TWI620748B - 氨基噻唑化合物及其用途 - Google Patents
氨基噻唑化合物及其用途 Download PDFInfo
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- TWI620748B TWI620748B TW106103165A TW106103165A TWI620748B TW I620748 B TWI620748 B TW I620748B TW 106103165 A TW106103165 A TW 106103165A TW 106103165 A TW106103165 A TW 106103165A TW I620748 B TWI620748 B TW I620748B
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- A61K31/5375—1,4-Oxazines, e.g. morpholine
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Abstract
本發明提供一種如式(I)之氨基噻唑化合物及包含其之醫藥組合物。本發明亦提供使用氨基噻唑化合物之一者來抑制蛋白激酶或治療與蛋白激酶相關之癌症的方法。
Description
本發明提供一種用來抑制蛋白激酶或治療與蛋白激酶相關之癌症的氨基噻唑化合物。
蛋白激酶在細胞訊號傳導路徑是重要的，其用以調節各種細胞功能，包括分化、增生、遷移、和凋亡，蛋白激酶的失調涉及癌症及許多其他疾病。
雜環化合物已經被廣泛研究做為有效的蛋白激酶抑制劑，在各種類的雜環化合物中，氨基噻唑化合物在許多生物活性化合物中為重複結構單元(structural motif)。
作為候選藥物，氨基噻唑化合物存在幾個挑戰。首先，他們通常缺乏足夠的體內暴露(in vivo exposure)以在臨床前或臨床研究中發揮所需的功效。再者，作為雜亂蛋白激酶抑制劑，氨基噻唑化合物具有差的激酶選擇性。此外，他們經常在毒性研究中引起動物死亡，引起安全性問題。
因此，有必要開發可有效抑制特定蛋白激酶的新氨基噻唑化合物，在治療標靶疾病時發揮足夠的體內功效，並且顯示出滿意的安全性。
本發明為基於意想不到的發現，特定氨基噻唑化合物能有效抑制多種蛋白激酶，發揮高的體內抗癌功效，且顯示出極大安全性。
在一態樣中，本發明涉及化學式(I)之氨基噻唑化合物：
其中，R1為H；X為O或NRa，Ra為H或C1-6烷基；Y為CRbRc或NRd，其中Rb和Rc各自獨立為H、鹵素、C1-6烷基、C1-6烷氧基或胺基，且Rd為H或C1-6烷基；或Rb與Ra、鍵結到Rb之碳原子及鍵結到Ra之氮原子一起為C3-10雜環烷基；或Rd與Ra及鍵結到Rd和Ra之氮原子一起為C3-10雜環烷基；R2為-CH2CH2Re或NRfRg，其中Re為H、鹵素、C1-6烷基或ORh，Rf和Rg各自獨立為C1-6烷基或C3-8環烷基，且Rh為H或C1-6烷基，或Rh與Rd、鍵結到Rh之氧原子及鍵結到Rd之氮原子一起為C3-10雜環烷基；R3和R4各自獨立為H、鹵素、硝基、氰基、胺基、C1-6烷基、C1-6烷氧基、C3-10環烷基、C3-10雜環烷基、芳基或雜芳基；m為1、2、3或4；以及n為1或2。
在另一態樣中，本發明涉及化學式(I)之氨基噻唑化合物，其中，R1為C1-6烷基或C1-6硫烷基(thioalkyl)；X為O或NRa，Ra為H或C1-6烷基；Y為CRbRc或NRd，其中Rb和Rc各自獨立為H、鹵素、C1-6烷基、C1-6烷氧基或胺基，且Rd為H或C1-6烷基；或Rb與Ra、鍵結到Rb之碳原子及鍵結到Ra之氮原子一起為C3-10雜
環烷基，或Rd與Ra及鍵結到Rd和Ra之氮原子一起為C3-10雜環烷基；R2為-CH2CH2Re或NRfRg，其中Re為鹵素、C1-6烷基或ORh，Rf和Rg各自獨立為C1-6烷基或C3-8環烷基，且Rh為H或C1-6烷基，或Rh與Rd、鍵結到Rh之氧原子及鍵結到Rd之氮原子一起為C3-10雜環烷基；R3為H、鹵素、硝基、氰基、胺基、C1-6烷基、C1-6烷氧基、C3-10環烷基、C3-10雜環烷基、芳基或雜芳基；R4為鹵素、氰基、C2-6烷基、C2-6烷氧基、C3-10環烷基、C3-10雜環烷基、芳基或雜芳基；m為1、2、3或4；n為1或2。
本文中的術語「烷基」是指飽和的，直鏈或支鏈的烴基團，如-CH3或支鏈的-C3H7。術語「環烷基」是指非芳香族的，單環、雙環、三環或四環的烴基團，如環己基、環己-3-基或金剛烷基(adamantly)。術語「烷氧基」是指-O-烷基，烷氧基的例子包含但不侷限於甲氧基、乙氧基、正-丙氧基、異-丙氧基、正-丁氧基、異-丁氧基、二級-丁氧基、及叔丁氧基。術語「硫烷基」是指-S-烷基，硫烷基的例子包含但不侷限於甲基硫醇、乙基硫醇和苄硫醇(benzylthiol)。術語「雜環烷基」是指非芳香族的，具有一或多個雜原子(如：N、O或S)之單環、雙環、三環或四環的基團，雜環烷基的例子包含但不侷限於4-嗎福林基(4-morpholinyl)、1-哌嗪基(1-piperazinyl)、4-四氫哌喃基(4-tetrahydropyranyl)和4-哌喃基。術語「芳基」是指具有一或多個芳香族環的烴基團，芳基的例子包含但不侷限於苯基(Ph)、伸苯基(phenylene)、萘基、伸萘基(naphthylene)、芘基(pyrenyl)、蒽基(anthryl)和菲基(phenanthryl)。術語「雜芳基」是指包含至少一雜原子(如：N、O或S)之一或多個芳香族環，雜芳基基團的例子包含呋喃基(furyl)、亞呋喃基(furylene)、芴基(fluorenyl)、吡咯基(pyrrolyl)、噻吩基(thienyl)、噁唑基(oxazolyl)、咪唑基(imidazolyl)、噻唑基(thiazolyl)、吡啶基(pyridyl)、嘧啶基
(pyrimidinyl)、喹唑啉基(quinazolinyl)、喹啉基(quinolyl)、異喹啉基(isoquinolyl)和吲哚基(indolyl)。
除非另有說明，本文提及之烷基、硫烷基、烷氧基、環烷基、雜環烷基、芳基和雜芳基包含經取代和未經取代的基團，環烷基、雜環烷基、芳基和雜芳基上可能的取代基包含C1-10烷基、C2-10烯基、C2-10炔基、C3-20環烷基、C3-20環烯基、C1-20雜環烷基、C1-20雜環烯基、C1-10烷氧基、芳基、芳氧基(aryloxy)、雜芳基、雜芳氧基(heteroaryloxy)、胺基、C1-10烷基胺基、C1-20二烷基胺基、芳基胺基、二芳基胺基、羥基、鹵素、硫、C1-10烷硫基、芳硫基、C1-10烷磺醯基(alkylsulfonyl)、芳磺醯基(arylsulfonyl)、醯胺基(acylamino)、胺醯基(aminoacyl)、胺硫醯基(aminothioacyl)、脒基(amidino)、胍基(guanidine)、脲基(ureido)、氰基、硝基、醯基、硫醯基、醯氧基(acyloxy)、羧基和羧酸酯。另一方面，烷基上可能的取代基包含所有上述取代基，除了C1-10烷基、C2-10烯基和C2-10炔基。環烷基、雜環烷基、芳基和雜芳基也可以彼此稠和。
上述氨基噻唑化合物包含化合物本身，如果適用也包含其鹽類、前驅藥和溶劑合物(solvate)。例如可以在氨基噻唑化合物上的陰離子和帶正電的基團(如氨基)間形成鹽類，合適的陰離包含氯、溴、碘、硫酸鹽、硝酸鹽、磷酸鹽、檸檬酸鹽(citrate)、甲磺酸鹽(methanesulfonate)、三氟醋酸鹽(trifluoroacetate)、醋酸鹽、蘋果酸鹽(malate)、甲苯磺酸鹽(tosylate)、酒石酸鹽(tartrate)、延胡索酸鹽(fumurate)、麩胺酸鹽(glutamate)、葡萄糖醛酸鹽(glucuronate)、乳酸鹽(lactate)、戊二酸鹽(glutarate)和順丁烯二酸鹽(maleate)。同樣，也可以在氨基噻唑化合物上的陽離子和帶負電的基團(如羧酸)間形成鹽類，合適的陽離子包含鈉離子、鉀離子、鎂離子、鈣離子和銨陽離子(如四甲基銨離子)。氨基噻唑化合物也包含那
些含有四級氮原子的鹽類。前驅藥的例子包含酯類和其他藥學上可接受的衍生物，其在給予一主體時能提供活性氨基噻唑化合物。溶劑合物是指在活性氨基噻唑化合物和藥學上可接受的溶劑之間形成的複合物，藥學上可接受的溶劑的例子包含水、乙醇、異丙醇、乙酸乙酯、乙酸和乙醇胺(ethanolamine)。
在另一態樣中，本發明涉及一種抑制蛋白激酶的方法。該方法包含使蛋白激酶與一有效劑量的一或多種上述氨基噻唑化合物接觸。
本發明的範圍內還包含一種治療與蛋白激酶相關之癌症的方法。該方法包含給予一有效劑量的一或多種上述式(I)之氨基噻唑化合物至一所需主體。
