乙基）-派啡-l-基l-丙—(S)-[3-Chloro-4-(3-fluoro-benzyloxyphenyl)-[6-(1-epoxyethylmethyl-1H-pyrrole_3_) in a 100 mL eggplant-shaped flask Base) - quinazoline-amine 185a (100 mg, 〇. 2 lysine 1) and 4-Brigade base brigade (43 mg 〇mmol) dissolved in 20 mL of anhydrous methanol, heated to reflux for 5 hours, reaction 2 The reaction solution is concentrated under reduced pressure, and the obtained residue is further separated and purified by chromatography (chromatography: di-methane methane: m alcohol =^b 5:1) to obtain the title product. Xing Bu Men "" Dipiperidinyl-^-base spoon a 94389 352 201016683 (3-{4-[3- gas-4-(3-fluoro-benzyloxy)-anilino]-喧. Sitting _ 6__美j 0 比洛-1 -yl)-propan-2-ol 207 (73 mg 'light yellow solid), yield: 54%. MS m/z (ESI): 669[M+1]]H NMR (400 MHz, CD30D-d〇: <5 9. 70 (s, 1H), 8.54 (s 1H) = 8.49 (s, 1H), = 8.03 (d, J = 8 Hz, 2H), 7.76 (d J = 8.4 Hz, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.48 (m, ijj) 7.41 (s, 1H), 7.33 (m, 3H), 7.19 (t, J = 8 Hz, 1H) ,6 88 (s, 1H), 6.65 (s, 1H), 5.27 (s, 2H), 4.88 (m, 1H), 4 〇 2 ^ (m, 1H), 3.87 (m, 2H), 2.90 (m , 2H), 2 .42 (m, 4H), 2 21 U (m, 3H), 1.94 (m, 2H), 1.64 (m, 2H), 1.36 (m, gH) Example 208 1-(3-{4-"3 - gas-4-(3-fluoro>-benzyloxy)-stupylamino~|-啥〇坐—6_ drought} • -° ratio -1-base)-3-[4-(2 -Phenylethyl)-parphine-l-yl l-propyl-

將[3-氯-4-(3-氟1-苄氧基）-苯基]-[6-(1-環氧乙基甲基-1H-吡咯-3-基）-喹唑啉-4-基]-胺187a(200 mg，〇. 4 mmo 1)溶於1 〇 mL甲醇中，攪拌下依次加入2 mL三乙胺和 2-fl底哄-1 -基-乙醇（〇. 06 mL，0· 44 mmo 1)，反應液力u熱回 353 201016683 流’ 4小時後反應完畢。將反應液在減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化（二氣甲院：甲醇=10 : 1)，得到本標題產物1-(3-{4-[3-氯-4-(3-氣-节氧基）-苯胺基]-喧唾琳-6-基}-°比洛-1-基）-3-[4-(2-經基乙基）-0底畊-1-基]-丙-2-醇208(156 mg，黃色固體），產率· 6 0 %。 MS m/z (ESI) ： 631[M+1] ]Η NMR (400 MHz, CD30D-d〇： 5 9. 71 (s, 1H), 8.54 (s, λ 1H), 8. 50 (s, 1H), 8. 04 (s, 1H), 8. 02 (d, J = 8. 8Hz, q 1H), 7. 85 (d, J = 8. 8Hz, 1H), 7. 69 (d, J = 8. 8Hz, 1H), 7.54 (t, J = 8. 8Hz, 1H), 7.42 (s, 1H), 7.32 (m, 3H), 7.19 (t, J = 8. 8Hz, 1H), 6.87 (s, 1H), 6.65 (s, 1H), 5. 27 (s, 2H), 4. 90 (d, J = 4. 0Hz, 1H), 4. 35 (m, 1H) -4. 06(t, J = 12.8Hz, 1H), 3. 94 (br, 1H), 3.85 (m, 1H), 3.49 (m, 2H), 2.35 (br，10H), 2.20 (m, 2H) 實施例209 Q 1-(3-丨4-「3-氣-4-(3-氟-芊孝其、-苹胺基]-喹唑啉-fi-其} ❹-吡咯-1-基）-3-(4-甲磺醯基-哌_-1二蓋_)_西-2-酵[3-Chloro-4-(3-fluoro-1-benzyloxy)-phenyl]-[6-(1-epoxyethylmethyl-1H-pyrrol-3-yl)-quinazoline-4 -Alkyl]-amine 187a (200 mg, 〇. 4 mmo 1) was dissolved in 1 mL of methanol, and 2 mL of triethylamine and 2-fl-endoxime-1 -yl-ethanol were added in sequence with stirring (〇. 06 mL , 0· 44 mmo 1), reaction hydraulic force u heat back to 353 201016683 flow '4 hours after the reaction is completed. The reaction mixture was concentrated under reduced pressure, and the obtained residue was further purified and purified by hexane column chromatography (2:3: methanol = 10:1) to give the title product 1-(3-{4-[ 3-Chloro-4-(3- gaso-oxy)-anilino]-indolyl-6-yl}-pilo-1-yl)-3-[4-(2-ylethyl) -0-growth-1-yl]-propan-2-ol 208 (156 mg, yellow solid), yield 650%. MS m/z (ESI): 631 [M+1]] NMR (400 MHz, CD30D-d: 5 9. 71 (s, 1H), 8.54 (s, λ 1H), 8. 50 (s, 1H), 8. 04 (s, 1H), 8. 02 (d, J = 8. 8Hz, q 1H), 7. 85 (d, J = 8. 8Hz, 1H), 7. 69 (d, J = 8. 8Hz, 1H), 7.54 (t, J = 8. 8Hz, 1H), 7.42 (s, 1H), 7.32 (m, 3H), 7.19 (t, J = 8. 8Hz, 1H), 6.87 ( s, 1H), 6.65 (s, 1H), 5. 27 (s, 2H), 4. 90 (d, J = 4. 0Hz, 1H), 4. 35 (m, 1H) -4. 06(t , J = 12.8Hz, 1H), 3. 94 (br, 1H), 3.85 (m, 1H), 3.49 (m, 2H), 2.35 (br,10H), 2.20 (m, 2H) Example 209 Q 1 -(3-丨4-"3-Gas-4-(3-Fluoro-oxime, -Phenylamino)-quinazoline-fi- its} ❹-pyrrol-1-yl)-3-(4 -Metsulfonyl-piperazine--1 diced _)_West-2-Yellow

354 94389 201016683 \Ρ354 94389 201016683 \Ρ

〇=S〇=S

p第一步 ^ l-曱磺醯基哌哄將哌畊（1. 72g，20 mmol)溶於l〇 mL二氣甲烧中，攪拌下加入三乙胺（2 mL，40mmol) ’冰浴冷卻下，加入甲續 .醯氯（5. 55 mL ’ 24mmol)，混合液在室溫下授掉i小時反應完畢。反應液在減歷下漢縮’得到的殘留物藉由石夕夥管柱層析法進一步分離純化’得到化合物1 -甲續醯基哌哄2〇9a (2g，白色固體），產率：64%。 Q MS m/z (ESI) ： 165[M+1] «第二步 1-(3-{4-[3-氣-4-(3-氟-苄氧基）-苯胺基]-喹唑啡_6_基j -吡咯-1-基）一3-(4-甲績醯基_哌啡4_基）_丙_2_醇 1-甲石頁醯基哌D井209a(66 mg，〇. 4mmol)溶於1〇 niL·甲醇中L攪拌下依次加入2mL三乙胺和[3_氯一4_(3_氟_节氧基）—苯基]-[6-(卜環氧乙基f基-1H-吼咯-3-基）-喹唑啉 —4-基]-胺I87a(200rog，04mm〇1)，混合液加熱回流2小 94389 355 201016683 時後反應完畢。反應液在減壓下濃縮，得听判的殘留物藉由矽膠管柱層析法進一步分離純化（二氯甲烷：甲醇=1〇: ^，得到本標題產物1-(3-{4-[3-氣-4-(3 -氟-苄氧基）_苯胺基]一喧哇嚇基}-吼哈-1-基）-3-(4-甲橫酿基-旅卩井-1- 基）-丙-2-酵209 (19 mg，白色固體），產率：7. 2%。 MS m/z (ESI) ： 665[M+1] ]H NMR (400 MHz, CD30D-JO : ^ 9. 67 (s, 1H), 8. 8 (s, 1H), 8.5 (s, 1H), 8.03 (d, J=8.8Hz, 2H), 7.76 (dd, J=2Hz, j% 1H), 7.70 (d, J=8.4Hz, 1H), 7.5 (m, 2H), 7.36 (m, 3H), ^ 7.2 (s, 1H), 6.93 (s, 1H), 6.60 (s, 1H), 5.27 (s, 2H), 5.0 (s, 1H), 4.0 (m, 3H), 3. 15 (t, J=17. 6Hz, 4H), 2.9 (s, 3H), 2. 6 (m, 4H), 2. 3 (s, 2H) 實施例210pStep 1 l-sulfonylhydrazide piperidine (1. 72g, 20 mmol) was dissolved in 1 mL of methane toluene, and triethylamine (2 mL, 40 mmol) was added with stirring. Under cooling, chlorobenzene (5.55 mL '24 mmol) was added, and the mixture was allowed to stand at room temperature for 1 hour. The residue obtained by the reduction of the reaction liquid under reduced pressure was further separated and purified by Shi Xibang column chromatography to obtain Compound 1 - methyl hydrazide 2哄9a (2 g, white solid). Yield: 64%. Q MS m/z (ESI): 165[M+1] «Step 2 1-(3-{4-[3-Ga-4-(3-fluoro-benzyloxy)-anilino]-quinazoline _6_yl j-pyrrol-1-yl)-3-(4-methylphenyl)-piperidinyl-4-yl)-propan-2-ol 1-methylsulfonylpiperazine D well 209a (66 mg , 〇. 4mmol) dissolved in 1〇niL·methanol L under stirring, add 2mL of triethylamine and [3_chloro-4-(3_fluoro-p-oxy)-phenyl]-[6-(ep-epoxy) Ethyl f-yl-1H-indol-3-yl)-quinazolin-4-yl]-amine I87a (200 rog, 04 mm 〇1), the mixture was heated under reflux for 2 hours 94389 355 201016683 and the reaction was completed. The reaction mixture was concentrated under reduced pressure, and the residue obtained was purified and purified by methylene chloride column chromatography (dichloromethane:methanol = 1 : : ) 3-ox-4-(3-fluoro-benzyloxy)-anilino]-wow wow base}-heha-1-yl)-3-(4-甲横酿基-旅卩井-1- Base)-propan-2-enzyme 209 (19 mg, white solid), yield: 7. 2%. MS m/z (ESI): 665[M+1]]H NMR (400 MHz, CD30D-JO: ^ 9. 67 (s, 1H), 8. 8 (s, 1H), 8.5 (s, 1H), 8.03 (d, J=8.8Hz, 2H), 7.76 (dd, J=2Hz, j% 1H) , 7.70 (d, J=8.4Hz, 1H), 7.5 (m, 2H), 7.36 (m, 3H), ^ 7.2 (s, 1H), 6.93 (s, 1H), 6.60 (s, 1H), 5.27 (s, 2H), 5.0 (s, 1H), 4.0 (m, 3H), 3. 15 (t, J=17. 6Hz, 4H), 2.9 (s, 3H), 2. 6 (m, 4H) , 2. 3 (s, 2H) Embodiment 210

II 「3-氣-4-(3- l二苄氧基）-策基l-丨6-「】-〔2-吡啶-2-某-Λ 基）-1 Η-ρ比咯-3-基1-啥ρ坐说-4-基丨-胺II "3-Gas-4-(3- l-Butyloxy)-Zhyl l-丨6-"]-[2-Pyridin-2-yl-fluorenyl)-1 Η-ρ 比咯-3- Base 1-啥ρ sits -4-ylindole-amine

356 94389 201016683356 94389 201016683

210a210a

Cl 第一步Cl first step

曱磺酸（2-吡啶-2-基）乙酯將2-吡啶-2-基-乙醇（2.4 20 mmol)溶於 20 mL 二氯曱烷中，在冰浴條件下，冷卻至〇。〇，依次加入三乙胺 (5. 5 mL ’ 40 mmol)和甲磺醯氯（2. 3 mL，30 mmol)，室溫 •下擾拌2小時，反應完畢。將反應液中加入3〇 mL水，減 -壓下蒸掉二氣甲烷，用乙酸乙酯萃取（60 mLx3)，合併的有機相依次經由飽和氯化鈉溶液洗滌，無水硫酸鈉脫水，過濾，減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一 g步分離純化（正己烧：乙酸乙s|=3: υ，得到甲績酸 «啶-2-基）乙酯21〇a(3.9g，黃色油狀液體），產率：97%。 MS m/z (ESI) ： 202[M+1] ° 第二步在50mL的燒瓶中，將[3_氣—4_(3_氟_苄氧基）_笨基 -[6-(lH-吡咯-3-基）-喹唑啉_4_基μ胺42(222邶，咖〇1)溶於6。虹無水N，N一二甲基甲醯胺中，在冰浴條件下’冷部至0 C ’加入氫化鈉（60 rag，L 5 mm〇1)，攪拌Μ 94389 357 201016683 分鐘後加入甲磺酸（2_吡啶_2_基）乙酯21〇a (151邮，〇 75 mmol ) ’室溫下攪拌2小時反應完畢。反應液減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化（二氯甲炫··甲醇=60 : 1)，得到本標題產物[3-氯-4-(3-氟-苄氧基）-苯基]-{6-[1-(2-«比啶-2-基-乙基）比咯-3-基]-喹唑啉-4-基卜胺210 (235 mg，黃色固體），產率：85. 6%。 MS m/z (ESI) ： 550[M+1] Ή NMR (400 MHz, CD30D-c/6) ： 5 9. 69 (s, 1H), 8.53 (m, φ 3H), 8.02 (m, 2H), 7.75 (m, 1H), 7. 70 (m, 2H), 7.48 0 (m, 1H), 7.42 (s, 1H), 7.25 (m, 6H), 6.85 (s, 1H), 6.62 (s, 1H), 5.27(s, 2H), 4. 35 (t, J=7. 2Hz, 2H), 3. 26 (t, J = 7.2Hz, 2H) ，實施例211 . 卜Γ3-{4-「3-氣-4-(3-氟-苄氣某茉胺基l-ϋ琳_6-某} -吡咯-1-基）-3-(1, 1-二側氣某-六氤-1又木⑭-噻喃-4-篡胺某丙-2-醇(2-Pyridin-2-yl)ethyl sulfonate 2-Pyridin-2-yl-ethanol (2.420 mmol) was dissolved in 20 mL of dichloromethane and cooled to hydr. 〇, triethylamine (5.5 mL '40 mmol) and methanesulfonium chloride (2.3 mL, 30 mmol) were added in sequence, and the mixture was stirred at room temperature for 2 hours, and the reaction was completed. To the reaction mixture, 3 mL of water was added, and the methane was evaporated under reduced pressure, and extracted with ethyl acetate (60 mL×3). The combined organic phases were washed sequentially with saturated sodium chloride solution, dried over anhydrous sodium sulfate and filtered. Concentration under reduced pressure, and the residue obtained was purified by hexane column chromatography, and then purified (yield: acetic acid ethyl s|=3: oxime to give a hydrazinyl acid). a (3.9 g, yellow oily liquid), yield: 97%. MS m/z (ESI): 202 [M+1] ° Step 2 In a 50 mL flask, [3_ gas-4_(3_fluoro_benzyloxy)-styl-[6-(lH- Pyrrol-3-yl)-quinazoline-4-yl-imamide 42 (222 邶, curry 1) was dissolved in 6. In the anhydrous N,N-dimethylformamide, add sodium hydride (60 rag, L 5 mm〇1) to the cold part to 0 C in ice bath, stir Μ 94389 357 201016683 minutes, add methyl sulfonate Acid (2_pyridine-2-yl)ethyl ester 21〇a (151 gram, 〇75 mmol) 'The reaction was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified and purified (jjjjjjjjjjjj Fluoro-benzyloxy)-phenyl]-{6-[1-(2-«pyridin-2-yl-ethyl)pyrrol-3-yl]-quinazolin-4-ylbumin 210 ( 。 235 mg, yellow solid), yield: 85.6%. MS m/z (ESI): 550 [M+1] NMR (400 MHz, CD30D-c/6): 5 9. 69 (s, 1H), 8.53 (m, φ 3H), 8.02 (m, 2H ), 7.75 (m, 1H), 7. 70 (m, 2H), 7.48 0 (m, 1H), 7.42 (s, 1H), 7.25 (m, 6H), 6.85 (s, 1H), 6.62 (s , 1H), 5.27(s, 2H), 4. 35 (t, J=7. 2Hz, 2H), 3. 26 (t, J = 7.2Hz, 2H), Example 211. 卜Γ3-{4- "3-Q4--4-(3-fluoro-benzyl-methyl-l-ammonyl l-ϋ琳_6-某}-pyrrol-1-yl)-3-(1, 1-di-side gas-six-anthracene- 1 wood 14-thiopyran-4-amine amine propan-2-ol

❹ 0❹ 0

187a 211 358 94389 201016683 、，卜二側氧基'六氫-1 口 6*-噻喃+基胺鹽酸鹽 (103 mg，〇·56 mffi0l)和[m(3_氣一节氧基笨基卜 [6-U-環氧乙基甲基-1H-吡咯一 3 一基）一喹唑啉-4_基]一胺 187a(163 mg，〇. 33 職〇1)溶於 1〇社入三一g，請叫加熱回流過夜減壓下濃縮’得到的殘留㈣由謂管柱層析法進一步分離純化（二氯甲烷：曱醇=4〇:1)，得到本標題產物卜（3一丨咎 [3-氯-4-(3-氟-苄氧基）-苯胺基μ喹唑啉_6_基卜吼咯4 — 基）-3-(1, 1-二侧氧基-六氫λ *6*_噻喃_4_基胺基）一丙 -2-醇211(92 mg，黃色固體）’產率：21. 7% MS m/z (ESI) · 650[M+1] H NMR (400 MHz, CdSOd-de) ： δ 8. 55 (s, 1H) 8 50 (s .1H)’ 8.04 (m，2H)，7.77 (d，J=9.2Hz，1H)，7.70 (d J=8.4Hz，1H)，7.48 (m’ 1H), 7.43 (s，ih>，7.32 (m，3H)， 7. 19 (t, J = 8. 8Hz, 1H), 6. 89 (s, 1H), 6. 66 (s, 1H), 5 27 (s, 2H), 5. 07 (s，1H), 4· 05 (m，1H)，3. 88 (m，2H)，3· 13 〇(dr，4H)，3.01 (m，2H)，2.72 (m，2H)，1.24 (m，4H) ®實施例212 [3-氣-4-(3-氟-苄氧基）-苯基— n比戍一某 - 1Η-ρ比洛-3-基）-啥°坐咐-4_基-胺187a 211 358 94389 201016683 、, bis-oxyl hexahydro-1 hydroxy 6*-thiopyranyl-amine hydrochloride (103 mg, 〇·56 mffi0l) and [m(3_qi oxy) Kebu [6-U-epoxyethylmethyl-1H-pyrrole-3-yl)-quinazolin-4-yl]monoamine 187a (163 mg, 〇. 33 〇1) is dissolved in 1〇社Into the Sanyi g, please call it under reflux under reduced pressure to obtain the residue (4) and further separate and purify by column chromatography (dichloromethane: decyl alcohol = 4 〇: 1) to obtain the title product (3) [丨咎-[3-Chloro-4-(3-fluoro-benzyloxy)-anilino-quinazoline -6-dibupyrrole 4-yl)-3-(1,1-di-oxyl- Hexahydroλ *6*_thiopyran-4-ylamino)propan-2-ol 211 (92 mg, yellow solid) 'yield: 21. 7% MS m/z (ESI) · 650 [M+ 1] H NMR (400 MHz, CdSOd-de): δ 8. 55 (s, 1H) 8 50 (s .1H)' 8.04 (m, 2H), 7.77 (d, J = 9.2 Hz, 1H), 7.70 (d J = 8.4 Hz, 1H), 7.48 (m' 1H), 7.43 (s, ih >, 7.32 (m, 3H), 7. 19 (t, J = 8. 8 Hz, 1H), 6. 89 ( s, 1H), 6. 66 (s, 1H), 5 27 (s, 2H), 5. 07 (s, 1H), 4· 05 (m, 1H), 3. 88 (m, 2H), 3 · 13 〇 (dr, 4H), 3 .01 (m, 2H), 2.72 (m, 2H), 1.24 (m, 4H) ® Example 212 [3-Ga-4-(3-fluoro-benzyloxy)-phenyl-n - 1Η-ρ比洛-3-yl)-啥°咐咐-4_yl-amine

94389 212 359 20101668394389 212 359 201016683

212a k212a k

第一步 ❾曱橫酸（吡啶-2-基）曱酯 0 將0比咬-2-基-甲醇（2. 18 g，20 mmol)溶於30 mL二氯曱烷中，在冰浴條件下，冷卻至，依次加入三乙胺（5. 5 mL ’ 40 mmol)和甲續醯氣（2.4 mL ’ 30 mmol) ’室溫下搜摔 • 2小時’反應完畢。將反應液中加入30 mL水，減壓下蒸掉二氯曱燒’用乙酸乙酯萃取（3〇 mLx3)，合併的有機相依次經由無水硫酸納脫水’過遽，減麼下濃縮’殘留物藉由矽膠管柱層析法分離純化（二氣曱烷：甲醇=1〇 : 1)，得到 ©甲磺酸（吡啶-2-基）甲酯212a(2.3g，紅褐色固體），產率： 0 61.5% ° MS m/z (ESI) : 188[M+1] 第二步 [3-氯-4-(3-氣-苄氧基）-苯基]-[6-(1_ η比n定_4_基甲基 -111-11比洛-3-基）-噎唾琳-4-基]-胺在50 mL的燒瓶中，將[3-氯-4-(3-氟-苄氧基）_苯基] -[6-(1Η-吡咯-3-基）-喹唑啉-4-基]-胺 42(222 mg，〇 5 94389 360 201016683 mmol)溶於6 mL無水Ν,Ν-二曱基曱醯胺中，在冰浴條件下’冷卻至〇C ’加入氫化納（60mg，1.5 mmo 1)，搜拌2 〇分鐘後加入甲磺酸（吡啶-2-基）曱酯212a( 136 mg，〇. 73 mmol)，室溫下攪拌2小時反應完畢。反應液減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化（二氯曱烧.曱醇-60 . 1 )，得到本標題產物[3一氣_4_(3-氟-苄氧基）-苯基]-[6-(1-吡啶-2-基曱基-1H-吡咯-3-基）-喹唑啉 -4-基]-胺212 (22 mg ’黃色固體），產率：84%。 0 MS m/z (ESI) ： 536[M+1] H NMR (400 MHz，CD30D-d<〇: (5 9.69 (s，1H)，8.57 (m， 2H)，8.50 (s’ 1H)’ 8.01 (m，2H)，7.76 (m，3H)，7.49 (m, 2H), 7. 33 (m, 4H), 7. 16 (m, 2H), 7. 02 (s, 1H), 6. 73 • (s, 1H), 5.27 (m, 4H) 實施例213 (R)-l-(3_-<4-[ lzL3_·-氟-至_基上』Η_吲唑-5_某脸其卜啐舛啉-6-基}-p比咯-1-基）-3-嗎嚷-4-某-而-?.-辞The first step is the acid (pyridin-2-yl) decyl ester 0. 0 butyl-2-yl-methanol (2.18 g, 20 mmol) is dissolved in 30 mL of dichloromethane in ice bath conditions. Next, cool down, add triethylamine (5.5 mL '40 mmol) and a continuous helium gas (2.4 mL '30 mmol) in turn, and search for "2 hours at room temperature". The reaction solution was added with 30 mL of water, and dichlorohydrin was distilled off under reduced pressure. The mixture was extracted with ethyl acetate (3 〇mL×3), and the combined organic phases were sequentially dehydrated by anhydrous sodium sulfate to reduce the residue. The product was isolated and purified by silica gel column chromatography (dioxane:methanol = 1 : 1 ) to give (yield: pyridin-2-yl)methyl ester 212a (2.3 g, reddish brown solid). Rate: 0 61.5% ° MS m/z (ESI): 188 [M+1] Step 2 [3-chloro-4-(3-carb-benzyloxy)-phenyl]-[6-(1_ η [3-chloro-4-(3-fluorine) in a 50 mL flask in a 50 mL flask than n-1,4-methyl-3-111-11pyrazin-3-yl]-amine -benzyloxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinazolin-4-yl]-amine 42 (222 mg, 〇5 94389 360 201016683 mmol) dissolved in 6 mL anhydrous In hydrazine, hydrazine-dimercaptoamine, add 'sodium hydride (60 mg, 1.5 mmo 1) to 'cooling to 〇C' under ice bath conditions, and mix for 2 〇 minutes, then add methanesulfonic acid (pyridin-2-yl) The oxime ester 212a (136 mg, 〇. 73 mmol) was stirred at room temperature for 2 hours and the reaction was completed. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified and purified by EtOAc EtOAc EtOAc EtOAc EtOAc Benzyloxy)-phenyl]-[6-(1-pyridin-2-ylindenyl-1H-pyrrol-3-yl)-quinazolin-4-yl]-amine 212 (22 mg 'yellow solid) , Yield: 84%. 0 MS m/z (ESI): 536 [M+1] H NMR (400 MHz, CD30D-d < 〇: (5 9.69 (s, 1H), 8.57 (m, 2H), 8.50 (s' 1H)' 8.01 (m, 2H), 7.76 (m, 3H), 7.49 (m, 2H), 7. 33 (m, 4H), 7. 16 (m, 2H), 7. 02 (s, 1H), 6. 73 • (s, 1H), 5.27 (m, 4H) Example 213 (R)-l-(3_-<4-[ lzL3_·-fluoro- to _ 上上上Η 吲吲 azole-5_ a face Its porphyrin-6-yl}-p-pyrrol-1-yl)-3-?嚷-4-one-and-?.-

94389 361 213 201016683 第一步 (R)-4-環氧乙基甲基嗎啉在100mL茄形瓶中，將嗎琳（5g，57mmo 1)溶於2 5 mL 第二丁醇中’在氬氣氛下，將反應液冷卻至0 °C，緩慢滴加（R)-2-氣甲基環氧乙燒213a(5.4g，59mmol)，保持攪拌30分鐘後，升至室溫反應過夜。在冰浴冷卻下，保持 15°C以下，滴加30 mL第三丁醇鉀（6.3g，56mm〇l)的四氫呋喃溶液’滴加完畢後，在此溫度下反應2小時後反應完 ❹畢。將反應液倒入1〇〇 mL冰水中，用二氯甲烷（5〇 mLx3) Φ萃取’合併的有機相依次經由餘和氯化鈉溶液洗膝，無水硫酸鈉脫水’過濾，減壓下濃縮’得到的殘留物藉由矽膠管柱層析法進一步分離純化’得到化合物（R)_4_環氧乙基 •甲基嗎啉213b(5· 65g ’黃色油狀液體），產率·· 69. 2%。 .MS m/z (ESI) ： 144[M+1] 第二步 (R)-l-(3-{4-[l-(3-氟-苄基）-ih-吲唑-5-基胺基]-喹唑鬱琳-6-基}-D比嘻-1-基）-3-嗎淋-4-基-丙-2-醇將{6 [1-(2 -—乙胺基乙基）~ 1Η_π比洛_3_基]-喧®坐咐 -4-基}-[1-(3-氟苄基）-1Η-吲唑-5-基]-胺 150(200 mg， 0.46mmol)溶於4 mL N，N-二甲基甲醯胺中，〇。〇下加入氫化鈉（150 mg，3. 75mmol)，攪拌3〇分鐘後，加入（R) 一 4__ 環氧乙基曱基嗎啉213b(98 mg，〇. 69mmol)，反應液在室溫下攪拌過夜。將反應液倒入1 〇〇 mL冰水中，用乙酸乙酯 (40 mLx4)萃取’合併有機相，依次用飽和氣化鈉溶液洗 362 94389 201016683 滌，無水硫酸鈉脫水，；藉由矽膠管柱層析法進一：八’得到的殘留物乂刀離純化’侍到標題產物（r) + (3-ί4-[1-(3—氟-节基)，“弓卜坐-5一基胺基]十坐啉 6基}吡咯-1-基）-3-嗎啉—4-基-丙-2-醇213(56 mg，淡黃色固體），產率：21.1%。 MS m/z (ESI) ： 578[M+1] 5HNMR (400MHz, CD30D-d〇: 5 9. 82 (s, 1H), 8. 60 (s, 1H) 8.44 (s, 1H), 8.23 (s, 1H), 8.17 (s, 1H), 8.03 (d 1H ^ J=8. 8Hz), 7.73 (m, 3H), 7.43 (s, 1H), 7.38 (m 1H) _ 7. 10 (m, 3H), 6· 88 (s, 1H), 6. 67 (s, 1H), 5· 72 (s，2H)， 4. 96 (s，1H)’ 3. 97 (m，3H)’ 3. 61 (m，4H)，2. 43 (m，4H)， 2. 26 (m, 2H) 實施例214 (8)-1-(3-{4-[1-(3-氟~"苄基）-111-°弓丨°坐-5-基胺基~[_|^0坐 *#•-6—基}_口比口各—1 一基）一3 —气黾琳_4一基一丙一2-_—94389 361 213 201016683 First step (R)-4-epoxyethylmethylmorpholine In a 100 mL eggplant-shaped flask, morphine (5g, 57mmo 1) is dissolved in 2 5 mL of dibutanol in argon The reaction solution was cooled to 0 ° C under an atmosphere, and (R)-2-methylmethylepoxyethane 213a (5.4 g, 59 mmol) was slowly added dropwise, and the mixture was stirred for 30 minutes, and then allowed to react to room temperature overnight. Under ice cooling, keep 15 ° C or less, add 30 mL of potassium tetrabutoxide (6.3 g, 56 mm 〇l) in tetrahydrofuran solution. After the dropwise addition, react at this temperature for 2 hours and then complete the reaction. . The reaction solution was poured into 1 mL of ice water, and extracted with dichloromethane (5 〇 mL x 3) Φ. The combined organic phases were washed successively with the residual sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 'The obtained residue was further separated and purified by the column chromatography to obtain the compound (R)_4_epoxyethyl•methylmorpholine 213b (5·65 g 'yellow oily liquid), yield·· 69 . 2%. .MS m/z (ESI): 144 [M+1]. Step 2 (R)-l-(3-{4-[l-(3-fluoro-benzyl)-ih-carbazole-5-yl Amino]-quinazoline-6-yl}-D than 嘻-1-yl)-3-oxalin-4-yl-propan-2-ol will be {6 [1-(2-ethylamino) Ethyl)~1Η_π比洛_3_yl]-喧®咐-4-yl}-[1-(3-fluorobenzyl)-1Η-indazol-5-yl]-amine 150 (200 mg, 0.46 mmol) was dissolved in 4 mL of N,N-dimethylformamide, hydrazine. Sodium hydride (150 mg, 3.75 mmol) was added under the stirring, and after stirring for 3 hrs, (R)- 4__epoxyethyl decylmorpholine 213b (98 mg, 〇. 69 mmol) was added at room temperature. Stir overnight. The reaction solution was poured into 1 〇〇mL of ice water, and extracted with ethyl acetate (40 mL×4). The combined organic phases were washed successively with saturated sodium carbonate solution, 362 94389 201016683, and dehydrated with anhydrous sodium sulfate; Chromatography into one: eight's obtained residue cleavage from the purification 'serving the title product (r) + (3-ί4-[1-(3-fluoro-nodal), "bamboo--5-ylamine十十十 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 56 56 56 56 56 56 56 56 56 56 56 MS MS MS MS MS MS MS MS MS MS MS MS MS ESI) : 578[M+1] 5HNMR (400MHz, CD30D-d〇: 5 9. 82 (s, 1H), 8. 60 (s, 1H) 8.44 (s, 1H), 8.23 (s, 1H), 8.17 (s, 1H), 8.03 (d 1H ^ J=8. 8Hz), 7.73 (m, 3H), 7.43 (s, 1H), 7.38 (m 1H) _ 7. 10 (m, 3H), 6· 88 (s, 1H), 6. 67 (s, 1H), 5· 72 (s, 2H), 4. 96 (s, 1H)' 3. 97 (m, 3H)' 3. 61 (m, 4H ), 2. 43 (m, 4H), 2. 26 (m, 2H) Example 214 (8)-1-(3-{4-[1-(3-Fluoro~"benzyl)-111- °弓丨°Sit-5-ylamino-~[_|^0 sitting*#•-6—基}_ mouth ratio mouth--1 base) one 3—气黾琳_4一基一丙一2 -_-

94389 363 201016683 (S)-4-環氧乙基甲基嗎啉在100 mL茄形瓶中，將嗎啉（5 g，57mm〇1)溶於2 5此第三丁醇中，在氬氣氛下，將反應液冷卻至〇°C，緩慢滴加（S)-2-氯甲基環氧乙烷2i4a(5. 4g，59mmol)，保持（TC 攪拌30分鐘後，升至室溫反應過夜。在冰浴冷卻下，保持 15 e以下’滴加30 mL第三丁醇鉀（6· 3g，56mmol)的四氫呋喃溶液’滴加完畢後’在此溫度下反應2小時後反應完畢。將反應液倒入1〇〇 mL冰水中，用二氯甲烷（50 mLx4) _萃取’合併的有機相依次經由飽和氣化鈉溶液洗滌，無水 ®硫酸鋼脫水，過濾，減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化，得到化合物（s)_4-環氧乙基甲基嗎啉214b(6. 3g，黃色油狀液體），產率：69. 2%。 • MS m/z (ESI) ： 144[M+1] 第二步 (S)_l_(3-{4-[l-(3 -說-节基）-1Η-0引 D坐 _5 -基胺基]-喧。坐啉-6-基}-吡咯-1-基）-3-嗎啉-4-基-丙-2-醇 ® 將{6-[1-(2-二乙胺基-乙基）-1Η-吡咯-3-基]-喹唑啉 m w -4-基卜[1-(3-氟苄基）-1Η-吲唑-5-基]-胺 150(200 mg，〇.46mmol)溶於4 mL N，N-二甲基曱醯胺中，〇°C下加入氫化鈉（150 mg，3. 75mmol)，攪拌30分鐘後，加入（S)-4-環氧乙基甲基嗎啉214b(98 mg，0. 69mniol)，反應液在室溫下攪拌過夜，反應完畢。將反應液倒入1 〇〇 mL冰水中，用乙酸乙酯（40 mLx4)萃取，合併有機相，依次用飽和氯化鈉溶液洗滌，無水硫酸鈉脫水，過濾，減壓下濃縮，得到 364 94389 201016683 的殘留物藉由矽膠管柱層析法進一步分離純化，得到標題產物（S)-卜（3-{4-[1-(3-氟-苄基）-1Η-吲唑-5-基胺基]一喧嗤琳-6-基}-»>比嘻_ι_基）_3_嗎淋-4-基-丙-2-醇214 (7〇 mg，淡黃色固體），產率：35. 1%。 MS m/z (ESI) ： 578[M+1] 實嫌例215 2-(3-{4-[3-氣-4-(3-氟-苄氧基）-苯胺基]-°1:°坐啦-^-早^ -ρ比嘻-1-基）-l-p底p定-1-基-乙酮94389 363 201016683 (S)-4-Epoxyethylmethylmorpholine In a 100 mL eggplant-shaped flask, morpholine (5 g, 57 mm〇1) was dissolved in 25 of this third butanol in an argon atmosphere. The reaction solution was cooled to 〇 ° C, and (S)-2-chloromethyloxirane 2i4a (5.4 g, 59 mmol) was slowly added dropwise, and the mixture was stirred for 30 minutes, and then allowed to react to room temperature overnight. Under ice cooling, keep 15 e or less 'drop 3 mL of potassium t-butoxide (6.3 g, 56 mmol) in tetrahydrofuran solution 'after the addition is completed', react at this temperature for 2 hours and then complete the reaction. The solution was poured into 1 mL of ice water, and extracted with dichloromethane (50 mL×4). The combined organic phases were washed sequentially with saturated sodium sulfate solution, dried over anhydrous sulphuric acid steel, filtered, and concentrated under reduced pressure. The product was further separated and purified by a ruthenium column chromatography to give the compound (s)- 4-epoxyethylmethylmorpholine 214b (6.3 g, a yellow oily liquid), yield: 69. 2%. m/z (ESI): 144 [M+1] The second step (S)_l_(3-{4-[l-(3 -say-knot)-1Η-0 leads D sits _5-ylamino ]-喧.Sormine-6-yl}-pyrrol-1-yl)-3-morpholin-4-yl- Prop-2-propanol® {6-[1-(2-diethylamino-ethyl)-1Η-pyrrol-3-yl]-quinazoline mw-4-yl b[1-(3-fluoro Benzyl)-1Η-indazol-5-yl]-amine 150 (200 mg, 〇.46 mmol) was dissolved in 4 mL of N,N-dimethyl decylamine, sodium hydride (150 mg) (3. 75 mmol), after stirring for 30 minutes, (S)-4-epoxyethylmethylmorpholine 214b (98 mg, 0.69 mniol) was added, and the reaction mixture was stirred at room temperature overnight, and the reaction was completed. The solution was poured into 1 mL of ice water, extracted with ethyl acetate (40 mL×4), and the organic phase was combined, washed successively with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 364 94389 201016683 The residue was further separated and purified by silica gel column chromatography to give the title product (S)-b (3-{4-[1-(3-fluoro-benzyl)-1 - oxazol-5-ylamino) ]一喧嗤琳-6-基}-»> 比嘻_ι_基)_3_Nupolin-4-yl-propan-2-ol 214 (7〇mg, light yellow solid), yield: 35 1% MS m/z (ESI): 578 [M+1] susceptibility 215 2-(3-{4-[3- gas-4-(3-fluoro-benzyloxy)-anilino] -°1:°Sit -^-早^ -ρ比嘻-1-base)-lp bottom p -1- Keto-ketone

第一步 2_氯-1-〇底咬-l-基-乙酮將哌啶（850 mg ’ 10 ramol)溶於4〇 mL二氣甲烷中，加入三乙胺（2. 02 g ’ 20 mmol) ’冰浴冷卻至_78〇c，搜拌下加入氯乙酿氯（1.13 g’ 10 mmol)，攪拌3〇分鐘後反應完 94389 365 201016683 畢。在反應液中加入10 mL冰水，減壓下蒸去二氣甲炫，殘質用乙酸乙酯萃取（20 roLx3) ’合併的有機相經由水洗滌’無水硫酸鈉脫水，過濾，減壓下濃縮，得到的殘留物藉由石夕膠管柱層析法進一步分離純化（二氯甲院：甲醇: 1)，得到化合物2 -氯底咬-1-基-乙S同215a(1.52g，紅褐色油狀液體），產率：94. 4%。 MS m/z (ESI) ： 162[M+1] 第二步 ❹2-(3-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-喹唑啉一6_基} ❹-π比略-1_基）-l-u底咬-1-基-乙酮在50 mL的燒瓶中，將[3-氣-4-(3-氟-苄氧基）-苯基] -[6-(1Η-吡咯-3-基）-喹唑啉-4-基]-胺 42(222 mg，0.5 • 则ι〇1)溶於4 mL N，N-二曱基甲醯胺中’在冰浴條件下，冷 •卻至0°C ’加入氫化鈉（60 mg，1. 5 mmol) ’攪拌20分鐘後加入2-氯-1-哌啶-1-基-乙酮215a(121 mg，〇. 75 mmol)，室溫下攪拌i. 5小時反應完畢。反應液減壓下濃 ®縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化（二 ❹氯甲烷：曱醇=30 : 1)，得到本標題產物2-(3-{4-[3-氣-4-(3-氟-苄氧基）-苯胺基]-喹唑啉_6_基卜吡咯-卜基卜丨一哌咬-1-基-乙酮215(101 mg，黃色固體），產率：35.4%。 MS m/z (ESI) ： 570 [M+1] ]H NMR (400 MHz，CD30D-A) :(5 9. 71 (s，1H)，8.54 (s’ 1H), 8.50 (s, 1H), 8.03 (m, 2H), 7.75 (m, 2H), 7.47 (m, 1H), 7.31 Cm, 4H), 7. 19 (m, 1H), 6.82 (s, 1H), 6.65 366 94389 201016683 (s, 1H), 5.27 (s, 2H), 4.94 (s, 2H), 3.46 (t, J=5. 2Hz, 4H), 3.31 (m, 1H), 1.46-1.61 (br, 6H) 實施例216 1_二（3二{4-[3-氣-4-(3-氟-苄氳某）-芏胺基~|-啥_喊_6-基} 二°比洛-1-基）-N，N-二乙基-乙脸The first step 2_Chloro-1-indole bite-l-yl-ethanone piperidine (850 mg '10 ramol) was dissolved in 4 mL of di-methane, and triethylamine (2. 02 g ' 20 Methyl) Cool in ice bath to _78〇c, add chlorine chloride to brew chlorine (1.13 g' 10 mmol), stir for 3 minutes and then react 94389 365 201016683. Add 10 mL of ice water to the reaction mixture, distill the dioxane under reduced pressure, and extract the residue with ethyl acetate (20 roLx3). The combined organic phase was washed with water and dried over anhydrous sodium sulfate. After concentration, the residue obtained was further separated and purified by Shixi gum column chromatography (dichloroform: methanol: 1) to give the compound 2 - chloro-dip-1-yl-ethyl s- 215a (1.52 g, red) 4%。 The yield was 94.4%. MS m/z (ESI): 162 [M + 1] </ RTI> 2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline 6_基} ❹-π ratio -1_yl)-lu bottom bite-1-yl-ethanone in a 50 mL flask, [3-gas-4-(3-fluoro-benzyloxy)- Phenyl]-[6-(1Η-pyrrol-3-yl)-quinazolin-4-yl]-amine 42 (222 mg, 0.5 • then ι〇1) was dissolved in 4 mL of N,N-didecyl Addition of sodium hydride (60 mg, 1.5 mmol) in meglumine under ice-cooling conditions to a temperature of 0 ° C. After stirring for 20 minutes, add 2-chloro-1-piperidin-1-yl- Ethyl ketone 215a (121 mg, 〇. 75 mmol), stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was further purified and purified by silica gel column chromatography (dichloromethane: decyl alcohol = 30: 1) to give the title product 2-(3-{4- [3-Gas-4-(3-fluoro-benzyloxy)-anilino]-quinazoline -6-pyridyl-bribupyridin-piperidin-1-yl-ethanone 215 (101 mg, Yield: 35.4%. MS m/z (ESI): 570 [M+1]]H NMR (400 MHz, CD30D-A): (5 9. 71 (s, 1H), 8.54 (s ' 1H), 8.50 (s, 1H), 8.03 (m, 2H), 7.75 (m, 2H), 7.47 (m, 1H), 7.31 Cm, 4H), 7. 19 (m, 1H), 6.82 (s , 1H), 6.65 366 94389 201016683 (s, 1H), 5.27 (s, 2H), 4.94 (s, 2H), 3.46 (t, J=5. 2Hz, 4H), 3.31 (m, 1H), 1.46- 1.61 (br, 6H) Example 216 1_二(3二{4-[3-Ga-4-(3-fluoro-benzyl)-decylamine~|-啥_叫_6-基} °Bilo-1-yl)-N,N-diethyl-ethyl face

2-氣-N，N-二乙基乙醯胺將二乙胺（11.6g，159 mmo 1)溶於6 0 mL四氫咬p南中，在乾冰乙醇浴冷卻至-78°C，攪拌下逐漸滴加氯乙醯氯（6 g ’ 53 mmol)，滴加完畢在冰浴冷卻下攪拌30分鐘，反應元畢。在反應液中加入20 mL水，減塵下卷去四氫D夫味，得到的溶液用乙酸乙酯萃取（100 mLx3)，合併的有機相依次經由水洗滌，無水硫酸鈉脫水，過濾，減壓下濃縮，得 367 94389 201016683 到粗品2-氯-N，N-二乙基乙醯胺216a(6. 2 g，黃色油狀液體）’產物不經分離直接進行下一步反應。 MS m/z (ESI) : 150[M+1] 第二步 2-(3-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-喹唑啉-6-基} 比洛-1-基）-N，N-二乙基-乙醯胺將化合物[3-氯-4-(3-氟-苄氧基）-苯基]-[6-(1Η-吼口各-3-基）-喹唑啉—4-基]-胺 42(500 mg，1.12 mmol)和氫 ❹化鈉（134 mg ’ 3. 36 mmol)溶於10 mL N，N-二甲基曱醯胺 ❹中’室溫下授拌30分鐘後加入2-氯-N，N-二乙基乙醯胺 216a(184 mg ’ 1. 23 mmol)，室溫下攪拌30分鐘後反應完畢。在反應液中加入10 0 mL飽和氣化納溶液淬滅反應，水相用乙酸乙酯萃取（100 mLx3) ’合併的有機相依次經由水 (100 mLx3)洗滌’飽和氯化鈉溶液洗滌（1〇〇 mLx3)，無水硫酸鈉脫水，過濾，減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化（乙酸乙酯：正己烷=1 :丨），得 ®到標題產物2-(3-{4-[3-氣_4-(3-氟-苄氧基）-苯胺基]-啥0坐淋-6-基}-°比咯-1-基）-N，N-二乙基-乙酿胺216(385 mg，黃色固體），產率：57. 4%。 MS m/z (ESI) ： 558[M+1] ]H NMR (400 MHz, CD30D-cf〇: (5 9.72 (s, 1H), 8.55 (s, 1H), 8.50 (s , 1H), 8.03 (d, J = 8. 8Hz, 2H), 7. 76 (dd, J=2Hz , 1H), 7. 71 (d, J = 8. 4Hz, 1H), 7. 47 (m, 1H), 7. 31 (m, 4H) , 7.19 (m, 1H), 6.84 (s, 1H), 6.66 (s, 1H), 94389 368 201016683 5.27 (s, 2H) , 4.93 (s, 2H), 3. 39 (m, 4H), 1.18 (t, J = 6.8Hz, 3H), 1.06 (t, J = 1.2Hz, 3H) 實施例217 him [ 氟_ f氧基)二^胺某卜喹唑啉_6_基} 二^比嘻-1-基）-N-璟丙篡-Λ 胗2-Gas-N,N-Diethylacetamidine Diethylamine (11.6g, 159 mmo 1) was dissolved in 60 mL of tetrahydrogenate, cooled to -78 ° C in a dry ice ethanol bath and stirred. Chloroacetyl chloride (6 g '53 mmol) was gradually added dropwise, and the mixture was stirred for 30 minutes under ice cooling, and the reaction was completed. 20 mL of water was added to the reaction solution, and the tetrahydrogen D-flavor was taken down by dust reduction. The obtained solution was extracted with ethyl acetate (100 mL×3), and the combined organic phases were washed with water, dried over anhydrous sodium sulfate, filtered, and reduced. Concentration under pressure gave 367 94389 201016683 to crude 2-chloro-N,N-diethylacetamide 216a (6.2 g, yellow oily liquid). MS m/z (ESI): 150 [M + 1]. Step 2 2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline- 6-yl}Bilo-1-yl)-N,N-diethyl-acetamide The compound [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-( 1Η-吼口-3-yl)-quinazoline-4-yl]-amine 42 (500 mg, 1.12 mmol) and sodium hydrosulfide (134 mg '3.36 mmol) dissolved in 10 mL N,N - dimethylammonium oxime in 'mixed at room temperature for 30 minutes, then added 2-chloro-N,N-diethylacetamide 216a (184 mg ' 1. 23 mmol), stirred at room temperature for 30 minutes After the reaction is completed. The reaction mixture was quenched by adding 10 mL of saturated sodium hydride solution, and the aqueous phase was extracted with ethyl acetate (100 mL×3). The combined organic phases were washed with water (100 mL×3) and washed with saturated sodium chloride solution (1) 〇〇mLx3), dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified and purified by EtOAc EtOAc EtOAc 2-(3-{4-[3-Gas_4-(3-Fluoro-benzyloxy)-anilino]-oxime-isosodium-6-yl}-°pyrrol-1-yl)-N, 4%。 N-diethyl-ethylamine 216 (385 mg, yellow solid), yield: 57.4%. MS m/z (ESI): 558[M+1]]H NMR (400 MHz, CD30D-cf〇: (5 9.72 (s, 1H), 8.55 (s, 1H), 8.50 (s, 1H), 8.03 (d, J = 8. 8Hz, 2H), 7. 76 (dd, J=2Hz, 1H), 7. 71 (d, J = 8. 4Hz, 1H), 7. 47 (m, 1H), 7 31 (m, 4H) , 7.19 (m, 1H), 6.84 (s, 1H), 6.66 (s, 1H), 94389 368 201016683 5.27 (s, 2H) , 4.93 (s, 2H), 3. 39 ( m, 4H), 1.18 (t, J = 6.8 Hz, 3H), 1.06 (t, J = 1.2 Hz, 3H) Example 217 him [ fluoro-f oxy) dimethylamine quinazoline _6_ Base} two^ than 嘻-1-yl)-N-璟丙篡-Λ 胗

217 ❹ 〇第一步 2~氣-Ν-環丙基_乙醯胺將氣乙醯氣（2.26 g，20 mmol)溶於3〇mL***中，在冰浴條件下’冷卻至代，緩慢滴加環丙基胺（2. 28 g，4〇 :〇1) ’ 1小時後滴加完畢，有固體析出。加人3()以氯仿，授拌15分鐘，過滤，濾液在減壓下濃縮，得到的白色固姊 :50mL二氣甲烷溶解，用水洗滌(5〇mLx3) : 無水硫酸鈉脫水，過濾，減壓下濃縮，得到的、、二由乙氣〜N〜環 94389 369 201016683 丙基-乙醯胺217a(1.32 g’白色固體），產率：5〇% MS ra/z (ESI) ： 134[M+1] 第二步 2-(3-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]—喹唑啉_6〜基$ -〇比嘻-1 -基）-N-環丙基-乙醢胺在50 mL的燒瓶中’將[3 -氯-4-(3 -氟-节氧基）-笨義] -[6-(1Η-吡咯-3-基）-喹唑啉-4-基]-胺 42(167 mg，〇. mmol)溶於2· 5 mL無水N，N-二甲基甲醯胺中，在冰浴條件 ❹下’冷卻至〇°C，加入氫化納（45 mg，1.13 mm〇 1)，授掉鲁20分鐘後加入2-氯-N-環丙基-乙酿胺217a(60 mg，0.45 mmol)’室溫下攪拌3小時反應完畢。在反應液中加入50 mL 水’用乙酸乙酯萃取反應液（5 0 mLx3 )，合併的有機相依次經由無水硫酸鈉脫水，過濾，減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化（二氯曱烷：甲醇= 10: 1)，得到本標題產物2-(3-{4-[3-氯-4-(3-氟-苄氧基） -苯胺基]-喹唑啉-6-基卜吡咯-1-基）-N-環丙基-乙醯胺 ◎ 217 (110 mg，黃色固體），產率：54%。 © MS m/z (ESI) ： 541[M+1] 5H NMR (400 MHz, CD30D-d〇: (5 9. 710 (s, 1H), 8. 546 (s, 1H), 8.495 (s, 1H), 8.230 (d, J=3. 2Hz, 1H), 8.028 (t, J=4.8Hz, 2H), 7.754 (m, 1H), 7. 705 (d, J=6. 8Hz, 1H), 7.469 (t, J = 5.4Hz, 1H), 7.322 (m, 4H), 7.197 (t, J = 3.8Hz, 1H), 6.833 (t, J = 1.6Hz, 1H), 6.665 (d, J = 1.2Hz, 1H), 5.266 (s, 2H), 4.540 (s, 1H), 2.670 (in, 370 943S9 201016683 1H), 0. 649 Cm, 2H), 0. 448 (m, 2H) 實施例218 4-「（4-{4-「3-氯-4-(3 -氟-节氧某）-笨胺基坐並二 -111-°比洛-2-基甲基）-胺某派咬-i-甲酸第三丁酉旨_217 ❹ 〇 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 The cyclopropylamine (2.28 g, 4 〇: 〇1) was added dropwise. After 1 hour, the addition was completed, and a solid precipitated. Add 3 () with chloroform, stir for 15 minutes, filter, concentrate the filtrate under reduced pressure, and obtain white solid: 50 mL of di-methane dissolved, washed with water (5〇mLx3): dehydrated with anhydrous sodium sulfate, filtered, reduced Concentration under pressure, the obtained, two from ethylene gas ~ N ~ ring 94389 369 201016683 propyl-acetamide 217a (1.32 g 'white solid), yield: 5 〇% MS ra / z (ESI): 134 [ M+1] The second step 2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-anilino]-quinazoline_6~yl$-〇比嘻-1 -yl)-N-cyclopropyl-acetamide in a 50 mL flask '[3-chloro-4-(3-fluoro-hydroxy)-stupid]-[6-(1Η-pyrrole- 3-yl)-quinazolin-4-yl]-amine 42 (167 mg, 〇. mmol) was dissolved in 2.5 mL of anhydrous N,N-dimethylformamide under ice bath conditions. Cool to 〇 ° C, add sodium hydride (45 mg, 1.13 mm 〇 1), and remove the ruthenium for 20 minutes, then add 2-chloro-N-cyclopropyl-ethylamine 217a (60 mg, 0.45 mmol) The reaction was completed by stirring for 3 hours. 50 mL of water was added to the reaction mixture. The reaction mixture was extracted with ethyl acetate (50 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Further separation and purification (dichloromethane:methanol = 10:1) gave the title product 2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-anilinyl] - quinazolin-6-ylpyrrole-1-yl)-N-cyclopropyl-acetamide 217 (110 mg, yellow solid), yield: 54%. © MS m/z (ESI): 541 [M+1] 5H NMR (400 MHz, CD30D-d〇: (5 9. 710 (s, 1H), 8. 546 (s, 1H), 8.495 (s, 1H), 8.230 (d, J=3. 2Hz, 1H), 8.028 (t, J=4.8Hz, 2H), 7.754 (m, 1H), 7. 705 (d, J=6. 8Hz, 1H), 7.469 (t, J = 5.4 Hz, 1H), 7.322 (m, 4H), 7.197 (t, J = 3.8 Hz, 1H), 6.833 (t, J = 1.6 Hz, 1H), 6.665 (d, J = 1.2 Hz, 1H), 5.266 (s, 2H), 4.540 (s, 1H), 2.670 (in, 370 943S9 201016683 1H), 0. 649 Cm, 2H), 0. 448 (m, 2H) Example 218 4- "(4-{4-"3-Chloro-4-(3-fluoro-oxygen)-stupyl-amino-sodium-di-111-°pyr-2-ylmethyl)-amine bite-i - formic acid third butyl _

4-丨4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-喹唑啉_6_基} ~1 H-n比嘻-2 -曱酸· 將30 niL N，N:二曱基曱醯胺，在冰浴條件下，冷卻至〇C，加入二氯氧麟（825 mg，5.392 mmol)，反應升至室、、田搜拌1小時後’冷卻反應液至〇°c，加入[3_氣_4_(3_[ 苄氧基）-苯基]~[6-(1Η-°比咯-3-基）-喹唑琳_4-基]—胺42 94389 371 201016683 (1. 565 g，3. 525 mmol)室溫攪拌3小時後反應完畢。將反應液中加入50 mL水’用2N氫氧化鈉溶液調整ρΗ>ΐι，加入50 mL四氫呋喃，水相用乙酸乙酯萃取（5〇 mLx3)，合併的有機相經由無水硫酸鈉脫水’過濾，減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化（正己烷：乙酸乙酯=2 : 1)，得到4-{4-[3-氣-4-(3-氟-苄氧基）-苯胺基]-喹唑啉-6-基卜1H-吡咯-2-甲醛218a(424 mg，黃色固體），產率：25. 5%。 ©第二步 ❹4-[ (4-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-喹唑啉-6-基} -1 比B各-2-基曱基）-胺基]-略π定一1 —甲酸第三丁酉旨4-丨4-[3-chloro-4-(3-fluoro-benzyloxy)-anilino]-quinazoline _6_yl} ~1 Hn than 嘻-2 - decanoic acid · 30 niL N, N: Dimercaptoamine, cooled to 〇C under ice bath, add chlorpheniramine (825 mg, 5.392 mmol), the reaction is raised to the chamber, and the mixture is stirred for 1 hour, then the reaction solution is cooled. 〇°c, adding [3_gas_4_(3_[benzyloxy)-phenyl]~[6-(1Η-°pyrol-3-yl)-quinazoline_4-yl]-amine 42 94389 371 201016683 (1. 565 g, 3. 525 mmol) After stirring at room temperature for 3 hours, the reaction was completed. Add 50 mL of water to the reaction mixture, adjust the pH of the mixture with 2N sodium hydroxide solution, add 50 mL of tetrahydrofuran, extract the aqueous phase with ethyl acetate (5 〇mL×3), and dehydrate the combined organic phase through anhydrous sodium sulfate. Concentration under reduced pressure, the residue obtained was purified by EtOAc EtOAc EtOAc EtOAc - benzyloxy)-anilino]-quinazoline-6-ylbu- 1H-pyrrole-2-carbaldehyde 218a (424 mg, yellow solid), yield: 25.5%. ©Second step ❹4-[ (4-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-anilino]-quinazolin-6-yl} -1 than B each -2- Base group)-amino group]-slightly π-deno-1-formic acid tert-butyl

將4-{4-[3-氣-4-(3-氟-苄氧基）-苯胺基]—喹唑啉 '―6一基卜1H-吡咯-2-甲醛218a(424 mg ’黃色固體）和4-胺基一0底啶一卜曱酸第三丁酯（133 mg，0.67 mmol)溶於20 mL 二氣曱烷中’在室溫下攪拌2小時後加入三（乙醯氧基）硼氫化鈉（313 mg，1.476 mmol)，混合液在室溫下攪拌過夜。 ©將反應液中加入50 mL水，減壓下蒸掉二氣曱烷，水相用 Ο v乙酸乙酯萃取（50mLx3)，合併的有機相經由無水硫酸鈉脫水’過濾，減壓下濃縮’得到的殘留物藉由Combi Flash 分離’得到標題產物4-[(4-{4-[3-氣-4-(3-氟-苄氧基）-苯胺基]-喹唑啉-6-基}-1Η-吡咯-2-基曱基）-胺基]-哌啶 -1-曱酸第三丁酯218(132 mg，黃色固體），產率：62. 6%。 MS m/z (ESI) ： 657[M+1] ]H NMR (400 MHz, CD30D-de): (5 11. 18 (dr, 1H), 9.85 (s, 372 94389 201016683 1H)，8.58 (m，2H)，8. 08 (s，1H)，7.95 (d，J = 8.8Hz，1H)， 7. 81 (m，2H), 7. 48 (ffl’ 1H)，7. 31 (m，3H)，7· 19 (m，1H), 7. 01 (s，1H)，6. 44 (s，1H)，5. 27 (s，2H)’ 4. 22 (dr, 2H)， 3.90 (m，2H)，3.18 (m，iH)，2· 68 (打，2H)，1.92 (m， 4H), 1.37 (s, 9H) 實施例219 氧基）-茉胺毛丄 -吡咯-1-基）基-乙胺基）二4-{4-[3-Ga-4-(3-fluoro-benzyloxy)-anilino]-quinazoline '-6-ylpyr 1H-pyrrole-2-carbaldehyde 218a (424 mg 'yellow solid And 4-amino-amino-pyridinic acid tert-butyl ester (133 mg, 0.67 mmol) dissolved in 20 mL of dioxane. Stir at room temperature for 2 hours and then add tris(ethyloxy) Sodium borohydride (313 mg, 1.476 mmol), and the mixture was stirred at room temperature overnight. To the reaction mixture, 50 mL of water was added, and dioxane was evaporated under reduced pressure. The aqueous phase was extracted with ethyl acetate (50 mL×3). The residue obtained was isolated by Combi Flash to give the title product 4-[(4-{4-[3- gas-4-(3-fluoro-benzyloxy)-anilino]-quinazoline-6-yl Η 吡吡吡吡吡吡吡。。。。。。。。。。。。。。。。。 MS m/z (ESI): 657[M+1]]H NMR (400 MHz, CD30D-de): (5 11. 18 (dr, 1H), 9.85 (s, 372 94389 201016683 1H), 8.58 (m , 2H), 8. 08 (s, 1H), 7.95 (d, J = 8.8Hz, 1H), 7. 81 (m, 2H), 7. 48 (ffl' 1H), 7. 31 (m, 3H ), 7· 19 (m, 1H), 7. 01 (s, 1H), 6. 44 (s, 1H), 5. 27 (s, 2H)' 4. 22 (dr, 2H), 3.90 (m , 2H), 3.18 (m, iH), 2·68 (h, 2H), 1.92 (m, 4H), 1.37 (s, 9H) Example 219 oxy)-methylamine lanolin-pyrrol-1-yl )-ethylamine)

219 將[3-氯-4-（3-氟-苄氧基）-苯基]一[6_(1_環氧乙基甲 ❿ 瘺 ◎ 基-1H-吡咯-3-基）_喹唑啉-4-基]-胺i87a(150 mg，〇 3 mmol)溶於10 mL曱醇中，攪拌下依次加入2_哌啶〜卜基— 乙胺（42.3 mg’ 0·33 mmol)，混合液加熱回流3小時後"反應完畢。反應液在減壓下濃縮’得到的殘留物藉由石夕柱：：法進—步分離純化(二氯甲烷：甲醇，：。，得到 ^ , ^ U i4 Ld氯4 —(3—齓-苄氧基）-苯胺基]- 6基}-吡咯-1-基）-3_(2_哌啶_丨_基—乙胺基卜丙 94389 373 201016683 -2-醇 219(22 mg，黃色固體），產率：11. 70/〇。 MS m/z (ESI) ： 629[M+1] ]H NMR (400 MHz, CD30D-d〇： 5 9. 70 (s, 1H), 8· 54 (s, 1H) =8.49 (s, 1H), =8.03 (d, J = 8Hz, 2H), 7.76 (d, J=8.4Hz, 1H), 7.70 (d, J=8. 8Hz, 1H), 7.48 (m, ih), 7.41 (s, 1H), 7.33 (m, 3H), 7.19 (t, J = 8Hz, 1H), 6.88 (s, 1H), 6. 65 (s, 1H), 5. 27 (s, 2H), 4. 01 (m, 1H), 3. 88 (m, 2H), 3.51 (m, 2H), 2.60 (t, J = 6. 6Hz, 2H), 2.35 (m, φ 6H), 1.47 (br, 4H) 1.36 (m, 2H) ^實施*例220 l-_(一3-U-「3-氯-4-(3-氟-苄氲篡茉胺基1-喹唑啉_6_基} 比咯-1-基）-3-(2-曱氣基-乙胺篡丙-2-醇219 [3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6_(1_epoxyethylformamidine oxime-1H-pyrrol-3-yl)-quinazoline 4-yl]-amine i87a (150 mg, 〇3 mmol) was dissolved in 10 mL of decyl alcohol, and 2-piperidine-diyl-ethylamine (42.3 mg '0·33 mmol) was added in sequence with stirring. After heating for 3 hours, the reaction was completed. The reaction mixture was concentrated under reduced pressure. The obtained residue was purified by EtOAc EtOAc EtOAc (EtOAc: EtOAc: EtOAc: Benzyloxy)-anilino]- 6yl}-pyrrol-1-yl)-3_(2_piperidine-indole-yl-ethylaminopropenyl 94389 373 201016683-2-ol 219 (22 mg, yellow solid ), Yield: 11.70/〇 MS m/z (ESI): 629[M+1]]H NMR (400 MHz, CD30D-d〇: 5 9. 70 (s, 1H), 8·54 (s, 1H) = 8.49 (s, 1H), =8.03 (d, J = 8Hz, 2H), 7.76 (d, J=8.4Hz, 1H), 7.70 (d, J=8. 8Hz, 1H), 7.48 (m, ih), 7.41 (s, 1H), 7.33 (m, 3H), 7.19 (t, J = 8Hz, 1H), 6.88 (s, 1H), 6. 65 (s, 1H), 5. 27 (s, 2H), 4. 01 (m, 1H), 3. 88 (m, 2H), 3.51 (m, 2H), 2.60 (t, J = 6. 6Hz, 2H), 2.35 (m, φ 6H), 1.47 (br, 4H) 1.36 (m, 2H) ^Implementation^Example 220 l-_(1-3-U-"3-Chloro-4-(3-fluoro-benzyl-myramine 1-quine Oxazoline _6_yl}pyrrol-1-yl)-3-(2-indole-ethylamine oxime-2-ol

將[3-氣-4_(3-氟-苄氧基）_苯基-環氧乙基曱基-1H-吡咯-3_基）-喹唑啉_4_基]_胺187a(15〇吨，〇 3 mmol)溶於20 mL異丙醇和1，2-二氯乙烷（1 : 1)的混合溶劑中，攪拌下加入2-甲氧基乙胺（67. 5 mg，〇. 9 mm〇i)，混合液加熱回流過夜。反應液在減壓下濃縮，得到的殘留 374 94389 201016683 物藉由矽膠管柱層析法進一步分離純化（二氣甲烷：甲醇 =15 : 1)，得到本標題產物1-(3-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-喹唑啉-6-基卜吼咯-1-基）-3-(2-曱氧基-乙胺基）-丙-2-醇220 (90 mg，黃色固體），產率：52. 3%。 MS m/z (ESI) ： 586 [M+1] Ή NMR (400 MHz, CD30D-d〇: (5 9. 70 (s, 1H), 8.54 (s, 1H)，8.49 (s，H)，8.03 (d，J = 8Hz，2H)，7.76 (d，J = 8.4Hz， 1H), 7. 70 (d, J = 8. 8Hz, 1H), 7. 48 (m, 1H), 7. 41 (s, 1H), ^ 7.33 (m, 3H), 7.19 (t, J = 8Hz, 1H), 6.88 (s, 1H), 6.65 0 (s, 1H), 5. 27 (s, 2H), 5. 05 (br, 1H), 4. 01 (in, 1H), 3. 88 (m, 2H), 3.51 (m, 2H), 3.26 (br, 2H), 3.25 (s, 3H), 2. 67 (t, J = 5. 6Hz, 2H) 實施例221 .1-(3-丨4-「3-氩-4-(3-氟-苄氣基）-笨胺基Ί-喹唑啉-6-某} -吡咯-1-基）-3-哌D井-1-基-丙-2-醇[3-Gas-4_(3-fluoro-benzyloxy)-phenyl-epoxyethylmercapto-1H-pyrrole-3-yl)-quinazoline-4-yl]-amine 187a (15〇吨, 〇3 mmol) is dissolved in a mixture of 20 mL of isopropanol and 1,2-dichloroethane (1:1), and 2-methoxyethylamine (67. 5 mg, 〇. 9) is added with stirring. Mm〇i), the mixture was heated to reflux overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue 374 94389 201016683 was further separated and purified by hydrazine column chromatography (di-methane:methanol = 15:1) to give the title product 1-(3-{4- [3-Chloro-4-(3-fluoro-benzyloxy)-anilino]-quinazolin-6-ylbupyrol-1-yl)-3-(2-decyloxy-ethylamino) - propyl-2-ol 220 (90 mg, yellow solid), yield: 52.3%. MS m/z (ESI): 586 [M+1] NMR (400 MHz, CD30D-d〇: (5 9. 70 (s, 1H), 8.54 (s, 1H), 8.49 (s, H), 8.03 (d, J = 8Hz, 2H), 7.76 (d, J = 8.4Hz, 1H), 7. 70 (d, J = 8. 8Hz, 1H), 7. 48 (m, 1H), 7. 41 (s, 1H), ^ 7.33 (m, 3H), 7.19 (t, J = 8Hz, 1H), 6.88 (s, 1H), 6.65 0 (s, 1H), 5. 27 (s, 2H), 5 . . . ( (,,,,,,,,,,,,, (t, J = 5. 6 Hz, 2H) Example 221. 1-(3-丨4-"3- Argon-4-(3-fluoro-benzyl)-phenylamino-quinazoline-6 - some} -pyrrol-1-yl)-3-piperidin D-l-yl-propan-2-ol

187a 221 375 94389 201016683 將[3-氯-4-(3-氟-苄氧基）_苯基]_[6_(卜環氧乙基甲基-1H-吡咯-3-基喹唑啉_4_基]_胺187a(15〇呢，〇. 3 mmol )’合於20 mL異丙醇中，攪拌下加入無水哌畊（8〇呢， 0· 9賴〇1)’混合液加熱回流過夜。反應液在減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化（二氯甲炼.甲醇=20: 1) ’得到本標題產物ι_(3-{4-[3-氣-4-(3-氟-> 氧基）-苯胺基]-啥唾琳-6_基}-<ι比τ»各-1-基）_3~娘啡 -1-基-丙-2-醇221 (140 mg，黃色固體），產率：70%。 φ MS m/z (ESI) ： 587[M+1] φ !H NMR (400 MHz, CD30D-d〇： (5 9. 70 (s, 1H), 8.54 (s, 1H), 8.49 (s, 1H), =8.03 (d, J = 8Hz, 2H), 7.76 (d, J = 8.4Hz, 1H), 7.70 (d, J=8. 8Hz, 1H), 7.48 (m, 1H), 7.41 (s, 1H), 7.33 (m, 3H), 7.19 (t, J = 8Hz, 1H), 6.88 (s, 1H), 6.65 (s, lH)^ 5.27 (s, 2H), 4.88 (br, 1H), 4. 09 (m, 1H), 3.94 (br, 1H), 3.84 (m, 1H), 2.68 (m, 4H), 2.33 (br, 4H), 2.25 (t, J = 2. 8Hz, 2H) ❿實施例222 ❾4-「3-(3-{4-「3-氯-4-(3-氟-节氣篡v苯胺某1-喹唑啾— 1比洛-1-基）-2-羥基-丙某脸基1 —瑷醢187a 221 375 94389 201016683 [3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]_[6_(epoxyethylmethyl-1H-pyrrol-3-ylquinazoline_4 _ base]_amine 187a (15 〇, 〇. 3 mmol) 'in 20 mL of isopropanol, add anhydrous piper (8 〇, 0·9 〇1) while stirring, and heat to reflux overnight. The reaction solution was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (dichloromethane. Methanol = 20: 1) to obtain the title product ι_(3-{4-[3 -gas-4-(3-fluoro->oxy)-anilino]-啥琳 -6 -6 _ _ _ _ ι τ τ τ τ τ τ τ τ τ Prop-2-propanol 221 (140 mg, yellow solid), yield: 70%. φ MS m/z (ESI): 587[M+1] φ !H NMR (400 MHz, CD30D-d〇: (5 9. 70 (s, 1H), 8.54 (s, 1H), 8.49 (s, 1H), =8.03 (d, J = 8Hz, 2H), 7.76 (d, J = 8.4Hz, 1H), 7.70 (d , J=8. 8Hz, 1H), 7.48 (m, 1H), 7.41 (s, 1H), 7.33 (m, 3H), 7.19 (t, J = 8Hz, 1H), 6.88 (s, 1H), 6.65 (s, lH)^ 5.27 (s, 2H), 4.88 (br, 1H), 4. 09 (m, 1H), 3.94 (br, 1H), 3.84 (m, 1H), 2.68 (m, 4H), 2.33 (br, 4H), 2.25 (t, J = 2. 8Hz, 2H) Example 222 ❾4-"3-(3-{4-"3-Chloro-4-(3-fluoro-gas 篡v aniline 1- 1-quinazolium-1 piropen-1-yl)-2-hydroxyl -Cai's face base 1 -瑷醢

94389 376 20101668394389 376 201016683

Xr1Xr1

私土衣己醇鹽酸鹽（75.8mg，〇·5丽〇1 ’ Ai fa)溶於 10此甲醇中，擾拌下依次加入2 mL三乙胺和[3-氣-4- (3-氟-苄氧基）-苯基]-[6-(卜環氧乙基曱基_1Η_Π比咯_3_基）_ 喹唑啉-4-基]-胺I87a(200 mg，0.4 mmol)，混合液加熱 ❾回流2小時後反應完畢。反應液在減壓下濃縮，得到的殘 ❾留物藉由矽膠管柱層析法進一步分離純化（二氯曱烷：曱醇 =10 : 1) ’ 得到本標題產物 4-[3-(3-{4-[3-氯-4- (3-氟-苄氧基）-苯胺基]-喹唑琳-6-基}-η比嘻-1-基）-2-經基-丙基胺基]-環己醇222(94 mg，黃色固體），產率：38. 3%。 MS m/z (ESI) ： 616[M+1] ]H NMR (400 MHz, CD30D-d〇: δ 9. 67 (s, 1H), 8. 8 (s, 1H), 8.5 (s, 1H), 8.03 (d, J=8. 8Hz, 2H), 7.76 (dd, J=2Hz, 〇 0 1H), 7. 70(d, J=8.4Hz, 1H), 7. 5 (m, 2H), 7. 36 (m, 3H), 7.2 (s, 1H), 6.93 (s, 1H), 6.60 (s, 1H), 5.27 (s, 2H), 4.5 (s, 1H), 4.05 (m, 1H), 3.95 (m, 2H), 2.7 (m, 1H), 2.55 (s, 1H), 2.5 (m, 2H), 2.2 (m, 1H), 1.8 (m, 4H), 1.25 (m, 4H) 實施例223 Π-「2-(3-ί4-「3-氩-4-(3-氟—-苄氧基）-苯^ -fi-臬丨-吡咯-1-基）-乙基>if各烧—2-基丨-ΧΑ 377 94389 201016683Benzyl hexanoate (75.8mg, 〇·5 〇 1 'Ai fa) was dissolved in 10 methanol, and 2 mL of triethylamine and [3-Q-4-(3-) were added in sequence. Fluoro-benzyloxy)-phenyl]-[6-(p-epoxyethyl decyl-1 Η Π 咯 _ _3_yl) quinazolin-4-yl]-amine I87a (200 mg, 0.4 mmol) The mixture was heated and refluxed for 2 hours and the reaction was completed. The reaction mixture was concentrated under reduced pressure, and the residue obtained was further purified and purified by silica gel column chromatography (dichloromethane: decyl alcohol = 10: 1) to give the title product 4-[3-(3 -{4-[3-Chloro-4-(3-fluoro-benzyloxy)-anilino]-quinazoline-6-yl}-n-pyridin-1-yl)-2-yl-propyl-propyl Amino]-cyclohexanol 222 (94 mg, yellow solid), yield: 38.3%. MS m/z (ESI): 616 [M+1]]H NMR (400 MHz, CD30D-d〇: δ 9. 67 (s, 1H), 8. 8 (s, 1H), 8.5 (s, 1H) ), 8.03 (d, J=8. 8Hz, 2H), 7.76 (dd, J=2Hz, 〇0 1H), 7. 70(d, J=8.4Hz, 1H), 7. 5 (m, 2H) , 7. 36 (m, 3H), 7.2 (s, 1H), 6.93 (s, 1H), 6.60 (s, 1H), 5.27 (s, 2H), 4.5 (s, 1H), 4.05 (m, 1H) ), 3.95 (m, 2H), 2.7 (m, 1H), 2.55 (s, 1H), 2.5 (m, 2H), 2.2 (m, 1H), 1.8 (m, 4H), 1.25 (m, 4H) Example 223 Π-"2-(3-ί4-"3- Argon-4-(3-fluoro--benzyloxy)-benzene^-fi-臬丨-pyrrol-1-yl)-ethyl> If each burns - 2-based 丨 - ΧΑ 377 94389 201016683

Q ❹ 氯一1 一（2~羥曱基-吡咯烷-1-基）-乙酮將2一羥甲基吡咯烷（505 mg，5誠〇1)溶於1〇 ‘四氫呋喃中，在丙乾冰浴條件下，冷卻至-78。(：，加入1汕二乙胺’授拌15小時後，滴加氯乙醢氯（〇. 38 mL，5 mmol)，搜摔1小時後反應完畢。反應物在減壓下濃縮，殘留物藉由石夕膠官柱層析法進行分離純化（二氯曱院：甲醇1)，得到無色油狀液體粗品2_氯-卜（2,甲基_料炫_卜基）乙酮223a，產物不經分離直接進行 MS ηι/ζ (ESI) : 178[M+1] ，心' 94389 378 201016683 第二步 2-(3-{4-[3-氣-4-(3-氟苄氧基）_苯胺基]_喹唑啉_6_基}_ 0比咯-1-基）-1-(2-羥甲基-吡咯烷一1_基）_乙酮在50 mL的燒瓶中，將[3-氣-4-(3-氟-苄氧基）-苯基] -[6-(1Η-吡咯-3-基）-喹唑啉-4-基]-胺 42(444 mg，丨 mm〇1) /谷於10 mL無水N，N-二曱基曱醯胺中，在冰浴條件下，冷卻至0°C，加入氫化鈉（72 mg，3 mmol)，攪拌30分鐘後加入2-氣-1-(2-羥曱基-吡咯烷―卜基卜乙酮223a(213 ❾mg，1.2 mmol)，室溫下攪拌i小時反應完畢。反應液減壓 ❺下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化（二氯甲烷：曱醇=8: υ，得到2_(3_{4_[3_氯一4_(3_氟苄氧基）-苯胺基]-喹唑啉-6-基}_吼咯_卜基）_丨_(2_羥曱 .基-吡咯烷_卜基）-乙酮223b (70 mg，淡黃色固體），產率： 10%。 MS m/z (ESI) ： 587[M+1] 第三步 $ [2-(3-{4-[3-氣-4-(3-氟-苄氧基）-苯胺基]_喹唑啉 ~6-基} 一吡咯_卜基）_乙基]_吡咯烷_2 一基卜曱醇將2-(3-{4-[3-氯-4-(3-氟苄氧基）-苯胺基μ喹唑啉 6-基}-吼洛-1-基）一ΐ-(2-羥甲基_吡咯烷-基）一乙綱 223b(190 mg，0· 29 mmol)溶於20 mL四氫呋喃中，攪拌下加入氫化紹鐘（32. 6 mg，0 _ 86 mmo 1)，3小時後反應完畢。在反應液中加入甲醇淬滅反應，減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化，得到標題產 94389 379 201016683 物{l-[2-(3-{4-[3 -氯-4- (3-氟-节氧基）-苯胺基]-喧》坐嘛 -6-基}-吡咯-1-基）-乙基]-吡咯烷-2-基}-曱醇223(40 mg，黃色固體），產率：24%。 MS m/z (ESI) ： 573[M+1] ]H NMR (400 MHz, CD30D-d〇 : (J 9. 67 (s, 1H), 8. 8 (s, 1H), 8.5 (s, 1H), 8.03 (d, J=8. 8Hz, 2H), 7.76 (dd, J=2Hz, 1H), 7. 70 (d, J = 8. 4Hz, 1H), 7. 5 (m, 2H), 7. 36 (m, 3H), 7. 2 (s, 1H), 6. 93 (s, 1H), 6. 60 (s, 1H), 5. 27 (s, 2H), ^ 4.4 (m, 2H), 4.05 (m, 2H), 3.45 (m, 5H), 2.33 (br, 1H), φ 1.82 (br, 1H), 1.62 (m, 2H), 1.55 (br, 1H) 實施例224 「3 -氣一4-(3 -氣一爷氧基）一笨基1-(2 -口比口定一4 -基一乙基比洛-3~基口奎口坐琳-4-基}-胺 ❹Q 氯 Chloro-1 (2-hydroxyindole-pyrrolidin-1-yl)-ethanone 2-hydroxymethylpyrrolidine (505 mg, 5 〇1) is dissolved in 1 〇 'tetrahydrofuran, in C Cool to -78 under dry ice bath conditions. (:, adding 1 汕 diethylamine) After 15 hours of mixing, chlorhexidine chloride (〇. 38 mL, 5 mmol) was added dropwise, and the reaction was completed after 1 hour of searching. The reactant was concentrated under reduced pressure, and the residue was Separation and purification by the Shixi gum column chromatography (dichlorohydrazine: methanol 1), to obtain a crude colorless liquid 2-chloro-b (2, methyl _ _ _ _ ke) ketone 223a, The product was directly subjected to MS ηι/ζ (ESI) without isolation. 178 [M+1], heart '94389 378 201016683 second step 2-(3-{4-[3-gas-4-(3-fluorobenzyloxy) ))-anilino]-quinazoline_6_yl}_ 0-r-but-1-yl)-1-(2-hydroxymethyl-pyrrolidine-1-yl)-ethanone in a 50 mL flask , [3-Ga-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinazolin-4-yl]-amine 42 (444 mg , 丨mm〇1) / gluten in 10 mL of anhydrous N,N-didecyl decylamine, cooled to 0 ° C under ice bath, sodium hydride (72 mg, 3 mmol), and stirred for 30 minutes Then, 2-gas-1-(2-hydroxydecyl-pyrrolidine-bipyl ethyl bromide 223a (213 ❾mg, 1.2 mmol) was added, and the mixture was stirred at room temperature for 1 hour, and the reaction was completed under reduced pressure. Residue by 矽Further separation and purification by column chromatography (dichloromethane: decyl alcohol = 8: hydrazine to give 2_(3_{4_[3_chloro- 4-(3-fluorobenzyloxy)-anilino]-quinazoline-6 - } 吼 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( (ESI) : 587[M+1] Third Step $ [2-(3-{4-[3-Gas-4-(3-fluoro-benzyloxy)-anilino]-quinazoline~6- 2-(3-{4-[3-chloro-4-(3-fluorobenzyloxy)-aniline-based μ-pyridyl-p-ethyl)-pyrrolidine Quinazoline 6-yl}-indol-1-yl)-indolyl-(2-hydroxymethyl-pyrrolidine-yl)-ethyl 223b (190 mg, 0·29 mmol) was dissolved in 20 mL of tetrahydrofuran. Hydrogenated hourly (32. 6 mg, 0 _ 86 mmo 1) was added with stirring, and the reaction was completed after 3 hours. The reaction was quenched by adding methanol to the reaction mixture, and concentrated under reduced pressure to give a residue. Further separation and purification by the analytical method, the title product 94389 379 201016683 substance {l-[2-(3-{4-[3-chloro-4-(3-fluoro-hydroxy)-phenylamino]-喧] is sitting. -6-yl}-pyrrol-1-yl)-ethyl]-pyrrolidin-2-yl}-nonanol 223 (40 mg, yellow solid ), yield: 24%. MS m/z (ESI): 573[M+1]]H NMR (400 MHz, CD30D-d〇: (J 9. 67 (s, 1H), 8. 8 (s, 1H), 8.5 (s, 1H), 8.03 (d, J=8. 8Hz, 2H), 7.76 (dd, J=2Hz, 1H), 7. 70 (d, J = 8. 4Hz, 1H), 7. 5 (m, 2H) , 7. 36 (m, 3H), 7. 2 (s, 1H), 6. 93 (s, 1H), 6. 60 (s, 1H), 5. 27 (s, 2H), ^ 4.4 (m , 2H), 4.05 (m, 2H), 3.45 (m, 5H), 2.33 (br, 1H), φ 1.82 (br, 1H), 1.62 (m, 2H), 1.55 (br, 1H) Example 224 3-gas- 4-(3- gas-one-oxyl)-stupyl 1-(2-porto-butyl- 4-ethyl-ethylpyrazine-3~basal Kuikou sit-4-yl} -amine

