TW201235041A - 6-amino quinazoline or 3-cyano quinoline derivatives, preparation process and pharmaceutical use thereof - Google Patents

6-amino quinazoline or 3-cyano quinoline derivatives, preparation process and pharmaceutical use thereof Download PDF

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TW201235041A
TW201235041A TW100105215A TW100105215A TW201235041A TW 201235041 A TW201235041 A TW 201235041A TW 100105215 A TW100105215 A TW 100105215A TW 100105215 A TW100105215 A TW 100105215A TW 201235041 A TW201235041 A TW 201235041A
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pharmaceutically acceptable
enantiomer
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TWI524893B (en
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Peng-Cho Tang
Xin Li
Bin Wang
Jun Wang
Li-Jun Chen
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Jiangsu Hengrui Medicine Co
Shanghai Hengrui Pharm Co Ltd
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Abstract

The present disclosure relates to 6-amino quinazoline or 3-cyano quinoline derivatives, preparation processes and pharmaceutical compositions containing them. Specifically, the present disclosure relates to novel 6-amino quinazoline or 3-cyano quinoline derivatives presented by formula (I), or its tautomer, enantiomer, diastereomer, racemate or pharmaceutically acceptable salts thereof, or metabolite, metabolic precursor or prodrug thereof, and the uses for treatment especially for protein kinase inhibitors, in which each substitute group of general formula (I) is as defined in the specification.

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201235041 六、發明說明： 【發明所屬之技術領域】 本發明涉及一種新的6-胺基喹唑啉或3〜氰基喹啉類 何生物、其製備方法及含有該衍生物的醫藥組成物以及其 作為'冶療劑特別是作為蛋白激酶抑制劑 的用途。 【先前技術】 信號傳導作為細胞的一種基礎調節機制，將胞外的各 種信號傳遞到細胞内部，使細胞做出相應的生物應答，實 現諸如增殖、分化、调亡等過程。大多數的信號傳導是利 用蛋白質可逆的磷酸化過程實現的，其中涉及到特定蛋白 激酶和礙酸酶。 蛋白激酶（PKS)可以分成兩類：蛋白酪胺酸激酶（pTKs) 和絲胺酸—蘇胺酸激酶（S T K s)。P T K s可使蛋白質上的酪胺 酸殘基磷酸化，STKs可以磷酸化絲胺酸、蘇胺酸殘基。酪 胺酸激酶又可以分為受體型（receptor tyrosine kinase， RTKs)和非受體型（non-receptor tyrosine kinase)。目 前，在人類基因中已有90種酪胺酸激酶編碼基因被識別， 其中約60種是受體型，約3〇種是非受體型。 RTKs豕族可劃分為許多亞族··諸如（1)表皮生長因子 文體豕族，成員包括EGFR，HER-2，HER-3，HER-4 ; (2)膜 島素受體家族，包括胰島素受體IR、胰島素樣生長因子工 受體（IGF-IR)和胰島素受體相關性受體（IRR);⑶m型 家族，如血小板衍生生長因子受體pDGFR，幹細胞因子 SCF(c-Kit)，fms-相關酪胺酸激酶3(Flt3)受體和集落刺 95119 4 -201235041 激因子1受體（CSF-1R)等等。此外，如肝細胞生長因 體c-Met，血管内皮生長因子受體VEGFR等也屬於打。二 族成員。它們在調節細胞週期和分化凋亡方面均起著關= 作用，也是誘導生長因子等細胞因子生成的信號通路上的 1992, 9, 383 關鍵信號傳遞者’參見Schlessinger and U1 lriλ,、201235041 VI. Description of the Invention: [Technical Field] The present invention relates to a novel 6-amino quinazoline or 3-cyanoquinoline-like organism, a preparation method thereof, and a pharmaceutical composition containing the same, and It is used as a therapeutic agent, especially as a protein kinase inhibitor. [Prior Art] Signal transduction, as a basic regulatory mechanism of cells, transmits extracellular signals to the interior of cells, allowing cells to respond to biological responses such as proliferation, differentiation, and apoptosis. Most of the signaling is achieved by a reversible phosphorylation process involving proteins that involve specific protein kinases and acid oxidases. Protein kinases (PKS) can be divided into two classes: protein tyrosine kinases (pTKs) and serine-threonine kinases (S T K s). P T K s phosphorylates tyrosine residues on proteins, and STKs phosphorylate serine and threonine residues. Tyrosine kinases can be further divided into receptor tyrosine kinases (RTKs) and non-receptor tyrosine kinases. Currently, 90 tyrosine kinase-encoding genes have been identified in human genes, of which about 60 are receptor-type and about 3 are non-receptor-type. RTKs can be divided into many subfamilies such as (1) epidermal growth factor streptozoic steroids, members including EGFR, HER-2, HER-3, HER-4; (2) mesangide receptor family, including insulin Receptor IR, insulin-like growth factor receptor (IGF-IR) and insulin receptor-associated receptor (IRR); (3) m-type family, such as platelet-derived growth factor receptor pDGFR, stem cell factor SCF (c-Kit), Fms-related tyrosine kinase 3 (Flt3) receptor and colony spur 95119 4 -201235041 stimulatory factor 1 receptor (CSF-1R) and the like. In addition, such as hepatocyte growth factor c-Met, vascular endothelial growth factor receptor VEGFR, etc. also belong to the fight. Two members. They play a role in regulating cell cycle and differentiation and apoptosis, and are also the signal transduction pathways for the induction of cytokine production such as growth factors. 1992, 9, 383 key signal transmitters' See Schlessinger and U1 lriλ,

…Λ .… cn> Neur〇L EGFR(ErbB，HER)亞族在調控細胞增殖和存活的 過程中都扮演著非常重要的角色。結構上，該家族受夕 ❹胞外的配體結合區域、跨膜區域及胞内催化區域三 成。其酪胺酸激酶活性經由配體介導的受體間同型或二1 二聚化過程被啟動’二聚化使受體催化區内㈣胺^殘^ 磷酸化，並作為後續信號分子的結合位元點（biMing site)’從而啟動下一級信號級聯，諸如絲裂原啟動蛋白激 酶（MAP激酶）和磷脂醯肌醇激酶（ριρ_3激酶），這些信號* 聯的啟動能夠調節細胞週期和細胞調亡。在大部分人類^ •體，瘤中’如乳腺癌、***癌、非小細胞肺癌、刀胃腸癌、 食官癌、印巢癌、姨腺癌等，都有_、職一2發生突變 異常活化或過度表現的情況，從而使其與腫瘤發生發展的 關聯性得到了進一步確認。 作為msClassI„成員的血小板衍生生長因子受 體（PDGFR) ’ C-Kit和fms—相關路胺酸激酶,並 結構和活化過程均與麵家族類似，經由二聚化過程活化 傳遞W，從而調節細胞的增殖，分化和遷移，以及血管 生成過程。因而該家族成員與腫瘤的發生發展也有著密切 95119 5 201235041 的關係。例如對不同實體瘤中的c-Kit表現情況進行研 究，在小細胞支氣管癌、睾丸瘤、黑素瘤、***癌、成神 經細胞瘤中都發現c_Kit的高度表現，尤其是胃腸道膠質 瘤（GIST)，參見 Weber 等，j. CUn. 〇nc〇1. 22(14S)，祁42 (2004)。大多數的（5〇至8〇%)(；1灯均是由於^忖基因發 生突變而產生。突變能夠使卜^七具有持續活化的酪胺酸 激酶活性，從而使細胞***率增加，導致基因組的不穩定， 從而誘發癌變。 受體酪胺酸激酶家族的另外一個重要成員是血管内 皮生長因子受體（VEGFR)。冗(；卯與血管生成密切相關， VEGF與其結合後可啟動相關信號通路促進血管生成。最近 的=據表明，VEGF能夠誘導内皮細胞增殖和遷移促進毛細 血管生成，從而形成超滲透、不成熟的血管網路，提供營 養幫助腫瘤生長。除了其促血管生成活性，VEGFR及vegf 也可以在腫瘤細胞内直接經由促存活（pro-survival)性質 促進腫瘤生長。研究發現，VEGFR在各種惡性實體腫瘤中， 如肺癌、乳腺癌、卵巢癌、胰腺癌和黑素瘤中均有強烈表 現，因此經由抑制VEGFR活性而實現抑制腫瘤生長，對於 腫瘤治療有很大的應用價值。 此外，作為RTKs成員的肝細胞生長因子受體c__Met (HGFR) ’經大量文獻證實其與腫瘤生成、侵襲和轉移，細 胞運動性增強等也密切相關（參見Ma，p.c等（2〇〇3b)....Λ.. cn> The Neur〇L EGFR (ErbB, HER) subfamily plays a very important role in regulating cell proliferation and survival. Structurally, the family is subjected to a ligand binding region, a transmembrane region, and an intracellular catalytic region of the extracellular sputum. Its tyrosine kinase activity is initiated by ligand-mediated interreceptor homotypic or dimerization, 'dimerization' phosphorylation of the (tetra)amine in the catalytic region of the receptor, and as a binding molecule for subsequent signaling molecules The biMing site' initiates the next level of signal cascade, such as mitogen-activated protein kinase (MAP kinase) and phospholipid spectinokinase (ριρ_3 kinase), which initiates cell cycle and cell regulation Transfer. In most humans, tumors, such as breast cancer, prostate cancer, non-small cell lung cancer, gastrointestinal cancer, appetite cancer, Indian cancer, parotid cancer, etc., have _, job one 2 mutation abnormalities The association with activation or over-expression is further confirmed by its association with tumor development. As a member of msClassI's platelet-derived growth factor receptor (PDGFR) 'C-Kit and fms-associated glutamate kinase, and the structure and activation process are similar to the noodle family, the W is regulated by the dimerization process, thereby regulating cells. The proliferation, differentiation and migration, and the process of angiogenesis. Therefore, the family members and the development of tumors are also closely related to the relationship of 95119 5 201235041. For example, the study of c-Kit performance in different solid tumors, in small cell bronchial carcinoma High expression of c_Kit in testicular tumors, melanoma, breast cancer, and neuroblastoma, especially gastrointestinal glioma (GIST), see Weber et al, j. CUn. 〇nc〇1. 22(14S) , 祁42 (2004). Most (5〇 to 8〇%) (1 lamp are caused by mutations in the ^忖 gene. Mutations can enable the sustained activation of tyrosine kinase activity, thus Increasing cell division rate leads to instability of the genome, which induces cancer. Another important member of the receptor tyrosine kinase family is the vascular endothelial growth factor receptor (VEGFR). The production is closely related, and VEGF can initiate a related signaling pathway to promote angiogenesis. Recently, it has been shown that VEGF can induce endothelial cell proliferation and migration to promote capillary formation, thereby forming a super-osmotic, immature vascular network and providing nutrition. Helping tumor growth. In addition to its pro-angiogenic activity, VEGFR and vegf can also promote tumor growth directly in tumor cells via pro-survival properties. Studies have found that VEGFR is found in various malignant solid tumors such as lung cancer and breast cancer. It has strong expression in ovarian cancer, pancreatic cancer and melanoma, so inhibition of tumor growth by inhibiting VEGFR activity has great application value for tumor therapy. In addition, hepatocyte growth factor receptor c__Met as a member of RTKs (HGFR) 'A large number of literatures have confirmed that it is closely related to tumor formation, invasion and metastasis, and cell motility enhancement (see Ma, pc et al. (2〇〇3b).

Cancer Metastasis Rev.， 22， 309-25; Maulik， G.等 (2002b). Cytokine Growth Factor Rev， 13， 41-59)。 95119 6 201235041 作為PTKs的另-成員，非受體㈣㈣ 隨5或CTKS(細胞質㈣酸激酶）]，是細胞f中的蛋白酿 胺酸激酶，與RTKs相比缺少胞外功能域和跨膜域結構。 ctks的路胺酸活性與腫瘤也有密切關係，關於為 詳盡的描述，可參見iB〇len，1993, 〇nc〇gen 8 : ’ 2025-203卜 癌症的兩個最主要特徵是腫瘤細胞基因組不穩定和 調節細胞週期和增殖***相關的信號通路的失控。基因組 不穩定導致部分信號傳導的關鍵調節蛋白的生物功能發生 改變或喪失，使信號傳導過程遭到干擾或破壞，異常的信 號通路無法正常調節控制細胞週期進程和細胞洞亡，使得 腫瘤細胞能夠在基因損傷的狀態下持續存活和增殖。作為 實現這些調節過㈣根本，PKs，包括上面討論的受體RTKs 和細胞質PTKs(CTKs)與腫瘤的發生發展過程息息相關，從 而成為治療腫瘤疾病的重要無點。 • 人們期待著能夠合成具有抑制腫瘤細胞增殖活性的 化合物’希望能夠經由抑制RTKs、CTKs或者STKs中的一 種或者多種，從而有效地治療和改善非正常條件下由 RTKs、CTKs或者STKs以及血管生成作用介導的細胞非正 常增殖造成的生理紊亂。 目前已公開一系列的蛋白激酶抑制劑的文獻，如 WOOO/18761A1 、 W02003089439A1 、 W02005028443A1 和 W02007055514A1等公開了噎淋或啥峻淋衍生物的藥物，其 用途及製備方法。Hwei-RU Ts〇u等，在/.於汶③ 7 95119 201235041 48’ ll〇m31 (2〇05)中也公開了喹啉類衍生物 激酶抑制劑。 F与蛋白 儘管目前已公開了一系列的治療腫瘤的蛋白激酶抑 制刎，但仍需要開發新的具有更好的藥效、藥代結 合物，經過不斷努力，本發明設計具有通式（示的化 合物，並發現具有此類結構的化合物表現出優異的^的化 作用。 衣和 【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^ 供一種通式（I)所示的新的6-胺基喧唾琳或3-氰基啥琳類 衍生物，以及它們的互變異構體、對映體、非對映體、、肖 旋體和可藥用的鹽，以及代謝產物和代謝前體或前藥， d4 R\ / „3 hn'r R \ Η ^Λα^2 (I) 其中： 八選自碳原子或氮原子； ^ A為碳原子時’ R選自風原子或烧氧基，其中所述 的烷氧基视需要進一步被一個或多個選自_素或烷氧基的 取代基所取代，R2選自氰基； 當A為氮原子時’ R1選自氫原子或烷氧基，其中所述 的烷氧基視需要進一步被一個或多個選自鹵素或燒氧基的 取代基所取代，R2無取代； 95119 8 201235041 R3具有下列結構··，D、*rL或—D ; 其中： D選自絲或雜綠，其巾所述的芳基或雜芳基各自 蜀立地視需要進-步被一個或多個選自齒素、烧基或三氣 甲基的取代基所取代； T 選自:(CH2)r-，—0(CH2)r—，_NH(CH2)r_^_s(CH2)r ; 鲁 L選自芳基或雜絲，其中所述的芳基或雜芳基各自 獨立地視需5要進-步被—個或多㈣素或炫基所取代； 、R和R各自獨立地選自氫原子、烷基、烷氧基、羥基、 羥烷基、齒素、羰基、胺基、氰基、硝基、羧酸或羧酸酯； B選自碳原子、氧原子或S(0)r基團； 當B為碳原子時，R6和^各自獨立地選自氫原子、烷 基、烧氧基、經基、經院基、鹵素、幾基、胺基、氰基、 硝基、羧酸或羧酸酯； H 當β為氧原子或S(0)r基團時，R6和R7無取代； R8選自氫原子或烷基； R9選自氫原子、烷基、環烷基、芳基、羧基或羧酸酯； r為0、1或2 ;且 η為卜2、3、4或5。 較佳地’―種通式（I)所示的化合物或其互變異構 體、外消旋體、對映異構體、非對映異構體、及其混合物 形式、及可藥用的鹽，其中包括通式（ΙΙΑ)或（ΙΙΒ)所示的 的化合物或其互變異構體、外消旋體、對映異構體、非對 9 95119 201235041 映異構體、及其混合物形式、及可藥用的鹽：Cancer Metastasis Rev., 22, 309-25; Maulik, G. et al. (2002b). Cytokine Growth Factor Rev, 13, 41-59). 95119 6 201235041 As an additional member of PTKs, non-receptor (d) (iv) with 5 or CTKS (cytoplasmic (tetra) acid kinase)] is a protein in the cell f, which lacks extracellular and transmembrane domains compared to RTKs. structure. The guanine activity of ctks is also closely related to tumors. For a detailed description, see iB〇len, 1993, 〇nc〇gen 8: '2025-203. The two most important features of cancer are tumor cell genomic instability. Loss of control of signaling pathways associated with regulation of cell cycle and proliferation division. Genomic instability leads to the alteration or loss of the biological function of key regulatory proteins of some signaling, which interferes or destroys the signaling process. Abnormal signaling pathways cannot regulate and control cell cycle progression and cell death, enabling tumor cells to Survival and proliferation continue in the state of genetic damage. As a basis for achieving these regulation (4), PKs, including the receptor RTKs and cytoplasmic PTKs (CTKs) discussed above, are closely related to the development and progression of tumors, and thus become an important point in the treatment of tumor diseases. • It is expected that a compound capable of synthesizing tumor cell proliferation-promoting activity can be effectively treated and improved by RTKs, CTKs or STKs and angiogenesis under abnormal conditions by inhibiting one or more of RTKs, CTKs or STKs. Mediates physiological disorders caused by abnormal proliferation of cells. A series of protein kinase inhibitors have been published, such as WOOO/18761A1, W02003089439A1, W02005028443A1 and W02007055514A1, etc., which disclose the use of a drug or a preparation thereof. Huni-RU Ts〇u et al., also disclosed quinoline derivative kinase inhibitors in U.S. Patent 3,7,9,9,9,9,9,5,5,0,0,0,0,0,0,0,0,0 F and protein Although a series of protein kinase inhibitors for tumors have been disclosed, there is still a need to develop new ones with better pharmacodynamics and pharmacokinetic combinations. Through continuous efforts, the present invention has a general formula (shown The compound and the compound having such a structure are found to exhibit excellent chemical action. [Invention] In order to overcome the deficiencies of the prior art, the object of the present invention is to provide a formula (I). New 6-aminos-hydrazin or 3-cyanophthalocyanine derivatives, as well as their tautomers, enantiomers, diastereomers, spirulina and pharmaceutically acceptable salts, and metabolism Product and metabolic precursor or prodrug, d4 R\ / „3 hn'r R \ Η ^Λα^2 (I) where: VIII is selected from a carbon atom or a nitrogen atom; ^ when A is a carbon atom, R is selected from the wind An atom or alkoxy group, wherein said alkoxy group is further substituted by one or more substituents selected from the group consisting of _ or alkoxy groups, and R 2 is selected from cyano; when A is a nitrogen atom, 'R1 is selected From a hydrogen atom or an alkoxy group, wherein the alkoxy group is further protected by one or more Substituted from a halogen or alkoxy substituent, R2 is unsubstituted; 95119 8 201235041 R3 has the following structure, D, *rL or -D; wherein: D is selected from silk or hybrid green, The aryl or heteroaryl groups are each independently substituted as desired by one or more substituents selected from the group consisting of dentate, alkyl or trimethyl; T is selected from: (CH2)r-, -0 (CH2)r-, _NH(CH2)r_^_s(CH2)r; Lu is selected from an aryl group or a hetero-line, wherein the aryl or heteroaryl group is independently required to be step-by-step- Substituted by one or more (tetra) or leuco; R, R and R are each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a hydroxyl group, a hydroxyalkyl group, a dentate, a carbonyl group, an amine group, a cyano group, a nitro group, a carboxylic acid or a carboxylic acid ester; B is selected from a carbon atom, an oxygen atom or a S(0)r group; when B is a carbon atom, R6 and ^ are each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a a group, a phenyl group, a halogen group, a aryl group, an amine group, a cyano group, a nitro group, a carboxylic acid or a carboxylic acid ester; H when β is an oxygen atom or a S(0)r group, R6 and R7 are unsubstituted; R8 is selected From a hydrogen atom or an alkyl group; R9 is selected from a hydrogen atom, an alkyl group, a cycloalkyl group, An aryl group, a carboxyl group or a carboxylic acid ester; r is 0, 1 or 2; and η is 2, 3, 4 or 5. Preferably, the compound represented by the formula (I) or a tautomer thereof , racemates, enantiomers, diastereomers, mixtures thereof, and pharmaceutically acceptable salts, including compounds of the formula (ΙΙΑ) or (ΙΙΒ) or Isomers, racemates, enantiomers, non-pairs 9 95119 201235041 enantiomers, mixtures thereof, and pharmaceutically acceptable salts:

其中，所述的A'B'R1至R9和n的定義如通式⑴中 所定義。 >較佳地，一種通式（ΙΙΑ)或（ΙΙΒ)所示的化合物或其互 變異構體、外消旋體、對映異構體、非對映異構體、及其 混合物形式、及可藥用的鹽，其中Α為碳原子，Rl選自烷 氧基，且R2選自氰基。 較佳地，一種通式（IIA)或（ΠΒ)所示的化合物或其互 ’憂異構體、外消奴體、對映異構體、非對映異構體、及其 混合物形式、及可藥用的鹽，其中Α為氮原子，Rl選自氣 原子，且R2無取代。 較佳地，一種通式（IIA)或（IIB)所示的化合物或其互 變異構體、外消旋體、對映異構體、非對映異構體、及其 混合物形式、及可藥用的鹽，其中〇為2。 較佳地，一種通式（ΠΑ)或（IIB)所示的化合物或其互 變異構體、外消旋體、對映異構體、非對映異構體、及其 混合物形式、及可藥用的鹽，其中包括通式（ΙΠΑ)或 所示的化合物或其互變異構體、外消旋體、對映異構體、 非對映異構體、及其混合物形式、及可藥用的鹽： 10 95119 201235041Wherein the definitions of A'B'R1 to R9 and n are as defined in the formula (1). > Preferably, a compound of the formula (ΙΙΑ) or (ΙΙΒ) or a tautomer, a racemate, an enantiomer, a diastereomer thereof, and a mixture thereof, And a pharmaceutically acceptable salt wherein hydrazine is a carbon atom, R1 is selected from alkoxy groups, and R2 is selected from cyano. Preferably, a compound of the formula (IIA) or (ΠΒ) or a mutual isomer, a racemate, an enantiomer, a diastereomer, and a mixture thereof, And a pharmaceutically acceptable salt, wherein hydrazine is a nitrogen atom, R1 is selected from a gas atom, and R2 is unsubstituted. Preferably, a compound of the formula (IIA) or (IIB) or a tautomer, a racemate, an enantiomer, a diastereomer thereof, a mixture thereof, and Medicinal salt, wherein strontium is 2. Preferably, a compound of the formula (ΠΑ) or (IIB) or a tautomer, a racemate, an enantiomer, a diastereomer thereof, a mixture thereof, and Medicinal salts, including the formula (ΙΠΑ) or the compounds shown or their tautomers, racemates, enantiomers, diastereomers, mixtures thereof, and pharmaceutically acceptable Salt used: 10 95119 201235041

(ΙΙΙΑ) (IIIB) 其中· A、R至R3、r6、r9和n的定義如通式（iia)或 (I IB)所定義。 較佳地’一種通式（IIA)或（IIB)所示的化合物或其互 變異構體、外消旋體、對映異構體、非對映異構體、及其 混合物形式、及可藥用的鹽，其中包括通式（IVA)或（ινβ) 所示的化合物或其互雙異構體、外消旋體、對映異構體、 非對映異構體、及其混合物形式、及可藥用的鹽：(ΙΙΙΑ) (IIIB) wherein A, R to R3, r6, r9 and n are as defined for the formula (iia) or (I IB). Preferably a compound of the formula (IIA) or (IIB) or a tautomer, a racemate, an enantiomer, a diastereomer thereof, a mixture thereof, and a pharmaceutically acceptable salt, which comprises a compound of the formula (IVA) or (ινβ) or a diisomer, a racemate, an enantiomer, a diastereomer thereof, and a mixture thereof And pharmaceutically acceptable salts:

(IVA) (IVB) 其中· A、R S R、R6和R9的定義如通式（ΠΑ)或（ΠΒ) 所定義。 本發明的較佳化合物包括，但不限於：(IVA) (IVB) wherein A, R S R, R6 and R9 are as defined by the formula (ΠΑ) or (ΠΒ). Preferred compounds of the invention include, but are not limited to:

95119 11 201235041 2 一[[3_氣—4 一（2~吡啶基曱氧基）苯基]胺 ί 〇 基乙氧基一6一啥淋基]_3_[(2幻_〇比咯 基]丙-2-烯醯脸 °^〇 3 2十[少[[3_氣一 4_(2_β比淀f氧基）苯基]胺 1氰基—7—乙氧基一6_啥淋基]_3_[(25<，4n 基-°比洛炫^2-基]丙-2-烯醯胺 — _ — . " —_ ΧΪ： 4 氣-4-(2-«*比咬基甲氧基）苯基]胺 =]喹唑啉-6-基]-3-[(250-1-甲基吡咯烷-2-基] 丙-2-烯醯胺 595119 11 201235041 2 A [[3_ gas-4 tetra(2-pyridinyloxy)phenyl]amine ί 乙 ethoxy ethoxy -6 啥 ]]]]]]]]]]]]] Prop-2-ene 醯 face ° ^ 〇 3 2 10 [less [[3_ gas a 4_(2_β than deoxy) phenyl]amine 1 cyano-7-ethoxy- 6-indole] _3_[(25<,4n base-°Biloxuan^2-yl]prop-2-enylamine- _ — . " —_ ΧΪ: 4 gas -4-(2-«* than bite methoxy Phenyl]amine =] quinazolin-6-yl]-3-[(250-1-methylpyrrolidin-2-yl)prop-2-enylamine 5

(幻-N-[4-[[3-氯-4-(2-吡啶基曱氧基）苯基]胺 基]-3-氰基-7-乙氧基-6-喹啉基]-3-[(2i〇-l-甲 基吡咯烷-2-基]丙-2-烯醯胺(Fanta-N-[4-[[3-chloro-4-(2-pyridinyloxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolinyl]- 3-[(2i〇-l-methylpyrrolidin-2-yl]prop-2-enylamine

^0 6 ⑷-N-[jH[3-氯-4-(2-"比。定基甲氧基）苯基]胺 基]-3-氰基-7-乙氧基-6-喹啉基]-3-(i-甲基-2. π辰唆基）丙-2-烯醯胺 95119 12 201235041^0 6 (4)-N-[jH[3-chloro-4-(2-" Ratio. Stationary Methoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinoline 3-(i-methyl-2. π-chenyl)prop-2-enylamine 95119 12 201235041

Η,XX： 7 氯氟-苯基〕胺基]乙氧基-啥 稀ί胺基~3—[⑽―1 —甲基鱗炫-2-基]丙-2-Η,XX: 7 chlorofluoro-phenyl]amino]ethoxy-oxime, succinylamino~3—[(10)-1-methyl dimethyl-2-yl]propan-2-

λ: 8 〆〇 氯_4_氟一苯基）胺基]_7_(2—曱氧基 基]~3_[(2奸甲基鱗烧-2- ---------- 9 Ολ: 8 〆〇 _ _ _ _ _ 苯基 苯基 苯基 ] ] ] ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- ---- Ο

A: 3H4~[[3_氯_4—(2_ι^σ定基甲氧基）苯基]胺 氧基-7-乙氧基~6-噎琳基]-3-( 1-曱基<»比ρ各 丙-2-烯醯胺 10 或其互變異構體、外消旋體、對映異構體、非對映異構體 及其混合物形式 '及可藥用的鹽。 本發明的另一方面涉及一種如下列通式（v)所示的化 合物’其作為通式（I)化合物合成的中間體： 13 95119 201235041A: 3H4~[[3_Chloro_4—(2_ι^σ定基methoxy)phenyl]aminooxy-7-ethoxy~6-indolyl]-3-(1-indenyl) a pharmaceutically acceptable salt of the present invention in the form of a pi-prop-2-endecamine 10 or a tautomer, a racemate, an enantiomer, a diastereomer thereof and a mixture thereof. Another aspect relates to a compound represented by the following formula (v) which is an intermediate for the synthesis of a compound of the formula (I): 13 95119 201235041

R2 (V) 其中： R為燒氣基； A R至R3如通式（！）所定義。 、本發月的另一方面涉及一種製備通式（V)化合物的方 法，所述方法包括以下步驟：R2 (V) wherein: R is a gas-burning group; A R to R3 are as defined by the formula (!). Another aspect of this month relates to a method of preparing a compound of formula (V), the method comprising the steps of:

(V-1) (V) 通式（V__l)化合物轉化為通式化合物； 其中：A和R1至R3的定義如通式（V)中所述。 本發明的另一個方面是提供一種製備通式（1)的化合 物或其可藥用的鹽的方法，所述方法包括以下步驟：(V-1) (V) The compound of the formula (V_-1) is converted into a compound of the formula; wherein: A and R1 to R3 are as defined in the formula (V). Another aspect of the present invention provides a process for the preparation of a compound of the formula (1) or a pharmaceutically acceptable salt thereof, the process comprising the steps of:

(V) (VI) (I) 通式（V)化合物與通式（VI)化合物反應得到通式（I) 化合物。 其中： 14 95119 201235041 R1為烷氧基； 的定義如通式（I)中所述。 本發明的另—個方面是提供—種製備通式（⑽或 7)的化合物或其可藥用的鹽的方法，所述方法包括以7 步驟.(V) (VI) (I) A compound of the formula (V) is reacted with a compound of the formula (VI) to give a compound of the formula (I). Wherein: 14 95119 201235041 R1 is alkoxy; is as defined in formula (I). Another aspect of the invention provides a method of preparing a compound of the formula ((10) or 7) or a pharmaceutically acceptable salt thereof, the method comprising the steps of 7 steps.

通式⑺化合物與通式⑽）化合物反應得到通式 (IIA)化合物；或者，The compound of the formula (7) is reacted with a compound of the formula (10)) to give a compound of the formula (IIA); or

通式（v)化合物與通式（νίΒ)化合物反應得到通式 (ΙΙΒ)化合物； 其中：八^、11、1^至1^的定義如通式（11八）或（116) 中所述。 本發明/步及作為抑制VEGFR、EGFR、HER-2、HER-3、 ' c-Met、Jak3受體酪胺酸激酶或它們的組合的激酶 的藥物的本發明通式（1；)化合物或其互變異構體、外消旋 體、對映異構體、非對映異構體、及其混合物形式、及可 藥用的鹽。 95119 15 201235041 本發明涉及本發明通式（i)化合物或其互變異構體、 外消旋體、對映異構體、非對映異構體、及其混合物形式 及可藥用的鹽在製備 VEGFR、EGFR、HER-2、HER-3、HER、4 c-Met、Jak3受體酪胺酸激酶或它們的組合的激酶抑 中的用途。The compound of the formula (v) is reacted with a compound of the formula (νίΒ) to give a compound of the formula (ΙΙΒ); wherein: VIII, 11, 1^ to 1^ are as defined in the formula (11) or (116) . The present invention/step and a compound of the formula (1;) of the present invention as a medicament for inhibiting a kinase of VEGFR, EGFR, HER-2, HER-3, 'c-Met, Jak3 receptor tyrosine kinase or a combination thereof It is a tautomer, a racemate, an enantiomer, a diastereomer, a mixture thereof, and a pharmaceutically acceptable salt. 95119 15 201235041 The present invention relates to a compound of the formula (i) of the present invention or a tautomer, a racemate, an enantiomer, a diastereomer thereof, a mixture thereof, and a pharmaceutically acceptable salt thereof. Use of a kinase inhibitor for the preparation of VEGFR, EGFR, HER-2, HER-3, HER, 4 c-Met, Jak3 receptor tyrosine kinase, or a combination thereof.

本發明涉及通式（I)化合物或其互變異構體、外消旋 體、對映異構體、非對映異構體、及其混合物形式、及可 藥用的鹽在製備治療與蛋白激酶有關的疾病的藥物中的用 途，所述蛋白激酶選自受體酪胺酸激酶、非受體酪胺醆教 酶或絲胺酸-蘇胺酸激酶，其中所述的受體酪胺酸激酶選 VEGFR、EGFR、HER-2、HER~3、HER-4、c-Met、Jak3 受體 路胺酸激酶或它們的組合。 本發明還涉及治療與蛋白激酶有關的疾病的藥物的 通式⑴化合物或其互變異構體、外消旋體、對映異構體、 非對映異構體、及其混合物形式、及可藥用的鹽，所述蛋The present invention relates to a compound of the general formula (I) or a tautomer, a racemate, an enantiomer, a diastereomer thereof, a mixture thereof, and a pharmaceutically acceptable salt for the preparation of a therapeutic and protein Use of a drug for a kinase-related disease selected from the group consisting of a receptor tyrosine kinase, a non-receptor tyramine sulfatase or a serine-threonine kinase, wherein the receptor tyrosine The kinase is selected from VEGFR, EGFR, HER-2, HER-3, HER-4, c-Met, Jak3 receptor glutamate kinase or a combination thereof. The present invention also relates to a compound of the formula (1) or a tautomer, a racemate, an enantiomer, a diastereomer thereof, a mixture thereof, and a drug thereof for treating a drug associated with a protein kinase. Medicinal salt, the egg

白激酶選自受舰祕_、非受祕胺酸_或絲胺酸_ 蘇胺酸激酶’其中所述的受體_酸激_自觀卜 EGFR、HER-2、HER-3、_、4、c Met、尬3 受體路胺酸激 酶或它們的組合。 、本發明涉及本發明通式（I)化合物或其互變異構體、 外消，體•映異構體、非對映異構體、及其混合物形式、 及可藥用的鹽在製備治療癌症的藥物中的用途，其中所述 的癌症為肺癌、乳腺癌、表皮鱗癌或胃癌。 本么月還"及作為治療癌症的藥物的本發明通式⑴ 16 95119 201235041 構體、外消旋體、對映異構體、非對映 異構體、及其混合物形式、及可藥用的鹽。 =發明的一個方面是提供一種醫藥組成物，含有通 二㈣化合物或其互變異構體、外消旋體、對映異構 體、非對映異構體、及盆、· ^ 八混δ物形式、及可藥用的鹽或其 引樂Π可藥用的载體或朗劑。所述醫藥組成物在製備治 療/、蛋白激酶有關的疾病的藥物中的用途，所 ❶ 選自 VEGFR、EGFR、ΗΕΗ、職_3、臓_4、c_Met、Jak3 交體赂胺酸_或它們的組合激酶。所述醫藥、组成物在製 備治療癌症的藥物中的用途，其中所述癌症是肺癌、乳腺 癌、表皮鱗癌或胃癌。 本發明的一個方面涉及一種製備醫藥組成物的方法，White kinase is selected from the group consisting of EGFR, HER-2, HER-3, _, which is not regulated by myosic acid _ or serine _ sulphonic acid kinase. 4. c Met, 尬3 receptor glutamate kinase or a combination thereof. The present invention relates to a compound of the formula (I) of the present invention or a tautomer, a foreign body, a diastereomer, a diastereomer thereof, a mixture thereof, and a pharmaceutically acceptable salt thereof. Use in a medicament for cancer, wherein the cancer is lung cancer, breast cancer, epidermal squamous cell carcinoma or gastric cancer. The present invention also has the formula (1) 16 95119 201235041 of the present invention as a medicament for treating cancer, a race, a racemate, an enantiomer, a diastereomer, a mixture thereof, and a pharmaceutically acceptable drug. Salt used. An aspect of the invention is to provide a pharmaceutical composition comprising a di(tetra) compound or a tautomer thereof, a racemate, an enantiomer, a diastereomer, and a basin, A pharmaceutically acceptable carrier or ampoules in the form of a pharmaceutically acceptable salt or a pharmaceutically acceptable salt thereof. The use of the pharmaceutical composition for the preparation of a medicament for treating/protein kinase-related diseases, selected from the group consisting of VEGFR, EGFR, ΗΕΗ, _3, 臓_4, c_Met, Jak3 tranexamic acid _ or Combination kinase. The use of the medicine or composition for the preparation of a medicament for treating cancer, wherein the cancer is lung cancer, breast cancer, epidermal squamous carcinoma or gastric cancer. One aspect of the invention relates to a method of preparing a pharmaceutical composition,

所述方法包括將通式（I)所示的化合物或其互變異構體、外 消旋體、對映異構體、非對映異構體、及其混合物形式、 及可藥用的鹽或其前藥與可藥用載體或稀釋劑相結合。 本發明的另一個方面是提供一種蛋白激酶催化活性 的調節方法，包括使蛋白激酶與通式（1)的化合物或其互變 異構體、外消旋體、對映異構體、非對映異構體、及其混 合物形式、及可藥用的鹽相接觸，所述蛋白激酶選自 VEGFR、EGFR、HER-2、HER-3、HER-4、C-Met、Jak3 受體 絡胺酸激酶或它們的組合激酶。 本發明涉及一種治療腫瘤的方法，該方法包括將通式 (I)化合物或其互變異構體、外消旋體、對映異構體、非對 映異構體、及其混合物形式、及可藥用的鹽單獨給藥，或 17 95119 201235041 與其他藥物聯合給藥。聯合給藥的藥物包括抗腫瘤類藥 物’其中所述的抗腫瘤藥物包括曲妥珠單抗（Trasfuzumab，The method comprises the compound of the formula (I) or a tautomer, a racemate, an enantiomer, a diastereomer, a mixture thereof, and a pharmaceutically acceptable salt thereof. Or a prodrug thereof in combination with a pharmaceutically acceptable carrier or diluent. Another aspect of the present invention provides a method for modulating the catalytic activity of a protein kinase, comprising a protein kinase and a compound of the formula (1) or a tautomer, a racemate, an enantiomer thereof, a diastereomer The isomers, and mixtures thereof, and pharmaceutically acceptable salts are selected from the group consisting of VEGFR, EGFR, HER-2, HER-3, HER-4, C-Met, Jak3 receptor lysine Kinases or their combination kinases. The present invention relates to a method for treating a tumor comprising the compound of the formula (I) or a tautomer, a racemate, an enantiomer, a diastereomer thereof, and a mixture thereof, and The pharmaceutically acceptable salt is administered alone or in combination with other drugs at 17 95119 201235041. The drug to be administered in combination includes an antitumor drug, wherein the antitumor drug includes trastuzumab (Trasfuzumab,

Herceptin) ’西妥昔單抗（Cetuximab)，拉帕替尼 (Lapatinib)’ 來那替尼（neratinib)，來曲 〇坐（Letrozole)， 卡培他濱（Capeci tabine)，拓撲替康（T〇p〇tecan)和多西他 賽（Docetaxel)等藥物。 (發明的詳細說明） 除非有相反陳述’在說明書和權利要求書中使用的術 語具有下述含義。 “烷基”指飽和的脂族烴基團，包括丨至2〇個碳原 子的直鏈和支鏈基團。較佳含有1至12個碳原子的烷基， 非限制性實施例包括甲基、乙基、正丙基、異丙基、正丁 基、異丁基、叔丁基、仲丁基、正戊基、丨，卜二曱基丙基、 1，2-二甲基丙基、2, 2-二曱基丙基、1-乙基丙基、2-甲基 丁基、3-曱基丁基、正己基、1-乙基一2-曱基丙基、丨，丨，2一 二曱基丙基、1,1-二甲基丁基、1，2-二甲基丁基、2, 2-二 曱基丁基、1，3-二曱基丁基、2-乙基丁基、2-甲基戊基、 3-甲基戊基、4-甲基戊基、2, 3-二曱基丁基、正庚基、2一 曱基己基、3-曱基己基、4-甲基己基、5-甲基己基、2,3- 二曱基戊基、2, 4-二曱基戊基、2, 2-二甲基戊基、3, 3-二 曱基戊基、2-乙基戊基、3-乙基戊基、正辛基、2, 3-二甲 基己基、2, 4-二甲基己基、2, 5-二曱基己基、2, 2-二曱基 己基、3, 3-二甲基己基、4, 4-二甲基己基、2-乙基己基、 3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2一曱基_3_ 95119 18 201235041 乙基戊基、正壬基、2_甲基一2一乙基己基、2_曱基—3_乙基 己基、2’2一二乙基戊基、正癸基、3, 3-二乙基己基、2, 2- - 一乙基己基，及其各種支鏈異構體等。更較佳的是含有1 至6個碳原子的低級烷基，非限制性實施例包括甲基、乙 基、正丙基、異丙基、正丁基、異丁基、叔丁基、仲丁基、 正戊基、1，1-二甲基丙基、1>2_二甲基丙基、2 2二甲基 丙基、卜乙基丙基、2_曱基丁基、3_甲基丁基、正己基、 卜乙基一2_甲基丙基、1，1，2-三甲基丙基、1，1 一二曱基丁 基、1，2-二甲基丁基、2, 2_二甲基丁基、h 3一二甲基丁基、 2-乙基丁基、甲基戊基、3-曱基戊基、4-曱基戊基、2, 3- 一甲基丁基專。院基可以是取代的或未取代的，當被取代 時，取代基可以在任何可使用的連接點上被取代，較佳為 一個或多個以下基團，獨立地選自烷基、烯基、炔基、烷 氧基、烷硫基、烷基胺基、_素、硫醇、羥基、硝基、氰 基、環烷基、雜環烷基、芳基、雜芳基、環烷氧基、雜環 •烷氧基、環烷硫基、雜環烷硫基、羰基、羧酸或羧酸酯。 %烧基指飽和或部分不飽和單環或多環環狀烴 取代基，其包括3至20個碳原子，較佳包括3至12個碳 原子，更較佳環烷基環包含3至1〇個碳原子。單環環烷基 的非限制性實施例包含環丙基、環丁基、環戊基、環戊烯 基環己基、環己烯基、環己二烯基、環庚基、環庚三烯 基、％辛基等。多環環烷基包括螺環、稠環和橋環的環烷 基。 螺環烷基”指5至20員，單環之間共用一個碳原 95119 19 201235041 子（稱螺原子）的多環基團，這些可以含有一個或多個雙 鍵，但沒有一個環具有完全共軛的π電子系統。較佳為6 至14員，更較佳為7至1〇員。根據環與環之間共用螺原 子的數目將螺環烷基分為單螺環烷基、雙螺環烷基基或多 螺環烷基，較佳為單螺環烷基和雙螺環烷基。更較佳為4 員/4員、4員/5員、4員/6員、5員/5員或5員/6員單螺 環烷基。螺環烷基的非限制性實施例包含Herceptin) 'Cetuximab, Lapatinib' neratinib, Letrozole, Capeci tabine, topotecan (T 〇p〇tecan) and docetaxel (Dacetaxel) and other drugs. (Detailed Description of the Invention) Unless otherwise stated, the terms used in the specification and claims have the following meanings. "Alkyl" means a saturated aliphatic hydrocarbon group including straight chain and branched chain groups of up to 2 carbon atoms. An alkyl group preferably having 1 to 12 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, and Pentyl, hydrazine, dimercaptopropyl, 1,2-dimethylpropyl, 2,2-dimercaptopropyl, 1-ethylpropyl, 2-methylbutyl, 3-mercapto Butyl, n-hexyl, 1-ethyl-2-mercaptopropyl, hydrazine, hydrazine, 2-dimercaptopropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2, 2-dimercaptobutyl, 1,3-dimercaptobutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimercaptobutyl, n-heptyl, 2-indolylhexyl, 3-decylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-didecylpentyl, 2, 4- Dimercaptopentyl, 2,2-dimethylpentyl, 3,3-dimercaptopentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethyl Hexyl, 2,4-dimethylhexyl, 2,5-didecylhexyl, 2,2-dimercaptohexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2- Ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl 2曱曱基_3_ 95119 18 201235041 Ethylpentyl, n-decyl, 2-methyl-2-ethylhexyl, 2-hydrazino-3-ethylhexyl, 2'2-diethylpentyl, N-decyl, 3, 3-diethylhexyl, 2,2-ethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups having from 1 to 6 carbon atoms, non-limiting examples including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec. Butyl, n-pentyl, 1,1-dimethylpropyl, 1>2-dimethylpropyl, 2 2 dimethylpropyl, ethylidenepropyl, 2-decylbutyl, 3-methyl Butyl, n-hexyl, ethyl 2-methylpropyl, 1,1,2-trimethylpropyl, 1,1,2-dimethylbutyl, 1,2-dimethylbutyl, 2, 2 _ dimethyl butyl, h 3 dimethyl butyl, 2-ethyl butyl, methyl amyl, 3-decylpentyl, 4-decylpentyl, 2, 3-methyl Basic. The substituent may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from alkyl, alkenyl. , alkynyl, alkoxy, alkylthio, alkylamino, _, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy A heterocyclic group, a heterocycloalkyloxy group, a cycloalkylthio group, a heterocycloalkylthio group, a carbonyl group, a carboxylic acid or a carboxylic acid ester. The % alkyl group refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably the cycloalkyl ring comprises from 3 to 1 One carbon atom. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenylcyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Base, % octyl, etc. Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups. "Spirocycloalkyl" means 5 to 20 members, a single ring having a polycyclic group of a carbon atom 95119 19 201235041 (referred to as a spiro atom), which may contain one or more double bonds, but none of the rings have complete Conjugated π-electron system, preferably from 6 to 14 members, more preferably from 7 to 1 member. The spirocycloalkyl group is divided into a monospirocycloalkyl group according to the number of common spiro atoms between the ring and the ring. A spirocycloalkyl group or a polyspirocycloalkyl group, preferably a monospirocycloalkyl group and a bispirocycloalkyl group. More preferably 4 members/4 members, 4 members/5 members, 4 members/6 members, 5 Non-limiting embodiment of a member or a member of the group of 5 members or 6 members of a monocycloalkylene group.

稠環烷基指5至20員，系統中的每個環與體系 中的其他％共用β比鄰的—對碳原子的全碳多環基團，其中 -，或多個環可以含有—個或多個雙鍵，但沒有—個環具 有完全共㈣π電子系統。較佳為6至14員，更較佳為 7至員。根據組成環的數目可以分為雙環、三環、四产 或多環稍環絲，較佳為雙環或三環，更較佳為5員/5^ 或5員/6員雙環燒基。稍環烧基的非限制性實施例包含A fused cycloalkyl group means 5 to 20 members, and each ring in the system shares a β-adjacent-to-carbon all-carbon polycyclic group with the other % in the system, wherein -, or more than one ring may contain - or Multiple double bonds, but none - one ring has a fully common (four) π electronic system. It is preferably 6 to 14 members, more preferably 7 to members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetra- or polycyclic ring-shaped filament, preferably a bicyclic or tricyclic ring, more preferably a 5-member/5^ or a 5-member/6 member bicyclic alkyl group. A non-limiting embodiment of a slightly cyclized base comprises

直接連絲”指5至20員，任意兩個環共用兩個不 接的奴原子的全碳多環基團，這些可以含 」 夕個又鍵，但沒有—個環具有完全共軛的冗電子 佳為6至14員，更較佳為7至10員。根據組成環的數Ε 95119 20 201235041 可以分為雙環 三環或四環，更有選為 環、四環或多環橋環烷基， 較佳為雙環 實施例包含 %或二％。橋環烷基的非限制性Directly connected filaments refer to 5 to 20 members. Any two rings share two carbon-free polycyclic groups of the unsuccessful slave atoms. These may contain the same bond, but none of the rings have full conjugate redundancy. The electronic is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings 95119 20 201235041, it may be classified into a bicyclic tricyclic ring or a tetracyclic ring, more preferably a cyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic ring embodiment containing % or 2%. Non-limiting

和 所述環烷基環可以稠人於# ° 其中與母體結構連接：二：二：芳基或雜環烧基環上’ 例包括茚滿基、四氫萘基基，非限制性實施 是視需要取代M本並衣庚烷基等。環烷基可以 疋U要取代的絲取代的，#被取 一個或多似下基H 一 取代純侄為And the cycloalkyl ring may be thicker than # ° where it is attached to the parent structure: two: two: aryl or heterocyclic alkyl ring on the 'example includes indanyl, tetrahydronaphthyl, non-limiting implementation is Substituting M pentylene and the like as needed. The cycloalkyl group may be substituted by the silk to be substituted by 疋U, and the one taken may be one or more like the lower group H.