蛋白激酶可以是野生型(wild type)或突變型。蛋白激酶的例子包含類FMS酪胺酸激酶3(FMS-like tyrosine kinase 3，FLT3)、類FMS酪胺酸激酶4(FMS-like tyrosine kinase 4，FLT4)、極光激酶(aurora kinase，AURK)A、極光激酶B(AURK B)、血管內皮生長因子受體(vascular endothelial growth factor receptor，VEGFR)、血小板源生長因子受體(platelet-derived growth factor receptor，PDGFR)A、血小板源生長因子受體B(PDGFR B)、c-Src激酶(SRC)、酪胺酸激酶Lyn(tyrosine-protein kinase LYN)A、酪胺酸激酶Lyn B(LYN B)、在轉染期間重排的酪胺酸激酶(rearranged during transfection tyrosine kinase，RET)、集落刺激因子1受體(colony stimulating factor 1 receptor，CSF1R)、淋巴細胞專一性蛋白質酪氨酸激酶(lymphocyte-specific protein tyrosine kinase，LCK)、加德納拉希德貓肉瘤病毒(v-fgr)致癌基因同源物(Gardner-Rasheed feline sarcoma viral(v-fgr)oncogene homolog，FGR)、盤狀結構域受體1(discoidin domain receptor 1，DDR1)、激酶插入區域受體(kinase insert domain receptor，KDR)、原肌球蛋白受
體激酶(tropomyosin receptor kinase，TRK)A、原肌球蛋白受體激酶B(TRK B)、B淋巴細胞激酶(B lymphocyte kinase，BLK)、酪胺酸激酶Yes(tyrosine-protein kinase Yes，YES1)、愛柏森鼠類白血病病毒致癌基因同源物1(Abelson murine leukemia viral oncogene homolog 1，ABL1)、酪胺酸激酶Kit(tyrosine-protein kinase Kit，KIT)、雙專一性有絲分裂活化蛋白質激酶1(dual specificity mitogen-activated protein kinase kinase 1，MEK1)、介白素-1受體相關激酶4(interleukin-1 receptor-associated kinase 4，IRAK4)、酪胺酸激酶Tek(TEK)、RET V804L、RET Y791F、FLT3 D835Y、PDGFR A V561D或ABL1 T315I。
癌症的例子包含急性骨髓性白血病(acute myeloid leukemia)、綠色白血病(chloroma)、慢性骨髓性白血病(chronic myelogenous leukemia)、急性淋巴細胞性白血病(acute lymphoblastic leukemia)、慢性淋巴細胞白血病(chronic lymphocytic leukemia)、霍奇金病(Hodgkin’s disease)、非霍奇金淋巴瘤(non-Hodgkin’s lymphoma)、B細胞淋巴瘤(B-cell lymphoma)、多發性骨髓瘤(multiple myeloma)、瓦爾登斯特倫巨球蛋白血症(Waldenstrom’s macroglobulinemia)、骨髓增生異常綜合徵(myelodysplastic syndrome)、胰腺癌(pancreatic cancer)、膀胱癌(bladder cancer)、結直腸癌(colorectal cancer)、乳癌(breast cancer)、男性生殖道癌(male genital tract cancer)、腎癌(renal cancer)、肝細胞癌(hepatocellular cancer)、肺癌(lung cancer)、卵巢癌(ovarian cancer)、子宮頸癌(cervical cancer)、子宮癌(uterus cancer)、妊娠滋養細胞疾病(gestational trophoblastic disease)、胃癌(gastric cancer)、膽道癌(bile duct cancer)、膽囊癌(gallbladder cancer)、小腸癌(small intestine cancer)、食管癌(esophageal cancer)、口咽癌(oropharyngeal cancer)、下嚥癌(hypopharyngeal cancer)、眼癌(eye cancer)、
神經癌(nerve cancer)、頭頸部癌症(head and neck cancer)、黑色素瘤(melanoma)、漿細胞瘤(plasmacytoma)、內分泌腺腫瘤(endocrine gland neoplasm)、神經內分泌癌(neuroendocrine cancer)、腦腫瘤(brain tumor)、骨癌(bone cancer)或肉瘤(sarcoma)。
本發明的範圍內還包含一種含有一或多種上述式(I)之氨基噻唑化合物的藥物組合物，該藥物組合物可以用於治療癌症。
本發明亦關於一或多種上述式(I)之氨基噻唑化合物於製備治療癌症藥物之用途。
術語「治療」是指將一或多種氨基噻唑化合物給予患有上述疾病(即癌症)，或具有這種疾病的症狀或有這種疾病傾向的主體，目的是給予治療效果，如治癒、緩解、改變、影響、改善或預防上述疾病、其症狀或傾向。術語「有效劑量」是指給予治療效果所需的活性化合物的量。如本領域技術人員所了解的，有效劑量會依據治療疾病的類型、施用途徑、賦形劑用法以及與其他治療共同使用的可能性而變化。
為了實施本發明之方法，具有一或多種上述氨基噻唑化合物可以腸胃外(parenterally)、口服、鼻、直腸、局部或頰內給藥。術語「腸胃外」是指皮下(subcutaneous)、皮內(intracutaneous)、靜脈內(intravenous)、腹膜內(intraperitoneal)、肌肉內(intramuscular)、關節內(intraarticular)、動脈(intraarterial)、滑囊(腔)內(intrasynovial)、胸骨內(intrasternal)、蜘蛛膜下腔(intrathecal)、疾病部位內(intralesional)或頭顱內(intracranial)注射，以及任何合適的灌注技術。
無菌可注射組合物可以是在無毒的腸胃外可接受的稀釋液或溶劑中的溶液或懸浮液，例如在1,3-丁二醇中的溶液。其中可接受的載體和溶劑可以採用甘露醇(mannitol)、水、林格氏溶液(Ringer’s solution)和等滲透壓氯化鈉溶液(isotonic sodium chloride solution)。此外，不揮發油(fixed oils)通常做為溶劑或懸浮介質(例如合成的單或雙甘油酯)。脂肪酸如油酸(oleic acid)及其甘油衍生物可用於注射劑之製備，作為天然的藥學上可接受的油，例如橄欖油和蓖麻油(castor oil)，尤其是其聚氧乙基化的形式。這些油溶液或懸浮液可以包含長鏈醇稀釋劑或分散劑，羧甲基纖維素(carboxymethyl cellulose)或類似的分散劑。也可以使用其他常用的界面活性劑(surfactant)於製劑上，例如Tweens和Spans或其他類似的乳化劑(emulsifying agent)或生物可利用強化劑(bioavailability enhancer)，其通常用於製備藥學上可接受的固體、液體或其他劑型。
用於口服給藥的組合物可以是任何口服可接受的劑型，包含膠囊、錠劑、乳劑和水性懸浮液、分散體和溶液。在錠劑的情況下，常用的載體包含乳糖和玉米澱粉，通常還加入潤滑劑(lubricating agent)，如硬脂酸鎂。對於以膠囊形式口服給藥，有用的稀釋劑包含乳糖和乾的玉米澱粉。當以水性懸浮液或乳劑口服給藥時，活性成分可以懸浮或溶解在與乳化劑或懸浮劑結合的油相中。如果需要，可以加入一些甜味劑、矯味劑或著色劑。
鼻噴劑(nasal aerosol)或吸入組合物可以根據藥物製劑領域已知的技術製備，例如組合物可以製備成鹽水溶液，並採用苯甲醇或其他合適的防腐劑、增加生物可用率的吸收促進劑、碳氟化合物及/或其他本領域已知的助溶劑或分散劑。
具有一或多種上述氨基噻唑化合物之組合物也可以以用於直腸給藥的栓劑形式給予。
藥學組合物中的載體必須是「可接受的」，在意義上其與組合物的活性成分相容(並且優選為能夠穩定該活性成分)，且對於治療者無害。一或多種助溶劑可以用來作為藥物賦形劑，以傳遞活性1,5-二苯基-戊-1,4-二烯-3-酮化合物。其他載體的例子包含膠質氧化矽(colloidal silicon oxide)、硬脂酸鎂，纖維素、硫酸月桂酯鈉(sodium lauryl sulfate)和D&C Yellow # 10。
在下面的描述中闡述了本發明之一或多個實施例的細節。本發明的其他特徵、目的及優點將於說明書和請求範圍中顯而易見。
本發明揭示如式(I)之氨基噻唑化合物：
如上式所示，兩組氨基噻唑化合物包含(i)其中R1為H；X為O或NRa，Ra為H或C1-6烷基；Y為CRbRc或NRd，其中Rb和Rc各自獨立為H、鹵素、C1-6烷基、C1-6烷氧基或胺基，且Rd為H或C1-6烷基；或Rb與Ra、鍵結到Rb之碳原子及鍵結到Ra之氮原子一起為C3-10雜環烷基；或Rd與Ra及鍵結到Rd和Ra之氮原子一起為C3-10雜環烷基；R2為-CH2CH2Re或NRfRg，其中Re為H、鹵素、C1-6烷基或ORh，
