TWI406853B - Dual inhibitors of egfr and vegfr-2 and uses and production processes thereof - Google Patents

Dual inhibitors of egfr and vegfr-2 and uses and production processes thereof Download PDF

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TWI406853B
TWI406853B TW99110796A TW99110796A TWI406853B TW I406853 B TWI406853 B TW I406853B TW 99110796 A TW99110796 A TW 99110796A TW 99110796 A TW99110796 A TW 99110796A TW I406853 B TWI406853 B TW I406853B
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compound
formula
egfr
cancer
alkyl
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TW99110796A
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TW201134816A (en
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Mann Yan Kuo
Shyh Fong Chen
Ta Tung Yuan
Ru Wen Wang
Tsung Hui Li
Hung Huang Liu
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Dev Center Biotechnology
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Abstract

The present invention relates to dual inhibitors of Epithelial Growth Factor Receptor and Vascular Endothelial Growth Factor Receptor-2, and the uses and preparation processes thereof.

Description

EGFR與VEGFR-2雙重抑制劑及其用途與製法Dual inhibitors of EGFR and VEGFR-2, use thereof and preparation method

本發明係關於新穎之4-苯胺基喹唑啉衍生物，及其用途與製法。詳言之，本發明之4-苯胺基喹唑啉衍生物為表皮細胞生長因子受體(Epithelial Growth Factor Receptor；EGFR)與血管內皮細胞生長因子受體-2(Vascular Endothelial Growth Factor Receptor-2；VEGFR-2)之雙重抑制劑，可用於抑制不正常細胞生長，及治療贅生性疾病、腫瘤或癌症。The present invention relates to novel 4-anilinoquinazoline derivatives, and uses and processes thereof. In particular, the 4-anilinoquinazoline derivative of the present invention is an epidermal growth factor receptor (EGFR) and a vascular endothelial growth factor receptor-2 (Vascular Endothelial Growth Factor Receptor-2; A dual inhibitor of VEGFR-2) that can be used to inhibit abnormal cell growth and to treat neoplastic diseases, tumors or cancer.

癌症是多數已開發國家之主要健康問題之一。依據衛生署之統計，癌症蟬聯國人十大死亡原因之首已逾廿餘年。單於民國九十五年，即有三萬六千三百五十七位國人死於癌症，平均每天即有約百人因此死亡。Cancer is one of the major health problems in most developed countries. According to the statistics of the Department of Health, the top ten causes of death among cancer-stricken people have been more than a year. In the 1990s alone, there were 36,357 Chinese people who died of cancer. On average, about 100 people died every day.

癌細胞或腫瘤係因多重基因之突變，經過長時間而形成。正常細胞可能因先天之遺傳因素，或受環境因素之刺激(例如，暴露於菸草、石棉、紫外線或放射線物質等，或受病毒感染等)，而發生基因突變，造成致癌基因之過量表現或者抑癌基因之表現降低，導致細胞癌化而快速***轉形、增生、腫大，進而形成惡性腫瘤。Cancer cells or tumor lines are formed over a long period of time due to mutations in multiple genes. Normal cells may be genetically mutated due to congenital genetic factors or stimulated by environmental factors (for example, exposure to tobacco, asbestos, ultraviolet rays or radioactive substances, or infection by viruses, etc.), causing excessive gene expression of oncogenes. The expression of oncogenes is reduced, leading to cell cancerization and rapid division, transformation, hyperplasia, and enlargement, thereby forming malignant tumors.

癌症之傳統治療係將癌症病灶連同部分之周圍正常組織及淋巴腺切除。此種療法在癌症初期之療效最好，若癌症已非初期，通常需要依據不同之癌症特性，合併放射線療法或化學療法。The traditional treatment of cancer removes the cancer lesion along with a portion of the surrounding normal tissue and lymph nodes. This type of therapy works best in the early stages of cancer. If the cancer is not early, it is usually necessary to combine radiotherapy or chemotherapy depending on the characteristics of the cancer.

放射線療法係利用高能量之放射線照射癌組織，阻止癌細胞之繼續生長與***，而達到治療癌症之目的。惟放射線不具細胞及組織專一性，因此會同時破壞正常細胞及組織，常見照射區域組織結痂、硬化及全身性倦怠、食慾不振等之副作用。Radiation therapy uses high-energy radiation to illuminate cancerous tissues, preventing cancer cells from continuing to grow and divide, and achieving cancer treatment. However, radiation does not have cell and tissue specificity, so it will destroy normal cells and tissues at the same time, and it often causes side effects such as scarring, sclerosis, systemic burnout, and loss of appetite.

化學療法則係利用具有細胞毒性之化學藥物，破壞或抑制細胞之染色體***，而達到殺死癌細胞之目的。惟細胞毒性化學藥物對正常細胞亦具有毒性，因此在殺死癌細胞之同時，也會造成正常細胞及骨髓之傷害。此種療法常見之副作用包括：噁心、嘔吐、食慾不振、腹瀉、口內炎、皮膚乾燥、發汗、發疹、心悸、掉髮、骨髓抑制(白血球過少、血小板過少、貧血)、神經毒性、腎臟毒性及肝毒性等。Chemotherapy uses cytotoxic chemicals to destroy or inhibit the chromosomal division of cells to kill cancer cells. However, cytotoxic chemicals are also toxic to normal cells, so they can cause damage to normal cells and bone marrow while killing cancer cells. Common side effects of this therapy include: nausea, vomiting, loss of appetite, diarrhea, endophthalmitis, dry skin, sweating, rash, palpitations, hair loss, myelosuppression (low white blood cells, excessive thrombocytopenia, anemia), neurotoxicity, kidney Toxicity and liver toxicity.

研究顯示，癌細胞之生長需有特定生長因子之刺激，因此，細胞生長抑制劑已成為新一類之癌症治療藥劑。Studies have shown that the growth of cancer cells requires the stimulation of specific growth factors, so cytostatics have become a new class of cancer therapeutics.

表皮細胞生長因子受體(EGFR)係分子量為17kDa之跨膜醣蛋白，有配體依賴性酪胺酸激酶活性。EGFR在多種癌症及腫瘤中均過量表現，例如結直腸癌、乳腺癌、胰腺癌、***癌及非小細胞肺癌。EGFR透過自體分泌而於癌症及腫瘤之細胞衍生、凋亡、去分化、血管新生(angiogenesis)、侵襲及移轉等過程扮演重要角色，其過度表現常與癌症及腫瘤之癒後不良及快速移轉相關。因此，抑制經由EGFR之訊號傳導，可抑制不正常細胞或腫瘤之生長。Epidermal growth factor receptor (EGFR) is a 17 kDa transmembrane glycoprotein with ligand-dependent tyrosine kinase activity. EGFR is overexpressed in a variety of cancers and tumors, such as colorectal cancer, breast cancer, pancreatic cancer, prostate cancer, and non-small cell lung cancer. EGFR plays an important role in cancer and tumor cell degeneration, apoptosis, dedifferentiation, angiogenesis, invasion and migration through autologous secretion. Its overexpression often coincides with cancer and tumors. Transfer related. Therefore, inhibition of signal transduction via EGFR can inhibit the growth of abnormal cells or tumors.

血管新生是既有微血管產生分枝及延伸之現象。研究顯示，血管新生在癌症之發生與惡化上扮演重要之角色。癌細胞可藉由新生的血管向宿主吸取養分，並轉移至其他部位。血管內皮細胞生長因子為癌細胞血管新生之最主要調控因子。血管內皮細胞生長因子受體-2(VEGFR-2)會啟動血管新生，造成血管內皮細胞增生及血管之通透性。因此，VEGFR-2亦為治療癌細胞之重要標的。Angiogenesis is a phenomenon in which microvessels are branched and extended. Studies have shown that angiogenesis plays an important role in the occurrence and deterioration of cancer. Cancer cells can take nutrients from the newborn blood vessels to the host and transfer them to other sites. Vascular endothelial growth factor is the most important regulator of angiogenesis in cancer cells. Vascular endothelial growth factor receptor-2 (VEGFR-2) initiates angiogenesis, resulting in vascular endothelial cell proliferation and vascular permeability. Therefore, VEGFR-2 is also an important target for the treatment of cancer cells.

美國專利第5,747,498及5,770,599號，與美國專利第5,457,105及6,414,148號分別揭示喹唑啉衍生物，其中前二者揭示之衍生物為EGFR抑制劑，而後二者揭示之衍生物則為EGFR與VEGFR-2之雙重抑制劑The quinazoline derivatives are disclosed in U.S. Patent Nos. 5,747,498 and 5,770, 599, respectively, and U.S. Patent Nos. 5,457,105 and 6,414,148, each of which discloses a derivative which is an EGFR inhibitor and the latter reveals a derivative of EGFR and VEGFR- 2 double inhibitor

本發明提供一種新穎之4-苯胺基喹唑啉衍生物。The present invention provides a novel 4-anilinoquinazoline derivative.

本發明亦提供本發明新穎4-苯胺基喹唑啉衍生物用於製備藥劑之用途，該藥劑為EGFR與VEGFR-2之雙重抑制劑，可用於抑制不正常細胞生長，及治療贅生性疾病、腫瘤或癌症。The invention also provides the use of the novel 4-anilinoquinazoline derivative of the invention for preparing a medicament, which is a dual inhibitor of EGFR and VEGFR-2, can be used for inhibiting abnormal cell growth, and treating neoplastic diseases, Tumor or cancer.

本發明並提供一種作為EGFR與VEGFR-2之雙重抑制劑之醫藥組合物，其含有治療有效量之本發明之新穎4-苯胺基喹唑啉衍生物。The invention also provides a pharmaceutical composition as a dual inhibitor of EGFR and VEGFR-2 comprising a therapeutically effective amount of a novel 4-anilinoquinazoline derivative of the invention.

本發明另提供一種抑制不正常細胞生長之醫藥組合物，其含有治療有效量之本發明新穎4-苯胺基喹唑啉衍生物。The invention further provides a pharmaceutical composition for inhibiting abnormal cell growth comprising a therapeutically effective amount of a novel 4-anilinoquinazoline derivative of the invention.

本發明復提供一種治療贅生性疾病、腫瘤或癌症之醫藥組合物，其含有治療有效量之本發明新穎4-苯胺基喹唑啉衍生物。The present invention provides a pharmaceutical composition for treating a neoplastic disease, tumor or cancer comprising a therapeutically effective amount of a novel 4-anilinoquinazoline derivative of the present invention.

本發明進一步提供一種製備本發明4-苯胺基喹唑啉衍生物之方法。The invention further provides a process for the preparation of the 4-anilinoquinazoline derivatives of the invention.

茲陳述本發明之詳細說明於下。本發明之其他特徵、目的及優勢可明顯見於本發明說明及申請專利範圍中。The detailed description of the invention is set forth below. Other features, objects, and advantages of the invention will be apparent from the description and appended claims.

本發明提供一種如下示之式(I)化合物The present invention provides a compound of formula (I) as shown below

其中：R為Y-(CH2 )n -，其中X為C=C，O或S，Y為O或直接鍵，n為0、1、2或3；R1 及R2 獨立選自：Where: R is Y-(CH 2 ) n -, wherein X is C=C, O or S, Y is O or a direct bond, n is 0, 1, 2 or 3; R 1 and R 2 are independently selected from:

1)H；1) H;

2)C1-6 -烷基，其可視情況經-NR5 R6 取代，其中R5 及R6 獨立為C1-6 -烷基，或者R5 及R6 與其接著之N一起形成含N之3-至10-員飽和雜環，其環上至少一個亞甲基-(CH2 )-可視情況為-O-、-(NR7 )-或-(CHR8 )-所取代，其中R7 為H或C1-6 -烷基，R8 為含N之3-至10-員飽和雜環，或經含N之3-至10-員飽和雜環取代之C1-6 -烷基；及2) C 1-6 -alkyl, which may optionally be substituted by -NR 5 R 6 wherein R 5 and R 6 are independently C 1-6 -alkyl, or R 5 and R 6 together with the subsequent N form a a 3- to 10-membered saturated heterocyclic ring of N, wherein at least one methylene-(CH 2 )- ring may be substituted by -O-, -(NR 7 )- or -(CHR 8 )-, wherein R 7 is H or C 1-6 -alkyl, R 8 is a 3- to 10-membered saturated heterocyclic ring containing N, or C 1-6 - substituted by a 3- to 10-membered saturated heterocyclic ring containing N Alkyl; and

3)含N之3-至10-員飽和雜環，其環上至少一個亞甲基-(CH2 )-可視情況為-O-、-(NR7 )-或-(CHR8 )-所取代；或者，R1 及R2 與其接著之N形成含N之3-至10-員飽和雜環，其環上至少一個亞甲基-(CH2 )-可視情況為-O-、-(NR7 )-或-(CHR8 )-所取代；R3 為H或C1-6 -烷基，其中該烷基可視情況經1至3個選自下述之群之取代基所取代：鹵素、C1-4 -烷氧基、-N(R9 )(R9 )及-SOR10 ，其中R9 獨立為H或R10 ，且R10 為C1-4 烷基；R4 係選自下述各組之基團：3) 3- to 10-membered saturated heterocyclic ring containing N, at least one methylene-(CH 2 ) ring on the ring - optionally -O-, -(NR 7 )- or -(CHR 8 )- Or substituted; or, R 1 and R 2 and its subsequent N form a 3- to 10-membered saturated heterocyclic ring containing N, at least one methylene-(CH 2 ) ring on the ring - optionally -O-, -( Substituted by NR 7 )- or -(CHR 8 )-; R 3 is H or C 1-6 -alkyl, wherein the alkyl group may be optionally substituted with from 1 to 3 substituents selected from the group consisting of: Halogen, C 1-4 -alkoxy, -N(R 9 )(R 9 ) and -SOR 10 , wherein R 9 is independently H or R 10 and R 10 is C 1-4 alkyl; R 4 is A group selected from the following groups:

1)羥基、胺基、羧基、胺甲醯基、脲基、C1-4 烷氧基胺甲醯基、N-C1-4 烷基胺甲醯基、N,N-二(C1-4 烷基)胺甲醯基、羥基胺基、C1-4 烷氧基胺基、C1-4 烷醯氧基胺基、三氟甲氧基、C1-4 烷基、C1-4 烷氧基或C1-3 烷二氧基；1) Hydroxy, amine, carboxyl, aminemethanyl, ureido, C 1-4 alkoxyamine, mercapto, NC 1-4 alkylamine, mercapto, N,N-di (C 1-4 Alkyl)aminecarboxymethyl, hydroxyamino, C 1-4 alkoxyamino, C 1-4 alkoxyamino, trifluoromethoxy, C 1-4 alkyl, C 1-4 Alkoxy or C 1-3 alkanedioxy;

2)二[(C1-4 -烷基)]胺基C2-4 -烷氧基、吡咯啶-1-基-C2-4 -烷氧基、六氫吡啶基C2-4 -烷氧基、嗎啉基C2-4 -烷氧基、哌嗪-1-基-C2-4 -烷氧基、4-C1-4 -烷基哌嗪-1-基-C2-4 -烷氧基、咪唑-1-基-C2-4 -烷氧基、二[(C1-4 -烷氧基)-C2-4 -烷基]-胺基-C2-4 -烷氧基、硫代嗎啉基C2-4 -烷氧基、1-氧硫代嗎啉基C2-4 -烷氧基、或1,1-二氧硫代嗎啉基C2-4 -烷氧基，其中前述任一基團所含亞甲基-(CH2 )-若不接於N或O原子，則可視情況經羥基所取代；2) bis[(C 1-4 -alkyl)]amino C 2-4 -alkoxy, pyrrolidin-1-yl-C 2-4 -alkoxy, hexahydropyridyl C 2-4 - Alkoxy, morpholinyl C 2-4 -alkoxy, piperazin-1-yl-C 2-4 -alkoxy, 4-C 1-4 -alkylpiperazin-1-yl-C 2 -4 - alkoxy, imidazol-1-yl-C 2-4 -alkoxy, bis[(C 1-4 -alkoxy)-C 2-4 -alkyl]-amino-C 2- 4 -alkoxy, thiomorpholinyl C 2-4 -alkoxy, 1-oxothiomorpholinyl C 2-4 -alkoxy, or 1,1-dioxothiomorpholinyl C a 2-4 -alkoxy group, wherein the methylene-(CH 2 )- contained in any of the foregoing groups may be optionally substituted with a hydroxyl group if it is not bonded to an N or O atom;

3)H、鹵素、羥基、羥基胺基、羧基、硝基、胍基、脲基、氰基、三氟甲基或C1-4 伸烷基-W-苯基，其中W為直接鍵、O、S或NH；3) H, halogen, hydroxy, hydroxyamino, carboxyl, nitro, decyl, ureido, cyano, trifluoromethyl or C 1-4 alkyl-W-phenyl, wherein W is a direct bond, O, S or NH;

4)經氰基取代之C1-4 烷基或R11 或，其中R11 係選自R10 、-OR9 、-NR9 R9 、-C(O)R12 、-NHOR10 、-OC(O)R9 、氰基、U及-VR10 ，其中R12 為R10 、-OR9 或-NR9 R9 ，U係選自六氫吡啶基、嗎啉基、吡咯啶基、4-R9 -哌嗪-1-基、咪唑-1-基、4-吡啶鎓-1-基、C1-4 伸烷基(CO2 H)、苯氧基、苯基、苯基磺醯胺基、C2-4 烯基及C1-4 伸烷基C(O)NR9 R9 ，V為S、SO、SO2 ，其中烷基、-OR9 及-NR9 R9 之烷基基團可視情況經1至3個鹵素所取代，且可視情況為1至2個R11 取代，而該R11 中之烷基基團復可視情況為鹵素或R11 所取代，其前題為：同一碳上不可有兩個雜原子，4) a C 1-4 alkyl group substituted by a cyano group or R 11 or wherein R 11 is selected from the group consisting of R 10 , -OR 9 , -NR 9 R 9 , -C(O)R 12 , -NHOR 10 , - OC(O)R 9 , cyano, U and —VR 10 , wherein R 12 is R 10 , —OR 9 or —NR 9 R 9 , and U is selected from the group consisting of hexahydropyridyl, morpholinyl, pyrrolidinyl, 4-R 9 -piperazin-1-yl, imidazol-1-yl, 4-pyridin-1-yl, C 1-4 alkyl (CO 2 H), phenoxy, phenyl, phenyl sulfonate Amidino, C 2-4 alkenyl and C 1-4 alkylene C(O)NR 9 R 9 , V is S, SO, SO 2 , wherein alkyl, -OR 9 and -NR 9 R 9 The alkyl group may be optionally substituted with 1 to 3 halogens, and optionally 1 to 2 R 11 may be substituted, and the alkyl group in R 11 may be optionally substituted by halogen or R 11 , before The title is: There must be no two heteroatoms on the same carbon.