380 94389 201016683 第一步甲石黃酸（2-°比咬-4-基）乙醋將 2—比啶-4-基-乙醇（174 mg，1. 42 mmol)溶於 2〇 mL 二氣曱燒中’在冰浴條件下，冷卻至〇。〇，依次加入三乙胺（352 mg，3· 5 mmol)和甲磺醯氯（200 rag，1. 75 mrool)，室溫下攪拌1小時，反應完畢。將反應液中加入50 mL水，減壓下蒸掉二氣甲烷，用乙酸乙酯萃取（100 mLx3)，合併的有機相依次經由無水硫酸鈉脫水，過濾，減壓下濃縮， ❹得到的粗品曱磺酸（2-吼啶一4-基）乙酯224a(266 mg，粉色 φ油狀液體）不經分離直接進行下一步反應。 MS m/z (ESI) ： 202[M+1] 第二步 . 在50 mL的燒瓶中，將[3-氣-4-(3-氟-苄氧基）-苯基] _[6-(1Η-吡咯-3-基）-喹唑啉—4-基]-胺 42(225 mg，0.51 mmol)溶於3 mL無水N，N-二甲基甲醯胺中，在冰浴條件下’冷卻至0 C，加入氫化鈉（45 mg，1. 13 mm〇i)，攪拌 ❹20分鐘後加入甲磺酸（2-吡啶_4_基）乙酯224a(266 mg， 1· 32 mmol)，室溫下攪拌丨.5小時反應完畢。反應液減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化（二氣甲烷：甲醇=60 : 1)，得到本標題產物[3一氣_4_(3_ 氟-苄氧基）-苯基]-{6-[l-(2-n比啶—4_基_乙基）_1珏_。比咯 -3-基]-喹唑啉-4-基卜胺224(5 mg，黃色固體），產率： 1.8%。 MS m/z (ESI) ： 550[M+1] 94389 381 201016683 NMR (400 MHz, CD30D-d6) ： 5 9. 68 (s, 1H), 8.49 (m, 4H), 8. 01 (m, 2H), 7. 75 (m, 1H), 7. 70 (d, J=8. 4Hz, 1H), 7. 49 (m, 1H), 7. 43 (s, 1H), 7. 32 (in, 3H), 7. 24 (m, 2H), 7. 19 (ra, 1H), 6. 87 (s, 1H), 6. 64 (s, 1H), 5. 27 (s, 2H), 4.25 (t, J=7. 2Hz, 2H), 3.14 (t, J=7. 2Hz, 2H) 實施例225 2-(3-(4-[3-氯-4-(3-氟-苄氫篡）-笨胺基l-啥咄嗞某} -吡咯-1-基）-N-(l,卜二侧囊‘基-六氫-1又*6*_g案吟_4一基、 _ -乙醯胺 0380 94389 201016683 First step, tartaric acid (2-° ratio -4- base) ethyl vinegar, 2-pyridine-4-yl-ethanol (174 mg, 1.42 mmol) dissolved in 2 〇 mL In the simmering simmer, in an ice bath, cool to 〇. Then, triethylamine (352 mg, 3.5 mmol) and methanesulfonyl chloride (200 rag, 1.75 mrool) were added in that order, and the mixture was stirred at room temperature for 1 hour, and the reaction was completed. 50 ml of water was added to the reaction mixture, the methylene chloride was evaporated under reduced pressure, and ethyl acetate was evaporated (100 mL×3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The oxime sulfonic acid (2-acridin-4-yl)ethyl ester 224a (266 mg, pink φ oily liquid) was directly subjected to the next reaction without isolation. MS m/z (ESI): 202 [M+1]. Step 2. In a 50 mL flask, [3- gas-4-(3-fluoro-benzyloxy)-phenyl] _[6- (1Η-pyrrol-3-yl)-quinazolin-4-yl]-amine 42 (225 mg, 0.51 mmol) dissolved in 3 mL anhydrous N,N-dimethylformamide in ice bath 'Cool to 0 C, add sodium hydride (45 mg, 1.13 mm〇i), stir for 20 minutes, then add (2-pyridyl-4-yl)ethyl sulfonate 224a (266 mg, 1·32 mmol) Stir at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue obtained was purified and purified by EtOAc EtOAc EtOAc EtOAc )-Phenyl]-{6-[l-(2-n-bipyridyl-4-yl-ethyl)_1珏_. Bilob-3-yl]-quinazolin-4-ylbumin 224 (5 mg, yellow solid), yield: 1.8%. MS m/z (ESI): 550 [M+1] 94389 381 201016683 NMR (400 MHz, CD30D-d6): 5 9. 68 (s, 1H), 8.49 (m, 4H), 8. 01 (m, 2H), 7. 75 (m, 1H), 7. 70 (d, J=8. 4Hz, 1H), 7. 49 (m, 1H), 7. 43 (s, 1H), 7. 32 (in , 3H), 7. 24 (m, 2H), 7. 19 (ra, 1H), 6. 87 (s, 1H), 6. 64 (s, 1H), 5. 27 (s, 2H), 4.25 (t, J = 7. 2 Hz, 2H), 3.14 (t, J = 7. 2 Hz, 2H) Example 225 2-(3-(4-[3-chloro-4-(3-fluoro-benzylhydroquinone) )--stupidyl-l-啥咄嗞}-pyrrol-1-yl)-N-(l, 卜二侧囊 '基-六氢-1也*6*_g案吟_4一基, _ - Acetamine 0

第一步 2-氯-N-(l，1-二側氧基-六氫-1又本6*-噻喃-4-基）-乙醯胺將1，1-二侧氧基-六氫-丨又噻喃-4_基胺鹽酸鹽 (32 mg，0. 173 mmol)溶於5 mL四氫呋喃中，在冰浴條件 382 94389 201016683 下’冷卻至0°C，加入三乙胺（37 mg’ 0.366 mmo 1)，授拌下加入氯乙醯氯（32 mg，0. 283 mmol)，（TC下攪拌2小時後反應完畢。反應物在減壓下濃縮，殘留物用二氯甲烷洗滌’得到化合物2-氯-N-(l，1-二侧氧基-六氫-1又外*一嘧喃-4-基）-乙醯胺225a，產物不經分離直接進行下一步反應。第二步 2-(3-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-喹唑啉_6_基} 〇 -吡咯-1·基）-N-(l，1-二侧氡基-六氤-1 λ *6*-噻喃-4-基） -乙醯胺在50 mL的燒瓶中’將[3_氯_4-(3-氟-苄氧基）-苯基] -[6-ΠΗ-吡咯-3-基）-喹唑啉-4-基]-胺 42(52 mg，0.1Π mmo 1)溶於1 mL N，N-二曱基曱醯胺中’在冰浴條件下，冷卻至0°C ’加入氫化鈉（29 mg，0. 725 mmol)，攪拌3〇分鐘後加入2-氯-N-(l，1-二側氧基-六氫-1又*6*_噻喃 -4-基）-乙醯胺 225a(39 mg，〇. 173 mmol)的 1 mL N，N-二〇甲基曱醯胺溶液，室溫下攪拌丨.5小時反應完畢。反應液加入50mL水，乙酸乙酯萃取（5〇mLx3)，合併的有機相經由無水硫酸鈉脫水，過濾，減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化（梯度沖提：二氣曱烷：曱醇= 100 : 1 ’ 60 : 1)，得到 2-(3-{4-[3-氣-4-(3-氟-节氧基）-笨胺基]-喹唑啉-6-基}-吡咯-1-基）-N-(l，1-二侧氧基-六氫-1 λ *6仁噻喃-4-基）-乙醯胺225(15 mg，黃色固體），產率：20. 3%。 383 94389 201016683 MS m/z (ESI) ： 634[M+1] ]H NMR (400 MHz, CD30D-d〇: ^ 9. 72 (s, 1H), 8.55 (s, 1H), 8.51 (s, 1H), 8.31 (d, J = 7. 2Hz 1H), 8.03 (in, 2H), 7. 76 (d, J = 8. 8Hz, 1H), 7. 71 (d, J = 8. 0Hz, 1H), 7. 49 (m, 1H), 7.34 (m, 3H), 7. 18 (m, 1H), 6. 86 (s, 1H), 6. 68 (s, 1H), 5.28 (s, 2H), 4.62 (s, 2H), 4.02 (m, 1H), 3.13 (m,4H), 1.31 (m, 4H) 實施例226The first step 2-chloro-N-(l,1-di-oxy-hexahydro-1 and 6*-thiopyran-4-yl)-acetamide will be 1,1-di-oxy-- Hydrogen-hydrazine and thiopyran-4-ylamine hydrochloride (32 mg, 0.73 mmol) was dissolved in 5 mL of THF and cooled to 0 ° C under ice-bath conditions 382 94 389. 37 mg' 0.366 mmo 1), adding chloroacetic acid chloride (32 mg, 0. 283 mmol) with stirring, and the reaction was completed after stirring for 2 hours at TC. The reaction was concentrated under reduced pressure and dichloromethane. Washing 'to give the compound 2-chloro-N-(l,1-di-oxy-hexahydro-1-exo-mono-pyran-4-yl)-acetamide 225a, the product is directly subjected to the next reaction without isolation The second step 2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-anilino]-quinazoline-6-yl} 〇-pyrrole-1·yl)- N-(l,1-di-l-fluorenyl-hexam-1-λ*6*-thiopyran-4-yl)-acetamide in a 50 mL flask '[3_氯_4-(3- Fluoro-benzyloxy)-phenyl]-[6-indole-pyrrol-3-yl)-quinazolin-4-yl]-amine 42 (52 mg, 0.1 Π mmo 1) dissolved in 1 mL N, N -In the case of dimethyl hydrazide, in an ice bath, cooled to 0 ° C. Add sodium hydride (29 mg, 0. 725 m Mol), after stirring for 3 minutes, 2-chloro-N-(l,1-di-oxy-hexahydro-1 and *6*-thiopyran-4-yl)-acetamide 225a (39 mg, 173. 173 mmol) of 1 mL of N,N-dimethylhydrazine solution, stirred at room temperature for 5 hours. The reaction mixture was added with 50 mL of water and ethyl acetate (5 mL mL), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Extraction: dioxane: decyl alcohol = 100 : 1 ' 60 : 1), 2-(3-{4-[3-gas-4-(3-fluoro-oxy)-phenylamino) -quinazolin-6-yl}-pyrrol-1-yl)-N-(l,1-di-oxy-hexahydro-1 λ *6-thiopyran-4-yl)-acetamide 225 ( 15重量。 Yellow solid), yield: 20.3%. 383 94389 201016683 MS m/z (ESI): 634[M+1] ]H NMR (400 MHz, CD30D-d〇: ^ 9. 72 (s, 1H), 8.55 (s, 1H), 8.51 (s, 1H), 8.31 (d, J = 7. 2Hz 1H), 8.03 (in, 2H), 7. 76 (d, J = 8. 8Hz, 1H), 7. 71 (d, J = 8. 0Hz, 1H ), 7. 49 (m, 1H), 7.34 (m, 3H), 7. 18 (m, 1H), 6. 86 (s, 1H), 6. 68 (s, 1H), 5.28 (s, 2H ), 4.62 (s, 2H), 4.02 (m, 1H), 3.13 (m, 4H), 1.31 (m, 4H) Example 226

「3-氣-4-(3-氟-苄氧基）-笨基卜「6-(1-環丙基甲基-1H-吡洛基）-·喧哇淋~~4~~基1~~胺"3-Ga-4-(3-fluoro-benzyloxy)-stupyl"6-(1-cyclopropylmethyl-1H-pyranyl)-·喧哇淋~~4~~Base 1 ~~amine

第一步曱磺酸環丙基曱酯將環丙基曱醇（720 g，10 mmol)溶於20 mL乙SI中， 384 94389 201016683 在冰浴條件下，冷卻至0°C，依次加入三乙胺（2. 8 mL，20 mmo 1)和甲續酿氯（1.2mL，15 mmo 1)，室溫下攪拌2小時，反應完畢.。過濾、反應液，濾餅用乙喊洗務，遽液在減壓下旋乾’得到甲石黃酸環丙基甲酯226a( 1. 49 g，無色油狀液體），產率：99. 3%。 MS m/z (ESI) ： 151[M+1] 第二步 [3-氣-4-(3 -氟-苄氧基）-苯基]-[6-(l -環丙基曱基-iΗ-〇比 ρ各-3-基）-啥嗤琳-4_基]-胺在50mL的燒瓶中，將[3 -氯-4_(3_氟-节氧基）-苯基] -[6-(1Η-吡咯-3-基）-喹唑啉-4-基]-胺 42(146 mg，0.33 mmol)溶於4 mL無水N，N-二甲基甲醯胺中，攪拌下加入氫 .化鈉（4〇 mg ’ 0. 99 mmol)，30分鐘後加入甲磺酸環丙基曱酯226a(74 mg，0· 5 mmol)，在55。(：下攪拌2小時反應完畢。反應液加入30 mL冰水’用乙酸乙醋萃取（3〇 mLx4)，合併的有機相依次經由飽和氣化鈉溶液洗滌（3〇 mLx2)，無 β水硫酸鈉脫水，過濾，減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化（二氯曱燒：甲醇=6〇 : 1)，知到本標題產物[3-氣-4-(3-氣-苄氧基）-苯基]_[6-(1_環丙基曱基-1Η-吡咯-3-基）-喹唑啉-4-基]-胺226(81 mg，黃色固體），產率：49. 6%。 MS m/z (ESI) ： 499[M+1] !H NMR (400 MHz, CD30D-d〇： (5 9.69 (s, 1H), 8.53 (s, 1H), 8.50 (s, 1H), 8.04 (m, 2H), 7.75 (m, 1H), 7.70 94389 385 201016683 (m，1H)，7. 49 (m，2H)， (s, 1H), 6. 67 (s, 1Η)} 2H)，1. 24 (m，1H)，〇實施例227 7. 2 8 ( m，3 H)，7. 1 9 ( m，；[ jj ) 6 9 5 5. 27 (s，2H)，3. 81 (d, j：^ 2{jz .56 (m，2H)，0. 39 (m，2H) 2-(3-{4-t ^ 吡咯-J-基苯胺基]_~:啥：^^〜6_基} 經基-環己基]-乙 ΟThe first step is sulfonic acid cyclopropyl decyl ester. Cyclopropyl sterol (720 g, 10 mmol) is dissolved in 20 mL of B, 384 94389 201016683. In an ice bath, it is cooled to 0 ° C, and then added three. Ethylamine (2.8 mL, 20 mmo 1) and chlorinated chlorine (1.2 mL, 15 mmo 1) were stirred at room temperature for 2 hours, and the reaction was completed. Filtration, the reaction mixture, the filter cake was washed with B, and the mash was spin-dried under reduced pressure to obtain cyclopropylmethyl 226 (1,49 g, colorless oily liquid). Yield: 99. 3%. MS m/z (ESI): 151 [M + 1]. Step 2 [3- -4- 4-(3-fluoro-benzyloxy)-phenyl]-[6-(l-cyclopropyl-decyl)- IΗ-〇比ρ-3-yl)-啥嗤琳-4_yl]-amine In a 50 mL flask, [3-chloro-4_(3-fluoro-oxy-oxy)-phenyl]-[ 6-(1Η-pyrrol-3-yl)-quinazolin-4-yl]-amine 42 (146 mg, 0.33 mmol) was dissolved in 4 mL anhydrous N,N-dimethylformamide and stirred. Hydrogen. Sodium (4 〇 mg '0. 99 mmol) was added, and after 30 minutes, cyclopropyl decyl methanesulfonate 226a (74 mg, 0.5 mmol) was added at 55. (The reaction was completed by stirring for 2 hours. The reaction solution was added with 30 mL of ice water' extracted with ethyl acetate (3 〇 mL x 4), and the combined organic phases were washed successively with saturated sodium carbonate solution (3 〇 mL x 2) without β water sulphuric acid. The sodium was dehydrated, filtered, and concentrated under reduced pressure. The obtained residue was purified and purified by EtOAc EtOAc EtOAc EtOAc -(3-Gas-benzyloxy)-phenyl]-[6-(1_cyclopropylindolyl-1Η-pyrrol-3-yl)-quinazolin-4-yl]-amine 226 (81 mg , y. s, 1H), 8.50 (s, 1H), 8.04 (m, 2H), 7.75 (m, 1H), 7.70 94389 385 201016683 (m, 1H), 7. 49 (m, 2H), (s, 1H) , 6. 67 (s, 1Η)} 2H), 1. 24 (m, 1H), 〇 Example 227 7. 2 8 ( m, 3 H), 7. 1 9 ( m,; [ jj ) 6 9 5 5. 27 (s, 2H), 3. 81 (d, j:^ 2{jz .56 (m, 2H), 0. 39 (m, 2H) 2-(3-{4-t ^ pyrrole - J-phenylanilino]_~:啥:^^~6_yl}]-based-cyclohexyl]-acetamidine

〇aF〇aF

JCrVJCrV

2—氣|[(lr，4r)—4,基-環己基]-乙醯胺將（li·，4〇-4,基環己醇鹽酸u 溶於10 mL無水二氣甲ρ击上 *6 mmol) ^ 甲烷中，加入三乙胺（8.3 mL，60 咖〇1)，在丙酮-乾冰浴條件下，冷卻至_78^，滴加氯乙酿氣（0· 38 mL ’ 5 mmo 1) ’授拌1小時後反應完畢。反應物在2-gas|[(lr,4r)-4, yl-cyclohexyl]-acetamide (Li·, 4〇-4, Cyclohexanol hydrochloride u dissolved in 10 mL of anhydrous two gas ρ hit* 6 mmol) ^ In methane, add triethylamine (8.3 mL, 60 caffe 1), cool to _78^ in acetone-dry ice bath, add chloroethene (0·38 mL ' 5 mmo 1 ) 'The reaction was completed after 1 hour of mixing. Reactant in

減壓下濃縮’加入50 mL乙酸乙酯，過濾，遽餅用30 mL 乙酸乙S旨洗滌，有機相在減壓下濃縮，得到化合物2 -氯 386 94389 201016683 -N-(4-經基-環己基）-乙醯胺227a(3.55g，紅褐色固體），產率：92. 7% MS m/z (ESI) ： 192[M+1] 第二步 2-(3-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-喹唑啉-6-基} 比嘻-1-基）-N-[(lr，4r)-(4-羥基-環己基]-乙醯胺在50 mL的燒瓶中，將[3-氯-4-(3-氟-苄氧基）-苯基] -[6-(1Η-吡咯-3-基）-喹唑啉-4-基]-胺 42(222 mg，0.5 〇 mmol)溶於10 mL無水N，N-二曱基甲醯胺中，在冰浴條件下，冷卻至0 C ’加入氫化納（8 〇 , 3 · 3 mmo 1)，授拌 30分鐘後加入2-氯-N-(4-羥基-環己基）-乙醯胺227a (115 mg，0. 6 mmol)，室溫下攪拌6小時反應完畢。將反應液中加入50 mL冰水淬滅反應’用乙酸乙酯萃取（5〇 mL .x3)，合併的有機相經由飽和氯化鈉溶液洗滌，無水硫酸鈉脫水，過濾，減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化（二氯甲烷：甲醇=2〇 : 1)，得到2-(3-β {4-[3-氣-4-(3-氟-苄氧基）_苯胺基]-喹唑啉基卜吡嘻 -1-基）_N-[(lr’4r)-(4-羥基-環己基]-乙醯胺 227(35 mg ’黃色固體），產率：11. 7%。 MS m/z (ESI) ： 600[M+1] H NMR (400 MHz, CD30D-d6):3 9.71 (s, 1H)，8.55 (s 1H), 8.50 (s, 1H), 8.02 (m, 3H), 7.75 (m, 1H), 7. 7〇 (m, 1H), 7.47(m, 1H), 7. 30 (m, 3H), 7.19(m, 1H), 6.83 (s, 1H), 6. 67 (s, 1H), 5. 27 (s, 2H), 4. 56 (s, 2H), 3. 51 94389 387 201016683 (m，1H)，3.38 (m，1H)，1.81 (m，4H) 1.2 (m，4H) 實施例228 .2-(3-{4-[3-氯-.4-(3-氟-1氧基茉胺基μ喹4嗞—^_芊} 二0比咯-1 -棊上：..1 - ( 4 -吡咯烷-1 -甚-畋嘧-1 -基Λ獅Concentrate under reduced pressure', add 50 mL of ethyl acetate, filter, and wash the cake with 30 mL of ethyl acetate. The organic phase is concentrated under reduced pressure to give compound 2 -chloro 386 94 </ RTI> </ RTI> </ RTI> Cyclohexyl)-acetamide 227a (3.55 g, reddish brown solid), Yield: 92. 7% MS m/z (ESI): 192 [M+1] Step 2 2-(3-{4-[ 3-chloro-4-(3-fluoro-benzyloxy)-anilino]-quinazolin-6-yl} than 嘻-1-yl)-N-[(lr,4r)-(4-hydroxy- [3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinoline in a 50 mL flask in cyclohexyl]-acetamide Oxazolin-4-yl]-amine 42 (222 mg, 0.5 〇 mmol) was dissolved in 10 mL of anhydrous N,N-dimercaptocarbamide and cooled to 0 C 'in the ice bath. 8 〇, 3 · 3 mmo 1), after mixing for 30 minutes, add 2-chloro-N-(4-hydroxy-cyclohexyl)-acetamide 227a (115 mg, 0.6 mmol), stir at room temperature 6 After the reaction was completed, the reaction mixture was quenched with 50 mL of ice water. The mixture was extracted with ethyl acetate (5 〇 mL.x3). The combined organic phases were washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. Press down to concentrate The residue was further separated and purified by silica gel column chromatography (dichloromethane: methanol = 2 〇: 1) to give 2-(3-[beta][4-[3- ))-anilino]-quinazolinylpyridin-1-yl)_N-[(lr'4r)-(4-hydroxy-cyclohexyl)-acetamide 227 (35 mg 'yellow solid) Rate: 11.7%. MS m/z (ESI): 600[M+1] H NMR (400 MHz, CD30D-d6): 3 9.71 (s, 1H), 8.55 (s 1H), 8.50 (s, 1H), 8.02 (m, 3H), 7.75 (m, 1H), 7. 7〇(m, 1H), 7.47(m, 1H), 7. 30 (m, 3H), 7.19(m, 1H), 6.83 (s, 1H), 6. 67 (s, 1H), 5. 27 (s, 2H), 4. 56 (s, 2H), 3. 51 94389 387 201016683 (m, 1H), 3.38 (m, 1H), 1.81 (m, 4H) 1.2 (m, 4H) Example 228. 2-(3-{4-[3-Chloro-.4-(3-Fluoro-1oxymosamine) —^_芊} dioxin-1 - 棊::. -1 - ( 4 -pyrrolidine-1 - sulphur -1 - fluorene - lion

第一步 0 2~氣-1-(4-0比洛烧-1-基-略〇定基乙酮將4-咐洛烧基派咬（350 mg，2.27 mmol)溶於6〇 mL 四氫呋喃中，在乾冰乙醇浴冷卻至_78°C ,攪拌下逐漸滴加 .At 虱乙醯氯（6 g ’ 53 mmol)，滴加完畢在冰浴冷卻下攪拌3〇刀鐘’反應完畢。在反應液中加入2〇 mL水，減壓下蒸去四氣咬喃’得到的溶液用乙酸乙酯萃取（100 mLx3)，合併的有機相依次經由水洗滌（100 mLx2)，無水硫酸鈉脫水，過濾，減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進 3S8 94389 201016683 一步分離純化（二氯甲烷：曱醇=10 : 1)，得到本標題產物 2-氯-1-(4-1¾ 略烧-1-基-〇底咬-1-基）-乙嗣 22 8a (225 mg，棕色固體），產率：13%。 MS m/z (ESI) : 231[M+1] 第二步 2-(3-{4-[3-氣-4-(3-氟-苄氧基）-苯胺基]-喹唑啉-6-基} 比洛-1-基比哈院-1-基-娘π定-1-基）-乙酮將化合物[3 -氯- 4- (3-氟-苄氧基）-苯基]-[6-(1Η-πΛ g 略-3-基）-喹唑啉-4-基]-胺 42(300 mg，0. 67 mmol)和氫化鈉（80 mg ’ 2 mmol)溶於10 mL N，N-二曱基甲醯胺中，室溫下擾拌30分鐘後加入2-氯-1-(4-°比嘻燒-1-基-0辰咬一1-基）_ 乙酮 228a(190 mg’ 0.8 mmol)的 1 mL N，N-二曱 .基甲醯胺溶液’室溫下攪拌3〇分鐘後反應完畢。在反應液 •中加入1 〇〇 mL飽和氯化鈉溶液淬滅反應’水相用乙酸乙酯萃取（100 mLx3) ’合併的有機相依次經由水，飽和氣化鈉溶液洗滌’無水硫酸鈉脫水，過濾，減壓下濃縮，得到的 ^殘留物藉由碎膠管柱層析法進一步分離純化（二氯曱烧：曱醇=10 : 1) ’得到標題產物2-(3-{4-[3-氯-4-(3-氟-节氧基）-苯胺基]-喹唑琳-6-基}-吡咯-1-基）-1-(吼洛烧-卜基-哌啶-1-基）-乙酮228(190 mg ’黃色固體），產率：44%。 MS m/z (ESI) · 639[M+1] H NMR (400 MHz, CDSOD-de): δ 9. 74 (s, 1H), 8 55 (s 1H), 8.50 (s, 1H), 8.03 (s, 2H), 7.76 (d, J = 8.8Hz, 1H), 7. 70 (d, J = 8. 8Hz, 1H), 7. 50 (t, J = 8. 8Hz, 1H), 94389 389 201016683 7.43 (s, 1H), 7.33 (m, 3H), 7.19 (t, J = 8. 8Hz, 1H), 6. 83 (s, 1H), 6. 66 (s, 1H), 5. 27 (s, 2H), 4. 95 (m, 2H), 4.14 (d, J = 13.2Hz, 1H), 3.83 (d, J = 12.0Hz, 1H), 3.14 (m, 1H), 2.84 (m, 1H), 2.50 (ra, 4H), 2.34 (br, 1H), 1.68 (m, 4H), 1.41 (m, 1H), 1. 28(m, 1H) 實施例2 2 9 [3-氧琿丙基胺某一广基）-111-°比°各-3-基嘴_4-其丨一軒The first step 0 2 ~ gas - 1 (4-0 than carbazin-1-yl-succinyl ethyl ketone - 4-indole-based bite (350 mg, 2.27 mmol) dissolved in 6 〇 mL of tetrahydrofuran After cooling in a dry ice ethanol bath to _78 ° C, gradually add .At 虱醯醯 ( (6 g ' 53 mmol), and add 3 knives in the ice bath to cool the reaction. 2 ml of water was added to the solution, and the solution obtained by distilling off the gas was distilled off under reduced pressure (100 mL×3). The combined organic phases were washed with water (100 mL×2), dried over anhydrous sodium sulfate and filtered. The residue was concentrated under reduced pressure. EtOAc m. -13⁄4 succinyl-1-yl-indole-1-yl)-acetoxime 22 8a (225 mg, brown solid), yield: 13%. MS m/z (ESI): 231[M+1] The second step 2-(3-{4-[3- gas-4-(3-fluoro-benzyloxy)-anilino]-quinazolin-6-yl} Bilo-1-kibiya- 1-yl-nitentyl-1-yl)-ethanone will give the compound [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-πΛ g -3- base)- Quinazolin-4-yl]-amine 42 (300 mg, 0.67 mmol) and sodium hydride (80 mg '2 mmol) dissolved in 10 mL of N,N-dimercaptocaramine, at room temperature After mixing for 30 minutes, add 2-chloro-1-(4-° 嘻嘻 -1- -1 - 0 - 0 bit ate 1-yl) _ ethyl ketone 228a (190 mg ' 0.8 mmol) of 1 mL N, N- II曱. The base amide solution was stirred at room temperature for 3 minutes and the reaction was completed. Add 1 〇〇mL of saturated sodium chloride solution to the reaction solution and quench the reaction. The aqueous phase was extracted with ethyl acetate (100 mL×3). The combined organic phases are sequentially dehydrated by water, saturated sodium carbonate solution, anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained is further separated and purified by a gel column chromatography (dichloropyrene: 曱Alcohol = 10 : 1) 'The title product 2-(3-{4-[3-chloro-4-(3-fluoro-oxy)-anilino]-quinazoline-6-yl}-pyrrole- 1-yl)-1-(indolyl-buki-piperidin-1-yl)-ethanone 228 (190 mg 'yellow solid), yield: 44%. MS m/z (ESI) · 639[ M+1] H NMR (400 MHz, CDSOD-de): δ 9. 74 (s, 1H), 8 55 (s 1H), 8.50 (s, 1H), 8.03 (s, 2H), 7.76 (d, J = 8.8Hz, 1H), 7. 70 (d, J = 8. 8Hz, 1H), 7. 50 (t, J = 8. 8Hz, 1H), 94389 389 201016683 7.43 (s, 1H), 7.33 (m, 3H), 7.19 (t, J = 8. 8Hz, 1H ), 6. 83 (s, 1H), 6. 66 (s, 1H), 5. 27 (s, 2H), 4. 95 (m, 2H), 4.14 (d, J = 13.2Hz, 1H), 3.83 (d, J = 12.0 Hz, 1H), 3.14 (m, 1H), 2.84 (m, 1H), 2.50 (ra, 4H), 2.34 (br, 1H), 1.68 (m, 4H), 1.41 (m , 1H), 1. 28(m, 1H) Example 2 2 9 [3-oxopropylamine a broad base)-111-° ratio ° -3- base mouth _4- 丨一轩

G 冑2-(3-{4-[3-氯-4-(3-氟1氧基）_苯胺基]—喧唾啉--基）+環丙基一乙酿胺217(54呢，〇1 mmol)溶於3 mL四氫咬嗔中，搜拌下加入氫化㈣⑴4 吨，0.3 mmol)’ 3小時後反應完畢。加入甲醇淬滅反應，減壓下濃縮，得到的殘留物藉由石夕谬管柱層析法進一步分離純化（二氣甲烧：甲醇=10:1)，得到標題產物[3 一氣_4_(3_ 乱-节氧基）-苯基]-{6-[1-(2-環丙基胺基_乙基）普〇比咯 -3-基]-噎唾琳+基卜胺229(8呢，淡黃色固體），座率： 94389 390 201016683 15. 2%。 MS m/z (ESI) ： 528[M+1] 'H NMR (400 MHz, CD30D-d〇 : <5 8. 467 (s, 1H), 8. 445 (s, 1H), 8.057 (d, J=8.4Hz, 1H), 7.920 (d, J = 2Hz, 1H), 7.729 (d, J = 8.8Hz, 1H), 7. 637 (t, J = 4. 2Hz, 1H), 7.436 (m, 1H), 7.319(ra, 3H), 7.165 (d, J = 8. 8Hz, 1H), 7.085 (t, J = 7.8Hz, 1H), 6.865 (s, 1H), 6. 708 (s, 1H), 5.229 (s, 2H), 4. 124(t, J = 6.4Hz, 2H), 3.134 (m, 2H), 2.213 (m, 1H), 0.532 (m, 2H), 0.394 (m , 2H) 實施例230 「3-氣-4-(3-氟-苄氣基）-笨基l-「6-(1-吼啶-4-基甲基 -1Η-°比口各-3-基）-唾〇坐琳-4-基1-胺G 胄 2-(3-{4-[3-chloro-4-(3-fluoromethoxy)-anilino]-hydrazinyl--yl)+cyclopropyl-ethylamine 217 (54, 〇1 mmol) was dissolved in 3 mL of tetrahydro-bite, and hydrogenation (4) (1) 4 tons, 0.3 mmol) was added under mixing for 3 hours. The reaction was quenched by the addition of EtOAc (EtOAc) (EtOAc). 3_ chaotic-nodaloxy)-phenyl]-{6-[1-(2-cyclopropylamino-ethyl)pyrrolidino-3-yl]-噎琳 ++ kebamine 229 (8 , light yellow solid), seating rate: 94389 390 201016683 15. 2%. MS m/z (ESI): 528 [M+1] <RTI ID=0.0> , J=8.4Hz, 1H), 7.920 (d, J = 2Hz, 1H), 7.729 (d, J = 8.8Hz, 1H), 7. 637 (t, J = 4. 2Hz, 1H), 7.436 (m , 1H), 7.319(ra, 3H), 7.165 (d, J = 8. 8Hz, 1H), 7.085 (t, J = 7.8Hz, 1H), 6.865 (s, 1H), 6. 708 (s, 1H) ), 5.229 (s, 2H), 4. 124 (t, J = 6.4 Hz, 2H), 3.134 (m, 2H), 2.213 (m, 1H), 0.532 (m, 2H), 0.394 (m , 2H) Example 230 "3-Gas-4-(3-fluoro-benzyl)-phenyl] 1-(6-(1-acridin-4-ylmethyl-1Η-° -3-yl) - 〇〇 sit -4--4-yl 1-amine

391 94389 201016683 第一步曱磺酸（吡啶-4-基）曱酯將0比啶一4-基-甲醇（536 mg，4. 92 mmol)溶於 40 inL 二氣甲燒中，在冰浴條件下，冷卻至〇°c，依次加入三乙胺（1.1 mg’ 10.83 mmo 1)和曱續醯氯（668 mg，5.83 mmo 1)，室溫下搜拌1小時，反應完畢。將反應液中加入50 mL水，減壓下蒸掉二氣曱烷’用乙酸乙酯萃取（100 mLx3)，合併的有機相依次經由無水硫酸鈉脫水，過濾，減壓下濃縮， g殘留物藉由矽膠管柱層析法分離純化（二氯甲烷：曱醇 =ι〇 · 1) ’得到甲磺酸（D比啶一4一基）甲酯230a(246 mg，白色固體），產率：26. 7%。 MS m/z (ESI) ： 188[M+1] •第二步 [3氯4 (3氟〜苄氧基）_苯基]— G —吼啶_4_基曱基 -111-啦嘻-3-基）-喹唑琳_4_基]_胺在5〇此的燒瓶中，將[3-氣-4-(3-氟-节氧基）-苯基] U _[6-UH-W一基)_啥终[基]一胺 42 (2〇3 呢，〇 46 mmol)，於2⑪無水Ν’Ν_:甲基甲酿胺中’在冰浴條件下’冷卻至〇°C，加入氫化納（46 mg，1.15 ramol)，授拌 20分鐘後加入甲確酸（比、夂1 比啶_4一基）曱酯 230a(136mg，〇 73 mmol)，室溫下授拌1 e ·小時反應完畢。反應液減壓下濃縮，得到的殘留物μ由石々棚μ p 辰初精由矽膠官柱層析法進一步分離純化氣甲烷：甲醇=60 : 1)，尸丨士描辛侍到本私題產物[3-氯-4-(3-氟、卞虱基）-本基]-[^卜吡啶_4_ 疋4卷甲基比σ各-3-基）-嗤 94389 392 201016683 唑啉-4-基]-胺230(22 mg，黃色固體），產率：84%。 MS ra/z (ESI) ： 536[M+1] !H NMR (400 MHz, CD30D-d〇: 5 9. 71 (s, 1H), 8.56 (m, 3H)，8.51 (s，1H)，8.06 (d，J=8.4Hz，1H)，8.01 (d， J = 2.0Hz，1H)，7.74 (m, 2H), 7. 49 (in, 2H), 7. 32 (ra, 3H), 7.21 (m, 3H), 7.03 (s, 1H), 6.77 (s, 1H), 5.27 (s, 4H) 實施例231 2-(3-U-「3-氯-4-(3-氟-苄氧基）-笨胺基1-喹唑啉-6-基} -口比口各-1-基）-N-口辰咬-4-基-乙醯胺391 94389 201016683 First step oxime sulfonic acid (pyridin-4-yl) oxime ester 0-pyridyl 4-yl-methanol (536 mg, 4.92 mmol) dissolved in 40 inL two gas, in an ice bath Under the conditions, the mixture was cooled to 〇 °c, and triethylamine (1.1 mg ' 10.83 mmo 1 ) and hydrazine chloride (668 mg, 5.83 mmo 1 ) were added in sequence, and the mixture was stirred at room temperature for 1 hour, and the reaction was completed. 50 ml of water was added to the reaction mixture, and dioxane was distilled off under reduced pressure and extracted with ethyl acetate (100 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Separation and purification by methylene chloride column chromatography (dichloromethane: decyl alcohol = ι 〇 1) to give methyl methanesulfonic acid (D-pyridyl-4-yl) methyl ester 230a (246 mg, white solid), yield : 26.7%. MS m/z (ESI): 188 [M + 1] • Step 2 [3 chloro 4 (3 fluoro - benzyloxy) phenyl] - G - acridine _4 yl thiol - 111 - 嘻-3-yl)-quinazoline _4_yl]-amine In a flask of 5 Torr, [3- gas-4-(3-fluoro-hydroxyl)-phenyl] U _[6- UH-W-based) 啥 [ [基]-amine 42 (2〇3 〇, 46 mmol), cooled to 〇° under ice bath conditions in 211 anhydrous Ν'Ν_: methyl ketoamine C, adding sodium hydride (46 mg, 1.15 ramol), and mixing for 20 minutes, then adding methic acid (ratio, 夂1 to pyridine-4-yl) oxime ester 230a (136 mg, 〇73 mmol), and mixing at room temperature 1 e · The hour reaction is completed. The reaction solution is concentrated under reduced pressure, and the obtained residue μ is further separated and purified from the sputum sputum by the sputum colloidal column chromatography. Methane: methanol = 60: 1), the corpse of the corpse Product [3-chloro-4-(3-fluoro, decyl)-benyl]-[^-pyridine _4_ 疋4-volume methyl ratio σ--3-yl)-嗤94389 392 201016683 oxazoline-4- Base]-amine 230 (22 mg, yellow solid), yield: 84%. MS ra/z (ESI): 536 [M+1] <EMI> NMR (400 MHz, CD30D-d: 5 9. 71 (s, 1H), 8.56 (m, 3H), 8.51 (s, 1H), 8.06 (d, J = 8.4 Hz, 1H), 8.01 (d, J = 2.0 Hz, 1H), 7.74 (m, 2H), 7. 49 (in, 2H), 7. 32 (ra, 3H), 7.21 (m, 3H), 7.03 (s, 1H), 6.77 (s, 1H), 5.27 (s, 4H) Example 231 2-(3-U-"3-chloro-4-(3-fluoro-benzyloxy) Base)-stupylamino-1-quinazolin-6-yl}-portal ratio-1-yl)-N-mouth butyl-4-yl-acetamide

231a 231b231a 231b

第一步 393 94389 201016683 N-(l -节基-旅咬-4-基）_2-氣-乙醯胺將 1-节基- π底η定-4-基胺 231a(2.1 mL，10 mmol， Aldrich)溶於25 mL四氫呋喃中，用乾冰-丙酮浴冷卻至 -78 °C ’滴加氣乙酿氯（0. 91 mL，12 mmo 1)，保持此溫度， 1小時後反應完畢。將反應液中加入50 mL水和50 mL乙酸乙醋’分液，水相用乙酸乙酯萃取（5〇 mLx2 )，合併的有機相經由飽和氯化納溶液洗務，無水硫酸納脫水，過濾，減壓下濃縮’得到N-(l-苄基底咬-4-基）-2-氣-乙酿胺乃231b(2. 5 g ’粉色固體），產率：91. 4%。 ^ MS m/z (ESI) ： 267[M+1] 第二步 N-( 1-苄基-哌啶-4-基）-2-(3-{4-[3-氣-4-(3-氟 f 氧基）- 苯胺基]-啥β坐琳-6-基}-°比嘻-1-基）-乙酿胺將[3-氣-4-(3^氣-苄氧基）-苯基]-[6 —(ΐΗ-β比略_3-基） -喹咬琳-4-基]-胺 42(445mg’ 1 mmol)溶於 1〇 mL 無水 Ν，Ν- 二甲基甲醯胺中，在冰浴條件下，冷卻至，加入氫化 ◎納（140 mg，3 mmol)，授掉30分鐘後加入N-(l-节基-娘咬-4-基）-2-氣-乙醯胺 231b(316 mg，1.2 mraol)，室溫下攪拌1小時反應完畢。反應液減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化（二氯曱燒：甲醇= 25 : 1) ’得到本標題產物n-U-苄基-哌啶_4-基）-2-(3- {4-[3 -乳-4-(3 -氟苄氧基）-苯胺基]-啥唾琳基卜^比嘻 -卜基）-乙醯胺231c (478 mg，淡黃色固體），產率：7〇 9〇/〇。 MS m/z (ESI) ： 675 [M+1] 94389 394 201016683 第三步 2-(3-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-喹唑啉_6-基} 比σ各-1-基）-N_略咬_4_基-乙酿胺將^(1-苄基-旅咬-4-基）-2-（3_{4-[3-氯-4-(3-氟苄氧基）-苯胺基]-喹唑啉-6-基卜吡咯-卜基）_乙醯胺 231C (429 mg，0. 64 mmol)溶於 5 mL 二氯曱烧和 5 mL 曱醇的混合溶劑中，加入Pd/C(45 mg，〇. 1 mmol)，在3atm 的氫氣壓下反應過夜。過濾反應液，濾液在減壓下濃縮， 0得到i的殘留物藉由石夕膠管柱層析法進一步分離純化（二氯甲烷：曱醇=2 : 1)，得到標題產物2-(3-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-喹唑啉-6-基卜吡咯-1-基）-N-哌啶 -4-基-乙醢胺231(78 mg，黃綠色固體），產率：39. 3%。 MS m/z (ESI) : 585[M+1] -】H NMR (400 MHz，CD30D-de): (5 9.73 (s，1H)，8.56 (s， 1H)，8.50 (s，1H)，8.09 (s，1H)，8.07 (d，J = 8.8Hz， 1H), 8.03 (s, 1H), 7.85 (d, J = 8. 8Hz, 1H), 7.69 (d, 〇 J = 8,8Hz, 1H), 7.54 (t, J = 8. 8Hz, 1H), 7. 42 (s, 1H), 7.32 (m, 3H), 7.19 (t, J = 8. 8Hz, 1H), 6.85 (s, 1H), 6. 67 (s, 1H), 5. 27 (s, 2H), 4. 58 (s, 2H), 4. 09 (s, 1H), 3.62 (m, 1H), 3.18 (s, 2H), 2.93 (d, J = 12.4Hz, 2H), 1. 71 (d, J = 9. 6Hz, 2H), 1. 32 (m, 2H) 實施例232 (5)-[3二皇-4-(3-氟-苄氣基）-茉某]-「6-(1-吡咯烷-3-篡甲基-111-°比隻-3-基）-啥g坐淋一基一胺 395 94389 201016683First step 393 94389 201016683 N-(l-nodal-tele-4-yl)_2-gas-acetamide 1-meryl-π- bottom η-4-amine 231a (2.1 mL, 10 mmol , Aldrich) was dissolved in 25 mL of tetrahydrofuran, cooled to -78 °C with a dry ice-acetone bath. The mixture was stirred with chlorine (0. 91 mL, 12 mmo 1). The temperature was maintained and the reaction was completed after 1 hour. The reaction solution was added with 50 mL of water and 50 mL of ethyl acetate vinegar. The aqueous phase was extracted with ethyl acetate (5 〇 mL×2). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and filtered. 4%。 The N-(l-benzyl-based butyl-4-yl)-2- ethane-ethyl amide is 231b (2.5 g 'yellow solid), yield: 91.4%. ^ MS m/z (ESI): 267 [M + 1] N-( 1-benzyl-piperidin-4-yl)-2-(3-{4-[3- 3-fluorofoxy)-anilino]-啥β sits -6-yl}-° than 嘻-1-yl)-ethanoamine [3- gas-4-(3^-benzyl-benzyloxy) )-Phenyl]-[6—(ΐΗ-β 比略_3-yl)-quinuclin-4-yl]-amine 42 (445 mg' 1 mmol) dissolved in 1 mL of anhydrous hydrazine, hydrazine - dimethyl In the carbamide, under ice-cooling conditions, cool to, add hydrogenated sodium (140 mg, 3 mmol), and add N-(l-knot-n-butyl-4-yl)-2 after 30 minutes. - Gas-acetamide 231b (316 mg, 1.2 mraol), stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified and purified by EtOAc EtOAc EtOAc EtOAc EtOAc )-2-(3-{4-[3 -lacto-4-(3-fluorobenzyloxy)-anilino]-啥琳基基 ^ 嘻卜卜卜 231 231 231 231 231 231 231 231 , light yellow solid), yield: 7〇9〇/〇. MS m/z (ESI): 675 [M+1] 94389 394 201016683 Step 3 2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-anilino]-quin Oxazoline _6-yl} σ σ-1-yl)-N_ slightly bite _4_yl-ethylamine II (1-benzyl-Becker-4-yl)-2-(3_{4 -[3-Chloro-4-(3-fluorobenzyloxy)-anilino]-quinazolin-6-ylpyrrole-buyl)-acetamide 231C (429 mg, 0.64 mmol) was dissolved Pd/C (45 mg, 〇. 1 mmol) was added to a mixed solvent of 5 mL of dichlorohydrazine and 5 mL of sterol, and the reaction was carried out under a hydrogen atmosphere of 3 atm overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. EtOAc (EtOAc m. {4-[3-Chloro-4-(3-fluoro-benzyloxy)-anilino]-quinazolin-6-ylpyrrolidin-1-yl)-N-piperidin-4-yl-acetamidine 3%。 Amine 231 (78 mg, yellow-green solid), yield: 39.3%. MS m/z (ESI): 585 [M+1]-]H NMR (400 MHz, CD30D-de): (5 9.73 (s, 1H), 8.56 (s, 1H), 8.50 (s, 1H), 8.09 (s,1H), 8.07 (d, J = 8.8Hz, 1H), 8.03 (s, 1H), 7.85 (d, J = 8. 8Hz, 1H), 7.69 (d, 〇J = 8,8Hz, 1H), 7.54 (t, J = 8. 8Hz, 1H), 7. 42 (s, 1H), 7.32 (m, 3H), 7.19 (t, J = 8. 8Hz, 1H), 6.85 (s, 1H) ), 6. 67 (s, 1H), 5. 27 (s, 2H), 4. 58 (s, 2H), 4. 09 (s, 1H), 3.62 (m, 1H), 3.18 (s, 2H ), 2.93 (d, J = 12.4Hz, 2H), 1. 71 (d, J = 9. 6Hz, 2H), 1. 32 (m, 2H) Example 232 (5)-[3 Erhuang-4 -(3-Fluoro-benzyl)-Momo]-"6-(1-Pyrrolidin-3-ylmethyl-111-°-only 3-yl)-啥g-sodium-amino-amine 395 94389 201016683

(S)-3-羥曱基-°比咯境—卜甲酸第三丁酯 G 將（s)-3_羥甲基〜吡咯垸（5. 〇5 g，5〇 mmol；)溶於15〇 raL 二氣曱烧中’氬氣保護，冰浴冷卻至0 °C，加入二碳酸二第二丁醋（11.44 g，52. 5 mmol )，室溫下擾拌6小時，反應元畢。將反應液用飽和碳酸氫納洗務，水相用乙酸乙酯萃取（50 mLx3) ’合併的有機相依次經由飽和氣化鈉溶液洗滌，無水硫酸鈉脫水，過濾，減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化（正己烷：乙酸乙酯 =1 : 1)，得到（S)-3-羥甲基-吡咯烷-1-甲酸第三丁酯232a 396 94389 201016683 (9.29 g，黃色油狀液體），產率：92.4%。 MS m/z (ESI) ： 201[M+1] 第二步 (S)-3-曱磺醯氧曱基-吡咯烷-1-甲酸第三丁酯將（S)-3-經甲基-〇比哈院-l-甲酸第三丁酯232a(2. 01 g，10 mmol)溶於50 mL二氯曱烷中，氬氣氛下加入三乙胺 (5. 6 mL’ 40 mmol)’攪拌10分鐘後加入曱績醯氯（1.55 mL， 20 mmo 1)’室溫下擾摔1小時’反應完畢。將反應液用飽 ◎和碳酸氫納洗條，水相用乙酸乙酯萃取（5〇 mLx3)，合併的有機相依次經由飽和氯化納溶液洗條，無水硫酸納脫水，過慮，減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化（正己烷：乙酸乙酯=4 : 1)，得到（S)-3-曱磺醯氧甲基-吡咯烷-1-甲酸第三丁酯232b(2.47g，黃色油 •狀液體），產率：88. 5%。第三步 (8)-3-(3-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-喹唑啉 © -6-基}-吡咯-1-基曱基）_吡咯烷甲酸第三丁酯將[3-氯-4-(3-氟-苄氧基）-苯基]-[β-(1Η-η比咯-3-基） ~噎唾啉-4-基]-胺 42 (220 mg，0. 49 mmol)溶於 10 mLN，N-二甲基曱醯胺中，攪拌下加入氫化鈉（60 mg，1.47 mmol) 和（S)-3-甲磺醯氧甲基-吡咯烷-1-甲酸第三丁酯232b (198 mg，〇. 74 mmol)的5 mL N，N-二甲基甲醯胺溶液，混合加熱至80T：，3小時後反應完畢。將反應液用水洗滌，乙酸乙酯萃取（50 mLx3 )，合併的有機相依次經由飽和氣化 397 94389 201016683 鈉溶液洗滌’無水硫酸納脫水，過遽’減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化（二氯甲烷：四氫呋喃=20 : 1)，得到（s)-3-(3-{4-[3-氯-4-(3-氟- 苄氧基）-苯胺基]-喹唑啉-6-基卜吼咯基甲基）_吼略燒 -卜甲酸第三丁酯232c(lll mg，黃色油狀液體），產率： 36. 1%。 MS m/z (ESI) ： 629[M+1] 第四步 0(5)-[3-氣-4-(3-氟-苄氧基）-苯基]~~[6~(1_11比1?各统_3_基曱基-111-°比洛-3-基）-〇奎〇坐琳-4-基]-胺將（S)-3-(3-{4-[3-氯-4-(3-氟-苄氧基）_苯胺基]_啥峻淋-6-基比哈-1-基曱基）-σ比η各燒甲酸第二丁酉t 232c(110 mg，0· 175 mmol)溶於 10 mL 二氯甲院中，授掉 •下加入3 mL鹽酸曱醚溶液’室溫下攪拌1小時反應完畢。將反應液在減廢下濃縮’得到的殘留物藉由石夕膠管^層析法進一步分離純化（梯度沖提：二氯曱烷：曱醇=2〇 : ^，一〇氯曱烷：甲醇：氨水=20 : 1 : Id)，得到（s) 一 [3_氣_4_(3_ 氟-苄氧基）-苯基]- [6-(1-°比0各烧-3-基甲基-1H-。比洛_3-基）-喹唑啉-4-基]-胺232 (30 mg，淡黃色固體），產率. 32. 6%。 MS m/z (ESI) ： 529[M+1] ]H NMR (400 MHz, CD30D-d〇： (5 9. 70 (s, 1H), 8.54 (s 1H)，8.50 (s，1H)，8.04 (s，2H)，7.72 (dd，J = 2.〇Hz’ 1H)，7.71(d，J= 8.4Hz, 1H)，7.48 (m，2H)，7. 32 (m， 94389 398 201016683 3H)，7. 19 (m，1H)，6.91 ( r 9ΪΠ 4 U’ 1H)，6.66 (s，1H)，5.27 (s, 2H), 4. 04 (m, in) 〇 9 fil , 9tn , )，3.84 (m，2H)，3.35 On, 1H)， 2.81 (m，2H)，U9 (m，3H)，i, ⑻ 實施例233(S)-3-hydroxyindole-° ratio-dicarboxylic acid tert-butyl ester G (s)-3-hydroxymethyl~pyrrole (5. 〇5 g, 5〇mmol;) is dissolved in 15 〇raL two gas smoldering in 'argon protection, cooled to 0 ° C in an ice bath, add dibutyl carbonate diacetate (11.44 g, 52.5 mmol), stir at room temperature for 6 hours, the reaction element was completed. The reaction mixture was washed with saturated sodium hydrogencarbonate and the aqueous phase was extracted with ethyl acetate (50 mL×3). The combined organic phases were washed sequentially with saturated aqueous sodium sulfate, dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was further separated and purified by hexane column chromatography (hexane: ethyl acetate = 1 : 1) to afford (S) 3-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester 232a 396 94389 201016683 (9.29 g, yellow oily liquid), yield: 92.4%. MS m/z (ESI): 201 [M + 1] Step 2 (S)-3-indolesulfonyloxy-pyrrolidine-1-carboxylic acid tert-butyl ester (S)-3-methyl group - 〇比哈院-l-carboxylic acid tert-butyl ester 232a (2.01 g, 10 mmol) was dissolved in 50 mL of dichloromethane, and triethylamine (5.6 mL '40 mmol) was added under argon atmosphere. After stirring for 10 minutes, the reaction was carried out by adding hydrazine (1.55 mL, 20 mmo 1) at room temperature for 1 hour. The reaction solution was washed with sodium hydride and sodium hydrogencarbonate, and the aqueous phase was extracted with ethyl acetate (5 〇mL×3). The combined organic phases were washed successively with saturated sodium chloride solution, dehydrated with anhydrous sodium sulfate, and under reduced pressure. After concentration, the residue obtained was further separated and purified by hexane column chromatography (hexane: ethyl acetate = 4:1) to give (S)-3-indolesulfonyloxymethyl-pyrrolidine-1-carboxylic acid. 5%。 The third butyl ester 232b (2.47g, yellow oil liquid), yield: 88. 5%. The third step (8)-3-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-anilino]-quinazoline © -6-yl}-pyrrole-1- [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[β-(1Η-ηpyr-3-yl)~噎Sodium porphyrin-4-yl]-amine 42 (220 mg, 0.449 mmol) was dissolved in 10 mL of N,N-dimethyl decylamine and sodium hydride (60 mg, 1.47 mmol) and (S) 3-methylsulfonyloxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester 232b (198 mg, 〇. 74 mmol) in 5 mL of N,N-dimethylformamide solution, mixed and heated to 80T: After 3 hours, the reaction was completed. The reaction solution was washed with water, ethyl acetate (50 mL×3), and the combined organic phase was washed with saturated sodium sulfate 397 94389 201016683 sodium solution, dried under anhydrous sodium sulfate, concentrated under reduced pressure, and the residue obtained was obtained. Further separation and purification by ruthenium column chromatography (dichloromethane: tetrahydrofuran = 20:1) gave (s)-3-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy) 。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。. MS m/z (ESI): 629 [M+1]. Step 4 0 (5)-[3- gas-4-(3-fluoro-benzyloxy)-phenyl]~~[6~(1_11 ratio 1? Each system _3_ 曱 --111-°Bilo-3-yl)-〇奎〇〇坐-4-yl]-amine will (S)-3-(3-{4-[3- Chloro-4-(3-fluoro-benzyloxy)-anilino]-啥峻淋-6-kibir-1-ylindenyl)-σ ratio η calcined formic acid second butyl t 232c (110 mg, 0· 175 mmol) Dissolved in 10 mL of dichloromethane, and added 3 mL of hydrazine hydrochloride solution. Stir at room temperature for 1 hour. The reaction mixture was concentrated under reduced waste. The residue obtained was further separated and purified by chromatography. (gradient elution: dichloromethane: decyl alcohol = 2 〇: ^, monochlorosilane: methanol : Ammonia water = 20 : 1 : Id), get (s) a [3_gas_4_(3_fluoro-benzyloxy)-phenyl]-[6-(1-° ratio 0 each burning-3-yl group A克-1H-.Bilo-3-(yl)-quinazolin-4-yl]-amine 232 (30 mg, pale yellow solid). MS m/z (ESI): 529 [M+1]]H NMR (400 MHz, CD30D-d〇: (5 9. 70 (s, 1H), 8.54 (s 1H), 8.50 (s, 1H), 8.04 (s, 2H), 7.72 (dd, J = 2.〇Hz' 1H), 7.71 (d, J = 8.4Hz, 1H), 7.48 (m, 2H), 7. 32 (m, 94389 398 201016683 3H ), 7. 19 (m, 1H), 6.91 (r 9ΪΠ 4 U' 1H), 6.66 (s, 1H), 5.27 (s, 2H), 4. 04 (m, in) 〇9 fil , 9tn , ) , 3.84 (m, 2H), 3.35 On, 1H), 2.81 (m, 2H), U9 (m, 3H), i, (8) Example 233

2一氣-W4_(2-羥基乙基）_哌畊—卜基]—乙酮將2底哄—卜基''乙醇（1.302 g，l〇mm〇i)溶於20mL 氫夫南中，在丙酮-乾冰浴條件下，冷卻至-781：，加入 2虮—乙胺，攪拌15小時後，滴加氣乙醯氯（0.75 mL， mmol)’攪拌i小時後反應完畢。反應物在減壓下濃縮，殘留物藉由矽膠管柱層析法進行分離純化（二氯曱烷：曱醇 )知到無色油狀液體粗品2-氯-1 — [ 4- (2-經基乙基） 94389 399 201016683 -哌畊-1-基]-乙酮233a’產物不經分離直接進行下一應。 ’ MS m/z (ESI) ： 207[M+1] 第二步 2 (3 {4 [3氣-4-(3-氟-苄氧基）_苯胺基]—噎唾琳_6_基} -吡略-1-基）-1-[4-(2_羥基乙基）一哌哄―丨―基ιμ乙酮在50mL的燒瓶中，將[3_氯_4_(3_氟_苄氧基）_苯基] -[6K1H-吡略-3-基）-喹唑啉_4_基]—胺42(444 mg，丨麵〇1) ◎溶於10 mL無水N，N-二甲基甲醯胺中，在冰浴條件下，冷卻至0 C ’加入氫化鈉（72 rag，3 mmol)’攪拌30分鐘後加入2-氣-l-[4-(2-羥基乙基）-哌畊-卜基μ乙酮233a (206 mg，1 mmol)，室溫下攪拌！小時反應完畢。反應液、減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化（二氣曱烷：甲醇=8: 1)，得到2-(3-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-啥唾琳-6 —基卜η比洛—1-基）_1_ [4-(2-羥基乙基）-哌畊-；!-基]—乙酮233 (215 mg，淡黃色 0固體），產率：34. 9%。 MS m/z (ESI) ： 586[M+1] JH NMR (400 MHz, CD30D-d6): ά 9. 67 (s, 1H), 8. 8 (s, 1H), 8.5 (s, 1H), 8.03 (d, J=8. 8Hz, 2H), 7.76 (dd, J = 2Hz, 1H), 7. 70 (d, J=8. 4Hz, 1H), 7. 5 (m, 2H), 7. 36 (m, 3H), 7.2 (s, 1H), 6.93 (s, 1H), 6.60 (s, 1H), 5.27 (s, 2H), 5.0 (s, 2H), 3.5 (m, 8H), 2.4 (t, J = 12Hz, 4H) 實施例234 94389 400 2010166832 gas-W4_(2-hydroxyethyl)_piperidin-buki]-ethanone 2 哄-哄基''ethanol (1.302 g, l〇mm〇i) is dissolved in 20mL of hydrogen funan, in Under acetone-dry ice bath conditions, cooled to -781:, 2 虮-ethylamine was added, and after stirring for 15 hours, gas acetonitrile (0.75 mL, mmol) was added dropwise. After stirring for 1 hour, the reaction was completed. The reactant was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (dichloromethane: decyl alcohol) to obtain a colorless oily liquid crude 2-chloro-1 - [4- (2- The base ethyl) 94389 399 201016683 - piperino-1-yl]-ethanone 233a' product was directly subjected to the next reaction without isolation. ' MS m/z (ESI) : 207 [M+1] second step 2 (3 {4 [3 gas-4-(3-fluoro-benzyloxy)-anilinyl]-噎琳 _____ }-pyridyl-1-yl)-1-[4-(2-hydroxyethyl)-piperazine-hydrazine-yl ivone in a 50 mL flask, [3_Chloro_4_(3_Fluorine_) Benzyloxy)-phenyl]-[6K1H-pyrrol-3-yl)-quinazoline-4-yl]-amine 42 (444 mg, 丨面〇1) ◎ Dissolved in 10 mL of anhydrous N,N- In dimethylformamide, under ice-cooling conditions, cool to 0 C 'add sodium hydride (72 rag, 3 mmol)', stir for 30 minutes, then add 2-gas-l-[4-(2-hydroxyethyl) )-Peptin-Bujiu Ethyl Ketone 233a (206 mg, 1 mmol), stir at room temperature! The hour reaction is completed. The reaction mixture was concentrated under reduced pressure, and the obtained residue was further purified and purified by hexane column chromatography (dioxane: methanol = 8:1) to give 2-(3-{4-[3-chloro- 4-(3-Fluoro-benzyloxy)-anilino]-啥琳 -6 -6 基 η 比 — 1- 1- 1- 1- 1- 1- 1- 1- 1- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4-乙乙乙乙233 (215 mg, pale yellow 0 solid), yield: 34.9%. MS m/z (ESI): 586 [M+1] JH NMR (400 MHz, CD30D-d6): ά 9. 67 (s, 1H), 8. 8 (s, 1H), 8.5 (s, 1H) , 8.03 (d, J=8. 8Hz, 2H), 7.76 (dd, J = 2Hz, 1H), 7. 70 (d, J=8. 4Hz, 1H), 7. 5 (m, 2H), 7 36 (m, 3H), 7.2 (s, 1H), 6.93 (s, 1H), 6.60 (s, 1H), 5.27 (s, 2H), 5.0 (s, 2H), 3.5 (m, 8H), 2.4 (t, J = 12 Hz, 4H) Example 234 94389 400 201016683

187a 234 4_°比洛烧—卜基—派啶⑽mg，〇. 45_卜Alfa)和[3 氣+ (3ϋ氧基）—笨基H6_(卜環氧乙基曱基魯。比洛-3-基）-噎料+基]-胺187a(15Q呢，G. 3 _υ溶於 10 mL甲醇中’ >&合液加熱回流過夜。反應液在減壓下濃187a 234 4_°Bilozepine-Bulk-Pyridinyl (10)mg, 〇. 45_卜Alfa) and [3 gas + (3ϋ oxy)-stupyl H6_(epoxyethyl fluorenyl. -Base)-噎料+基]-Amine 187a (15Q, G. 3 υ in 10 mL of methanol' >& mixture was heated to reflux overnight. The reaction was concentrated under reduced pressure.

縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化（二氯曱烷：甲醇= 10: 1)，得到本標題產物 (3-氟-苄氧基）-苯胺基]-喹唑啉_6__基}比咯_丨—基）_3_ 醇234(35 mg，黃色固籲（4-吡咯烷-1-基-哌啶-卜基）-丙—2-體），產率：15%。 MS m/z (ESI) ： 655[M+1] 丨H NMR (400 MHz，CD30D-A): 6 9. 713 (s，1H)，8 546 (s， 1H), 8.494 (s, 1H), 8.034 (t, J=5. 2Hz, 2H), 7.764 (t, J=5. 6Hz, 1H), 7.703 (d, J=8. 4Hz, 1H), 7.484 (m, 1H), 7.417 (s, 1H), 7.319 (m, 3H), 7. 193 (t, J = 8. 6Hz, 1H), 6.868 (s, 1H), 6.655 (s, 1H), 5.274 (s, 2H), 4.896 (s, 94389 401 201016683 1H)，4.030 (d，J = 13.6Hz，1H)，3.877 (m，2H)，3 486 (s 2H), 3. 427 (m, 1H), 2. 848 (m, 2H), 2. 652 (m, 2H) 2 245 (d, J=17.6Hz, 2H), 2. 000 (t, J = 11.6Hz, 2H), 1.815 (m 2H), 1. 501 (m, 2H), 1. 254 (m, 4H) ’ 實施例235The residue obtained is further purified by hydrazine column chromatography (dichloromethane:methanol = 10:1) to give the title product (3-fluoro-benzyloxy)-anilinyl]-quinazole Porphyrin_6__yl}pyrrole_丨-yl)_3_ alcohol 234 (35 mg, yellow solid (4-pyrrolidin-1-yl-piperidinyl)-propan-2-yl), yield: 15%. MS m/z (ESI): 655 [M+1] 丨H NMR (400 MHz, CD30D-A): 6 9. 713 (s, 1H), 8 546 (s, 1H), 8.494 (s, 1H) , 8.034 (t, J=5. 2Hz, 2H), 7.764 (t, J=5. 6Hz, 1H), 7.703 (d, J=8. 4Hz, 1H), 7.484 (m, 1H), 7.417 (s , 1H), 7.319 (m, 3H), 7. 193 (t, J = 8. 6Hz, 1H), 6.868 (s, 1H), 6.655 (s, 1H), 5.274 (s, 2H), 4.896 (s , 94389 401 201016683 1H), 4.030 (d, J = 13.6Hz, 1H), 3.877 (m, 2H), 3 486 (s 2H), 3. 427 (m, 1H), 2. 848 (m, 2H) , 2. 652 (m, 2H) 2 245 (d, J=17.6Hz, 2H), 2. 000 (t, J = 11.6Hz, 2H), 1.815 (m 2H), 1. 501 (m, 2H) , 1. 254 (m, 4H) ' Example 235

°坐琳-4 -基）-胺°坐琳-4-yl)-amine

將2-(3-{4-[3-氯-4-(3-氟-苄氧基）-笨胺基]坐琳—6-基}-°比嘻-1-基）-N-(l, 1-二侧氧基-六氫〜1 a外*-嘆口南-4-基）-乙酿胺225(54 mg，0.1 mmol)溶於3 mL四氣咬D南中，攪拌下加入氫化鋁鋰⑴· 4 mg，〇. 3 mmol)，3小時後反應完畢。加入甲醇淬滅反應，減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化（二氯甲烷：甲醇=10 : 1)，得到標題產物[3_氯_4_(3_氟_苄氧基苯基] -C6~U-[2-(l，1-二側氧基_六氫-丨λ 噻喃_4_基胺基） 94389 402 201016683 -乙基]-1H-0比p各-3-基}-°|：哇淋-4-基）-胺235(8 mg，淡黃色固體），產率：15. 2%。 MS m/z (ESI) ： 528[M+1] !H NMR (400 MHz, CD30D-d6): (5 9. 68 (s, 1H), 8.53 (s, 1H)，8.50 (s，1H)，8.03 (m，2H)，7.76 (dd，J = 8.8Hz 2. 4Hz，1H)，7.70 (d，J:8.8Hz，1H)，7.48 (m，1H)，7.45 (s, 1H), 7.32 (m, 3H), 7.19(m, 1H), 6. 93 (s, 1H), 6.67 (s, 1H), 5.27(s, 2H), 3. 99 (m, 2H), 3. 10 (m, 2H), 2.98 (m, 2H), 2.90 (m, 2H), 2.79 (m, 1H), 1.24 (m, 4H) 〇實施例236 {4-「3-(3-{4-「3-氣-4-(3-氟-苄氧基）-笨胺基1-喹唑啉 -6-基}-口比p各-1-基）- 2-經基-丙基]-旅啡-1-基}-環丙基-2-(3-{4-[3-Chloro-4-(3-fluoro-benzyloxy)- phenylamino]Salina-6-yl}-°-嘻-1-yl)-N-( l, 1-di-sideoxy-hexahydro~1 a-external *-sighing south-4-yl)-ethylamine 225 (54 mg, 0.1 mmol) dissolved in 3 mL of four gas bites D South, stirring Lithium aluminum hydride (1)·4 mg, 〇. 3 mmol) was added, and the reaction was completed after 3 hours. The reaction was quenched by the addition of EtOAc (EtOAc) (EtOAc). Fluoro-benzyloxyphenyl]-C6~U-[2-(l,1-di-oxo-hexahydro-丨λ thiopyran-4-ylamino) 94389 402 201016683 -Ethyl]-1H- 0%。 The ratio of p--3-yl}-°|: wow--4-yl)-amine 235 (8 mg, pale yellow solid), yield: 15. 2%. MS m/z (ESI): 528 [M+1] <RTI ID=0.0>> , 8.03 (m, 2H), 7.76 (dd, J = 8.8Hz 2. 4Hz, 1H), 7.70 (d, J: 8.8Hz, 1H), 7.48 (m, 1H), 7.45 (s, 1H), 7.32 (m, 3H), 7.19(m, 1H), 6. 93 (s, 1H), 6.67 (s, 1H), 5.27(s, 2H), 3. 99 (m, 2H), 3. 10 (m , 2H), 2.98 (m, 2H), 2.90 (m, 2H), 2.79 (m, 1H), 1.24 (m, 4H) 〇Example 236 {4-"3-(3-{4-"3- Gas-4-(3-fluoro-benzyloxy)-phenylamino-1-quinazolin-6-yl}-port ratio p-l-yl)-2-yl-propyl]-bromo- 1-yl}-cyclopropyl-

187a 236 403 94389 201016683 第一步 4-環丙基羰基-哌哄―丨-甲酸第三丁酯氬氣氛下，將哌口并1甲酸第二丁醋（1.86 g，10 mmol)和碳酸卸（4. 15 g， 30 mmol)溶於1〇〇 mL二氣曱烷中，攪拌下加入環丙基甲醯氯（1.17g’ 11.2 mmol)，混合液在室溫下攪拌過夜。將反應液倒入30 mL水中’乙酸乙酯萃取（3〇 mLx3)，合併的有機相經由無水硫酸鈉脫水，過濾，減壓下濃縮，得到4_環丙基幾基-哌畊-1-甲酸第三丁酯236a(2. 5 g，白色固體），產率：99%。 ❹ MS m/z (ESI) : 255[M+1] 第二步壞丙基-派□井-1-基-甲酮 4-環丙基羰基-哌哄-1-曱酸第三丁酯236a(2. 1 g，8 -mmol)溶於10此無水二氯甲烷中，攪拌下加入三氟醋酸 (14. 28 g ’ 125 mmol) ’室溫下攪拌2小時後反應完畢。將反應液在減壓下濃縮’加入2〇 mL飽和碳酸鈉溶液，分液， _濃縮水相’得到的殘質加入2 〇 mL甲醇，授拌，過濾，遽餅用甲醇洗滌三次’濾液經由無水硫酸鈉脫水，過濾，減壓下濃縮’得到環丙基-哌哄-卜基—曱酮236b(l. 5 g，白色固體），產率：99%。 MS m/z (ESI) ： 155[M+1] 第三步 {4-[3-(3-{4-[3-氯-4-(3-氟-苄氧基）—苯胺基]-喹唑啉 —6_基}-吼咯-1-基）-2-羥基-丙基]-哌畊-l-基}-環丙基- 404 94389 201016683 甲綱將環丙基-哌畊-卜基—甲酮236b(51 mg，〇 33mm〇i)和 [3氯-4-(3-氟-苄氧基）_笨基]環氧乙基甲基_ih_ 吡咯基 > 喹唑啉 ~4-基]-胺 187a(150 mg，0.3 mmol) /今於50 mL曱醇中，混合液加熱回流過夜。反應液在減壓下濃縮，得到的殘留物藉由石夕膠管柱層料進一步分離純化（二氯甲烷：甲醇=40:1)，得到本標題產物丨4_[3_(3_{4一 [3_氯-4-(3-氟-苄氧基）-苯胺基]_喹唑啉_6_基}_吨咯一^ 基）-2-羥基-丙基]-哌哄-丨-基卜環丙基_甲酮236(21吨， ❹黃色固體），產率：10.7%。 MS m/z (ESI) ： 655[M+1] NMR (400 MHz, CD30D-d6) ： <5 8. 468 (s, H), 8.446 (s H), 8.079 (d, J=8.8Hz, 1H), 7.921 (s, lH), 7.731 (dJ=8.8Hz, 1H)，7.640 (d, J = 9.2Hz，1H), 7.431 (t J=7Hz, 1H), 7.352 (t, J = 8. 6Hz, 2H), 7.290 (d, J = 9. 2Hz, 1H), 7.178 (d, J-9. 2Hz, 1H), 7.091 (t, J=8. 6Hz 1H) 6.74 (s, 1H)，6.696 (s，1H)，5.242 (s，2H)，4.122 (m: 2H)，4. 013 (t，J = 7· 2Hz，1H)，3. 593 (m，2H)，3. 816 (br， 2H), 3.650 (br, 2H), 2.605 (br, 2H), 2.431 (d, J = 6Hz! 2H), 2.253 (s, 1H), 1.322 (s, 1H) 實施例237 二^{4-[3-氧-4-(3-氟-苄氧基）-笔|^^唑啉-6_某} -;ί-棊）-3-_ϋ-環丙棊 94389 405 201016683187a 236 403 94389 201016683 First step 4-cyclopropylcarbonyl-piperazine-hydrazine-carboxylic acid tert-butyl ester Under argon atmosphere, piperazine and 1 formic acid second butyl vinegar (1.86 g, 10 mmol) and carbonic acid ( 4. 15 g, 30 mmol) was dissolved in 1 mL of dioxane, and cyclopropylmethylhydrazine chloride (1.17 g ' 11.2 mmol) was added with stirring, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 30 mL of water, ethyl acetate (3 mL mL), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and evaporated. Tert-butyl formate 236a (2.5 g, white solid), Yield: 99%. ❹ MS m/z (ESI): 255 [M+1] second step of propyl-pyrene- -1-yl-ketone 4-cyclopropylcarbonyl-piperidine-1-furic acid tert-butyl ester 236a (2.1 g, 8-mmol) was dissolved in 10 anhydrous methylene chloride. Trifluoroacetic acid (14.28 g '125 mmol) was added with stirring. The mixture was stirred at room temperature for 2 hours and then the reaction was completed. The reaction solution was concentrated under reduced pressure. The residue obtained by adding 2 mL of saturated sodium carbonate solution, and the mixture was separated, and the residue obtained by concentrating the aqueous phase was added to 2 mL of methanol, and the mixture was filtered, and the cake was washed three times with methanol. Dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; MS m/z (ESI): 155 [M+1]. Step 3: 4-[3-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-anilinyl]- Quinazoline-6-yl}-pyrrol-1-yl)-2-hydroxy-propyl]-piperidine-l-yl}-cyclopropyl-404 94389 201016683 A class of cyclopropyl-piperon- Benzyl-methanone 236b (51 mg, 〇33mm〇i) and [3chloro-4-(3-fluoro-benzyloxy)-phenyl]epoxyethylmethyl_ih_pyrrolyl> quinazoline ~4-Methoxy]-amine 187a (150 mg, 0.3 mmol) / present in 50 mL of methanol, the mixture was heated to reflux overnight. The reaction solution was concentrated under reduced pressure, and the obtained residue was further purified (dichloromethane:methanol = 40:1) to afford the title product 丨4_[3_(3_{4_[3 _Chloro-4-(3-fluoro-benzyloxy)-anilino]-quinazoline_6_yl}_tonol-yl)-2-hydroxy-propyl]-piperidin-丨-kib Cyclopropyl-methanone 236 (21 ton, yellow solid), yield: 10.7%. MS m/z (ESI): 655 [M+1] NMR (400 MHz, CD30D-d6): <5 8. 468 (s, H), 8.446 (s H), 8.079 (d, J = 8.8 Hz , 1H), 7.921 (s, lH), 7.731 (dJ=8.8Hz, 1H), 7.640 (d, J = 9.2Hz, 1H), 7.431 (t J=7Hz, 1H), 7.352 (t, J = 8 6Hz, 2H), 7.290 (d, J = 9. 2Hz, 1H), 7.178 (d, J-9. 2Hz, 1H), 7.091 (t, J=8. 6Hz 1H) 6.74 (s, 1H), 6.696 (s, 1H), 5.242 (s, 2H), 4.122 (m: 2H), 4. 013 (t, J = 7 · 2Hz, 1H), 3. 593 (m, 2H), 3. 816 (br , 2H), 3.650 (br, 2H), 2.605 (br, 2H), 2.431 (d, J = 6Hz! 2H), 2.253 (s, 1H), 1.322 (s, 1H) Example 237 II^{4- [3-Oxo-4-(3-fluoro-benzyloxy)-pen|^^oxazoline-6_某} -; ί-棊)-3-_ϋ-cyclopropene 94389 405 201016683

第一步first step

226a ^Οη 237a226a ^Ο 237a

Ο • 1-環丙基甲基-哌π井 • 將甲確酸環丙基甲醋226a(l 49 g，1G _υ和旅哄 (1.77g，20 mmol)溶於3〇 mL乙腈中’攪拌下加入碳酸鉀 a〇7g，15 minol)，混合液加熱回流，反應過夜。將反應 ❹液倒入30 mL水中，分液，有機相經由無水硫酸鈉脫水，過濾，減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化（二氯甲烷：甲醇=5: υ，得到卜環丙基甲基-哌畊237a(373 mg，黃色油狀液體），產率：26. 8%。 MS m/z (ESI) ： 141[M+1] 第二步將1-環丙基甲基-派哄237a(57mg’ 〇 42mm〇1)和[3一氯4-(3-氟-卡氧基笨基]-[6-(1_環氣乙基甲基一比 94389 406 201016683 咯-3-基）-喹唑啉-4-基]-胺187a(u〇吨，ο」mm〇1)溶於 25 mL甲醇中，混合液加熱回流過夜。反應液在減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化（二氯甲烷.甲醇=40 : 1) ’得到本標題產物〗_(3_{4一[3一氯—4-(3-氟-苄氧基）-苯胺基]-喹唑琳基丨_ 比洛_丨_基） -3-(4-環丙基甲基-哌畊-1-基）-丙_2 一醇237G16 mg，黃色固體），產率：30. 1%。 MS m/z (ESI) ： 641[M+1] 'H NMR (400 MHz, CD30D-c/〇： 5 9. 72 (s, 1H), 8.54 (s, 〇 1H), 8.50 (s, 1H), 8.04 (s, 1H), 8.02 (d, J = 8. 8Hz, 1H), 7.77 (d, J = 8.8Hz, 1H), 7.69 (d, J = 8. 8Hz, 1H), 7.54 (t, J = 8.8Hz, 1H), 7.42 (s, 1H), 7.32 (m, 3H), ' 7.19 (t, J = 8.8Hz, 1H), 6.87 (s, 1H), 6.65 (s, 1H), -5.27 (s, 2H), 4.92 (d, J = 4.0Hz, 1H), 4.06 (t, J = 12.8Hz, 1H), 3.94(s, 1H), 3. 85 (m, 1H), 2.48 (br, 8H), 2.25 (br, 2H), 2.19 (br, 2H), 0.80 (m, 1H), 0.45 (d, ^ J = 6.8Hz, 2H), 0.06 (d, J = 4.4Hz, 2H) 實施例238 2-(3-{4-「3-氣-4-(3-氟-节氣基笨胺基吐被-6-基} -g比略-1-基）-l_g辰啡基-乙_Ο • 1-Cyclopropylmethyl-piperazine pi well • Add methacrylate 226a (1 49 g, 1G _ υ and 哄 (1.77 g, 20 mmol) in 3 〇mL acetonitrile 'stirring Potassium carbonate a7g, 15 minol) was added, and the mixture was heated to reflux and allowed to react overnight. The reaction mash was poured into 30 mL of water, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was further separated and purified by silica gel column chromatography (dichloromethane:methanol = 5: υ 得到得到得到得到 237 237 237 237 373 373 373 373 373 373 373 373 373 373 373 373 373 373 373 373 373 373 373 373 373 373 373 MS MS MS MS MS MS MS MS MS MS MS MS 1-cyclopropylmethyl-pyrene 237a (57 mg' 〇42mm〇1) and [3-chloro-4-(3-fluoro-caloxy)-[6-(1_cyclohexalethyl) Base one ratio 94389 406 201016683 pyren-3-yl)-quinazolin-4-yl]-amine 187a (u〇 tons, ο"mm〇1) was dissolved in 25 mL of methanol, and the mixture was heated to reflux overnight. Concentration under reduced pressure, the residue obtained was further purified by silica gel column chromatography (dichloromethane.methanol = 40 : 1) to give the title product _ (3_{4 -[3 - chloro - 4 -(3-fluoro-benzyloxy)-anilino]-quinazolineylhydrazine_Bilo_丨_yl)-3-(4-cyclopropylmethyl-piped-1-yl)-propion_ 2 monool 237G16 mg, yellow solid), yield: 30. 1%. MS m/z (ESI): 641[M+1] 'H NMR (400 MHz, CD30D-c/〇: 5 9 72 (s, 1H), 8.54 (s, 〇1H), 8.50 (s, 1H), 8.04 (s, 1H), 8.02 (d, J = 8. 8Hz, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 8. 8Hz, 1H), 7.54 (t, J = 8.8Hz, 1H), 7.42 (s, 1H), 7.32 (m, 3H), ' 7.19 (t, J = 8.8Hz, 1H), 6.87 (s, 1H), 6.65 (s, 1H), -5.27 (s, 2H), 4.92 (d, J = 4.0Hz, 1H), 4.06 (t, J = 12.8Hz, 1H), 3.94(s, 1H), 3. 85 (m, 1H), 2.48 (br, 8H), 2.25 (br, 2H), 2.19 (br, 2H), 0.80 (m, 1H), 0.45 (d , ^ J = 6.8 Hz, 2H), 0.06 (d, J = 4.4 Hz, 2H) Example 238 2-(3-{4-"3-Gas-4-(3-Fluoro-halo-based phenylamino) Spit is 6-yl}-g than -1-yl)-l_g morphine-ethyl