Rf和Rg各自獨立為C1-6烷基或C3-8環烷基，且Rh為H或C1-6烷基，或Rh與Rd、鍵結到Rh之氧原子及鍵結到Rd之氮原子一起為C3-10雜環烷基；R3和R4各自獨立為H、鹵素、硝基、氰基、胺基、C1-6烷基、C1-6烷氧基、C3-10環烷基、C3-10雜環烷基、芳基或雜芳基；m為1、2、3或4；以及n為1或2；以及(ii)其中R1為C1-6烷基或C1-6硫烷基；X為O或NRa，Ra為H或C1-6烷基；Y為CRbRc或NRd，其中Rb和Rc各自獨立為H、鹵素、C1-6烷基、C1-6烷氧基或胺基，且Rd為H或C1-6烷基；或Rb與Ra、鍵結到Rb之碳原子及鍵結到Ra之氮原子一起為C3-10雜環烷基，或Rd與Ra及鍵結到Rd和Ra之氮原子一起為C3-10雜環烷基；R2為-CH2CH2Re或NRfRg，其中Re為鹵素、C1-6烷基或ORh，Rf和Rg各自獨立為C1-6烷基或C3-8環烷基，且Rh為H或C1-6烷基，或Rh與Rd、鍵結到Rh之氧原子及鍵結到Rd之氮原子一起為C3-10雜環烷基；R3為H、鹵素、硝基、氰基、胺基、C1-6烷基、C1-6烷氧基、C3-10環烷基、C3-10雜環烷基、芳基或雜芳基；R4為鹵素、氰基、C2-6烷基、C2-6烷氧基、C3-10環烷基、C3-10雜環烷基、芳基或雜芳基；m為1、2、3或4；n為1或2。
在一實施例中，上述氨基噻唑化合物為式(II)之化合物：
其中，R1、R2、R3、R4、X和Y如同上述式(I)所定義。
在一亞群中，式(II)之化合物的R1為H且X為O。優選地，Y為NRd且R2為-CH2CH2Re，其中Re為ORh，Rh與Rd、鍵結到Rh之氧原子及鍵結到Rd之氮
原子一起為C3-10雜環烷基；R3為H、鹵素或C1-6烷基；且R4為C1-6烷基或C3-10環烷基。例示性化合物為
在另一亞群中，式(II)之化合物的R1為H且X為NRa，Ra為H或C1-6烷基。尤其是，在此亞群中之一些化合物的Y為CRbRc，其中，Rb與Ra、鍵結到Rb之碳原子及鍵結到Ra之氮原子一起為C3-10雜環烷基，且Rc為H、鹵素、C1-6烷基、C1-6烷氧基或胺基；R2為NRfRg，Rf和Rg各自獨立為C1-6烷基或C3-8環烷基；R3為H、鹵素、C1-6烷基或C3-10環烷基；R4為C1-6烷基或C3-10環烷基。優選地，Rb與Ra、鍵結到Rb之碳原子及鍵結到Ra之氮原子一起為吡咯啶基(pyrrolidinyl)或哌啶基(piperidinyl)。在此亞群中之其他化合物的Y為NRd，其中，Rd與Ra及鍵結到Rd和Ra之氮原子一起為C3-10雜環烷基；R2為-CH2CH2Re，其中Re為H、鹵素、C1-6烷基或ORh，Rh為H或C1-6烷基；R3為H、鹵素、C1-6烷基或C3-10環烷基；且R4為C1-6烷基或C3-10環烷基。優選地，Rd與Ra及鍵結到Rd和Ra之氮原子一起為哌嗪基(piperazinyl)。這組化合物的例子包含
、以及
在另一亞群中，式(II)之化合物的R1為C1-6烷基(如-CH3)或C1-6硫烷基(如-SCH3)且X為O。
在另一亞群中，式(II)之化合物的R1為C1-6烷基(如-CH3)或C1-6硫烷基(如-SCH3)且X為NRa，Ra為H或C1-6烷基。尤其是，在此亞群中之一些化合物的Y為CRbRc，其中，Rb與Ra、鍵結到Rb之碳原子及鍵結到Ra之氮原子一起為C3-10雜環烷基，且Rc為H、鹵素、C1-6烷基、C1-6烷氧基或胺基；R2為NRfRg，Rf和Rg各自獨立為C1-6烷基或C3-8環烷基；R3為H、鹵素、C1-6烷基或C3-10環烷基；R4為C1-6烷基或C3-10環烷基。優選地，Rb與Ra、鍵結到Rb之碳原子及鍵結到Ra之氮原子一起為吡咯啶基(pyrrolidinyl)或哌啶基(piperidinyl)。例示性化合物包含
以及。
在此亞群中之其他化合物的Y為NRd，其中，Rd與Ra及鍵結到Rd和Ra之氮原子一起為C3-10雜環烷基；R2為-CH2CH2Re，其中Re為鹵素、C1-6烷基或ORh，Rh為H或C1-6烷基；R3為H、鹵素、C1-6烷基或C3-10環烷基；且R4為C1-6烷基或C3-10環烷基。優選地，Rd與Ra及鍵結到Rd和Ra之氮原子一起為哌嗪基(piperazinyl)。實施例包含
以及。
本發明的範圍內還包含一種含有一或多種式(I)之氨基噻唑化合物用於治療癌症的藥物組合物。
本發明還包含一種治療癌症的方法，該方法包含給予有效劑量的式(I)之化合物至一所需主體。
用於合成式(I)之化合物的合成化學轉化和保護基團(保護和去保護)的方法是本領域已知的。參見例如R.Larock,Comprehensive Organic Transformations(2nd Ed.,VCH Publishers 1999)；P.G.M.Wuts and T.W.Greene,Greene’s Protective Groups in Organic Synthesis(4th Ed.,John Wiley and Sons 2007)；L.Fieser and M.Fieser,Fieser and Fieser’s Reagents for Organic Synthesis(John Wiley and Sons 1994)；L.Paquette,ed.,Encyclopedia of Reagents for Organic Synthesis(2nd ed.,John Wiley and Sons 2009)；以及G.J.Yu et al.,J.Med.Chem.2008,51,6044-6054。
如此製備的式(I)之化合物可以使用生化測定方法初步篩選，例如下面實施例21所描述之激酶測定法，測定其抑制蛋白激酶之效力。接著使用體內測定法，例如異種移植動物模型測定法，來評估他們在哺乳類動物中抑制腫瘤生長的活性。可以進一步測試選擇的化合物以驗證其在治療腫瘤中的療效，例如可以將化合物給予患有癌症之動物(例如小鼠)，然後評估其治療效果。基於結果，可以研究和確定適當的劑量範圍以及給予途徑。
不需要進一步詳細描述，相信本領域技術人員可基於上述描述最大程度地利用本發明。因此，以下的具體實施例應被解釋為僅僅是說明性的，而不以任何方式限制本公開的其餘部分，本文引用的所有文獻均整體併入本發明以供參酌。
以下實施例1-20顯示20種式(I)之例示性化合物的結構及如何製備，由此製備的化合物其分析數據也列於實施例1-20中，且測試這些化合物的步驟描述於以下實施例21-25中。
實施例1：化合物1之合成
化合物1根據Chen等人於European Journal of Medicinal Chemistry,2015,100,151-161.中描述的合成方法製備。
所有的化學藥品和溶劑自商業供應商購買且按原樣使用，所有反應在乾燥氮氣氣氛下執行，使用Merck 60 F254矽膠玻璃背板(5×10cm)之TLC監測反應；並且在紫外光下(254nm)或藉由噴塗磷鉬酸試劑(Aldrich)接著在80℃下加熱，來目測檢測區域。所有快速管柱層析法(flash column chromatography)用Merck Kieselgel 60,No.9385,230-400目(mesh)ASTM矽膠作為固定相進行。質子(1H)核磁共振譜以Varian Mercury-300或Varian Mercury-400光譜儀測量，化學位移以相對於溶劑峰共振的δ的刻度以百萬分之一(ppm)記錄，使用以下縮寫描述耦合：s=單峰；d=雙重峰；t=三重峰；q=四重峰；quin=五重峰；br=寬；m=多重峰。LCMS數據以Agilent MSD-1100 ESI-MS/MS,Agilent 1200 series LC/MSD VL和Waters Acquity UPLC-ESI-MS/MS系統測量。
1-(5-乙基異噁唑-3-基)-3-(4-(2-((6-(4-(2-羥乙基)哌嗪-1-基)-2-甲基嘧啶-4-基)胺)噻唑-5-基)苯基)尿素(1-(5-Ethylisoxazol-3-yl)-3-(4-(2-((6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazol-5-yl)phenyl)urea)(鹽酸鹽)
1H NMR(400MHz,DMSO-d6)：δ 10.87(s,1H),9.79(s,1H),9.74(s,1H),7.75(s,1H),7.51(q,J=8.8Hz,4H),6.54(s,1H),6.34(s,1H),5.55(br s,1H),4.37(d,J=4.0Hz,2H),3.78(t,J=4.8Hz,2H),3.61(d,J=12.0Hz,2H),3.48(t,J=12.8Hz,2H),3.19-3.12(m,4H),2.69(q,J=8.0Hz,2H),2.47(s,3H),1.19(t,J=6.0Hz,3H)；MS(ES+)m/z(C26H31N9O3S)理論值：549.23；實際值：550.3(M+H+).