匕 蜀立地選***基、稀基、伊芙、P 氧基、烧硫基、燒義脸其点主 沛基诀基说 基、環烷基、雜環烷基、芳基 ：土虱 方丞雜方基、核烷氧基、雜環 疋乳基:環烧硫基、雜魏硫基、録、_鎌酸醋。 芳基”指6至14員全碳單環或稠合多環（也就是共 用毗鄰碳原子對的環）基團，具有共軛的π電子體系的多 %(即其帶有相鄰對碳原子的環）基團，較佳為6至1〇員， 例如笨基和萘基。所述芳基環可以稠合於雜芳基、雜環基 或環烧基環上，其中與母體結構連接在一起的環為芳基 環，非限制性實施例包含··匕蜀 地 选自 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧Doped square group, nuclear alkoxy group, heterocyclic oxime group: cycloalkylthio group, hetero Weithio group, recorded, _ vinegar vinegar. "Aryl" means a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (ie, a ring that shares a pair of adjacent carbon atoms) having a % of a conjugated π-electron system (ie, having an adjacent pair of carbons) a ring of an atom, preferably 6 to 1 member, such as a stupid group and a naphthyl group. The aryl ring may be fused to a heteroaryl group, a heterocyclic group or a cycloalkyl ring, wherein the parent structure The rings joined together are aryl rings, non-limiting examples include

95119 21 20123504195119 21 201235041

多。 芳基可以是取錢絲料的，當娜代時，取代基較佳 為一個或多個以下基團，猸 团獨立地選自烷基、烯基、炔基、 烧氧基、烧硫基、境基胗其 上± I胺基、i素、硫醇、羥基、硝基、 鼠基、環烧基、雜環燒基、公且 - ^ 衣此泰方基、雜芳基、環烷氧基、雜 環烧氧基、壞烧硫基、雜J罗、ρ β甘 “ ^ ” 土雜墩烷硫基、羰基、羧酸或羧酸酯。 雜方基指包含l$y|ytoAkn* 1至4個雜原子，5至14個環原子 的雜芳族體系’其中雜©子台紅备 '、匕括氧、硫和氮。較佳為6至 10員0雜芳基較佳為是5員式r吕 Θ疋D貝或6員，例如呋喃基、噻吩基、 啦咬基、t各基、各基、較基、辦基、味吐 基、四峻基等。所述雜芳基環可叫合於芳基、雜環基或 環烧基環上’其中與母體結構連接在—起的環為雜芳基 環，非限制性實施例包含：many. The aryl group may be a money-drawing material. When Nade, the substituent is preferably one or more of the following groups, and the oxime group is independently selected from the group consisting of an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, and a sulfur-burning group. , on the basis of ±I amine, i, thiol, hydroxy, nitro, murine, cycloalkyl, heterocycloalkyl, public -^, taifang, heteroaryl, naphthenic An oxy group, a heterocyclic alkoxy group, a sulphur group, a hetero J, a ρ β 甘 " ^ " oxalate thio group, a carbonyl group, a carboxylic acid or a carboxylic acid ester. Heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatom is red, sulfur, and nitrogen. Preferably, the 6 to 10 membered 0 heteroaryl group is preferably a 5-membered R. sulphide or a 6 member, such as a furyl group, a thienyl group, a butyl group, a t group, a group, a base group, Base, taste sputum, Si Junji, etc. The heteroaryl ring may be referred to as an aryl group, a heterocyclic group or a cycloalkyl ring, wherein the ring to which the parent structure is attached is a heteroaryl ring, and the non-limiting examples include:

雜芳基可以是視需要取代的或未取代的，當被取代 時，取代基較佳為—個或多如下基ϋ，獨立_***基、 烯基、炔基、域基、烧硫基、燒基胺基 經基、硝基、氰基、環絲、雜魏基、綠、雜芳基、 環烧氧基、轉錄基、環料基、雜奴硫基、幾^、 綾酸或羧酸酯。 95119 22 201235041 “雜環基”錢和或部分殘和 取代基，其包括3至20個環原子，其中一個或;二子 選自氮、氧或_其中n是 ：為原子 ^ if- η π Λ 至2)的雜原子，作不 =二 S，部分，其餘環原子為碳:: ί=12個環原子，其中…個是雜原子，更較: 1G個環原子。單環環燒基的非限制性實 施例包含吡咯烷基、哌啶基、哌 、"只 基、高娘嗪基等。多環環燒基包括二、:硫代嗎琳 環基。“螺雜環基，，指5至20員括!，、_和橋環的雜 (稱螺原子）的多 貝’㈣之間共用-個原子 备〜 基團’其中一個或多個環々子撰白 :為，或賴其中?是整數〇至2)的雜原子，其= 子為奴。這些Μ含有― 、衣原 有完全共轆的"子系統雙鍵=有7環具 分為單螺雜環基、雙螺雜产其=原子的數目將螺環燒基 環烷基和㈣環燒基 f㈣為早螺 員員或5=為 限制性實施例包含 ”衣说基。螺％烧基的非 kThe heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently - a pyridyl group, an alkenyl group, an alkynyl group, a domain group, a sulfur-burning group. , an alkylamino group, a nitro group, a cyano group, a cyclofilament, a heteroweiyl group, a green group, a heteroaryl group, a cycloalkyloxy group, a transcribed group, a cyclic group, a sulfonyl group, a hydrazine group, a decanoic acid or Carboxylic acid ester. 95119 22 201235041 "Heterocyclyl" money and or partial residues and substituents, which include 3 to 20 ring atoms, one of which is or two, selected from nitrogen, oxygen or _ where n is: is an atom ^ if- η π Λ To 2) heteroatoms, not = two S, part, the remaining ring atoms are carbon:: ί = 12 ring atoms, of which ... are heteroatoms, more: 1G ring atoms. Non-limiting examples of monocyclic cycloalkyl groups include pyrrolidinyl, piperidinyl, piperid, " benzyl, oxazinyl and the like. The polycyclic cycloalkyl group includes two: a thiomorphin ring group. "Spiroheterocyclyl, meaning 5 to 20 members of the group!,, _ and the bridged ring (called a spiro atom) of the dopa' (four) share - an atomic preparation ~ group 'one or more of the ring 々 Sub-writing: Is it, or depends on it? It is an integer 〇 to 2) of a hetero atom, and its = sub is a slave. These Μ contain ―, the original is completely shared 子***; subsystem double key = 7 ring Divided into a monospiroheterocyclic group, a double spiro heterogeneously produced = the number of atoms will be a spirocycloalkylcycloalkyl group and (iv) a cycloalkyl group f (d) is an early screwer or 5 = as a limiting example comprises a "clothing base." Non-k of snail

οο

Ο •ΝΟ •Ν

-ν\ Ο- « Η ° “稠雜環基”指5 5 9Λ 3 β 他環共用晚鄰的—對原子員二统中的每個環與體系中的 可以含有-個或多個:: 環基團，一個或多個: 戈夕個雙鍵，但沒有—個環具有完全共輕 95119 23 201235041 =子t统’其中一個或多個環原子選自氮、氧或s(〇)p 為、6^ΐΓ^數G至2)的雜原子’其餘環原子為碳。較佳P 為6至14員，更較佳為7 狄罕乂住 以分為雙環、三環、四環^ ^㈣Μ環的數目可 或三環，更較佳為觀基，較佳為雙環 雜環基的非限難實Lt 員雙環稠雜環基。稠-ν\ Ο- « Η ° "Heteroheterocyclic" means 5 5 9 Λ 3 β The other ring shares the neighbors - each ring in the atomic system and the system may contain - or more:: a ring group, one or more: a double bond, but not a ring having a total total light 95119 23 201235041 = sub-t' wherein one or more of the ring atoms are selected from nitrogen, oxygen or s(〇)p For the hetero atom of 6 to G^ to G), the remaining ring atoms are carbon. Preferably, P is from 6 to 14 members, more preferably 7 Dijon is divided into bicyclic, tricyclic, and tetracyclic rings. The number of the anthracene rings may be three or more, more preferably a viewing group, preferably a bicyclic ring. A non-limiting, hard-acting Lt-membered bicyclic fused heterocyclic group of a heterocyclic group. thick

NN

橋雜％_基”指^ 連接的原子的Ρ㈣個環共用兩個不直接 鍵’作沒右衣基團’這些可以含有一個或多個雙 或多個2 具有完全聽的^電子⑽，其中一個 的雜為:、子選自氮、氧或S(〇)P(其中ρ是整數0至2) 7至10 Μ，。其餘環原子為碳。較佳為6至14員，更較佳為 二環 7至1 〇員。根據組成環的數目可以分為雙環、 更右、s四環或多環橋環烷基，較佳為雙環、三環或四環， 、、為雙％或二環。橋環院基的非限制性實施例包含：Bridge %_基" means that the 连接 (four) rings of the connected atoms share two non-direct bonds 'for the right-hand group' which may contain one or more double or more 2 with a fully audible electron (10), wherein One of the impurities: the sub-selection is selected from nitrogen, oxygen or S(〇)P (where ρ is an integer of 0 to 2) 7 to 10 Μ. The remaining ring atoms are carbon. Preferably, 6 to 14 members, more preferably It is a two-ring 7 to 1 member. It can be divided into bicyclic, more right, s-tetracyclic or polycyclic bridged cycloalkyl groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, and is double % or A second ring. A non-limiting embodiment of a bridge ring base includes:

% Λ孑 >Cw% Λ孑 >Cw

述雜％基環可以稠合於芳基、雜芳基或環烧基環上，其 95119 24 201235041 起的環為雜環基，非限制性實施例 -中與母體結構連接在一 包含The heterocyclic ring may be fused to an aryl, heteroaryl or cycloalkyl ring, the ring of 95119 24 201235041 being a heterocyclic group, in a non-limiting embodiment - linked to the parent structure

等。雜環基可以3带 、 和S / 取代基較佳為一 未取代的’當被取代時 烯 m 環 羧 其 乙 取代基較佳為一個或;禾取代的’當被取+ 基、炔爲^ &個下基團，獨立地選***基 、土 燒軋基、烷硫基、浐其茸 ^ * 基、硝基μ 自素、硫醇 烧氧基、雜Γ 環烧基、芳基、雜芳基 酸錢酸醋Γ 環烧硫基、雜環烧硫基、幾基 中狀^(絲）和令（未取代的環烧基） 中：基的，義如上所述。非限制性實施例包含甲氧基、乙 氧基、丙氧基、丁氧美王 淨Pirn 减、環了氧基、環戍氧基、 <、土#。絲基可以是視需要取代的或未取代的，當 代時’取代基較佳為—個或多個以下基團，獨立地選 i為烧基、烯基、快基、烧氧基、烧硫基、烧基胺基、函 素、硫醇、絲、石肖基、氰基、魏基、雜雜基、芳基、 雜方基、環烧氧基、雜環燒氧基、魏硫基、雜環烧硫基、 羰基、羧酸或羧酸酯。“羥基，，指_0H基團。 減基”指i基-0H’其中絲定義如上所述。 函素”指敦、氯、漠或硬，較佳為氧或氯。 罗炭基”指-C(=0)-。 确基指-N〇2。 氰基指-CN。 95119 25 201235041 胺基”指-nh2。 羧酸指-C(=〇)〇{}。 羧酸酯，，指~C〇0)0烷基。 視需要 ,,,,s 或“視需要地”意味著隨後所描述地事 :或壤境可則料必發生，該說明包括該事件或環境發生 7，生地場合°例如，“視需要被絲取代_環基團” :未著烧基可以但不必須存在，該說明包括雜環基團被烧 土取代的情形和雜環基團不被烧基取代的情形。 醫藥組成物”表示含有一種或多種本文所述化合 物或其生理學上/可藥用的鹽或前體藥物與其他化學組分 的混合物，以及其他組分例如生理學/可藥用的载體和賦形 劑。醫藥組成物的目的是促進對生物體的給藥，利於活性 成分的吸收進而發揮生物活性。 、 (本發明化合物的合成方法） 為了完成本發明的目的，本發明採用如下技術方案 本發明通式（I)化合物或其可藥用的鹽的製備方法， 包括以下步驟：Wait. The heterocyclic group may have 3 bands, and the S / substituent is preferably an unsubstituted 'when substituted, the ene m ring carboxy group has an ethyl substituent preferably one or a; the substituted 'when taken + base, the alkyne is ^ & lower group, independently selected from the group consisting of a burnt base, a soil-rolled base, an alkylthio group, a ruthenium group, a nitro group, a thiol alkoxy group, a heterocyclic ring group, and a aryl group. Base, heteroaryl acid vinegar oxime Cyclo thiol group, heterocyclic thiol group, several groups in the form of ^ (filament) and (unsubstituted cycloalkyl) in the base: meaning as described above. Non-limiting examples include methoxy, ethoxy, propoxy, butoxyxan, net Pirn minus, cyclooxy, cyclodecyloxy, <, earth#. The silk group may be optionally substituted or unsubstituted. In the contemporary case, the substituent is preferably one or more of the following groups, and independently selected as a group, an alkyl group, an alkenyl group, a fast group, an alkoxy group, and a sulfur-burning group. Base, alkylamino group, hydroxyl, thiol, silk, schiffyl, cyano, weigen, hetero, aryl, heteroaryl, cycloalkoxy, heterocyclic alkoxy, thiol, hetero A ring-burning thio group, a carbonyl group, a carboxylic acid or a carboxylic acid ester. "Hydroxy," means a group of -0H. Subunits refer to i groups - 0H' wherein the filaments are as defined above. The term "character" means Dun, chlorine, desert or hard, preferably oxygen or chlorine. Rotam-based means -C(=0)-. It is true that -N〇2. Cyano refers to -CN. 95119 25 201235041 Amino" means -nh2. Carboxylic acid means -C(=〇)〇{}. Carboxylic acid ester, means ~C〇0)0 alkyl. Depending on the need,,,, s or "optionally "means that the following describes: or the soil may have occurred, the description includes the occurrence of the event or the environment. 7, the place of the habitat. For example, "replace the _ ring group as needed": no base can be burned However, it does not have to be present, and the description includes the case where the heterocyclic group is substituted by the burnt earth and the case where the heterocyclic group is not substituted by the alkyl group. "Pharmaceutical composition" means containing one or more of the compounds described herein or physiologically / A pharmaceutically acceptable salt or mixture of prodrugs with other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration of the organism, and to facilitate the absorption of the active ingredient to exert biological activity. (Synthesis method of the compound of the present invention) In order to accomplish the object of the present invention, the present invention adopts the following technical scheme. The preparation method of the compound of the formula (I) of the present invention or a pharmaceutically acceptable salt thereof comprises the following steps:

在縮合試劑存在的條件下，將通式（v_n化合物與鱗 95119 26 201235041 酸二乙酯基乙酸反應製備通式（v)化合物；乾冰浴冷卻下， 通式（V)化合物與雙三曱基矽基胺基鋰反應’反應液升至室 溫與通式（VI)化合物發生Wittig反應得到通式（I)化合 物； 其中：基團A’B，n和R1至R9的定義如通式（I)中所 述0 本發明通式（IIA)或（IIB)化合物或其可藥用的鹽的 製備方法，包括以下步驟：The compound of the formula (v) is prepared by reacting a compound of the formula (v_n with scaly 95119 26 201235041 diethyl acetate) in the presence of a condensing reagent; the compound of the formula (V) and the bis-indenyl group are cooled under a dry ice bath. The mercaptoamine lithium reaction' reaction solution is raised to room temperature and Wittig reaction with a compound of the formula (VI) gives a compound of the formula (I); wherein: the groups A'B, n and R1 to R9 are as defined in the formula ( The process for the preparation of the compound of the formula (IIA) or (IIB) of the present invention or a pharmaceutically acceptable salt thereof, comprising the following steps:

乾冰浴冷卻下，通式（V)化合物與雙三甲基矽基胺基 鋰反應，反應液升至室溫與通式（VIA)化合物發生Wittig 反應得到通式（IIA)化合物；或者，The compound of the formula (V) is reacted with lithium bistrimethylguanidinoamine under cooling in a dry ice bath, and the reaction solution is allowed to rise to room temperature to undergo Wittig reaction with the compound of the formula (VIA) to obtain a compound of the formula (IIA);

(ΠΒ) 乾冰浴冷卻下，通式（V)化合物與雙三甲基矽基胺基 鋰反應，反應液升至室溫與通式（VIB)化合物發生Wittig 反應得到通式（IIB)化合物； 其中··基團A’ n’ R1至R9的定義如通式（πα)或（IIB) 中所述。 【實施方式】 27 95119 201235041 以下結合實施例用於進一步描述本發明，但這些實施 例並非限制著本發明的範圍。 (實施例） 化合物的結構是經由核磁共振（ijj N服）和/或質譜（MS) 來確疋的。HNMR位移（δ)以百萬分之一（ppm)的單位給出。 MR的測定是用Bruker AVANCE-400核磁儀，測定溶劑 為氛代甲醇（CD·)、氘代氣仿（cdc13)，六氘代二曱基亞 颯（腦⑹’内標為四甲基矽烧（TMS)。 MS的測定用finnIGAN LCQAd (ESI)質譜儀（生產商： Thermo,型號：Finnigan LCQ advantage MAX)。 HPLC的測定使用安捷倫1200DAD高壓液相色譜儀 (Sunf ire C18 150x4. 6mm 色譜柱）和 Waters 2695-2996 高 壓液相色譜儀（Gimini C18 150x4. 6mm色譜柱）。 1C5。值的測定用NovoStar酶標儀（德國BMG公司）。 薄層層析矽膠板使用煙臺黃海HSGF254或青島GF254 矽膠板，薄層色譜法（TLC)使用的矽膠板採用的規格是 0. 15 ram至0. 2 mm，薄層層析分離純化產品採用的規格是 0. 4 mm 至 0. 5 _ ° 矽膠柱一般使用煙臺黃海矽膠200至300目矽膠為載 體。 鹼性氧化鋁柱一般使用國藥層析用FCP200至300目 鹼性氧化鋁為載體。 本發明的已知的起始原料可以採用或按照本領域已 知的方法來合成，或可以於ABCR GmbH & Co. KG，Acros 95119 28 201235041(ΠΒ) reacting a compound of the general formula (V) with lithium bistrimethylguanidinoamine under cooling in a dry ice bath, and reacting the reaction solution to room temperature to form a Wittig reaction with a compound of the formula (VIB) to obtain a compound of the formula (IIB); Wherein the group A' n' R1 to R9 are as defined in the formula (πα) or (IIB). [Embodiment] 27 95119 201235041 The following examples are provided to further describe the present invention, but these examples are not intended to limit the scope of the present invention. (Example) The structure of the compound was confirmed by nuclear magnetic resonance (ijj N) and/or mass spectrometry (MS). The HNMR shift (δ) is given in parts per million (ppm). The MR was measured by a Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was determined to be methanol (CD·), deuterated gas (cdc13), and hexamethylenediamine (brain (6)' internal standard was tetramethylguanidine. Burning (TMS). The MS was measured using a finnIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX). The HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunf ire C18 150 x 4. 6 mm column). And Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150x4. 6mm column). 1C5. The value is determined by NovoStar microplate reader (BMG, Germany). Thin layer chromatography tantalum sheet using Yantai Yellow Sea HSGF254 or Qingdao GF254 _ _ 矽 矽 矽 矽 矽 矽 矽 矽 矽 矽 矽 矽 矽 矽 矽 矽 矽 矽 矽 矽 矽 矽 矽 矽 矽 矽 矽 矽 矽 矽 矽 矽 矽 矽 矽 矽 矽 矽 矽 矽 矽 矽 矽 矽 矽 矽 矽 矽The column generally uses Yantai Huanghai Silicone 200 to 300 mesh silicone as a carrier. The basic alumina column generally uses FCP 200 to 300 mesh basic alumina as a carrier. The known starting materials of the present invention may be used or according to the present invention. Methods known in the art to synthesize Or at ABCR GmbH & Co. KG, Acros 95119 28 201235041

Organics，Aldrich Chemical Company ’ 韶遠化學科技 (Accela ChemBio Inc)和達瑞化學品等公司處購買。 實施例中無特殊說明，反應均在氮氣或氬氣氛圍下進 行。 氬氣氛或氣氛是指反應瓶連接一個約1 l容積 氣或氮氣氣球。 氫氣氛是指反應瓶連接一個約1 L容積的氫氣氣球^ 加壓氫化反應使用Parr 3916EKX型氫化儀和清藍 QL-500型氫氣發生器或HC2-SS型氫化儀。 虱化反應通常抽真空，充入氫氣，反複操作3次。 實施例中無特殊說明，溶液是指水溶液。 實施例中無特殊說明，反應的溫度為室溫。 室溫為最適宜的反應溫度，為2〇艺至3〇〇c。 實施例中的反應進㈣監測採用薄層色譜法（TLc)， 反應所使用的展關的體系有：二氯曱院和甲醇體系，正 己烷和乙酸乙醋體系，石油醚和乙酸乙酉旨體系，丙酮，溶 劑的體積比根據化合物的極性不同而進行調節。 純化化合物採用的柱層析的洗脫劑的體系和薄層色 譜法的展開劑的«包括：A:二氯代和曱醇體系，B: 正己烧和乙酸乙酿體系，c:二氯甲院和丙喊系，溶劑的 體積比根據化合物的極性不同而進行調節，也可以加入少 量的三乙胺等驗性或醋酸等酸性試劑進行調節。 實施例1 ⑻-N-[4-[[3-氣-4—(2_対基曱氧基）苯基]胺基]_3_氮 95119 29 201235041 基-7-乙氧基-6-嗜琳基]-3-(^(25^-1-曱基D比嘻烧-2-基]丙 -2-烯醯胺Organics, Aldrich Chemical Company ’ purchased from companies such as Accela ChemBio Inc and Dary Chemical. Unless otherwise stated in the examples, the reactions were all carried out under a nitrogen or argon atmosphere. An argon atmosphere or atmosphere means that the reaction flask is connected to a volume of about 1 l of gas or a nitrogen balloon. The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume. The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenation apparatus and a clear blue QL-500 hydrogen generator or a HC2-SS type hydrogenation apparatus. The deuteration reaction is usually evacuated, charged with hydrogen, and operated three times. Unless otherwise stated in the examples, the solution means an aqueous solution. There is no particular description in the examples, and the reaction temperature is room temperature. Room temperature is the most suitable reaction temperature, from 2 〇 to 3 〇〇c. The reaction in the examples is monitored by thin layer chromatography (TLc). The systems used in the reaction are: dichlorohydrazine and methanol system, n-hexane and ethyl acetate system, petroleum ether and acetic acid. The volume ratio of acetone to solvent is adjusted depending on the polarity of the compound. Purification of the compound using the column chromatography eluent system and the thin layer chromatography of the developing agent «includes: A: dichloro and decyl alcohol system, B: hexane and acetic acid, brewing system, c: dichloro In the hospital and the system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of an acidic reagent such as triethylamine or an acid reagent such as acetic acid may be added for adjustment. Example 1 (8)-N-[4-[[3-Gaxo-4-(2-indolyloxy)phenyl]amino]]_3_nitrogen 95119 29 201235041 -7-ethoxy-6-琳基]-3-(^(25^-1-曱-D-pyrrol-2-yl)prop-2-enylamine

