TW202237585A - Cdk inhibitors - Google Patents

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TW202237585A
TW202237585A TW110144250A TW110144250A TW202237585A TW 202237585 A TW202237585 A TW 202237585A TW 110144250 A TW110144250 A TW 110144250A TW 110144250 A TW110144250 A TW 110144250A TW 202237585 A TW202237585 A TW 202237585A
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狄伯納斯 布尼雅
史里肯特 維斯瓦納達
史華洛普 K V S 弗卡蘭卡
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瑞士商瑞森製藥公司
印度商印蔻真治療公司
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Abstract

The present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof as cyclin-dependent kinase inhibitors (one or more of CDK1, CDK2, CDK4, and CDK6), methods of preparing them, and pharmaceutical compositions containing them. The compounds of the present invention are useful in the treatment, prevention and/or amelioration of diseases or disorders associated with one or more of CDK1, CDK2, CDK4, and CDK6.

Description

CDK抑制劑CDK inhibitors

本申請案主張2020年11月27日提出申請之印度專利申請案第202041051646號之權益,該專利申請案在此係以引用的方式併入。 This application claims the benefit of Indian Patent Application No. 202041051646 filed on November 27, 2020, which is hereby incorporated by reference.

本發明提供式 (I)化合物,其為週期蛋白依賴性激酶(CDK1、CDK2、CDK4及CDK6中之一或多者)抑制劑(諸如CDK2及/或CDK 4/6之抑制劑);製備該等化合物之方法;含有該等化合物之醫藥組合物;及治療、預防及/或改善涉及CDK1、CDK2、CDK4及CDK6中之一或多者之疾病或病症之方法。 The present invention provides a compound of formula (I) , which is an inhibitor of cyclin-dependent kinase (one or more of CDK1, CDK2, CDK4 and CDK6) (such as an inhibitor of CDK2 and/or CDK 4/6); preparing the Methods of the compounds; pharmaceutical compositions containing the compounds; and methods of treating, preventing and/or improving diseases or conditions involving one or more of CDK1, CDK2, CDK4 and CDK6.

週期蛋白依賴性激酶(CDK)係絲胺酸/蘇胺酸激酶,其活性依賴於一種調控性亞單元,亦即週期蛋白。基於激酶結構域之序列,CDK連同促分裂原活化之蛋白激酶(MAPK)、肝糖合酶激酶-3β (Gsk3β)、雙重特異性酪胺酸調控激酶(DYRK)家族成員及CDK樣激酶一起屬於CMGC激酶群組(以一些成員之首字母命名)。在諸如MAPK等相關激酶中,受質特異性由與催化位點分開之停泊位點賦予,而CDK之特徵在於依賴於提供酶活性所需額外序列之分開的蛋白質亞單元。為有助於CDK之命名及分析,已將屬於此家族之蛋白質重新命名為Cdk1至Cdk20。Cyclin-dependent kinases (CDKs) are serine/threonine kinases whose activity depends on a regulatory subunit, cyclins. Based on the sequence of the kinase domain, CDKs belong together with mitogen-activated protein kinase (MAPK), glycogen synthase kinase-3β (Gsk3β), members of the dual specificity tyrosine-regulated kinase (DYRK) family, and CDK-like kinases CMGC kinase group (named after some members' initials). In related kinases such as MAPKs, substrate specificity is conferred by a docking site separate from the catalytic site, whereas CDKs are characterized by reliance on separate protein subunits that provide the additional sequences required for enzymatic activity. To facilitate the nomenclature and analysis of CDKs, the proteins belonging to this family have been renamed Cdk1 to Cdk20.

CDK最早係在對諸如酵母及青蛙等模式生物體之遺傳學及生物化學研究中發現的。此項工作確立了CDK在促進細胞週期轉變中之重要性。另外,該等研究顯示,催化性亞單元CDK必須與調控性亞單元週期蛋白締合,該週期蛋白之蛋白質水準在細胞週期中受調控(此振盪賦予該等調控因子其週期蛋白名稱)。自1980年代開展該等開創性研究以來,已明確確立CDK作為主要真核蛋白激酶家族參與細胞外及細胞內信號整合以調節基因轉錄及細胞分裂之重要性。CDKs were first discovered in genetic and biochemical studies of model organisms such as yeast and frogs. This work establishes the importance of CDKs in promoting cell cycle transitions. In addition, these studies show that the catalytic subunit CDK must associate with the regulatory subunit cyclins whose protein levels are regulated during the cell cycle (this oscillation gives these regulators their cyclin name). Since these pioneering studies in the 1980s, the importance of CDKs as a major family of eukaryotic protein kinases involved in the integration of extracellular and intracellular signals to regulate gene transcription and cell division has been clearly established.

CDK之數量在演化過程中增加,且以細胞週期相關群組之更大擴展為標誌。真菌含有6至8種CDK及9至15種週期蛋白,而蠅類及棘皮動物含有11種CDK及14種週期蛋白,且人類細胞具有20種CDK及29種週期蛋白。演化研究表明,CDK分為八個亞家族,其由Cdk1、Cdk4及Cdk5 (來自酵母細胞週期相關CDK)及Cdk7、Cdk8、Cdk9、Cdk11及Cdk20 (起轉錄CDK之作用)代表。(Marcos Malumbres , Genome Biology, 2014, 15:122)The number of CDKs increases during evolution and is marked by a greater expansion of cell cycle-associated groups. Fungi contain 6 to 8 CDKs and 9 to 15 cyclins, while flies and echinoderms contain 11 CDKs and 14 cyclins, and human cells have 20 CDKs and 29 cyclins. Evolutionary studies have shown that CDKs are divided into eight subfamilies represented by Cdk1, Cdk4 and Cdk5 (from yeast cell cycle-associated CDKs) and Cdk7, Cdk8, Cdk9, Cdk11 and Cdk20 (functioning as transcriptional CDKs). (Marcos Malumbres , Genome Biology, 2014, 15:122) .

週期蛋白依賴性激酶1 (CDK1)係驅動細胞進入正常有絲分裂之主要蛋白激酶。CDK1藉由與B型週期蛋白(主要為週期蛋白B1)結合而活化,其接著使對進入有絲分裂至關重要之受質磷酸化。破壞週期蛋白B1提供一種使CDK1快速不活化且使細胞退出有絲分裂之機制(R.Y.C. Poon ,  Encyclopedia of Cell Biology, 2016)。CDK1存在於整個細胞週期。相比之下,在進入S期後,週期蛋白B1累積且與CDK1形成複合物。在MYT1及WEE1經由使CDK1 Thr14/Tyr15磷酸化進入有絲分裂之前,該複合物保持不活化。在G2期結束時,不活化週期蛋白B1-CDK1之儲備由CDC25磷酸酶家族之成員突然活化。週期蛋白B1-CDK1藉由同時刺激CDC25活化及WEE1不活化來催化其自身之活化(Lindqvist等人, 2009, JCB (2009), 185 (2): 193-202)。據信,此雙穩態系統由PLK1啟動,從而起始CDC25之活化及WEE1/MYT1之不活化(Van Vugt及Medema, Oncogene,第24卷,第2844-2859頁(2005))。PLK1之活化繼而需要Aurora A磷酸化PLK1 Thr210,此為由Bora輔助之事件。Bora與PLK1之結合受週期蛋白B1-CDK1依賴性磷酸化刺激,從而在CDK1之活化中產生另一正反饋迴路。 Cyclin-dependent kinase 1 (CDK1) is the main protein kinase that drives cells into normal mitosis. CDK1 is activated by binding to B-type cyclins, primarily cyclin B1, which in turn phosphorylates substrates critical for entry into mitosis. Disruption of cyclin B1 provides a mechanism to rapidly inactivate CDK1 and exit cells from mitosis (RYC Poon , Encyclopedia of Cell Biology, 2016 ). CDK1 is present throughout the cell cycle. In contrast, upon entry into S phase, cyclin B1 accumulates and forms a complex with CDK1. This complex remains inactive until MYT1 and WEE1 enter mitosis by phosphorylating CDK1 Thr14/Tyr15 . At the end of the G2 phase, the reserve of inactive cyclin B1-CDK1 is suddenly activated by members of the CDC25 phosphatase family. Cyclin B1-CDK1 catalyzes its own activation by simultaneously stimulating CDC25 activation and WEE1 inactivation (Lindqvist et al., 2009, JCB (2009), 185(2): 193-202 ). This bistable system is believed to be activated by PLK1, thereby initiating the activation of CDC25 and the inactivation of WEE1/MYT1 (Van Vugt and Medema, Oncogene , Vol. 24, pp. 2844-2859 (2005)). Activation of PLK1 in turn requires phosphorylation of PLK1 Thr210 by Aurora A, an event assisted by Bora. Binding of Bora to PLK1 is stimulated by cyclin B1-CDK1-dependent phosphorylation, creating another positive feedback loop in the activation of CDK1.

CDK1係主要細胞週期調控因子。在酵母中,細胞週期進展由單一CDK控制,在啤酒酵母(Saccharomyces cerevisiae)中稱為Cdc28且在粟酒裂殖酵母(Schizosaccharomyces pombe)中稱為Cdc2,且此CDK在細胞週期之不同階段結合至特定週期蛋白。藉由對小鼠之遺傳學研究,系統性敲除小鼠生殖系之Cdk已顯示Cdk2、Cdk4及Cdk6對於大多數細胞類型之細胞週期並非必要的。只有Cdk1之消除才引起細胞週期停滯及兩細胞階段之胎死。CDK1活性控制M期進入及退出。在G2/M轉變期,CDK1-週期蛋白B1活化導致控制染色體緊縮、核套膜分解及紡錘體組裝之各種蛋白質磷酸化。在後期開始時,CDK1-週期蛋白B1藉由控制分離酶(一種裂解將姊妹染色分體保持在一起之黏蛋白複合物之蛋白酶)之活性而參與此事件。CDK1活性之調控在多個層面上受控制,諸如與其調控性亞單元(週期蛋白A及B)結合、與週期蛋白依賴性激酶抑制劑(CKI)相互作用及藉由活化性激酶CAK (CDK活化性激酶)或藉由若干抑制劑激酶(包括Wee1及Myt1或磷酸酶Cdc25)使特定殘基磷酸化及去磷酸化。亦參見Brown等人, Nat Commun., 6, 6769 (2015)CDK1 is a major cell cycle regulator. In yeast, cell cycle progression is controlled by a single CDK, called Cdc28 in Saccharomyces cerevisiae and Cdc2 in Schizosaccharomyces pombe, and this CDK binds at different stages of the cell cycle to specific cycle proteins. Systematic knockout of Cdk in the mouse germline has shown that Cdk2, Cdk4 and Cdk6 are not essential for the cell cycle of most cell types by genetic studies in mice. Only depletion of Cdk1 caused cell cycle arrest and fetal death at the two-cell stage. CDK1 activity controls M phase entry and exit. During the G2/M transition, CDK1-cyclin B1 activation leads to phosphorylation of various proteins that control chromosome compaction, nuclear envelope breakdown, and spindle assembly. At the onset of anaphase, CDK1-cyclin B1 participates in this event by controlling the activity of separase, a protease that cleaves the mucin complex that holds sister chromatids together. Regulation of CDK1 activity is controlled at multiple levels, such as binding to its regulatory subunits (cyclins A and B), interaction with cyclin-dependent kinase inhibitors (CKIs), and activation by the activating kinase CAK (CDK kinases) or by phosphorylation and dephosphorylation of specific residues by several inhibitor kinases including Wee1 and Myt1 or the phosphatase Cdc25. See also Brown et al., Nat Commun., 6, 6769 (2015) .

CDK2過表現與異常細胞週期調控相關,且CDK2 /週期蛋白E參與細胞週期G1期至S期之調控。在G1期結束時,CDK2 /週期蛋白E複合物亦可催化Rb磷酸化,藉此促進細胞週期自G1期進展至S期;在S期,CDK2 /週期蛋白A複合物可促進DNA複製過程。Asghar等人, Nat. Rev. Drug. Discov., 2015;14(2):130-146。腫瘤中常見對應於CDK2之週期蛋白E。週期蛋白E1之擴增及過表現與卵巢癌、胃癌及乳癌之不良預後相關。Nakayama等人, Cancer, 2010, 116:2621-34);Etemadmoghadam等人, Clin cancer res,2013, 19:5960-71;Au-Yeung等人, Clin. Cancer Res.2017, 30:297-303);Ooi等人, Hum Pathol., 2017, 61:58-67 Noske等人, Oncotarget, 2017, 8:14794-14805。週期蛋白E2過表現與乳癌對內分泌療法之抗性相關,且抑制對他莫昔芬(tamoxifen)具有抗性之CDK2細胞。Caldon等人, Mol Cancer Ther., 2012, 11:1488-99;Herrera-Abreu等人, Cancer Res., 2016, 76:2301-2313。在HER2陽性乳癌中,週期蛋白E擴增亦與曲妥珠單抗(trastuzumab)抗性相關。Scaltriti等人, Proc Natl Acad Sci.2011, 108:3761-6。CDK4之發現驗證了D型週期蛋白可別構調控新穎CDK之假設,據揭示,CDK4物理結合至三種D型週期蛋白中之任一者且由其酶促活化。2年後,鑑別出一種具有類似性質之相關週期蛋白D依賴性激酶CDK6。儘管CDK 1及2與週期蛋白E、A及B之複合物驅動細胞週期進展通過S期及M期 (有絲分裂),但週期蛋白D依賴性CDK在G 1期期間起作用,以推動已進入細胞週期之靜止細胞或已完成有絲分裂之增殖性細胞向S期進展。與使數百種細胞蛋白質受質磷酸化之CDK 1及2不同,CDK4係一種令人驚訝之挑剔酶,其具有有限之使視網膜母細胞瘤蛋白質(RB1,下文稱為RB)及兩種其他RB家族蛋白質[RB2 (p130)、RBL1 (p107)]磷酸化之傾向性,且其他受質極少。 CDK2 overexpression is associated with abnormal cell cycle regulation, and CDK2/cyclin E is involved in the regulation of cell cycle G1 phase to S phase. At the end of the G1 phase, the CDK2/cyclin E complex can also catalyze the phosphorylation of Rb, thereby promoting the progression of the cell cycle from the G1 phase to the S phase; in the S phase, the CDK2/cyclin A complex can promote the DNA replication process. Asghar et al., Nat. Rev. Drug. Discov. , 2015;14(2):130-146. Cyclin E corresponding to CDK2 is commonly found in tumors. Amplification and overexpression of cyclin El is associated with poor prognosis in ovarian, gastric and breast cancers. Nakayama et al., Cancer , 2010, 116:2621-34); Etemadmoghadam et al., Clin cancer res, 2013, 19:5960-71; Au-Yeung et al., Clin. Cancer Res. 2017, 30:297-303) ; Ooi et al., Hum Pathol. , 2017, 61:58-67 ; Noske et al., Oncotarget , 2017, 8:14794-14805. Cyclin E2 overexpression is associated with breast cancer resistance to endocrine therapy and suppresses CDK2 cells resistant to tamoxifen. Caldon et al., Mol Cancer Ther. , 2012, 11:1488-99; Herrera-Abreu et al., Cancer Res. , 2016, 76:2301-2313. In HER2-positive breast cancer, cyclin E amplification is also associated with trastuzumab resistance. Scaltriti et al., Proc Natl Acad Sci. 2011, 108:3761-6. The discovery of CDK4 validated the hypothesis that D-type cyclins can allosterically regulate novel CDKs, revealing that CDK4 physically binds to and is enzymatically activated by any of the three D-type cyclins. Two years later, a related cyclin D-dependent kinase CDK6 with similar properties was identified. While complexes of CDK 1 and 2 with cyclins E, A and B drive cell cycle progression through S and M phases (mitosis), cyclin D-dependent CDKs act during G1 phase to drive cells that have entered Cyclic quiescent cells or proliferative cells that have completed mitosis progress to S phase. Unlike CDK 1 and 2, which phosphorylate hundreds of cellular protein substrates, CDK4 is a surprisingly finicky enzyme with limited retinoblastoma protein (RB1, hereinafter referred to as RB) and two other The propensity for phosphorylation of RB family proteins [RB2 (p130), RBL1 (p107)], and very few other substrates.

RB係視網膜母細胞瘤中及許多其他癌症中之典型腫瘤抑制基因。隨著細胞歷經分裂週期,RB蛋白經歷週期性磷酸化。RB在細胞退出有絲分裂時去磷酸化,且G 1期中偵測到之低磷酸化形式在G1晚期變成過度磷酸化(不活化)的,且在通過S期進展至有絲分裂之整個期間保持如此。研究已突出低磷酸化(活性) RB限制增殖且用作強效腫瘤抑制基因之作用,指示RB之生長抑制功能可因其與DNA腫瘤病毒致癌蛋白(人類乳頭瘤病毒E7、腺病毒E1A及SV40 T抗原;)結合而不活化。在由促分裂原刺激自靜止狀態(G0)進入分裂週期之哺乳動物細胞中,CDK4/6介導之RB磷酸化首先在週期蛋白D誘導後但在週期蛋白E及A依賴性CDK2活化前之G 1期中期偵測到。總之,該等結果暗示CDK4/6之作用係使RB磷酸化,從而啟動RB以供在G1後期由其他CDK不活化,且自RB約束中釋放E2F轉錄因子以容許該等轉錄因子協同誘導一系列活性為起始S期共同需要之基因。Sherr等人, Cancer Discovery 2016年4月,6(4):353-367CD-15-0894。 RB is a canonical tumor suppressor gene in retinoblastoma and in many other cancers. As cells go through the division cycle, RB proteins undergo periodic phosphorylation. RB is dephosphorylated when cells exit mitosis, and the hypophosphorylated form detected in G1 phase becomes hyperphosphorylated (inactive) in late G1 and remains so throughout progression through S phase to mitosis. Studies have highlighted the role of hypophosphorylated (active) RB in limiting proliferation and serving as a potent tumor suppressor gene, indicating that the growth inhibitory function of RB may be due to its association with DNA tumor virus oncoproteins (human papillomavirus E7, adenovirus E1A, and SV40 T antigen;) binds without activation. In mammalian cells that enter the division cycle from quiescence (G0) stimulated by mitogens, CDK4/6-mediated RB phosphorylation precedes cyclin D induction but precedes cyclin E and A-dependent CDK2 activation Detected in the middle of G1 phase. Taken together, these results suggest that the role of CDK4/6 is to phosphorylate RB, thereby priming RB for inactivation by other CDKs in late G1, and to release E2F transcription factors from RB constraints to allow them to coordinately induce a series of Activity is a common requirement for the initiation of S phase genes. Sherr et al., Cancer Discovery , 2016 April, 6(4):353-367CD-15-0894.

CDK4 (INK4)-視網膜母細胞瘤(Rb)路徑藉由控制G1 (DNA合成前)至S (DNA合成)細胞週期檢查點來調控細胞增殖。在癌症中常觀察到週期蛋白D-CDK4/6-INK4-Rb路徑之失調,且該失調有助於細胞週期進展及繼續生長。CDK4/6藉由與D型週期蛋白締合且調控Rb之磷酸化狀態而介導自G1向S期轉變。非磷酸化Rb結合E2家族(E2F)轉錄因子並抑制其功能;在磷酸化後,Rb自E2F轉錄因子解離,釋放該等因子以使其能夠參與DNA複製及細胞分裂。週期蛋白D-CDK4/6活性增加促進Rb之磷酸化,其可經由若干種機制發生,包括D型週期蛋白之過表現、CDK4/6之突變或擴增或週期蛋白D-CDK4/6陰性調控因子(諸如p16INK4A)之丟失,且最終導致癌細胞生長。因此,選擇性CDK4/6抑制劑之開發為患有晚期癌症之患者提供新穎治療方法。Hamilton等人, Cancer Treatment Reviews, 45 (2016) 129-138。 The CDK4 (INK4)-retinoblastoma (Rb) pathway regulates cell proliferation by controlling the G1 (pre-DNA synthesis) to S (DNA synthesis) cell cycle checkpoints. Dysregulation of the cyclin D-CDK4/6-INK4-Rb pathway is frequently observed in cancer and contributes to cell cycle progression and continued growth. CDK4/6 mediates the transition from G1 to S phase by associating with D-type cyclins and regulating the phosphorylation state of Rb. Non-phosphorylated Rb binds E2 family (E2F) transcription factors and inhibits their function; upon phosphorylation, Rb dissociates from E2F transcription factors, releasing the factors so that they can participate in DNA replication and cell division. Increased cyclin D-CDK4/6 activity promotes phosphorylation of Rb, which can occur through several mechanisms, including overexpression of D-type cyclins, mutation or amplification of CDK4/6, or negative regulation of cyclin D-CDK4/6 Factors such as p16INK4A are lost and ultimately lead to cancer cell growth. Therefore, the development of selective CDK4/6 inhibitors provides novel therapeutic approaches for patients with advanced cancer. Hamilton et al., Cancer Treatment Reviews , 45 (2016) 129-138.

週期蛋白依賴性激酶4 (CDK4)及密切相關之CDK6在哺乳動物細胞增殖中起關鍵作用,其中該等激酶有助於驅動細胞進展至細胞分裂週期之DNA合成(S)期。與在細胞週期後期中因應於週期蛋白E、A及B之週期振盪而起作用以使DNA複製與有絲分裂協調之CDK 1及2不同,CDK4及CDK6在週期之第一間隔期(G1)中之酶活性受D型週期蛋白管控,該等D型週期蛋白因應於各種細胞外信號而表現,包括刺激性促分裂原、抑制性細胞介素、分化誘導物、細胞-細胞接觸及其他空間誘因。三種D型週期蛋白(D1、D2及D3)在不同的細胞譜系中單獨或組合差異表現,在該等細胞譜系中其與CDK4及CDK6組裝形成具有酶活性之全酶複合物。瞭解三種不同的D型週期蛋白如何作為環境感受器動態地因應於各種細胞類型中之細胞外誘因,有助於解釋CDK4/6活性如何差異地受調控,並預測正常細胞及癌細胞中促分裂原信號傳導路徑與CDK4/6活性之間的功能相互作用之基礎。在發現CDK4及CDK6後二十多年,抑制其活性之藥物現在癌症治療中展現顯著功效。Cyclin-dependent kinase 4 (CDK4) and the closely related CDK6 play key roles in mammalian cell proliferation, where these kinases help drive cell progression through the DNA synthesis (S) phase of the cell division cycle. Unlike CDK 1 and 2, which act in response to cycle oscillations of cyclins E, A, and B in late cell cycle to coordinate DNA replication with mitosis, CDK4 and CDK6 interact during the first interval (G1) of the cycle. Enzyme activity is regulated by D-type cyclins that are expressed in response to a variety of extracellular signals, including stimulatory mitogens, inhibitory cytokines, inducers of differentiation, cell-cell contacts, and other steric triggers. Three D-type cyclins (D1, D2 and D3) are differentially expressed individually or in combination in different cell lineages where they assemble with CDK4 and CDK6 to form enzymatically active holoenzyme complexes. Understanding how three distinct D-type cyclins act as environmental sensors dynamically in response to extracellular cues in various cell types helps explain how CDK4/6 activity is differentially regulated and predicts mitogens in normal and cancer cells. Basis for functional interplay between signaling pathways and CDK4/6 activity. More than two decades after the discovery of CDK4 and CDK6, drugs that inhibit their activity are now showing significant efficacy in cancer treatment.

CDK4/6抑制劑作用於G1至S細胞週期檢查點。此檢查點受D型週期蛋白以及CDK4及CDK6嚴格控制。當CDK4及CDK6由D型週期蛋白活化時,其使視網膜母細胞瘤相關蛋白(pRb)磷酸化。此釋放pRb對E2F轉錄因子家族之抑制,且最終容許細胞繼續進行細胞週期並分裂。在HR+乳癌中,週期蛋白D過表現係常見的且pRb丟失罕見,此使得G1至S檢查點成為理想治療靶標。CDK4/6抑制劑阻止通過此檢查點進展,從而導致細胞週期停滯。CDK4/6 inhibitors act on G1 to S cell cycle checkpoints. This checkpoint is tightly controlled by D-type cyclins as well as CDK4 and CDK6. When CDK4 and CDK6 are activated by D-type cyclins, they phosphorylate retinoblastoma-associated protein (pRb). This releases pRb's repression of the E2F family of transcription factors and ultimately allows the cell to proceed through the cell cycle and divide. In HR+ breast cancer, cyclin D overexpression is common and pRb loss is rare, making the G1 to S checkpoint an ideal therapeutic target. CDK4/6 inhibitors prevent progression through this checkpoint, resulting in cell cycle arrest.

儘管有多種療法,但激素受體(HR)陽性之人類表皮生長因子受體2 (HER2)陰性(HR+/HER2-)晚期乳癌很少治愈。HR+/HER2-晚期乳癌之當前治療範式涉及排序內分泌療法、靶向療法及/或化學療法以延長患者壽命、延遲疾病進展及最小化癌症相關之症狀。週期蛋白依賴性激酶4及6 (CDK4/6)抑制劑正在迅速轉變此治療格局。目前有三種CDK4/6抑制劑已獲美國食品藥品管理局(U.S. Food and Drug Administration)批准:帕博西尼(Palbociclib)、瑞博西尼(Ribociclib)及阿貝西尼(Abemaciclib)。Hormone receptor (HR)-positive human epidermal growth factor receptor 2 (HER2)-negative (HR+/HER2-) advanced breast cancer is rarely cured despite multiple therapies. Current treatment paradigms for HR+/HER2- advanced breast cancer involve sequencing endocrine therapy, targeted therapy, and/or chemotherapy to prolong patient life, delay disease progression, and minimize cancer-related symptoms. Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are rapidly changing the treatment landscape. There are currently three CDK4/6 inhibitors approved by the U.S. Food and Drug Administration: Palbociclib, Ribociclib, and Abemaciclib.

CDK4/6抑制劑作為一個類別通常耐受性良好。最常見之全類不良效應包括噁心、腹瀉、疲勞、嗜中性球減少、白血球減少、貧血及血小板減少。帕博西尼及瑞博西尼最常引起嗜中性球減少,而腹瀉係與阿貝西尼相關之獨特胃腸(GI)毒性,有可能係由於阿貝西尼對CDK4之親和力大於CDK6。Shah等人, Oncology (Williston Park), 2018年5月15日; 32(5): 216-222。 CDK4/6 inhibitors as a class are generally well tolerated. The most common class-wide adverse effects included nausea, diarrhea, fatigue, neutropenia, leukopenia, anemia, and thrombocytopenia. Palbociclib and ribociclib most commonly cause neutropenia, while diarrhea is a unique gastrointestinal (GI) toxicity associated with abeciclib, possibly due to abeciclib's higher affinity for CDK4 than CDK6. Shah et al., Oncology (Williston Park) , 2018 May 15; 32(5): 216-222.

美國食品藥品管理局(FDA)警告,用於治療某些患有晚期乳癌之患者之Ibrance (帕博西尼)、Kisqali (瑞博西尼)及Verzenio (阿貝西尼)可能引起罕見但嚴重之肺部發炎。參見USFDA, Drugs Safety Communications,日期2019年9月13日,標題為「FDA warns about rare severe lung inflammation-Ibrance, Kisqali and Verzeni breast cancer」。The U.S. Food and Drug Administration (FDA) warns that Ibrance (palbociclib), Kisqali (ribociclib), and Verzenio (abeciclib), used to treat certain patients with advanced breast cancer, may cause rare but serious Inflammation of the lungs. See USFDA, Drugs Safety Communications, dated September 13, 2019, titled "FDA warns about rare severe lung inflammation-Ibrance, Kisqali and Verzeni breast cancer."

與CDK抑制劑有關之專利文獻包括且不限於國際公開案第WO 2000/064900號、第WO 2000/035908號、第WO 2004/031158號、第WO 2004/046130號、第WO 2004/101549號、第WO 2005/111019號、第WO 2006/105386號、第WO 2006/040050號、第WO 2006/040036號、第WO 2006/002828號、第WO 2006/040052號、第WO 2018/033815號、第WO 2020/223558號、第WO 2020/205560號、第WO 2020/180959號、第WO 2020/168197號、第WO 2020/157652號、第WO 2020/223469號、第WO 2021/072232號、第WO 2021/030537號、第WO 2021/170076號、第WO 2021/073593號、第WO 2019/161224號、第WO 2019/148161號、第WO 2019/170055號、第WO 2019/222521號、第WO 2019/035008號、第WO 2018/106870號、第WO 2018/108167號、第WO 2018/113771號、第WO 2018/045957號、第WO 2018/081211號、第WO 2018/081204號、第WO 2017/020065號、第WO 2017/114512號、第WO 2017/177836號、第WO 2017/177837號、第WO 2017/114351號、第WO 2017/133701號、第WO 2017/193872號、第WO 2017/041535號、第WO 2017/054484號、第WO 2016/058501號、第WO 2016/141881號、第WO 2016/194831號、第WO 2016/014904號、第WO 2016/015597號、第WO 2015/101293號、第WO 2015/180642號、第WO 2014/183520號、第WO 2011/101417號、第WO 2011/101409號、第WO 2010/132725號、第WO 2009/061345號、第WO 2006/008874號、第WO 2002/002550號、第WO 2021/030623號、第WO 2019/161224號,其中每一者出於所有目的均係以全文引用的方式併入本文中。Pfizer開發之CDK 2/4/6抑制劑PF-06873600 (WO 2018/033815)對CDK 2/4/6同種型具有選擇性。Patent documents related to CDK inhibitors include, but are not limited to, International Publication Nos. WO 2000/064900, WO 2000/035908, WO 2004/031158, WO 2004/046130, WO 2004/101549, WO 2005/111019, WO 2006/105386, WO 2006/040050, WO 2006/040036, WO 2006/002828, WO 2006/040052, WO 2018/033815, WO 2020/223558, WO 2020/205560, WO 2020/180959, WO 2020/168197, WO 2020/157652, WO 2020/223469, WO 2021/072232, WO 2021/030537, WO 2021/170076, WO 2021/073593, WO 2019/161224, WO 2019/148161, WO 2019/170055, WO 2019/222521, WO 2019 /035008, WO 2018/106870, WO 2018/108167, WO 2018/113771, WO 2018/045957, WO 2018/081211, WO 2018/081204, WO 2017/ 020065, WO 2017/114512, WO 2017/177836, WO 2017/177837, WO 2017/114351, WO 2017/133701, WO 2017/193872, WO 2017/041535 No., WO 2017/054484, WO 2016/058501, WO 2016/141881, WO 2016/194831, WO 2016/014904, WO 2016/015597, WO 2015/101293 , WO 2015/180642, WO 2014/183520, WO 2011/101417, WO 2011/101409, WO 2010/132725, WO 2009/061345, WO 2006/008874, WO 2002/002550, WO 2021/030623, WO 20 19/161224, each of which is hereby incorporated by reference in its entirety for all purposes. The CDK 2/4/6 inhibitor PF-06873600 (WO 2018/033815) developed by Pfizer is selective for CDK 2/4/6 isoforms.

業內仍持續需要對CDK1、CDK2及/或CDK4/6 (諸如對CDK2及/或CDK4/6)具有活性之CDK抑制劑,以供治療與細胞增殖相關之各種疾病及病症,諸如癌症。There remains a continuing need for CDK inhibitors having activity against CDK1, CDK2 and/or CDK4/6, such as against CDK2 and/or CDK4/6, for the treatment of various diseases and disorders associated with cell proliferation, such as cancer.

本發明係關於式 (I)化合物、其製備方法、含有其之醫藥組合物及使用該等化合物之治療方法。特定而言,該等式 (I)化合物及其醫藥學上可接受之鹽可用於治療、預防及/或改善與CDK1、CDK2及/或CDK4/6相關之疾病或病症。 The present invention relates to compounds of formula (I) , processes for their preparation, pharmaceutical compositions containing them and methods of treatment using these compounds. Specifically, the compounds of the formula (I) and pharmaceutically acceptable salts thereof can be used to treat, prevent and/or improve diseases or conditions related to CDK1, CDK2 and/or CDK4/6.

在一態樣中,本發明係關於式 (I)化合物:

Figure 02_image001
(I)或其互變異構物、其前藥、其N-氧化物、其立體異構物、其醫藥學上可接受之酯或其醫藥學上可接受之鹽, 其中 Y 1選自CR a或N; Y 2選自CR b或N;條件係Y 1及Y 2中之至少一者為N; R a、R b、R c、R d、R e、R f及R g在每次出現時獨立地選自氫、鹵素、羥基、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之鹵烷基、經取代或未經取代之烷氧基、經取代或未經取代之胺基烷基、經取代或未經取代之羥基烷基、經取代或未經取代之環烷基、經取代或未經取代之環烷基烷基、經取代或未經取代之雜環基或經取代或未經取代之雜環基烷基; Y選自CR h或N; Z選自CR i或N;條件係Y及Z中之至少一者為N; R h及R i在每次出現時獨立地選自氫、鹵素、經取代或未經取代之C (1-3)烷基或經取代或未經取代之C (1-3)鹵烷基; X 1選自CR 1或N; X 2選自CR 2或N; X 3選自CR 3或N; X 4選自CR 4或N; R 1、R 2、R 3、R 4、R 5及R 6在每次出現時獨立地選自氫、鹵素、羥基、經取代或未經取代之烷基、經取代或未經取代之鹵烷基、經取代或未經取代之烷氧基、經取代或未經取代之環烷基、經取代或未經取代之環烷基烷基、經取代或未經取代之雜環基或經取代或未經取代之雜環基烷基; L為不存在、NH、O、-S-、-SO-、-SO 2-、-C(=O)-或經取代或未經取代之烷基; 環A為經取代或未經取代之雜環基環; R 7在每次出現時獨立地選自氫、羥基、鹵素、經取代或未經取代之烷基、經取代或未經取代之烷氧基、經取代或未經取代之烯基、經取代或未經取代之炔基、經取代或未經取代之環烷基、經取代或未經取代之環烯基、經取代或未經取代之環烷基烷基、經取代或未經取代之環烯基烷基、經取代或未經取代之雜環基、經取代或未經取代之雜環基烷基、經取代或未經取代之芳基、經取代或未經取代之芳基烷基、經取代或未經取代之雜芳基、經取代或未經取代之雜芳基烷基、側氧基(=O)、-C(=O)OR z、-C(=O)R z、-C(=S)R z、-C(=O)NR zR z、-C(=O)ONR zR z、-NR zR z、-NR zC(=O)NR zR z、-NR zS(=O)R z、-NR zS(=O) 2R z、-N=NR z、-NR zC(=O)OR z、-NR zC(=O)R z、-NR xC(=S)R y、-NR zC(=S)NR zR z、-SONR zR z、-SO 2NR zR z、-OR z、-OC(=O)NR zR z、-OC(=O)OR z、-OC(=O)R z、-OC(=O)NR zR z、-CR xR y-NR zC(=O)R z、-CR xR y-OR z、-CR xR y-C(=O)OR z、-CR xR y-C(=O)NR zR z、-CR xR y-OC(=O)R z、-SR z、-SOR z、-SO 2R z、-CR xR yC(=O)R z或-CR xR yC(=S)R z; R z選自氫、經取代或未經取代之烷基、經取代或未經取代之烷氧基、經取代或未經取代之烯基、經取代或未經取代之炔基、經取代或未經取代之芳基、經取代或未經取代之芳基烷基、經取代或未經取代之雜芳基、經取代或未經取代之雜芳基烷基、經取代或未經取代之環烷基、經取代或未經取代之環烷基烷基、經取代或未經取代之環烯基、經取代或未經取代之雜環基、經取代之雜環基烷基或經取代或未經取代之胺基,或任兩個R z在結合至共用原子時可連結以形成(i)經取代或未經取代之飽和或不飽和3員至14員環,其可視情況包括一或多個雜原子,該(等)雜原子可相同或不同且選自O、NR za及S,或(ii) 側氧基(=O)、硫基(=S)或亞胺基(=NR za);其中R za、R x及R y在每次出現時獨立地選自 氫、鹵基、羥基、胺基、烷氧基、C 1-5烷基、C 3-7環烷基、C 5-7芳基、 C 5-7雜芳基或C 3-7雜環烷基;且 n為選自0、1、2、3及4之整數。 In one aspect, the present invention relates to compounds of formula (I) :
Figure 02_image001
(I) or its tautomer, its prodrug, its N - oxide, its stereoisomer, its pharmaceutically acceptable ester or its pharmaceutically acceptable salt, wherein Y is selected from CR a or N; Y 2 is selected from CR b or N; proviso that at least one of Y 1 and Y 2 is N; R a , R b , R c , R d , Re , R f and R g are in each The second occurrence is independently selected from hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted Alkoxy, substituted or unsubstituted aminoalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkane group, substituted or unsubstituted heterocyclyl or substituted or unsubstituted heterocyclylalkyl; Y is selected from CR h or N; Z is selected from CR i or N; the proviso is that at least one of Y and Z One is N; R h and R i are independently selected from each occurrence of hydrogen, halogen, substituted or unsubstituted C (1-3) alkyl or substituted or unsubstituted C ( 1-3) 3) Haloalkyl; X 1 is selected from CR 1 or N; X 2 is selected from CR 2 or N; X 3 is selected from CR 3 or N; X 4 is selected from CR 4 or N; R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen, halogen, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted Substituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heterocyclic L is absent, NH, O, -S-, -SO-, -SO 2 -, -C(=O)-, or substituted or unsubstituted alkyl; Ring A is substituted or Unsubstituted heterocyclyl ring ; each occurrence of R is independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or Unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkane substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, Substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, side oxy (=O), -C(=O)OR z , -C(=O)R z , -C(=S)R z , -C(=O)NR z R z , -C(=O)ONR z R z , -NR z R z , -NR z C(=O)NR z R z , -NR z S(=O)R z , -NR z S(=O) 2 R z , -N=N R z , -NR z C(=O)OR z , -NR z C(=O)R z , -NR x C(=S)R y , -NR z C(=S)NR z R z , - SONR z R z , -SO 2 NR z R z , -OR z , -OC(=O)NR z R z , -OC(=O)OR z , -OC(=O)R z , -OC(= O)NR z R z , -CR x R y -NR z C(=O)R z , -CR x R y -OR z , -CR x R y -C(=O)OR z , -CR x R y -C(=O)NR z R z , -CR x R y -OC(=O)R z , -SR z , -SOR z , -SO 2 R z , -CR x R y C(=O) R z or -CR x R y C (= S) R z ; R z is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted Alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted Substituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted A heterocyclyl group, a substituted heterocyclylalkyl group or a substituted or unsubstituted amino group, or any two R z may be linked when bound to a common atom to form (i) a substituted or unsubstituted A saturated or unsaturated 3- to 14-membered ring, which optionally includes one or more heteroatoms, the (etc) heteroatoms may be the same or different and are selected from O, NR za and S, or (ii) side oxy ( =O), thio (=S) or imino (=NR za ); wherein R za , R x and R y are independently selected from each occurrence of hydrogen, halo, hydroxyl, amine, alkoxy base, C 1-5 alkyl, C 3-7 cycloalkyl, C 5-7 aryl, C 5-7 heteroaryl or C 3-7 heterocycloalkyl; and n is selected from 0, 1, Integers of 2, 3 and 4.