在以下實施例2-20中，各自以與實施例1中所述相同之方法合成化合物；僅顯示化合物的結構和分析數據。
實施例2
1-(5-乙基異噁唑-3-基)-3-(4-(2-((6-(4-乙基哌嗪-1-基)嘧啶-4-基)胺)噻唑-5-基)苯基)尿素(1-(5-Ethylisoxazol-3-yl)-3-(4-(2-((6-(4-ethylpiperazin-1-yl)pyrimidin-4-yl)amino)thiazol-5-yl)phenyl)urea)(鹽酸鹽)
1H NMR(400MHz,DMSO-d6)：811.14(s,1H),9.78(s,1H),9.62(s,1H),8.48(s,1H),7.74(s,1H),7.50(q,J=8.8Hz,4H),6.55(s,1H),6.38(s,1H),4.34(d,J=14.0Hz,2H),3.55(d,J=11.6Hz,2H),3.44-3.38(m,2H),3.14-3.08(m,2H),3.00(q,J=9.6Hz,2H),2.69(q,J=7.6Hz,2H),1.26(t,J=7.6Hz,3H),1.19(t,J=7.6Hz,3H)；MS(ES+)m/z(C25H29N9O2S)理論值：519.22；實際值：520.2(M+H+).
實施例3
1-(5-乙基異噁唑-3-基)-3-(4-(2-((6-(2-嗎福林代乙氧基)嘧啶-4-基)胺)噻唑-5-基)苯基)尿素(1-(5-Ethylisoxazol-3-yl)-3-(4-(2-((6-(2-morpholinoethoxy)pyrimidin-4-yl)amino)thiazol-5-yl)phenyl)urea)(鹽酸鹽)
1H NMR(400MHz,DMSO-d6)：δ 11.08(s,1H),9.75(s,1H),9.56(s,1H),8.62(s,1H),7.73(s,1H),7.50(q,J=8.8Hz,4H),6.54(s,1H),6.50(s,1H),4.71(s,2H),3.95(d,J=11.6Hz,2H),3.79(t,J=12.4Hz,2H),3.56(s,2H),3.47(d,J=12.4Hz,2H),3.15(d,J=10.0Hz,2H),2.69(q,J=7.6Hz,2H),1.19(t,J=7.6Hz,3H)；MS(ES+)m/z(C25H28N8O4S)理論值：536.20；實際值：537.2(M+H+).
實施例4
1-(5-乙基異噁唑-3-基)-3-(4-(2-((6-(4-(2-羥乙基)哌嗪-1-基)嘧啶-4-基)胺)噻唑-5-基)苯基)尿素(1-(5-Ethylisoxazol-3-yl)-3-(4-(2-((6-(4-(2-hydroxyethyl)piperazin-1-yl)pyrimidin-4-yl)amino)thiazol-5-yl)phenyl)urea)(鹽酸鹽)
1H NMR(300MHz,DMSO-d6)：δ 10.69(s,1H),9.75(s,1H),9.57(s,1H),8.48(s,1H),7.73(s,1H),7.52(s,4H),6.56(s,1H),6.39(s,1H),5.27(br s,1H),4.34(d,J=12.9Hz,2H),3.80(s,2H),3.62(d,J=11.4Hz,2H),3.44(t,J=11.7Hz,2H),3.22-312(m,4H),2.71(q,J=7.2Hz,2H),1.21(t,J=7.2Hz,3H)；MS(ES+)m/z(C25H29N9O3S)理論值：535.21；實際值：536.2(M+H+).
實施例5
1-(5-乙基異噁唑-3-基-3-(4-(2-((6-(4-(2-氟乙基)哌嗪-1-基)嘧啶-4-基)胺)噻唑-5-基)苯基)尿素(1-(5-Ethylisoxazol-3-yl)-3-(4-(2-((6-(4-(2-fluoroethyl)piperazin-1-yl)pyrimidin-4-yl)amino)thiazol-5-yl)phenyl)urea)(鹽酸鹽)
1H NMR(400MHz,DMSO-d6)：δ 11.56(s,1H),9.78(s,1H),9.62(s,1H),8.48(s,1H),7.74(s,1H),7.52(q,J=8.8Hz,4H),6.56(s,1H),6.39(s,1H),4.99(t,J=3.6Hz,1H),4.88(t,J=3.6Hz,1H),4.38(d,J=10.4Hz,2H),3.59(s,2H),3.44(d,J=
12.0Hz,4H),3.19(s,2H),2.71(q,J=7.2Hz,2H),1.21(t,J=7.6Hz,3H)；MS(ES+)m/z(C25H28FN9O2S)理論值：537.21；實際值：538.2(M+H+).
實施例6
1-(5-乙基異噁唑-3-基)-3-(4-(2-((6-(4-(2-氟乙基)哌嗪-1-基)-2-甲基嘧啶-4-基)胺)噻唑-5-基)苯基)尿素(1-(5-Ethylisoxazol-3-yl)-3-(4-(2-((6-(4-(2-fluoroethyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazol-5-yl)phenyl)urea)(鹽酸鹽)
H NMR(300MHz,DMSO-d6)：δ 11.56(s,1H),9.76(s,1H),9.63(s,1H),7.75(s,1H),7.52(t,J=13.2Hz,4H),6.55(s,1H),6.30(s,1H),5.01(s,1H),4.85(s,1H),4.39(s,2H),3.75-3.30(m,6H),3,19(s,2H),2.50(s,3H),2.71(q,J=7.2Hz,2H),1.21(t,J=7.5Hz,3H)；MS(ES+)m/z(C26H30FN9O2S)理論值：551.22；實際值：552.2(M+H+).
實施例7
1-(5-乙基異噁唑-3-基)-3-(2-氟-4-(2-((6-(4-(2-羥乙基)哌嗪-1-基)-2-甲基嘧啶-4-基)胺)噻唑-5-基)苯基)尿素(1-(5-Ethylisoxazol-3-yl)-3-(2-fluoro-4-(2-((6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazol-5-yl)phenyl)urea)(游離鹼)
1H NMR(400MHz,DMSO-d6)：δ 11.17(s,1H),9.80(s,1H),8.86(s,1H),8.11(t,J=8.6Hz,1H),7.75(s,1H),7.54(d,J=12.8Hz,1H),7.33(d,J=8.8Hz,1H),6.53(s,1H),6.02(s,1H),4.43(t,J=5.4Hz,1H),3.54-3.48(m,6H),2.70(q,J=8.2Hz,2H),2.48-2.39(m,9H，與DMSO重疊)，1.20(t,J=8.2Hz,3H)；MS(ES+)m/z(C26H30FN9O3S)理論值：567.22；實際值：568.2(M+H+).