5)選自-NHSO2 R10 、酞亞胺基C1-4 烷基磺醯基胺基、苯甲醯胺基、苯磺醯胺基、3-苯基脲基、2-氧雜吡咯啶-1-基、2,5-二氧雜吡咯啶-1-基及R13 C2-4 烷醯胺基，其中R13 係選自鹵素、-OR9 、C2-4 烷醯氧基，-C(O)R12 及-NR9 R9 ，且前述定義之R4 基團可視情況經1至2個獨立選自下示基團者所代：鹵素、R10 、氰基、甲磺醯基及C1-4 烷氧基；及5) selected from the group consisting of -NHSO 2 R 10 , quinone imine C 1-4 alkylsulfonylamino, benzylideneamine, benzenesulfonylamino, 3-phenylureido, 2-oxapyrrole Pyridin-1-yl, 2,5-dioxapyrrolidin-1-yl and R 13 C 2-4 alkanoylamino, wherein R 13 is selected from the group consisting of halogen, -OR 9 , C 2-4 alkoxy a group, -C(O)R 12 and -NR 9 R 9 , and the R 4 group as defined above may optionally be substituted by one to two groups selected from the group consisting of halogen, R 10 , cyano, Methanesulfonyl and C 1-4 alkoxy; and

6)兩個R4 與其附著之碳形成5至8員環，其含有1或2個選自O、S及N之雜原子；且m為1、2或3；或其立體異構物、前體藥物或醫藥上可接受鹽或溶劑化物。6) two R 4 and its attached carbon form a 5 to 8 membered ring containing 1 or 2 heteroatoms selected from O, S and N; and m is 1, 2 or 3; or a stereoisomer thereof, Prodrug or pharmaceutically acceptable salt or solvate.

本文使用之術語，當其代表一取代基或基團時，若其出現超過一次時，其在各存在處之定義係與其在各其他存在處之定義無關。而且，各取代基或基團之組合，只有在該組合形成安定之化合物之前題下才可允許存在。The terminology used herein, when it refers to a substituent or group, if it occurs more than once, its definition at each occurrence is independent of its definition at each other. Moreover, each substituent or combination of groups is only allowed to exist before the combination forms a stable compound.

除非另經指明，否則下示各術語適用於本專利說明書(包函申請專利範圍)全文。下述有關各術語之定義，同時適用於該術語單獨使用及與其他術語併用之狀況。例如，對於"烷基"之定義，亦適用於"烷氧基"之"烷基"部份。Unless otherwise indicated, the terms shown below apply to the full text of this patent specification (the scope of the patent application). The following definitions of terms are used in conjunction with the term alone and in conjunction with other terms. For example, the definition of "alkyl" also applies to the "alkyl" portion of "alkoxy".

"烷基"係指直鏈或分岐之飽和烴鏈，其烴鏈具有1至20個碳原子，較佳為1至12個碳原子，更佳為1至6個碳原子或為1至4個碳原子。"Alkyl" means a straight or branched saturated hydrocarbon chain having from 1 to 20 carbon atoms, preferably from 1 to 12 carbon atoms, more preferably from 1 to 6 carbon atoms or from 1 to 4 carbon atoms. One carbon atom.

"烷氧基"係指經醚氧基團(-O-)與母體鍵結之烷基-O-基團。其中之"烷基"如上文之定義。烷氧基之非限制性實例包括：甲氧基、乙氧基、正-丙氧基、異-丙氧基及正-丁氧基。"Alkoxy" means an alkyl-O- group bonded to the parent via an etheroxy group (-O-). The "alkyl group" therein is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, n-propoxy, iso-propoxy and n-butoxy.

"炔基"係指直鏈或分歧之脂族烴基，其具有至少一個碳≡碳鍵，與2至15個碳原子，較佳為2至12個碳原子，且更佳為2至4個碳原子。炔基之非限制性實例，包括乙炔基、丙炔基、2-丁炔基、3-甲基丁炔基、正-戊炔基及癸炔基。"Alkynyl" means a straight or divalent aliphatic hydrocarbon group having at least one carbonium carbon bond, and 2 to 15 carbon atoms, preferably 2 to 12 carbon atoms, and more preferably 2 to 4 carbon atom. Non-limiting examples of alkynyl groups include ethynyl, propynyl, 2-butynyl, 3-methylbutynyl, n-pentynyl and decynyl.

"鹵素"係指氟、氯、溴或碘。較佳為氟、氯或溴，而更佳為氟與氯。"Halogen" means fluoro, chloro, bromo or iodo. It is preferably fluorine, chlorine or bromine, and more preferably fluorine and chlorine.

"含N之飽和雜環"係指含N之非芳族飽和單環狀系統，其含有3至10個環原子，例如3至7個環原子，較佳為5至10個環原子，其中一個環原子為N，其餘之環原子為碳。或者，該含N之環系統中，除N、碳之環原子外，亦可含有額外之N原子，或O原子。較佳之飽和雜環具有5或6個環原子。"含N之飽和雜環"之非限制性實例包括：吡啶、吡咯啶、吡唑啶、咪唑啶、吡咯酮、哌嗪、吲唑、苯并咪唑、苯喃、咪唑啉酮、異噁唑、吡唑、吲唑、噻唑、噁唑及嗎啉。"N-containing saturated heterocyclic ring" means a non-aromatic saturated monocyclic system containing N, which contains 3 to 10 ring atoms, for example 3 to 7 ring atoms, preferably 5 to 10 ring atoms, wherein One ring atom is N and the remaining ring atoms are carbon. Alternatively, the N-containing ring system may contain an additional N atom or an O atom in addition to the ring atom of N and carbon. Preferred saturated heterocyclic rings have 5 or 6 ring atoms. Non-limiting examples of "saturated heterocyclic ring containing N" include: pyridine, pyrrolidine, pyrazole, imidazolium, pyrrolidone, piperazine, oxazole, benzimidazole, benzopyran, imidazolidinone, isoxazole , pyrazole, carbazole, thiazole, oxazole and morpholine.

此外，參照化學結構或化學式，本文中使用之"Me"表示甲基。Further, reference to the chemical structure or chemical formula, "Me" as used herein means a methyl group.

本發明之一較佳具體實例為下示之式(I)-1化合物：A preferred embodiment of the present invention is a compound of the formula (I)-1 shown below:

其中Y及R1 至R4 、n與m之定義如前述。Wherein Y and R 1 to R 4 , n and m are as defined above.

式(I)-1化合物中，較佳者為下示之化合物：Among the compounds of the formula (I)-1, preferred are the compounds shown below:

其中R及NR1 R2 之定義如下示：The definitions of R and NR 1 R 2 are as follows:

或者，較佳之式(I)-1化合物為如下示之化合物：Alternatively, preferred compounds of formula (I)-1 are those shown below:

其中R及NR1 R2 之定義如下示：The definitions of R and NR 1 R 2 are as follows:

本發明之另一較佳具體實例為下示之式(I)-2化合物：Another preferred embodiment of the invention is the compound of formula (I)-2 shown below:

其中Y及R1 至R4 、n與m之定義如前述。Wherein Y and R 1 to R 4 , n and m are as defined above.

式(I)-2化合物中，較佳者為下示之化合物：Among the compounds of the formula (I)-2, preferred are the compounds shown below:

其中NR1 R2 之定義如下示：The definition of NR 1 R 2 is as follows:

或者，較佳之式(I)-2化合物為如下示之化合物：Alternatively, preferred compounds of formula (I)-2 are the compounds shown below:

其中NR1 R2 之定義如下示：Wherein NR 1 R 2 is defined as follows shown:

本發明之再一較佳具體實例為下示式(I)-3化合物中，Still another preferred embodiment of the present invention is as shown in the compound of the formula (I)-3 below.

其中Y及R1 至R4 、n與m之定義如前述。Wherein Y and R 1 to R 4 , n and m are as defined above.

式(I)-3化合物中，較佳者為下示之化合物：Among the compounds of the formula (I)-3, preferred are the compounds shown below:

其中NR1 R2 之定義如下示：The definition of NR 1 R 2 is as follows:

或者，較佳之式(I)-3化合物為如下示之化合物：Alternatively, preferred compounds of formula (I)-3 are the compounds shown below:

其中NR1 R2 之定義如下示：Wherein NR 1 R 2 is defined as follows shown:

本發明式(I)化合物可依下示流程圖所示之方法製備。The compound of the formula (I) of the present invention can be produced by the method shown in the scheme shown below.

其中T為鹵素或甲磺醯基，R3 、R4 及m如前述Wherein T is halogen or methylsulfonyl, and R 3 , R 4 and m are as defined above

詳言之，可使用下示之式(II)化合物In detail, the compound of formula (II) shown below can be used.

其中R3 、R4 、R5 及R6 之定義如前述，T為鹵素或甲磺醯基，在適當之鹼及催化劑存在下，於適當之溶劑中，以適當之Suzuki偶合劑，如雙(平南基)二硼酸鹽或雙戊醯二硼硼化，產生硼化中間體，如流程圖中所示之式(III)化合物；接著，使硼化之式(II)化合物與RCONR1 R2 之式(VI)醯胺，其中R、R1 及R2 之定義如前述，在適當之鹼及催化劑存在下反應，獲得式(I)化合物。Wherein R 3 , R 4 , R 5 and R 6 are as defined above, and T is halogen or methylsulfonyl, in the presence of a suitable base and a catalyst, in a suitable solvent, with a suitable Suzuki coupling agent, such as a double (Pingnan) diborate or dipentane boron diboration to produce a boronated intermediate, such as the compound of formula (III) as shown in the scheme; followed by boronation of the compound of formula (II) with RCONR 1 R of formula (Vl) Amides of 2, wherein R, R 1 and R 2 defined in the preceding, where appropriate, the presence of a base and of a catalyst, to obtain a compound of formula (I).

式(II)化合物可依習知技術製備。例如，R3 為H之式(II)化合物可依美國專利第5,457,105、5,747,498及5,770,599之教示製備；R3 為可經取代之C1-6 烷基之式(II)化合物，則可依美國專利第5,747,498號之教示製備。該等專利之全文併於本專利說明書，為本文之參考。Compounds of formula (II) can be prepared according to conventional techniques. For example, a compound of formula (II) wherein R 3 is H can be prepared according to the teachings of U.S. Patent Nos. 5,457,105, 5,747,498 and 5,770,599; R 3 is a substituted C 1-6 alkyl group of formula (II), The teachings of Patent No. 5,747,498 are prepared. The entire text of these patents is incorporated herein by reference.

可依習知之方法進行Suzuki偶合反應，使式(II)化合物硼化；即可在升高之溫度下，在適當之催化劑及鹼存在下，於適當之溶劑中，使用適當之Suzuki偶合劑與式(II)化合物反應，形成硼化之式(II)化合物。The Suzuki coupling reaction can be carried out by a conventional method to boricize the compound of the formula (II); that is, at an elevated temperature, in the presence of a suitable catalyst and a base, in a suitable solvent, using a suitable Suzuki coupling agent. The compound of formula (II) is reacted to form a boronated compound of formula (II).

適用之Suzuki偶合劑包括但不限於硼酸、硼酸酯或經取代甲硼烷。例如，雙(平南基)二硼酸鹽(bis(pinacolato)diboron；PIN2B2)、雙戊醯二硼酯(Pinacol borate;PINB)及異丙基雙戊醯二硼酯(Isopropyl Pinacol Borate;PINBOP)，均適用於在鈀催化劑存在下，將T為鹵素之式(II)化合物硼化。T為甲磺醯基之式(II)化合物則可在釕或銠催化劑存在下硼化。Suitable Suzuki coupling agents include, but are not limited to, boric acid, boric acid esters or substituted borane. For example, bis(pinacolato diboron; PIN2B2), Pinacol borate (PINB) and Isopropyl Pinacol Borate (PINBOP) Both are suitable for the boronation of a compound of formula (II) wherein T is halogen in the presence of a palladium catalyst. The compound of formula (II) wherein T is a methanesulfonyl group can be boronated in the presence of a rhodium or ruthenium catalyst.

例如，使用PIN2B2使式(II)化合物硼化，可形成如流程圖所示之式(III)硼化化合物。For example, boronation of a compound of formula (II) using PIN2B2 can form a boronated compound of formula (III) as shown in the scheme.

適用於進行Suzuki偶合反應之鈀催化劑包括但不限於：Pd(OAc)2 、PdCl2 (dppf)、Pd(Ph3 P)4 、Pd(dba)2 PCy3 、PdCl2 (Ph3 P)2 及鈀黑(Pd black)；適用之釕或銠催化劑包括但不限於：RuCl2 (Ph3 P)2 、RuCl3 、銠碳催化劑、銠氧化鋁催化劑及銠黑(Rhodium black)。Palladium catalysts suitable for carrying out the Suzuki coupling reaction include, but are not limited to, Pd(OAc) 2 , PdCl 2 (dppf), Pd(Ph 3 P) 4 , Pd(dba) 2 PCy 3 , PdCl 2 (Ph 3 P) 2 And pd black; suitable rhodium or ruthenium catalysts include, but are not limited to, RuCl 2 (Ph 3 P) 2 , RuCl 3 , rhodium carbon catalyst, rhodium alumina catalyst, and rhodium black.

適用於進行Suzuki偶合反應之鹼包括但不限於：KOAc、K2 CO3 、三乙基胺、KOH、NaOEt、NaOH、Cs2 CO3 及CsF。Bases suitable for carrying out the Suzuki coupling reaction include, but are not limited to, KOAc, K 2 CO 3 , triethylamine, KOH, NaOEt, NaOH, Cs 2 CO 3 and CsF.

適用於進行Suzuki偶合反應之溶劑包括但不限於：二甲基甲醯胺(DMF)、二甲基亞碸(DMSO)、甲苯、苯(Benzene)、四氫呋喃(THF)、異丙醇、乙醇、二噁烷(Dioxane)、CH2 Cl2 及CHCl3 。Suitable solvents for the Suzuki coupling reaction include, but are not limited to, dimethylformamide (DMF), dimethyl hydrazine (DMSO), toluene, Benzene, tetrahydrofuran (THF), isopropanol, ethanol, Dioxane, CH 2 Cl 2 and CHCl 3 .

Suzuki偶合反應可在室溫或升高溫度至190℃之升高溫度下進行，例如在80℃下進行。The Suzuki coupling reaction can be carried out at room temperature or elevated temperature to an elevated temperature of 190 ° C, for example at 80 ° C.

RCONR1 R2 式(VI)之醯胺可依習知方法，使用對應之醯鹵(RCOZ，其中Z為鹵素)或醯酸(RCOOH)，與對應之二取代胺R1 R2 NH反應而獲得。RCONR 1 R 2 The indoleamine of formula (VI) can be reacted with the corresponding disubstituted amine R 1 R 2 NH by a conventional method using a corresponding hydrazine halide (RCOZ, wherein Z is a halogen) or decanoic acid (RCOOH). obtain.

硼化之式(II)化合物與RCONR1 R2 之式(VI)醯胺，可在適當之鹼及催化劑存在下反應，獲得式(I)化合物。適用之鹼及催化劑包括但不限於鹼KOAc、K2 CO3 、三乙基胺、KOH、NaOEt、NaOH、Cs2 CO3 及CsF與催化劑Pd(OAc)2 、PdCl2 (dppf)、Pd(Ph3 P)4 、Pd(dba)2 PCy3 、PdCl2 (Ph3 P)2 及鈀黑(Pd black)。The boronated compound of formula (II) and the guanamine of formula (VI) of RCONR 1 R 2 can be reacted in the presence of a suitable base and a catalyst to provide a compound of formula (I). Suitable bases and catalysts include, but are not limited to, alkali KOAc, K 2 CO 3 , triethylamine, KOH, NaOEt, NaOH, Cs 2 CO 3 and CsF with catalysts Pd(OAc) 2 , PdCl 2 (dppf), Pd ( Ph 3 P) 4 , Pd(dba) 2 PCy 3 , PdCl 2 (Ph 3 P) 2 and pd black (Pd black).

本發明之某些化合物可以不同立體異構物形式(例如對掌異構物、非對映異構物及非向性異構物)存在。本發明意欲涵蓋所有此種立體異構物，呈純形式與呈混合物兩者，包括外消旋混合物。異構物可使用習用方法製備。Certain compounds of the invention may exist in different stereoisomeric forms (e.g., palmier isomers, diastereomers, and atropisomers). The present invention is intended to cover all such stereoisomers, both in pure form and in mixtures, including racemic mixtures. Isomers can be prepared using conventional methods.

某些化合物在本性上為酸性，例如具有羧基或酚性羥基之化合物。此等化合物可形成藥學上可接受之鹽。此種鹽之實例可包括鈉、鉀、鈣、鋁、金及銀鹽。亦意欲涵蓋在內者，為與藥學上可接受之胺類，譬如氨、烷基胺類、羥烷基胺類、N-甲基葡萄糖胺等所形成之鹽。Certain compounds are acidic in nature, such as compounds having a carboxy or phenolic hydroxyl group. These compounds form pharmaceutically acceptable salts. Examples of such salts may include sodium, potassium, calcium, aluminum, gold, and silver salts. Also intended to be included, are salts formed with pharmaceutically acceptable amines such as ammonia, alkylamines, hydroxyalkylamines, N-methylglucamine, and the like.

某些鹼性化合物亦會形成藥學上可接受之鹽，例如酸加成鹽。例如，吡啶并-氮原子可與強酸形成鹽，而具有鹼性取代基譬如胺基之化合物亦與較弱酸形成鹽。供鹽形成之適當酸之實例，係為鹽酸、硫酸、磷酸、醋酸、檸檬酸、草酸、丙二酸、柳酸、蘋果酸、反丁烯二酸、琥珀酸、抗壞血酸、順丁烯二酸、甲烷磺酸及熟諳此藝者所習知之其他礦酸與羧酸類。此鹽類係以習用方式，經由將自由態鹼形式與足量所要之酸接觸以產生鹽而製成。自由態鹼形式可經由以適當稀鹼水溶液，譬如稀氫氧化鈉水溶液、碳酸鉀、氨及碳酸氫鈉，處理該鹽而再生。自由態鹼形式與其個別鹽形式，在某些物理性質上稍有不同，譬如在極性溶劑中之溶解度，但對本發明之目的而言，酸與鹼鹽係在其他方面相當於其個別自由態鹼形式。Certain basic compounds also form pharmaceutically acceptable salts, such as acid addition salts. For example, a pyrido-nitrogen atom can form a salt with a strong acid, while a compound having a basic substituent such as an amine group also forms a salt with a weaker acid. Examples of suitable acids for salt formation are hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, malic acid, fumaric acid, succinic acid, ascorbic acid, maleic acid. Methanesulfonic acid and other mineral acids and carboxylic acids known to those skilled in the art. This salt is prepared in a conventional manner by contacting the free base form with a sufficient amount of the desired acid to produce a salt. The free base form can be regenerated by treating the salt with a suitable dilute aqueous base such as dilute aqueous sodium hydroxide, potassium carbonate, ammonia and sodium bicarbonate. The free-form base form and its individual salt forms differ slightly in some physical properties, such as solubility in polar solvents, but for the purposes of the present invention, the acid and base salts are otherwise equivalent to their individual free bases. form.