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238 第一步238 first step

4-(2 -氯乙醯基）-π辰[[井一1_曱酸第三丁酉旨 . 將哌哄_1_甲酸第三丁酯（1 g，5.38 mmol)溶於10 mL -四氫呋喃中，攪拌下加入三乙胺（651 mg，6. 45 mmol)，反應液在丙酮-乾冰浴冷卻至_78t：，滴加氯乙醯氯（〇8niL， 6.45 mmol) ’反應液在室溫下攪拌24小時，反應完畢。將 ❹反應液在減壓下濃縮，殘留物加入5〇 mL水，用乙酸乙醋萃取（50 mLx3) ’合併的有機相經由無水硫酸鈉脫水，過濾’減壓下濃縮’得到的殘留物藉由矽膠管柱層析法進一步分離純化（正己烧：乙酸乙醋=1M)，得到4_(2_氯乙酿基）-哌畊-1-甲酸第三丁酯238a(l.ig，黃色固體），產率： 70% 〇 MS m/z (ESI) ： 264[M+1] 第二步 94389 408 201016683 4-[2-(3-{4-[3-氯-4-(3-氟苄氧基）-苯胺基]—喹唑啉_6一基}-°比嘻-1-基）-乙醯基]辰啡_1_甲酸第三丁酯在50 mL的燒瓶中，將[3-氯-4-(3-氟-苄氧基）-苯基] -[6-(1Η-咬略-3-基）-喹唑啉_4_基]_胺42(444呵，1咖〇1) 溶於10 mL無水N，N-二甲基甲醯胺中，在冰浴條件下，冷卻至0°C，加入氫化鈉（72 mg，3 mmol)，攪拌3〇分鐘後加入4-(2-氯乙醯基）-哌哄一卜甲酸第三丁酯238a(263 mg，1 mmol)，室溫下攪拌】小時反應完畢。在反應液中加入飽和氯化鈉溶液，乙酸乙酯萃取（1〇〇 mLx3)，合併的有 ©機相經由無水硫酸鈉脫水，過濾，減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化（二氯甲烷：甲醇 =40 : 1)，得到 4-[2-(3-{4-[3-氯-4-(3-氟苄氧基）-苯胺 .基]-喹唑啉_6-基}-吡咯基）—乙醯基]—哌畊_丨_甲酸第 -三丁酯238b (300 mg，淡黃色固體），產率：51%。 MS m/z (ESI) ： 671[M+1] 第三步拳2-(3-{4-[3-氯-4-(3-氟-苄氧基）_苯胺基]_喹唑啉_6_基} 比咯-1-基）-1-派啡-1，基—乙嗣將4-[2-(3-{4-[3-氯-4-(3-氟节氧基）一苯胺基卜啥唑啉-6-基卜叫+基）_乙酿基]—派哄+甲酸第三丁酯 238b(400 mg，U mmol)溶於1〇社二氯甲烧中，擾摔下加入3 mL三氟醋酸’室溫下授拌2小時後反應完畢。將反應液中加入飽和碳酸氫鈉溶液，調整pH=8，用乙酸乙酯萃取（100 mLx3)，合併的有機相經由無水硫酸納脫水，過遽， 94389 409 201016683 減壓下濃縮，殘留物藉由矽膠管柱層析法進—步八 (二氯曱烷：甲醇=10 : 1)，得到標題產物2一離純化 -4-(3-氟-苄氧基）-苯胺基]-喹唑啉基卜n比哈 -卜哌畊-卜基-乙酮238(270 mg，黃色固體），產率：) MS m/z (ESI) ： 571[M+1] ^ NMR (400 MHz，CD30D-山）：ά 9. 70 (s，1H)，8. 54 (s 1H)，8.49 (s，1H)，8.03 (d，J=8Hz，2H)，7.76 (d， J=8.4Hz, 1H), 7.70 (d, J = 8. 8Hz, 1H) , 7.48 (m, 1H), 7.41 (s, lH), 7.33 (m, 3H), 7. 19 (t, J = 8Hz, 1H), 6.88 © (s, 1H), 6.65 (s, 1H) , 5.27 (s, 2H), 4. 95 (s, 2H), 3.44 (br, 4H), 2.72 (m, 4H) 實施例239 1^-(彳-「3-(3-{4-「3-氣-4-(3-氟-苄氣某）-装胺基上_^^^ -fi-暮丨-g比洛-1-基）-2-經基-丙基l-p底难-4-基}二乙酸腔·4-(2-chloroethenyl)-π辰[[井一1_曱酸三丁酉的.. Piperazine_1_carboxylic acid tert-butyl ester (1 g, 5.38 mmol) dissolved in 10 mL - tetrahydrofuran Triethylamine (651 mg, 6.45 mmol) was added with stirring, and the reaction solution was cooled to -78t in acetone-dry ice bath, and chloroacetic acid chloride (〇8niL, 6.45 mmol) was added dropwise. After stirring for 24 hours, the reaction was completed. The hydrazine reaction solution was concentrated under reduced pressure, and the residue was purified by ethyl acetate (yield, ethyl acetate) (50 mL×3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Further separation and purification by hydrazine column chromatography (n-hexane: ethyl acetate = 1 M) gave 4-(2-chloroethyl)-piperidine-1-carboxylic acid tert-butyl ester 238a (l.ig, yellow solid ), Yield: 70% 〇MS m/z (ESI): 264 [M+1] Second step 94389 408 201016683 4-[2-(3-{4-[3-chloro-4-(3-fluoro) Benzyloxy)-anilino]-quinazoline-6-yl}-° than 嘻-1-yl)-ethenyl] phenanphin-1_carboxylic acid tert-butyl ester in a 50 mL flask, [ 3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-hexane-3-yl)-quinazoline-4-yl]-amine 42 (444 ̄, 1 Curry 1) Dissolved in 10 mL of anhydrous N,N-dimethylformamide, cooled to 0 ° C under ice bath, added sodium hydride (72 mg, 3 mmol), stirred for 3 min, then added Tetrabutyl 4-(2-chloroethyl)-piperidin-benzoate 238a (263 mg, 1 mmol), stirred at room temperature. A saturated sodium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate (1 mL mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Further separation and purification by chromatography (dichloromethane:methanol = 40:1) gave 4-[2-(3-{4-[3-chloro-4-(3-fluorobenzyloxy)-aniline. -quinazoline-6-yl}-pyrrolyl)-ethinyl]-piperidine-indole-carboxylic acid-tributyl ester 238b (300 mg, pale yellow solid), yield: 51%. MS m/z (ESI): 671 [M+1] Step 3: 2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-anilino]-quinazoline _6_yl}pyr-l-yl)-1-pyphin-1, yl-acetamidine 4-[2-(3-{4-[3-chloro-4-(3-fluoro- oxy) ) monoaniline oxazoline-6-ylpyridinium + yl) _ ethyl ketone] - hydrazine + formic acid tert-butyl ester 238b (400 mg, U mmol) dissolved in 1 〇 dichloromethane, After adding 3 mL of trifluoroacetic acid under the disturbance, the reaction was completed after 2 hours of mixing at room temperature. The reaction mixture was added with a saturated aqueous solution of sodium hydrogencarbonate, and the mixture was adjusted to pH = 8 and extracted with ethyl acetate (100 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, 94389 409 201016683 The title product 2 was isolated from the purified 4-(3-fluoro-benzyloxy)-anilino]-quinazoline by a ruthenium column chromatography (hexanes:methanol = 10:1).啉卜比比比比比比比比比比比比比比比比比比比比比比比比比比比比比比比比 400 400 400 400 400 400 400 400 400 400 400 400 400 400 400 400 400 400 400 -Mountain):ά 9. 70 (s,1H), 8.54 (s 1H), 8.49 (s,1H), 8.03 (d, J=8Hz, 2H), 7.76 (d, J=8.4Hz, 1H ), 7.70 (d, J = 8. 8Hz, 1H), 7.48 (m, 1H), 7.41 (s, lH), 7.33 (m, 3H), 7. 19 (t, J = 8Hz, 1H), 6.88 © (s, 1H), 6.65 (s, 1H), 5.27 (s, 2H), 4. 95 (s, 2H), 3.44 (br, 4H), 2.72 (m, 4H) Example 239 1^-(彳-"3-(3-{4-"3-Gas-4-(3-Fluoro-Benzyl)-Amine-based _^^^-fi-暮丨-gbi-l-yl) -2-Phenyl-propyl lp bottom difficult-4-yl}diacetate cavity

187a 94389 410 239 201016683 第一步 N-旅咬-4-基-乙醯胺乙酸鹽將0底咬-4-基胺（〇·52 mL，5 mmol)溶於20 inL乙鍵中，逐漸滴加醋·酸酥（0.57 mL，6 mmo 1)的20 mL***溶液，滴加完畢後，室溫下攪拌1小時，反應完畢。過濾反應液，遽餅用***洗滌’濾液在減壓下濃縮，得到底啶_4_基_ 乙酿胺乙酸鹽239a(962 mg，白色固體），產率：95. 7%。第二步 N-哌啶-4-基-乙醯胺翁將N-痕啶—4-基-乙醢胺乙酸鹽239a(500 mg，2. 48 mmol)溶於i〇 mL甲醇中，滴加2〇 ‘飽和碳酸鉀的甲醇溶液，室溫下攪拌1小時，反應完畢。將反應液在減壓下濃縮’得到的殘留物用乙酸乙酯萃取（丨〇〇 mLx3) ’所得的殘 -留物藉由矽膠管柱層析法分離純化（二氯甲烷：甲醇=1〇: D，得到N~哌啶—4-基-乙醯胺239b (224 mg，無色油狀液體）’產率：63. 7%。 φ MS m/z (ESI) : 143[M+1] 第三步187a 94389 410 239 201016683 First step N-Big bit-4-yl-acetamide acetate Dissolve 0-Butyl-4-ylamine (〇·52 mL, 5 mmol) in 20 inL of B bond, gradually drip A solution of vinegar and sour (0.57 mL, 6 mmo 1) in 20 mL of diethyl ether was added. After the addition was completed, the mixture was stirred at room temperature for 1 hour, and the reaction was completed. The reaction mixture was filtered, and the mixture was washed with diethyl ether. The filtrate was concentrated under reduced pressure to give the titled </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The second step N-piperidin-4-yl-acetamidone N-pyridin-4-yl-acetamide acetate 239a (500 mg, 2.48 mmol) was dissolved in i〇mL methanol, dripping A methanol solution of 2 〇 'saturated potassium carbonate was added, and the mixture was stirred at room temperature for 1 hour, and the reaction was completed. The reaction mixture was concentrated under reduced pressure. The obtained residue was purified ethyl acetate (yield: </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> : D, N-piperidin-4-yl-acetamide 239b (224 mg, EtOAc: EtOAc: EtOAc: third step

{1_[3_(3-{4~[3-氯-4-(3-氟-苄氧基）-苯胺基]-喹唑啉基}比咯-1-基）_2一羥基_丙基]_哌啶一4_基卜乙醯胺將N辰定、基-乙醯胺239b(60 mg，0 42 mmol)和 -[6-(1-環氧乙基曱基-1H- 一4-基]-胺 187a(165 mg，0.33 mmol) ，混合液加熱回流過夜。反應液在減壓 94389 411 201016683 下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化（二氣曱烧：甲醇=50: 1)，得到本標題產物一 {4-[3 -氣-4-(3 -氟- > 乳基）-苯胺基]-喧t»坐琳-6-基}-1»比嘻 ~1-基）-2-羥基-丙基]-哌啶-4-基}-乙醯胺239(33 mg，黃色固體），產率：22. 9%。 MS m/z (ESI) ： 643[M+1] *H NMR (400 MHz, CD30D-de)： δ 10. 00 (s, 1H), 8. 72 (s, 1H)，8.48 (s，1H)，8. 11 (s，1H)，8.02 (d，J = 8.8Hz， ^ 1H), 7.85 (d, J = 8.8Hz, 1H), 7.69 (d, J = 8. 8Hz, 1H), 7.54 (t, J = 8.8Hz, 1H), 7.42 (s, 1H), 7. 32 (m, 3H), 7.19 (t, J = 8.8Hz, 1H), 6.86 (s, 1H), 6.73 (s, 1H), 5. 27 (s, 2H), 5. 17 (br, 1H), 4. 14 (d, J = 12. 4Hz, 1H), 4.06 (t, J = 12.8Hz, 1H), 3.94 (s, 1H), 3.85 (m, 1H), 3.72 (d, J = 13.2Hz, 1H), 3.34 (s, 1H), 3.04 (t, J = 11.6Hz’ 1H)’ 2.70 (t，J = 10.8Hz, 1H)，2.60 (m，2H), 1.97 (s, 3H), 1.74 (br> 2H), 1.15 (m, 2H) 蟓實施例24〇 13-氧-1：：(1:11_^_^11^基1_{6_「1一（2 —畋畊-卜基—乙基）_ mu-养ί-啥峰嘛―4—莘卜脸{1_[3_(3-{4~[3-chloro-4-(3-fluoro-benzyloxy)-anilino]-quinazolinyl}pyrrol-1-yl)_2-hydroxy-propyl] _ piperidine- 4-yl acetamide, N-butyl, benzyl-acetamide 239b (60 mg, 0 42 mmol) and -[6-(1-epoxyethyl decyl-1H--4- Base]-amine 187a (165 mg, 0.33 mmol), the mixture was heated and refluxed overnight. The reaction mixture was concentrated under reduced pressure of 94389 411 201016683, and the residue obtained was further separated and purified by silica gel column chromatography. :Methanol = 50: 1), the title product - {4-[3 - gas-4-(3-fluoro- > milyl)-anilino]-喧t»坐琳-6-yl}-1 。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。. MS m/z (ESI): 643 [M+1] OH (400 MHz, CD30D-de): δ 10. 00 (s, 1H), 8. 72 (s, 1H), 8.48 (s, 1H) ), 8. 11 (s, 1H), 8.02 (d, J = 8.8Hz, ^ 1H), 7.85 (d, J = 8.8Hz, 1H), 7.69 (d, J = 8. 8Hz, 1H), 7.54 (t, J = 8.8Hz, 1H), 7.42 (s, 1H), 7. 32 (m, 3H), 7.19 (t, J = 8.8Hz, 1H), 6.86 (s, 1H), 6.73 (s, 1H), 5. 27 (s, 2H), 5. 17 (br, 1H), 4. 14 (d, J = 12. 4Hz, 1H), 4.06 (t, J = 12.8Hz, 1H), 3.94 ( s, 1H), 3.85 (m, 1H), 3.72 (d, J = 13.2Hz, 1H), 3.34 (s, 1H), 3.04 (t, J = 11.6Hz' 1H)' 2.70 (t, J = 10.8 Hz, 1H), 2.60 (m, 2H), 1.97 (s, 3H), 1.74 (br> 2H), 1.15 (m, 2H) 蟓Example 24〇13-Oxygen-1::(1:11_^_ ^11^基1_{6_"1一(2 - 畋耕-卜基-乙)_ mu-养ί-啥峰——4—莘卜脸

412 94389 201016683412 94389 201016683

0·21 _i)溶於 10 mL 四氯咬土乙_ 238020 mg’ 氛化銘鋰⑽mg，2.lm_)，室溫下授護下，加A 將反應液在減壓下濃縮小時反應完畢£ ❹法進-步分離純化（二氣殘留物藉_膠管柱層析軋甲院：甲醇=ΐς.·«、 -4-(3-氟-苄氧基）-苯基]_丨6 ，付到[3-氯 -1HH3-基]坐琳—4_基} H卜基—乙基） m 胺(44吨’黃色固體)’產 • MS m/z (ESI) ： 557[M+1] !H NMR (400 MHz, CD30D-d〇： 5 ο 7n . y.M (s，1H)，8.54 (s， 1H), 8.49 (s, 1H), 8.03 (d, j-〇H^ n 」 5 J'8Hz, 2H), 7.76 (d, ©J = 8. 4Hz, 1H), 7.70 (d, J=8. 8Hz ih、 n ’ 1H)，7.48 (m，1H)， 7.41 (s，1H)，7.33 (m，3H)，7 19 “ T。 (t，J=8HZ，1H)，6.88 (s, 1H), 6. 65 (s, 1H), 5. 27 (s 〇nx , ，）’ 4. 05 (t，J = 8Hz， 2H), 2.92 (m，4H)，2.72 (m，2In 叫，2.53 (br，4H) 實施例241 基）~~ 1 H -圯 94389 413 2010166830·21 _i) Dissolved in 10 mL of tetrachlorobita B _ 238020 mg' Lithium (10) mg, 2.lm_), under the protection of room temperature, add A and concentrate the reaction under reduced pressure for a few hours. Separation and purification by hydrazine method (two gas residue borrowing - hose column chromatography rolling mill: methanol = ΐς.·«, -4-(3-fluoro-benzyloxy)-phenyl]_丨6, pay To [3-Chloro-1HH3-yl]-salt- 4-yl}H-bu-ethyl) m amine (44 ton 'yellow solids' yield: MS m/z (ESI): 557[M+1] !H NMR (400 MHz, CD30D-d〇: 5 ο 7n . yM (s, 1H), 8.54 (s, 1H), 8.49 (s, 1H), 8.03 (d, j-〇H^ n ” 5 J '8Hz, 2H), 7.76 (d, ©J = 8. 4Hz, 1H), 7.70 (d, J=8. 8Hz ih, n ' 1H), 7.48 (m,1H), 7.41 (s,1H), 7.33 (m, 3H), 7 19 “T. (t, J=8HZ, 1H), 6.88 (s, 1H), 6. 65 (s, 1H), 5. 27 (s 〇nx , ,)' 4 05 (t, J = 8Hz, 2H), 2.92 (m, 4H), 2.72 (m, 2In called, 2.53 (br, 4H) Example 241 base) ~~ 1 H -圯94389 413 201016683

178a ^ 在100 mL茄形瓶中，將[卜（3-氟-苄基）-1Η-吲唑-5-基]-[6-(1-環氧乙基甲基-1H-B比略-3-基）-喧〇坐琳-4-基]-胺178a(565 mg，1.15 mmol)溶於30 mL甲醇中，氬氣保護下加入卜甲基0辰哄（461 mg，4.6 mmo 1 )，反應液加熱回 ' 流過夜。將反應液在減壓下濃縮，得到的殘留物藉由薄層層析板進一步分離純化（二氯甲烷：甲醇=7: 1)，得到本標題產物1-(3-{4-[1-(3-氟-苄基）-1Η-吲唑-5-基胺基]-喹 ❿0坐琳_6_基} -σ比洛-1-基）-3_(4_曱基-派哄-1-基）-丙-2_醇 241 (296 mg，黃色固體），產率：43. 5%。 MS m/z (ESI) ： 591[M+1] ^NMR (400MHz, DMS0-d6): 5 9. 83 (s, 1H), 8. 61 (s, 1H), 8.44(s, 1H), 8.23(s, 1H), 8. 17 (s, 1H), 8.04 (d, 1H, J = 8. 8 Hz ), 7. 75 (m, 3H), 7. 41 (m, 2H), 7. 14 (m, 3H), 6.87 (s, 1H), 6.67 (s, 1H), 5.72 (s, 2H), 4.94 (br s, 1H), 4. 04 (m, 2H), 3. 94 (m, 1H), 3. 88 (m, 1H), 3. 18 414 94389 201016683 (d，2H，J = 3.6 Hz)，2.47 (m，5H)，2.27 (m，5H) 實施例242 2-(3-{4-[3-氧-4-(3-氟-苄氣某）-茉胺某1-喹吔嗞j 「°比洛二1-基)_z!-((3S，5R_)-3, 5-二甲基-哌啡-1-其 7 阳178a ^ In a 100 mL eggplant-shaped flask, [b-(3-fluoro-benzyl)-1Η-indazol-5-yl]-[6-(1-epoxyethylmethyl-1H-B ratio -3-yl)-indole-4-yl]-amine 178a (565 mg, 1.15 mmol) was dissolved in 30 mL of methanol, and then added under the protection of argon to give methyl oxalate (461 mg, 4.6 mmo 1 ). The reaction was heated back to 'flow overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified (yield: methylene chloride:methanol = 7:1) to afford the title product 1-(3-{4-[1- (3-Fluoro-benzyl)-1Η-indazol-5-ylamino]-quinoline 0 sitting _6_yl}-σBilo-1-yl)-3_(4_曱基-派哄- 1-5%)-propan-2-ol 241 (296 mg, yellow solid), yield: 43.5%. MS m/z (ESI): 591 [M+1] NMR (400 MHz, DMS0-d6): 5 9. 83 (s, 1H), 8. 61 (s, 1H), 8.44 (s, 1H), 8.23(s, 1H), 8. 17 (s, 1H), 8.04 (d, 1H, J = 8. 8 Hz ), 7. 75 (m, 3H), 7. 41 (m, 2H), 7. 14 (m, 3H), 6.87 (s, 1H), 6.67 (s, 1H), 5.72 (s, 2H), 4.94 (br s, 1H), 4. 04 (m, 2H), 3. 94 (m , 1H), 3. 88 (m, 1H), 3. 18 414 94389 201016683 (d, 2H, J = 3.6 Hz), 2.47 (m, 5H), 2.27 (m, 5H) Example 242 2-(3 -{4-[3-Oxy-4-(3-fluoro-benzyl)--monosylamine 1-quinoline j "° 洛二二1-基)_z!-((3S,5R_)-3 , 5-dimethyl-piperidin-1-y 7 yang

⑩2-氣-i-[(3s，5R)-3, 5-二曱基-哌畊-1-基]-乙酮鹽酸鹽102-Gas-i-[(3s,5R)-3,5-dimercapto-piperidin-1-yl]-ethanone hydrochloride

(2S，6R)-2, 6-一甲基〇底哄（229 mg，2 mmol)溶於 10 mL 一氯甲烷中，溶液在乾冰—丙酮浴下冷卻至—78。〇，攪拌下(2S,6R)-2,6-monomethyl hydrazine (229 mg, 2 mmol) was dissolved in 10 mL of methyl chloride and the solution was cooled to -78 in dry ice-acetone bath. Hey, stirring

加入氯乙醯氯（242 mg，2. 14 mmol )，5分鐘後加入10 mL 水’升至室溫’反應完畢。將反應液在減壓下蒸掉二氯甲炫1真空/東乾機除去水’得到2-氯-1-[(3S, 5R)-3, 5-二曱基-η辰啡-| η 乙酮鹽酸鹽242a(456 mg，白色固體），產率：100% 415 94389 201016683 MS m/z (ESI) ： 191[M+l] 第二步 2_(3-{4-[3-氣-4-(3-氟-苄氧基）-苯胺基]—喹唑啉_6 —基} 一吡咯 _1一基）—/ —((3S，5R) 一3,5_二甲基-哌哄-1-基）-乙^ 在50mL的燒瓶中，將[3_氯_4_(3_氟_苄氧基）—笨基] -[6-(1Η-吡咯-3-基）-喹唑啉_4_基]-胺 42(487 mg，1. 〇97 mmol)溶於10 mL無水N，N-二甲基曱醯胺中，在冰浴條件下，冷卻至0°C，加入氫化鈉（176 mg，4.4 mmol)，攪拌 30分鐘後加入2-氣-l-[(3S，5R)-3,5-二甲基-哌畊-1-基]-乙酿I鹽.酉夂鹽242a(362 mg ’ 1. 6 mmo 1)，室溫下授摔1 小時反應完畢。反應液中加入50 mL水，乙酸乙酯萃取（50 mLx3) ’合併的有機相經由無水硫酸鈉脫水，過濾，減壓下 -濃縮’得到的殘留物藉由矽膠管柱層析法進一步分離純化 (一乳曱烧.甲醇=40 : 1)，得到本標題產物2-(3-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-啥唾琳—6-基}-°比洛-1-基） -1-((33,51〇-3,5-二甲基-哌哄-1-基）-乙酮 242(27 11^，擊黃色固體）’產率：64.9%。 MS m/z (ESI) ： 599[M+1] *H NMR (400 MHz, CD30D-JO: <5 9. 71 (s, 1H), 8.54 (s, 1H), 8. 50 (s, 1H), 8. 03 (m, 2H), 7. 76 (d, J=8. 8Hz, 1H), 7. 71 (d, J=8. 8Hz, 1H), 7. 48 (m, 1H), 7. 33 (m, 4H), 7. 19 Cm, 1H), 6.82(s, 1H), 6. 66 (s, 1H), 5. 27 (s, 2H), 4.96 (dd, J = 72.0Hz 16.4Hz, 2H), 4.22 (d, J=12.8Hz, 1H), 3 · 7 6 ( d， J = 12. 0 H z， 1H )，2. 5 9 ( m， 3 H)， 2. 11 (t， 416 94389 201016683 J -12. 0 Η z，1Η )，〇. 9 9 ( m，6 Η ) 實施例243 -吡呔j-其卜唓唑啉茉某 1-脸Chloroethyl chloride (242 mg, 2.14 mmol) was added, and after 5 minutes, 10 mL of water was added to 'well to room temperature' and the reaction was completed. The reaction solution was distilled off under reduced pressure to dichloromethane 1 vacuum / Donggan machine to remove water' to give 2-chloro-1-[(3S, 5R)-3, 5-didecyl-n- nin----- η Ethyl ketone hydrochloride 242a (456 mg, white solid), yield: 100% 415 94389 201016683 MS m/z (ESI): 191 [M+l] 2nd step 2_(3-{4-[3-gas -4-(3-Fluoro-benzyloxy)-anilino]-quinazoline-6-yl}-pyrrolo-l-yl)-/((3S,5R)-3,5-dimethyl- [piperidin-1-yl)-ethane in a 50 mL flask, [3_chloro_4_(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrol-3-yl)- Quinazoline _4_yl]-amine 42 (487 mg, 1. 〇97 mmol) was dissolved in 10 mL of anhydrous N,N-dimethyl decylamine and cooled to 0 ° C under ice bath. Sodium hydride (176 mg, 4.4 mmol) was added, and after stirring for 30 minutes, 2-gas-l-[(3S,5R)-3,5-dimethyl-piperidin-1-yl]-ethyl I salt was added.酉夂 salt 242a (362 mg ' 1. 6 mmo 1), the reaction was completed at room temperature for 1 hour. 50 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL×3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue obtained was further purified by silica gel column chromatography. (1 曱曱. methanol = 40 : 1), the title product 2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-anilino]-啥啥琳 - 6-yl}-°Pilo-1-yl)-1-((33,51〇-3,5-dimethyl-piperazin-1-yl)-ethanone 242 (27 11^, yellow solid 'Yield: 64.9%. MS m/z (ESI): 599[M+1] *H NMR (400 MHz, CD30D-JO: <5 9.71 (s, 1H), 8.54 (s, 1H ), 8. 50 (s, 1H), 8. 03 (m, 2H), 7. 76 (d, J=8. 8Hz, 1H), 7. 71 (d, J=8. 8Hz, 1H), 7. 48 (m, 1H), 7. 33 (m, 4H), 7. 19 Cm, 1H), 6.82(s, 1H), 6. 66 (s, 1H), 5. 27 (s, 2H) , 4.96 (dd, J = 72.0 Hz 16.4 Hz, 2H), 4.22 (d, J = 12.8 Hz, 1H), 3 · 7 6 (d, J = 12. 0 H z, 1H ), 2. 5 9 ( m, 3 H), 2. 11 (t, 416 94389 201016683 J -12. 0 Η z,1 Η ), 〇. 9 9 ( m,6 Η ) Example 243 -pyridinium j-boxazoline Some 1-face

Ο—OH 〇Ν^01ς 243aΟ—OH 〇Ν^01ς 243a

O-sjCXpO-sjCXp

Cl 第一步 ❸曱磺酸2-氮雜環庚-卜基—乙酯將2-氮雜環庚-卜基_乙醇（1.43 g，1〇咖〇1)溶於1〇 mL —氯甲烷中，在冰浴條件下，冷卻至〇。〇，依次加入三乙胺（2. 〇2 g ’ 20 mm〇1)和曱磺醯氣（17 g，15 _υ，室孤下攪拌1小時，反應完畢。將反應液中加入20 mL水淬 j反應，旋乾二氯甲烷，水相用乙酸乙酯萃取（30 mLx3)，。併的有機相經由飽和氯化納溶液洗⑮，無水硫酸納脫水，過濾，減壓下濃縮，得到的殘留物藉由矽膠管柱層析 94389 417 201016683 法進一步分離純化，得到曱磺酸2—氮雜環庚—丨—基―乙酯 243a(2· 1 g，黃色油狀液體），產率：95%。 MS m/z (ESI) : 222[M+1] 第二步 {6-[1-( 2-氮雜環庚-1-基-乙基）_ι η-»比咯_3_基]—喹唑淋 -4-基卜[3 -氣-4-(3 -默-苄氧基）—苯基]-胺在50 mL的燒瓶中，將[3-氯-4-(3-氟-苄氧基）_苯基] -[6-C1H-吡咯-3-基）-喹唑啉-4-基]-胺 42(222 mg，0.5 mmol)溶於6 mL無水N，N-二甲基甲醯胺中，攪拌下加入氫化鈉（60 mg ’ 2. 5 mmol)，30分鐘後加入甲磺酸2-氮雜環庚―卜基-乙酯243a(166 mg，0· 75 mmol)，室溫下授拌1 小時反應完畢。反應液加入2 0 mL冰水，用乙酸乙醋萃取 (30 mLx4 )，合併的有機相依次經由飽和氯化納溶液洗條， '無水硫酸鈉脫水，過濾，減壓下濃縮，得到的殘留物藉由石夕膠管柱層析法進一步分離純化（二氯甲烧：甲醇= 10: 1)，得到本標題產物{6-[1-(2-氮雜環庚-卜基-乙基）-1Η-吡咯 ❿-3-基]-喹唑啉-4-基}-[3-氯-4-(3-氟-苄氧基）-苯基]-胺 243(230 mg，黃色固體），產率：81%。 MS m/z (ESI) ： 570[M+1] !H NMR (400 MHz, CD30D-d〇: (5 9. 68 (s, 1H), 8.52 (s, 1H), 8.50 (s, 1H), 8.02 (m, 2H), 7.76 (m, 1H), 7.70 (m, 1H), 7.47(m, 2H), 7.32 (m, 3H), 7. 19 (m, 1H), 6.92 (s, 1H), 6.65(s, 1H), 5. 27 (s, 2H), 4. 00 (t, J=6. 0Hz, 2H), 2.86 (m, 2H), 2.67 (m, 4H), 1.56 (m, 8H) 418 94389 201016683 實施例244 2-(3-U-「3-氩-4-(3-氟-苄氣某芏胳某1-喹唑啉-6-篡1 _η比略一1 一基）_N— (4_經基一1，1_二伤!1氣基一六氣一 1 λ 木一違喃-4-基曱基）-乙醯胺Cl First step oxime sulfonate 2-azacycloheptin-buyl-ethyl ester 2-Azepan-buyl-ethanol (1.43 g, 1 〇〇 1) is dissolved in 1 〇 mL-chloromethane In the ice bath, cool to 〇. 〇, successively add triethylamine (2. 〇2 g '20 mm〇1) and sulfonium sulfonate (17 g, 15 υ υ, stir the chamber for 1 hour, the reaction is completed. Add 20 mL of water to the reaction solution. The reaction was carried out, the methylene chloride was evaporated, the aqueous phase was extracted with ethyl acetate (30 mL×3), and the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was further separated and purified by a silica gel column chromatography 94389 417 201016683 to give 2-oxazin-2-ylheteroyl-yl-ethyl ester 243a (2·1 g, yellow oily liquid), yield: 95 MS m/z (ESI): 222 [M+1] Step 2 {6-[1-(2-Azepan-1-yl-ethyl)_ι η-»比比_3_基]-quinazolin-4-ylbu [3- gas-4-(3-m-benzyloxy)-phenyl]-amine in a 50 mL flask, [3-chloro-4-(3- Fluoro-benzyloxy)-phenyl]-[6-C1H-pyrrol-3-yl)-quinazolin-4-yl]-amine 42 (222 mg, 0.5 mmol) dissolved in 6 mL anhydrous N,N- In dimethylformamide, sodium hydride (60 mg '2.5 mmol) was added with stirring, and after 30 minutes, 2-azacycloheptyl-ethyl-ethane 243a (166 mg, 0) was added. 75 mmol), stirred for 1 hour the reaction was completed grant at room temperature. The reaction solution was added with 20 mL of ice water, extracted with ethyl acetate (30 mL×4), and the combined organic phases were washed successively with saturated sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give residue. The product was further separated and purified (dichloromethane:methanol = 10:1) to give the titled product (6-[1-(2-azepan-bu-ethyl)-) 1Η-pyrrole-3-yl]-quinazolin-4-yl}-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-amine 243 (230 mg, yellow solid) Yield: 81%. MS m/z (ESI): 570 [M+1].H NMR (400 MHz, CD30D-d〇: (5 9. 68 (s, 1H), 8.52 (s, 1H), 8.50 (s, 1H) , 8.02 (m, 2H), 7.76 (m, 1H), 7.70 (m, 1H), 7.47 (m, 2H), 7.32 (m, 3H), 7. 19 (m, 1H), 6.92 (s, 1H ), 6.65(s, 1H), 5. 27 (s, 2H), 4. 00 (t, J=6. 0Hz, 2H), 2.86 (m, 2H), 2.67 (m, 4H), 1.56 (m , 8H) 418 94389 201016683 Example 244 2-(3-U-"3-argon-4-(3-fluoro-benzyl 芏芏某 1- 1- oxazoline-6-篡1 _η ratio slightly 1 1基)_N—(4_经基一1,1_二伤!1气基一六气一1 λ木一违喃-4-基曱基)-acetamide

Ο ΟΟ Ο

42 244 第一步 2-氯-N-(4 -經基_1，1_二侧氧基-六氯-1 λ *6* -嗟喃-4 -基 ©甲基）-乙醯胺將4-胺基甲基_1，1_二側氧基-六氫_1又*6*-嗔喃-4-醇（358 mg，2 mmol)溶於10 mL二氯曱烷中，攪拌下三乙胺（0. 5 5 mL，4 mmo 1)，加入在乾冰-丙酮浴條件下，冷卻至-78°〇，氬氣氛下，加入和氯乙酿氯（226 111忌，2 111111〇1)，溫度升至-30°C下擾拌1小時，反應完畢。反應液減壓下旋乾溶劑’加入20 mL乙酸乙酯，過濾，濾液在減壓下濃縮，得到2-氯-N-(4-羥基-1，卜二侧氧基-六氫-1 λ *6*-噻。南 419 94389 201016683 -4-基甲基）-乙醯胺244a(430 mg，紅褐色固體），產率： 84. 3%。 MS m/z (ESI) ： 256[M+1] 第二步 2-(3-{4-[3-氣-4-(3-氟-苄氧基）-苯胺基]-喹唑啉_6_基） -吡咯-1-基）-N-(4-羥基-1，1-二側氧基-六氫—！又*6木_噻喃基曱基）-乙酿胺在50 mL的燒瓶中，將[3-氣-4-(3-氟-苄氧基）-苯基] -[6-(1Η-吡咯-3-基）-喹唑啉-4-基]-胺 42(222 mg，0.5 ® mmol)溶於8 mL無水四氫呋喃中，氬氣氛下，加入第三丁醇鉀（224 mg，2 mmol) ’ 30分鐘後加入2-氯-N-(4-經基 -1，I - 一側氧基_六虱-1 λ *6*-嗟喃-4-基甲基）-乙醯胺 • 244a(192 rag，0. 75 mmol) ’室溫下攪拌3小時反應完畢。 •反應液加入20 mL甲醇’減壓下濃縮’得到的殘留物藉由石夕膠管柱層析法進一步分離純化（二氣曱院：曱醇=3〇: 1)，得到本標題產物2-(3-{4-[3-氣-4-(3-氟-苄氧基）-苯胺 ❿基]-喹唑啉-6-基卜吡咯-1-基）-N-(4-羥基-1，1-二側氧基 -六氳-1λ*6*-嘆鳴-4-基曱基）-乙醢胺244(92 mg，黃色固體），產率：49%。 MS m/z (ESI) ： 664[M+1] ]H NMR (400 MHz, CD30D-d〇： (5 9. 71 (s, 1H), 8.55 (s, 1H), 8.50 (s, 1H), 8.13 (m, 1H), 8.03 (m, 2H), 7.74 (m, 2H), 7.49 (m, 1H), 7.33 (m, 4H), 7. 19 (m, 1H), 6.86 (s, 1H), 6.68(s, 1H), 5. 27 (s, 2H), 4. 68 (s, 2H), 3. 18 94389 420 201016683 (m，4H)，2· 98 (m，2H)，l. 93 (m，4H) 實施例245 l-(3-{4-[3-氧-4-(3-_氳~苄氳某I胺基μ喹唑啾其^ 比咯-卜基J_-.3-(2-甲磺醯某-乙孽基）-丙-2—醇42 244 First step 2-chloro-N-(4-carbyl-1,1-di-oxy-hexachloro-1 λ*6*-indol-4-yl-methyl)-acetamide 4-Aminomethyl_1,1-di-oxy-hexahydro_1-*6*-indol-4-ol (358 mg, 2 mmol) was dissolved in 10 mL of dichloromethane and stirred Triethylamine (0.55 mL, 4 mmo 1), added to dry ice-acetone bath, cooled to -78 ° 〇, added under argon atmosphere, and added chlorine and chlorine (226 111 bogey, 2 111111 〇 1 ), the temperature was raised to -30 ° C and the mixture was stirred for 1 hour, and the reaction was completed. The reaction solution was stirred under reduced pressure and the solvent was evaporated. <RTI ID=0.0>>&&&&&&&&&&&&&&&&&&&&& *6*-thiophene. South 419 94389 201016683 -4-ylmethyl)-acetamide 244a (430 mg, reddish brown solid), yield: 84.3%. MS m/z (ESI): 256 [M + 1], Step 2, 2-(3-{4-[3- </RTI> 4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline 6_yl)-pyrrole-1-yl)-N-(4-hydroxy-1,1-di-oxy-hexahydro-! and *6-xylo-thiopyranyl)-ethylamine in 50 mL [3-Gas-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinazolin-4-yl]-amine 42 (222 mg, 0.5 ® mmol) was dissolved in 8 mL of anhydrous tetrahydrofuran under an argon atmosphere. Potassium tert-butoxide (224 mg, 2 mmol) was added. After 30 min, 2-chloro-N-(4-carbyl- 1, I - one side oxy _ hexam-1 λ * 6 * - oxime -4-ylmethyl) - acetamamine • 244a (192 rag, 0. 75 mmol) 'Stirring at room temperature for 3 hours Finished. • The residue obtained by adding the reaction solution to 20 mL of methanol 'concentrated under reduced pressure> was further separated and purified by Shixi rubber column chromatography (dioxet: sterol = 3 〇: 1) to obtain the title product 2- (3-{4-[3-Gas-4-(3-fluoro-benzyloxy)-anilinium]-quinazoline-6-ylpyrrolidin-1-yl)-N-(4-hydroxy- 1,1-di- oxy-hexa-yl-1λ*6*- sin-4-ylindenyl)-acetamide 244 (92 mg, yellow solid), yield: 49%. MS m/z (ESI): 664[M+1]]H NMR (400 MHz, CD30D-d〇: (5 9. 71 (s, 1H), 8.55 (s, 1H), 8.50 (s, 1H) , 8.13 (m, 1H), 8.03 (m, 2H), 7.74 (m, 2H), 7.49 (m, 1H), 7.33 (m, 4H), 7. 19 (m, 1H), 6.86 (s, 1H ), 6.68(s, 1H), 5. 27 (s, 2H), 4. 68 (s, 2H), 3. 18 94389 420 201016683 (m, 4H), 2· 98 (m, 2H), l. 93 (m, 4H) Example 245 l-(3-{4-[3-oxo-4-(3-_氲~benzyl hydrazide) I-amino-pyrazole oxazolidine pyrrole-b-based J_-. 3-(2-methanesulfonyl-ethenyl)-propan-2-ol

在lOOmL茄形瓶中，將碳酸鉋（274 mg，〇 84mm〇1)溶於N，N-二曱基甲醯胺中，攪拌下加入[3_氣—4_(3_氟_苄氧In a lOOmL eggplant-shaped flask, the carbonic acid planer (274 mg, 〇 84 mm 〇1) was dissolved in N,N-dimercaptocarhamamine, and [3_gas-4_(3_fluoro-benzyloxy) was added with stirring.

-4-基]-胺178a(140 mg，〇·28賴〇1)和甲磺醯基乙醇 ❹（104 mg，0.84 mmol)溶於1〇 mL無水甲醇中，加熱回流過夜。將反應液加入100 mL水，用乙酸乙酯（1〇〇 mLx3)萃取，合併的有機相依次經由無水硫酸鈉脫水，過濾，減壓下濃縮’得到的殘留物藉由矽膠管柱層析法進一步分離純化（二氯甲烷：甲醇=50 : 1)，得到本標題產物^(^{4一[3一氣_4_ (3-氟-苄氧基）-苯胺基]—喹唑啉_6_基丨比咯_卜基）_3一 (2-甲磺醯基-乙氧基）_丙一 2_醇245(42吨，黃色固體），產率：24%。 94389 421 201016683 MS m/z (ESI) ： 625[M+1] 'H NMR (400 MHz, CD30D-^) : <5 9. 67 (s, 1H), 8. 8 (s, 1H), 8.5 (s, 1H), 8.03 (d, J=8. 8Hz, 2H), 7.76 (dd, J = 2Hz, 1H), 7.70 (d, J=8.4Hz, 1H), 7.5 (m, 2H), 7. 36 (m, 3H), 7.2 (s, 1H), 6.93 (s, 1H), 6.60 (s, 1H), 5.27 (s, 2H), 4.01 (m, 1H), 3.90 (m, 1H), 3.80 (m, 2H), 3.50 (m, 3H), 3.39 (m, 2H), 3.02 (s, 3H), 1.98 (br, 1H) 實施例246 N-{l-[2-(3-{4_「3-氣-4-(3-氟-苄氧基）-芙胺基1_唾1*坐被 ❿-6 -基卜°比°各-1-基）-乙醯基底咬-4-某丨-乙醯胺4-Methoxy]-amine 178a (140 mg, 〇28 〇〇 1) and methanesulfonylethanol oxime (104 mg, 0.84 mmol) were dissolved in 1 mL of dry methanol and heated to reflux overnight. The reaction solution was added to 100 mL of water and extracted with ethyl acetate (1 mL mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Further separation and purification (dichloromethane:methanol = 50:1) gave the title product ((^{4-[3] gas_4_(3-fluoro-benzyloxy)-anilinyl]-quinazoline_6_丨丨 _ 卜 ) ) 一一一 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 245 245 245 245 245 245 245 245 245 245 245 。 </ RTI> </ RTI> <RTIgt; 8.5 (s, 1H), 8.03 (d, J=8. 8Hz, 2H), 7.76 (dd, J = 2Hz, 1H), 7.70 (d, J=8.4Hz, 1H), 7.5 (m, 2H), 7. 36 (m, 3H), 7.2 (s, 1H), 6.93 (s, 1H), 6.60 (s, 1H), 5.27 (s, 2H), 4.01 (m, 1H), 3.90 (m, 1H) , 3.80 (m, 2H), 3.50 (m, 3H), 3.39 (m, 2H), 3.02 (s, 3H), 1.98 (br, 1H) Example 246 N-{l-[2-(3-{ 4_"3-Gas-4-(3-fluoro-benzyloxy)- propylamino 1_salt 1* sitting ❿-6 - kib°°°-1-yl)-acetonitrile base bite-4 -A certain 丨-acetamide

第一步 N-[l-(2-氯-乙酿基）_〇底σ定-4 -基]-乙酿胺將 Ν-0底咬-4-基-乙醯胺 23 9b (150 mg，1.05 mmol)溶於15 mL二氯甲烷中，加入三乙胺（1 mL ’ 2. 1 mmol)，反 422 94389 201016683 應液在丙酮-乾冰浴冷卻至_78。(：，滴加氯乙醯氣（119mg， 1.05 mmol) ’攪拌1小時反應完畢。反應液中加入5〇 mL 水和50 mL乙酸乙酯’分液，水相用乙酸乙酯萃取（loo mL x2) ’合併的有機相經由無水硫酸鈉脫水，過濾，減壓下濃縮’得到的殘留物藉由矽膠管柱層析法進一步分離純化（二氯甲烷：甲醇=50 : 1)，得到本標題產物氯—乙醯基）-派啶-4-基]-乙醯胺246a(27 mg，黃色油狀液體），產率：12% 〇 MS m/z (ESI) ： 219[M+1] ®第二步 N-{l-[2-(3-{4-[3-氣-4-(3-氟-苄氧基）-苯胺基]-喹唑啉 -6-基}-'1比嘻-1-基）-乙酿基]-〇辰咬_4_基}_乙醯胺在50 mL的燒瓶中，將[3-氯-4-(3-氟-苄氧基）-苯基] --[6-(1Η-吡咯-3-基）-喹唑啉-4-基]_胺 42(59 mg，〇11 mmo 1) ί谷於1 〇 mL無水N，N-二曱基曱酿胺中，在冰浴條件下，冷卻至（TC，加入氫化鈉（16 mg，〇· 33 mmol)，攪拌鷂30分鐘後加入N-[l-(2-氣-乙醯基）-哌啶_4_基]_乙醯胺 246a(27 mg，0. 12 mmol)，室溫下攪拌i小時反應完畢。反應液中加入5 0 mL水和5 0 mL乙酸乙酯，分液，水相用乙酸乙酯萃取（100 mLx2)，合併的有機相經由無水硫酸鋼脫水，過濾，減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化（二氣曱烷：甲醇=5〇 : 1)，得到本標題產物^{卜匕-⑶^七-氯-斗-⑶氟-节氧基卜苯胺基] -喹唑啉-6-基卜吡咯-1-基）-乙醯基]—哌啶_4_基卜乙醯胺 94389 423 201016683 246 (18 mg，淡黃色固體），產率：26. 1%。 MS m/z (ESI) ： 627[M+1] Ή NMR (400 MHz, CD30D-d〇: 5 10.05 (s, 1H), 8.76 (s, 1H), 8.53 (s, 1H), 8.50 (s, 1H), 8.11 (s, 1H), 8.02 (d, J - 8.8Hz, 1H), 7.85 (d, J = 8. 8Hz, 1H), 7.69 (d, J = 8.8Hz, 1H), 7. 54 (t, J = 8. 8Hz, 1H), 7.42 (s, 1H), 7.32 (m, 3H), 7.19 (t, J = 8. 8Hz, 1H), 6.85 (s, 1H), 6.76 (s, 1H), 5.27 (s, 2H), 4.63 (s, 2H), 4.17 (d, J =12.8Hz, 1H), 3.79(br, 2H), 3. 14 (t, J = 11.6Hz, 1H), ® 2.79 (t, J = 11.4Hz, 1H), 2.00 (s, 3H), 1. 77 (m, 2H), 1.30 (ra, 2H) 實施例247 • (1〇-1-(3-丨4-「3-氣-4-(3-氟-苄氧基）-笨胺基]-喹唑啉 -6-基丨-吡咯-：!-基）-3-「（R)-2-吡咯烷-1-基甲基-吡咯烷 -1-基]-丙-2 -醇The first step N-[l-(2-chloro-ethyl-branched)_〇 σ 定 -4 -4 -yl]-ethinylamine Ν-0 bottom bit-4-yl-acetamide 23 9b (150 mg , 1.05 mmol) was dissolved in 15 mL of dichloromethane, triethylamine (1 mL ' 2. 1 mmol) was added, and 422 94389 201016683 was cooled to -78 in an acetone-dry ice bath. (:, dropwise addition of chloroacetic acid (119 mg, 1.05 mmol) 'The reaction was completed after stirring for 1 hour. 5 ml of water and 50 mL of ethyl acetate were added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (loo mL) X2) 'The combined organic phase is dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained is further purified by chromatography (methylene chloride:methanol = 50:1). The product chloro-ethenyl)-pyridin-4-yl]-acetamide 246a (27 mg, yellow oily). Yield: 12% 〇MS m/z (ESI): 219[M+1] ®Step 2 N-{l-[2-(3-{4-[3-Gas-4-(3-fluoro-benzyloxy)-anilino]-quinazolin-6-yl}-'1 (3-chloro-4-(3-fluoro-benzyloxy)- in a 50 mL flask, 嘻基基基基 ] ] 咬咬咬咬咬咬咬咬咬咬咬Phenyl]-[6-(1Η-pyrrol-3-yl)-quinazolin-4-yl]-amine 42 (59 mg, 〇11 mmo 1) ί谷 in 1 〇 mL anhydrous N,N-II In the thiol-brown amine, under ice bath, cool to (TC, add sodium hydride (16 mg, 〇·33 mmol), stir for 30 minutes, then add N-[l-(2-gas-ethenyl) )- piperidine_4_yl]-acetamide 246a (27 m g,0. 12 mmol), stirring at room temperature for 1 hour. The reaction mixture was added with 50 mL of water and 50 mL of ethyl acetate. The mixture was separated and the aqueous phase was extracted with ethyl acetate (100 mL×2). The organic phase is dehydrated through anhydrous sulfuric acid steel, filtered, and concentrated under reduced pressure, and the obtained residue is further purified and purified by silica gel column chromatography (dioxane: methanol = 5 〇: 1) to give the title product.匕-(3)^Hepta-Chloro-Dragon-(3)Fluoro-oxypoxyanilino]-quinazoline-6-ylpyrrolidin-1-yl)-ethenyl]-piperidine _4_ kib 1%。醯 94 94389 423 201016683 246 (18 mg, light yellow solid), yield: 26.1%. MS m/z (ESI): 627[M+1] NMR (400 MHz, CD30D-d: 5 10.05 (s, 1H), 8.76 (s, 1H), 8.53 (s, 1H), 8.50 (s , 1H), 8.11 (s, 1H), 8.02 (d, J - 8.8Hz, 1H), 7.85 (d, J = 8. 8Hz, 1H), 7.69 (d, J = 8.8Hz, 1H), 7. 54 (t, J = 8. 8Hz, 1H), 7.42 (s, 1H), 7.32 (m, 3H), 7.19 (t, J = 8. 8Hz, 1H), 6.85 (s, 1H), 6.76 (s , 1H), 5.27 (s, 2H), 4.63 (s, 2H), 4.17 (d, J = 12.8Hz, 1H), 3.79(br, 2H), 3. 14 (t, J = 11.6Hz, 1H) , ® 2.79 (t, J = 11.4Hz, 1H), 2.00 (s, 3H), 1. 77 (m, 2H), 1.30 (ra, 2H) Example 247 • (1〇-1-(3-丨) 4-"3-Gas-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylindole-pyrrole-:!-yl)-3-"(R)-2- Pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-propan-2-ol

424 94389 201016683424 94389 201016683

第一步 (S)-3-羥曱基-吡咯烷-1-曱酸第三丁酯First step (S)-3-hydroxydecyl-pyrrolidine-1-decanoic acid tert-butyl ester

將（S)-3-羥甲基-吡咯烷（5· 05 g’50 mmol)溶於150 mL 一氯甲炫中’在冰浴條件下’冷卻至〇°c，加入乙酸酐 (11.44 g，52. 5 mmol)，反應液在室溫下攪拌過夜。將反 '應液用飽和碳酸氫鈉洗滌，乙酸乙酯萃取（5〇 mLx3)，合併的有機相經由飽和氯化納溶液洗滌，無水硫酸納脫水，過濾’減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一馨步分離純化（正己烷··乙酸乙酯=3 : 1)，得到（s)-3-羥曱基比洛烧-1-曱酸第三丁酯247a(9. 54 g ’黃色油狀液體），產率：94. 9%。 MS m/z (ESI) ： 202[M+1] 第二步 (S)-3-甲磺醯氧曱基-吡咯烷-i-曱酸第三丁酯將（S)-3-羥曱基-吡咯烷-1-甲酸第三丁酯247a(5 g， 24. 8 mmol)溶於100 mL二氯甲烧中，在氬氣氛下，滴加三 425 94389 201016683 乙胺（13.8 mL ’ 100 mmol) ’冰浴冷卻至〇〇c，加入甲礦酿氯（3.9 mL ’ 49. 6 mmol)，反應液在室溫下攪拌1小時反應完畢。將反應液用飽和碳酸氫鈉洗蘇，乙酸乙醋萃取（5 〇 mL x3)，合併的有機相經由水和飽和氣化鈉溶液洗滌，無水硫酸鈉脫水’過滤減壓下濃縮，得到的殘留物藉由砍膠管柱層析法進一步分離純化（正己烧：乙酸乙酯: 1 )，得到 (S)-3-曱續醯氧甲基-D比σ各烧-1-曱酸第三丁酯247b(6. 14 g，黃色油狀液體），產率：88. 7%。 MS m/z (ESI) ： 280 [M+1] ®第三步 (R) -3-n比嘻炫-1-基曱基-〇比嘻烧-1-曱酸第三丁酯 (S)-3-曱石黃醯氧曱基比洛烧-1-甲酸第三丁醋247b (1. 5 g，5. 37 mmol)和吡咯烷（〇· 49 mL，5. 9 mmol)溶於 …· 5 5 mL乙醇和四氫D夫鳴（10 : 1)的混合溶劑中，授掉下加入碳酸鉀（1. 11 g ’ 8. 05 mmol)，加熱回流反應過夜。將反應液在減壓下濃縮，殘留物藉由矽膠管柱層析法進一步分離響純化（正己烧：乙酸乙酯=1 : 1)，得到（R)-3-n比嘻院—1_基甲基-吡咯烷-1-曱酸第三丁酯247c(215mg，黃色油狀液體），產率：13.4%。 MS m/z (ESI) ： 255 [M+l] 第四步 (S) -l-(吡咯烷-3-基曱基）吡咯烷鹽酸鹽將（R)-3-0比洛烧-1-基甲基-〇比η各烧-1-曱酸第三丁酉旨 247c(215 mg’ 0.98 mmol)溶於 10 mL 二氯甲院中，擾拌 426 94389 201016683 下加入10 mL 4N曱醚-氯化氫溶液，室溫下攪拌3小時，反應完♦。將反應液在減壓下濃縮，得到的殘留物用乙酸乙酯洗滌（50 mLx3)，得到吡咯烷_3_基甲基）吡咯烷鹽酸鹽247d(100 mg，灰白色固體），產率· 67. 6%。第五步 (R)-l-(3-{4-[3-氯-4-(3-氟-苄氧基）_苯胺基]_喹唑啉 -6-基}-吡咯-1-基）-3-(2-吡咯烷一卜基曱基_吡咯烷基） -丙-2-醇 (R)_[3-氯-4—(3~氟-苄氧基）-苯基]-[6-(1-環氧乙基曱基-1H-吡咯-3-基）-喹唑啉-4—基]-胺186a(17〇 mg，〇.託 mmol)溶於30 mL甲醇中，氬氣氛下，攪拌下加入（幻一卜（吡咯烷-3-基曱基）吡咯烷鹽酸鹽247d(l〇l mg，0.52 和碳酸钟（〇· 〇71 g，〇. 52 mmol)，混合物加熱回流過夜。將反應液在減壓下濃縮，得到的殘留物藉由石夕膠管柱層析法進一步分離純化（二氣甲烷：甲醇=40 : 1，3〇 : 1，15 : i， 10 . 1) ’传到標題產物（R)-l-(3-{4-[3-氯- 4- (3 -氟-节氧 ❹基）-苯胺基]-喹唑啉-6-基}-吡咯-1-基）-3-(2-吡洛姨;-1一基甲基比洛统基）-丙-2-醇247(35 mg，黃色固體），產率：24. 1%。 MS m/z (ESI) ： 656 [M+l] !H NMR (400 MHz, CD30D-d6): (5 9. 70 (s, ih), 8.54 (s, 1H), 8.50(s, 1H), 8.03(m, 2H), 7. 76 (d, J=8. 8Hz, 1H), 7.70 (d, J = 8.8Hz , 1H), 7.47 (m, 1H), 7.42 (s, 1H), 7.36 (m, 3H) , 7.19 (m, 1H) , 6.88 (s, 1H) , 6.65 (s, 94389 427 201016683 1H)，5. 27(s’ 2H)，3. 98 (m，1H)，3· 85 (m，2H)，3· i2 (m, 1H), 2.64 (m, 1H), 2.59 (m, 1H), 2.41 (br, 6H), 2.27 (m, 2H)’ 1.85 (m，1H)，i 66 (br，6H)，j 45 & 1H) ，(S)-3-Hydroxymethyl-pyrrolidine (5· 05 g'50 mmol) was dissolved in 150 mL of chloroform, cooled to 〇 °c under ice bath conditions, and acetic anhydride (11.44 g) was added. , 52.5 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction solution was washed with saturated sodium bicarbonate, extracted with ethyl acetate (5 〇mL×3), and the combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give residue. The product was separated and purified by hydrazine column chromatography (n-hexane·ethyl acetate = 3:1) to obtain (s)-3-hydroxydecylpyrrolidin-1-butyric acid tert-butyl ester 247a. (9. 54 g 'Yellow oily liquid), Yield: 94.9%. MS m/z (ESI): 202 [M+1] (2) (S)-3-Methanesulfonyloxycarbonyl-pyrrolidine-i-decanoic acid tert-butyl ester (S)-3-oxindole Base-pyrrolidine-1-carboxylic acid tert-butyl ester 247a (5 g, 24. 8 mmol) was dissolved in 100 mL of methylene chloride. Under argon, three 425 94389 201016683 ethylamine (13.8 mL '100) was added dropwise. Methyl) Cooled to 〇〇c in an ice bath, added chlorine to the mine (3.9 mL '49. 6 mmol), and the reaction was stirred at room temperature for 1 hour. The reaction mixture was washed with saturated sodium bicarbonate and extracted with ethyl acetate (5 〇mL×3). The combined organic phases were washed with water and saturated sodium carbonate solution and dried over anhydrous sodium sulfate. The product was further separated and purified by chopping column chromatography (n-hexane: ethyl acetate: 1) to obtain (S)-3-indolizine oxymethyl-D ratio σ each calcined -1-decanoic acid tertidine 7%。 The ester 247b (6. 14 g, a yellow oily liquid), yield: 88.7%. MS m/z (ESI): 280 [M+1] ® third step (R) -3-n 嘻 -1- -1- 曱〇〇〇〇嘻曱曱曱曱曱曱曱 ( (曱曱醯醯醯醯比比比比 -1- -1- -1- -1- 247 247 247 247 247b (1. 5 g, 5. 37 mmol) and pyrrolidine (〇 · 49 mL, 5. 9 mmol) soluble In a mixed solvent of 5 mL of ethanol and tetrahydro-D-fuss (10:1), potassium carbonate (1.11 g '8.55 mmol) was added thereto, and the mixture was heated under reflux overnight. The reaction solution was concentrated under reduced pressure, and the residue was further purified by silica gel column chromatography (yield: ethyl acetate = 1: 1) to give (R)-3-n ratio 嘻院-1_ Methyl-pyrrolidine-1-decanoic acid tert-butyl ester 247c (215 mg, yellow oily liquid), yield: 13.4%. MS m/z (ESI): 255 [M+l] Step 4 (S) -l-(pyrrolidin-3-ylmercapto)pyrrolidine hydrochloride (R)-3-0 1-ylmethyl-indole ratio η each calcined-1-decanoic acid tributyl hydrazine 247c (215 mg' 0.98 mmol) dissolved in 10 mL of dichloromethane, disturbed with 426 94389 201016683 added 10 mL of 4N oxime ether - a hydrogen chloride solution, stirred at room temperature for 3 hours, and the reaction was completed. The reaction mixture was concentrated under reduced pressure. EtOAc mjjjjjjjjj 67. 6%. The fifth step (R)-l-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-anilino]-quinazolin-6-yl}-pyrrol-1-yl )-3-(2-pyrrolidin-p-indenyl-pyrrolidinyl)-propan-2-ol (R)_[3-chloro-4—(3~fluoro-benzyloxy)-phenyl]- [6-(1-Epoxyethylmercapto-1H-pyrrol-3-yl)-quinazolin-4-yl]-amine 186a (17 mg, 〇. tommol) was dissolved in 30 mL of methanol. Under argon atmosphere, phantom (pyrrolidin-3-ylindenyl)pyrrolidine hydrochloride 247d (l〇l mg, 0.52 and carbonic acid clock (〇·〇71 g, 〇. 52 mmol) were added under stirring. The mixture was heated and refluxed overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was further purified and purified by silica gel column chromatography (di gas methane: methanol = 40: 1, 3 〇: 1,15: i, 10 . 1) 'Received to the title product (R)-l-(3-{4-[3-chloro-4-(3-fluoro-oxycarbonyl)-anilino]-quinazolin-6-yl }-pyrrol-1-yl)-3-(2-pyrrolidine; -1 -ylmethylpyroxy)-propan-2-ol 247 (35 mg, yellow solid), yield: 24.1 MS m/z (ESI): 656 [M+l] !H NMR (400 MHz, CD30D-d6): (5 9. 70 (s, ih), 8.54 (s, 1H), 8.50 (s, 1H), 8.03(m, 2H), 7. 76 (d, J=8. 8Hz, 1H), 7.70 (d, J = 8.8Hz, 1H), 7.47 (m, 1H), 7.42 (s, 1H), 7.36 (m, 3H), 7.19 ( m, 1H), 6.88 (s, 1H), 6.65 (s, 94389 427 201016683 1H), 5.27 (s' 2H), 3. 98 (m, 1H), 3· 85 (m, 2H), 3 · i2 (m, 1H), 2.64 (m, 1H), 2.59 (m, 1H), 2.41 (br, 6H), 2.27 (m, 2H)' 1.85 (m, 1H), i 66 (br, 6H) , j 45 & 1H) ,

2相〇在l〇0 mL茄形瓶中，將[l-(3_氟-苄基）一1H_吲唑_5_ 基]-[6-(1-環氧乙基曱基-1 Η-吡咯-3-基）-喹唑啉_4_基]— 胺178a(225 g，0· 46 mmol)溶於25 mL曱醇中，授摔下加入4-羥基旅唆（186 mg，1.84 mmol)，反應液加熱回流過夜。將反應液在減壓下濃縮，得到的殘留物藉由石夕膠管柱層析法進一步分離純化（二氯甲烷：甲醇=10 : 1)，得到本標題產物1-[3-(3-{4-[1-(3-氟-苄基）-iH-吲唑基胺基]-喹唑啉_6-基}_吡咯-1-基）-2-羥基-丙基]-哌啶_4 一醇 94389 428 201016683 248(29 mg，黃棕色固體），產率：48%。 MS m/z (ESI) ： 592[M+1] 'HNMR (400MHz, DMS0-c?〇: 5 9.86 (s, 1H), 8. 63 (s, 1H), 8.45 (s, 1H), 8.23 (s, 1H), 8.17 (s, 1H), 8.03 (d, 1H, J = 8.8Hz), 7.77 (s, 2H), 7.70 (d，1H, J = 8. 8Hz)，7.45 (s, 1H), 7.38(m, 1H), 7. 08 (m, 3H), 6. 68 (s, 1H), 6.70 (s, 1H), 5. 72 (s, 2H), 4. 56 (m, 1H), 4. 06 (m, 2H), 3. 91 (m, 2H), 3.50(m, 1H), 3. 18 (m, 2H), 2.90 (m, 1H), 2.74 (m, 1H), 2.51 (m, 2H), 1.78 (m, 2H), 1.52 (m, 2H) ®實施例249 1-(1，1-二側氧基-六氮-1入嗟口南~~4 -基胺基）-3-(3-{4 -「1-(3-氟-爷基）-1Η -口引嗤-5 -基胺基-啥口坐琳-6-基} '-吡咯-1-基）-丙-2-醇2 phase 〇 in l〇0 mL eggplant-shaped flask, [l-(3_fluoro-benzyl)-1H_carbazole_5_yl]-[6-(1-epoxyethyl decyl-1 Η -pyrrol-3-yl)-quinazoline-4-yl]-amine 178a (225 g, 0·46 mmol) was dissolved in 25 mL of decyl alcohol and added to the 4-hydroxyurethane (186 mg, 1.84). (mmol), the reaction solution was heated to reflux overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified and purified by chromatography (dichloromethane:methanol = 10:1) to give the title product 1-[3-(3-{ 4-[1-(3-Fluoro-benzyl)-iH-carbazolylamino]-quinazoline-6-yl}-pyrrol-1-yl)-2-hydroxy-propyl]-piperidine _ 4 monool 94389 428 201016683 248 (29 mg, yellow-brown solid), yield: 48%. MS m/z (ESI): 592 [M+1] 'HNMR (400 MHz, DMS0-c?: 5 9.86 (s, 1H), 8. 63 (s, 1H), 8.45 (s, 1H), 8.23 (s, 1H), 8.17 (s, 1H), 8.03 (d, 1H, J = 8.8Hz), 7.77 (s, 2H), 7.70 (d,1H, J = 8. 8Hz), 7.45 (s, 1H) ), 7.38(m, 1H), 7. 08 (m, 3H), 6. 68 (s, 1H), 6.70 (s, 1H), 5. 72 (s, 2H), 4. 56 (m, 1H) ), 4. 06 (m, 2H), 3. 91 (m, 2H), 3.50 (m, 1H), 3. 18 (m, 2H), 2.90 (m, 1H), 2.74 (m, 1H), 2.51 (m, 2H), 1.78 (m, 2H), 1.52 (m, 2H) ® Example 249 1-(1,1-di- oxo-hexanitro-l-indolyl~~4-ylamine -3(3-{4 -"1-(3-Fluoro-aryl)-1Η-口嗤-5-ylamino-啥口坐琳-6-yl} '-pyrrole-1- -propan-2-ol

在100 mL茄形瓶中，將1，卜二侧氧基-六氫-1又*6*-0塞喃-4-基胺鹽酸鹽（302 mg，1.63 mmol)溶於20 mL曱醇 429 94389 201016683 中，加入三乙胺（165 mg，1.63 mmo 1)，挽拌3 0分鐘後加入[1-(3-氟-苄基）-1Η-吲唑-5-基]-[6-(1-環氧乙基甲基基）-啥唾淋-4-基]-胺 178a(200 g，0.41 mmol) ’反應液加熱回流過夜。將反應液在減壓下濃縮，得到的殘留物藉由製備型薄層層析板分離純化（二氣甲烷··曱醇=10 : 1) ’得到本標題產物1-(1，1_二側氧基—六氫 -1 又 *6*-噻喃-4-基胺基）-3-(3-{4-[1-(3-氟-苄基）-1Η-吲唑-5-基胺基]-喹唑啉-6-基}-吡咯—1-基）_丙-2-醇249 (45 mg，黃棕色固體），產率：17. 3%。 ® MS m/z (ESI) ： 640[M+1] ^NMR (400MHz, DMSO-ds): (5 9. 88 (s, 1H), 8. 63 (s, 1H) 8.44 (s, 1H), 8.23 (s, 1H), 8. 18 (s, 1H), 8. 03 (d, .1H, J = 8. 8Hz), 7. 76 (s, 2H), 7. 72 (d, 1H, J = 8. 8Hz), -7. 45 (s, 1H), 7. 39 (m, 1H), 7. 09 (in, 3H), 6. 90 (s, 1H), 6.70 (s, 1H), 5.72 (s, 2H), 4.06 (m, 2H), 3.92 (m, 1H), 3.06 (m, 9H), 2.13 (m, 2H), 1.92 (m, 2H) ❹實施例250 _1-「1，4jJ 二旅咬基-1’二—(3_氩-芊篡吲嗤-5二盖胺基1-♦唾i-6-基卜吡呔_i-基丙-2_薛In a 100 mL eggplant-shaped flask, 1, bis-oxo-hexahydro-1 and *6*-0-propan-4-ylamine hydrochloride (302 mg, 1.63 mmol) was dissolved in 20 mL of sterol. In 429 94389 201016683, triethylamine (165 mg, 1.63 mmo 1) was added, and after mixing for 30 minutes, [1-(3-fluoro-benzyl)-1Η-carbazol-5-yl]-[6- (1-Epoxyethylmethyl)-indenyl-4-yl]-amine 178a (200 g, 0.41 mmol). The reaction solution was concentrated under reduced pressure, and the obtained residue was purified (yield m. Sideoxy-hexahydro-1 and *6*-thiopyran-4-ylamino)-3-(3-{4-[1-(3-fluoro-benzyl)-1Η-carbazole-5- 3%。 Aminoamino]-quinazolin-6-yl}-pyrrole-1-yl)-propan-2-ol 249 (45 mg, yellow-brown solid), yield: 17.3%. ® MS m/z (ESI): 640 [M+1] NMR (400 MHz, DMSO-ds): (5 9. 88 (s, 1H), 8. 63 (s, 1H) 8.44 (s, 1H) , 8.23 (s, 1H), 8. 18 (s, 1H), 8. 03 (d, .1H, J = 8. 8Hz), 7. 76 (s, 2H), 7. 72 (d, 1H, J = 8. 8Hz), -7. 45 (s, 1H), 7. 39 (m, 1H), 7. 09 (in, 3H), 6. 90 (s, 1H), 6.70 (s, 1H) , 5.72 (s, 2H), 4.06 (m, 2H), 3.92 (m, 1H), 3.06 (m, 9H), 2.13 (m, 2H), 1.92 (m, 2H) ❹Example 250 _1-"1 , 4jJ two brigade bite base 1 'di-(3_argon-indole-5-di-amylamine 1-♦ salivation i-6-kibpyridinium _i-ylpropane-2_Xue

94389 430 20101668394389 430 201016683

在100 mL茄形瓶中，將[1-(3-氟-苄基）_1H_吲唑—5_ 基]-[6-(1-環氧乙基曱基-1 Η-吡咯-3-基）-啥唾嘛一美]一胺178a(200 g，〇. 41 mmol)溶於20 mL甲醇中，攪拌下加入4-哌啶基哌啶（274 mg，1. 63 mmol)，反應液加熱回流 ®過夜。將反應液在減壓下濃縮，得到的殘留物藉由製備型薄層層析板分離純化（二氯甲烧：曱醇=1〇 : 1)，得到本標題產物 1-[1，4’ ]二 β底0定基-1’ -基~3-(3-{4-[1-(3 -氟-节基）-1Η_ο引吐-5 -基胺基]-喧嗤琳^-基}-吼洛-1-基）-丙 -2-醇250(109 mg，黃掠色固體）’產率：41%。 MS m/z (ESI) ： 659[M+1] !HNMR (400MHz, DMS0-d〇: (5 9. 89 (s, 1H), 8. 65 (s, 1H), φ 8.45 (s, 1H), 8. 23 (s, 1H), 8. 17 (s, 1H), 8. 03 (d, 1H, J = 8.8Hz), 7.75 (s, 1H), 7.70 (d, 2H, J = 8.8Hz), 7. 45 (s, 1H), 7. 37 (m, 1H), 7. 06 (m, 3H), 6. 88 (s, 1H), 6. 69 (s, 1H), 5. 72 (s, 2H), 3. 96 (m, 3H), 3. 01 (m, 5H), 2. 29 (in, 3H), 1. 98 (ra, 4H), 1. 70 (m, 6H), 1.44 (m, 4H) 實施例251 卜環丙基胺基-3-(3-{4-「1-(3-1^苄基）-111-吲唑-5-篡脍基l-1#0圭蛛-6-基}-°比洛-1-基）-丙-2-辞 431 94389 201016683[1-(3-Fluoro-benzyl)_1H-indazole-5-yl]-[6-(1-epoxyethylmercapto-1 Η-pyrrol-3-yl) in a 100 mL eggplant-shaped flask ) - 啥嘛一 ] ] ] ] ] ] ] ] 178 178 178 178 178 178 178 178 178 178 178 178 178 178 178 178 178 178 178 178 178 178 178 178 178 178 178 178 178 178 178 178 178 178 178 178 178 Reflux® overnight. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified (yield: methylene chloride: decyl alcohol = 1 : 1) to afford the title product 1-[1,4 Di-β- bottom 0-based-1'-yl-~3-(3-{4-[1-(3-fluoro-)-yl)-1Η_ο引吐-5-ylamino]-喧嗤琳^-yl} - yttrium-1-yl)-propan-2-ol 250 (109 mg, yellow-brown solid). Yield: 41%. MS m/z (ESI): 659[M+1] !HNMR (400MHz, DMS0-d〇: (5 9. 89 (s, 1H), 8. 65 (s, 1H), φ 8.45 (s, 1H) ), 8. 23 (s, 1H), 8. 17 (s, 1H), 8. 03 (d, 1H, J = 8.8Hz), 7.75 (s, 1H), 7.70 (d, 2H, J = 8.8 Hz), 7. 45 (s, 1H), 7. 37 (m, 1H), 7. 06 (m, 3H), 6. 88 (s, 1H), 6. 69 (s, 1H), 5. 72 (s, 2H), 3. 96 (m, 3H), 3. 01 (m, 5H), 2. 29 (in, 3H), 1. 98 (ra, 4H), 1. 70 (m, 6H ), 1.44 (m, 4H) Example 251 Cyclopropylamino-3-(3-{4-"1-(3-1)benzyl)-111-oxazol-5-indenyl- 1#0圭蛛-6-基}-°Bilo-1-yl)-propyl-2-character 431 94389 201016683

251251

AA

178a178a

在100 mL茄形瓶中，將[1-(3-氟-苄基）_1^-11引11坐_5_ 基]-[6-(1-環氧乙基曱基-1H-0比洛-3-基）-啥唾琳—4-其]__ 胺178a(200 g’ 0.41 mmol)溶於20 mL甲醇中，授掉下加入環丙基胺（93 mg ’ 1.63 mmo 1)，反應液加熱回流過夜。將·反應液在減壓下濃縮’得到的殘留物藉由製備型薄層層析板分離純化（二氯曱烷：曱醇=10 : D，得到本標題產物 1-環丙基胺基^-^-“-^-^-氟-节基^^吲唑—卜基胺 ❹基]-喹唑啉-6-基卜吡咯-卜基）-丙_2_醇251(95邶，黃棕色固體），產率：41%。 ' ” MS m/z (ESI) ： 548[M+1] 'HNMR (400MHz, CD30D-JO : 8. 47 (s, 1H), 8 43 (s 1H) 8.11 (s, 1H), 8.09 (s, 1H)，8.07 (d，ih, j = 8 8Hz；) ’ 7. 74 (s, 1H), 7. 70 (d, 2H, J = 8· 8Hz), 7. 43 (s ih) 7. 30 (m，1H), 6. 97 (m, 3H), 6. 79 (s，1H)，6 63 (s 1H) 5. 62 (s，2H)，4. 02 (m，3H)，2. 87 (m，iH)，2. 74 (m ijj) 94389 432 201016683 2. 28 (m，1H)，〇. 57 (m，4H) 實施例252 1-(3-14二L3·羞苄氣基）_茉胺基喹唑啉 •°比洛基）環-丙基-畈呷基丙_2一醇In a 100 mL eggplant-shaped flask, [1-(3-fluoro-benzyl)_1^-11 leads 11 to sit _5_yl]-[6-(1-epoxyethyl decyl-1H-0 pirin -3-yl)-啥啥琳—4-其]__amine 178a (200 g' 0.41 mmol) dissolved in 20 mL of methanol, added cyclopropylamine (93 mg ' 1.63 mmo 1), reaction solution Heat to reflux overnight. The residue obtained by concentrating the reaction mixture under reduced pressure was purified by preparative thin-layer chromatography (dichloromethane: decyl alcohol = 10: D to give the title product 1-cyclopropylamine. -^-"-^-^-Fluoro-nodal group ^^carbazole-bromoamine fluorenyl]-quinazoline-6-ylpyrrole-buki)-propan-2-ol 251 (95 邶, yellow Yield: 41%. ' ” MS m/z (ESI): 548[M+1] 'HNMR (400MHz, CD30D-JO: 8. 47 (s, 1H), 8 43 (s 1H) 8.11 (s, 1H), 8.09 (s, 1H), 8.07 (d, ih, j = 8 8Hz;) ' 7. 74 (s, 1H), 7. 70 (d, 2H, J = 8· 8Hz) , 7. 43 (s ih) 7. 30 (m,1H), 6. 97 (m, 3H), 6. 79 (s,1H),6 63 (s 1H) 5. 62 (s,2H), 4. 02 (m, 3H), 2. 87 (m, iH), 2. 74 (m ijj) 94389 432 201016683 2. 28 (m, 1H), 〇. 57 (m, 4H) Example 252 1- (3-14 two L3 · shame benzyl group) - melamine quinazoline · ° piroxime) cyclopropyl-mercaptopropan-2-ol

參1 -環丙基-旅哄將4-環丙基-哌畊-1-甲酸第三丁酯MSaUoomg，2 2 mmol)溶於20 mL二氯曱烷中’攪拌下滴加3 mL三氟乙峻，室溫下授拌1小時，反應完畢。將反應液在減壓下濃縮得到的殘留物溶於15 mL甲醇中，用飽和碳酸鈉溶液調整 pH-8至9，濃縮反應液，得到的殘留物藉由石夕膠管柱層析法進一步分離純化（二氣甲烷：曱醇：氨水=2〇 : 2 : ，得到1-環丙基-哌畊252b(277 mg，白色固體），產率：1〇〇%。 94389 433 201016683 MS m/z (ESI) : 127[M+1] 第二步 1- (3-{4-[3-氯-4-(3-氟-苄氧基）_苯胺基]_喹唑啉_6_基} -0比咯-1-基）-3-(4-環丙基-哌畊_1_基）_丙_2_醇將 1-環丙基-派畊 252b(61 mg，0. 48 mmol)溶於 25 mL 甲醇中，攪拌下加入[3-氣-4-(3-氟-苄氧基）-苯基]-[6-(1-環氧乙基甲基-1H-吼洛-3-基）-喧。坐琳-4一基]-胺i87a (200 mg，〇. 4 mmol)，混合液加熱回流過夜。反應液在減壓下濃縮’得到的殘留物藉由矽膠管柱層析法進一步分離純化（梯度沖提：二氯甲烷：甲醇=5〇 : 1，25 : 1)，得到本標題產物1-(3-{4-[3-氯-4-(3-氟-苄氧基苯胺基]-喹 0坐琳-6-基丨-η比嘻-1-基）-3-(4-環丙基-旅n井_1_基）_丙_2_ 醇252 (46 mg，黃色固體），產率：29.7%。 'MS m/z (ESI) ： 627[M+] 沱 NMR (400 MHz, CD30D-A) :(5 9.70 (s，1H)，8.54 (s， 1H), 8.38 (s, 1H) , 8.04 (m, 2H), 7.77 (dd, J=2.4Hz, φ 1H), 7.71 (d, J=8.4Hz , 1H), 7.48 (m, 1H), 7.41 (s , 1H), 7.32 (m, 3H), 7.19 (m, 1H), 6.87 (s, 1H), 6.65 (s, 1H)，5. 27 (s，2H)，4. 03 (m，1H)，3. 88 (br, 1H), 3.81 (m, 1H), 2.57 (br, 4H), 2.40 (br, 4H), 2.23 (br, 2H), 1.58 (br, 1H), 0.39 (m, 2H), 0.27 (m, 2H) 實施例253 2- (3-{4-「3-氧-4-(3-氟-苄氧基上笨胺基]_喹吨啉_6_基} -吡咯-1-基）-1-(4-環丙基曱基哄一卜基）—乙酮 94389 434 2010166831 1-Cyclopropyl-L. 4- 4-cyclopropyl-piperidine-1-carboxylic acid tert-butyl ester MSaUoomg, 2 2 mmol) dissolved in 20 mL of dichloromethane. BJ, the mixture was stirred for 1 hour at room temperature and the reaction was completed. The residue obtained by concentrating the reaction mixture under reduced pressure was dissolved in 15 mL of methanol, and the mixture was adjusted to pH-8 to 9 with a saturated sodium carbonate solution, and the residue was concentrated, and the residue obtained was further separated by the column chromatography. Purification (di-hydrogen methane: methanol: ammonia = 2 〇: 2: , 1-cyclopropyl-piperidine 252b (277 mg, white solid), yield: 1%. 94389 433 201016683 MS m/z (ESI): 127 [M+1] Step 2 1-(3-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-anilino]-quinazoline_6_yl} -0-rhodo-1-yl)-3-(4-cyclopropyl-piperidin-1_yl)-propan-2-ol- 1-cyclopropyl-p. 252b (61 mg, 0. 48 mmol Dissolved in 25 mL of methanol and added [3-gas-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1-epoxyethylmethyl-1H-吼洛- 3-yl)-oxime. Isoline-4-yl]-amine i87a (200 mg, 〇. 4 mmol), and the mixture was heated to reflux overnight. The reaction mixture was concentrated under reduced pressure. Further separation and purification by chromatography (gradient elution: dichloromethane:methanol = 5 〇: 1,25:1) afforded the title product 1-(3-{4-[3-chloro-4-(3-fluoro) -benzyloxyanilino]-quino 0 sitting -6-丨-η 嘻嘻-1-yl)-3-(4-cyclopropyl-Break n-l_1_yl)-propan-2-ol 252 (46 mg, yellow solid), yield: 29.7%. m/z (ESI): 627[M+] NMR (400 MHz, CD30D-A): (5 9.70 (s, 1H), 8.54 (s, 1H), 8.38 (s, 1H), 8.04 (m, 2H) ), 7.77 (dd, J=2.4Hz, φ 1H), 7.71 (d, J=8.4Hz, 1H), 7.48 (m, 1H), 7.41 (s , 1H), 7.32 (m, 3H), 7.19 ( m, 1H), 6.87 (s, 1H), 6.65 (s, 1H), 5.27 (s, 2H), 4. 03 (m, 1H), 3. 88 (br, 1H), 3.81 (m, 1H), 2.57 (br, 4H), 2.40 (br, 4H), 2.23 (br, 2H), 1.58 (br, 1H), 0.39 (m, 2H), 0.27 (m, 2H) Example 253 2- ( 3-{4-"3-oxo-4-(3-fluoro-benzyloxyphenylamino)]-quinoxaline-6-yl}-pyrrol-1-yl)-1-(4-cyclopropyl曱基哄一卜基)-Ethyl Ketone 94389 434 201016683

2-氯-1-(4-環丙基曱基哌畊_丨_基乙酮 • 將卜環丙基甲基哌畊237a(200 mg，1. 05 mmol)溶於 10 mL二氣甲烧和1 〇 mL四氫°夫喃的混合溶劑中，加入三乙胺（1 mL ’ 2. 1 mmol)，反應液在丙酮-乾冰浴冷卻至-μ °C，滴加氯乙醯氣（0. 2 mL，1. 43 mmol)，攪拌1小時後反 φ應完畢。反應液中加入50 mL水和50 mL乙酸乙醋，分液，水相用乙酸乙酯萃取（100 mLx2)，合併的有機相經由無水硫酸鈉脫水，過濾，減壓下濃縮，得到2_氯-1-(4-環丙基曱基派哄-1-基）-乙酮25 3a (151 mg，棕色油狀液體），產率：48. 8%。 MS m/z (ESI) : 239[M+23] 第二步 2-(3-丨4-[3-氯-4-(3-氟-节氧基）-苯胺基]-啥唾琳-6-基} 435 94389 201016683 -吼咯-1-基）-1-(4-環丙基曱基-哌哄一卜基卜乙酮在50 mL的燒瓶中，將[3_氯_4一（3—氟_苄氧基）〜笨基]-[6-(1Η-吡咯-3-基）-喹唑啉基]_胺 42(335 mg，〇. 7 mmol)溶於20 mL無水N，N-二曱基甲醯胺中，在冰浴條件下，冷卻至0°C，加入氫化鈉（108 mg，2.丄丽〇1)，攪拌 30分鐘後加入2-氯-1-(4-環丙基曱基哌啡_卜基乙酮 253a(150 mg，0. 7 mmol)，室溫下攪拌3小時反應完畢。反應液中加入5 0 mL水和5 0 mL乙酸乙s旨，分液，水相用乙酸乙酯萃取（100 mLx2)，合併的有機相經由無水硫酸鈉 ®脫水，過濾，減壓下濃縮’得到的殘留物藉由矽膠管柱層析法進一步分離純化（二氯曱烷：甲醇=25 : 1)，得到本標題產物2-(3-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-啥哇嚇*-6-基}-0比嘻-1-基）-1-(4-環丙基甲基底哄-1-基）-乙酮253(215 mg，黃色固體），產率：49%。 MS m/z (ESI) ： 625[M+1] 4 NMR (400 MHz, CD30D-d〇 : (5 10.00 (s，1H)，8.72 (s， 0 1H), 8.49 (s, 1H), 8.10 (s, 1H), 8.02 (d, J = 8. 8Hz, 1H), 7. 85 (d, J = 8. 8Hz, 1H), 7. 69 (d, J = 8. 8Hz, 1H), 7.54 (t, J = 8.8Hz, 1H), 7.42 (s, 1H), 7.32 (m, 3H), 7.19 (t, J = 8.8Hz, 1H), 6.80 (s, 1H), 6.74 (s, 1H), 5.27 (s, 2H), 4.96 (s, 2H), 3.51 (br, 4H), 2.51 (br, 2H), 2. 43 (br, 2H), 2. 22 (d, J = 6. 0Hz, 2H), 0. 85 (m, 1H), 0.47 (m, 2H), 0.09 (m, 2H) 實施例254 436 94389 201016683 吲 4 —其膝篡卜喹唑喊基}-°比洛羥基乙其、-政嘧-1-基1-而-?-2-Chloro-1-(4-cyclopropyl hydrazinopiperidinyl hydrazinyl ketone) Dissolve cyclopropylmethyl peptone 237a (200 mg, 1. 05 mmol) in 10 mL of two gas To a mixed solvent of 1 〇mL of tetrahydrofuran, triethylamine (1 mL '2.1 mmol) was added, and the reaction solution was cooled to -μ ° C in an acetone-dry ice bath, and chloroacetone was added dropwise (0 2 mL, 1.43 mmol), after 1 hour of stirring, the anti-φ should be completed. Add 50 mL of water and 50 mL of ethyl acetate to the reaction solution, and separate the liquid. The aqueous phase is extracted with ethyl acetate (100 mL×2). The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated and evaporated, evaporated,]]]]~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ), yield: 48.8%. MS m/z (ESI): 239 [M+23] Step 2 2-(3-丨4-[3-chloro-4-(3-fluoro- ethoxy) )-anilino]-啥琳琳 -6-6 base 435 94389 201016683 - fluoren-1-yl)-1-(4-cyclopropyl decyl-piperidin- propyl bromide in 50 mL flask In the middle, [3_chloro-4-iso-(3-fluoro-benzyloxy)~p-yl]-[6-(1Η-pyrrol-3-yl)-quinazolinyl]-amine 42 (335 mg, 〇 . 7 mmol) dissolved in 20 mL of anhydrous N,N-dimercaptocaramine Under ice-cooling conditions, cool to 0 ° C, add sodium hydride (108 mg, 2. 丄〇 1), stir for 30 minutes, then add 2-chloro-1-(4-cyclopropyl decyl piperazine _ Ethyl ethyl ketone 253a (150 mg, 0.7 mmol) was stirred at room temperature for 3 hours. The reaction mixture was added with 50 mL of water and 50 mL of ethyl acetate. (100 mL×2), the combined organic phases were dried over anhydrous sodium sulfate®, filtered, and concentrated under reduced pressure. The residue obtained was further separated and purified by silica gel column chromatography (dichloromethane:methanol = 25:1) , the title product 2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-anilino]-啥wow scare *-6-yl}-0-嘻-1- 1-(4-cyclopropylmethyl-indol-1-yl)-ethanone 253 (215 mg, yellow solid), yield: 49%. MS m/z (ESI): 625[M+ 1] 4 NMR (400 MHz, CD30D-d〇: (5 10.00 (s, 1H), 8.72 (s, 0 1H), 8.49 (s, 1H), 8.10 (s, 1H), 8.02 (d, J = 8. 8Hz, 1H), 7. 85 (d, J = 8. 8Hz, 1H), 7. 69 (d, J = 8. 8Hz, 1H), 7.54 (t, J = 8.8Hz, 1H), 7.42 (s, 1H), 7.32 (m, 3H), 7.19 (t, J = 8.8Hz, 1H), 6.80 (s, 1H), 6.74 (s, 1H), 5.27 (s, 2H), 4.96 (s, 2H), 3.51 (br, 4H), 2.51 (br, 2H), 2. 43 (br, 2H), 2. 22 (d, J = 6. 0 Hz, 2H), 0. 85 (m, 1H), 0.47 (m, 2H), 0.09 (m, 2H) Example 254 436 94389 201016683 吲4 — 篡 — — } } - - - - - B, and - 嘧 -1- -1 -1 - -??