實施例8
1-(5-(叔丁基)異噁唑-3-基)-3-(4-(2-((6-(4-(2-羥乙基)哌嗪-1-基)-2-甲基嘧啶-4-基)胺)噻唑-5-基)-2-甲苯基)尿素(1-(5-(Tert-butyl)isoxazol-3-yl)-3-(4-(2-((6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazol-5-yl)-2-methylphenyl)urea)(游離鹼)
1H NMR(400MHz,DMSO-d6)：δ 11.12(s,1H),9.93(s,1H),8.33(s,1H),7.90(d,J=8.8Hz,1H),7.67(s,1H),7.43(s,1H),7.38(d,J=8.8Hz,1H),6.47(s,1H),6.04(s,1H),4.46(s,1H),3.53-3.49(m,6H),2.50-2.43(m,6H，與溶劑D-DMSO峰重疊)，2.42(s,3H),2.28(s,3H),1.30(s,9H)；MS(ES+)m/z(C29H37N9O3S)理論值：591.27；實際值：592.3(M+H+).
實施例9
1-(5-乙基異噁唑-3-基)-3-(4-(2-((6-(4-(2-羥乙基)哌嗪-1-基)-2-甲基嘧啶-4-基)胺)噻唑-5-基)-2-甲苯基)尿素(1-(5-Ethylisoxazol-3-yl)-3-(4-(2-((6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazol-5-yl)-2-methylphenyl)urea)(鹽酸鹽)
1H NMR(400MHz,DMSO-d6)：δ 10.88(s,1H),10.18(s,1H),8.72(s,1H),7.92(d,J=8.4Hz,1H),7.56(s,1H),7.45(s,1H),7.40(d,J=8.8Hz,1H),6.52(s,1H),6.33(s,1H),6.08(bs,1H),4.29(d,J=6.6Hz,2H),3.81(d,J=4.8Hz,2H),3.64-3.61(m,2H),3.51-3.41(m,2H),3.22(s,2H),3.16-3.13(m,2H),2.71(q,J=7.4Hz,2H),2.54(s,3H),2.31(m,3H),1.21(t,J=7.6Hz,3H)；MS(ES+)m/z(C27H33N9O3S)理論值：563.24；實際值：564.2(M+H+).
實施例10
1-(5-環丙基異噁唑-3-基)-3-(4-(2-((6-(4-(2-羥乙基)哌嗪-1-基)-2-甲基嘧啶-4-基)胺)噻唑-5-基)-2-甲苯基)尿素(1-(5-Cyclopropylisoxazol-3-yl)-3-(4-(2-((6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazol-5-yl)-2-methylphenyl)urea)(鹽酸鹽)
1H NMR(400MHz,DMSO-d6)：δ 11.01(s,1H),10.21(s,1H),8.78(s,1H),7.92(d,J=8.8Hz,1H),7.78(s,1H),7.45(s,1H),7.40(d,J=8.4Hz,1H),6.45(s,1H),6.38(s,1H),6.18(bs,1H),4.38(bs,2H),3.82(d,J=5.0Hz,2H),3.64(d,J=5.6Hz,2H),3.52(t,J=6.1Hz,2H),3.22(m,2H),3.16-3.13(m,2H),2.53(s,3H),2.30(s,3H),2.13-2.07(m,1H),1.07-1.01(m,2H),0.89-0.86(m,2H)；MS(ES+)m/z(C28H33N9O3S)理論值：575.24；實際值：576.3(M+H+).
實施例11
1-(5-環丙基異噁唑-3-基)-3-(2-氟-4-(2-((6-(4-(2-羥乙基)哌嗪-1-基)-2-甲基嘧啶-4-基)胺)噻唑-5-基)苯基)尿素(1-(5-Cyclopropylisoxazol-3-yl)-3-(2-fluoro-4-(2-((6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazol-5-yl)phenyl)urea)(鹽酸鹽)
1H NMR(400MHz,DMSO-d6)：δ 11.16(s,1H),10.16(s,1H),9.23(s,1H),8.09(t,J=8.4Hz,1H),7.82(s,1H),7.55(d,J=12.4Hz,1H),7.34(d,J=8.4Hz,1H),6.45(s,1H),6.28(s,1H),4.33(bs,2H),3.80(t,J=4.8Hz,2H),3.60(d,J=11.6Hz,2H),3.49-3.40(m,2H),3.19-3.11(m,4H),2.35(s,3H),2.10-2.06(m,1H),1.04-0.99(m,2H),0.88-0.84(m,2H)；MS(ES+)m/z(C27H30FN9O3S)理論值：579.22；實際值：580.2(M+H+).
實施例12
1-(5-乙基異噁唑-3-基)-3-(4-(2-((6-(4-(2-羥乙基)哌嗪-1-基)-2-(甲硫基)嘧啶-4-基)胺)噻唑-5-基)苯基)尿素(1-(5-Ethylisoxazol-3-yl)-3-(4-(2-((6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)amino)thiazol-5-yl)phenyl)urea)(鹽酸鹽)
1H NMR(400MHz,DMSO-d6)：δ 10.66(s,1H),9.74(s,1H),9.58(s,1H),7.71(s,1H),7.52-7.50(s,3H),6.56(s,2H),6.06(s,1H),4.27(d,J=6.0Hz,2H),3.79(t,J=5.0Hz,2H),3.60(d,J=6.0Hz,2H),3.58(t,J=6.0Hz,2H),3.22-3.08(m,4H),2.71(q,J=7.6Hz,2H),2.61(s,3H),2.51(s,3H,overlapping with DMSO),1.18-1.23(m,3H)；MS(ES+)m/z(C26H33Cl2N9O3S2)理論值：581.20；實際值：582.2(M+H+).
實施例13
1-(5-乙基異噁唑-3-基)-3-(2-氟-4-(2-((6-(4-(2-羥乙基)哌嗪-1-基)-2-(甲硫基)嘧啶-4-基)胺)噻唑-5-基)苯基)尿素(1-(5-Ethylisoxazol-3-yl)-3-(2-fluoro-4-(2-((6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)amino)thiazol-5-yl)phenyl)urea)(鹽酸鹽)
1H NMR(300MHz,DMSO-d6)：δ 11.45(s,1H),10.58(s,1H),9.97(s,1H),9.03(s,1H),8.11(t,J=8.6Hz,1H),7.78(s,1H),7.51(d,J=12.9Hz,1H),7.29(d,J=9.0Hz,1H),6.52(s,1H),6.03(s,1H),4.26(d,J=12.6Hz,2H),3.77(d,J=4.8Hz,2H),3.58(d,J=11.4Hz,2H),3.38(t,J=12.3Hz,2H),3.20-3.08(m,4H),2.70(q,J=7.6Hz,2H),2.6(s,3H),1.19(t,J=7.5Hz,3H)；MS(ES+)m/z(C26H30FN9O3S2)理論值：599.19；實際值：600.3(M+H+).
實施例14
1-(5-乙基異噁唑-3-基)-3-(4-(2-((6-(4-(2-羥乙基)哌嗪-1-基)-2-(甲硫基)嘧啶-4-基)胺)噻唑-5-基)-2-甲苯基)尿素(1-(5-Ethylisoxazol-3-yl)-3-(4-(2-((6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)amino)thiazol-5-yl)-2-methylphenyl)urea)(鹽酸鹽)
1H NMR(400MHz,DMSO-d6)：δ 10.72(s,1H),10.12(s,1H),8.66(s,1H),7.90(d,J=8.4Hz,1H),7.71(s,1H),7.41(s,1H),7.35(d,J=8.4Hz,1H),6.51(s,1H),6.07(s,1H),5.96(bs,1H),4.28(d,J=6.6Hz,2H),3.80(d,J=5.0Hz,2H),3.60(d,J=5.8Hz,2H),3.46-3.38(m,2H),3.21-3.20(m,2H),3.16-3.10(m,2H),2.71(q,J=7.5Hz,2H),2.61(s,3H),2.30(s,3H),1.21(t,J=7.6Hz,3H)；MS(ES+)m/z(C27H33N9O3S2)理論值：595.21；實際值：596.3(M+H+).
實施例15
1-(4-(2-((6-(3-(二甲基胺)吡咯啶-1-基)-2-甲基嘧啶-4-基)胺)噻唑-5-基)-2-甲苯基)-3-(5-乙基異噁唑-3-基)尿素(1-(4-(2-((6-(3-(Dimethylamino)pyrrolidin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazol-5-yl)-2-methylphenyl)-3-(5-ethylisoxazol-3-yl)urea)(鹽酸鹽)
1H NMR(400MHz,DMSO-d6)：δ 11.70(s,1H),10.22(s,1H),8.75(s,1H),7.93(d,J=8.8Hz,1H),7.78(s,1H),7.45(s,1H),7.39(d,J=8.8Hz,1H),6.52(s,1H),6.16(s,1H),4.02(s,2H),3.89(s,1H),3.75(s,1H),3.48(s,1H),2.80(s,6H),2.71(q,J=7.2Hz,2H),2.59(s,3H),2.44-2.39(m,2H),1.07-1.03(m,3H)；MS(ES+)m/z(C27H33N9O2S)理論值：547.25；實際值：548.2(M+H+).