另一較佳者係式 (I)化合物,其中X 1、X 2、X 3及X 4獨立地選自CH或N。 Another preferred compound is the compound of formula (I) , wherein X 1 , X 2 , X 3 and X 4 are independently selected from CH or N.

另一較佳者係式 (I)化合物,其中X 1及X 2為N。 Another preferred compound is the compound of formula (I) , wherein X 1 and X 2 are N.

另一較佳者係式 (I)化合物,其中X 1為N。 Another preferred compound is the compound of formula (I) , wherein X 1 is N.

另一較佳者係式 (I)化合物,其中X 2、X 3及X 4為CH。 Another preferred compound is the compound of formula (I) , wherein X 2 , X 3 and X 4 are CH.

另一較佳者係式 (I)化合物,其中Y及Z獨立地選自CH或N。 Another preferred compound is a compound of formula (I) , wherein Y and Z are independently selected from CH or N.

另一較佳者係式 (I)化合物,其中Y及Z為N。 Another preferred compound is the compound of formula (I) , wherein Y and Z are N.

在另一態樣中,本發明係關於式 (IA)(IB)(IC)(ID)化合物:

Figure 02_image004
Figure 02_image006
(IA)                                                          (IB)
Figure 02_image008
Figure 02_image010
(IC)                                                            (ID)或其互變異構物、其前藥、其N-氧化物、其立體異構物、其醫藥學上可接受之酯或其醫藥學上可接受之鹽, 其中所有變數(包括環A、L、R 5、R 6、R 7、R c、R d、R e、R f、R g、Y 1、Y 2及n)係如上文關於式 (I)化合物所定義。 In another aspect, the present invention relates to compounds of formula (IA) , (IB) , (IC) or (ID) :
Figure 02_image004
Figure 02_image006
(IA) (IB)
Figure 02_image008
Figure 02_image010
(IC) (ID) or its tautomers, its prodrugs, its N-oxides, its stereoisomers, its pharmaceutically acceptable esters or its pharmaceutically acceptable salts, wherein all variables (including rings A, L, R 5 , R 6 , R 7 , R c , R d , Re , R f , R g , Y 1 , Y 2 and n) are as defined above for compounds of formula (I) .

另一較佳者係式 (I)(IA)(IB)(IC)(ID)化合物,其中環A選自

Figure 02_image012
Figure 02_image013
另一較佳者係式 (I)(IB)(ID)化合物,其中L為不存在或CH 2。 Another preferred compound is a compound of formula (I) , (IA) , (IB) , (IC) or (ID) , wherein ring A is selected from
Figure 02_image012
Figure 02_image013
Another preferred is a compound of formula (I) , (IB) or (ID) , wherein L is absent or CH2 .

另一較佳者係式 (I)(IB)(ID)化合物,其中L為不存在。 Another preferred compound is a compound of formula (I) , (IB) or (ID) , wherein L is absent.

另一較佳者係式 (I)(IB)(ID)化合物,其中L為CH 2Another preferred compound is a compound of formula (I) , (IB) or (ID) , wherein L is CH 2 .

另一較佳者係式 (I)(IA)(IB)(IC)(ID)化合物,其中R 5為氫或鹵素。 Another preferred compound is a compound of formula (I) , (IA) , (IB) , (IC) or (ID) , wherein R 5 is hydrogen or halogen.

另一較佳者係式 (I)(IA)(IB)(IC)(ID)化合物,其中R 5為氫或氟。 Another preferred compound is a compound of formula (I) , (IA) , (IB) , (IC) or (ID) , wherein R 5 is hydrogen or fluorine.

另一較佳者係式 (I)(IA)(IB)(IC)(ID)化合物,其中R 6為氫。 Another preferred compound is a compound of formula (I) , (IA) , (IB) , (IC) or (ID) , wherein R 6 is hydrogen.

另一較佳者係式 (I)(IA)(IB)(IC)(ID)化合物,其中Y 1為N。 Another preferred compound is a compound of formula (I) , (IA) , (IB) , (IC) or (ID) , wherein Y 1 is N.

另一較佳者係式 (IA)(IB)(IC)(ID)化合物,其中R 7為烷基(例如甲基、乙基或異丙基)、羥基(-OH)、側氧基(=O)、-N(R z)R z(例如-N(CH 3) 2)、環烷基(例如環丙基)、乙醯基(-C(O)CH 3)、鹵烷基(例如-CF 3或-CH 2CF 3)、磺醯基烷基(例如-SO 2Me)、-C(O)環烷基(例如-C(O)環丙基)或-C(=O)OR z(例如-C(=O)O-第三丁基),且n為整數1或2。 Another preferred compound is formula (IA) , (IB) , (IC) or (ID) , wherein R 7 is an alkyl group (such as methyl, ethyl or isopropyl), hydroxyl (-OH), side Oxy (=O), -N(R z )R z (eg -N(CH 3 ) 2 ), cycloalkyl (eg cyclopropyl), acetyl (-C(O)CH 3 ), halo Alkyl (eg -CF 3 or -CH 2 CF 3 ), sulfonylalkyl (eg -SO 2 Me), -C(O)cycloalkyl (eg -C(O)cyclopropyl) or -C (=O)OR z (eg -C(=O)O-tert-butyl), and n is an integer 1 or 2.

另一較佳者係式 (I)(IA)(IB)(IC)(ID)化合物,其中n為1或2。 Another preferred compound is a compound of formula (I) , (IA) , (IB) , (IC) or (ID) , wherein n is 1 or 2.

另一較佳者係式 (I)(IA) (IB)(IC) (ID)化合物,其中環

Figure 02_image015
選自
Figure 02_image017
Another preferred compound is formula (I) , (IA) , (IB) , (IC) or (ID) , wherein ring
Figure 02_image015
selected from
Figure 02_image017

本發明之代表性化合物包括下文所指定之彼等化合物及其醫藥學上可接受之鹽。本發明不應解釋為限於彼等化合物及其醫藥學上可接受之鹽。Representative compounds of the present invention include those designated hereinafter and pharmaceutically acceptable salts thereof. The present invention should not be construed as being limited to these compounds and pharmaceutically acceptable salts thereof.

4-(6-((5-氟-4-(喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-1-甲酸第三丁基酯; 5-氟-N-(5-(六氫吡嗪-1-基)吡啶-2-基)-4-(喹啉-6-基)嘧啶-2-胺; 5-氟-N-(5-(六氫吡嗪-1-基)吡啶-2-基)-4-(喹啉-6-基)嘧啶-2-胺鹽酸鹽; 4-(6-((5-氟-4-(8-氟喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-1-甲酸第三丁基酯; 5-氟-4-(8-氟喹啉-6-基)-N-(5-(六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺; 5-氟-4-(8-氟喹啉-6-基)-N-(5-(六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺鹽酸鹽; N-(5-((4-乙基六氫吡嗪-1-基)甲基)吡啶-2-基)-5-氟-4-(8-氟喹啉-6-基)嘧啶-2-胺; N-(5-((4-乙基六氫吡嗪-1-基)甲基)吡啶-2-基)-5-氟-4-(8-氟喹啉-6-基)嘧啶-2-胺鹽酸鹽; N-(5-((4-乙基六氫吡嗪-1-基)甲基)吡啶-2-基)-5-氟-4-(喹啉-6-基)嘧啶-2-胺; N-(5-((4-乙基六氫吡嗪-1-基)甲基)吡啶-2-基)-5-氟-4-(喹啉-6-基)嘧啶-2-胺鹽酸鹽; 4-(6-((5-氟-4-(8-氟-2-甲基-4-(丙-1-烯-2-基)喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-1-甲酸第三丁基酯; 5-氟-4-(8-氟-2-甲基-4-(丙-1-烯-2-基)喹啉-6-基)-N-(5-(六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺; 5-氟-4-(8-氟-2-甲基-4-(丙-1-烯-2-基)喹啉-6-基)-N-(5-(六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺鹽酸鹽; 5-氟-N-(5-(4-甲基六氫吡嗪-1-基)吡啶-2-基)-4-(喹啉-6-基)嘧啶-2-胺; 5-氟-N-(5-(4-甲基六氫吡嗪-1-基)吡啶-2-基)-4-(喹啉-6-基)嘧啶-2-胺鹽酸鹽; 5-氟-4-(8-氟喹啉-6-基)-N-(5-(4-甲基六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺; 5-氟-4-(8-氟喹啉-6-基)-N-(5-(4-甲基六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺鹽酸鹽; N-(5-(4-乙基六氫吡嗪-1-基)吡啶-2-基)-5-氟-4-(8-氟喹啉-6-基)嘧啶-2-胺; N-(5-(4-乙基六氫吡嗪-1-基)吡啶-2-基)-5-氟-4-(8-氟喹啉-6-基)嘧啶-2-胺鹽酸鹽; N-(5-((4-乙基六氫吡嗪-1-基)甲基)吡啶-2-基)-5-氟-4-(8-氟-2-甲基喹啉-6-基)嘧啶-2-胺; N-(5-((4-乙基六氫吡嗪-1-基)甲基)吡啶-2-基)-5-氟-4-(8-氟-2-甲基喹啉-6-基)嘧啶-2-胺鹽酸鹽; 4-(6-((5-氟-4-(8-氟-2-甲基喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-1-甲酸第三丁基酯; 5-氟-4-(8-氟-2-甲基喹啉-6-基)-N-(5-(六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺; 5-氟-4-(8-氟-2-甲基喹啉-6-基)-N-(5-(六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺鹽酸鹽; 4-(6-((5-氟-4-(8-氟-4-異丙基-2-甲基喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-1-甲酸第三丁基酯; 5-氟-4-(8-氟-4-異丙基-2-甲基喹啉-6-基)-N-(5-(六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺; 5-氟-4-(8-氟-4-異丙基-2-甲基喹啉-6-基)-N-(5-(六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺鹽酸鹽; N-(5-(4-乙基六氫吡嗪-1-基)吡啶-2-基)-5-氟-4-(喹啉-6-基)嘧啶-2-胺; N-(5-(4-乙基六氫吡嗪-1-基)吡啶-2-基)-5-氟-4-(喹啉-6-基)嘧啶-2-胺鹽酸鹽; 5-氟-4-(8-氟喹啉-6-基)-N-(5-(4-異丙基六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺; 5-氟-4-(8-氟喹啉-6-基)-N-(5-(4-異丙基六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺鹽酸鹽; 5-氟-N-(5-(4-異丙基六氫吡嗪-1-基)吡啶-2-基)-4-(喹啉-6-基)嘧啶-2-胺; 5-氟-N-(5-(4-異丙基六氫吡嗪-1-基)吡啶-2-基)-4-(喹啉-6-基)嘧啶-2-胺鹽酸鹽; 5-氟-4-(8-氟喹啉-6-基)-N-(5-((4-甲基六氫吡嗪-1-基)甲基)吡啶-2-基)嘧啶-2-胺; 5-氟-4-(8-氟喹啉-6-基)-N-(5-((4-甲基六氫吡嗪-1-基)甲基)吡啶-2-基)嘧啶-2-胺鹽酸鹽; 2-(6-(2-((5-((4-乙基六氫吡嗪-1-基)甲基)吡啶-2-基)胺基)-5-氟嘧啶-4-基)-8-氟-2-甲基喹啉-4-基)丙-2-醇; 2-(6-(2-((5-((4-乙基六氫吡嗪-1-基)甲基)吡啶-2-基)胺基)-5-氟嘧啶-4-基)-8-氟-2-甲基喹啉-4-基)丙-2-醇鹽酸鹽; 4-(6-((5-氟-4-(8-氟-4-(2-羥基丙-2-基)-2-甲基喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-1-甲酸第三丁基酯; 2-(8-氟-6-(5-氟-2-((5-(六氫吡嗪-1-基)吡啶-2-基)胺基)嘧啶-4-基)-2-甲基喹啉-4-基)丙-2-醇; 2-(8-氟-6-(5-氟-2-((5-(六氫吡嗪-1-基)吡啶-2-基)胺基)嘧啶-4-基)-2-甲基喹啉-4-基)丙-2-醇鹽酸鹽; 2-(6-(2-((5-(4-乙基六氫吡嗪-1-基)吡啶-2-基)胺基)-5-氟嘧啶-4-基)-8-氟-2-甲基喹啉-4-基)丙-2-醇; 2-(6-(2-((5-(4-乙基六氫吡嗪-1-基)吡啶-2-基)胺基)-5-氟嘧啶-4-基)-8-氟-2-甲基喹啉-4-基)丙-2-醇鹽酸鹽; 4-(4-(二氟甲基)-8-氟-2-甲基喹啉-6-基)-N-(5-(4-乙基六氫吡嗪-1-基)吡啶-2-基)-5-氟嘧啶-2-胺; 4-(4-(二氟甲基)-8-氟-2-甲基喹啉-6-基)-N-(5-(4-乙基六氫吡嗪-1-基)吡啶-2-基)-5-氟嘧啶-2-胺鹽酸鹽; 4-(6-((4-(4-(二氟甲基)-8-氟-2-甲基喹啉-6-基)-5-氟嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-1-甲酸第三丁基酯; 4-(4-(二氟甲基)-8-氟-2-甲基喹啉-6-基)-5-氟-N-(5-(六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺; 4-(4-(二氟甲基)-8-氟-2-甲基喹啉-6-基)-5-氟-N-(5-(六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺鹽酸鹽; 4-(4-(二氟甲基)-8-氟-2-甲基喹啉-6-基)-N-(5-((4-乙基六氫吡嗪-1-基)甲基)吡啶-2-基)-5-氟嘧啶-2-胺; 4-(4-(二氟甲基)-8-氟-2-甲基喹啉-6-基)-N-(5-((4-乙基六氫吡嗪-1-基)甲基)吡啶-2-基)-5-氟嘧啶-2-胺鹽酸鹽; N-(5-((4-乙基六氫吡嗪-1-基)甲基)吡啶-2-基)-5-氟-4-(8-氟-4-(2-氟丙-2-基)-2-甲基喹啉-6-基)嘧啶-2-胺; N-(5-((4-乙基六氫吡嗪-1-基)甲基)吡啶-2-基)-5-氟-4-(8-氟-4-(2-氟丙-2-基)-2-甲基喹啉-6-基)嘧啶-2-胺鹽酸鹽; 4-(6-((5-氟-4-(8-氟-4-(2-氟丙-2-基)-2-甲基喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-1-甲酸第三丁基酯; 5-氟-4-(8-氟-4-(2-氟丙-2-基)-2-甲基喹啉-6-基)-N-(5-(六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺; 5-氟-4-(8-氟-4-(2-氟丙-2-基)-2-甲基喹啉-6-基)-N-(5-(六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺鹽酸鹽; 5-氟-N-(5-((4-甲基六氫吡嗪-1-基)甲基)吡啶-2-基)-4-(喹啉-6-基)嘧啶-2-胺; 5-氟-N-(5-((4-甲基六氫吡嗪-1-基)甲基)吡啶-2-基)-4-(喹啉-6-基)嘧啶-2-胺鹽酸鹽; N-(5-((4-乙基六氫吡嗪-1-基)甲基)吡啶-2-基)-5-氟-4-(7-氟喹啉-6-基)嘧啶-2-胺; N-(5-((4-乙基六氫吡嗪-1-基)甲基)吡啶-2-基)-5-氟-4-(7-氟喹啉-6-基)嘧啶-2-胺鹽酸鹽; 4-(6-((5-氟-4-(7-氟喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-1-甲酸第三丁基酯; 5-氟-4-(7-氟喹啉-6-基)-N-(5-(六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺; 5-氟-4-(7-氟喹啉-6-基)-N-(5-(六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺鹽酸鹽; N-(5-(4-乙基六氫吡嗪-1-基)吡啶-2-基)-5-氟-4-(7-氟喹啉-6-基)嘧啶-2-胺; N-(5-(4-乙基六氫吡嗪-1-基)吡啶-2-基)-5-氟-4-(7-氟喹啉-6-基)嘧啶-2-胺鹽酸鹽; N-(5-(4-(二甲基胺基)六氫吡啶-1-基)吡啶-2-基)-5-氟-4-(8-氟喹啉-6-基)嘧啶-2-胺; N-(5-(4-(二甲基胺基)六氫吡啶-1-基)吡啶-2-基)-5-氟-4-(8-氟喹啉-6-基)嘧啶-2-胺鹽酸鹽; 4-(6-((5-氟-4-(8-氟喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-2-酮; 4-(6-((5-氟-4-(8-氟喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-2-酮鹽酸鹽; N-(5-(4-環丙基六氫吡嗪-1-基)吡啶-2-基)-5-氟-4-(8-氟喹啉-6-基)嘧啶-2-胺; N-(5-(4-環丙基六氫吡嗪-1-基)吡啶-2-基)-5-氟-4-(8-氟喹啉-6-基)嘧啶-2-胺鹽酸鹽; 1-(4-(6-((5-氟-4-(8-氟喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-1-基)乙-1-酮; 1-(4-(6-((5-氟-4-(8-氟喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-1-基)乙-1-酮鹽酸鹽; 5-氟-4-(8-氟喹啉-6-基)-N-(5-(4-(2,2,2-三氟乙基)六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺; 5-氟-4-(8-氟喹啉-6-基)-N-(5-(4-(2,2,2-三氟乙基)六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺鹽酸鹽; 5-氟-4-(8-氟喹啉-6-基)-N-(5-(4-(甲基磺醯基)六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺; 5-氟-4-(8-氟喹啉-6-基)-N-(5-(4-(甲基磺醯基)六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺鹽酸鹽; 環丙基(4-(6-((5-氟-4-(8-氟喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-1-基)甲酮; 環丙基(4-(6-((5-氟-4-(8-氟喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-1-基)甲酮鹽酸鹽; 5-氟-4-(8-氟喹啉-6-基)-N-(5-(3-(三氟甲基)-5,6-二氫-[1,2,4]三唑并[4,3-a]吡嗪-7(8H)-基)吡啶-2-基)嘧啶-2-胺; 5-氟-4-(8-氟喹啉-6-基)-N-(5-(3-(三氟甲基)-5,6-二氫-[1,2,4]三唑并[4,3-a]吡嗪-7(8H)-基)吡啶-2-基)嘧啶-2-胺鹽酸鹽; N-(5-((4-乙基六氫吡嗪-1-基)甲基)吡啶-2-基)-5-氟-4-(8-氟-4-異丙基-2-甲基喹啉-6-基)嘧啶-2-胺; N-(5-((4-乙基六氫吡嗪-1-基)甲基)吡啶-2-基)-5-氟-4-(8-氟-4-異丙基-2-甲基喹啉-6-基)嘧啶-2-胺鹽酸鹽; N-(5-(4-乙基六氫吡嗪-1-基)吡啶-2-基)-5-氟-4-(8-氟-4-異丙基-2-甲基喹啉-6-基)嘧啶-2-胺; N-(5-(4-乙基六氫吡嗪-1-基)吡啶-2-基)-5-氟-4-(8-氟-4-異丙基-2-甲基喹啉-6-基)嘧啶-2-胺鹽酸鹽; 1-(6-((5-氟-4-(8-氟喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)-4-甲基六氫吡啶-4-醇; 1-(6-((5-氟-4-(8-氟喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)-4-甲基六氫吡啶-4-醇鹽酸鹽; (±)-4-(6-((4-(4-(1-((第三丁氧基羰基)胺基)乙基)-8-氟-2-甲基喹啉-6-基)-5-氟嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-1-甲酸第三丁基酯; (±)-4-(4-(1-胺基乙基)-8-氟-2-甲基喹啉-6-基)-5-氟-N-(5-(六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺; (±)-4-(4-(1-胺基乙基)-8-氟-2-甲基喹啉-6-基)-5-氟-N-(5-(六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺鹽酸鹽; (±)-4-(6-((4-(4-(1-((第三丁氧基羰基)胺基)乙基)-8-氟喹啉-6-基)-5-氟嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-1-甲酸第三丁基酯; (±)-4-(4-(1-胺基乙基)-8-氟喹啉-6-基)-5-氟-N-(5-(六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺; (±)-4-(4-(1-胺基乙基)-8-氟喹啉-6-基)-5-氟-N-(5-(六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺二鹽酸鹽; (±)-4-(6-((5-氟-4-(8-氟-4-(1-羥基乙基)喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-1-甲酸第三丁基酯; (±)-1-(8-氟-6-(5-氟-2-((5-(六氫吡嗪-1-基)吡啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)乙醇; (±)-1-(8-氟-6-(5-氟-2-((5-(六氫吡嗪-1-基)吡啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)乙醇三甲磺酸鹽; (±)-(1-(8-氟-6-(5-氟-2-((5-(4-甲基六氫吡嗪-1-基)吡啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)乙基)胺基甲酸第三丁基酯; (±)-4-(4-(1-胺基乙基)-8-氟喹啉-6-基)-5-氟-N-(5-(4-甲基六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺; (±)-4-(4-(1-胺基乙基)-8-氟喹啉-6-基)-5-氟-N-(5-(4-甲基六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺三鹽酸鹽; (±)-1-(6-(2-((5-(4-乙基六氫吡嗪-1-基)吡啶-2-基)胺基)-5-氟嘧啶-4-基)-8-氟喹啉-4-基)乙醇; (±)-1-(6-(2-((5-(4-乙基六氫吡嗪-1-基)吡啶-2-基)胺基)-5-氟嘧啶-4-基)-8-氟喹啉-4-基)乙醇三鹽酸鹽; (±)-1-(8-氟-6-(5-氟-2-((5-(4-異丙基六氫吡嗪-1-基)吡啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)乙醇; (±)-1-(8-氟-6-(5-氟-2-((5-(4-異丙基六氫吡嗪-1-基)吡啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)乙醇三鹽酸鹽; N-(5-(4-乙基六氫吡嗪-1-基)吡啶-2-基)-5-氟-4-(8-氟-2-甲基喹啉-6-基)嘧啶-2-胺; N-(5-(4-乙基六氫吡嗪-1-基)吡啶-2-基)-5-氟-4-(8-氟-2-甲基喹啉-6-基)嘧啶-2-胺鹽酸鹽; (±)-4-(6-((5-氟-4-(8-氟-4-(1-羥基乙基)-2-甲基喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-1-甲酸第三丁基酯; (±)-1-(8-氟-6-(5-氟-2-((5-(六氫吡嗪-1-基)吡啶-2-基)胺基)嘧啶-4-基)-2-甲基喹啉-4-基)乙醇; (±)-1-(8-氟-6-(5-氟-2-((5-(六氫吡嗪-1-基)吡啶-2-基)胺基)嘧啶-4-基)-2-甲基喹啉-4-基)乙-1-醇鹽酸鹽; (±)-1-(8-氟-6-(5-氟-2-((5-(4-甲基六氫吡嗪-1-基)吡啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)乙醇; (±)-1-(8-氟-6-(5-氟-2-((5-(4-甲基六氫吡嗪-1-基)吡啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)乙醇三鹽酸鹽; 4-(6-((5-氟-4-(8-氟-4-(2-羥基丙-2-基)喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-1-甲酸第三丁基酯; 2-(8-氟-6-(5-氟-2-((5-(六氫吡嗪-1-基)吡啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)丙-2-醇; 2-(8-氟-6-(5-氟-2-((5-(六氫吡嗪-1-基)吡啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)丙-2-醇; (±)-4-(6-((5-氟-4-(8-氟-4-(1-羥基乙基)喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-1-甲酸第三丁基酯; (±)-1-(8-氟-6-(5-氟-2-((5-(六氫吡嗪-1-基)吡啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)乙醇; (±)-1-(8-氟-6-(5-氟-2-((5-(六氫吡嗪-1-基)吡啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)乙醇三鹽酸鹽; (±)-4-(6-((5-氟-4-(8-氟-4-(1-羥基乙基)喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡啶-1-甲酸第三丁基酯; (±)-1-(8-氟-6-(5-氟-2-((5-(六氫吡啶-4-基)吡啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)乙醇; (±)-1-(8-氟-6-(5-氟-2-((5-(六氫吡啶-4-基)吡啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)乙醇三鹽酸鹽; 4-(6-((5-氟-4-(8-氟-4-(2-羥基丙-2-基)喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡啶-1-甲酸第三丁基酯; 2-(8-氟-6-(5-氟-2-((5-(六氫吡啶-4-基)吡啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)丙-2-醇; 2-(8-氟-6-(5-氟-2-((5-(六氫吡啶-4-基)吡啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)丙-2-醇三鹽酸鹽; 4-(6-((5-氟-4-(8-氟-4-(2-羥基丙-2-基)-2-甲基喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡啶-1-甲酸第三丁基酯; 2-(8-氟-6-(5-氟-2-((5-(六氫吡啶-4-基)吡啶-2-基)胺基)嘧啶-4-基)-2-甲基喹啉-4-基)丙-2-醇; 2-(8-氟-6-(5-氟-2-((5-(六氫吡啶-4-基)吡啶-2-基)胺基)嘧啶-4-基)-2-甲基喹啉-4-基)丙-2-醇三鹽酸鹽; (±)-4-(6-((5-氟-4-(8-氟-4-(1-羥基乙基)-2-甲基喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡啶-1-甲酸第三丁基酯; (±)-1-(8-氟-6-(5-氟-2-((5-(六氫吡啶-4-基)吡啶-2-基)胺基)嘧啶-4-基)-2-甲基喹啉-4-基)乙醇; (±)-1-(8-氟-6-(5-氟-2-((5-(六氫吡啶-4-基)吡啶-2-基)胺基)嘧啶-4-基)-2-甲基喹啉-4-基)乙醇三鹽酸鹽; 4-(2-((5-氟-4-(8-氟-4-(2-羥基丙-2-基)喹啉-6-基)嘧啶-2-基)胺基)嘧啶-5-基)六氫吡啶-1-甲酸第三丁基酯; 2-(8-氟-6-(5-氟-2-((5-(六氫吡啶-4-基)嘧啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)丙-2-醇; 2-(8-氟-6-(5-氟-2-((5-(六氫吡啶-4-基)嘧啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)丙-2-醇三鹽酸鹽; (±)-4-(2-((5-氟-4-(8-氟-4-(1-羥基乙基)喹啉-6-基)嘧啶-2-基)胺基)嘧啶-5-基)六氫吡啶-1-甲酸第三丁基酯; (±)-1-(8-氟-6-(5-氟-2-((5-(六氫吡啶-4-基)嘧啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)乙醇; (±)-1-(8-氟-6-(5-氟-2-((5-(六氫吡啶-4-基)嘧啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)乙醇三鹽酸鹽; 2-(8-氟-6-(5-氟-2-((5-(1-甲基六氫吡啶-4-基)吡啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)丙-2-醇; 2-(8-氟-6-(5-氟-2-((5-(1-甲基六氫吡啶-4-基)吡啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)丙-2-醇三鹽酸鹽; (±)-1-(8-氟-6-(5-氟-2-((5-(1-甲基六氫吡啶-4-基)吡啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)乙醇; (±)-1-(8-氟-6-(5-氟-2-((5-(1-甲基六氫吡啶-4-基)吡啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)乙醇三鹽酸鹽; (±)-4-(6-((4-(4-(1-((第三丁氧基羰基)胺基)乙基)-8-氟喹啉-6-基)-5-氟嘧啶-2-基)胺基)吡啶-3-基)六氫吡啶-1-甲酸第三丁基酯; (±)-4-(4-(1-胺基乙基)-8-氟喹啉-6-基)-5-氟-N-(5-(六氫吡啶-4-基)吡啶-2-基)嘧啶-2-胺;及 (±)-4-(4-(1-胺基乙基)-8-氟喹啉-6-基)-5-氟-N-(5-(六氫吡啶-4-基)吡啶-2-基)嘧啶-2-胺三鹽酸鹽; 及其醫藥學上可接受之鹽。 tert-butyl 4-(6-((5-fluoro-4-(quinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazine-1-carboxylate; 5-fluoro-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)-4-(quinolin-6-yl)pyrimidin-2-amine; 5-fluoro-N-(5 -(Hexahydropyrazin-1-yl)pyridin-2-yl)-4-(quinolin-6-yl)pyrimidin-2-amine hydrochloride; 4-(6-((5-fluoro-4- (8-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazine-1-carboxylic acid tert-butyl ester; 5-fluoro-4-(8-fluoro Quinoline-6-yl)-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine; 5-fluoro-4-(8-fluoroquinoline-6- Base)-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine hydrochloride; N-(5-((4-ethylhexahydropyrazine-1 -yl)methyl)pyridin-2-yl)-5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-amine; N-(5-((4-ethylhexahydropyridine Oxazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-amine hydrochloride; N-(5-((4 -ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(quinolin-6-yl)pyrimidin-2-amine; N-(5-((4 -Ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(quinolin-6-yl)pyrimidin-2-amine hydrochloride; 4-(6- ((5-fluoro-4-(8-fluoro-2-methyl-4-(prop-1-en-2-yl)quinolin-6-yl)pyrimidin-2-yl)amino)pyridine-3 - Base) tertiary butyl hexahydropyrazine-1-carboxylate; 5-fluoro-4-(8-fluoro-2-methyl-4-(prop-1-en-2-yl) quinoline-6 -yl)-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine; 5-fluoro-4-(8-fluoro-2-methyl-4-( Prop-1-en-2-yl)quinolin-6-yl)-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine hydrochloride; 5- Fluoro-N-(5-(4-methylhexahydropyrazin-1-yl)pyridin-2-yl)-4-(quinolin-6-yl)pyrimidin-2-amine; 5-fluoro-N- (5-(4-methylhexahydropyrazin-1-yl)pyridin-2-yl)-4-(quinolin-6-yl)pyrimidin-2-amine hydrochloride; 5-fluoro-4-( 8-fluoroquinolin-6-yl)-N-(5-(4-methylhexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine; 5-fluoro-4-(8 -Fluoroquinolin-6-yl)-N-(5-(4-methylhexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine hydrochloride; N-(5-( 4-Ethylhexahydropyrazin-1-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-amine; N-(5-(4-ethylhexahydropyrazin-1-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-amine hydrochloride Salt; N-(5-((4-ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-2-methylquinoline- 6-yl)pyrimidin-2-amine; N-(5-((4-ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(8-fluoro -2-methylquinolin-6-yl)pyrimidin-2-amine hydrochloride; 4-(6-((5-fluoro-4-(8-fluoro-2-methylquinolin-6-yl) Pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazine-1-carboxylic acid tert-butyl ester; 5-fluoro-4-(8-fluoro-2-methylquinolin-6-yl )-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine; 5-fluoro-4-(8-fluoro-2-methylquinolin-6-yl )-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine hydrochloride; 4-(6-((5-fluoro-4-(8-fluoro- 4-isopropyl-2-methylquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazine-1-carboxylic acid tert-butyl ester; 5-fluoro- 4-(8-fluoro-4-isopropyl-2-methylquinolin-6-yl)-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)pyrimidine-2- Amine; 5-fluoro-4-(8-fluoro-4-isopropyl-2-methylquinolin-6-yl)-N-(5-(hexahydropyrazin-1-yl)pyridine-2- Base) pyrimidin-2-amine hydrochloride; N-(5-(4-ethylhexahydropyrazin-1-yl)pyridin-2-yl)-5-fluoro-4-(quinolin-6-yl ) pyrimidine-2-amine; N-(5-(4-ethylhexahydropyrazin-1-yl)pyridin-2-yl)-5-fluoro-4-(quinolin-6-yl)pyrimidine-2 -Amine hydrochloride; 5-fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(4-isopropylhexahydropyrazin-1-yl)pyridin-2-yl) Pyrimidin-2-amine; 5-fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(4-isopropylhexahydropyrazin-1-yl)pyridin-2-yl) Pyrimidin-2-amine hydrochloride; 5-fluoro-N-(5-(4-isopropylhexahydropyrazin-1-yl)pyridin-2-yl)-4-(quinolin-6-yl) Pyrimidin-2-amine; 5-fluoro-N-(5-(4-isopropylhexahydropyrazin-1-yl)pyridin-2-yl)-4-(quinolin-6-yl)pyrimidine-2 -Amine hydrochloride; 5-fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-((4-methylhexahydropyrazin-1-yl)methyl)pyridine-2 -yl)pyrimidin-2-amine; 5-fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-((4-methylhexahydropyrazin-1-yl)methyl) Pyridin-2-yl)pyrimidin-2-amine hydrochloride; 2-(6-(2-((5-((4-ethylhexahydropyrazin-1-yl)methyl)pyridine -2-yl)amino)-5-fluoropyrimidin-4-yl)-8-fluoro-2-methylquinolin-4-yl)propan-2-ol; 2-(6-(2-(( 5-((4-Ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-8-fluoro-2-methylquinoline -4-yl)propan-2-ol hydrochloride; 4-(6-((5-fluoro-4-(8-fluoro-4-(2-hydroxypropan-2-yl)-2-methylquin Lin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazine-1-carboxylic acid tert-butyl ester; 2-(8-fluoro-6-(5-fluoro-2 -((5-(Hexahydropyrazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylquinolin-4-yl)propan-2-ol; 2- (8-fluoro-6-(5-fluoro-2-((5-(hexahydropyrazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylquinoline -4-yl)propan-2-ol hydrochloride; 2-(6-(2-((5-(4-ethylhexahydropyrazin-1-yl)pyridin-2-yl)amino)- 5-fluoropyrimidin-4-yl)-8-fluoro-2-methylquinolin-4-yl)propan-2-ol; 2-(6-(2-((5-(4-ethylhexahydro Pyrazin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-8-fluoro-2-methylquinolin-4-yl)propan-2-ol hydrochloride ; 4-(4-(Difluoromethyl)-8-fluoro-2-methylquinolin-6-yl)-N-(5-(4-ethylhexahydropyrazin-1-yl)pyridine- 2-yl)-5-fluoropyrimidin-2-amine; 4-(4-(difluoromethyl)-8-fluoro-2-methylquinolin-6-yl)-N-(5-(4- Ethylhexahydropyrazin-1-yl)pyridin-2-yl)-5-fluoropyrimidin-2-amine hydrochloride; 4-(6-((4-(4-(difluoromethyl)-8 -Fluoro-2-methylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazine-1-carboxylic acid tert-butyl ester; 4-( 4-(Difluoromethyl)-8-fluoro-2-methylquinolin-6-yl)-5-fluoro-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl) Pyrimidin-2-amine; 4-(4-(difluoromethyl)-8-fluoro-2-methylquinolin-6-yl)-5-fluoro-N-(5-(hexahydropyrazine-1 -yl)pyridin-2-yl)pyrimidin-2-amine hydrochloride; 4-(4-(difluoromethyl)-8-fluoro-2-methylquinolin-6-yl)-N-(5 -((4-ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-5-fluoropyrimidin-2-amine; 4-(4-(difluoromethyl)-8-fluoro -2-methylquinolin-6-yl)-N-(5-((4-ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-5-fluoropyrimidine-2- Amine hydrochloride; N-(5-((4-ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-4-(2 -Fluoropropane-2 -yl)-2-methylquinolin-6-yl)pyrimidin-2-amine; N-(5-((4-ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl) -5-fluoro-4-(8-fluoro-4-(2-fluoroprop-2-yl)-2-methylquinolin-6-yl)pyrimidin-2-amine hydrochloride; 4-(6- ((5-fluoro-4-(8-fluoro-4-(2-fluoroprop-2-yl)-2-methylquinolin-6-yl)pyrimidin-2-yl)amino)pyridine-3- Base) tert-butyl hexahydropyrazine-1-carboxylate; 5-fluoro-4-(8-fluoro-4-(2-fluoroprop-2-yl)-2-methylquinolin-6-yl )-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine; 5-fluoro-4-(8-fluoro-4-(2-fluoropropane-2- Base)-2-methylquinolin-6-yl)-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine hydrochloride; 5-fluoro-N -(5-((4-methylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-4-(quinolin-6-yl)pyrimidin-2-amine; 5-fluoro-N -(5-((4-methylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-4-(quinolin-6-yl)pyrimidin-2-amine hydrochloride; N- (5-((4-Ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(7-fluoroquinolin-6-yl)pyrimidin-2-amine ; N-(5-((4-ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(7-fluoroquinolin-6-yl)pyrimidine- 2-amine hydrochloride; 4-(6-((5-fluoro-4-(7-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazine - tert-butyl 1-carboxylate; 5-fluoro-4-(7-fluoroquinolin-6-yl)-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)pyrimidine -2-amine; 5-fluoro-4-(7-fluoroquinolin-6-yl)-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)pyrimidine-2-amine salt acid salt; N-(5-(4-ethylhexahydropyrazin-1-yl)pyridin-2-yl)-5-fluoro-4-(7-fluoroquinolin-6-yl)pyrimidine-2- Amine; N-(5-(4-ethylhexahydropyrazin-1-yl)pyridin-2-yl)-5-fluoro-4-(7-fluoroquinolin-6-yl)pyrimidin-2-amine Hydrochloride; N-(5-(4-(dimethylamino)hexahydropyridin-1-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoroquinolin-6-yl ) pyrimidine-2-amine; N-(5-(4-(dimethylamino)hexahydropyridin-1-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoroquinoline- 6-yl)pyrimidin-2-amine hydrochloride; 4-(6-((5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridine-3- Base) hexahydropyrazin-2-one; 4-(6-((5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridine Pyridin-3-yl)hexahydropyrazin-2-one hydrochloride; N-(5-(4-cyclopropylhexahydropyrazin-1-yl)pyridin-2-yl)-5-fluoro-4 -(8-fluoroquinolin-6-yl)pyrimidin-2-amine; N-(5-(4-cyclopropylhexahydropyrazin-1-yl)pyridin-2-yl)-5-fluoro-4 -(8-fluoroquinolin-6-yl)pyrimidine-2-amine hydrochloride; 1-(4-(6-((5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidine- 2-yl)amino)pyridin-3-yl)hexahydropyrazin-1-yl)ethan-1-one; 1-(4-(6-((5-fluoro-4-(8-fluoroquinoline -6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazin-1-yl)ethan-1-one hydrochloride; 5-fluoro-4-(8-fluoroquinoline -6-yl)-N-(5-(4-(2,2,2-trifluoroethyl)hexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine; 5-fluoro -4-(8-fluoroquinolin-6-yl)-N-(5-(4-(2,2,2-trifluoroethyl)hexahydropyrazin-1-yl)pyridin-2-yl) Pyrimidin-2-amine hydrochloride; 5-fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(4-(methylsulfonyl)hexahydropyrazin-1-yl )pyridin-2-yl)pyrimidin-2-amine; 5-fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(4-(methylsulfonyl)hexahydropyrazine -1-yl)pyridin-2-yl)pyrimidin-2-amine hydrochloride; Cyclopropyl (4-(6-((5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidine- 2-yl)amino)pyridin-3-yl)hexahydropyrazin-1-yl)methanone; cyclopropyl (4-(6-((5-fluoro-4-(8-fluoroquinoline-6 -yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazin-1-yl)methanone hydrochloride; 5-fluoro-4-(8-fluoroquinolin-6-yl) -N-(5-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl) Pyridin-2-yl)pyrimidin-2-amine; 5-fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(3-(trifluoromethyl)-5,6-di Hydrogen-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)pyridin-2-yl)pyrimidin-2-amine hydrochloride; N-(5-( (4-Ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-4-isopropyl-2-methylquinoline-6- Base) pyrimidin-2-amine; N-(5-((4-ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-4 -isopropyl-2-methylquinolin-6-yl)pyrimidin-2-amine hydrochloride; N-(5-(4-ethylhexahydropyrazin-1-yl)pyridin-2-yl) -5-fluoro-4-(8-fluoro-4-isopropyl-2-methylquinolin-6-yl)pyrimidin-2-amine; N-(5-(4-ethylhexahydropyrazine- 1- Base) pyridin-2-yl)-5-fluoro-4-(8-fluoro-4-isopropyl-2-methylquinolin-6-yl)pyrimidin-2-amine hydrochloride; 1-(6 -((5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)-4-methylhexahydropyridin-4-ol; 1- (6-((5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)-4-methylhexahydropyridin-4-olate (±)-4-(6-((4-(4-(1-((tertiary butoxycarbonyl)amino)ethyl)-8-fluoro-2-methylquinoline-6 -yl)-5-fluoropyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazine-1-carboxylic acid tert-butyl ester; (±)-4-(4-(1-amino Ethyl)-8-fluoro-2-methylquinolin-6-yl)-5-fluoro-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine (±)-4-(4-(1-aminoethyl)-8-fluoro-2-methylquinolin-6-yl)-5-fluoro-N-(5-(hexahydropyrazine- 1-yl)pyridin-2-yl)pyrimidin-2-amine hydrochloride; (±)-4-(6-((4-(4-(1-((tertiary butoxycarbonyl)amino) Ethyl)-8-fluoroquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazine-1-carboxylic acid tert-butyl ester; (±) -4-(4-(1-aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl ) pyrimidine-2-amine; (±)-4-(4-(1-aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-(hexahydropyrazine -1-yl)pyridin-2-yl)pyrimidin-2-amine dihydrochloride; (±)-4-(6-((5-fluoro-4-(8-fluoro-4-(1-hydroxyethyl Base) quinolin-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) tert-butyl hexahydropyrazine-1-carboxylate; (±)-1-(8-fluoro-6 -(5-fluoro-2-((5-(hexahydropyrazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl)ethanol; (±)- 1-(8-fluoro-6-(5-fluoro-2-((5-(hexahydropyrazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinoline-4- base) ethanol trimesylate; (±)-(1-(8-fluoro-6-(5-fluoro-2-((5-(4-methylhexahydropyrazin-1-yl)pyridine-2 -yl) amino) pyrimidin-4-yl) quinoline-4-yl) ethyl) tert-butyl carbamate; (±)-4-(4-(1-aminoethyl)-8 -Fluoroquinolin-6-yl)-5-fluoro-N-(5-(4-methylhexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine; (±)-4 -(4-(1-aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-(4-methylhexahydropyrazin-1-yl) )pyridin-2-yl)pyrimidin-2-amine trihydrochloride; (±)-1-(6-(2-((5-(4-ethylhexahydropyrazin-1-yl)pyridine-2 -yl)amino)-5-fluoropyrimidin-4-yl)-8-fluoroquinolin-4-yl)ethanol; (±)-1-(6-(2-((5-(4-ethyl Hexahydropyrazin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-8-fluoroquinolin-4-yl)ethanol trihydrochloride; (±)-1 -(8-fluoro-6-(5-fluoro-2-((5-(4-isopropylhexahydropyrazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinone (±)-1-(8-fluoro-6-(5-fluoro-2-((5-(4-isopropylhexahydropyrazin-1-yl)pyridine-2 -yl)amino)pyrimidin-4-yl)quinolin-4-yl)ethanol trihydrochloride; N-(5-(4-ethylhexahydropyrazin-1-yl)pyridin-2-yl) -5-fluoro-4-(8-fluoro-2-methylquinolin-6-yl)pyrimidin-2-amine; N-(5-(4-ethylhexahydropyrazin-1-yl)pyridine- 2-yl)-5-fluoro-4-(8-fluoro-2-methylquinolin-6-yl)pyrimidin-2-amine hydrochloride; (±)-4-(6-((5-fluoro -4-(8-fluoro-4-(1-hydroxyethyl)-2-methylquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazine-1 - tert-butyl formate; (±)-1-(8-fluoro-6-(5-fluoro-2-((5-(hexahydropyrazin-1-yl)pyridin-2-yl)amino ) pyrimidin-4-yl)-2-methylquinolin-4-yl)ethanol; (±)-1-(8-fluoro-6-(5-fluoro-2-((5-(hexahydropyrazine -1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylquinolin-4-yl)ethan-1-ol hydrochloride; (±)-1-(8- Fluoro-6-(5-fluoro-2-((5-(4-methylhexahydropyrazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl ) Ethanol; (±)-1-(8-fluoro-6-(5-fluoro-2-((5-(4-methylhexahydropyrazin-1-yl) pyridin-2-yl) amino) Pyrimidin-4-yl)quinolin-4-yl)ethanol trihydrochloride; 4-(6-((5-fluoro-4-(8-fluoro-4-(2-hydroxyprop-2-yl)quinone Lin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazine-1-carboxylic acid tert-butyl ester; 2-(8-fluoro-6-(5-fluoro-2 -((5-(Hexahydropyrazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl)propan-2-ol; 2-(8-fluoro- 6-(5-fluoro-2-((5-(hexahydropyrazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl)propan-2-ol ; (±)-4-(6-((5-fluoro-4-(8-fluoro-4-(1-hydroxyethyl)quinolin-6-yl)pyrimidine-2 -yl)amino)pyridin-3-yl)hexahydropyrazine-1-carboxylic acid tert-butyl ester; (±)-1-(8-fluoro-6-(5-fluoro-2-((5- (Hexahydropyrazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl)ethanol; (±)-1-(8-fluoro-6-(5- Fluoro-2-((5-(hexahydropyrazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl)ethanol trihydrochloride; (±)- 4-(6-((5-fluoro-4-(8-fluoro-4-(1-hydroxyethyl)quinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexa tert-butyl hydropyridine-1-carboxylate; (±)-1-(8-fluoro-6-(5-fluoro-2-((5-(hexahydropyridin-4-yl)pyridin-2-yl ) amino) pyrimidin-4-yl) quinoline-4-yl) ethanol; (±)-1-(8-fluoro-6-(5-fluoro-2-((5-(hexahydropyridine-4- yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl)ethanol trihydrochloride; 4-(6-((5-fluoro-4-(8-fluoro-4- (2-Hydroxypropan-2-yl)quinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyridine-1-carboxylic acid tert-butyl ester; 2-(8- Fluoro-6-(5-fluoro-2-((5-(hexahydropyridin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl)propan-2- Alcohol; 2-(8-fluoro-6-(5-fluoro-2-((5-(hexahydropyridin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinoline-4 -yl)propan-2-ol trihydrochloride; 4-(6-((5-fluoro-4-(8-fluoro-4-(2-hydroxyprop-2-yl)-2-methylquinoline -6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) tert-butyl hexahydropyridine-1-carboxylate; 2-(8-fluoro-6-(5-fluoro-2-( (5-(hexahydropyridin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylquinolin-4-yl)propan-2-ol; 2-(8- Fluoro-6-(5-fluoro-2-((5-(hexahydropyridin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylquinolin-4-yl ) propan-2-ol trihydrochloride; (±)-4-(6-((5-fluoro-4-(8-fluoro-4-(1-hydroxyethyl)-2-methylquinoline- 6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyridine-1-carboxylic acid tert-butyl ester; (±)-1-(8-fluoro-6-(5-fluoro- 2-((5-(Hexahydropyridin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylquinolin-4-yl)ethanol; (±)-1- (8-fluoro-6-(5-fluoro-2-((5-(hexahydropyridin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylquinoline- 4-yl)ethanol trihydrochloride; 4-(2-((5-fluoro-4-(8-fluoro-4 -(2-Hydroxypropan-2-yl)quinolin-6-yl)pyrimidin-2-yl)amino)pyrimidin-5-yl)hexahydropyridine-1-carboxylic acid tert-butyl ester; 2-(8 -Fluoro-6-(5-fluoro-2-((5-(hexahydropyridin-4-yl)pyrimidin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl)propan-2 -alcohol; 2-(8-fluoro-6-(5-fluoro-2-((5-(hexahydropyridin-4-yl)pyrimidin-2-yl)amino)pyrimidin-4-yl)quinoline- 4-yl)propan-2-ol trihydrochloride; (±)-4-(2-((5-fluoro-4-(8-fluoro-4-(1-hydroxyethyl)quinoline-6- Base) pyrimidin-2-yl) amino) pyrimidin-5-yl) tert-butyl hexahydropyridine-1-carboxylate; (±)-1-(8-fluoro-6-(5-fluoro-2- ((5-(Hexahydropyridin-4-yl)pyrimidin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl)ethanol; (±)-1-(8-fluoro-6- (5-fluoro-2-((5-(hexahydropyridin-4-yl)pyrimidin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl)ethanol trihydrochloride; 2- (8-fluoro-6-(5-fluoro-2-((5-(1-methylhexahydropyridin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinoline-4 -yl)propan-2-ol; 2-(8-fluoro-6-(5-fluoro-2-((5-(1-methylhexahydropyridin-4-yl)pyridin-2-yl)amino ) pyrimidin-4-yl) quinolin-4-yl) propan-2-ol trihydrochloride; (±)-1-(8-fluoro-6-(5-fluoro-2-((5-(1 -methylhexahydropyridin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl)ethanol; (±)-1-(8-fluoro-6-(5 -Fluoro-2-((5-(1-methylhexahydropyridin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl)ethanol trihydrochloride; (±)-4-(6-((4-(4-(1-((3-butoxycarbonyl)amino)ethyl)-8-fluoroquinolin-6-yl)-5-fluoropyrimidine -2-yl)amino)pyridin-3-yl)hexahydropyridine-1-carboxylic acid tert-butyl ester; (±)-4-(4-(1-aminoethyl)-8-fluoroquinoline -6-yl)-5-fluoro-N-(5-(hexahydropyridin-4-yl)pyridin-2-yl)pyrimidin-2-amine; and (±)-4-(4-(1-amine Ethyl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-(hexahydropyridin-4-yl)pyridin-2-yl)pyrimidin-2-amine trihydrochloride; and pharmaceutically acceptable salts thereof.