Λ 在100 mL莊形瓶中，將K3一氟一苄基卜1H_0弓卜坐_5_ 基]-[6-(1-環軋乙基曱基一1{{-«»比嘻-3-基）-嗤峻琳-4-基]- 胺178a(100 g，〇· 204 mmol)溶於20 mL·甲醇中，攪拌下加入2-哌啶-4-基乙醇（79 mg，〇. 61 mmol)，反應液加熱 ❹回流過夜。將反應液在減壓下濃縮，得到的殘留物藉由製備型薄層層析板分離純化（二氣甲烷：甲醇=1 〇 : 1 )，得到本標題產物卜（3-{4-[1-(3-氟-苄基）-111-吲唑-5-基胺基]-喹唑啉-6-基}-吡咯-1-基）-3-[4-(2-羥基乙基）-哌啶 -卜基]-丙-2-醇254(105 mg，黃棕色固體），產率：83%。 MS m/z (ESI) ： 620[M+1] !HNMR (400MHz, DMSO-de): ^ 9. 85 (s, 1H), 8. 63 (s, 1H) 8.45 (s, 1H), 8.23 (s, 1H), 8. 17 (s, 1H), 8. 03 (d, 94389 437 201016683 7·44 (s，1H)，7.38 u, 1H)，6. 70 (s，1H)，5 72 3H^ 3.91 (m, 1H) 70 (m，2H)，I24(m，5H’) 1H，J = 8. 8Hz)，7. 74 (m, 3H)， 1H)，7. 08 (m，3h)，6. 89 (s， (s，2H)，4.36 (m，ih)，4.04 3. 44 (m，2H)，2. 51 (m，6H)，i. 實施例255 參Λ In a 100 mL bottle, K3-fluoro-benzylidene 1H_0 bows sit _5_ ki]-[6-(1-cyclo-ethyl fluorenyl- 1{{-«» 嘻-3- Base)-嗤琳琳 -4- yl]-amine 178a (100 g, 〇·204 mmol) dissolved in 20 mL·methanol, and added 2-piperidin-4-ylethanol (79 mg, 〇. 61) with stirring. (mmol), the reaction solution was heated and refluxed overnight. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by preparative thin-layer chromatography (di. methane: methanol = 1 〇: 1 ) to give the title product (3-{4-[1 -(3-fluoro-benzyl)-111-oxazol-5-ylamino]-quinazolin-6-yl}-pyrrol-1-yl)-3-[4-(2-hydroxyethyl) - piperidine-buki]-propan-2-ol 254 (105 mg, yellow-brown solid). Yield: 83%. MS m/z (ESI): 620 [M+1] "HNMR (400 MHz, DMSO-de): </ RTI> 9. 85 (s, 1H), 8. 63 (s, 1H) 8.45 (s, 1H), 8.23 (s, 1H), 8. 17 (s, 1H), 8. 03 (d, 94389 437 201016683 7·44 (s, 1H), 7.38 u, 1H), 6. 70 (s, 1H), 5 72 3H^ 3.91 (m, 1H) 70 (m, 2H), I24(m, 5H') 1H, J = 8. 8Hz), 7. 74 (m, 3H), 1H), 7. 08 (m, 3h) ), 6. 89 (s, (s, 2H), 4.36 (m, ih), 4.04 3. 44 (m, 2H), 2. 51 (m, 6H), i. Example 255

HOHO

心加形瓶干，將氟—节基）—111〇引基]-[6-U-環氧乙基曱基-1H-咣咯_3_基）—喹唑啉—*〜基= 胺 178a(150 g，〇· 306 mmol)溶於 2〇 mL 甲醇中，攪二下加入2-哌畊-1-基乙醇（79 mg，〇.61 mmol)，反應液加= 回流過伏。將反應液在減壓下濃縮，得到的殘留物藉由製備型薄層層析板分離純化（二氯甲烷：甲醇=1 0 : 1 )，得到本標題產物1-(3-{4-[1-(3-氟-苄基）— ih-吲唾-5-基胺基] 94389 438 201016683 基]-丙-2-醇255(95 mg，黃棕色固體），產率：50°/〇。 MS m/z (ESI) ： 621[M+1] !HNMR (400MHz, DMSO-d〇: 5 9. 84 (s, 1H), 8. 62 (s, 1H), 8. 45 (s, 1H), 8. 23 (s, 1H), 8. 17 (s, 1H), 8. 03 (d, 1H, J = 8.8Hz), 7.73 (m, 3H), 7.43 (s, 1H), 7.38 (m, 1H), 7.12 (m, 3H), 6.87 (s, 1H), 6.67 (s, 1H), 5.72 (s, 2H), 4. 94 (m, 1H), 4. 45 (m, 1H), 4. 07 (m, 2H), 4. 03 (m, 1H), 3.87(m, 1H), 3.52 (m, 2H), 3. 18 (m, 2H), 2.33 ® (m, 9H) 實施例256 卜（3-H-「l-(3-氟-苄基）-1Η-吲唑-5-基胺基1-喹唑啉-6-. 基卜吡咯-1-基）-3-「（2-羥基乙基）-甲基-胺基1-丙-2-醇Heart-shaped bottle, dry, fluorine-based group - 111 〇 ]]-[6-U-epoxyethyl fluorenyl-1H-fluorenyl _3_yl)-quinazoline-*~yl = amine 178a (150 g, 306· 306 mmol) was dissolved in 2 mL of methanol, and 2-peptidin-1-ylethanol (79 mg, 〇.61 mmol) was added with stirring, and the reaction mixture was refluxed. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified (yield: methylene chloride:methanol = 1:1) to give the title product 1-(3-{4-[ 1-(3-Fluoro-benzyl)-ih-indole-5-ylamino] 94389 438 201016683 yl]-propan-2-ol 255 (95 mg, yellow-brown solid), yield: 50°/〇 MS m/z (ESI): 621 [M+1] "HNMR (400 MHz, DMSO-d〇: 5 9. 84 (s, 1H), 8. 62 (s, 1H), 8. 45 (s, 1H), 8. 23 (s, 1H), 8. 17 (s, 1H), 8. 03 (d, 1H, J = 8.8Hz), 7.73 (m, 3H), 7.43 (s, 1H), 7.38 (m, 1H), 7.12 (m, 3H), 6.87 (s, 1H), 6.67 (s, 1H), 5.72 (s, 2H), 4. 94 (m, 1H), 4. 45 (m, 1H ), 4. 07 (m, 2H), 4. 03 (m, 1H), 3.87 (m, 1H), 3.52 (m, 2H), 3. 18 (m, 2H), 2.33 ® (m, 9H) Example 256 (3-H-"1-(3-Fluoro-benzyl)-1 oxime-oxazol-5-ylamino-1-quinazoline-6-. phenylpyrrol-1-yl)-3 - "(2-hydroxyethyl)-methyl-amino 1-propan-2-ol

在100 mL茄形瓶中，將[1-(3-氟-苄基）-1Η-吲唑-5-基]-[6-U-環氧乙基甲基-1H-吡咯-3-基）-喹唑啉-4-基]- 439 94389 201016683 胺178a(150 g ’ 〇· 306 mmol)溶於20 mL甲醇中’攪拌下加入2-甲胺基乙醇（92 mg，1. 224 mmol)，反應液加熱回流過夜。將反應液在減壓下濃縮，得到的殘留物藉由製備型薄層層析板分離純化（二氣甲烷：甲醇=1 〇 : 1 )，得到本標題產物卜（3-{4-[1-(3-氟-苄基）-iH-吲唑-5-基胺基]-喹唑啉-6-基}-吡咯-1-基）-3-[(2-羥基乙基）-甲基-胺基]-丙-2-醇256(49 mg，黃棕色固體），產率：30%。 MS m/z (ESI) ： 566[M+1] !HNMR (400MHz, CD30D-d〇： <5 8.48 (s, 1H), 8. 23 (s, 1H), ® 7. 97 (s, 1H), 7. 88 (s, 1H), 7. 73 (d, 1H, J = 8. 8Hz), 7.65(m, 1H), 7. 53 (m, 1H), 7. 16 (in, 2H), 7. 05 (s, 1H), 6.87 (m, 2H), 6.77 (d, 1H, J = 8. 8Hz), 6.57 (s, 1H), • 6.38(s, 1H), 5.42(s, 2H), 3.96 (in, 2H), 3. 69 (m, 3H), 2.61 (m, 1H), 2.52 (m, 1H), 2.38 (m, 2H). 2.26 (s, 3H) 實施例257 1-(3-丨4-「1-(3-氟-苄基）-1Η-吲唑-5-基胺基l-t#嗤啦-6-❹暮比略-1-基）-3-n辰啡-1-裏-丙-2-醇[1-(3-Fluoro-benzyl)-1Η-indazol-5-yl]-[6-U-epoxyethylmethyl-1H-pyrrol-3-yl in a 100 mL eggplant-shaped flask )-quinazolin-4-yl]- 439 94389 201016683 Amine 178a (150 g ' 〇· 306 mmol) dissolved in 20 mL of methanol. Add 2-methylaminoethanol (92 mg, 1.224 mmol) with stirring. The reaction solution was heated to reflux overnight. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by preparative thin-layer chromatography (di. methane: methanol = 1 〇: 1 ) to give the title product (3-{4-[1 -(3-fluoro-benzyl)-iH-indazol-5-ylamino]-quinazolin-6-yl}-pyrrol-1-yl)-3-[(2-hydroxyethyl)-- Amino-amino]-propan-2-ol 256 (49 mg, yellow-brown solid), yield: 30%. MS m/z (ESI): 566[M+1] !HNMR (400MHz, CD30D-d〇: <5 8.48 (s, 1H), 8. 23 (s, 1H), ® 7. 97 (s, 1H), 7. 88 (s, 1H), 7. 73 (d, 1H, J = 8. 8Hz), 7.65(m, 1H), 7. 53 (m, 1H), 7. 16 (in, 2H ), 7. 05 (s, 1H), 6.87 (m, 2H), 6.77 (d, 1H, J = 8. 8Hz), 6.57 (s, 1H), • 6.38(s, 1H), 5.42(s, 2H), 3.96 (in, 2H), 3. 69 (m, 3H), 2.61 (m, 1H), 2.52 (m, 1H), 2.38 (m, 2H). 2.26 (s, 3H) Example 257 1 -(3-丨4-"1-(3-fluoro-benzyl)-1Η-oxazol-5-ylamino lt#嗤啦-6-❹暮比略-1-yl)-3-nchen Carin-1-li-propan-2-ol

A 440 94389 201016683A 440 94389 201016683

在100 mL茄形瓶中，將[卜㈡一氟-苄基）— 1H_吲唑-5_ 基]- [6_(1_環氧乙基甲基-IH-0比洛_3 -基）-啥〇坐琳-4 -基]-胺178a(150 g’ 0.306 mmol)溶於20 mL甲醇中，授拌下加入派哄（1 〇5 mg，1. 224 mmol )，反應液加熱回流過夜。 ❹將反應液在減壓下濃縮，得到的殘留物藉由製備型薄層層析板分離純化（二氯甲烷：甲醇=1〇 : 1)，得到本標題產物 1-(3-{4-[ 1-(3-氟-苄基）-1Η-吲唑-5-基胺基]-喹唑琳— 6- -基卜吡咯-1-基）-3-哌畊-1-基-丙-2-醇257(20 mg，黃棕 -色固體），產率：12%。. MS m/z (ESI) ： 577[M+1] !HNMR (400MHz, CD30D-dO ： <5 8. 49 (s, 1H), 8. 38 (s, 1H) ^ 8.10 (s, 1H), 8.06 (s, 1H), 7.97 (d, 1H, J = 8.8Hz), 7. 76 (d, 1H, J = 8. 8Hz), 7. 67 (d, 1H, J = 8. 8Hz), 7 37 (s, 1H), 7. 29(m, 2H), 6.96 (m, 2H), 6.86 (d, 1H), 6.76 (s, 1H), 6. 61 (s, 1H), 5. 60 (s, 2H), 4. 03 (m, 2H), 3. 93 (m, 1H), 3.07 (m, 4H), 2.68 (m, 4H), 2.42 (m, 2H) 實施例258 1-(3-{4-[1-(3-氟-苄基）-111-°弓丨峻-5-基胺基~|-啥峰设_丹'_ 基}-a比嘻-1-基）-3-(4 -嗎啦-4-基-派咬-1-基）-丙-2-西亨 94389 441 201016683In a 100 mL eggplant-shaped flask, [b (di)-fluoro-benzyl)-1H-indazole-5-yl]-[6_(1_epoxyethylmethyl-IH-0 pyloryl-3-yl) - 啥〇琳 - 4 - yl]-amine 178a (150 g '0.306 mmol) was dissolved in 20 mL of methanol, and the mixture was added with hydrazine (1 〇 5 mg, 1. 224 mmol), and the reaction solution was heated to reflux overnight. . The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified (yield: methylene chloride:methanol = 1 : 1) to afford the title product 1-(3-{4- [1-(3-Fluoro-benzyl)-1Η-indazol-5-ylamino]-quinazoline-6--pyopyrrol-1-yl)-3-piped-1-yl-propyl 2-Alkyl 257 (20 mg, yellow brown-color solid), yield: 12%. MS m/z (ESI): 577[M+1] !HNMR (400MHz, CD30D-dO: <5 8. 49 (s, 1H), 8. 38 (s, 1H) ^ 8.10 (s, 1H ), 8.06 (s, 1H), 7.97 (d, 1H, J = 8.8Hz), 7. 76 (d, 1H, J = 8. 8Hz), 7. 67 (d, 1H, J = 8. 8Hz) , 7 37 (s, 1H), 7. 29(m, 2H), 6.96 (m, 2H), 6.86 (d, 1H), 6.76 (s, 1H), 6. 61 (s, 1H), 5. 60 (s, 2H), 4. 03 (m, 2H), 3. 93 (m, 1H), 3.07 (m, 4H), 2.68 (m, 4H), 2.42 (m, 2H) Example 258 1- (3-{4-[1-(3-Fluoro-benzyl)-111-°丨丨峻-5-ylamino~~-啥峰_丹'_ base}-a than 嘻-1-yl )-3-(4 -?la-4-yl-trans- -1-yl)-prop-2- xihang 94389 441 201016683

在100 mL茄形瓶中，將[1-(3-氟-苄基）-1Η-吲唑-5-基]-[6-(1-環氧乙基曱基-iH-n比u各_3-基）-喹嗤琳-4-基]- 胺178a(100 g ’ 〇. 203 mmol)溶於20 mL甲醇中，擾拌下加入4-哌啶-4-基-嗎啉（1〇4 mg，〇. 609 mmol)，反應液加熱回流過夜。將反應液在減壓下濃縮，得到的殘留物藉由製備型薄層層析板分離純化（二氯甲燒：曱醇=1〇: ，得到本標題產物1-(3-{4-[1-(3_氟-苄基引β坐-5-基胺基]-喧唾琳-6-基}-π比洛-1-基）-3-(4-嗎琳-4-基-旅咬-1一 ❾基）-丙-2-醇258(21 mg，黃棕色固體），產率：16%。 MS m/z (ESI) ： 661[M+1] 'HNMR (400MHz, CD30D-d〇 : (5 8.50 (s, 1H), 8. 36 (s, 1H) 8.11 (s, 1H), 8.06 (s, 1H), 7.96 (d, 1H, J = 8.8Hz), 7. 76 (d, 1H, J = 8. 8Hz)，7. 67 (d, 1H，J = 8. 8Hz)，7. 37 (s，1H)，7· 28 (s，2H)，6. 98 (s，2H)，6. 86 (s，1H)，6. 76 (s，1H)，6. 61 (s, 1H)，5. 60 (s，2H)，3. 95 (m，3H)，3. 73 (m, 4H), 3.09(m, 2H), 2. 56 (m, 4H), 2.46 (m, 2H), 2.36 94389 442 201016683 (m, 1H), 2.24 (m, 2H), 1.90 (m, 2H), 1.61 (m, 2H) 實施例259 1-(4 -胺基-派 °定-1-基）-3-(3-{4-[3-氣-4-(3-氟-苄氳基）-笨胺基1-喹唑啉-6-基卜吡咯-1-基V丙-2-酵[1-(3-Fluoro-benzyl)-1Η-indazol-5-yl]-[6-(1-epoxyethyl fluorenyl-iH-n ratio u each in a 100 mL eggplant-shaped flask _3-yl)-quinoxaline-4-yl]-amine 178a (100 g ' 〇. 203 mmol) was dissolved in 20 mL of methanol, and 4-piperidin-4-yl-morpholine was added with stirring. 〇 4 mg, 609. 609 mmol), and the reaction mixture was heated to reflux overnight. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified (yield: m. 1-(3_Fluoro-benzyl-induced β-s--5-ylamino)-indolyl-6-yl}-πpyr-1-yl)-3-(4-morphin-4-yl- TB-1-mercapto)-propan-2-ol 258 (21 mg, yellow-brown solid), yield: 16%. MS m/z (ESI): 661[M+1] 'HNMR (400MHz, CD30D -d〇: (5 8.50 (s, 1H), 8. 36 (s, 1H) 8.11 (s, 1H), 8.06 (s, 1H), 7.96 (d, 1H, J = 8.8Hz), 7. 76 (d, 1H, J = 8. 8Hz), 7.67 (d, 1H, J = 8. 8Hz), 7. 37 (s, 1H), 7· 28 (s, 2H), 6. 98 (s , 2H), 6.86 (s, 1H), 6.76 (s, 1H), 6. 61 (s, 1H), 5. 60 (s, 2H), 3. 95 (m, 3H), 3 . . . (m, 2H) m, 2H), 1.61 (m, 2H) Example 259 1-(4-Amino-Phenyl-1-yl)-3-(3-{4-[3-Ga-4-(3-fluoro) -benzylbenzyl)-stanoamino-1-quinazolin-6-ylpyrrolidin-1-yl V-propan-2-ferment

第一步 (1~卞基-〇底咬-4-基）-胺基曱酸第二丁醋將醋酸酐（2. 43 g，11 mmol)溶於20 mL二氯甲烧中，用恆壓滴液漏斗緩慢滴加卜苄基-哌啶-4-基胺259a (2. 05 mL，10 mmol，Aldrich)的 20 mL 二氯甲烷溶液中，滴加凡畢後，至概下攪拌過夜。將反應液在減麗下濃縮， 94389 443 201016683 得到的殘留物藉由矽膠管柱層析法進一步分離純化（二氯甲烷.甲醇=25 : 1)，得到（1-苄基_哌啶_4_基）_胺基甲酸第二丁醋25 9b (2.91g’白色固體），產率： MS ra/z (ESI) ： 291[M+1] 第二步哌啶-4-基-胺基甲酸第三丁酯將（1-苄基-哌啶-4-基）-胺基甲酸第三丁酯259b(2. 9 g ’ 10 mmol)溶於150 mL甲醇中，攪拌下加入Pd/C，用氫氣置換空氣，4次後，在3(TC下催化加氫，24小時後反應完畢。過濾反應液，減壓下濃縮濾液，得到哌啶_4_基-胺基甲酸第三丁酯259c(1.96 g，白色固體），產率：98%。 MS m/z (ESI) ： 201[M+1] 第三步 {l-[3-(3-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-喹唑嘛 -6-基}-吡咯-1-基）-2-羥基-丙基]-哌啶-4-基卜胺基甲酸第三丁酯〇將[3_氣_4_(3-氟-苄氧基）-苯基]-[6-0-環氧乙基甲基-1H-吡咯-3-基）-喹唑啉-4-基]-胺 I87a(200 mg，0.4 mmol)溶於20 mL曱醇中’攪拌下加入哌啶—4-基-胺基甲酸第三丁酯259c(118 mg’ 0.5 6 mmo 1)，混合液加熱回流過夜。反應液在減壓下濃縮，得到的殘留物藉由石夕膠管柱層析法進一步分離純化（二氯甲烷：曱醇=25 : 1)，得到{1-[3-(3-{4-[3-氣-4-(3-氟-苄氧基）-苯胺基]-啥唾琳_6-基} -σ比11各-1-基）-2-經基-丙基]-η底咬-4-基}-胺基甲酸第三丁 444 94389 201016683 酯259d (178 mg，黃色固體），產率：74· 2%。 MS m/z (ESI) ： 701[M+l] 第四步 1-(4-胺基-哌啶-1-基）-3-(3_{4_[3_氣_4_(3_氟-苄氧基） -苯胺基]-喹唑啉-6-基}-吡咯-i_基）_丙_2一醇將{1-[3-(3-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-喹唾琳-6-基}-«比洛-1 —基）_2-羥基-丙基]_旅唆_4-基}-胺基甲酸第二丁醋 25 9d (58.6 mg ’ 〇.〇9 mmol)溶於 15 mL 二氯 ❹曱院中’在冰浴條件下’冷卻至〇。〇，加入3 mL三氟乙酸，保持此溫度攪拌3小時後反應完畢。將反應液中加入飽和碳酸氫鈉溶液，調整pH=8，加入5〇 mL乙酸乙酯和5〇 mL 四氫呋喃，分液，水相用乙酸乙酯萃取（50 mLx3)，合併的有機相經由無水硫酸鈉脫水，過濾，減壓下濃縮，得到的 '殘留物藉由矽膠管柱層析法進一步分離純化（甲醇：氨水 40 : 1)，得到卜（4-胺基-哌啶-1-基）_3_(3_{4〜[3_氯_4一 (3-氟-苄氧基）_苯胺基]—喹唑啉_6_基}_π比咯—1 —基）一丙 β ~2-醇259(35 mg，淡黃色固體），產率：69· 7%。土 MS m/z (ESI) : 6〇1[Μ+1] 4 NMR (400 MHz，CD30D-c/U9.71 (s，1H)，8 55 (s’ 1H)，8.50 (s, 1H), 8.11 (s, 1H), 8.02 (d, j ^ 〇〇Hz 7.85 (d, J = 8.8Hz, 1H), 7. 69 (d, J = 8. 8Hz； 1H)； 7*54(t, J = 8.8Hz, 1H), 7.42(s, 1H), 7. 32 (m 3H), (t, J = 8.8Hz, 1H), 6.87 (s, 1H), 6.65 (s ih) 5*27(s, 2H), 4.40 (br, 1H), 4. 06 (t, Ι^^.δΗζ, 1H)! 94389 445 201016683 3.94 (s，1Η)，3·85 (m，1Η)，3·18 (d，J = 3.2Hz，2H)， 2.78 (br，2H)，2.49 (br，2H)，2.19 (m，3H)，1.66 (br， 2H), 1. 28 (br, 2H) 實施例260The first step (1~ thiol-hydrazin-4-yl)-amino phthalic acid dibutyl vinegar dissolves acetic anhydride (2.33 g, 11 mmol) in 20 mL of dichloromethane. The dropping funnel was slowly added dropwise to a solution of benzylidene-piperidin-4-ylamine 259a (2. 05 mL, 10 mmol, Aldrich) in 20 mL of dichloromethane, and the mixture was stirred overnight. The reaction mixture was concentrated under reduced Celite, and the residue obtained from 94389 443 201016683 was further separated and purified by methylene chloride column chromatography (dichloromethane, methanol = 25:1) to give (1-benzyl-piperidine _4). _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Tributyl carboxylic acid tert-butyl (1-benzyl-piperidin-4-yl)-carbamic acid 259b (2.9 g '10 mmol) was dissolved in 150 mL of methanol, and Pd/C was added with stirring. After replacing the air with hydrogen, after 4 times, catalytic hydrogenation was carried out at 3 (TC), and the reaction was completed after 24 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give the tert-butyl ester of piperidin-4-yl-carbamic acid. 259c (1.96 g, white solid), yield: 98%. MS m/z (ESI): 201[M+1] Step 3 {l-[3-(3-{4-[3-chloro-4 -(3-Fluoro-benzyloxy)-anilino]-quinazolyl-6-yl}-pyrrol-1-yl)-2-hydroxy-propyl]-piperidin-4-yl-p-aminocarboxylic acid Tributyl ester oxime [3_gas_4_(3-fluoro-benzyloxy)-phenyl]-[6-0-epoxyethylmethyl-1H-pyrrol-3-yl)-quinazoline- 4-yl]-amine I87a (200 mg, 0.4 mmol) dissolved in 20 mL In the sterol, piperidine-4-yl-carbamic acid tert-butyl ester 259c (118 mg' 0.5 6 mmo 1) was added with stirring, and the mixture was heated to reflux overnight. The reaction solution was concentrated under reduced pressure, and the obtained residue was further purified and purified by chromatography (dichloromethane: hexane = 25:1) to give {1-[3-(3-{4- [3-Gas-4-(3-fluoro-benzyloxy)-anilino]-indole _6-yl}-σ ratio 11-1-yl)-2-yl-propyl]-η Bottom-4-yl}-carbamic acid tert-butyl 444 94389 201016683 ester 259d (178 mg, yellow solid), yield: 74. 2%. MS m/z (ESI): 701 [M+l] Step 4 1-(4-Amino-piperidin-1-yl)-3-(3_{4_[3_ gas_4_(3_fluoro- Benzyloxy)-anilino]-quinazolin-6-yl}-pyrrole-i-yl)-propan-2-ol will be {1-[3-(3-{4-[3-chloro-4-) (3-fluoro-benzyloxy)-anilino]-quinalin-6-yl}-«Bilo-1 -yl)_2-hydroxy-propyl]_旅唆_4-yl}-aminocarboxylic acid The second vinegar 25 9d (58.6 mg '〇.〇9 mmol) was dissolved in 15 mL of Dichlorohydrazine and cooled to 〇 under ice bath conditions. 〇, 3 mL of trifluoroacetic acid was added, and the reaction was completed after stirring at this temperature for 3 hours. Add the saturated sodium hydrogen carbonate solution to the reaction solution, adjust the pH to 8, add 5 mL of ethyl acetate and 5 mL of tetrahydrofuran, and separate the liquid. The aqueous phase is extracted with ethyl acetate (50 mL×3). The sodium sulfate was dehydrated, filtered, and concentrated under reduced pressure. The obtained residue was further separated and purified by hexane column chromatography (methanol: aqueous ammonia 40:1) to afford (4-amino-piperidin-1-yl) )_3_(3_{4~[3_chloro_4-(3-fluoro-benzyloxy)-anilino]-quinazoline_6_yl}_πpyr-l-yl)-propanyl β ~2- Alcohol 259 (35 mg, pale yellow solid), yield: 69.7%. Soil MS m/z (ESI): 6〇1[Μ+1] 4 NMR (400 MHz, CD30D-c/U9.71 (s, 1H), 8 55 (s' 1H), 8.50 (s, 1H) , 8.11 (s, 1H), 8.02 (d, j ^ 〇〇Hz 7.85 (d, J = 8.8Hz, 1H), 7. 69 (d, J = 8. 8Hz; 1H); 7*54(t, J = 8.8 Hz, 1H), 7.42 (s, 1H), 7. 32 (m 3H), (t, J = 8.8 Hz, 1H), 6.87 (s, 1H), 6.65 (s ih) 5*27 ( s, 2H), 4.40 (br, 1H), 4. 06 (t, Ι^^.δΗζ, 1H)! 94389 445 201016683 3.94 (s,1Η),3·85 (m,1Η),3·18 ( d, J = 3.2 Hz, 2H), 2.78 (br, 2H), 2.49 (br, 2H), 2.19 (m, 3H), 1.66 (br, 2H), 1. 28 (br, 2H) Example 260

2二（3-U~[3-氯-4-(3-氟-芊氫基^>-苳胺基1_-喹唑尨~6-基}_ 二啤4-1-基)-1-(4-環丙臬甲某一畹种—卜基）-乙饮2二(3-U~[3-chloro-4-(3-fluoro-hydrazinyl)>-nonylamino 1_-quinazolium~6-yl}_2 beer 4-1-1)-1 -(4-cyclopropyl guanidine a certain species - Bu Ji) - Yi drinking

260260

將2-(3-{4-[3-氣-4-(3-氟-苄氧基）-苯胺基喹唑啉-6-基卜吡咯―；!一基）一卜以―環丙基甲基一哌畊一^基卜乙酮253(53 mg，0. 08 mmol)溶於1〇 mL四氫呋喃中，攪拌 β下加入氫化鋁鋰（4〇 mg，〇. 〇8 mm〇i)，室溫下攪拌如分鐘後反應完畢。反應液用甲醇淬滅，減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化（二氯甲烷：甲醇 -25 · 1) ’得到標題產物2—(3-{4-[3-氯-4-(3-氟-苄氧基）一苯胺基]-喹唑啉_6_基}_吡咯基卜卜^—環丙基甲基一哌啡-1-基）-乙烷260(8 mg ’黃色固體），產率：15. 4%。2-(3-{4-[3-Ga-4-(3-fluoro-benzyloxy)-anilinoquinazolin-6-ylpyrrole-; Methyl-Peptinol- phenylethanone 253 (53 mg, 0.08 mmol) was dissolved in 1 mL of tetrahydrofuran, and lithium aluminum hydride (4 〇 mg, 〇. 〇 8 mm〇i) was added under stirring β. The reaction was completed after stirring at room temperature for several minutes. The reaction mixture was quenched with EtOAc (EtOAc)EtOAc. [3-Chloro-4-(3-fluoro-benzyloxy)-anilino]-quinazoline-6-yl}-pyrrolylbubu^-cyclopropylmethyl-piperidin-1-yl)- 4%。 Ethane 260 (8 mg 'yellow solid), yield: 15. 4%.

Ms ni/z (ESI) ： 611[M+1] >H NMR (400 MHz, CD30D-d6): (5 8.64 (s, 1H), 8.41 (s, 94389 446 201016683 1H), 7.97 (d, J = 2. 8Hz, 1H), 7.90 (d, J = 8. 8Hz, 1H), 7.84 (d, J = 8.8Hz, 1H), 7.70 (m, 1H), 7.34 (m, 1H), 7.22 (m, 3H), 7.02 (m, 1H), 6.94 (d, J - 8. 8Hz, 1H), 6.69 (d, J = 2.0Hz, 1H), 6.56 (d, J = 1. 6Hz, 1H), 5.13 (s, 2H), 4.02 (t, J = 6.0Hz, 3H), 2.90 (m, 5H), 2.80 (s, 4H), 2.59 (d, J = 6.8Hz, 2H), 0.88 (m, 1H), 0.62 (m, 2H), 0. 24 (m, 2H) 實施例261 2-(3-{4-「3 -氯- 4-(3-氟-节氧基）-笨胺基1-啥峻琳-6-基} ❺ -°比嘻-I-基）- 1-〇比洛烧-1~~基-乙嗣Ms ni/z (ESI): 611 [M+1] >H NMR (400 MHz, CD30D-d6): (5 8.64 (s, 1H), 8.41 (s, 94389 446 201016683 1H), 7.97 (d, J = 2. 8Hz, 1H), 7.90 (d, J = 8. 8Hz, 1H), 7.84 (d, J = 8.8Hz, 1H), 7.70 (m, 1H), 7.34 (m, 1H), 7.22 ( m, 3H), 7.02 (m, 1H), 6.94 (d, J - 8. 8Hz, 1H), 6.69 (d, J = 2.0Hz, 1H), 6.56 (d, J = 1. 6Hz, 1H), 5.13 (s, 2H), 4.02 (t, J = 6.0Hz, 3H), 2.90 (m, 5H), 2.80 (s, 4H), 2.59 (d, J = 6.8Hz, 2H), 0.88 (m, 1H) ), 0.62 (m, 2H), 0. 24 (m, 2H) Example 261 2-(3-{4-"3-Chloro-4-(3-fluoro-hydroxy)-phenylaminol 1-啥峻琳-6-基} ❺ -°比嘻-I-基)- 1-〇比洛烧-1~~基-乙嗣

〇〇

第一步 2-氣-1-吡咯烷-1-基-乙酮將°比洛（71 mg，1 mmo 1)溶於10mL二氯甲烧中，溶液 447 94389 201016683 在冰冷下冷卻至0〇c，攪拌下加入氯乙醯氣（17〇 mg，1. 5 mm〇1) ’室溫下攪拌1小時反應完畢。反應液中加入50mL 水’ 一氯甲燒萃取（5〇 mLx3)，合併的有機相依次經由水，飽和氯化納溶液洗滌，無水硫酸鈉脫水，過濾，減壓下濃縮’得到2-氯吡咯烷_卜基-乙酮261a(115呢，白色固體），產率：78% 第二步 2 -（3-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-喹唑啉-6-基} -吼洛-1-基）-1-„比洛烧一卜基―乙酮 ® 在50 mL的燒瓶中，將[3-氯-4-(3-氟-苄氧基）-苯基] -[6-(1Η-η比咯-3—基）_喹唑啉_4_基]_胺 42(m mg，〇 25 mmol)溶於1〇社無水N，N-二曱基曱醯胺中，在冰浴條件下’冷卻至〇°C，加入氫化納（30 mg，0.75 mmo 1)，擾拌 -30分鐘後加入2-氯-1-吡咯烷-1-基-乙酮261a(55 mg， 0.375 mmol)，室溫下攪拌1小時反應完畢。反應液加入 50 mL水’二氯甲烷萃取（50 mLx3)，合併的有機相經由無 ⑩水硫酸鈉脫水’過濾，減壓下濃縮，得到的殘留物藉由石夕膠管柱層析法進一步分離純化（正己烷：乙酸乙酯=2 : ，得到本標題產物2-(3-{4-[3-氯- 4- (3-氟-节氧基）—笨胺基]-哇°坐琳_6_基}-°比p各-1-基）-1-π比p各烧_1-基-乙酮261 (72 mg，黃色固體），產率：51.9%。, MS m/z (ESI) ： 556[M+1] NMR (400 MHz, CD30D-d〇 : 5 9. 713 (s, 1H), 8.545 (d, J二 1.2Hz，1H)，8.499 (s，1H)，8.027 (m，2H)，7.759 (m， 94389 448 201016683 1H)，7.708 (d, J = 8.8Hz，1H), 7.479 (m，1H)，7.323 (m， 4H)，7.192 (m，1H)，6.282 (t，J=2.4Hz，1H)，6.056 (m, 1H), 5.268 (s,2H), 4.853 (s, 2H), 3. 500 (t, J = 6. 8Hz, 2H), 3.345 (t, J = 7.2Hz, 2H)，1.925 (m，2H), 1.810 (瓜， 2H) 實施例262 「3-氧-4-(3-氟r苄氧棊）-苯基]咕-4_芊萨芊、 -111-°比洛-3 -基1-唾吨淋-4-基丨-脸The first step 2-gas-1-pyrrolidin-1-yl-ethanone is dissolved in 10 mL of methylene chloride in a solution of pyridine (71 mg, 1 mmo 1), and the solution is cooled to 0 Torr under ice cooling. c. Add chloroacetamidine (17 〇 mg, 1.5 mm 〇1) with stirring. Stir at room temperature for 1 hour. 50 mL of water was added to the reaction mixture to extract (5 〇mL×3), and the combined organic phases were washed successively with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2-chloropyrrole. Alkano-ethylidene- ketone 261a (115 g, white solid), yield: 78%. Step 2 2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-aniline [-] quinazolin-6-yl}-indol-1-yl)-1-„ piroxicam-ethyl ketone® in a 50 mL flask, [3-chloro-4-(3) -Fluoro-benzyloxy)-phenyl]-[6-(1Η-ηpyr-3-yl)-quinazoline-4-yl]-amine 42 (m mg, 〇25 mmol) is dissolved in 1 〇 In the anhydrous N,N-didecyl decylamine, 'cooled to 〇 ° C under ice bath conditions, added sodium hydride (30 mg, 0.75 mmo 1), and then turbid for -30 minutes, then added 2-chloro-1 -pyrrolidin-1-yl-ethanone 261a (55 mg, 0.375 mmol), stirred at room temperature for 1 hour. The reaction mixture was taken up in 50 mL water-dichloromethane (50 mL×3). Dehydration of sodium sulfate 10 'filtered, concentrated under reduced pressure, and the residue obtained was further separated and purified by hexanes column chromatography (n-hexane) Ethyl acetate = 2 : , the title product 2-(3-{4-[3-chloro-4-(3-fluoro-hydroxy)-phenylamino]-wow________ -° ratio p-1--1-yl)-1-π ratio p each 1-1-yl-ethanone 261 (72 mg, yellow solid), yield: 51.9%., MS m/z (ESI): 556 [M+1] NMR (400 MHz, CD30D-d〇: 5 9. 713 (s, 1H), 8.545 (d, J II 1.2 Hz, 1H), 8.499 (s, 1H), 8.027 (m, 2H) , 7.759 (m, 94389 448 201016683 1H), 7.708 (d, J = 8.8 Hz, 1H), 7.479 (m, 1H), 7.323 (m, 4H), 7.192 (m, 1H), 6.282 (t, J = 2.4Hz, 1H), 6.056 (m, 1H), 5.268 (s, 2H), 4.853 (s, 2H), 3. 500 (t, J = 6. 8Hz, 2H), 3.345 (t, J = 7.2Hz , 2H), 1.925 (m, 2H), 1.810 (melon, 2H) Example 262 "3-Oxo-4-(3-fluororbenzyloxyindole)-phenyl]indole-4_芊萨芊, -111 -°Bilo-3 - base 1-salt lysyl-4-pyrene-face

Ο 在氬氣氛下，將4_{4-[3~氯-4-(3-氟-苄氧基）-苯胺基]-喹唑啉-6-基}-111-吡咯-2-甲醛 218a(94.4 mg，0.2 mmol)和哌啶-4-基胺（26 mg，〇. 26 mmol)溶於 20 mL 二氯曱烷中’在室溫下攪拌30分鐘後，加入三（乙醯氧基）硼氫化鈉（212 mg，1 mmol)，混合液在室溫下攪拌過夜。在反應液中加入50 mL水，減壓下蒸掉二氯曱烷，水相用乙酸乙酯萃取（50 mLx3)，合併的有機相經由無水硫酸鈉脫水，過濾，減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進 94389 449 201016683 一步分離純化（二氯甲烷：曱醇=5 : 1)，得到標題產物[3-氯-4-(3-氟-苄氧基）-苯基]-{6-[5-(哌啶-4-基胺基）-1Η-σ比洛-3-基]-°|：σ坐琳-4-基丨-胺262 (8 mg，黃色固體），產率：71·4% 。 MS m/z (ESI) ： 557[M+1] ^ NMR (400 MHz，CD30D-d〇: 5 10. 919 (s，1H)，9. 684 (s， 1H), 8.533 (s, 1H), 8.441 (d, J = 12Hz, 1H), 8.143 (d, J = 8. 4Hz, 1H), 8. 044 (s, 1H), 7. 740 (m, 2H), 7. 461 (br, 1H), 7. 282 (m, 3H), 7. 179 (m, 1H), 6. 791 (s, 1H), 6. 452 (d, J = 20. 8Hz, 1H), 5.244 (s, 2H), 3. 864 (s, 1H), 3.480 (m, 2H), 3.327 (br, 4H), 1.913 (br, 2H), 1.264 (br, 2H) 實施例263 (R)-「3 -氯-4-(3 -氟-节氧基）-笨基環氧丙烧基 -2-基甲基-1 Η-口比口各-3-基）-唾0坐琳-4-基"I-胺4 4_{4-[3~Chloro-4-(3-fluoro-benzyloxy)-anilino]-quinazolin-6-yl}-111-pyrrole-2-carbaldehyde 218a (under argon) 94.4 mg, 0.2 mmol) and piperidin-4-ylamine (26 mg, 〇. 26 mmol) dissolved in 20 mL of dichloromethane. After stirring at room temperature for 30 min, tris(ethyloxy) was added. Sodium borohydride (212 mg, 1 mmol) was added and the mixture was stirred at room temperature overnight. 50 ml of water was added to the reaction mixture, and dichloromethane was evaporated. The mixture was evaporated to ethyl acetate. The residue was purified by a sep. column chromatography, EtOAc (EtOAc: EtOAc: EtOAc) Phenyl]-{6-[5-(piperidin-4-ylamino)-1Η-σpyrrol-3-yl]-°|: σ sitin-4-ylindole-amine 262 (8 mg, Yellow solid), yield: 71.4%. MS m/z (ESI): 557 [M+1] NMR (400 MHz, CD30D-d: 5 10. 919 (s, 1H), 9. 684 (s, 1H), 8.533 (s, 1H) , 8.441 (d, J = 12Hz, 1H), 8.143 (d, J = 8. 4Hz, 1H), 8. 044 (s, 1H), 7. 740 (m, 2H), 7. 461 (br, 1H ), 7. 282 (m, 3H), 7. 179 (m, 1H), 6. 791 (s, 1H), 6. 452 (d, J = 20. 8Hz, 1H), 5.244 (s, 2H) , 3. 864 (s, 1H), 3.480 (m, 2H), 3.327 (br, 4H), 1.913 (br, 2H), 1.264 (br, 2H) Example 263 (R)-"3-Chloro-4 -(3-fluoro-oxy-oxy)-stupyl-glycidyl-2-ylmethyl-1 Η-oral ratio -3-yl)-salt 0 sit -4- group "I- amine

450 94389 201016683 在50 mL的燒瓶中’將[3-氯-4-(3-氟-苄氧基）-笨基] -[6-(1Η-吼略-3-基）-喹唑啉 _4_ 基]_胺 42(223 mg，〇.5 mmol)溶解於10 mL無水N，N-二曱基曱醯胺中，在冰浴條件下’冷卻至0 C ’加入氫化納（6 〇 mg，2. 5 mmo 1)，授拌 30分鐘後加入（S)-2-(2-氣乙基）環氧乙烷（80 mg，0. 75 mmol)，室溫下攪拌1小時反應完畢。反應液減壓下濃縮，得到的殘留物進一步藉由管柱層析法分離純化（二氯甲烧：曱醇=10 : 1)，得到本標題產物（R)一[3-氣-4-(3-氟〜苄氧基）-苯基]-[6-(1-環氧丙烷基—2-基甲基-lH-η比咯-3、 ©基）-喹唑啉-4-基]-胺263(40 mg，淡黃色固體），產率： 19. 32% ° MS m/z (ESI) ： 515[M+1] *11 NMR (400 MHz, CD30D-d〇： 5 9.710 (s, 1H), 8.552 (s, 1H), 8.056 (s, 1H), 8.026 (s, 1H), 7.762 (d, J=8. 8Hz, 1H), 7.709 (d, J=9.2Hz, 1H), 7.484 (m, 2H), 7.323 (m, 3H), 7.192 (m, 1H), 933 (s，1H)，6.696 (s, 1H), 5.274 φ (s, 2H), 4.989 (m, 1H), 4.518 (m, 1H), 4.336 (m, 1H), 4.186 (m, 2H), 2.666 (m, 1H), 2.364 (m, 2H) 實施例264 1 - (3-{4-[3-氯-4-(3-氟-苄氩某笨胺基L·哇《*坐被- ft-羊丄 -g比略_1~~基）-3-((3S，5R)-3, 5-二甲派卩井- 甚)-丙二贬 451 94389 201016683450 94389 201016683 '[3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-吼-3-yl)-quinazoline in a 50 mL flask 4_ base]_amine 42 (223 mg, 〇.5 mmol) was dissolved in 10 mL of anhydrous N,N-didecyl decylamine, and cooled to 0 C in ice bath to add sodium hydride (6 〇mg) 2, 5 mmo 1), after 30 minutes of mixing, (S)-2-(2-ethylethyl)oxirane (80 mg, 0.75 mmol) was added, and the reaction was completed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified and purified by column chromatography (dichloromethane: decyl alcohol = 10:1) to give the title product (R)-[3- -4- (3-Fluoro-benzyloxy)-phenyl]-[6-(1-epoxypropenyl-2-ylmethyl-lH-npyrrole-3, yl)-quinazolin-4-yl ]-amine 263 (40 mg, pale yellow solid), Yield: 19.32%, MS m/z (ESI): 515 [M+1] *11 NMR (400 MHz, CD30D-d〇: 5 9.710 ( s, 1H), 8.552 (s, 1H), 8.056 (s, 1H), 8.026 (s, 1H), 7.762 (d, J=8. 8Hz, 1H), 7.709 (d, J=9.2Hz, 1H) , 7.484 (m, 2H), 7.323 (m, 3H), 7.192 (m, 1H), 933 (s, 1H), 6.696 (s, 1H), 5.274 φ (s, 2H), 4.989 (m, 1H) , 4.518 (m, 1H), 4.336 (m, 1H), 4.186 (m, 2H), 2.666 (m, 1H), 2.364 (m, 2H) Example 264 1 - (3-{4-[3-chloro -4-(3-fluoro-benzyl argon a certain amino group L · wow "* sitting quilt - ft-羊羊-g ratio slightly _1 ~ ~ base) -3- ((3S, 5R)-3, 5-二甲派卩井- 甚)-丙二贬451 94389 201016683

mg，0. 6 mmol，ABCR)溶 C2S,6R)-2,6-Mg, 0.6 mmol, ABCR) dissolved C2S, 6R)-2,6-

’攪拌下依次加入2 mL 1,2-二氯乙 A基）-苯基]-[6-(1-環氧乙基甲基琳-4-基]-胺 I87a(200 mg，0. 4 mmol) ’混合液在65它加熱回流過夜。反應液在減壓下濃縮，得到的殘留物藉由矽膠管柱層析法分離純化（二氯曱 .烷：甲醇=1〇 : 1)，得到本標題產物1一（3-{4-[3-氯一4-(3-氟-苄氧基）-苯胺基]-啥唾淋-6_基丨_n比略__1_基）一3_ ((3S，5R)-3，5-—甲基_〇底卩井-1-基）-丙—2-醇 264(211 mg， ❿黃色固體），產率：86. 1°/〇。 MS m/z (ESI) ： 616[M+1] 'H NMR(400 MHz , DMS0-c?6)： 5 9.70 (s, 1H), 8.55 (s, 1H)’ 8.50 (s, 1H)’ 8.05 (m，1H)，8. 02 (m，ih)，7·73 (m，2H)，7· 52 (m，2H)，7· 34 (m，3H)，7. 19 (m，1H)，7. 01 (s，1H)，6.72 (s，1H)，5.27 (s，2H)，4.91 (br，1H)， 4.03 (m, 3H), 2.87 (br, 2H), 2.77 (m, 2H), 2.22 (m, 2H), 1.61 (m, 2H), 0.96 (t, J = 6Hz, 6H) 94389 452 201016683 實施例265 氧基）-苯胺基1-崦地今τ 1 一吡咯-1 二暴)~ZLj~:=^iA^A-哌啡-卜某)-λ酾'2 mL of 1,2-dichloroethyl A)-phenyl]-[6-(1-epoxyethylmethyl-lin-4-yl)-amine I87a (200 mg, 0.4) was added in sequence. The mixture was heated to reflux overnight at 65. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified and purified by hexane column chromatography (dichloromethane:methanol = 1 : 1 ). The title product 1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-anilino]-indenyl-6-ylindole_n is slightly __1_yl) 3_((3S,5R)-3,5-methyl- 〇卩 -1--1-yl)-propan-2-ol 264 (211 mg, ❿ yellow solid), yield: 86. 1 ° / 〇 MS m/z (ESI): 616 [M+1] 'H NMR (400 MHz, DMS0-c?6): 5 9.70 (s, 1H), 8.55 (s, 1H)' 8.50 (s, 1H) ' 8.05 (m,1H), 8. 02 (m,ih),7·73 (m,2H),7· 52 (m,2H),7· 34 (m,3H),7. 19 (m, 1H), 7. 01 (s, 1H), 6.72 (s, 1H), 5.27 (s, 2H), 4.91 (br, 1H), 4.03 (m, 3H), 2.87 (br, 2H), 2.77 (m , 2H), 2.22 (m, 2H), 1.61 (m, 2H), 0.96 (t, J = 6Hz, 6H) 94389 452 201016683 Example 265 oxy)-anilino 1-indole τ 1 pyrrole- 1 二暴)~ZLj~:=^iA^A-piper - BU a) -λ Shai

FF

265265

第一步 2-乳_l-(4-J衣丙基_π底哄_1 —基）_乙酿^The first step 2-milk _l-(4-J propyl _ π 哄 — _1 — base)

0 將卜環丙基''哌哄252b(l g，7.94 mm〇i)溶於1〇 mL 二氯甲烷中，溶液在丙酮_乾冰浴下冷卻至_78。〇，攪拌下加入lmL三乙胺和氯乙醯氯（12g，119 mm〇1)，維持此溫度攪拌40分鐘反應完畢。反應液中加入5〇此水，二氯甲烷萃取（50 mLx3)，合併的有機相依次經由水，飽和氯化鈉溶液洗滌，無水硫酸鈉脫水，過濾，減壓下濃縮，得到 2_氯-卜（4-環丙基-哌畊—1-基）一乙酮265a(n5 mg，白色固體），產物不經分離直接進行下一步反應。 94389 453 201016683 MS m/z (ESI) ： 203[M+1] 第二步 2-(3-{4-[3-氯-4-(3-氟-苄氧基卜苯胺基卜喹唑啉_6_基} 比嘻-1-基）-1-(4-環丙基-娘π井-1-基）_乙酮在50mL的燒瓶中，將[3-氯一 4-(3_氟_苄氧基）_苯基] -[6-(1Η-吡咯-3-基）-喹唑啉-4-基]-胺 42(257 mg，〇.58 mmol)溶於10 mL無水N，N-二曱基甲醯胺中，在冰浴條件下’冷卻至0C，加入氫化鈉（69 mg，2.9 mmol)，攪拌3〇 _分鐘後加入2-氯-1-(4-環丙基-哌畊―丨―基乙酮265a (140 mg，0· 69 mmol)，室溫下攪拌i小時反應完畢。反應液加入50mL水，用乙酸乙酯萃取（5〇mLx3)，合併的有機相經由無水硫酸鈉脫水’過濾，減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化（二氯甲烷：甲醇 -=4〇 : 1) ’得到本標題產物2-(3-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-喹唑啉-6-基卜吼咯-丨—基）—卜（4_環丙基__哌哄-1-基）-乙酮265 (148 mg，黃色固體），產率：35.2%。 ❹ MS m/z (ESI) : 611[M+1] NMRC400 MHz , DMS0-d5): δ 9. 74 (s, 1Η), 8. 65 (s, 1H) 8.53(s, 1H), 8.37(s, 1H), 8. 04 (m, 2H), 7.76 (m, 2H), 7. 60 (m, 1H), 7. 49 (m, 1H), 7. 32 (m, 4H), 7. 19 (m, 1H), 5.27 (s, 2H), 4.96 (s, 2H), 3.45 (br, 4H), 2.57 (br! 4H), 1.64 (m，1H), 0.45 (m, 2H)，0.35 (m，2H) 實施例266 4-{4-[j-氯-4-(3-氟-苄氧基）-笨胺葚1-喹唑啾 94389 454 201016683 -1Η-°比洛-2-甲酸- λ胺某-乙基）-醯胺0 Cyclopropyl propyl ''piperazine 252b (1 g, 7.94 mm 〇i) was dissolved in 1 mL of dichloromethane and the solution was cooled to _78 in acetone-dry ice bath. 〇, while stirring, add 1 mL of triethylamine and chloroacetic acid chloride (12 g, 119 mm 〇1), and stir at this temperature for 40 minutes to complete the reaction. 5 Torr of this water was added to the reaction mixture, and the mixture was extracted with methylene chloride (50 mL×3). The combined organic phases were washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced (4-cyclopropyl-piperidin-1-yl)-ethanone 265a (n5 mg, white solid). 94389 453 201016683 MS m/z (ESI): 203[M+1] Step 2 2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylaminoquinazoline _6_基} 嘻-1-yl)-1-(4-cyclopropyl-Nanxi-1-yl)-ethanone in a 50 mL flask, [3-chloro-4-(3_ Fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinazolin-4-yl]-amine 42 (257 mg, 〇.58 mmol) dissolved in 10 mL anhydrous N , N-dimercaptocaramine, 'cooled to 0C under ice bath conditions, sodium hydride (69 mg, 2.9 mmol) was added, stirred for 3 〇 _ min, then added 2-chloro-1-(4-cyclopropane Base-piperidine-hydrazine-ethyl ethyl ketone 265a (140 mg, 0·69 mmol), stirring at room temperature for 1 hour. The reaction mixture was added with 50 mL of water and extracted with ethyl acetate (5 〇mL×3), combined organic The residue was subjected to dehydration through anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified and purified by methylene chloride column chromatography (dichloromethane:methanol:=4:1). 3-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-anilino]-quinazoline-6-ylpyrrole-indole-yl)-b (4_cyclopropyl_ _piperazin-1-yl)-ethanone 265 (148 mg, yellow solid) Yield: 35.2% ❹ MS m/z (ESI): 611 [M+1] NMRC 400 MHz, DMS0-d5): δ 9. 74 (s, 1 Η), 8. 65 (s, 1H) 8.53 (s , 1H), 8.37(s, 1H), 8. 04 (m, 2H), 7.76 (m, 2H), 7. 60 (m, 1H), 7. 49 (m, 1H), 7. 32 (m , 4H), 7. 19 (m, 1H), 5.27 (s, 2H), 4.96 (s, 2H), 3.45 (br, 4H), 2.57 (br! 4H), 1.64 (m, 1H), 0.45 ( m, 2H), 0.35 (m, 2H) Example 266 4-{4-[j-chloro-4-(3-fluoro-benzyloxy)- succinimide 1- quinazolium 94389 454 201016683 -1Η- °Bilo-2-carboxylic acid-λ-amylamine-ethylamine-decylamine

266 將雙（2-侧氧基-3-噚唑烷基）次磷醯氯（191呢，0.75 mmol)溶於1〇 mL無水二氯甲烷中，攪拌下加入三乙胺（〇1 mL，0. 75 mmol)’室溫下攪拌15分鐘後，依次加入4_丨4_[3_ 氯-4-(3-氟-苄氧基）-苯胺基]-喹峻啉_6_基丨_111_吡咯 -2-甲酸 184g(244 mg，〇. 5 ramol)和 N*l*，N*l*-二乙基乙烷-1，2-二胺（58 mg，〇. 5 mmol)，室溫下攪拌1小時反應 _完畢。將反應液在減壓下濃縮，殘質中加入2〇1^水，用乙酸乙醋萃取（50 mLx3)’合併的有機相依次經由無水硫酸鈉脫水’過濾’減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化（二氯甲烷：曱醇=15 :丨），得到標題產物4-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基喹唑啉 6基}'-ΙΗ-0比洛-2-曱酸（2 -二乙胺基-乙基）-酿胺266 (115 mg，黃色固體），產率：39. 2%。 MS m/z (ESI) ： 587[M+1] 94389 455 201016683 Ή NMR(400 MHz , DMS0-c?6): 5 =11. 97 (s, 1H), 9.85 (s, 1H), 8.75 (s, 1H), 8.52 (s, 1H), 8.05 (m, 2H), 7.80 (m, 2H) 7.68 (s, 1H), 7.47 (m, 2H), 7.31 (m, 3H), 7.19 (m, 1H), 6.98(s, 1H), 6. 86 (s, 1H), 5. 27 (s, 2H), 3.62 (m, 2H), 3.33 (m, 2H), 3. 17 (m, 2H), 3. 05 (m, 2H), 1.12 (m, 6H) 實施例267 (4-胺基-哌啶-1-基）-(4-{4-「3-氣-4-(3-氟苄氧基）-笨胺基1 —喧口坐琳-6一基}-1{]_〇比口各-2-基）_甲酮266 Di-(2-oxo-3-oxazolidinyl)phosphinium chloride (191, 0.75 mmol) was dissolved in 1 mL of anhydrous dichloromethane, and triethylamine (〇1 mL, 0. 75 mmol) After stirring at room temperature for 15 minutes, 4_丨4_[3_chloro-4-(3-fluoro-benzyloxy)-anilino]-quinoline_6_ylindole_111 was added in sequence. _Pyrrol-2-carboxylic acid 184g (244 mg, 〇. 5 ramol) and N*l*, N*l*-diethylethane-1,2-diamine (58 mg, 〇. 5 mmol), room Stirring for 1 hour under temperature was completed. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. The product was further separated and purified by silica gel column chromatography (dichloromethane: decyl alcohol = 15 : hydr.) to give the title product 4-{4-[3-chloro-4-(3-fluoro-benzyloxy)- Anthracene quinazoline 6-yl}'- oxime-bipiro-2-decanoic acid (2-diethylamino-ethyl)-nitramine 266 (115 mg, yellow solid), yield: 39.2% . MS m/z (ESI): 587[M+1] 94389 455 201016683 NMR (400 MHz, DMS0-c?6): 5 = 11.97 (s, 1H), 9.85 (s, 1H), 8.75 ( s, 1H), 8.52 (s, 1H), 8.05 (m, 2H), 7.80 (m, 2H) 7.68 (s, 1H), 7.47 (m, 2H), 7.31 (m, 3H), 7.19 (m, 1H), 6.98(s, 1H), 6. 86 (s, 1H), 5. 27 (s, 2H), 3.62 (m, 2H), 3.33 (m, 2H), 3. 17 (m, 2H) , 3. 05 (m, 2H), 1.12 (m, 6H) Example 267 (4-Amino-piperidin-1-yl)-(4-{4-"3- gas-4-(3-fluoro) Benzyloxy)-phenylamino 1 - 喧口坐琳-6-基}-1{]_〇口各 each-2-yl) ketone

第一步 [1-(4-{4-[3-氯-4-(3-氟苄氧基）-苯胺基]-喹唑啉-6-基} 456 94389 201016683 -1Η-°比洛-2-羰基）-派咬-4-基]-胺基曱酸第三丁醋將雙（2-侧氧基-3-噚唑烷基）次磷醯氣（191呢，〇75 mmol)溶於10 mL無水二氣甲烷中，攪拌下加入三乙胺（〇. i mL，0. 75 mmol)’室溫下攪拌15分鐘後，依次加入4_{4—[3一氯-4-(3-氟-苄氧基）-苯胺基]-喹唑琳—6_基}_111_11比洛_2_ 甲酸184g(244 mg ’ 〇· 5 mmol)和0辰嘴>4-基-胺基甲酸第三丁酉旨（10 0 mg ’ 0. 5 mmo 1)’室溫下授拌1小時反應完畢。將反應液在減壓下濃縮，殘質中加入2 〇 mL水，用乙酸乙酯萃取（50 mLx3) ’合併的有機相依次經由無水硫酸納脫醫 …、水，過濾，減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化（二氯甲烧：曱醇=30 : 1 )，得到標題產物[1-(4-{4-[3-氯-4-(3-氟苄氧基）-苯胺基]-啥嗤琳_6_ 基} -1H-吼嘻-2-幾基）-娘《定-4-基]-胺基甲酸第三丁酯 267a(225 mg，黃色固體），產率：67.2%。 MS ra/z (ESI) ： 671[M+1] 第二步 ⑩（4-胺基-e底咬-1-基）-(4-{4-[3 -氯- 4-(3 -氟苄氧基）-苯胺基]-喹0坐琳-6-基}-111-0比咯-2-基）-曱明將[1-(4-{4-[3-氯-4-(3-敗苄氧基）-苯胺基]-啥β坐琳 -6-基}-111-吡咯-2-羰基）-派啶-4-基]-胺基曱酸第三丁酯 267a(215 mg，0.32 mmol)溶於 10 mL 二氣甲烧中，槐拌下加入10 mL三氟乙酸，室溫下攪拌2小時反應完畢。反應液在減壓下濃縮，加入30 mL飽和碳酸氫鈉溶液，乙酸乙酯萃取（50 mLx3)，合併的有機相依次經由飽和氯化鈉溶 457 94389 201016683 液洗滌，無水硫酸鈉脫水，過濾，減壓下濃縮，得到的殘留物藉由鹼性氧化鋁管柱層析法分離純化（二氯甲烷：甲醇 =30 : 1) ’得到本標題產物（4-胺基-哌啶-1-基）_(4__丨4_[3_ 氣-4-(3-氟苄氧基）-苯胺基]-喹唑啉_6_基}_1Η—β比咯一^ 基）-甲酮267(125 mg，黃色固體）’產率：65. 4%。 MS m/z (ESI) ： 571[M+1] ]H NMRC400 MHz, MS0-d6): δ 11. 78 (s, 1H), 9. 67 (s 1H) 8.63 (s，1H)’ 8.52 (s，1H)，8.18 (s，1H)，8.03 (d ❹ J = 2.4Hz，1H)，7.75(m，2H)7.60(m，1H)，7.50(m，1H): 7. 31 (m, 3H), 7. 19 (m, 1H), 7. 08 (s, 1H), 5. 27 (s, 2H)! 4.38(m, 2H), 3. 59 (m, 1H), 3. 14 (m, 2H), 1.84(m, 2H) 1.40 (m, 2H) ’ ’ • 實施例268 (31?)-1二13-(3-_11_-[3-氧基卜喹崦淋-6-棊丨比嘻-1-基）-2-經基-丙某ι_η比味梭First step [1-(4-{4-[3-chloro-4-(3-fluorobenzyloxy)-anilino]-quinazolin-6-yl} 456 94389 201016683 -1Η-°Bilo - 2-carbonyl)-pyrylene-4-yl]-amino decanoic acid tert-butyl vinegar dissolves bis(2-oxo-3-oxazolidinyl)phosphorus (191, 〇75 mmol) In 10 mL of anhydrous di-methane, add triethylamine (〇. i mL, 0.75 mmol) under stirring for 15 minutes at room temperature, then add 4_{4-[3-chloro-4-(3) -Fluoro-benzyloxy)-anilino]-quinazoline-6-yl}_111_11Bilo_2_ formic acid 184g (244 mg ' 〇· 5 mmol) and 0 嘴 &> 4-yl-aminocarboxylic acid The reaction of the three Dingzhi (10 0 mg '0.5 mm 1) was allowed to stand for 1 hour at room temperature. The reaction mixture was concentrated under reduced pressure. EtOAc EtOAc (EtOAc m. The residue obtained was further separated and purified by silica gel column chromatography (dichloromethane: decyl alcohol = 30:1) to give the title product [1-(4-{4-[3-chloro-4-(3) -fluorobenzyloxy)-anilino]-indolyl _6_yl} -1H-indole-2-yl)-nivine "di-4-yl]-carbamic acid tert-butyl ester 267a (225 mg , yellow solid), yield: 67.2%. MS ra/z (ESI): 671 [M+1] Step 2 10 (4-amino-e-Bottom-l-yl)-(4-{4-[3-chloro-4-(3-fluoro) Benzyloxy)-anilino]-quinoquinone-6-yl-1-yl}-111-0pyr-2-yl)-曱明[1-(4-{4-[3-chloro-4-() 3- Benzyloxy)-anilino]-啥β-shen-6-yl}-111-pyrrole-2-carbonyl)-pyridin-4-yl]-amino decanoic acid tert-butyl 267a (215 Mg, 0.32 mmol) was dissolved in 10 mL of methane toluene, and 10 mL of trifluoroacetic acid was added under stirring, and the reaction was completed by stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc) (EtOAc (EtOAc) Concentration under reduced pressure, the residue obtained was purified by EtOAc EtOAc EtOAc EtOAc )_(4__丨4_[3_ gas-4-(3-fluorobenzyloxy)-anilino]-quinazoline_6_yl}_1Η-βpyr-yl)-methanone 267 (125 mg , yield: 65.4%. MS m/z (ESI): 571[M+1]]H NMRC 400 MHz, MS0-d6): δ 11.78 (s, 1H), 9. 67 (s 1H) 8.63 (s,1H)' 8.52 ( s, 1H), 8.18 (s, 1H), 8.03 (d ❹ J = 2.4 Hz, 1H), 7.75 (m, 2H) 7.60 (m, 1H), 7.50 (m, 1H): 7. 31 (m, 3H), 7. 19 (m, 1H), 7. 08 (s, 1H), 5. 27 (s, 2H)! 4.38(m, 2H), 3. 59 (m, 1H), 3. 14 ( m, 2H), 1.84 (m, 2H) 1.40 (m, 2H) ' ' • Example 268 (31?)-1 2 13-(3-_11_-[3-oxybuquinoline-6-棊丨比嘻-1-yl)-2-carbyl-propyl ι_η

甲醇中，攪拌下加入[3-氯-4-(3-氟-苄氧基）一苯基]一[6- 94389 458 201016683 (1-環氧乙基甲基-111-11比嘻_3-基）-啥0坐琳_4-基]-胺187& (100 mg，0. 2 mmol)，混合液加熱回流3小時後反應完畢。反應液在減壓下濃縮，得到的殘留物藉由碎膠管柱層析法分離純化（二氯甲烷：甲醇=10 : 1)，得到本標題產物 (31〇-1-[3-(3-{4_[3-氣-4-(3-氟节氧基）-苯胺基]-啥嗤琳-6-基}-0比嘻-1-基）-2-經基-丙基]比咯烧—3-醇268 (85 mg，黃色固體），產率：43%。 MS m/z (ESI) ： 588[M+1] !H NMRC400 MHz , MS0-d6): δ 10. 026 (s, 1H), 8. 760 (s, 參 1H)，8.491 (s，1H)，8. 124 (s，1H)，8.034 (s，1H)，7.863 (s, 1H), 7.699 (s, 1H), 7.510 (s, 2H), 7.263 (m, 3H), 6.874 (s, 1H), 6.748 (s, 1H), 5. 267 (s, 2H), 4. 252 (s, ' 1H), 3. 981 (m, 2H), 3. 387 (s, 2H), 2. 642 (s, 2H), 2. 008 • (s, 2H), 1.655 (s, 2H) 實施例269 2-(3_{4-「3 -氣-4-(3 -氟-节氣基）-笨胺基]-喧°坐啦-fi-莘} ❹比洛基）洛院-1-基-乙基）Ί—酿胺[3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-94389 458 201016683 (1-epoxyethylmethyl-111-11 than 嘻3) was added to methanol with stirring. -Base) - 啥0 琳琳_4-yl]-amine 187 & (100 mg, 0.2 mmol), and the mixture was heated to reflux for 3 hours and then the reaction was completed. The reaction mixture was concentrated under reduced pressure. EtOAc mjjjjjjj {4_[3-Gas-4-(3-fluoro-oxy)-anilino]-indolyl-6-yl}-0-pyridin-1-yl)-2-yl-propyl]pyr - 3-Alcohol 268 (85 mg, yellow solid), yield: 43%. MS m/z (ESI): 588[M+1] <RTI ID=0.0> , 1H), 8. 760 (s, Ref. 1H), 8.491 (s, 1H), 8. 124 (s, 1H), 8.034 (s, 1H), 7.863 (s, 1H), 7.699 (s, 1H) , 7.510 (s, 2H), 7.263 (m, 3H), 6.874 (s, 1H), 6.748 (s, 1H), 5. 267 (s, 2H), 4. 252 (s, ' 1H), 3. 981 (m, 2H), 3. 387 (s, 2H), 2. 642 (s, 2H), 2. 008 • (s, 2H), 1.655 (s, 2H) Example 269 2-(3_{4 - "3-gas-4-(3-fluoro-anthraquinone)-stupidylamino]-喧°坐啦-fi-莘} ❹比洛基)洛院-1-基-ethyl)Ί- amine

459 94389 201016683459 94389 201016683

nh2第一步Nh2 first step

第一步參 2-氯-N-(2-吡咯烷-i-基-乙基）-乙醯胺 2 0比嘻燒-1-基-乙胺（228 mg，2 mmol)溶於15 mL四氫呋喃中，在丙酮-乾冰浴冷卻下冷卻至_78〇c，攪拌下依次加入二乙胺（〇. 83 mL，6 mmol)和氯乙醯氯（〇. 48 ，6 mmol)，混合液在-78°C下攪拌1小時後反應完畢。將反應液在減壓下濃縮，得到2-氯-N-(2-吡咯烷-卜基-乙基）_乙醯胺269a(290 mg ’黃色固體），產物不經分離直接進行下 €> —步反應。 MS m/z (ESI) ： 291[M+1] 第二步 2-（3-{4-[3-氯-4-(3-氟-苄氧基）—笨胺基]-喹0坐琳_6_基} -0比洛-1-基）比略燒-1-基-乙基）_乙醯胺將[3-氯-4-(3-氟-苄氧基）-苯基]-[6-(iH-rr比咯_3〜基） -喹唑琳-4-基]-胺42(177 mg，〇· 4 mmol)溶解於1〇 mL無水N，N-二甲基曱醢胺中，在冰浴條件下，冷卻至〇亡，加 94389 460 201016683 入氫化鈉（112 mg，2. 8 mmol)，攪拌30分鐘後加入2-氯 -N-(2-吡咯烷-1-基-乙基）_乙醯胺269a(290 mg)，室溫下攪拌1小時反應完畢《將反應液在減壓下濃縮，殘質經由水洗滌，二氣甲烷萃取（100 mLx3)，合併的有機相經由無水硫酸鈉脫水，過濾，減壓下濃縮，得到的殘留物藉由管挺層析法進一步分離純化（二氯曱烷：曱醇=5〇 : 1 )，得到 2-（3-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-噎η坐琳式} -吡咯-1-基）-Ν-(2-吡咯烷-卜基-乙基）-乙醯胺269(45 ❿mg ’黃色固體），產率：18. 8%。 MS m/z (ESI) ： 599[M+1] 'H NMR(400 MHz , DMS0-dl5) : 5 9. 722 (s, 1H), 8.563 (d /=1. 6Hz，1H)，8. 504 (s，1H)，8. 051 (s，1H)，7. 766 (m 1H)，7.713 (d，/=8. 8Hz，1H)，7.474 (m，1H)，7.344 (m’ ' 3H)，7. 190 (m，1H), 6. 868 (m，2H)，6. 687 (s，iH)，6 6扣 (s, 1H)，5.273 (s，2H)，4.622 (s，2H)，3.607 (m，2H) 3. 243 (m，2H)，2. 191 (s，2H)，1. 765 (s，2H)，i. 679 (s _ 4H) ’ 實施例270 _(3-丨4-「3-氣-4-〔3-氟-苄氣基）-笨胺^11^逢啉-^：^^ °比咯-1-基）-乙腈The first step is as follows: 2-chloro-N-(2-pyrrolidin-i-yl-ethyl)-acetamide 20 is more soluble in 15 mL than terpine-1-yl-ethylamine (228 mg, 2 mmol). In tetrahydrofuran, cool to _78 〇c with cooling in an acetone-dry ice bath, and then add diethylamine (〇. 83 mL, 6 mmol) and chloroethyl chlorobenzene (〇. 48, 6 mmol) in a mixture. After stirring at -78 ° C for 1 hour, the reaction was completed. The reaction solution was concentrated under reduced pressure to give 2-chloro-N-(2-pyrrolidine-diethyl-ethyl)-acetamide 269a (290 mg of <RTIgt; ; - Step reaction. MS m/z (ESI): 291 [M+1]. Step 2 2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quino Lin_6_yl}-0bi-l-yl)-pyrrol-1-yl-ethyl)-acetamido[3-chloro-4-(3-fluoro-benzyloxy)-phenyl ]-[6-(iH-rr is more than _3~yl)-quinazoline-4-yl]-amine 42 (177 mg, 〇· 4 mmol) dissolved in 1 mL of anhydrous N,N-dimethyl In the guanamine, under ice bath conditions, cool to death, add 94389 460 201016683 to sodium hydride (112 mg, 2. 8 mmol), stir for 30 minutes and then add 2-chloro-N-(2-pyrrolidine- 1-yl-ethyl)-acetamidamine 269a (290 mg), stirred at room temperature for 1 hour. The reaction was completed. The reaction mixture was concentrated under reduced pressure and the residue was washed with water. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and evaporated, evaporated, evaporated, m. m. m m m m m m m m m m m m m m m m m m m m m m m m 3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-anilino]-噎η sitin}-pyrrol-1-yl)-indole-(2-pyrrolidine-buji 8%。 Ethyl)-acetamide 269 (45 ❿ mg 'yellow solid), yield: 18.8%. MS m/z (ESI): </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; 504 (s, 1H), 8. 051 (s, 1H), 7. 766 (m 1H), 7.713 (d, /=8. 8Hz, 1H), 7.474 (m, 1H), 7.344 (m' ' 3H ), 7. 190 (m, 1H), 6. 868 (m, 2H), 6. 687 (s, iH), 6 6 deductions (s, 1H), 5.273 (s, 2H), 4.622 (s, 2H) ), 3.607 (m, 2H) 3. 243 (m, 2H), 2. 191 (s, 2H), 1. 765 (s, 2H), i. 679 (s _ 4H) ' Example 270 _(3 -丨4-"3-Gas-4-[3-fluoro-benzyl)-stupylamine^11^, porphyrin-^:^^ °,rho-1-yl)-acetonitrile

94389 270 461 20101668394389 270 461 201016683

270270

Cl 在50 mL的燒瓶中，將[3-氯-4-(3_氟-苄氧基）_苯基] -[6-(1Η-吡咯-3-基）-喹唑啉-4-基]-胺 42(400 mg，0.9 mmol)溶解於10 mL無水N，N-二曱基曱醯胺中，在冰洛條件下’冷卻至0(3’加入氫化納（6〇111运，1.5111111〇1)，搜掉 ® 30分鐘後加入氯-乙腈（82 mg，1· 08 mmol )，室溫下攪拌1 小時反應完畢。反應液減壓下濃縮，得到的殘留物進—步藉由管柱層析法分離純化（二氯曱烷：曱醇=40 : 1 )，得到本標題產物（3_{4-[3-氯-4- (3 -敦-节氧基）-苯胺基]-唛β生琳-6-基丨比洛-I-基）-乙腈270 (70 mg，淡黃色固體），產率：16%。 MS m/z (ESI) ： 484[M+] φ !H NMR(400 MHz , DMSO-d^) ： ά 9. 67 (s, 1H), 8. 5 (s, 2H), 8.0 (s，2H)，7.7 (s，1H)，7.69 (m，1H)，7.5 (m，2H)， 7.36 (m，3H)，7.2 (m，1H)，6.93 (m，1H)，6.60 (s，iH)， 5.34 (s, 2H), 5.27 (s, 2H) 實施例271 l-(3-M-「3-氣-4-(3-氟-苄氣篡v笨胺基]-喹唑啉 -吡咯-1-基）-3-「（2-羥基-乙篡V甲基-胺基]-丙-2-醇— 462 94389 201016683Cl [3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinazolin-4-yl in a 50 mL flask ]-Amine 42 (400 mg, 0.9 mmol) was dissolved in 10 mL of anhydrous N,N-didecyl decylamine and cooled to 0 (3' in the ice-cold condition (6 〇 111 liters, 1.5111111) 〇1), after searching for 30 minutes, add chloro-acetonitrile (82 mg, 1.08 mmol), stir at room temperature for 1 hour, complete the reaction. The reaction solution is concentrated under reduced pressure, and the residue obtained is taken in a tube. Separation and purification by column chromatography (dichloromethane: decyl alcohol = 40:1) gave the title product (3_{4-[3-chloro-4-(3-di- hydroxy)-phenylamino]-唛β生琳-6-ylindole-I-yl)-acetonitrile 270 (70 mg, pale yellow solid), yield: 16%. MS m/z (ESI): 484[M+] φ !H NMR (400 MHz , DMSO-d^) : ά 9. 67 (s, 1H), 8. 5 (s, 2H), 8.0 (s, 2H), 7.7 (s, 1H), 7.69 (m, 1H), 7.5 (m, 2H), 7.36 (m, 3H), 7.2 (m, 1H), 6.93 (m, 1H), 6.60 (s, iH), 5.34 (s, 2H), 5.27 (s, 2H) 271 l-(3-M-"3-Gas-4-(3-fluoro-benzyl gas oxime-m-amino)-quinazoline-pyrrol-1-yl)-3-"(2- Yl - methyl acetate usurp V - amino] - propan-2-ol - 462 94389201016683