實施例16
1-(4-(2-((6-(3-(二甲基胺)吡咯啶-1-基)-2-甲基嘧啶-4-基)胺)噻唑-5-基)-2-氟苯基)-3-(5-乙基異噁唑-3-基)尿素(1-(4-(2-((6-(3-(Dimethylamino)pyrrolidin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazol-5-yl)-2-fluorophenyl)-3-(5-ethylisoxazol-3-yl)urea)(鹽酸鹽)
1H NMR(400MHz,DMSO-d6)：δ 11.78(s,1H),10.16(s,1H),9.21(s,1H),8.11(t,J=8.8Hz,1H),7.86(s,1H),7.57(d,J=12.0Hz,1H),7.34(d,J=8.0Hz,1H),6.52(s,1H),6.17(s,1H),4.10-3.76(m,4H),3.49(bs,1H),2.78(s,6H),2.69(q,J=
7.6Hz,2H),2.61(s,3H),1.19(t,J=7.6Hz,3H)；MS(ES+)m/z(C26H30FN9O2S)理論值：551.22；實際值：552.2(M+H+).
實施例17
1-(4-(2-((6-(3-(二甲基胺)吡咯啶-1-基)-2-甲基嘧啶-4-基)胺)噻唑-5-基)苯基)-3-(5-乙基異噁唑-3-基)尿素(1-(4-(2-((6-(3-(Dimethylamino)pyrrolidin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazol-5-yl)phenyl)-3-(5-ethylisoxazol-3-yl)urea)(鹽酸鹽)
1H NMR(400MHz,DMSO-d6)：δ 11.73(s,1H),9.85(s,1H),9.84(s,1H),7.79(s,1H),7.55-7.47(m,4H),6.56(s,1H),6.19(s,1H),4.03(d,J=6.4Hz,2H),3.93(s,1H),3.77(s,1H),3.50(s,1H),2.81(s,6H),2.61(s,3H),2.80-2.68(m,2H),2.43(q,J=8.4Hz,2H),1.21(t,J=7.6Hz,3H)；MS(ES+)m/z(C26H31N9O2S)理論值：533.23；實際值：534.2(M+H+).
實施例18
1-(4-(2-((6-(4-(二甲基胺)哌啶-1-基)-2-甲基嘧啶-4-基)胺)噻唑-5-基)-2-甲苯基)-3-(5-乙基異噁唑-3-基)尿素(1-(4-(2-((6-(4-(Dimethylamino)piperidin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazol-5-yl)-2-methylphenyl)-3-(5-ethylisoxazol-3-yl)urea)(鹽酸鹽)
1H NMR(400MHz,DMSO-d6)：δ 11.10(s,1H),10.23(s,1H),8.77(s,1H),7.92(d,J=8.4Hz,1H),7.78(s,1H),7.45(s,1H),7.40(d,J=6.4Hz,1H),6.52(s,1H),6.44(s,1H),4.44(s,2H),3.46(bs,1H),3.05(t,J=12.0Hz,2H),2.74-2.68(m,8H),2.55(s,3H),2.31(s,3H),2.46(d,J=10.8Hz,2H),2.66(q,J=11.6Hz,2H),1.20(t,J=7.6Hz,3H)；MS(ES+)m/z(C28H35N9O2S)理論值：561.26；實際值：562.2(M+H+).
實施例19
1-(4-(2-((6-(4-(二甲基胺)哌啶-1-基)-2-甲基嘧啶-4-基)胺)噻唑-5-基)苯基)-3-(5-乙基異噁唑-3-基)尿素(1-(4-(2-((6-(4-(Dimethylamino)piperidin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazol-5-yl)phenyl)-3-(5-ethylisoxazol-3-yl)urea)(鹽酸鹽)
1H NMR(300MHz,DMSO-d6)：δ 10.98(s,1H),9.78(s,1H),9.72(s,1H),7.76(s,1H),7.55-7.48(m,4H),6.54(s,1H),6.40(s,1H),4.42(bs,2H),3.43(t,J=6.8Hz,1H),3.02(t,J=12.3Hz,2H),2.73-2.66(m,8H),2.52-2.48(m,3H，與DMSO重疊)，
2.16(t,J=10.8Hz,2H),1.64(q,J=11.1Hz,2H),1.22-1.17(m,3H)；MS(ES+)m/z(C27H33N9O2S)理論值：547.25；實際值：548.2(M+H+).
實施例20
1-(4-(2-((6-(4-(二甲基胺)哌啶-1-基)-2-甲基嘧啶-4-基)胺)噻唑-5-基)-2-氟苯基)-3-(5-乙基異噁唑-3-基)尿素(1-(4-(2-((6-(4-(Dimethylamino)piperidin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazol-5-yl)-2-fluorophenyl)-3-(5-ethylisoxazol-3-yl)urea)(鹽酸鹽)
1H NMR(400MHz,DMSO-d6)：δ 10.78(s,1H),9.98(s,1H),9.05(s,1H),8.11(t,J=8.8Hz,1H),7.82(s,1H),7.57(d,J=12.4Hz,1H),7.34(d,J=8.8Hz，1H),6.52(s,1H),6.26(s,1H),4.39(bs,2H),3.41(t,J=6.8Hz,1H),2.95(t,J=11.2Hz,2H),2.74-2.68(m,8H),2.52-2.47(m,3H，與DMSO重疊),2.13(d,J=10.8Hz,2H),1.60(q,J=12.0Hz,2H),1.19(t,J=7.6Hz,3H)；MS(ES+)m/z(C27H32FN9O2S)理論值：565.24；實際值：566.2(M+H+).
實施例21：蛋白激酶之抑制
激酶抑制的數據由SelectScreen® Biochemical Kinase Profiling Service獲得。
更具體地，在384-孔盤的孔洞中於160nL之1% DMSO溶液中篩選測試化合物；激酶/抗體混合物(8μl)以合適的激酶緩衝液(3.84μl)稀釋至2倍操作濃度，且
於激酶緩衝液中配製4倍的AlexaFluor®示蹤劑(4μl)；將測試溶液於室溫下培養60分鐘；並以螢光孔盤測讀儀(fluorescence plate reader)紀錄和分析。
觀察到一些式(I)之化合物，如化合物1、2和3意外地以半抑制濃度(half maximal inhibitory concentrations)或IC50值低於100nM抑制多種蛋白激酶。
該結果表示式(I)之化合物在抑制多種蛋白激酶具有高活性表現。
實施例22：體外細胞活性
AC220為臨床試驗中之小分子FLT3抑制劑，其對抵抗FLT3-內部串聯重複(FLT3-internal tandem duplication，FLT3-ITD)突變具有高效力，臨床相關之AC220抵抗-授予(resistance-conferring)突變已經被侷限在FLC3激酶區域(FLC3 kinase domain)中的殘基，例如ITD-D835Y、ITD-D835V、ITD-D835F、ITD-F691L和ITD-F691I。
評估式(I)化合物，與化合物AC220相比，在包含這些突變之細胞株中的抑制生長效力，研究結果如下。
自American Type Culture Collection(ATCC,Manassas,VA,USA)購買五種白血病32D細胞株。將包含ITO突變(32D-ITD細胞)、ITD與D835Y(32D-ITD/D835Y細胞)、ITD與D835V(32D-ITD/D835V細胞)、ITD與D835F(32D-ITD/D835F細胞)、以及ITD與F691L(32D-ITD/F691L細胞)突變之編碼人類FLT3之表現載體，穩定轉染至老鼠原-B淋巴球(pro-B lymphocyte)32D細胞株，其導致FLT3下游信號蛋白的組成性活化。以描述於PLoS One,2014,9,e97116之MST測定法評估細胞活性。將32D-ITD/D835Y、32D-ITD/D835V、32D-ITD/D835F、32D-ITD/F691L以及32D-ITD/F691I細胞以1×104cells/mL接種於96-孔盤中(100μL/孔)培養24小時，接著將測試化合物(各種濃度溶於DMSO)加入至培養基中培養72小時，藉由MTS測定法測定細胞活性(Promega,Madison,WI,USA)。