代表性結構示於下表1中。 -1 實例 結構 實例 結構               實例 結構 1

Figure 02_image018
1A
Figure 02_image020
1B   
Figure 02_image022
  
2
Figure 02_image024
2A
Figure 02_image026
2B
Figure 02_image028
  
3
Figure 02_image030
3A
Figure 02_image032
  
4
Figure 02_image034
4A
Figure 02_image036
  
5
Figure 02_image038
5A
Figure 02_image040
5B
Figure 02_image042
6
Figure 02_image044
6A
Figure 02_image046
  
7
Figure 02_image048
7A
Figure 02_image050
  
8
Figure 02_image052
8A
Figure 02_image054
  
9
Figure 02_image056
9A
Figure 02_image058
  
10
Figure 02_image060
10A
Figure 02_image062
10B
Figure 02_image064
  
11
Figure 02_image066
11A
Figure 02_image068
11B
Figure 02_image070
  
12
Figure 02_image072
12A
Figure 02_image074
  
13
Figure 02_image076
13A
Figure 02_image078
  
14
Figure 02_image080
14A
Figure 02_image082
  
15
Figure 02_image084
15A
Figure 02_image086
  
16
Figure 02_image088
16A
Figure 02_image090
  
17
Figure 02_image092
17A
Figure 02_image094
17B
Figure 02_image096
  
18
Figure 02_image098
18A
Figure 02_image100
  
19
Figure 02_image102
19A
Figure 02_image104
20
Figure 02_image106
20A
Figure 02_image108
20B
Figure 02_image110
  
21
Figure 02_image112
21A
Figure 02_image114
  
22
Figure 02_image116
22A
Figure 02_image118
  
23
Figure 02_image120
23A
Figure 02_image122
23B
Figure 02_image124
  
24
Figure 02_image126
24A
Figure 02_image128
  
25
Figure 02_image130
25A
Figure 02_image132
  
26
Figure 02_image134
26A
Figure 02_image136
26B
Figure 02_image138
  
27
Figure 02_image140
27A
Figure 02_image142
  
28
Figure 02_image144
28A
Figure 02_image146
  
29
Figure 02_image148
29A
Figure 02_image150
  
30
Figure 02_image152
30A
Figure 02_image154
  
31
Figure 02_image156
31A
Figure 02_image158
  
32
Figure 02_image160
32A
Figure 02_image162
  
33
Figure 02_image164
33A
Figure 02_image166
  
34
Figure 02_image168
34A
Figure 02_image170
  
35
Figure 02_image172
35A
Figure 02_image174
  
36
Figure 02_image176
36A
Figure 02_image178
  
37
Figure 02_image180
37A
Figure 02_image182
  
38
Figure 02_image184
38A
Figure 02_image186
  
39
Figure 02_image188
39A
Figure 02_image190
39B
Figure 02_image192
  
40
Figure 02_image194
40A
Figure 02_image196
40B
Figure 02_image198
  
41
Figure 02_image200
41A
Figure 02_image202
41B
Figure 02_image204
  
42
Figure 02_image206
42A
Figure 02_image208
42B
Figure 02_image210
  
43
Figure 02_image212
43A
Figure 02_image214
  
44
Figure 02_image216
44A
Figure 02_image218
  
45
Figure 02_image220
45A
Figure 02_image222
  
46
Figure 02_image224
46A
Figure 02_image226
46B
Figure 02_image228
  
47
Figure 02_image230
47A
Figure 02_image232
  
48
Figure 02_image234
48A
Figure 02_image236
48B
Figure 02_image238
  
49
Figure 02_image240
49A
Figure 02_image242
49B
Figure 02_image244
  
50
Figure 02_image246
50A
Figure 02_image248
50B
Figure 02_image250
  
51
Figure 02_image252
51A
Figure 02_image254
51B
Figure 02_image256
  
52
Figure 02_image258
52A
Figure 02_image260
52B
Figure 02_image262
  
53
Figure 02_image264
53A
Figure 02_image266
53B
Figure 02_image268
  
54
Figure 02_image270
54A
Figure 02_image272
54B
Figure 02_image274
  
55
Figure 02_image276
55A
Figure 02_image278
55B
Figure 02_image280
  
56
Figure 02_image282
56A
Figure 02_image284
  
57
Figure 02_image286
57A
Figure 02_image288
  
58
Figure 02_image290
58A
Figure 02_image292
58B
Figure 02_image294
  
           
4-(4-(1-胺基乙基)-8-氟喹啉-6-基)-5-氟-N-(5-(六氫吡嗪-1-基)吡啶-2-基)吡啶-2-胺; 4-(4-(2-胺基丙-2-基)-8-氟喹啉-6-基)-5-氟-N-(5-(六氫吡嗪-1-基)吡啶-2-基)吡啶-2-胺; 4-(4-(1-胺基乙基)-8-氟喹啉-6-基)-5-氟-N-(5-(4-甲基六氫吡嗪-1-基)吡啶-2-基)吡啶-2-胺; 4-(4-(1-胺基乙基)-8-氟喹啉-6-基)-5-氟-N-(5-(六氫吡啶-4-基)吡啶-2-基)嘧啶-2-胺; 4-(4-(2-胺基丙-2-基)-8-氟喹啉-6-基)-5-氟-N-(5-(六氫吡啶-4-基)吡啶-2-基)嘧啶-2-胺; 4-(4-(1-胺基乙基)-8-氟喹啉-6-基)-5-氟-N-(5-(1-甲基六氫吡啶-4-基)吡啶-2-基)嘧啶-2-胺; 2-(8-氟-6-(5-氟-2-((5-(六氫吡嗪-1-基)吡啶-2-基)胺基)吡啶-4-基)喹啉-4-基)丙-2-醇; 2-(8-氟-6-(5-氟-2-((5-(六氫吡啶-4-基)嘧啶-2-基)胺基)吡啶-4-基)喹啉-4-基)丙-2-醇; 2-(8-氟-6-(5-氟-2-((5-(六氫吡啶-4-基)吡啶-2-基)胺基)吡啶-4-基)喹啉-4-基)丙-2-醇; 2-(8-氟-6-(5-氟-2-((1',2',3',6'-四氫-[3,4'-聯吡啶]-6-基)胺基)嘧啶-4-基)喹啉-4-基)丙-2-醇; 1-(8-氟-6-(5-氟-2-((1',2',3',6'-四氫-[3,4'-聯吡啶]-6-基)胺基)嘧啶-4-基)喹啉-4-基)乙-1-醇; N-(4-(4-(1-胺基乙基)-8-氟喹啉-6-基)-5-氟嘧啶-2-基)-1',2',3',6'-四氫-[3,4'-聯吡啶]-6-胺; 2-(8-氟-6-(5-氟-2-((5-(六氫吡啶-3-基)吡啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)丙-2-醇; 2-(8-氟-6-(5-氟-2-((5-(六氫吡啶-3-基)吡啶-2-基)胺基)嘧啶-4-基)-2-甲基喹啉-4-基)丙-2-醇; 5-氟-4-(8-氟喹啉-6-基)-N-(5-(六氫吡啶-3-基)吡啶-2-基)嘧啶-2-胺; 2-(8-氟-6-(5-氟-2-((5-(吡咯啶-3-基)吡啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)丙-2-醇; 1-(8-氟-6-(5-氟-2-((5-(吡咯啶-3-基)吡啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)乙-1-醇; 4-(4-(1-胺基乙基)-8-氟喹啉-6-基)-5-氟-N-(5-(吡咯啶-3-基)吡啶-2-基)嘧啶-2-胺; 2-(6-(2-((5-(1-乙基六氫吡啶-4-基)吡啶-2-基)胺基)-5-氟嘧啶-4-基)-8-氟喹啉-4-基)丙-2-醇; 2-(8-氟-6-(5-氟-2-((5-(1-異丙基六氫吡啶-4-基)吡啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)丙-2-醇;及 2-(6-(2-((5-(1-環丙基六氫吡啶-4-基)吡啶-2-基)胺基)-5-氟嘧啶-4-基)-8-氟喹啉-4-基)丙-2-醇; 或其醫藥學上可接受之鹽。 Representative structures are shown in Table 1 below. Table -1 example structure example structure example structure 1
Figure 02_image018
1A
Figure 02_image020
1B
Figure 02_image022
2
Figure 02_image024
2A
Figure 02_image026
2B
Figure 02_image028
3
Figure 02_image030
3A
Figure 02_image032
4
Figure 02_image034
4A
Figure 02_image036
5
Figure 02_image038
5A
Figure 02_image040
5B
Figure 02_image042
6
Figure 02_image044
6A
Figure 02_image046
7
Figure 02_image048
7A
Figure 02_image050
8
Figure 02_image052
8A
Figure 02_image054
9
Figure 02_image056
9A
Figure 02_image058
10
Figure 02_image060
10A
Figure 02_image062
10B
Figure 02_image064
11
Figure 02_image066
11A
Figure 02_image068
11B
Figure 02_image070
12
Figure 02_image072
12A
Figure 02_image074
13
Figure 02_image076
13A
Figure 02_image078
14
Figure 02_image080
14A
Figure 02_image082
15
Figure 02_image084
15A
Figure 02_image086
16
Figure 02_image088
16A
Figure 02_image090
17
Figure 02_image092
17A
Figure 02_image094
17B
Figure 02_image096
18
Figure 02_image098
18A
Figure 02_image100
19
Figure 02_image102
19A
Figure 02_image104
20
Figure 02_image106
20A
Figure 02_image108
20B
Figure 02_image110
twenty one
Figure 02_image112
21A
Figure 02_image114
twenty two
Figure 02_image116
22A
Figure 02_image118
twenty three
Figure 02_image120
23A
Figure 02_image122
23B
Figure 02_image124
twenty four
Figure 02_image126
24A
Figure 02_image128
25
Figure 02_image130
25A
Figure 02_image132
26
Figure 02_image134
26A
Figure 02_image136
26B
Figure 02_image138
27
Figure 02_image140
27A
Figure 02_image142
28
Figure 02_image144
28A
Figure 02_image146
29
Figure 02_image148
29A
Figure 02_image150
30
Figure 02_image152
30A
Figure 02_image154
31
Figure 02_image156
31A
Figure 02_image158
32
Figure 02_image160
32A
Figure 02_image162
33
Figure 02_image164
33A
Figure 02_image166
34
Figure 02_image168
34A
Figure 02_image170
35
Figure 02_image172
35A
Figure 02_image174
36
Figure 02_image176
36A
Figure 02_image178
37
Figure 02_image180
37A
Figure 02_image182
38
Figure 02_image184
38A
Figure 02_image186
39
Figure 02_image188
39A
Figure 02_image190
39B
Figure 02_image192
40
Figure 02_image194
40A
Figure 02_image196
40B
Figure 02_image198
41
Figure 02_image200
41A
Figure 02_image202
41B
Figure 02_image204
42
Figure 02_image206
42A
Figure 02_image208
42B
Figure 02_image210
43
Figure 02_image212
43A
Figure 02_image214
44
Figure 02_image216
44A
Figure 02_image218
45
Figure 02_image220
45A
Figure 02_image222
46
Figure 02_image224
46A
Figure 02_image226
46B
Figure 02_image228
47
Figure 02_image230
47A
Figure 02_image232
48
Figure 02_image234
48A
Figure 02_image236
48B
Figure 02_image238
49
Figure 02_image240
49A
Figure 02_image242
49B
Figure 02_image244
50
Figure 02_image246
50A
Figure 02_image248
50B
Figure 02_image250
51
Figure 02_image252
51A
Figure 02_image254
51B
Figure 02_image256
52
Figure 02_image258
52A
Figure 02_image260
52B
Figure 02_image262
53
Figure 02_image264
53A
Figure 02_image266
53B
Figure 02_image268
54
Figure 02_image270
54A
Figure 02_image272
54B
Figure 02_image274
55
Figure 02_image276
55A
Figure 02_image278
55B
Figure 02_image280
56
Figure 02_image282
56A
Figure 02_image284
57
Figure 02_image286
57A
Figure 02_image288
58
Figure 02_image290
58A
Figure 02_image292
58B
Figure 02_image294
4-(4-(1-aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl) Pyridin-2-amine; 4-(4-(2-aminopropan-2-yl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-(hexahydropyrazine-1 -yl)pyridin-2-yl)pyridin-2-amine; 4-(4-(1-aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-( 4-methylhexahydropyrazin-1-yl)pyridin-2-yl)pyridin-2-amine; 4-(4-(1-aminoethyl)-8-fluoroquinolin-6-yl)- 5-fluoro-N-(5-(hexahydropyridin-4-yl)pyridin-2-yl)pyrimidin-2-amine; 4-(4-(2-aminopropan-2-yl)-8-fluoro Quinolin-6-yl)-5-fluoro-N-(5-(hexahydropyridin-4-yl)pyridin-2-yl)pyrimidin-2-amine; 4-(4-(1-aminoethyl )-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-(1-methylhexahydropyridin-4-yl)pyridin-2-yl)pyrimidin-2-amine; 2-( 8-fluoro-6-(5-fluoro-2-((5-(hexahydropyrazin-1-yl)pyridin-2-yl)amino)pyridin-4-yl)quinolin-4-yl)propane -2-alcohol; 2-(8-fluoro-6-(5-fluoro-2-((5-(hexahydropyridin-4-yl)pyrimidin-2-yl)amino)pyridin-4-yl)quinone phen-4-yl)propan-2-ol; 2-(8-fluoro-6-(5-fluoro-2-((5-(hexahydropyridin-4-yl)pyridin-2-yl)amino) Pyridin-4-yl)quinolin-4-yl)propan-2-ol; 2-(8-fluoro-6-(5-fluoro-2-((1',2',3',6'-tetra Hydrogen-[3,4'-bipyridyl]-6-yl)amino)pyrimidin-4-yl)quinolin-4-yl)propan-2-ol; 1-(8-fluoro-6-(5- Fluoro-2-((1',2',3',6'-tetrahydro-[3,4'-bipyridyl]-6-yl)amino)pyrimidin-4-yl)quinolin-4-yl ) ethyl-1-ol; N-(4-(4-(1-aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoropyrimidin-2-yl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-amine; 2-(8-fluoro-6-(5-fluoro-2-((5-(hexahydropyridine-3 -yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl)propan-2-alcohol; 2-(8-fluoro-6-(5-fluoro-2-((5 -(hexahydropyridin-3-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylquinolin-4-yl)propan-2-ol; 5-fluoro-4-( 8-fluoroquinolin-6-yl)-N-(5-(hexahydropyridin-3-yl)pyridin-2-yl)pyrimidin-2-amine; 2-(8-fluoro-6-(5-fluoro -2-((5-(pyrrolidin-3-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl)propan-2-ol; 1-(8-fluoro-6-(5-fluoro-2-((5-(pyrrolidin-3-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl) Ethan-1-ol; 4-(4-(1-aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-(pyrrolidin-3-yl)pyridine- 2-yl)pyrimidin-2-amine; 2-(6-(2-((5-(1-ethylhexahydropyridin-4-yl)pyridin-2-yl)amino)-5-fluoropyrimidine- 4-yl)-8-fluoroquinolin-4-yl)propan-2-ol; 2-(8-fluoro-6-(5-fluoro-2-((5-(1-isopropylhexahydropyridine -4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl)propan-2-ol; and 2-(6-(2-((5-(1-ring Propylhexahydropyridin-4-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-8-fluoroquinolin-4-yl)propan-2-ol; or its pharmaceutical acceptable salt.

surface -1a-1a :預示性實例: Predictive instance 實例example 結構structure 實例example 結構structure 實例example 結構structure P-1 P-1

Figure 02_image296
Figure 02_image296
P-2 P-2
Figure 02_image298
Figure 02_image298
P-3 P-3
Figure 02_image300
Figure 02_image300
P-4 P-4
Figure 02_image302
Figure 02_image302
P-5 P-5
Figure 02_image304
Figure 02_image304
P-6 P-6
Figure 02_image306
Figure 02_image306
P-7 P-7
Figure 02_image308
Figure 02_image308
P-8 P-8
Figure 02_image310
Figure 02_image310
P-9 P-9
Figure 02_image312
Figure 02_image312
P-10 P-10
Figure 02_image314
Figure 02_image314
P-11 P-11
Figure 02_image316
Figure 02_image316
P-12 P-12
Figure 02_image318
Figure 02_image318
P-13 P-13
Figure 02_image320
Figure 02_image320
P-14 P-14
Figure 02_image322
Figure 02_image322
P-15 P-15
Figure 02_image324
Figure 02_image324
P-16 P-16
Figure 02_image326
Figure 02_image326
P-17 P-17
Figure 02_image328
Figure 02_image328
P-18 P-18
Figure 02_image330
Figure 02_image330
P-19 P-19
Figure 02_image332
Figure 02_image332
P-20 P-20
Figure 02_image334
Figure 02_image334
P-21 P-21
Figure 02_image336
Figure 02_image336

本發明之另一實施例係抑制患者中之CDK1、CDK2、CDK4及CDK6中之一或多者之方法,該方法藉由向該患者投與有效量之至少一種如以式 (I)(IA)(IB)(IC)(ID)所定義之本發明化合物來實施。 一個實施例係抑制患者中之CDK2、CDK4及CDK6 (例如CDK2及CDK4/6)之方法,該方法藉由向該患者投與有效量之至少一種如以式 (I)(IA)(IB)(IC)(ID)所定義之本發明化合物來實施。 Another embodiment of the present invention is a method of inhibiting one or more of CDK1, CDK2, CDK4 and CDK6 in a patient by administering to the patient an effective amount of at least one of the formulas (I) , ( IA) , (IB) , (IC) or (ID) defined compounds of the invention to implement. One embodiment is a method of inhibiting CDK2, CDK4, and CDK6 (eg, CDK2 and CDK4/6) in a patient by administering to the patient an effective amount of at least one of the formulas (I) , (IA) , ( IB) , (IC) or (ID) defined compounds of the invention to implement.

本發明之另一實施例係治療發炎性、自體免疫性或增殖性疾病之方法,該方法藉由向需要此治療之患者投與有效量之至少一種本發明化合物來實施。 在一個實施例中,以有效量投與本發明之化合物以抑制CDK1、CDK2、CDK4及CDK6中之一或多者。Another embodiment of the invention is a method of treating an inflammatory, autoimmune or proliferative disease by administering to a patient in need of such treatment an effective amount of at least one compound of the invention. In one embodiment, a compound of the invention is administered in an effective amount to inhibit one or more of CDK1, CDK2, CDK4, and CDK6.

本發明之另一實施例係治療發炎性、自體免疫性或增殖性疾病之方法(例如經由抑制CDK1、CDK2、CDK4及CDK6中之一或多者),該方法藉由向需要此治療之患者投與(同時或依序)有效量之至少一種本發明化合物與至少一種其他抗發炎劑、免疫調節劑或抗癌劑之組合來實施。在一個實施例中,本發明之化合物抑制CDK1、CDK2、CDK4及CDK6中之一或多者。 在另一實施例中,本發明之化合物抑制CDK2及/或CDK4/6。Another embodiment of the invention is a method of treating an inflammatory, autoimmune or proliferative disease (eg, by inhibiting one or more of CDK1, CDK2, CDK4, and CDK6) by introducing The patient is administered (simultaneously or sequentially) an effective amount of at least one compound of the present invention in combination with at least one other anti-inflammatory, immunomodulatory or anti-cancer agent. In one embodiment, compounds of the invention inhibit one or more of CDK1, CDK2, CDK4, and CDK6. In another embodiment, the compounds of the invention inhibit CDK2 and/or CDK4/6.

更特定而言,可投與式 (I)(IA)(IB)(IC)(ID)化合物及其醫藥學上可接受之酯或鹽以用於治療、預防及/或改善與選自CDK1、CDK2、CDK4、CDK6及上述中任一者之任一組合之CDK酶相關之疾病或病症,尤其改善由此一CDK酶介導之疾病或病症,包括(但不限於)發炎性疾病或病症、自體免疫性疾病或病症及癌症以及其他增殖性疾病或病症。 More specifically, compounds of formula (I) , (IA) , (IB) , (IC) or (ID) and pharmaceutically acceptable esters or salts thereof may be administered for treatment, prevention and/or amelioration Diseases or conditions associated with a CDK enzyme selected from the group consisting of CDK1, CDK2, CDK4, CDK6, and any combination of any of the foregoing, particularly amelioration of a disease or condition mediated by such a CDK enzyme, including but not limited to inflammation diseases or conditions, autoimmune diseases or conditions and cancer and other proliferative diseases or conditions.

本發明之化合物可用於治療多種癌症,包括(但不限於): l  癌,包括膀胱癌、乳癌、結腸癌、腎癌、肝癌、肺癌(包括小細胞肺癌)及食管癌、膽囊癌、卵巢癌、胰臟癌、胃癌、子宮頸癌、甲狀腺癌、前列腺癌及皮膚癌(包括鱗狀細胞癌); l  淋巴譜系之造血腫瘤,包括白血病、急性淋巴球性白血病、急性淋巴母細胞性白血病、B細胞淋巴瘤、T細胞淋巴瘤、霍奇金氏淋巴瘤(Hodgkin's lymphoma)、非霍奇金氏淋巴瘤、毛細胞淋巴瘤及柏基特氏淋巴瘤(Burkett's lymphoma); l  骨髓譜系之造血腫瘤,包括急性及慢性骨髓性白血病、骨髓發育不良症候群及前骨髓細胞性白血病; l  間質起源之腫瘤,包括纖維肉瘤及橫紋肌肉瘤; l  中樞及周圍神經系統之腫瘤,包括星細胞瘤、神經母細胞瘤、神經膠質瘤及神經鞘瘤;及 l  其他腫瘤,包括黑色素瘤、精原細胞瘤、畸形癌、骨肉瘤、著色性乾皮病、角化棘皮瘤、甲狀腺濾泡癌及卡波西氏肉瘤(Kaposi's sarcoma)。 The compounds of the present invention are useful in the treatment of a variety of cancers, including (but not limited to): l Cancer, including bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer (including small cell lung cancer) and esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, gastric cancer, cervical cancer, thyroid cancer, prostate cancer and skin cancer (including squamous cell carcinoma); l Hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma tumor, pilocytic lymphoma and Burkett's lymphoma (Burkett's lymphoma); l Hematopoietic tumors of the myeloid lineage, including acute and chronic myelogenous leukemia, myelodysplastic syndrome and promyelocytic leukemia; l Tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; l Tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma and schwannoma; and l Other tumors, including melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosa, keratoacanthoma, thyroid follicular carcinoma, and Kaposi's sarcoma.

本發明之化合物可用於癌症之化學預防。化學預防定義為藉由阻斷起始誘變事件或藉由阻斷已遭受損害之惡化前細胞之進展或抑制腫瘤復發來抑制侵襲性癌症之發展。 本文所闡述之化合物亦可用於抑制腫瘤血管生成及轉移。 本發明之一個實施例係抑制有需要之患者之腫瘤血管生成或轉移之方法,該方法藉由投與有效量之一或多種本發明之化合物來實施。The compounds of the present invention are useful in the chemoprevention of cancer. Chemoprevention is defined as the inhibition of the development of aggressive cancers by blocking the initial mutagenic event or by blocking the progression of pre-malignant cells that have already suffered damage or inhibiting tumor recurrence. The compounds described herein are also useful for inhibiting tumor angiogenesis and metastasis. One embodiment of the invention is a method of inhibiting tumor angiogenesis or metastasis in a patient in need thereof by administering an effective amount of one or more compounds of the invention.

本發明之化合物亦可與以下組合使用(一起或依序投與):已知之抗癌治療,諸如(但不限於)放射療法,或細胞生長抑制劑、細胞毒性劑或抗癌劑,諸如(但不限於) DNA相互作用劑,諸如順鉑(cisplatin)或多柔比星(doxorubicin);拓撲異構酶II抑制劑,諸如依託泊苷(etoposide);拓撲異構酶I抑制劑,諸如CPT-11或托泊替康(topotecan);天然或合成之微管蛋白相互作用劑,諸如太平洋紫杉醇(paclitaxel)、多西他賽(docetaxel)或埃博黴素(epothilone) (例如伊沙匹隆(ixabepilone));激素劑,諸如他莫昔芬;胸苷酸合酶抑制劑,諸如5-氟尿嘧啶;抗代謝物,諸如胺甲喋呤(methotrexate);其他酪胺酸激酶抑制劑,諸如艾瑞莎(Iressa)及OSI-774;血管生成抑制劑;EGF抑制劑;VEGF抑制劑;HDAC抑制劑;SRC抑制劑;c-Kit抑制劑;Her1/2抑制劑;針對生長因子受體之單株抗體,諸如爾必得舒(erbitux) (EGF)及賀癌平(herceptin) (Her2);以及其他蛋白激酶調節劑。The compounds of the invention may also be used in combination (administered together or sequentially) with known anticancer treatments such as, but not limited to, radiation therapy, or cytostatic, cytotoxic or anticancer agents such as ( But not limited to) DNA interactors such as cisplatin or doxorubicin; topoisomerase II inhibitors such as etoposide; topoisomerase I inhibitors such as CPT -11 or topotecan; natural or synthetic tubulin interacting agents such as paclitaxel, docetaxel or epothilone (e.g. ixabepilone (ixabepilone)); hormone agents, such as tamoxifen; thymidylate synthase inhibitors, such as 5-fluorouracil; antimetabolites, such as methotrexate; other tyrosine kinase inhibitors, such as axa Iressa and OSI-774; Angiogenesis Inhibitors; EGF Inhibitors; VEGF Inhibitors; HDAC Inhibitors; SRC Inhibitors; c-Kit Inhibitors; Her1/2 Inhibitors; Strain antibodies, such as erbitux (EGF) and herceptin (Her2); and other protein kinase modulators.

本發明之化合物亦可與以下組合使用(一起或依序投與):一或多種類固醇抗發炎性藥物、非類固醇抗發炎性藥物(NSAID)或免疫選擇性抗發炎性衍生物(ImSAID)。The compounds of the invention may also be used in combination (administered together or sequentially) with one or more steroidal anti-inflammatory drugs, non-steroidal anti-inflammatory drugs (NSAIDs) or immunoselective anti-inflammatory derivatives (ImSAIDs).

本發明進一步提供醫藥組合物,其包含一或多種本發明之化合物(諸如具有式 (I)(IA)(IB)(IC)(ID)之化合物)以及醫藥學上可接受之載劑。醫藥組合物可進一步包含上文所鑑別之活性成分中之一或多者,諸如其他抗癌劑。 The present invention further provides pharmaceutical compositions comprising one or more compounds of the present invention (such as compounds of formula (I) , (IA) , (IB) , (IC) or (ID) ) and pharmaceutically acceptable carrier. The pharmaceutical composition may further comprise one or more of the active ingredients identified above, such as other anticancer agents.

在一個實施例中,醫藥組合物包括治療有效量之一或多種式 (I)(IA)(IB)(IC)(ID)化合物。 In one embodiment, the pharmaceutical composition comprises a therapeutically effective amount of one or more compounds of formula (I) , (IA) , (IB) , (IC) or (ID) .