--p--p

第一步 (250-1-甲基吡咯烷-2-甲醛 乾冰浴下將草醯氯（1. 1 mL，13. 02 mmol)溶解於二曱 亞石風（1. 9 mL，26. 04 mmol)中，反應30分鐘，滴加25 mL [(251)-卜甲基吡咯烷-2-基]曱醇la(l g，8·68 mmol)的二 氯曱烷溶液，-30°C繼續攪拌45分鐘，滴加三乙胺（6. 15 g， 60. 77 mmol)，室溫反應12小時。向反應液中加入250 mL 二氯曱烷，依次用飽和碳酸氫鈉溶液（100 mL)，飽和氣化 銨溶液（100 mL)和飽和氯化納溶液洗蘇（100 mL)，有機相 用無水硫酸鈉乾燥，過濾、，減壓濃縮，用驗性氧化I呂柱色 譜法以洗脫劑體系A純化所得殘餘物，得到標題產物 (25)-1-曱基吡咯烷-2-甲醛lb(308 mg，淡黃色液體），產 率：31.4%。 第二步 30 95119 201235041 N-[4-[[3-氯-4-(2-吡啶基甲氧基）苯基]胺基]一3_氰基— 乙氧基-6-喹啉基]-2-磷酸二乙酯-乙醯胺 將N，N，-幾基二口米嗤（487 mg，3min〇1)溶解於4此四 氫吱喃中，油浴升溫至就，向反應液中滴加4乩磷酸 二乙醋基乙酸（588 mg，3 mmol)的四氫咬喃溶液，反應 分鐘備用。 40 C下將6-胺基-4-[ [3-氯-4-(2-吡啶基甲氧基）笨 基]胺基]-7-乙氧基-嗤琳-3-腈lc(446 mg，i _〇1，採用 公知的方法“觀005028443”製備而得）溶解於4虬四氣 吱喃中’滴加上述備用反應液，反應12㈣。反應液減堡 濃縮，用二氯曱烧萃取（50 mLx3)，合併有機相，用飽和氯 化鈉溶液（30 mLx2)洗滌，無水硫酸鈉乾燥，過濾，濾液減 壓濃縮，用矽膠柱色譜法以洗脫劑體系A純化所得殘留/ 物，得到標題產物N-[4-[[3-氣-4-(2-吡啶基曱氧基）苯基] 胺基]-3-氰基-7-乙氧基-6-喧琳基]—2_磷酸二乙酯—乙酿 胺ld(624 mg，淡黃色固體），產率：99. 9%。 MS m/z (ESI): 624 [M+l] 第三步 ⑺-N-[4-[[3-氯-4-(2-口比絲甲氧基）苯基]胺基]_3_氰 基-7-乙氧基-6-喧琳基]-3-[⑽-1-甲基π比略院_2_基]丙 -2-烯醢胺 -78°C下將ΙΗ4-[[3-氣-4-(2i絲甲氧基）苯基] 胺基]-3-氰基-7-乙氧基-6-啥琳基]磷酸二乙醋_乙醯 胺ld(50 mg，0.08 mmol)溶解於2 mL四氫呋喃中，滴加 95119 31 201235041 1 Μ雙二甲基石夕基胺基經的曱苯溶液（go ，0.08 mmol)， 攪拌45分鐘’向反應液中加入（25)-1-甲基-吡咯烷_2一曱 酸lb(20 mg，0. 17 mmol)，繼續攪拌1小時後，室溫反應 12小時。向反應液中加入1 mL水和1 mL甲醇。用二氯甲 烧萃取（50 mLx3)，合併有機相，用飽和氣化鈉溶液洗滌（3〇 mLx2) ’無水硫酸鈉乾燥，過濾，減壓濃縮，用矽膠柱色譜 法以洗脫劑體系A純化所得殘留物，得到標題產物 (β-Ν-[4-[[3-氣-4-(2-吡啶基曱氧基）苯基]胺基]-3-氰 基-7-乙氧基-6-喹啉基]-3-[(25·)-1-甲基吡咯烷-2-基]丙 -2-烯醯胺1 (25 mg，黃色固體），產率：53. 5%。 MS m/z (ESI)： 583 [M+l] NMR (400 MHz, DMSO-^): 5 9.63 (s, 2H), 8.95 (s, 1H), 8.60 (d, 1H), 8.48 (s, 1H), 7.89 (t, 1H), 7.59 (d, 1H), 7.37 (in, 3H), 7.27-7.20 (m, 2H), 6.80-6.60 (m, 2H), 5.29 (s, 2H), 4.34 (dd, 2H), 2.33-2.24 (in, 3H), 2.23-2.15 (m, 2H), 1.99-1.88 (m, 3H), 1.80-1.78 (in, 2H), 1.49 (t, 3H) 實施例2 (幻-N-[4-[[3-氯-4-(2-吡啶基甲氧基）苯基]胺基]-3-氰 基一乙氧基-6-啥琳基]-3-[(25*)_π比洛烧-2-基]丙-2-稀 醯胺 32 95119 201235041The first step (250-1-methylpyrrolidine-2-carboxaldehyde in a dry ice bath, the grass chloroform (1.1 mL, 13.2 mmol) was dissolved in the diterpene stone (1.9 mL, 26.04 In mmol), the reaction was carried out for 30 minutes, and 25 mL of [(251)-po-methylpyrrolidin-2-yl]nonanol la (lg, 8.68 mmol) in dichloromethane was added dropwise, and stirring was continued at -30 °C. In a minute, triethylamine (6. 15 g, 60.77 mmol) was added dropwise, and the reaction was carried out for 12 hours at room temperature. 250 mL of dichloromethane was added to the reaction mixture, followed by saturated sodium bicarbonate solution (100 mL). Gasification of ammonium solution (100 mL) and saturated sodium chloride solution (100 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, using an oxidative Ilu column chromatography to eluent system The residue obtained was purified to give the title product (25)-l- ylpyrrolidine-2-carbaldehyde lb (308 mg, pale yellow liquid), yield: 31.4%. Step 2 30 95119 201235041 N-[4- [[3-Chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-ethoxy-6-quinolinyl]-2-phosphate diethyl ester-acetamide Dissolve N, N, - a few bases of rice bran (487 mg, 3 min 〇 1) in 4 tetrahydrofuran, oil bath To the temperature of the reaction, a solution of 4 乩 diacetic acid diacetate (588 mg, 3 mmol) in tetrahydrogenate was added dropwise, and the reaction was taken for a minute. 6-amino-4-[[3] -Chloro-4-(2-pyridylmethoxy)phenyl]amino]-7-ethoxy-indolyl-3-carbonitrile lc (446 mg, i _〇1, using a known method "view 005028443 "Prepared by preparation" dissolved in 4 虬 four gas 吱 ' 'Drip the above alternate reaction solution, reaction 12 (four). The reaction solution is reduced by concentration, extracted with dichlorohydrazine (50 mL x 3), the organic phase is combined, saturated with chlorination The sodium solution (30 mL×2) was washed with anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure, and the residue obtained was purified by eluent column chromatography to afford the title product N-[4-[[3- -4-(2-Pyridinyloxy)phenyl]amino]-3-cyano-7-ethoxy-6-mercapto]-2-diphosphate-ethylamine ld (624 Mg, light yellow solid), Yield: 99.9% MS m/z (ESI): 624 [M+l] Step 3 (7)-N-[4-[[3-chloro-4-(2- Oral methoxy)phenyl]amino]_3_cyano-7-ethoxy-6-indolyl]-3-[(10)-1-methyl π 略 院_2_基] -2-eneamine -78 ° C 4-[[3-Ga-4-(2i-silyloxy)phenyl]amino]]-3-cyano-7-ethoxy-6-indolyl]phosphoric acid diethyl acetoacetate (50 mg, 0.08 mmol) was dissolved in 2 mL of tetrahydrofuran, and 95119 31 201235041 1 Μ bis dimethyl fluorenyl hydrazine solution (go, 0.08 mmol) was added dropwise and stirred for 45 minutes. (25)-1-Methyl-pyrrolidine-2-monodecanoic acid lb (20 mg, 0.17 mmol) was added, and stirring was continued for 1 hour, and then allowed to react at room temperature for 12 hours. 1 mL of water and 1 mL of methanol were added to the reaction solution. Extracted with methylene chloride (50 mL×3), combined with organic phase, washed with saturated sodium carbonate solution (3 〇mL×2) dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, eluent column chromatography using eluent column chromatography The obtained residue was purified to give the title product (?-?-[4-[[3- -4-(2-pyridinyloxy)phenyl]amino]-3-cyano-7-ethoxy -6-quinolinyl]-3-[(25.)-1-methylpyrrolidin-2-yl]prop-2-enylamine 1 (25 mg, yellow solid), yield: 53. 5% MS m/z (ESI): 583 [M+l] NMR (400 MHz, DMSO-^): 5 9.63 (s, 2H), 8.95 (s, 1H), 8.60 (d, 1H), 8.48 (s , 1H), 7.89 (t, 1H), 7.59 (d, 1H), 7.37 (in, 3H), 7.27-7.20 (m, 2H), 6.80-6.60 (m, 2H), 5.29 (s, 2H), 4.34 (dd, 2H), 2.33-2.24 (in, 3H), 2.23-2.15 (m, 2H), 1.99-1.88 (m, 3H), 1.80-1.78 (in, 2H), 1.49 (t, 3H) Example 2 (Phantom-N-[4-[[3-chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-ethoxy-6-indolyl]- 3-[(25*)_πpyroxy-2-yl]propan-2-phosphamide 32 95119 201235041

22

第一步 (250-2-(羥曱基）吡咯烧-1—羧酸叔丁酯 冰洛下將[(251)-。比洛院-2-基]曱醇2a(5. 06 g ’ 〇. 〇5 mmol)和三乙胺（ίο. 12 g ’ 〇. mmol)溶解於100社二氣 曱烷中，分批加入二碳酸二叔丁基酯（16.37 g，0.08 ❺ mm〇l)，室溫反應12小時。反應液減壓濃縮，用乙酸乙酯 (50 mLx3)萃取，合併有機相’用飽和氯化鈉溶液洗滌（3〇 mLx2)，無水硫酸鈉乾燥，過濾，濾液減壓濃縮，得到標題 產物（260-2-(羥曱基）吡咯烷-1-羧酸叔丁酯2b(l〇 g，淡 黃色液體），產率：99. 9%。 第二步 (250-2-曱醯基吡咯烷-1-羧酸叔丁酯 乾冰洛下將草醯氣（3· 2 mL，0. 04 mo 1)和二曱亞石風 (4. 3 mL，〇.〇6 m〇l)溶解於100虬二氯曱烷中，反應30 33 95119 201235041 分鐘，滴加20 mL (250-2-(羥曱基）吡咯烷_丨_羧酸叔丁酯 2b(2 g，0· 01 m〇i)的二氣甲烷溶液，繼續攪拌45分鐘， 滴加三乙胺（7. 〇8g，0.07mol)，攪拌反應j小時。向 反應液中加入500 mL二氯曱烷，有機相用飽和氣化鈉溶液 洗滌（100 mLx2)，無水硫酸鈉乾燥，過濾，濾液減壓濃縮， 用矽膠柱色譜法以洗脫劑體系A純化所得殘餘物，得到標 題產物（2^)-2-甲醯基吨洛院-1-致酸叔丁酯2c(i 1〇 g 淡黃色液體），產率：55. 4%。 第三步 (2«-2-[(幻-3-[[4-[[3-氣-4-(2-咐•啶基ψ氧基）苯基]胺 基]-3-氰基-7-乙氧基-6-喹啉基]胺基]-3-氧代—丙-卜烯 基]吡咯烷-1-羧酸叔丁酯 乾冰浴下將N-[4-[ [3-氯-4-(2-吼°定基甲氧基）笨灵]胺 基]-3-氰基-7-乙氧基-6-喹啉基]-2-磷酸二乙酯、乙酿胺 Id (156 mg ’ 〇. 25 mmol)溶解於3 mL四氫σ夫喃中，滴加1 Μ雙三曱基矽基胺基鋰的曱苯溶液（375;tzL，0.38 mmc)1)， 攪拌反應45分鐘，向反應液中加入2 mL (25·)~2〜甲醯美 吡咯烷-1-羧酸叔丁酯2c(l〇〇 mg，〇·50 mmol)的四氫咬^南 溶液，反應1小時，室溫繼續反應12小時。反應液減壓噥 縮，用矽膠柱色譜法以洗脫劑體系A純化所得殘餘物，尸 到心通產物（251)-2-[(五)-3-[[4-[[3-氣-4-(2~1»比交式甲氧 基）笨基]胺基]-3-氰基-7-乙氧基-6-啥淋基]胺基]氧 代-丙-1-烯基]吡咯烷-丨―羧酸叔丁酯2d(161 mg，淡t 固體）’產率：96. 2%。 汽 95119 34 201235041 MS m/z (ESI): 669 [M+l] 第四步 (幻邛-[4-[[3-氯-4-(2-n比啶基曱氧基）苯基]胺基]-3一氰 基-7-乙氧基-6-喹啉基]-3-[(251)-吡咯烷-2-基]丙-2-烯 醯胺 將（2v9)-2-[(〇-3-[ [4-[ [3-氯-4-(2-0比0定基曱氧基） 苯基]胺基]-3-氰基-7-乙氧基-6-啥琳基]胺基]-3-氧代-丙-卜烯基]吡咯烷-1-羧酸叔丁酯2d( 161 mg，0. 24 mmol) 胃溶解於25 mL 2M1, 4-二氧六環的氯化氫溶液中，反應12 小時。反應液減壓濃縮，用二氣甲烷萃取（5〇 mLx3)，合併 有機相’用飽和氣化鈉溶液洗務（30 mLx2)，無水硫酸鈉乾 燥’過濾，濾液減壓濃縮’用矽膠柱色譜法以洗脫劑體系 A純化所得殘餘物’得到標題產物（幻_N_ [4_ [ [ 3_氯_4_(2_ °比啶基甲氧基）苯基]胺基]-3-氰基-7-乙氧基-6-喹啉 基]-3-[(25*)-吡咯烷-2-基]丙-2-烯醯胺2(20 mg，黃色 鲁固體），產率：14. 6%。 MS m/z (ESI): 569.4 [M+l] 'H NMR (400M Hz, DMSO-^)： (5 1〇.〇l(s, 1H), 9.76 (s, 1H), 9.71 (s, 2H), 9.40 (s, 1H), 8. 92 (s, 1H), 8. 61(s, 1H), 8.60 (s, 1H), 7.90 (t, 1H), 7.60 (d, 1H), 7.58-7.41 (s, 2H), 7.39-7.38 (m, 2H), 6.95 (dd, 1H), 6.79 (d, 1H), 5. 29 (s, 1H), 4. 35 (t, 2H), 4. 21-4. 20 (in, 1H), 3.23-3.22 (m, 3H), 2.21-2.20 (m, 1H), 2.039-1.94 (m, ΪΗ), 1.84-1.76 (m, 1H),1.49 (t, 3H) 35 95119 201235041 實施例3 (-N-[4-[ [3-氯-4-(2-0比0定曱氧基）苯基]胺基]-3-氰基 -7-乙氧基-6-喹啉基]-3-[(25；4>?)-4-羥基-1-曱基-吡咯 烧_2_基]丙_2-稀酿胺The first step (250-2-(hydroxyindenyl)pyrrole-1-carboxylic acid tert-butyl ester ice-cold [(251)-. Biloin-2-yl]sterol 2a (5. 06 g ' 〇. 5 mmol) and triethylamine (ίο. 12 g '〇. mmol) were dissolved in 100 dioxane, and di-tert-butyl dicarbonate (16.37 g, 0.08 ❺ mm〇l) was added in portions. The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was evaporated, evaporated, evaporated,jjjjjjjjjjjjjjjj The title product (260-2-(hydroxyindenyl)pyrrolidine-1-carboxylic acid tert-butyl ester 2b (1 g, pale yellow liquid), yield: 99.9%. 2-mercaptopyrrolidine-1-carboxylic acid tert-butyl ester dry ice under the grass 醯 gas (3 · 2 mL, 0. 04 mo 1) and diterpenoid stone (4.3 mL, 〇.〇6 M〇l) dissolved in 100 虬 dichloromethane, reaction 30 33 95119 201235041 minutes, dropwise addition of 20 mL (250-2-(hydroxyindole) pyrrolidine 丨 丨 carboxylic acid tert-butyl ester 2b (2 g, 0· 01 m〇i) of the two-gas methane solution, stirring was continued for 45 minutes, triethylamine (7. 〇8g, 0.07 mol) was added dropwise, and the reaction was stirred. 500 mL of dichloromethane was added to the reaction solution, and the organic phase was washed with saturated sodium carbonate solution (100 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. A. The residue obtained was purified to give the titled product (2^)-2-carbazol-t-l-l-l-l-acid tert-butyl ester 2c (i 1 〇g pale yellow liquid), yield: 55.4%. Three steps (2«-2-[(幻-3-[[4-[[3- gas-4-(2-咐•pyridyloxy)phenyl]amino]-3-cyano-7 -ethoxy-6-quinolinyl]amino]-3-oxo-prop-enyl]pyrrolidine-1-carboxylic acid tert-butyl ester N-[4-[[3-chloro] -4-(2-吼°-based methoxy) stupid]amino]-3-cyano-7-ethoxy-6-quinolinyl]-2-phosphate diethyl ester, ethanoamine Id ( 156 mg ' 〇. 25 mmol) was dissolved in 3 mL of tetrahydro-sulphur, and a solution of 1 Μ bis-trimethyl decylamino lithium in benzene (375; tzL, 0.38 mm)) was added dropwise. In a minute, add 2 mL of (25·)~2~methionine pyrrolidine-1-carboxylic acid tert-butyl ester 2c (l〇〇mg, 〇·50 mmol) to the tetrahydrogenate solution. The reaction was continued for 12 hours at room temperature for 1 hour. The mixture was decompressed under reduced pressure, and the obtained residue was purified by eluent column chromatography using eluent column chromatography. The physic product (251)-2-[(5)-3-[[4-[[3-gas-4] -(2~1» than methoxy)phenyl]amino]-3-cyano-7-ethoxy-6-indole]amino]oxo-prop-1-enyl] 2%。 Pyrrolidine-hydrazine-tert-butyl carboxylic acid 2d (161 mg, light t solid) yield: 96.2%. Vapor 95119 34 201235041 MS m/z (ESI): 669 [M+l] Step 4 (Fantasy-[4-[[3-chloro-4-(2-n-pyridyloxy)phenyl]] Amino]-3-cyano-7-ethoxy-6-quinolinyl]-3-[(251)-pyrrolidin-2-yl]prop-2-enylamine (2v9)-2- [(〇-3-[[4-[[3-chloro-4-(2-0)0-decyloxy)phenyl]amino]-3-cyano-7-ethoxy-6-oxime琳基]amino]-3-oxo-prop-enyl]pyrrolidine-1-carboxylic acid tert-butyl ester 2d (161 mg, 0.24 mmol) stomach dissolved in 25 mL 2M1, 4-dioxane The reaction was carried out for 12 hours in a hydrogen chloride solution of the ring. The reaction mixture was concentrated under reduced pressure and extracted with methylene chloride (5 〇mL×3). The organic phase was combined and washed with saturated sodium carbonate solution (30 mL×2), dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure. The residue obtained was purified by eluent column chromatography eluting with eluent system A to give the title product (Fantasy_N_[4_[[3_chloro_4_(2_~pyridylmethoxy)phenyl) Amino]-3-cyano-7-ethoxy-6-quinolinyl]-3-[(25*)-pyrrolidin-2-yl]prop-2-enylamine 2 (20 mg, Yellow Lu solid), Yield: 14.6% MS m/z (ESI): 569.4 [M+l] 'H NMR (400M Hz, DMSO-^): (5 1 〇.〇l(s, 1H ) , 9.76 (s, 1H), 9.71 (s, 2H), 9.40 (s, 1H), 8. 92 (s, 1H), 8. 61(s, 1H), 8.60 (s, 1H), 7.90 (t , 1H), 7.60 (d, 1H), 7.58-7.41 (s, 2H), 7.39-7.38 (m, 2H), 6.95 (dd, 1H), 6.79 (d, 1H), 5. 29 (s, 1H ), 4. 35 (t, 2H), 4. 21-4. 20 (in, 1H), 3.23-3.22 (m, 3H), 2.21-2.20 (m, 1H), 2.039-1.94 (m, ΪΗ) , 1.84-1.76 (m, 1H), 1.49 (t, 3H) 35 95119 201235041 Example 3 (-N-[4-[[3-chloro-4-(2-0) decyloxy)phenyl) Amino]-3-cyano-7-ethoxy-6-quinolinyl]-3-[(25;4>?)-4-hydroxy-1-indolyl-pyrrole_2_yl] C-_2-thin amine

第一步 (么S；從)-4-羥基-1-曱基-吡咯烷-2-羧酸曱酯 冰浴下將（25"，4友)-4-經基_°比p各烧_2-叛酸曱酉旨3a (5. 53 g，38 mmol)溶解於80 mL曱醇中，加入40%曱酸溶 液（31 mL，380 mmo 1)，緩慢分批加入氰基棚氫化納（12 g， 190 mmol)，攪拌反應0. 5小時，室溫繼續攪拌3小時。加 入40mL水淬滅反應，減壓濃縮，用二氯甲烷萃取（80 mLx3)，合併有機相，用飽和氯化納溶液洗蘇（30 mLx2)， 無水硫酸納乾燥，過濾，減壓濃縮，得到標題產物 (么S；狀)-4-羥基-1-曱基-吡咯烷-2-羧酸曱酯3b(粗品，無 36 95119 201235041 .色油狀物），直接用。 第二步 . ⑽肩—4_(叔丁基（二甲基）石夕基）氧基+甲基』比洛烷 - 羧酸曱酯 ㈣腿⑷溶解於咖此二氣甲烧^依次加入^以⑽ g ’ 113動1)和二甲基叔丁基氣石夕烧（6.80 g，45 mmol)， 反應12小時。用loo虬二氯曱烧稀釋反應液，依次用水 (50mL) ’飽和氣化鈉溶液洗滌（5〇mL)，無水硫酸鈉乾燥， 過渡，減壓濃縮’用石夕膠柱色譜法以洗脫劑體系A純化所 得殘餘物，得到標題產物（25；獨-4-(叔丁基（二甲基）石夕基) 氧基-1-曱基-吼洛燒〜2,酸曱醋3c(粗品，無色油狀物）， 產物不經純化直接進行下一步反應。 MS m/z (ESI): 274[M+l] 第三步 • [(2$4灼_4_(叔丁基（二曱基）矽基）氧基曱基-吡咯烷 ~2-基]甲醇 冰浴下將（25；4灼~4~(叔丁基（二曱基）矽基）氧基 甲基-吼咯烧-2-魏甲酉旨3c (2 5〇 g，91〇 _υ溶解於 50 inL二氣甲烧中，緩慢滴加二異丁基氫化叙（18虬，^、 nmol) ’反應6小時。加入j虬甲醇淬滅反應，用2〇〇虮 二氣曱烧稀釋反應液，再向其中加入無水硫酸納擾掉如 分鐘，過濾，濾液減壓濃縮，用鹼性氧化鋁柱色譜法以洗 脫劑體系A純化所得殘餘物，得到標題產物[(2又4斤 95119 37 201235041 (叔丁基（二曱基）石夕基）氧基-1-甲基比IT各院-2-基]甲醇 3d (570 mg ’黃色油狀物），產率：50. 〇%。 MS m/z (ESI)： 246 [M+l] 第四步 (2&47P)-4-(叔丁基（二甲基）矽基）氧基一卜甲基-n比咯院 -2-曱醛 乾冰浴下將二甲亞颯（174// L ’ 2. 45 mmol)溶解於2〇 mL二氯甲烧中’待體系溫度穩定後，缓慢滴加草醯氯（156 //L，1. 80 mmol)，反應 30 分鐘，滴加 2 mL [(25； 4)?)-4-(叔 _ 丁基（二曱基）石夕基）氧基-卜曱基-吡咯烧-2-基]甲醇3d (300 mg，1. 20 mm〇i)的二氣曱烷溶液，反應45分鐘，加 入二乙胺（510 ，3. 67 mmol)，繼續攪拌反應1〇分鐘， 至溫反應1小時，用100 mL二氯甲烷稀釋反應液，依次用 飽和碳酸氫鈉溶液（2〇 mL)，飽和氯化銨（2〇 mL)，飽和氯 化鈉溶液洗滌（2〇虬），無水硫酸鈉乾燥，過濾，減壓濃縮， 得到標題產物（25； 4灼-4-(叔丁基（二甲基）矽基）氧基_丨_ 曱基^比咯燒(320 mg，黃色油狀物），粗品直· 接下一步反應。 第五步 ⑺-3-[(25；切+(叔丁基（二甲基）石夕基）氧基_卜甲基一 轉烧-2-基]|[4_[[3_氯_4_(2ι絲甲氧基）苯基]胺 基]I氣基-7-乙氧基-6-嗤咐基]丙_2_烯醯胺 乾冰岭下將絲曱氧基）苯基] 胺基]I氛基乙氧基+㈣基]—2_鱗酸二乙酉旨-乙醯 95119 38 201235041 胺 ld(418 mg ’ 〇. 67 _)溶解於 2, 5 此 :::雙三甲基彻基鐘的甲苯溶液(imL，imm〇i)， 鐘’向反應液中加入2. 5此似从⑷叔丁基 二甲基）㈣氧基+甲基n2^3e(326 mg， 1.34 mmol)的四氫呋喃溶液，反應i小時，室严The first step (M?S) from 4-hydroxy-1-indolyl-pyrrolidine-2-carboxylic acid decyl ester under ice bath (25", 4 friends)-4-base group _° ratio p _2-Resistance 3a (5. 53 g, 38 mmol) was dissolved in 80 mL of sterol, 40% citric acid solution (31 mL, 380 mmo 1) was added, and cyano sulphide was slowly added in portions. (12 g, 190 mmol), stirring the reaction for 0.5 hours, stirring at room temperature for 3 hours. The reaction was quenched by the addition of 40 mL of EtOAc (EtOAc (EtOAc) The title product (M.S.). 4-hydroxy-1-indolyl-pyrrolidine-2-carboxylic acid oxime ester 3b (crude, no. 36 95 119 201235041. color oil), used directly. The second step. (10) shoulder -4_(tert-butyl (dimethyl) sylylene) oxy + methyl serotonane - carboxylic acid oxime ester (four) legs (4) dissolved in the coffee two gas a fire ^ add ^ The reaction was carried out for 12 hours with (10) g '113 1) and dimethyl tert-butyl gas (6.80 g, 45 mmol). The reaction mixture was diluted with loo 虬 dichloro hydrazine, washed successively with water (50 mL) 'saturated sodium sulphate solution (5 〇 mL), dried over anhydrous sodium sulfate, and then evaporated, and concentrated under reduced pressure. The resulting residue was purified to give the titled product (25; s. 4-(t-butyl (dimethyl) succinyl) oxy-1-indolyl- sulphonic sul. The crude product was obtained as a crude oil. The product was taken to the next step without purification. MS m/z (ESI): 274 [M+l] Step 3 • [(2$4 灼_4_(tert-butyl) (25; 4?~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ -2- Weijia 酉 3c (2 5 〇 g, 91 〇 υ υ dissolved in 50 inL two gas aeration, slowly adding diisobutyl hydride (18 虬, ^, nmol) 'reaction 6 hours. Add j淬Methanol quenching reaction, dilute the reaction solution with 2 〇〇虮 two gas ,, then add anhydrous sodium sulphate to disturb, such as minutes, filter, the filtrate is concentrated under reduced pressure, using alkaline alumina column chromatography to eluent System A purifies the resulting residue to obtain the standard Product [(2 and 4 kg 95119 37 201235041 (tert-butyl(difluorenyl) fluorenyl)oxy-1-methyl ratio IT 院-2-yl]methanol 3d (570 mg 'yellow oily substance) Yield: 50. 〇% MS m/z (ESI): 246 [M+l] Step 4 (2 & 47P)-4-(tert-butyl(dimethyl)indenyl)oxy-methyl -n dimethyl hydrazine (174// L ' 2. 45 mmol) was dissolved in 2 〇 mL of dichloromethane in a dry bath of -2- aldehyde. After the temperature of the system was stable, slowly add the grass. Chlorofluorene (156 //L, 1.80 mmol), react for 30 minutes, add 2 mL [(25; 4)?)-4-(tert-butyl(difluorenyl)shityl)oxyl- Dibromo-2-pyrrol-2-yl]methanol 3d (300 mg, 1.20 mm〇i) in dioxane solution, reacted for 45 minutes, added diethylamine (510, 3.67 mmol), and continued to stir the reaction 1 〇min, react to temperature for 1 hour, dilute the reaction solution with 100 mL of dichloromethane, and then wash with saturated sodium bicarbonate solution (2 mL), saturated ammonium chloride (2 mL), and saturated sodium chloride solution (2) 〇虬), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title product (25; Methyl)hydrazino)oxy_丨_ fluorenyl^ is more calcined (320 mg, yellow oil), the crude product is straight to the next reaction. The fifth step (7)-3-[(25; cut + (uncle) Butyl (dimethyl) succinyloxy)-methyl-transalkyl-2-yl]|[4_[[3_chloro_4_(2ι-methyl)phenyl]amino]I]- 7-ethoxy-6-mercapto]propan-2-ene decylamine under dry glacial oxooxy)phenyl]amino]I-arylethoxy+(tetra)yl]-2- squaric acid乙酉 - - 醯 95119 38 201235041 Amine ld (418 mg ' 〇. 67 _) dissolved in 2, 5 This::: bistrimethyl-based clock in toluene solution (imL, imm〇i), clock 'reaction The solution was added to a solution of (4) tert-butyldimethyl)(tetra)oxy+methyln2^3e (326 mg, 1.34 mmol) in tetrahydrofuran for 1 hour.