下表2中所顯示的結果由測試化合物於包含ITD突變之細胞株中的抑制生長研究中獲得。
與AC220相比，可以觀察到化合物1、2和4對所有突變體ITD-D835Y、ITD-D835V、ITD-D835F、ITD-F691L以及ITD-F691I，皆意外地展現出較高的細
胞生長抑制效力。更具體地，與由AC220所表現的19-103nM之GI50值相比，所有化合物1、2、4意外地表現出對突變體ITD-D835Y、ITD-D835V以及ITD-D835F具有低於6nM之GI50值的高細胞生長抑制效力；並且，與由AC220所表現大於100nM之GI50值相比，化合物4意外地表現出對突變體ITD-F691L以及ITD-F691I具有低於20nM之GI50值的高細胞生長抑制效力。
比較數據指出式(I)之化合物意外地發揮高細胞效力，且在抑制特定蛋白激酶突變上優於臨床化合物。
實施例23：式(I)化合物之口服生物可利用性(Oral Bioavailability，F%)
此研究係評估式(I)化合物當以如下的口服給藥時之體內暴露。
由BioLASCO(Taiwan Co.,Ltd,Ilan,Taiwan)獲得每隻重25-35g之ICR雄性小鼠，根據國家衛生研究院(National Health Research Institutes，NHRI)的實驗動物照護及委員會(Institutional Animal Care and Use Committee)批准之方法進行動物研究。向總共33隻雄性小鼠各自透過靜脈(IV)施用單一劑量2.0mg/kg之化合物2、3、5、6。向總共27隻雄性小鼠各自透過口服(PO)施用單一劑量10mg/kg之四種化合物。每隻老鼠藉由尾靜脈注射給予100mL之IV給藥溶液，且藉由口服管餵給予200mL之PO給藥溶液。接受IV給藥的動物不禁食，且接受PO給藥的動物在給藥前禁食過夜。在0(給藥前的當下)、2(僅IV)、5(僅IV)、15和30分鐘，以及在給藥後1、2、4、6、8、16、24小時後，在每個時間點從3隻小鼠的組中藉由心臟穿刺收集血液(約500mL)，並於保存於冰中(0-4℃)。
使用伸乙二胺四乙酸(Ethylenediaminetetraacetic acid，EDTA)作為抗凝血劑，藉由離心(Beckman Model Allegra 6R離心機，3000rpm，4℃，15分鐘)將血漿從血液中分離，並儲存於冷凍櫃中(-20℃)。從沒有接受化合物的老鼠中獲得對照血漿，用來作為建構標準曲線和用於製備品質控制(QC)之樣品，並藉由LC-MS/MS分析所有樣品的母化合物(parent compound)。
通過將PO給藥後化合物平均曲線下面積(AUC)除以劑量標準化後之IV給藥後化合物平均曲線下面積，計算口服生物可利用性，以百分比表示(F%)。AUC和F%值顯示於下表3。
可以觀察到4種化合物，即2、3、5、6意外地發揮高暴露，如IV AUC和PO AUC值所表示，並且，化合物2、3、5、6意外地表現出高口服生物可利用性，其F%值分別為38、96、67、89。
上表3中所列之結果表示，當口服給藥時，式(I)化合物意外地表現出高體內暴露。
實施例24：在異種移植老鼠模型中之功效
評估式(I)化合物在體內之功效，即腫瘤生長抑制(TGI)，研究結果如下。
從BioLASCO(Taipei,Taiwan,R.O.C.)購買8週齡的雄性裸鼠(Nu-Fox1 nu )，將人類直腸Colo205、胰臟Mia-PaCa 2腫瘤細胞或MOLM-13、32D-ITD/D835Y白血病細胞以每隻裸鼠1×106細胞數接種至皮下，在他們注入動物前，所有人類癌症
細胞被檢測不含有黴漿菌屬(Mycoplasma spp)。腫瘤細胞作為異種移植腫瘤生長，且在準備用於劑量治療的裸鼠中腫瘤大小達到約200-250mm3時，將測試化合物分別溶解於20%之2-羥丙基-β-環糊精，用於口服管餵給裸鼠。以各種劑量之測試化合物處理荷瘤小鼠(tumor-bearing)，每週5次，持續2週。藉由電子測徑器測量腫瘤尺寸，並以式計算：腫瘤大小=長×寬2/2。在整個觀察期間，於腫瘤細胞接種前後每週測量腫瘤大小和動物體重2次。動物的使用和其實驗方法由國家衛生研究院的實驗動物照護及使用委員會(Institutional Animal Care and Use Committee，IACUA)所批准。
如上表4中顯示，在異種移植colo205之裸鼠模型中，所有測試化合物，即化合物1(PO；50mg/kg)、2(PO；50mg/kg)、3(PO；100mg/kg)、4(PO；150mg/kg)、6(PO；25mg/kg)，在第18天意外地表現80%之高TGI值。
如上表5中顯示，在異種移植Mia-paca2之腫瘤模型中，化合物5和6兩者在口服給藥25mg/kg的第18天，意外地分別表現出65%和68%的高TGI值。
*起始腫瘤大小約250mm3。在第18天，對照組腫瘤大小>2000mm3並犧牲小鼠。
如上表6所顯示，在異種移植MOLM-13之裸鼠模型中，化合物2(PO；25和50mg/kg)以及4(PO；150mg/kg)兩者在第25天皆意外地表現高TGI及腫瘤退化。
如上表7所顯示，在異種移植FLT3-ITD-D835Y之裸鼠模型中，化合物2(PO；25mg/kg)和5(PO；25mg/kg)兩者在第12天皆意外地表現出具有>20%值之高腫瘤退化。
這些結果表示，當以口服給藥式(I)之化合物時，在異種移植之動物模型中意外地表現出高抗腫瘤功效。
實施例25：小鼠毒性研究
評估式(I)化合物在體內之毒性，研究結果如下。
依照實施例24所描述之方法，在動物中測試式(I)化合物之體內功效。對9週齡的nu/nu裸鼠在第1-5天以及第8-12天時，口服給予每日一次25、50、100或150mg/kg之劑量，在治療後14天觀察期間觀察臨床症狀和測量體重。
如上表8所顯示，異種移植colo205之裸鼠耐受性良好，每日口服給予化合物1、2、3、4、6一次(50、50、100、150、25mg/kg)，在研究期間沒有觀察到死亡率。
如上表9所顯示，異種移植Mia-pzca2之裸鼠耐受性良好，每日口服給予化合物5和6一次(25mg/kg)，同樣在研究期間沒有觀察到死亡率。
如上表10所顯示，異種移植MOLM-13之裸鼠耐受性良好，每日口服給予化合物2和4一次(25和50、50或150mg/kg)，在研究期間沒有觀察到死亡率。
表11.式(I)化合物對異種移植FLT3-ITD-D835Y之裸鼠的體內毒性研究
如上表11所顯示，異種移植FLT3-ITD-D835Y之裸鼠耐受性良好，每日口服給予化合物2和5一次(25mg/kg)，在研究期間沒有觀察到死亡率。
上述這些結果證明式(I)之化合物意外地表現出令人滿意的安全性。
其他實施例
在本說明書揭露之所有特徵可以以任何組合進行結合，本說明書揭露之每一特徵可以由具有相同、等同或類似目的之替代特徵來替換，因此，除非另有明確說明，本揭露之每一特徵僅為等同或類似特徵的一般系列之例子。
從以上描述中，本領域之技術人員可以容易的確定本發明之基本特徵，且在不背離本發明之精神及範圍下，可以對本發明進行各種改變和修飾以適應各種用途和條件。因此，其他實施例也在所附權利要求的範圍內。
Claims (27)
- 一種式(II)之化合物：
- 如申請專利範圍第1項所述之化合物，其中，X為O。
- 如申請專利範圍第2項所述之化合物，其中，Y為NRd且R2為-CH2CH2Re，其中Re為ORh，Rh與Rd、鍵結到Rh之氧原子及鍵結到Rd之氮原子一起為C3-10雜環烷基；R3為H、鹵素或C1-6烷基；且R4為C1-6烷基或C3-10環烷基。
- 如申請專利範圍第3項所述之化合物，其中該化合物為
- 如申請專利範圍第1項所述之化合物，其中，X為NRa，Ra為H或C1-6烷基。
- 如申請專利範圍第5項所述之化合物，其中，Y為CRbRc，其中，Rb與Ra、鍵結到Rb之碳原子及鍵結到Ra之氮原子一起為C3-10雜環烷基，且Rc為H、鹵素、C1-6烷基、C1-6烷氧基或胺基；R2為NRfRg，Rf和Rg各自獨立為C1-6烷基或C3-8環烷基；R3為H、鹵素、C1-6烷基或C3-10環烷基；以及R4為C1-6烷基或C3-10環烷基。
- 如申請專利範圍第6項所述之化合物，其中，Rb與Ra、鍵結到Rb之碳原子及鍵結到Ra之氮原子一起為吡咯啶基或哌啶基。
- 如申請專利範圍第5項所述之化合物，其中，Y為NRd，其中，Rd與Ra及鍵結到Rd和Ra之氮原子一起為C3-10雜環烷基；R2為-CH2CH2Re，其中，Re為H、鹵素、C1-6烷基或ORh，Rh為H或C1-6烷基； R3為H、鹵素、C1-6烷基或C3-10環烷基；以及R4為C1-6烷基或C3-10環烷基。