另一實施例係治療有需要之患者之癌症的方法,該方法藉由投與治療有效量之本發明化合物來實施。舉例而言,本發明之化合物有效治療淋巴譜系之造血腫瘤:白血病、急性淋巴球性白血病、急性淋巴母細胞性白血病、B細胞淋巴瘤、T細胞淋巴瘤、霍奇金氏淋巴瘤、非霍奇金氏淋巴瘤、毛細胞淋巴瘤及柏基特氏淋巴瘤;骨髓譜系之造血腫瘤:急性骨髓性白血病、慢性骨髓性白血病、骨髓發育不良症候群及前骨髓細胞性白血病。 本發明之化合物亦有效治療膀胱癌、乳癌、結腸癌、腎癌、肝癌、肺癌、小細胞肺癌、食管癌、膽囊癌、卵巢癌、胰臟癌、胃癌、子宮頸癌、甲狀腺癌、前列腺癌、皮膚癌、鱗狀細胞癌;間質起源之腫瘤,纖維肉瘤、橫紋肌肉瘤;中樞及周圍神經系統之腫瘤,星細胞瘤、神經母細胞瘤、神經膠質瘤、神經鞘瘤;黑色素瘤、精原細胞瘤、畸形癌、骨肉瘤、著色性乾皮病、角化棘皮瘤、甲狀腺濾泡癌及卡波西氏肉瘤。Another embodiment is a method of treating cancer in a patient in need thereof by administering a therapeutically effective amount of a compound of the invention. For example, the compounds of the present invention are effective in the treatment of hematopoietic neoplasms of the lymphoid lineage: leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Chiggin's Lymphoma, Pilocytic Lymphoma, and Burkitt's Lymphoma; Hematopoietic Neoplasms of the Myeloid Lineage: Acute Myeloid Leukemia, Chronic Myelogenous Leukemia, Myelodysplastic Syndrome, and Promyelocytic Leukemia. The compound of the present invention is also effective in the treatment of bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, gastric cancer, cervical cancer, thyroid cancer, prostate cancer , skin cancer, squamous cell carcinoma; tumors of mesenchymal origin, fibrosarcoma, rhabdomyosarcoma; tumors of the central and peripheral nervous system, astrocytoma, neuroblastoma, glioma, schwannoma; Primary cell tumor, teratocarcinoma, osteosarcoma, xeroderma pigmentosa, keratoacanthoma, follicular carcinoma of the thyroid, and Kaposi's sarcoma.

另一實施例係治療有需要之患者之白血病的方法,該方法藉由投與治療有效量之本發明化合物來實施。舉例而言,本發明之化合物有效治療乳癌、卵巢癌、肝癌、肺癌、小細胞肺癌、食管癌、膽囊癌、卵巢癌、胰臟癌或胃癌。Another embodiment is a method of treating leukemia in a patient in need thereof by administering a therapeutically effective amount of a compound of the invention. For example, the compounds of the present invention are effective in the treatment of breast cancer, ovarian cancer, liver cancer, lung cancer, small cell lung cancer, esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer or gastric cancer.

如本文所用,除非另有指示,否則以下定義應適用。此外,本文所定義之許多基團可視情況經取代。定義中之取代基列表係例示性的,且不應解釋為限制本說明書中別處所定義之取代基。As used herein, the following definitions shall apply unless otherwise indicated. Furthermore, many of the groups defined herein may be optionally substituted. The lists of substituents in the definitions are exemplary and should not be construed as limiting the substituents defined elsewhere in this specification.

除非另有指定,否則術語「CDK4/6」係指CDK4及CDK6二者。 舉例而言,抑制「CDK4/6」係指抑制(程度相同或不同) CDK4及CDK6二者。Unless otherwise specified, the term "CDK4/6" refers to both CDK4 and CDK6. For example, inhibiting "CDK4/6" refers to inhibiting (to the same or different extent) both CDK4 and CDK6.

除非另有指定,否則術語「烷基」係指僅由碳及氫原子組成之直鏈或具支鏈烴鏈基團,其不含不飽和現象,具有1至8個碳原子,且藉由單鍵連接至分子之其餘部分,例如甲基、乙基、正丙基、1-甲基乙基(異丙基)、正丁基、正戊基及1,1-二甲基乙基(第三丁基)。 術語「C 1-6烷基」係指具有最多6個碳原子之如上文所定義之烷基。在適當情況下,術語「烷基」係指為二價之如上文所提及之烴鏈基團。 Unless otherwise specified, the term "alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, free of unsaturation, having from 1 to 8 carbon atoms, and consisting of A single bond to the rest of the molecule, such as methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and 1,1-dimethylethyl ( tertiary butyl). The term "C 1-6 alkyl" refers to an alkyl group as defined above having up to 6 carbon atoms. The term "alkyl" refers to a hydrocarbon chain group as mentioned above which is divalent, where appropriate.

除非另有指定,否則術語「烯基」係指含有一或多個碳-碳雙鍵之脂肪族烴基,且其可為具有約2至約10個碳原子之直鏈或具支鏈,例如乙烯基、1-丙烯基、2-丙烯基(烯丙基)、異丙烯基、2-甲基-1-丙烯基、1-丁烯基及2-丁烯基。 術語「C2-6烯基」係指具有最多6個碳原子之如上文所定義之烯基。在適當情況下,術語「烯基」係指為二價之如上文所提及之烴基。Unless otherwise specified, the term "alkenyl" refers to an aliphatic hydrocarbon group containing one or more carbon-carbon double bonds, and which may be straight or branched chain having from about 2 to about 10 carbon atoms, for example Vinyl, 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl and 2-butenyl. The term "C2-6 alkenyl" refers to an alkenyl group as defined above having up to 6 carbon atoms. The term "alkenyl" refers to a hydrocarbyl group as mentioned above which is divalent, where appropriate.

除非另有指定,否則術語「炔基」係指具有至少一個碳-碳三鍵且具有範圍為2至最多12個碳原子之直鏈或具支鏈烴基(目前,具有範圍為2至最多10個碳原子之基團較佳),例如乙炔基、丙炔基及丁炔基。術語「C2-6炔基」係指具有最多6個碳原子之如上文所定義之炔基。 在適當情況下,術語「炔基」係指為二價之如上文所提及之烴基。Unless otherwise specified, the term "alkynyl" refers to a straight or branched chain hydrocarbon group having at least one carbon-carbon triple bond and having a range of 2 to up to 12 carbon atoms (presently, having a range of 2 to up to 10 carbon atoms are preferred), such as ethynyl, propynyl and butynyl. The term "C2-6 alkynyl" refers to an alkynyl group as defined above having up to 6 carbon atoms. The term "alkynyl" refers to a hydrocarbyl group as mentioned above which is divalent, where appropriate.

除非另有指定,否則術語「烷氧基」表示經由氧鍵聯連接至分子之其餘部分的如上文所定義之烷基、環烷基或環烷基烷基。 術語「經取代之烷氧基」係指烷基成分經取代之烷氧基(亦即-O-(經取代之烷基))。舉例而言,「烷氧基」係指基團-O-烷基,包括經由氧原子連接至母體結構之1至8個碳原子之直鏈、具支鏈、環狀構形及其組合。實例包括甲氧基、乙氧基、丙氧基、異丙氧基、環丙基氧基及環己基氧基。在適當情況下,術語「烷氧基」係指為二價之如上文所提及之基團。Unless otherwise specified, the term "alkoxy" denotes an alkyl, cycloalkyl or cycloalkylalkyl group as defined above attached to the rest of the molecule via an oxygen linkage. The term "substituted alkoxy" refers to an alkoxy group in which the alkyl component is substituted (ie -O-(substituted alkyl)). By way of example, "alkoxy" refers to the group -O-alkyl, including straight chain, branched chain, cyclic configurations and combinations thereof of 1 to 8 carbon atoms attached to the parent structure through an oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy and cyclohexyloxy. The term "alkoxy" refers to a radical as mentioned above which is divalent, where appropriate.

術語「羥基烷基(hydroxyalkyl或hydroxylalkyl)」意指經一或多個羥基取代之烷基,其中烷基係如上文所定義。「羥基烷基」之實例包括(但不限於)羥基甲基、羥基乙基、羥基丙基、丙-2-醇及諸如此類。The term "hydroxyalkyl or hydroxylalkyl" means an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above. Examples of "hydroxyalkyl" include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, propan-2-ol, and the like.

術語「胺基烷基」意指經一或多個胺基取代之烷基,其中烷基係如上文所定義。「胺基烷基」之實例包括(但不限於)胺基甲基、胺基乙基、2-胺基丙基及諸如此類。The term "aminoalkyl" means an alkyl group substituted with one or more amino groups, wherein alkyl is as defined above. Examples of "aminoalkyl" include, but are not limited to, aminomethyl, aminoethyl, 2-aminopropyl, and the like.

除非另有指定,否則術語「環烷基」表示具有約3至12個碳原子之非芳香族單環或多環環系統,諸如環丙基、環丁基、環戊基及環己基。 多環環烷基之實例包括全氫萘基、金剛烷基及降莰基、橋接環狀基團及螺二環基團,例如螺(4,4)壬-2-基。 術語「C 3-6環烷基」係指具有最多6個碳原子之如上文所定義之環烷基。 Unless otherwise specified, the term "cycloalkyl" denotes a non-aromatic monocyclic or multicyclic ring system having about 3 to 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Examples of polycyclic cycloalkyl groups include perhydronaphthyl, adamantyl, and norbornyl, bridged cyclic groups, and spirobicyclic groups, such as spiro(4,4)nonan-2-yl. The term "C 3-6 cycloalkyl" refers to a cycloalkyl group as defined above having up to 6 carbon atoms.

除非另有指定,否則術語「環烷基烷基」係指含有範圍為約3至8個碳原子且直接連接至烷基之含環基團,其接著在來自該烷基之任一碳處連接至主結構,諸如環丙基甲基、環丁基乙基及環戊基乙基。Unless otherwise specified, the term "cycloalkylalkyl" refers to a ring-containing group containing in the range of about 3 to 8 carbon atoms directly attached to an alkyl group followed by Attached to main structures such as cyclopropylmethyl, cyclobutylethyl and cyclopentylethyl.

除非另有指定,否則術語「環烯基」係指含有範圍為約3至8個碳原子且具有至少一個碳-碳雙鍵之含環基團,諸如環丙烯基、環丁烯基及環戊烯基。 術語「環烯基烷基」係指直接連接至烷基之環烯基,其接著在來自該烷基之任一碳處連接至主結構。Unless otherwise specified, the term "cycloalkenyl" refers to a ring-containing group containing in the range of about 3 to 8 carbon atoms and having at least one carbon-carbon double bond, such as cyclopropenyl, cyclobutenyl and ring pentenyl. The term "cycloalkenylalkyl" refers to a cycloalkenyl group attached directly to an alkyl group, which is then attached to the main structure at any carbon from the alkyl group.

除非另有指定,否則術語「芳基」係指具有範圍為6至20個碳原子之芳香族基團,諸如苯基、萘基、四氫萘基、二氫茚基及聯苯基。Unless otherwise specified, the term "aryl" refers to an aromatic group having carbon atoms ranging from 6 to 20, such as phenyl, naphthyl, tetrahydronaphthyl, indenyl and biphenyl.

除非另有指定,否則術語「芳基烷基」係指直接鍵結至如上文所定義之烷基的如上文所定義之芳基,例如-CH 2C 6H 5及-C 2H 5C 6H 5Unless otherwise specified, the term "arylalkyl" refers to an aryl group as defined above directly bonded to an alkyl group as defined above, for example -CH 2 C 6 H 5 and -C 2 H 5 C 6 H 5 .

除非另有指定,否則術語「雜環」係指由碳原子及至少一個選自氮、磷、氧及硫之雜原子組成之非芳香族3員至15員環基團。出於本發明之目的,雜環基團可為單環、二環、三環或四環環系統,其可包括稠合、橋接或螺環系統,且雜環基團中之氮、磷、碳、氧或硫原子可視情況氧化成各種氧化態。另外,氮原子可視情況經四級銨化。雜環基團可在任一雜原子或碳原子處連接至主結構。Unless otherwise specified, the term "heterocycle" refers to a non-aromatic 3- to 15-membered ring group consisting of carbon atoms and at least one heteroatom selected from nitrogen, phosphorus, oxygen and sulfur. For purposes of this invention, a heterocyclic group may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, Carbon, oxygen or sulfur atoms are optionally oxidized into various oxidation states. In addition, nitrogen atoms can optionally be quaternary ammonized. A heterocyclic group can be attached to the main structure at any heteroatom or carbon atom.

除非另有指定,否則術語「雜環基」係指如上文所定義之雜環基團。雜環基環基團可在任一雜原子或碳原子處連接至主結構。Unless otherwise specified, the term "heterocyclyl" refers to a heterocyclic group as defined above. A heterocyclyl ring group can be attached to the main structure at any heteroatom or carbon atom.

除非另有指定,否則術語「雜環基烷基」係指直接鍵結至烷基之如上文所定義之雜環基團。雜環基烷基可在烷基中之任一碳原子處連接至主結構。 此等雜環烷基之實例包括(但不限於)二氧雜環戊烷基、噻吩基[1,3]二噻烷基、十氫異喹啉基、咪唑啉基、咪唑啉啶基、異噻唑啶基、異噁唑啶基、嗎啉基、八氫吲哚基、八氫異吲哚基、2-側氧基六氫吡嗪基、2-側氧基六氫吡啶基、2-側氧基吡咯啶基、噁唑啶基、六氫吡啶基、六氫吡嗪基、4-六氫吡啶酮基、吡咯啶基、吡唑啶基、奎寧環基、噻唑啶基、四氫呋喃基、三噻烷基、四氫吡喃基、硫嗎啉基(thiomorpholinyl、thiamorpholinyl)、1-側氧基-硫嗎啉基及1,1-二側氧基-硫嗎啉基。Unless otherwise specified, the term "heterocyclylalkyl" refers to a heterocyclic group as defined above directly bonded to an alkyl group. A heterocyclylalkyl group can be attached to the main structure at any carbon atom in the alkyl group. Examples of such heterocycloalkyl groups include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, Isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxohexahydropyrazinyl, 2-oxohexahydropyridyl, 2 - side oxypyrrolidinyl, oxazolidinyl, hexahydropyridyl, hexahydropyrazinyl, 4-hexahydropyridinyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, Tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl (thiomorpholinyl, thiamorpholinyl), 1-oxo-thiomorpholinyl and 1,1-dioxo-thiomorpholinyl.

除非另有指定,否則術語「雜芳基」係指具有一或多個選自N、O及S作為環原子之雜原子的視情況經取代之5員至14員芳香族環。 雜芳基可為單環、二環或三環環系統。此等「雜環」或「雜芳基」之實例包括(但不限於)噁唑基、噻唑基、咪唑基、吡咯基、呋喃基、吡啶基、嘧啶基、吡嗪基、苯并呋喃基、吲哚基、苯并噻唑基、苯并噁唑基、咔唑基、喹啉基、異喹啉基、氮雜環丁基、吖啶基、苯并二氧雜環戊烯基、苯并二噁烷基、苯并呋喃基、咔唑基、噌啉基、二氧雜環戊烷基、吲嗪基、萘啶基、全氫氮呯基、吩嗪基、吩噻嗪基、吩噁嗪基、酞嗪基、喋啶基、嘌呤基、喹唑啉基、喹喏啉基、四唑基、四氫異喹啉基、六氫吡啶基、六氫吡嗪基、2-側氧基六氫吡嗪基、2-側氧基六氫吡啶基、2-側氧基吡咯啶基、2-側氧基氮呯基、氮呯基、4-六氫吡啶酮基、吡咯啶基、嗒嗪基、噁唑啉基、噁唑啶基、三唑基、二氫茚基、異噁唑基、異噁唑啶基、嗎啉基、噻唑啉基、噻唑啶基、異噻唑基、奎寧環基、異噻唑啶基、異吲哚基、吲哚啉基、異吲哚啉基、八氫吲哚基、八氫異吲哚基、十氫異喹啉基、苯并咪唑基、噻二唑基、苯并吡喃基、四氫呋喃基、四氫吡喃基、噻吩基、苯并噻吩基、硫嗎啉基、硫嗎啉基亞砜、 硫嗎啉基砜、二氧雜磷雜環戊烷基、噁二唑基、苯并二氫吡喃基及異苯并二氫吡喃基。 雜芳基環基團可在任一雜原子或碳原子處連接至主結構。 術語「經取代之雜芳基」亦包括經一或多個氧化物 取代基取代之環系統,諸如吡啶基N-氧化物。Unless otherwise specified, the term "heteroaryl" refers to an optionally substituted 5- to 14-membered aromatic ring having one or more heteroatoms selected from N, O and S as ring atoms. Heteroaryl groups can be monocyclic, bicyclic or tricyclic ring systems. Examples of such "heterocycle" or "heteroaryl" include, but are not limited to, oxazolyl, thiazolyl, imidazolyl, pyrrolyl, furyl, pyridyl, pyrimidinyl, pyrazinyl, benzofuryl , indolyl, benzothiazolyl, benzoxazolyl, carbazolyl, quinolinyl, isoquinolyl, azetidinyl, acridinyl, benzodioxolyl, benzene Dioxanyl, benzofuryl, carbazolyl, cinnolinyl, dioxolyl, indolizinyl, naphthyridinyl, perhydroazinyl, phenazinyl, phenothiazinyl, Phenoxazinyl, phthalazinyl, pteridyl, purinyl, quinazolinyl, quinoxalinyl, tetrazolyl, tetrahydroisoquinolinyl, hexahydropyridyl, hexahydropyrazinyl, 2- Pendant oxyhexahydropyrazinyl, 2- pendant oxyhexahydropyridyl, 2- pendant oxypyrrolidinyl, 2- pendant oxahydropyrrolidinyl, nitrogen sulphate, 4-hexahydropyridonyl, pyrrole Pyridyl, pyrazinyl, oxazolyl, oxazolyl, triazolyl, dihydroindenyl, isoxazolyl, isoxazolyl, morpholinyl, thiazolinyl, thiazolidinyl, iso Thiazolyl, quinuclidinyl, isothiazolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, decahydroisoquinolinyl, benzene Imidazolyl, thiadiazolyl, benzopyranyl, tetrahydrofuranyl, tetrahydropyranyl, thienyl, benzothienyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, Dioxaphospholanyl, oxadiazolyl, chromanyl and isochromanyl. A heteroaryl ring group can be attached to the main structure at any heteroatom or carbon atom. The term "substituted heteroaryl" also includes ring systems substituted with one or more oxide substituents, such as pyridyl N-oxides.

除非另有指定,否則術語「雜芳基烷基」係指直接鍵結至烷基之如上文所定義之雜芳基環基團。雜芳基烷基可在來自烷基之任一碳原子處連接至主結構。Unless otherwise specified, the term "heteroarylalkyl" refers to a heteroaryl ring group as defined above directly bonded to an alkyl group. Heteroarylalkyl groups can be attached to the main structure at any carbon atom from the alkyl group.

術語「環」係指含有3至10個碳原子之環。The term "ring" refers to a ring containing 3 to 10 carbon atoms.

除非另有指定,否則術語「經取代」係指用以下取代基中之任一者或任一組合取代,該等取代基可相同或不同且獨立地選自氫、羥基、鹵素、羧基、氰基、硝基、側氧基(=O)、硫基(=S)、經取代或未經取代之烷基、經取代或未經取代之烷氧基、經取代或未經取代之烯基、經取代或未經取代之炔基、經取代或未經取代之芳基、經取代或未經取代之芳基烷基、經取代或未經取代之環烷基、經取代或未經取代之環烷基烷基、經取代或未經取代之環烯基、經取代或未經取代之環烯基烷基、經取代或未經取代之雜芳基、經取代或未經取代之雜芳基烷基、經取代或未經取代之雜環、經取代之雜環基烷基環、經取代或未經取代之胍、-COOR t、-C(O)R v、-C(S)R v、-C(O)NR tR u、-C(O)ONR tR u、-NR tR u、-NR tCONR uR v、-N(R t)SOR u、-N(R t)SO 2R u、-(=N-N(R t)R u)、- NR tC(O)OR u、-NR tR u、-NR tC(O)R u-、-NR tC(S)R u-NR tC(S)NR tR u、-SONR tR u-、-SO 2NR tR u-、-OR t、-OC(O)NR uR v、-OC(O)OR u-、-OC(O)R t、-OC(O)NR tR u、-R tNR uC(O)R v、-R tOR u、-R tC(O)OR u、-R tC(O)NR uR v、-R tC(O)R u、-R tOC(O)R u、-SR t、-SOR t、-SO 2R t及-ONO 2,其中以上基團中之每一者中之R t、R u及R v可為氫、經取代或未經取代之烷基、經取代或未經取代之烷氧基、經取代或未經取代之烯基、經取代或未經取代之炔基、經取代或未經取代之芳基、經取代或未經取代之芳基烷基、經取代或未經取代之環烷基、經取代或未經取代之環烷基烷基、經取代或未經取代之環烯基、經取代或未經取代之胺基、經取代或未經取代之雜芳基、經取代或未經取代之雜芳基烷基、經取代或未經取代之雜環或經取代之雜環基烷基環,或R t、R u及R v中之任兩者可連結以形成經取代或未經取代之飽和或不飽和3員至10員環,其可視情況包括雜原子,該等雜原子可相同或不同且選自O、NR t(例如R t可為氫或C 1-6烷基)或S。 本發明所設想之取代或取代基組合較佳為使得形成穩定或化學可行化合物之彼等取代或取代基組合。如本文所用之術語穩定係指如下化合物或結構:當經受容許其產生、偵測且較佳其回收、純化及併入至醫藥組合物中之條件時,其不會實質上改變。上文所提及之「經取代」基團中之取代基可進一步經取代。 Unless otherwise specified, the term "substituted" means substituted with any one or any combination of the following substituents, which may be the same or different and independently selected from hydrogen, hydroxyl, halogen, carboxyl, cyano substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl , substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted hetero Arylalkyl, substituted or unsubstituted heterocycle, substituted heterocyclylalkyl ring, substituted or unsubstituted guanidine, -COOR t , -C(O)R v , -C(S )R v , -C(O)NR t R u , -C(O)ONR t R u , -NR t R u , -NR t CONR u R v , -N(R t )SOR u , -N( R t )SO 2 R u , -(=NN(R t )R u ), -NR t C(O)OR u , -NR t R u , -NR t C(O)R u -, -NR t C(S)R u -NR t C(S)NR t R u , -SONR t R u -, -SO 2 NR t R u -, -OR t , -OC(O)NR u R v , -OC (O)OR u -, -OC(O)R t , -OC(O)NR t R u , -R t NR u C(O)R v , -R t OR u , -R t C(O) OR u , -R t C(O)NR u R v , -R t C(O)R u , -R t OC(O)R u , -SR t , -SOR t , -SO 2 R t and - ONO 2 , wherein R t , Ru and R v in each of the above groups can be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or Unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, Substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted heteroaryl, substituted or unsubstituted A substituted heteroarylalkyl ring, a substituted or unsubstituted heterocycle or a substituted heterocyclylalkyl ring, or any two of R t , R u and R v may be joined to form a substituted or unsubstituted Substituted saturated or unsaturated 3- to 10-membered rings, optionally including heteroatoms, which may be the same or different and selected from O, NR t (for example R t can be hydrogen or C 1-6 alkyl) or S. Substitutions or combinations of substituents contemplated by the present invention are preferably those substitutions or combinations of substituents which result in the formation of stable or chemically feasible compounds. The term stable as used herein refers to a compound or structure that does not substantially change when subjected to conditions that allow its production, detection and, preferably, its recovery, purification and incorporation into pharmaceutical compositions. A substituent in a "substituted" group mentioned above may be further substituted.

術語「鹵基」、「鹵化物」或替代地「鹵素」意指氟、氯、溴或碘。術語「鹵烷基」、「鹵烯基」、「鹵炔基」及「鹵烷氧基」包括經一或多個鹵基或其組合取代之烷基、烯基、炔基及烷氧基結構。舉例而言,術語「氟烷基」及「氟烷氧基」分別包括鹵烷基及鹵烷氧基,其中鹵基為氟。The term "halo", "halide" or alternatively "halogen" means fluorine, chlorine, bromine or iodine. The terms "haloalkyl", "haloalkenyl", "haloalkynyl" and "haloalkoxy" include alkyl, alkenyl, alkynyl and alkoxy groups substituted with one or more halo groups or combinations thereof structure. For example, the terms "fluoroalkyl" and "fluoroalkoxy" include haloalkyl and haloalkoxy, respectively, wherein halo is fluorine.

術語「保護基團」或「PG」係指用於封阻或保護特定官能基之取代基。化合物上之其他官能基可仍為反應性的。舉例而言,「胺基保護基團」係連接至胺基之取代基,其封阻或保護化合物中之該胺基官能基。適宜胺基保護基團包括(但不限於)乙醯基、三氟乙醯基、第三丁氧基羰基(BOC)、苄氧基羰基(CBz)及9-茀基亞甲氧基羰基(Fmoc)。類似地,「羥基保護基團」係指封阻或保護羥基官能基之羥基取代基。適宜羥基保護基團包括(但不限於)乙醯基及矽基。「羧基保護基團」係指封阻或保護羧基官能基之羧基取代基。適宜羧基保護基團包括(但不限於) -CH 2CH 2SO 2Ph、氰基乙基、2-(三甲基矽基)乙基、2-(三甲基矽基)乙氧基甲基、2-(對甲苯磺醯基)乙基、2-(對硝基苯基亞磺醯基)乙基、2-(二苯基膦基)-乙基及硝基乙基。關於保護基團及其使用之一般說明,參見T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991。 The term "protecting group" or "PG" refers to a substituent used to block or protect a specific functional group. Other functional groups on the compound may remain reactive. For example, an "amino protecting group" is a substituent attached to an amine group that blocks or protects the amine functionality in a compound. Suitable amine protecting groups include, but are not limited to, acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz), and 9-fenylmethyleneoxycarbonyl ( Fmoc). Similarly, a "hydroxyl protecting group" refers to a hydroxy substituent that blocks or protects the hydroxy functionality. Suitable hydroxy protecting groups include, but are not limited to, acetyl and silyl. "Carboxy protecting group" refers to a carboxyl substituent that blocks or protects the carboxyl functionality. Suitable carboxyl protecting groups include, but are not limited to, -CH2CH2SO2Ph , cyanoethyl, 2- (trimethylsilyl)ethyl, 2- (trimethylsilyl)ethoxymethyl 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfinyl)ethyl, 2-(diphenylphosphino)-ethyl and nitroethyl. For a general description of protecting groups and their use, see TW Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

本文所闡述之某些化合物含有一或多個不對稱中心,且可由此產生就絕對立體化學而言可定義為(R)-或(S)-之鏡像異構物、非鏡像異構物及其他立體異構形式。本發明化學實體、醫藥組合物及方法意欲包括所有此等可能的異構物,包括外消旋混合物、光學純形式及中間物混合物。中間物混合物之非限制性實例包括比率為10:90、13:87、17:83、20:80或22:78之異構物混合物。可使用手性合成子或手性試劑製備光學活性(R)-及(S)-異構物,或使用習用技術拆分。當本文所闡述之化合物含有烯烴雙鍵或其他幾何不對稱性中心時,且除非另有指定,否則預期該等化合物包括E及Z幾何異構物二者。Certain of the compounds described herein contain one or more asymmetric centers from which enantiomers, diastereoisomers and Other stereoisomeric forms. The present chemical entities, pharmaceutical compositions and methods are intended to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures. Non-limiting examples of intermediate mixtures include isomeric mixtures in ratios of 10:90, 13:87, 17:83, 20:80, or 22:78. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, it is intended that such compounds include both E and Z geometric isomers.

術語「互變異構物」係指特徵在於平衡狀態下異構形式相對容易相互轉化之化合物。本發明意欲涵蓋該等異構物。「互變異構物」係藉由互變異構化相互轉化之在結構上不同之異構物。「互變異構化」係一種異構化形式且包括質子異變互變異構化或質子移位互變異構化,其視為酸-鹼化學之子集。「質子異變互變異構化」或「質子移位互變異構化」涉及質子之遷移,伴隨有鍵級改變,通常為單鍵與毗鄰雙鍵之互換。在可能發生互變異構化之情形下(例如在溶液中),可達到互變異構物之化學平衡。互變異構化之實例為酮-烯醇互變異構化。酮-烯醇互變異構化之具體實例為戊烷-2,4-二酮與4-羥基戊-3-烯-2-酮互變異構物之相互轉化。互變異構化之另一實例為酚-酮互變異構化。酚-酮互變異構化之具體實例為吡啶-4-醇與吡啶-4(1H)-酮互變異構物之相互轉化。The term "tautomer" refers to compounds characterized by the relative ease with which isomeric forms are interconvertible under equilibrium conditions. The present invention is intended to cover such isomers. "Tautomers" are structurally different isomers that are interconverted by tautomerization. "Tautomerization" is a form of isomerization and includes prototropic or protonotropic tautomerization, which are considered a subset of acid-base chemistry. "Prototropic tautomerization" or "protonotropic tautomerization" involves the migration of protons with concomitant changes in bond order, usually the interchange of a single bond for an adjacent double bond. In situations where tautomerization is possible (eg, in solution), chemical equilibrium of the tautomers can be achieved. An example of tautomerization is keto-enol tautomerization. A specific example of keto-enol tautomerization is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerization is phenol-keto tautomerization. A specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4(1H)-one tautomers.

「脫離基或脫離原子」係在反應條件下將自起始材料裂解,由此促進在指定位點反應之任何基團或原子。除非另有指定,否則此等基團之適宜實例為鹵素原子及甲磺醯基氧基、對硝基苯磺醯基氧基及甲苯磺醯基氧基。A "leaving group or atom" is any group or atom which, under the reaction conditions, will cleave from the starting material, thereby facilitating reaction at the designated site. Suitable examples of such groups, unless otherwise specified, are halogen atoms and methanesulfonyloxy, p-nitrobenzenesulfonyloxy and tosyloxy.

術語「前藥」係指如下化合物:其為無活性之化合物前體,在體內藉由正常代謝過程轉化成該化合物之活性形式。前藥設計概言之論述於Hardma等人(編輯),Goodman及Gilman,The Pharmacological Basis of Therapeutics,第9版,第11-16頁(1996)中。詳盡論述提供於Higuchi等人,Prodrugs as Novel Delivery Systems,第14卷,ASCD Symposium Series及Roche (編輯),Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987)中。為進行闡釋,可經由水解(例如)酯或醯胺鍵聯,藉此在所得產物上引入官能基或使官能基暴露而將前藥轉化成藥理學活性形式。前藥可經設計以與內源性化合物反應形成水溶性結合物,該結合物進一步增強化合物之藥理學性質,例如延長循環半衰期。或者,前藥可經設計以在官能基上經歷用(例如)葡萄糖醛酸、硫酸鹽、麩胱甘肽、胺基酸或乙酸鹽共價修飾。可使所得結合物去活化且在尿液中排泄出,或使其較母體化合物更強效。高分子量結合物亦可排泄至膽汁中,經受酶裂解,且釋放回至循環中,藉此有效地延長最初投與化合物之生物半衰期。The term "prodrug" refers to a compound that is an inactive precursor of a compound that is converted in the body by normal metabolic processes to the active form of the compound. An overview of prodrug design is discussed in Hardma et al. (eds.), Goodman and Gilman, The Pharmacological Basis of Therapeutics, 9th Ed., pp. 11-16 (1996). A thorough discussion is provided in Higuchi et al., Prodrugs as Novel Delivery Systems, Vol. 14, ASCD Symposium Series and Roche (eds.), Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987). For illustration, prodrugs may be converted to pharmacologically active forms by hydrolysis of, for example, ester or amide linkages, thereby introducing or exposing functional groups on the resulting product. Prodrugs can be designed to react with endogenous compounds to form water-soluble conjugates that further enhance the pharmacological properties of the compound, such as increasing circulating half-life. Alternatively, prodrugs can be designed to undergo covalent modification at functional groups with, for example, glucuronic acid, sulfate, glutathione, amino acids, or acetate. The resulting conjugates can be deactivated and excreted in urine, or made more potent than the parent compound. High molecular weight conjugates can also be excreted into bile, undergo enzymatic cleavage, and be released back into circulation, thereby effectively extending the biological half-life of the originally administered compound.

術語「酯」係指藉由酸與醇之間的反應消除水而形成之化合物。 酯可由通式RCOOR'表示。The term "ester" refers to a compound formed by the reaction between an acid and an alcohol with the elimination of water. Esters can be represented by the general formula RCOOR'.

該等前藥及酯意欲涵蓋在本發明之範圍內。Such prodrugs and esters are intended to be encompassed within the scope of this invention.

另外,本發明亦包括不同之處僅在於存在一或多個同位素富集原子(例如用氘或氚替代氫,或用 13C或 14C富集碳替代碳)之化合物。 In addition, the invention also includes compounds that differ only in the presence of one or more isotopically enriched atoms (eg deuterium or tritium in place of hydrogen, or 13 C or 14 C enriched carbon in place of carbon).

本發明之化合物亦可在構成此等化合物之一或多個原子處含有非天然比例之原子同位素。舉例而言,化合物可經放射性同位素放射標記,該等放射性同位素諸如為氚( 3H)、碘-125 ( 125I)或碳-14 ( 14C)。本發明化合物之所有同位素變化形式(無論是否具有放射性)均涵蓋在本發明之範圍內。 The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms constituting such compounds. For example, compounds may be radiolabeled with radioisotopes such as tritium ( 3H ), iodine-125 ( 125I ), or carbon-14 ( 14C ). All isotopic variations of the compounds of the invention, whether radioactive or not, are encompassed within the scope of the invention.

形成本發明之一部分之醫藥學上可接受之鹽包括衍生自無機鹼之鹽,諸如Li、Na、K、Ca、Mg、Fe、Cu、Zn及Mn鹽;有機鹼之鹽,諸如N,N'-二乙醯基乙二胺、葡萄糖胺、三乙胺、膽鹼、氫氧化物、二環己胺、二甲雙胍、苄胺、三烷基胺及硫胺素之鹽;手性鹼之鹽,諸如烷基苯基胺、甘胺醇及苯基甘胺醇之鹽;天然胺基酸之鹽,諸如甘胺酸、丙胺酸、纈胺酸、白胺酸、異白胺酸、正白胺酸、酪胺酸、胱胺酸、半胱胺酸、甲硫胺酸、脯胺酸、羥脯胺酸、組胺酸、鳥胺酸、離胺酸、精胺酸及絲胺酸之鹽;本發明之化合物與烷基鹵化物、硫酸烷基酯(諸如MeI及(Me) 2SO 4)之四級銨鹽;非天然胺基酸(諸如D-異構物或經取代之胺基酸)之鹽;胍鹽;及經取代之胍鹽,其中取代基選自硝基、胺基、烷基、烯基、炔基、銨或經取代之銨鹽及鋁鹽。適當時,鹽可包括酸加成鹽,其為硫酸鹽、硝酸鹽、磷酸鹽、過氯酸鹽、硼酸鹽、氫鹵化物(例如鹽酸鹽)、乙酸鹽、酒石酸鹽、馬來酸鹽、檸檬酸鹽、富馬酸鹽、琥珀酸鹽、雙羥萘酸鹽、甲磺酸鹽、苯甲酸鹽、柳酸鹽、苯磺酸鹽、抗壞血酸鹽、甘油磷酸鹽及酮戊二酸鹽。 Pharmaceutically acceptable salts which form part of the present invention include salts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn and Mn salts; organic bases such as N,N Salts of '-diacetylethylenediamine, glucosamine, triethylamine, choline, hydroxide, dicyclohexylamine, metformin, benzylamine, trialkylamine and thiamine; salts of chiral bases , such as salts of alkylphenylamines, glycinol and phenylglycol; salts of natural amino acids, such as glycine, alanine, valine, leucine, isoleucine, orthowhite Amino acid, tyrosine, cystine, cysteine, methionine, proline, hydroxyproline, histidine, ornithine, lysine, arginine and serine salts; quaternary ammonium salts of compounds of the invention with alkyl halides, alkyl sulfates such as MeI and (Me) 2 SO 4 ; unnatural amino acids such as D-isomers or substituted amines salts of amino acids); guanidinium salts; and substituted guanidinium salts, wherein the substituents are selected from nitro, amino, alkyl, alkenyl, alkynyl, ammonium or substituted ammonium and aluminum salts. Salts may include acid addition salts, as appropriate, such as sulfates, nitrates, phosphates, perchlorates, borates, hydrohalides (e.g. hydrochlorides), acetates, tartrates, maleates , citrate, fumarate, succinate, pamoate, mesylate, benzoate, salicylate, besylate, ascorbate, glycerophosphate and ketoglutarate Salt.

在本文中針對物理性質(諸如分子量)或化學性質(諸如化學式)使用範圍時,意欲包括其中之範圍及具體實施例之所有組合及亞組合。在提及數量或數值範圍時,術語「約」意指所提及之數量或數值範圍係實驗可變性內(或統計學實驗誤差內)之近似值,且因此數量或數值範圍可(例如)在所述數量或數值範圍之1%與15%之間變化。術語「包含(comprising)」(及諸如「包含(comprise或comprises)」或「具有」或「包括」等相關術語)包括例如如下彼等實施例:任何物質組成、組合物、方法或製程或諸如此類「由所闡述特徵組成」或「基本上由所闡述特徵組成」之實施例。Where ranges are used herein for a physical property (such as molecular weight) or chemical property (such as a chemical formula), all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "about" when referring to a quantity or a numerical range means that the referred quantity or numerical range is an approximation within experimental variability (or within statistical experimental error), and thus the quantity or numerical range may, for example, be within Vary between 1% and 15% of the stated amount or range of values. The term "comprising" (and related terms such as "comprises or comprises" or "has" or "including") includes, for example, such embodiments as: any composition of matter, method or process, or the like Embodiments that "consist of" or "consist essentially of" the recited features.

術語「細胞增殖」係指細胞數量由於分裂而變化之現象。此術語亦涵蓋細胞形態學發生變化(例如大小增加)之細胞生長,其與增殖信號一致。The term "cell proliferation" refers to the phenomenon in which the number of cells changes due to division. The term also encompasses cell growth in which cell morphology changes (eg, increase in size) consistent with a proliferative signal.

如本文所用,術語「共投與」、「組合投與」及其文法等效形式涵蓋向動物投與兩種或更多種劑,使得兩種劑及/或其代謝物同時存在於該動物中。共投與包括以分開組合物同時投與、以分開組合物在不同時間投與或以存在兩種劑之組合物投與。As used herein, the terms "co-administration", "combination administration" and their grammatical equivalents encompass the administration of two or more agents to an animal such that both agents and/or their metabolites are present in the animal simultaneously middle. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present.