小時。反應液減壓濃縮，㈣膠柱色譜法以洗^劑體系A 純化所付殘餘物，得到標題產物⑻_3_[⑽，切_4_(叔丁hour. The reaction solution is concentrated under reduced pressure, and the residue is purified by a column chromatography chromatography to give the title product (8) _3_[(10), cut _4_ (t-butyl)

基（一曱基）石夕基）氧基-卜甲基_n比略燒_2_基]—N_[4_[[3_ 氯-4-(2-t定基甲氧基）苯基]胺基]_3_氛基+乙氧基+ 喹啉基]丙-2-烯醯胺3f (292 mg，黃色固體 61.2%。 MS m/z (ESI)： 713 [M+l] 第六步 ⑻-Ν-[4-[[3-氯-4-(2-吼咬曱氧基）苯基]胺基]_3—氰基 -7-乙氧基-6 一喹啉基]_3-[(25；4灼_4_羥基——甲基-吡咯 ❿ 烧_2-基]丙-2-稀醯胺 將（五)-3-[(25； 4^-4-(叔丁基（二甲基）石夕美）氣基 曱基-吡咯烷-2 一基]—N 一 [4—[[3一氯_4—(2〜π比二基甲氧基） 苯基]胺基]-3-氰基-7-乙氧基-6-啥淋基]丙稀醯胺3f (50 mg，〇. 〇7 mm〇i)和四丁基氟化鍵⑸ mg，〇. 21 顏〇1) 溶解於5mL四氫呋喃中，反應12小時。加入lmL水，反 應液減壓濃縮，用二氯甲烷萃取（50 mLx3)，合併有機相， 用飽和氣化鈉溶液洗滌（30 mLx2)，無水硫酸鈉乾燥，過 濾，減壓濃縮，用矽膠柱色譜法以洗脫劑體系4純化所得 95119 39 201235041 殘餘物’得到標題產物（幻-N-[4-[[3-氯-4-(2-吼啶曱氧基) 苯基]胺基]-3-氰基-7-乙氧基-6-喹啉基]-3-[(2及4τ?)-4-羥基-1-曱基-吡咯烷-2-基]丙-2-烯醯胺3(17 mg，黃色固 體），產率：40.4%。 MS m/z (ESI)： 599.4 [M+l] !Η NMR (400M Hz, DMSO-^)： δ 9.63 (s, 1H), 9.52 (s, 1H), 8.97 (s, 1H), 8.61-8.60 (m, 1H), 8.48 (s, 1H), 7.904-7.862 (m, 1H), 7.60 (d, 1H), 7.41-7.36 (m, 3H), 7.28-7.20 (m, 2H), 6.76 (dd, 1H), 6.61 (d, 1H), 5.29 (s, 2H), 4. 82 (s, 1H), 4. 35-4. 29 (m, 2H), 4. 21 (d, 1H), 3.42-3.38 (m, 2H), 3.36-3.33 (m, 3H), 2.93 (d, 1H), 2.41-2.37 (m, 1H), 2.20-2.18 (m, 1H), 1.49 (t, 3H) 實施例4 (幻4-[4-[[3-氣-4-(2-吡啶基甲氧基）苯基]胺基]喹唑啉 -6-基]-3-[(25·)-1-曱基吡咯烷-2-基]丙-2-烯醯胺Alkyl (an fluorenyl) oxa-yl-oxyl-p-methyl-n-r-sinter _2_yl]-N_[4_[[3_ chloro-4-(2-t-decylmethoxy)phenyl]amino] _3_ aryl + ethoxy + quinolyl] prop-2-enylamine 3f (292 mg, 61.2% of a yellow solid. MS m/z (ESI): 713 [M+l] Step 6 (8)-Ν -[4-[[3-chloro-4-(2-indolyloxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolinyl]-3-[(25; 4 _ _ 4 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ ) Shi Ximei) gas-based thiol-pyrrolidine-2-yl]-N-[4-[[3-chloro-4-[(2~π~diylmethoxy)phenyl]amino]-3- Cyano-7-ethoxy-6-indole] acrylamide 3f (50 mg, 〇. 〇7 mm〇i) and tetrabutyl fluorinated bond (5) mg, 〇. 21 〇1) The reaction was carried out for 12 hours in 5 mL of tetrahydrofuran. The reaction mixture was evaporated to dryness eluted with methylene chloride (50 mL×3). Filtration, concentration under reduced pressure, purification by eluent column chromatography using gel column chromatography, 95119 39 201235041 Remaining 'obtained the title product (Phantom-N-[4-[[3-chloro-4-(2-acridinyloxy)phenyl]amino]-3-cyano-7-ethoxy-6 -quinolinyl]-3-[(2 and 4τ?)-4-hydroxy-1-indolyl-pyrrolidin-2-yl]prop-2-enylamine 3 (17 mg, yellow solid), yield : 40.4% MS m/z (ESI): 599.4 [M+l] Η NMR (400M Hz, DMSO-^): δ 9.63 (s, 1H), 9.52 (s, 1H), 8.97 (s, 1H) ), 8.61-8.60 (m, 1H), 8.48 (s, 1H), 7.904-7.862 (m, 1H), 7.60 (d, 1H), 7.41-7.36 (m, 3H), 7.28-7.20 (m, 2H) ), 6.76 (dd, 1H), 6.61 (d, 1H), 5.29 (s, 2H), 4. 82 (s, 1H), 4. 35-4. 29 (m, 2H), 4. 21 (d , 1H), 3.42-3.38 (m, 2H), 3.36-3.33 (m, 3H), 2.93 (d, 1H), 2.41-2.37 (m, 1H), 2.20-2.18 (m, 1H), 1.49 (t , 3H) Example 4 (Phantom 4-[4-[[3-carb-4-(2-pyridylmethoxy)phenyl]amino]quinazolin-6-yl]-3-[(25 ·)-1-decylpyrrolidin-2-yl]prop-2-enylamine

40 95119 20123504140 95119 201235041

將 6-石肖基-3H-口奎唾琳-4-酮 4a (18. 88 g，99. 40 mmol) 加入到五虱化鱗（31.03 g，149 mmo 1)中，混合液加熱至 160°C ’反應3小時。將反應液趁熱加入到250 mL正己烷 中，攪拌有大量固體析出，過濾，濾餅用正己烷洗滌，真 空下乾餘’付到粗品4-氯-6-硝基-啥唾琳4b (18. 14g， 黃色固體），產率：87. 2%。 • 第二步 N-[3-氯-4-(2-吼啶基甲氧基）苯基]_6—硝基_喹唑啉_4_胺 將粗品4-氯-6-硝基-喹唑啉4b (6.06 g，28. 90 mmol) 溶解於100 mL異丙醇中，加入3_氯_4_(吡啶_2_基曱氧 基）-苯胺4c (7. 47g，31. 8 mmol)，加熱回流反應5小時。 反應液冷卻至室溫，有固體析出，韻，遽餅依次用乙酸 乙酯，飽和氯化鈉溶液（50mL)和水洗滌（15〇mL)， 真空下 乾燥，得到N-[3-氯-4-(2-t定基曱氧基）苯基卜6一靖基_ 喹唑啉-4-胺4d (8. 38 g，黃色固體），產率：74.脒。 95119 41 201235041 MS m/z (ESI): 319 [M+l] 第三步 似-[3-氯-4-(2-11比0定基曱氧基）苯基]啥〇坐琳_4,6-二胺 將N-[3-氯-4-(2-n比啶基甲氧基）苯基]_6_硝基_喹唑 啉-4-胺 4d (4. 07g，10 mmol)和濃鹽酸（2 mL，24 mmol) 溶解於130 mL 95%乙醇和水的混合溶劑（V/V = 10:3)中， 加入鐵粉（11. 17 g，200 mmol)，反應液加熱回流反應2 小時。趁熱過濾，遽液在減壓下蒸出乙醇，殘留液用胺水 調節至pH>7，過濾，濾餅在真空下乾燥，用石夕膠柱色譜法 Φ 以洗脫劑體系A純化所得固體，得到N4-[3-氯-4-(2-吡啶 基曱氧基）苯基]喹峻琳-4, 6-二胺4e (2.04 g，白色固 體），產率：’ 54. 1%。 MS m/z (ESI): 378 [M+l] 第四步 N~[4-[ [3-氯-4-(2-°比咬基曱氧基）苯基]胺基]啥〇坐琳一6一 基]-2-磷酸二乙酯-乙醯胺 冰浴下將磷酸二乙酯基乙酸（1. 04 g，5. 30 mmol)溶 ® 解於10 mL二氯甲烧中，向反應液中滴加草醯氯（1.34 g，ι〇 mmol)和1滴N，N-二曱基曱醢胺，反應1小時，室溫繼續 攪拌1小時，減壓濃縮，加入10 mL四氫呋喃備用。 冰浴下將N4-[3-氯-4-(2-吡啶基曱氧基）笨基]唾唾 啉-4, 6-二胺 4e (1 g，2. 65 mmol)溶解於 N，N-二異丙基 乙胺中（1.03g，7.94 mmo 1) ’滴加上述備用溶液，室溫反 應1小時。將反應液減壓濃縮，用二氣曱烷萃取（5〇 mLXM， 95119 42 201235041 合併有機相，用飽和氯化納溶液洗蘇（30 mLx2)，無水硫酸 鈉乾燥，過濾，減壓濃縮，用矽膠柱色譜法以洗脫劑體系 . A純化所得殘留物，得到標題產物N-[4-[[3-氯-4-(2-吡啶 基曱氧基）苯基]胺基]喹唑啉-6-基]-2-磷酸二乙酯-乙醯 胺4f (671 mg，棕色固體），產率：45. 7°/〇。 MS m/z (ESI): 556 [M+l] 第五步 (方)-N- [ 4- [ [ 3-氣-4-(2-。比咬基曱氧基）苯基]胺基]喧。坐琳 ❶ -6_基]_3_[(2|5")_1_甲基〇比洛院_2_基]丙-2_稀酿胺 乾冰浴下將N-[4-[ [3-氯-4-(2-吼啶基曱氧基）苯基] 胺基]喹唑啉-6-基]-2-磷酸二乙酯-乙醯胺4f (277 mg， 0. 50 mmol)溶解於2. 5 mL四氫α夫喃中，擾拌下滴加1 Μ 雙三曱基矽基胺基鋰的甲苯溶液（750 /zL，0.75 mmol)，攪 拌反應45分鐘，向反應液中加入（250-1-甲基吡咯烷-2-曱醛lb(113 mg，2顏〇1)，繼續攪拌反應1小時，室溫反 φ 應12小時。反應液減壓濃縮，用矽膠柱色譜法以洗脫劑體 系A純化所得殘餘物，得到標題產物（五)-N-[4-[[3-氯 -4-(2-吡啶基甲氧基）苯基]胺基]喹唑啉-6-基]-3-[(25")-1-曱基0比p各院-2-基]丙-2-烯醢胺4(85 mg，黃色 固體），產率：33. 0%。 MS ra/z (ESI): 515.3 [M+l] 沱丽R(400 MHz，DMSO-A): <T10.47(s，1H)，9.82(s， 1H)，8. 79 (s，1H)，8. 61 (d，1H)，8. 52 (s，1H)，8. 00 (s， 1H), 7.91-7.89 (ra, 2H), 7.78-7.69 (m, 2H), 7.61 (d, 43 95119 201235041 1H)，7.38 (d，1H)，7.28 (d，1H)，6.78-6.72 (m, 1H)， 6.47 (d, 1H), 5.30 (s, 2H), 3.14-3.00 (m, 2H), 3.001 (s, 1H), 2. 31 (m, 4H), 2. 10-2. 07 (m, 1H), 1. 81 (m, 2H), 1. 63 (m, 1H) 實施例5 (β-Ν-[4-[[3-氯-4-(2-咕啶基曱氧基）苯基]胺基]-3-氰 基一乙氧基-6-嗤琳基]-3-[(2_Λ〇-1-甲基°比洛烧-2-基]丙 -2-烯醯胺Add 6-Shoshyl-3H-hydroxy quinalin-4-one 4a (18. 88 g, 99. 40 mmol) to the saponin (31.03 g, 149 mmo 1) and heat the mixture to 160 °C. 'Reaction for 3 hours. The reaction solution was added to 250 mL of n-hexane while stirring, and a large amount of solid was precipitated, filtered, and the filter cake was washed with n-hexane, and dried under vacuum to give the crude 4-chloro-6-nitro-hydrazine 4b ( 2重量。 18. 14g, yellow solid), yield: 87.2%. • The second step of N-[3-chloro-4-(2-acridinylmethoxy)phenyl]_6-nitro-quinazoline-4-amine will be crude 4-chloro-6-nitro-quin Oxazoline 4b (6.06 g, 28.90 mmol) was dissolved in 100 mL of isopropanol and added 3_chloro_4_(pyridine-2-yloxy)-phenylamine 4c (7. 47 g, 31.8 mmol) The reaction was heated to reflux for 5 hours. The reaction solution was cooled to room temperature, and a solid precipitated, and the cake was washed with ethyl acetate, saturated sodium chloride solution (50 mL) and water (15 mL), and dried under vacuum to give N-[3-chloro- 4-(2-t-decyloxy)phenyl b-6-Jingji-quinazoline-4-amine 4d (8. 38 g, yellow solid), yield: 74. 95119 41 201235041 MS m/z (ESI): 319 [M+l] The third step is similar to [3-chloro-4-(2-11~0-decyloxy)phenyl]indole_4, 6-Diamine will be N-[3-chloro-4-(2-n-pyridylmethoxy)phenyl]_6-nitro-quinazolin-4-amine 4d (4.77 g, 10 mmol) and Concentrated hydrochloric acid (2 mL, 24 mmol) was dissolved in 130 mL of a mixed solvent of 95% ethanol and water (V/V = 10:3), iron powder (11.17 g, 200 mmol) was added, and the reaction solution was heated to reflux. 2 hours. The mixture was filtered while hot, and the hydrazine was evaporated to dryness under reduced pressure. The residue was adjusted to pH <7> with amine water, filtered, and the filter cake was dried under vacuum, and purified by eluent system A using zea gel column chromatography. Solid, N4-[3-chloro-4-(2-pyridinyloxy)phenyl]quinolin-4,6-diamine 4e (2.04 g, white solid). %. MS m/z (ESI): 378 [M+l] Step 4 N~[4-[[3-chloro-4-(2-° 咬 曱 曱 曱 )))]]]]] In the ice bath, a solution of diethyl phosphate-based acetic acid (1. 04 g, 5.30 mmol) was dissolved in 10 mL of methylene chloride. To the reaction mixture were added dropwise hydrazine chloride (1.34 g, ι〇mmol) and 1 drop of N,N-didecylguanamine, and the mixture was reacted for 1 hour, and the mixture was further stirred at room temperature for 1 hour, concentrated under reduced pressure, and 10 mL of tetrahydrofuran was added. spare. Dissolving N4-[3-chloro-4-(2-pyridinyloxy)phenyl]pyrazine-4,6-diamine 4e (1 g, 2.65 mmol) in N,N under ice-bath -diisopropylethylamine (1.03 g, 7.94 mmo 1) 'The above-mentioned standby solution was added dropwise, and reacted at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. The residue obtained was purified by column chromatography on eluent column chromatography to afford the title product N-[4-[[3-chloro-4-(2-pyridinyloxy)phenyl]amino] quinazoline. 6-yl]-2-phosphate diethyl ester-acetamide 4f (671 mg, brown solid), yield: 45. 7° / 〇 MS m/z (ESI): 556 [M+l] Five-step (square)-N- [4- [ [ 3- gas-4-(2-. 咬 曱 曱 曱 )))]]]]]]] 坐 ❶ -6 _ _ _ _ _ _ _ _ _ _ |5")_1_Methylpyrrolidol_2_yl]propan-2_thin amine dry ice bath N-[4-[[3-chloro-4-(2-acridinyloxy) , phenyl]amino]quinazolin-6-yl]-2-phosphate diethyl ester-acetamide 4f (277 mg, 0.50 mmol) dissolved in 2. 5 mL of tetrahydro-α A toluene solution (750 / zL, 0.75 mmol) of 1 Μ bis tridecyl decylamino lithium was added dropwise, and the reaction was stirred for 45 minutes, and (250-1-methylpyrrolidin-2-indole was added to the reaction mixture. Aldehyde lb (113 mg, 2 〇1), continue to stir the reaction After 1 hour, the room temperature is reversed for φ. The reaction mixture is concentrated under reduced pressure. The residue obtained is purified eluting from EtOAc (EtOAc) -4-(2-Pyridylmethoxy)phenyl]amino]quinazolin-6-yl]-3-[(25")-1-indolyl 0 to p 院-2-基] -2- eneamine 4 (85 mg, yellow solid), yield: 30.0%. MS s/z (ESI): 515.3 [M+l] R R (400 MHz, DMSO-A): <;T10.47(s,1H), 9.82(s, 1H), 8.79 (s,1H), 8.61 (d,1H), 8. 52 (s,1H), 8. 00 (s, 1H), 7.91-7.89 (ra, 2H), 7.78-7.69 (m, 2H), 7.61 (d, 43 95119 201235041 1H), 7.38 (d, 1H), 7.28 (d, 1H), 6.78-6.72 (m , 1H), 6.47 (d, 1H), 5.30 (s, 2H), 3.14-3.00 (m, 2H), 3.001 (s, 1H), 2. 31 (m, 4H), 2. 10-2. 07 (m, 1H), 1. 81 (m, 2H), 1. 63 (m, 1H) Example 5 (β-Ν-[4-[[3-chloro-4-(2-acridinyl)oxyl Phenyl]amino]-3-cyano-ethoxy-6-indolyl]-3-[(2_Λ〇-1-methyl~pyrrol-2-yl]prop-2-ene Guanamine

第一步 [(27?)-1-曱基吡咯烷-2-基]甲醇 冰’谷下分批將氫化紹經（2 3 0 mg，6 mmo 1)和Ν-叔丁氧 獄基—R_脯胺醇5a(400 mg，2 mmol)加入10 mL乾燥的 四氫呋喃溶液中’待無明顯氣體產生後，回流反應2小時。 44 95119 201235041 冰浴下緩慢滴加5 mL曱醇後再滴加5 mL水，加入無水硫 酸鎂乾燥，過濾，濾液減壓濃縮’得到標題產物 * 甲基吡咯烷-2-基]曱醇5b(221 mg ’無色液體），產率： . 77%。 MS m/z (ESI): 116 [M+l] 第二步 (2左)-1-甲基°比π各院-2-曱酸 乾冰浴下將二甲亞砜（820此，11.46 mm〇i)加入二氯 曱烷5 mL中，緩慢滴加草醯氯（968 mg，7.64 mmol)，反 應45分在里，滴加2 mL [曱基〇比嘻燒一2-基]曱醇 5b (220 mg，1.91 mmol)的二氣甲烷溶液’繼續檀 45分鐘，加入三乙胺（1.9mL，13.37_)，反^^ 鐘，室溫反應1小時，反應液依次用水（2〇mL)和飽和鹽水 洗滌（10 mL)，無水硫酸鈉乾燥，過濾，減壓濃縮，用ς性 氧化鋁色譜法以洗脫劑體系八純化所得殘餘物，得到標題 •產物（2灼—1 一曱基吡咯烷_2一甲醛5c(30〇mg，黃色液體）， 粗品不經純化直接進行下一步反應。 第三步 (幻-N-[4-[[3-氣-4-(2-吨啶基曱氧基）苯基]胺基]_3_氰 基-7-乙氧基-6-喹啉基]-3~[(2及)—丨_曱基吡咯烷—2_基]丙 一2—烯醯胺 乾冰洛下將N-[4-[ [3~氯-4-(2-吼啶基甲氧基）苯基] 胺基]-3-氰基-7-乙氧基-6~嗤琳基]_2_磷酸二乙酷_乙醯 胺Id (250 mg，〇.4〇題〇1)溶解於1〇乩無水四氫呋喃中， 95119 45 201235041 逐滴加入1 Μ雙三甲基矽基胺基鋰的甲苯溶液（440〆！^， 0. 44 mmol)，反應30分鐘，逐滴加入5 mL (2及)-1-甲基 0比洛院-2-曱搭5c (90 mg ’0· 80 mmol)的四氫吱喃溶液， 攪拌反應3 0分鐘，室溫繼續反應12小時，反應液減壓濃 縮，用矽膠柱色譜法以洗脫劑體系A純化所得殘餘物，得 到標題產物（方)-N-[4-[ [3-氯-4-(2-0比咬基曱氧基）苯基] 胺基]-3-氰基-7-乙氧基奎琳基]-3-[ (2无)-1-曱基n比洛 貌-2-基]丙-2-烯酿胺5(46 mg，黃色固體），產率：19. 7%。 MS m/z (ESI): 583.4 [M+l] 4 NMR (400 MHz，DMS0-&amp;): (5 9. 16 (s，1H)，8.63 (d， 1H)，8.56 (s，1H)，8.26 (s，1H)，7. 83-7.80 (dd，1H)， 7.76-7.50 (m, 2H), 7.57-7.56 (m, 1H), 7.40 (s, 1H), 7. 38(s, 1H), 7. 19(d, 1H), 7.06-7.03 (m, 2H), 6.34- 6.31 (d, 1H), 5.35 (s, 2H), 4.39 (m, 2H), 4.27-4.26 (m, 1H), 3.32 (m, 1H), 3.10 (m, 1H), 2.73 (s, 3H), 2.37-2.36 (m, 2H), 2.07-2.01 (in, 2H), 1.64 (t, 3H) 實施例6 (£)-N-[4-[[3-氯-4-(2-吼啶基曱氧基）苯基]胺基]-3-氰 基-7-乙氧基-6-喹啉基]-3-(1-曱基-2-哌啶基）丙-2-烯醯 胺The first step [(27?)-1-indolylpyrrolidin-2-yl]methanol ice in the bottom of the valley will be hydrogenated in a batch (2 3 0 mg, 6 mmo 1) and Ν-tert-butoxy bastyl - R_Proline 5a (400 mg, 2 mmol) was added to 10 mL of dry tetrahydrofuran solution. After no significant gas evolution, the reaction was refluxed for 2 hours. 44 95119 201235041 5 mL of sterol was slowly added dropwise to the ice bath, and then 5 mL of water was added dropwise, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product &lt;RTI ID=0.0&gt; (221 mg 'colorless liquid), yield: . 77%. MS m/z (ESI): 116 [M+l] The second step (2 left) -1-methyl ° ratio π each hospital -2- decanoic acid dry ice bath under dimethyl sulfoxide (820 this, 11.46 mm 〇i) Add 5 mL of dichloromethane, slowly add oxaloquinone chloride (968 mg, 7.64 mmol), react 45 minutes, add 2 mL [曱 〇 〇 嘻 一 2- 2- 2- 2- 曱 曱 曱 曱 曱 曱 曱5b (220 mg, 1.91 mmol) of a two-gas methane solution' continued for 45 minutes, added triethylamine (1.9 mL, 13.37_), reacted at room temperature for 1 hour at room temperature, and the reaction solution was washed with water (2 mL) Washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated. Pyrrolidine-2-carbaldehyde 5c (30 〇mg, yellow liquid), the crude product was directly subjected to the next reaction without purification. The third step (magic-N-[4-[[3- gas-4-(2-ton) Pyridyloxy)phenyl]amino]_3_cyano-7-ethoxy-6-quinolinyl]-3~[(2 and)-丨-mercaptopyrrolidine-2-yl]-propyl 2-2-4-[4-[[3-chloro-4-(2-acridylmethoxy)phenyl]amino]-3-cyano-7-ethoxyl -6~嗤琳]_2_Diethyl phosphate _ acetamide Id (250 mg, 〇.4〇 〇1) was dissolved in 1 〇乩 anhydrous tetrahydrofuran, 95119 45 201235041 1 Μ bis trimethyl decyl amide lithium was added dropwise Toluene solution (440 〆!^, 0. 44 mmol), react for 30 minutes, add 5 mL (2 and) -1-methyl 0 to 洛洛院-2-曱5c (90 mg '0· 80) Ethyl tetrahydrofuran solution, the reaction is stirred for 30 minutes, and the reaction is continued for 12 hours at room temperature. The reaction mixture is concentrated under reduced pressure. The residue obtained is purified by chromatography on eluent column chromatography to afford the title product. -N-[4-[[3-chloro-4-(2-0) methoxy)phenyl]amino]-3-cyano-7-ethoxyquininyl]-3-[ (2) 曱 曱 n 比 洛 洛 -2- 基 基 基 基 基 烯 烯 烯 烯 烯 烯 烯 烯 烯 ( ( ( MS MS MS MS MS MS MS MS MS MS </ RTI> </ RTI> <RTIgt; 7. 83-7.80 (dd,1H), 7.76-7.50 (m, 2H), 7.57-7.56 (m, 1H), 7.40 (s, 1H), 7. 38(s, 1H), 7. 19(d , 1H), 7.06-7.03 (m, 2H), 6.34- 6.31 (d, 1H), 5.35 (s, 2H), 4.39 (m, 2H), 4.27-4.26 (m, 1H), 3 .32 (m, 1H), 3.10 (m, 1H), 2.73 (s, 3H), 2.37-2.36 (m, 2H), 2.07-2.01 (in, 2H), 1.64 (t, 3H) Example 6 ( £)-N-[4-[[3-chloro-4-(2-acridinyloxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolinyl] -3-(1-mercapto-2-piperidyl)prop-2-enylamine