- 如申請專利範圍第8項所述之化合物，其中，Rd與Ra及鍵結到Rd和Ra之氮原子一起為哌嗪基。
- 如申請專利範圍第9項所述之化合物，其中該化合物為
- 一種式(II)之化合物：
- 如申請專利範圍第11項所述之化合物，其中，X為O。
- 如申請專利範圍第11項所述之化合物，其中，X為NRa，Ra為H或C1-6烷基。
- 如申請專利範圍第13項所述之化合物，其中，Y為NRd，其中Rd與Ra及鍵結到Rd和Ra之氮原子一起為C3-10雜環烷基；R2為-CH2CH2F；R3為H、鹵素、C1-6烷基或C3-10環烷基；以及R4為C1-6烷基或C3-10環烷基。
- 如申請專利範圍第14項所述之化合物，其中Rd與Ra及鍵結到Rd和Ra之氮原子一起為哌嗪基。
- 如申請專利範圍第15項所述之化合物，其中，R1為-CH3。
- 如申請專利範圍第16項所述之化合物，其中該化合物為
- 一種醫藥組成物，包含如申請專利範圍第1項所述之化合物和藥學上可接受之載體。
- 一種醫藥組成物，包含如申請專利範圍第11項所述之化合物和藥學上可接受之載體。
- 一種體外抑制蛋白激酶的方法，包含使有效劑量的如專利申請範圍第1項所述之化合物與體外的該蛋白激酶接觸。
- 一種體外抑制蛋白激酶的方法，包含使有效劑量的如專利申請範圍第11項所述之化合物與體外的該蛋白激酶接觸。
- 一種化合物於用以製備治療與蛋白激酶相關之癌症的藥物之用途，其中該化合物為如申請專利範圍第1項所述之化合物。
- 一種化合物於用以製備治療與蛋白激酶相關之癌症的藥物之用途，其中該化合物為如申請專利範圍第11項所述之化合物。
- 如申請專利範圍第22項所述之用途，其中該癌症為急性骨髓性白血病、綠色白血病、慢性骨髓性白血病、急性淋巴細胞性白血病、慢性淋巴細胞白血病、霍奇金病、非霍奇金淋巴瘤、B細胞淋巴瘤、多發性骨髓瘤、瓦爾登斯特倫巨球蛋白血症、骨髓增生異常綜合徵、胰腺癌、膀胱癌、結直腸癌、乳 癌、男性生殖道癌、腎癌、肝細胞癌、肺癌、卵巢癌、子宮頸癌、子宮癌、妊娠滋養細胞疾病、胃癌、膽道癌、膽囊癌、小腸癌、食管癌、口咽癌、下嚥癌、眼癌、神經癌、頭頸部癌症、黑色素瘤、漿細胞瘤、內分泌腺腫瘤、神經內分泌癌、腦腫瘤、骨癌或肉瘤。
- 如申請專利範圍第22項所述之用途，其中該蛋白激酶為類FMS酪胺酸激酶3(FLT3)、類FMS酪胺酸激酶4(FLT4)、極光激酶A(AURK A)、極光激酶B(AURK B)、血管內皮生長因子受體(VEGFR)、血小板源生長因子受體A(PDGFR A)、血小板源生長因子受體B(PDGFR B)、c-Src激酶(SRC)、酪胺酸激酶LynA(LYN A)、酪胺酸激酶Lyn B(LYN B)、在轉染期間重排的酪胺酸激酶(RET)、集落刺激因子1受體(CSF1R)、淋巴細胞專一性蛋白質酪氨酸激酶(LCK)、加德納拉希德貓肉瘤病毒(v-fgr)致癌基因同源物(FGR)、盤狀結構域受體1(DDR1)、激酶插入區域受體(KDR)、原肌球蛋白受體激酶A(TRK A)、原肌球蛋白受體激酶B(TRK B)、B淋巴細胞激酶(BLK)、酪胺酸激酶Yes(YES1)、愛柏森鼠類白血病病毒致癌基因同源物1(ABL1)、酪胺酸激酶Kit(KIT)、雙專一性有絲分裂活化蛋白質激酶1(MEK1)、介白素-1受體相關激酶4(IRAK4)、酪胺酸激酶Tek(TEK)、RET V804L、RET Y791F、FLT3 D835Y、PDGFR A V561D或ABL1 T315I。
- 如申請專利範圍第23項所述之用途，其中該癌症為急性骨髓性白血病、綠色白血病、慢性骨髓性白血病、急性淋巴細胞性白血病、慢性淋巴細胞白血病、霍奇金病、非霍奇金淋巴瘤、B細胞淋巴瘤、多發性骨髓瘤、瓦爾登斯特倫巨球蛋白血症、骨髓增生異常綜合徵、胰腺癌、膀胱癌、結直腸癌、乳癌、男性生殖道癌、腎癌、肝細胞癌、肺癌、卵巢癌、子宮頸癌、子宮癌、妊 娠滋養細胞疾病、胃癌、膽道癌、膽囊癌、小腸癌、食管癌、口咽癌、下嚥癌、眼癌、神經癌、頭頸部癌症、黑色素瘤、漿細胞瘤、內分泌腺腫瘤、神經內分泌癌、腦腫瘤、骨癌或肉瘤。
- 如申請專利範圍第23項所述之用途，其中所述蛋白激酶為FLT3、FLT4、AURK A、AURK B、VEGFR、PDGFR A、PDGFR B、SRC、LYN A、LYN B、RET、CSF1R、LCK、FGR、DDR1、KDR、TRK A、TRK B、BLK、YES1、ABL1、KIT、MEK1、IRAK4、TEK、RET V804L、RET Y791F、FLT3 D835Y、PDGFR A V561D或ABL1 T315I。
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| KR20240005751A (ko) * | 2021-04-12 | 2024-01-12 | 에이2에이 파마수티칼스, 잉크. | 암 치료를 위한 조성물 및 방법 |
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| KR100722344B1 (ko) * | 1999-04-15 | 2007-05-29 | 브리스톨-마이어스스퀴브컴파니 | 환형 단백질 티로신 키나제 억제제 |
| DE60117605T2 (de) * | 2000-12-21 | 2006-12-07 | Bristol-Myers Squibb Co. | Thiazolyl-inhibitoren von tyrosinkinasen der tec-familie |
| WO2004041164A2 (en) * | 2002-10-30 | 2004-05-21 | Merck & Co., Inc. | Kinase inhibitors |
| CA2593803A1 (en) * | 2005-01-26 | 2006-08-03 | Irm Llc | Thiazole-amide compounds and compsitions as protein kinase inhibitors |
| AU2008355098B2 (en) | 2008-04-21 | 2012-11-15 | Gpcr Therapeutics, Inc | Heterocyclic compounds |
| WO2010046780A2 (en) | 2008-10-22 | 2010-04-29 | Institut Pasteur Korea | Anti viral compounds |
| PL2604601T3 (pl) | 2010-08-10 | 2016-09-30 | Związek heteropierścieniowy | |
| BR112014007310A2 (pt) | 2011-09-27 | 2017-04-04 | Novartis Ag | 3-pirimidin-4-il-oxazolidin-2-onas como inibidores de idh mutante |
| CN104024246B (zh) * | 2012-03-27 | 2016-03-02 | 广东东阳光药业有限公司 | 作为欧若拉激酶抑制剂的取代嘧啶衍生物 |
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Also Published As
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| US10047078B2 (en) | 2018-08-14 |
| CN109069504B (zh) | 2022-06-28 |
| WO2017136315A1 (en) | 2017-08-10 |
| JP6883049B2 (ja) | 2021-06-02 |
| EP3411035A4 (en) | 2019-08-14 |
| CN109069504A (zh) | 2018-12-21 |
| EP3411035B1 (en) | 2022-03-02 |
| EP3411035A1 (en) | 2018-12-12 |
| US20170226100A1 (en) | 2017-08-10 |
| HK1258689A1 (zh) | 2019-11-15 |
| KR102449712B1 (ko) | 2022-09-30 |
| JP2019511564A (ja) | 2019-04-25 |
| ES2909612T3 (es) | 2022-05-09 |
| KR20180132618A (ko) | 2018-12-12 |
| TW201728583A (zh) | 2017-08-16 |
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