術語「有效量」或「治療有效量」係指本文所闡述之化合物足以顯示預期應用之量,該預期應用包括(但不限於)如下文所定義之疾病治療。治療有效量可端視預期應用(活體外或活體內)或所治療之個體及疾病病狀而變化,例如個體之體重及年齡、疾病病狀之嚴重程度、投與方式及諸如此類,其可由熟習此項技術者容易地確定。該術語亦適用於將在靶細胞中誘導特定反應(例如減少血小板黏附及/或細胞遷移)之劑量。具體劑量將端視以下因素而變化:所選化合物、擬遵循之投藥方案、是否與其他化合物組合投與、投與時間、所投與組織及攜帶其之物理遞送系統。 在一個實施例中,化合物投與量在約0.1 mg至5 g、約1 mg至2.0 g、約100 mg至1.5 g、約200 mg至1.5 g、約400 mg至1.5 g及約400 mg至1.0 g範圍內。The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound described herein sufficient to demonstrate the intended use including, but not limited to, the treatment of disease as defined below. A therapeutically effective amount may vary depending on the intended use (in vitro or in vivo) or on the subject and the disease condition being treated, such as the weight and age of the subject, severity of the disease condition, mode of administration, and the like, which can be determined by skilled Easily determined by those skilled in the art. The term also applies to doses that will induce a particular response in target cells, such as reduced platelet adhesion and/or cell migration. The specific dosage will vary depending on the compound selected, the dosing regimen to be followed, whether it is administered in combination with other compounds, the time of administration, the tissue to which it is administered, and the physical delivery system carrying it. In one embodiment, the compound is administered in an amount of about 0.1 mg to 5 g, about 1 mg to 2.0 g, about 100 mg to 1.5 g, about 200 mg to 1.5 g, about 400 mg to 1.5 g, and about 400 mg to 1.0 g range.

如本文所用,「治療(treatment、treating)」或「改善」可互換使用。該等術語係指獲得有益或期望結果之方法,該等結果包括(但不限於)治療益處及/或預防益處。治療益處意指根除或改善所治療之潛在病症。同樣,藉由根除或改善與潛在病症相關之一或多種生理學症狀達成治療益處,使得在患者中觀察到改良,但患者可能仍受到潛在病症之折磨。為獲得預防益處,可向處於發生特定疾病風險下之患者或向報告疾病之一或多種生理學症狀之患者投與組合物,即使可能尚未作出對此疾病之診斷。As used herein, "treatment, treating" or "improvement" are used interchangeably. These terms refer to means of obtaining beneficial or desired results including, but not limited to, therapeutic benefit and/or prophylactic benefit. Therapeutic benefit means eradication or amelioration of the underlying condition being treated. Likewise, therapeutic benefit is achieved by eradicating or ameliorating one or more physiological symptoms associated with the underlying condition, such that improvement is observed in a patient, but the patient may still be afflicted by the underlying condition. For prophylactic benefit, compositions may be administered to patients at risk of developing a particular disease or to patients reporting one or more physiological symptoms of a disease, even though a diagnosis of the disease may not have been made.

「治療效應」在該術語用於本文中時涵蓋如上文所闡述之治療益處及/或預防益處。預防效應包括延遲或消除疾病或疾患之出現、延遲或消除疾病或疾患之症狀之發作、減緩、停止或逆轉疾病或疾患之進展或其任何組合。"Therapeutic effect" as the term is used herein encompasses therapeutic and/or prophylactic benefits as set out above. A preventive effect includes delaying or eliminating the onset of a disease or disorder, delaying or eliminating the onset of symptoms of a disease or disorder, slowing, stopping or reversing the progression of a disease or disorder, or any combination thereof.

術語「個體」或「患者」係指動物,諸如哺乳動物,例如人類。本文所闡述之方法可用於人類治療及獸醫學應用二者(例如狗、貓、牛、綿羊、豬、馬、山羊、雞、火雞、鴨及鵝)中。The term "individual" or "patient" refers to an animal, such as a mammal, eg a human. The methods described herein can be used in both human therapy and veterinary applications such as dogs, cats, cattle, sheep, pigs, horses, goats, chickens, turkeys, ducks and geese.

。在一些實施例中,患者為哺乳動物,且在一些實施例中,患者為人類。. In some embodiments, the patient is a mammal, and in some embodiments, the patient is a human.

「放射療法」意指使用執業醫師已知之常規方法及組合物,使患者暴露于輻射發射體,諸如發射α粒子之放射性核種(例如錒及釷放射性核種)、低線性能量轉移(LET)輻射發射體(亦即β發射體)、轉換電子發射體(例如鍶-89及釤-153-EDTMP)或高能輻射,包括(但不限於) x射線、γ射線及中子。"Radiation therapy" means exposing a patient to radiation emitters, such as alpha-emitting radionuclides (e.g., actinium and thorium radionuclides), low linear energy transfer (LET) radiation emitters, using conventional methods and compositions known to the practitioner. Emitters (ie, beta emitters), converted electron emitters (such as strontium-89 and samarium-153-EDTMP), or high-energy radiation including, but not limited to, x-rays, gamma rays, and neutrons.

術語「醫藥學上可接受之賦形劑」包括(但不限於)任何及所有溶劑、分散介質、包衣、抗細菌劑及抗真菌劑、等滲劑及吸收延遲劑、一或多種適宜稀釋劑、填充劑、鹽、崩解劑、黏合劑、潤滑劑、助流劑、潤濕劑、受控釋放基質、著色劑/矯味劑、載劑、緩衝劑、穩定劑、增溶劑及其組合。除非任何習用介質或劑與活性成分不相容,否則考慮將其用於本發明之治療組合物中。亦可將補充性活性成分併入至組合物中。The term "pharmaceutically acceptable excipient" includes, but is not limited to, any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, one or more suitable diluents, Agents, fillers, salts, disintegrants, binders, lubricants, glidants, wetting agents, controlled release matrices, colorants/flavors, carriers, buffers, stabilizers, solubilizers, and combinations thereof . Unless any conventional media or agents are incompatible with the active ingredients, they are contemplated for use in the therapeutic compositions of the present invention. Supplementary active ingredients can also be incorporated into the compositions.

本發明之方法可應用於活體內或離體細胞群體。「活體內」意指活個體內,如動物或人類或個體體內。在此背景下,本發明之方法可治療性地或預防性地用於個體中。「離體」或「活體外」意指在活個體體外。離體細胞群體之實例包括活體外細胞培養物及生物樣品,包括(但不限於)自個體獲得之流體或組織樣品。此等樣品可藉由此項技術中已知之方法來獲得。例示性生物流體樣品包括血液、腦脊髓液、尿液及唾液。例示性組織樣品包括腫瘤及其生檢。在此背景下,本發明可用於多種目的,包括治療及實驗目的。舉例而言,本發明可用於離體或活體外確定針對給定適應症、細胞類型、個體及其他參數投與CDK抑制劑之最佳時間表及/或劑量。自此用途收集之資訊可用於實驗性或診斷性目的,或在診療所中用於設定活體內治療之方案。本發明可能適用之其他離體應用闡述於下文中,或將對熟習此項技術者變得顯而易見。 醫藥組合物 The methods of the invention can be applied to cell populations in vivo or ex vivo. "In vivo" means within a living subject, such as an animal or human being or subject. In this context, the methods of the invention can be used therapeutically or prophylactically in an individual. "Ex vivo" or "in vitro" means outside the body of a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples including, but not limited to, fluid or tissue samples obtained from an individual. Such samples can be obtained by methods known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. Exemplary tissue samples include tumors and biopsies thereof. In this context, the present invention can be used for a variety of purposes, including therapeutic and experimental purposes. For example, the invention can be used ex vivo or in vitro to determine the optimal schedule and/or dose of CDK inhibitor administration for a given indication, cell type, individual, and other parameters. Information collected from this use may be used for experimental or diagnostic purposes, or in a clinic to plan in vivo therapy. Other ex vivo applications to which the present invention may be applicable are described below, or will become apparent to those skilled in the art. pharmaceutical composition

本發明提供包含一或多種本發明化合物之醫藥組合物。醫藥組合物可包括一或多種如本文所闡述之額外活性成分。醫藥組合物可針對本文所闡述之任一病症投與。The invention provides pharmaceutical compositions comprising one or more compounds of the invention. Pharmaceutical compositions may include one or more additional active ingredients as set forth herein. Pharmaceutical compositions can be administered for any of the conditions described herein.

標的醫藥組合物通常經調配以提供治療有效量之本發明化合物作為活性成分。若期望,醫藥組合物含有作為活性成分之本發明化合物以及一或多種醫藥學上可接受之載劑或賦形劑,諸如惰性固體稀釋劑及填充劑、稀釋劑(包括無菌水溶液及各種有機溶劑)、滲透增強劑、增溶劑及佐劑。A subject pharmaceutical composition is generally formulated to provide a therapeutically effective amount of a compound of the invention as an active ingredient. If desired, pharmaceutical compositions contain a compound of the present invention as the active ingredient together with one or more pharmaceutically acceptable carriers or excipients, such as inert solid diluents and fillers, diluents (including sterile aqueous solutions and various organic solvents) ), penetration enhancers, solubilizers and adjuvants.

醫藥組合物可單獨投與或與一或多種其他劑組合投與,該等其他劑通常亦以醫藥組合物之形式投與。若期望,可將標的化合物及其他劑混合成製劑,或可將兩種組分調配成單獨製劑以分開或同時組合使用。Pharmaceutical compositions can be administered alone or in combination with one or more other agents, which are also typically administered in the form of pharmaceutical compositions. If desired, the subject compound and other agents may be mixed into a formulation, or the two components may be formulated into separate formulations for separate or simultaneous combined use.

方法包括以自身或以如本文所闡述之組合投與本發明之化合物,且在每一情形中視情況包括一或多種適宜稀釋劑、填充劑、鹽、崩解劑、黏合劑、潤滑劑、助流劑、潤濕劑、受控釋放基質、著色劑/矯味劑、載劑、賦形劑、緩衝劑、穩定劑、增溶劑及其組合。The method involves administering a compound of the invention by itself or in combination as described herein, and in each case optionally including one or more suitable diluents, fillers, salts, disintegrants, binders, lubricants, auxiliary agents, etc. Fluids, wetting agents, controlled release matrices, colorants/flavors, carriers, excipients, buffers, stabilizers, solubilizers, and combinations thereof.

各種醫藥組合物之製備為此項技術中所已知,例如Anderson, Philip O.; Knoben, James E.; Troutman, William G編輯,Handbook of Clinical Drug Data,第十版,McGraw-Hill, 2002;Pratt及Taylor編輯,Principles of Drug Action,第三版,Churchill Livingston, New York, 1990;Katzung編輯,Basic and Clinical Pharmacology,第九版,McGraw Hill, 2003;Goodman及Gilman編輯,The Pharmacological Basis of Therapeutics,第十版,McGraw Hill, 2001;Remingtons Pharmaceutical Sciences,第20版,Lippincott Williams & Wilkins., 2000;Martindale, The Extra Pharmacopoeia,第三十二版(The Pharmaceutical Press, London, 1999),所有該等文獻均係以全文引用的方式併入本文中。The preparation of various pharmaceutical compositions is known in the art, for example Anderson, Philip O.; Knoben, James E.; Troutman, William G, ed., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Edited by Pratt and Taylor, Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Edited by Katzung, Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 2003; Edited by Goodman and Gilman, The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001; Remingtons Pharmaceutical Sciences, 20th Edition, Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999), all of which All are incorporated herein by reference in their entirety.

本發明之化合物或醫藥組合物可藉由任一使得能夠將化合物遞送至作用部位之途徑來投與,諸如經口途徑、十二指腸內途徑、非經腸注射(包括靜脈內、動脈內、皮下、肌內、血管內、腹膜內或輸注)、局部投與(例如經皮施加)、經直腸投與、藉由導管或支架或經由吸入而經由局部遞送。 亦可脂肪內或鞘內投與化合物。The compounds or pharmaceutical compositions of the present invention may be administered by any route that enables delivery of the compound to the site of action, such as oral, intraduodenal, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal, or infusion), local administration (eg, transdermal application), rectal administration, local delivery via a catheter or stent, or via inhalation. Compounds can also be administered intralipidally or intrathecally.

組合物可以固體、半固體、液體或氣態形式投與,或可呈乾粉形式,諸如凍乾形式。醫藥組合物可以便於遞送之形式包裝,包括(例如)固體劑型,諸如膠囊、小藥囊、扁囊劑、明膠、紙、錠劑、膠囊、栓劑、團粒、丸粒、糖錠劑及菱形錠劑。包裝類型通常將取決於期望投與途徑。亦考慮可植入之持續釋放調配物以及經皮調配物。 治療方法 Compositions may be administered in solid, semi-solid, liquid or gaseous form, or may be in dry powder form, such as lyophilized form. Pharmaceutical compositions can be packaged in a form convenient for delivery including, for example, solid dosage forms such as capsules, sachets, cachets, gelatin, papers, lozenges, capsules, suppositories, granules, pellets, dragees, and lozenges. agent. The type of packaging will generally depend on the desired route of administration. Implantable sustained release formulations as well as transdermal formulations are also contemplated. treatment method

本發明亦提供使用本發明之化合物或醫藥組合物治療疾病病狀之方法,該等疾病病狀包括(但不限於)與CDK1、CDK2、CDK4及CDK6中之一或多者之過表現相關及/或由於CDK1、CDK2、CDK4及CDK6中之一或多者過量所引起之疾病。The invention also provides methods of using the compounds or pharmaceutical compositions of the invention to treat disease conditions including, but not limited to, those associated with overexpression of one or more of CDK1, CDK2, CDK4, and CDK6 and /or diseases caused by excess of one or more of CDK1, CDK2, CDK4 and CDK6.

本文所提供之治療方法包括向個體投與治療有效量之本發明化合物。在一個實施例中,本發明提供治療發炎病症之方法,該發炎病症包括哺乳動物之自體免疫性疾病。該方法包括向哺乳動物投與治療有效量之本發明化合物。The methods of treatment provided herein comprise administering to a subject a therapeutically effective amount of a compound of the invention. In one embodiment, the present invention provides methods of treating inflammatory disorders, including autoimmune diseases in mammals. The method comprises administering to the mammal a therapeutically effective amount of a compound of the invention.

應瞭解,本發明之治療方法可用於人類醫學及獸醫學領域。因此,欲治療之個體可為哺乳動物、較佳人類,或另一動物。出於獸醫學目的,個體包括(但不限於)農場動物,包括牛、綿羊、豬、馬及山羊;伴侶動物,諸如狗及貓;外來及/或動物園動物;實驗室動物,包括小鼠、大鼠、兔、天竺鼠及倉鼠;及家禽,諸如雞、火雞、鴨及鵝。It will be appreciated that the methods of treatment of the present invention have application in the fields of human medicine as well as veterinary medicine. Thus, the individual to be treated may be a mammal, preferably a human, or another animal. For veterinary purposes, subjects include, but are not limited to, farm animals, including cattle, sheep, pigs, horses, and goats; companion animals, such as dogs and cats; exotic and/or zoo animals; laboratory animals, including mice, rats, rabbits, guinea pigs and hamsters; and poultry such as chickens, turkeys, ducks and geese.

本發明亦提供使用本發明之化合物或醫藥組合物治療疾病病狀之方法,該等疾病病狀包括(但不限於)與CDK1、CDK2、CDK4及CDK6中之一或多者之過表現相關及/或由於CDK1、CDK2、CDK4及CDK6中之一或多者過量所引起之疾病。The invention also provides methods of using the compounds or pharmaceutical compositions of the invention to treat disease conditions including, but not limited to, those associated with overexpression of one or more of CDK1, CDK2, CDK4, and CDK6 and /or diseases caused by excess of one or more of CDK1, CDK2, CDK4 and CDK6.

本文所提供之治療方法包括向個體投與治療有效量之本發明化合物。在一個實施例中,本發明提供治療發炎病症之方法,該發炎病症包括哺乳動物之自體免疫性疾病。該方法包括向哺乳動物投與治療有效量之本發明化合物。The methods of treatment provided herein comprise administering to a subject a therapeutically effective amount of a compound of the invention. In one embodiment, the present invention provides methods of treating inflammatory disorders, including autoimmune diseases in mammals. The method comprises administering to the mammal a therapeutically effective amount of a compound of the invention.

應瞭解,本發明之治療方法可用於人類醫學及獸醫學領域。因此,欲治療之個體可為哺乳動物、較佳人類,或另一動物。出於獸醫學目的,個體包括(但不限於)農場動物,包括牛、綿羊、豬、馬及山羊;伴侶動物,諸如狗及貓;外來及/或動物園動物;實驗室動物,包括小鼠、大鼠、兔、天竺鼠及倉鼠;及家禽,諸如雞、火雞、鴨及鵝。It will be appreciated that the methods of treatment of the present invention have application in the fields of human medicine as well as veterinary medicine. Thus, the individual to be treated may be a mammal, preferably a human, or another animal. For veterinary purposes, subjects include, but are not limited to, farm animals, including cattle, sheep, pigs, horses, and goats; companion animals, such as dogs and cats; exotic and/or zoo animals; laboratory animals, including mice, rats, rabbits, guinea pigs and hamsters; and poultry such as chickens, turkeys, ducks and geese.

本發明亦係關於治療哺乳動物之過度增殖性病症之方法,其包括向該哺乳動物投與治療有效量之本發明化合物或其醫藥學上可接受之鹽、酯、前藥、溶劑合物、水合物或衍生物。在一些實施例中,該方法係關於廣譜腫瘤之治療,包括統稱為癌症之所有實體腫瘤及血液惡性病。此等腫瘤之實例包括(但不限於)以下部位之良性或惡性腫瘤:腦、肺(尤其小細胞肺癌及非小細胞肺癌)、鱗狀細胞、膀胱、胃、胰臟、乳房、頭頸部、腎(renal、kidney)、輸尿管、卵巢、前列腺、結腸直腸、食管、睪丸、婦科腫瘤(例如子宮肉瘤、輸卵管癌、子宮內膜癌、子宮頸癌、陰道癌或外陰癌)、甲狀腺、胰臟、骨、皮膚、黑色素瘤、子宮、卵巢、直腸、肛門、結腸、睪丸、霍奇金氏病、食管、小腸、內分泌系統(例如甲狀腺、副甲狀腺或腎上腺)、軟組織肉瘤、尿道、陰莖、白血病、淋巴瘤、中樞神經系統贅瘤、肉瘤、骨髓瘤、膽、肝臟、神經纖維瘤病、急性骨髓性白血病(AML)、骨髓發育不良症候群(MDS)及卡波西氏肉瘤。The present invention also relates to a method for treating a hyperproliferative disorder in a mammal, which comprises administering to the mammal a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt, ester, prodrug, solvate, Hydrates or derivatives. In some embodiments, the method relates to the treatment of a broad spectrum of tumors, including all solid tumors and hematological malignancies collectively referred to as cancer. Examples of such tumors include, but are not limited to, benign or malignant tumors of the brain, lung (especially small cell and non-small cell lung cancer), squamous cell, bladder, stomach, pancreas, breast, head and neck, Kidney (renal, kidney), ureter, ovary, prostate, colorectum, esophagus, testis, gynecologic tumors (eg, uterine sarcoma, fallopian tube, endometrial, cervix, vagina, or vulva), thyroid, pancreas , bone, skin, melanoma, uterus, ovary, rectum, anus, colon, testis, Hodgkin's disease, esophagus, small intestine, endocrine system (such as thyroid, parathyroid, or adrenal), soft tissue sarcomas, urethra, penis, leukemia , lymphoma, central nervous system neoplasm, sarcoma, myeloma, gallbladder, liver, neurofibromatosis, acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS) and Kaposi's sarcoma.

本發明亦係關於治療增殖性疾病之方法,該增殖性疾病諸如為黑色素瘤、肺癌(包括非小細胞肺癌(NSCLC))、結腸直腸癌(CRC)、乳癌、腎癌(諸如腎細胞癌(RCC))、肝癌、子宮內膜癌、急性骨髓性白血病(AML)、骨髓發育不良症候群(MDS)、甲狀腺癌(特定而言乳頭狀甲狀腺癌)、胰臟癌、神經纖維瘤病或肝細胞癌。The invention also relates to methods of treating proliferative diseases such as melanoma, lung cancer (including non-small cell lung cancer (NSCLC)), colorectal cancer (CRC), breast cancer, kidney cancer (such as renal cell carcinoma ( RCC), liver cancer, endometrial cancer, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), thyroid cancer (specifically papillary thyroid cancer), pancreatic cancer, neurofibromatosis, or hepatocellular carcinoma cancer.

本發明亦係關於治療增殖性疾病之方法,該增殖性疾病諸如為實體腫瘤,其包括黑色素瘤、乳癌、卵巢癌、結腸直腸癌及通常胃腸道癌、子宮頸癌、肺癌(包括小細胞肺癌及非小細胞肺癌)、頭頸癌、膀胱癌、前列腺癌或卡波西氏肉瘤。The present invention also relates to methods of treating proliferative diseases, such as solid tumors, including melanoma, breast cancer, ovarian cancer, colorectal cancer and generally gastrointestinal cancer, cervical cancer, lung cancer (including small cell lung cancer) and non-small cell lung cancer), head and neck cancer, bladder cancer, prostate cancer, or Kaposi's sarcoma.

在一些實施例中,該方法用於治療選自由CDK1、CDK2、CDK4及CDK6中之一或多者介導之癌症組成之群的疾病,包括(例如)實體腫瘤(例如乳癌(例如ER+乳癌)及前列腺癌)、白血病(例如急性淋巴母細胞性白血病、急性骨髓樣白血病、慢性淋巴球性白血病、慢性骨髓性白血病、毛細胞白血病及骨髓樣白血病)、淋巴瘤(例如柏基特氏淋巴瘤、皮膚性T細胞淋巴瘤、瀰漫性大B細胞淋巴瘤(DLBCL)、濾泡性淋巴瘤(FL)、霍奇金氏淋巴瘤、套細胞淋巴瘤及非霍奇金氏淋巴瘤(NHL))、腎上腺皮質癌、AIDS相關之癌症、肛門癌、星細胞瘤、基底細胞癌、皮膚癌(非黑色素瘤)、膽管癌、膀胱癌、骨癌(例如纖維肉瘤/骨肉瘤/惡性纖維性組織細胞瘤)、腦瘤(例如大腦星細胞瘤、室管膜瘤、神經膠質瘤、髓母細胞瘤及幕上原始神經外胚層腫瘤(PNET))、腦幹神經膠質瘤、支氣管腺瘤/類癌、類癌瘤、中樞神經系統贅瘤、子宮頸癌、膽道癌、慢性骨髓增殖性病症、結腸癌、子宮內膜癌、食管癌、黑色素瘤(例如皮膚性或眼內)、膽囊癌、胃腸癌(例如結腸直腸癌、十二指腸癌及胃癌(gastric cancer、stomach cancer))、生殖細胞瘤、頭頸癌、肝細胞癌(肝癌)、下咽癌、胰島細胞癌、卡波西氏肉瘤、腎癌(腎細胞癌)、喉癌、唇癌及口腔癌、肺癌(小細胞肺癌及非小細胞肺癌)、默克細胞癌(Merkel cell carcinoma)、間皮瘤、內分泌癌(例如多發性內分泌贅瘤形成症候群)、多發性骨髓瘤/漿細胞贅瘤蕈狀肉芽腫、骨髓發育不良症候群、骨髓增殖性病症、鼻腔癌及副鼻竇癌、鼻咽癌、神經母細胞瘤、口咽癌、卵巢癌、胰臟癌、副甲狀腺癌、陰莖癌、垂體癌、胸膜肺母細胞瘤、直腸癌、視網膜母細胞瘤、橫紋肌肉瘤、唾液腺癌、尤恩氏肉瘤(Ewing sarcoma)、軟組織肉瘤、塞紮里症候群(Sezary syndrome)、鱗狀細胞癌、鱗狀頸癌、滑膜肉瘤、睪丸癌、胸腺瘤、胸腺癌、甲狀腺癌、移行細胞癌、滋養細胞腫瘤、尿道癌、子宮癌、輸卵管癌、陰道癌、視覺通路及下視丘神經膠質瘤、外陰癌、華氏巨球蛋白血症(Waldenstrom's macroglobulinemia)及威爾姆氏瘤(Wilms' tumor)。In some embodiments, the method is used to treat a disease selected from the group consisting of cancers mediated by one or more of CDK1, CDK2, CDK4, and CDK6, including, for example, solid tumors (e.g., breast cancer (e.g., ER+ breast cancer) and prostate cancer), leukemia (such as acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cell leukemia and myeloid leukemia), lymphoma (such as Burkitt's lymphoma , cutaneous T-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Hodgkin's lymphoma, mantle cell lymphoma, and non-Hodgkin's lymphoma (NHL) ), adrenocortical carcinoma, AIDS-related cancers, anal cancer, astrocytoma, basal cell carcinoma, skin cancer (non-melanoma), bile duct cancer, bladder cancer, bone cancer (such as fibrosarcoma/osteosarcoma/malignant fibrous tissue cell tumors), brain tumors (such as cerebral astrocytomas, ependymomas, gliomas, medulloblastomas, and supratentorial primitive neuroectodermal tumors (PNETs)), brainstem gliomas, bronchial adenomas/types Carcinoma, carcinoid tumor, central nervous system neoplasm, cervical cancer, biliary tract cancer, chronic myeloproliferative disorder, colon cancer, endometrial cancer, esophageal cancer, melanoma (eg, cutaneous or intraocular), gallbladder cancer , gastrointestinal cancer (such as colorectal cancer, duodenal cancer and gastric cancer (gastric cancer, stomach cancer)), germ cell tumor, head and neck cancer, hepatocellular carcinoma (liver cancer), hypopharyngeal cancer, islet cell carcinoma, Kaposi's sarcoma, Kidney cancer (renal cell carcinoma), laryngeal cancer, lip cancer and mouth cancer, lung cancer (small cell lung cancer and non-small cell lung cancer), Merkel cell carcinoma (Merkel cell carcinoma), mesothelioma, endocrine cancer (such as multiple endocrine neoplastic syndrome), multiple myeloma/plasma cell neoplasm mycosis fungoides, myelodysplastic syndrome, myeloproliferative disorders, nasal cavity and paranasal sinus cancers, nasopharyngeal cancer, neuroblastoma, oropharyngeal cancer, Ovarian cancer, pancreatic cancer, parathyroid cancer, penile cancer, pituitary cancer, pleuropulmonary blastoma, rectal cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, Ewing sarcoma, soft tissue sarcoma, plug Sezary syndrome, squamous cell carcinoma, squamous neck carcinoma, synovial sarcoma, testicular carcinoma, thymoma, thymus carcinoma, thyroid carcinoma, transitional cell carcinoma, trophoblastic tumor, urethral carcinoma, uterine carcinoma, fallopian tube carcinoma , vaginal cancer, visual pathway and hypothalamic glioma, vulvar cancer, Waldenstrom's macroglobulinemia and Wilms' tumor.

本發明進一步提供抑制選自CDK1、CDK2、CDK4、CDK6及上述中任一者之任一組合之CDK酶之方法,該等方法藉由使該CDK酶與足以抑制該CDK酶活性之量的本發明化合物接觸來實施。The present invention further provides a method for inhibiting a CDK enzyme selected from CDK1, CDK2, CDK4, CDK6, and any combination of any of the above. Invention compounds are practiced in contact.

在一些實施例中,本發明提供抑制CDK酶活性之方法,其中該CDK酶選自CDK1、CDK2、CDK4、CDK6及上述中任一者之任一組合,該方法藉由使該CDK酶與足以抑制該CDK酶活性之量的本發明化合物接觸來實施。In some embodiments, the present invention provides a method for inhibiting CDK enzyme activity, wherein the CDK enzyme is selected from CDK1, CDK2, CDK4, CDK6 and any combination of any of the above, the method is by making the CDK enzyme and enough This is done by contacting with a compound of the invention in an amount that inhibits the enzymatic activity of the CDK.

在一些實施例中,本發明提供抑制CDK酶活性之方法,其中該CDK酶選自CDK1、CDK2、CDK4、CDK6及上述中任一者之任一組合。此抑制可發生在溶液中、表現一或多種選自CDK1、CDK2、CDK4及CDK6之CDK酶之細胞中、包含表現CDK酶之細胞之組織中或表現CDK酶之生物體中。在一些實施例中,本發明提供抑制動物(包括哺乳動物,諸如人類)中之CDK酶活性之方法,該等方法藉由使該動物與足以抑制該動物中之CDK酶活性之量的本發明化合物接觸來實施。In some embodiments, the present invention provides a method for inhibiting CDK enzyme activity, wherein the CDK enzyme is selected from CDK1, CDK2, CDK4, CDK6 and any combination of any of the above. This inhibition can occur in solution, in a cell expressing one or more CDK enzymes selected from CDK1, CDK2, CDK4, and CDK6, in a tissue comprising cells expressing a CDK enzyme, or in an organism expressing a CDK enzyme. In some embodiments, the present invention provides methods of inhibiting CDK enzymatic activity in an animal (including mammals, such as humans) by administering to the animal an amount of the present invention sufficient to inhibit CDK enzymatic activity in the animal. compound contact.

本文所闡述之以下一般方法提供製備及使用本發明化合物之方式及過程,且其為闡釋性的而非限制性的。亦可設計對所提供方法之進一步修改及另外的新方法,以達成並服務於本發明之目的。因此,可存在屬於如由本說明書所界定之本發明之精神及範圍之其他實施例。 製備本發明化合物之一般方法 方案 -1 步驟 -1

Figure 02_image338
步驟 -2
Figure 02_image339
步驟 -1 The following general methods set forth herein provide means and procedures for making and using the compounds of the invention, and are illustrative rather than limiting. Further modifications to the presented methods and additional new methods can also be devised to achieve and serve the objectives of the present invention. Accordingly, there may be other embodiments that fall within the spirit and scope of the invention as defined by this specification. General Process for the Preparation of Compounds of the Invention Scheme -1 : Step -1 :
Figure 02_image338
Step -2 :
Figure 02_image339
Step -1 :

式(a)化合物(其中X為脫離基,諸如鹵素)與式(b)化合物偶合,形成式(c)化合物。向式(c)化合物添加保護基團,形成式(d)化合物。式(d)化合物轉化成式(e)化合物。A compound of formula (a) wherein X is a leaving group such as halogen is coupled with a compound of formula (b) to form a compound of formula (c). A protecting group is added to a compound of formula (c) to form a compound of formula (d). Compounds of formula (d) are converted to compounds of formula (e).

或者,式(a)化合物(其中X為脫離基,諸如鹵素)經式(j)化合物N-芳基化,形成式(k)化合物。式(k)化合物藉由還原轉化成式(l)化合物。Alternatively, a compound of formula (a) wherein X is a leaving group such as halogen is N-arylated with a compound of formula (j) to form a compound of formula (k). Compounds of formula (k) are converted to compounds of formula (l) by reduction.

式(a)化合物(其中X為脫離基,諸如鹵素)在經雙頻哪醇二硼硼化後形成式(m)化合物。式(m)化合物可與式(n)化合物在赫克(Heck)偶合條件下偶合,形成式(o)化合物。式(o)化合物藉由還原轉化形成式(p)化合物。 步驟 -2 Compounds of formula (a) wherein X is a leaving group, such as halogen, form compounds of formula (m) upon diborylation with bispinacol. Compounds of formula (m) can be coupled with compounds of formula (n) under Heck coupling conditions to form compounds of formula (o). Compounds of formula (o) form compounds of formula (p) by reductive transformation. Step -2 :

藉由使用雙(頻哪醇二硼)及乙酸鉀,可使式(f)化合物轉化成式(g)化合物。式(g)化合物可與式(h)化合物在鈴木(Suzuki)反應條件下偶合,例如在適宜鹼及鈀觸媒(諸如Pd(dppf) 2Cl 2.CH 2Cl 2)存在下偶合,形成式(i)化合物。式(i)化合物可與式(e)或式(p)化合物在布赫瓦爾德(Buchwald)偶合反應條件下偶合,例如在適宜鹼及鈀觸媒(諸如參(二亞苄基丙酮)二鈀(0))存在下偶合,形成式(1a)或式(1)化合物。使式(1a)化合物去保護,形成式(I)化合物。 圖解說明 -1

Figure 02_image340
圖解說明 -2
Figure 02_image342
圖解說明 -3
Figure 02_image343
圖解說明 -4
Figure 02_image345
圖解說明 -5
Figure 02_image347
方案 -2 步驟 -1
Figure 02_image349
步驟 -2
Figure 02_image351
步驟 -1 Compounds of formula (f) can be converted to compounds of formula (g) by using bis(pinacol diboron) and potassium acetate. Compounds of formula (g) can be coupled with compounds of formula (h) under Suzuki reaction conditions, for example in the presence of a suitable base and a palladium catalyst (such as Pd(dppf) 2 Cl 2 .CH 2 Cl 2 ) to form Compounds of formula (i). The compound of formula (i) can be coupled with the compound of formula (e) or formula (p) under Buchwald (Buchwald) coupling reaction conditions, for example, in a suitable base and a palladium catalyst (such as ginseng (dibenzylidene acetone) di palladium(0)) to form compounds of formula (1a) or formula (1). Compounds of formula (1a) are deprotected to form compounds of formula (I). Illustration -1
Figure 02_image340
Illustration -2
Figure 02_image342
Illustration -3 :
Figure 02_image343
Illustration -4 :
Figure 02_image345
Illustration- 5 :
Figure 02_image347
Scenario -2 Step -1 :
Figure 02_image349
Step -2 :
Figure 02_image351
Step -1 :

式(a1)化合物(其中X為脫離基,諸如鹵素)可與式(b1)化合物(其中LG為脫離基)偶合,形成式(c1)化合物。式(c1)化合物轉化成式(e1)化合物。 步驟 -2 Compounds of formula (a1) wherein X is a leaving group such as halogen can be coupled with compounds of formula (b1) wherein LG is a leaving group to form compounds of formula (c1). Compounds of formula (c1) are converted into compounds of formula (e1). Step -2 :

藉由使用雙(頻哪醇二硼)及乙酸鉀,可使式(f)化合物轉化成式(g)化合物。式(g)化合物可與式(h)化合物在鈴木反應條件下偶合,例如在適宜鹼及鈀觸媒(諸如Pd(dppf) 2Cl 2.CH 2Cl 2)存在下偶合,形成式(i)化合物。式(i)化合物可與式(e1)化合物在布赫瓦爾德偶合反應條件下偶合,例如在適宜鹼及鈀觸媒(諸如參(二亞苄基丙酮)二鈀(0))存在下偶合,形成式(I)化合物。 圖解說明 -6

Figure 02_image352
實驗數據 Compounds of formula (f) can be converted to compounds of formula (g) by using bis(pinacol diboron) and potassium acetate. Compounds of formula (g) can be coupled with compounds of formula (h) under Suzuki reaction conditions, for example in the presence of a suitable base and a palladium catalyst (such as Pd(dppf) 2 Cl 2 .CH 2 Cl 2 ) to form formula (i ) compounds. Compounds of formula (i) can be coupled with compounds of formula (e1) under Buchwald coupling reaction conditions, for example in the presence of a suitable base and a palladium catalyst (such as ginseng (dibenzylideneacetone) dipalladium (0)) , forming a compound of formula (I). Illustration- 6 :
Figure 02_image352
Experimental data

概述:除非另有提及,否則後處理意味著將反應混合物分配至括號中所提及之水相及有機相中,分離有機層,經無水硫酸鈉乾燥,過濾並蒸發有機層以獲得粗產物。 General: Unless mentioned otherwise, work-up means partitioning the reaction mixture into the aqueous and organic phases mentioned in brackets, separating the organic layer, drying over anhydrous sodium sulfate, filtering and evaporating the organic layer to obtain the crude product .

一般程序 -1 :芳基硼酸頻哪醇酯之製備:向芳基溴化物(1 eq.)於DMSO中之溶液中添加雙(頻哪醇二硼) (1.5 eq)及乙酸鉀(3.0 eq)。利用氮氣使混合物脫氣15 min。添加乙酸鈀(0.11 eq)及三環己基膦(0.17 eq),且使混合物再脫氣15 min並在80℃下攪拌,直至如藉由TLC所監測起始材料消失為止。在反應完成後,在矽藻土上過濾反應混合物且用乙酸乙酯洗滌床。相繼用鹽水及水洗滌合併的濾液及洗滌液,且使有機層經無水硫酸鈉乾燥並在真空下蒸餾以獲得粗產物,該粗產物藉由管柱層析進行純化。 General Procedure -1 : Preparation of Arylboronic Acid Pinacol Ester: To a solution of aryl bromide (1 eq.) in DMSO was added bis(pinacol diboron) (1.5 eq) and potassium acetate (3.0 eq. ). The mixture was degassed with nitrogen for 15 min. Palladium acetate (0.11 eq) and tricyclohexylphosphine (0.17 eq) were added, and the mixture was degassed for another 15 min and stirred at 80 °C until the starting material disappeared as monitored by TLC. After the reaction was complete, the reaction mixture was filtered on celite and the bed was washed with ethyl acetate. The combined filtrate and washings were washed successively with brine and water, and the organic layer was dried over anhydrous sodium sulfate and distilled under vacuum to obtain crude product, which was purified by column chromatography.

一般程序 -2 :鈴木偶合反應:向2,4-二氯-4-氟嘧啶(1 eq.)於二噁烷及水(5:1)中之溶液中添加芳基硼酸或芳基硼酸頻哪醇酯(1.3 eq)、四(三苯基膦)鈀(0) (0.08 eq)及碳酸鉀(3.3 eq)。利用氮氣使混合物脫氣30 min,且使其回流。如藉由TLC所指示在反應完成後,後處理(H 2O/AcOEt)及純化得到期望產物。 General Procedure -2 : Suzuki Coupling Reaction: To a solution of 2,4-dichloro-4-fluoropyrimidine (1 eq.) in dioxane and water (5:1) is added arylboronic acid or arylboronic acid Nacohol ester (1.3 eq), tetrakis(triphenylphosphine)palladium(0) (0.08 eq) and potassium carbonate (3.3 eq). The mixture was degassed with nitrogen for 30 min and allowed to reflux. After completion of the reaction as indicated by TLC, work-up ( H2O /AcOEt) and purification afforded the desired product.

一般程序 -3 :布赫瓦爾德偶合反應:使氯化合物(1 eq)、苯胺(1 eq)、Xantphos (0.2 eq)及第三丁醇鈉(1.6 eq)懸浮於二噁烷(15 Vol)中並脫氣15 min。添加參(二亞苄基丙酮)二鈀(0) (0.17 eq)且再脫氣15 min。將反應混合物在90℃下攪拌1.5 h。藉由TLC監測反應進程。在反應完成後,經由矽藻土過濾,用DCM-MeOH (9:1)洗滌矽藻土墊,之後進行後處理(H 2O/DCM-MeOH 9:1)及純化,得到期望產物。 General Procedure -3 : Buchwald Coupling Reaction: Suspend chlorine compound (1 eq), aniline (1 eq), Xantphos (0.2 eq) and sodium tert-butoxide (1.6 eq) in dioxane (15 Vol) Neutralize and degas for 15 min. Gins(dibenzylideneacetone)dipalladium(0) (0.17 eq) was added and degassed for another 15 min. The reaction mixture was stirred at 90 °C for 1.5 h. The progress of the reaction was monitored by TLC. After completion of the reaction, filtration through celite, washing the celite pad with DCM-MeOH (9:1 ) followed by work-up (H 2 O/DCM-MeOH 9:1 ) and purification afforded the desired product.