46 95119 6 20123504146 95119 6 201235041

第一步 1_甲基-娘咬-2 -甲酸· 乾冰浴下將二甲亞石風（3. 3 raL，46 mmo 1)溶解於15 mL 一氯曱燒中’緩慢滴加草酿氯（2· 6 mL，31 mmol)，擾拌反 應45分鐘’滴加5 mL(l-甲基-2-派啶）甲醇6a(l g，7. 74 mmol)的二氯曱烷溶液，繼續反應45分鐘，加入三乙胺（7. 2 roL，52 mmol) ’攪拌反應1〇分鐘，室溫反應1小時，反應 液依次用水（20 mL)和飽和氯化鈉溶液洗滌（2〇 mL)，無水 硫酸鋼乾燥’過濾，減壓濃縮，用鹼性氧化鋁柱色譜法以 • 洗脫劑體系A純化所得殘餘物，得到標題產物卜曱基-哌 °定-2-甲盤6b(300 mg ’棕色液體），產率：31. 0%，粗品不 經純化直接進行下一步反應。 第二步 (β-Ν-[4-[[3-氣-4-(2-吼啶基曱氧基）苯基]胺基]_3-氰 基-7-乙氧基-6-喹啉基]-3—(1_甲基_2_哌啶基）丙_2_烯醯 胺 乾冰浴下將N-[4-[[3-氣-4-(2-吡啶基曱氧基）苯基] 胺基]-3-氰基-7-乙氧基-6-喹啉基]-2-磷酸二乙酯—乙醯 9 47 95119 201235041 胺Id (300 mg，0. 48 mmol)溶解於10 mL四氫咬喃中，逐 滴加入1 Μ雙三曱基矽基胺基鋰的甲苯溶液（53〇以[，〇. 53 mmol) ’反應30分鐘’逐滴加入5 mL卜曱基-派咬-2-甲 經6b (120 mg，0. 96 mmol)四氫呋喃溶液，繼續攪拌反應 30分鐘，室溫反應12小時，反應液減壓濃縮，用矽膠柱 色譜法以洗脫劑體系A純化所得殘餘物，得到標題產物 (幻-N-[4-[[3-氯-4-(2-°比啶基曱氧基）苯基]胺基]_3_氰 基-7-乙氧基-6-喹啉基]-3-(1-曱基-2-哌啶基）丙-2-烯醯 胺6 (14 mg，黃色固體），產率：4. 9%。 MS m/z (ESI): 597.3 [M+l] 'H NMR (400 MHz, dUSO-de): δ 9.09 (s, 1H), 8.63 (d, 1H), 8.51(s, 1H), 7.83-7.79 (m, 2H), 7. 58-7. 56 (m, 1H), 7· 30-7. 27 (m, 3H)，7. 14-7. 12 (m, 2H)，7. 04 (d, 1H)， 6.69-6.66 (m, 1H), 5.32 (s, 2H) » 4.32-4.29 (m, 2H), 4.27-4.24 (in, 2H) » 3. 60-3. 40 (m, 2H), 2.71 (s, 3H), 2.05-1.72 (m, 6H), 1.62 (t, 3H) 實施例7 d)-N-[4-[ (3-氯-4-氟-苯基）胺基]-7-乙氧基-喧唾淋一 基]-3-[(250-1-甲基吡洛烧-2-基]丙-2-烯醯胺First step 1_Methyl-Ningbite-2 - Formic acid · Dissolve dimethyl sapphire (3.3 raL, 46 mmo 1) in 15 mL of chloranil in a dry ice bath. (2.6 mL, 31 mmol), stir-fry for 45 minutes' drop 5 mL (l-methyl-2-pyridinyl)methanol 6a (lg, 7.74 mmol) in dichloromethane to continue the reaction After 45 minutes, triethylamine (7.2 roL, 52 mmol) was added. The reaction was stirred for 1 minute, and reacted at room temperature for 1 hour. The reaction solution was washed with water (20 mL) and saturated sodium chloride solution (2 mL). Anhydrous sulfuric acid steel was dried <filtered, concentrated under reduced pressure, and the residue obtained was purified using basic alumina column chromatography eluting with eluent system A to give the title product bismuth-piperidine-2-methyl 6b (300 mg 'brown brown Liquid), Yield: 31.0%, crude material was taken directly to the next step without purification. The second step (β-Ν-[4-[[3-Ga-4-(2-Aridinyloxy)phenyl]amino]_3-cyano-7-ethoxy-6-quinoline N-[4-[[3- gas-4-(2-pyridyloxy)oxyl) under dry ice bath with 3-(1-methyl-2-piperidinyl)propan-2-eneamine Phenyl]amino]-3-cyano-7-ethoxy-6-quinolinyl]-2-phosphate diethyl ester-acetamidine 9 47 95119 201235041 Amine Id (300 mg, 0. 48 mmol) dissolved To a solution of 1 Μ bis-tridecylsulfonyl lithium in toluene (53 〇 to [, 〇. 53 mmol) 'reaction for 30 minutes' was added dropwise to 5 mL of tetrahydromethane. The solution was incubated with 6b (120 mg, 0.996 mmol) in tetrahydrofuran. The reaction was stirred for 30 minutes and allowed to react at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure and purified by eluent column chromatography. The residue gave the title product (Fanta-N-[4-[[3-chloro-4-(2-pyridinyloxy)phenyl]amino]-3-cyano-7-ethoxy- 6- quinolinyl]-3-(1-indolyl-2-piperidyl)prop-2-enylamine 6 (14 mg, yellow solid), yield: 4.9% MS m/z ( ESI): 597.3 [M+l] 'H NMR (400 MHz, dUSO-de): δ 9.09 (s, 1H), 8.63 (d, 1H), 8.51 (s, 1H), 7. 83-7.79 (m, 2H), 7. 58-7. 56 (m, 1H), 7· 30-7. 27 (m, 3H), 7. 14-7. 12 (m, 2H), 7. 04 (d, 1H), 6.69-6.66 (m, 1H), 5.32 (s, 2H) » 4.32-4.29 (m, 2H), 4.27-4.24 (in, 2H) » 3. 60-3. 40 (m , 2H), 2.71 (s, 3H), 2.05-1.72 (m, 6H), 1.62 (t, 3H) Example 7 d)-N-[4-[(3-chloro-4-fluoro-phenyl) Amino]-7-ethoxy-oxime-based]-3-[(250-1-methylpyrrolidino-2-yl)prop-2-enylamine

48 95119 20123504148 95119 201235041

第一步 N_[4-[(3-氯-4-氟-苯基）胺基-7-乙氧基-唾唾琳-6-基]-2-磷酸二乙酯-乙醯胺 將 Ν, Ν’ -叛基二咪σ坐（292 mg, 1. 80 mmol)溶解於 4 mL ® 四氫呋喃中，油浴升溫至50°C，向反應液中滴加3 mL磷 酸二乙酯基乙酸（353 mg, 1.8 mmol)的四氫咬喃溶液，反 應1. 5小時備用。 N4-(3 -氣-4-氣-苯基）-7 -乙氧基-啥。坐琳-4，6-二胺 7a (200 mg，0. 60 mmol，採用公知的方法 “W02005028443” 製備而得）溶解於10 mL四氫呋喃中，在50°C滴加上述備 用反應液，在40°C反應3小時。反應液減壓濃縮，用二氯 φ 甲烷萃取（50 mLx3)，合併有機相，用飽和氯化鈉溶液洗滌 (50 mLx2)，無水硫酸鈉乾燥，過濾，濾液減壓濃縮，用矽 膠柱色譜法以洗脫劑體系A純化所得殘餘物，得到標題產 物N-[4-[(3-氯-4-氟-苯基）胺基-7-乙氧基-喹唑啉-6-基]-2-磷酸二乙酯-乙醯胺7b (100 mg，淡黃色固體），產 率：33. 3%。 MS m/z (ESI): 511.1 [M+l] 第二步 (瓦)-1^-[4-[ (3-氯-4-氟-苯基）胺基]-7-乙氧基-σ奎吐琳-6- 49 95119 201235041 基]-3-[(25·)-1-甲基吡咯烷_2一基]丙_2_烯醯胺 將Ν-[4-[(3-氯-4-氟-苯基）胺基_7_乙氧基_喹唑啉 -6-基]-2-磷酸二乙酯-乙醯胺 7b (100 mg，〇·2〇 mm〇i) 溶解於10 mL四氫呋喃中，在乾冰浴冷卻至—78°c下，滴加 1 Μ雙三曱基矽基胺基鋰的甲苯溶液（4〇〇/zL，〇. 4〇職〇1)， 攪拌45分鐘，向反應液中加入（25)-1-甲基一吡咯烷_2_甲 醛lb(100 mg，0. 85 mmol)，繼續攪拌1小時後，室溫反 應12小時。向反應液中加入1 mL水和1 mL曱醇。用二氣 甲烧萃取（100 mLx3)，合併有機相，用飽和氯化鈉溶液洗 條（30 mLx2)，無水硫酸鈉乾燥，過濾，濾液減壓濃縮，用 矽膠柱色譜法以洗脫劑體系A純化所得殘餘物，得到標題 產物（五)-[[4-[(3-氯-4-氟-苯基）胺基]-7-乙氧基-喹唑 啉-6-基]-3-1:(25)-1-甲基吡咯烷一2-基]丙-2-烯醯胺7 (60 mg ’黃色固體），產率：65. 2%。 MS m/z (ESI): 470.2 [M+l] !H NMR (400 MHz, dUSO-de)： d 9.78 (s, 1H), 9.53 (s, 1H), 8.91 (s, 1H), 8.52 (s, 1H), 8.13-8.15 (m, 1H), 7.79-7.81 (in, 1H), 7.39-7.43 (m, 1H), 7.26 (s, 1H), 6. 67-6. 69 (m, 2H), 4. 26-4. 31 (m, 2H), 4. 09-4. 10 (m, 1H), 3. 17-3. 15 (m, 2H), 3. 08-3. 04 (in, 1H), 2. 77-2. 79 (m, 1H), 2. 87-2. 82 (m, 1H), 2. 23 (s, 3H), 1. 74-1. 76 Cm, 1H), 1. 47 (m,3H) 實施例8 (i〇-N-[4-[(3-氯-4-氟-笨基）胺基]-7-(2-甲氧基乙氧基） 95119 50 201235041 喧喷淋-6-基]-3-[(2/?)-l-甲基吼嘻烧-2〜基]丙-2—烯醯胺The first step is N_[4-[(3-chloro-4-fluoro-phenyl)amino-7-ethoxy-sevolin-6-yl]-2-phosphate diethyl-acetamide , Ν ' - 叛 二 二 咪 292 (292 mg, 1. 80 mmol) dissolved in 4 mL ® tetrahydrofuran, the oil bath was heated to 50 ° C, 3 mL of diethyl phosphate-based acetic acid was added dropwise to the reaction solution ( 3-5 mg, 1.8 mmol) of a tetrahydrogen urethane solution, the reaction was 1. 5 hours standby. N4-(3- gas-4-oxo-phenyl)-7-ethoxy-oxime. Selenium-4,6-diamine 7a (200 mg, 0. 60 mmol, prepared by the well-known method "W02005028443") was dissolved in 10 mL of tetrahydrofuran, and the above-mentioned alternate reaction solution was added dropwise at 50 ° C. The reaction was carried out at ° C for 3 hours. The reaction mixture is concentrated under reduced pressure. EtOAc (EtOAc) (EtOAc (EtOAc) The obtained residue was purified to afford the title product N-[4-[(3-chloro-4-fluoro-phenyl)amino-7-ethoxy-quinazolin-6-yl]- Diethyl 2-ethyl acetate-acetamide 7b (100 mg, pale yellow solid), yield: 33.3%. MS m/z (ESI): 511.1 [M+l]. Step 2 (W)-1^-[4-[(3-chloro-4-fluoro-phenyl)amino]-7-ethoxy- σ奎吐琳-6- 49 95119 201235041 ]]-3-[(25·)-1-methylpyrrolidine-2-yl]propan-2-ene decylamine Ν-[4-[(3-chloro 4-fluoro-phenyl)amino _7-ethoxy-quinazolin-6-yl]-2-phosphate diethyl ester-acetamide 7b (100 mg, 〇·2〇mm〇i) dissolved In 10 mL of tetrahydrofuran, cool in a dry ice bath to -78 ° C, add 1 Μ of bis-tridecyl decylamino lithium in toluene solution (4 〇〇 / zL, 〇. 4〇 job 〇 1), stir After 45 minutes, (25)-1-methyl-pyrrolidine-2-formaldehyde lb (100 mg, 0.85 mmol) was added to the reaction mixture, and the mixture was stirred for 1 hour, and then reacted at room temperature for 12 hours. 1 mL of water and 1 mL of decyl alcohol were added to the reaction solution. The mixture was extracted with two gas (100 mL×3), and the organic phase was combined, washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified to give the title product (5)-[[4-[(3-chloro-4-fluoro-phenyl)amino]-7-ethoxy-quinazolin-6-yl]-3 -2: (25)-1-methylpyrrolidin-2-yl]prop-2-enylamine 7 (60 mg 'yellow solid), yield: 65.2%. MS m/z (ESI): 470.2 [M+l] &quot;H NMR (400 MHz, dUSO-de): d 9.78 (s, 1H), 9.53 (s, 1H), 8.91 (s, 1H), 8.52 ( s, 1H), 8.13-8.15 (m, 1H), 7.79-7.81 (in, 1H), 7.39-7.43 (m, 1H), 7.26 (s, 1H), 6. 67-6. 69 (m, 2H ), 4. 26-4. 31 (m, 2H), 4. 09-4. 10 (m, 1H), 3. 17-3. 15 (m, 2H), 3. 08-3. 04 (in , 1H), 2. 77-2. 79 (m, 1H), 2. 87-2. 82 (m, 1H), 2. 23 (s, 3H), 1. 74-1. 76 Cm, 1H) , 1. 47 (m, 3H) Example 8 (i〇-N-[4-[(3-chloro-4-fluoro-phenyl)amino]-7-(2-methoxyethoxy) 95119 50 201235041 喧 Spray-6-yl]-3-[(2/?)-l-methyloxime-2~yl]propan-2-eneamine

第一步 N-(3-氯-4-氟-苯基）-7-(2-曱氧基乙氧基）-6-硝基-唾唑 琳-4-胺 將甲氧基乙醇（152 mg，2 mmol)溶解於30 mL二甲基 亞颯中，冰浴冷卻下’加入60%氫化鈉（80 mg，2 mmol)， 升溫至40°C攪拌2小時後，加入N-(3-氣-4-氟-苯基）-7-氟-6-确基-喧:嗤淋-4-胺 8a (336 mg，1 mmol)，在 40°C 攪拌4小時，在50°C攪拌12小時。在反應液中加入20 mL 水，過濾固體，依次用水洗滌（50 mL)，真空下乾燥，得到 51 95119 201235041 N-(3-氯-4-氟-苯基）-7-(2-曱氧基乙氧基）-6-硝基-喹唑 啉-4-胺8b (392 mg，黃色固體），產率：100%。產物直接 進行下一步反應。 MS m/z (ESI): 393.0 [M+l] 第二步 N4-(3-氯-4-氟-苯基）-7-(2-曱氧基乙氧基）喹唑啉-4, 6- 二胺 N-(3-氯-4-氟-苯基）-7-(2-曱氧基乙氧基）-6-硝基-喧唾琳-4-胺 8b (392 mg，1 mmol)和鐵粉（392 mg，7 mmol) ® 溶解於20 mL醋酸中，回流4小時。減壓濃縮反應液，加 入100 mL飽和碳酸氫鈉溶液，用二氯甲烷萃取（100 mLx3)， 合併有機相，用飽和氯化鈉溶液洗滌（50 mLx2)，無水硫酸 鈉乾燥，過濾，減壓濃縮，得到標題產物M-(3-氯-4-氟-苯基）-7-(2-曱氧基乙氧基）啥°坐琳-4, 6-二胺8c(200 mg， 淡黃色固體），產率：55. 2%。 MS ra/z (ESI): 363.1 [M+l] · 第三步 N-[4-[(3-氯-4-氟-苯基）胺基]-7-(2-曱氧基乙氧基）喹唑 嚇6-基]-2-礎酸二乙S旨-乙酿胺 將 N，Ν’ -幾基二咪π坐（292 mg，1. 80 mmol)溶解於 4 mL 四氫呋喃中，油浴升溫至50°C，向反應液中滴加3 mL磷 酸二乙酯基乙酸（353 mg，1.8 mmol)的四氫°夫喃溶液，反 應1. 5小時備用。 N4-(3-氯-4-氟-苯基）-7-(2-曱氧基乙氧基）喹唑啉 52 95119 201235041 4’ 6 -8= (200 mg，〇. 55 mm〇1)溶解於 i〇 mL 四氮咬 喃中’在50°C滴加上述備用反應液，在4(rc攪拌反應3 .小日夺。反應液減壓濃縮，用二氯曱燒萃取（5〇mLx3)，合併 有機相，用飽和氯化納溶液絲⑼_)，無水硫酸納乾 燥，過濾、’濾、液減壓濃縮，用石夕膠柱色譜法以洗脫劑體系 A純化所得殘餘物，得到標題產物卜[4_[(3_氯+氟_苯基) 胺基]7 (2 f氧基乙氧基）噎嗤琳基]_2一破酸二乙醋一 乙酿胺8d (150 mg，淡黃色固體），產率：5〇. 5%。 • MS m/z (ESI)： 541.2 [M+l] 第四步 (β-Ν-[4-[(3-氣-4-氟-苯基）胺基]_7_(2—曱氧基乙氧基） 喹唑啉-6-基]-3-[(2iP)-l-曱基吡咯烷_2_基]丙_2_烯醯胺 將N-[4-[(3-氯-4-氟-苯基）胺基]-7-(2-曱氧基乙氧 基）喹唑啉-6-基]-2-磷酸二乙酯-乙醯胺8d (2〇〇 mg，〇. 37 mmol)溶解於1〇 mL四氫呋喃中，在乾冰浴冷卻至_78Qc， •氬氣保護下，滴加1 μ雙三曱基矽基胺基鋰的甲苯溶液（74〇 ’ 0. 74 mmol)，攪拌30分鐘，向反應液中加入（无)一卜 曱基-吡咯烷-2-曱醛5c(84 mg，0· 74 mmol)，繼續攪拌1 小時後，室溫反應12小時。濃縮反應液，加入1〇mL水， 用二氯甲烷萃取（25 mLx3) ’合併有機相，用飽和氯化鈉溶 液洗務（30 mLx2) ’無水硫酸鈉乾燥，過濾，減壓濃縮，用 矽膠柱色譜法以洗脫劑體系A純化所得殘餘物，得到標題 產物⑺-N-[4-[(3-氯-4-氟-苯基）胺基]-7-(2-曱氧基乙 氧基）噎唾琳-6-基]-3-[(2/?)-1-曱基吼π各烧-2-基]丙-2- 53 95119 201235041 稀醯胺8 (100 mg，黃色固體），產率：54. 2%。 MS m/z (ESI): 500.2 [M+l] 4 NMR(400 MHz, DMSO-c/ff): (5 9.82 (s，1H)，9 58 (s 1H)，8.89 (s，1H)，8.53 (s，1H)，8.12-8.13 (m，1H): 7.79-7.81 (m, 1H), 7.40-7.44 (m, 1H), 7.32 (s, 1H) 6. 57-6. 75 (m, 2H), 4. 36-4. 37 (m, 2H), 3. 80-3. 81 (m 2H)&gt; 3. 35-3. 32 (m, 4H), 3. 15-3. 13 (m, 1H), 2. 5(s 3{j) 2.40-2.31 (m，2H)，2.08 (m，1H)，1.90-1.81(m，1H)’ 1.70-1.64 (m, 1H) ’ 實施例9 ⑺-N-[4-[(3-氯-4-|1-苯基）胺基]-7_乙氧基_啥11坐琳__6_ 基]-3-[(2^-1-甲基吼咯烷-2-基]丙_2_烯醯胺The first step N-(3-chloro-4-fluoro-phenyl)-7-(2-decyloxyethoxy)-6-nitro-soxazolin-4-amine will be methoxyethanol (152 Mg, 2 mmol) dissolved in 30 mL of dimethyl hydrazine, cooled to 60% sodium hydride (80 mg, 2 mmol), cooled to 40 ° C for 2 hours, then added N-(3- Gas 4-fluoro-phenyl)-7-fluoro-6-de-yl-indole: oxime 4-amine 8a (336 mg, 1 mmol), stirred at 40 ° C for 4 hours, stirred at 50 ° C 12 hour. 20 mL of water was added to the reaction mixture, and the solid was filtered, washed with water (50 mL) and dried under vacuum to give 51 95119 201235041 N-(3-chloro-4-fluoro-phenyl)-7-(2-oxime Ethyl ethoxy)-6-nitro-quinazolin-4-amine 8b (392 mg, yellow solid), yield: 100%. The product is directly subjected to the next reaction. MS m/z (ESI): 393.0 [M+l] N-(3-chloro-4-fluoro-phenyl)-7-(2-decyloxyethoxy)quinazoline-4, 6-Diamine N-(3-chloro-4-fluoro-phenyl)-7-(2-decyloxyethoxy)-6-nitro-hydrazin-4-amine 8b (392 mg, 1 Methyl) and iron powder (392 mg, 7 mmol) ® were dissolved in 20 mL of acetic acid and refluxed for 4 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc) (EtOAc m. Concentration gave the title product M-(3-chloro-4-fluoro-phenyl)-7-(2-decyloxyethoxy) 啥 ° 坐琳-4,6-diamine 8c (200 mg, light yellow 2%。 Yield: 55.2%. MS ra/z (ESI): 363.1 [M+l] · Step 3 N-[4-[(3-chloro-4-fluoro-phenyl)amino]-7-(2-methoxyethoxy) ) 喹 吓 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 5小时备用。 The oil was heated to 50 ° C, the reaction solution was added dropwise 3 mL of diethyl phosphate solution (353 mg, 1.8 mmol) in tetrahydrofuran solution, the reaction was 1.5 hours. N4-(3-chloro-4-fluoro-phenyl)-7-(2-decyloxyethoxy)quinazoline 52 95119 201235041 4' 6 -8= (200 mg, 〇. 55 mm〇1) Dissolve in i〇mL tetranitrogenate. Add the above-mentioned alternate reaction solution at 50 °C, and stir the reaction at 4 (rc. small day. The reaction solution is concentrated under reduced pressure and extracted with dichlorohydrazine (5〇mLx3). The organic phase is combined, and the obtained residue is purified by using a saturated sodium chloride solution (9)-), dried over anhydrous sodium sulfate, filtered, filtered, and concentrated under reduced pressure. The title product is [4_[(3_chloro+fluoro-phenyl)amino]7(2foxyethoxy)indolyl]_2-acid-breaking diacetic acid-ethylamine 8d (150 mg, Light yellow solid), yield: 5 〇. 5%. • MS m/z (ESI): 541.2 [M+l] Step 4 (β-Ν-[4-[(3-Ga-4-fluoro-phenyl)amino]_7_(2-methoxyl) Oxy) quinazolin-6-yl]-3-[(2iP)-l-indolylpyrrolidine-2-yl]propan-2-eneamine N-[4-[(3-chloro-4) -Fluoro-phenyl)amino]-7-(2-decyloxyethoxy)quinazolin-6-yl]-2-phosphate diethyl ester-acetamide 8d (2〇〇mg, 〇. 37 mmol) was dissolved in 1 mL of tetrahydrofuran and cooled to _78Qc in a dry ice bath. • Under a argon atmosphere, a solution of 1 μ of bis-mercaptosylamine lithium in toluene (74 〇 '0. 74 mmol) was added dropwise. After stirring for 30 minutes, to the reaction mixture was added (no)-didecyl-pyrrolidine-2-furaldehyde 5c (84 mg, 0. 74 mmol), stirring was continued for 1 hour, and the reaction was allowed to stand at room temperature for 12 hours. Add 1 mL of water, extract with dichloromethane (25 mL×3), combine with organic phase, wash with saturated sodium chloride solution (30 mL×2), dry over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by eluent system A to give the title product (7)-N-[4-[(3-chloro-4-fluoro-phenyl)amino]-7-(2-decyloxyethoxy)唾琳-6-基]-3-[(2/?)-1-吼 各 各 -2- 基 基 基 丙 53 53 53 53 53 53 53 53 53 53 53 53 53 53 53 53 53 53 53 53 53 53 53 53 53 53 53 54 54 54 54 54 54 54 54 54 54 54 54 54 MS 4 NMR (400 MHz, DMSO-c/ff): (5 9.82 (s, 1H), 9 58 (s 1H), 8.89 (s, 1H), 8.53 (s, 1H), 8.12 - 8.13 (m, 1H): 7.79-7.81 (m, 1H), 7.40-7.44 (m, 1H), 7.32 (s, 1H) 6. 57-6. 75 (m, 2H), 4. 36-4. 37 (m, 2H), 3. 80-3. 81 (m 2H)&gt; 3. 35-3. 32 (m, 4H), 3. 15-3. 13 (m, 1H), 2. 5(s 3{j ) 2.40-2.31 (m, 2H), 2.08 (m, 1H), 1.90-1.81 (m, 1H)' 1.70-1.64 (m, 1H) ' Example 9 (7)-N-[4-[(3-chloro) -4-|1-phenyl)amino]-7_ethoxy_啥11 sits __6_ yl]-3-[(2^-1-methylpyrrolidin-2-yl]propan-2- _ olefinamide