第一步 187aFirst step 187a

Η〇、^Ν，γ^Ν-丨OHΗ〇, ^Ν, γ^Ν-丨OH

鲁 ❹ 2-曱胺基-乙醇（22.5 mg ’ 0.3 mmol ’ Aldrich)溶解於 10mL甲醇中，攪拌下加入[3 —氯—4 一（3_氟_苄氧基）_苯基卜 [6-(1-環氧乙基曱基_1H一吡咯_3__基）_喹唑啉_4一基]-胺 187a( 150 mg，〇. 3 mmol)，混合液加熱回流過夜。反應液在減壓下濃縮’得到的殘留物藉由石夕膠管柱層析法分離純化（二氣甲烧：甲醇=10:1)，得到卜（3一{4_[3—氯_4_(3_ 氟-苄氧基）-苯胺基]-喹唑啉-6〜基卜吡咯― 減-乙基）-甲基-胺基]-丙—2_醇271⑽吨，黃色固體），產率：81. 2%。、 MS m/z (ESI) ： 576[M+1] 'HNMR(400 MHz,DMSO^)：,9.67(S) 1Ηχ ^ ^ 8.〇(s，2H), 7.7(s，1H), 7.69(m，1H), 7 5(m 2H), 7.36〇n，3H)，7.2〇n，1H)，6.93(m，1H) 66〇(s ih)， 5.27(S’2H)，4.9(S，1H)，4.44(m，1H)，4.G7(m’iH)， 3.87 U，2H)，3.49 (m，2H)，2.49 (m，2H)，2·32 (d， J=5.6Hz， 2H)， 2.26 (s， 3H) 94389 463 201016683 實施例272 1-(3-(1γ_Ι3-4Κ3-氟氧某笼胺基]-喹唑啾-β-某1 一吡咯士-基）-·1ιί!ζ^§Αι_4~·基-哌啶基）-丙-2-生R&D 2-nonylamino-ethanol (22.5 mg '0.3 mmol 'Aldrich) was dissolved in 10 mL of methanol and [3-chloro-4-(3-fluoro-benzyloxy)-phenyl b[6- (1-Epoxyethyl indenyl-1H-pyrrole_3__yl)-quinazoline-4-yl]-amine 187a (150 mg, EtOAc. 3 mmol). The reaction solution was concentrated under reduced pressure. The obtained residue was purified and purified by chromatography on silica gel column chromatography (di-methane: methanol = 10:1) to give b (3 -{4_[3-chloro_4_( 3_Fluoro-benzyloxy)-anilino]-quinazoline-6-ylpyrrole-min-ethyl)-methyl-amino]-propan-2-ol 271 (10) ton, yellow solid), yield: 81. 2%. , MS m/z (ESI): 576 [M+1] 'HNMR (400 MHz, DMSO^):, 9.67 (S) 1 Ηχ ^ ^ 8. 〇 (s, 2H), 7.7 (s, 1H), 7.69 (m,1H), 7 5(m 2H), 7.36〇n,3H), 7.2〇n,1H), 6.93(m,1H) 66〇(s ih), 5.27(S'2H),4.9(S ,1H), 4.44(m,1H),4.G7(m'iH), 3.87 U,2H), 3.49 (m,2H), 2.49 (m,2H),2·32 (d, J=5.6Hz , 2H), 2.26 (s, 3H) 94389 463 201016683 Example 272 1-(3-(1γ_Ι3-4Κ3-fluorooxyl-carboxamino)-quinazolium-β-一一一咯尔-基)-· 1ιί!ζ^§Αι_4~·yl-piperidinyl)-propan-2-sheng

1-(3-{4-[3-氣-4-(3-氟-苄氧基）_苯胺基]-喹唑啉_6_基} -吡咯-1-基）-3-(4-嗎啉_4_基-哌啶—卜基卜丙^一醇 φ 4一（卜曱基—哌啶-4-基）-嗎啉（54. 8 mg, 0.32 mmol， Aldrich)溶解於1〇 mL甲醇中，攪拌下加入[3_氯一4_(3_ 氟-苄氧基）-苯基]-[6-(1-環氧乙基甲基_1Η_σ比咯_3_基戶喹唑啉-4-基]-胺187a(160 mg，0.32 mmol)，混合液加熱回流過夜。反應液在減壓下濃縮，得到的殘留物藉由石夕膠管柱層析法分離純化（二氯曱提：甲醇=1〇 : 1 )，得到本標題產物1-(3-{4-[3-氯-4-(3-氟-苄氧基苯胺基]-喹唑嚇 6基} - °比洛-1基）3 ( 4.~嗎琳—4 —基—旅咬-1 -基）__兩 -2-醇 272 (123 mg ’ 黃色固體），產率：57.4%。 943S9 464 201016683 MS m/z (ESI) ： 671[M+1] NMRC400 MHz , DMS0-J6): <5 9. 67 (s, 1H), 8. 5 (s, 2H), 8.0 (s, 2H), 7.7 (s, 1H), 7.69 (m, 1H), 7.5 (m, 2H), 7.36 (m, 3H), 7.2 (m, 1H), 6.93 (m, 1H), 6.60 (s, 1H), 5.27 (s, 2H), 4.9 (s, 1H), 4.05 (m, 1H), 3.89 (m, 2H), 3.54 (m, 4H), 2.88 (m, 2H), 2.42 (S, 4H), 2.21 (t, J=4.8, 3H), 2.08(t，J = 10.8，1H), 1.95(t，J = 10.4, 2H)， 1. 72 (d, J = ll. 2, 2H), 1. 42 (m, 2H) 實施例273 ❹「3 -氯- 4- (3 -氟-辛氧基）-笨基1-(3 -乙基-環氧丙院 -3-基甲基）-1Η-吡咯-3-基1-喹唑啉-4-基卜胺1-(3-{4-[3-Ga-4-(3-fluoro-benzyloxy)-anilino]-quinazoline-6-yl}-pyrrol-1-yl)-3-(4- Morpholine_4_yl-piperidine-bipip-propanol φ 4-(b-yl-piperidin-4-yl)-morpholine (54. 8 mg, 0.32 mmol, Aldrich) was dissolved in 1 mL of methanol Add [3_chloro-4_(3_fluoro-benzyloxy)-phenyl]-[6-(1-epoxyethylmethyl-1Η_σ比咯_3_ phenyl quinazoline-4) with stirring -Alkyl--amine 187a (160 mg, 0.32 mmol), the mixture was heated and refluxed overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified and purified by chromatography. =1〇: 1), the title product 1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxyanilino)-quinazoyl 6-yl}- °Bilo-1 was obtained. Base) 3 ( 4.~ 琳琳 - 4 - yl-Brigade bite - 1 - base) __ 2-2-alcohol 272 (123 mg 'yellow solid), yield: 57.4%. 943S9 464 201016683 MS m/z (ESI): 671[M+1] NMRC400 MHz, DMS0-J6): <5 9. 67 (s, 1H), 8. 5 (s, 2H), 8.0 (s, 2H), 7.7 (s, 1H), 7.69 (m, 1H), 7.5 (m, 2H), 7.36 (m, 3H), 7.2 (m, 1H), 6.93 (m, 1H), 6.60 (s, 1H), 5.27 (s, 2H) ), 4.9 (s, 1H), 4.05 (m , 1H), 3.89 (m, 2H), 3.54 (m, 4H), 2.88 (m, 2H), 2.42 (S, 4H), 2.21 (t, J=4.8, 3H), 2.08(t,J = 10.8 , 1H), 1.95 (t, J = 10.4, 2H), 1. 72 (d, J = ll. 2, 2H), 1. 42 (m, 2H) Example 273 ❹ "3 - chloro- 4- ( 3-fluoro-octyloxy)-phenyl 1-(3-ethyl-epoxypropyl-3-ylmethyl)-1Η-pyrrol-3-yl-1-quinazolin-4-ylpamine

第一步 465 94389 201016683 甲磺酸（3-乙基-環氧丙烷一3_基）甲酯將（3-乙基-環氧丙烷-3-基）-曱醇（580 mg，5 mmol) 溶於15 mL二氣甲烷中，攪拌下加入三乙胺（758呢，7. 6 mmol) ’將反應液在冰浴下冷卻至，逐漸加入甲磺醯氯 (687 mg ’ 6 mmol)，室溫下攪拌3〇分鐘，反應完畢。將反應液在減壓下濃縮’加入2〇 mL水，乙酸乙酯萃取（4〇 mL x3)，合併的有機相依次經由飽和氣化鈉溶液洗滌，無水硫酸鈉脫水，過濾，減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化（二氯甲烷：曱醇=4〇 : 1 )，得到甲磺酸（3-乙基-環氧丙烷一3_基）甲酯273a (945 mg，無色油狀液體），產率：97.4%。 MS m/z (ESI) ： 195[M+1] 第二步 '[3_氯_4-(3_氟_苄氧基）_苯基]-{6-[l-(3_乙基-環氧丙烷 - 3-基曱基）-1Η_ο比略-3-基]-啥〇坐淋_4-基}-胺在50 mL的燒瓶中，將[3-氯-4-(3-氟-苄氧基）-苯基] ❹-[6-(1Η-吡咯-3-基）-喹唑啉-4-基]-胺 42(223 mg，〇.5 mmol)溶解於10 mL無水N，N-二甲基曱醯胺中，在冰浴條件下，冷卻至0C，加入風化納（6〇 mg，2.5 mmo 1)，授拌 30分鐘後加入曱石黃酸（3-乙基-環氧丙烧_3_基）甲酯273a (145 mg，0.75 mmol)，室溫下攪拌i小時反應完畢。反應液加入20mL水，乙酸乙酯萃取（40mLx3)，合併的有機相依次經由飽和氯化納溶液洗務’無水硫酸鈉脫水，過渡，減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分 94389 466 201016683 離純化（二氯曱烷：曱醇=40 : 1)，得到本標題產物[3 一氯 -4-(3-氟-苄氧基）—苯基]-{6-[ 1-(3-乙基-環氧丙烷_3一基甲基）-1Η-吡咯-3-基]-喹唑啉-4-基}-胺273(125 mg，淡黃色固體），產率：46. 1%。 MS m/z (ESI) ： 543[M+1] Ή NMR(400 MHz , DMS0-J6): =9. 68 (s, 1H), 8.53 (s, 1H), 8.50(s, 1H), 8. 06 (d, J=8. 8Hz, 1H), 8. 02 (m, 1H), 7.75 (m, 2H), 7.47 (m, 1H), 7.41 (m, 1H)，7.31 (m，3H)， 7. 19 (m, 1H), 6. 91 (s, 1H), 6. 70 (s, 1H), 5. 27 (s, 2H), ® 4. 55 (d, J=6. 0Hz, 2H), 4. 31 (d, J=6. 0Hz, 2H), 4. 20 (s, 2H), 1.54 (m, 2H), 0.96 (t, J = 7. 2Hz, 3H) 實施例274 ’ 1 -〔3-Η-「3-氯-4-(3-氟-苄氧基）-笨胺基卜啥吨被—矣} -n比洛-1-基）-3-((R)-3-二曱基胺基-η比嘻炫—1-基）_丙_2一 Μ-First step 465 94389 201016683 (3-ethyl-epoxypropane-3-yl)methyl methanesulfonate (3-ethyl-epoxypropan-3-yl)-nonanol (580 mg, 5 mmol) Dissolve in 15 mL of di-methane and add triethylamine (758, 7.6 mmol) with stirring. Cool the reaction to an ice bath and gradually add methanesulfonate chloride (687 mg '6 mmol). Stir for 3 minutes at warm and the reaction is complete. The reaction mixture was concentrated under reduced pressure. EtOAc (2 mL, EtOAc, EtOAc (EtOAc) The residue obtained is further separated and purified by silica gel column chromatography (dichloromethane: decyl alcohol = 4 〇: 1 ) to obtain (3-ethyl- propylene oxide-3-yl)methyl methanesulfonate. 273a (945 mg, colorless oily liquid), yield: 97.4%. MS m/z (ESI): 195 [M + 1]. Step 2 '[3_Chloro_4-(3_fluoro-benzyloxy)-phenyl]-{6-[l-(3_ethyl - propylene oxide-3-ylindenyl)-1Η_οbido-3-yl]-indole _4-yl}-amine in a 50 mL flask, [3-chloro-4-(3- Fluoro-benzyloxy)-phenyl]indole-[6-(1Η-pyrrol-3-yl)-quinazolin-4-yl]-amine 42 (223 mg, 〇.5 mmol) dissolved in 10 mL anhydrous In N,N-dimethyl decylamine, cooled to 0 C under ice bath, adding weathered sodium (6 〇 mg, 2.5 mmo 1), and mixing for 30 minutes, then adding fluorite (3-ethyl) - Glycidyl _3_yl)methyl ester 273a (145 mg, 0.75 mmol), stirred at room temperature for 1 hour. The reaction solution was added with 20 mL of water, and extracted with ethyl acetate (40 mL×3). The combined organic phases were successively washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the mixture was concentrated under reduced pressure to give a residue. The analytical method is further divided into 94389 466 201016683 by purification (dichloromethane: decyl alcohol = 40: 1) to give the title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-{6 -[ 1-(3-ethyl-epoxypropane-3-ylmethyl)-1Η-pyrrol-3-yl]-quinazolin-4-yl}-amine 273 (125 mg, pale yellow solid) Yield: 46.1%. MS m/z (ESI): 543 [M+1] NMR (400 MHz, DMS0-J6): = 9.68 (s, 1H), 8.53 (s, 1H), 8.50 (s, 1H), 8 06 (d, J=8. 8Hz, 1H), 8. 02 (m, 1H), 7.75 (m, 2H), 7.47 (m, 1H), 7.41 (m, 1H), 7.31 (m, 3H) , 7. 19 (m, 1H), 6. 91 (s, 1H), 6. 70 (s, 1H), 5. 27 (s, 2H), ® 4. 55 (d, J=6. 0Hz, 2H), 4. 31 (d, J=6. 0Hz, 2H), 4. 20 (s, 2H), 1.54 (m, 2H), 0.96 (t, J = 7. 2Hz, 3H) Example 274 ' 1-[3-Η-"3-Chloro-4-(3-fluoro-benzyloxy)- phenylaminopyrazine---}-n-bi-l-yl)-3-((R) -3-didecylamino-n-rhodium-l-yl)-propan-2-one-

(R)-N, Ν-二甲基°比洛烧-3-胺（52 mg，〇. 46 mmol)溶解鲁 94389 467 201016683(R)-N, Ν-dimethyl ° piroxicam-3-amine (52 mg, 〇. 46 mmol) dissolved Lu 94389 467 201016683

應液在減屢下濃縮，得到的殘留物藉由石夕膠管柱層析法分離純化（二氣甲烷：甲醇=1〇: n，得到本標題產物 [3-虱-4-(3-氟-苄氧基）-笨胺基]-喧唾琳_6_基}_11比嘻_1_ 基）-3-( (R)-3-二甲基胺基-吡咯统-1-基）一丙_2一醇274 (80 mg，黃色固體），產率：54. 3%。 MS m/z (ESI) ： 616[M+1] ^ 5H NMR(400 MHz , DMSO-dl5): ^9.69 (s, 1H), 8. 54 (s, 1H), 8.50 (s, 1H), 8.04 (m, 2H), 7.75 (m, 2H), 7.47 (m, 1H), 7. 40 (m, 1H), 7. 30 (m, 3H), 7. 19 (m, 1H), 6.88 (s, 1H), 6.68 (s, 1H), 5.27 (s, 2H), 5.09 (br, 1H), 3. 82 (m, 3H), 2. 67 (m, 4H), 2. 51 (m, 3H), 2. 16 (s, 6H), 1. 87 (m, 1H), 1. 65 (m, 1H) 實施例275 ❿K3-U-「3-氯-4-(3-氟-苄氣某）-裳胺基唑啉-fi-篡1 -p比洛基）~~N-(1-環丙基~a底唆- 4· -幕乙醯胺The liquid was concentrated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (di gas methane: methanol = 1 〇: n) to give the title product [3-虱-4-(3-fluoro -benzyloxy)-phenylamino]-hydrazinyl _6_yl}_11 嘻_1_yl)-3-((R)-3-dimethylamino-pyrrol-1-yl) Propyl alcohol 274 (80 mg, yellow solid), yield: 54.3%. MS m/z (ESI): 564 [M.sup.. 8.04 (m, 2H), 7.75 (m, 2H), 7.47 (m, 1H), 7. 40 (m, 1H), 7. 30 (m, 3H), 7. 19 (m, 1H), 6.88 ( s, 1H), 6.68 (s, 1H), 5.27 (s, 2H), 5.09 (br, 1H), 3. 82 (m, 3H), 2. 67 (m, 4H), 2. 51 (m, 3H), 2. 16 (s, 6H), 1. 87 (m, 1H), 1. 65 (m, 1H) Example 275 ❿K3-U-"3-Chloro-4-(3-fluoro-benzyl) a)-salbenylazoline-fi-篡1 -p-l- yl)~~N-(1-cyclopropyl~a-bottom--4·-acetamide

468 94389 201016683468 94389 201016683

U -環丙基-哌啶-4-基胺基）-甲酸第三丁酯 ® 將哌啶-4-基胺基-曱酸第三丁酯（1. 2 g，5 mmol)溶於 40 mL甲醇中，攪拌下依次加入（1-乙氧基一卜甲基-丙氧基） -三曱基矽烷（1.52mL，7. 5 mmol)，氰基硼氫化鈉（1.26g， 2 0 mmo 1)和乙酸（2.86 mL，50 mmo 1)，混合液加熱回流反應過夜。將反應液在減壓下濃縮，得到的殘質中加入2〇 mL 乙酸乙酯’攪拌下加入飽和氫氧化鈉溶液，調整pH為驗性’用乙酸乙酯萃取（50 mLx3)，合併的有機相經由無水硫 ❹酸鈉脫水’過濾’減壓下濃縮，得到的殘留物用矽膠管柱層析法分離純化（二氯甲烷：甲醇=50 : 1)，得到（1-環丙基 -哌啶-4-基胺基）-曱酸第三丁酯275a(1.12 g，白色固體），產率：80. 4%。 MS m/z (ESI) ： 241[M+l] 第二步卜環丙基-哌啶-4-基胺將（1-環丙基-哌啶-4-基胺基）-甲酸第三丁醋275a(l 94389 469 201016683 g ’ 4. 16 mmo 1)溶於5 0 mL二氯曱烧中，授拌下加入mL 二氟乙酸，室溫下攪拌2小時反應完畢。將反應液在減壓下濃縮’得到的殘質加入5 mL曱醇’加入無水碳酸鉀，調整pH=8 ’旋乾，得到的殘留物用矽膠管柱層析法分離純化 (一乳曱烧.曱醇=20 : 1)，得到1-環丙基_0底咬_4_基胺 275b(1.317 g，白色固體），產率：80.4%。 MS m/z (ESI) ： 141[M+1] 第三步 1- 氯-N-(l-環丙基-哌啶_4_基）_乙醯胺 ❹ 將卜環丙基-哌啶_4_基胺275b(350 mg，2. 5 mmol)溶於10mL四氫吱喃中，溶液在丙酮—乾冰浴下冷卻至_了8。〇，攪拌下加入0.7 mL三乙胺和氯乙醯氯（339 mg，3 mmol)，維持此溫度攪拌40分鐘反應完畢。反應液中加入2〇此 •四氫呋喃，有白色固體析出，過濾’濾液在減壓下濃縮，得到的殘留物藉由矽膠管柱層析法分離純化（二氯曱烷：甲醇=10 : 1)，得到1-氣-N_(1_環丙基-哌啶—4_基）_乙醯胺 ❹275c(297 mg，白色固體），產率：51〇/〇。 MS m/z (ESI) : 217[M+1] 第四步 2- (3-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-喹唾啉-6_基} 一°比洛_1_基環丙基-哌啶-4-基）-乙醢胺在50 mL的燒瓶中，將[3-氯-4-(3-氟-苄氧基）-苯基] -[6-(1Η-β比略-3-基）-啥唑啉—4-基]-胺 42(338 mg’ 0.76 mmol)溶於1〇 mL無水N，n一二甲基甲醯胺中，在冰浴條件 470 94389 201016683 下’冷部至0 C ’加入氫化鈉（91 mg，3. 8 mmol)，攪拌30 刀鐘後加入1-氣-N-(l-環丙基一哌啶_4_基）_乙醯胺275c (297 mg，0. 91 mmol)，室溫下攪拌丄小時反應完畢。反應液加入50mL水，用乙酸乙酯萃取（5〇mLx3)，合併的有機相經由無水硫酸鈉脫水，過濾，減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化（二氯甲烷：甲醇 =20 : 1)，得到本標題產物2-(3-{4-[3-氯-4-(3-氟-苄氣基）-苯胺基]-喹唑啉-6-基}-吼咯-1-基）-N-C1-環丙基、哌啶-4-基）-乙酿胺275 (397 mg ’黃色固體），產率：46. 3%。 ^ MS m/z (ESI) ： 625[M+1] *11 NMR(400 MHz , DMS0-ci6) ： δ 9. 69 (s, 1H), 8. 54 (s, 1¾) 8.50(s，1H)，8.04 (m，2H)，7.75 (m，2H)，7.47 (m，1H)， 7. 40 (m，1H)，7. 30 (m，3H)，7· 19 (m, 1H)，6. 88 (s，1H)， ' 6. 68 (s，1H)，5. 27 (s，2H)，4. 59 (s，2H)，3. 80 (m，1H), 3.57(m，2H)，2.88 (m，2H)，2.25 (m，2H)，1.73 (m，2H)， 1.58 (br, 1H), 0.39 (m, 2H), 0.27 (br, 2H) 蝙實施例276 l-(3-{4-[3 -氯-4-(3 -氟-苄氣基茉胺基1-啥嗤啦 -°比略-1 -基）-3-( 1，1-二側氡某A *6*-疏代嗎琳-4~Ί^ 丙-2_醇U-cyclopropyl-piperidin-4-ylamino)-carboxylic acid tert-butyl ester® Dissolve piperidin-4-ylamino-decanoic acid tert-butyl ester (1.2 g, 5 mmol) in 40 (1-Ethoxy-p-methyl-propoxy)-tridecyldecane (1.52 mL, 7.5 mmol), sodium cyanoborohydride (1.26 g, 2 0 mmo 1) And acetic acid (2.86 mL, 50 mmo 1), the mixture was heated and refluxed overnight. The reaction solution was concentrated under reduced pressure, and the obtained residue was added 2 mL of ethyl acetate. A saturated sodium hydroxide solution was added under stirring, and the pH was adjusted to be inspected. (Extracted with ethyl acetate (50 mL×3), combined organic The phase was dehydrated by filtration with anhydrous sodium sulphate. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 50:1) to give 4%。 pyridine-4-ylamino)-decanoic acid tert-butyl ester 275a (1.12 g, white solid), yield: 80.4%. MS m/z (ESI): 241 [M+l] s. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> Butyl vinegar 275a (l 94389 469 201016683 g ' 4. 16 mmo 1) was dissolved in 50 mL of dichlorohydrazine, and added with mL difluoroacetic acid under stirring, and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure. The residue obtained was added to 5 mL of decyl alcohol. Add anhydrous potassium carbonate, adjust pH = 8 'spin dry, and the residue obtained was separated and purified by column chromatography. . Hydroxide = 20 : 1) gave 1-cyclopropyl </ RTI> </ RTI> <RTIgt; </RTI> <RTIgt; MS m/z (ESI): 141 [M + 1] Step 3 1-chloro-N-(l-cyclopropyl-piperidine-4-yl)-acetamide oxime-cyclopropyl-piperidine The _4_ylamine 275b (350 mg, 2.5 mmol) was dissolved in 10 mL of tetrahydrofuran, and the solution was cooled to -8 in an acetone-dry ice bath. 0.7, 0.7 mL of triethylamine and chloroacetamidine chloride (339 mg, 3 mmol) were added with stirring, and the reaction was completed by stirring at this temperature for 40 minutes. 2 Torr of this tetrahydrofuran was added to the reaction mixture, and a white solid was precipitated. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (dichloromethane:methanol = 10:1). 1-H-N-(1_cyclopropyl-piperidine-4-yl)-acetamidamine 275c (297 mg, white solid). MS m/z (ESI): 217 [M + 1] Step 4 2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-anilinyl]-quinoline- 6_基}1°Pilo-1_ylcyclopropyl-piperidin-4-yl)-acetamide In a 50 mL flask, [3-chloro-4-(3-fluoro-benzyloxy) )-Phenyl]-[6-(1Η-β-l-yl-3-yl)-oxazoline-4-yl]-amine 42 (338 mg' 0.76 mmol) dissolved in 1 mL of anhydrous N, n-II In methylformamide, add sodium hydride (91 mg, 3.8 mmol) in the 'cold portion to 0 C' under ice bath conditions 470 94389 201016683, stir for 30 knives and add 1-gas-N-(l- Cyclopropyl-piperidine-4-yl)-acetamide 275c (297 mg, 0.91 mmol) was stirred at room temperature for a few hours. The reaction mixture was poured into 50 mL of water and extracted with ethyl acetate (5 mL mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Dichloromethane:methanol = 20 : 1) gave the title product 2-(3-{4-[3-chloro-4-(3-fluoro-benzyl)-anilinyl]-quinazoline-6- 。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。. ^ MS m/z (ESI): 625 [M+1] *11 NMR (400 MHz, DMS0-ci6): δ 9. 69 (s, 1H), 8. 54 (s, 13⁄4) 8.50 (s, 1H) ), 8.04 (m, 2H), 7.75 (m, 2H), 7.47 (m, 1H), 7. 40 (m, 1H), 7. 30 (m, 3H), 7· 19 (m, 1H), 6. 88 (s, 1H), ' 6. 68 (s, 1H), 5. 27 (s, 2H), 4. 59 (s, 2H), 3. 80 (m, 1H), 3.57 (m, 2H), 2.88 (m, 2H), 2.25 (m, 2H), 1.73 (m, 2H), 1.58 (br, 1H), 0.39 (m, 2H), 0.27 (br, 2H) bat Example 276 l- (3-{4-[3-Chloro-4-(3-fluoro-benzyl-yl-methyl-l-amino-l-yl-l-l-yl)-3-(1,1-di- 氡) A *6*- 疏代琳-4~Ί^ 丙-2_ol

276 471 94389 201016683276 471 94389 201016683

硫代嗎琳 1，1 -二氧化物（54 mg ’ 0. 4 mmo 1，A1 dr i ch ) 溶解於10 mL甲醇中，攪拌下加入[3-氣-4-(3一氟-节氧基） -本基]-[6-(1-壤氧乙基曱基-ΐΗ-σΛ^~3-基）-啥唾琳一斗一基]-胺187a(200 mg ’ 0. 4 mmol)，混合液加熱回流過夜。 ®反應液在減壓下濃縮’得到的殘留物藉由石夕膠管柱層析法分離純化（二氯甲烷：曱醇= 10: 1)，得到標題產物^(3^^ [3-氯-4-(3-氟-苄氧基）-苯胺基]-啥唾琳-6-基} — n比^ — 基）-3-(1，1-二側氧基-1又*6*-硫代嗎琳-4-基）-丙-2~|| ' 276(20 mg，黃色固體），產率：7. 9%。 MS m/z (ESI) ： 636[M+1] 'H NMRC400 MHz , DMSO-d^) ： ^ 9. 67 (s, 1H), 8. 5 (s, 2H) φ 8.0 (s, 2H), 7.7 (s, 1H), 7.69 (m, 1H), 7.5 (m, 2H), 7.36 (m, 3H), 7.2 (m, 1H), 6.93 (m, 1H), 6.60 (s, 1H), 5.27 (s，2H)，5.05 (s，1H), 4.06 (d, J=ll. 2，1H)，3.89 (m，2H)，3.13 (s，4H)，2.96 (s，4H)，2.43 (d，J=4.8, 2H) 實施例277 1-(3-丨4-「3-氣-4-(3-氟-笮氳某装胺基1_-喹唑啉-f；-u -g比洛-1-基）-3-((R)-3 -氟- η比哈炫-1-基）_丙-2-醇_ 472 94389 201016683Thioline 1 ,1 -dioxide (54 mg ' 0. 4 mmo 1,A1 dr i ch ) was dissolved in 10 mL of methanol and [3- gas-4-(3-fluoro-oxygen) was added with stirring. -) [6-(1-Lys oxyethyl fluorenyl- ΐΗ-σΛ^~3-yl)-啥琳一一 ] 】】】】 amide 187a (200 mg ' 0. 4 mmol) The mixture was heated to reflux overnight. The reaction mixture was concentrated under reduced pressure. The residue obtained was purified by chromatography eluting eluted eluted eluted eluted eluted eluted eluted eluted 4-(3-Fluoro-benzyloxy)-anilino]-indenyl-6-yl}-n-^-yl)-3-(1,1-di-oxy-1 and *6*- Thioline-4-yl)-propanoid-2~|| ' 276 (20 mg, yellow solid), yield: 7.9%. MS m/z (ESI): 636 [M+1] "H NMRC 400 MHz , DMSO-d^) : ^ 9. 67 (s, 1H), 8. 5 (s, 2H) φ 8.0 (s, 2H) , 7.7 (s, 1H), 7.69 (m, 1H), 7.5 (m, 2H), 7.36 (m, 3H), 7.2 (m, 1H), 6.93 (m, 1H), 6.60 (s, 1H), 5.27 (s, 2H), 5.05 (s, 1H), 4.06 (d, J=ll. 2,1H), 3.89 (m, 2H), 3.13 (s, 4H), 2.96 (s, 4H), 2.43 ( d, J = 4.8, 2H) Example 277 1-(3-indole 4-"3-gas-4-(3-fluoro-indole amine 1_-quinazoline-f;-u-g ratio洛-1-yl)-3-((R)-3-fluoro-nbihaxen-1-yl)-propan-2-ol_472 94389 201016683

(R) 3氟π比洛院鹽酸鹽（5〇·4 mg，0.4 mmol)溶解於 10 mL甲醇中’攪拌下依次加入2 mL三乙胺和[3_氯一4—(3_ I-节氧基）-苯基]-[6-(卜環氧乙基甲基_1H—π比咯一3_基）_ 喹唑啉-4-基]-胺I87a(200 mg，0.4mmol)，混合液加熱回流2小時後反應完畢。反應液在減壓下濃縮，得到的殘留物藉由石夕膠管柱層析法分離純化（二氯曱烧：曱醇=1〇: ^)，得到本標題產物1-(3-{4-[3-氯-4-(3-氟-苄氧基）_苯胺籲基]-喹唑啉-6-基}-吡咯-1-基）-3-((R)-3-氟-吡洛烧-1- 基）-丙-2-醇277(110 mg，黃色固體），產率：46. 7%。 MS m/z (ESI) ： 590[M+1] !H NMRC400 MHz , DMS0-d6): δ 9. 67 (s, 1H), 8. 5 (s, 2H), 8.0 (s, 2H), 7.7 (s, 1H), 7.69 (m, 1H), 7.5 (m, 2H), 7.36 (m, 3H), 7.2 (m, 1H), 6.93 (m, 1H), 6.60 (s, 1H), 5.27(s, 2H), 5. 05(s, 1H), 4.06 (m, 1H), 3.89 (m, 2H), 2.88(m, 2H), 2. 42 (m, 3H), 2.22 (m, 1H), 1.89(m, 1H), 94389 473 201016683 1.23 (m, 2H) 實施例2 7 8 l-(3-{4-[3-氣二·4-(3_氟-苄氧基）一苯胺基1：：喹唑啉—6—基} -吡咯-1-基）-3-噻唑烷-3-基-丙-2-酵(R) 3F pipyrazine hydrochloride (5〇·4 mg, 0.4 mmol) was dissolved in 10 mL of methanol. Stirringly added 2 mL of triethylamine and [3_Chloro-4-(3_I-)节oxy)-phenyl]-[6-(p-epoxyethylmethyl-1H-πpyrrol-3-yl)-quinazolin-4-yl]-amine I87a (200 mg, 0.4 mmol) The mixture was heated to reflux for 2 hours and the reaction was completed. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified and purified by chromatography (dichlorobenzene: decyl alcohol = 1 〇: ^) to give the title product 1-(3-{4- [3-chloro-4-(3-fluoro-benzyloxy)-anilino]-quinazolin-6-yl}-pyrrol-1-yl)-3-((R)-3-fluoro-pyridyl L-yield-1-yl)-propan-2-ol 277 (110 mg, yellow solid), yield: 46.7%. MS m/z (ESI): 590 [M+1] <RTI ID=0.0>>> 7.7 (s, 1H), 7.69 (m, 1H), 7.5 (m, 2H), 7.36 (m, 3H), 7.2 (m, 1H), 6.93 (m, 1H), 6.60 (s, 1H), 5.27 (s, 2H), 5. 05(s, 1H), 4.06 (m, 1H), 3.89 (m, 2H), 2.88(m, 2H), 2. 42 (m, 3H), 2.22 (m, 1H) ), 1.89 (m, 1H), 94389 473 201016683 1.23 (m, 2H) Example 2 7 8 l-(3-{4-[3-Gas-4-(3-fluoro-benzyloxy)-phenylamine Base 1: quinazoline-6-yl}-pyrrol-1-yl)-3-thiazolidine-3-yl-propan-2-lactam

在100 mL茄形瓶中，將[i-(3-氟-苄基）_ijj-吲吐-5-基]-[6-(1-環氧乙基甲基-in—吡咯_3_基喹唑啉_4_基]— 胺178a(200 mg ’ 〇· 41 mmol)溶解於25 mL甲醇中，攪拌下加入β塞嗤院（4 3 mg，0 · 4 8 mmo 1)，反應液加熱回流過夜。籲將反應液在減壓下濃縮，得到的殘留物藉由石夕膠管柱層析法分離純化（二氯甲烷：曱醇=60 :丨），得到本標題產物 1-(3-{4-[3 -乳-4-(3-氣_午氧基）-苯胺基]-啥嗤琳_6_基} -吡咯-1-基）-3-噻唑烷-3-基-丙-2-醇278 (152 mg，黃色固體），產率：54%。 MS m/z (ESI) ： 590 [M+1] ^ NMRC400 MHz, DMSO-c/5): ^ 9. 69 (s, 1H), 8. 54 (s, 1H), 8.50(s, 1H), 8. 04 (m, 2H), 7.75 (m, 2H), 7. 47 (m, 1H), 94389 474 201016683 7.40 (m, 1H), 7. 30 (m, 3H), 7. 19 (m, 1H), 6. 88 (s, 1H), 6.68(s, 1H), 5.27(s, 2H), 5. 15 (s, 1H), 4. 13 (in, 3H), 3.89 (m, 2H), 3.05 (m, 2H), 2.79 (m, 2H), 2.27 (m, 2H) 實施例279 「3-氧-4-(3-氟-苄氧基）-苯_羞^]-(6-丨〗—「9_(4_環丙基_气哄-1-基）-乙基]_1H-口比咯-3-墓}-唾唾啦一[其、—胗[i-(3-Fluoro-benzyl)_ijj-吲吐-5-yl]-[6-(1-epoxyethylmethyl-in-pyrrole_3_yl) in a 100 mL eggplant-shaped flask Quinazoline _4_yl]-amine 178a (200 mg ' 〇· 41 mmol) was dissolved in 25 mL of methanol, and added to β 嗤嗤 (4 3 mg, 0 · 4 8 mmo 1) with stirring, and the reaction solution was heated. After refluxing overnight, the reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by chromatography (dichloromethane: EtOAc: EtOAc: {4-[3 -Ethyl-4-(3-gas-n-oxy)-anilino]-啥嗤琳_6_yl}-pyrrol-1-yl)-3-thiazolidine-3-yl-propane -2-Alkyl 278 (152 mg, mp. , 1H), 8. 54 (s, 1H), 8.50(s, 1H), 8. 04 (m, 2H), 7.75 (m, 2H), 7. 47 (m, 1H), 94389 474 201016683 7.40 ( m, 1H), 7. 30 (m, 3H), 7. 19 (m, 1H), 6. 88 (s, 1H), 6.68(s, 1H), 5.27(s, 2H), 5. 15 ( s, 1H), 4. 13 (in, 3H), 3.89 (m, 2H), 3.05 (m, 2H), 2.79 (m, 2H), 2.27 (m, 2H) Example 279 "3-Oxy-4 -(3-fluoro-benzyloxy)-benzene_shame^]-(6-丨〗-"9_(4_环Propyl _ gas 哄-1-yl)-ethyl]_1H-mouth than -3-tomb}-saliva one [its, - 胗

' 將2-(3_{4_[3-氯_4-(3_氟-苄氧基）-苯胺基]-喹唑啉-6-基卜吼咯-1-基）-1-(4-環丙基-哌哄-卜基）_乙綱 265(50 mg，0. 082 mmol)溶於1〇社四氫吱喃中，搜摔下 ⑩加入氫化銘鐘（31. 4 mg ’ 0. 82 mmol)，室溫下搜拌過夜。將反應液在減壓下濃縮’得到的殘留物藉由矽膠管柱層析法分離純化（二氣甲烷：甲醇=20 :1)，得到本標題產物θ[3_ 氯_4-(3-氟-苄氧基）-苯基]-(6-{卜[2_(私環丙基-哌畊 -1-基）-乙基]-1H-吡咯-3-基}-喹唑啉_4_基）_胺279(48 mg，黃色固體），產率：97. 9%。 MS m/z (ESI) ： 597[M+1] NMR(400 MHz，DMSO-M) : 6 9, 69 (s，1H)，8. 54 (s 1H) 94389 475 201016683 8. 50 (s，1H)，8. 04 (m, 2H)’ 7· 75 (m，2Η)，7· 47 (瓜，1H)， 7.40 (m, 1H), 7.30 (m, 3H), 7. 19 (m, 1H), 6. 88 (s, 1H), 6. 68 (s，1H)，5. 27 (s’ 2H)，4· 〇5 (m，2H)，2. 67 (m，2H)， 2.54 (br, 4H), 2.42 (br, 4H), 1.59 (br, 1H), 0.38 (m, 2H), 0. 27 (m, 2H) 實施例280 l-笨胺基 Ί_ 崦崎啉_fi_ 碁卜吡咯-卜基）-lzl氣基二一哌啶_4一甲醯松'2-(3_{4_[3-Chloro-4-(3_fluoro-benzyloxy)-anilino]-quinazoline-6-ylbupyrol-1-yl)-1-(4- Cyclopropyl-piperazine-buji)-B-class 265 (50 mg, 0.082 mmol) was dissolved in 1 〇 tetrahydrofuran, and it was dropped to 10 to add hydrogenated Mingzhong (31. 4 mg ' 0. 82 mmol), mix overnight at room temperature. The reaction mixture was concentrated under reduced pressure. The obtained residue was purified and purified by hexane column chromatography (di-methane:methanol = 20:1) to give the title product θ[3_ chloro- 4-(3-fluoro -benzyloxy)-phenyl]-(6-{Bu[2_(Pentylcyclopropyl-piped-1-yl)-ethyl]-1H-pyrrol-3-yl}-quinazoline_4_ 9%。 Amine 279 (48 mg, yellow solid), yield: 97.9%. MS m/z (ESI): 597 [M+1] NMR (400 MHz, DMSO-M): 6 9, 69 (s, 1H), 8. 54 (s 1H) 94389 475 201016683 8. 50 (s, 1H), 8. 04 (m, 2H)' 7· 75 (m, 2Η), 7·47 (melon, 1H), 7.40 (m, 1H), 7.30 (m, 3H), 7. 19 (m, 1H), 6. 88 (s, 1H), 6. 68 (s, 1H), 5. 27 (s' 2H), 4· 〇 5 (m, 2H), 2. 67 (m, 2H), 2.54 (br, 4H), 2.42 (br, 4H), 1.59 (br, 1H), 0.38 (m, 2H), 0. 27 (m, 2H) Example 280 l- phenylamino Ί 崦啉啉 _ _ fi 碁碁卜pyrrole-buji)-lzl gas-based dipiperidine _4-methanone

280 ❹280 ❹

280 ❿ 哌啶一4_甲醯胺（8〇呢，0.63 mmol)溶解於2〇乩曱醇中，攪拌下加入[3-氣-4-(3-氟-苄氧基）一苯基]_[6_(卜環氧乙基甲基-1H-吡咯-3-基）一喹唑啉_4 —基]_胺187a(26〇，0. 52 mmol)，混合液加熱回流過夜。反應液在減壓下濃縮，得到的殘留物藉由矽膠管柱層析法分離純化(二氯甲烷··甲醇=5:1)，得到本標題產物卜[3_(3_{4_[3—氯氣节氧基）—苯胺基卜啥唾琳+基}-料+基）m 丙基]-痕咬-4一甲醯胺28〇 (222 mg，黃色固體），產率土 94389 476 201016683 67. 90/〇。 MS m/z (ESI) ： 629[M+] !H NMR(400 MHz , DMS0-d5): 5 9. 72 (s, 1H), 8. 56 (s, 1H), 8.55 (s, 1H), 8.05 (m, 2H), 7.78 (d, J = 6Hz, 1H), 7.69 (d, J = 6.8Hz, 1H), 7.51 (m, 1H), 7.41 (s, 1H), 7.31 (m, 3H), 7.21 (in, 2H), 6.88 (m, 1H), 6.65 (m, 2H), 5.27 (s, 2H), 4.91 (br, 1H), 4.08 (m, 1H), 3.94 (br, 1H), 3.85 (m, 1H), 2.91 (m, 2H), 2.24 (br, 2H), 1.98 (m, 3H), 1. 63 (m, 4H) ❹實施例281 1-( (3S, 5R)-3, 5-二甲基-哌啡-1-基）-3-(3-U-Π-(3-氟-苄基）-1Η-口引〇坐-5_基胺基卜啥〇坐淋-6-基}-口比ρ各-1-基）-丙 • -2-醇280 哌 piperidine 4- 4 carbamide (8 〇, 0.63 mmol) was dissolved in 2 sterol and [3- -4-(3-fluoro-benzyloxy)-phenyl] was added with stirring. _[6_(p-Epoxyethylmethyl-1H-pyrrol-3-yl)-quinazoline-4-yl]-amine 187a (26 〇, 0.25 mmol). The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by methylene chloride column chromatography (dichloromethane·methanol = 5:1) to give the title product [3_(3_{4_[3—chloride节oxy)-aniline-based 啥啥啥 + 基基基基基 m 一一一一一一一一一一 222 222 222 222 222 222 222 222 222 222 222 222 222 222 222 222 222 222 222 222 222 222 222 222 222 222 222 90/〇. MS m/z (ESI): 629 [M+].H NMR (400 MHz, DMS0-d5): 5 9. 72 (s, 1H), 8. 56 (s, 1H), 8.55 (s, 1H), 8.05 (m, 2H), 7.78 (d, J = 6Hz, 1H), 7.69 (d, J = 6.8Hz, 1H), 7.51 (m, 1H), 7.41 (s, 1H), 7.31 (m, 3H) , 7.21 (in, 2H), 6.88 (m, 1H), 6.65 (m, 2H), 5.27 (s, 2H), 4.91 (br, 1H), 4.08 (m, 1H), 3.94 (br, 1H), 3.85 (m, 1H), 2.91 (m, 2H), 2.24 (br, 2H), 1.98 (m, 3H), 1. 63 (m, 4H) ❹ Example 281 1-( (3S, 5R)-3 , 5-Dimethyl-piperidin-1-yl)-3-(3-U-Π-(3-fluoro-benzyl)-1Η-口引〇 sitting-5_基胺基卜啥〇坐淋-6-yl}-port ratio ρ-1--1-yl)-propan-2-ol

在100 mL茄形瓶中，將[卜（3-氟-苄基）-1Η-吲唑-5-基]-[6-U-環氧乙基曱基-1H-吡咯-3-基）-喹唑啉-4-基]- 477 94389 201016683[Bu (3-fluoro-benzyl)-1 Η-indazol-5-yl]-[6-U-epoxyethyl fluorenyl-1H-pyrrol-3-yl) in a 100 mL eggplant-shaped flask -quinazolin-4-yl]- 477 94389 201016683

胺178a(200 mg ’ 0. 41 mmol)溶解於25 mL甲醇中，搜掉下加入（2S，6R)-2, 6-二甲基哌畊（140 mg，i. 22 mm〇i)，反應液加熱回流過夜。將反應液在減壓下濃縮，得到的殘留物藉由薄層層析板分離純化（二氣甲院：甲醇=8 : ^)，得到本標題產物1-((3S，5R)-3,5-二曱基-派哄-1 —基）_3一（3_ {4-[1-(3-氟-苄基）-1Η-吲嗤-5-基胺基]-喹唾琳某}_ 吡咯-1-基）-丙-2-醇281 (53 mg，黃色固體），產率 MS m/z (ESI)：605[M+1] ^ 2U !HNMR (400MHz, DMS0-c?l5): 5 9. 90 (s, 1H), 8. 66 (s 1H) ® 8.45(s, 1H), 8.24(s, 1H), 8. 17 (s, 1H), 8. 02 (m, 1H), 7.75 (s, 2H), 7.70 (m 1H), 7.47 (s, 1H), 7. 39 (m, 1H), 7.13(m, 3H), 6. 88 (s, 1H), 6. 69 (s, 1H), 5. 72 (s 2H) 5. 03 (m, 1H), 3. 98 (m, 3H), 3. 26 (m, 2H), 2. 96 (m 2H) 2.29 (m，2H), 2.02 (m’ 2H)，1.20 (m, 6H) 實施例282 4-「3-(3-{4-[1-(3-氟-苄基）-111-咕丨唑-5-|脸基1-喹唑啉傷-6-基}-吡咯-1-基丄-2-羥基-丙基]-哌哄-i -甲醅Λ醢Amine 178a (200 mg '0.41 mmol) was dissolved in 25 mL of methanol, and (2S,6R)-2,6-dimethylpiped (140 mg, i. 22 mm〇i) was added. The liquid was heated to reflux overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified (yield: m. 5-dimercapto-pyrene-1 —yl)_3-(3_{4-[1-(3-fluoro-benzyl)-1Η-吲嗤-5-ylamino]-quinoxaline}_ Pyrrol-1-yl)-propan-2-ol 281 (53 mg, yellow solid), mp. MS m/z (ESI): 605[M+1] ^ 2U !HNMR (400MHz, DMS0-c?l5) : 5 9. 90 (s, 1H), 8. 66 (s 1H) ® 8.45(s, 1H), 8.24(s, 1H), 8. 17 (s, 1H), 8. 02 (m, 1H) , 7.75 (s, 2H), 7.70 (m 1H), 7.47 (s, 1H), 7. 39 (m, 1H), 7.13(m, 3H), 6. 88 (s, 1H), 6. 69 ( s, 1H), 5. 72 (s 2H) 5. 03 (m, 1H), 3. 98 (m, 3H), 3. 26 (m, 2H), 2. 96 (m 2H) 2.29 (m, 2H), 2.02 (m' 2H), 1.20 (m, 6H) Example 282 4- "3-(3-{4-[1-(3-fluoro-benzyl)-111-carbazole-5- |Face 1 -quinazolinein-6-yl}-pyrrol-1-ylindole-2-hydroxy-propyl]-piperidin-i-carboquinone

94389 478 20101668394389 478 201016683

在100 mL茄形瓶中，將[1 -（3_氟-苄基）一 1H_吲唑— 基]-[6-(1-環氧乙基甲基-1 Η-吡咯-3-基）一喹唑淋_4_基]— 胺178a(200 mg，0. 41 mmol)溶解於25 mL甲醇中，授掉 ®下加入派哄-1-曱酸乙酯（194 mg ’ 1‘ 22 mmol)，反應液加熱回流過夜。將反應液在減壓下濃縮，得到的殘留物藉由薄層層析板分離純化（二氯曱烷：曱醇=10 : 1)，得到本標 •題產物4-[3-(3-{4-[1-(3-氟-苄基）-lH-吲唑-5-基胺基]-噎坐琳_6-基}-α比洛-1-基）-2_輕·基-丙基]-旅啡-..1__甲酸乙酯282 (80 mg，黃色固體），產率：30%。 MS m/z (ESI) ： 649[M+1] Q ^NMR (400MHz, DMSO-c/6): 5 9. 84 (s, 1H), 8. 61 (s, 1H), 8· 45 (s，1H), 8. 24 (s，1H), 8. 17 (s，1H)，8. 04 (m, 1H), 7. 75 (s，2H)，7. 70 (m 1H)，7. 44 (s，1H)，7· 40 (m，1H)， 7. 08(m, 3H), 6. 88 (s, 1H), 6. 67 (s, 1H), 5. 73 (s, 2H), 4. 99 (s, 1H), 4. 05 (m, 2H), 3. 90 (in, 3H), 3. 39 (m, 4H), 2.41 (m, 4H), 2.28 (m, 2H), 1.18 (m, 3H) 實施例283 1-(3-丨4-「1-(3-氟-笮基）-111-吲唑-5-基胺基]-喹生^6_ 479 94389 201016683 基}-°比洛-1-基）-3-(2-甲氣基-乙胺基）-丙- 2-¾^[1 -(3_Fluoro-benzyl)-1H-indazole-yl]-[6-(1-epoxyethylmethyl-1 Η-pyrrol-3-yl) in a 100 mL eggplant-shaped flask a quinazoline _4_yl]-amine 178a (200 mg, 0.41 mmol) was dissolved in 25 mL of methanol, and then added 哄哄哄曱 ethyl phthalate (194 mg ' 1 ' 22 (mmol), the reaction solution was heated to reflux overnight. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by chromatography (dichloromethane: decyl alcohol = 10:1) to give the title product 4-[3-(3- {4-[1-(3-Fluoro-benzyl)-lH-indazol-5-ylamino]-indole _6-yl}-α-pyr-1-yl)-2_light·yl -propyl]-branol-..1__ethyl formate 282 (80 mg, yellow solid), yield: 30%. MS m/z (ESI): 649 [M+1] Q NMR (400 MHz, DMSO-c/6): 5 9. 84 (s, 1H), 8. 61 (s, 1H), 8·45 ( s,1H), 8. 24 (s,1H), 8. 17 (s,1H), 8. 04 (m, 1H), 7. 75 (s,2H), 7. 70 (m 1H),7 44 (s,1H),7·40 (m,1H), 7. 08(m, 3H), 6. 88 (s, 1H), 6. 67 (s, 1H), 5. 73 (s, 2H), 4. 99 (s, 1H), 4. 05 (m, 2H), 3. 90 (in, 3H), 3. 39 (m, 4H), 2.41 (m, 4H), 2.28 (m, 2H), 1.18 (m, 3H) Example 283 1-(3-丨4-"1-(3-Fluoro-indenyl)-111-oxazol-5-ylamino]-quinoline^6_ 479 94389 201016683 基}-°Bilo-1-yl)-3-(2-methyl-ethylamino)-propyl-2-3⁄4^

AA

Λ 在100 mL茄形瓶中，將[1-(3-氟-苄基1H_吲唑基]-[6-(1-環氧乙基甲基-1Η-»比嘻-3-基）-噎唾琳_4一基]— 胺178a(200 mg ’ 0. 41 mmol)溶解於25 mL甲醇中，授掉下加入2-甲氧基乙胺（92 mg，1.22 mmol)，反應液加熱回流過夜。將反應液在減壓下濃縮，得到的殘留物藉由薄層層析板分離純化（二氯甲烷：甲醇=8: 1)，得到本標題產響物1_(3_{4_[1-(3_乱基°坐-5_基胺基]_啥唾琳 -6-基}-吡咯-1-基）-3-(2-曱氧基-乙胺基）-丙-2-醇283 (100 mg，黃色固體），產率：43%。 MS m/z (ESI) ： 566[M+1] !HNMR (400MHz, DMSO-d^): (5 9. 86 (s, 1H), 8. 63 (s, 1H), 8.45(s, 1H), 8.23(s, 1H), 8. 17 (s, 1H), 8. 04 (m, 1H), 7.78 (s, 2H), 7.70 (m 1H), 7.44 (m, 1H), 7.37 (m, 1H), 7. 08(m, 3H), 6. 89 (s, 1H), 6. 69 (s, 1H), 5. 72 (s, 2H), 480 94389 201016683 4.09 (m, 3H), 3.92 (m, 2H), 3.18 (m, 3H), 2.59 (m, 4H) 實施例284 N-{(3R)-1-[3-(3-{4-「1-(3 -氟-爷基弓丨 p坐-5-基胺基 i -喹嗤琳-6-基}-吡咯-i-基）-2-羥基-丙篡i-叫哈烧_3_基} -乙醯胺[ [1-(3-Fluoro-benzyl 1H-carbazolyl]-[6-(1-epoxyethylmethyl-1Η-» than indole-3-yl) in a 100 mL eggplant-shaped flask - 噎琳 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ After refluxing overnight, the reaction mixture was concentrated under reduced pressure, and the obtained residue was purified (yield: methylene chloride:methanol = 8:1) to give the title product 1_(3_{4_[1 -(3_乱基°坐-5_ylamino)_啥啥琳-6-yl}-pyrrol-1-yl)-3-(2-decyloxy-ethylamino)-propan-2- Alcohol 283 (100 mg, mp. ), 8. 63 (s, 1H), 8.45(s, 1H), 8.23(s, 1H), 8. 17 (s, 1H), 8. 04 (m, 1H), 7.78 (s, 2H), 7.70 (m 1H), 7.44 (m, 1H), 7.37 (m, 1H), 7. 08(m, 3H), 6. 89 (s, 1H), 6. 69 (s, 1H), 5. 72 (s, 2H), 480 94389 201016683 4.09 (m, 3H), 3.92 (m, 2H), 3.18 (m, 3H), 2.59 (m, 4H) Example 284 N-{(3R)-1-[3 -(3-{4-"1-(3-fluoro--------------5-ylamino i-quinoline-6-yl}- Slightly -i- yl) -2-hydroxy - propyl usurp i- _3_ called burn-yl} Ha - as acetamide

在100 mL茄形瓶中’將[1-(3-氟-苄基）_1H一吲唑_5_ 基]-[6-(1 -環氧乙基甲基-1H-0比略-3-基）-啥u坐琳_4_基]一參胺178a(200 mg，〇_ 41 mmol)溶解於25 mL甲醇中，攪拌下加入（R)-N-(吡咯烷-3-基）乙醯胺（174mg，122nim〇1)，反應液加熱回流過夜。將反應液在減壓下濃縮，得到的殘留物藉由薄層層析板分灕純化（二氯曱烷：曱醇=8 :丨），得到本標題產物 N-{(3R)-l-[3-(3-{4-[l-(3-氟-苄基）_lH-α引唾-5-基胺基]-啥α坐琳_6_基卜II比m)—2_經基_丙基] -吡咯烷-3-基}-乙醯胺284(50 mg，黃色固體），產率：2〇%。 MS m/z (ESI) ： 619[M+1] 94389 481 201016683 !HNMR (400MHz, DMS0-cf6): ^ 9. 87 (s> 8. 64 (s, 1H) 8· 45 (s, 1H), 8. 23 (s，1H)’ 8. 17 (s，iH)，8. 04 (m，1H), 7· 75 (m，3H)’ 7. 41 (s，1H)，7. 37 (m，1H)，7. 〇8 (m，3H)， 6. 89 (s, 1H), 6. 69 (s, 1H), 5. 72 (s, 2H), 4. 04 (m, 2H), 3. 98 (m, 1H), 3. 53 (m, 2H), 3. 28 (m, 3H), 3. 00 (in, 2H), 2. 50 (m, 3H), 1. 83 (m, 2H) 實施例285 1-(3-{4-[1二(3-氟-苄基）-11^敗逢〜5_1胺基1_喹唑1^_^_ 基}-"比洛-1-基）-3-[1，2,31***二]^_丙_2_醇'1-(3-Fluoro-benzyl)_1H-carbazole-5-yl]-[6-(1-epoxyethylmethyl-1H-0 ratio -3- in a 100 mL eggplant-shaped flask Base)-啥u sitting on _4_base] ginseng 178a (200 mg, 〇_41 mmol) was dissolved in 25 mL of methanol and (R)-N-(pyrrolidin-3-yl)B was added with stirring. The guanamine (174 mg, 122 nim 〇 1) was heated to reflux overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified (jjjjjjjjjjjjj [3-(3-{4-[l-(3-Fluoro-benzyl)_lH-α-lead--5-ylamino]-啥α坐琳_6_基卜II比m)—2_经_-propyl]-pyrrolidin-3-yl}-acetamide 284 (50 mg, yellow solid), yield: 2%. MS m/z (ESI): 619 [M+1] 94389 481 201016683 !HNMR (400MHz, DMS0-cf6): ^ 9. 87 (s> 8. 64 (s, 1H) 8· 45 (s, 1H) , 8. 23 (s,1H)' 8. 17 (s,iH), 8. 04 (m,1H), 7· 75 (m,3H)' 7. 41 (s,1H), 7.37 ( m,1H),7. 〇8 (m,3H), 6. 89 (s, 1H), 6. 69 (s, 1H), 5. 72 (s, 2H), 4. 04 (m, 2H) , 3. 98 (m, 1H), 3. 53 (m, 2H), 3. 28 (m, 3H), 3. 00 (in, 2H), 2. 50 (m, 3H), 1. 83 ( m, 2H) Example 285 1-(3-{4-[1 bis(3-fluoro-benzyl)-11^ 逢〜~5_1 amide 1 quinazoline 1^_^ _ base}-"洛-1-yl)-3-[1,2,31 triazole bis]^_propan-2-ol

在100 mL茄形瓶中’將苄基）_1H-吲唑_5_ 基]-[6-(1-環氧乙基曱基-in-吡咯〜3_基）_喹唑啉_4_基]_ 胺 178a(100 mg，0.23 mmol)溶解於 5 mL 無水 N，N-二甲'将benzyl}_1H-carbazole_5_yl]-[6-(1-epoxyethylindenyl-in-pyrrole~3_yl)-quinazoline_4_yl in a 100 mL eggplant-shaped flask ]_ Amine 178a (100 mg, 0.23 mmol) dissolved in 5 mL of anhydrous N,N-dimethyl

基甲醯胺中，在冰浴條件下，冷卻至〇。€，加入氫化鈉（22 mg ’〇· 92 mmol) ’ 攪拌 30 分鐘後加入[1, 2, 3]***（43 mg， 0. 63 mmol)，加熱至50°C授拌過夜。反應液中加入20 mL 482 94389 201016683 冰水和20虬二氯甲烷，分液，水相用二氣甲烷萃取（2〇mL x3)，合併的有機相經由無水硫酸鈉脫水，過濾，減壓下濃縮’得到的歹戔留物進一步藉由薄層層析板分離純化（二氯甲烷.甲醇=10 : 1)，得到本標題產物卜（3勹4一"-(3-氟〜苄基MH-吲唑-5-基胺基]_喹唑啉_6_基卜吡咯+基 [1，2,3]***-1-基—丙_2_醇285(19呢，黃色固體），產率. 15%。 MS m/z (ESI) ： 560[M+1] *HNMR (400MHz, DMS0-c?6) ： 5 9. 93 (s, 1H), 8. 68 (s, 1H) ® 8. 44 (s, 1H), 8. 24 (s, 1H), 8. 17 (s, 1H), 8. 11 (s, 1H)' 8. 05 (m, 1H), 7. 74 (m, 4H), 7. 49 (s, 1H), 7. 37 (m, 1H) 7.08(m, 3H), 6. 89 (s, 1H), 6. 74 (s, 1H), 5. 72 (s, 2H) 4. 49 (m, 1H), 4. 35 (m, 1H), 4. 22 (m, 1H), 4. 09 (m, 1H), 3. 94 (m, 1H) 實施例286 卜（3-{4-[1-·(3-氟-苄基）-〗h-吲唑-5-某胺基1-喹唑 . ---^ 鬱基比嘻-jz基）-3-(2-嗎喊-4-基-乙胺基）-丙-2-醇In the carbamide, it was cooled to hydrazine under ice bath conditions. €, sodium hydride (22 mg 〇 · 92 mmol) was added. After stirring for 30 minutes, [1, 2, 3]triazole (43 mg, 0.63 mmol) was added and heated to 50 ° C overnight. 20 mL of 482 94389 201016683 ice water and 20 虬 of dichloromethane were added to the reaction mixture, and the aqueous phase was extracted with di-methane (2 〇mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and evaporated. The obtained retort was concentrated and purified by a thin layer chromatography plate (dichloromethane.methanol = 10:1) to give the title product (3 勹 4 &"-(3-fluoro-benzyl) MH-carbazol-5-ylamino]-quinazoline_6_pyopyrrol+yl[1,2,3]triazol-1-yl-propan-2-ol 285 (19, yellow solid) , yield. 15%. MS m/z (ESI): 560[M+1] *HNMR (400MHz, DMS0-c?6): 5 9. 93 (s, 1H), 8. 68 (s, 1H ) ® 8. 44 (s, 1H), 8. 24 (s, 1H), 8. 17 (s, 1H), 8. 11 (s, 1H)' 8. 05 (m, 1H), 7. 74 (m, 4H), 7. 49 (s, 1H), 7. 37 (m, 1H) 7.08 (m, 3H), 6. 89 (s, 1H), 6. 74 (s, 1H), 5. 72 (s, 2H) 4. 49 (m, 1H), 4. 35 (m, 1H), 4. 22 (m, 1H), 4. 09 (m, 1H), 3. 94 (m, 1H) Example 286 (3-{4-[1-(3-fluoro-benzyl)-]h-carbazole-5-an amino-1-quinazole. ---^ 基基比嘻-jz base )-3-(2-?--4-yl-ethylamino)-propan-2-ol

94389 483 20101668394389 483 201016683

Ο 在100 mL$形瓶中，將[卜（3_說—节基）冬令坐一5 基]-[6-U-環氧乙基甲基_1Η-吡咯|基)_喹唑啉_4 一基] 胺178a(250 mg，〇. 51 mm〇i)溶解於3〇 ‘曱醇中，攪拌下加入2-嗎啉-4-基-乙胺（199 mg，！ 53 mmol)，反應液加熱回流過夜。將反應液在減壓下濃縮，得釗的殘留物藉由薄層層析板分離純化（二氣甲烧：曱醇=1〇 : 1) ’得到本標題產物1-(3-{4-[1-(3-氟-苄基）-ih-吲唑―5—基胺基]、喹唑啉-6-基}-吡咯-1-基）-3-(2-嗎啉-4-基—匕胺基）〜丙 -2-醇286 (54 mg，黃色固體），產率：17%。 MS m/z (ESI) ： 619[M+1] !HNMR (400MHz, DMS0-J6): ^ 9. 99 (s, 1H), 8. 73 (s, ΐΗ)^ 馨 8.45 (s，1H)，8.27 (s，1H)，8.17 (s，1H)，8.04 (m，1H)， 7. 76 (m，3H)，7· 51 (s，1H)，7. 37 (m，1H)，7. 08 (m，3H)， 6.92(s，1H)，6.75 (s，1H)，5.72 (s，2H)，4.23 (m’ 1们， 4. 07 (m，2H)，3. 56 (m，4H)，3. 18 (s，1H)，2. 84 (m，iH)， 2.60 (m, 4H), 2.39 (m, 4H) 實施例287 [卜（3-氟-苄某）-111-吲唑-5-基1-“-「1-(3-^^1^^、气臬）-1 H-吡咯-3-基1-喹唑琳-4-基丨-胺 484 94389 201016683Ο In a 100 mL $-shaped flask, [Bu (3_说-节基)) will sit a 5-base]-[6-U-epoxyethylmethyl-1Η-pyrrole|yl)_quinazoline_ 4 A group] Amine 178a (250 mg, 〇. 51 mm〇i) was dissolved in 3 〇 'sterol, and 2-morpholin-4-yl-ethylamine (199 mg, ! 53 mmol) was added with stirring. The liquid was heated to reflux overnight. The reaction solution was concentrated under reduced pressure, and the residue obtained was purified by chromatography (yield: dimethyl alcohol: oxime = 1 〇: 1) to give the title product 1-(3-{4- [1-(3-Fluoro-benzyl)-ih-carbazole-5-ylamino], quinazolin-6-yl}-pyrrol-1-yl)-3-(2-morpholin-4- Base-nonylamino)~propan-2-ol 286 (54 mg, yellow solid), yield: 17%. MS m/z (ESI): 619[M+1] !HNMR (400MHz, DMS0-J6): ^ 9. 99 (s, 1H), 8. 73 (s, ΐΗ)^ 馨 8.45 (s, 1H) , 8.27 (s, 1H), 8.17 (s, 1H), 8.04 (m, 1H), 7. 76 (m, 3H), 7· 51 (s, 1H), 7. 37 (m, 1H), 7 . . . (m, 3H) , 4H), 3. 18 (s, 1H), 2. 84 (m, iH), 2.60 (m, 4H), 2.39 (m, 4H) Example 287 [Bu (3-fluoro-benzyl)-111 -carbazol-5-yl 1-"-"1-(3-^^1^^, gas oxime)-1 H-pyrrol-3-yl-1-quinazoline-4-ylindole-amine 484 94389 201016683

287287

第一步 4-(3-溴-丙基）-嗎琳將嗎琳（4 mL，49.36 mmol )、1，3-二漠丙基（25 mL， 245 mmol)溶於三乙胺（27.5 mL，197 mmol)中，室溫下搜 _拌過夜，有白色固體生成’加入2 mL甲醇溶解，混合物藉 g ’淡黃色固體），產由石夕膠管柱層析法進一步分離純化(沖提劑：乙酸乙醋）：得到4-(3_溴-丙基）-嗎啉287a(l. 率：12% 。第二步 -(3 -嗎嚇_-4-基-丙 ¥ 基）-1H-10引嗤-5_ [1-（3-氟-节基）-111-吲唑-5-基]-{6〜[1 基）-1Η-吡咯-3-基]-喹唑啉_4_基卜胺在100此茄形瓶中，將[1-(3~氣 94389 485 201016683 基]-[6-(卜環氧乙基甲基_ih-吡咯-3-基）—喹唑啉_4_基卜胺 178a(100 mg，0.23 mmol)溶解於 5 mL 無水 Ν，Ν-二甲基曱醯胺中，在冰浴條件下，冷卻至〇〇c，加入氫化鈉（22 mg ’ 0. 92 mmol)，攪拌30分鐘後加入4-(3-溴-丙基）-嗎啉287a(79 mg’ 0.38 mmol)’室溫下攪拌3小時反應完畢。反應液中加入20 mL冰水和20 mL二氣甲烷，分液，水相用一乳曱烧萃取（20 mLx3 )’合併的有機相經由無水硫酸鈉脫水，過濾，減壓下濃縮，得到的殘留物進一步藉由薄層層析板分離純化（二氣甲烷：甲醇=10 : 1)，得到本標題產 ® 物[1-(3-氟-苄基）-1Η-,β坐-5-基]-{6-[1-(3-嗎琳-4-基-丙基）-1Η-σ比ρ各-3-基]-啥嗤琳-4-基}-胺287(19 mg，黃色固體），產率：15%。 ’ MS m/z (ESI) ： 562[M+1] !HNMR (400MHz, DMSO-c?^): ^ 9. 82 (s, 1H), 8. 61 (s, 1H), 8.45 (s, 1H), 8.247 (s, 1H), 8.17 (s, 1H), 8.05 (m, 1H), 7.77 (m, 3H), 7.44 (m, 2H), 7.14 (m, 3H), 6.91 〇 (s, 1H), 6. 68 (s, 1H), 5. 72 (s, 2H), 4. 00 (m, 2H), 3. 60 (m, 4H), 2. 50 (m, 6H), 1. 94 (m, 2H) 實施例2 8 8 4-「3_(3-{4-「3-氯-4-(3-氟苄氧某）-装胺基]-嗜啥咐—只_ 11-吡咯某）-2-羥基-丙某1-哌啡-2-酮The first step 4-(3-bromo-propyl)-Merline was dissolved in triethylamine (27.5 mL) (4 mL, 49.36 mmol), 1,3-di-propylpropyl (25 mL, 245 mmol). , 197 mmol), at room temperature, _ overnight, a white solid formed 'add 2 mL of methanol to dissolve, the mixture borrowed g 'light yellow solid), and the product was further separated and purified by Shixi rubber column chromatography (purification agent) : ethyl acetate (acetic acid): 4-(3-bromo-propyl)-morpholine 287a (l. rate: 12%. second step - (3 - stimuli _-4-yl-propyl base)-1H -10引嗤-5_ [1-(3-Fluoro-nodal)-111-oxazol-5-yl]-{6~[1yl)-1Η-pyrrol-3-yl]-quinazoline_4 _Kipamine in 100 eggplant-shaped flasks, [1-(3~gas 94389 485 201016683 yl]-[6-(p-epoxyethylmethyl-ih-pyrrol-3-yl)-quinazoline _4_Kipamine 178a (100 mg, 0.23 mmol) was dissolved in 5 mL of anhydrous hydrazine, hydrazine-dimethyl decylamine, cooled to 〇〇c under ice bath, and sodium hydride (22 mg ' was added. 0. 92 mmol), after stirring for 30 minutes, 4-(3-bromo-propyl)-morpholine 287a (79 mg '0.38 mmol) was added. The reaction was stirred at room temperature for 3 hours. 20 mL of ice water was added to the reaction mixture. And 20 mL Dihydromethane, liquid separation, aqueous phase extraction with a decidient (20 mL×3 ). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was further separated by thin layer chromatography. Purification (di-gas methane:methanol = 10:1) gave the title product [1-(3-fluoro-benzyl)-1Η-, β-s--5-yl]-{6-[1-(3 -Mulline-4-yl-propyl)-1 Η-σ ratio ρ-3-yl]-indolyl-4-yl}-amine 287 (19 mg, yellow solid), yield: 15%. MS m/z (ESI): 562 [M+1] "HNMR (400 MHz, DMSO-c?): ^ 9. 82 (s, 1H), 8. 61 (s, 1H), 8.45 (s, 1H) ), 8.247 (s, 1H), 8.17 (s, 1H), 8.05 (m, 1H), 7.77 (m, 3H), 7.44 (m, 2H), 7.14 (m, 3H), 6.91 〇(s, 1H ), 6. 68 (s, 1H), 5. 72 (s, 2H), 4. 00 (m, 2H), 3. 60 (m, 4H), 2. 50 (m, 6H), 1. 94 (m, 2H) Example 2 8 8 4-"3_(3-{4-"3-Chloro-4-(3-fluorobenzyloxy)-amino group]-isophilic-only _ 11-pyrrole -2-hydroxy-propyl 1-piperidin-2-one

94389 268 486 20101668394389 268 486 201016683

哌卩井-2-酮（60 mg，〇· 6 mm〇i)溶解於3〇 mL曱醇中，攪拌下加入[3-氣-4-(3-•氟-苄氧基）_苯基]_[6_(卜環氧乙基甲基-1H-吡咯-3-基）一喹唑啉_4_基]一胺187a(25〇呃，瘺0.51 mmol)’混合液加熱回流過夜。反應液在減壓下濃縮，得到的殘留物藉由矽膠管柱層析法分離純化（二氣甲烷：甲醇=30 : 1)，得到本標題產物4-[3-(3-{4-[3-氯-4-(3-氟苄氧基）-苯胺基]-喹唑啉—6_基丨―„比咯-卜基）_2_經基-丙基]-〇辰哄-2-酮288(72 mg，黃色固體），產率：4〇.1%。 MS m/z (ESI) ： 601[M+] !H NMRC400 MHz, DMS0-d6) ： <5 9. 69 (s, 1H), 8. 54 (s, 1H), 8. 50(s, 1H), 8.04(m, 2H), 7.75 (m, 2H), 7.47 (m, 1H), ^ 7. 40 (m, 1H), 7. 30 (m, 3H), 7. 19 (m, 1H), 6. 88 (s, 1H), 6.68 (s, 1H), 5.27 (s, 2H), 5.05 (br, 1H), 3.98 (m, 3H), 3.19 (m, 2H), 2.64 (m, 2H), 2.35 (m, 2H), 1.23 (m, 2H) 實施例289 {6_「5~(4_胺基_口底口定_1_基甲基）-111-。比口各-3-某~|-喧1»坐淋 -4-基卜「3-氣-4-(3-氟-苄氣某策基1-胺 487 94389 201016683Piperazine-2-one (60 mg, 〇·6 mm〇i) was dissolved in 3 mL of sterol and [3- gas-4-(3-•fluoro-benzyloxy)-phenyl was added with stirring. ]_[6_(p-Epoxyethylmethyl-1H-pyrrol-3-yl)-quinazoline-4-yl]monoamine 187a (25 〇呃, 瘘 0.51 mmol). The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by methylene chloride column chromatography (di-methane:methanol = 30:1) to give the title product 4-[3-(3-{4-[ 3-Chloro-4-(3-fluorobenzyloxy)-anilino]-quinazoline-6-ylindole-„比咯-卜基)_2_ 经基-propyl]-〇辰哄-2- Ketone 288 (72 mg, yellow solid), yield: 4 〇.1% MS m/z (ESI): 601 [M+] !H NMRC400 MHz, DMS0-d6): <5 9. 69 (s, 1H), 8. 54 (s, 1H), 8. 50(s, 1H), 8.04(m, 2H), 7.75 (m, 2H), 7.47 (m, 1H), ^ 7. 40 (m, 1H) ), 7. 30 (m, 3H), 7. 19 (m, 1H), 6. 88 (s, 1H), 6.68 (s, 1H), 5.27 (s, 2H), 5.05 (br, 1H), 3.98 (m, 3H), 3.19 (m, 2H), 2.64 (m, 2H), 2.35 (m, 2H), 1.23 (m, 2H) Example 289 {6_"5~(4_胺基_口底口定_1_基基)-111-. Comparing the mouth of each -3-some ~|-喧1» sitting -4- keb "3-gas-4-(3-fluoro-benzyl sulfene 1-amine 487 94389 201016683

h2nH2n

289289

(1-苄基-旅唆-4-基）-胺基曱酸第三丁酯(1-benzyl-tray-4-yl)-aminobutyl citrate

將卜苄基-哌啶-4-基胺（2. 05 mL，10 mmol)溶於20 mL —氣甲院中’用惶壓滴液漏斗緩慢滴加二碳酸二第三丁醋 (2.43 g，11 mmol)的20 mL二氯甲烷溶液，室溫下攪拌過夜。將反應液在減壓下濃縮，得到的殘留物藉由矽膠技衽層析法進一步分離純化（二氯甲烷：甲醇=25:丨），得 94389 488 201016683 苄基-派啶-4-基）-胺基曱酸第三丁酯289a(2.91 g,白色固體），產率：100%。 MS m/z (ESI) ： 291[M+1] 第二步哌啶-4-基-胺基甲酸第三丁酯將（1-苄基-哌啶-4-基）-胺基曱酸第三丁酯289a(2. 9 g’ 10 mmol)溶於150 mL曱醇中，攪拌下加入pd/C(〇. 4 g)，用氫氣置換空氣4次，在30°C下催化加氫反應24小時。過濾’減壓下濃縮濾液’得到π辰唆_4_基-胺基甲酸第三丁 ® 酯 289b(l· 96 g ’ 白色固體），產率·· 98〇/〇。 MS m/z (ESI) ： 201[M+1] 第三步 4 {4 [3氯- 4- (3 -氣卞乳基）-苯胺基]-啥嗤淋—6_基丨吡咯-2-曱醛將30 mL無水N，N-二甲基曱醯胺，冰浴下冷卻至，加入三氣氧磷（918 mg，6 mmol)，攪拌1小時後，〇°c下加鑤入[3-氣_4-(3-氟-苄氧基）-苯基]_[β_(1Η_σ比咯_3_基）一喹唑啉-4-基]-胺42(1· 776 g，4 mmol)，室溫下攪拌3小時反應完畢。加入10 mL水淬滅反應，用乙酸乙酯萃取（1 〇〇 mL x3)，合併的有機相經由無水硫酸鈉脫水，過濾，減壓下濃縮’得到的殘留物藉由石夕膠管柱層析法進一步分離純化（正己烷：乙酸乙酯=2:1)，得到4-{4-[3-氯-4-(3-氟苄氧基）-苯胺基]-喹唑琳-6-基}-111-吼洛-2-甲醛289c(300 mg，黃色固體），產率：15. 9%。 94389 489 201016683 MS m/z (ESI) ： 473[M+1] 第四步 [1-(4-{4-[3-氯-4-(3-氟苄氧基）-苯胺基]-喹唑啉-6-基丨-ΙΗ-吡咯-2-基甲基）-哌啶-4-基]-胺基曱酸第三丁酯將4-{4-[3-氯-4-(3-氟苄氧基）-苯胺基]-喹唑啉-6-基}-111-0比洛-2-曱酸 289c(216 mg，0.46 mmol)，0底0定-4-基-胺基曱酸第三丁醋（183mg，0.92 mmo 1)和三（乙醯氧基）棚氫化鈉（1. 94 g，9.2 mmol)溶於20 mL二氯曱烧中，在 35C下挽摔過夜。在反應液中加入20 mL飽和碳酸氮納溶 v液谇滅反應’用二氯曱烷萃取（100 mLx3)，合併的有機相經由無水硫酸鈉脫水，過濾，減壓下濃縮，得到的殘留物藉由石夕谬管柱層析進一步分離純化（二氯甲烧：甲醇=1〇〇 : 1)，得到[1-(4-{4-[3-氯-4-(3-氟苄氧基）-苯胺基]-喹唾啉-6-基卜1H-吡咯-2-基甲基）-哌啶-4-基]-胺基曱酸第三丁酯289d (210 mg ’黃色固體），產率：7〇%。 MS m/z (ESI) ： 657[M+1] ❾第五步 {6-[5-(4-胺基-哌啶_：i-基曱基）一1H_咄咯_3基]一喹唑啉 -4-基}-[3-氯-4-(3-氟-苄氧基）-苯基μ胺將[1 (4 {4-[3-氯-4-(3-氟节氧基）一苯胺基]_啥0坐琳 -6-基卜1H-料-2-基甲基基]胺基甲酸第三丁酯289d(210 mg，〇. 32 mmol)溶於1〇虬二氯曱烷中攪摔下加入1.05 mL三氟乙酸，室溫下授拌時反^完畢= 在反應液中加入氨水，使溶液呈驗性，分出有機層，水相 94389 490 201016683 用二氯甲烷萃取（100 mLx3)，合併的有機相經由無水硫酸鈉脫水，過濾，減壓下濃縮，得到的殘留物藉由石夕膠管柱層析進一步分離純化（二氯曱烷：甲醇=1〇〇 : 1)，得到標題產物{6-[5-（4-胺基-旅咬-1-基曱基）-lH-〇比洛—3-基]一嗤唑啉-4-基}-[3-氯-4-(3-氟-苄氧基）-苯基]—胺289(17〇 mg，黃色固體），產率：95%。 MS m/z (ESI) ： 557[M+1] !H NMRC400 MHz , CD30D-d(5): (5 8. 746 (s, 1H), 8 677 (s 1H), 8.296 (d, /=1. 2Hz, 1H), 7.94 (S, 1H), 7. 823 ® /=9. 2Hz, 1H), 7.661 (in, 1H), 7.465 (m, 2H), 7. 398 實施例2 9 0 1H)，7.266 (s, 1H), 7.237 (s, 1H), 7.089 (m, 1H)，6·二 (s，1H)，5.282 (s，2H)，4· 399 (s，2H)，3·645 (d * /=12. 8Hz，2H)，3.161 (m，2H)，2.309 (d，/=12· 〇Hz 2fn’ ' 2.018 (m，2H) ’ ’Dissolve benzyl-piperidin-4-ylamine (2. 05 mL, 10 mmol) in 20 mL - gas chamber. Slowly add diacetate diacetate (2.43 g, 11) with a dropping funnel. A solution of 20 mL of dichloromethane in mmol) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was further purified and purified by chromatography (dichloromethane:methanol = 25: hexane) to give 94 389 488. - Amino butyl citrate 289a (2.91 g, white solid), Yield: 100%. MS m/z (ESI): 291 [M + 1], </RTI> <RTIgt; </RTI> </RTI> <RTIgt; The third butyl ester 289a (2.9 g' 10 mmol) was dissolved in 150 mL of decyl alcohol, and pd/C (〇. 4 g) was added with stirring, and the air was replaced with hydrogen for 4 times, and catalytic hydrogenation was carried out at 30 °C. Reaction for 24 hours. Filtration and concentration of the filtrate under reduced pressure afforded π 唆唆 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ MS m/z (ESI): 201 [M+1] Step 3 4 [4 [3 chloro- 4- (3 - acetonyl)-anilinyl]-indole- 6-ylpyrrole-2 - furfural 30 mL of anhydrous N,N-dimethyl decylamine, cooled to an ice bath, added with phosphorus oxyphosphorus (918 mg, 6 mmol), stirred for 1 hour, then added under 〇 °c [ 3-Gas_4-(3-Fluoro-benzyloxy)-phenyl]_[β_(1Η_σ比咯_3_yl)-quinazolin-4-yl]-amine 42 (1·776 g, 4 Methyl), the reaction was completed by stirring at room temperature for 3 hours. The reaction was quenched by the addition of 10 mL EtOAc (EtOAc)EtOAc. Further separation and purification (n-hexane:ethyl acetate = 2:1) gave 4-{4-[3-chloro-4-(3-fluorobenzyloxy)-anilino]-quinazoline-6-yl 9%。 </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 94389 489 201016683 MS m/z (ESI): 473[M+1] Step 4 [1-(4-{4-[3-chloro-4-(3-fluorobenzyloxy)-anilino]-quin 3-oxazol-6-ylindole-indole-pyrrol-2-ylmethyl)-piperidin-4-yl]-amino decanoic acid tert-butyl 4-(4-[3-chloro-4-(3) -fluorobenzyloxy)-anilino]-quinazolin-6-yl}-111-0, piroxime-2-decanoic acid 289c (216 mg, 0.46 mmol), 0-but-4-yl-amino group Sodium citrate (183 mg, 0.92 mmo 1) and tris(acetoxy) sodium hydride (1. 94 g, 9.2 mmol) were dissolved in 20 mL of dichlorohydrazine and allowed to fall overnight at 35 °C. The reaction mixture was quenched by the addition of 20 mL of a saturated solution of sodium carbonate. The mixture was extracted with dichloromethane (100 mL×3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered and evaporated. Further separation and purification by means of Shi Xixi column chromatography (dichloromethane: methanol = 1 〇〇: 1) gave [1-(4-{4-[3-chloro-4-(3-fluorobenzyloxy) - phenylamino]-quinoline-6-ylbu- 1H-pyrrol-2-ylmethyl)-piperidin-4-yl]-amino decanoic acid tert-butyl ester 289d (210 mg 'yellow solid) , Yield: 7〇%. MS m/z (ESI): 657 [M+1] ❾ Step 5 {6-[5-(4-Amino-piperidine-:i-ylindenyl)-1H_咄_3yl] Quinazolin-4-yl}-[3-chloro-4-(3-fluoro-benzyloxy)-phenylimamine will [1 (4 {4-[3-chloro-4-(3-fluoro] Oxy)monophenylamino]_啥0 sitin-6-kib 1H-benzyl-2-ylmethyl]aminobutyl butyl tert-butyl 289d (210 mg, 〇. 32 mmol) dissolved in 1 〇虬Add 1.05 mL of trifluoroacetic acid to the dichloromethane and add it to the mixture at room temperature. Add the ammonia solution to the reaction solution to make the solution detectable. The organic layer is separated. The aqueous phase is 94389 490 201016683. The methyl chloride was extracted (100 mL×3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue obtained was further purified by chromatography on silica gel column chromatography (dichloromethane: methanol = 1 〇) 〇: 1), the title product is obtained {6-[5-(4-Amino-Brigade-1-ylindenyl)-lH-indolo-3-yl]-oxazolin-4-yl}- [3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-amine 289 (17 mg, yellow solid), yield: 95%. MS m/z (ESI): 557[M+ 1] !H NMRC400 MHz , CD30D-d(5): (5 8. 746 (s, 1H), 8 677 (s 1H), 8.2 96 (d, /=1. 2Hz, 1H), 7.94 (S, 1H), 7. 823 ® /=9. 2Hz, 1H), 7.661 (in, 1H), 7.465 (m, 2H), 7. 398 Example 2 9 0 1H), 7.266 (s, 1H), 7.237 (s, 1H), 7.089 (m, 1H), 6·2 (s, 1H), 5.282 (s, 2H), 4· 399 (s , 2H), 3·645 (d * /=12. 8Hz, 2H), 3.161 (m, 2H), 2.309 (d, /=12· 〇Hz 2fn' ' 2.018 (m, 2H) ' '