一般程序 -4 Boc 去保護反應:將Boc保護胺(1 eq)溶解於DCM (20 Vol)中且冷卻至0℃。 向此混合物中添加三氟乙酸(5 eq)且在25℃下攪拌2 h。如藉由TLC所指示在反應完成後,利用飽和NaHCO 3水溶液使反應混合物鹼化至pH約8,獲得固體。過濾固體並乾燥,獲得標題化合物。若在鹼化期間未形成固體,則進行後處理(H 2O/AcOEt)得到標題化合物。 General Procedure -4 : Boc deprotection reaction: Boc protected amine (1 eq) was dissolved in DCM (20 Vol) and cooled to 0 °C. To this mixture was added trifluoroacetic acid (5 eq) and stirred at 25 °C for 2 h. After completion of the reaction as indicated by TLC, the reaction mixture was basified to pH ~8 with saturated aqueous NaHCO 3 to obtain a solid. The solid was filtered and dried to afford the title compound. If no solid was formed during basification, workup ( H2O /AcOEt) afforded the title compound.

中間物 1 6-(4,4,5,5- 四甲基 -1,3,2- 二氧雜硼雜環戊烷 -2- ) 喹啉:遵循一般程序-1,自6-溴喹啉(3.0 g, 14.42 mmol)合成標題化合物。在後處理後,藉由管柱層析在60-120目矽膠上使用EtOAc及石油醚(5:95)作為溶析液來純化粗產物,獲得呈褐色液體之標題化合物(3.2 g)。產率:87%。 1H-NMR (δ ppm, CDCl 3, 400 MHz): 8.92-8.96 (m, 1H), 8.35 (s, 1H), 8.19 (dd, J = 8.0, 1.2, 1H), 8.08 (br. s, 2H), 7.41 (dd, J = 8.0, 4.0, 1H), 1.34 (s, 12H)。 Intermediate 1 : 6-(4,4,5,5 -Tetramethyl -1,3,2-dioxaborolan - 2- yl ) quinoline: Following General Procedure-1, from 6- Bromoquinoline (3.0 g, 14.42 mmol) to synthesize the title compound. After work-up, the crude product was purified by column chromatography on 60-120 mesh silica gel using EtOAc and petroleum ether (5:95) as eluents to obtain the title compound (3.2 g) as a brown liquid. Yield: 87%. 1 H-NMR (δ ppm, CDCl 3 , 400 MHz): 8.92-8.96 (m, 1H), 8.35 (s, 1H), 8.19 (dd, J = 8.0, 1.2, 1H), 8.08 (br.s, 2H), 7.41 (dd, J = 8.0, 4.0, 1H), 1.34 (s, 12H).

中間物 2 6-(2- -5- 氟嘧啶 -4- ) 喹啉:遵循一般程序-2,自中間物1 (3.0 g, 11.75 mmol)及2,4-二氯-4-氟嘧啶(1.96 g, 11.75 mmol)合成標題化合物。在後處理後,藉由combi-flash使用EtOAc及石油醚(21:79)作為溶析液純化粗產物,獲得呈淡黃色固體之標題化合物(1.7 g)。產率:55%。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 8.90-9.05 (m, 2H), 8.74 (s, 1H), 8.62 (d, J = 8.4, 1H), 8.35 (d, J = 8.8, 1H), 8.20 (d, J = 9.2, 1H), 7.65 (dd, J = 8.4, 4.4, 1H)。 Intermediate 2 : 6-(2- Chloro -5- fluoropyrimidin - 4 -yl ) quinoline: Following general procedure-2, from Intermediate 1 (3.0 g, 11.75 mmol) and 2,4-dichloro-4- Fluoropyrimidine (1.96 g, 11.75 mmol) was used to synthesize the title compound. After work-up, the crude product was purified by combi-flash using EtOAc and petroleum ether (21:79) as eluents to obtain the title compound (1.7 g) as a light yellow solid. Yield: 55%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 8.90-9.05 (m, 2H), 8.74 (s, 1H), 8.62 (d, J = 8.4, 1H), 8.35 (d, J = 8.8, 1H), 8.20 (d, J = 9.2, 1H), 7.65 (dd, J = 8.4, 4.4, 1H).

中間物 3 1-(6- 硝基吡啶 -3- ) 六氫吡嗪:使5-溴-2-硝基吡啶(13 g, 64 mmol)、六氫吡嗪(7.17 g, 83 mmol)、四丁基碘化銨(1.18 g, 3.2 mmol)及碳酸鉀(13 g, 94 mmol)懸浮於DMSO (158 ml)中。將此混合物在90℃下攪拌16 h。在反應完成後,用水稀釋反應混合物並用DCM萃取。使DCM層在真空下蒸餾,獲得呈褐色固體之標題化合物。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 8.23 (d, J = 3.2, 1H), 8.13 (d, J = 9.2, 1H), 7.44 (dd, J = 9.2, 3.2, 1H), 3.42 (t, J = 5.2, 4H), 2.85 (t, J = 5.2, 4H)。 Intermediate 3 : 1-(6 -nitropyridin- 3 -yl ) hexahydropyrazine: make 5-bromo-2-nitropyridine (13 g, 64 mmol), hexahydropyrazine (7.17 g, 83 mmol ), tetrabutylammonium iodide (1.18 g, 3.2 mmol) and potassium carbonate (13 g, 94 mmol) were suspended in DMSO (158 ml). This mixture was stirred at 90 °C for 16 h. After completion of the reaction, the reaction mixture was diluted with water and extracted with DCM. The DCM layer was distilled under vacuum to afford the title compound as a tan solid. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 8.23 (d, J = 3.2, 1H), 8.13 (d, J = 9.2, 1H), 7.44 (dd, J = 9.2, 3.2, 1H ), 3.42 (t, J = 5.2, 4H), 2.85 (t, J = 5.2, 4H).

中間物 4 4-(6- 硝基吡啶 -3- ) 六氫吡嗪 -1- 甲酸第三丁基酯:將中間物3 (11.6 g, 55.7 mmol)溶解於THF (135 ml)中且添加水(13.5 ml)及碳酸氫鈉(2.81 g, 33.4 mmol)。將此混合物攪拌5 min且緩慢添加Boc酸酐(6.08 g, 27.9 mmol)。將反應混合物在室溫下攪拌1 h。1 h後,用水淬滅反應混合物並用DCM (2*250 ml)萃取。用鹽水(250 ml)洗滌合併的DCM層。使DCM層經無水Na 2SO 4乾燥且在真空下蒸發,獲得黃色固體,將該黃色固體與二乙醚(50 ml)一起攪拌15 min並過濾,獲得呈黃色固體之標題化合物(11.2 g)。產率:65%。 1H-NMR (δ ppm, CDCl 3, 400 MHz): 8.18 (d, J = 9.2, 1H), 8.13 (d, J = 2.8, 1H), 7.21 (dd, J = 9.2, 2.8, 1H), 3.64 (t, J = 5.2, 4H), 3.45 (t, J = 5.2, 4H), 1.49 (s, 9H)。 Intermediate 4 : tert-butyl 4-(6 -nitropyridin- 3 -yl ) hexahydropyrazine- 1 -carboxylate: Intermediate 3 (11.6 g, 55.7 mmol) was dissolved in THF (135 ml) And water (13.5 ml) and sodium bicarbonate (2.81 g, 33.4 mmol) were added. This mixture was stirred for 5 min and Boc anhydride (6.08 g, 27.9 mmol) was added slowly. The reaction mixture was stirred at room temperature for 1 h. After 1 h, the reaction mixture was quenched with water and extracted with DCM (2*250 ml). The combined DCM layers were washed with brine (250 ml). The DCM layer was dried over anhydrous Na2SO4 and evaporated in vacuo to give a yellow solid which was stirred with diethyl ether (50 ml) for 15 min and filtered to give the title compound (11.2 g) as a yellow solid. Yield: 65%. 1 H-NMR (δ ppm, CDCl 3 , 400 MHz): 8.18 (d, J = 9.2, 1H), 8.13 (d, J = 2.8, 1H), 7.21 (dd, J = 9.2, 2.8, 1H), 3.64 (t, J = 5.2, 4H), 3.45 (t, J = 5.2, 4H), 1.49 (s, 9H).

中間物 5 4-(6- 胺基吡啶 -3- ) 六氫吡嗪 -1- 甲酸第三丁基酯:將中間物4 (11 g, 35.7 mmol)置於高壓釜中,溶解於甲醇(110 ml)與乙醇(110 ml)之混合物中且添加碳載5%鈀(2.42 g)。將此混合物在室溫下在5 kg氫壓下攪拌5 h。在反應完成後,經由矽藻土床過濾反應混合物,且用甲醇與乙醇之1:1混合物(200 ml)洗滌該床。將濾液及洗滌液合併,且使溶劑蒸發。向殘餘物中添加水並用EtOAc (2*250 ml)萃取。相繼用水(150 ml)及鹽水(150 ml)洗滌合併的有機層,經無水Na 2SO 4乾燥並蒸餾,獲得呈褐色固體之標題化合物(7 g)。產率:70%。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 7.60 (d, J = 2.8, 1H), 7.16 (dd, J = 8.8, 2.8, 1H), 6.38 (d, J = 8.8, 1H), 5.44 (br. s, 2H), 3.41 (t, J = 4.8, 4H), 2.84 (t, J = 4.8, 4H), 1.40 (s, 9H)。 Intermediate 5 : tert-butyl 4-(6 -aminopyridin- 3 -yl ) hexahydropyrazine- 1 -carboxylate: Intermediate 4 (11 g, 35.7 mmol) was placed in an autoclave and dissolved in A mixture of methanol (110 ml) and ethanol (110 ml) was added and 5% palladium on carbon (2.42 g) was added. This mixture was stirred at room temperature under 5 kg hydrogen pressure for 5 h. After the reaction was complete, the reaction mixture was filtered through a bed of celite, and the bed was washed with a 1:1 mixture of methanol and ethanol (200 ml). The filtrate and washings were combined and the solvent was evaporated. Water was added to the residue and extracted with EtOAc (2*250 ml). The combined organic layers were washed successively with water (150 ml) and brine (150 ml), dried over anhydrous Na2SO4 and distilled to give the title compound (7 g) as a brown solid. Yield: 70%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 7.60 (d, J = 2.8, 1H), 7.16 (dd, J = 8.8, 2.8, 1H), 6.38 (d, J = 8.8, 1H ), 5.44 (br. s, 2H), 3.41 (t, J = 4.8, 4H), 2.84 (t, J = 4.8, 4H), 1.40 (s, 9H).

中間物 6 8- -6-(4,4,5,5- 四甲基 -1,3,2- 二氧雜硼雜環戊烷 -2- ) 喹啉:遵循一般程序-1,自6-溴-8-氟喹啉(3.0 g, 13.27 mmol)合成標題化合物。在後處理後,藉由管柱層析在60-120目矽膠上使用EtOAc及石油醚(20:80)作為溶析液來純化粗產物,獲得呈褐色液體之標題化合物(1.6 g)。產率:44%。 1H-NMR (δ ppm, CDCl 3, 400 MHz): 9.00 (dd, J = 4.0, 1.6, 1H), 8.22 (br. d, J = 8.4, 1H), 8.13 (s, 1H), 7.76 (d, J = 9.8, 1H), 7.48 (dd, J = 8.4, 4.4, 1H)。 Intermediate 6 : 8- Fluoro -6-(4,4,5,5 -tetramethyl- 1,3,2-dioxaborolan - 2- yl ) quinoline: following general procedure-1 , the title compound was synthesized from 6-bromo-8-fluoroquinoline (3.0 g, 13.27 mmol). After work-up, the crude product was purified by column chromatography on 60-120 mesh silica gel using EtOAc and petroleum ether (20:80) as eluents to obtain the title compound (1.6 g) as a brown liquid. Yield: 44%. 1 H-NMR (δ ppm, CDCl 3 , 400 MHz): 9.00 (dd, J = 4.0, 1.6, 1H), 8.22 (br. d, J = 8.4, 1H), 8.13 (s, 1H), 7.76 ( d, J = 9.8, 1H), 7.48 (dd, J = 8.4, 4.4, 1H).

中間物 7 6-(2- -5- 氟嘧啶 -4- )-8- 氟喹啉:遵循一般程序-2,自中間物6 (1.5 g, 5.49 mmol)及2,4-二氯-4-氟嘧啶(917 mg, 5.49 mmol)合成標題化合物。在後處理後,藉由combi-flash使用EtOAc及石油醚(20:80)作為溶析液純化粗產物。將來自combi-flash之純淨溶離份合併並蒸餾,獲得呈褐色固體之標題化合物(1.1 g)。產率:80%。 1H-NMR (δ ppm, CDCl 3, 400 MHz): 9.06-9.12 (m, 1H), 8.62 (d, J = 2.8, 1H), 8.53 (s, 1H), 8.35 (d, J = 8.4, 1H), 8.24 (d, J = 11.6, 1H), 7.59 (dd, J = 8.4, 4.0, 1H)。 Intermediate 7 : 6-(2- Chloro -5- fluoropyrimidin - 4 -yl )-8- fluoroquinoline: following general procedure-2, from intermediate 6 (1.5 g, 5.49 mmol) and 2,4-di Chloro-4-fluoropyrimidine (917 mg, 5.49 mmol) was used to synthesize the title compound. After work-up, the crude product was purified by combi-flash using EtOAc and petroleum ether (20:80) as eluents. The pure fractions from the combi-flash were combined and distilled to give the title compound (1.1 g) as a tan solid. Yield: 80%. 1 H-NMR (δ ppm, CDCl 3 , 400 MHz): 9.06-9.12 (m, 1H), 8.62 (d, J = 2.8, 1H), 8.53 (s, 1H), 8.35 (d, J = 8.4, 1H), 8.24 (d, J = 11.6, 1H), 7.59 (dd, J = 8.4, 4.0, 1H).

中間物 8 1-((6- 溴吡啶 -3- ) 甲基 )-4- 乙基六氫吡嗪:將6-溴菸鹼醛(5 g, 26.9 mmol)及1-乙基六氫吡嗪(3.38 g, 29.6 mmol)溶解於DCM (50 ml)中且在室溫下攪拌5 min。添加三乙醯氧基硼氫化鈉(6.15 g, 29.03 mmol)且繼續攪拌18 h。後處理(2 N NaOH水溶液/DCM)得到粗產物,使該粗產物與EtOAc一起共蒸餾,獲得呈褐色液體之標題化合物(7.2 g)。產率:95%。 1H-NMR (δ ppm, CDCl 3, 400 MHz): 8.28 (d, J = 2.4, 1H), 7.54 (dd, J = 8.0, 2.4, 1H), 7.42 (d, J = 8.0, 1H), 3.46 (s, 2H), 2.49 (br. s, 8H), 2.42 (q, J = 7.2, 2H), 1.08 (t, J = 7.2, 3H)。 Intermediate 8 : 1-((6- bromopyridin - 3 -yl ) methyl )-4 -ethylhexahydropyrazine: 6-bromonicotinic aldehyde (5 g, 26.9 mmol) and 1-ethylhexahydropyrazine Hydropyrazine (3.38 g, 29.6 mmol) was dissolved in DCM (50 ml) and stirred at room temperature for 5 min. Sodium triacetyloxyborohydride (6.15 g, 29.03 mmol) was added and stirring was continued for 18 h. Workup (2 N aq. NaOH/DCM) gave a crude product which was co-distilled with EtOAc to afford the title compound (7.2 g) as a brown liquid. Yield: 95%. 1 H-NMR (δ ppm, CDCl 3 , 400 MHz): 8.28 (d, J = 2.4, 1H), 7.54 (dd, J = 8.0, 2.4, 1H), 7.42 (d, J = 8.0, 1H), 3.46 (s, 2H), 2.49 (br. s, 8H), 2.42 (q, J = 7.2, 2H), 1.08 (t, J = 7.2, 3H).

中間物 9 5-((4- 乙基六氫吡嗪 -1- ) 甲基 ) 吡啶 -2- 胺:使中間物8 (21.0 g, 73.6 mmol)、(二環己基膦基)聯苯(2.6 g, 7.3 mmol)及參(二亞苄基丙酮)二鈀(3.3 g, 3.6 mmol)懸浮於THF (210 ml)中,且用氮氣脫氣30 min。30 min後,將混合物加熱至50℃且逐滴添加1 M LiHMDS於THF中之溶液(184.6 ml, 184.6 mmol)。在添加完成後,將混合物在65℃下加熱隔夜。使混合物冷卻至室溫,添加水(200 ml)且使THF蒸發。向殘餘水層中添加36%鹽酸水溶液(200 ml),且用DCM (3*250 ml)洗滌。分離水層,用10% NaOH水溶液(900 ml)鹼化且萃取至DCM (6*500 ml)中。使合併的有機層經無水硫酸鈉乾燥且使溶劑蒸發。用二乙醚洗滌殘餘物,獲得呈淡黃色固體之標題化合物(8.6 g)。產率:52.8%。 1H-NMR (δ ppm, CDCl 3, 400 MHz): 7.60 (d, J = 2.0, 1H), 7.42 (dd, J 8.4, 2.0, 1H), 6.48 (d, J 8.4, 1H), 4.37 (br. s, 2H), 3.38 (s, 2H), 2.30-2.70 (m, 10H), 1.07 (t, J = 7.2, 3H)。 Intermediate 9 : 5-((4- Ethylhexahydropyrazin- 1 -yl ) methyl ) pyridin -2- amine: Intermediate 8 (21.0 g, 73.6 mmol), (dicyclohexylphosphino) Benzene (2.6 g, 7.3 mmol) and para(dibenzylideneacetone)dipalladium (3.3 g, 3.6 mmol) were suspended in THF (210 ml) and degassed with nitrogen for 30 min. After 30 min, the mixture was heated to 50 °C and a solution of 1 M LiHMDS in THF (184.6 ml, 184.6 mmol) was added dropwise. After the addition was complete, the mixture was heated at 65 °C overnight. The mixture was cooled to room temperature, water (200 ml) was added and THF was evaporated. To the residual aqueous layer was added 36% aqueous hydrochloric acid (200 ml) and washed with DCM (3*250 ml). The aqueous layer was separated, basified with 10% aqueous NaOH (900 ml) and extracted into DCM (6*500 ml). The combined organic layers were dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was washed with diethyl ether to obtain the title compound (8.6 g) as a light yellow solid. Yield: 52.8%. 1 H-NMR (δ ppm, CDCl 3 , 400 MHz): 7.60 (d, J = 2.0, 1H), 7.42 (dd, J 8.4, 2.0, 1H), 6.48 (d, J 8.4, 1H), 4.37 ( br. s, 2H), 3.38 (s, 2H), 2.30-2.70 (m, 10H), 1.07 (t, J = 7.2, 3H).

中間物 10 1- 甲基 -4-(6- 硝基吡啶 -3- ) 六氫吡嗪:使5-溴-2-硝基吡啶(6 g, 29.56 mmol)、1-甲基六氫吡嗪(4.44 g, 44.3 mmol)、四丁基碘化銨(546 mg, 1.48 mmol)及碳酸鉀(6.12 g, 44.3 mmol)懸浮於DMSO (60 ml)中,且在80℃下攪拌16 h。用水(400 ml)稀釋反應混合物,用DCM (3*250 ml)萃取且在真空下蒸餾合併的有機層,獲得粗產物。藉由combi-flash使用甲醇及DCM (3.5:96.5)作為溶析液進行純化,得到呈黃色固體之標題化合物(4 g)。產率:61%。 1H-NMR (δ ppm, CDCl 3, 400 MHz): 8.17 (d, J = 9.2, 1H), 8.14 (d, J = 3.2, 1H), 7.20 (dd, J = 9.2, 3.2, 1H), 3.48 (t, J = 4.8, 4H), 2.59 (t, J = 4.8, 4H), 2.37 (s, 3H)。 Intermediate 10 : 1 -methyl- 4-(6 -nitropyridin- 3 -yl ) hexahydropyrazine: make 5-bromo-2-nitropyridine (6 g, 29.56 mmol), 1-methylhexahydro Hydropyrazine (4.44 g, 44.3 mmol), tetrabutylammonium iodide (546 mg, 1.48 mmol) and potassium carbonate (6.12 g, 44.3 mmol) were suspended in DMSO (60 ml), and stirred at 80°C for 16 h. The reaction mixture was diluted with water (400 ml), extracted with DCM (3*250 ml) and the combined organic layers were distilled under vacuum to obtain crude product. Purification by combi-flash using methanol and DCM (3.5:96.5) as eluents gave the title compound (4 g) as a yellow solid. Yield: 61%. 1 H-NMR (δ ppm, CDCl 3 , 400 MHz): 8.17 (d, J = 9.2, 1H), 8.14 (d, J = 3.2, 1H), 7.20 (dd, J = 9.2, 3.2, 1H), 3.48 (t, J = 4.8, 4H), 2.59 (t, J = 4.8, 4H), 2.37 (s, 3H).

中間物 11 5-(4- 甲基六氫吡嗪 -1- ) 吡啶 -2- 胺:將中間物10 (4 g, 18.0  mmol)置於高壓釜中且溶解於甲醇(20 ml)與乙醇(20 ml)之混合物中,且添加碳載5%鈀(957 mg)。將此混合物在室溫下在4.5 kg氫壓下攪拌5 h。在反應完成後,經由矽藻土床過濾反應混合物,且用甲醇與乙醇之混合物(1:1, 50 ml)洗滌該床。使合併的濾液及洗滌液蒸發。向殘餘物中添加水並用EtOAc (2*50 ml)萃取。將合併的有機層用水(50 ml)及鹽水(50 ml)洗滌,經無水Na 2SO 4乾燥並蒸餾,獲得粗產物。藉由combi-flash層析,利用於DCM中之3.5% MeOH作為溶析液進行純化,得到呈褐紅色固體之標題化合物(2.5 g)。產率:72%。 1H-NMR (δ ppm, CDCl 3, 400 MHz): 7.57 (d, J = 2.8, 1H), 7.14 (dd, J = 8.8, 2.8, 1H), 6.37 (d, J = 8.8, 1H), 5.36 (br. s, 2H), 2.90 (t, J = 4.8, 4H), 2.41 (t, J = 4.8, 4H), 2.19 (s, 3H)。 Intermediate 11 : 5-(4 -Methylhexahydropyrazin- 1 -yl ) pyridin -2- amine: Intermediate 10 (4 g, 18.0 mmol) was placed in an autoclave and dissolved in methanol (20 ml) In a mixture with ethanol (20 ml), and 5% palladium on carbon (957 mg) was added. This mixture was stirred at room temperature under 4.5 kg hydrogen pressure for 5 h. After completion of the reaction, the reaction mixture was filtered through a bed of celite, and the bed was washed with a mixture of methanol and ethanol (1:1, 50 ml). The combined filtrate and washings were evaporated. Water was added to the residue and extracted with EtOAc (2*50 ml). The combined organic layers were washed with water (50 ml) and brine (50 ml), dried over anhydrous Na2SO4 and distilled to obtain crude product. Purification by combi-flash chromatography using 3.5% MeOH in DCM as eluent afforded the title compound (2.5 g) as a maroon solid. Yield: 72%. 1 H-NMR (δ ppm, CDCl 3 , 400 MHz): 7.57 (d, J = 2.8, 1H), 7.14 (dd, J = 8.8, 2.8, 1H), 6.37 (d, J = 8.8, 1H), 5.36 (br. s, 2H), 2.90 (t, J = 4.8, 4H), 2.41 (t, J = 4.8, 4H), 2.19 (s, 3H).

中間物 12 5- -7- 氟吲哚啉 -2,3- 二酮:將7-氟吲哚啉-2,3-二酮(50 g, 303 mmol)溶解於乙酸(330 ml)中且冷卻至0℃。將溴(48.4 g, 303 mmol)逐滴添加至攪拌溶液中,且在0℃至5℃下繼續攪拌1 h。1 h後,將混合物傾倒至冰冷水(500 ml)中。過濾沈澱固體,用水(100 ml)洗滌且於烘箱中乾燥,獲得呈磚紅色固體之標題化合物(65 g)。產率:88%。 1H-NMR (δ ppm, CDCl 3, 400 MHz): 11.66 (s, 1H), 7.87 (dd, J = 9.6, 1.6, 1H), 7.56 (s, 1H)。 Intermediate 12 : 5- Bromo -7- fluoroindoline- 2,3- dione: 7-fluoroindoline-2,3-dione (50 g, 303 mmol) was dissolved in acetic acid (330 ml) and cooled to 0°C. Bromine (48.4 g, 303 mmol) was added dropwise to the stirred solution and stirring was continued at 0°C to 5°C for 1 h. After 1 h, the mixture was poured into ice-cold water (500 ml). The precipitated solid was filtered, washed with water (100 ml) and dried in an oven to afford the title compound (65 g) as a brick red solid. Yield: 88%. 1 H-NMR (δ ppm, CDCl 3 , 400 MHz): 11.66 (s, 1H), 7.87 (dd, J = 9.6, 1.6, 1H), 7.56 (s, 1H).

中間物 13 6- -8- -2- 甲基喹啉 -4- 甲酸:使中間物12 (65 g, 0.27 mol)懸浮於氫氧化鉀(103.4 g, 1.84 mol)於水(2.3 L)中之溶液中,且添加丙酮(260 ml)。將此混合物在50℃下攪拌4 h。再向反應混合物中添加一批丙酮(260 ml)且在50℃下攪拌16 h。使反應混合物冷卻至室溫,且當固體沈澱時,使用6 N HCl將pH調整至約3。過濾固體,用熱水(650 ml)洗滌且於烘箱中在70℃下乾燥15 h,獲得呈灰白色固體之標題化合物。 1H-NMR (δ ppm, CDCl 3, 400 MHz): 14.14 (br. s, 1H), 8.72 (s, 1H), 8.00 (s, 1H), 7.90-7.96 (m, 1H), 2.72 (s, 3H)。 Intermediate 13 : 6- bromo -8- fluoro -2 -methylquinoline- 4 - carboxylic acid: Intermediate 12 (65 g, 0.27 mol) was suspended in potassium hydroxide (103.4 g, 1.84 mol) in water (2.3 L) and acetone (260 ml) was added. This mixture was stirred at 50 °C for 4 h. A further batch of acetone (260 ml) was added to the reaction mixture and stirred at 50 °C for 16 h. The reaction mixture was cooled to room temperature, and when a solid precipitated, the pH was adjusted to about 3 using 6 N HCl. The solid was filtered, washed with hot water (650 ml) and dried in an oven at 70 °C for 15 h to afford the title compound as an off-white solid. 1 H-NMR (δ ppm, CDCl 3 , 400 MHz): 14.14 (br. s, 1H), 8.72 (s, 1H), 8.00 (s, 1H), 7.90-7.96 (m, 1H), 2.72 (s , 3H).

中間物 14 6- -8- -N- 甲氧基 -N,2- 二甲基喹啉 -4- 甲醯胺:將中間物13 (800 mg, 2.82 mmol)溶解於DCM (16 mL)中且冷卻至0℃。向此混合物中添加一滴DMF,之後逐滴添加草醯氯(429 mg, 3.38 mmol)。在草醯氯添加完成後,使反應混合物升溫至室溫並攪拌2 h。自混合物中蒸餾出二氯甲烷及草醯氯且與DCM (10 mL)一起共蒸餾,獲得醯氯殘餘物。單獨地,將N,O-二甲基羥胺鹽酸鹽(275 mg, 2.82 mmol)溶解於DCM中,冷卻至0℃,添加三乙胺(627 mg, 6.2 mmol)且在0℃下攪拌30 min。在0℃下向此混合物中緩慢添加上述醯氯於DCM (16 ml)中之溶液。在添加完成後,使反應混合物升溫至25℃且攪拌16 h。用水稀釋反應混合物且分離各層。用DCM (2*30 ml)萃取水層。相繼用飽和NaHCO 3水溶液(30 ml)及鹽水(30 ml)洗滌合併的有機層。使有機層經硫酸鈉乾燥且將溶劑蒸餾出,獲得粗產物。藉由管柱層析在60-120目矽膠上使用EtOAc及石油醚(2:8)作為溶析液進行純化,得到呈黃色固體之標題化合物(500 mg)。產率:54%。 1H-NMR (δ ppm, CDCl 3, 400 MHz): 7.75 (br. s, 1H), 7.54 (dd, J = 9.6, 1.6, 1H), 7.35 (s, 1H), 3.48 (br. s, 3H), 3.41 (br. s, 3H), 2.79 (s, 3H)。 Intermediate 14 : 6- Bromo -8- fluoro -N- methoxy- N,2 -dimethylquinoline- 4 -carboxamide: Intermediate 13 (800 mg, 2.82 mmol) was dissolved in DCM (16 mL) and cooled to 0 °C. To this mixture was added one drop of DMF followed by the dropwise addition of oxalyl chloride (429 mg, 3.38 mmol). After the oxalyl chloride addition was complete, the reaction mixture was allowed to warm to room temperature and stirred for 2 h. Dichloromethane and oxalyl chloride were distilled from the mixture and co-distilled with DCM (10 mL) to obtain the oxalyl chloride residue. Separately, N,O-dimethylhydroxylamine hydrochloride (275 mg, 2.82 mmol) was dissolved in DCM, cooled to 0 °C, added triethylamine (627 mg, 6.2 mmol) and stirred at 0 °C for 30 min. To this mixture was slowly added a solution of the above acid chloride in DCM (16 ml) at 0 °C. After the addition was complete, the reaction mixture was warmed to 25 °C and stirred for 16 h. The reaction mixture was diluted with water and the layers were separated. The aqueous layer was extracted with DCM (2*30 ml). The combined organic layers were washed sequentially with saturated aqueous NaHCO 3 (30 ml) and brine (30 ml). The organic layer was dried over sodium sulfate and the solvent was distilled off to obtain a crude product. Purification by column chromatography on 60-120 mesh silica gel using EtOAc and petroleum ether (2:8) as eluents gave the title compound (500 mg) as a yellow solid. Yield: 54%. 1 H-NMR (δ ppm, CDCl 3 , 400 MHz): 7.75 (br. s, 1H), 7.54 (dd, J = 9.6, 1.6, 1H), 7.35 (s, 1H), 3.48 (br. s, 3H), 3.41 (br. s, 3H), 2.79 (s, 3H).

中間物 15 1-(6- -8- -2- 甲基喹啉 -4- ) -1- 酮:將中間物14 (45 g, 137.4 mmol)溶解於THF (450 ml)中並冷卻至0℃,且緩慢添加甲基氯化鎂(3 M於THF中,69 ml, 207 mmol)。將混合物在室溫下攪拌2 h。用NH 4Cl水溶液淬滅反應混合物。且用EtOAc萃取。相繼用水及鹽水溶液洗滌有機層,經無水Na 2SO 4乾燥並蒸餾,獲得粗產物。藉由combi-flash,使用EtOAc及石油醚(12:88)作為溶析液進行純化,得到呈褐色固體之標題化合物(27.4 g)。產率:71%。 1H-NMR (δ ppm, CDCl 3, 400 MHz): 8.46 (br. s, 1H), 7.61 (s, 1H), 7.57 (dd, J = 10.0, 2.0, 1H), 2.84 (s, 3H), 2.75 (s, 3H)。 Intermediate 15 : 1-(6- Bromo -8- fluoro -2 -methylquinolin- 4 -yl ) ethan - 1 -one: Intermediate 14 (45 g, 137.4 mmol) was dissolved in THF (450 ml) and cooled to 0 °C, and slowly added methylmagnesium chloride (3 M in THF, 69 ml, 207 mmol). The mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with aqueous NH4Cl . and extracted with EtOAc. The organic layer was washed successively with water and brine solution, dried over anhydrous Na2SO4 and distilled to obtain crude product. Purification by combi-flash using EtOAc and petroleum ether (12:88) as eluents afforded the title compound (27.4 g) as a brown solid. Yield: 71%. 1 H-NMR (δ ppm, CDCl 3 , 400 MHz): 8.46 (br. s, 1H), 7.61 (s, 1H), 7.57 (dd, J = 10.0, 2.0, 1H), 2.84 (s, 3H) , 2.75 (s, 3H).

中間物 16 6- -8- -2- 甲基 -4-( -1- -2- ) 喹啉:將甲基三苯基溴化鏻(50.65 g, 0.142 mol)溶解於THF (50 ml)中,添加第三丁醇鉀(15.91 g, 0.142 mol)且在室溫下攪拌5 min。經30 min之時期向此混合物中逐滴添加中間物15 (20 g, 71 mol)於THF (100 ml)中之溶液,且在室溫下攪拌8 h。用飽和NaHCO 3水溶液淬滅反應物並用EtOAc (2*500 ml)萃取。相繼用鹽水(2*250 ml)及水(250 ml)洗滌有機層,經無水Na 2SO 4乾燥並蒸餾,獲得粗產物。藉由管柱層析在60-120目矽膠上使用EtOAc及石油醚(0.5:99.5)作為溶析液進行純化,得到呈灰白色固體之標題化合物(5.7 g)。產率:29%。 1H-NMR (δ ppm, CDCl 3, 400 MHz): 7.93 (s, 1H), 7.50 (dd, J = 8.0, 1.6, 1H), 7.18 (s, 1H), 5.50 (s, 1H), 5.12 (s, 1H), 2.76 (s, 3H), 3.19 (s, 3H)。 Intermediate 16 : 6- Bromo -8- fluoro -2- methyl- 4-( prop- 1 -en -2- yl ) quinoline: Dissolve methyltriphenylphosphonium bromide (50.65 g, 0.142 mol) In THF (50 ml), potassium tert-butoxide (15.91 g, 0.142 mol) was added and stirred at room temperature for 5 min. To this mixture was added a solution of intermediate 15 (20 g, 71 mol) in THF (100 ml) dropwise over a period of 30 min and stirred at room temperature for 8 h. The reaction was quenched with saturated aqueous NaHCO 3 and extracted with EtOAc (2*500 ml). The organic layer was washed successively with brine (2*250 ml) and water (250 ml), dried over anhydrous Na 2 SO 4 and distilled to obtain crude product. Purification by column chromatography on 60-120 mesh silica gel using EtOAc and petroleum ether (0.5:99.5) as eluents gave the title compound (5.7 g) as an off-white solid. Yield: 29%. 1 H-NMR (δ ppm, CDCl 3 , 400 MHz): 7.93 (s, 1H), 7.50 (dd, J = 8.0, 1.6, 1H), 7.18 (s, 1H), 5.50 (s, 1H), 5.12 (s, 1H), 2.76 (s, 3H), 3.19 (s, 3H).

中間物 17 8- -2- 甲基 -4-( -1- -2- )-6-(4,4,5,5- 四甲基 -1,3,2- 二氧雜硼雜環戊烷 -2- ) 喹啉:遵循一般程序-1,自中間物16 (1.0 g, 3.57 mmol)合成標題化合物。在後處理後,藉由combi-flash使用EtOAc及石油醚(7:93)作為溶析液純化粗產物,獲得呈灰白色固體之標題化合物(500 mg)。產率:43%。 1H-NMR (δ ppm, CDCl 3, 400 MHz): 8.22 (s, 1H), 7.72 (d, J = 10.8, 1H), 7.16 (s, 1H), 5.50 (s, 1H), 5.14 (s, 1H), 2.78 (s, 1H), 2.22 (s, 3H), 1.37 (s, 12H)。 Intermediate 17 : 8- fluoro -2- methyl- 4-( prop- 1 -en -2- yl )-6-(4,4,5,5 -tetramethyl -1,3,2- dioxo Borolan -2- yl ) quinoline: The title compound was synthesized from Intermediate 16 (1.0 g, 3.57 mmol) following General Procedure-1. After work-up, the crude product was purified by combi-flash using EtOAc and petroleum ether (7:93) as eluents to obtain the title compound (500 mg) as an off-white solid. Yield: 43%. 1 H-NMR (δ ppm, CDCl 3 , 400 MHz): 8.22 (s, 1H), 7.72 (d, J = 10.8, 1H), 7.16 (s, 1H), 5.50 (s, 1H), 5.14 (s , 1H), 2.78 (s, 1H), 2.22 (s, 3H), 1.37 (s, 12H).

中間物 18 6-(2- -5- 氟嘧啶 -4- )-8- -2- 甲基 -4-( -1- -2- ) 喹啉:藉由一般程序-2,自中間物17 (2.5 g, 7.64 mmol)及2,4-二氯-4-氟嘧啶(1.53 g, 9.17 mmol)合成標題化合物,但有以下修改:使用 氟化鉀(1.33 g, 22.9 mmol)代替碳酸鉀作為鹼。在後處理(EtOAc/鹽水)後,藉由combi-flash使用石油醚及EtOAc (99:1)作為溶析液純化粗產物,獲得呈灰白色固體之標題化合物(1.4 g)。產率:55%。 1H-NMR (δ ppm, CDCl 3, 400 MHz): 8.65 (s, 1H), 8.57 (d, J = 2.8, 1H), 8.19 (dd, J = 11.6, 1.6, 1H), 7.27 (s, 1H), 5.57 (s, 1H), 5.19 (s, 1H), 2.82 (s, 3H), 2.25 (s, 3H)。 Intermediate 18 : 6-(2- Chloro -5- fluoropyrimidin - 4 -yl )-8- fluoro -2- methyl- 4-( prop- 1 -en -2- yl ) quinoline: by general procedure -2, the title compound was synthesized from intermediate 17 (2.5 g, 7.64 mmol) and 2,4-dichloro-4-fluoropyrimidine (1.53 g, 9.17 mmol) with the following modifications: Potassium fluoride (1.33 g, 22.9 mmol) instead of potassium carbonate as base. After work-up (EtOAc/brine), the crude product was purified by combi-flash using petroleum ether and EtOAc (99:1) as eluents to obtain the title compound (1.4 g) as an off-white solid. Yield: 55%. 1 H-NMR (δ ppm, CDCl 3 , 400 MHz): 8.65 (s, 1H), 8.57 (d, J = 2.8, 1H), 8.19 (dd, J = 11.6, 1.6, 1H), 7.27 (s, 1H), 5.57 (s, 1H), 5.19 (s, 1H), 2.82 (s, 3H), 2.25 (s, 3H).