第一步 (β-Ν-[4-[(3-氯-4-氟-苯基）胺基]-7-乙氧基〜喧哇琳 基]-3-[ (2及)-1_曱基η比洛院-2-基]丙烯酿胺 將Ν-[4-[(3-氯-4-氟-苯基）胺基-7-乙氧基_啥嗤琳 -6_基]_2-鱗酸一乙酉旨''乙酿胺7b(300 mg，〇· 59咖〇ι )、、六 95119 54 201235041 解於1〇mL四氫咬喃中，在乾冰浴冷卻至-m：，氬氣保護 下’滴加雙三甲基矽基胺基鋰的甲苯溶液U.2mL，l 18 麵〇1)，攪拌30分鐘，向反應液中加入（灼—卜甲基_吡咯烷 -2-甲醛5c(133 mg ’ 1. is mm〇i)，繼續攪拌1小時後，室 /JDL反應1 2小時。濃縮反應液，加入1 〇 mL水，用二氯甲烧 萃取（25 mLx3)，合併有機相，用飽和氯化納溶液洗滌（3〇 mLx2)，無水硫酸鈉乾燥，過滤，遽液減壓濃縮，用石夕膠柱 色譜法以洗脫劑體系A純化所得殘餘物，得到標題產物 •(幻_N_[4-[(3—氣-4-氟-苯基）胺基]-7-乙氧基-喹唑啉一6— 基]-3-[(2疋)-1-曱基吡咯烷-2-基]丙-2-烯醯胺9 (130 mg ’黃色固體），產率：47. 3%。 MS m/z (ESI): 470.2 [M+l] ^ NMR (400 MHz，DMSO-oW: (5 9.79 (s，1H)，9. 53 (s， 1H), 8.93 (s, 1H), 8.53 (s, 1H), 8.12-8.15 (in, 1H), 7.79-7.83 (m, 1H), 7.40-7.45 (m, 1H), 7.27 (s, 1H), φ 6.67-6.73 (m, 1H), 6.56-6.60 (m, 1H), 4.27-4.32 (m, 2H), 4.09-4.10 (m, 1H), 3.17 (m, 2H), 3.04 (m, 1H), 2.77-2.79 (in, 1H), 2.18-2.16 (m, 1H), 2.21 (s, 3H), 1.74-1.76 (m, 1H), 1.47 (t, 3H) 實施例10 (五)4-[4-[[3-氯-4-(2-咐1啶基曱氧基）苯基]胺基]-3-氰 基-7-乙氧基-6-啥琳基]-3-（1-曱基°比洛烧-2-基）-丙-2- 烯酿胺 55 95119 201235041The first step (β-Ν-[4-[(3-chloro-4-fluoro-phenyl)amino]-7-ethoxy~喧Wallinyl]-3-[ (2 and)-1_曱-n 比 洛 院-2-yl] acrylamide amine Ν-[4-[(3-chloro-4-fluoro-phenyl)amino-7-ethoxy 啥嗤 -6 -6-6 base] _2-Squaric acid-Ethyl acetate-'Ethylamine 7b (300 mg, 〇·59 ca 〇ι), and hexa 95119 54 201235041 were dissolved in 1 〇mL tetrahydrogenate and cooled to -m: in a dry ice bath. Under the protection of argon, add dropwise toluene solution of bis-trimethylsulfonylamino lithium in U.2mL, l 18 〇1), stir for 30 minutes, and add to the reaction solution (cob-methyl-pyrrolidine-2-carbaldehyde) 5c (133 mg ' 1. is mm〇i), after stirring for 1 hour, the chamber/JDL reaction was carried out for 12 hours. The reaction solution was concentrated, 1 mL of water was added, and the mixture was extracted with dichloromethane (25 mL×3). The phase was washed with a saturated sodium chloride solution (3 mL mL), dried over anhydrous sodium sulfate, filtered, and evaporated. (Fantasy_N_[4-[(3-carb-4-fluoro-phenyl)amino]-7-ethoxy-quinazoline-6-yl]-3-[(2疋)-1-曱Pyrrolidin-2-yl]prop-2-ene Amine 9 (130 mg 'yellow solid), Yield: 47. 3%. MS m/z (ESI): 470.2 [M+l] NMR (400 MHz, DMSO-oW: (5 9.79 (s, 1H) , 9. 53 (s, 1H), 8.93 (s, 1H), 8.53 (s, 1H), 8.12-8.15 (in, 1H), 7.79-7.83 (m, 1H), 7.40-7.45 (m, 1H) , 7.27 (s, 1H), φ 6.67-6.73 (m, 1H), 6.56-6.60 (m, 1H), 4.27-4.32 (m, 2H), 4.09-4.10 (m, 1H), 3.17 (m, 2H ), 3.04 (m, 1H), 2.77-2.79 (in, 1H), 2.18-2.16 (m, 1H), 2.21 (s, 3H), 1.74-1.76 (m, 1H), 1.47 (t, 3H) Example 10 (5) 4-[4-[[3-Chloro-4-(2-indole-1-yloxy)phenyl]amino]-3-cyano-7-ethoxy-6-oxime琳基]-3-(1-indolylpyrrol-2-yl)-prop-2-enylamine 55 95119 201235041

第一步 吡咯烷-2-羧酸曱酯 冰浴條件下，將7 mL二氯亞砜滴加到50 mL曱醇中， 加入°比ρ各院-2-竣酸10a(5 g，43. 40 mmol)，在室溫擾拌 24小時。將反應液在減壓下濃縮，得到粗品吡咯烷-2-羧 酸甲酯1 Ob (10 g，白色固體），產物不經純化直接進行下 一步反應。 MS m/z (ESI): 130. 1 [M+l] 第二步 卜甲基-吡咯烷-2-羧酸甲酯 將粗品吡咯烷-2-羧酸甲酯10b(5 g)溶解於100 mL曱 醇中，將反應液在冰浴下冷卻至0至5°C，加入13 mL40% 甲醛溶液，反應液升至室溫攪拌2小時後，冰浴繼續冷卻 至0至5°C，分批加入氰基删氫化納（5. 45g，87. 20 mmol)， 56 95119 201235041 在室溫攪拌24小時。將反應液在減壓下濃縮，加入5 mL 水，用二氯甲烷萃取（5 mLx3)，合併的有機相依次用無水 硫酸鈉乾燥，過濾，減壓下濃縮，得到粗品1-曱基-吡咯 烷-2-羧酸曱酯10c(4. 7g，棕色液體），產率：70. 1%。 MS m/z (ESI): 144.1 [M+l] 第三步 (1-甲基比咯烷-2-基）-曱醇 將二異丁基氫化銘（6 0 mL，6 6 mmo 1)滴加至5 0 mL 1 -_ 甲基-吡咯烷-2-羧酸甲酯10c(4. 7 g，33 mmol)的二氯曱 烷溶液中，反應液在冰浴下反應6小時後，加入10 mL甲 醇。反應液在減壓下濃縮，得到標題產物得到（1-曱基-吼 咯烷-2-基）-曱醇10d(l. 8 g，棕色液體），產率：47. 4%。 第四步 1-曱基-吡咯烷-2-曱醛 將二曱基亞颯（2. 2 mL，31. 20 mmol)溶解於20 mL二 ❶ 氯曱烧中，乾冰丙酮浴下加入草醯氯（2 mL，23. 40 mmol)， 並在-18°C反應45分鐘後，加入（1-曱基-吡咯烷-2-基）-曱醇10d(1.8g，15.60 mmol)，45分鐘後加入三乙胺（6. 5 mL，46. 80 mmol)，自然升至室溫，反應1小時。將反應液 用飽和氯化納溶液洗務（50 mL)，無水硫酸鈉乾燥，過遽， 濾液減壓下濃縮，用鹼性氧化鋁柱色譜法以洗脫劑體系A 純化所得殘餘物，得到1-曱基比咯貌-2-曱搭10e (1 g， 棕色液體），產率：56. 8%。 第五步 57 95119 201235041 (幻-卜[4-[[3-氣-4-(2-吼啶基甲氧基）苯基]胺基]-3-氰 基-7-乙氧基-6-喹啉基]-3-(卜甲基吡咯烷-2-基）_丙_2_ 烯醯胺 乾冰浴下將N-[4-[[3-氯-4-(2-吡啶基甲氧基）苯基] 胺基]-3-氰基-7-乙氧基-6-喹琳基]-2-磷酸二乙酯-乙醯 胺Id (3 g ’ 4. 40丽〇1)溶解於30 mL四氫π夫喃中，逐滴 加入1Μ雙三甲基矽基胺基鋰的曱苯溶液（9. 6 mL，8.80 丽〇1) ’攪拌反應30分鐘，逐滴加入5 mL 1-甲基-吡洛院 -2-曱醛10e(l g，8. 80 mmol)四氫呋喃溶液，繼續反應 3 0为1里，至溫反應2 4小時，反應液減壓濃縮，用梦膠柱 色譜法以洗脫劑體系A純化所得殘餘物，得到標題產物 (i*)-N-[4-[[3-氯-4-(2-吡啶基曱氧基）苯基]胺基]_3—氮 基-7-乙氧基-6-喹啉基]-3-(1-曱基吡咯烷-2-基）一丙 烯醯胺10 (500 mg，黃色固體），產率：20. 8%。 MS m/z (ESI): 583.2 [M+l] iNMRUOOMHz，DMSO-A): 5 11.59(s，1H), 11.28(s 1H), 9.19 (s, 1H), 9.05 (s, 1H), 8.71 (d, 1H), 8.09-8.07 (in, 1H), 7.74-7.68 (m, 3H), 7.56-7.55 (m, 1H) 7.45-7.37 (m, 2H), 7.04-7.00 (m, 1H), 6.88-6.84 (m 1H), 5.43 (s, 2H), 4.38 (dd, 2H), 4.10 (m, 2H), 3 g3_ 3.60 (m, 1H), 3.13-3.08 (ra, 1H), 2.73-2.72 (m, 3H) 2.31-2.29 (m, 1H), 2.08-2.02 (m, 2H), 1.53 (t, 3H) 測試例： 生物學評價 95119 58 201235041 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EGFR 高表現的細胞株人表皮鱗癌A431的增殖抑制活性。 以下所述的體外細胞試驗可測定受試化合物的對高 表現EGFR的腫瘤細胞的抑制增殖活性，其活性可用IC5〇 值來表示。此類試驗的一般方案如下：首先選擇高表現 EGFR的人類腫瘤細胞A431(購於Institute of biochemistry and cell biology)，以適宜細胞濃度（e.g. ❿ 5000個細胞/mL medium)接種在96孔培養板上，然後將細 胞在二氧化碳恒溫箱内進行培養，當它們生長至85%匯合， 更換培養基為加有一系列濃度梯度（一般6或7個濃度）受 試化合物溶液的培養基繼續培養。72小時後，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。 IC5〇值可經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。 本發明化合物的活性In the first step, pyrrolidine-2-carboxylic acid decyl ester was added to 50 mL of sterol in an ice bath, and the ratio of ρ 院 竣 竣 竣 10 10 10 (5 g, 43 40 mmol), disturbed for 24 hours at room temperature. The reaction mixture was concentrated under reduced pressure toieldield, md. MS m/z (ESI): 130. 1 [M+l] The second step is methyl-pyrrolidine-2-carboxylate. The crude pyrrolidine-2-carboxylate 10b (5 g) is dissolved in 100 mL. In the sterol, the reaction solution was cooled to 0 to 5 ° C in an ice bath, 13 mL of 40% formaldehyde solution was added, and the reaction solution was stirred at room temperature for 2 hours, and then cooled to 0 to 5 ° C in an ice bath, batchwise. Add cyanohydrazine (5. 45 g, 87.20 mmol), 56 95119 201235041 and stir at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. 1%。 The alkane-2-carboxylate 10c (4.7 g, brown liquid), yield: 70.1%. MS m/z (ESI): 144.1 [M+l] Step 3 (1-Methylpyrrolidin-2-yl)-nonanol Hydrogenated diisobutyl hydride (60 mL, 6 6 mmo 1) Add dropwise to 50 mL of 1 -_methyl-pyrrolidine-2-carboxylic acid methyl ester 10c (4.7 g, 33 mmol) in dichloromethane, and react the reaction solution in an ice bath for 6 hours. Add 10 mL of methanol. 4%。 The reaction mixture was concentrated under reduced pressure to give the titled product (l-mercapto- </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; The fourth step is 1 - mercapto-pyrrolidine-2-furaldehyde. Dimercaptoarthracene (2.2 mL, 31.20 mmol) is dissolved in 20 mL of dichloropyrene, and added to the grass under dry ice acetone bath. Chlorine (2 mL, 23.40 mmol), and after reacting at -18 ° C for 45 min, (1-mercapto-pyrrolidin-2-yl)-nonanol 10d (1.8 g, 15.60 mmol), 45 min After adding triethylamine (6.5 mL, 46.80 mmol), it was naturally warmed to room temperature and reacted for 1 hour. The reaction solution was washed with a saturated aqueous solution of sodium chloride (50 mL), dried over anhydrous sodium sulfate, and then evaporated, and the filtrate was concentrated under reduced pressure. 1-8% 比 比 曱 曱 曱 曱 曱 曱 e 10e (1 g, brown liquid), yield: 56.8%. Step 5 57 95119 201235041 (Fanta-Bu [4-[[3-Ga-4-(2-Acrylylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6 - quinolinyl]-3-(b-methylpyrrolidin-2-yl)-propan-2-enebenzamide N-[4-[[3-chloro-4-(2-pyridylmethoxy)] Phenyl]amino]-3-cyano-7-ethoxy-6-quinolinyl]-2-phosphate diethyl ester-acetamide Id (3 g ' 4. 40 丽〇1) dissolved in 30 In a solution of 1 Μ bis-trimethyl decylamino lithium (9.6 mL, 8.80 丽〇1) was added dropwise to mL tetrahydropyrene, and the reaction was stirred for 30 minutes, and 5 mL of 1-A was added dropwise. Base-Pyloline-2-furaldehyde aldehyde 10e (lg, 8.80 mmol) in tetrahydrofuran solution, continue to react for 30 ° 1 liter, to warm reaction for 24 hours, the reaction solution is concentrated under reduced pressure, using a gel column chromatography The residue obtained was purified by eluent system A to give the title product (i*)-N-[4-[[3-chloro-4-(2-pyridinyloxy)phenyl]amino]amino] -7-ethoxy-6-quinolinyl]-3-(1-indolylpyrrolidin-2-yl)-propenylamine 10 (500 mg, yellow solid), yield: 20.8%. m/z (ESI): 583.2 [M+l]: NMR OOOO, DMSO-A): 5 11.59 (s, 1H), 11.28 (s 1H), 9.19 (s, 1H) , 9.05 (s, 1H), 8.71 (d, 1H), 8.09-8.07 (in, 1H), 7.74-7.68 (m, 3H), 7.56-7.55 (m, 1H) 7.45-7.37 (m, 2H), 7.04-7.00 (m, 1H), 6.88-6.84 (m 1H), 5.43 (s, 2H), 4.38 (dd, 2H), 4.10 (m, 2H), 3 g3_ 3.60 (m, 1H), 3.13-3.08 (ra, 1H), 2.73-2.72 (m, 3H) 2.31-2.29 (m, 1H), 2.08-2.02 (m, 2H), 1.53 (t, 3H) Test Example: Biological Evaluation 95119 58 201235041 Example 1 EGFR Inhibition of Cell Proliferation Assay The following in vitro assay was used to determine the proliferation inhibitory activity of the compounds of the invention against human epidermal squamous cell carcinoma A431, a cell line with high expression of EGFR. The in vitro cell assay described below can determine the proliferative activity of a test compound against tumor cells exhibiting high expression of EGFR, and the activity can be expressed by the IC5〇 value. The general protocol for such an experiment is as follows: First, human tumor cell A431 (acquired from Institute of biochemistry and cell biology) with high expression of EGFR is selected and seeded on a 96-well culture plate at a suitable cell concentration (eg ❿ 5000 cells/mL medium). Then, the cells were cultured in a carbon dioxide incubator, and when they grew to 85% confluence, the medium was changed to a medium supplemented with a series of concentration gradients (generally 6 or 7 concentrations) of the test compound solution. After 72 hours, the test compound was 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. Activity of the compounds of the invention

S 本發明化合物的生化學活性經由以上的試驗進行測 定，測得的IC5〇值見下表。 實施例編號 IC5〇 (EGFR/A431)(^M) 1 0. 022 2 0. 003 3 0. 036 5 0. 045 9 0. 008 結論：本發明化合物對A 4 31細胞具有明顯的抑制增殖活性。 59 95119 201235041 例2 · EGFR激酶活性測定 體外EGFR激酶活性經由以下的方法進行測試。 下面所述的方法是用來測定本發明化合物的抑制 EGFR激酶活性。化合物的半抑制濃度IC5。（把酶活性抑制 至50%時所需的化合物的濃度）是以固定的酶混合特定底 物及不同濃度的待測化合物來測定的。本實驗所用的EGFR 激酶為人源重組蛋白（購於Cell signaling technology #7908)，該酶在含有 60 mM HEPES (ρΗ7· 5)，5 mM MgCl2 ’S The biochemical activity of the compound of the present invention was measured by the above test, and the measured IC5 enthalpy value is shown in the following table. Example No. IC5〇(EGFR/A431)(^M) 1 0. 022 2 0. 003 3 0. 036 5 0. 045 9 0. 008 Conclusion: The compound of the present invention has significant inhibitory activity against A 4 31 cells. . 59 95119 201235041 Example 2 · Measurement of EGFR kinase activity In vitro EGFR kinase activity was tested by the following method. The methods described below were used to determine the inhibition of EGFR kinase activity by the compounds of the invention. The semi-inhibitory concentration of the compound is IC5. (The concentration of the compound required to inhibit the enzymatic activity to 50%) is determined by mixing a specific substrate with a fixed enzyme and different concentrations of the test compound. The EGFR kinase used in this experiment is a human recombinant protein (purchased from Cell signaling technology #7908) containing 60 mM HEPES (ρΗ7.5), 5 mM MgCl2'