所有此種酸與鹼鹽係意欲成為在本發明範圍內之藥學上可接受鹽，且對本發明之目的而言，所有酸與鹼鹽係被認為相當於相應化合物之自由態形式。All such acid and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention, and for the purposes of the present invention, all acid and base salts are considered equivalent to the free form of the corresponding compound.

本發明化合物可以非溶劑化合或溶劑化合形式存在，包括水合形式。一般而言，具有藥學上可接受之溶劑譬如水、乙醇等之溶劑化合形式，對本發明之目的而言，係相當於未溶劑化合形式。The compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms. In general, a solvated compound form having a pharmaceutically acceptable solvent such as water, ethanol or the like is equivalent to the unsolvated form for the purpose of the present invention.

本發明亦包括本發明化合物之前體藥物。The invention also includes prodrugs of the compounds of the invention.

本文中所用之"前體藥物"一詞，表示在活體內，例如經由在血液中之水解，迅速地轉變成上式母體化合物之化合物。請參考T.Higuchi與V.Stella發表之文獻"前體藥物作為新穎傳輸系統"A.C.S.論集系列第14卷，及Edward B.Roche編著之"藥物設計之生物可逆載劑"，美國醫藥協會與Pergamon出版社(1987)。此二文獻之全文均併於本文，為本文之參考。As used herein, the term "prodrug" means a compound which is rapidly converted to the parent compound of the above formula in vivo, for example, via hydrolysis in blood. Please refer to the T. Higuchi and V. Stella publication "Prodrugs as a Novel Transmission System" in the ACS Collection Series, Volume 14, and Edward B. Roche, "Bioreversible Drugs for Drug Design", American Medical Association and Pergamon Publishing House (1987). The entire contents of these two documents are incorporated herein by reference.

經測試，本發明化合物可抑制EGFR，亦可抑制VEGFR-2，係EGFR與VEGFR-2之雙重抑制劑，可用於抑制患者之不正常細胞生長，及以治療患者之贅生性疾病、腫瘤或癌症。The compounds of the present invention have been tested to inhibit EGFR and also inhibit VEGFR-2, a dual inhibitor of EGFR and VEGFR-2, which can be used to inhibit abnormal cell growth in patients, and to treat neoplastic diseases, tumors or cancer in patients. .

因此，本發明提供本發明新穎4-苯胺基喹唑啉衍生物用於製備藥劑之用途，該藥劑為EGFR與VEGFR-2之雙重抑 制劑。Accordingly, the present invention provides the use of the novel 4-anilinoquinazoline derivative of the present invention for the preparation of a medicament which is a dual inhibitor of EGFR and VEGFR-2. preparation.

本發明亦提供本發明新穎4-苯胺基喹唑啉衍生物用於製備藥劑之用途，該藥劑係用於抑制不正常細胞生長。The invention also provides the use of a novel 4-anilinoquinazoline derivative of the invention for the preparation of a medicament for inhibiting abnormal cell growth.

本發明並提供本發明新穎4-苯胺基喹唑啉衍生物用於製備藥劑之用途，該藥劑係用以治療贅生性疾病、腫瘤或癌症。The invention also provides the use of a novel 4-anilinoquinazoline derivative of the invention for the preparation of a medicament for the treatment of neoplastic diseases, tumors or cancer.

此外，本發明提供一種作為EGFR與VEGFR-2之雙重抑制劑之醫藥組合物，其含有治療有效量之本發明之新穎4-苯胺基喹唑啉衍生物，及醫藥上可接受之稀釋劑、佐劑或載劑。Further, the present invention provides a pharmaceutical composition comprising a dual inhibitor of EGFR and VEGFR-2 comprising a therapeutically effective amount of the novel 4-anilinoquinazoline derivative of the present invention, and a pharmaceutically acceptable diluent, Adjuvant or carrier.

本發明另提供一種抑制不正常細胞生長之醫藥組合物，其含有治療有效量之本發明新穎4-苯胺基喹唑啉衍生物，及醫藥上可接受之稀釋劑、佐劑或載劑。The invention further provides a pharmaceutical composition for inhibiting abnormal cell growth comprising a therapeutically effective amount of a novel 4-anilinoquinazoline derivative of the invention, and a pharmaceutically acceptable diluent, adjuvant or carrier.

本發明復提供一種治療贅生性疾病、腫瘤或癌症之醫藥組合物，其含有治療有效量之本發明新穎4-苯胺基喹唑啉衍生物，及醫藥上可接受之稀釋劑、佐劑或載劑。The present invention provides a pharmaceutical composition for treating a neoplastic disease, tumor or cancer comprising a therapeutically effective amount of the novel 4-anilinoquinazoline derivative of the present invention, and a pharmaceutically acceptable diluent, adjuvant or carrier. Agent.

本文所用術語"患者"係指動物，包括人類及其他哺乳動物。在一較佳具體實施例中，患者係指人類。The term "patient" as used herein refers to animals, including humans and other mammals. In a preferred embodiment, the patient is referred to as a human.

本文所用術語"治療"係包括與疾病相關之病徵之緩解，腫瘤生長之抑制，腫瘤之實際縮小，或轉移之抑制等。The term "treatment" as used herein includes alleviation of a disease-related condition, inhibition of tumor growth, actual reduction of the tumor, or inhibition of metastasis.

本文所用術語"治療有效量"係指單獨或併用其他藥物之本發明化合物，對於症狀可提供治療有利之量，例如可如前述可緩解病徵，抑制腫瘤生長，使腫瘤縮小，或抑治腫瘤轉移等之量。The term "therapeutically effective amount" as used herein, refers to a compound of the invention, alone or in combination with other drugs, which provides a therapeutically beneficial amount for the symptoms, for example, to alleviate the symptoms, inhibit tumor growth, shrink the tumor, or inhibit tumor metastasis as described above. Wait for the amount.

本文所用術語"醫藥學上可接受之稀釋劑、佐劑及載劑"係指本領域一般技藝人士熟知之可用於製備醫藥組合物之稀釋劑、佐劑及賦形劑，或其類似物。The term "pharmaceutically acceptable diluents, adjuvants, and carriers" as used herein refers to diluents, adjuvants, and excipients, or analogs thereof, which are well known to those of ordinary skill in the art for the preparation of pharmaceutical compositions.

本發明新穎化合物、或以其製備之藥劑或醫藥組合物可單獨使用，以抑制不正長細胞生長，或治療贅生性疾病、腫瘤或癌症。The novel compounds of the present invention, or the agents or pharmaceutical compositions prepared therefrom, can be used alone to inhibit the growth of non-regular cells, or to treat neoplastic diseases, tumors or cancer.

或者，本發明新穎化合物、或以其製備之藥劑或醫藥組合物，亦可與下述活性成份或藥劑或療法同時或相繼使用而併用，以抑制不正長細胞生長，或治療贅生性疾病、腫瘤或癌症：(a)微管影響劑；(b)抗腫瘤或抗癌劑；(c)抗血管生成劑；(d)EGF受體激酶抑制劑；(e)bFGF受體激酶抑制劑；(f)VEGF受體激酶抑制劑；(g)干擾素；及/或(h)放射線療法。Alternatively, the novel compounds of the present invention, or the agents or pharmaceutical compositions prepared therefrom, may be used simultaneously or sequentially with the following active ingredients or agents or therapies to inhibit the growth of non-regular cells, or to treat neoplastic diseases, tumors. Or cancer: (a) microtubule affecting agent; (b) antitumor or anticancer agent; (c) anti-angiogenic agent; (d) EGF receptor kinase inhibitor; (e) bFGF receptor kinase inhibitor; f) VEGF receptor kinase inhibitor; (g) interferon; and/or (h) radiation therapy.

本發明所述以本發明新穎化合物製備之藥劑及醫藥組合物，不論其中本發明化合物係為單獨使用，或係為與其他活性成份併用(同時或相繼使用)，可依習知之方法製備。The medicaments and pharmaceutical compositions prepared by the novel compounds of the present invention, whether or not the compounds of the present invention are used alone or in combination with other active ingredients (simultaneously or sequentially), can be prepared by conventional methods.

固體形式製劑包括粉末、片劑、可分散顆粒、膠囊、扁囊劑及栓劑。粉末與片劑可包含約5至約95百分比之活性成份。適當固體載劑係為此項技藝中已知的，例如碳酸鎂、硬脂酸鎂、滑石、糖或乳糖。片劑、粉末、扁囊劑及膠囊可作為適於口服投藥之固體劑量形式使用。藥學上可接受載劑之實例，及各種組合物之製法，可參閱A.Gennaro(編著)，Remington氏醫藥科學 ，第18版，(1990),Mack出版公司(Easton,pennsylvania)。Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories. The powders and tablets may contain from about 5 to about 95 percent of the active ingredient. Suitable solid carriers are known in the art, such as magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers, and methods of making the various compositions, can be found in A. Gennaro (ed.), Remington's Medical Sciences , 18th ed., (1990), Mack Publishing Company (Easton, Pennsylvania).

液體形式製劑包括溶液、懸浮液及乳化液。以下述作為實例，可指出水或水-丙二醇溶液供非經腸注射用，或添加增甜劑與乳白劑，供口服溶液、懸浮液及乳化液用。液體形式製劑亦可包括供鼻內投藥之溶液。Liquid form preparations include solutions, suspensions, and emulsions. By way of example below, water or water-propylene glycol solutions may be indicated for parenteral injection, or sweeteners and opacifiers may be added for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.

適用於吸入之氣溶膠製劑可包括溶液及呈粉末形式之固體，其可併用藥學上可接受之載劑，譬如惰性壓縮氣體，例如氮。Aerosol formulations suitable for inhalation may include solutions and solids in powder form in admixture with a pharmaceutically acceptable carrier such as an inert compressed gas such as nitrogen.

亦包括固體形式製劑，其係意欲在使用之前不久，被轉化成液體形式製劑，無論是供口服或非經腸投藥。此種液體形式包括溶液、懸浮液及乳化液。Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations, whether administered orally or parentally. Such liquid forms include solutions, suspensions and emulsions.

本發明化合物亦可以經皮方式傳輸。經皮組合物可採取乳膏、洗劑、氣溶膠及/或乳化液之形式，並可被包含在基質或儲器型之經皮貼藥中，如同此項技藝中習用於此項目的之方式。The compounds of the invention may also be delivered transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of a matrix or reservoir type, as is the art used in the art. the way.

此醫藥製劑較佳係呈單位劑量形式。在此種形式中，製劑係被再分成適當大小之單位劑量，含有適當量之活性成份，例如達成所要目的之有效量。Preferably, the pharmaceutical preparation is in unit dosage form. In this form, the preparation is subdivided into unit doses of the appropriate size, containing an appropriate amount of active ingredient, such as an effective amount to achieve the desired purpose.

活性化合物在單位劑量製劑中之量，可以改變或調整，從約0.01毫克至約1000毫克，較佳為約0.01毫克至約750毫克，更佳為約0.01毫克至約500毫克，且最佳為約0.01毫克至約250毫克，根據特定應用而定。The amount of active compound in a unit dosage formulation may vary or vary from about 0.01 mg to about 1000 mg, preferably from about 0.01 mg to about 750 mg, more preferably from about 0.01 mg to about 500 mg, and most preferably From about 0.01 mg to about 250 mg, depending on the particular application.

所採用之實際劑量可依病患之需要量及被治療症狀之嚴重性而改變。對於特定狀況之適當劑量服法之測定，係在此項技藝之技術範圍內。為方便起見，可在一天期間，將總劑量區分，並分次投予，按需要而定。The actual dosage employed can vary depending on the amount of the patient's needs and the severity of the condition being treated. Determination of the appropriate dosage regimen for a particular condition is within the skill of the art. For convenience, the total dose can be divided and administered in divided doses, as needed.

本發明化合物及/或其藥學上可接受鹽之投藥量與頻率，係根據負責臨床醫師之判斷作調整，考慮到一些因素，譬如病患之年齡、症狀及大小，以及被治療病徵之嚴重性。對口服投藥之典型建議每日劑量服法，其範圍可為約0.04毫克/天至約4000毫克/天，在二至四份分離劑量中。The dosage and frequency of the compound of the present invention and/or its pharmaceutically acceptable salt are adjusted according to the judgment of the responsible clinician, taking into consideration factors such as the age, symptoms and size of the patient, and the severity of the symptom being treated. . A typical recommended daily dosage regimen for oral administration may range from about 0.04 mg/day to about 4000 mg/day in two to four divided doses.

可與本發明化合物、以其製備之藥劑或醫藥組合物併用之微管影響劑，為一種會經由影響微管形成及/或作用、干擾細胞有絲***之化合物，意即具有抗有絲***作用。此種藥劑可為例如微管安定劑或瓦解微管形成之藥劑。可用於本發明中之微管影響劑係為熟諳此藝者所習知，包括但不限於別秋水仙素(allocolchicine，NSC406042)、哈利軟骨素B(Halichondrin B，NSC 609395)、秋水仙素(Colchicine，NSC757)、秋水仙素衍生物(colchicine derivatives，例如NSC33410)、多拉制菌素10(dolastatin-10，NSC376128)、美坦生(maytansine，NSC153858)、利坐素(Rhizoxin，NSC332598)、培克里他索(paclitaxel，，NSC125973)、衍生物(NSC608832)、硫基秋水仙素(thiocolchicine，NSC361792)、三苯甲基半胱胺酸(3-tritylthio-L-alanine，NSC83265)、長春花鹼硫酸鹽(Vinblastine sulfate，NSC49842)、長春新鹼硫酸鹽(Vincristine，NSC67574)、艾普西隆A(epsilon A)、艾波希酮(Epothilone)及迪斯可得內酯(discodermolide)(參閱Service,(1996)Science,274：2009)雌氮芥(estramustine)、諾可達唑(nocodazole)、MAp4等。此種藥劑之實例亦描述於科學與專利文獻中，參閱例如Bulinski(1997) J. CellSci.110：3055-3064；Panda(1997) Proc. Natl. Acad. Sci. USA94：10560-10564；Muhlradt(1997)CancerRes. 57：3344-3346；Nicolaou(1997) Nature387：268-272；Vasquez(1997) Mol. Biol. Cell. 8：973-985；Panda(1996) J. Biol. Chem. 271：29807-29812。A microtubule-influencing agent which can be used in combination with a compound of the present invention, an agent or a pharmaceutical composition prepared therefrom, is a compound which affects microtubule formation and/or action and interferes with cell mitosis, that is, has an anti-mitotic effect. Such agents may be, for example, microtubule stabilizers or agents that disrupt microtubule formation. Microtubule affecting agents useful in the present invention are well known to those skilled in the art, including, but not limited to, allocolchicine (NSC 406042), Halicondronin B (NSC 609395), colchicine. (Colchicine, NSC757), colchicine derivatives (eg NSC33410), dolastatin-10 (NSC376128), maytansine (NSC153858), lysin (Rhizoxin, NSC332598) , peclitaxel, , NSC125973), Derivatives (NSC608832), thiocolchicine (NSC361792), 3-tritylthio-L-alanine (NSC83265), Vinblastine sulfate (NSC49842), Changchun Neobase sulfate (Vincristine, NSC67574), epsilon A, Epothilone, and discodermolide (see Service, (1996) Science, 274: 2009) Estramustine, nocodazole, MAp4, and the like. Examples of such agents are also described in the scientific and patent literature, see, for example, Bulinski (1997) J. Cell Sci. 110: 3055-3064; Panda (1997) Proc. Natl. Acad. Sci. USA 94: 10560-10564; Muhlradt ( 1997) Cancer Res. 57: 3344-3346; Nicolaou (1997) Nature 387: 268-272; Vasquez (1997) Mol. Biol. Cell. 8: 973-985; Panda (1996) J. Biol. Chem. 271: 29807- 29812.

可與本發明化合物、以其製備之藥劑或醫藥組合物併用之抗腫瘤劑包括但不限於：真西塔賓(gemcitabine)、培克里他索、5-氟尿嘧啶(5-FU)、環磷醯胺()、天莫洛醯胺(temozolomide)、紅豆杉帖里(taxotere)及長春新鹼。Antitumor agents which may be used in combination with a compound of the present invention, an agent or a pharmaceutical composition prepared therewith include, but are not limited to, gemcitabine, peclitaxel, 5-fluorouracil (5-FU), cyclophosphazene amine( ), temozolomide, taxotere and vincristine.

可與本發明化合物、以其製備之藥劑或醫藥組合物併用之抗癌劑，包括但不限於：烷基化劑、抗新陳代謝劑、天然產物及其衍生物、激素、抗激素、抗血管生成劑及類固醇以及合成物質。An anticancer agent which can be used in combination with a compound of the present invention, an agent or a pharmaceutical composition prepared thereby, including but not limited to: an alkylating agent, an anti-metabolizing agent, a natural product and a derivative thereof, a hormone, an anti-hormone, an anti-angiogenesis Agents and steroids as well as synthetic substances.

烷基化劑包括氮芥末類(N-Mustard)、次乙亞胺衍生物、烷基磺酸鹽、亞硝基脲及三氮烯類，其非限制實例為：尿嘧啶芥(uracil mustard)、氯甲川、環磷醯胺()、異環磷醯胺(ifosfamide)、***酸氮芥(phenylalanine mustard l-pam)、苯丁酸氮芥(Chlorambucil)、雙溴丙基哌嗪、三乙烯-三聚氰胺、三乙烯硫代磷胺、白血福恩(Busulfan)、亞硝基脲氮芥、環己亞硝脲、鏈黴亞硝基素、氮烯咪胺及天莫洛醯胺(temozolomide)。Alkylating agents include nitrogen mustards (N-Mustard), ethylenemethine derivatives, alkyl sulfonates, nitrosoureas, and triazenes, non-limiting examples of which are: uracil mustard , chloroform, cyclophosphamide ( ), ifosfamide, phenylalanine mustard l-pam, chlorambucil, bromopropyl piperazine, triethylene melamine, triethylene thiophosphoramide , Busulfan, nitrosourea mustard, cyclohexyl nitrosourea, streptavidin, nitromethamine and temozolomide.