中間物 19 1- 乙基 -4-(6- 硝基吡啶 -3- ) 六氫吡嗪:使5-溴-2-硝基吡啶(4 g, 19.7 mmol)、1-乙基六氫吡嗪(3.38 g, 29.56 mmol)、四丁基碘化銨(364 mg, 0.99 mmol)及碳酸鉀(4.09 g, 29.6 mmol)懸浮於DMSO (37.5 ml)中,且在80℃下攪拌15 h。用水(400 ml)稀釋反應混合物,用DCM (3*250 ml)萃取,且將合併的有機層用鹽水(100 ml)及水(100 ml)洗滌,經無水硫酸鈉乾燥且在真空下蒸餾,獲得粗產物。藉由combi-flash使用甲醇及DCM (4:96)作為溶析液進行純化,得到呈黃色固體之標題化合物(3 g)。產率:64%。 1H-NMR (δ ppm, CDCl 3, 400 MHz): 8.17 (d, J = 9.2, 1H), 8.14 (d, J = 3.2, 1H), 7.20 (dd, J = 9.2, 3.2, 1H), 3.48 (t, J = 5.2, 4H), 2.61 (t, J = 5.2, 4H), 2.49 (q, J = 7.2, 3H), 1.14 (t, J = 7.2, 3H)。 Intermediate 19 : 1- ethyl- 4-(6 -nitropyridin- 3 -yl ) hexahydropyrazine: make 5-bromo-2-nitropyridine (4 g, 19.7 mmol), 1-ethylhexahydropyridine Hydropyrazine (3.38 g, 29.56 mmol), tetrabutylammonium iodide (364 mg, 0.99 mmol) and potassium carbonate (4.09 g, 29.6 mmol) were suspended in DMSO (37.5 ml), and stirred at 80°C for 15 h. The reaction mixture was diluted with water (400 ml), extracted with DCM (3*250 ml), and the combined organic layer was washed with brine (100 ml) and water (100 ml), dried over anhydrous sodium sulfate and distilled under vacuum, A crude product is obtained. Purification by combi-flash using methanol and DCM (4:96) as eluents afforded the title compound (3 g) as a yellow solid. Yield: 64%. 1 H-NMR (δ ppm, CDCl 3 , 400 MHz): 8.17 (d, J = 9.2, 1H), 8.14 (d, J = 3.2, 1H), 7.20 (dd, J = 9.2, 3.2, 1H), 3.48 (t, J = 5.2, 4H), 2.61 (t, J = 5.2, 4H), 2.49 (q, J = 7.2, 3H), 1.14 (t, J = 7.2, 3H).

中間物 20 5-(4- 乙基六氫吡嗪 -1- ) 吡啶 -2- 胺:將中間物19 (5 g, 18.  mmol)置於高壓釜中且溶解於甲醇(25 ml)與乙醇(25 ml)之混合物中,且添加碳載5%鈀(1.13 g)。將此混合物在室溫下在4.5 kg氫壓下攪拌5 h。在反應完成後,經由矽藻土床過濾反應混合物,且用甲醇與乙醇之混合物(1:1, 50 ml)洗滌該床。使合併的濾液及洗滌液蒸發。向殘餘物中添加水並用EtOAc (2*50 ml)萃取。將合併的有機層用水(50 ml)及鹽水(50 ml)洗滌,經無水Na 2SO 4乾燥並蒸餾,獲得粗產物。藉由combi-flash層析利用於DCM中之3.2% MeOH作為溶析液進行純化,得到呈灰色固體之標題化合物(4.0 g)。產率:92%。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 7.57 (d, J = 2.8, 1H), 7.14 (dd, J = 8.8, 2.8, 1H), 6.38 (d, J = 8.8, 1H), 5.36 (s, 2H), 2.93-2.85(m,  4H), 2.48-2.42(m, 4H), 2.33 (q, J = 7.2, 2H), 1.00 (t, J = 7.2, 3H)。 Intermediate 20 : 5-(4- Ethylhexahydropyrazin- 1 -yl ) pyridin -2- amine: Intermediate 19 (5 g, 18. mmol) was placed in an autoclave and dissolved in methanol (25 ml ) and ethanol (25 ml), and 5% palladium on carbon (1.13 g) was added. This mixture was stirred at room temperature under 4.5 kg hydrogen pressure for 5 h. After completion of the reaction, the reaction mixture was filtered through a bed of celite, and the bed was washed with a mixture of methanol and ethanol (1:1, 50 ml). The combined filtrate and washings were evaporated. Water was added to the residue and extracted with EtOAc (2*50 ml). The combined organic layers were washed with water (50 ml) and brine (50 ml), dried over anhydrous Na2SO4 and distilled to obtain crude product. Purification by combi-flash chromatography using 3.2% MeOH in DCM as eluent afforded the title compound (4.0 g) as a gray solid. Yield: 92%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 7.57 (d, J = 2.8, 1H), 7.14 (dd, J = 8.8, 2.8, 1H), 6.38 (d, J = 8.8, 1H ), 5.36 (s, 2H), 2.93-2.85(m, 4H), 2.48-2.42(m, 4H), 2.33 (q, J = 7.2, 2H), 1.00 (t, J = 7.2, 3H).

中間物 21 6- -8- -2- 甲基喹啉:將巴豆醛(612 mg, 8.74 mmol)添加至4-溴-2-氟苯胺(2.00 g, 10.5 mmol)與6 N鹽酸水溶液(42.1 ml)之混合物中,且在室溫下攪拌1 h。添加甲苯(11 ml),且將混合物在110℃下加熱17 h,冷卻至室溫且分離各層。用6 N HCl水溶液(50 ml)萃取有機層。利用10%氫氧化鈉水溶液使合併的水層鹼化至pH 10-11且萃取至DCM (3*100 ml)中。相繼用鹽水溶液(100 ml)及水(100 ml)洗滌合併的有機層,經硫酸鈉乾燥並濃縮。藉由combi-flash層析系統,利用石油醚-EtOAc (95:5)作為溶析液純化殘餘物,得到呈淡黃色固體之標題化合物(1.2 g)。產率:47%。 1H-NMR (δ ppm, CDCl 3, 400 MHz):7.80 (dd, J = 8.4, 1.2, 1H), 7.74 (s, 1H), 7.51 (dd, J = 9.6, 1.6, 1H), 7.37 (d, J = 8.4, 1H), 2.78 (s, 3H)。 Intermediate 21 : 6- Bromo -8- fluoro -2 -methylquinoline: Crotonaldehyde (612 mg, 8.74 mmol) was added to 4-bromo-2-fluoroaniline (2.00 g, 10.5 mmol) with 6 N hydrochloric acid aqueous solution (42.1 ml) and stirred at room temperature for 1 h. Toluene (11 ml) was added and the mixture was heated at 110 °C for 17 h, cooled to room temperature and the layers were separated. The organic layer was extracted with 6 N aqueous HCl (50 ml). The combined aqueous layers were basified to pH 10-11 with 10% aqueous sodium hydroxide and extracted into DCM (3*100 ml). The combined organic layers were washed sequentially with brine solution (100 ml) and water (100 ml), dried over sodium sulfate and concentrated. The residue was purified by combi-flash chromatography system using petroleum ether-EtOAc (95:5) as eluent to give the title compound (1.2 g) as light yellow solid. Yield: 47%. 1 H-NMR (δ ppm, CDCl 3 , 400 MHz): 7.80 (dd, J = 8.4, 1.2, 1H), 7.74 (s, 1H), 7.51 (dd, J = 9.6, 1.6, 1H), 7.37 ( d, J = 8.4, 1H), 2.78 (s, 3H).

中間物 22 8- -2- 甲基 -6-(4,4,5,5- 四甲基 -1,3,2- 二氧雜硼雜環戊烷 -2- ) 喹啉:遵循一般程序-1,自中間物21 (1.0 g, 3.57 mmol)合成標題化合物。在後處理後,藉由combi-flash使用EtOAc及石油醚(8:92)作為溶析液純化粗產物,獲得呈淡黃色固體之標題化合物(3.5 g)。產率:60%。 1H-NMR (δ ppm, CDCl 3, 400 MHz): 8.03-8.12 (m, 2H), 7.72 (d, J = 11.2, 1H), 7.35 (d, J = 8.4, 1H), 2.80 (s, 3H), 1.37 (s, 12H)。 Intermediate 22 : 8- fluoro -2- methyl -6-(4,4,5,5 -tetramethyl- 1,3,2-dioxaborolan - 2- yl ) quinoline: The title compound was synthesized from Intermediate 21 (1.0 g, 3.57 mmol) following General Procedure-1. After work-up, the crude product was purified by combi-flash using EtOAc and petroleum ether (8:92) as eluents to obtain the title compound (3.5 g) as a light yellow solid. Yield: 60%. 1 H-NMR (δ ppm, CDCl 3 , 400 MHz): 8.03-8.12 (m, 2H), 7.72 (d, J = 11.2, 1H), 7.35 (d, J = 8.4, 1H), 2.80 (s, 3H), 1.37 (s, 12H).

中間物 23 6-(2- -5- 氟嘧啶 -4- )-8- -2- 甲基喹啉:遵循一般程序-2,自中間物22 (3.5 g, 12.19 mmol)及2,4-二氯-4-氟嘧啶(2.24 g, 13.41 mmol)合成標題化合物。在後處理後,藉由combi-flash使用EtOAc及石油醚(20:80)作為溶析液純化粗產物,獲得呈灰白色固體之標題化合物(2.5 g)。產率:70%。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 9.04 (d, J = 3.2, 1H), 8.45-8.60 (m, 2H), 8.07 (d, J = 12.0, 1H), 7.63 (d, J = 8.4, 1H), 2.73 (s, 3H)。 Intermediate 23 : 6-(2- Chloro -5- fluoropyrimidin - 4 -yl )-8- fluoro -2 -methylquinoline: Following general procedure-2, from Intermediate 22 (3.5 g, 12.19 mmol) and 2,4-Dichloro-4-fluoropyrimidine (2.24 g, 13.41 mmol) was used to synthesize the title compound. After work-up, the crude product was purified by combi-flash using EtOAc and petroleum ether (20:80) as eluents to obtain the title compound (2.5 g) as an off-white solid. Yield: 70%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.04 (d, J = 3.2, 1H), 8.45-8.60 (m, 2H), 8.07 (d, J = 12.0, 1H), 7.63 ( d, J = 8.4, 1H), 2.73 (s, 3H).

中間物 24 1- 異丙基 -4-(6- 硝基吡啶 -3- ) 六氫吡嗪 使5-溴-2-硝基吡啶(5 g, 25.6 mmol)、1-異丙基六氫吡嗪(4.11 g, 32.0 mmol)、四丁基碘化銨(455 mg, 1.23 mmol)及碳酸鉀(5.11 g, 36.9 mmol)懸浮於DMSO (253 ml)中,且在90℃下攪拌16 h。用水(400 ml)稀釋反應混合物,用DCM (3*250 ml)萃取,且將合併的有機層用鹽水(100 ml)及水(100 ml)洗滌,經無水硫酸鈉乾燥且在真空下蒸餾,獲得粗產物。藉由combi-flash使用甲醇及DCM (2:98)作為溶析液進行純化,得到呈黃色固體之標題化合物(3.4 g)。產率:55%。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 8.16 (d, J 8, 1H), 8.13 (d, J 3.2, 1H), 7.19 (d, J 8, 3.2, 1H), 3.46 (t, J 5.2, 4 H), 2.76 (七重峰,J 6.4, 1H), 2.69 (t, J 5.2, 4H), 1.09 (d, J 6.4, 6H)。 Intermediate 24 : 1- isopropyl- 4-(6 -nitropyridin- 3 -yl ) hexahydropyrazine : make 5-bromo-2-nitropyridine (5 g, 25.6 mmol), 1-isopropyl Hexahydropyrazine (4.11 g, 32.0 mmol), tetrabutylammonium iodide (455 mg, 1.23 mmol) and potassium carbonate (5.11 g, 36.9 mmol) were suspended in DMSO (253 ml), and at 90°C Stir for 16 h. The reaction mixture was diluted with water (400 ml), extracted with DCM (3*250 ml), and the combined organic layer was washed with brine (100 ml) and water (100 ml), dried over anhydrous sodium sulfate and distilled under vacuum, A crude product is obtained. Purification by combi-flash using methanol and DCM (2:98) as eluents afforded the title compound (3.4 g) as a yellow solid. Yield: 55%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 8.16 (d, J 8, 1H), 8.13 (d, J 3.2, 1H), 7.19 (d, J 8, 3.2, 1H), 3.46 (t, J 5.2, 4H), 2.76 (septet, J 6.4, 1H), 2.69 (t, J 5.2, 4H), 1.09 (d, J 6.4, 6H).

中間物 25 5-(4- 異丙基六氫吡嗪 -1- ) 吡啶 -2- 胺:將中間物24 (3.4 g, 14  mmol)置於高壓釜中且溶解於甲醇(35 ml)與乙醇(35 ml)之混合物中,且添加碳載5%鈀(1.13 g)。將此混合物在室溫下在4.5 kg氫壓下攪拌5 h。在反應完成後,經由矽藻土床過濾反應混合物,且用甲醇與乙醇之混合物(1:1, 50 ml)洗滌該床。使合併的濾液及洗滌液蒸發。向殘餘物中添加水並用EtOAc (2*50 ml)萃取。將合併的有機層用水(50 ml)及鹽水(50 ml)洗滌,經無水Na 2SO 4乾燥並蒸餾,獲得粗產物。將粗產物與二乙醚一起濕磨,得到呈灰色固體之標題化合物(2.3 g)。產率:76%。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz):7.57 (d, J 3.2, 1H), 7.13 (dd, J 8.8, 3.2, 1H), 6.37 (d, J 8.8, 1H), 5.35 (s, 2H), 2.88 (t, J 4.4, 4 H), 2.63 (七重峰,J 6.8, 1H), 0.98 (d, J 6.8, 6 H)。 Intermediate 25 : 5-(4- Isopropylhexahydropyrazin- 1 -yl ) pyridin -2- amine: Intermediate 24 (3.4 g, 14 mmol) was placed in an autoclave and dissolved in methanol (35 ml ) and ethanol (35 ml), and 5% palladium on carbon (1.13 g) was added. This mixture was stirred at room temperature under 4.5 kg hydrogen pressure for 5 h. After completion of the reaction, the reaction mixture was filtered through a bed of celite, and the bed was washed with a mixture of methanol and ethanol (1:1, 50 ml). The combined filtrate and washings were evaporated. Water was added to the residue and extracted with EtOAc (2*50 ml). The combined organic layers were washed with water (50 ml) and brine (50 ml), dried over anhydrous Na2SO4 and distilled to obtain crude product. The crude product was triturated with diethyl ether to give the title compound (2.3 g) as a gray solid. Yield: 76%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 7.57 (d, J 3.2, 1H), 7.13 (dd, J 8.8, 3.2, 1H), 6.37 (d, J 8.8, 1H), 5.35 (s, 2H), 2.88 (t, J 4.4, 4H), 2.63 (septet, J 6.8, 1H), 0.98 (d, J 6.8, 6H).

中間物 26 1-((6- 溴吡啶 -3- ) 甲基 )-4- 甲基六氫吡嗪:將6-溴菸鹼醛(5 g, 27 mmol)及1-甲基六氫吡嗪(2.96 g, 29.5 mmol)溶解於DCM (50 ml)中,且在室溫下攪拌5 min。添加三乙醯氧基硼氫化鈉(9.25 g, 43.6 mmol)且繼續攪拌24 h。後處理(2 N NaOH水溶液/DCM)得到粗產物,使該粗產物與EtOAc一起共蒸餾,獲得呈褐色液體之標題化合物(7.2 g)。產率:99%。 1H-NMR (δ ppm, CDCl 3, 400 MHz): 8.30 (d, J 2, 1H), 7.56 (dd, J = 8, 2, 1H), 7.43 (d, J  8, 1H), 3.46 (s, 2H), 2.60-2.38 (m, 8H), 2.28 (s, 3H)。 Intermediate 26 : 1-((6- bromopyridin - 3 -yl ) methyl )-4 -methylhexahydropyrazine: 6-bromonicotinic aldehyde (5 g, 27 mmol) and 1-methylhexahydro Hydropyrazine (2.96 g, 29.5 mmol) was dissolved in DCM (50 ml) and stirred at room temperature for 5 min. Sodium triacetyloxyborohydride (9.25 g, 43.6 mmol) was added and stirring was continued for 24 h. Workup (2 N aq. NaOH/DCM) gave a crude product which was co-distilled with EtOAc to afford the title compound (7.2 g) as a brown liquid. Yield: 99%. 1 H-NMR (δ ppm, CDCl 3 , 400 MHz): 8.30 (d, J 2, 1H), 7.56 (dd, J = 8, 2, 1H), 7.43 (d, J 8, 1H), 3.46 ( s, 2H), 2.60-2.38 (m, 8H), 2.28 (s, 3H).

中間物 27 5-((4- 甲基六氫吡嗪 -1- ) 甲基 ) 吡啶 -2- 胺:使中間物25 (7 g, 25.9 mmol)、(二環己基膦基)聯苯(908 mg, 2.6 mmol)及參(二亞苄基丙酮)二鈀(1.19 g, 1.3 mmol)懸浮於THF (70 ml)中,且用氮氣脫氣30 min。30 min後,將混合物加熱至50℃且逐滴添加1 M LiHMDS於THF中之溶液(64.8 ml, 64.8 mmol)。在添加完成後,將混合物在65℃下加熱隔夜。使混合物冷卻至室溫,添加水(200 ml)且使THF蒸發。向殘餘水層中添加36%鹽酸水溶液(200 ml),且用DCM (3*250 ml)洗滌。分離水層,用10% NaOH水溶液(900 ml)鹼化且萃取至DCM (6*500 ml)中。使合併的有機層經無水硫酸鈉乾燥且使溶劑蒸發。用二乙醚洗滌殘餘物,獲得呈淡黃色固體之標題化合物(3.2 g)。產率:60%。 1H-NMR (δ ppm, CDCl 3, 400 MHz): 7.96 (d, J = 2.5, 1H), 7.42 (dd, J = 8.4, 2.5, 1H), 6.48 (d, J = 8.4, 1H), 4.37 (bs, 2H), 3.37 (s, 2H), 2.70-2.30 (m, 8H), 2.27 (s, 3H)。 Intermediate 27 : 5-((4 -Methylhexahydropyrazin- 1 -yl ) methyl ) pyridin -2- amine: Intermediate 25 (7 g, 25.9 mmol), (dicyclohexylphosphino) Benzene (908 mg, 2.6 mmol) and ginseng(dibenzylideneacetone)dipalladium (1.19 g, 1.3 mmol) were suspended in THF (70 ml) and degassed with nitrogen for 30 min. After 30 min, the mixture was heated to 50 °C and a solution of 1 M LiHMDS in THF (64.8 ml, 64.8 mmol) was added dropwise. After the addition was complete, the mixture was heated at 65 °C overnight. The mixture was cooled to room temperature, water (200 ml) was added and THF was evaporated. To the residual aqueous layer was added 36% aqueous hydrochloric acid (200 ml) and washed with DCM (3*250 ml). The aqueous layer was separated, basified with 10% aqueous NaOH (900 ml) and extracted into DCM (6*500 ml). The combined organic layers were dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was washed with diethyl ether to obtain the title compound (3.2 g) as a light yellow solid. Yield: 60%. 1 H-NMR (δ ppm, CDCl 3 , 400 MHz): 7.96 (d, J = 2.5, 1H), 7.42 (dd, J = 8.4, 2.5, 1H), 6.48 (d, J = 8.4, 1H), 4.37 (bs, 2H), 3.37 (s, 2H), 2.70-2.30 (m, 8H), 2.27 (s, 3H).

中間物 28 6- -8- -2- 甲基喹啉 -4- 甲酸甲基酯:將硫酸(12 mL, 0.22 mmol)添加至6-溴-8-氟-2-甲基喹啉-4-甲酸(中間物13,36 g, 130 mmol)於甲醇(360 mL)中之溶液中,且使混合物回流48 h。藉由蒸餾去除甲醇,且向殘餘物中添加水(200 mL)並用飽和NaHCO 3水溶液鹼化。過濾固體,溶解於甲醇-二氯甲烷(1:9, 400 mL)中。用飽和NaHCO 3水溶液(3*100 mL)洗滌溶液,使有機層經硫酸鈉乾燥並蒸發,得到呈黃色固體之標題化合物(31.5 g)。產率:83%。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 8.61 (d, J = 2.0, 1H), 8.0 (s, 1H), 7.96 (dd, J = 10.0, 2.0, 1H), 3.98 (s, 3H), 2.73 (s, 3H)。 Intermediate 28 : Methyl 6- bromo -8- fluoro -2 -methylquinoline- 4 -carboxylate: Add sulfuric acid (12 mL, 0.22 mmol) to 6-bromo-8-fluoro-2-methylquinoline Oline-4-carboxylic acid (Intermediate 13, 36 g, 130 mmol) was in a solution in methanol (360 mL), and the mixture was refluxed for 48 h. Methanol was removed by distillation, and water (200 mL) was added to the residue and basified with saturated aqueous NaHCO 3 . The solid was filtered and dissolved in methanol-dichloromethane (1:9, 400 mL). The solution was washed with saturated aqueous NaHCO 3 (3*100 mL), the organic layer was dried over sodium sulfate and evaporated to give the title compound (31.5 g) as a yellow solid. Yield: 83%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 8.61 (d, J = 2.0, 1H), 8.0 (s, 1H), 7.96 (dd, J = 10.0, 2.0, 1H), 3.98 ( s, 3H), 2.73 (s, 3H).

中間物 29 2-(6- -8- -2- 甲基喹啉 -4- ) -2- 醇:在0℃下將1 M甲基溴化鎂於THF中之溶液(290 mL, 290 mmol)緩慢添加至6-溴-8-氟-2-甲基喹啉-4-甲酸甲基酯(中間物28,17 g, 57 mmol)於THF (250 mL)中之溶液中,且在相同溫度下攪拌2 h。將飽和氯化銨水溶液(50 mL)添加至混合物中且萃取至乙酸乙酯(2*50 mL)中。相繼用水(50 mL)及鹽水(50 mL)洗滌有機層,經硫酸鈉乾燥並蒸發,得到殘餘物,藉由矽膠管柱層析在combi-flash系統上利用乙酸乙酯-己烷(15:85)溶析來純化該殘餘物,得到呈灰白色固體之標題化合物(11 g)。產率:65%。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 8.89 (br. s, 1H), 7.78 (dd, J = 10.0, 2.0, 1H), 7.50 (s, 1H), 2.65 (s, 3H), 1.64 (s, 6H)。 Intermediate 29 : 2-(6- Bromo -8- fluoro -2 -methylquinolin- 4 -yl ) propan -2- ol: 1 M methylmagnesium bromide in THF at 0°C ( 290 mL, 290 mmol) was slowly added to a solution of methyl 6-bromo-8-fluoro-2-methylquinoline-4-carboxylate (Intermediate 28, 17 g, 57 mmol) in THF (250 mL) and stirred at the same temperature for 2 h. Saturated aqueous ammonium chloride (50 mL) was added to the mixture and extracted into ethyl acetate (2*50 mL). The organic layer was washed successively with water (50 mL) and brine (50 mL), dried over sodium sulfate and evaporated to give a residue, which was purified by silica gel column chromatography on a combi-flash system using ethyl acetate-hexane (15: 85) The residue was purified by elution to give the title compound (11 g) as an off-white solid. Yield: 65%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 8.89 (br. s, 1H), 7.78 (dd, J = 10.0, 2.0, 1H), 7.50 (s, 1H), 2.65 (s, 3H), 1.64 (s, 6H).

中間物 30 (8- -4-(2- 羥基丙 -2- )-2- 甲基喹啉 -6- ) 硼酸:在-78℃下在氮氣氣氛下將硼酸三異丙酯(8.1 mL, 35.0 mmol)逐滴添加至2-(6-溴-8-氟-2-甲基喹啉-4-基)丙-2-醇(中間物29,5.1 g, 17 mmol)於無水THF (20 mL)中之溶液。將2.5 M n-Buli於THF中之溶液(8.1 mL, 35 mmol)逐滴添加至上述混合物中且在相同溫度下攪拌2小時。使混合物升溫至室溫且用2 N HCl酸化,攪拌30 min,藉由添加10% NaOH水溶液中和,攪拌20 min,且萃取至乙酸乙酯(2*100 mL)中。相繼用水(100 mL)及鹽水(100 mL)洗滌合併的有機層,經硫酸鈉乾燥並濃縮。將殘餘物與石油醚(10 mL)一起攪拌20 min,且過濾所形成之固體並乾燥。灰白色固體(3.0 g)。產率:68%。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 8.85 (s, 1H), 8.30 (s, 2H), 7.74 (dd, J = 11.6, 1H), 7.32 (s, 1H), 2.65 (s, 3H), 1.69 (s, 6H)。 Intermediate 30 : (8- Fluoro - 4-(2 -hydroxypropan- 2- yl )-2 -methylquinolin -6- yl ) boronic acid: Triisopropyl borate was added at -78 °C under nitrogen atmosphere (8.1 mL, 35.0 mmol) was added dropwise to 2-(6-bromo-8-fluoro-2-methylquinolin-4-yl)propan-2-ol (Intermediate 29, 5.1 g, 17 mmol) in Solution in anhydrous THF (20 mL). A solution of 2.5 M n -Buli in THF (8.1 mL, 35 mmol) was added dropwise to the above mixture and stirred at the same temperature for 2 hours. The mixture was allowed to warm to room temperature and acidified with 2 N HCl, stirred for 30 min, neutralized by addition of 10% aqueous NaOH, stirred for 20 min, and extracted into ethyl acetate (2*100 mL). The combined organic layers were washed successively with water (100 mL) and brine (100 mL), dried over sodium sulfate and concentrated. The residue was stirred with petroleum ether (10 mL) for 20 min, and the solid formed was filtered and dried. Off-white solid (3.0 g). Yield: 68%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 8.85 (s, 1H), 8.30 (s, 2H), 7.74 (dd, J = 11.6, 1H), 7.32 (s, 1H), 2.65 (s, 3H), 1.69 (s, 6H).

中間物 31 2-(6-(2- -5- 氟嘧啶 -4- )-8- -2- 甲基喹啉 -4- ) -2- 醇:遵循一般程序-2,自(8-氟-4-(2-羥基丙-2-基)-2-甲基喹啉-6-基)硼酸(3.0 g, 11.4 mmol)及2,4-二氯-4-氟嘧啶(2.09 g, 12.5 mmol)合成標題化合物。在後處理後,藉由combi-flash使用MeOH及DCM (1:99)作為溶析液純化粗產物,獲得呈淡黃色固體之標題化合物(2.5 g)。產率:63%。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 9.49 (s, 1H), 9.02 (d, J = 3.2, 1H), 8.02 (d, J = 11.6, 1H), 7.60 (s, 1H), 2.94 (s, 3H), 1.70 (s, 6H)。 Intermediate 31 : 2-(6-(2- Chloro -5- fluoropyrimidin - 4 -yl )-8- fluoro -2 -methylquinolin- 4 -yl ) propan -2- ol: following general procedure-2 , from (8-fluoro-4-(2-hydroxypropan-2-yl)-2-methylquinolin-6-yl)boronic acid (3.0 g, 11.4 mmol) and 2,4-dichloro-4-fluoro Pyrimidine (2.09 g, 12.5 mmol) to synthesize the title compound. After work-up, the crude product was purified by combi-flash using MeOH and DCM (1:99) as eluents to obtain the title compound (2.5 g) as a light yellow solid. Yield: 63%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.49 (s, 1H), 9.02 (d, J = 3.2, 1H), 8.02 (d, J = 11.6, 1H), 7.60 (s, 1H), 2.94 (s, 3H), 1.70 (s, 6H).

中間物 32 (6- -8- -2- 甲基喹啉 -4- ) 甲醇:使6-溴-8-氟-2-甲基喹啉-4-甲酸甲基酯(中間物28,100 g, 335 mmol)於乙醇(1.0 L)中之溶液冷卻至10℃,且經45 min分多次添加硼氫化鈉(50.8, 1.34 mol),並將混合物在60℃下攪拌90 min。使混合物冷卻至25℃,用水(1.5 L)稀釋並攪拌1 h。過濾所形成之固體,用水洗滌且在真空下乾燥5 h,且接著於熱空氣烘箱中在70℃下乾燥17 h,得到呈灰白色固體之標題化合物(74 g)。產率:82%。 Intermediate 32 : (6- bromo -8- fluoro -2 -methylquinolin- 4 -yl ) methanol: methyl 6-bromo-8-fluoro-2-methylquinoline-4-carboxylate (intermediate 28, 100 g, 335 mmol) in ethanol (1.0 L) was cooled to 10 °C, and sodium borohydride (50.8, 1.34 mol) was added in portions over 45 min, and the mixture was stirred at 60 °C for 90 min. The mixture was cooled to 25 °C, diluted with water (1.5 L) and stirred for 1 h. The solid formed was filtered, washed with water and dried under vacuum for 5 h and then in a hot air oven at 70 °C for 17 h to give the title compound (74 g) as an off-white solid. Yield: 82%.

中間物 33 6- -8- -2- 甲基喹啉 -4- 甲醛:在-78℃下經30 min將二甲亞碸(45.4 mL, 640 mmol)逐滴添加至草醯氯(36.55, 418 mmol)於二氯甲烷(300 mL)中之溶液中且再攪拌20 min。在-78℃下經45 min將(6-溴-8-氟-2-甲基喹啉-4-基)甲醇(中間物32,60 g, 222.1 mmol)於二氯甲烷(300 mL)中之溶液添加至上述混合物中且再攪拌30 min。將三乙胺(111 mL, 800 mmol)緩慢添加至反應混合物中且攪拌30 min。添加水(500 mL)後,使混合物升溫至室溫且萃取至二氯甲烷(2*500 mL)中。相繼用水(500 mL)及鹽水(500 mL)洗滌合併的有機層,經硫酸鈉乾燥並濃縮。藉由矽膠層析在combi-flash系統上使用石油醚-EtOAc (90:10)作為溶析液純化殘餘物,得到呈灰白色固體之產物(40 g)。產率:67%。 1H-NMR (δ ppm, CDCl 3, 400 MHz): 10.37 (s, 1H), 9.00 (s, 1H), 7.76 (s, 1H), 7.63 (dd, J = 9.6, 2.0, 1H), 2.90 (s, 3H)。 Intermediate 33 : 6- Bromo -8- fluoro -2 -methylquinoline- 4 - carbaldehyde: Add dimethylsulfoxide (45.4 mL, 640 mmol) to oxalyl chloride dropwise at -78 °C over 30 min (36.55, 418 mmol) in dichloromethane (300 mL) and stirred for another 20 min. (6-Bromo-8-fluoro-2-methylquinolin-4-yl)methanol (Intermediate 32, 60 g, 222.1 mmol) was dissolved in dichloromethane (300 mL) at -78 °C for 45 min The solution was added to the above mixture and stirred for another 30 min. Triethylamine (111 mL, 800 mmol) was slowly added to the reaction mixture and stirred for 30 min. After adding water (500 mL), the mixture was allowed to warm to room temperature and extracted into dichloromethane (2*500 mL). The combined organic layers were washed successively with water (500 mL) and brine (500 mL), dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography on a combi-flash system using petroleum ether-EtOAc (90:10) as eluent to afford the product (40 g) as an off-white solid. Yield: 67%. 1 H-NMR (δ ppm, CDCl 3 , 400 MHz): 10.37 (s, 1H), 9.00 (s, 1H), 7.76 (s, 1H), 7.63 (dd, J = 9.6, 2.0, 1H), 2.90 (s, 3H).

中間物 34 6- -4-( 二氟甲基 )-8- -2- 甲基喹啉:在25℃下將(二乙基胺基)三氟化硫(20.97 g, 130.1 mmol)添加至6-溴-8-氟-2-甲基喹啉-4-甲醛(中間物33,10.0 g, 37.3 mmol)於二氯甲烷(108 mL)中之溶液中,且將混合物攪拌16 h。藉由在0℃下添加飽和碳酸氫鈉水溶液將pH調整為介於7.0與8.0之間後,將混合物萃取至二氯甲烷(2*500 mL)中。將合併的有機層用水(250 mL)及鹽水(250 mL)洗滌,經硫酸鈉乾燥並濃縮。藉由矽膠層析在combi-flash系統上使用石油醚-EtOAc (92:8)作為溶析液純化殘餘物,得到呈灰白色固體之產物(8.0 g)。產率:74%。 1H-NMR (δ ppm, CDCl 3, 400 MHz): 7.99 (s, 1H), 7.60 (dd, J = 9.6, 2.0, 1H), 7.55 (s, 1H), 7.03 (t, J = 54.0, 1H), 2.83 (s, 3H)。 Intermediate 34 : 6- bromo - 4-( difluoromethyl )-8- fluoro -2 -methylquinoline: (diethylamino)sulfur trifluoride (20.97 g, 130.1 mmol ) was added to a solution of 6-bromo-8-fluoro-2-methylquinoline-4-carbaldehyde (Intermediate 33, 10.0 g, 37.3 mmol) in dichloromethane (108 mL), and the mixture was stirred for 16 h. After adjusting the pH between 7.0 and 8.0 by adding saturated aqueous sodium bicarbonate at 0°C, the mixture was extracted into dichloromethane (2*500 mL). The combined organic layers were washed with water (250 mL) and brine (250 mL), dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography on a combi-flash system using petroleum ether-EtOAc (92:8) as eluent to afford the product (8.0 g) as an off-white solid. Yield: 74%. 1 H-NMR (δ ppm, CDCl 3 , 400 MHz): 7.99 (s, 1H), 7.60 (dd, J = 9.6, 2.0, 1H), 7.55 (s, 1H), 7.03 (t, J = 54.0, 1H), 2.83 (s, 3H).

中間物 35 (4-( 二氟甲基 )-8- -2- 甲基喹啉 -6- ) 硼酸:在-78℃下在氮氣氣氛下將硼酸三異丙酯(9.93 mL, 43.0 mmol)逐滴添加至6-溴-4-(二氟甲基)-8-氟-2-甲基喹啉(中間物34,6.0 g, 20.7 mmol)於無水THF (215 mL)中之溶液中。將2.5 M n-Buli於THF中之溶液(16.1 mL, 40.3 mmol)逐滴添加至上述混合物中且在相同溫度下攪拌2小時。使混合物升溫至室溫且用2 N HCl酸化,攪拌30 min,藉由添加10% NaOH水溶液中和,攪拌20 min,且萃取至乙酸乙酯(2*100 mL)中。相繼用水(100 mL)及鹽水(100 mL)洗滌合併的有機層,經硫酸鈉乾燥並濃縮。將殘餘物與二乙醚(30 mL)一起攪拌30 min,且過濾所形成之固體並乾燥。黃色固體(4.1 g)。產率:78%。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 8.48 (br. s, 2H), 8.37 (s, 1H), 7.89 (d, J =11.6, 1H), 7.73 (s, 1H), 7.62 (t, J = 53.6, 1H), 2.75 (s, 3H)。 Intermediate 35 : (4-( Difluoromethyl )-8- fluoro -2 -methylquinolin -6- yl ) boronic acid: Triisopropyl borate (9.93 mL, 43.0 mmol) was added dropwise to 6-bromo-4-(difluoromethyl)-8-fluoro-2-methylquinoline (Intermediate 34, 6.0 g, 20.7 mmol) in anhydrous THF (215 mL) in solution. A solution of 2.5 M n -Buli in THF (16.1 mL, 40.3 mmol) was added dropwise to the above mixture and stirred at the same temperature for 2 hours. The mixture was allowed to warm to room temperature and acidified with 2 N HCl, stirred for 30 min, neutralized by addition of 10% aqueous NaOH, stirred for 20 min, and extracted into ethyl acetate (2*100 mL). The combined organic layers were washed successively with water (100 mL) and brine (100 mL), dried over sodium sulfate and concentrated. The residue was stirred with diethyl ether (30 mL) for 30 min, and the solid formed was filtered and dried. Yellow solid (4.1 g). Yield: 78%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 8.48 (br. s, 2H), 8.37 (s, 1H), 7.89 (d, J =11.6, 1H), 7.73 (s, 1H) , 7.62 (t, J = 53.6, 1H), 2.75 (s, 3H).

中間物 36 6-(2- -5- 氟嘧啶 -4- )-4-( 二氟甲基 )-8- -2- 甲基喹啉:遵循一般程序-2,自(4-(二氟甲基)-8-氟-2-甲基喹啉-6-基)硼酸(中間物35,4.0 g, 15.7 mmol)及2,4-二氯-4-氟嘧啶(2.88 g, 17.3 mmol)合成標題化合物。在後處理後,藉由combi-flash使用石油醚-EtOAc (8:2)作為溶析液純化粗產物,獲得呈灰白色固體之標題化合物(2.5 g)。產率:46.6%。 1H-NMR (δ ppm, CDCl 3, 400 MHz): 8.70 (br. s, 1H), 8.65 (d, J = 3.2, 1H), 8.30 (d, J = 11.2, 1H), 7.66 (s, 1H), 7.20 (t, J = 54.0, 1H), 2.93 (s, 3H)。 Intermediate 36 : 6-(2- Chloro -5- fluoropyrimidin - 4 -yl )-4-( difluoromethyl )-8- fluoro -2 -methylquinoline: following general procedure-2, from (4 -(difluoromethyl)-8-fluoro-2-methylquinolin-6-yl)boronic acid (intermediate 35, 4.0 g, 15.7 mmol) and 2,4-dichloro-4-fluoropyrimidine (2.88 g , 17.3 mmol) to synthesize the title compound. After work-up, the crude product was purified by combi-flash using petroleum ether-EtOAc (8:2) as eluent to obtain the title compound (2.5 g) as an off-white solid. Yield: 46.6%. 1 H-NMR (δ ppm, CDCl 3 , 400 MHz): 8.70 (br. s, 1H), 8.65 (d, J = 3.2, 1H), 8.30 (d, J = 11.2, 1H), 7.66 (s, 1H), 7.20 (t, J = 54.0, 1H), 2.93 (s, 3H).