鑛-n比略-I-基）-l-嘆唾烧-3-基-乙綱Ore-n ratio slightly-I-based)-l-snail-salt-3-yl-ethyl

94389 491 201016683 第一步 290a94389 491 201016683 First step 290a

290290

CNH 第一步 2-氯-1-嗟《坐烧-3-基-乙酮將嗟唾燒（332 mg，3.73麵1)溶於1G虹二氯甲院中’溶液在丙酮-乾冰浴下冷卻至_7rc，攪拌下加入lmL 三乙胺和氯乙醯氯(505吨，4.47随〇1)，維持此溫度攪拌 40分鐘反應完畢。反應液在減壓下濃縮，得到的殘留物藉由矽膠管柱層析法分離純化（二氯甲烷：甲醇=丨〇 : ^ 得到2-氯-1-噻唑烷-3-基-乙酮29〇a(338 mg，無色油狀液體），產率：54. 6% 〇 φ MS m/z (ESI) ： 167[M+1] 第二步 2-(3-{4-[3-氣-4-(3-氟-苄氧基）-苯胺基]-喹唑琳_6〜基} 比嘻-1-基）-1-嗟唾烧-3-基-乙酮在50 mL的燒瓶中，將[3-氣-4-(3-氟-苄氧基）-笨基] -[6-(1Η-吡咯-3-基）-喹唑啉-4-基]-胺 42(500 mg，112 mmol)溶於1〇 mL無水N，N-二曱基曱醯胺中，在冰浴條件下’冷卻至0(2，加入氫化納（13411^，5.62111111〇1)，授摔 94389 492 201016683 30分鐘後加入2-氯-1-隹〇坐烧_3_基-乙鋼290a(224 mg， 1. 35 mmol) ’室溫下攪拌2小時反應完畢。反應液加入50 mL水，用乙酸乙醋萃取（50 mLx4)，合併的有機相經由無水硫酸鈉脫水’過濾，減壓下濃縮，得到的殘留物藉由發膠管柱層析法進一步分離純化（二氯曱烷：曱醇=40 : 1)，付到本標題產物2-(3-{4-[3 -氯-4-(3 -氟-爷氧基）-苯胺基]-噎0坐琳-6-基}-»比洛-1-基）-i-嗟嗤烧-3-基-乙酿I 290 (442 mg ’黃色固體），產率：60%。 MS m/z (ESI) ： 574[M+1] Φ !H NMRC400 MHz, DMS0-d6): 5 9. 69 (s, 1H), 8. 54 (s, 1H), 8. 50 (s, 1H), 8. 04 (m, 2H), 7. 75 (in, 2H), 7. 47 (m, 1H), 7.40 (m, 1H), 7.30 (m, 3H), 7. 19 (m, 1H), 6. 88 (s, 1H), 6.68(s, 1H), 5.27(s, 2H), 4. 98 (s, 2H), 4. 65 (s, 1H), 4. 51 (s, 1H), 3. 82 (m, 1H), 3. 71 (m, 1H), 3. 18 (m, 1H), 3. 04 (m, 1H) 實施例291CNH First Step 2-Chloro-1-indole "Sit-burn-3-yl-ethanone sputum sputum (332 mg, 3.73 face 1) dissolved in 1G iridium dichloride chamber" solution in acetone-dry ice bath Cool to _7rc and add 1 mL of triethylamine and chloroacetic chloride (505 ton, 4.47 followed by )1) with stirring. Maintain the temperature and stir for 40 minutes. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by methylene chloride column chromatography (dichloromethane:methanol: hexane: 〇a (338 mg, colorless oily liquid), yield: 54.6% 〇φ MS m/z (ESI): 167[M+1] Step 2 2-(3-{4-[3-gas -4-(3-Fluoro-benzyloxy)-anilino]-quinazoline _6-yl} 嘻-1-yl)-1-hydrazin-3-yl-ethanone in 50 mL flask , [3-Ga-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinazolin-4-yl]-amine 42 (500 Mg, 112 mmol) dissolved in 1 mL of anhydrous N,N-didecylamine, cooled to 0 (2, added sodium hydride (13411^, 5.62111111〇1), dropped 94389 under ice bath conditions 492 201016683 After 30 minutes, add 2-chloro-1-indole _3_yl-ethylene 290a (224 mg, 1. 35 mmol). Stir at room temperature for 2 hours. Add 50 mL of water to the reaction solution. It was extracted with ethyl acetate (50 mL×4), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was further purified by gel column chromatography (dichloromethane: =40 : 1), to the title product 2-(3-{4-[3-chloro-4-(3-fluoro-yloxy)-anilino]-噎0 sits 琳-6-yl}- »Bilo-1-yl)-i-oxime-3-yl-ethyl I 290 (442 mg 'yellow solid), yield: 60%. MS m/z (ESI): 574[M+1 ] Φ !H NMRC400 MHz, DMS0-d6): 5 9. 69 (s, 1H), 8. 54 (s, 1H), 8. 50 (s, 1H), 8. 04 (m, 2H), 7 75 (in, 2H), 7. 47 (m, 1H), 7.40 (m, 1H), 7.30 (m, 3H), 7. 19 (m, 1H), 6. 88 (s, 1H), 6.68 (s, 1H), 5.27(s, 2H), 4. 98 (s, 2H), 4. 65 (s, 1H), 4. 51 (s, 1H), 3. 82 (m, 1H), 3 . 71 (m, 1H), 3. 18 (m, 1H), 3. 04 (m, 1H) Example 291

94389 493 20101668394389 493 201016683

jOlf 第一步酯 «1.6mg’ 〇.39_卜 Alfa)溶解於 '醇中’授拌下加入[3-氯+ (3-氟-节氧基）—苯基]一 [6-U-環氧乙基ψ基鲁吼㈣幻啥㈣_4_基卜胺 187a(196 mg，〇· 39 mmol) ’混合液加熱回流過夜。反應 ❹液在減壓下濃縮，得到的殘留物藉由石夕谬管柱層析法分離純化（二氯甲烷：甲醇=10 : 1：)，得到標題產物 [3-氯-4-(3-氟苄氧基）_苯胺基]-喹唑啉_6_基卜吼咯_卜基）-2-羥基-丙基]-哌啶_3_甲酸乙酯291 (220 mg，黃色固體），產率：85. 4%。 ’ MS m/z (ESI) ： 658[M+1] 1HNMR(400 MHz, DMSO-^)： ^ 9. 67 (s, 1H), 8. 5 (s, 2H), 8.0 (s, 2H), 7.7 (s, 1H), 7.69 (m, 1H), 7.5 (m, 2H), φ 7.36 (m, 3H), 7.2 (m, 1H), 6.93 (m, 1H), 6.60 (s, 1H), 5. 27 (s, 2H), 5. 05 (s, 1H), 4. 06 (m, 1H), 3. 89 (m, 2H), 2. 83 (in, 1H), 2. 62 (m, 2H), 2. 27 (m, 4H), 1. 76 (m, 2H), 1.50 (m, 2H), 1.44 (m, 2H), 1.24 (m, 3H) 實施例292 2-(3-{4-「3-氣-4-(3-氟-苄1篡赛胺某1-喹唑啉-fi-篡} -吡咯-1-基）-1-(1, 1-二側氳篡-1 \ 木-硫代嗎啉-4-篡）-乙酮 494 94389 201016683jOlf first ester «1.6mg' 〇.39_卜 Alfa) dissolved in 'alcohol' with the addition of [3-chloro + (3-fluoro-oxyl)-phenyl]-[6-U- Epoxyethyl decyl ruthenium (4) illusion (4) _4_ ketamine 187a (196 mg, 〇· 39 mmol) The mixture was heated to reflux overnight. The reaction mash was concentrated under reduced pressure, and the obtained residue was purified by chromatography (dichloromethane: methanol = 10: 1:) to give the title product [3-chloro-4- (3) -fluorobenzyloxy)-anilino]-quinazoline -6- carbazyl-bromo-2-hydroxy-propyl]-piperidine _3-carboxylic acid ethyl ester 291 (220 mg, yellow solid) , yield: 85.4%. ' MS m/z (ESI): 658 [M+1] 1H NMR (400 MHz, DMSO-^): </ RTI> </ RTI> </ RTI> , 7.7 (s, 1H), 7.69 (m, 1H), 7.5 (m, 2H), φ 7.36 (m, 3H), 7.2 (m, 1H), 6.93 (m, 1H), 6.60 (s, 1H) , 5. 27 (s, 2H), 5. 05 (s, 1H), 4. 06 (m, 1H), 3. 89 (m, 2H), 2. 83 (in, 1H), 2. 62 ( m, 2H), 2. 27 (m, 4H), 1. 76 (m, 2H), 1.50 (m, 2H), 1.44 (m, 2H), 1.24 (m, 3H) Example 292 2-(3 -{4-"3-Gas-4-(3-fluoro-benzyl- 1 oxetamide-l-quinazoline-fi-篡}-pyrrol-1-yl)-1-(1,1-di-terpenoid篡-1 \木-thiomorpholine-4-篡)-ethanone 494 94389 201016683

第一步 2-氯-1-(1, 1-一侧氧基-1 λ *6*-硫代嗎琳-4-基）-乙酮將硫代嗎琳1，1-二氧化物（150 mg，1.11 mm〇i)溶於 20 mL四氫吱喃中，在乾冰乙醇浴冷卻至，授拌下逐漸滴加三乙胺（〇. 14 mL，1. 11 mmol)和氣乙醯氯（126 mg，瘳1. 11 mmol)，滴加完畢在冰浴冷卻下攪拌2小時反應完畢。反應液在減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化（二氯甲烷：曱醇=1 : 1)，得到2_氯-卜 (1，1-二側氧基-1又)硫代嗎琳-4-基）-乙酮192a，產物不經分離直接進行下一步反應。第二步 2-(3-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-啥唾琳—6-基} -吡咯-1-羞J-卜（1，卜二側氧基又硫代嗎啉_4_基）_ 495 94389 201016683 乙酮將化合物[3-氯-4-(3-氟-苄氧基）-苯基]-[6-(1Η-吼嘻一3_基喹唑啉-4-基]-胺42(444 mg，1 mmol)和氫化納（120 mg ’ 5 mmol)溶於10 mL N，N-二甲基甲醯胺中，室溫下攪拌30分鐘後加入2-氯-1-(1,卜二侧氧基-1 λ *6* -硫代嗎啉-4-基）-乙酮292a(235 mg，1. 11 mmol)，反應液加熱至501，2小時後反應完畢。反應液在減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化（二氯 ©甲垸：甲醇=50 : 1)，得到標題產物2-(3-{4-[3-氯-4-(3-氟-卞氧基）-苯胺基]-喧〇坐嚇-6-基}-°比哈_1_基）-1-(1，1-二侧氧基-1又*6*-硫代嗎啉-4-基）-乙酮292(15 mg，黃色固體），產率：5. 1%。 MS m/z (ESI) ·· 620[M+1] • !H NMR(400 MHz , MS0-d6)： 69. 67 (s, 1H), 8. 5 (s, 2H), 8.0 (s, 2H), 7.7 (s, 1H), 7.69 (m, 1H), 7.5 (m, 2H), 7.36 (m, 3H), 7.2 (m, 1H), 6.93 (m, 1H), 6. 60 (s, 1H), Q 5.27 (s, 2H), 3.92 (s, 4H), 3.15 (s, 2H) 實施例293 2-U-{4-「3-氣-4-(3-氟-苄氧其V养胺基]二喹唑啾-fi-篡} ~〇比洛-1-基嗎嚇 -4-某-娘攻-i-基）_乙酮The first step of 2-chloro-1-(1,1-one-oxy-1 λ *6*-thio- phenanthryl-4-yl)-ethanone will be thiomorphin 1,1-dioxide ( 150 mg, 1.11 mm〇i) was dissolved in 20 mL of tetrahydrofuran, cooled in a dry ice ethanol bath, and gradually added triethylamine (〇. 14 mL, 1.11 mmol) and acetonitrile (with stirring). 126 mg, 瘳1. 11 mmol), and the reaction was completed by stirring for 2 hours under ice-cooling. The reaction solution was concentrated under reduced pressure, and the obtained residue was further purified and purified by methylene chloride column chromatography (dichloromethane: decyl alcohol = 1 : 1) to give 2-chloro-b Base-1 again) thiomorphin-4-yl)-ethanone 192a, the product was directly subjected to the next reaction without isolation. The second step 2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-anilino]-啥琳 — - 6-yl}-pyrrole-1- shy J-b ( 1, bis-oxo-thiomorpholine _4_yl)_495 94389 201016683 Ethyl ketone will be the compound [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-( 1Η-吼嘻-3_ quinazolin-4-yl]-amine 42 (444 mg, 1 mmol) and sodium hydride (120 mg '5 mmol) dissolved in 10 mL of N,N-dimethylformamide After stirring at room temperature for 30 minutes, 2-chloro-1-(1,b-dioxy-1 λ*6*-thiomorpholin-4-yl)-ethanone 292a (235 mg, 1. 11 mmol), the reaction liquid was heated to 501, and the reaction was completed after 2 hours. The reaction liquid was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (dichloro-methylhydrazine: methanol = 50: 1), the title product 2-(3-{4-[3-chloro-4-(3-fluoro-indolyl)-anilinyl]-anthracene--6-yl}-°biha_1 _基)-1-(1,1-di-l-oxy-1 and *6*-thiomorpholin-4-yl)-ethanone 292 (15 mg, yellow solid), yield: 5. 1% MS m/z (ESI) ·· 620[M+1] • !H NMR (400 MHz , MS0-d6): 69. 67 (s, 1H), 8. 5 (s, 2H), 8.0 (s , 2H), 7.7 (s, 1H), 7.69 ( m, 1H), 7.5 (m, 2H), 7.36 (m, 3H), 7.2 (m, 1H), 6.93 (m, 1H), 6. 60 (s, 1H), Q 5.27 (s, 2H), 3.92 (s, 4H), 3.15 (s, 2H) Example 293 2-U-{4-"3-Gas-4-(3-fluoro-benzyloxy)V-amino-amine]diquinazolium-fi-篡} ~ 〇洛洛 -1- 吗吗 -4- 某某某某某某娘娘娘娘娘娘娘娘

496 94389 201016683496 94389 201016683

第一步 2-氣-1-(4-嗎琳-4-基-娘咬_；[一基）_乙酮將4-嗎啉-4-基-哌啶（176 mg，丨· 〇3咖〇1)溶於2〇虹四氫呋喃中，在乾冰乙醇浴冷卻至_78。〇，攪拌下依次加入二乙胺（0. 13 mL，1. 03 mmol)和氯乙醯氯（115 mg，！〇2 mmol)’滴加完畢在冰浴冷卻下攪拌2小時反應完畢。反應液在減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一 .步分離純化（二氯曱烷：甲醇=1 : 1)，得到2-氣-1-(4-嗎啉-4-基-哌啶-1 —基）_乙酮293a，產物不經分離直接進行下一步反應。 ❹第二步 2_(3-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-喹唑啉-6 —基} 比洛-1-基）-1-(4-嗎啉-4-基-哌啶-1-基）-乙酮將化合物[3-氣- 4-(3 -氟-节氧基）-苯基]-[6-(1Η-π比嘻-3-基）-喹唑啉_4-基]-胺42(444 mg，1 mmol)和氫化納（120 mg，5 mmol)溶於10 mL N，N-二曱基甲醯胺中，至〉皿下擾摔30分鐘後加入2_氯_1-(4_嗎嚇·_4 -基-娘咬_1-基）-乙酮 293a(252 mg，1. 02 mmol)，反應液加熱至 50。(：， 497 94389 201016683 2小時後反應完畢。反應液在減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化（二氯曱烷：甲醇 = 50: 1)’得到標題產物2-(3-{4-[3 -氯- 4- (3 -說-节氧基）-苯胺基]-啥°坐琳-6-基}-σ比洛-1-基）-1-(4-嗎琳-4-基-派啶-卜基）-乙酮293(240 mg，黃色固體），產率：36. 7%。 MS m/z (ESI) ： 655[M+1] NMRC400 MHz , DMS0-d5): 5 9. 67 (s, 1H), 8. 5 (s, 2H), 8.0 (s, 2H), 7.7 (s, 1H), 7.69 (m, 1H), 7.5 (m, 2H), 7.36 (m, 3H), 7.2 (m, 1H), 6.93 (m, 1H), 6.60 (s, 1H), ® 5.27 (s, 2H), 4.96 (m, 2H), 4.34 (d, J = 8, 1H), 3.92 (d，J = 13.6, 1H)，3.56 (d，J:4, 4H)，3.18 (d, J=5.2, 1H)，3.06 (t，J = 12，1H)，2.67 (t，J = 12.8，1H)，2.47 ’ (m, 4H), 1. 8 (s, 2H)1. 3 (m, 2H) : 實施例294 「1-(3-氟-苄基）-1Η-吲唑-5-基l-「6-(1-嗎啉-2-基曱基 -1 Η-口比口各-3-基）-喧口坐琳-4-基]-胺The first step 2-gas-1-(4-morphin-4-yl-ninja bite_; [monoyl]-ethanone 4-morpholin-4-yl-piperidine (176 mg, 丨·〇3 Curry 1) Dissolved in 2 〇 rainbow tetrahydrofuran and cooled to _78 in a dry ice ethanol bath. After stirring, diethylamine (0.13 mL, 1.03 mmol) and chloroacetic chloride (115 mg, 〇2 mmol) were successively added, and the mixture was stirred under ice-cooling for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by methylene chloride column chromatography (dichloromethane:methanol =1:1) 4-yl-piperidine-1-yl)-ethanone 293a, the product was directly subjected to the next reaction without isolation. ❹Step 2 2_(3-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-anilino]-quinazolin-6-yl}Bilo-1-yl)-1- (4-morpholin-4-yl-piperidin-1-yl)-ethanone compound [3- gas-4-(3-fluoro-hydroxy)-phenyl]-[6-(1Η-π) More than indol-3-yl)-quinazoline-4-yl]-amine 42 (444 mg, 1 mmol) and sodium hydride (120 mg, 5 mmol) dissolved in 10 mL of N,N-dimercaptocaramine In the middle, to the dish under the dish for 30 minutes, add 2_chloro_1-(4_?, _4-yl-nitopic bite-l-yl)-ethanone 293a (252 mg, 1.02 mmol), reaction The liquid is heated to 50. (:, 497 94389 201016683 After 2 hours, the reaction was completed. The reaction mixture was concentrated under reduced pressure, and the obtained residue was further purified and purified by hexane column chromatography (dichloromethane:methanol = 50:1) The product 2-(3-{4-[3-chloro-4-(3-)-hydroxy]-anilino]-啥°坐琳-6-yl}-σpyr-1-yl)-1 -(4-Mallin-4-yl-p-pyridyl-bu)-ethanone 293 (240 mg, yellow solid), yield: 36. 7% MS m/z (ESI): 655[M+1 ] NMRC400 MHz , DMS0-d5): 5 9. 67 (s, 1H), 8. 5 (s, 2H), 8.0 (s, 2H), 7.7 (s, 1H), 7.69 (m, 1H), 7.5 (m, 2H), 7.36 (m, 3H), 7.2 (m, 1H), 6.93 (m, 1H), 6.60 (s, 1H), ® 5.27 (s, 2H), 4.96 (m, 2H), 4.34 (d, J = 8, 1H), 3.92 (d, J = 13.6, 1H), 3.56 (d, J: 4, 4H), 3.18 (d, J = 5.2, 1H), 3.06 (t, J = 12 , 1H), 2.67 (t, J = 12.8, 1H), 2.47 ' (m, 4H), 1. 8 (s, 2H) 1. 3 (m, 2H): Example 294 "1-(3-Fluorine -benzyl)-1Η-oxazol-5-yl-l-6-(1-morpholin-2-ylindenyl-1 oxime-oral ratio-3-yl)-喧口坐琳-4- Amine

498 94389 201016683498 94389 201016683

在50 mL茄形瓶中，將硫酸單_(2_胺基乙基）酯（15〇 mg’ 1 mmol)和氫氧化鈉（40 mg，！咖⑷溶於i乩水中，攪拌15分鐘後依次加入[丨_(；3_氟_苄基）_1H_吲唑_5基] _[6-(1-環氧乙基曱基-1H_吡咯_3_基）_喹唑啉_4_基]-胺霤178a(157mg，0.32mm〇l)的2mL二曱基亞砜溶液和2〇乩甲醇，反應液加熱回流過夜。將反應液在減壓下濃縮，加 •入15 40%氫氧化鈉溶液，繼續加熱回流反應過夜。將反應液冷卻至室溫，調整pH=12，用乙酸乙酯和甲醇的混合溶劑萃取，合併的有機相經由飽和氯化鈉溶液洗滌，無水硫酸鈉脫水，過濾，減壓下濃縮，得到的殘留物藉由薄層層析板進一步分離純化（二氣甲烷：曱醇：氨水=12〇:1〇: ⑩Id)，得到本標題產物[1_(3_氟_苄基）_1H_吲唑基] _[6-(1-嗎啉-2-基甲基-111-吡咯_3_基;)_喹唑啉_4—基]_胺 294(92 mg，黃色固體），產率：29 3%。 MS m/z (ESI) ： 534[M+1] 'HNMR (400MHz, DUS0-d6)： <5 9.81 (s, 1H), 8. 59 (s, 1H) 8.45 (s,lH), 8.23 (s, 1H), 8.17 (s, 1H), 8.03 (d, 1H! J=8.8Hz), 7.73 (m，3H)，7.38 (m，2H)，7.10 (m，3H)， 6.87(s, 1H), 6. 67(s, 1H), 5.72 (s, 2H), 3. 94 (m, 2H), 94389 499 201016683 3.76 (d，1H，J = 11.2Hz)，3.65 (m，1H)，3.42 (m，1Η) 2.76 (d，1H，J=11.2Hz)，2.66 (m, 2H)，2·37 (m，in) 實施例295 l-[2-(3-{4-[3-氧-4-(3-1^ 氧胺基 1_喹唑啾〜R — 基}-°比洛-1-基）-乙酿基1-略哈一4-甲酸Λ喃In a 50 mL eggplant bottle, mono-(2-aminoethyl) sulfate (15 〇 mg' 1 mmol) and sodium hydroxide (40 mg, ! coffee (4) were dissolved in water and stirred for 15 minutes. Add [丨_(;3_fluoro-benzyl)_1H_carbazole-5 base] _[6-(1-epoxyethylmercapto-1H_pyrrole_3_yl)-quinazoline_4 _ base]-amine slip 178a (157 mg, 0.32 mm 〇l) of 2 mL of a solution of dimethyl sulfoxide and 2 〇乩 of methanol, and the reaction solution was heated to reflux overnight. The reaction solution was concentrated under reduced pressure, and then added to 15 40%. The sodium hydroxide solution was further heated and refluxed overnight. The reaction solution was cooled to room temperature, adjusted to pH = 12, extracted with a mixed solvent of ethyl acetate and methanol, and the combined organic phases were washed with saturated sodium chloride solution, anhydrous sodium sulfate Dehydration, filtration, and concentration under reduced pressure, and the obtained residue was further separated and purified by a thin layer chromatography plate (di-methane: methanol: ammonia = 12 〇: 1 〇: 10 id) to obtain the title product [1_(3) _Fluoro-benzyl)_1H_carbazolyl] _[6-(1-morpholin-2-ylmethyl-111-pyrrole_3_yl;)-quinazoline-4-yl]-amine 294 ( 92 mg, yellow solid), Yield: 29 3%. MS m/z (ESI): 534[M+1] 'HNMR (400 MHz, DUS0-d6): <5 9.81 (s, 1H), 8. 59 (s, 1H) 8.45 (s,lH), 8.23 (s, 1H), 8.17 (s, 1H), 8.03 (d, 1H! J=8.8Hz), 7.73 (m,3H), 7.38 (m,2H), 7.10 (m,3H), 6.87(s, 1H), 6.67(s, 1H), 5.72 (s, 2H) ), 3. 94 (m, 2H), 94389 499 201016683 3.76 (d, 1H, J = 11.2Hz), 3.65 (m, 1H), 3.42 (m, 1Η) 2.76 (d, 1H, J = 11.2Hz) , 2.66 (m, 2H), 2·37 (m, in) Example 295 l-[2-(3-{4-[3-Oxy-4-(3-1) Oxoamine 1 - quinazoline 〜R — 基}-°Bilo-1-yl)-Ethyl 1 - slightly haha 4-carboxylic acid

第一步 1_(2 -氯乙酿基）-旅咬-4-甲酸乙醋 ❿ 將派0定—4-甲酸乙酯（895 mg，5. 7随〇1)溶於20虹四氫呋喃中，攪拌下加入三乙胺（2 mL，6· 3 mmol)，在乾冰乙醇浴冷卻至-78°C，攪拌下逐漸滴加氯乙醯氯（0.78 mL，6· 3 mmol )，滴加完畢，室溫下攪拌3小時反應完畢。在反應液中加入20 mL水，減壓下蒸去四氫呋喃’得到的溶液用乙酸乙酯萃取（1〇〇 mLx3)，合併的有機相依次經由水洗務（10 0 mLx2 )’無水硫酸納脫水，過滤，減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化（二氯 500 94389 201016683 曱烷：曱醇=10 : 1)，得到^(卜氣乙醯基）一哌啶_4_曱酸乙酯295a(l. 168 g，黃色油狀液體），產率：87. 6%。 MS m/z (ESI) : 235[M+1] 第二步卜[2-(3-{4-[3-氯-4-(3-氟苄氧基）_苯胺基]_喹唑啉_6_ 基}-吡咯-1 -基）一乙醯基]一哌啶_4一曱酸乙酯將化合物[3-氯-4-(3-氟-苄氧基）_苯基]吡洛_3_基）_啥峻啉_4_基]_胺42(227呢，〇 5匪〇1)和氫化鈉（78 mg ’ 3. 25 mmol)溶於1〇 mL N，N-二甲基甲醯胺 ❹中，室温下攪拌30分鐘後加入1-(2-氯乙醢基）-派咬_4一甲酸乙酯 295a(140 mg ’ 0· 6 mmol)的 1 mL N，N-二甲基甲、醯胺溶液，室溫下攪拌3小時反應完畢。在反應液中加入 ^ 100 mL乙酸乙酯和100 mL水’分液，水相用乙酸乙醋萃取（100 mLx3) 合併的有機相依次經由水，飽和氣化納溶液洗務’無水硫酸納脫水’過滤，減壓下濃縮，得.到的殘留物藉由石夕膠管柱層析法進一步分離純化（二氯甲烧：甲醇瘳=5〇 : 1)，得到標題產物1-[2-(3_{4-[3-氯—4_(3_敦节氧基）-苯胺基]-喹唑啉-6-基}-吼咯-1-基）-乙醯基底咬 -4-甲酸乙酯295(190 mg，黃色固體），產率：44%。 MS m/z (ESI) ： 643 [M+l] ^ NMR(400 MHz，DMSO-M): 5 9· 71 (s，1H)，8. 55 (m，1H)， 8. 50 (m，1H)，8. 03 (m. 2H)，7. 76 (m. 1H)，7 (d 8Hz，110，7. 47 (m，1H)，7. 31 (m，1H)，7. 18 (m，’ 1H)，6.82 (m，1H)，6.66 (m，1H)，5.27 (s，2H)，4 96 94389 501 201016683 (m，2H)，4.22 (s，1H)4. 08 (m，2H)，3.85 (m，1H)，3.17 (m，1H)，2.77(m，1H)，6.63(m，⑻，l 87(m，2H)，158 (m，2H)，1. 22 (t，/=7. 2 Hz, 3H) 實施例296 基}-g比哈-1-基）-乙酿基1-派喷-立〜The first step 1_(2-chloroethyl aryl)-Brigade bite-4-formic acid acetate ❿ 派定 4- 4-ethyl 4-carboxylate (895 mg, 5.7 with 〇 1) dissolved in 20 rainbow tetrahydrofuran, Triethylamine (2 mL, 6.3 mmol) was added with stirring, and the mixture was cooled to -78 ° C in a dry ice ethanol bath. chloroacetic chloride (0.78 mL, 6.3 mmol) was gradually added dropwise with stirring, and the addition was completed. The reaction was completed by stirring at room temperature for 3 hours. To the reaction mixture, 20 mL of water was added, and the solution obtained by distilling off tetrahydrofuran under reduced pressure was extracted with ethyl acetate (1 mL mL), and the combined organic phases were sequentially dehydrated by water washing (10 0 mL x 2 ) Filtration and concentration under reduced pressure, and the residue obtained is further separated and purified by silica gel column chromatography (dichloro-500 94 </ br> 201016683 decane: decyl alcohol = 10:1) to give ^(b ethane) 6%。 pyridine _4_ decanoic acid ethyl ester 295a (l. 168 g, yellow oily liquid), yield: 87.6%. MS m/z (ESI): 235 [M + 1]. Step 2 [2-(3-{4-[3-chloro-4-(3-fluorobenzyloxy)-anilinyl]-quinazoline _6_基}-pyrrole-1 -yl)-ethinyl]-piperidine -4-tetradecanoate ethyl ester compound [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]pyrrol _3_基)_啥啉 _ _4_ yl] _ amine 42 (227, 〇 5 匪〇 1) and sodium hydride (78 mg ' 3. 25 mmol) dissolved in 1 〇 mL N, N-dimethyl After stirring for 30 minutes at room temperature, add 1-(2-chloroethenyl)-pyro- 4 ethyl formate 295a (140 mg '0.66 mmol) in 1 mL of N,N- The solution of dimethylformamide and decylamine was stirred at room temperature for 3 hours and the reaction was completed. Add 100 mL of ethyl acetate and 100 mL of water to the reaction solution, and extract the aqueous phase with ethyl acetate (100 mL×3). The combined organic phases were washed successively with water, saturated sodium hydride solution 'Filtering, concentrating under reduced pressure, and the residue obtained was further separated and purified by silica gel column chromatography (dichloromethane: methanol 瘳 = 5 〇: 1) to give the title product 1-[2-( 3_{4-[3-Chloro-4_(3_Denyloxy)-anilino]-quinazolin-6-yl}-pyrrole-1-yl)-acetamidine base bite 4-carboxylic acid ethyl ester 295 (190 mg, yellow solid). Yield: 44%. MS m/z (ESI): 643 [M+l] NMR (400 MHz, DMSO-M): 5 9· 71 (s, 1H), 8. 55 (m, 1H), 8. 50 (m, 1H), 8. 03 (m. 2H), 7.76 (m. 1H), 7 (d 8Hz, 110, 7.47 (m, 1H), 7. 31 (m, 1H), 7. 18 ( m, ' 1H), 6.82 (m, 1H), 6.66 (m, 1H), 5.27 (s, 2H), 4 96 94389 501 201016683 (m, 2H), 4.22 (s, 1H) 4. 08 (m, 2H), 3.85 (m, 1H), 3.17 (m, 1H), 2.77 (m, 1H), 6.63 (m, (8), l 87 (m, 2H), 158 (m, 2H), 1. 22 (t , /=7. 2 Hz, 3H) Example 296 base}-g than ha-1-yl)-Ethyl-based 1-spray-立~

0 1-(2-氯-乙醯基）_哌啶-4-甲醯胺將哌啶-4-甲醯胺252b(150 mg，i 17 rom〇1)溶於1〇 mL四氫呋喃中，溶液在丙酮-乾冰浴下冷卻至—781，攪拌下加入1 mL二乙私和氯乙酿氯（159 mg，1 · 41 mmo 1)，維持此溫度攪拌40分鐘反應完畢。過濾反應液，得到的殘留物藉由矽膠管柱層析法分離純化（二氯甲烷：甲醇=3〇: 1}，得到1-(2-氯-乙醯基）_旅啶一4-甲醯胺296a(115 mg，白色固體），產率·· 85. 4%。 502 94389 201016683 MS m/z (ESI) ： 205[M+1] 第二步 l-[2-(3-{4-[3-氯-4-(3-氟苄氧基）_苯胺基]-喹唑啉一6_ 基}-D比洛-1-基）-乙醯基]一旅咬甲醯胺在50 inL的燒瓶令，將[3_氯-4 — (3_氟_苄氧基）_苯基] -[6-(1Η-吡咯-3-基）-喹唑啉-4-基]-胺 42(327 mg，0.74 mmol)溶於10 mL無水N，N-二甲基曱醯胺中，在冰浴條件下’冷卻至0°C，加入氫化納（88 mg，3. 7 mmol)，攪拌3〇分鐘後加入1-(2-氯-乙醯基）_哌啶一4-甲醯胺296a(180 ® mg，0.88 mmol)，室溫下攪拌2小時反應完畢。反應液加入50mL水’用乙酸乙酯萃取（5〇 mLx3)，合併的有機相經 •由無水硫酸鈉脫水，過濾，減壓下濃縮，得到的殘留物藉、由矽膠管柱層析法進一步分離純化（二氯甲烷：曱醇=4〇: 1) ’得到本標題產物1-[2-(3-{4-[3-氯-4-(3-氟节氧基）一苯胺基]-喹唑啉-6-基}-吡咯-1-基）_乙醯基]—哌啶_4_曱醯胺296(100 mg ’黃色固體），產率：18· 5%。 φ MS m/z (ESI) ： 613[M+1] ΐ NMR(400 MHz，DMS0-c?<5): 510. 00 (s，1H)，8· 73 (s，1H) 8. 48(s，1H)，8.10(d，1H)，8.00(m，1H)，7.84(m，1H), 7. 48 (m，1H)，7· 29 (m，4H)，7. 16 (m，1H)，6. 79 (s，2H)， 6· 74 (m，1H)’ 5. 27 (s，2H)，4. 95 (m，2H)，4. 3〇 (m，1H)， 2. 92 (m, 1H), 3. 32 (m, 1H), 3. 09 (m, 1H), 2. 67 (m, 1H) 1.77 (m, 2H), 1.55 (m, 1H), 1.41 (m, 1H) 實施例297 94389 503 201016683 1^-{(抑）-1-[3~：^-{4-「氯-4-(3-氟苄氳其）_茉胺基~|-〇|：1>坐琳 -ϋ..·). .:ρ生咯二Ll基）-2 -羥基-丙某1 -吡咯烷—3 _基卜乙醯0 1-(2-Chloro-ethenyl)-piperidine-4-carboxamide A solution of piperidine-4-carbamide 252b (150 mg, i 17 rom〇1) in 1 mL of tetrahydrofuran. Cool to -781 in an acetone-dry ice bath, and add 1 mL of diethyl and chloroethyl chloride (159 mg, 1 · 41 mmo 1) with stirring. Maintain the temperature and stir for 40 minutes. The reaction solution was filtered, and the obtained residue was separated and purified by silica gel column chromatography (dichloromethane: methanol = 3 〇: 1) to give 1-(2-chloro-ethenyl)-br. Indoleamine 296a (115 mg, white solid), yield · · 85.4%. 502 94389 201016683 MS m/z (ESI): 205 [M+1] second step l-[2-(3-{4 -[3-Chloro-4-(3-fluorobenzyloxy)-anilino]-quinazoline- 6-yl}-D-l-l-yl)-ethenyl]-Brigade bite-carbamide in 50 InL flask, [3_chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinazolin-4-yl]-amine 42 (327 mg, 0.74 mmol) was dissolved in 10 mL of dry N-N-dimethylamine, and then cooled to 0 ° C under ice-cooling, and sodium hydride (88 mg, 3. After stirring for 3 minutes, 1-(2-chloro-ethinyl)-piperidine- 4-carbamidamine 296a (180 mg, 0.88 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was added with 50 mL of water. 'Extracted with ethyl acetate (5 〇 mL×3), the combined organic phases were dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue obtained was further separated and purified by column chromatography. Methyl chloride: decyl alcohol = 4 〇: 1) 'The title product 1-[2-(3-{4-[3-chloro-4-(3-fluoro-oxy)-phenylamino]-quinazoline was obtained. -6-yl}-pyrrol-1-yl)-ethinyl]-piperidine-4-nonylamine 296 (100 mg 'yellow solid), yield: 18·5%. φ MS m/z (ESI ) : 613[M+1] NMR NMR (400 MHz, DMS0-c?<5): 510. 00 (s, 1H), 8·73 (s, 1H) 8. 48(s, 1H), 8.10 (d, 1H), 8.00 (m, 1H), 7.84 (m, 1H), 7. 48 (m, 1H), 7. 29 (m, 4H), 7. 16 (m, 1H), 6.79 (s, 2H), 6· 74 (m, 1H)' 5. 27 (s, 2H), 4. 95 (m, 2H), 4. 3〇 (m, 1H), 2. 92 (m, 1H ), 3. 32 (m, 1H), 3. 09 (m, 1H), 2. 67 (m, 1H) 1.77 (m, 2H), 1.55 (m, 1H), 1.41 (m, 1H) 297 94389 503 201016683 1^-{(?)-1-[3~:^-{4-"Chloro-4-(3-fluorobenzidine)_mosamine~|-〇|:1> -ϋ..·). .: ρ生咯二Ll基)-2 -Hydroxy-propanyl 1-pyrrolidine-3 _ kib

在100 mL茄形瓶中，將[3_氯_4_(3_氟_苄氧基）_苯基] -[6-(1 -環氧乙基甲基-if}-»比嘻-3-基）-喹唾淋_4一基]-胺 ❹ 187a(200 mg，〇. 41 mmol)溶解於25 mL·甲醇中，攪拌下加入（R)-N-(l-甲基吡咯烷_3一基）乙醯胺（614 mg，〇 48 mmol)，反應液加熱回流過夜。將反應液在減壓下濃縮，得到的殘留物藉由矽膠管柱層析法分離純化（二氣甲烷：甲醇 ❹=20: 1)，得到本標題產物[氯_4_(3_ 氟苄氧基）-苯胺基]-喹唑啉-6-基卜D比咯_ι_基）_2__羥基一丙基]-吡咯烷-3-基卜乙醯胺297(122 mg，淡黃色固體），產率·· 40. 5% 〇 MS m/z (ESI) ： 629[M+1] JH NMR(400 MHz, DMS0-ci5): (5 9. 69 (s, 1H), 8. 54 (s, 1H), 8. 50 (s，1H)，8. 04 (m，2H)，7. 75 (m，2H)，7. 47 (m, 1H)， 7. 40 (m，1H)，7. 30 (m，3H)，7. 19 (m，1H)，6. 88 (s，1H), 94389 504 201016683 6.68 (s’ 1H)’ 5.27 (s，2H)，4.95 〇?r，1H)，4.06 (m， 1H), 3.86 (m, 2H), 2.68 (m, 2H), 2.36 (m, 4H), 2.08 (m，1H)’ 1.79 (s，3H)，154 (m，1H) 實施例298 1 - [3_(H4~·^Αγ·—4二.(3-氟-芊攀.篡v苯胺基]-」查唑啉-r-[3_Chloro_4_(3_Fluoro-benzyloxy)-phenyl]-[6-(1-epoxyethylmethyl-if}-» 嘻-3 in a 100 mL eggplant-shaped flask -yl)-quinoline _4-amino]-amine 187 187a (200 mg, 〇. 41 mmol) was dissolved in 25 mL·methanol, and (R)-N-(l-methylpyrrolidine) was added with stirring. 3-yl)acetamide (614 mg, 〇48 mmol), and the reaction was heated to reflux overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified and purified by methylene chloride column chromatography (dichloromethane:methanol = 20:1) to give the title product [chloro_4_(3_fluorobenzyloxy) --anilino]-quinazoline-6-ylbu-D-r-buty_yl)_2__hydroxy-propyl]-pyrrolidin-3-yl-acetamide 297 (122 mg, pale yellow solid), Yield··············· , 1H), 8. 50 (s, 1H), 8. 04 (m, 2H), 7. 75 (m, 2H), 7. 47 (m, 1H), 7. 40 (m, 1H), 7 . 30 (m, 3H), 7. 19 (m, 1H), 6. 88 (s, 1H), 94389 504 201016683 6.68 (s' 1H)' 5.27 (s, 2H), 4.95 〇?r, 1H) , 4.06 (m, 1H), 3.86 (m, 2H), 2.68 (m, 2H), 2.36 (m, 4H), 2.08 (m,1H)' 1.79 (s,3H),154 (m,1H) Example 298 1 - [3_(H4~·^Αγ·—4二.(3-Fluoro-芊攀.篡v-anilinyl]-”Chaazoline-r-

酸乙酯Ethyl acetate

底哄4甲酸乙酯（94 mg ’ 〇. 6 mmol ’ Alfa)溶解於 30 mL無水乙醇中，攪拌下加入[3-氯-4-(3-氟-苄氧基）一苯基]-[6-(1-環氧乙基甲基_1H_吡咯_3_基）_喹唑啉一4一 ❹基]-胺187a(250 mg，〇. 5 mm〇i)，混合液加熱回流過夜。反應液在減壓下濃縮’得到的殘留物藉由矽膠管柱層析法分離純化（二氯甲烷：甲醇=6〇 : υ，得到本標題產物 1-[3-(3-{4-[3-氣-4-(3-氟-苄氧基）-苯胺基]—喹唑啉_6一基卜吡咯-1-基）-2-羥基-丙基]-哌啶一4_甲酸乙酯2的 (260 mg’黃色固體），產率：79%。 MS m/z (ESI) ： 658[M+] ]H NMRC400 MHz, DMS0-cf6)； 5 9. 69 (s, 1H), 8.54 (s, 1H) 94389 505 201016683 8. 50 (s, 1H), 8. 04 (ffi, 2H), 7. 75 (m, 2H), 7. 47 (m, 1H), 7. 40 (m，1H)，7. 30 (m，3H), 7. 19 (m，1H), 6. 88 (s, 1H), 6. 68 (s, 1H), 5. 27 (s, 2H), 4. 90 (s> in), 4. 05 (m, 3H), 3. 89 (m, 2H), 2. 81 (m, 2H), 2. 30 (m, 3H), 2. 06 (m, 2H), 1.81 (m, 2H), 1.64 (m, 2H), 1. 17 (t, J=6. 8Hz, 3H) 實施例299 1-(3-{4-[1-(3-氟免吲唑-5_基胺基i —喹唑啉^ •基Ηϋ：：ϋ,.) -·3·Ί比啶-4-基甲基-哌啡-i-某、生Ethyl 4-carboxylate (94 mg ' 〇. 6 mmol ' Alfa) was dissolved in 30 mL of absolute ethanol and [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[ 6-(1-Epoxyethylmethyl-1H_pyrrole_3_yl)-quinazoline- 4-indolyl]-amine 187a (250 mg, 〇. 5 mm〇i), the mixture was heated to reflux overnight. . The reaction mixture was concentrated under reduced pressure. The obtained residue was purified and purified by silica gel column chromatography (dichloromethane:methanol = 6 〇: υ) 3-oxo-4-(3-fluoro-benzyloxy)-anilino]-quinazoline_6-ylpyrrrol-1-yl)-2-hydroxy-propyl]-piperidine-4-formic acid B Ester 2 (260 mg 'yellow solid), yield: 79%. MS m/z (ESI): 658[M+]]H NMRC 400 MHz, DMS0-cf6); 5 9. 69 (s, 1H), 8.54 (s, 1H) 94389 505 201016683 8. 50 (s, 1H), 8. 04 (ffi, 2H), 7. 75 (m, 2H), 7. 47 (m, 1H), 7. 40 (m, 1H), 7. 30 (m, 3H), 7. 19 (m, 1H), 6. 88 (s, 1H), 6. 68 (s, 1H), 5. 27 (s, 2H), 4. 90 (s> in), 4. 05 (m, 3H), 3. 89 (m, 2H), 2. 81 (m, 2H), 2. 30 (m, 3H), 2. 06 (m, 2H ), 1.81 (m, 2H), 1.64 (m, 2H), 1. 17 (t, J = 6. 8 Hz, 3H) Example 299 1-(3-{4-[1-(3-fluoro-free) Azole-5-ylamino i-quinazoline^: Ηϋ::ϋ,.) -·3·Ίpyridin-4-ylmethyl-piperidin-i-, sheng

00

在100 inL茄形瓶中，將[1-(3 一氟—苄基）_1Η__吲唑_5一基]-[6-(1-環氧乙基曱基-111-吼略-3-基）-啥唾琳一4~夷]一胺178a(225 mg，〇. 46 mmol)溶解於20 mL甲醇中，攪拌下加入1-吡啶-4-基甲基-哌畊（163 mg，0.92 mm〇l)，反應液加熱回流過夜。將反應液在減壓下濃縮，得到的殘留物藉由薄層層析板分離純化（二氯曱烷：曱醇=1〇 : D，得 94389 506 201016683 到本標題產物1_(3-{4-[1-(3-氟节基）-1Η-σ引β坐_5 -基胺基]-喧唾琳_6-基j-π比嘻-1-基）-3-(4-吼唆-4-基甲基辰哄-卜基）-丙-2-醇299 (1 00 mg，黃棕色固體），產率：33%。 MS m/z (ESI) ： 668[M+1] !MMR (400MHz，DMSO-M)·· (5 9.81 (s，1H)，8.59 (s, 1H)， 8. 51 (m, 2H), 8. 44 (s, 1H), 8. 22 (s, 1H), 8. 17 (s, 1H), 8.03(m, 1H), 7.73 (m, 3H), 7. 42 (s, 1H), 7.39 (m, 1Ή), 7. 31 (m, 2H), 7. 11 (m, 3H), 6. 87 (s, 1H), 6. 66 (s, 1H), 5. 72 (s, 2H), 4. 93 (m, 1H), 4. 06 (m, 3H), 3. 51 (s, 2H), ® 2. 44 (m, 7H), 2. 36 (m, 3H) 實施例300 .卜（3-U-「l-(3-氟苄基）-1Η-吲唑-5-基胺基1-喹唑啉-6-基}_°比|?各-1-基）-3-(4-口比〇定一3 —基曱基-13底〇井—1一基）-丙一2—In a 100 inL eggplant-shaped flask, [1-(3-fluoro-benzyl)_1Η__carbazole-5-yl]-[6-(1-epoxyethyl fluorenyl-111-吼略-3- Base ) 178 琳一 4 一一一一 178 178 178 178 178 178 178 178 178 178 178 178 178 178 178 178 178 178 178 178 178 178 178 178 178 178 178 178 178 178 178 178 178 178 178 178 178 178 Mm〇l), the reaction solution was heated to reflux overnight. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified and purified by chromatography (dichloromethane: decyl alcohol = 1 〇: D, yielding 94389 506 201016683 to the title product 1_(3-{4 -[1-(3-fluoronosyl)-1Η-σ引β坐_5-ylamino]-喧琳琳_6-yl j-π than 嘻-1-yl)-3-(4-吼唆-4-ylmethyl oxime-buki)-propan-2-ol 299 (1 00 mg, yellow-brown solid), yield: 33%. MS m/z (ESI): 668[M+1] !MMR (400MHz, DMSO-M)·· (5 9.81 (s, 1H), 8.59 (s, 1H), 8. 51 (m, 2H), 8. 44 (s, 1H), 8. 22 (s , 1H), 8. 17 (s, 1H), 8.03 (m, 1H), 7.73 (m, 3H), 7. 42 (s, 1H), 7.39 (m, 1Ή), 7. 31 (m, 2H) ), 7. 11 (m, 3H), 6. 87 (s, 1H), 6. 66 (s, 1H), 5. 72 (s, 2H), 4. 93 (m, 1H), 4. 06 (m, 3H), 3. 51 (s, 2H), ® 2. 44 (m, 7H), 2. 36 (m, 3H) Example 300. Bu (3-U-"l-(3-Fluorine Benzyl)-1Η-oxazol-5-ylamino-1-quinazoline-6-yl}_° ratio|?-1-yl)-3-(4-port ratio 一1 - 3 曱Base-13 bottom well - 1 base) - C 1 -

A 在100 mL茄形瓶中，將[1-(3-氟-苄基）-1Η-吲唑-5- 507 94389 201016683 基]-[6-(1-環氧乙基曱基-111-«1比洛-3-基）-〇1:°坐1#-4-基]_ 胺178a(225 mg，0. 46 mmol)溶解於20 mL甲醇中’擾拌下加入.2-嗎琳-3-基-乙胺（163 mg·，0.92 mm。1)，反應液加熱回流過夜。將反應液在減壓下濃縮，得到的殘留物藉由薄層層析板分離純化（二氯甲院：甲薛= 〗η·ι、少 9 吁iυ . 1)，得到太標題產物1-(3-{4-[1-(3-氟苄基）— 1H_吲唑_5_基胺基喧嗤琳-6-基}-吼洛-1-基）-3-(4-吡啶一3一基甲基_派哄二基）-丙-2-醇300 (92 mg ’黃色固體），產率：。 MS m/z (ESI) ： 668[M+1]A [1-(3-Fluoro-benzyl)-1 Η-carbazole-5- 507 94389 201016683 yl]-[6-(1-epoxyethyl fluorenyl-111- in a 100 mL eggplant-shaped flask «1 比洛-3-yl)-〇1:° sit 1#-4-yl]_amine 178a (225 mg, 0. 46 mmol) dissolved in 20 mL of methanol. -3-yl-ethylamine (163 mg·, 0.92 mm. 1), and the reaction mixture was heated to reflux overnight. The reaction solution was concentrated under reduced pressure, and the obtained residue was separated and purified by a thin layer chromatography plate (dichlorocarbazone: Axel = η η·ι, less 9 υ iυ. 1), obtained too title product 1- (3-{4-[1-(3-fluorobenzyl)-1H-indazole-5-ylamino-indolyl-6-yl}-indol-1-yl)-3-(4-pyridine A 3-methyl-methyl-pyrenediyl)-propan-2-ol 300 (92 mg 'yellow solid), yield: . MS m/z (ESI) : 668 [M+1]

]HNMR (400MHz, dUS0-d6): ^9.81(s, iH), 8 59 (§ 8. 51 (m, 2H), 8. 44 (s, 1H), 8. 22 (s, 1H), 8. 17 8.03(m, IH), 7.73 (m, 3H), 7.42(s, IH), 7.39 (^ 7. 31 (m，2H)，7. 11 (m，3H)，6. 87 (s, ih)，6. 66 (s，1{n’ 5. 72 (s，2H)，4. 93 (m，1H)，U6 (m，3H)，3. &1 ( ’ 2.44 (m, 7H), 2.36 (m, 3H) ’ 實施例301HNMR (400MHz, dUS0-d6): ^9.81(s, iH), 8 59 (§ 8. 51 (m, 2H), 8. 44 (s, 1H), 8. 22 (s, 1H), 8 17 8.03(m, IH), 7.73 (m, 3H), 7.42(s, IH), 7.39 (^ 7. 31 (m, 2H), 7. 11 (m, 3H), 6. 87 (s, Ih),6. 66 (s,1{n' 5. 72 (s,2H), 4.93 (m,1H), U6 (m,3H),3. &1 ( ' 2.44 (m, 7H ), 2.36 (m, 3H) 'Example 301

N ^4389 508 301 201016683N ^4389 508 301 201016683

第一步 ® (S)-[l-(3-氟-苄基）-1Η-吲唑-5-基]-[6-(1-環氧乙基甲基-1Η-π比洛_3_基）-啥嗤嚇基]-胺 - 在100 mL茄形瓶中，將[1-(3-氟-苄基-1Η-吲唾〜基）-[6-(1Η-π比嘻-3-基）-喧0坐*#-4-基]-胺 15〇(3〇〇 mg，〇· 69mmol).溶於5 mL的N，N-二曱基曱醢胺中，冰浴冷卻至0°C，加入氫化納（60 mg，2. 76 mmol)，擾拌30分鐘後，室溫下加入（R)-2-氯甲基環氧乙娱>(148 mg，1. 6 mmol)，1 ❹小時後反應完畢。將反應液倒入10 0 mL冰水中，.用乙酸乙酯（100 mLx3)萃取’合併的有機相依次經由水洗膝，飽和氯化鈉溶液洗滌，無水硫酸鈉脫水，過濾，減壓下濃縮，得到的粗品（S)-[ 1-(3-氟-苄基）-lH-吲唑-5-基]-[6-(i-環氧乙基曱基-1H-0比p各-3-基）-啥嗤琳-4-基]一胺3〇ia(黃色固體）’產物不經分離直接進行下一步反應。第二步 (S)-l-一乙胺基_3-(3-{4-[1-(3-氟-苄基）~1珏_0引唆_5一基 94389 509 201016683 胺基]-喹唑啉-6-基卜吡咯—基）_丙 1一基）-丙-2 -醇將上述步驟所得的粗品—H 基]-[6-(1-環氧乙基甲基〜1H_〇比咯基]•胺301a溶於25 mL甲醇中，p掉_ r (S)-[l-(3-氟-苄基）-1Η-吲唑基-1H-吡咯-3-基）-喹唑啉-4-淳中，攪拌下加入二乙胺（152 mg，2. 07 mmol)，反應液加熱回流過夜。將反應液在減壓下濃縮，得到的殘留物藉由薄層層析板分離純化，得到標First Step® (S)-[l-(3-Fluoro-benzyl)-1Η-indazol-5-yl]-[6-(1-epoxyethylmethyl-1Η-π比洛_3 _基)-啥嗤啥嗤基]-Amine - In a 100 mL eggplant-shaped flask, [1-(3-fluoro-benzyl-1Η-吲salt~yl)-[6-(1Η-π比嘻- 3-yl)-喧0 sitting *#-4-yl]-amine 15〇 (3〇〇mg, 〇·69mmol). Dissolved in 5 mL of N,N-didecylguanamine, cooled in ice bath To 0 ° C, sodium hydride (60 mg, 2.76 mmol) was added, and after stirring for 30 minutes, (R)-2-chloromethyl Ethylene Ethylene was added at room temperature (148 mg, 1.6). Mmmol), the reaction is completed after 1 hour. The reaction mixture was poured into 100 mL of ice water, and extracted with ethyl acetate (100 mL×3). The combined organic phases were washed with water, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude (S)-[1-(3-fluoro-benzyl)-lH-indazol-5-yl]-[6-(i-epoxyethyl decyl-1H-0 ratio p-3 -Methyl)-indolyl-4-yl]monoamine 3〇ia (yellow solid) product was directly subjected to the next reaction without isolation. The second step (S)-l-monoethylamino_3-(3-{4-[1-(3-fluoro-benzyl)~1珏_0引唆_5-based 94389 509 201016683 Amino] -quinazoline-6-ylpyrrole-yl)-propan-1-yl)-propan-2-ol The crude product obtained in the above step -H-]][6-(1-epoxyethylmethyl~1H _〇比罗基••amine 301a is dissolved in 25 mL of methanol, p _ r (S)-[l-(3-fluoro-benzyl)-1 Η-oxazolyl-1H-pyrrol-3-yl) To the quinazoline-4-indole, diethylamine (152 mg, 2.07 mmol) was added with stirring, and the reaction mixture was heated to reflux overnight. The reaction solution was concentrated under reduced pressure, and the obtained residue was separated and purified by thin layer chromatography.

唑-5-基胺基]-喹唑啉-6-基卜吡咯-卜基卜丙_2_醇3〇1 (60 mg，黃棕色固體），產率·· 15%。 ® MS m/z (ESI) ： 564[M+1] ^I^MRMOOMHz，DMSO-de): (5 9.93(s，1H)，8. 69(s，ih)， -8.45 (s，1H)，8.24 (s，1H)，8.17 (s，1H)，8.04 (m，iH)， ,7.75 (m, 3H), 7.51 (s, 1H), 7.41 Cm, 1H), 7.09 (m, 3H), 6. 93 (s, 1H), 6. 74 (s, 1H), 5. 72 (s,'2H), 4. 25 (m, iH), 4. 11 (m, 1H), 3. 98 (m, 1H), 3. 03 (m, 6H), 1. 24 (m, 6H) 實施例302 ❹l-二乙胺基-3-(3-{4-[l-(3-荦.苄基）-1Η-°引嗤-5^^胺基1-喹嗤蛛-6-基}-吡洛-1-某丫-雨-2-醇Zyrom-5-ylamino]-quinazolin-6-ylpyrrole-bukibpropan-2-ol 3〇1 (60 mg, yellow-brown solid), yield 15%. ® MS m/z (ESI): 564[M+1] ^I^MRMOOMHz, DMSO-de): (5 9.93(s,1H), 8. 69(s,ih), -8.45 (s,1H) , 8.24 (s, 1H), 8.17 (s, 1H), 8.04 (m, iH), , 7.75 (m, 3H), 7.51 (s, 1H), 7.41 Cm, 1H), 7.09 (m, 3H), 6. 93 (s, 1H), 6. 74 (s, 1H), 5. 72 (s, '2H), 4. 25 (m, iH), 4. 11 (m, 1H), 3. 98 ( m, 1H), 3. 03 (m, 6H), 1. 24 (m, 6H) Example 302 ❹l-diethylamino-3-(3-{4-[l-(3-荦.benzyl) )-1Η-°引嗤-5^^Amino 1-quinoid 6-yl}-pyrrol-1-one-rain-2-ol

AA

94389 510 20101668394389 510 201016683

302 ❺第-步 (R)-[l-(3-氟一辛基）—1H一吲唑-5-基]-[6-(1 一環氧乙基甲 -基-ΙΗ-吡咯-3-基）_喹峻啉基]-胺在100 mL茄形瓶中，將[1-(3-氟-苄基_iH一吲唉〜$ 基）-[6-(1Η-吡咯一3-基）-喹唑啉-.4-基]-胺150(；3〇〇崎，〇.69mmol)溶於5 mL的N，N-二甲基曱醯胺中，冰浴冷却至0 °C ’加入星化納（6 〇 mg ’ 2. 7 6 mmo 1)，攪拌3 0分鐘後〇室溫下加入（S)-2-氯甲基環氧乙烧（148 mg，1. 6 mmol)，j 小時後反應完畢。將反應液倒入100 mL冰水中，用乙酸乙醋（100 mLx3)萃取，合併的有機相依次經由水洗滌，飽和氯化鈉溶液洗滌，無水硫酸鈉脫水，過濾，減壓下漢縮，得到的粗品（R)-[l-(3-氟-苄基吲唑-5-基]-[6-(卜 %氧乙基甲基-1H-吡咯-3-基）-喹唑啉_4_基]-胺3〇2a(黃色固體），產物不經分離直接進行下一步反應。第二步 . 94389 511 201016683302 ❺Step-(R)-[l-(3-Fluoro-octyl)-1H-indazole-5-yl]-[6-(1-epoxyethylmethyl-yl-indole-pyrrole-3 -yl)- quinacridino]-amine in a 100 mL eggplant-shaped flask, [1-(3-fluoro-benzyl-iH- 吲唉~$yl)-[6-(1Η-pyrrole-3- Base)-quinazoline-.4-yl]-amine 150 (;3〇〇崎, 〇.69mmol) was dissolved in 5 mL of N,N-dimethyl decylamine and cooled to 0 °C in an ice bath. 'Add star sulphate (6 〇mg ' 2. 7 6 mmo 1), stir for 30 minutes, then add (S)-2-chloromethyl Ethylene bromide (148 mg, 1. 6 mmol) at room temperature. After j hours, the reaction is completed. The reaction solution was poured into 100 mL of ice water, and extracted with ethyl acetate (100 mL×3). The combined organic phases were washed successively with water, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and reduced under reduced pressure. Crude (R)-[l-(3-fluoro-benzylcarbazol-5-yl]-[6-(b% oxyethylmethyl-1H-pyrrol-3-yl)-quinazoline_4 _ base]-amine 3〇2a (yellow solid), the product is directly subjected to the next reaction without isolation. Step 2. 94389 511 201016683

胺基]-喹唑啉-6-基}-吡咯-卜基）_丙-2一醇將上述步驟所得的粗品（"-[丨兴^氟―苄基）_1H_吲唑 -5-基]-[6-(1-環氧乙基甲基-1H_吡咯—3_基）_喹唑琳_4_ 基]-胺302a溶於25 mL曱醇中，攪拌下加入二乙胺（152 mg，2 · 0 7 mmo 1 )，反應液加熱回流過夜。將反應液在減壓下濃縮，得到的殘留物藉由薄層層析板分離純化，得到標題產物（R)-l-二乙胺基-3-(3-{4-[1-(3-氟-苄基）-1Η-吲唑-5-基胺基]-喹唑啉-6-基}-吡咯-1-基）_丙-2-醇302 ® (35 mg，黃棕色固體），產率：10°/〇。 MS m/z (ESI) ·· 564[M+1] .'HNMR (400MHz, dUS0-d6): 9. 93 (s, 1H), 8. 69 (s, 1H), 8. 45 (s, 1H), 8. 24 (s, 1H), 8. 17 (s, 1H), 8. 04 (m, 1H), 7.75 (m, 3H), 7. 51 (s, 1H), -7.41 (m, 1H), 7. 09 Cm, 3H), 6.93(s, 1H>, 6.74(s, 1H), 5. 72 (s, 2H), 4.25 (m, 1H), 4. ll(m, 1H), 3. 98 (m, 1H), 3. 03 (m, 6H), 1.24 (m, 6H) ®實施例303 「3-氣-4-(3-氟爷氧基）-笨基卜{6-「1-( 2二曱胺基-心_ 基）-111-°比洛~~3-基1-坐琳-4-基丨-胺Amino]-quinazolin-6-yl}-pyrrole-buyl)-propan-2-ol The crude product obtained in the above step ("-[丨兴^Fluoro-benzyl)_1H_carbazole-5- [6-(1-Epoxyethylmethyl-1H_pyrrole-3-yl)- quinazoline _4_yl]-amine 302a is dissolved in 25 mL of decyl alcohol, and diethylamine is added with stirring ( 152 mg, 2 · 0 7 mmo 1 ), the reaction solution was heated to reflux overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified and purified to afford the title product (R)-l-diethylamino-3-(3-{4-[1-(3) -fluoro-benzyl)-1 - oxazol-5-ylamino]-quinazolin-6-yl}-pyrrol-1-yl)-propan-2-ol 302 ® (35 mg, yellow-brown solid) , Yield: 10 ° / 〇. MS m/z (ESI) ··564[M+1] .HNMR (400MHz, dUS0-d6): 9. 93 (s, 1H), 8. 69 (s, 1H), 8. 45 (s, 1H), 8. 24 (s, 1H), 8. 17 (s, 1H), 8. 04 (m, 1H), 7.75 (m, 3H), 7. 51 (s, 1H), -7.41 (m , 1H), 7. 09 Cm, 3H), 6.93(s, 1H>, 6.74(s, 1H), 5. 72 (s, 2H), 4.25 (m, 1H), 4. ll(m, 1H) , 3. 98 (m, 1H), 3. 03 (m, 6H), 1.24 (m, 6H) ® Example 303 "3-Gas-4-(3-fluoro-yloxy)-stupyl {6 -"1-( 2 dioxin-cardio-yl)-111-° piroxime~~3-yl-1-isoline-4-ylindole-amine

512 94389 201016683512 94389 201016683

第三步 ®第-步甲磺酸2-(第三丁氧羰基-甲胺基）-乙酯 . 將2-甲胺基-乙醇溶於10 mL四氫呋喃和1 mL水的混合溶劑中，攪拌下依次加入碳酸氫鈉（840 mg，10 mmol) 和二碳酸二第三丁酯（2.18 g，10 mmol)，室溫下攪拌過夜·。將反應液在減壓下濃縮，殘質中加入50 mL乙酸乙酯，得到的混合液依次經由水洗滌，飽和氯化鈉溶液洗滌，無水像硫酸鈉脫水，過濾，減壓下濃縮，得到的殘質（1· 7 g)備用。將上述步驟的殘質溶於20 mL二氣甲烷中，授拌下加入三乙胺（2. 1 mL，15 mmol)，將反應液在冰浴下冷卻至〇 C ’逐漸加入甲績醯氯（981 mg，12 mmol)，室溫下攪拌 30分鐘，反應完畢。將反應液在減壓下濃縮，加入乩乙酸乙酉旨，得到的溶液依次經由水洗務，如氯化納溶液洗滌，無水硫酸鈉脫水，過濾，減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化（二氯甲烷：甲醇 94389 513 201016683 = 15:1)，得到曱磺酸2-(第三丁氧羰基_甲胺基）_乙酯3〇3a (2.4 g’黃色油狀液體），產率：94.8%。 MS m/z (ESI) ： 254[M+1] 第二步 [2-(3-H-[3-氯-4-(3-氟-苄氧基）_苯胺基]-喹唑啉_6一基}-·1比咯-1-基）-乙基]-甲基_胺基甲酸第三丁酯在50 mL的燒瓶中，將[3-氯-4-(3-氟-苄氧基）-苯基] -[6-(1Η-吡咯-3-基）-喹唑啉-4-基]-胺 42(223 mg，0.5 罄mmol)溶解於25 mL無水N，N-二甲基甲醯胺中，在冰浴條件下’冷卻至〇 C ’加入氫化納（8 〇 mg，3. 3 mmo 1)，授拌 3〇分鐘後加入曱磺酸2-(第三丁氧羰基-甲胺基）一乙酯 .303a(190 mg，0.75 mmol)，室溫下攪拌3小時反應完畢。反應液加入20 mL水，乙酸乙酯萃取（3〇 mLx3)，合併的有機相依次經由飽和氯化鈉溶液洗滌，無水硫酸鈉脫水，過濾’減壓下濃縮’得到的殘留物藉由矽膠管柱層析法進一步分離純化（二氯甲烷：曱醇=1〇 : 1)，得到[2_(3_{4_[3 一 ❷氯-4-(3-氟-苄氧基）-苯胺基]-喹唑啉_6_基卜吡咯-卜基）一乙基]一甲基-胺基曱酸第三丁酯303b(285 mg，黃色固體），產率：95%。 MS m/z (ESI) ： 602[M+1] 第三步 [3-氣-4-(3-氟苄氧基）-苯基]-{6-[l-(2-甲胺基-乙基） -1Η-β比哈-3-基]―喧唾淋_4-基}-胺將[2-(3-{4-[3-氯-4-(3-氟-苄氧基）_苯胺基]_啥嗤 94389 514 201016683 啉一6—基丨-吡咯-1-基）-乙基]-甲基-胺基甲酸第三丁酯 303b(285 mg，〇. 47 mmol)溶於5 mL二氯曱烷中，攪拌下加入5 mL三氟乙酸，室溫下攪拌2小時反應完畢。反應液在減壓下濃縮，加入30 mL飽和碳酸氩鈉溶液，乙酸乙酯萃取（50 mLx3 )，合併的有機相依次經由飽和氯化納溶液洗滌’無水硫酸鈉脫水’過濾’減壓下濃縮，得到的粗品藉由乙酸乙醋再結晶’得到本標題產物[3-氯~4-(3-襄节氧基）-本基]-{6-[1-(2 -曱胺基-乙基®各-3-基]-啥唾啉-4-基卜胺303(195 mg，黃色固體），產率：83%。 ® MS m/z (ESI) ： 502[M+1] !H NMR(400MHz, dUS0-d6): 6 10. 18 (s, 1H), 8. 91 (s 1H) .8. 49 (s, 1H)，8. 18 (d, J = 2. 4Hz，1H), 8. 03 (d, J=8 8Hz 1H)，7.92 (m，1H)，7.70 (m，2H)，7.47 (m，1H)，7 31 (m，3H)，7.17 (m，1H)，6.98 (s，1H)，6.86 (S，.1H)，5 27The third step is the first step of 2-(t-butoxycarbonyl-methylamino)-ethyl methanesulfonate. Dissolve 2-methylamino-ethanol in a mixed solvent of 10 mL of tetrahydrofuran and 1 mL of water, stir. Sodium hydrogencarbonate (840 mg, 10 mmol) and dibutyltributate dicarbonate (2.18 g, 10 mmol) were added in that order, and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and 50 mL of ethyl acetate was added to the residue, and the mixture was washed with water, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Residual (1·7 g) spare. The residue of the above step was dissolved in 20 mL of di-methane, and triethylamine (2.1 mL, 15 mmol) was added with stirring. The reaction solution was cooled to 〇C in an ice bath. (981 mg, 12 mmol), stirred at room temperature for 30 minutes and the reaction was completed. The reaction solution is concentrated under reduced pressure, and the solution is added with ethyl acetate. The obtained solution is washed successively with water, washed with sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Further separation and purification by column chromatography (dichloromethane:methanol 94389 513 201016683 = 15:1) afforded 2-(t-butoxycarbonyl-methylamino) ethyl ester 3〇3a (2.4 g' yellow Oily liquid), yield: 94.8%. MS m/z (ESI): 254 [M + 1], [2-(3-H-[3-chloro-4-(3-fluoro-benzyloxy)-anilinyl]-quinazoline 6-yl}-·1-pyrrol-1-yl)-ethyl]-methyl-aminocarboxylic acid tert-butyl ester [3-chloro-4-(3-fluoro-benzyl) in a 50 mL flask Oxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinazolin-4-yl]-amine 42 (223 mg, 0.5 罄mmol) dissolved in 25 mL of anhydrous N,N- In methylformamide, add 'sintered to 〇C' under ice bath conditions to add sodium hydride (8 〇mg, 3. 3 mmo 1), and mix for 3 minutes to add bismuth sulfonate 2-(third butyloxy) Carbonyl-methylamino)-ethyl ester .303a (190 mg, 0.75 mmol) was stirred at room temperature for 3 hours. The reaction solution was added with 20 mL of water and extracted with ethyl acetate (3 mL mL 3). The combined organic phases were washed successively with saturated sodium chloride solution, dried over anhydrous sodium sulfate and filtered and evaporated. Further separation and purification by column chromatography (dichloromethane: decyl alcohol = 1 〇: 1) gave [2_(3_{4_[3 monochloro-4-(3-fluoro-benzyloxy)-anilinyl]- Quinazoline -6-kibpyrrole-bry-ethyl) monoethyl]-methyl-amino decanoic acid tert-butyl ester 303b (285 mg, yellow solid), yield: 95%. MS m/z (ESI): 602 [M + 1]. Step 3 [3- -4- 4-(3-fluorobenzyloxy)-phenyl]-{6-[l-(2-methylamino)- Ethyl) -1 Η-β than hexyl-3-yl]-喧喧 _ 4-yl}-amine [2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy) )_anilino]_啥嗤94389 514 201016683 porphyrin-6-ylindole-pyrrol-1-yl)-ethyl]-methyl-carbamic acid tert-butyl ester 303b (285 mg, 〇. 47 mmol) 5 mL of trifluoroacetic acid was added to 5 mL of dichloromethane, and the reaction was completed by stirring at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and then added with 30 mL of saturated sodium bicarbonate solution, ethyl acetate (50 mL×3), and the combined organic phases were washed sequentially with saturated sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. , the obtained crude product was recrystallized from ethyl acetate to give the title product [3-chloro~4-(3-indoleoxy)-benzyl]-{6-[1-(2-anthranamine-B Benzyl-3-methyl]-indole porphyrin-4-ylbumin 303 (195 mg, yellow solid), yield: 83%. MS m/z (ESI): 502[M+1] !H NMR (400MHz, dUS0-d6): 6 10. 18 (s, 1H), 8. 91 (s 1H) .8. 49 (s, 1H), 8. 18 (d, J = 2. 4Hz, 1H) , 8. 03 (d, J=8 8Hz 1H), 7.92 (m,1H), 7.70 (m,2H), 7.47 (m,1H),7 31 (m,3H),7.17 (m,1H), 6.98 (s, 1H), 6.86 (S, .1H), 5 27

Cs, 2H), 4. 35 (d, J=6. 4Hz, 2H), 3. 32 (d, J=6. 4HZ 2H) 2.47 (s, 3H) ’ U實施例304 (6-{ l-[4-(2_二乙胺基-乙基）_嗎某甲早‘ i 一i % _3_基}-啥唾蛛-4-基）_ [ 1 -(3-氟-苄基引口由_c；__芊·i — Μ.Cs, 2H), 4. 35 (d, J=6. 4Hz, 2H), 3. 32 (d, J=6. 4HZ 2H) 2.47 (s, 3H) ' U Example 304 (6-{ l- [4-(2-diethylamino-ethyl)_?一一甲早' i 一i % _3_基}-啥啥蛛-4-yl)_ [1-(3-fluoro-benzyl) By _c;__芊·i — Μ.