抗代謝劑包括葉酸拮抗劑、嘧啶類似物、嘌呤類似物及腺苷脫胺酶抑制劑，其非限制實例為：胺甲喋呤、5-氟尿嘧啶、5-氟脫氧尿苷、阿糖胞苷、6-巰基嘌呤、6-巰基鳥嘌呤、弗達拉賓(fludarabine)磷酸鹽、戊托制菌素(pentostatin)及真西塔賓(gemcitabine)。Antimetabolites include folic acid antagonists, pyrimidine analogs, purine analogs, and adenosine deaminase inhibitors, non-limiting examples of which are: methotrexate, 5-fluorouracil, 5-fluorodeoxyuridine, cytarabine , 6-mercaptopurine, 6-mercapto guanine, fludarabine phosphate, pentostatin, and gemcitabine.

天然產物及其衍生物包括長春花植物鹼、抗腫瘤抗生素、酵素、淋巴細胞活素及表鬼臼脂素，其非限制實例為：長春花鹼、長春新鹼、長春花素、博來霉素、達克汀霉素、道諾紅菌素、多克索紅菌素、表紅菌素、依達紅菌素、培克里他索(paclitaxel)、光神霉素、脫氧共-間型霉素、絲裂霉素-C、L-天冬醯胺酶、干擾素(尤其是IFN-a)、依托泊苷(etoposide)。Natural products and their derivatives include vinca alkaloids, antitumor antibiotics, enzymes, lymphokines, and epipodophyllotoxin, non-limiting examples of which are: vinblastine, vincristine, vinca, bacillus , dydoxin, daunorubicin, erythromycin, erythromycin, idadamycin, paclitaxel, mithramycin, deoxy-co- Phenomycin, mitomycin-C, L-aspartate, interferon (especially IFN-a), etoposide.

激素與類固醇之非限制實例為：17α-炔雌醇、二乙基己烯雌酚、睪酮、潑尼松、氟羥甲睪酮、卓莫史坦酮(Dromostanolone)丙酸鹽、睪丸內脂、甲地羥孕酮醋酸酯、他摩西吩(tamoxifen)、甲基氫化潑尼松、甲基-睪酮、氫化潑尼松、氟羥脫氫皮質甾醇、三對甲氧苯氯乙烯、羥孕甾酮、胺基導眠能、雌氮芥(estramustine)、甲孕酮醋酸酯、留普內酯(leuprolide)、弗如醯胺(flutamide)、托里米吩(toremifene)、卓拉地斯(Zoladex)。Non-limiting examples of hormones and steroids are: 17α-ethinylestradiol, diethylstilbestrol, anthrone, prednisone, fludroxanone, Dromostanolone propionate, sputum lactone, alpha hydroxyl Progesterone acetate, tamoxifen, methylprednisolone, methyl-fluorenone, prednisolone, fluorohydrodehydrocorticosterol, tri-p-methoxyphenyl chloride, hydroxypregnane, amine Base-sleeping energy, estramustine, medroxyprogesterone acetate, leuprolide, flutamide, toremifene, Zoladex.

合成物質包括無機錯合物，譬如鉑配位錯合物，其非限制實例為：順鉑(Cisplatin)、草酸鉑(Oxaliplatin)、卡鉑(Carboplatin)、阿姆薩素(amsacrine)、米托坦(mitotan)、米托蔥醌(mitoxantrone)。Synthetic materials include inorganic complexes such as platinum coordination complexes, non-limiting examples of which are: Cisplatin, Oxaliplatin, Carboplatin, Amsacrine, Mitre Mitotan, mitoxantrone.

可與本發明化合物、以其製備之藥劑或醫藥組合物併用之抗血管生成劑、EGF受體激酶抑制劑、EGF受體抑制劑、VEGF受體激酶抑制劑、VEGF受體激酶抑制劑之非限制性實例包括(但不限於)：前述美國專利第5,457,105、5,745,498、5,770、599及6,414,148號專利中所揭示或記載者。An anti-angiogenic agent, an EGF receptor kinase inhibitor, an EGF receptor inhibitor, a VEGF receptor kinase inhibitor, or a VEGF receptor kinase inhibitor which can be used in combination with a compound of the present invention, an agent or a pharmaceutical composition prepared thereby Illustrative examples include, but are not limited to, those disclosed or described in the aforementioned U.S. Patent Nos. 5,457,105, 5,745,498, 5,770, 599, and 6, 414, 148.

前述可與本發明化合物、藥劑或醫藥組合物併用治療劑，其安全且有效之投藥方法係為熟諳此藝者所已知。此外，其投藥係描述於標準文獻中。例如，許多化學治療劑之投藥係描述於"醫師之桌上參考資料"(PDR)，例如2002版(醫學經濟學公司，Montvale,NJ07645-1742,USA)中；其揭示之全文併於本文，為本文之參考。The foregoing can be used in combination with a compound, a medicament or a pharmaceutical composition of the present invention, and a safe and effective method of administration is known to those skilled in the art. In addition, its administration is described in the standard literature. For example, many chemotherapeutic agents are described in the "Physician's Desk Reference" (PDR), for example, in the 2002 edition (Medical Economics Corporation, Montvale, NJ 07645-1742, USA); For the reference of this article.

與本發明化合物併用之治療劑及/或放射線療法可根據此項技藝中所習知之方式投予或施用。熟諳此藝者將顯而易見的是，該併用之治療劑及/或放射線療法，可依被治療之疾病，及併用之治療劑及/或放射線療法對所欲抑制或治療之病況或疾病之已知作用而改變。而且，根據熟練臨床醫師之知識，療法(例如投藥之劑量與次數)可基於所投予之治療劑(意即本發明化合物、以其製備之藥劑或醫藥組合物、併用之藥劑或放射線療法)對病患所發現之效果，及基於該病況或疾病對所投予治療劑之所發現回應而改變。Therapeutic agents and/or radiation therapy for use in combination with a compound of the invention can be administered or administered in a manner well known in the art. It will be apparent to those skilled in the art that the combination of therapeutic agents and/or radiation therapy may be known for the condition or disease to be inhibited or treated depending on the condition being treated, and the therapeutic agent and/or radiation therapy used in combination. Change by function. Moreover, according to the knowledge of the skilled clinician, the therapy (for example, the dose and the number of administrations) may be based on the administered therapeutic agent (ie, the compound of the present invention, the agent or pharmaceutical composition prepared thereby, the agent used in combination or the radiotherapy) The effect found by the patient and the response to the condition being discovered by the condition or disease to which the therapeutic agent was administered is altered.

判斷所投予之劑量是否有效時，負責之臨床醫師將考量病患之一般療效，以及更明確之跡象，譬如是否又與疾病相關病徵之緩解，腫瘤生長之抑制，腫瘤之實際縮小，或轉移之抑制。腫瘤之大小可藉由標準方法度量，譬如放射-邏輯研究，例如CAT或MRI掃描，而連續度量法可用以判斷腫瘤之生長是否已被減緩或甚至逆轉。疾病相關病徵譬如疼痛之緩解，及整個症狀之改善，亦可用以幫助判斷治療之有效性。When determining whether the dose administered is effective, the responsible clinician will consider the general efficacy of the patient, as well as more specific signs, such as whether or not the disease-related symptoms are alleviated, the inhibition of tumor growth, the actual shrinkage of the tumor, or the metastasis. Suppression. The size of the tumor can be measured by standard methods, such as radio-logical studies, such as CAT or MRI scans, while continuous measures can be used to determine whether tumor growth has been slowed or even reversed. Disease-related symptoms such as pain relief and improvement in overall symptoms can also be used to help determine the effectiveness of treatment.

茲以下列非限制性實例進一步說明本發明。本發明所屬技術領域中具有通常知識者依據本發明之教示所可輕易完成之修飾及改變，均涵括於本發明之範圍內。下述實例非本發明之限制條件，而本案之權利範圍界定於申請專利範圍之請求項中。The invention is further illustrated by the following non-limiting examples. Modifications and variations that may be readily made by those skilled in the art in light of the teachings of the present invention are included in the scope of the invention. The following examples are not limiting of the invention, and the scope of the claims is defined in the claims of the scope of the claims.

實施例Example 一般程序General procedure

利用核磁共振光譜儀(Bruker AC 500MHz NMR)獲得質子NMR(1 H NMR)光譜，且揭示相對於四甲基矽烷(TMS)習知文獻。利用液相層析儀加串聯式質譜儀(Perkin-Elmer Sciex API 300LC/MS/MS system)獲得低解析度質量光譜。在flash conditions下，使用具有0.040至0.063毫米粒徑之矽膠60在柱狀層析儀(默克)中進行層析。由商業來源獲得試劑及溶劑，及在收到後使用。Proton NMR ( 1 H NMR) spectra were obtained using a nuclear magnetic resonance spectrometer (Bruker AC 500 MHz NMR) and revealed relative to tetramethyl decane (TMS). A low resolution mass spectrum was obtained using a liquid chromatography coupled to a tandem mass spectrometer (Perkin-Elmer Sciex API 300 LC/MS/MS system). Chromatography was carried out in a column chromatography (Merck) using a silicone 60 having a particle size of 0.040 to 0.063 mm under flash conditions. Reagents and solvents are obtained from commercial sources and used after receipt.

本發明之化合物可依以下流程(流程圖1、流程圖2、流程圖3及流程圖4)所示之方法製備。The compounds of the present invention can be prepared by the methods shown in the following schemes (Scheme 1, Flowchart 2, Flowchart 3, and Flowchart 4).

實例一Example one 4-[(3-溴苯基)胺基]-6,7-二甲氧基喹唑啉(4a)及4-[(4-溴苯基)胺基]-6,7-二甲氧基喹唑啉(4b)之製備(流程圖1)4-[(3-bromophenyl)amino]-6,7-dimethoxyquinazoline (4a) and 4-[(4-bromophenyl)amino]-6,7-dimethoxy Preparation of quinazoline (4b) (Flowchart 1)

(1). 6,7-二甲氧基喹唑啉-4(3H)-酮(2)(1). 6,7-Dimethoxyquinazoline-4(3H)-one (2)

將2-胺基-4,5-二甲氧基苯甲酸(10.0克，50毫莫耳)(1)與甲醯胺(8毫升，200毫莫耳)在油浴中充分混合及快速加熱至190℃。在190℃下歷經2小時後，將反應混合物冷卻至室溫，及然後以50毫升之蒸餾水稀釋。收集所得之深灰色固體，以水及丙酮沖洗，及以60℃真空乾燥以獲得6,7-二甲氧基喹唑啉-4(3H)-酮(2)(2.51克，24%)，其可直接使用。2-Amino-4,5-dimethoxybenzoic acid (10.0 g, 50 mmol) (1) and melamamine (8 mL, 200 mmol) thoroughly mixed in an oil bath and rapidly heated To 190 ° C. After 2 hours at 190 ° C, the reaction mixture was cooled to room temperature and then diluted with 50 ml of distilled water. The resulting dark gray solid was collected, washed with water and acetone, and dried under vacuum at 60[deg.] C. to afford 6,7-dimethoxyquinazolyl-4(3H)-one (2) (2.51 g, 24%). It can be used directly.

1 H NMR[(CD3 )2 SO]δ12.00(br s,1H,NH),7.92(s,1H,H-2),7.39(s,1H,H-5),7.09(s,1H,H8),3.88,3.85(2s,6H,2-OCH3 ) 1 H NMR [(CD 3 ) 2 SO] δ 12.00 (br s, 1H, NH), 7.92 (s, 1H, H-2), 7.39 (s, 1H, H-5), 7.09 (s, 1H) , H8), 3.88, 3.85 (2s, 6H, 2-OCH 3 )

(2). 4-氯-6,7-二甲氧基喹唑啉(3)(2). 4-Chloro-6,7-dimethoxyquinazoline (3)

在25℃氮氣下，將二甲基甲醯胺(DMF)(0.5克，6毫莫耳)加入亞硫醯氯(7.85毫升，66毫莫耳)及6,7-二甲氧基喹唑啉-4(3H)-酮(2)(206.1毫克，1.0毫莫耳)之攪拌溶液中，造成放熱反應及發氣。當發氣停止，將混合物加熱至回流歷經24小時，及冷卻至25℃，然後以稀釋NaHCO3 水溶液將反應驟冷。在冰浴上攪拌所得混合物歷經10分鐘，及收集固體，以水沖洗，及在45℃真空乾燥，以獲得4-氯-6,7-二甲氧基喹唑啉(3)(198.4毫克，88%)，其可直接使用。Dimethylformamide (DMF) (0.5 g, 6 mmol) was added to sulfinium chloride (7.85 mL, 66 mmol) and 6,7-dimethoxyquinazole under nitrogen at 25 °C. An agitated solution of porphyrin-4(3H)-one (2) (206.1 mg, 1.0 mmol) caused an exothermic reaction and gas evolution. When the gas evolution ceased, the mixture was heated to reflux for 24 hours and cooled to 25 ° C, then quenched with diluted aqueous NaHCO 3 . The resulting mixture was stirred on an ice bath for 10 minutes, and a solid was collected, washed with water, and dried under vacuum at 45 ° C to give 4-chloro-6,7-dimethoxyquinazoline (3) (198.4 mg, 88%), which can be used directly.

1 H NMR(CD3 OD)δ9.13(s,1H,H-2),7.64(s,1H,H-5),7.37(s,1H,H-8),4.11,4.05(2s,6H,2-OCH3 ) 1 H NMR (CD 3 OD) δ 9.13 (s, 1H, H-2), 7.64 (s, 1H, H-5), 7.37 (s, 1H, H-8), 4.11, 4.05 (2s, 6H) , 2-OCH 3 )

(3). 4-[(3-溴苯基)胺基]-6,7-二甲氧基喹唑啉(4a)(3). 4-[(3-Bromophenyl)amino]-6,7-dimethoxyquinazoline (4a)

將在110℃氮氣下歷經24小時，4-氯-6,7-二甲氧基喹唑啉(677毫克，3毫莫耳)與3-溴苯胺(516毫克，3毫莫耳)在攪拌DMF(6毫升)中之反應，以水驟冷，得到4-[(3-溴苯基)胺基]-6,7-二甲氧基喹唑啉(962毫克，78%)。4-chloro-6,7-dimethoxyquinazoline (677 mg, 3 mmol) and 3-bromoaniline (516 mg, 3 mmol) were stirred at 110 ° C under nitrogen for 24 hours. The reaction in DMF (6 mL

1 H NMR[(CD3 )2 SO]δ8.88(1H,s),8.43(1H,s),8.05(1H,t,J=1.85),7.80(1H,d,J=8.46),7.45(1H,t,J=8.02),7.40(1H,s) 1 H NMR [(CD 3 ) 2 SO] δ 8.88 (1H, s), 8.43 (1H, s), 8.05 (1H, t, J = 1.85), 7.80 (1H, d, J = 8.46), 7.45 (1H, t, J = 8.02), 7.40 (1H, s)

(4). 4-[(4-溴苯基)胺基]-6,7-二甲氧基喹唑啉(4b)(4). 4-[(4-Bromophenyl)amino]-6,7-dimethoxyquinazoline (4b)

在110℃氮氣下，歷24小時，將4-氯-6,7-二甲氧基喹唑啉(3)(677毫克，3毫莫耳)與4-溴苯胺(516毫克，3毫莫耳)在攪拌DMF(6毫升)中之反應，以水驟冷，得到4-[(4-溴苯基)胺基]-6,7-二甲氧基喹唑啉(765毫克，62%)。4-Chloro-6,7-dimethoxyquinazoline (3) (677 mg, 3 mmol) with 4-bromoaniline (516 mg, 3 mmol) at 110 ° C under nitrogen for 24 hours. The reaction in stirring in DMF (6 mL) EtOAc (EtOAc) ).

1 H NMR[(CD3 )2 SO]δ11.20(1H,s),8.84(1H,s),8.24(1H,s),7.68(4H,t,J=9.55),7.32(1H,s),4.01(6H,d,J=6.7) 1 H NMR [(CD 3 ) 2 SO] δ 11.20 (1H, s), 8.84 (1H, s), 8.24 (1H, s), 7.68 (4H, t, J = 9.55), 7.32 (1H, s ), 4.01 (6H, d, J = 6.7)

實例二Example two 溴芳族醯胺或溴雜芳香族醯胺之製備(7)(流程圖2)Preparation of bromoaromatic decylamine or bromide aromatic decylamine (7) (Flowchart 2)

將5-溴噻吩-2-羧酸(207毫克，1毫莫耳)、1-羥基苯基疊氮(162毫克，1.2毫莫耳)及1-(3-二甲基胺基)丙基-3-乙基碳化二醯亞胺　鹽酸鹽(230毫克，1.2毫莫耳)置於一經乾燥、10毫升之圓底燒瓶中，其配備有經鐵氟龍塗佈之磁攪拌棒及橡膠隔片。將混合物在25℃下攪拌10分鐘，然後在冰水浴中冷卻至0℃。將1-甲基哌嗪(120毫克，1.2毫莫耳)及三乙基胺(542μl，3.91毫莫耳)加入經冷卻溶液中。將混合物在0℃下攪拌10分鐘，然後加溫至25℃。在25℃下攪拌24小時候，將混合物轉換於一30毫升之具有10毫升之二氯甲烷的分離用漏斗中。接著以10毫升之1N的鹽酸水溶液、10毫升的飽和碳酸氫鈉水溶液及10毫升的水萃取產品溶液。以無水硫酸鈉乾燥有機層，在降壓下濃縮以得到粗產物。藉由在矽膠或自溶劑再結晶，進行層析，得溴芳族醯胺或溴雜芳香族醯胺。5-bromothiophene-2-carboxylic acid (207 mg, 1 mmol), 1-hydroxyphenyl azide (162 mg, 1.2 mmol) and 1-(3-dimethylamino)propyl 3-Ethylcarbodiimide hydrochloride (230 mg, 1.2 mmol) in a dry, 10 mL round bottom flask equipped with a Teflon coated magnetic stir bar and rubber bead. The mixture was stirred at 25 ° C for 10 minutes and then cooled to 0 ° C in an ice water bath. 1-Methylpiperazine (120 mg, 1.2 mmol) and triethylamine (542 μl, 3.91 mmol) were added to the cooled solution. The mixture was stirred at 0 °C for 10 minutes and then warmed to 25 °C. After stirring at 25 ° C for 24 hours, the mixture was transferred to a 30 ml portion of a separating funnel with 10 ml of dichloromethane. The product solution was then extracted with 10 ml of 1N aqueous hydrochloric acid solution, 10 ml of saturated aqueous sodium hydrogen carbonate solution and 10 ml of water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude. Chromatography is carried out by recrystallization from cerium or from a solvent to obtain a bromine aromatic decylamine or a bromide aromatic decylamine.