5 mM MnCl2，3/iM Na3V〇4，1. 25 M DTT (lOOOx)和 20 μΜ ATP 的緩衝溶液中與多肽底物以及不同濃度的受試化合物共同 進行反應（25°C，45分鐘），使用時間分辨螢光的方法對該 蛋白激酶活性加以定量測定。 本發明化合物的活性 本發明化合物的生化學活性經由以上的試驗進行測定，測 得的IC5〇值見下表。 實施例編號 ICs〇 (EGFR/BI0)(^M) 1 0. 048 2 0. 006 3 0. 059 5 0. 013 7 0. 004 8 0. 002 9 0. 002 結論：本發明化合物對EGFR激酶具有明顯的抑制增殖活 性。 60 95119 201235041 藥物代謝動力學評價 測試例1 本發明實施例1和實施例5化合物的藥物代謝 動力學測試 1、 摘要 以大鼠為受試動物，應用LC/MS/MS法測定了大鼠分 別灌胃給予實施例1化合物與實施例5化合物後不同時刻 血漿中的藥物濃度。研究本發明化合物在大鼠體内的藥物 代謝動力學行為，評價其藥動學特徵。 • 2、試驗方案 2. 1試驗樂品 實施例1化合物和實施例5化合物 2. 2試驗動物 健康成年SD大鼠8隻，雌雄各半，購自上海西普爾-必凱實驗動物有限公司，動物生產許可證號： SCXK(滬）2003-0002。 H 2. 3藥物配製 稱取適量藥物，加入0. 5%羧曱基纖維素鈉研磨至樣品 均勻混懸，吐溫（Tween)80終濃度為1°/。，樣品濃度為2. 5 mg/mL ° 2.4給藥 健康成年SD大鼠8隻，雌雄各半，禁食過夜後分別灌 胃給藥，給藥劑量均為25. 0 mg/kg，給藥體積10 mL/kg。 2. 5樣品採集 SD大鼠8隻，雌雄各半，平均分成2組，禁食一夜後 61 95119 201235041 灌胃給藥’劑量為25 mg/kg。於給藥前及給藥後〇. 5，1. 〇, 2.0，3.0，4.0，5.0，7.0，9.0，12.0，24. 0，30.0 小時 由眼眶采血0· 2 mL，置於肝素化試管中，3500轉/分鐘， 離心10分鐘分離血漿，於— 2〇°c保存，給藥後2小時進 食0 3、操作 取給藥後大鼠各大鼠血漿5〇eL，分別加入標準系列 溶液 50//L，使血藥濃度為 5〇 〇，1〇〇，2〇〇，5〇〇，1〇〇〇, 2000, 5000 ng/mL，甲醇50/zL ’混勻後渦旋混合3分鐘， 離心10分鐘（13500轉/分鐘），取上清液1〇//]L進行 LC-MS/MS分析。主要藥物代謝動力學參數採用DAS 2. 〇軟 體計算。 藥物代謝動力學參數結果 本發明化合物的藥物代謝動力學來射如下 編號 實施例1 __爭物代謝資驗 血樂 &gt;展度 曲線面積 半衰期 滞留時間 清除率 矣猶公你玄it CllldX C^g/mL) ^4. 48+1.88 AUC (βg/mL^h) 52. 58±38. 96 ^ tl/2 —_ 4. 04+1. 39 MRT _Ch) 7. 78+1^0^ CL/F _〇/h/kg) Vz/F (1/kg) T狍例 5 丨 6.47±1.81 結論：太發明音故4 52. 81±23. 59 5ιί於.合物越λΧ 3. 4±0. 45 7. 66±〇Γ75~ -J· 76±0. 53 -_Λ13±0.18 3. 71+1.68 2. 6+0. 94 1、摘要 人肺癌Calu-3裸小鼠移植瘤 的療效評價 裸小鼠移植瘤 的生長，小鼠能 評價並比較實施例1對人肺癌Calu〜3 的療效。實施例1明顯抑制人肺癌Calu〜3 很好地耐受。 95119 62 201235041 2、實驗目的 評價並比較實施例i和實施例5化合物對人肺癌 • calu-3裸小鼠移植瘤的療效。 . 3、受試藥物 藥物名稱和批號：實施例i化合物和實施例5化合物 配製方法：實施例1和實施例5化合物用含〇. 1% Tween-80的蒸餾水配成所需濃度。 4、 實驗動物 BALB/cA-nude裸小鼠，6至7周，早，購自上海斯萊 克實驗動物有限責任公司。合格證號：Scxk(滬）2〇〇7 — 0005。 飼養環境：SPF級。 5、 實驗步驟 裸小鼠皮下接種人肺癌Calu-3細胞，待腫瘤生長至 150至250 mm後’將動物隨機分組（d〇)。 每週測2至3次瘤體積，稱鼠重’記錄資料。 ㉚ 腫瘤體積（V)計算公式為：V= l/2xaxb2其中a、b分 別表示長、寬。 6、 結果 實施例1明顯抑制人肺癌Calu-3的生長。實施例1 化合物低劑量（100 mg/kg)導致2/6個腫瘤縮小，高劑量 (200 mg/kg)導致1/6個腫瘤縮小，另外1/6腫瘤完全消 退’實施例5化合物低劑量（1 〇〇 mg/kg)導致3/6個腫瘤縮 小，高劑量（200 mg/kg)導致4/6個腫瘤縮小。按照目前的 給藥方案，小鼠對實施例1和實施例5化合物均能很好地 95119 63 201235041 而才受。 【圖式簡單說明】 無 【主要元件符號說明】5 mM MnCl2, 3/iM Na3V〇4, 1.25 M DTT (lOOOOx) and 20 μΜ ATP buffer solution were reacted with the peptide substrate and different concentrations of the test compound (25 ° C, 45 minutes), The protein kinase activity was quantified using time-resolved fluorescence. 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 IC5 enthalpy value is shown in the following table. EXAMPLES ICs〇(EGFR/BI0)(^M) 1 0. 048 2 0. 006 3 0. 059 5 0. 013 7 0. 004 8 0. 002 9 0. 002 Conclusion: Compounds of the invention against EGFR kinase It has obvious inhibitory activity against proliferation. 60 95119 201235041 Pharmacokinetic evaluation test example 1 Pharmacokinetic test of the compounds of Example 1 and Example 5 of the present invention 1. Abstract Rats were used as test animals, and the rats were determined by LC/MS/MS method. The concentration of the drug in the plasma at different times after administration of the compound of Example 1 and the compound of Example 5 by gavage. The pharmacokinetic behavior of the compounds of the present invention in rats was investigated and their pharmacokinetic characteristics were evaluated. 2. Test protocol 2.1 Test compound Example 1 compound and Example 5 compound 2. 2 test animals 8 healthy adult SD rats, male and female, purchased from Shanghai Xipuer-Beikai Experimental Animal Co., Ltd. Animal Production License No.: SCXK (Shanghai) 2003-0002. H 2. 3 Preparation of the drug Weigh the appropriate amount of the drug, add 0.5% sodium carboxymethyl cellulose to the sample and evenly suspend, the final concentration of Tween 80 is 1 ° /. The sample concentration is 2. 5 mg / mL ° 2.4 administration of healthy adult SD rats, 8 males and females, respectively, after fasting overnight, respectively, administered at a dose of 25.0 mg / kg, administered Volume 10 mL/kg. 2. 5 sample collection 8 SD rats, male and female, divided into 2 groups, after fasting overnight 61 95119 201235041 intragastric administration 'dose 25 mg / kg. Before, and after administration, ,. 5,1. 〇, 2.0,3.0,4.0,5.0,7.0,9.0,12.0,24. 0,30.0 hours from the orbital blood collection 0·2 mL, placed in heparinized test tubes At 3500 rpm, the plasma was separated by centrifugation for 10 minutes, stored at -2 °C, and fed for 0 hours 2 hours after administration. The plasma of each rat was administered 5 〇eL, and the standard series solution 50 was added. //L, make the blood concentration 5 〇〇, 1 〇〇, 2 〇〇, 5 〇〇, 1 〇〇〇, 2000, 5000 ng / mL, methanol 50 / zL 'mix and vortex for 3 minutes After centrifugation for 10 minutes (13,500 rpm), the supernatant was taken 1 〇//] L for LC-MS/MS analysis. The main pharmacokinetic parameters were calculated using DAS 2. 〇 software. Pharmacokinetic parameters results The pharmacokinetics of the compounds of the present invention are as follows. No. Example 1 __Competitive metabolism test blood music> Spread curve area Half-life retention time clearance rate 矣 公 公 You Xuan it CllldX C^ g/mL) ^4. 48+1.88 AUC (βg/mL^h) 52. 58±38. 96 ^ tl/2 —_ 4. 04+1. 39 MRT _Ch) 7. 78+1^0^ CL /F _〇/h/kg) Vz/F (1/kg) T狍Example 5 丨6.47±1.81 Conclusion: Too invented the sound 4 52. 81±23. 59 5ιί于. The compound λΧ 3. 4± 0. 45 7. 66±〇Γ75~ -J· 76±0. 53 -_Λ13±0.18 3. 71+1.68 2. 6+0. 94 1. Efficacy evaluation of human lung cancer Calu-3 nude mice xenografts The growth of nude mice xenografts, the mice can evaluate and compare the efficacy of Example 1 on human lung cancer Calu~3. Example 1 significantly inhibited human lung cancer Calu~3 well tolerated. 95119 62 201235041 2. Experimental Objectives The efficacy of the compounds of Example i and Example 5 on human lung cancer • calu-3 nude mice xenografts was evaluated and compared. 3. Test Drugs Drug Name and Lot Number: Example I Compound and Example 5 Compound Formulation Method: The compounds of Example 1 and Example 5 were formulated to a desired concentration with distilled water containing 0.1% Tween-80. 4. Experimental animals BALB/cA-nude nude mice, 6 to 7 weeks old, were purchased from Shanghai Slack Laboratory Animals Co., Ltd. Certificate No.: Scxk (Shanghai) 2〇〇7 — 0005. Feeding environment: SPF level. 5. Experimental procedure Nude mice were subcutaneously inoculated with human lung cancer Calu-3 cells, and the animals were randomly grouped (d〇) after the tumors were grown to 150 to 250 mm. Two to three tumor volumes were measured weekly, and the rats were weighed to record data. 30 The tumor volume (V) is calculated as: V = l/2xaxb2 where a and b represent length and width, respectively. 6. Results Example 1 significantly inhibited the growth of human lung cancer Calu-3. Example 1 Low dose (100 mg/kg) of the compound resulted in 2/6 tumor shrinkage, high dose (200 mg/kg) resulted in 1/6 tumor shrinkage, and 1/6 tumor completely resolved 'Example 5 compound low dose (1 〇〇mg/kg) resulted in 3/6 tumor shrinkage, and high dose (200 mg/kg) resulted in 4/6 tumor shrinkage. According to the current dosing regimen, the mice were able to receive the compounds of Examples 1 and 5 well 95119 63 201235041. [Simple description of the diagram] None [Main component symbol description]

Claims (1)

201235041 七、申請專利範圍： 體、對映異構 可藥用的鹽： h 一種所;;的化合物或其互變異構體、外消旋 、、 #對映異構體、及其混合物形式、及201235041 VII. Scope of application: a compound, an enantiomerically pharmaceutically acceptable salt: h a compound; or a tautomer thereof, a racemic, an enantiomer, and a mixture thereof, and 其中： A選自碳原子或氮原子； 、，當A為碳原子時’R1選自氫原子或烧氧基，其中所 述的炫氧基視需要進—步被—個或多個選自鹵素或烧 氧基的取代基所取代，R2選自氰基； 、當A為氮原子時，Rl選自氫原子或烧氧基，其中所 述的烧氧基視需要進—步被—個或多個選自鹵素或烧 氧基的取代基所取代，R2無取代； R3具有下列結構：或一D ; 其中： β選自芳基或雜芳基’其中所述的芳基或雜芳基各 自獨立地視需要進一步被一個或多個選自函素、烷基或 三氟甲基的取代基所取代； Τ 選自-(CH2)r- ’ -〇(CH2)r-，-NH(CH2)r-或 -S(0)r(CH2)r-； 95119 201235041 L選自芳基或雜芳基’其+所述的芳基或雜芳基各 自獨立地視需要進一步被一個或多個齒素或烧基所取 代； R4和R5各自獨立地選自氫原子、烧基、烧氧基、 羥基、經烧基、i素、幾基、胺基、氰基、确基、幾酸 或羧酸酯； B選自碳原子、氧原子或S(0)r基團； 當B為碳原子時’R7各自獨立地選自氫原子、 烷基、烧氧基、經基、經烧基、自素、幾基、胺基、氰 基、硝基、羧酸或羧酸酯； 當B為氧原子或s(〇)r基團時，^和f無取代； R8選自氫原子或烷基； R選自氫原子、烷基、芳基、羧基或羧酸酯； r為0、1或2 ;且 η為 1、2、3、4 或 5。 2.如申明專利範圍第1項所述的化合物或其互變異構體、 外消旋體、對映異構體、非對映異構體、及其混合物形 式、及可藥用的鹽，其中包括通式（ΠΑ)或（ΙΙΒ)所述的 化合物或其互變異構體、外消旋體、對映異構體、非對 映異構體、及其混合物形式、及可藥用的鹽：Wherein: A is selected from a carbon atom or a nitrogen atom; and, when A is a carbon atom, 'R1 is selected from a hydrogen atom or an alkoxy group, wherein the oxo group is further selected from one or more Substituted by a halogen or alkoxy substituent, R2 is selected from a cyano group; when A is a nitrogen atom, R1 is selected from a hydrogen atom or an alkoxy group, wherein the alkoxy group is further stepped as needed Or a plurality of substituents selected from halogen or alkoxy groups, R2 is unsubstituted; R3 has the following structure: or a D; wherein: β is selected from aryl or heteroaryl, wherein said aryl or heteroaryl The groups are each independently substituted with one or more substituents selected from a functional element, an alkyl group or a trifluoromethyl group as needed; Τ is selected from the group consisting of -(CH2)r- '-〇(CH2)r-, -NH (CH2)r- or -S(0)r(CH2)r-; 95119 201235041 L is selected from aryl or heteroaryl 'the + aryl or heteroaryl group thereof is independently further optionally one or Substituted by a plurality of dentates or alkyl groups; R4 and R5 are each independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkoxy group, a hydroxyl group, a pyridyl group, an i group, a aryl group, an amine group, a cyano group, a certain group, a few groups Acid Or a carboxylic acid ester; B is selected from a carbon atom, an oxygen atom or a S(0)r group; when B is a carbon atom, 'R7 is each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a trans group, and a burnt group. a group, a self group, a aryl group, an amine group, a cyano group, a nitro group, a carboxylic acid or a carboxylic acid ester; when B is an oxygen atom or a s(〇)r group, ^ and f are unsubstituted; R8 is selected from a hydrogen atom. Or an alkyl group; R is selected from a hydrogen atom, an alkyl group, an aryl group, a carboxyl group or a carboxylic acid ester; r is 0, 1 or 2; and η is 1, 2, 3, 4 or 5. 2. A compound according to the first aspect of the invention, or a tautomer, a racemate, an enantiomer, a diastereomer, a mixture thereof, and a pharmaceutically acceptable salt, These include compounds of the formula (ΠΑ) or (ΙΙΒ) or their tautomers, racemates, enantiomers, diastereomers, mixtures thereof, and pharmaceutically acceptable salt: (ΠΑ) 或 （ΠΒ&gt; 2 95119 201235041 其中’所述的A、B、R!至R9和n的定義如申 利範圍第1項所定義。 μ專 申叫專利範固第2項所述的化合物或其互變里 外消旋體^映異構體、非對映異構體、及其混合物形 式、2及可藥用的鹽，其中Α為碳原子，R1選自烷氧基二 且R2選自氰基。 土 ’ 如申°月專利範圍第2項所述的化合物或其互變異構體、 卜肖旋體對映異構體、非對映異構體、及其混合物形 式、2及可藥用的鹽，其中A為氮原子，Rl選自氫原子^ 且R無取代。 申明專利範圍第2項所述的化合物或其互變里構體、 外消旋體、對映異構體、非對映異構體、及其混合物形 式、及可藥用的鹽，其中11為2。(ΠΑ) or (ΠΒ&gt; 2 95119 201235041 where 'the definitions of A, B, R! to R9 and n are as defined in claim 1 of the scope of the application. a compound or a tautomer thereof, a diastereomer, a diastereomer, a mixture thereof, and a pharmaceutically acceptable salt, wherein hydrazine is a carbon atom and R1 is selected from alkoxy group and R2 is selected from the group consisting of cyano. The soil as described in the second paragraph of the patent scope of the invention, or the tautomers thereof, the bromide enantiomers, the diastereomers, and mixtures thereof, 2 A pharmaceutically acceptable salt, wherein A is a nitrogen atom, R1 is selected from a hydrogen atom and R is unsubstituted. The compound of claim 2 or its tautomeric complex, racemate, enantiomer And diastereoisomers, mixtures thereof, and pharmaceutically acceptable salts, of which 11 is 2. 申月專利範圍第2項所述的化合物或其互變異構體、 外请旋體:對映異構體、非對映異構體、及其混合物形 式^可藥用的鹽，其中包括通式⑴⑷或⑴⑻所述 、 物或其互變異構體、外消旋體、對映異構體、非 對映異構體、及其混合物形式、及可藥用的鹽：The compound described in the second paragraph of the patent application, or the tautomers thereof, the external rotation: enantiomers, diastereomers, and mixtures thereof, pharmaceutically acceptable salts, including Or a tautomer, a racemate, an enantiomer, a diastereomer, a mixture thereof, and a pharmaceutically acceptable salt as described in the formula (1) (4) or (1) (8): 直1A) (IIIB) 其中：A、R丨至“、。”的定義如申請專 範圍第2項所定義。 95119 3 201235041 如申請專利範圍第2項所述的化合物或其互變異構體、 外消旋體、對映異構體、非對映異構體、及其混合物形 式、及可藥用的鹽，所述的通式結構為：Straight 1A) (IIIB) where: A, R 丨 to ",." is defined as defined in item 2 of the application scope. 95119 3 201235041 The compound of claim 2, or a tautomer, racemate, enantiomer, diastereomer, mixture thereof, and pharmaceutically acceptable salt thereof, as claimed in claim 2; , the general structure is: (IVA) (IVB) 其中：A、R1至R3、R6和R9的定義如申請專利範圍 第2項所定義。 .如申清專利範圍第1項所述的化合物或其互變異構體、 外消旋體、對映異構體、非對映異構體、及其混合物形 式、及可樂用的鹽，其中該化合物為下列化合物：(IVA) (IVB) wherein: A, R1 to R3, R6 and R9 are as defined in the second paragraph of the patent application. The compound of claim 1, or the tautomer, racemate, enantiomer, diastereomer, mixture thereof, and cola salt thereof, wherein This compound is the following compound: 9·—種通式（V)所示的化合物： 95119 4 2012350419. A compound of the formula (V): 95119 4 201235041 R2 (V) 其中： R1為烷氧基； A和R1至R3如申請專利範圍第1項所定義。 10. 一種製備申請專利範圍第g項所述的通式（¥)化合物的 方法，該方法包括以下步驟： I j Η〆 ⑽~ (V_l) (V) 通式（V_l)化合物轉化為通式（v)化合物； 其中：A和R1至R3的定義如申請專利範圍第9項 所述。 U· —種製備申請專利範圍第丨項所述的通式（〗）化合物的 方法，該方法包括以下步驟：R2 (V) wherein: R1 is an alkoxy group; and A and R1 to R3 are as defined in the first item of the patent application. 10. A process for the preparation of a compound of the formula (¥) according to item g of the patent application, the process comprising the steps of: I j Η〆(10)~(V_l) (V) conversion of a compound of the formula (V-1) into a formula (v) a compound; wherein: A and R1 to R3 are as defined in claim 9 of the scope of the patent application. U. A method of preparing a compound of the formula (] as described in the scope of the patent application, the method comprising the steps of: (V) (1) 通式（V)化合物與通式（VI)化合物反應得到通式（I) 化合物； 5 95119 201235041 其中： R為燒氧基； 申請專利範圍第1項 A、B、n和R1至R9的定義如 所述。(V) (1) A compound of the formula (V) is reacted with a compound of the formula (VI) to give a compound of the formula (I); 5 95119 201235041 wherein: R is an alkoxy group; Patent Application No. 1, A, B, n And R1 to R9 are as defined. 通式（V)化合物與通式（VIA)化合物反應得到通式 (IIA)化合物；或者，The compound of the formula (V) is reacted with a compound of the formula (VIA) to give a compound of the formula (IIA); or 通式（V)化合物與通式（VIB)化合物反應得到通式 (IIB)化合物； 其中：A、B、n、R1至R9的定義如申請專利範圍第 2項所述。 13. —種醫藥組成物，含有治療有效劑量的申請專利範圍第 1項所述的化合物或其互變異構體、外消旋體、對映異 構體、非對映異構體、及其混合物形式、及可藥用的鹽 及可藥用的載體。 6 95119 201235041 14. -種製備中請專利範圍第14項所述的醫藥組成物的方 法’該方法包括將申請專利範圍第i項所述的化合物或 • 其互變異構體、外消旋體、對映異構體、非對映異構體、 • 及其混合物形式、及可藥用的鹽與可藥用的載體或稀釋 劑相結合。 15·-種調節蛋白激酶催化活性的方法，其中包括將所述的 蛋白激酶與申請專利範圍第1項所述的化合物或其互 ^ 變異構體、外消旋體、對映異構體、非對映異構體、及 其混合物形式、及可藥用的鹽相接觸，該蛋白激酶選自 EGFR受體酪胺酸激酶或HER_2受體酪胺酸激酶。 16. —種申請專利範圍第丨項所述的化合物或其互變異構 體、外消旋體、對映異構體、非對映異構體、及其混合 物形式、及可藥用的鹽，或申請專利範圍第14項所述 的醫藥組成物在製備治療與蛋白激酶有關的疾病的藥 物中的用途，其中該蛋白激酶選自EGFR受體赂胺酸激 _ 酶或HER-2受體酪胺酸激酶。 作為治療與蛋白激酶有關的疾病的藥物的申請專 利乾圍第1項所述的化合物或其互變異構體、外消旋 體三對映異構體、非對映異構體、及其混合物形式、及 可藥用的鹽’或巾請專利範圍第U項所述的醫藥組成 物其中忒蛋白激酶選自EGFR受體酪胺酸激酶或her_2 受體酪胺酸激酶。 申明專利範圍第1項所述的化合物或其互變異構體、 外满旋體、對映異構體、非對映異構體、及其混合物形 7 95119 201235041 式、及可藥用的鹽，如申請專利範圍帛14項所述的醫 藥組成物在製備EGFR受體酪胺酸激酶或HER_2受體酪 胺酸激酶抑制劑中的用途。 19. 一種申請專利範圍第丨項所述的化合物或其互變異構 體、外消旋體、對映異構體、非對映異構體、及其混合 物形式、及可藥用的鹽’或申請專利範圍第14項所述 的醫藥組成物在製備治療癌症的藥物t的用途，其中該 癌症是肺癌、乳腺癌、表皮鱗癌或胃癌。 2〇·-種治療癌症的方法，該方法包括給予需要治療的患者 有效治療量的申請專利範圍第1項所述的化合物或其 互變異構體、外消旋體、對映異構體、非對映異構體、 及其混合物形式、及可藥用的鹽。 21.作為治療癌症的藥物的申請專利範圍第上項所述的化 4或異構體 '外消旋體、對映異構體、非對映 異構體、及其混合物形式、及可藥用的鹽。 95119 8 201235041 .四、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： 五、本案若有化學式時，請揭示最能顯示發明特徵的化學式：The compound of the formula (V) is reacted with a compound of the formula (VIB) to give a compound of the formula (IIB); wherein: A, B, n, R1 to R9 are as defined in the second item of the patent application. 13. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or a tautomer, racemate, enantiomer, diastereomer thereof, and In the form of a mixture, a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier. 6 95119 201235041 14. A method of preparing a pharmaceutical composition according to item 14 of the patent application, which comprises the compound described in claim i or the tautomer, racemate thereof The enantiomers, diastereomers, and mixtures thereof, and pharmaceutically acceptable salts are combined with a pharmaceutically acceptable carrier or diluent. A method for modulating the catalytic activity of a protein kinase, which comprises the method of the protein kinase described in the first aspect of the patent application, or a homo-isomer, a racemate, an enantiomer thereof, The diastereomer, in the form of a mixture thereof, and a pharmaceutically acceptable salt are contacted, and the protein kinase is selected from the group consisting of an EGFR receptor tyrosine kinase or a HER 2 receptor tyrosine kinase. 16. The compound of claim 3, or a tautomer, racemate, enantiomer, diastereomer, mixture thereof, and pharmaceutically acceptable salt thereof Or the use of the pharmaceutical composition according to claim 14 in the preparation of a medicament for treating a protein kinase-related disease, wherein the protein kinase is selected from the group consisting of the EGFR receptor glycosidase or HER-2 receptor Tyrosine kinase. A compound or a tautomer thereof, a racemic tri-enantiomer, a diastereomer, and a mixture thereof, as a drug for treating a protein kinase-related disease Forms, and pharmaceutically acceptable salts, or the pharmaceutical compositions of the U.S. Patent Application, wherein the prion protein kinase is selected from the group consisting of EGFR receptor tyrosine kinase or her_2 receptor tyrosine kinase. A compound according to the first aspect of the patent, or a tautomer thereof, an external full-rotation, an enantiomer, a diastereomer, and a mixture thereof, and a pharmaceutically acceptable salt thereof. The use of a pharmaceutical composition as described in claim 14 in the preparation of an EGFR receptor tyrosine kinase or a HER 2 receptor tyrosine kinase inhibitor. 19. A compound according to the scope of claim 2, or a tautomer, a racemate, an enantiomer, a diastereomer thereof, a mixture thereof, and a pharmaceutically acceptable salt. Or the use of the pharmaceutical composition according to claim 14 in the preparation of a medicament for treating cancer, wherein the cancer is lung cancer, breast cancer, epidermal squamous cell carcinoma or gastric cancer. A method for treating cancer, which comprises administering to a patient in need of treatment a therapeutically effective amount of a compound described in claim 1 or a tautomer, a racemate, an enantiomer thereof, Diastereomers, mixtures thereof, and pharmaceutically acceptable salts. 21. The invention as claimed in the above paragraph of the invention for the treatment of cancer, the 4 or isomer 'racemate, enantiomer, diastereomer, mixture thereof, and medicinal Salt used. 95119 8 201235041 . IV. Designated representative map: There is no schema in this case (1) The representative representative figure of this case is: (). (2) A brief description of the symbol of the representative figure: 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: 3 951193 95119
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115697994A (en) * 2020-06-10 2023-02-03 江苏恒瑞医药股份有限公司 Fused quinazoline derivative, preparation method and medical application thereof

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115697994A (en) * 2020-06-10 2023-02-03 江苏恒瑞医药股份有限公司 Fused quinazoline derivative, preparation method and medical application thereof

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