94389 304 515 20101668394389 304 515 201016683

294294

將[1-(3-氟- 曱基-1H-吡咯-3-基）-喹唑啉_4一基]_胺294(1〇〇吨，〇. i9 mmol)溶於2 mL二甲基亞砜，氬氣保護下，加入氳氧化鉀 (100 mg，1. 8 mmol)，室溫下攪拌3〇分鐘後加入（2_溴— 乙基）-二乙基-胺（59 mg，〇. 23 mmol)，25°C下授拌3小時反應完畢。將反應液倒入5 0 mL冰水中，乙酸乙酯萃取（5 〇 • mLx4)，合併的有機相依次經由無水硫酸鈉脫水，過濾，減 .壓下濃縮，得到的殘留物藉由矽膠管柱層析法分離純化（二氯甲娱：：甲醇=10 : 1)，得到本標題產物（6_{卜[4-(2-二乙胺基-乙基）-嗎琳-2-基甲基]比洛-3-基}_啥唾淋-4- 基）-[1-(3-氟-苄基）-1Η-吲唑-5-基]-胺304(30 mg，淡黃 ❹色固體），產率：24. 9%。 MS m/z (ESI) : 633[M+1] !HNMR (400MHz, DMSO-c/6): <5 9.85 (s, 1H), 8.62 (s, 1H), 8.45 (s,lH), 8.23 (s, 1H), 8.17 (s, 1H), 8.03 (d, 1H, J=8.8Hz), 7.74 (m, 3H), 7.39 (m, 2H), 7.08 (m, 3H), 6. 88 (s, 1H), 6. 68 (s, 1H), 5. 72 (s, 2H), 4. 00 (m, 2H), 3.82 (d, 1H, J=11.2Hz), 3.75 (m, 1H), 3. 49 (m, 1H), 2.80 (d, 1H, J=11.2Hz), 2.70 (m, 1H), 2.55 (m, 3H), 94389 516 201016683 2.42 (m，3H)，2.06 (t，2H，J = 10.4Hz)，1.83 (t, 2H J = 10.4Hz)，0. 98 (m, 6H) ’ 實施例305 (4-{4-[3-氯氟苄氳某笑胺基i_喹峻啉— -1E-0比口各-2-某）[1-(3-Fluoro-indolyl-1H-pyrrol-3-yl)-quinazoline-4-yl]-amine 294 (1 ton, 〇. i9 mmol) was dissolved in 2 mL of dimethyl Sulfoxide, under argon, add potassium hydride (100 mg, 1.8 mmol), stir at room temperature for 3 minutes, then add (2-bromo-ethyl)-diethyl-amine (59 mg, hydrazine) 23 mmol), the reaction was completed at 25 ° C for 3 hours. The reaction solution was poured into 50 mL of ice water, extracted with ethyl acetate (5 〇 • mL×4), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Chromatography separation and purification (dichloromethane: methanol = 10: 1) gave the title product (6_{Bu[4-(2-diethylamino-ethyl)-morphin-2-ylmethyl) ]Bilo-3-yl}-啥啥-4-yl)-[1-(3-fluoro-benzyl)-1Η-indazol-5-yl]-amine 304 (30 mg, pale yellow ochre Solid), Yield: 24.9%. MS m/z (ESI): 633 [M+1] "HNMR (400 MHz, DMSO-c/6): <5 9.85 (s, 1H), 8.62 (s, 1H), 8.45 (s, lH), 8.23 (s, 1H), 8.17 (s, 1H), 8.03 (d, 1H, J=8.8Hz), 7.74 (m, 3H), 7.39 (m, 2H), 7.08 (m, 3H), 6. 88 (s, 1H), 6. 68 (s, 1H), 5. 72 (s, 2H), 4. 00 (m, 2H), 3.82 (d, 1H, J=11.2Hz), 3.75 (m, 1H) ), 3. 49 (m, 1H), 2.80 (d, 1H, J = 11.2Hz), 2.70 (m, 1H), 2.55 (m, 3H), 94389 516 201016683 2.42 (m, 3H), 2.06 (t , 2H, J = 10.4Hz), 1.83 (t, 2H J = 10.4Hz), 0. 98 (m, 6H) ' Example 305 (4-{4-[3-chlorofluorobenzidine) _Quinoline - -1E-0 than each -2-)

❹❹

將4-{4-[3-氯-4-(3-氟-苄氧基苯胺基μ喹唑咻 -6-基}-1-(甲苯基_4 一磺醯基）一1Η_吡咯一 2_甲酸甲靡 (1 g，1. 5 mmol)溶於3〇 mL四氫呋喃中，冰浴冷卻至〇亡，瘳攪拌下分批加入氫化鋁鋰（470 mg，7 5随〇1)，保持〇七擾拌1小時反應完畢。加入5 mL曱醇淬滅反應，反應液在減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化（二氣曱烷：甲醇=50:1)，得到標題產物（4—{轸[3 一氯-4-(3-氟苄氧基）-苯胺基]-喹唑啉_6—基卜1Η_π比洛_2_ 基>-甲醇305 (300 mg，黃色固體），產率：42 2%。 MS m/z (ESI) ： 475[M+1] WNMR (400MHz，DMS0-(i6): δ 11.02 (s，1H) 9 69 (m 1H) 94389 517 201016683 8. 55 (m, 1H), 8. 49 (m, 1H), 8. 05 (m, 2H), 7. 78 (m, 1H), 7.69(d, /=8. 0Hz, 1H), 7. 47 (m, iH), 7. 31 (m, 4H) 7 17 (m, 1H), 6.60(m, 1H), 5. 27 (s, 2H), 4.45 (d, /=5 2Hz 2H) ，實施例306 2-(3-{4-[3-氣-4-(3~盏- -g比哈-1-基）-乙薛4-{4-[3-Chloro-4-(3-fluoro-benzyloxyanilinyl μ quinazolyl-6-yl}-1-(tolyl-4 sulfonyl)-1 Ηpyrrole 2_Methylformate formic acid (1 g, 1.5 mmol) was dissolved in 3 mL of tetrahydrofuran, cooled to death in an ice bath, and lithium aluminum hydride (470 mg, 7 5 with 〇1) was added in portions while stirring. The mixture was stirred for 1 hour and the reaction was completed. The reaction was quenched by adding 5 mL of decyl alcohol, and the reaction mixture was concentrated under reduced pressure. The obtained residue was further purified and purified by silica gel column chromatography (dioxane: methanol = 50) :1), the title product is obtained (4-{轸[3-chloro-4-(3-fluorobenzyloxy)-anilino]-quinazoline_6-ylbu 1Η_π比洛_2_ base>-methanol 305 (300 mg, mp. m 1H) 94389 517 201016683 8. 55 (m, 1H), 8. 49 (m, 1H), 8. 05 (m, 2H), 7. 78 (m, 1H), 7.69 (d, /=8. 0Hz, 1H), 7. 47 (m, iH), 7. 31 (m, 4H) 7 17 (m, 1H), 6.60(m, 1H), 5. 27 (s, 2H), 4.45 (d, /=5 2Hz 2H) , Example 306 2-(3-{4-[3-Ga-4-(3~盏--g-ha-1-yl)-Bei Xue

hmXXc'^'" 將2 (3 {4 [3-氯-4~(3~氟_节氧基）_苯胺基]_喧嗤啉+基卜比咯+基)-N，N_二乙基_乙酿胺216⑴“g， ❹0.2 mmol)溶於5 mL四氫^南中，冰浴冷卻至〇t：，授掉下分批加入三乙基硼氫化鐘四氯咬喃溶液室溫下擾拌過夜。加入5 mL甲醇淬減反應，反應液在減麗下浪縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化（二氯甲烷：甲醇=50 : 1)，得到標題產物2_(3_μ_[3_ 氯-4-(3-氟-苄氧基）-苯胺基]-喹唑啉_6_基卜吼咯_丨_基） -乙醇306(26 mg，黃色固體），產率：26. 6%。 MS m/z (ESI) ： 544[M+1] 94389 518 201016683 !H NMRC400 MHz , DMS〇-d6): (5 9. 70 (s, 1H), 8. 52 (m, 2H), 8.04(m, 2H), 7.73 (m, 2H), 7.49 (m, 2H), 7. 34 (m, 2H), 7. 29(m, 1H), 7. 19 (m, 1H), 6.90 (m, 1H), 6. 66 (m, 1H), 5. 27 (s, 2H), 4. 97 (t, /=4. 8Hz, 1H), 3. 99 (m, 2H), 3. 72 (m, 2H) 實施例307 (R)-2-(3-{4-「3-氯-4-(3 -氟-苄氣基）-|脸基 -6-基}-11比洛-1-基）-1-(3-二甲基胺基比來检.基）_乙hmXXc'^'" will 2 (3 {4 [3-chloro-4~(3~fluoro-p-hydroxy)-anilino]-porphyrin + kibbidol+yl)-N,N_ Ethyl ethoxide 216(1) "g, ❹0.2 mmol" was dissolved in 5 mL of tetrahydrogen hydride, cooled to 〇t: in an ice bath, and added triethyl borohydride clock tetrachlorine solution The mixture was stirred overnight at room temperature. The reaction was quenched by adding 5 mL of methanol, and the reaction solution was reduced under reduced pressure. The residue obtained was further separated and purified by silica gel column chromatography (dichloromethane:methanol = 50:1). , the title product 2_(3_μ_[3_ chloro-4-(3-fluoro-benzyloxy)-anilino]-quinazoline_6_ kibbromo- 丨-yl)-ethanol 306 (26 mg, yellow Solid), Yield: 26.6%. MS m/z (ESI): 544[M+1] 94389 518 201016683 !H NMRC400 MHz , DMS〇-d6): (5 9. 70 (s, 1H), 8. 52 (m, 2H), 8.04 (m, 2H), 7.73 (m, 2H), 7.49 (m, 2H), 7. 34 (m, 2H), 7. 29 (m, 1H), 7. 19 (m, 1H), 6.90 (m, 1H), 6. 66 (m, 1H), 5. 27 (s, 2H), 4. 97 (t, /=4. 8Hz, 1H), 3. 99 (m, 2H), 3. 72 (m, 2H) Example 307 (R)-2-(3-{4-"3-Chloro-4-(3-fluoro-benzyl)--- 6-yl}-11 piroxi-1-yl)-1-(3-dimethyl Ratio of amine to the subject. Yl) acetate _

第一步 00-2-氯-1-(3-(二甲基胺基）吡咯烷_丨一基）乙酮、將（R)-N, N-二甲基胺基吡咯烷一3_胺（52 mg, 〇· 46腿〇1) 命於10 mL—氯曱烷中，溶液在丙__乾冰浴下冷卻至 ◦C ’攪拌下加入1 mL三乙胺和氯乙醯氯(60 mg，〇 55 94389 519 201016683 mmol) ’維持此溫度攪拌40分鐘反應完畢。反應液在減壓下濃縮，得到的殘留物藉由矽膠管柱層析法分離純化（二氯曱烧：甲醇= 10: 1)，得到無色油狀液體（R)_2一氯Ut(二甲基胺基）吡咯烷-1-基）乙酮307a ’產物不經分離直接進行下一步反應。 MS m/z (ESI) ： 167[M+1] 第二步 (R)-2-(3-{4-[3-氯-4-(3-氟-苄氧基）-苯胺基]-喹唑啉 -6-基}-吡咯-1-基）-；[一（3一二曱基胺基_吡咯烷_卜基）_乙 .酮在50mL的燒瓶中，將[3一氯_4_(3_氟_苄氧基）—苯基] .-[6-(lH-吡咯-3-基）-喹唑啉_4_基]-胺 42(260 mg，0.58 .mmol)溶於1〇 mL無水n，N-二曱基曱醯胺中，在冰浴條件下，冷卻至〇 C，加入氫化鈉（ίο! mg，3· 48 mmol)，授拌 30分鐘後加入（R)-2-氯二甲基胺基）吡咯烷4—基乙酮307a( 133 mg，0. 7 mmol)，室溫下攪拌3小時反應完 ©畢。反應液加入50mL水，用乙酸乙酯萃取（5〇mLx3)，合併的有機相經由無水硫酸鈉脫水，過濾，減壓下濃縮，得到的殘留物藉由矽膠管柱層析法進一步分離純化（二氯甲烷：甲醇=40 : 1) ’得到本標題產物（[〇_2_(3_{4_[3_氯〜4— (3-氟-节氧基）-苯胺基卜喹唑啉基卜吡咯_丨_基卜卜 (3~—甲基胺基-吡咯烷一；1_基）一乙酮3〇7 (8〇呢，黃色固體）’產率：19%。 MS m/z (ESI) ： 599[M+1] 94389 520 201016683 4 丽R(400 MHz，DMS0-M):(5= 9.69 (s，1H) 8 54 1H)，8.50 (s，1H)，8.04 (m，2H)，7. 75 (m，2H)，7 (m, 1H), 7.40 (m, 1H), 7.30 (m, 3H), 7. 19 (m, 1H), 6.88 (s, 1H)’ 6.68 (s, 1H), 5.27 (s, 2Ή)，4.85 (m，2H), 3.65 (m, 4H), 3. 25 Cm, 1H), 2. 68 (m, 1H), 2. 17 (g 6H) 1 72 (m, 1H) 實施例308 丄?_(3- {4-「3-氧-4-(3- 1^_^基）_ 茉胺基卜变逢基）-乙酿基^烷甚丨_Λ醯脸First step 00-2-chloro-1-(3-(dimethylamino)pyrrolidine-indenyl)ethanone, (R)-N,N-dimethylaminopyrrolidine-3_ Amine (52 mg, 〇·46 leg 〇1) In 10 mL of chlorodecane, the solution was cooled to ◦C under stirring in a dry ice bath. Add 1 mL of triethylamine and chloroethyl chloride (60). Mg, 〇55 94389 519 201016683 mmol) 'Stirring at this temperature for 40 minutes was completed. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by EtOAc EtOAc EtOAc EtOAc EtOAc The aminoaminopyrrolidin-1-yl)ethanone 307a 'product was directly subjected to the next reaction without isolation. MS m/z (ESI): 167 [M + 1]. Step 2 (R)-2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-anilinyl]- Quinazoline-6-yl}-pyrrol-1-yl)-;[mono(3,2-didecylamino)-pyrrolidinyl)- ketone in a 50 mL flask, [3-chloro_ 4-(3-fluoro-benzyloxy)-phenyl].-[6-(lH-pyrrol-3-yl)-quinazoline-4-yl]-amine 42 (260 mg, 0.58. mmol) was dissolved 1 〇 mL of anhydrous n,N-didecyl decylamine, cooled to 〇C under ice bath, add sodium hydride (ίο! mg, 3·48 mmol), and mix for 30 minutes, then add (R) 2-Chlorodimethylamino)pyrrolidine 4-ketanone 307a (133 mg, 0.7 mmol) was stirred at room temperature for 3 hours. The reaction mixture was poured into 50 mL of water and extracted with ethyl acetate (5 mL mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Dichloromethane:methanol = 40 : 1) 'The title product was obtained ([〇_2_(3_{4_[3_chloro~4-(3-fluoro-p-oxy)-anilinoquinazolinylpyrrole) _丨_Kibb (3~-Methylamino-pyrrolidine- 1; yl) 1-ethanone 3〇7 (8 ,, yellow solid) 'Yield: 19%. MS m/z (ESI ) : 599[M+1] 94389 520 201016683 4 Li R (400 MHz, DMS0-M): (5 = 9.69 (s, 1H) 8 54 1H), 8.50 (s, 1H), 8.04 (m, 2H) , 7. 75 (m, 2H), 7 (m, 1H), 7.40 (m, 1H), 7.30 (m, 3H), 7. 19 (m, 1H), 6.88 (s, 1H)' 6.68 (s , 1H), 5.27 (s, 2Ή), 4.85 (m, 2H), 3.65 (m, 4H), 3. 25 Cm, 1H), 2. 68 (m, 1H), 2. 17 (g 6H) 1 72 (m, 1H) Example 308 丄?_(3- {4-"3-oxo-4-(3- 1^_^)- _ 胺基 ) ) ) -丨_Λ醯脸

(R)-N_[l-(2-氯-乙醯基吡咯烷_3_基卜乙醯胺將（R)_N_°比洛燒'3—基-乙醯胺（2〇〇吨，1.56腳1)交於20知氫料中，溶液在__乾冰浴下冷卻至-赃 94389 521 201016683 授拌下加入1 mL三乙胺和氯乙醯氯（212 mg，1. 88 mmol)，維持此溫度攪拌1小時反應完畢。過濾反應液，濾液在減壓下濃縮’得到的殘留物藉由矽膠管柱層析法分離純化（二氯甲烧··曱醇=40 : 1) ’得到（R) 一 n-[1-(2-氯-乙醯基）-吡咯烷-3-基]-乙醯胺308a(205 mg，淡黃色油狀液體），產率：21. 4%。 MS m/z (ESI) ： 205[M+] 第二步 ❿（R)-N-U-[2-(3-{4-[3-氯-4-(3-氟苄氧基）-苯胺基]-喹唑啉-6-基}-吡咯-1-基）-乙醯基]-吡咯烷_3_基卜乙醯胺在50 mL的燒瓶中，將[3-氯-4-(3-氟-苄氧基）-苯基] • -[6-(1Η-吡咯-3-基）-喹唑啉-4-基]-胺 42(472 mg，1.06 mmo 1)溶於10 mL無水N，N-二曱基曱醯胺中，在冰浴條件下’冷卻至0°C ’加入氫化鈉（127 mg，5. 3 nmol)，攪拌 30分鐘後力口入（R)-N-[ 1-(2 -氯-乙醢基）-«比洛燒_3-基]一乙醯胺308a(261mg，1.27 mmol)，室溫下授拌2小時反參應元畢。反應液加入50 mL水，1用乙酸乙醋萃取（.5〇 mLx3)，合併的有機相經由無水硫酸鈉脫水，過濾，減壓下濃縮，得到的殘留物藉由石夕膠管柱層析法進一步分離純化（二氯曱烷：曱醇=20 : 1)，得到本標題產物 [3-氯-4-(3-氟苄氧基）-苯胺基]-啥峻琳_6_基）_11比略_1__ 基）-乙醯基]-吡咯烷-3-基卜乙酿胺308(302 mg，黃色固體），產率：39%。 MS m/z (ESI) ： 615[M+1] 94389 522 201016683 'H NMR(400 MHz , DMS0-d6): (5 = 9. 69 (s, 1H), 8. 54 (s, 1H), 8.50 (s, 1H), 8.04 (m, 2H), 7.75 (m, 2H), 7.47 (m, 1H), 7. 40 (m, 1H), 7. 30 (m, 3H), 7. 19 (m, 1H), 6. 88 (s, 1H), 6. 68 (s, 1H), 5. 27 (s, 2H), 4. 85 (m, 2H), 3. 61 (m, 3H), 3. 28 (s, 3H), 1. 19 (m, 4H) 實施例309 1-(3-胺基-哌啶-1-基）-2-(3-丨4-「3-氣-4-(3-氟-苄氣基） -笨基胺基1-喹唑啉-6-基卜吡咯-1-基）-乙酮(R)-N_[l-(2-Chloro-ethenylpyrrolidine_3_ylbudecylamine will be (R)_N_°biluo'3-yl-acetamide (2〇〇 tons, 1.56 Feet 1) In the 20 known hydrogen material, the solution was cooled to __ dry ice bath to -赃94389 521 201016683 Add 1 mL of triethylamine and chloroacetamidine chloride (212 mg, 1.88 mmol), and maintain The reaction was completed by stirring at this temperature for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by hexane column chromatography (dichloromethane· decyl alcohol = 40:1). R)-n-[1-(2-Chloro-ethenyl)-pyrrolidin-3-yl]-acetamide 308a (205 mg, mp. m/z (ESI): 205 [M+]. Step 2 ❿(R)-NU-[2-(3-{4-[3-chloro-4-(3-fluorobenzyloxy)-anilinyl]- [3-oxa-4-(3-fluoro) in a 50 mL flask in a quinazolin-6-yl}-pyrrol-1-yl)-ethinyl]-pyrrolidine-3-ylbudecalamine -benzyloxy)-phenyl] • -[6-(1Η-pyrrol-3-yl)-quinazolin-4-yl]-amine 42 (472 mg, 1.06 mmo 1) dissolved in 10 mL anhydrous N. In N-dimercaptodecylamine, add sodium hydride (127 mg, 'cooled to 0 ° C' under ice bath conditions. 5. 3 nmol), stirring for 30 minutes and then injecting (R)-N-[ 1-(2-chloro-ethenyl)-«Bilozepine_3-yl]-acetamide 308a (261 mg, 1.27 Methyl), the mixture was stirred for 2 hours at room temperature. The reaction solution was added with 50 mL of water, and 1 was extracted with ethyl acetate (.5 mL mL3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by further separation (dichloromethane: decyl alcohol = 20:1) to give the title product [3-chloro-4-(3-fluorobenzyloxy). ))-anilino]-啥君琳_6_基)_11 比略_1__ 基)-Ethyl]-pyrrolidin-3-yl b-amine 308 (302 mg, yellow solid), yield: 39%. MS m/z (ESI): 615 [M+1] 94389 522 201016683 'H NMR (400 MHz, DMS0-d6): (5 = 9. 69 (s, 1H), 8. 54 (s, 1H), 8.50 (s, 1H), 8.04 (m, 2H), 7.75 (m, 2H), 7.47 (m, 1H), 7. 40 (m, 1H), 7. 30 (m, 3H), 7. 19 ( m, 1H), 6. 88 (s, 1H), 6. 68 (s, 1H), 5. 27 (s, 2H), 4. 85 (m, 2H), 3. 61 (m, 3H), 3. 28 (s, 3H), 1. 19 (m, 4H) Example 309 1-(3-Amino-piperidin-1-yl)-2-(3-indole4-"3-gas-4 -(3-fluoro-benzyl)-phenylamino-1-quinazolin-6-ylpyrrolidin-1-yl)-ethanone

第一步 (S)-[1-(2-氯-乙醯基）-哌啶-3-基]-胺基曱酸第三丁酯 523 94389 201016683 (S)-哌啶-3-基胺基甲酸第三丁酯（20 0 mg，1 mmol) 溶於30 mL四氫吱喃中，在丙酮-乾冰浴冷卻下冷卻至-78 °C，攪拌下依次加入三乙胺（0.42 mL，3 mmol)和氯乙醯氣 (〇. 1 mL ’ 1. 2 mmol)，混合液在-78°C下攪拌1小時後反應完畢。將反應液在減壓下濃縮，殘質經由水洗蘇，乙酸乙酯萃取（1〇〇 mLx3)，合併的有機相經由無水硫酸納脫水，過濾’減壓下濃縮，得到（S)-[l-(2-氯-乙醯基）-哌啶-3- 基]-胺基甲酸第三丁酯30 9a(2 71 mg，灰色固體），產率： 98% 〇 ® MS m/z (ESI) ： 276[M+] 第二步 .(S)-{l-[2-(3-{4-[3-氯-4-(3-氟-苄氧基）-苯基胺基]-喹唑琳-6-基}-吡嘻-1-基）一乙醯基]_哌啶基卜胺基曱酸第三·丁酯將[3-氣-4-(3-氟-苄氧基）_苯基]_[.6_(1H_吼咯—3_基）喹唑啉 4-基]-胺 42(317 mg，0.71 mmol)溶解於 1〇 ©無水N，N-二甲基甲醯胺中，在冰浴條件下，冷卻至，加入氫化鈉（86 mg，3. 6 mmol)，攪拌30分鐘後加入（〇_〇_ (2-氯-乙醯基）-派唆_3_基卜胺基甲酸第三丁醋獅 mg、’、0.、98 mmol)，室溫下授拌1小時反應完畢。將反應液在減壓下/辰、缩殘質經由水洗5条，乙酸乙醋萃取（1 〇〇 mLx3) σ併的有機相經由無水硫酸鈉脫水，過濾，減壓下濃縮’得到的殘留物藉由管柱層析法進—步分離純化（二氯甲烷：曱醇=50 : D，得到⑻-{卜[2-（3-{4-[3-氯一 4一（3— 94389 524 201016683 苄氧基）_苯基胺基]-啥°坐琳-6 一基卜吼嘻-1~基）~乙醯基]-哌啶-3-基}-胺基甲酸第三丁酯309K100 mg，棕黃色固體），產率：38. 5%。 MS m/z (ESI) ： 685[M+] 第三步 (S)-l-(3-胺基-旅咬-1-基）-2-(3_{4-[3 -氯- 4-(3~氟氧基）-苯基胺基]-啥嗤琳-6-基}-1*比洛_1-基）-乙阔.First step (S)-[1-(2-Chloro-ethenyl)-piperidin-3-yl]-amino decanoic acid tert-butyl ester 523 94389 201016683 (S)-piperidin-3-ylamine The third butyl carboxylic acid ester (20 0 mg, 1 mmol) was dissolved in 30 mL of tetrahydrofuran, cooled to -78 °C under cooling with acetone-dry ice bath, and then added triethylamine (0.42 mL, 3). Methyl) and chloroacetamidine (〇. 1 mL '1.2 mmol), the mixture was stirred at -78 °C for 1 hour and the reaction was completed. The reaction solution was concentrated under reduced pressure, and the residue was washed with water and ethyl acetate (1 〇〇mL×3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (S)-[l -(2-Chloro-ethinyl)-piperidin-3-yl]-carbamic acid tert-butyl ester 30 9a (2 71 mg, gray solid), yield: 98% 〇® MS m/z (ESI ) : 276[M+] Step 2. (S)-{l-[2-(3-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quina [3-ox-4-(3-fluoro-benzyloxy) benzoate-6-yl}-pyridin-1-yl)-ethinyl]-piperidinyl amide decanoic acid )_phenyl]_[.6_(1H_吼-l-3) quinazolin-4-yl]-amine 42 (317 mg, 0.71 mmol) dissolved in 1 〇 anhydrous N,N-dimethyl In the guanamine, it was cooled to an ice bath, and sodium hydride (86 mg, 3.6 mmol) was added, and after stirring for 30 minutes, it was added (〇_〇_(2-chloro-ethinyl)-pyrene~3 _ kibamine formic acid terpene vinegar mg, ', 0., 98 mmol), the reaction was completed at room temperature for 1 hour. The reaction mixture was dehydrated under reduced pressure/min, and the residue was washed with water, and extracted with ethyl acetate (1 〇〇mL×3) σ. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (dichloromethane: decyl alcohol = 50: D, to give (8)-{Bu [2-(3-{4-[3-chloro-4-1 (3-94389 524) 201016683 Benzyloxy)-phenylamino]-啥°坐琳-6-基基吼嘻-1~基)~Ethyl]-piperidin-3-yl}-carbamic acid tert-butyl ester 309K100 The yield was 38.5%. MS m/z (ESI): 685 [M+]. Step 3 (S)-l-(3-Amino-Behind-1-yl)-2-(3_{4-[3-chloro-4- 3~Fluorooxy)-phenylamino]-啥嗤琳-6-yl}-1*Bilo-1-yl)-B.

將（S)-{l-[2-(3-{4_[3-氯-4-(3 -氟-苄氧基）~ 苯基胺基]-嗤嗤琳-6_基}-π比u各-1-基）__乙醢基]_π底唆_3_基丨一胺基甲酸第三丁酯 309b(100 mg，〇. 15 mmol)溶於 20 mL 二氯曱烷中’攪拌下加入5 mL三氟乙酸，室溫下攪拌2小時 ’反應完畢。反應液在減壓下濃縮，加入3 0 mL飽和碳酸氫鈉洛液’乙酸乙醋萃取（5 0 mLx3 )，合併的有機相依次經由飽和氯化鈉溶液洗滌，無水硫酸嗍脫水，過濾，減壓下濃縮，得到的殘留物藉由鹼性氧化鋁管柱層析法分離純化（二氣甲烷：曱醇=50 : 1)，得到本標題產物 _哌啶-1-基）-2-(3-{4-[3-氯-4-(3-氟-苄氧基）_苯基胺基] -喹唑啉-6-基}-吡咯-1-基）-乙酮3〇9(；6〇mg，黃色固體），產率：70. 6% 〇 MS m/z (ESI) ： 585[M+] H NMR(400 MHz, DMS0-J5): 5 9· 69 (s，1H)，8· 73 (s，1H)， 8.48(s, 1H), 8.10(m, 1H), 8. 00 (m, 1H), 7. 84 (m, 1H), ^.48 (m, 1H), 7.29(m, 4H), 7. 16 (m, 1H), 6. 79 (s, 2H), 6.74(m, 1H), 5. 27 (s, 2H), 4. 95 (s, 2H), 3. 72 (m, 1H), 94389 525 201016683 2.99(m，1H)，2.88 (m，1H)，2.72 (m, 1H)，2.40 (m，1H) 1. 73 (m， 4H) 實施例310 1-(3-氟-苄基}1!1-吲唑-5-基~|-(6-{1-「4-(2-噍乙基）-嗎嚇·- 2~~基甲基]-1H~p比嗜·-3-基}-啥p坐蛛一4__就(S)-{l-[2-(3-{4_[3-chloro-4-(3-fluoro-benzyloxy)~phenylamino]-inden-6-yl}-π ratio U-1-yl)__ethylidene]_π bottom 唆_3_ylaminocarbamic acid tert-butyl ester 309b (100 mg, 〇. 15 mmol) dissolved in 20 mL of dichloromethane 5 mL of trifluoroacetic acid was added thereto, and the mixture was stirred at room temperature for 2 hours to complete the reaction. The reaction solution was concentrated under reduced pressure, and was added with 30 mL of saturated sodium bicarbonate solution, ethyl acetate (50 mL×3), and the combined organic phases were washed sequentially with saturated sodium chloride solution, dehydrated with anhydrous barium sulfate, filtered, reduced The mixture was concentrated under reduced pressure, and the obtained residue was purified (yield: methane: decyl alcohol = 50:1) to give the title product (piperidin-1-yl)-2-( 3-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl)-ethanone 3〇9 ( ; 6 〇 mg, yellow solid), Yield: 70. 6% 〇MS m/z (ESI): 585 [M+] H NMR (400 MHz, DMS0-J5): 5 9· 69 (s, 1H), 8· 73 (s,1H), 8.48(s, 1H), 8.10(m, 1H), 8. 00 (m, 1H), 7. 84 (m, 1H), ^.48 (m, 1H), 7.29(m, 4H), 7. 16 (m, 1H), 6. 79 (s, 2H), 6.74(m, 1H), 5. 27 (s, 2H), 4. 95 (s, 2H), 3. 72 (m, 1H), 94389 525 201016683 2.99 (m, 1H), 2.88 (m, 1H), 2.72 (m, 1H), 2.40 (m, 1H) 1. 73 (m, 4H) Example 310 1-(3-Fluoro-benzyl}1!1-oxazol-5-yl~|-(6-{1-"4-(2-indolyl)-?---- 2~~ylmethyl ]-1H~p is more than -3-yl}-啥p sitting on a spider 4__

❹ 310a❹ 310a

_第一步曱石黃酸（2-嗎淋-4-基）-乙酯將2-嗎淋-4-基-乙醇（〇.〇36 1111^，0.3 111111〇1)溶於5 111[ 二氯甲烷中，攪拌下加入三乙胺（〇. 〇5 inL，〇· 36随〇1)，混合液在丙酮-乾冰浴冷卻至-78°C，氬氣保護下，加入曱確酿氯（0. 06 mL，0. 33 mmol)，保持-78°C下反應1小時，薄層層析追蹤，顯示反應完畢，有甲磺酸（2-嗎啉-4-基）-乙酯310a生成，反應液不經處理直接進行下一步反應。 526 94389 201016683 MS m/z (ESI) ： 210[M+1] 第二步 1-(3-氟-苄基）-1Η-吲唑-5-基]-(6-U-[4-(2-嗎啉-4-基一乙基）-嗎嚇^-2-基曱.基]-1 Η-吼嘻-3-基卜喹η坐琳-4-基）-胺在上述步驟的反應液中加入[1-(3-氟-苄基）-ιη-π引唾 -5-基]-[6-(1-嗎淋-2-基甲基-1H-d比略-3-基）-喧唾嘛-4-基]-胺294(80 mg，0· 15 mmol)’加熱回流40小時。在反應液中加入5 0 idL -一亂曱焼I ’用飽和碳酸乳納洗蘇，飽和氯化鈉溶液洗蘇，無水硫酸鈉脫水，過濾，減壓下濃縮，得到的殘留物藉由薄層層析板分離純化（二氯曱烷：甲醇：氨水=15 : 1 : Id) ’得到本標題產物1-(3-氟-苄基）-1Η-吲 .〇坐-5-基]-(6-{1-[4-(2-嗎琳-4-基-乙基）-嗎琳-2-基甲基]-1H-吡咯-3-基卜喹唑啉-4-基）-胺310(35 mg，淡黃色固體），產率：36. 1%。·· MS m/z (ESI) ： 647[M+1] AMR (400MHz，DMSO-洲）：（5 9.81 (s，1H)，8.60 (s，1H)，參 8.45 (s，1H)，8.23 (s，1H)，8.17 (s，1H)，8.03 (d，1H， J=8.8Hz)，7.73 (m，3H)，7.39 (m，2H)，7.11 (m，3H)， 6. 88 (s, 1H), 6. 67 (s, 1H), 5. 72 (s, 2H), 4. 00 (m, 2H), 3.81 (d, 1H, J=11. 2Hz), 3.74 (m, 1H), 3. 54 (m, 5H), 2.80 (d, 1H, J=11.2Hz), 2. 71 (d, 1H, J=11.2Hz), 2.41 (m, 4H), 2.37 (m, 4H), 2.06 (t, 1H, J = l〇.4Hz), L 82 (t, 1H, J=10.4Hz) 實施例311 527 94389 201016683 L1-I3-氟-节基ΊΗ_吲唑—5_基_The first step of fluorescein (2-oxalin-4-yl)-ethyl ester dissolves 2-oxo-4-yl-ethanol (〇.〇36 1111^, 0.3 111111〇1) in 5 111 [ In dichloromethane, triethylamine (〇. 〇5 inL, 〇·36 with 〇1) was added with stirring. The mixture was cooled to -78 ° C in an acetone-dry ice bath. Under the protection of argon, the chlorine was added. (0. 06 mL, 0.33 mmol), kept at -78 ° C for 1 hour, traced by thin layer chromatography, showing completion of reaction, methanesulfonic acid (2-morpholin-4-yl)-ethyl ester 310a The reaction solution was directly subjected to the next reaction without treatment. 526 94389 201016683 MS m/z (ESI): 210[M+1] Step 2 1-(3-Fluoro-benzyl)-1Η-indazol-5-yl]-(6-U-[4-( 2-morpholin-4-yl-ethyl)- 吓 ^ -2- -2- -2- -2- -2- -2- 基基 -2- -2- -2- -2- -2- 吼嘻基基基基基基基在在在在在在[1-(3-Fluoro-benzyl)-ιη-π-lead--5-yl]-[6-(1-oxalin-2-ylmethyl-1H-d ratio -3- Base)-喧嘛-4-yl]-amine 294 (80 mg, 0·15 mmol) was heated to reflux for 40 hours. Add 50 idL - 曱焼曱焼 I ' to the reaction solution, wash the sulphate with saturated sodium carbonate, wash the sodium chloride solution with saturated sodium chloride solution, dehydrate the anhydrous sodium sulfate, filter, concentrate under reduced pressure, and obtain the residue by thin Separation and purification by layer chromatography (dichloromethane:methanol: ammonia = 15 : 1 : Id) 'The title product 1-(3-fluoro-benzyl)-1Η-吲.〇-5-yl]- (6-{1-[4-(2-Molin-4-yl-ethyl)-morphin-2-ylmethyl]-1H-pyrrol-3-ylquinazolin-4-yl)- 1%。 Amine 310 (35 mg, pale yellow solid), yield: 36.1%. MS m/z (ESI): 647 [M+1] AMR (400 MHz, DMSO-C): (5 9.81 (s, 1H), 8.60 (s, 1H), Ref. 8.45 (s, 1H), 8.23 (s, 1H), 8.17 (s, 1H), 8.03 (d, 1H, J = 8.8 Hz), 7.73 (m, 3H), 7.39 (m, 2H), 7.11 (m, 3H), 6. 88 ( s, 1H), 6. 67 (s, 1H), 5. 72 (s, 2H), 4. 00 (m, 2H), 3.81 (d, 1H, J=11. 2Hz), 3.74 (m, 1H) ), 3. 54 (m, 5H), 2.80 (d, 1H, J=11.2Hz), 2. 71 (d, 1H, J=11.2Hz), 2.41 (m, 4H), 2.37 (m, 4H) , 2.06 (t, 1H, J = l〇.4Hz), L 82 (t, 1H, J = 10.4 Hz) Example 311 527 94389 201016683 L1-I3-Fluoro-nodal hydrazine _ carbazole-5-yl

-(4-甲碏醯篡-噍-(4-甲碏醯篡-噍

A A 將[l-(3-A A will [l-(3-

α, -甲基-1H-吡咯-3一基）_喹唑啉_4一基]_胺294(ι〇〇呵，〇 i9 .mmol)溶於5 mL二氯甲烷中，攪拌下加入三乙胺（〇〇33 mL，0· 23 mmol) ’ ·混合液在丙酮_乾冰浴冷卻至_78弋，氬氣保護下，加入甲磺醯氯（0.017mL，〇 21 mm〇1)，保持-78 C下反應3小時反應完畢。將反應液加入mL二氣曱烷 ❿中’依次經由飽和碳酸氫鈉洗滌，飽和氯化鈉溶液洗滌，無水硫酸鈉脫水，過濾，減壓下濃縮，殘留物藉由薄層層析板分離純化（二氯曱烷：甲醇=15 : 1 )，得到本標題產物 [1-(3-氟-苄基）-lH-吲唑-5-基]-{6-[1-(4-甲磺醯基-嗎啉-2-基曱基）-1Η-吡咯-3-基]-喹唑琳-4-基卜胺311(50 mg，淡黃色固體），產率：43%。 MS m/z (ESI) ： 612[M+1] ]HNMR (400MHz, MS0-d6): <5 9. 84 (s, 1H), 8.61 (s, 1H), 528 94389 201016683 8.46 (s, 1H), 8.23 (s, 1H), 8.17 (s, 1H), 8.03 (d, 1H, J=8.8Hz), 7. 72 (m, 3H), 7.44 (s, 1H), 7. 39 (m, 1H), 7. ll (m, 3H),6.92 (s, 1H), 6.69 (s, 1H), 5. 72 (s, 2H), 4. 12(ra, 3H), 3. 83 (m, 1H), 3. 55 (m, 2H), 3.35 (m, 1H), 2.92 (s, 3H), 2.84 (t, 1H, J=11. 2Hz), 2. 59 (m, 1H) 實施例312 「1-(3-氟-苄某）-彳11-吲唑-5-基]-(6-{1-[4-(2-甲碚醯其-乙基）-嗎嗛-2-其甲篡比洛-3-基喹嗤喊-4-基脸α, -Methyl-1H-pyrrole-3-yl)-quinazoline-4-yl]-amine 294 (ι〇〇, 〇i9.mmol) was dissolved in 5 mL of dichloromethane and stirred under three Ethylamine (〇〇33 mL, 0·23 mmol)' · The mixture was cooled to _78 Torr in acetone _ dry ice bath, and added with methane sulfonium chloride (0.017 mL, 〇21 mm 〇1) under argon atmosphere. The reaction was completed at -78 C for 3 hours. The reaction solution was added to mL of dioxane hydrazine, washed sequentially with saturated sodium hydrogen carbonate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. (Chlorochlorosilane:methanol = 15 : 1 ) gave the title product [1-(3-fluoro-benzyl)-lH-indazol-5-yl]-{6-[1-(4-methane) Mercapto-morpholin-2-ylindenyl)-1Η-pyrrol-3-yl]-quinazoline-4-ylpamine 311 (50 mg, pale yellow solid), yield: 43%. MS m/z (ESI): 612 [M+1]]HNMR (400 MHz, MS0-d6): <5 9. 84 (s, 1H), 8.61 (s, 1H), 528 94389 201016683 8.46 (s, 1H), 8.23 (s, 1H), 8.17 (s, 1H), 8.03 (d, 1H, J=8.8Hz), 7. 72 (m, 3H), 7.44 (s, 1H), 7. 39 (m , 1H), 7. ll (m, 3H), 6.92 (s, 1H), 6.69 (s, 1H), 5. 72 (s, 2H), 4. 12(ra, 3H), 3. 83 (m , 1H), 3. 55 (m, 2H), 3.35 (m, 1H), 2.92 (s, 3H), 2.84 (t, 1H, J=11. 2Hz), 2. 59 (m, 1H) 312 "1-(3-Fluoro-benzyl)-oxime 11-oxazol-5-yl]-(6-{1-[4-(2-carbazyl-ethyl)-??-2- Its hyperthyroidism is more than -3- quinolin

第一步甲磺酸（2-甲磺醯基）-乙酯將2-甲石黃醯基-乙醇（47 mg，0.38 mmol)溶於5 mL二氯甲烧中，授拌下加入三乙胺（〇. 065 mL，0. 46 mmol )，混合液在丙_ -乾冰浴冷卻至，氬氣保護下，加入曱石黃 94389 529 201016683 醯氯（0. 027 mL，0· 34 mmol)，升至室溫反應1小時。將反應液在減壓下濃縮’得到的粗品曱磺酸（2—甲磺醯基）_乙酯 312a不經分離直接進行下一步反應。 MS iii/z (ESI) ： 203[M+1] 第二步 [1-（3-氟-苄基）-111-吲唑-5-基]-(6-{1-[4-(2-曱續醯基-乙基）-嗎啉-2-基甲基]-1 Η-吡嘻-3-基}-喹唑啉-4-基）-胺將粗品曱磺酸（2-甲績醯基）-乙酯溶於5 mL乙腈中，攪拌下加入[1-(3-氟-苄基）-1Η-吲唑-5-基]-[6-(1-嗎琳 -2-基甲基-1H-0比嘻-3-基）-啥《坐琳-4-基]-胺294 (100 mg ’ 0. 19 mmol)和碳酸鉀（105 mg，〇· 76 mmol)，加熱回流 •反應過夜。在反應液中加入50 mL二氯甲烷中，抽滤，滤液在減壓下濃縮’得到的殘留物藉由薄層層析板分離純化 (一氯甲娱*.甲醇= 12. 1) ’得到本標題產物ι_(3 -氟-节基） -111-11引唑-5-基]-(6-{1-[4-(2-甲石黃醯基-乙基）_嗎琳_2-基甲基]-1Η-π比洛-3-基}-啥嗤琳-4-基）-胺312(75 mg，淡 _黃色固體），產率：61. 7%。 MS m/z (ESI) ： 640[M+1] 'HNMR (400MHz, DMS0-d5): 5 9. 81 (s, 1H), 8. 60 (s, 1H), 8.45 (s, 1H), 8.23 (s, 1H), 8. 17 (s, 1H), 8.03 (d, 1H, J=8. 8Hz), 7.73 (m, 3H), 7.38 (m, 2H), 7.08 (m, 3H), 6. 88 (s, 1H), 6. 67 (s, 1H), 5. 72 (s, 2H), 4. 02 (m, 2H), 3. 79 (m, 2H), 3. 49 (m, 1H), 3. 28 (m, 2H), 3. 03 (s, 3H), 2.75 (m, 4H), 2. 07 (t, 1H, J = 10.4Hz), 1.88 (t, 1H, 94389 530 201016683 J=10.4Hz) 實施例313Step 1 (2-Methanesulfonyl)-ethyl methanesulfonate 2-Mercaptoxyl-ethanol (47 mg, 0.38 mmol) was dissolved in 5 mL of dichloromethane, and triethylamine was added with stirring. 065 065 mL, 0. 46 mmol ), the mixture was cooled in a __ dry ice bath, and under argon atmosphere, fluorite yellow 94389 529 201016683 醯 chlorine (0. 027 mL, 0·34 mmol) was added to the mixture. The reaction was carried out for 1 hour at room temperature. The reaction solution was concentrated under reduced pressure. The obtained crude sulfonic acid (2-methanesulfonyl)-ethyl ester 312a was directly subjected to the next reaction without isolation. MS iii/z (ESI): 203 [M + 1]. Step 2 [1-(3-fluoro-benzyl)-111-oxazol-5-yl]-(6-{1-[4-(2) - 醯醯 --ethyl)-morpholin-2-ylmethyl]-1 Η-pyridin-3-yl}-quinazolin-4-yl)-amine will be crude sulfonic acid (2-A) Ethyl ester was dissolved in 5 mL of acetonitrile, and [1-(3-fluoro-benzyl)-1Η-oxazol-5-yl]-[6-(1-Merlin-2-) was added with stirring. Methyl-1H-0 is more than indole-3-yl)-indole "Shenyl-4-yl]-amine 294 (100 mg '0. 19 mmol) and potassium carbonate (105 mg, 〇 · 76 mmol), heated Reflux • Reaction overnight. 50 ml of dichloromethane was added to the reaction mixture, and the mixture was filtered with suction, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by chromatography (yield: m. The title product ι_(3-fluoro-nodal)-111-11-azol-5-yl]-(6-{1-[4-(2-methyl-stone-ethyl)-]-lin-2-yl Methyl]-1 Η-π 比洛-3-yl}-indolyl-4-yl)-amine 312 (75 mg, pale-yellow solid), yield: 61.7%. MS m/z (ESI): 640 [M+1] <RTI ID=0.0>> 8.23 (s, 1H), 8. 17 (s, 1H), 8.03 (d, 1H, J=8. 8Hz), 7.73 (m, 3H), 7.38 (m, 2H), 7.08 (m, 3H), 6. 88 (s, 1H), 6. 67 (s, 1H), 5. 72 (s, 2H), 4. 02 (m, 2H), 3. 79 (m, 2H), 3. 49 (m , 1H), 3. 28 (m, 2H), 3. 03 (s, 3H), 2.75 (m, 4H), 2. 07 (t, 1H, J = 10.4Hz), 1.88 (t, 1H, 94389 530 201016683 J=10.4Hz) Embodiment 313

Lbllr氣吲卜（6-U-「4-(3-甲氣基基）基]-】r—吡咯-3-基卜喹唑啉-4-基）-胺Lbllr gas 卜 (6-U-"4-(3-methyl))]]]r-pyrrol-3-ylquinazolin-4-yl)-amine

⑩甲磺酸3-甲氧基丙酯將3 -甲氧基—丙一醇（μ mg，0.38 mmol)溶於5 mL 二氯甲燒中’攪拌下加入三乙胺（0. 065 mL，0. 46 mmol)，混合液在丙酮-乾冰浴冷卻至-78°C，氬氣保護下，加入甲石尹、醯氯（〇· 027 mL , 0. 34 mmol)，升至室溫反應1小時。將反應液在減壓下濃縮，得到的粗品曱磺酸3_甲氧基丙酯 313a不經分離直接進行下一步反應。 MS m/z (ESI) ： 203[MH] 94389 531 201016683 第二步 [1-(3-氟-苄基）-1 Η-吲唑-5-基]-(6-{l-[4-(3-曱氧基-丙基）-嗎淋-2-基甲基]-1H-0比σ各~3-基}-啥唾淋-4-基）-胺將粗品甲磺酸3-曱氧基丙酯313a溶於5 mL乙腈中，攪拌下加入[1-(3-氟-苄基）-1Η-吲唑-5-基]-[6-(1-嗎啉 -2-基曱基-1H-吡咯-3-基）-喹唑啉—4-基]一胺294(ι〇〇 mg ’ 0. 19顏〇1)和碳酸鉀（105 mg，〇. 76 mmol)，加熱回流反應過夜。在反應液中加入5〇 mL二氯甲烷中，抽滤，濾液在減壓下濃縮，得到的殘留物藉由薄層層析板分離純化 (二氯曱烷：甲醇= 12: 1)，得到本標題產物一氟一苄基） -1Η-η引嗤-5-基]-(6-{1-[4-(3-甲氧基-丙基）_嗎啉一2_基 •曱基]-1Η-吡咯-3-基}-喹唑啉-4-基）-胺313(40 mg，淡黃色固體），產率：34· 8%。 MS m/z (ESI) ： 606[M+1] !HNMR (400MHz, DMS0-d6): (5 9.81 (s, 1H), 8. 59 (s, 1H), 8.45 (s, 1H), 8.23 (s, 1H), 8. 17 (s, 1H), 8.03 (d, 1H, ⑩ J=8.8Hz)，7.73 (m，3H)’ 7.39 (m，2H)，7.06 (m，3H)， 6· 88 (s，1H)，6. 67 (s’ 1H)，5. 72 (s，2H)，4· 02 (m，2H)， 3.82 (d, 1H, J = 10.4Hz), 3.74 (m , 1H), 3.50 (m, 1H), 3.33 (m, 2H), 3.21 (s, 3H), 2.75 (d, 1H, J = 10.4Hz), 2.67 Cd, 1H, J=10.4Hz), 2.30 (m, 2H), 2.00 (m, 1H), 1. 75 (t, 1H, J=10. 4Hz), 1. 66 (m, 2H) 實施例314 2-「2-(3-{4-[1-(_3-氟-苄暴)二111-吲4-5-基胺基1-喹唑嗷 94389 532 201016683 -6-基卜吼咯-卜基嗎啉-4_其ι_7|10 3-methoxypropyl methanesulfonate 3 -Methoxy-propanol (μ mg, 0.38 mmol) was dissolved in 5 mL of dichloromethane, and triethylamine (0. 065 mL, 0. 46 mmol), the mixture was cooled to -78 ° C in an acetone-dry ice bath. Under argon atmosphere, a solution of sulphate and sulphur chloride (〇· 027 mL, 0. 34 mmol) was added and the mixture was allowed to react to room temperature. hour. The reaction solution was concentrated under reduced pressure, and the obtained crude succinic acid 3-methoxypropyl ester 313a was directly subjected to the next reaction without isolation. MS m/z (ESI): 203 [MH] 94389 531 201016683 Step 2 [1-(3-Fluoro-benzyl)-1 Η-carbazol-5-yl]-(6-{l-[4- (3-methoxy-propyl)-oxalin-2-ylmethyl]-1H-0 ratio σ~3-yl}-oxime-4-yl)-amine crude methanesulfonic acid 3- The methoxypropyl ester 313a was dissolved in 5 mL of acetonitrile, and [1-(3-fluoro-benzyl)-1Η-indazol-5-yl]-[6-(1-morpholin-2-yl) was added with stirring. Mercapto-1H-pyrrol-3-yl)-quinazolin-4-yl]monoamine 294 (ι〇〇mg '0. 19 〇 1) and potassium carbonate (105 mg, 〇. 76 mmol), heated The reaction was refluxed overnight. 5 毫升 mL of dichloromethane was added to the reaction mixture, and the mixture was filtered with suction, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by chromatography (dichloromethane:methanol = 12:1). The title product: monofluoro-benzyl) -1Η-η 嗤-5-yl]-(6-{1-[4-(3-methoxy-propyl)-morpholine-2-yl-yl) ]-1Η-pyrrol-3-yl}-quinazolin-4-yl)-amine 313 (40 mg, pale yellow solid), yield: 34·8%. MS m/z (ESI): 606 [M+1].HNMR (400MHz, DMS0-d6): (5 9.81 (s, 1H), 8. 59 (s, 1H), 8.45 (s, 1H), 8.23 (s, 1H), 8. 17 (s, 1H), 8.03 (d, 1H, 10 J=8.8Hz), 7.73 (m,3H)' 7.39 (m,2H),7.06 (m,3H), 6 · 88 (s, 1H), 6.67 (s' 1H), 5. 72 (s, 2H), 4 · 02 (m, 2H), 3.82 (d, 1H, J = 10.4Hz), 3.74 (m , 1H), 3.50 (m, 1H), 3.33 (m, 2H), 3.21 (s, 3H), 2.75 (d, 1H, J = 10.4Hz), 2.67 Cd, 1H, J = 10.4Hz), 2.30 ( m, 2H), 2.00 (m, 1H), 1. 75 (t, 1H, J=10. 4Hz), 1. 66 (m, 2H) Example 314 2-"2-(3-{4-[ 1-(_3-fluoro-benzylidene)di 111-indole-4-5-ylamino-1-pyrazolium 94389 532 201016683 -6-gibromo-bubumorpho-4_ its ι_7|

第一步 2-(第三丁基-二甲基-矽氧基）_乙醇將氫化鈉（800 mg，20 mmol)溶於20 mL四氫吱喃中，氬氣保護下，冰浴冷卻至〇。〇，滴加乙二醇（1. 24 g，2〇 mm〇l) ’室溫下攪拌1小時反應完畢。將反應液倒入1〇〇 mL 冰水中，乙酸乙酯萃取（50 mLx3)，合併的有機相依次經由飽和碳酸氫鈉溶液洗滌，飽和氯化鈉溶液洗滌，無水硫酸 533 94389 201016683 納脫水’過濾，減屋下濃縮，得到粗品2-(第三丁基-二曱基-矽氧基）-乙醇314a(3. 8 g，無色油狀液體），產物不經分離直接進行下一步反應。第二步甲磺酸2-(第三丁基—二甲基一矽氧基）一乙酯將粗品2-(第三丁基-二曱基-矽氧基乙醇314a (3. 8 g)溶於30 mL二氯甲烷中，攪拌下加入三乙胺（4 g， 30 mmol)，混合液在丙嗣—乾冰浴冷卻至_78艺，氬氣保護鬌下，加入甲磺醯氯（3 4 g , 30職〇1)，升至室溫反應i小時。將反應液倒入1〇〇 mL冰水中，乙酸乙酯萃取（5〇瓜^ 3)，合併的有機相依次經由飽和碳酸氫鈉溶液洗滌，飽和 .氯化鈉溶液洗滌，無水硫酸鈉脫水，過濾，減壓下濃縮， -殘留物藉由矽膠管柱層析法分離純化（正己烷：乙酸乙酯 =4: 1)，得到甲磺酸2 —(第三丁基—二甲基_矽氧基)_乙酯 3l4b(3.5 g，無色油狀液體），產率：68 8%。 MS m/z (ESI) ： 255[M+1] .第三步第三丁基-二曱基—矽氧基）_乙基]_嗎啉_2_ 基曱基}-1Η-吼咯-3-基）-喹唑啉氟苄基） •~1H-吲唑-5-基]-胺將甲石買酸2-(第二丁基-二甲基-矽氧基乙酯314b (84 mg，0.33 mmol)溶於5 mL乙腈中，攪拌下加入[卜仏氟-节基MH-，唑-5-基]-[6-(1-嗎啉基曱基_1H_吡咯基）-喧嗤琳_4_基卜胺294(6〇吨，m酿〇1)和碳酸 94389 534 201016683 鉀（61 mg，0. 44 mmol)，加熱回流反應過夜。在反應液中加入20 mL二氣甲烷中，抽濾，濾液在減壓下濃縮，得到的殘留物藉由薄層層析板分離純化（二氯曱烷：甲醇=12: 1)，得到[6-(1-{4-[2-(第三丁基-二甲基-矽氧基）_乙基]_ 馬琳2-基曱基比嘻-3-基）-啥〇坐淋-4-基]-[卜（3_氟节基）-1Η-吲唑-5-基]-胺314c(40 mg，淡黃色固體），產率：39. 4% 〇 MS m/z (ESI) ： 692[M+1] 第四步 2-[2-(3-{4-[l-(3-氟-苄基）-lH-吲唑-5-基胺基]-喹唑啉 -6-基}-吡咯-1，基甲基）-嗎啉_4一基]_乙醇將[6-(1-{4-[2-(第三丁基-二甲基-矽氧基）一乙基;μ -嗎啉-2-基甲基}-lH-吡咯-3-基）-喹唑啉-4-基]-[1-(3-氣苄基）-1Η-吲唑-5」基]-胺 314c(30 mg，0.043 mmol)溶於 2 mL四氫呋喃中’攪拌下加入四丁基氟化鍵（5〇 mg，〇. 16 mmo 1)’至溫下擾样1小時反應完畢。將反應液倒入2 〇 ❿冰水中’加入2 mL飽和碳酸氫鈉溶液，乙酸乙酯萃取（2〇 mL x3) ’合併的有機相依次經由飽和碳酸氫納溶液洗條，飽和氯化鈉溶液洗滌，無水硫酸鈉脫水，過濾’減壓下濃縮，殘留物藉由薄層層析板分離純化(二氯甲烷：甲醇=10:1)，得到2-[2-(3-{4-[1-(3-氟-苄基）-1Η-吲唑-5-基胺基]-喹唑啉-6-基}-吡咯-1-基甲基）-嗎啉-4-基]-乙醇314(19 mg，淡黃色固體），產率：76. 5%。 MS m/z (ESI) ： 578[M+1] 535 94389 201016683 ^NMR (400MHz, DMS0-d6): δ 9. 81 (s, 1H), 8 60 (s 1H) 8.45 (s, 1H), 8.23 (s, 1H), 8.17 (s. 1H), 8.03 (d, 1H, J=8.8Hz), 7.73 (m, 3H), 7.38 (m, 2H), 7.08 (m, 3H), 6.88 (s, 1H), 6.67 (s, 1H), 5.72 (s, 2H), 4.40 (t, 1H, J=5.2Hz), 4.00 (m, 2H), 3.83 (m, 2H), 3.51 (m, 3H), 2.79 (d, 1H, J=10.4Hz), 2.70 (d, 1H, J = 10.4Hz), 2.39 (in, 2H), 2.08 (t, 1H, J = 10.4Hz), 1.85 (t, 1H, J=10.4Hz) 實驗例： ❹ 生物學評價例1. EGFR抑制細胞增殖測試下面的體外試驗是用來測定本發明化合物對於人類腫瘤細胞A431 EGFR大量表現的細胞株之抑制增殖活性。下面所述的體外細胞試驗可確定受試化合物的對大量表現EGFR的腫瘤細胞的抗血管生成活性和抑制增殖活性，其活性可用1C5。值來表示。此類試驗的一般方法如下：馨首先選擇大量表現EGFR的人類腫瘤細胞，以適宜細胞濃度 (exp 5000個細胞/ml培養基）接種在96扎培養盤上，然後將細胞在二氧化碳恆溫箱内進行培養，當細胞生長至 85%匯合（C〇nfluence)時，將培養基更換為加有一系列濃度梯度（一般6到7個濃度）受試化合物溶液的培養基，將= 養盤重新放回培養箱，連續培養72個小時。72小時後，可用續醯羅丹明B(sulf〇rh〇damineB ; SRB)方法進行測試化合物對於抑制細胞增瘦活性。IC5。值可藉由一系列- 不门 94389 536 201016683 濃度下’受試化合物對於細胞的抑制數值進行計算。材料和方法： a. 二曱基亞爾<(Sinophma chemical reagent company，目錄 T20050806 號） b. A431 細胞（購於 Institute of biochemistry and cell biology) c. Falcon 100 ram 細胞培養盤（Baton Dickison Labware, Baton Dickison and company,目錄 18677 號） d. 康寧（corning)96 孔培養盤（Corning Incorporated,目彎錄3599號） e. 費氏移液管（Fisher scientific，目錄 03-692-164 號） f. DMEM/F12 細胞培養基（Gibco，目錄 12400-024 號） .g.澳大利亞胎牛血清（Gibco ’目錄10099-141號） h. 磷酸鹽緩衝鹽水（Gibco，目錄10010-072號） i. 0.25% 胰島素-EDTi(Gibco，目錄 25200-056 號） j. 續醯羅丹明B(Sigma，目錄3520-42-1號） ❹ k.醋酸（Sinophma chemical reagent company，目錄 T20060508 號） l. 三氯醋酸（Sinophma chemical reagent company，目錄 T20060305 號） m. Tris 驗（Amresco，目錄 0826 號） η. II級A/B3型生物安全操作櫃（ThermoForma目錄， HB0053-03 號）〇.系列11水套式二氧化碳培養箱（ThermoForma模型： 537 94389 201016683 3111) p. 離心機（Fisher Scienti fic Marathon 8 k，目錄 0027-02 號） q. Novastar 盤讀取器（BMGLabtech，目錄 700-0081 號） r·迴轉式震盪器（Qilinbeier，目錄TS-1號）方法：下面的方法是用來測試本發明受試化合物對於A431 細胞的抑制細胞增殖I Cso值。 1.將A431細胞接種於1 〇〇mm康寧培養盤，在培養基（以 DMEM/F12+10%胎牛金清為培養液）中進行培養（37¾，5% CO2)，直至細胞充分匯合； .2.在1〇〇 mm培養盤中用胎牛血清洗滌A43i細胞，以胰蛋 -白酶水解細胞後，再將細胞接種在康寧96孔細胞培養盤上”·濃度為50000細胞/ml,每個盤空6孔，作為對照孔； 3.在37°C ’ 5% CCh條件下’將細胞在96孔盤中培養，直至達到約85%匯合；纏M·用DMS0溶解受試化合物，配置20 mM母液，後用DMS0 稀釋母液，得到一系列濃度的受試化合物的溶液，即2 、 1 mM、0 · 2 mM、2 0 // Μ、2 v Μ、0. 2 # Μ ; 5·使用細胞培養基（DMEM/F12 +10%胎牛血清為培養液）稀釋上面所配置的化合物溶液。每個DMS0系列濃度化合物溶液稀釋20倍，每次在細胞培養基中加入5仏1 DMS0化合物溶液和95 a 1培養液，確保Α431細胞暴露在DMS0溶液中的;辰度不超過0 · 5 % ’用涡旋（vort ex )混合； 94389 538 201016683 6. 當A431細胞貼壁，生長達到85%匯合後，將培養其換為加有DMEM/F12 +10%胎牛血清培養液的新培養基，每孔中再加入180/ζ 1培養液和20/ζ 1在第五步中所製備的a ▲戈化合物溶液。陰性對照組細胞’加入含有〇.5%DMS〇的2〇 # ί培養液’這樣A431細胞暴露在受試化合物溶液中的最終濃度為 100^、10//Μ、5/ζΜ、1//Μ、〇. ι#Μ、〇. 〇1//Μ 以及 0. 001 " Μ ; 7. 將培養盤放入恆溫箱内，在37〇c ’ 5% c〇2條件下，連續培養7 2小時；鲁8. 72小時後，將培養盤從恆溫箱中轉移到無菌工作室； 9'將試藥級純水加入到TCA中製備固定劑（5〇%三氯醋酸 --TCA)，將細胞慢慢地分層放在5〇// 1冷TCA溶液中； -1 〇.在4°C下，培養1小時’然後用水洗滌數次以除去TCA、 ’血清蛋白等。培養盤在空氣中乾燥，存儲待用。空白背景光學密度值的測定是在沒有細胞生長的培養基中溫育培養所得的數值。 © 11.用10%醋酸溶液製備〇. 4%磺醯羅丹明B溶液，並於每孔中加入50 # 1磺醯羅丹明b溶液； 12.細胞染色30分鐘； 13·製備1〇%醋酸洗滌溶液。當染色將要完畢時，棄去染色劑，用10%的醋酸溶液快速沖洗細胞。重複上述的操作直至染色劑洗淨為止，儘量減少沖洗次數以減少與蛋白、妹合的染色劑的去吸附。沖洗完畢後，將培養盤在空氣中乾 94389 539 201016683 14.混合的染色劑溶解在一定體積的磺醯羅丹明b中，溶解溶液（10 mM Tris)與培養基原體積相同，將培養盤在室溫下放置5分鐘’用震盪器緩慢擾拌加快與染色劑的混合； 15·用分光光度測量，在波長565 nm下讀取吸光度值。吸光度數值為565 nm下吸光度減去690 nm下96孔盤背景吸光度所得的數值； 16.使用如下方法計算抑制率比值： IR=100X(對照組吸光度值—用藥組吸光度值）/對照組吸光度值％ 1C5。值可藉由不同濃度下化合物抑制率比值計算得到。本發明化合物的活性定’測得的I Cso值見下表。 _實施例編號 1 —__i£^__^FR/A431)(弘 Μ) 1 η 0.36 2 η 0. 27 3 r 〇. 77 5 〇 0. 78 8 1. 08 9 0.136 10 0. 57 11 1.45 12 0.12 13 0. 68 14 0, 2 15 __0. 02 • 本發明化合物的生化學活性藉由以上的試驗進行測 94389 540 201016683Step 2 2-(Terbutyl-dimethyl-decyloxy)-ethanol Sodium hydride (800 mg, 20 mmol) was dissolved in 20 mL of tetrahydrofuran, cooled under argon and cooled to ice bath. Hey. 〇, dropwise addition of ethylene glycol (1. 24 g, 2〇 mm〇l) was stirred at room temperature for 1 hour and the reaction was completed. The reaction solution was poured into 1 mL of ice water, extracted with ethyl acetate (50 mL×3), and the combined organic phases were washed sequentially with saturated sodium hydrogen carbonate solution and washed with saturated sodium chloride solution, anhydrous sulphuric acid 533 94389 201016683 Concentration under reduced house afforded crude 2-(t-butyl-didecyl-decyloxy)-ethanol 314a (3.8 g, colorless oily). The second step of 2-(t-butyl-dimethyl-decyloxy)-ethyl methanesulfonate as the crude 2-(t-butyl-didecyl-decyloxyethanol 314a (3.8 g) Dissolve in 30 mL of dichloromethane, add triethylamine (4 g, 30 mmol) with stirring, and cool the mixture in a acetonitrile-dry ice bath to _78 art, under argon atmosphere, add methanesulfonate chloride (3 4 g , 30 jobs 1), and raised to room temperature for 1 hour. The reaction solution was poured into 1 mL of ice water, extracted with ethyl acetate (5 〇 ^ 3), and the combined organic phases were passed through saturated hydrogen carbonate. The sodium solution is washed, saturated with sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue is purified by hexane column chromatography (hexane: ethyl acetate = 4:1). 2-(T-butyl-dimethyl-decyloxy)-ethyl ester methanesulfonate 3l4b (3.5 g, colorless oily liquid), yield: 68 8%. MS m/z (ESI): 255 [M+1] . Third Step Third Butyl-Dimercapto-indenyloxy)-Ethyl]-morpholine_2_ylindenyl}-1Η-indol-3-yl)-quinazoline Fluoride Benzyl) •~1H-indazol-5-yl]-amine will buy acid 2-methyl-t-butyl-dimethyl-methoxyl Ester 314b (84 mg, 0.33 mmol) was dissolved in 5 mL of acetonitrile and stirred under stirring. [Bus Fluorine-Fluoryl MH-,oxazol-5-yl]-[6-(1-morpholinylfluorenyl-1H_) Pyrrolyl)-喧嗤琳_4_ylbumin 294 (6 ton, m 〇 1) and carbonic acid 94389 534 201016683 potassium (61 mg, 0.44 mmol), heated under reflux overnight. In 20 mL of two-gas methane, the mixture was filtered under suction, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by chromatography (dichloromethane:methanol = 12:1) to give [6-(1- {4-[2-(Tertiary-butyl-dimethyl-decyloxy)-ethyl]_Marine 2-ylindenyl-3-indolyl-3-yl)-indenyl-4-yl]-[ (3_Fluoro)-indolyl-5-yl]-amine 314c (40 mg, pale yellow solid), yield: 39. 4% 〇MS m/z (ESI): 692[M+ 1] Step 4 2-[2-(3-{4-[l-(3-Fluoro-benzyl)-lH-indazol-5-ylamino]-quinazolin-6-yl}-pyrrole -1,ylmethyl)-morpholine-4-yl]-ethanol [6-(1-{4-[2-(t-butyl-dimethyl-decyloxy)-ethyl; Morpholin-2-ylmethyl}-lH-pyrrol-3-yl)-quinazolin-4-yl]-[1-(3-acetobenzyl)-1Η-indazol-5"yl]-amine 314c (30 mg, 0.043 mmol) is soluble In 2 mL of tetrahydrofuran, a tetrabutylfluorinated bond (5 〇 mg, 〇. 16 mmo 1) was added under stirring, and the reaction was completed by shaking for 1 hour under temperature. Pour the reaction into 2 〇❿ ice water 'Add 2 mL of saturated sodium bicarbonate solution, extract with ethyl acetate (2 〇 mL x 3) 'The combined organic phases are washed sequentially with saturated sodium bicarbonate solution, saturated sodium chloride solution Washed, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography (dichloromethane:methanol = 10:1) to give 2-[2-(3-{4-[ 1-(3-Fluoro-benzyl)-1Η-indazol-5-ylamino]-quinazolin-6-yl}-pyrrol-1-ylmethyl)-morpholin-4-yl]-ethanol 314 (19 mg, pale yellow solid), yield: 76.5%. MS m/z (ESI): 578 [M+1] </ </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 8.23 (s, 1H), 8.17 (s. 1H), 8.03 (d, 1H, J=8.8Hz), 7.73 (m, 3H), 7.38 (m, 2H), 7.08 (m, 3H), 6.88 (s , 1H), 6.67 (s, 1H), 5.72 (s, 2H), 4.40 (t, 1H, J=5.2Hz), 4.00 (m, 2H), 3.83 (m, 2H), 3.51 (m, 3H) , 2.79 (d, 1H, J = 10.4 Hz), 2.70 (d, 1H, J = 10.4 Hz), 2.39 (in, 2H), 2.08 (t, 1H, J = 10.4 Hz), 1.85 (t, 1H, J = 10.4 Hz) Experimental Example: 生物学 Biological Evaluation Example 1. EGFR inhibition cell proliferation test The following in vitro test is used to determine the inhibitory activity of the compound of the present invention against a cell strain in which human tumor cells A431 EGFR is abundantly expressed. The in vitro cell assay described below determines the anti-angiogenic activity and the proliferative activity of the test compound against a large number of EGFR-expressing tumor cells, and its activity can be 1C5. The value is expressed. The general method for such an experiment is as follows: Xin first selects a large number of human tumor cells expressing EGFR, inoculates on a 96-tray culture plate at a suitable cell concentration (exp 5000 cells/ml medium), and then cultures the cells in a carbon dioxide incubator. When the cells are grown to 85% confluence, the medium is replaced with a medium supplemented with a series of concentration gradients (generally 6 to 7 concentrations) of the test compound solution, and the = dish is returned to the incubator for continuous Cultivate for 72 hours. After 72 hours, the compound can be tested for inhibition of cell growth-reducing activity by the method of sulfonium rhodamine B (SRB). IC5. The value can be calculated by a series of - in the case of 94389 536 201016683 concentration of the test compound for cell inhibition values. Materials and Methods: a. Siniphma chemical reagent company (catalog T20050806) b. A431 cells (purchased in Institute of biochemistry and cell biology) c. Falcon 100 ram cell culture plate (Baton Dickison Labware, Baton Dickison and company, catalog 18677) d. Corning 96-well culture plate (Corning Incorporated, Bulletin No. 3599) e. Fisher Scientific Pipette (Fisher scientific, catalog 03-692-164) f. DMEM/F12 Cell Culture Medium (Gibco, Catalog 12400-024) .g. Australian Fetal Bovine Serum (Gibco 'Cat. No. 10099-141) h. Phosphate Buffered Saline (Gibco, Catalogue 10010-072) i. 0.25% Insulin -EDTi(Gibco, catalogue 25200-056) j. Continued Rhodamine B (Sigma, catalogue 3520-42-1) ❹ k. Acetic acid (Sinophma chemical reagent company, catalog T20060508) l. Trichloroacetic acid (Sinophma) Chemical reagent company, catalog T20060305) m. Tris test (Amresco, catalogue 0826) η. Class II A/B3 biosafety control cabinet (ThermoForma catalog, HB0053-03) 〇. Series 11 water Nested Carbon Dioxide Incubator (ThermoForma Model: 537 94389 201016683 3111) p. Centrifuge (Fisher Scienti fic Marathon 8 k, Catalog 0027-02) q. Novastar Disk Reader (BMGLabtech, Catalog No. 700-0081) r· Rotary Oscillator (Qilinbeier, Catalog TS-1) Method: The following method was used to test the inhibitory cell proliferation I Cso value of the test compound of the present invention for A431 cells. 1. Inoculate A431 cells in 1 〇〇mm Corning plate and culture in medium (DMEM/F12+10% fetal calamine as culture) (373⁄4, 5% CO2) until the cells are fully confluent; .2. Wash A43i cells with fetal bovine serum in a 1 mm culture dish, hydrolyze the cells with trypsin-white enzyme, and then inoculate the cells on a Corning 96-well cell culture plate. · Concentration 50,000 cells/ml, each plate 6 wells were used as control wells; 3. The cells were cultured in 96-well plates at 37 ° C '5% CCh until approximately 85% confluence was reached; WM was immersed in DMS0 to dissolve the test compound, 20 mM was configured The mother liquor is diluted with DMS0 to obtain a series of solutions of the test compound, ie 2, 1 mM, 0 · 2 mM, 2 0 // Μ, 2 v Μ, 0. 2 # Μ; The medium (DMEM/F12 + 10% fetal bovine serum is used as the culture solution) is diluted with the compound solution configured above. Each DMS0 series concentration compound solution is diluted 20 times, and 5 仏 1 DMS0 compound solution and 95 a are added to the cell culture medium each time. 1 culture medium to ensure that Α431 cells are exposed to DMS0 solution; the degree does not exceed 0 · 5 % ' with vortex Vort ex ) mixed; 94389 538 201016683 6. When A431 cells adhered to 85% confluence, they were cultured and replaced with new medium supplemented with DMEM/F12 +10% fetal bovine serum, and added to each well. 180/ζ 1 culture solution and 20/ζ 1 a ▲ 戈 compound solution prepared in the fifth step. Negative control cells 'added to 〇.5% DMS〇 2〇# 培养 culture solution' such that A431 cells were exposed The final concentration in the test compound solution is 100^, 10//Μ, 5/ζΜ, 1//Μ, 〇. ι#Μ, 〇. 〇1//Μ and 0. 001 "Μ; Place the culture plate in an incubator and continue to culture for 72 hours under conditions of 37〇c ' 5% c〇2; after 8. 72 hours, transfer the plate from the incubator to the sterile studio; 9' The reagent grade pure water was added to the TCA to prepare a fixative (5〇% trichloroacetic acid-TCA), and the cells were slowly layered in a 5〇//1 cold TCA solution; -1 〇. at 4 Incubate at °C for 1 hour' and then wash several times with water to remove TCA, 'serum protein, etc. The plate is dried in air and stored for use. The optical density value of the blank background is determined without fine The value obtained by incubating the culture medium in the growth medium. © 11. Prepare 〇. 4% sulfonium rhodamine B solution with 10% acetic acid solution, and add 50 # 1 sulfonium rhodamine b solution to each well; Dyeing for 30 minutes; 13. Preparing a 1% acetic acid wash solution. When the staining is about to be completed, discard the dye and rinse the cells quickly with 10% acetic acid. Repeat the above procedure until the stain is washed, and minimize the number of rinses to reduce the desorption of the dye with the protein and sister. After the rinsing is completed, the culture plate is dried in the air 94389 539 201016683 14. The mixed dye is dissolved in a certain volume of sulfonium rhodamine b, and the dissolved solution (10 mM Tris) is the same as the original volume of the medium, and the culture tray is placed in the chamber. Leave it under warm for 5 minutes' Slowly stir with a shaker to speed up mixing with the stain; 15. Use spectrophotometry to read the absorbance at 565 nm. The absorbance values were the absorbance at 565 nm minus the absorbance of the 96-well plate background at 690 nm; 16. The inhibition ratio was calculated using the following method: IR = 100X (absorbance value of the control group - absorbance value of the drug group) / absorbance value of the control group % 1C5. The value can be calculated from the ratio of compound inhibition rates at different concentrations. The I Cso values measured for the activity of the compounds of the present invention are shown in the table below. _Example No. 1 —__i£^__^FR/A431) (Hong Μ) 1 η 0.36 2 η 0. 27 3 r 〇. 77 5 〇0. 78 8 1. 08 9 0.136 10 0. 57 11 1.45 12 0.12 13 0. 68 14 0, 2 15 __0. 02 • The biochemical activity of the compounds of the invention is determined by the above test 94389 540 201016683

17 1. 43 18 2. 36 21 0. 2 24 0. 01 25 0. 05 26 0. 09 27 0.16 28 0.22 29 0. 39 30 0. 21 31 0. 16 34 0. 16 36 0. 48 37 0. 83 38 0. 31 39 1. 04 42 0. 05 43 0.08 44 0. 01 45 0.09 46 0.57 47 0. 81 48 0.07 49 0.021 50 0. 24 53 0.008 54 0.025 55 0.2 56 0. 12 541 94389 20101668317 1. 43 18 2. 36 21 0. 2 24 0. 01 25 0. 05 26 0. 09 27 0.16 28 0.22 29 0. 39 30 0. 21 31 0. 16 34 0. 16 36 0. 48 37 0 83 38 0. 31 39 1. 04 42 0. 05 43 0.08 44 0. 01 45 0.09 46 0.57 47 0. 81 48 0.07 49 0.021 50 0. 24 53 0.008 54 0.025 55 0.2 56 0. 12 541 94389 201016683

58 0. 05 59 0. 13 61 0. 21 62 0. 25 64 0. 04 65 0. 29 66 0.14 69 0.003 70 0. 03 80 0. 49 89 0. 14 91 0. 56 92 0. 13 108 0.56 121 0. 22 122 0.21 139 0.06 140 0.15 158 0. 02 159 0. 09 164 2.87 165 >1 166 1. 1 169 1.03 170 1.32 173 1. 98 174 0. 1 175 0. 612 176 0. 647 542 94389 20101668358 0. 05 59 0. 13 61 0. 21 62 0. 25 64 0. 04 65 0. 29 66 0.14 69 0.003 70 0. 03 80 0. 49 89 0. 14 91 0. 56 92 0. 13 108 0.56 121 0. 22 122 0.21 139 0.06 140 0.15 158 0. 02 159 0. 09 164 2.87 165 >1 166 1. 1 169 1.03 170 1.32 173 1. 98 174 0. 1 175 0. 612 176 0. 647 542 94389 201016683

178 0. 17 179 0. 43 180 1. 39 181 2. 86 182 1. 37 183 0. 77 185 0.32 186 0.511 187 0. 431 188 0. 45 189 0.35 190 0. 295 191 0. 562 192 0.298 193 0. 084 194 3. 62 195 · 0. 12 196 0. 706 197 1. 78 198 0. 443 199 0. 352 201 1.36 202 0. 252 203 0. 66 204 0.708 206 0. 462 207 0. 415 208 0. 714 209 1.18 543 94389 201016683178 0. 17 179 0. 43 180 1. 39 181 2. 86 182 1. 37 183 0. 77 185 0.32 186 0.511 187 0. 431 188 0. 45 189 0.35 190 0. 295 191 0. 562 192 0.298 193 0 084 194 3. 62 195 · 0. 12 196 0. 706 197 1. 78 198 0. 443 199 0. 352 201 1.36 202 0. 252 203 0. 66 204 0.708 206 0. 462 207 0. 415 208 0. 714 209 1.18 543 94389 201016683

210 1.19 211 0. 468 212 0.889 213 0. 749 214 0. 733 224 0.874 225 3.714 227 0.327 228 0. 24 229 0. 747 230 0.049 233 0. 051 234 0. 362 235 1.42 236 1. 088 237 0.409 •238 0.661 · 239 1. 28 241 0. 768 242 0. 771 243 0. 657 244 1. 547 245 0.615 246 0.952 247 0. 746 248 1. 564 249 0.922 250 0.521 251 0. 356 544 94389 201016683210 1.19 211 0. 468 212 0.889 213 0. 749 214 0. 733 224 0.874 225 3.714 227 0.327 228 0. 24 229 0. 747 230 0.049 233 0. 051 234 0. 362 235 1.42 236 1. 088 237 0.409 •238 0.661 · 239 1. 28 241 0. 768 242 0. 771 243 0. 657 244 1. 547 245 0.615 246 0.952 247 0. 746 248 1. 564 249 0.922 250 0.521 251 0. 356 544 94389 201016683

252 0.521 253 1. 979 254 0. 273 255 0. 459 260 1.529 261 0. 481 263 0. 384 268 0.36 276 1.455 277 0.682 278 0.553 279 1.26 280 0. 139 282 0. 27 283 0.582 284 0. 35 285 0. 4 286 0. 714 287 0. 426 288 1.216 289 >5 290 0.5 291 1.7 292 1. 49 293 0. 853 294 0.71 295 3.321 296 >5 297 3.769 545 94389 201016683 298 2.001 299 4. 199 300 1. 292 301 0. 22 302 0. 39 303 3. 424 304 0. 501 305 4. 56 306 0. 04 307 2.594 308 0. 626 309 0. 729 310 1.3 311 0.243 312 0.572 313 0.832 314 • 0.477 例2. EGFR激酶活性測定體外EGFR激酶活性藉由以下的方法進行測試。材料與試劑： a. 洗滌緩衝液（PBS-T 缓衝液）：lxPBS(137 mM NaCl，2.7 1^1^1，4.3 11^如2肝〇4，1.4 111虬〇2?〇4，調整01!至7.2) 和 0·05% Tween-20 b. 1%牛血清白蛋白（BSA，Calbiochem #136593)PBS-T 缓衝液 c. 反應中止緩衝液：50 mM EDTA，pH 8.0. 546 94389 201016683 d. DELFIA*销標記抗鼠 IgG(PerkinElmer Life Sciences #AD0124) e. DELFIA*信號增強液（PerkinElmer Life Sciences #1244-105) f. DELFIA* Streptavidin 塗覆 96 孔黃盤（PerkinElmer Life Sciences#AAAND-0005) g. EGFR 激酶（50 mM Tris-HCl (pH 8.0)，100 mM NaCl，5 mM DTT，15 mM穀醯基胱胺醯甘胺酸和20%甘油，Cell signaling technology #7908) h. 10 mM ATP 溶液（Cell signaling technology #9804). i. PTPlB(Tyr66)生物素酿化蛋白（Cell signaling technology #1325). j. 碟-絡胺酸鼠 mAb(P-Tyr-100)(Cell signaling technology #9411). k. HTScan™酷胺酸激酶緩衝液（4x) lx激酶緩衝液：252 0.521 253 1. 979 254 0. 273 255 0. 459 260 1.529 261 0. 481 263 0. 384 268 0.36 276 1.455 277 0.682 278 0.553 279 1.26 280 0. 139 282 0. 27 283 0.582 284 0. 35 285 0 4 286 0 。。。。。。。。 292 301 0. 22 302 0. 39 303 3. 424 304 0. 501 305 4. 56 306 0. 04 307 2.594 308 0. 626 309 0. 729 310 1.3 311 0.243 312 0.572 313 0.832 314 • 0.477 Example 2. EGFR Kinase Activity Assay The in vitro EGFR kinase activity was tested by the following method. Materials and reagents: a. Wash buffer (PBS-T buffer): lxPBS (137 mM NaCl, 2.7 1^1^1, 4.3 11^ as 2 liver 〇 4, 1.4 111 虬〇 2? 〇 4, adjust 01 To 7.2) and 0. 05% Tween-20 b. 1% bovine serum albumin (BSA, Calbiochem #136593) PBS-T buffer c. Reaction stop buffer: 50 mM EDTA, pH 8.0. 546 94389 201016683 d DELFIA* Pin-labeled anti-mouse IgG (PerkinElmer Life Sciences #AD0124) e. DELFIA* Signal Enhancer (PerkinElmer Life Sciences #1244-105) f. DELFIA* Streptavidin-coated 96-well yellow plate (PerkinElmer Life Sciences #AAAND-0005 g. EGFR kinase (50 mM Tris-HCl (pH 8.0), 100 mM NaCl, 5 mM DTT, 15 mM glutathione glycine and 20% glycerol, Cell signaling technology #7908) h. 10 mM ATP solution (Cell signaling technology #9804). i. PTPlB (Tyr66) Biotinylated protein (Cell signaling technology #1325). j. Dish-lysine rat mAb (P-Tyr-100) (Cell signaling technology # 9411). k. HTScanTM carbamic acid kinase buffer (4x) lx kinase buffer:

❹ 60 mM HEPES 5 mM MgCU 5 mM MnCh 3 βΐ Na3Y〇4 (細胞訊息傳i技術#9805) 1· 1. 25 M DTT (1000x)(細胞訊息傳遞技術）方法：使用如下方法進行測試： 547 94389 201016683 1 ·用MS0稀釋受試化合物達到最終濃度值. 在每個試驗巾加人受試化合物對照（不接受任何受試化合物），只加人^職和工白 2.用0 1 ·· 1稀釋6μΜ受質 W到每個測試中； 4蛋白（τπ·_’並加15 3.將酶從-80。。直接轉移到冰上，沉抑酶在冰上解凍’· 4·取3 #gEGFR酶到每個測試中； 5. 加入 lOel DTTU.25 M)到 2.5 ω1 4x HTScan™ 酪胺❹ 60 mM HEPES 5 mM MgCU 5 mM MnCh 3 βΐ Na3Y〇4 (Cell Message Transmission Technology #9805) 1· 1. 25 M DTT (1000x) (Cell Message Technology) Method: Test using the following method: 547 94389 201016683 1 · Dilute the test compound to the final concentration value with MS0. Add test compound control to each test towel (do not accept any test compound), only add people and work white 2. Use 0 1 ·· 1 Dilute 6μΜ of the substance to each test; 4 protein (τπ·_' and add 15 3. Transfer the enzyme from -80. directly to the ice, and the enzyme will thaw on the ice'· 4· take 3 # gEGFR enzyme to each test; 5. Add lOel DTTU.25 M) to 2.5 ω1 4x HTScanTM tyramine

❹酸激酶緩衝液（240 mM HEPES pH 7· 5, 20 mM MgCI2, 20 mMCitrate kinase buffer (240 mM HEPES pH 7.5, 20 mM MgCI2, 20 mM

MnCL·，NaaVO4)中，製得DTT/激酶緩衝液； 6. 轉移0. 75 ml DTT/激酶緩衝液到每個測試中，製得4χ反 .應混合液，並在每個測試中加入7· 5 μΐ 4χ反應液； 7. 加入2" 1 ATP(l〇 mM)至496 /U dH2〇中，並在每個測試中加入7. 5 " 1 ; 30//1反應最終測試條件為： 60// M HEPES pH 7. 5 〇 5 mM MgCl2 5 mM MnCh M Na3V〇4In MnCL·, NaaVO4), DTT/kinase buffer was prepared; 6. Transfer 0.75 ml DTT/kinase buffer to each test to prepare a mixture of 4 χ, and add 7 to each test. · 5 μΐ 4χ reaction solution; 7. Add 2" 1 ATP (l〇mM) to 496 /U dH2〇, and add 7.5 "1; 30//1 reaction in each test. The final test conditions are : 60// M HEPES pH 7. 5 〇5 mM MgCl2 5 mM MnCh M Na3V〇4

1. 25 mM DTT 20//M ATP 1. 5以M多肽受質 30 ng EGFR 激酶 8.在25°C下’將反應管溫育45分鐘； 548 94389 201016683 9. 每個測試中加入30//1中止反應緩衝液（5〇 mM EDTA， pH 8. 0)中止反應； 10. 在96孔鏈親和素（streptavidin)塗覆的培養盤每孔中加入25/z 1反應液和75以1 dlhO，在室溫下，並振搖分鐘； Π.每孔用200 // 1 PBS-T緩衝液洗務3次，在紙巾上輕拍以除去剩餘的液體； 12. 用1%牛血清白蛋白PBS_T緩衝液} : 1〇〇〇稀釋抗體磷 ❹-酪胺酸mAb (P-Tyr-l〇〇)，在每孔中加入i〇0/W !稀釋的抗體； 13. 在室溫下，振搖溫育6〇分鐘； • 14.按第11步所述方法洗滌； .15.用1%牛血清白蛋白PBS_T緩衝液ι :5〇〇稀釋銪標記抗鼠IgG，並在每.孔中加入1〇〇 y 1稀釋抗體； 16.在室溫下’振搖溫育3〇分鐘； Π·每孔用PBS-T緩衝液200 //1洗滌5次，在紙巾上輕 ®拍以除去剩餘的液體； 18.每孔中加入1〇〇私1 DELFIA*信號增強液； 19·在室溫下，振搖溫育5分鐘； 20.在615 nm處，用合適的時間分辨盤讀取器讀取螢光強度。計算抑制率比值：IR(%) = 100-I00*(x-B)/(N-B) x=受試化合物螢光值 N=陰性對照 549 94389 201016683 B=空白 I，。值可藉由受試化合物不同濃度梯度下的抑制率比值計算得到。本發明化合物的活性本發明化合物的生化學活性藉由以上的試驗進行測定，測得的IC5。值見下表。實施例編號 IC50 (EGFR/ΒΙΟΚμΜ) 1 0.003 2 0. 012 3 0. 0225 5 0. 05 6 0.031 7 0.028 8 0. 004 9 , 0.006 10 0. 005 11 0.018 12 0. 0026 13 ^ 1 0/0036 14 0. 008 15 0. 003 16 0.002 17 0. 005 18 0. 02 21 0.009 22 0. 042 23 0.053 550 94389 2010166831. 25 mM DTT 20//M ATP 1. 5 with M polypeptide substrate 30 ng EGFR kinase 8. Incubate the reaction tube for 45 minutes at 25 ° C; 548 94389 201016683 9. Add 30/ per test /1 stop the reaction buffer (5 mM EDTA, pH 8.0) to stop the reaction; 10. Add 25/z 1 reaction solution and 75 to 1 per well of a 96-well streptavidin-coated culture plate. DlhO, at room temperature, and shake for a few minutes; Π. Wash each well with 200 // 1 PBS-T buffer 3 times, pat on a paper towel to remove the remaining liquid; 12. Use 1% bovine serum white Protein PBS_T buffer} : 1〇〇〇 diluted antibody phosphonium-tyrosine mAb (P-Tyr-l〇〇), add i〇0/W ! diluted antibody to each well; 13. at room temperature Incubate for 6 〇 minutes; • 14. Wash as described in step 11; .15. Dilute 抗 labeled anti-mouse IgG with 1% bovine serum albumin PBS_T buffer ι :5〇〇, and in each. Add 1 〇〇 y 1 diluted antibody to the well; 16. Incubate for 3 〇 minutes at room temperature; Π· Wash each well with PBS-T buffer 200 //1 5 times, lightly on the paper towel® To remove the remaining liquid; 18. Add 1 〇〇 private 1 DELFIA to each well * Signal Enhancer; 19) Incubate for 5 minutes at room temperature with shaking; 20. At 615 nm, read the fluorescence intensity with a suitable time-resolving disk reader. Calculate the inhibition ratio: IR (%) = 100 - I00 * (x - B) / (N - B) x = test compound fluorescence value N = negative control 549 94389 201016683 B = blank I,. The value can be calculated from the inhibition ratio at different concentration gradients of the test compound. Activity of the Compound of the Invention The biochemical activity of the compound of the present invention was determined by the above test, and IC5 was measured. The values are shown in the table below. Example No. IC50 (EGFR/ΒΙΟΚμΜ) 1 0.003 2 0. 012 3 0. 0225 5 0. 05 6 0.031 7 0.028 8 0. 004 9 , 0.006 10 0. 005 11 0.018 12 0. 0026 13 ^ 1 0/0036 14 0. 008 15 0. 003 16 0.002 17 0. 005 18 0. 02 21 0.009 22 0. 042 23 0.053 550 94389 201016683

Ο 24 0.0075 25 0. 003 26 0. 015 27 0. 008 28 0. 054 29 0.007 30 0.004 31 0. 009 32 0. 008 33 0. 032 34 0.032 35 0. 01 36 0. 049 37 0.016 38 0. 043 .39 0. 055 40 0.091 41 0. 016 42 0. 004 43 0. 006 44 0. 006 45 0.005 46 0.013 47 0. 008 48 0. 061 49 0. Oil 50 0. 008 52 0. 066 551 94389 201016683 Ο ❹ 53 0.025 54 0. 03 55 0. 078 56 0. 108 57 0. 096 58 0. 049 59 0.06 60 0. 03 61 0. 026 62 0.011 63 0. 197 64 0. 004 65 0. 032 67 0. 005 68 0. 095 69 0. 032 70 0. 007 86 0. 04 88 0. 022 99 0.105 111 0. 276 112 0. 127 113 0.376 114 0.291 115 0. 056 116 0.071 117 0.031 118 0. 102 552 94389 201016683Ο 24 0.0075 25 0. 003 26 0. 015 27 0. 008 28 0. 054 29 0.007 30 0.004 31 0. 009 32 0. 008 33 0. 032 34 0.032 35 0. 01 36 0. 049 37 0.016 38 0. 043 .39 0. 055 40 0.091 41 0. 016 42 0. 004 43 0. 006 44 0. 006 45 0.005 46 0.013 47 0. 008 48 0. 061 49 0. Oil 50 0. 008 52 0. 066 551 94389 201016683 Ο ❹ 53 0.025 54 0. 03 55 0. 078 56 0. 108 57 0. 096 58 0. 049 59 0.06 60 0. 03 61 0. 026 62 0.011 63 0. 197 64 0. 004 65 0. 032 67 0. 005 68 0. 095 69 0. 032 70 0. 007 86 0. 04 88 0. 022 99 0.105 111 0. 276 112 0. 127 113 0.376 114 0.291 115 0. 056 116 0.071 117 0.031 118 0. 102 552 94389 201016683