依前述方法製得下述化合物：The following compounds were prepared as described above:

(3-溴-苯基)-(4-甲基-哌嗪-1-基)-甲酮(7a)(3-bromo-phenyl)-(4-methyl-piperazin-1-yl)-methanone (7a)

1 H-NMR(CDCl3 )δ7.55(2H,t,J=5.8),7.27(2H,m),3.87(2H,s),3.5(2H,s),2.56(2H,s),2.44(2H,s),2.38(3H,s). 1 H-NMR (CDCl 3 ) δ 7.55 (2H, t, J = 5.8), 7.27 (2H, m), 3.87 (2H, s), 3.5 (2H, s), 2.56 (2H, s), 2.44 (2H, s), 2.38 (3H, s).

(4-溴-苯基)-(4-甲基-哌嗪-1-基)-甲酮(7b)(4-bromo-phenyl)-(4-methyl-piperazin-1-yl)-methanone (7b)

1 H-NMR(CDCl3 )δ7.58(2H,d,J=8.33),7.34(2H,d,J=8.285),2.88(3H,d,J=4.595). 1 H-NMR (CDCl 3 ) δ 7.58 (2H, d, J = 8.33), 7.34 (2H, d, J = 8.285), 2.88 (3H, d, J = 4.595).

2-(3-溴-苯基)-1-(4-甲基-哌嗪-1-基)-乙酮(7c)2-(3-bromo-phenyl)-1-(4-methyl-piperazin-1-yl)-ethanone (7c)

1 H NMR(CD3 OD)δ7.41(2H,m),7.22(2H,q,J=9.015),3.78(2H,s),3.61(2H,t,J=4.91),3.55(2H,t,J=5.11),2.39(2H,t,J=5.125),2.2758(3H,s). 1 H NMR (CD 3 OD) δ 7.41 (2H, m), 7.22 (2H, q, J = 9.015), 3.78 (2H, s), 3.61 (2H, t, J = 4.91), 3.55 (2H, t, J = 5.11), 2.39 (2H, t, J = 5.125), 2.2758 (3H, s).

2-(4-溴-苯基)-1-(4-甲基-哌嗪-1-基)-乙酮(7d)2-(4-bromo-phenyl)-1-(4-methyl-piperazin-1-yl)-ethanone (7d)

1 H-NMR(CDCl3 )δ7.44(2H,d,J=8.31),7.11(2H,d,J=8.265),3.65(4H,d,J=9.16),3.44(2H,t,J=4.99),2.35(2H,t,J=5.01),2.25(5H,t,J=4.84). 1 H-NMR (CDCl 3 ) δ 7.44 (2H, d, J = 8.31), 7.11 (2H, d, J = 8.265), 3.65 (4H, d, J = 9.16), 3.44 (2H, t, J) =4.99), 2.35 (2H, t, J = 5.01), 2.25 (5H, t, J = 4.84).

2-(4-溴-苯氧基)-1-(4-甲基-哌嗪-1-基)-乙酮(7e)2-(4-Bromo-phenoxy)-1-(4-methyl-piperazin-1-yl)-ethanone (7e)

1 H NMR(CD3 OD)δ7.39(2H,d,J=8.95),6.89(2H,d,J=8.965),4.79(2H,d,J=4.175),3.58(4H,d,J=20.275),2.43(4H,d,J=23.835),2.31(3H,s). 1 H NMR (CD 3 OD) δ 7.39 (2H, d, J = 8.95), 6.89 (2H, d, J = 8.965), 4.79 (2H, d, J = 4.175), 3.58 (4H, d, J) =20.275), 2.43 (4H, d, J = 23.835), 2.31 (3H, s).

(5-溴-噻吩-2-基)-(4-甲基-哌嗪-1-基)-甲酮(7f-a)(5-bromo-thiophen-2-yl)-(4-methyl-piperazin-1-yl)-methanone (7f-a)

1 H NMR(CD3 OD)δ7.20(1H,d,J=3.91),7.12(1H,d,J=3.96),3.74(4H,t,J=5.04),2.48(4H,t,J=5.095),2.32(3H,s). 1 H NMR (CD 3 OD) δ 7.20 (1H, d, J = 3.91), 7.12 (1H, d, J = 3.96), 3.74 (4H, t, J = 5.04), 2.48 (4H, t, J) =5.095), 2.32 (3H, s).

(5-溴-噻吩-2-基)-(4-吡咯啶-1-基-六氫吡啶-1-基)-甲酮(7f-b)(5-bromo-thiophen-2-yl)-(4-pyrrolidin-1-yl-hexahydropyridin-1-yl)-methanone (7f-b)

1 H NMR(CD3 OD)δ7.22(1H,d,J=3.855),7.15(1H,d,J=3.845),4.41(2H,s),3.14(2H,d,J=7.12),2.68(4H,d,J=5.555),2.40(1H,m),2.07(2H,d,J=12.985),1.84(4H,q,J=3.2),1.46(2H,m). 1 H NMR (CD 3 OD) δ 7.22 (1H, d, J = 3.855), 7.15 (1H, d, J = 3.845), 4.41 (2H, s), 3.14 (2H, d, J = 7.12), 2.68 (4H, d, J = 5.555), 2.40 (1H, m), 2.07 (2H, d, J = 12.985), 1.84 (4H, q, J = 3.2), 1.46 (2H, m).

(5-溴-噻吩-2-基)-(2-吡咯啶-1-基甲基-吡咯啶-1-基)-甲酮(7f-c)(5-bromo-thiophen-2-yl)-(2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone (7f-c)

1 H NMR(CD3 OD)δ7.40(1H,d,J=3.335),7.16(1H,d,J=4.065),4.43(1H,s),3.80(2H,s),2.78(1H,s),2.59(5H,q,J=9.09),2.06(2H,t,J=6.89),1.99(2H,d,J=10.095),1.81(4H,s). 1 H NMR (CD 3 OD) δ 7.40 (1H, d, J = 3.335), 7.16 (1H, d, J = 4.065), 4.43 (1H, s), 3.80 (2H, s), 2.78 (1H, s), 2.59 (5H, q, J = 9.09), 2.06 (2H, t, J = 6.89), 1.99 (2H, d, J = 10.095), 1.81 (4H, s).

5-溴-噻吩-2-羧酸(3-二乙基胺基-丙基)-醯胺(7f-d)5-bromo-thiophene-2-carboxylic acid (3-diethylamino-propyl)-decylamine (7f-d)

1 H NMR(CD3 OD)δ7.44(1H,d,J=3.98),7.14(1H,d,J=3.96),3.34(2H,t,J=8.355),2.58(6H,m),1.78(2H,s), 1.06(6H,t,J=7.205). 1 H NMR (CD 3 OD) δ7.44 (1H, d, J = 3.98), 7.14 (1H, d, J = 3.96), 3.34 (2H, t, J = 8.355), 2.58 (6H, m), 1.78(2H,s), 1.06(6H,t,J=7.205).

5-溴-噻吩-2-羧酸(2-二乙基胺基-乙基)-醯胺(7f-e)5-bromo-thiophene-2-carboxylic acid (2-diethylamino-ethyl)-decylamine (7f-e)

1 H NMR(CD3 OD)δ7.42(1H,d,J=3.71),7.12(1H,d,J=3.71),3.42(2H,t,J=7.11),2.67(2H,t,J=7.11),2.62(4H,t,J=7.11),1.06(6H,t,J=7.11). 1 H NMR (CD 3 OD) δ 7.42 (1H, d, J = 3.71), 7.12 (1H, d, J = 3.71), 3.42 (2H, t, J = 7.11), 2.67 (2H, t, J =7.11), 2.62 (4H, t, J = 7.11), 1.06 (6H, t, J = 7.11).

5-溴-噻吩-2-羧酸(3-二甲基胺基-丙基)-醯胺(7f-f)5-bromo-thiophene-2-carboxylic acid (3-dimethylamino-propyl)-decylamine (7f-f)

1 H NMR(CD3 OD)δ7.69(1H,d,J=4.00),7.3951(1H,d,J=4.00),3.61(2H,t,J=6.97),2.71(2H,t,J=7.62),2,05(2H,quin,J=7.62,6.97). 1 H NMR (CD 3 OD) δ 7.69 (1H, d, J = 4.00), 7.3951 (1H, d, J = 4.00), 3.61 (2H, t, J = 6.97), 2.71 (2H, t, J) =7.62), 2,05 (2H, quin, J=7.62, 6.97).

5-溴-噻吩-2-羧酸(2-二甲基胺基-乙基)-醯胺(7f-g)5-bromo-thiophene-2-carboxylic acid (2-dimethylamino-ethyl)-decylamine (7f-g)

1 H NMR(CD3 OD)δ7.48(1H,d,J=4.03),7.16(1H,d,J=3.96),3.48(2H,t,J=6.78),2.56(2H,t,J=6.715),2.32(6H,s). 1 H NMR (CD 3 OD) δ 7.48 (1H, d, J = 4.03), 7.16 (1H, d, J = 3.96), 3.48 (2H, t, J = 6.78), 2.56 (2H, t, J) =6.715), 2.32 (6H, s).

5-溴-噻吩-2-羧酸(2-二乙基胺基-乙基)-甲基-醯胺(7f-h)5-bromo-thiophene-2-carboxylic acid (2-diethylamino-ethyl)-methyl-decylamine (7f-h)

1 H NMR(CD3 OD)δ7.31(1H,d,J=3.65),7.15(1H,d,J=3.65),3.64(2H,m),3.32(3H,m),2.6778(6H,m),1.07(6H,s). 1 H NMR (CD 3 OD) δ 7.31 (1H, d, J = 3.65), 7.15 (1H, d, J = 3.65), 3.64 (2H, m), 3.32 (3H, m), 2.6778 (6H, m), 1.07 (6H, s).

5-溴-噻吩-2-羧酸(4-甲基-哌嗪-1-基)-醯胺(7f-i)5-bromo-thiophene-2-carboxylic acid (4-methyl-piperazin-1-yl)-decylamine (7f-i)

1 H NMR(CD3 OD)δ7.76(1H,d,J=4.13),7.18(1H,d,J=4.13),2.86(4H,t,J=11.055),2.52(4H,s),2.39(3H,s). 1 H NMR (CD 3 OD) δ 7.76 (1H, d, J = 4.13), 7.18 (1H, d, J = 4.13), 2.86 (4H, t, J = 11.055), 2.52 (4H, s), 2.39 (3H, s).

5-溴-噻吩-2-羧酸(2-六氫吡啶-1-基-乙基)-醯胺(7f-j)5-bromo-thiophene-2-carboxylic acid (2-hexahydropyridin-1-yl-ethyl)-decylamine (7f-j)

1 H NMR(CD3 OD)δ7.47(1H,d,J=3.95),7.16(1H,d,J=4.01),3.50(2H,t,J=6.915),2.57(2H,t,J=6.945), 2.53(4H,s),1.63(4H,q,J=5.665),1.51(2H,s). 1 H NMR (CD 3 OD) δ 7.47 (1H, d, J = 3.95), 7.16 (1H, d, J = 4.01), 3.50 (2H, t, J = 6.915), 2.57 (2H, t, J) =6.945), 2.53(4H,s), 1.63(4H,q,J=5.665), 1.51(2H,s).

5-溴-噻吩-2-羧酸(2-吡咯啶-1-基-乙基)-醯胺(7f-k)5-bromo-thiophene-2-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-decylamine (7f-k)

1 H NMR(CD3 OD)δ7.48(1H,d,J=4.03),7.14(1H,d,J=3.99),3.53(2H,t,J=6.625),2.85(2H,t,J=6.575),2.82(4H,s),1.88(4H,q,J=3.46). 1 H NMR (CD 3 OD) δ 7.48 (1H, d, J = 4.03), 7.14 (1H, d, J = 3.99), 3.53 (2H, t, J = 6.625), 2.85 (2H, t, J) =6.575), 2.82 (4H, s), 1.88 (4H, q, J = 3.46).

5-溴-噻吩-2-羧酸嗎啉-4-基醯胺(7f-l)5-bromo-thiophene-2-carboxylic acid morpholin-4-yl decylamine (7f-l)

1 H NMR(CD3 OD)δ7.39(1H,d,J=3.92),7.09(1H,d,J=3.92),3.75(4H,s(br.)),3.30(4H,s(br.)). 1 H NMR (CD 3 OD) δ 7.39 (1H, d, J = 3.92), 7.09 (1H, d, J = 3.92), 3.75 (4H, s (br.)), 3.30 (4H, s (br) .)).

(5-溴-呋喃-2-基)-(4-甲基-哌嗪-1-基)-甲酮(7g-a)(5-bromo-furan-2-yl)-(4-methyl-piperazin-1-yl)-methanone (7g-a)

1 H NMR(CD3 OD)δ7.02(1H,d,J=3.54),6.59(1H,d,J=3.54),3.79(4H,s(br.)),2.52(4H,m),2.34(3H,s). 1 H NMR (CD 3 OD) δ 7.02 (1H, d, J = 3.54), 6.59 (1H, d, J = 3.54), 3.79 (4H, s (br.)), 2.52 (4H, m), 2.34 (3H, s).

5-溴-呋喃-2-羧酸(4-甲基-六氫吡啶-1-基)-醯胺(7g-i)5-bromo-furan-2-carboxylic acid (4-methyl-hexahydropyridin-1-yl)-decylamine (7g-i)

1 H NMR(CD3 OD)δ7.16(1H,d,J=3.41),6.63(1H,d,J=3.41),3.37(4H,s(br.)),2.95(4H,s(br.)),2.34(3H,s). 1 H NMR (CD 3 OD) δ 7.16 (1H, d, J = 3.41), 6.63 (1H, d, J = 3.41), 3.37 (4H, s (br.)), 2.95 (4H, s (br) .)), 2.34 (3H, s).

5-溴-呋喃-2-羧酸(2-六氫吡啶-1-基-乙基)-醯胺(7g-j)5-bromo-furan-2-carboxylic acid (2-hexahydropyridin-1-yl-ethyl)-decylamine (7g-j)

1 H NMR(CD3 OD)δ6.95(1H,d,J=3.44),6.32(1H,d,J=3.44),3.42(2H,m),2.48(2H,m),2.39(4H,m),1.53(4H,m),1.37(2H,m). 1 H NMR (CD 3 OD) δ6.95 (1H, d, J = 3.44), 6.32 (1H, d, J = 3.44), 3.42 (2H, m), 2.48 (2H, m), 2.39 (4H, m), 1.53 (4H, m), 1.37 (2H, m).

5-溴-呋喃-2-羧酸(2-吡咯啶-1-基-乙基)-醯胺(7g-k)5-bromo-furan-2-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-decylamine (7g-k)

1 H NMR(CD3 OD)δ7.10(1H,d,J=3.49),6.60(1H,d,J=3.49),3.53(2H,t,J=6.783),2.75(2H,t,J=6.783),2.68(4H,m),1.84(4H,m). 1 H NMR (CD 3 OD) δ 7.10 (1H, d, J = 3.49), 6.60 (1H, d, J = 3.49), 3.53 (2H, t, J = 6.783), 2.75 (2H, t, J) =6.783), 2.68 (4H, m), 1.84 (4H, m).

實例三Example three [3'-(6,7-二甲氧基-喹唑啉-4-基胺基)-聯苯基-3-基]-(4-甲基-哌嗪-1-基)-甲酮(化合物9a-7a )(流程圖3)[3'-(6,7-Dimethoxy-quinazolin-4-ylamino)-biphenyl-3-yl]-(4-methyl-piperazin-1-yl)-methanone (Compound 9a-7a ) (Flowchart 3)

將4-[(3-溴苯基)胺基]-6,7-二甲氧基喹唑啉(180毫克，0.5毫莫耳)、雙(平南基)二硼(139.5毫克，0.55毫莫耳)、KOAc(147毫克，1.5毫莫耳)及二氯[1,1'-二茂鐵磷酸]鈀(PdCl2 (dppf))(12毫克，0.015毫莫耳)置於一經乾燥、10毫升之圓底燒瓶中，其配備有經鐵氟龍塗佈之磁攪拌棒及橡膠隔片，以氮氣沖洗。加入DMF(3毫升)及在80℃下攪拌反應物2分鐘。將溶液冷卻到室溫後，然後在冰水浴中冷卻至0℃。將(3-溴-苯基)-(4-甲基-哌嗪-1-基)-甲酮(7a)(283毫克，1毫莫耳)、PdCl2 (dppf)(12毫克,0.015毫莫耳)及2M之Na2 CO3 (1.3毫升,2.5eq)加入，在80℃氮氣下攪拌混合物過夜。將溶液冷卻至室溫，將產物以乙酸乙基(15毫升)萃取，即以水、鹽水清洗，及以硫酸鎂乾燥。最後，使用乙酸乙酯及己烷作為洗提溶劑在矽膠上純化，以得到[3'-(6,7-二甲氧基-喹唑啉-4-基胺基)-聯苯基-3-基]-(4-甲基-哌嗪-1-基)-甲酮(9a-7a)。 4-[(3-Bromophenyl)amino]-6,7-dimethoxyquinazoline (180 mg, 0.5 mmol), bis(Pentamic) diboron (139.5 mg, 0.55 m) Mohr), KOAc (147 mg, 1.5 mmol) and dichloro[1,1'-ferrocenephosphoric acid]palladium (PdCl 2 (dppf)) (12 mg, 0.015 mmol) were placed on a dry A 10 ml round bottom flask equipped with a Teflon coated magnetic stir bar and a rubber septum was flushed with nitrogen. DMF (3 mL) was added and the mixture was stirred at <RTI ID=0.0></RTI></RTI><RTIgt; After cooling the solution to room temperature, it was then cooled to 0 ° C in an ice water bath. (3-Bromo-phenyl)-(4-methyl-piperazin-1-yl)-methanone (7a) (283 mg, 1 mmol), PdCl 2 (dppf) (12 mg, 0.015 m mole) and of 2M Na 2 CO 3 (1.3 mL, 2.5eq) was added, the mixture was stirred at 80 deg.] C under nitrogen overnight. The solution was cooled to room temperature and the product was extracted with ethyl acetate (15 mL), washed with water, brine and dried over magnesium sulfate. Finally, ethyl acetate and hexane were used as eluting solvents to purify on tannin to obtain [3'-(6,7-dimethoxy-quinazolin-4-ylamino)-biphenyl-3. -yl]-(4-methyl-piperazin-1-yl)-methanone (9a-7a).

1 H NMR(CD3 OD)δ8.43(1H,s),8.04(1H,s),7.79(3H,m),7.72(1H,s),7.57(1H,t,J=7.63),7.51(1H,t,J=7.78),7.46(1H,d,J=7.78),7.42(1H,d,J=7.63),7.17(1H,s),4.04(3H,s),3.99(3H,s),2.56(2H,s),2.44(2H,s),2.34(3H,s). 1 H NMR (CD 3 OD) δ 8.43 (1H, s), 8.04 (1H, s), 7.79 (3H, m), 7.72 (1H, s), 7.57 (1H, t, J = 7.63), 7.51 (1H, t, J = 7.78), 7.46 (1H, d, J = 7.78), 7.42 (1H, d, J = 7.63), 7.17 (1H, s), 4.04 (3H, s), 3.99 (3H, s), 2.56 (2H, s), 2.44 (2H, s), 2.34 (3H, s).

參照前述方法及流程圖3所示，使用適當起始化物製得下述化合物：Referring to the foregoing method and Scheme 3, the following compounds were prepared using the appropriate starting materials:

[3'-(6,7-二甲氧基-喹唑啉-4-基胺基)-聯苯基-4-基]-(4-甲[3'-(6,7-Dimethoxy-quinazolin-4-ylamino)-biphenyl-4-yl]-(4-A 基-哌嗪-1-基)-甲酮(9a-7b)Base-piperazin-1-yl)-methanone (9a-7b)

1 H NMR(CD3 OD)δ8.43(1H,s),8.07(1H,s),7.78(4H,m),7.51(4H,m),7.18(1H,s),4.04(3H,s),4.01(3H,s),3.81(2H,s(br.)),3.55(2H,s(br.)),2.56(2H,s(br.)),2.46(2H,s(br.)),2.35(3H,s). 1 H NMR (CD 3 OD) δ 8.43 (1H, s), 8.07 (1H, s), 7.78 (4H, m), 7.51 (4H, m), 7.18 (1H, s), 4.04 (3H, s ), 4.01 (3H, s), 3.81 (2H, s (br.)), 3.55 (2H, s (br.)), 2.56 (2H, s (br.)), 2.46 (2H, s (br.) )), 2.35 (3H, s).

2-[3'-(6,7-二甲氧基-喹唑啉-4-基胺基)-聯苯基-3-基]-1-(4-甲基-哌嗪-1-基)-乙酮(9a-7c)2-[3'-(6,7-Dimethoxy-quinazolin-4-ylamino)-biphenyl-3-yl]-1-(4-methyl-piperazin-1-yl )-Ethyl Ketone (9a-7c)

1 H NMR(CD3 OD)δ8.39(1H,s),7.97(1H,s),7.71(1H,d,J=7.86),7.67(1H,s),7.54(2H,d,J=7.80,7.41(3H,m),7.22(1H,d,J=7.50),7.08(1H,s),3.98(3H,s),3.94(3H,s),3.83(2H,s),3.62(2H,s(br.)),3.56(2H,s(br.)),2.36((2H,s(br.)),2.2780(2H,s(br.)),2.21(3H,s). 1 H NMR (CD 3 OD) δ 8.39 (1H, s), 7.97 (1H, s), 7.71 (1H, d, J = 7.86), 7.67 (1H, s), 7.54 (2H, d, J = 7.80, 7.41 (3H, m), 7.22 (1H, d, J = 7.50), 7.08 (1H, s), 3.98 (3H, s), 3.94 (3H, s), 3.83 (2H, s), 3.62 ( 2H, s(br.)), 3.56 (2H, s(br.)), 2.36 ((2H, s(br.)), 2.2780 (2H, s(br.)), 2.21 (3H, s).

2-[3'-(6,7-二甲氧基-喹唑啉-4-基胺基)-聯苯基-4-基]-1-(4-甲基-哌嗪-1-基)-乙酮(9a-7d)2-[3'-(6,7-Dimethoxy-quinazolin-4-ylamino)-biphenyl-4-yl]-1-(4-methyl-piperazin-1-yl )-Ethyl Ketone (9a-7d)

1 H NMR(CD3 OD)δ8.38(1H,s),7.96(1H,s),7.72(1H,d,J=7.82),7.66(1H,s),7.60(2H,d,J=8.16),7.42(1H,t,J=7.82),7.37(1H,d,J=7.82),7.30(2H,d,J=8.16),7.07(1H,s),3.98(3H,s),3.94(3H,s),3.80(2H,s),3.63(2H,s(br.)),3.56(2H,t,J=4.80),2.39(2H,t,J=4.99),2.31(3H,2H,t,J=4.80),2.25(3H,s). 1 H NMR (CD 3 OD) δ 8.38 (1H, s), 7.96 (1H, s), 7.72 (1H, d, J = 7.82), 7.66 (1H, s), 7.60 (2H, d, J = 8.16), 7.42 (1H, t, J = 7.82), 7.37 (1H, d, J = 7.82), 7.30 (2H, d, J = 8.16), 7.07 (1H, s), 3.98 (3H, s), 3.94 (3H, s), 3.80 (2H, s), 3.63 (2H, s (br.)), 3.56 (2H, t, J = 4.80), 2.39 (2H, t, J = 4.99), 2.31 (3H) , 2H, t, J = 4.80), 2.25 (3H, s).

2-[3'-(6,7-二甲氧基-喹唑啉-4-基胺基)-聯苯基-4-基氧基1-1-(4-甲基-哌嗪-1-基)-乙酮(9a-7e)2-[3'-(6,7-Dimethoxy-quinazolin-4-ylamino)-biphenyl-4-yloxy1-1-(4-methyl-piperazine-1 -yl)-ethanone (9a-7e)

1 H NMR(CD3 OD)δ8.41(1H,s),7.93(1H,s),7.77(1H,s),7.69(1H,d,J=8.68),7.61(2H,d,J=8.68),7.45(1H,t,J=7.83),7.39(1H,d,J=7.83),7.16(1H,s),7.05(2H,d,J=8.68),4.88(2H,s),4.03(3H,s),3.99(3H,s),3.63(4H,m),2.51(2H,t,J=4.89),2.45(2H,t,J=4.8),2.32(3H,s). 1 H NMR (CD 3 OD) δ 8.41 (1H, s), 7.93 (1H, s), 7.77 (1H, s), 7.69 (1H, d, J = 8.68), 7.61 (2H, d, J = 8.68), 7.45 (1H, t, J = 7.83), 7.39 (1H, d, J = 7.83), 7.16 (1H, s), 7.05 (2H, d, J = 8.68), 4.88 (2H, s), 4.03 (3H, s), 3.99 (3H, s), 3.63 (4H, m), 2.51 (2H, t, J = 4.89), 2.45 (2H, t, J = 4.8), 2.32 (3H, s).

[4'-(6,7-二甲氧基-喹唑啉-4-基胺基)-聯苯基-4-基]-(4-甲基-哌嗪-1-基)-甲酮(9b-7b)[4'-(6,7-Dimethoxy-quinazolin-4-ylamino)-biphenyl-4-yl]-(4-methyl-piperazin-1-yl)-methanone (9b-7b)

1 H-NMR(CD3 OD)δ8.42(1H,s),7.85(2H,d,J=8.52),7.74(3H,d,J=7.07),7.67(2H,d,J=8.58),7.49(2H,d,J=8.17),7.14(1H,s),4.02(1H,s),3.98(1H,s),3.80(2H,s),3.55(2H,s),2.54(2H,s),2.45(2H,s),2.34(3H,s). 1 H-NMR (CD 3 OD) δ 8.42 (1H, s), 7.85 (2H, d, J = 8.52), 7.74 (3H, d, J = 7.07), 7.67 (2H, d, J = 8.58) , 7.49 (2H, d, J = 8.17), 7.14 (1H, s), 4.02 (1H, s), 3.98 (1H, s), 3.80 (2H, s), 3.55 (2H, s), 2.54 (2H) , s), 2.45 (2H, s), 2.34 (3H, s).

2-[4'-(6,7-二甲氧基-喹唑啉-4-基胺基)-聯苯基-3-基]-1-(4-甲基-哌嗪-1-基)-乙酮(9b-7c)2-[4'-(6,7-Dimethoxy-quinazolin-4-ylamino)-biphenyl-3-yl]-1-(4-methyl-piperazin-1-yl )-Ethyl Ketone (9b-7c)

1 H-NMR(CD3 OD)δ8.42(1H,s),7.82(2H,d,J=8.56),7.78(1H,s),7.66(2H,d,J=8.585),7.56(2H,d,J=1.805),7.40(1H,t,J=7.98),7.23(1H,d,J=7.58),7.17(1H,s),4.04(3H,s),4.00(3H,s),3.88(2H,s),3.60(4H,q,J=5.08),2.41(2H,t,J=5.095),2.28(2H,q,J=13.75),2.26(3H,d,J=5.115). 1 H-NMR (CD 3 OD) δ 8.42 (1H, s), 7.82 (2H, d, J = 8.56), 7.78 (1H, s), 7.66 (2H, d, J = 8.585), 7.56 (2H) , d, J = 1.805), 7.40 (1H, t, J = 7.98), 7.23 (1H, d, J = 7.58), 7.17 (1H, s), 4.04 (3H, s), 4.00 (3H, s) , 3.88 (2H, s), 3.60 (4H, q, J = 5.08), 2.41 (2H, t, J = 5.095), 2.28 (2H, q, J = 13.75), 2.26 (3H, d, J = 5.115) ).

2-[4'-(6,7-二甲氧基-喹唑啉-4-基胺基)-聯苯基-4-基]-1-(4-甲基-哌嗪-1-基)-乙酮(9b-7d)2-[4'-(6,7-Dimethoxy-quinazolin-4-ylamino)-biphenyl-4-yl]-1-(4-methyl-piperazin-1-yl )-Ethyl Ketone (9b-7d)

1 H-NMR(CD3 OD)δ8.42(1H,s),7.79(3H,t,J=8.5),7.63(4H,q,J=9.07),7.34(2H,d,J=8.075),7.17(1H,s),4.04(3H,s),4.01(3H,s),3.84(2H,s),3.65(2H,s),3.59(2H,t,J=4.995),2.41(2H,t,J=5.005),2.32(2H,t,J=4.895),2.28(3H,s). 1 H-NMR (CD 3 OD) δ 8.42 (1H, s), 7.79 (3H, t, J = 8.5), 7.63 (4H, q, J = 9.07), 7.34 (2H, d, J = 8.075) , 7.17 (1H, s), 4.04 (3H, s), 4.01 (3H, s), 3.84 (2H, s), 3.65 (2H, s), 3.59 (2H, t, J = 4.995), 2.41 (2H) , t, J = 5.005), 2.32 (2H, t, J = 4.895), 2.28 (3H, s).

2-[4'-(6,7-二甲氧基-喹唑啉-4-基胺基)-聯苯基-4-基氧基]-1-(4-甲基-哌嗪-1-基)-乙酮(9b-7e)2-[4'-(6,7-Dimethoxy-quinazolin-4-ylamino)-biphenyl-4-yloxy]-1-(4-methyl-piperazine-1 -yl)-ethanone (9b-7e)

1 H-NMR(CD3 OD)δ8.41(1H,s),7.77(3H,t,J=5.61),7.59(4H,q,J=8.76),7.17(1H,s),7.05(2H,d,J=8.725),4.86(2H,s),4.04(3H,s),4.01(3H,s),3.64(4H,d,J=4.195),2.44(4H,d,J=4.95),2.33(3H,s). 1 H-NMR (CD 3 OD) δ 8.41 (1H, s), 7.77 (3H, t, J = 5.61), 7.59 (4H, q, J = 8.76), 7.17 (1H, s), 7.05 (2H) , d, J = 8.725), 4.86 (2H, s), 4.04 (3H, s), 4.01 (3H, s), 3.64 (4H, d, J = 4.195), 2.44 (4H, d, J = 4.95) , 2.33 (3H, s).

實例四Example four

依實例三及流程圖4所示方法，使用適當之起始物製備下述化合物：The following compounds were prepared according to the procedure shown in Example 3 and Scheme 4 using the appropriate starting materials:

{5-[3-(6,7-二甲氧基-喹唑啉-4-基胺基)-苯基]-噻吩-2-基}-(4-甲基-哌嗪-1-基)-甲酮(9a-7f-a){5-[3-(6,7-Dimethoxy-quinazolin-4-ylamino)-phenyl]-thiophen-2-yl}-(4-methyl-piperazin-1-yl )--ketone (9a-7f-a)

1 H NMR(CD3 OD)δ8.47(1H,s),8.13(1H,s),7.82(1H,d,J=7.33),7.48(2H,m),7.44(1H,d,J=3.81),7.42(1H,d,J=3.81),7.18(1H,s),4.06(3H,s),4.02(3H,s),3.85(4H,s(br.)),2.55(4H,t,J=4.87),2.37(3H,s). 1 H NMR (CD 3 OD) δ 8.47 (1H, s), 8.13 (1H, s), 7.82 (1H, d, J = 7.33), 7.48 (2H, m), 7.44 (1H, d, J = 3.81), 7.42 (1H, d, J = 3.81), 7.18 (1H, s), 4.06 (3H, s), 4.02 (3H, s), 3.85 (4H, s (br.)), 2.55 (4H, t, J = 4.87), 2.37 (3H, s).

{5-[3-(6,7-二甲氧基-喹唑啉-4-基胺基)-苯基]-呋喃-2-基}-(4-甲基-哌嗪-1-基)-甲酮(9a-7g-a){5-[3-(6,7-Dimethoxy-quinazolin-4-ylamino)-phenyl]-furan-2-yl}-(4-methyl-piperazin-1-yl )--ketone (9a-7g-a)

1 H NMR(CD3 OD)δ8.44(1H,s),8.22(1H,s),7.76(1H,s),7.74(1H,d,J=7.83),7.56(1H,d,J=7.83),7.47(1H,t=7.83),7.16(1H,s),7.15(1H,d,J=3.56),6.95(1H,d,J=3.56),4.04(3H,s),4.00(3H,s),3.89(4H,s(br.)),2.56(4H,t,J=5.00),2.35(3H,s). 1 H NMR (CD 3 OD) δ 8.44 (1H, s), 8.22 (1H, s), 7.76 (1H, s), 7.74 (1H, d, J = 7.83), 7.56 (1H, d, J = 7.83), 7.47 (1H, t = 7.83), 7.16 (1H, s), 7.15 (1H, d, J = 3.56), 6.95 (1H, d, J = 3.56), 4.04 (3H, s), 4.00 ( 3H, s), 3.89 (4H, s (br.)), 2.56 (4H, t, J = 5.00), 2.35 (3H, s).

{5-[3-(6,7-二甲氧基-喹唑啉-4-基胺基)-苯基]-噻吩-2-基}-(4-吡咯啶-1-基-六氫吡啶-1-基)-甲酮(9a-7f-b){5-[3-(6,7-Dimethoxy-quinazolin-4-ylamino)-phenyl]-thiophen-2-yl}-(4-pyrrolidin-1-yl-hexahydro) Pyridin-1-yl)-methanone (9a-7f-b)

1 H NMR(CD3 OD)δ8.45(1H,s),8.12(1H,s),7.80(2H,m),7.44(4H,m),7.18(2H,s),4.04(3H,s),4.56(2H,m),4.01(3H,s),3.12(2H,s(br.)),2.73(4H,s(br.)),2.49(1H,m),2.10(2H,d,J=12.32),1.86(4H,s(br.)),1.53(2H,m). 1 H NMR (CD 3 OD) δ 8.45 (1H, s), 8.12 (1H, s), 7.80 (2H, m), 7.44 (4H, m), 7.18 (2H, s), 4.04 (3H, s ), 4.56 (2H, m), 4.01 (3H, s), 3.12 (2H, s (br.)), 2.73 (4H, s (br.)), 2.49 (1H, m), 2.10 (2H, d , J = 12.32), 1.86 (4H, s (br.)), 1.53 (2H, m).

{5-[3-(6,7-二甲氧基-喹唑啉-4-基胺基)-苯基]-噻吩-2-基}-(2-吡咯啶-1-基甲基-吡咯啶-1-基)-甲酮(9a-7f-c){5-[3-(6,7-Dimethoxy-quinazolin-4-ylamino)-phenyl]-thiophen-2-yl}-(2-pyrrolidin-1-ylmethyl- Pyrrolidin-1-yl)-methanone (9a-7f-c)

1 H NMR(CD3 OD)δ8.47(1H,s),8.16(1H,s),7.81(2H,m),7.63(1H,s(br.)),7.49(3H,m),7.20(1H,s),4.51(1H,s),4.06(3H,s),4.03(3H,s),3.90(2H,s),2.90(2H,s(br.)),2.71(4H,s(br.)),2.13((2H,s(br.)),2.03(2H,s(br.)),1.86(4H,s(br.)). 1 H NMR (CD 3 OD) δ 8.47 (1H, s), 8.16 (1H, s), 7.81 (2H, m), 7.63 (1H, s (br.)), 7.49 (3H, m), 7.20 (1H, s), 4.51 (1H, s), 4.06 (3H, s), 4.03 (3H, s), 3.90 (2H, s), 2.90 (2H, s (br.)), 2.71 (4H, s (br.)), 2.13 ((2H, s(br.)), 2.03 (2H, s(br.)), 1.86 (4H, s(br.)).

5-[3-(6,7-二甲氧基-喹唑啉-4-基胺基)-苯基]-噻吩-2-羧酸(2-二乙基胺基-乙基)-醯胺(9a-7f-e)5-[3-(6,7-Dimethoxy-quinazolin-4-ylamino)-phenyl]-thiophene-2-carboxylic acid (2-diethylamino-ethyl)-indole Amine (9a-7f-e)

1 H NMR(CD3 OD)δ8.44(1H,s),8.11(1H,s),7.78(1H,d,J=7.59),7.74(1H,s),7.63(1H,d,J=3.83),7.45(2H,m),7.41(1H,d,J=3.83),7.14(1H,s),4.03(3H,s),3.98(3H,s),3.49(2H,t,J=7.16),2.73(2H,t,J=7.16),2.67(4H,q,J=7.15),1.11(6H,t,J=7.15). 1 H NMR (CD 3 OD) δ 8.44 (1H, s), 8.11 (1H, s), 7.78 (1H, d, J = 7.59), 7.74 (1H, s), 7.63 (1H, d, J = 3.83), 7.45 (2H, m), 7.41 (1H, d, J = 3.83), 7.14 (1H, s), 4.03 (3H, s), 3.98 (3H, s), 3.49 (2H, t, J = 7.16), 2.73 (2H, t, J = 7.16), 2.67 (4H, q, J = 7.15), 1.11 (6H, t, J = 7.15).