119 0.014 123 0. 037 124 0. 039 125 0. 019 126 0. 024 127 0.011 128 0. 025 129 0. 072 130 0. 015 131 0. 057 132 0. 05 133 0. 062 134 0.156 135 0. 115 136 0. 023 137 0. 016 138 0.012 141 0. 065 142 0.076 143 0. 127 145 0.016 148 0. 042 149 0. 021 150 0.003 151 0. 012 152 0.015 153 0.025 154 0.047 553 94389 201016683119 0.014 123 0. 037 124 0. 039 125 0. 019 126 0. 024 127 0.011 128 0. 025 129 0. 072 130 0. 015 131 0. 057 132 0. 05 133 0. 062 134 0.156 135 0. 136 0. 023 137 0. 016 138 0.012 141 0. 065 142 0.076 143 0. 127 145 0.016 148 0. 042 149 0. 021 150 0.003 151 0. 012 152 0.015 153 0.025 154 0.047 553 94389 201016683

Ο 155 0.017 156 0. 072 157 0.086 158 0. 094 159 0. 387 164 0. 006 165 0.004 166 0. 007 169 0. 006 170 0. 074 172 0.012 173 0. 009 174 0. 006 177 0.131 178 0. 005 179 0. 001 180 0, 027 182 0. 039 183 0. 022 184 0.024 185 0. 031 186 0.018 187 0. 022 188 0. 021 189 0. 023 190 0. 079 191 0. 079 192 0. 006 554 94389 201016683155 155 0.017 156 0. 072 157 0.086 158 0. 094 159 0. 387 164 0. 006 165 0.004 166 0. 007 169 0. 006 170 0. 074 172 0.012 173 0. 009 174 0. 006 177 0.131 178 0. 005 179 0. 001 180 0, 027 182 0. 039 183 0. 022 184 0.024 185 0. 031 186 0.018 187 0. 022 188 0. 021 189 0. 023 190 0. 079 191 0. 079 192 0. 006 554 94389 201016683

193 0. 036 194 0.011 195 0. 02 196 0. 116 197 0.017 213 0.019 214 0. 008 215 0.066 216 0. 14 217 0. 013 218 0. 47 219 0.092 220 0. Oil 221 0. 03 222 0. 049 223 0.06 224 0. 166 225 0. 14 227 0. 263 228 0.106 229 0.239 230 0. 08 231 0.034 232 0. 638 233 0.051 234 0. 039 235 0. 492 236 0.197 555 94389 201016683193 0. 036 194 0.011 195 0. 02 196 0. 116 197 0.017 213 0.019 214 0. 008 215 0.066 216 0. 14 217 0. 013 218 0. 47 219 0.092 220 0. Oil 221 0. 03 222 0. 049 223 0.06 224 0. 166 225 0. 14 227 0. 263 228 0.106 229 0.239 230 0. 08 231 0.034 232 0. 638 233 0.051 234 0. 039 235 0. 492 236 0.197 555 94389 201016683

237 0. 079 238 0. 041 239 0. 001 240 0. 002 241 0. 002 242 0.012 243 0. 027 244 0. 017 245 0. 038 246 0. 102 247 0. 095 248 0.024 251 0.012 252 0. 117 253 0. 443 260 0. 094 285 0. 058 299 0. 598 300 0. 282 301 0. 038 302 0.071 .303 0.073 304 0. 248 306 0. 052 307 0. 133 308 0.129 309 0. 038 310 0. 276 556 94389 201016683 311 0. 257 312 0.236 313 0.291 314 0.205 例3 : HER-2激酶抑制劑活性測定本試驗用酵素連結免疫吸附分析法（ELISA)來測定體外HER-2激酶抑制劑活性。材料與試劑： φ a.洗滌緩衝液（PBS-T 緩衝液）：lx PBS (137 mM NaCl，2. 7 mM KC1，4· 3 mM NazHPCh，1· 4 mM KH2P〇4，調整 pH7. 2)和 0. 05% Tween-20 • b. 1%牛血清蛋白（BSA，Calbiochem #136593) PBS-T 緩衝 ..液 . c. 中止反應緩衝液：50 mM EDTA，pH 8.0 d. DELFIA*銪標記抗鼠 IgG(PerkinElmer Life Sciences #AD0124) e. DELFIA*信號增強液（PerkinElmer Life Sciences #1244-105) f. DELFIA* Streptavidin 塗覆 96 孔黃盤（PerkinElmer Life Sciences #AAAND-0005) g. HER-2/ErbB2 激酶（Invitrogen corporation #PV3366) h. 10 mM ATP溶液（Cell signaling technology #9804) 1. FLT3(Tyr589)生物素酿化蛋白（Cell signaling 557 94389 201016683 technology #1305) j. 磷酷·胺酸鼠 mAb(P-Tyr-100)(Cell signaling technology #9411) k. HTScan™酪胺酸激酶緩衝液（4X) lx激酶緩衝液 60 mM HEPES 5 mM MgCh 5 mM MnCh 3/zM Na3V〇4 (細胞訊息傳遞技術#98〇5) 1. 1·25 M DTT (1〇〇〇χ)(細胞訊息傳遞技術）方法·· 使用如下方法進行測試·· 1.用DMS0稀釋受試化合物達到最終濃度值；在每個試驗中加入受試化合物、陰性對照（不接受任何受試化合物）、和1从i DMS0 ; β 2.用副1 : 1稀釋“ Μ受質蛋白咖87)，並在每個測試中加入15/^1; 3·將HER-2酶從-8(TC直接轉移到冰上，猶_2酶在冰上解凍； 4.取4.5/zg HER-2酶到酶管中； 2·5 ml 4x HTScan™ 酪胺 7· 5, 20 mM MgCI2, 20 mM DTT/激酶緩衝液； 5.加入 10# 1 DTT(1· 25 M)到酸激酶緩衝液（240 mM HEPES pH MnCL·，12/zM Na3V〇4)中，製得 94389 558 201016683 6. 轉移0.75 ml DTT/激酶緩衝液到每個酶管中，製得4x 反應混合液’並在每個測試中加入7. 5 # 1 4x反應液； 7. 加入2 # 1 ATP(10 mM)至496 /z 1 dH2〇中，並在每個測試中加入7. 5/z 1 ; 30 β 1反應最終試驗條件為： 60 mM HEPES pH 7. 5 5 mM MgCh 5 mM MnCh 0 3 /z M Na3V〇4 1.25 mM DTT 20 私 M ATP 1.5/zM受質蛋白 45 ng HER-2 激酶 8.在25°C下，將反應管溫育60分鐘； 9·.每個測試中加入30//1中止反應缓衝液（50 mM EDTA， pH 8. 0)終止反應； _ 10.在96孔鏈親和素（streptavidin)塗覆的培養盤每孔中加入25# 1反應液和75# 1 dHA，在室溫下，並伴隨振搖 6 0分鐘； 11.每孔用200 # 1 PBS-Τ缓衝液洗滌3次，在紙巾上輕拍以除去過量的液體； 12.用1%牛血清白蛋白PBS-T缓衝液1 : 1000稀釋主要抗體磷-路胺酸mAb(P~Tyr-100)，並在每孔中加入100/U稀釋的主要抗體； 559 94389 201016683 13.室溫下’伴隨振搖下溫育6〇分鐘； 14·按第11步所述方法進行洗滌； 15. 用1%牛血清白蛋白PBS_T緩衝液1:5〇〇稀釋銪標記的抗鼠IgG，並在每個孔中加入1〇〇#丨稀釋的抗體； 16. 室溫下’伴隨振搖下溫育3〇分鐘； 17. 每孔用PBS-T緩衝液 200 /^1洗滌5次，在紙巾上輕拍以除去過量的液體； 18·每孔中加入IOOwDelfja•信號增強液；鬱I9.室溫下，伴隨振搖下溫育5分鐘； 20.在波長615 nm下.，用合適的時間分辨盤讀取器讀取吸光度。 •計算抑制率比值：— .受試化合物螢光值 ‘· N=陰性對照 .· 空白237 0. 079 238 0. 041 239 0. 001 240 0. 002 241 0. 002 242 0.012 243 0. 027 244 0. 017 245 0. 038 246 0. 102 247 0. 095 248 0.024 251 0.012 252 0. 253 0 。 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 276 556 94389 201016683 311 0. 257 312 0.236 313 0.291 314 0.205 Example 3: HER-2 kinase inhibitor activity assay This assay uses an enzyme-linked immunosorbent assay (ELISA) to determine HER-2 kinase inhibitor activity in vitro. Materials and reagents: φ a. Wash buffer (PBS-T buffer): lx PBS (137 mM NaCl, 2.7 mM KC1, 4·3 mM NazHPCh, 1.4 mM KH2P〇4, adjusted pH 7.2) And 0. 05% Tween-20 • b. 1% bovine serum albumin (BSA, Calbiochem #136593) PBS-T buffer.. solution. c. Stop reaction buffer: 50 mM EDTA, pH 8.0 d. DELFIA*铕 mark Anti-mouse IgG (PerkinElmer Life Sciences #AD0124) e. DELFIA* Signal Enhancer (PerkinElmer Life Sciences #1244-105) f. DELFIA* Streptavidin Coated 96-well yellow plate (PerkinElmer Life Sciences #AAAND-0005) g. HER- 2/ErbB2 kinase (Invitrogen corporation #PV3366) h. 10 mM ATP solution (Cell signaling technology #9804) 1. FLT3 (Tyr589) biotin brewing protein (Cell signaling 557 94389 201016683 technology #1305) j. Phosphate amine Acid mouse mAb (P-Tyr-100) (Cell signaling technology #9411) k. HTScanTM tyrosine kinase buffer (4X) lx kinase buffer 60 mM HEPES 5 mM MgCh 5 mM MnCh 3/zM Na3V〇4 ( Cell Signaling Technology #98〇5) 1. 1·25 M DTT (1〇〇〇χ) (Cell Message Technology) Method ·· Use Method for testing · 1. Dilute the test compound to the final concentration value with DMS0; add test compound, negative control (do not accept any test compound), and 1 from i DMS0; β 2. 1 : 1 diluted " Μ receptor protein coffee 87), and added 15 / ^ 1 in each test; 3 · HER-2 enzyme from -8 (TC directly transferred to ice, still 2 enzyme on ice Thaw; 4. Take 4.5/zg HER-2 enzyme into the enzyme tube; 2·5 ml 4x HTScanTM tyramine 7. 5, 20 mM MgCI2, 20 mM DTT/kinase buffer; 5. Add 10# 1 DTT ( 1· 25 M) to acid kinase buffer (240 mM HEPES pH MnCL·, 12/zM Na3V〇4), prepared 94389 558 201016683 6. Transfer 0.75 ml DTT/kinase buffer to each enzyme tube. 4x reaction mixture was obtained and 7. 5 # 1 4x reaction solution was added in each test; 7. 2 # 1 ATP (10 mM) was added to 496 /z 1 dH2〇, and 7 was added to each test. The final test conditions are: 60 mM HEPES pH 7. 5 5 mM MgCh 5 mM MnCh 0 3 /z M Na3V〇4 1.25 mM DTT 20 Private M ATP 1.5/zM receptor protein 45 Ng HER-2 kinase 8. Temperature of the reaction tube at 25 ° C 60 minutes; 9. Each reaction was stopped by adding 30//1 suspension reaction buffer (50 mM EDTA, pH 8.0); _ 10. Each plate was coated with 96-strept streptavidin. Add 25# 1 reaction solution and 75# 1 dHA to the well, and shake it for 60 minutes at room temperature. 11. Wash each well with 200 # 1 PBS-Τ buffer for 3 times and tap on paper towel. Remove excess liquid; 12. Dilute the primary antibody phospho-glycine mAb (P~Tyr-100) with 1% bovine serum albumin PBS-T buffer 1: 1000 and add 100/U dilution to each well. Primary antibody; 559 94389 201016683 13. Incubate for 6 minutes at room temperature with shaking; 14. Wash as described in step 11; 15. Use 1% bovine serum albumin PBS_T buffer 1:5〇〇 Diluted 铕 labeled anti-mouse IgG and add 1〇〇#丨 diluted antibody to each well; 16. Incubate for 3 〇 minutes with shaking at room temperature; 17. Buffer with PBS-T per well Wash the liquid 200 / ^ 1 5 times, pat on the paper towel to remove excess liquid; 18 · add 100w Delfja • signal enhancement solution per well; Yu I9. Incubate for 5 minutes at room temperature with shaking; in The length 615 nm., The disc reader with a suitable resolving time the absorbance was read. • Calculate the inhibition ratio: -. Fluorescence value of test compound ‘· N=negative control.· blank

The ICs。值可藉由受試化合物不同梯度濃度下的抑制率比 ©值計算得到。本發明化合物的活性本發明化合物的生化學活性藉由以上的試驗進行測疋，測得的I C 5 D值見下表。實施例編號 JC50 (HER2/BI0)(mM) 1 0. 1 2 3. 5 5 一 0. 6 •---- 94389 560 201016683 φ 6 0. 42 8 0. 0018 9 0. 19 10 0. 13 11 0. 03 12 0. 035 13 0.12 14 0. 087 15 0. 07 16 0. 064 17 0. 07 18 0.001 21 0. 035 22 0. 018 23 0. 43 24 0. 045 25 0.032 26 0.073 27 0. 029 28 0. Oil 29 0. 0038 31 0.071 33 0.2 34 0. 24 35 0. 022 39 0. 14 40 0.1 41 0. 046 561 94389 201016683 ❿ ⑩ 42 0. 004 43 0. 016 45 0. 024 46 0. 032 49 0. 029 50 0.001 52 0. 56 53 0. 029 54 0. 079 57 0. 59 58 >1 59 >1 60 0. 27 61 0. 186 62 0.03 63 0. 13 64 0. 024 65 0.083 66 0. 029 67 0. 44 68 0.32 69 0. 304 70 0. 004 71 0.21 88 0.19 99 0, 89 115 0. 17 116 0.053 562 94389 201016683 117 0. 044 118 0. 015 124 0. 07 125 0. 023 126 0. 018 127 0.11 128 0. 24 130 0.27 131 0. 05 136 0. 06 137 0. 038 138 0.016 142 0. 18 143 0. Oil 144 0. 93 145 0.25 146 0. 27 148 0. 008 150 0. 035 151 0. 048 152 0. 25 153 0.059 154 0. 001 155 0.045 156 0.38 158 0. 79 159 0.11 160 0. 021 563 94389 201016683 ΟThe ICs. The value can be calculated from the inhibition ratio at the different gradient concentrations of the test compound. Activity of the compound of the present invention The biochemical activity of the compound of the present invention was measured by the above test, and the measured I C 5 D value is shown in the following table. Example No. JC50 (HER2/BI0) (mM) 1 0. 1 2 3. 5 5 A 0. 6 •---- 94389 560 201016683 φ 6 0. 42 8 0. 0018 9 0. 19 10 0. 13 11 0. 03 12 0. 035 13 0.12 14 0. 087 15 0. 07 16 0. 064 17 0. 07 18 0.001 21 0. 035 22 0. 018 23 0. 43 24 0. 045 25 0.032 26 0.073 27 0 029 28 0. Oil 29 0. 0038 31 0.071 33 0.2 34 0. 24 35 0. 022 39 0. 14 40 0.1 41 0. 046 561 94389 201016683 ❿ 10 42 0. 004 43 0. 016 45 0. 024 46 0. 032 49 0. 029 50 0.001 52 0. 56 53 0. 029 54 0. 079 57 0. 59 58 >1 59 >1 60 0. 27 61 0. 186 62 0.03 63 0. 13 64 0. 024 65 0.083 66 0. 029 67 0. 44 68 0.32 69 0. 304 70 0. 004 71 0.21 88 0.19 99 0, 89 115 0. 17 116 0.053 562 94389 201016683 117 0. 044 118 0. 015 124 0. 07 125 0. 023 126 0. 018 127 0.11 128 0. 24 130 0.27 131 0. 05 136 0. 06 137 0. 038 138 0.016 142 0. 18 143 0. Oil 144 0. 93 145 0.25 146 0. 27 148 0 008 150 0. 035 151 0. 048 152 0. 25 153 0.059 154 0. 001 155 0.045 156 0.38 15 8 0. 79 159 0.11 160 0. 021 563 94389 201016683 Ο

G 161 0. 009 164 0. 27 165 0. 86 166 0. 62 167 3. 27 168 0. 12 169 0. Oil 170 0. 18 171 0. 1 172 0.061 173 0. 027 174 0. 028 175 0. Oil 176 0. 07 178 0. 023 179 0.009 180 0.011 181 0. 033 182 0. 046 183 0. 01 185 0.003 186 0. 511 187 0.431 189 0. 24 190 0.006 191 0.006 192 0.007 193 0. 002 564 94389 201016683 瘳 Ο 194 0. 004 195 0. 009 196 0. 002 197 0. 004 198 0.008 199 0. 004 203 0.001 204 0. Oil 205 0. 03 206 0.003 207 0. 013 208 0.001 209 0. 11 211 0. 004 213 0. 004 214 0. 001 225 0. 021 227 0. 02 228 0. Oil 229 0.056 230 0.015 232 0.02 233 0.015 234 0. 014 235 0. 034 236 0. 012 237 0. 013 238 0. 004 565 94389 201016683 239 0.012 240 0. 14 241 0. 01 242 0. 012 243 0. 007 244 0. 072 245 0. 064 246 0. 561 247 0. 001 248 0. 01 251 0. 021 252 0. 146 274 0. 027 294 0. 01 297 0.007 301 • 0.005 302 0. 01 304 0.032 309 0. 07 例4 : HER-2抑制細胞增殖測試下面的體外試驗是用來測定本發明化合物對於人類腫瘤細胞SK-BR-3 HER-2大量表現的細胞株抑制增瘦活性。下面所述的體外細胞試驗可確定受試化合物的對大量表現HER-2的腫瘤細胞的抗血管生成活性和抑制增殖活性，其活性可用IC5Q值來表示。此類試驗的一般方法如下：首先選擇大量表現HER-2的人類腫瘤細胞，以適宜細胞濃 566 94389 201016683 度接種在96孔培養盤上，然後將細胞在二氧化碳恆溫箱内 .進行培養，當細胞生長至60%匯合時，將培養基更換為加有一系列濃度梯度（一般6到7個濃度）受試化合物溶液的培養基，將培養盤重新放回培養箱，連續培養96個小時。 96小時後，可用磺醯羅丹明B(SRB)方法進行測試化合物對於抑制細胞增殖活性。IC5〇值可藉由一系列不同濃度下，受試化合物對於細胞的抑制數值進行計算。材料和方法._ • a.二曱基亞風(Sinophma chemical reagent company,目 V 錄 T20050806 號） b. SK-BR-3 細胞（購於 Institute of biochemistry and cell biology) c. Falcon 100 mm 細胞培養盤（Baton Dickison Labware， Baton Dickison and company ·，目錄 18677 號） d. 康寧 96孔培養盤（Corning Incorporated，目錄 3599 號） © e.費氏移液管（Fisherscientific，目錄 03-692-164 號） f. RPMI1640 細胞培養基（Gibco，目錄 12400-021 號） g. 澳大利亞胎牛血清（Gibco，目錄10099-141號） h. 磷酸鹽缓衝鹽水（Gibco，目錄10010-072號） i· 0.25% 胰島素-EDTA(Gibco，目錄 25200-056 號） j·磺醯羅丹明B(Sigma，目錄3520-42-1號） k.醋酸（Sinophma chemical reagent company，目錄 T20060508 號） 567 94389 201016683 l. 三氯醋酸（Sinophma chemical reagent company，目錄 T20060305 號） m. Tris 驗（Amresco，目錄 0826 號） η. II級A/B3型生物學安全操作櫃（ThermoForma目錄， HB0053-03 號）〇.系列II水套式二氧化碳培養箱（ThermoForma模型： 3111) P.離心機（Fisher Scienti fic Marathon 8 k，目錄 0027-02 ▲號） η q. Novastar 盤讀取器（BMGLabtech，目錄 700-0081 號） r. 迴轉式震盪器（Qilinbeier，目錄TS-1號）方法：下面的方法是用來測試本發明受試化合物對於 SK-BR-3細胞的抑制細胞增瘦IC5。值。 1.將SK-BR-3細胞接種於l〇〇mm康寧培養盤，在培養基 (以RPMI1640+10%胎牛血清為培養液）中進行培養（37。(：， ⑩5% C〇2)，直至細胞充分匯合； 2·在100 mm培養盤中用胎牛血清洗滌SK-BR-3細胞，以胰蛋白酶水解細胞後，再將細胞接種在康寧96孔細胞培養盤上，濃度為50000細胞/ml，每個盤空6孔，作為對照孔； 3. 在37°C、5% C(h條件下，將細胞在96孔盤中培養，直至達到約60%匯合； 4. 用DMS0溶解受試化合物，配置20 mM母液，後用DMS0 568 94389 201016683 稀釋母液’传到一系列濃度的受試化合物的溶液，即2 、 1 mM、0. 2 mM、20# Μ、2# Μ、0. 2# Μ ; 5·使用細胞培養基（RPMI1640+10%胎牛血清為培養液）稀釋上面所配置的化合物溶液。每個DMSO系列濃度化合物溶液稀釋20倍，每次在細胞培養基中加入5// 1 DMS〇化合物溶液和95# 1培養液’確保31(：-]81?-3細胞暴露在1)1^0溶液中的濃度不超過0. 5%，用渦旋混合； 6·當SK-BR-3細胞貼壁，生長達到60%匯合後，將培養基瘳換為加有RPMI1640 + 10%胎牛血清培養液的新培養基，每孔中再加入180^1培養液和20 #1在第五步中所製備的受試化合物溶液。陰性對照組細胞，加入含有〇. 5% DMS〇的2〇 '以1培養液，這樣SK-BR-3細胞暴露在受試化合物溶液中的最終濃度為 100/zM、10#M、5//M、1//M、0.1//M、〇.〇1 "Μ 以及〇. 0O1//M ; ·. 7·將培養盤放入恆溫箱内，在37。(：，5% C〇2條件下，連續培養96小時； ⑩8. 96小時後，將培養盤從恆溫箱中轉移到無菌工作室； 9.將試藥級純水加入到TCA中製備固定劑（5〇%三氯醋酸 ~TCA) ’將細胞慢慢地分層放在50私1冷TCA溶液中； 1 〇.在4°C下，培養1小時，後用水洗務數次以除去tca、血清蛋白等。培養盤在空氣中乾燥，存儲待用。空白背景光學密度值的測定是在沒有細胞生長的培養基中溫育培養所得的數值。 11.用10%醋酸溶液製備0.4%磺醯羅丹明b溶液，並於每 94389 569 201016683 孔中加入50 # I磺醯羅丹明B溶液； 12. 細胞染色30分鐘； 13. 製備1 〇%醋酸洗滌溶液。當染色將要完畢時，棄去染色劑，用10%的醋酸溶液快速沖洗細胞。重複上述的操作直至染色劑洗淨為止，儘量減少沖洗次數以減少與蛋白結合的染色劑的去吸附。沖洗完畢後，將培養盤在空氣中乾燥； 14. 混合的染色劑溶解在一定體積的磺醯羅丹明b中，溶參解溶液（10 mMTr is)與培養基原體積相同，將培養盤在室溫下放置5分鐘’用震盪器緩慢攪拌加快與染色劑的混合； 15. 用分光光度測量，在波長565 nm下讀取吸光度值。吸 '光度數值為565 nm下吸光度減去690 nm下96孔盤背景吸光度所得的數值； 16. 使用如下方法計算抑制率比值： IR=100x(對照組吸光度值-用藥組吸光度值）/對照組吸光度值％ ©ICw值可藉由不同濃度下化合物抑制率比值計算得到。本發明化合物的活性本發明化合物的生化學活性藉由以上的試驗進行測定，測得的ICso值見下表。 94389 570 201016683G 161 0. 009 164 0. 27 165 0. 86 166 0. 62 167 3. 27 168 0. 12 169 0. Oil 170 0. 18 171 0. 1 172 0.061 173 0. 027 174 0. 028 175 0. Oil 176 0. 07 178 0. 023 179 0.009 180 0.011 181 0. 033 182 0. 046 183 0. 01 185 0.003 186 0. 511 187 0.431 189 0. 24 190 0.006 191 0.006 192 0.007 193 0. 002 564 94389 201016683 194 194 0. 004 195 0. 009 196 0. 002 197 0. 004 198 0.008 199 0. 004 203 0.001 204 0. Oil 205 0. 03 206 0.003 207 0. 013 208 0.001 209 0. 11 211 0. 004 213 0. 004 214 0. 001 225 0. 021 227 0. 02 228 0. Oil 229 0.056 230 0.015 232 0.02 233 0.015 234 0. 014 235 0. 034 236 0. 012 237 0. 013 238 0. 004 565 94389 201016683 239 0.012 240 0. 14 241 0. 01 242 0. 012 243 0. 007 244 0. 072 245 0. 064 246 0. 561 247 0. 001 248 0. 01 251 0. 021 252 0. 146 274 0. 027 294 0. 01 297 0.007 301 • 0.005 302 0. 01 304 0.032 309 0. 07 Example 4: HER-2 inhibition cell proliferation test The following in vitro test is used to determine the compounds of the invention A cell line exhibiting a large amount of human tumor cell SK-BR-3 HER-2 inhibits lean growth activity. The in vitro cell assay described below can determine the anti-angiogenic activity and the proliferative activity of the test compound against a large number of tumor cells exhibiting HER-2, and the activity can be expressed by the IC5Q value. The general method for such a test is as follows: First, a large number of human tumor cells expressing HER-2 are selected, and seeded in a 96-well culture plate at a suitable cell concentration of 566 94389 201016683, and then the cells are cultured in a carbon dioxide incubator. When growing to 60% confluence, the medium was changed to a medium supplemented with a series of concentration gradients (generally 6 to 7 concentrations) of the test compound solution, and the plate was returned to the incubator for 96 hours. After 96 hours, the test compound can be tested for its ability to inhibit cell proliferation using the sulforhodamine B (SRB) method. The IC5 enthalpy can be calculated from the inhibition values of the test compound for the cells at a range of different concentrations. Materials and Methods._ • a. Sodium phlegm (Sinophma chemical reagent company, M. T20050806) b. SK-BR-3 cells (from Institute of biochemistry and cell biology) c. Falcon 100 mm cell culture Plate (Baton Dickison Labware, Baton Dickison and company, catalogue 18677) d. Corning 96-well plate (Corning Incorporated, catalog 3599) © e. Fisher's pipette (Fisherscientific, catalog 03-692-164) f. RPMI1640 Cell Culture Medium (Gibco, catalog 12400-021) g. Australian Fetal Bovine Serum (Gibco, catalogue 10099-141) h. Phosphate buffered saline (Gibco, catalogue 10010-072) i· 0.25% insulin - EDTA (Gibco, catalogue 25200-056) j. sulfonium rhodamine B (Sigma, catalogue 3520-42-1) k. acetic acid (Sinophma chemical reagent company, catalog T20060508) 567 94389 201016683 l. trichloroacetic acid (Sinophma chemical reagent company, catalog T20060305) m. Tris test (Amresco, catalog No. 0826) η. Class II A/B3 biological safety operation cabinet (ThermoForma catalog, HB0053-03) 〇.Series II water jacketed carbon dioxide incubator (ThermoForma model: 3111) P. Centrifuge (Fisher Scienti fic Marathon 8 k, catalog 0027-02 ▲) η q. Novastar disc reader (BMGLabtech, catalog 700-0081 No.) r. Rotary oscillator (Qilinbeier, catalog TS-1) Method: The following method was used to test the inhibitory cell thinning IC5 of the test compound of the present invention for SK-BR-3 cells. value. 1. Inoculate SK-BR-3 cells in a l〇〇mm Corning plate and culture in medium (with RPMI1640 + 10% fetal bovine serum as culture medium) (37. (:, 105% C〇2), Until the cells are fully confluent; 2. Wash the SK-BR-3 cells with fetal bovine serum in a 100 mm culture dish, hydrolyze the cells with trypsin, and then inoculate the cells on a Corning 96-well cell culture plate at a concentration of 50,000 cells/ Ml, 6 wells per well as a control well; 3. Incubate the cells in 96-well plates at 37 ° C, 5% C (h) until approximately 60% confluence is achieved; 4. Dissolve with DMS0 The test compound was configured with a 20 mM mother liquor, and then diluted with DMS0 568 94389 201016683 to transfer a mother's solution to a series of concentrations of the test compound, ie 2, 1 mM, 0.2 mM, 20# Μ, 2# Μ, 0. 2# Μ ; 5 · Dilute the compound solution prepared above using cell culture medium (RPMI1640 + 10% fetal bovine serum as culture medium). Dilute each compound solution of DMSO series concentration 20 times, add 5// each time to the cell culture medium. 1 DMS〇 compound solution and 95# 1 culture solution ensure that the concentration of 31(:-]81?-3 cells exposed to 1)1^0 solution is not After 0.5% 5%, mixed with vortex; 6. When SK-BR-3 cells adhered to 60% confluence, the medium was replaced with new medium supplemented with RPMI1640 + 10% fetal bovine serum. 180 μl of the culture solution and 20 #1 of the test compound solution prepared in the fifth step were added to each well. The negative control cells were added with 2% of the 5% DMS〇 to the 1 culture solution. The final concentrations of SK-BR-3 cells exposed to the test compound solution were 100/zM, 10#M, 5//M, 1//M, 0.1//M, 〇.〇1 "Μ and 〇. 0O1//M ; ·. 7· Put the culture plate into the incubator and continue to culture for 96 hours at 37° (:, 5% C〇2; 108. 96 hours, the plate from the incubator Transfer to a sterile laboratory; 9. Add reagent-grade pure water to TCA to prepare fixative (5〇% trichloroacetic acid ~TCA) 'Layer the cells slowly in 50 private 1 cold TCA solution; 1培养. Incubate at 4 ° C for 1 hour, then wash with water several times to remove tca, serum protein, etc. The plate is dried in air and stored for use. The optical density value of the blank background is determined without cell growth. Training The value obtained by incubation in the base medium 11. Prepare a 0.4% sulfonium rhodamine b solution with 10% acetic acid solution, and add 50 # I sulfonium rhodamine B solution per 94389 569 201016683 well; 12. Cell staining 30 Minutes; 13. Prepare 1 〇% acetic acid wash solution. When the staining is about to be completed, discard the dye and rinse the cells quickly with 10% acetic acid. Repeat the above procedure until the stain is washed, minimizing the number of rinses to reduce the desorption of the protein-bound stain. After the rinsing is completed, the culture tray is dried in the air; 14. The mixed stain is dissolved in a certain volume of sulfonium rhodamine b, and the lysate solution (10 mM Triis) is the same as the original volume of the medium, and the culture tray is placed in the chamber. Place at warm for 5 minutes' Slowly stir with a shaker to speed up mixing with the stain; 15. Read the absorbance at a wavelength of 565 nm using spectrophotometry. The absorbance 'photometric value is the absorbance at 565 nm minus the absorbance of the 96-well plate background at 690 nm; 16. Calculate the inhibition ratio using the following method: IR = 100 x (absorbance value of the control group - absorbance value of the drug group) / control group Absorbance value % The ICw value can be calculated from the compound inhibition ratio at different concentrations. Activity of the compound of the present invention The biochemical activity of the compound of the present invention was measured by the above test, and the measured ICso value is shown in the following table. 94389 570 201016683

實施例編號 IC50 (HER2/SK-BR-3)(#M) 1 0. 01 3 0. 34 4 1.497 5 0. 486 9 0. 678 10 0. 11 11 0.349 12 0.239 13 0. 21 14 0. 084 15 0.227 16 0. 299 17 0. 17 18 0. 18 19 0. 116 20· 0. 384 21 0. 081 22 0. 045 23 0. 306 24 0. 248 25 0. 366 26 0.168 27 0. 084 28 0. 233 29 0.039 30 0. 2 31 0. 18 32 0. 177 571 94389 201016683Example No. IC50 (HER2/SK-BR-3) (#M) 1 0. 01 3 0. 34 4 1.497 5 0. 486 9 0. 678 10 0. 11 11 0.349 12 0.239 13 0. 21 14 0. 084 15 0.227 16 0. 299 17 0. 17 18 0. 18 19 0. 116 20· 0. 384 21 0. 081 22 0. 045 23 0. 306 24 0. 248 25 0. 366 26 0.168 27 0. 084 28 0. 233 29 0.039 30 0. 2 31 0. 18 32 0. 177 571 94389 201016683

33 0.561 35 0· 8 39 0. 59 40 2. 85 42 0. 042 45 0. 933 50 0.25 58 0. 547 60 0.714 61 0.05 64 0. 45 67 0. 85 69 0.42 70 0. 56 84 . 0. 71 85 0. 43 86 0.-066 88 0.024 111 0. 12 112 0.485 113 0.217 114 0.263 115 0. 589 116 0.381 117 0. 39 119 0.885 120 0.716 121 0.175 122 0. 69 572 94389 20101668333 0.561 35 0· 8 39 0. 59 40 2. 85 42 0. 042 45 0. 933 50 0.25 58 0. 547 60 0.714 61 0.05 64 0. 45 67 0. 85 69 0.42 70 0. 56 84 . 71 85 0. 43 86 0.-066 88 0.024 111 0. 12 112 0.485 113 0.217 114 0.263 115 0. 589 116 0.381 117 0. 39 119 0.885 120 0.716 121 0.175 122 0. 69 572 94389 201016683

123 0. 27 124 0. 2 127 0. 48 128 0. 28 129 0. 31 130 0. 45 131 0. 28 136 0. 92 138 0. 34 139 0. 63 140 0. 7 144 0. 54 145 0. 4 146 >5 147 >5 148 0. 92 149 • 0.46 150 0. 29 151 0.35 152 0.55 153 0. 67 155 0. 12 164 0.27 165 0. 86 166 0. 62 167 3.27 168 0. 12 169 0. 048 170 0.22 573 94389 201016683123 0. 27 124 0. 2 127 0. 48 128 0. 28 129 0. 31 130 0. 45 131 0. 28 136 0. 92 138 0. 34 139 0. 63 140 0. 7 144 0. 54 145 0 4 146 >5 147 >5 148 0. 92 149 • 0.46 150 0. 29 151 0.35 152 0.55 153 0. 67 155 0. 12 164 0.27 165 0. 86 166 0. 62 167 3.27 168 0. 12 169 0. 048 170 0.22 573 94389 201016683

172 0. 432 174 0. 44 175 0. 16 176 0. 424 178 0. 37 179 0. 39 180 0.478 181 0. 656 182 0. 233 183 0. 25 185 0. 12 186 0. 276 187 0. 346 188 0.378 189 0. 213 190 0. 484 191 0.248 192 0. 209 193 0. 325 194 1.55 195 0. 09 196 0. 513 197 0. 248 198 0.604 199 0.33 200 3. 82 201 0. 267 202 0. 447 203 0.418 574 94389 201016683172 0 。。。。。。。。。。。 188 0.378 189 0. 213 190 0. 484 191 0.248 192 0. 209 193 0. 325 194 1.55 195 0. 09 196 0. 513 197 0. 248 198 0.604 199 0.33 200 3. 82 201 0. 267 202 0. 447 203 0.418 574 94389 201016683

204 0. 23 205 1. 1 206 0. 74 207 0. 577 208 0. 26 209 0. 436 210 0. 53 211 0. 535 212 0. 35 213 0.174 214 0. 1 224 0.425 225 0. 359 226 4. 12 227 0. 354 228 0. 548 229 0. 628 230 0.176 232 0. 537 233 0. 589 235 0. 449 236 1.313 237 0. 25 238 0. 494 239 0. 412 240 2. 538 241 0. 268 242 0. 07 243 0. 228 575 94389 201016683 φ204 0. 23 205 1. 1 206 0. 74 207 0. 577 208 0. 26 209 0. 436 210 0. 53 211 0. 535 212 0. 35 213 0.174 214 0. 1 224 0.425 225 0. 359 226 4 12 227 0. 354 228 0. 548 229 0. 628 230 0.176 232 0. 537 233 0. 589 235 0. 449 236 1.313 237 0. 25 238 0. 494 239 0. 412 240 2. 538 241 0. 268 242 0. 07 243 0. 228 575 94389 201016683 φ

244 0. 197 245 0. 179 247 0. 362 248 0. 128 250 0. 41 251 0. 283 252 0. 302 253 0.544 254 0. 233 255 0. 29 256 0. 261 260 0. 513 261 0. 359 263 0.414 264 0. 48 267 0. 665 269 0.478 · 274 0.444 276 0.818 277 Ο. 382 278 0. 227 279 0. 284 280 0. 183 281 0. 394 282 1. 32 283 0.694 285 0. 727 286 0. 627 287 0. 682 576 94389 201016683 288 0. 341 289 >5 290 0. 36 291 0. 22 292 0. 516 293 0. 521 294 0. 266 295 1.485 296 0. 743 297 0.09 298 0. 48 299 0.807 300 0. 434 301 0. 039 302 0. 17 304 0. 22 305 _ >5 306 0. 296 307 0. 623 308 0.303 309 0.203 310 0. 651 312 0. 724 314 0. 434 【圖式簡單說明】無。【主要元件符號說明】無。 577 94389244 0 。。。。。。。。。。 263 0.414 264 0. 48 267 0. 665 269 0.478 · 274 0.444 276 0.818 277 Ο. 382 278 0. 227 279 0. 284 280 0. 183 281 0. 394 282 1. 32 283 0.694 285 0. 727 286 0. 627 287 0. 682 576 94389 201016683 288 0. 341 289 >5 290 0. 36 291 0. 22 292 0. 516 293 0. 521 294 0. 266 295 1.485 296 0. 743 297 0.09 298 0. 48 299 0.807 300 0. 434 301 0. 039 302 0. 17 304 0. 22 305 _ >5 306 0. 296 307 0. 623 308 0.303 309 0.203 310 0. 651 312 0. 724 314 0. 434 】 No. [Main component symbol description] None. 577 94389

Claims

201016683 十、申請專利範圍：種由通式（I)、（II)和（ΠΙ)表示的化合物或其鹽·· HN R2201016683 X. Patent application scope: A compound represented by the general formula (I), (II) and (ΠΙ) or a salt thereof··HN R2

(I)(I)

(II)(II)

其中： A 1 R係選自烷基、雜環烷基、芳基或雜芳基，其中該烷基、雜環烷基、芳基或雜芳基進一步被一個或多個選 • 自烷基、齒素、芳基、羥基、胺基、炔基、烯基、氰基、硝基、二氟甲基、卣代苄基、雜環烷基、羧酸或羧酸酯的取代基所取代；其中該芳基或餘芳基進一步併成雙環，此雙環進一步被一個苄基或齒代苄基所取代；或者R1爲結構式： ❹其中： B係選自芳基或雜芳基，其中該芳基或雜芳基進一步被一個或多個選自烷基、鹵素、芳基、羥基、胺基、炔基、烯基、氰基、靖基、三氟^甲基、齒代苄基、雜環烷基、羧酸或羧酸酯的取代基所取代； T 係選自-〇(CH2)r-、-N(CH〇r-或-S(CH〇r ; L係選自芳基或雜芳基，其中該芳基或雜芳基進一步被一個或多個鹵素或烧基所取代； 578 201016683 R係選自氫原子、烷基、環烷基、三氟p基、雜環烷基、芳基、雜芳基或芳烷基，其中該烷基、環烷基、雜環烷基、芳基、雜芳基、芳烷基進一步被一個或多個選自烷基、芳基、羥基、齒素、胺基、氰基、烷氧基、羧酸、羧酸酯或-NR6R7的取代基所取代； R3和R4係各自獨立地選自氫原子、烷基、三氟曱基、環烧基、雜環烧基、芳基、羧酸酯、_S〇2r6、_CH2C(=〇) NR6R7、-C(=0)NR6R7、-(CH〇nNR6R7 或-NC(=0)R6，其中該烧基、環燒基、雜環烧基進一步被一個或多個選*** 基、i素、三氟甲基、芳基、羥基、烷氧基、芳氧基、環烷基、雜環烷基、雜芳基、雜環烷氧基、氰基、羧酸、緩酸醋、-S〇2R6或-(CH2)nNR6R7的取代基所取代； . 同時’ R3和R4 一起形成一個4至8員環基；其中5 至8員雜環内含有一個或多個.n、〇、s原子，並且4 至8員雜環上進一步被一個或多個選自烷基、鹵素、芳基、雜芳基、i代烷基、豳代烷氧基、羥基、烷氧基、〇芳氧基、羰基、雜環烷基、羧酸、羧酸酯、=N-0R6或-NR6R7 的取代基所取代； R5係選自氫原子、烷基、環烷基、-C(=0)0R6，其中該烷基或環烷基進一步被一個或多個選自烷基、羥基、烷氧基、氰基、-nr6r7、羧酸或羧酸酯的取代基所取代； R6和R7係分別選自氫原子、烷基、烯基、環烷基、雜環烷基、芳基或雜芳基，其中該烷基、烯基、環烷基、 579 201016683 雜環烷基、芳基或雜芳基進一步被一個或多個選自烷基、環烷基、齒素、芳基、羥基、胺基、烷氧基、烯基、雜環烧基、經烧基、-S〇2R6、-C(=0) R6、敌酸、叛酸酯或-NR6R7的取代基所取代；同時，R6和R7—起形成一個4至8員雜環基；其中5 至8員雜環内含有一個或多個N、0、S原子，並且4 至8員雜環上進一步被一個或多個選自燒基、鹵素、芳基、雜方基、鹵代芳基、鹵代烧氧基、胺基、羥基、氰基、烷氧基、芳氧基、胺烷基、羥烷基、環烧基、雜環 ❷ 烧基、羰基、羧酸、羧酸酯、-C(=0)NR6R7、--NC〇〇)R6、 _S〇2R6、或-NR6R7的取代基所取代； • η是0至6 ; r是0至2。 2.如申請專利範圍第1項之化合物或其鹽，其中，該化合物爲由通式（I)表示的化合物：Wherein: A 1 R is selected from an alkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, wherein the alkyl group, heterocycloalkyl group, aryl group or heteroaryl group is further selected from one or more alkyl groups. Substituted by a substituent of dentate, aryl, hydroxy, amino, alkynyl, alkenyl, cyano, nitro, difluoromethyl, deuterated benzyl, heterocycloalkyl, carboxylic acid or carboxylic acid ester Wherein the aryl or residual aryl group is further bicyclic, the bicyclic ring is further substituted by a benzyl or a dentyl benzyl group; or R 1 is a structural formula: ❹ wherein: B is selected from an aryl or heteroaryl group, wherein The aryl or heteroaryl group is further selected from one or more selected from the group consisting of alkyl, halogen, aryl, hydroxy, amine, alkynyl, alkenyl, cyano, jing, trifluoromethyl, dentylbenzyl, Substituted by a heterocycloalkyl, carboxylic acid or carboxylic acid ester substituent; T is selected from -〇(CH2)r-, -N(CH〇r- or -S(CH〇r; L is selected from aryl) Or a heteroaryl group, wherein the aryl or heteroaryl group is further substituted by one or more halogen or alkyl; 578 201016683 R is selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a trifluorop group, a heterocycloalkane base An aryl, heteroaryl or aralkyl group, wherein the alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, aralkyl group is further selected from one or more selected from the group consisting of an alkyl group, an aryl group, a hydroxyl group, a dentate, an amine group, a cyano group, an alkoxy group, a carboxylic acid, a carboxylic acid ester or a substituent of -NR6R7; wherein R3 and R4 are each independently selected from a hydrogen atom, an alkyl group, a trifluoromethyl group, a cycloalkyl group, a heterocyclic alkyl group, an aryl group, a carboxylic acid ester, _S〇2r6, _CH2C(=〇) NR6R7, -C(=0)NR6R7, -(CH〇nNR6R7 or -NC(=0)R6, wherein The alkyl group, the cycloalkyl group, the heterocyclic group are further selected from one or more selected from the group consisting of an alkyl group, an i group, a trifluoromethyl group, an aryl group, a hydroxyl group, an alkoxy group, an aryloxy group, a cycloalkyl group, and a heterocyclic ring. Substituted by a substituent of an alkyl group, a heteroaryl group, a heterocycloalkoxy group, a cyano group, a carboxylic acid, a buffered acid vinegar, -S〇2R6 or -(CH2)nNR6R7; while 'R3 and R4 together form a 4 to An 8-membered ring group; wherein the 5 to 8 membered heterocyclic ring contains one or more .n, hydrazine, s atoms, and the 4 to 8 membered heterocyclic ring is further further selected from one or more selected from the group consisting of alkyl, halogen, aryl, Heteroaryl, i-alkyl, deuterated alkoxy, hydroxy Substituted by a substituent of an alkoxy group, a aryloxy group, a carbonyl group, a heterocycloalkyl group, a carboxylic acid, a carboxylic acid ester, =N-0R6 or -NR6R7; R5 is selected from a hydrogen atom, an alkyl group, a cycloalkyl group And -C(=0)0R6, wherein the alkyl or cycloalkyl group is further substituted by one or more substituents selected from the group consisting of alkyl, hydroxy, alkoxy, cyano, -nr6r7, carboxylic acid or carboxylic acid esters Substituted; R6 and R7 are each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, wherein the alkyl group, the alkenyl group, the cycloalkyl group, and the 579 201016683 heterocyclic ring. The alkyl, aryl or heteroaryl group is further selected from one or more selected from the group consisting of alkyl, cycloalkyl, dentate, aryl, hydroxy, amine, alkoxy, alkenyl, heterocycloalkyl, alkyl. Substituting -S〇2R6, -C(=0) R6, diacid acid, tarenic acid ester or substituent of -NR6R7; at the same time, R6 and R7 together form a 4- to 8-membered heterocyclic group; 5 to 8 The heterocyclic ring contains one or more N, 0, S atoms, and the 4 to 8 membered heterocyclic ring is further further selected from one or more selected from the group consisting of an alkyl group, a halogen group, an aryl group, a heterocyclic group, a halogenated aryl group, and a halogen. Alkoxy, amine, hydroxyl , cyano, alkoxy, aryloxy, aminoalkyl, hydroxyalkyl, cycloalkyl, heterocyclic alkyl, carbonyl, carboxylic acid, carboxylic acid ester, -C(=0)NR6R7, --NC 〇〇) Substituted by a substituent of R6, _S〇2R6, or -NR6R7; • η is 0 to 6; r is 0 to 2. 2. The compound of claim 1 or a salt thereof, wherein the compound is a compound represented by the formula (I):

其中： R係選***基、雜環烧基、芳基或雜芳基，其中該烧基、雜環烧基、芳基或雜芳基進一步被一個或多個選自烷基、鹵素、芳基、羥基、胺基、炔基、烯基、氰基、硝基、三氟甲基、齒代苄基、雜環烷基、羧酸或羧酸酯的取代基所取代；其中該芳基或雜芳基進一步併成雙 580 201016683 環，此雙環進一步被苄基或_代苄基所取代；或者R1爲結構式：其中： B係選自芳基或雜芳基，其中該芳基或雜芳基進一步被一個或多個選自烷基、鹵素、芳基、羥基、胺基、炔基、烯基、氰基、硝基、三氟曱基、鹵代苄基、雜環烧基、緩酸或緩酸醋的取代基所取代； T 係選自-〇(CH2)r-、-N(CH2)r-或-S(CH2)r ; • L·係選自芳基或雜芳基，其中該芳基或雜芳基進一步被一個或多個鹵素或烷基所取代； R2係選自氫原子、烷基、環烷基、三氟曱基、雜環烷基、芳基、雜芳基、芳烷基，其中該烧基、環烷基、雜環烷基、芳基、雜芳基、芳烷基進一步被一個或多傭選自烷基、芳基、幾基、鹵素、胺基、氰基、烷氧基..、羧酸、羧酸酯或-NR6R7的取代基所取代； R3和R4係各自獨立地選自氳原子、烷基、三氟甲 ® 基、環烧基、雜環烷基、芳基、羧酸酯、-SO2R6、-CH2C(=0) NR6R7、-C(=0)NR6R7、-(CH2)nNR6R7 或-NC(=0)R6，其中該院基、環烧基、雜環烧基進一步被一個或多個選*** 基、鹵素、三氟甲基、芳基、羥基、烷氧基、芳氧基、環烷基、雜環烷基、雜芳基、雜環烷氧基、氰基、羧酸、羧酸酯、-S〇2R6、或-(CH2)nNR6R7的取代基所取代；同時’ R3和R4 —起形成一個4至8員環基；其中5 至8員雜環内含有一個或多個n、〇、s原子，並且4 581 201016683 至8員雜環上進一步被一個或多個選***基、鹵素、芳基、雜芳基、齒代烷基、_代烧氧基、羥基、烷氧基、芳氧基、羰基、雜環烷基、羧酸、羧酸酯、=N-0R6或-NR6R7 的取代基所取代； R6和R7係分別選自氫原子、烷基、烯基、環烷基、雜環燒基、芳基或雜芳基，其中該烷基、烯基、環烷基、雜環烷基、芳基或雜芳基進一步被一個或多個選自烷基、環烷基、_素、芳基、羥基、胺基、烷氧基、烯基、 φ 雜環烷基、羥烷基、-S〇2R6、-C(=0)R6、羧酸、羧酸醋或-NR6R7的取代基所取代；同時’ R6和R7—起形成一個4至8員雜環基；其中5至8員雜環内含有一個或多個n、〇、S原子，並且， 4至8員雜環上進一步被一個或多個選自烷基、鹵素、芳基、雜芳基、·齒代芳基、南代烷氧基、胺基、.經基、氰基、烷氧基、芳氧基、胺烷基、羥烷基'環烷基、雜環烷基、羰基、羧酸、羧酸酯、-C(=〇)NR6R7、-NC〇0)R6、 ® 4〇2R6、或_NR6r7的取代基所取代； η是〇至6 ; r是〇至2。 3 如申請專利範圍第1項之化合物或其鹽，其中，該化合 %爲由通式（II)表示的化合物：Wherein: R is selected from the group consisting of an alkyl group, a heterocyclic alkyl group, an aryl group or a heteroaryl group, wherein the alkyl group, the heterocyclic alkyl group, the aryl group or the heteroaryl group is further selected from one or more selected from the group consisting of an alkyl group and a halogen. Substituted with a substituent of an aryl group, a hydroxyl group, an amine group, an alkynyl group, an alkenyl group, a cyano group, a nitro group, a trifluoromethyl group, a dentylbenzyl group, a heterocycloalkyl group, a carboxylic acid or a carboxylic acid ester; Or a heteroaryl group further merged into a double 580 201016683 ring, which is further substituted by a benzyl or benzyl group; or R1 is a structural formula: wherein: B is selected from an aryl or heteroaryl group, wherein the aryl group Or a heteroaryl group further further selected from one or more selected from the group consisting of alkyl, halogen, aryl, hydroxy, amine, alkynyl, alkenyl, cyano, nitro, trifluoromethyl, halobenzyl, heterocyclic Substituted by a base, a slow acid or a slow acid vinegar substituent; T is selected from the group consisting of -〇(CH2)r-, -N(CH2)r- or -S(CH2)r; • L· is selected from aryl or a heteroaryl group, wherein the aryl or heteroaryl group is further substituted by one or more halogen or alkyl groups; R2 is selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a trifluoromethyl group, a heterocycloalkyl group, and an aromatic group. base, a heteroaryl group, an aralkyl group, wherein the alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, aralkyl group is further one or more selected from an alkyl group, an aryl group, a aryl group, a halogen Substituted with a substituent of an amine group, a cyano group, an alkoxy group, a carboxylic acid, a carboxylic acid ester or -NR6R7; R3 and R4 are each independently selected from the group consisting of a halogen atom, an alkyl group, a trifluoromethyl group, and a ring. An alkyl group, a heterocycloalkyl group, an aryl group, a carboxylic acid ester, -SO2R6, -CH2C(=0)NR6R7, -C(=0)NR6R7, -(CH2)nNR6R7 or -NC(=0)R6, wherein The aryl group, the cycloalkyl group, the heterocyclic alkyl group are further further selected from one or more selected from the group consisting of an alkyl group, a halogen, a trifluoromethyl group, an aryl group, a hydroxyl group, an alkoxy group, an aryloxy group, a cycloalkyl group, and a heterocycloalkyl group. Substituted by a substituent of a heteroaryl, heterocycloalkoxy, cyano, carboxylic acid, carboxylic acid ester, -S〇2R6, or -(CH2)nNR6R7; at the same time 'R3 and R4 together form a 4 to 8 a ring group; wherein the 5 to 8 member heterocyclic ring contains one or more n, 〇, s atoms, and 4 581 201016683 to 8 member heterocyclic ring is further further selected from one or more selected from the group consisting of an alkyl group, a halogen group, an aryl group, Heteroaryl, dentate alkyl, _ alkoxy Substituted by a substituent of a hydroxyl group, an alkoxy group, an aryloxy group, a carbonyl group, a heterocycloalkyl group, a carboxylic acid, a carboxylic acid ester, =N-0R6 or -NR6R7; R6 and R7 are each selected from a hydrogen atom, an alkyl group, An alkenyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, wherein the alkyl group, alkenyl group, cycloalkyl group, heterocycloalkyl group, aryl group or heteroaryl group is further selected from one or more selected from Alkyl, cycloalkyl, _, aryl, hydroxy, amine, alkoxy, alkenyl, φ heterocycloalkyl, hydroxyalkyl, -S〇2R6, -C(=0)R6, carboxylic acid Substituted by a carboxylic acid vinegar or a substituent of -NR6R7; and 'R6 and R7' form a 4 to 8 membered heterocyclic group; wherein the 5 to 8 membered heterocyclic ring contains one or more n, 〇, S atoms, Further, the 4 to 8 membered heterocyclic ring is further selected from one or more selected from the group consisting of an alkyl group, a halogen, an aryl group, a heteroaryl group, a dentate aryl group, a southern alkoxy group, an amine group, a thiol group, and a cyano group. , alkoxy, aryloxy, aminoalkyl, hydroxyalkyl 'cycloalkyl, heterocycloalkyl, carbonyl, carboxylic acid, carboxylic acid ester, -C(=〇)NR6R7, -NC〇0)R6, Substituted by a substituent of ® 4〇2R6, or _NR6r7; η is 〇 to 6; r To 2 billion. 3. The compound of claim 1 or a salt thereof, wherein the compound % is a compound represented by the formula (II):

(II) 582 201016683 其中： R係選自烷基、雜環院基、芳基或雜芳基其中詨烷基、雜環烷基、芳基或雜芳基進一步被一個或多個選自烷基、_素、芳基、羥基、胺基、炔基、烯基、氰基、硝基、二氟曱基、_代苄基、雜環烷基、鲮酸或羧酸酯的取代基所取代；其中該芳基或雜芳基進一步併成雙環’此雙環進一步被苄基或_代苄基所取代；或者R1爲結構式：其中： ® B係選自芳基或雜芳基，其中該芳基或雜芳基進一步被一個或多個選自烷基、鹵素、芳基、羥基、胺基、炔基、烯基、氰基、硝基、三氟曱基、鹵代苄基、雜環烷基、羧酸或羧酸酯的取代基所取代； T 係選自-0(CH2)r-、-N(CH2)r-或-S(CH2)r ; L係選自芳基或雜芳基，其中該芳基或雜芳基進_ 步被一個或多個鹵素或烧基所取代； ❾ R係選自氳原子、烧基、環烧基、三氟甲基.、雜環烷基、芳基、雜芳基、芳烷基，其中該烷基、環烷基、雜環炫基、芳基、雜芳基、芳烧基進一步被一個或多個選自烷基、芳基、羥基、鹵素、胺基、氰基、烷氧基、羧酸、羧酸酯或-NR6R7的取代基所取代； R3係選自氫原子、烷基、三氟甲基、環烷基、雜環烷基、芳基、羧酸酯、-S〇2R6、-CH2C(=0)NR6R7、-C(=0) NR6R7、-(CH〇nNR6R7或-NC(=0) R6 ’ 其中該烷基、環烷 583 201016683 基、雜環烷基進一步被一個或多個選自烷基、鹵素、三氟甲基、芳基、羥基、烷氧基、芳氧基、環烷基、雜環烷基、雜芳基、雜環烷氧基、氰基、羧酸、羧酸酯、 -S〇2R6、或-(CH2)nNR6R7的取代基所取代； R5係選自氫原子、烷基、環烷基或-C〇〇)〇R6，其中該烧基或環烧基進一步被一個或多個選***基、經基、烷氧基、氰基、-NR6R7、羧酸或羧酸酯的取代基所取代； ©R6和R7係分別選自氫原子、烷基、烯基、環烷基、 _ 雜環烷基、芳基或雜芳基，其中該烷基、烯基、環烷基、雜環烷基、芳基或雜芳基進一步被一個或多個選自烷 - 基、環烷基、鹵素、芳基、羥基、胺基、烷氧基、烯基、 . 雜環烧基、沒烧基、-SO2R6、-C(=0)R6、+致酸、瘦酸醋或-nr6’r7的取代基所取代；同時’ R6和R7—起形成一個4至8員雜環基；其中5至8員雜環内含有一個或多個n、〇、s原子，並且 ® 4至8員雜環上進一步被一個或多個選自烷基、鹵素、芳基、雜芳基、鹵代芳基、齒代烷氧基、胺基、羥基、氰基、烷氧基、芳氧基、胺烷基、羥烷基、環烷基、雜環烷基、羰基、羧酸、羧酸酯、-C(=〇)NR6R7、-NC(=〇)R6、 -S〇2R6、或-NR6R7的取代基所取代； η是0至6 ; r是0至2。 4.如申請專利範圍第1項之化合物或其鹽，其中，該化合 584 201016683 物爲由通式（III)表示的化合物：(II) 582 201016683 wherein: R is selected from the group consisting of alkyl, heterocyclic, aryl or heteroaryl wherein decyl, heterocycloalkyl, aryl or heteroaryl is further selected from one or more selected from alkane a substituent of a group, a aryl group, an aryl group, a hydroxyl group, an amine group, an alkynyl group, an alkenyl group, a cyano group, a nitro group, a difluoroantimony group, a benzyl group, a heterocycloalkyl group, a decanoic acid or a carboxylic acid ester. Substituted; wherein the aryl or heteroaryl group further forms a bicyclic ring. 'This bicyclic ring is further substituted by a benzyl group or a benzyl group; or R1 is a structural formula: wherein: ® B is selected from an aryl group or a heteroaryl group, wherein The aryl or heteroaryl group is further selected from one or more selected from the group consisting of alkyl, halogen, aryl, hydroxy, amine, alkynyl, alkenyl, cyano, nitro, trifluoromethyl, halobenzyl, Substituted by a heterocycloalkyl, carboxylic acid or carboxylate substituent; T is selected from -0(CH2)r-, -N(CH2)r- or -S(CH2)r; L is selected from aryl Or a heteroaryl group, wherein the aryl or heteroaryl group is substituted with one or more halogen or alkyl groups; ❾ R is selected from the group consisting of a ruthenium atom, a ruthenium group, a cycloalkyl group, a trifluoromethyl group, and a heterocyclic group. Cycloalkyl, aryl, hetero a aryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group, the heteroaryl group, and the aryl group are further selected from one or more selected from the group consisting of an alkyl group, an aryl group, a hydroxyl group, a halogen group, and an amine group. Substituting a cyano group, an alkoxy group, a carboxylic acid, a carboxylic acid ester or a substituent of -NR6R7; R3 is selected from the group consisting of a hydrogen atom, an alkyl group, a trifluoromethyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a carboxylate, -S〇2R6, -CH2C(=0)NR6R7, -C(=0)NR6R7, -(CH〇nNR6R7 or -NC(=0)R6 ' wherein the alkyl group, naphthenic 583 201016683, The heterocycloalkyl group is further selected from one or more selected from the group consisting of alkyl, halogen, trifluoromethyl, aryl, hydroxy, alkoxy, aryloxy, cycloalkyl, heterocycloalkyl, heteroaryl, heterocycle. Substituted by a substituent of an alkoxy group, a cyano group, a carboxylic acid, a carboxylic acid ester, -S〇2R6, or -(CH2)nNR6R7; R5 is selected from a hydrogen atom, an alkyl group, a cycloalkyl group or a -C〇〇) R6, wherein the alkyl or cycloalkyl is further substituted with one or more substituents selected from the group consisting of an alkyl group, a thiol group, an alkoxy group, a cyano group, a -NR6R7, a carboxylic acid or a carboxylic acid ester; R7 is selected from a hydrogen atom, an alkyl group, and an alkenyl group, respectively. a cycloalkyl, _heterocycloalkyl, aryl or heteroaryl group, wherein the alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is further selected from one or more selected from the group consisting of alkane- Base, cycloalkyl, halogen, aryl, hydroxy, amine, alkoxy, alkenyl, . heterocycloalkyl, non-alkyl, -SO2R6, -C(=0)R6, +acid, acidity Substituted by a vinegar or a substituent of -nr6'r7; and 'R6 and R7' form a 4 to 8 membered heterocyclic group; wherein the 5 to 8 membered heterocyclic ring contains one or more n, 〇, s atoms, and ® 4 to 8 membered heterocyclic ring further further selected from one or more selected from the group consisting of alkyl, halogen, aryl, heteroaryl, haloaryl, dentate alkoxy, amine, hydroxy, cyano, alkoxy , aryloxy, aminoalkyl, hydroxyalkyl, cycloalkyl, heterocycloalkyl, carbonyl, carboxylic acid, carboxylic acid ester, -C(=〇)NR6R7, -NC(=〇)R6, -S〇 Substituted by a substituent of 2R6 or -NR6R7; η is 0 to 6; r is 0 to 2. 4. The compound of claim 1 or a salt thereof, wherein the compound 584 201016683 is a compound represented by the formula (III):

其中： R1係選自烷基、雜環烷基、芳基或雜芳基，其中該烷基、雜環烷基、芳基或雜芳基進一步被一個或多個選自烷基、4素、芳基、羥基、胺基、炔基、烯基、氰基、 ❹墙基、三m、齒代节基、雜環絲、㈣或緩酸醋的取代基所取代；其中該芳基或雜芳基進一步併成雙環’此雙環進一步被苄基或豳代苄基所取代； • 或者R1爲結構式：其中： B係選自芳基或雜芳基，其中該芳基或雜芳基進一步被一個或多個選自烷基、i素、芳基、羥基、胺基、炔基、烯基、氰基、硝基、三氟曱基、齒代苄基、雜環 β 烷基、羧酸或羧酸酯的取代基所取代； Τ 係選自-〇(CH2)r-、-N(CH2)r-或-S(CH2)r ; L係選自芳基或雜芳基，其中該芳基或雜芳基進一步被一個或多個齒素或烷基所取代； R3和R4係各自獨立地選自氫原子、烷基、三氟曱基、環烷基、雜環烷基、芳基、羧酸酯、_s〇2R6、_CH2C(=〇) NR6R7、-C(=0)NR6R7、_(CH2)nNR6R7 或-NC(=〇)r6，其中該烷基、％烷基、雜環烷基進一步被一個或多個選自烷 585 201016683 基、鹵素、三氟甲基、芳基、羥基、烷氧基、芳氧基、環烧基、雜環烷基、雜芳基、雜環烷氧基、氰基、羧酸、幾酸酯、-S〇2R6、或-(CH2)nNR6R7的取代基所取代；同時，R3和R4—起形成一個4至8員環基；其中5 至8員雜環内含有一個或多個n、〇、s原子，並且4 至8員雜環上進一步被一個或多個選自烷基、鹵素、芳基、雜芳基、齒代烷基、齒代烷氧基、羥基、烷氧基、芳氧基、羰基、雜環烷基、羧酸、羧酸酯、=N_〇r6或_nr6r7 的取代基所取代； R6和R7係分別選自氫原子、烷基、烯基、環烷基、雜環烷基、芳基或雜芳基，其中該烷基、烯基、環烷基、 . 雜環烧基、芳基或雜芳基進一步被一個或多個選自院 . 基、環烷基、齒素、芳基、羥基、胺基、烷氧基、烯基、雜環烧基、羥烷基、-SO2R6、-C(=0)R6、護酸、綾酸酯或-NR6R7的取代基所取代，· 同時，R6和R7 —起形成一個4至8員雜環基；其鬱中5至8員雜環内含有一個或多個N、〇、s原子，並且 4至8員雜環上進一步被一個或多個選自烷基、鹵素、芳基、雜芳基、鹵代芳基、齒代烷氧基、胺基、羥基、氰基、烧氧基、芳氧基、胺燒基、經烧基、環院基、雜環院基、叛基、缓酸、緩酸酯、-C(=〇)nr6r7、-nc(=〇)r6、 -S〇2R6、或_NR6R7的取代基所取代·; η是0至6 ; r是0至2。 586 201016683 5.如申請專利範圍第1項之化合物或其鹽，其中，該化合物係選自：Wherein: R1 is selected from the group consisting of an alkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, wherein the alkyl group, heterocycloalkyl group, aryl group or heteroaryl group is further selected from one or more selected from the group consisting of alkyl groups and 4 elements. Substituted with a substituent of an aryl group, a hydroxyl group, an amino group, an alkynyl group, an alkenyl group, a cyano group, a fluorene group, a tris, a dentate group, a heterocyclic group, a (iv) or a slow acid vinegar; wherein the aryl group or The heteroaryl group further forms a bicyclic ring. The bicyclic ring is further substituted by a benzyl or deuterated benzyl group; or R1 is a structural formula: wherein: B is selected from an aryl or heteroaryl group, wherein the aryl or heteroaryl group Further further selected from one or more selected from the group consisting of alkyl, i-, aryl, hydroxy, amine, alkynyl, alkenyl, cyano, nitro, trifluoromethyl, dentylbenzyl, heterocyclic beta alkyl, Substituted by a substituent of a carboxylic acid or a carboxylic acid ester; the lanthanide is selected from the group consisting of -〇(CH2)r-, -N(CH2)r- or -S(CH2)r; the L series is selected from an aryl or heteroaryl group, Wherein the aryl or heteroaryl group is further substituted by one or more dentants or alkyl groups; R3 and R4 are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a trifluoromethyl group, a cycloalkyl group, a heterocycloalkyl group. , aryl, carboxylic acid , _s〇2R6, _CH2C(=〇) NR6R7, -C(=0)NR6R7, _(CH2)nNR6R7 or -NC(=〇)r6, wherein the alkyl group, the % alkyl group, the heterocycloalkyl group are further Or a plurality selected from the group consisting of alkane 585 201016683, halogen, trifluoromethyl, aryl, hydroxy, alkoxy, aryloxy, cycloalkyl, heterocycloalkyl, heteroaryl, heterocycloalkoxy, cyanide Substituted by a substituent of a carboxylic acid, a carboxylic acid, a certain acid ester, -S〇2R6, or -(CH2)nNR6R7; at the same time, R3 and R4 together form a 4 to 8 membered ring group; wherein the 5 to 8 membered heterocyclic ring Containing one or more n, 〇, s atoms, and further 4 or 8 membered heterocyclic rings, one or more selected from the group consisting of alkyl, halogen, aryl, heteroaryl, dentate alkyl, dentate alkoxy Substituted by a substituent of a hydroxyl group, an alkoxy group, an aryloxy group, a carbonyl group, a heterocycloalkyl group, a carboxylic acid, a carboxylic acid ester, =N_〇r6 or _nr6r7; R6 and R7 are each selected from a hydrogen atom and an alkane a base, alkenyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group wherein the alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is further protected by one or more Selected from the hospital. Base, cycloalkyl, tooth Substituted by a substituent of an aryl group, a hydroxyl group, an amine group, an alkoxy group, an alkenyl group, a heterocycloalkyl group, a hydroxyalkyl group, -SO2R6, -C(=0)R6, a acid protecting acid, a decanoic acid ester or a -NR6R7 Meanwhile, R6 and R7 together form a 4- to 8-membered heterocyclic group; the 5- to 8-membered heterocyclic ring contains one or more N, 〇, s atoms, and the 4 to 8 member heterocyclic ring further One or more selected from the group consisting of alkyl, halogen, aryl, heteroaryl, haloaryl, dentate alkoxy, amine, hydroxy, cyano, alkoxy, aryloxy, amine alkyl, Substituents for alkyl, ring-based, heterocyclic, decarbyl, acid-lowering, acid-lowering, -C(=〇)nr6r7, -nc(=〇)r6, -S〇2R6, or _NR6R7 Substituted·; η is 0 to 6; r is 0 to 2. The compound of claim 1 or a salt thereof, wherein the compound is selected from the group consisting of:

587587

588 201016683588 201016683

589 201016683589 201016683

590 201016683 Q590 201016683 Q

591 201016683591 201016683

592 201016683592 201016683

593 201016683593 201016683

594 201016683594 201016683

595 201016683595 201016683

QQ

,XK'n,XK'n

596 201016683596 201016683

597 201016683597 201016683

201016683 201016683201016683 201016683

❹6.如申請專利範圍第1項之化合物或其鹽，其中，該鹽爲該化合物與選自下列的酸所形成的鹽：類果酸、乳酸、馬來酸、鹽酸、甲磺酸、對曱苯磺酸、硫酸、磷酸、檸 - 樣酸、酒石酸、乙酸或三氟乙酸。 -7. —種醫藥組成物，其含有治療有效量的如申請專利範圍一至6項中任一項之化合物或其鹽，以及醫藥上可接受的载劑或賦形劑。種如申請專利範圍第2項之通式⑴化合物的製備方忐，該方法包括以下步驟： ⑴ 6〇〇 201016683The compound of claim 1 or a salt thereof, wherein the salt is a salt of the compound and an acid selected from the group consisting of acidoid, lactic acid, maleic acid, hydrochloric acid, methanesulfonic acid, Toluenesulfonic acid, sulfuric acid, phosphoric acid, lemon-like acid, tartaric acid, acetic acid or trifluoroacetic acid. -7. A pharmaceutical composition comprising a therapeutically effective amount of a compound or a salt thereof according to any one of claims 1 to 6, and a pharmaceutically acceptable carrier or excipient. The preparation method of the compound of the formula (1) as claimed in the second item of the patent application, the method comprises the following steps: (1) 6〇〇 201016683

在硬化亞銅和磷酸鉀的條件下，將第6位置㈣取喧唾琳化合物a與6, 7、二氫普—[3，[啦^ ^進打偶合，得到㈣内㈣料類化合物b"比略内醋噎唾_化合物b_取狀就應，㈣通式化合物（I a) ’ la可與甲伽氯、經取代之胺反應，進一得到通式化合物（I b);㈣，^叫内§旨料琳類化合Under the conditions of hardening cuprous and potassium phosphate, the sixth position (four) is taken from the salin compound a and 6,7, dihydropro-[3, [la ^ ^ into the coupling, to get the (four) inner (four) material compound b&quot比内内 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ ^叫内§要琳琳类合

物b與氫化脑反應，得到二經基化合物C，二經^ ^物⑽部分氧化得到的料搭基化合物d與經取二之胺和三乙醯氧基鄉氫化制進行還原胺化得到通式化合物（I c) ; ° (2) 601 201016683The material b reacts with the hydrogenated brain to obtain the di-based compound C, and the second compound obtained by partial oxidation of the compound (10) is subjected to reductive amination by hydrogenation of the diamine and triethyloxy group. Compound (I c) ; ° (2) 601 201016683

(«)(«)

(h)(h)

IBX.DMSOIBX.DMSO

0) (1) (CH3)3〇H (2) TFA,CHZCIZ0) (1) (CH3)3〇H (2) TFA, CHZCIZ

nhrV NaBH(OAc)3nhrV NaBH(OAc)3

㈣在碘化亞銅和磷酸鉀的條件下，將第6位置經碘取代之啥°坐琳化合物a與4-三氣甲基-111-°比洛-3 -甲酸乙g旨進(iv) Under the conditions of cuprous iodide and potassium phosphate, the 6th position is replaced by iodine, 坐 ° sitin compound a and 4-trimethylmethyl-111-° bilo-3-formate B g

行偶合’得到三氟甲基吡咯甲酸乙g旨取代之喹唑琳類合物e，e與疊氮磷酸二苯酯反應，得到疊氮基甲醯吡咯=合物f，f與甲醇反應，然後在三氟醋酸的條 :，得到胺基吡咯化合物g，g與醯氯反應得到通式。物（I d),或者，化合物e與氫化鋁鋰反應，得^ 基還原產物h’h經部分氧化得到的化合物i $ e 之胺和二乙醯氧基獨氫化納反應得到通式化合物（I ^ 602 (3) 201016683Row coupling 'to obtain the quinazoline compound e, e substituted with trifluoromethylpyrrolecarboxylic acid, e, e reacted with diphenyl azide to obtain azidopyridinium pyrimide = f, and react with methanol, Then, in the strip of trifluoroacetic acid: an aminopyrrole compound g, g is obtained by reacting with ruthenium chloride to obtain a general formula. The compound (I d ) or the compound e is reacted with lithium aluminum hydride to obtain a compound of the formula (e. I ^ 602 (3) 201016683

在碘化亞銅和磷酸鉀的條件下，將第6位置經碘取代之喹唑啉化合物a與3-吡咯曱醛進行偶合，得到吡略甲醛喹唑啉類化合物j，j與經取代之胺和三乙醯氧基硼氫化鈉反應，得到通式化合物（I f);化合物&與^比洛進行Suzuki偶合反應，得到吼洛取代之化合物k，让與N，N-—甲基曱酿胺和二氯氧磷反應，得到^比嘻甲酿化產物1，1經還原胺化得到通式化合物（I g); ⑷The quinazoline compound a substituted with iodine at the 6th position is coupled with 3-pyrrolefural under conditions of cuprous iodide and potassium phosphate to obtain pyridyl quinazoline compound j,j and substituted The amine is reacted with sodium triethoxysulfonate to obtain a compound of the formula (I f); the compound & is subjected to a Suzuki coupling reaction with piroxicam to obtain a compound K substituted with valpro, and N,N-methyl The reaction between the brewing amine and the phosphorus oxychloride gives the compound (I g) which is obtained by reductive amination of the brewing product 1,1; (4)

在碘化亞銅和磷酸鉀的條件下，將第6位置經碘取代之喹唑啉化合物a與1H-吡咯-3, 4_二甲酸乙酯進行偶合^得到吡咯二甲酸乙酯取代之喹唑啉類化合物^，瓜與氫化鋁鋰反應’吡咯二甲酸乙酯被還原爲吡咯二羥甲基產物η，η進一步被氧化得到吡洛二甲合物。經還原胺化得到通式化合物(Ih);產物。’化 (5) 603 201016683Under the conditions of cuprous iodide and potassium phosphate, the quinazoline compound a substituted with iodine at the 6th position is coupled with 1H-pyrrole-3,4-dicarboxylic acid ethyl ester to obtain quinolin substituted with ethyl pyrrolate dicarboxylate. The oxazoline compound ^, the melon and the lithium aluminum hydride reaction 'ethyl pyrrolate dicarboxylate is reduced to the pyrrole dimethylol product η, and η is further oxidized to obtain pyrrole dimethyl compound. Reductive amination gives the compound of the formula (Ih); product. ‘化(5) 603 201016683

在硬化亞銅和填酸卸的條件下’將第6位置經蛾取代之喹唑啉化合物a與化合物P進行偶合，得到吡咯取代之喧唑啉類通式化合物（〗i)。 9. 一種如申請專利範圍第3項之通式（π)化合物的製備方法，該方法包括以下步驟：The quinazoline compound a substituted with moth at position 6 is coupled with the compound P under conditions of hardening cuprous and acid-removal to obtain a pyrrole-substituted oxazoline-based compound (I). 9. A method of preparing a compound of the formula (π) according to item 3 of the patent application, the method comprising the steps of:

在肆（三苯基膦）鈀和碳酸鉀的條件下’將第6位置經碘取代之喧β坐琳化合物a與2 _爛酸吼p各化合物q進行 ® Suzukl偶合反應，得到吡咯取代之喹唑啉類化合物Γ， r在鹼性條件下脫去對σ比咯N的保護，得到6_吡咯取代的啥唾琳類化合物s ’ s與Ν，Ν-二曱基甲醯胺和三氣氧 g反應，進行Vilsemier反應，得到2-藤基取代的0比 π各化合物t’ t在三乙醯氧基硼氫.化鈉和經取代之胺的條件下進行化合物胺化，得到通式化合物（II a); (2) 604 201016683Under the conditions of ruthenium (triphenylphosphine)palladium and potassium carbonate, 'Suzukl coupling reaction is carried out with the iodine-substituted 喧β 琳化合物 compound a at the 6th position and 2 _ 烂吼各 p respective compound q, to obtain a pyrrole substitution reaction. The quinazoline compound Γ, r is deprotected under basic conditions for the protection of σ-pyrrol N, and the 6-pyrrole-substituted 啥啥琳 s s 's with Ν, Ν-dimercaptocaramine and three The gas-oxygen g reaction is carried out to carry out the Vilsemier reaction to obtain a 2-nano-substituted 0-π compound t't, which is subjected to amination of the compound under the conditions of triethylphosphonium borohydride, sodium and substituted amine. Compound (II a); (2) 604 201016683

將6-吡咯取代的喹唑啉類化合物s與三異丙基氯矽烷進行反應，得到的化合物u進一步與n，N—二甲基甲酿胺和三氣氧磷反應得到吡咯曱醯化産物v，v經還原胺化得到通式化合物（II b)，化合物s在強鹼氫化鈉條件下與1-齒代烷基如鐵甲烷反應，得到通式化合物（II 10· —種如申請專利範圍第4項之通式（in)化合物的製備方法，該方法包括以下步驟：The 6-pyrrole-substituted quinazoline compound s is reacted with triisopropylchloromethane, and the obtained compound u is further reacted with n,N-dimethylamine and tris-phosphorus to obtain a pyrrole deuterated product. v,v is reductively aminated to obtain the compound of the formula (II b), and the compound s is reacted with a 1-dentate alkyl group such as iron methane under strong sodium hydride to obtain a compound of the formula (II 10 · as a patent application) A method for preparing a compound of the formula (in) of the fourth aspect, the method comprising the steps of:

在碳酸鉀和肆（三苯基膦）鈀的條件下，將第6位置經峨取代之喹唑琳化合物a與3-硼酸吡洛化合物w進行 605 201016683 Suzuki偶合反應，得到的吡咯取代之喹唑啉化合物χ 在氫化納條件下，與㈣素或甲確酿基取代的化合物即R X或R SOsCIL·反應，得到通式化合物（丨丨丨a)，·化合物X在氫化納條件下，也可以與代酿胺反應，，到通式化合物（III d)，醯胺的羰基也可以進一步被 ^化鋁鋰還原，得到通式化合物（In e);化合物叉在虱化鋼條件與消旋環氧氯丙燒反應得到通式化合物 (ΙΠ f)’與NHR6R7開環反應，得到通式化合物（III g)， φ 在相同的條件下’化合物4R型或3型環氧氯丙烧反應，進一步開環反應，對應得到s型或R型通式化合物 (ΙΙΪ g);化合物叉與N，N_二甲基曱醯胺和三氯氧磷反 -應，得到的甲醯化産物y，在高錳酸鉀的氧化下，將吡 ^熟H錢H步與經取狀減應得到通八化合物（III b)，化合物y也可以直接被還原胺化得到通式化合物（III 。 11.-種調節蛋白激酶催化活性的方法，包括將該蛋 ©與如申請專利範圍第丨至6項中任—項之化合物或其鹽接觸。. 12·知申請專利範圍第Η項之方法，其中，該蛋白激酶係選自爻體酪胺酸激酶、非受體酪胺酸激酶或絲胺胺酸激酶。咪 13·=種如申請專利範圍《 1至6項中任一項之化合物或其鹽之用途’係用於製備治療與蛋白激酶相關的疾病的藥 606 201016683 14. 一種如申請專利範圍第7項之組成物之用途，係甩於製備治療與蛋白激酶相關的疾病的藥物。Under the conditions of potassium carbonate and cesium (triphenylphosphine) palladium, the quinazoline compound a substituted with hydrazine at the 6th position is subjected to a 605 201016683 Suzuki coupling reaction with a pyrrole compound of 3-borate to obtain a pyrrole-substituted quinolin. The oxazoline compound χ is reacted with a compound substituted with (tetra) or a carboxylic acid under the condition of sodium hydride, that is, RX or R SOsCIL· to obtain a compound of the formula (丨丨丨a), which is also under the condition of sodium hydride. It can be reacted with a substituted amine. To the compound of formula (III d), the carbonyl group of the indoleamine can be further reduced by aluminum lithium to obtain a compound of the formula (In e); the compound fork is in the condition of deuterated steel and racemic The epichlorohydrin reaction gives a ring-opening reaction of the general compound (ΙΠ f)' with NHR6R7 to obtain a compound of the formula (III g), φ under the same conditions, 'the compound 4R type or the type 3 epichlorohydrin reaction, Further ring-opening reaction, corresponding to the s-type or R-type compound of the formula (ΙΙΪ g); the compound fork and N,N-dimethyl decylamine and phosphorus oxychloride counter--, the obtained formazanization product y, Under the oxidation of potassium permanganate, the H-step and the recovery of the extract To the compound (III b), the compound y can also be directly reductively aminated to obtain a compound of the formula (III. 11.-A method for regulating the catalytic activity of a protein kinase, including the egg © and the scope of the patent application The method of claim 6 or the salt thereof, wherein the protein kinase is selected from the group consisting of a steroidal tyrosine kinase, a non-receptor tyrosine kinase or a silk. Amino acid kinase. The use of a compound or a salt thereof according to any one of claims 1 to 6 is used for the preparation of a medicament for treating a protein kinase-related disease 606 201016683 14. The use of the composition of claim 7 is for the preparation of a medicament for treating a protein kinase-related disease.

607 201016683 · 七、指定代表圖：本案無圖式。 (一）本案指定代表圖為：第（）圖。 (二) 本代表圖之元件符號簡單說明：八、本案若有化學式時，請揭示最能顯示發明特徵的化學式：607 201016683 · VII. Designated representative map: There is no schema in this case. (1) The representative representative of the case is: (). (2) A brief description of the symbol of the representative figure: 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention:

6 943896 94389