5-[3-(6,7-二甲氧基-喹唑啉-4-基胺基)-苯基]-噻吩-2-羧酸(3-二甲基胺基-丙基)-醯胺(9a-7f-f)5-[3-(6,7-Dimethoxy-quinazolin-4-ylamino)-phenyl]-thiophene-2-carboxylic acid (3-dimethylamino-propyl)-oxime Amine (9a-7f-f)

1 H NMR(CD3 OD)δ8.44(1H,s),8.12(1H,s),7.78(1H,d,J=7.77),7.76(1H,s),7.63(1H,d,J=3.93),7.47(1H,m),7.42(1H,d,J=3.93),7.15(1H,s),4.03(3H,s),3.99(3H,s),3.40(2H,t,J=7.25),2.43(2H,t,J=7.25),2.28(6H,s),1.8129(2H,m). 1 H NMR (CD 3 OD) δ 8.44 (1H, s), 8.12 (1H, s), 7.78 (1H, d, J = 7.77), 7.76 (1H, s), 7.63 (1H, d, J = 3.93), 7.47 (1H, m), 7.42 (1H, d, J = 3.93), 7.15 (1H, s), 4.03 (3H, s), 3.99 (3H, s), 3.40 (2H, t, J = 7.25), 2.43 (2H, t, J = 7.25), 2.28 (6H, s), 1.8129 (2H, m).

5-[3-(6,7-二甲氧基-喹唑啉-4-基胺基)-苯基]-噻吩-2-羧酸(2-二乙基胺基-乙基)-甲基-醯胺(9a-7f-h)5-[3-(6,7-Dimethoxy-quinazolin-4-ylamino)-phenyl]-thiophene-2-carboxylic acid (2-diethylamino-ethyl)-A Base-nonylamine (9a-7f-h)

1 H NMR(CD3 OD)δ8.4272(1H,s),8.1005(1H,s),7.7875(1H,d,J=7.12),7.7149(1H,s),7.4161(4H,m),7.1219(1H,s),4.0161(3H,s),3.9724(3H,s),3.6719(2H,s),3.3099(3H,s),2.7568(2H,s),2.6189(4H,s(br.)),1.0674(6H,s(br.)). 1 H NMR (CD 3 OD) δ 8.4272 (1H, s), 8. 005 (1H, s), 7.7875 (1H, d, J = 7.12), 7.7149 (1H, s), 7.4161 (4H, m), 7.1219 (1H, s), 4.0161 (3H, s), 3.9724 (3H, s), 3.6719 (2H, s), 3.3099 (3H, s), 2.7568 (2H, s), 2.6189 (4H, s (br.) ), 1.0674 (6H, s (br.)).

5-[3-(6,7-二甲氧基-喹唑啉-4-基胺基)-苯基]-噻吩-2-羧酸(4-甲基-哌嗪-1-基)-醯胺(9a-7f-i)5-[3-(6,7-Dimethoxy-quinazolin-4-ylamino)-phenyl]-thiophene-2-carboxylic acid (4-methyl-piperazin-1-yl)- Guanamine (9a-7f-i)

1 H NMR(CD3 OD)δ8.47(1H,d,J=12.93),8.21(1H,m),7.91(2H,m),7.69(1H,d,J=3.97),7.46(3H,m),7.18(1H,s),4.08(3H,s),4.01(3H,s),3.10(2H,d,J=10.62),2.94(4H,m),2.61(2H,m),2.34(3H,d,J=11.22). 1 H NMR (CD 3 OD) δ 8.47 (1H, d, J = 12.93), 8.21 (1H, m), 7.91 (2H, m), 7.69 (1H, d, J = 3.97), 7.46 (3H, m), 7.18 (1H, s), 4.08 (3H, s), 4.01 (3H, s), 3.10 (2H, d, J = 10.62), 2.94 (4H, m), 2.61 (2H, m), 2.34 (3H,d,J=11.22).

5-[3-(6,7-二甲氧基-喹唑啉-4-基胺基)-苯基]-噻吩-2-羧酸(2-六氫吡啶-1-基-乙基)-醯胺(9a-7f-j)5-[3-(6,7-Dimethoxy-quinazolin-4-ylamino)-phenyl]-thiophene-2-carboxylic acid (2-hexahydropyridin-1-yl-ethyl) - guanamine (9a-7f-j)

1 H NMR(CD3 OD)δ8.44(1H,s),8.13(1H,s),7.78(1H,d,J=7.63),7.74(1H,s),7.64(1H,d,J=3.87),7.45(2H,m),7.42(1H,d,J=3.87),7.14(1H,s),7.14(1H,s),4.03(3H,s),3.99(3H,s),3.55(2H,t,J=6.85),2.65(2H,t,J=6.85),2.59(4H,s(br.)),1.66(4H,m),1.51(2H,m). 1 H NMR (CD 3 OD) δ 8.44 (1H, s), 8.13 (1H, s), 7.78 (1H, d, J = 7.63), 7.74 (1H, s), 7.64 (1H, d, J = 3.87), 7.45 (2H, m), 7.42 (1H, d, J = 3.87), 7.14 (1H, s), 7.14 (1H, s), 4.03 (3H, s), 3.99 (3H, s), 3.55 (2H, t, J = 6.85), 2.65 (2H, t, J = 6.85), 2.59 (4H, s (br.)), 1.66 (4H, m), 1.51 (2H, m).

5-[3-(6,7-二甲氧基-喹唑啉-4-基胺基)-苯基1-噻吩-2-羧酸 　嗎啉-4-基醯胺(9a-7f-l) 5- [3- (6,7-dimethoxy - quinazolin-4-ylamino) - phenyl 1 thiophene-2-carboxylic acid morpholin-4-yl Amides (9a-7f-l )

1 H NMR(CD3 OD)δ8.46(1H,d,J=3.85),8.23(1H,m),7.89(2H,m),7.70(1H,d,J=3.50),7.47(3H,m),7.18(1H,s),4.05(3H,s),4.01(3H,s),3.82(2H,m),2.91(2H,m),1.29(4H,s(br.)). 1 H NMR (CD 3 OD) δ 8.46 (1H, d, J = 3.85), 8.23 (1H, m), 7.89 (2H, m), 7.70 (1H, d, J = 3.50), 7.47 (3H, m), 7.18 (1H, s), 4.05 (3H, s), 4.01 (3H, s), 3.82 (2H, m), 2.91 (2H, m), 1.29 (4H, s (br.)).

5-[3-(6,7-二甲氧基-喹唑啉-4-基胺基)-苯基]-呋喃-2-羧酸(4-甲基-哌嗪-1-基)-醯胺(9a-7g-i)5-[3-(6,7-Dimethoxy-quinazolin-4-ylamino)-phenyl]-furan-2-carboxylic acid (4-methyl-piperazin-1-yl)- Indoleamine (9a-7g-i)

1 H NMR(CD3 OD)δ8.43(1H,s),8.21(1H,s),7.75(1H,d,J=7.89),7.72(1H,s),7.70(1H,d,J=7.89),7.26(1H,d,J=3.56),7.13(1H,s),6.94(1H,d,J=3.56),4.04(3H,s),3.99(3H,s),2.98(4H,s(br.)),2.66(4H,s(br.)),2.34(4H,s). 1 H NMR (CD 3 OD) δ 8.43 (1H, s), 8.21 (1H, s), 7.75 (1H, d, J = 7.89), 7.72 (1H, s), 7.70 (1H, d, J = 7.89), 7.26 (1H, d, J = 3.56), 7.13 (1H, s), 6.94 (1H, d, J = 3.56), 4.04 (3H, s), 3.99 (3H, s), 2.98 (4H, s(br.)), 2.66 (4H, s(br.)), 2.34 (4H, s).

55 -[3-(6,7-二甲氧基-喹唑啉-4-基胺基)-苯基]-呋喃-2-羧酸(2-六氫吡啶-1-基-乙基)-醯胺(9a-7g-j)-[3-(6,7-Dimethoxy-quinazolin-4-ylamino)-phenyl]-furan-2-carboxylic acid (2-hexahydropyridin-1-yl-ethyl)- Guanamine (9a-7g-j)

1 H NMR(CD3 OD)δ8.41(1H,s),8.24(1H,s),7.68(1H,s),7.65(2H,m),7.46(1H,t,J=7.91),7.15(1H,d,J=3.29),7.05(1H,s),6.88(1H,d,J=3.29),4.04(3H,s),3.98(3H,s),3.47(2H,t,J=6.49),2.58(2H,t,J=6.49),2.53(4H,m),1.59(4H,m),1.4434(2H,m). 1 H NMR (CD 3 OD) δ 8.41 (1H, s), 8.24 (1H, s), 7.68 (1H, s), 7.65 (2H, m), 7.46 (1H, t, J = 7.91), 7.15 (1H, d, J = 3.29), 7.05 (1H, s), 6.88 (1H, d, J = 3.29), 4.04 (3H, s), 3.98 (3H, s), 3.47 (2H, t, J = 6.49), 2.58 (2H, t, J = 6.49), 2.53 (4H, m), 1.59 (4H, m), 1.4434 (2H, m).

5-[3-(6,7-二甲氧基-喹唑啉-4-基胺基)-苯基]-呋喃-2-羧酸(2-吡咯啶-1-基-乙基)-醯胺(9a-7g-k)5-[3-(6,7-Dimethoxy-quinazolin-4-ylamino)-phenyl]-furan-2-carboxylic acid (2-pyrrolidin-1-yl-ethyl)- Guanamine (9a-7g-k)

1 H NMR(CD3 OD)δ8.41(1H,s),8.24(1H,s),7.69(1H,s),7.65(2H,m),7.46(1H,t,J=7.89),7.15(1H,d,J=3.32),7.06(1H,s),6.89(1H,d,J=3.32),4.04(3H,s),3.98(3H,s),3.47(2H,t,J=6.49),2.66(2H,t,J=6.49),1.78(4H,s). 1 H NMR (CD 3 OD) δ 8.41 (1H, s), 8.24 (1H, s), 7.69 (1H, s), 7.65 (2H, m), 7.46 (1H, t, J = 7.89), 7.15 (1H, d, J = 3.32), 7.06 (1H, s), 6.89 (1H, d, J = 3.32), 4.04 (3H, s), 3.98 (3H, s), 3.47 (2H, t, J = 6.49), 2.66 (2H, t, J = 6.49), 1.78 (4H, s).

{5-[4-(6,7-二甲氧基-喹唑啉-4-基胺基)-苯基]-噻吩-2-{5-[4-(6,7-Dimethoxy-quinazolin-4-ylamino)-phenyl]-thiophene-2- 基}-(4-甲基-哌嗪-1-基)-甲酮(9b-7f-a)}--(4-methyl-piperazin-1-yl)-methanone (9b-7f-a)

1 H-NMR(CD3 OD)δ8.46(1H,s),7.71(4H,m),7.38(2H,q,J=3.81),7.34(1H,d,J=2.045),7.18(1H,s),4.04(3H,s),4.01(3H,s),3.83(4H,s),2.52(4H,t,J=5.095),2.35(3H,s). 1 H-NMR (CD 3 OD) δ 8.46 (1H, s), 7.71 (4H, m), 7.38 (2H, q, J = 3.81), 7.34 (1H, d, J = 2.045), 7.18 (1H) , s), 4.04 (3H, s), 4.01 (3H, s), 3.83 (4H, s), 2.52 (4H, t, J = 5.095), 2.35 (3H, s).

{5-[4-(6,7-二甲氧基-喹唑啉-4-基胺基)-苯基]-噻吩-2-基}-(4-吡咯啶-1-基-六氫吡啶-1-基)-甲酮(9b-7f-b){5-[4-(6,7-Dimethoxy-quinazolin-4-ylamino)-phenyl]-thiophen-2-yl}-(4-pyrrolidin-1-yl-hexahydro Pyridin-1-yl)-methanone (9b-7f-b)

1 H-NMR(CD3 OD)δ8.44(1H,s),7.83(2H,d,J=8.555),7.72(1H,s),7.64(2H,d,J=8.575),7.32(2H,q,J=3.775),7.13(1H,s),4.02(3H,s),3.98(3H,s),2.64(4H,s),2.36(1H,d,J=3.805),1.82(4H,s),1.48(2H,q,J=3.695),1.27(2H,s). 1 H-NMR (CD 3 OD) δ 8.44 (1H, s), 7.83 (2H, d, J = 8.055), 7.72 (1H, s), 7.64 (2H, d, J = 8.575), 7.32 (2H) , q, J = 3.775), 7.13 (1H, s), 4.02 (3H, s), 3.98 (3H, s), 2.64 (4H, s), 2.36 (1H, d, J = 3.805), 1.82 (4H) , s), 1.48 (2H, q, J = 3.695), 1.27 (2H, s).

{5-[4-(6,7-二甲氧基-喹唑啉-4-基胺基)-苯基]-噻吩-2-基}-(2-吡咯啶-1-基甲基-吡咯啶-1-基)-甲酮(9b-7f-c){5-[4-(6,7-Dimethoxy-quinazolin-4-ylamino)-phenyl]-thiophen-2-yl}-(2-pyrrolidin-1-ylmethyl- Pyrrolidin-1-yl)-methanone (9b-7f-c)

1 H-NMR(CD3 OD)δ8.46(1H,s),7.86(2H,d,J=8.475),7.75(1H,s),7.69(2H,d,J=8.56),7.58(1H,d,J=3.15),7.38(1H,d,J=3.915),7.16(1H,s),4.04(3H,s),4.00(3H,s),2.60(4H,q,J=9.485),2.10(5H,s),1.82(4H,s). 1 H-NMR (CD 3 OD) δ 8.46 (1H, s), 7.86 (2H, d, J = 8.475), 7.75 (1H, s), 7.69 (2H, d, J = 8.56), 7.58 (1H) , d, J = 3.15), 7.38 (1H, d, J = 3.915), 7.16 (1H, s), 4.04 (3H, s), 4.00 (3H, s), 2.60 (4H, q, J = 9.485) , 2.10 (5H, s), 1.82 (4H, s).

5-[4-(6,7-二甲氧基-喹唑啉-4-基胺基)-苯基]-噻吩-2-羧酸(3-二乙基胺基-丙基)-醯胺(9b-7f-d)5-[4-(6,7-Dimethoxy-quinazolin-4-ylamino)-phenyl]-thiophene-2-carboxylic acid (3-diethylamino-propyl)-hydrazine Amine (9b-7f-d)

1 H-NMR(CD3 OD)δ8.42(1H,s),7.81(2H,d,J=8.565),7.59(4H,m),7.32(1H,d,J=3.84),7.09(1H,s),4.00(3H,s),3.95(3H,s),3.37(2H,t,J=6.89),2.55(6H,m),1.76(2H,q,J=7.005),1.05(6H,t,J=7.165). 1 H-NMR (CD 3 OD) δ 8.42 (1H, s), 7.81 (2H, d, J = 8.565), 7.59 (4H, m), 7.32 (1H, d, J = 3.84), 7.09 (1H) , s), 4.00 (3H, s), 3.95 (3H, s), 3.37 (2H, t, J = 6.89), 2.55 (6H, m), 1.76 (2H, q, J = 7.005), 1.05 (6H) ,t,J=7.165).

5-[4-(6,7-二甲氧基-喹唑啉-4-基胺基)-苯基]-噻吩-2-羧5-[4-(6,7-Dimethoxy-quinazolin-4-ylamino)-phenyl]-thiophene-2-carboxylate 酸(2-二乙基胺基-乙基)-醯胺(9b-7f-e)Acid (2-diethylamino-ethyl)-decylamine (9b-7f-e)

1 H-NMR(CD3 OD)δ8.44(1H,s),7.84(2H,d,J=8.66),7.75(1H,s),7.68(2H,d,J=8.695),7.63(1H,d,J=3.915),7.37(1H,d,J=3.91),7.15(1H,s),4.02(3H,d,J=6.62),3.99(3H,s),3.51(2H,t,J=7.225),2.73(6H,m),1.11(6H,q,J=7.265). 1 H-NMR (CD 3 OD) δ 8.44 (1H, s), 7.84 (2H, d, J = 8.66), 7.75 (1H, s), 7.68 (2H, d, J = 8.695), 7.63 (1H) , d, J = 3.915), 7.37 (1H, d, J = 3.91), 7.15 (1H, s), 4.02 (3H, d, J = 6.62), 3.99 (3H, s), 3.51 (2H, t, J = 7.225), 2.73 (6H, m), 1.11 (6H, q, J = 7.265).

5-[4-(6,7-二甲氧基-喹唑啉-4-基胺基)-苯基]-噻吩-2-羧酸(4-甲基-哌嗪-1-基)-醯胺(9b-7f-i)5-[4-(6,7-Dimethoxy-quinazolin-4-ylamino)-phenyl]-thiophene-2-carboxylic acid (4-methyl-piperazin-1-yl)- Guanamine (9b-7f-i)

1 H-NMR(CD3 OD)δ8.45(1H,s),7.86(2H,d,J=5.165),7.67(4H,m),7.38(1H,d,J=3.905),7.16(1H,s),4.04(3H,s),3.99(3H,s),2.92(4H,d,J=11.81),2.34(3H,s). 1 H-NMR (CD 3 OD) δ 8.45 (1H, s), 7.86 (2H, d, J = 5.165), 7.67 (4H, m), 7.38 (1H, d, J = 3.905), 7.16 (1H) , s), 4.04 (3H, s), 3.99 (3H, s), 2.92 (4H, d, J = 11.81), 2.34 (3H, s).

5-[4-(6,7-二甲氧基-喹唑啉-4-基胺基)-苯基]-噻吩-2-羧酸(2-六氫吡啶-1-基-乙基)-醯胺(9b-7f-j)5-[4-(6,7-Dimethoxy-quinazolin-4-ylamino)-phenyl]-thiophene-2-carboxylic acid (2-hexahydropyridin-1-yl-ethyl) - guanamine (9b-7f-j)

1 H-NMR(CD3 OD)δ8.46(1H,s),7.86(2H,d,J=8.6),7.79(1H,s),7.72(2H,d,J=8.615),7.65(1H,d,J=3.935),7.40(1H,d,J=3.87),7.18(1H,s),4.04(3H,s),4.0078(3H,s),3.54(2H,t,J=6.92),2.62(2H,t,J=6.885),2.57(4H,s),1.66(4H,d,J=5.615),1.51(2H,s). 1 H-NMR (CD 3 OD) δ 8.46 (1H, s), 7.86 (2H, d, J = 8.6), 7.79 (1H, s), 7.72 (2H, d, J = 8.615), 7.65 (1H) , d, J = 3.935), 7.40 (1H, d, J = 3.87), 7.18 (1H, s), 4.04 (3H, s), 4.0078 (3H, s), 3.54 (2H, t, J = 6.92) , 2.62 (2H, t, J = 6.885), 2.57 (4H, s), 1.66 (4H, d, J = 5.615), 1.51 (2H, s).

5-[4-(6,7-二甲氧基-喹唑啉-4-基胺基)-苯基]-噻吩-2-羧酸(2-吡咯啶-1-基-乙基)-醯胺(9b-7f-k)5-[4-(6,7-Dimethoxy-quinazolin-4-ylamino)-phenyl]-thiophene-2-carboxylic acid (2-pyrrolidin-1-yl-ethyl)- Guanamine (9b-7f-k)

1 H-NMR(CD3 OD)δ8.45(1H,s),7.85(2H,d,J=8.61),7.77(1H,s),7.70(2H,d,J=8.65),7.65(1H,d,J=3.91),7.38(1H,d,J=3.865),7.17(1H,s),4.04(3H,s),4.00(3H,s),3.53(2H,t,J=6.925),2.72(2H,t,J=6.87),2.65(4H,s),1.83(4H,m). 1 H-NMR (CD 3 OD) δ 8.45 (1H, s), 7.85 (2H, d, J = 8.61), 7.77 (1H, s), 7.70 (2H, d, J = 8.65), 7.65 (1H) , d, J = 3.91), 7.38 (1H, d, J = 3.865), 7.17 (1H, s), 4.04 (3H, s), 4.00 (3H, s), 3.53 (2H, t, J = 6.925) , 2.72 (2H, t, J = 6.87), 2.65 (4H, s), 1.83 (4H, m).

{5-[4-(6,7-二甲氧基-喹唑啉-4-基胺基)-苯基]-呋喃-2-基}-(4-甲基-哌嗪-1-基)-甲酮(9b-7g-a){5-[4-(6,7-Dimethoxy-quinazolin-4-ylamino)-phenyl]-furan-2-yl}-(4-methyl-piperazin-1-yl )--ketone (9b-7g-a)

1 H-NMR(CD3 OD)δ8.45(1H,s),7.88(2H,d,J=8.64),7.74(3H,t,J=8.685),7.14(2H,t,J=3.59),6.88(1H,d,J=3.585),4.03(3H,s),3.99(3H,s),2.56(4H,t,J=4.94),2.36(3H,s). 1 H-NMR (CD 3 OD) δ 8.45 (1H, s), 7.88 (2H, d, J = 8.64), 7.74 (3H, t, J = 8.685), 7.14 (2H, t, J = 3.59) , 6.88 (1H, d, J = 3.585), 4.03 (3H, s), 3.99 (3H, s), 2.56 (4H, t, J = 4.94), 2.36 (3H, s).

5-[4-(6,7-二甲氧基-喹唑啉-4-基胺基)-苯基]-呋喃-2-羧酸(4-甲基-哌嗪-1-基)-醯胺(9b-7g-i)5-[4-(6,7-Dimethoxy-quinazolin-4-ylamino)-phenyl]-furan-2-carboxylic acid (4-methyl-piperazin-1-yl)- Guanamine (9b-7g-i)

1 H-NMR(CD3 OD)δ8.47(1H,s),7.92(2H,d,J=7.45),7.67(4H,m),7.34(1H,s),7.19(1H,s),4.05(3H,s),4.01(3H,s),2.93(4H,s),2.66(4H,s),2.31(3H,s). 1 H-NMR (CD 3 OD) δ 8.47 (1H, s), 7.92 (2H, d, J = 7.45), 7.67 (4H, m), 7.34 (1H, s), 7.19 (1H, s), 4.05 (3H, s), 4.01 (3H, s), 2.93 (4H, s), 2.66 (4H, s), 2.31 (3H, s).

5-[4-(6,7-二甲氧基-喹唑啉-4-基胺基)-苯基]-呋喃-2-羧酸(2-六氫吡啶-1-基-乙基)-醯胺(9b-7g-j)5-[4-(6,7-Dimethoxy-quinazolin-4-ylamino)-phenyl]-furan-2-carboxylic acid (2-hexahydropyridin-1-yl-ethyl) - guanamine (9b-7g-j)

1 H-NMR(CD3 OD)δ8.45(1H,s),7.85(4H,q,J=8.875),7.74(1H,s),7.19(1H,d,J=3.55),7.14(1H,s),6.87(1H,d,J=3.56),4.03(3H,s),3.98(3H,s),3.65(2H,s),2.84(2H,t,J=6.515),2.76(4H,q,J=8.525),1.91(6H,s). 1 H-NMR (CD 3 OD) δ 8.45 (1H, s), 7.85 (4H, q, J = 8.875), 7.74 (1H, s), 7.19 (1H, d, J = 3.55), 7.14 (1H) , s), 6.87 (1H, d, J = 3.56), 4.03 (3H, s), 3.98 (3H, s), 3.65 (2H, s), 2.84 (2H, t, J = 6.515), 2.76 (4H , q, J = 8.525), 1.91 (6H, s).

5-[4-(6,7-二甲氧基-喹唑啉-4-基胺基)-苯基]-呋喃-2-羧酸(2-吡咯啶-1-基-乙基)-醯胺(9b-7g-k)5-[4-(6,7-Dimethoxy-quinazolin-4-ylamino)-phenyl]-furan-2-carboxylic acid (2-pyrrolidin-1-yl-ethyl)- Guanamine (9b-7g-k)

1 H-NMR(CD3 OD)δ8.45(1H,s),7.86(4H,d,J=9.48),7.75(1H,s),7.18(1H,d,J=3.585),7.15(1H,s),6.86(1H,d,J=3.605),4.03(3H,s),3.99(3H,s),3.56(2H,t,J=6.8),2.74(2H,t,J=6.82),2.64(4H,d,J=5.45),1.83(4H,q,J=3.12). 1 H-NMR (CD 3 OD) δ 8.45 (1H, s), 7.86 (4H, d, J = 9.48), 7.75 (1H, s), 7.18 (1H, d, J = 3.585), 7.15 (1H) , s), 6.86 (1H, d, J = 3.605), 4.03 (3H, s), 3.99 (3H, s), 3.56 (2H, t, J = 6.8), 2.74 (2H, t, J = 6.82) , 2.64 (4H, d, J = 5.45), 1.83 (4H, q, J = 3.12).

實例五Example five

依下述方法測試本發明代表性化合物之酵素抑制活性：利用Upstate的human EGFR kinase domain，是一種純化且已經活化過的酵素，可以直接對受質進行磷酸化過程。EGFR激酶測試(Kinase Assay)則是利用這種酵素，同時加入受測化合物以及放射性(radioactive)的三磷酸腺(ATP)，由於受測化合物是一種ATP競爭物，會與放射性的ATP彼此競爭，最後藉由受質上放射性同位素的強弱，以篩選出強力的ATP競爭物，也就是有效的EGFR抑制劑，以相同的方式進行VEGFR Kinase Assay。The enzyme inhibitory activity of a representative compound of the present invention was tested by the following method: The human EGFR kinase domain of Upstate is a purified and activated enzyme which can directly phosphorylate the receptor. The EGFR kinase assay (Kinase Assay) uses this enzyme while adding the test compound and the radioactive adenosine triphosphate (ATP). Since the test compound is an ATP competitor, it competes with the radioactive ATP. Finally, the VEGFR Kinase Assay was performed in the same manner by screening the strong ATP competitor, that is, a potent EGFR inhibitor, by the strength of the radioisotope on the substrate.

本發明代表性化合物之酵素抑制活性如下表1及2所示：The enzyme inhibitory activities of representative compounds of the present invention are shown in Tables 1 and 2 below:

Claims (18)

一種式(I)化合物， 其中：R為，其中X為C=C，O或S，Y為O或直接鍵，n為0、1、2或3；R1 及R2 獨立選自：1)H；2)C1-6 -烷基，其可視情況經-NR5 R6 取代，其中R5 及R6 獨立為C1-6 -烷基，或者R5 及R6 與其接著之N一起形成含N之3-至10-員飽和雜環，其環上至少一個亞甲基-(CH2 )-可視情況為-O-、-(NR7 )-或-(CHR8 )-所取代，其中R7 為H或C1-6 -烷基，R8 為含N之3-至10-員飽和雜環，或經含N之3-至10-員飽和雜環取代之C1-6 -烷基；及3)含N之3-至10-員飽和雜環，其環上至少一個亞甲基-(CH2 )-可視情況為-O-、-(NR7 )-或-(CHR8 )-所取代；或者，R1 及R2 與其接著之N形成含N之3-至10-員飽和雜環，其環上至少一個亞甲基-(CH2 )-可視情況為-O-、-(NR7 )-或-(CHR8 )-所取代；R3 為H或C1-6 -烷基，其中該烷基可視情況經1至3個選自 下述之群之取代基所取代：鹵素、C1-4 -烷氧基、-N(R9 )(R9 )及-SOR10 ，其中R9 獨立為H或R10 ，且R10 為C1-4 烷基；R4 係選自下述各組之基團：1)羥基、胺基、羧基、羥基胺基、C1-4 烷氧基胺基、三氟甲氧基、C1-4 烷基或C1-4 烷氧基；2)二[(C1-4 -烷基)]胺基C2-4 -烷氧基或二[(C1-4 -烷氧基)-C2 -4 -烷基]-胺基-C2-4 -烷氧基，其中前述任一基團所含亞甲基-(CH2 )-若不接於N或O原子，則可視情況經羥基所取代；3)H、鹵素、硝基、氰基或三氟甲基；4)經氰基取代之C1 -4 烷基；及5)兩個R4 與其附著之碳形成5至8員環，其含有1或2個選自O、S及N之雜原子；且m為1、2或3；或其立體異構物、前體藥物或醫藥上可接受鹽或溶劑化物。a compound of formula (I), Where: R is Wherein X is C=C, O or S, Y is O or a direct bond, n is 0, 1, 2 or 3; R 1 and R 2 are independently selected from: 1) H; 2) C 1-6 - alkane a group which may optionally be substituted by -NR 5 R 6 wherein R 5 and R 6 are independently C 1-6 -alkyl, or R 5 and R 6 together with the subsequent N form a 3- to 10-member containing N a saturated heterocyclic ring having at least one methylene-(CH 2 )-- optionally substituted by -O-, -(NR 7 )- or -(CHR 8 )-, wherein R 7 is H or C 1- 6 -alkyl, R 8 is a 3- to 10-membered saturated heterocyclic ring containing N, or a C 1-6 -alkyl group substituted by a 3- to 10-membered saturated heterocyclic ring containing N; and 3) N-containing a 3- to 10-membered saturated heterocyclic ring having at least one methylene-(CH 2 )-- optionally substituted by -O-, -(NR 7 )- or -(CHR 8 )-; R 1 and R 2 and the subsequent N form a 3- to 10-membered saturated heterocyclic ring containing N, at least one methylene-(CH 2 ) ring on the ring - optionally -O-, -(NR 7 )- Or -(CHR 8 )-substituted; R 3 is H or C 1-6 -alkyl, wherein the alkyl group may be optionally substituted with from 1 to 3 substituents selected from the group consisting of halogen, C 1 -4-- alkoxy, -N (R 9) (R 9) and -SOR 10, wherein R 9 is independently H or R 10, and R 10 is C 1-4 Group; R 4 is selected from groups of the following groups: 1) hydroxyl, amine, carboxyl, hydroxyl group, C 1-4 alkoxy group, trifluoromethoxy group, C 1-4 alkyl Or C 1-4 alkoxy; 2) bis[(C 1-4 -alkyl)]amino C 2-4 -alkoxy or bis[(C 1-4 -alkoxy)-C 2 - 4 -alkyl]-amino-C 2-4 -alkoxy, wherein the methylene-(CH 2 )- contained in any of the above groups may be optionally a hydroxyl group if it is not bonded to an N or O atom. substituted; 3) H, halogen, nitro, cyano or trifluoromethyl; 4) of the cyano-substituted C 1 - 4 alkyl; and 5) R 4 attached thereto, the two carbon ring formed from 5 to 8 And it contains 1 or 2 heteroatoms selected from O, S and N; and m is 1, 2 or 3; or a stereoisomer, prodrug or pharmaceutically acceptable salt or solvate thereof. 如請求項1之化合物，其為下式化合物： 其中R及NR1 R2 之定義如下示： A compound of claim 1 which is a compound of the formula: Wherein R and NR 1 R 2 is defined as follows shown: 如請求項1之化合物，其為下式化合物： 其中R及NR1 R2 之定義如下示： A compound of claim 1 which is a compound of the formula: The definitions of R and NR 1 R 2 are as follows: 如請求項1之化合物，其為下式化合物： 其中NR1 R2 之定義如下示： A compound of claim 1 which is a compound of the formula: The definition of NR 1 R 2 is as follows: 如請求項1之化合物，其為下式化合物： 其中NR1 R2 之定義如下示： A compound of claim 1 which is a compound of the formula: The definition of NR 1 R 2 is as follows: 如請求項1之化合物，其為下式化合物： 其中NR1 R2 之定義如下示： A compound of claim 1 which is a compound of the formula: The definition of NR 1 R 2 is as follows: 如請求項1之化合物，其為下式化合物： 其中NR1 R2 之定義如下示： A compound of claim 1 which is a compound of the formula: The definition of NR 1 R 2 is as follows: 一種作為表皮細胞生長因子受體(EGFR)與血管內皮細胞生長因子受體-2(VEGFR-2)之雙重抑制劑之醫藥組合物，其含有請求項1之化合物或其醫藥上可接受鹽，及醫藥上可接受之稀釋劑、佐劑或載劑。 A pharmaceutical composition comprising a dual inhibitor of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor-2 (VEGFR-2), which comprises the compound of claim 1 or a pharmaceutically acceptable salt thereof, And a pharmaceutically acceptable diluent, adjuvant or carrier. 一種用於抑制不正常細胞生長之醫藥組合物，其含有請求項1之化合物或其醫藥上可接受鹽，及醫藥上可接受之稀釋劑、佐劑或載劑。 A pharmaceutical composition for inhibiting abnormal cell growth, which comprises the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent, adjuvant or carrier. 一種用於治療贅生性疾病、腫瘤或癌症之醫藥組合物，其含有請求項1之化合物或其醫藥上可接受鹽，及醫藥上可接受之稀釋劑、佐劑或載劑。 A pharmaceutical composition for treating a neoplastic disease, tumor or cancer comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent, adjuvant or carrier. 9或10之醫藥組合物，其含有可用於抑制不正常細胞生長或治療贅生性疾病、腫瘤或癌症之另一治療劑，或者，其係與可用於抑制不正常細胞生長或治療贅生性疾病、腫瘤或癌症之另一治療劑或療法併用。a pharmaceutical composition according to 9 or 10, which comprises another therapeutic agent which can be used for inhibiting abnormal cell growth or treating a neoplastic disease, tumor or cancer, or which is useful for inhibiting abnormal cell growth or treating neoplastic diseases, Another therapeutic agent or therapy for tumor or cancer is used in combination. 如請求項11之醫藥組合物，其中該另一治療劑為微管影響劑、抗腫瘤劑、抗癌劑、抗血管生成劑、EGFR激酶抑制劑、EGFR抑制劑、VEGFR激酶抑制劑、VEGFR抑制劑、EGFR與VEGFR雙重抑制劑，或干擾素；該療法為放射線療法。 The pharmaceutical composition according to claim 11, wherein the another therapeutic agent is a microtubule affecting agent, an antitumor agent, an anticancer agent, an antiangiogenic agent, an EGFR kinase inhibitor, an EGFR inhibitor, a VEGFR kinase inhibitor, and a VEGFR inhibitor. Agent, dual inhibitor of EGFR and VEGFR, or interferon; the therapy is radiation therapy. 一種如請求項1之化合物用於製備藥劑之用途，其中該藥劑係作為EGFR及VEGFR-2之雙重抑制劑。 A use of a compound according to claim 1 for the preparation of a medicament, wherein the medicament is a dual inhibitor of EGFR and VEGFR-2. 一種如請求項1之化合物用於製備藥劑之用途，其中該藥劑係用於抑制不正常細胞生長。 A use of a compound according to claim 1 for the preparation of a medicament, wherein the medicament is for inhibiting abnormal cell growth. 一種如請求項1之化合物用於製備藥劑之用途，其中該藥劑係用於治療贅生性疾病、腫瘤或癌症。 A use of a compound of claim 1 for the manufacture of a medicament, wherein the medicament is for the treatment of a neoplastic disease, tumor or cancer. 如請求項13、14或15之用途，其中該藥劑含有可用於抑制不正常細胞生長或治療贅生性疾病、腫瘤或癌症之另一活性成份，或者該藥劑係與可用於抑制不正常細胞生 長或治療贅生性疾病、腫瘤或癌症之另一治療劑或療法併用。 The use of claim 13, 14, or 15, wherein the agent comprises another active ingredient useful for inhibiting abnormal cell growth or treating a neoplastic disease, tumor or cancer, or the agent is useful for inhibiting abnormal cell growth Use in combination with another therapeutic or therapist that treats a neoplastic disease, tumor, or cancer. 如請求項16之用途，其中該另一活性成份或治療劑為微管影響成份或製劑、抗腫瘤成份或製劑、抗癌成份或製劑、抗血管生成成份或製劑、EGFR激酶抑制成份或製劑、EGFR抑制成份或製劑、VEGFR激酶抑制成份或製劑、VEGFR抑制成份或製劑、EGFR與VEGFR雙重抑制成份或製劑，或干擾素；該療法為放射線療法。 The use of claim 16, wherein the other active ingredient or therapeutic agent is a microtubule-influencing component or formulation, an anti-tumor component or formulation, an anti-cancer component or formulation, an anti-angiogenic component or formulation, an EGFR kinase inhibitory component or formulation, An EGFR inhibitory component or formulation, a VEGFR kinase inhibitory component or formulation, a VEGFR inhibitory component or formulation, a dual inhibitory component or formulation of EGFR and VEGFR, or an interferon; the therapy is radiation therapy. 一種製備如請求項1之化合物之方法，其包括下述步驟：(a)使用如下示之式(II)化合物 其中R3 及R4 與m如請求項1所定義，T為鹵素或甲磺醯基，在鹼及催化劑存在下，於溶劑中，以Suzuki偶合劑硼化；(b)使步驟(a)所得硼化之式(II)化合物與RCONR1 R2 之式(VI)醯胺，其中R、R1 及R2 如請求項1所定義，在鹼及催化劑存在下反應，以獲得R、R1 、R2 、R3 及R4 與m對應之式(I)化合物。A process for the preparation of a compound of claim 1, which comprises the steps of: (a) using a compound of formula (II) as shown below Wherein R 3 and R 4 and m are as defined in claim 1, T is a halogen or a methylsulfonyl group, which is boronated with a Suzuki coupling agent in a solvent in the presence of a base and a catalyst; (b) step (a) The resulting boronated compound of formula (II) and RCONR 1 R 2 of formula (VI) decylamine wherein R, R 1 and R 2 are as defined in claim 1 are reacted in the presence of a base and a catalyst to obtain R, R A compound of the formula (I) wherein R 2 , R 3 and R 4 correspond to m.
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