中間物 37 6- -8- -4-(2- 氟丙 -2- )-2- 甲基喹啉:在10℃-15℃下將(二乙基胺基)三氟化硫(5.41 g, 33.5 mmol)添加至2-(6-溴-8-氟-2-甲基喹啉-4-基)丙-2-醇(中間物29,5.0 g, 16.8 mmol)於二氯甲烷(50 mL)中之溶液中,且將混合物攪拌隔夜。用二氯甲烷(100 mL)稀釋該混合物且相繼用飽和碳酸氫鈉水溶液(2*50 mL)、水(100 mL)及鹽水(100 mL)洗滌,經硫酸鈉乾燥並濃縮。藉由矽膠層析在combi-flash系統上使用石油醚-EtOAc (90:10)作為溶析液純化殘餘物,得到呈灰白色固體之產物(2.30 g)。產率:50%。 1H-NMR (δ ppm, CDCl 3, 400 MHz): 8.23 (s, 1H), 7.52 (dd, J = 11.2, 1.2, 1H), 8.30 (d, J = 11.2, 1H), 7.37 (s, 3H), 2.72 (s, 1H), 1.92 (d, J = 22.4, 3H)。 Intermediate 37 : 6- Bromo -8- fluoro - 4-(2- fluoropropan- 2- yl )-2 -methylquinoline: (diethylamino) trifluorination at 10°C-15°C Sulfur (5.41 g, 33.5 mmol) was added to 2-(6-bromo-8-fluoro-2-methylquinolin-4-yl)propan-2-ol (intermediate 29, 5.0 g, 16.8 mmol) in di chloride (50 mL), and the mixture was stirred overnight. The mixture was diluted with dichloromethane (100 mL) and washed sequentially with saturated aqueous sodium bicarbonate (2*50 mL), water (100 mL) and brine (100 mL), dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography on a combi-flash system using petroleum ether-EtOAc (90:10) as eluent to afford the product (2.30 g) as an off-white solid. Yield: 50%. 1 H-NMR (δ ppm, CDCl 3 , 400 MHz): 8.23 (s, 1H), 7.52 (dd, J = 11.2, 1.2, 1H), 8.30 (d, J = 11.2, 1H), 7.37 (s, 3H), 2.72 (s, 1H), 1.92 (d, J = 22.4, 3H).

中間物 38 (8- -4-(2- 氟丙 -2- )-2- 甲基喹啉 -6- ) 硼酸:在-78℃下在氮氣氣氛下將硼酸三異丙酯(0.792 mL, 3.43 mmol)逐滴添加至6-溴-4-(二氟甲基)-8-氟-2-甲基喹啉(中間物37,500 mg, 1.67 mmol)於無水THF (20 mL)中之溶液中。將2.5 M n-Buli於己烷中之溶液(2.0 mL, 5.0 mmol)逐滴添加至上述混合物中且在相同溫度下攪拌2小時。使混合物升溫至室溫且用2 N HCl酸化,攪拌30 min,藉由添加10% NaOH水溶液中和,攪拌20 min,且萃取至乙酸乙酯(2*100 mL)中。相繼用水(100 mL)及鹽水(100 mL)洗滌合併的有機層,經硫酸鈉乾燥並濃縮。將殘餘物與石油醚(20 mL)一起攪拌20 min,且過濾所形成之固體並乾燥。灰白色固體(170 mg)。產率:38.5%。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 8.49 (s, 1H), 8.42 (s, 2H), 7.79 (d, J = 11.2, 1H), 7.52 (s, 1H), 2.69 (s, 3H), 1.92 (d, J = 23.2, 6H)。 Intermediate 38 : (8- Fluoro - 4-(2- fluoropropan- 2- yl )-2 -methylquinolin -6- yl ) boronic acid: triisopropyl borate at -78 °C under nitrogen atmosphere (0.792 mL, 3.43 mmol) was added dropwise to 6-bromo-4-(difluoromethyl)-8-fluoro-2-methylquinoline (intermediate 37, 500 mg, 1.67 mmol) in anhydrous THF (20 mL) in solution. A solution of 2.5 M n -Buli in hexane (2.0 mL, 5.0 mmol) was added dropwise to the above mixture and stirred at the same temperature for 2 hours. The mixture was allowed to warm to room temperature and acidified with 2 N HCl, stirred for 30 min, neutralized by addition of 10% aqueous NaOH, stirred for 20 min, and extracted into ethyl acetate (2*100 mL). The combined organic layers were washed successively with water (100 mL) and brine (100 mL), dried over sodium sulfate and concentrated. The residue was stirred with petroleum ether (20 mL) for 20 min, and the solid formed was filtered and dried. Off-white solid (170 mg). Yield: 38.5%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 8.49 (s, 1H), 8.42 (s, 2H), 7.79 (d, J = 11.2, 1H), 7.52 (s, 1H), 2.69 (s, 3H), 1.92 (d, J = 23.2, 6H).

中間物 39 6-(2- -5- 氟嘧啶 -4- )-8- -4-(2- 氟丙 -2- )-2- 甲基喹啉:遵循一般程序-2,自(8-氟-4-(2-氟丙-2-基)-2-甲基喹啉-6-基)硼酸(中間物38,1.80 g, 6.79 mmol)及2,4-二氯-4-氟嘧啶(1.25 g, 7.47 mmol)合成標題化合物。在後處理後,藉由combi-flash使用甲醇-二氯甲烷(9:1)作為溶析液純化粗產物。在自彙集之溶離份中去除溶劑後,將殘餘物與石油醚(20 mL)一起攪拌,過濾固體並乾燥,獲得呈黃色固體之標題化合物(1.3 g)。產率:54.4%。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 9.03 (d, J = 3.2, 1H), 8.90 (s, 1H), 8.06 (d, J = 11.6, 1H), 7.65 (s, 1H), 2.74 (s, 1H), 1.93 (d, J =22.4, 6H)。 Intermediate 39 : 6-(2- Chloro -5- fluoropyrimidin - 4 -yl )-8- fluoro - 4-(2- fluoropropan- 2- yl )-2 -methylquinoline: following general procedure-2 , from (8-fluoro-4-(2-fluoroprop-2-yl)-2-methylquinolin-6-yl)boronic acid (intermediate 38, 1.80 g, 6.79 mmol) and 2,4-dichloro -4-fluoropyrimidine (1.25 g, 7.47 mmol) to synthesize the title compound. After work-up, the crude product was purified by combi-flash using methanol-dichloromethane (9:1) as eluent. After removal of solvent from the pooled fractions, the residue was stirred with petroleum ether (20 mL), the solid was filtered and dried to afford the title compound (1.3 g) as a yellow solid. Yield: 54.4%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.03 (d, J = 3.2, 1H), 8.90 (s, 1H), 8.06 (d, J = 11.6, 1H), 7.65 (s, 1H), 2.74 (s, 1H), 1.93 (d, J =22.4, 6H).

中間物 40 7- -6-(4,4,5,5- 四甲基 -1,3,2- 二氧雜硼雜環戊烷 -2- ) 喹啉:如Fei等人, bioorganic & medicinal Chemistry 2016, 24(18), 4281-4290中所闡述製備6-溴-7-氟喹啉。遵循一般程序-1,自6-溴-7-氟喹啉(500 mg, 2.21 mmol)合成標題化合物。在後處理後,藉由combi-flash使用EtOAc及石油醚(3:97)作為溶析液純化粗產物,獲得呈黃色液體之標題化合物(200 mg)。產率:33%。產率:33%。 1H-NMR (δ ppm, CDCl 3, 400 MHz): 8.93 (dd, J = 4.4, 1.6, 1H), 8.31 (d, J = 6.4, 1H), 8.19 (br. d, J = 8.4, 1H), 7.71 (br. d, J = 10.8, 1H), 7.37 (dd, J = 8.4, 4.4, 1H), 1.42 (s, 12H)。MS (m/z):274.24 (M+H);[C 15H 17BFNO 2+H]計算值:274.14。 Intermediate 40 : 7- fluoro -6-(4,4,5,5 -tetramethyl- 1,3,2-dioxaborolan - 2- yl ) quinoline: as Fei et al., The preparation of 6-bromo-7-fluoroquinoline is described in bioorganic & medicinal Chemistry 2016 , 24(18), 4281-4290. The title compound was synthesized from 6-bromo-7-fluoroquinoline (500 mg, 2.21 mmol) following General Procedure-1. After work-up, the crude product was purified by combi-flash using EtOAc and petroleum ether (3:97) as eluents to obtain the title compound (200 mg) as a yellow liquid. Yield: 33%. Yield: 33%. 1 H-NMR (δ ppm, CDCl 3 , 400 MHz): 8.93 (dd, J = 4.4, 1.6, 1H), 8.31 (d, J = 6.4, 1H), 8.19 (br. d, J = 8.4, 1H ), 7.71 (br. d, J = 10.8, 1H), 7.37 (dd, J = 8.4, 4.4, 1H), 1.42 (s, 12H). MS (m/z): 274.24 (M+H); Calcd. for [ C15H17BFNO2 + H]: 274.14 .

中間物 41 7- -6-(4,4,5,5- 四甲基 -1,3,2- 二氧雜硼雜環戊烷 -2- ) 喹啉:遵循一般程序-2,自7-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)喹啉(中間物40,5.0 g, 18.3 mmol)及2,4-二氯-5-氟嘧啶(3.67 g, 22.0 mmol)合成標題化合物。在後處理後,藉由combi-flash使用石油醚-EtOAc (8:2)作為溶析液純化粗產物,獲得呈灰白色固體之標題化合物(3.1g)。產率:61%。 1H-NMR (δ ppm, CDCl 3, 400 MHz): 9.02 (dd, J = 4.4, 1.6, 1H), 8.63 (d, J = 1.6, 1H), 8.28 (d, J = 8.4, 1H), 8.26 (d, J = 7.6, 1H), 7.91 (d, J = 9.6, 1H), 7.49 (dd, J = 8.0, 4.0, 1H)。 Intermediate 41 : 7- Fluoro -6-(4,4,5,5 -tetramethyl- 1,3,2-dioxaborolan - 2- yl ) quinoline: following general procedure-2 , from 7-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (intermediate 40, 5.0 g, 18.3 mmol) and 2,4-dichloro-5-fluoropyrimidine (3.67 g, 22.0 mmol) to synthesize the title compound. After work-up, the crude product was purified by combi-flash using petroleum ether-EtOAc (8:2) as eluent to obtain the title compound (3.1 g) as an off-white solid. Yield: 61%. 1 H-NMR (δ ppm, CDCl 3 , 400 MHz): 9.02 (dd, J = 4.4, 1.6, 1H), 8.63 (d, J = 1.6, 1H), 8.28 (d, J = 8.4, 1H), 8.26 (d, J = 7.6, 1H), 7.91 (d, J = 9.6, 1H), 7.49 (dd, J = 8.0, 4.0, 1H).

中間物 42 N,N- 二甲基 -1-(6- 硝基吡啶 -3- ) 六氫吡啶 -4- 使5-溴-2-硝基吡啶(5 g, 24.6 mmol)、N,N-二甲基六氫吡啶-4-胺(4.11 g, 32.0 mmol)及碳酸鉀(5.11 g, 36.9 mmol)懸浮於DMSO (50 ml)中,且在90℃下攪拌16 h。用水(500 ml)稀釋反應混合物,用DCM (2*200 ml)萃取,且將合併的有機層用鹽水(100 ml)及水(100 ml)洗滌,經無水硫酸鈉乾燥且在真空下蒸餾,獲得粗產物。藉由combi-flash使用甲醇及DCM (2:98)作為溶析液進行純化,得到呈黃色固體之標題化合物(3.6 g)。產率:58%。 1H-NMR (δ ppm, CDCl 3, 400 MHz): 8.15 (d, J 9.2, 1H), 8.13 (d, J 3.2, 1H), 7.19 (dd, J 9.2, 3.2, 1H), 4.00-3.93 (m, 2H), 3.10-3.02 (m, 2H), 2.46-2.36 (m, 1H), 2.31 (s, 6H), 2.00 (d, J 12.4, 2H), 1.70-1.56 (m, 2H)。 Intermediate 42 : N,N -Dimethyl- 1-(6 -nitropyridin- 3 -yl ) hexahydropyridin- 4 -amine 5-bromo-2-nitropyridine (5 g, 24.6 mmol), N,N-Dimethylhexahydropyridin-4-amine (4.11 g, 32.0 mmol) and potassium carbonate (5.11 g, 36.9 mmol) were suspended in DMSO (50 ml), and stirred at 90°C for 16 h. The reaction mixture was diluted with water (500 ml), extracted with DCM (2*200 ml), and the combined organic layer was washed with brine (100 ml) and water (100 ml), dried over anhydrous sodium sulfate and distilled under vacuum, A crude product is obtained. Purification by combi-flash using methanol and DCM (2:98) as eluents afforded the title compound (3.6 g) as a yellow solid. Yield: 58%. 1 H-NMR (δ ppm, CDCl 3 , 400 MHz): 8.15 (d, J 9.2, 1H), 8.13 (d, J 3.2, 1H), 7.19 (dd, J 9.2, 3.2, 1H), 4.00-3.93 (m, 2H), 3.10-3.02 (m, 2H), 2.46-2.36 (m, 1H), 2.31 (s, 6H), 2.00 (d, J 12.4, 2H), 1.70-1.56 (m, 2H).

中間物 43 5-(4-( 二甲基胺基 ) 六氫吡啶 -1- ) 吡啶 -2- 將中間物42 (2.7 g, 11  mmol)置於高壓釜中且溶解於甲醇(25 ml)與乙醇(25 ml)之混合物中,且添加碳載5%鈀(1.08 g)。將此混合物在室溫下在4.5 kg氫壓下攪拌4 h。在反應完成後,經由矽藻土床過濾反應混合物,且用MeOH與DCM之混合物(1:9, 100 ml)洗滌該床。使合併的濾液及洗滌液蒸發,獲得固體。 將固體與石油醚一起濕磨,得到呈灰色固體之標題化合物(2.1 g)。產率:88%。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 7.58 (d, J 3.0, 1H), 7.14 (dd, J 8.8, 3.0, 1H), 6.36 (d, J 8.8, 1H), 5.35 (s, 2H), 3.40-3.32 (m, 2H), 2.55-2.45 (m, 2H), 2.17 (s, 6H), 2.15-2.06 (m, 1H), 1.78 (d, J 12.4, 2H), 1.52-1.40 (m, 2H)。 Intermediate 43 : 5-(4-( Dimethylamino ) hexahydropyridin- 1 -yl ) pyridin -2- amine Intermediate 42 (2.7 g, 11 mmol) was placed in an autoclave and dissolved in methanol ( 25 ml) and ethanol (25 ml), and 5% palladium on carbon (1.08 g) was added. This mixture was stirred at room temperature under 4.5 kg hydrogen pressure for 4 h. After completion of the reaction, the reaction mixture was filtered through a bed of celite, and the bed was washed with a mixture of MeOH and DCM (1:9, 100 ml). The combined filtrate and washings were evaporated to give a solid. The solid was triturated with petroleum ether to give the title compound (2.1 g) as a gray solid. Yield: 88%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 7.58 (d, J 3.0, 1H), 7.14 (dd, J 8.8, 3.0, 1H), 6.36 (d, J 8.8, 1H), 5.35 (s, 2H), 3.40-3.32 (m, 2H), 2.55-2.45 (m, 2H), 2.17 (s, 6H), 2.15-2.06 (m, 1H), 1.78 (d, J 12.4, 2H), 1.52-1.40 (m, 2H).

中間物 44 4-(6- 硝基吡啶 -3- ) 六氫吡嗪 -2- 酮:使5-溴-2-硝基吡啶(4.04 g, 19.9 mmol)、六氫吡嗪-2-酮(2.39 g, 23.9 mmol)及DIPEA (9.26 g, 71.6 mmol)懸浮於DMSO (50 ml)中,且於密封管中在120℃下攪拌16 h。蒸餾出DIPEA,獲得殘餘物。向殘餘物中添加EtOAc (30 ml)且攪拌30 min,獲得固體。過濾固體且在真空下乾燥3 h,獲得呈黃色固體之標題化合物(2.5 g)。產率:57%。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz):8.27 (bs, 1H), 8.22-8.15 (m, 2H), 7.44 (dd, J 9.2, 3, 1H), 4.04 (s, 2H), 3.72-3.65 (m, 2H), 3.41-3.32 (m, 2H)。 Intermediate 44 : 4-(6 -nitropyridin- 3 -yl ) hexahydropyrazin -2- one: 5-bromo-2-nitropyridine (4.04 g, 19.9 mmol), hexahydropyrazin-2 - Ketone (2.39 g, 23.9 mmol) and DIPEA (9.26 g, 71.6 mmol) were suspended in DMSO (50 ml) and stirred at 120 °C for 16 h in a sealed tube. DIPEA was distilled off to obtain a residue. EtOAc (30 ml) was added to the residue and stirred for 30 min to obtain a solid. The solid was filtered and dried under vacuum for 3 h to obtain the title compound (2.5 g) as a yellow solid. Yield: 57%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz):8.27 (bs, 1H), 8.22-8.15 (m, 2H), 7.44 (dd, J 9.2, 3, 1H), 4.04 (s, 2H ), 3.72-3.65 (m, 2H), 3.41-3.32 (m, 2H).

中間物 45 4-(6- 胺基吡啶 -3- ) 六氫吡嗪 -2- 酮:將中間物44 (1.9 g, 8.55 mmol)置於高壓釜中且溶解於甲醇(15 ml)與乙醇(15 ml)之混合物中,且添加碳載5%鈀(760 mg)。將此混合物在室溫下在4.5 kg氫壓下攪拌4 h。在反應完成後,經由矽藻土床過濾反應混合物,且用MeOH與DCM之混合物(1:9, 100 ml)洗滌該床。使合併的濾液及洗滌液蒸發,獲得固體。 將固體與石油醚一起濕磨,得到呈褐色固體之標題化合物(800 mg)。產率:49%。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 7.58 (d, J 3.2, 1H), 7.27 (dd, J 8.8, 3.2, 1H), 6.46 (d, J 8.8, 1H), 5.89 (bs, 2H), 3.48 (s, 2H), 3.27-3.22 (m, 2H), 3.48 (s, 2H), 3.18-3.13 (m, 2H)。 Intermediate 45 : 4-(6 -Aminopyridin- 3 -yl ) hexahydropyrazin -2- one: Intermediate 44 (1.9 g, 8.55 mmol) was placed in an autoclave and dissolved in methanol (15 ml) In a mixture with ethanol (15 ml), and 5% palladium on carbon (760 mg) was added. This mixture was stirred at room temperature under 4.5 kg hydrogen pressure for 4 h. After completion of the reaction, the reaction mixture was filtered through a bed of celite, and the bed was washed with a mixture of MeOH and DCM (1:9, 100 ml). The combined filtrate and washings were evaporated to give a solid. The solid was triturated with petroleum ether to give the title compound (800 mg) as a tan solid. Yield: 49%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 7.58 (d, J 3.2, 1H), 7.27 (dd, J 8.8, 3.2, 1H), 6.46 (d, J 8.8, 1H), 5.89 (bs, 2H), 3.48 (s, 2H), 3.27-3.22 (m, 2H), 3.48 (s, 2H), 3.18-3.13 (m, 2H).

中間物 46 1- 環丙基 -4-(6- 硝基吡啶 -3- ) 六氫吡嗪:使5-溴-2-硝基吡啶(5 g, 24.6 mmol)、(六氫吡嗪-1-基)環丙烷(3.73 g, 29.6 mmol)及碳酸鉀(5.11 g, 36.9 mmol)懸浮於DMSO (63.25 ml)中,且在90℃下攪拌16 h。用水(500 ml)稀釋反應混合物,用DCM (2*200 ml)萃取,且將合併的有機層用鹽水(100 ml)及水(100 ml)洗滌,經無水硫酸鈉乾燥且在真空下蒸餾,獲得粗產物。藉由combi-flash使用甲醇及DCM (2:98)作為溶析液進行純化,得到呈黃色固體之標題化合物(4 g)。產率:65%。 1H-NMR (δ ppm, CDCl 3, 400 MHz): 8.16 (d, J 9.2, 1H), 8.13 (d, J 3.0, 1H), 7.20 (dd, J 9.2, 3.0 (1H), 3.42 (t, J 5.2, 4H), 2.78 (t, J 5.2, 4H), 1.72-1.65 (m, 1H), 0.55-0.49 (m, 2H), 0.48-0.42 (m, 2H)。 Intermediate 46 : 1 -cyclopropyl- 4-(6 -nitropyridin- 3 -yl ) hexahydropyrazine: make 5-bromo-2-nitropyridine (5 g, 24.6 mmol), (hexahydropyridine Azin-1-yl)cyclopropane (3.73 g, 29.6 mmol) and potassium carbonate (5.11 g, 36.9 mmol) were suspended in DMSO (63.25 ml) and stirred at 90°C for 16 h. The reaction mixture was diluted with water (500 ml), extracted with DCM (2*200 ml), and the combined organic layer was washed with brine (100 ml) and water (100 ml), dried over anhydrous sodium sulfate and distilled under vacuum, A crude product is obtained. Purification by combi-flash using methanol and DCM (2:98) as eluents afforded the title compound (4 g) as a yellow solid. Yield: 65%. 1 H-NMR (δ ppm, CDCl 3 , 400 MHz): 8.16 (d, J 9.2, 1H), 8.13 (d, J 3.0, 1H), 7.20 (dd, J 9.2, 3.0 (1H), 3.42 (t , J 5.2, 4H), 2.78 (t, J 5.2, 4H), 1.72-1.65 (m, 1H), 0.55-0.49 (m, 2H), 0.48-0.42 (m, 2H).

中間物 47 5-(4- 環丙基六氫吡嗪 -1- ) 吡啶 -2- 胺:將中間物46 (2.7 g, 11  mmol)置於高壓釜中且溶解於甲醇(25 ml)與乙醇(25 ml)之混合物中,且添加碳載5%鈀(1.08 g)。將此混合物在室溫下在4.5 kg氫壓下攪拌4 h。在反應完成後,經由矽藻土床過濾反應混合物,且用MeOH與DCM之混合物(1:9, 100 ml)洗滌該床。使合併的濾液及洗滌液蒸發,獲得固體。 將固體與石油醚一起濕磨,得到呈灰色固體之標題化合物(2.1 g)。產率:88%。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 7.56 (d, J 3, 1H), 7.13 (dd, J 9.2, 3, 1H), 6.37 (d, J 9.2, 1H), 5.36 (s, 2H), 2.85 (t, J 4.8, 4H), 2.62 (t, J 4.8, 4H), 1.62 (quintet, J 3.2, 1H), 0.45-0.38 (m, 2H), 0.32-0.26 (m, 2H)。 Intermediate 47 : 5-(4- Cyclopropylhexahydropyrazin- 1 -yl ) pyridin -2- amine: Intermediate 46 (2.7 g, 11 mmol) was placed in an autoclave and dissolved in methanol (25 ml ) and ethanol (25 ml), and 5% palladium on carbon (1.08 g) was added. This mixture was stirred at room temperature under 4.5 kg hydrogen pressure for 4 h. After completion of the reaction, the reaction mixture was filtered through a bed of celite, and the bed was washed with a mixture of MeOH and DCM (1:9, 100 ml). The combined filtrate and washings were evaporated to give a solid. The solid was triturated with petroleum ether to give the title compound (2.1 g) as a gray solid. Yield: 88%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 7.56 (d, J 3, 1H), 7.13 (dd, J 9.2, 3, 1H), 6.37 (d, J 9.2, 1H), 5.36 (s, 2H), 2.85 (t, J 4.8, 4H), 2.62 (t, J 4.8, 4H), 1.62 (quintet, J 3.2, 1H), 0.45-0.38 (m, 2H), 0.32-0.26 (m , 2H).

中間物 48 1-(4-(6- 硝基吡啶 -3- ) 六氫吡嗪 -1- ) -1- 將中間物3 (1.50 g, 7.20 mmol)及三乙胺(729 mg, 7.20 mmol)溶解於DCM (30 ml)中,且在0℃下攪拌30 min。將乙醯氯(679 mg, 8.64 mmol)添加至上述混合物中且在室溫下攪拌30 min。用水(100 ml)淬滅反應混合物且分離有機層及水層。用DCM (3*80 ml)萃取水層。蒸餾合併的有機層,獲得固體。將固體與二乙醚一起濕磨並過濾。在真空下乾燥過濾固體,獲得呈黃色固體之標題化合物(1.5 g)。產率:83%。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 8.25 (s, 1H), 8.18 (d, J 9.2, 1H), 7.48 (d, J 9.2, 1H), 3.60 (bs, 6H), 3.52 (bs, 2H), 2.05 (s, 3H)。 Intermediate 48 : 1-(4-(6 -nitropyridin- 3 -yl ) hexahydropyrazin- 1 -yl ) ethan - 1 -one Intermediate 3 (1.50 g, 7.20 mmol) and triethylamine ( 729 mg, 7.20 mmol) was dissolved in DCM (30 ml) and stirred at 0 °C for 30 min. Acetyl chloride (679 mg, 8.64 mmol) was added to the above mixture and stirred at room temperature for 30 min. The reaction mixture was quenched with water (100 ml) and the organic and aqueous layers were separated. The aqueous layer was extracted with DCM (3*80 ml). The combined organic layers were distilled to obtain a solid. The solid was triturated with diethyl ether and filtered. The filtered solid was dried under vacuum to obtain the title compound (1.5 g) as a yellow solid. Yield: 83%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 8.25 (s, 1H), 8.18 (d, J 9.2, 1H), 7.48 (d, J 9.2, 1H), 3.60 (bs, 6H) , 3.52 (bs, 2H), 2.05 (s, 3H).

中間物 49 1-(4-(6- 胺基吡啶 -3- ) 六氫吡嗪 -1- ) -1- 酮:將中間物48 (1.50 g, 5.99 mmol)置於高壓釜中且溶解於甲醇(13 ml)與乙醇(13 ml)之混合物中,且添加碳載5%鈀(600 mg)。將此混合物在室溫下在4.5 kg氫壓下攪拌24 h。在反應完成後,經由矽藻土床過濾反應混合物,且用MeOH與DCM之混合物(1:9, 170 ml)洗滌該床。使合併的濾液及洗滌液蒸發,獲得固體。 將固體與二乙醚一起濕磨,得到呈灰色固體之標題化合物(1 g)。產率:80%。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 7.60 (d, J 3.0, 1H), 7.17 (dd, J 8.8, 3.0, 1H), 6.39 (d, J 8.8, 1H), 5.44 (s, 2H), 3.53 (q, J 5, 4H), 2.89 (t, J 5, 2H), 2.82 (, J 5, 2H), 2.00 (s, 3H)。 Intermediate 49 : 1-(4-(6 -Aminopyridin- 3 -yl ) hexahydropyrazin- 1 -yl ) ethan - 1 -one: Intermediate 48 (1.50 g, 5.99 mmol) was placed in autoclave and dissolved in a mixture of methanol (13 ml) and ethanol (13 ml), and 5% palladium on carbon (600 mg) was added. This mixture was stirred at room temperature under 4.5 kg hydrogen pressure for 24 h. After the reaction was complete, the reaction mixture was filtered through a bed of celite, and the bed was washed with a mixture of MeOH and DCM (1:9, 170 ml). The combined filtrate and washings were evaporated to give a solid. The solid was triturated with diethyl ether to give the title compound (1 g) as a gray solid. Yield: 80%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 7.60 (d, J 3.0, 1H), 7.17 (dd, J 8.8, 3.0, 1H), 6.39 (d, J 8.8, 1H), 5.44 (s, 2H), 3.53 (q, J 5, 4H), 2.89 (t, J 5, 2H), 2.82 (, J 5, 2H), 2.00 (s, 3H).

中間物 50 1-(6- 硝基吡啶 -3- )-4-(2,2,2- 三氟乙基 ) 六氫吡嗪:使5-溴-2-硝基吡啶(1.5 g, 7.4 mmol)、1-(2,2,2-三氟乙基)六氫吡嗪(1.5 g, 8.9 mmol)及碳酸鉀(1.5 g, 11 mmol)懸浮於DMSO (20 ml)中,且在90℃下攪拌16 h。用水(200 ml)稀釋反應混合物,用DCM (2*200 ml)萃取,且將合併的有機層用鹽水(100 ml)及水(100 ml)洗滌,經無水硫酸鈉乾燥且在真空下蒸餾,獲得粗產物。藉由combi-flash使用甲醇及DCM (2.5:97.5)作為溶析液進行純化,得到呈黃色固體之標題化合物(1.1 g)。產率:51%。 1H-NMR (δ ppm, CDCl 3, 400 MHz): 8.17 (d, J 9.2, 1H), 8.14 (d, J 3.0, 1H), 7.22 (d, J 9.2, 3.2, 1H), 3.48 (t, J 5, 4H), 3.08 (q, J 9.6, 2H), 2.87 (t, J 5, 4H)。 Intermediate 50 : 1-(6 -nitropyridin- 3 -yl )-4-(2,2,2- trifluoroethyl ) hexahydropyrazine: make 5-bromo-2-nitropyridine (1.5 g , 7.4 mmol), 1-(2,2,2-trifluoroethyl) hexahydropyrazine (1.5 g, 8.9 mmol) and potassium carbonate (1.5 g, 11 mmol) were suspended in DMSO (20 ml), and Stir at 90 °C for 16 h. The reaction mixture was diluted with water (200 ml), extracted with DCM (2*200 ml), and the combined organic layer was washed with brine (100 ml) and water (100 ml), dried over anhydrous sodium sulfate and distilled under vacuum, A crude product is obtained. Purification by combi-flash using methanol and DCM (2.5:97.5) as eluents gave the title compound (1.1 g) as a yellow solid. Yield: 51%. 1 H-NMR (δ ppm, CDCl 3 , 400 MHz): 8.17 (d, J 9.2, 1H), 8.14 (d, J 3.0, 1H), 7.22 (d, J 9.2, 3.2, 1H), 3.48 (t , J 5, 4H), 3.08 (q, J 9.6, 2H), 2.87 (t, J 5, 4H).

中間物 51 5-(4-(2,2,2- 三氟乙基 ) 六氫吡嗪 -1- ) 吡啶 -2- 胺:將中間物50 (1.1 g, 3.8 mmol)置於高壓釜中且溶解於甲醇(10 ml)與乙醇(10 ml)之混合物中,且添加碳載5%鈀(440 mg)。將此混合物在室溫下在4.5 kg氫壓下攪拌4 h。在反應完成後,經由矽藻土床過濾反應混合物,且用MeOH與DCM之混合物(1:9, 100 ml)洗滌該床。使合併的濾液及洗滌液蒸發,獲得呈褐色固體之標題化合物(800 mg)。產率:81%。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 7.60 (d, J 2.5, 1H), 7.16 (dd, J 8.8, 3.0, 1H), 6.40 (d, J 8.8, 1H), 5.39 (s, 2H), 3.23 (q, J 10, 2H), 2.92 (t, J 5, 4H), 2.74 (t, J 5, 4H)。 Intermediate 51 : 5-(4-(2,2,2- trifluoroethyl ) hexahydropyrazin- 1 -yl ) pyridin -2- amine: Intermediate 50 (1.1 g, 3.8 mmol) was placed under high pressure in a kettle and dissolved in a mixture of methanol (10 ml) and ethanol (10 ml) and 5% palladium on carbon (440 mg) was added. This mixture was stirred at room temperature under 4.5 kg hydrogen pressure for 4 h. After completion of the reaction, the reaction mixture was filtered through a bed of celite, and the bed was washed with a mixture of MeOH and DCM (1:9, 100 ml). The combined filtrate and washings were evaporated to give the title compound (800 mg) as a tan solid. Yield: 81%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 7.60 (d, J 2.5, 1H), 7.16 (dd, J 8.8, 3.0, 1H), 6.40 (d, J 8.8, 1H), 5.39 (s, 2H), 3.23 (q, J 10, 2H), 2.92 (t, J 5, 4H), 2.74 (t, J 5, 4H).

中間物 52 1-( 甲基磺醯基 )-4-(6- 硝基吡啶 -3- ) 六氫吡嗪:將中間物3 (1.50 g, 7.20 mmol)及三乙胺(729 mg, 7.20 mmol)溶解於DCM (30 ml)中,且在0℃下攪拌30 min。將甲磺醯氯(990 mg, 8.64 mmol)添加至上述混合物中且在室溫下攪拌30 min。用水(100 ml)淬滅反應混合物且分離有機層及水層。用MeOH:DCM (1:9) (2*100 ml)萃取水層。蒸餾合併的有機層,獲得固體。將固體與二乙醚一起濕磨並過濾。在真空下乾燥過濾固體,獲得呈黃色固體之標題化合物(1.8 g)。產率:87%。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 8.31 (d, J 2.8, 1H), 8.19 (d, J 9.2, 1H), 7.55 (dd, J 9.2, 2.8, 1H), 3.65 (t, J 5, 4H), 3.26 (t, J 5, 4H), 2.93 (s, 3H)。 Intermediate 52 : 1-( Methylsulfonyl )-4-(6 -nitropyridin- 3 -yl ) hexahydropyrazine: Intermediate 3 (1.50 g, 7.20 mmol) and triethylamine (729 mg , 7.20 mmol) was dissolved in DCM (30 ml) and stirred at 0 °C for 30 min. Methanesulfonyl chloride (990 mg, 8.64 mmol) was added to the above mixture and stirred at room temperature for 30 min. The reaction mixture was quenched with water (100 ml) and the organic and aqueous layers were separated. The aqueous layer was extracted with MeOH:DCM (1:9) (2*100 ml). The combined organic layers were distilled to obtain a solid. The solid was triturated with diethyl ether and filtered. The filtered solid was dried under vacuum to obtain the title compound (1.8 g) as a yellow solid. Yield: 87%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 8.31 (d, J 2.8, 1H), 8.19 (d, J 9.2, 1H), 7.55 (dd, J 9.2, 2.8, 1H), 3.65 (t, J 5, 4H), 3.26 (t, J 5, 4H), 2.93 (s, 3H).

中間物 53 5-(4-( 甲基磺醯基 ) 六氫吡嗪 -1- ) 吡啶 -2- 胺:將中間物53 (1.7 g, 5.94 mmol)置於高壓釜中且溶解於甲醇(13 ml)與乙醇(13 ml)之混合物中,且添加碳載5%鈀(600 mg)。將此混合物在室溫下在4.5 kg氫壓下攪拌4 h。在反應完成後,經由矽藻土床過濾反應混合物,且用MeOH與DCM之混合物(1:9, 170 ml)洗滌該床。使合併的濾液及洗滌液蒸發,獲得固體。將固體與二乙醚一起濕磨,獲得呈褐色固體之標題化合物(1.3 g)。產率:85%。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 7.64 (d, J 2.8, 1H), 7.20 (d, J 8.8, 2.8, 1H), 6.41 (d, J 8.8, 1H), 5.47 (s, 2H), 3.22 (t, J 4.8, 4H), 3.00 (t, J 4.8, 4H), 2.91 (s, 3H)。 Intermediate 53 : 5-(4-(Methylsulfonyl ) hexahydropyrazin - 1 -yl ) pyridin -2- amine: Intermediate 53 (1.7 g, 5.94 mmol) was placed in an autoclave and dissolved in In a mixture of methanol (13 ml) and ethanol (13 ml), and 5% palladium on carbon (600 mg) was added. This mixture was stirred at room temperature under 4.5 kg hydrogen pressure for 4 h. After the reaction was complete, the reaction mixture was filtered through a bed of celite, and the bed was washed with a mixture of MeOH and DCM (1:9, 170 ml). The combined filtrate and washings were evaporated to give a solid. The solid was triturated with diethyl ether to afford the title compound (1.3 g) as a tan solid. Yield: 85%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 7.64 (d, J 2.8, 1H), 7.20 (d, J 8.8, 2.8, 1H), 6.41 (d, J 8.8, 1H), 5.47 (s, 2H), 3.22 (t, J 4.8, 4H), 3.00 (t, J 4.8, 4H), 2.91 (s, 3H).

中間物 54 環丙基 (4-(6- 硝基吡啶 -3- ) 六氫吡嗪 -1- ) 甲酮 步驟-1:將環丙基甲酸(744 mg, 8.64 mmol)溶解於DCM (10 ml)中且冷卻至0℃。將草醯氯(1.37 g, 10.8 mmol)及DMF (0.05 ml)添加至上述溶液中且在室溫下攪拌2 h。2 h後,蒸餾出反應混合物,獲得環丙基羰基氯,其不經進一步純化即可用於下一步驟中。 步驟-2:將中間物3 (1.50 g, 7.20 mmol)及三乙胺(1.09 g, 10.8 mmol)溶解於DCM (10 ml)中,且在0℃下攪拌30 min。藉由溶解於DCM (10 ml)中將環丙基羰基氯添加至上述混合物中,且在室溫下攪拌30 min。用pH至多約7之NaHCO 3水溶液淬滅反應混合物且分離有機層及水層。用DCM (2*100 ml)萃取水層。蒸餾合併的有機層,獲得固體。將固體與二乙醚一起濕磨並過濾。在真空下乾燥過濾固體,獲得呈黃色固體之標題化合物(1.6 g)。產率:80%。 1H-NMR (δ ppm, CDCl 3, 400 MHz): 8.25 (d, J 2.8, 1H), 8.17 (d, J 9.2, 1H), 7.47 (dd, J 9.2, 2.8, 1H), 3.91-3.80 (m, 2H), 3.70-3.49 (m, 6H), 2.05-1.95 (m, 1H), 0.80-0.68 (m, 4H)。 Intermediate 54 : Cyclopropyl (4-(6 -nitropyridin- 3 -yl ) hexahydropyrazin- 1 -yl ) methanone : Step-1: Cyclopropylcarboxylic acid (744 mg, 8.64 mmol) was dissolved in DCM (10 ml) and cooled to 0 °C. Oxalyl chloride (1.37 g, 10.8 mmol) and DMF (0.05 ml) were added to the above solution and stirred at room temperature for 2 h. After 2 h, the reaction mixture was distilled off to obtain cyclopropylcarbonyl chloride, which was used in the next step without further purification. Step-2: Intermediate 3 (1.50 g, 7.20 mmol) and triethylamine (1.09 g, 10.8 mmol) were dissolved in DCM (10 ml) and stirred at 0 °C for 30 min. Cyclopropylcarbonyl chloride was added to the above mixture by dissolving in DCM (10 ml) and stirred at room temperature for 30 min. The reaction mixture was quenched with aqueous NaHCO 3 pH up to about 7 and the organic and aqueous layers were separated. The aqueous layer was extracted with DCM (2*100 ml). The combined organic layers were distilled to obtain a solid. The solid was triturated with diethyl ether and filtered. The filtered solid was dried under vacuum to obtain the title compound (1.6 g) as a yellow solid. Yield: 80%. 1 H-NMR (δ ppm, CDCl 3 , 400 MHz): 8.25 (d, J 2.8, 1H), 8.17 (d, J 9.2, 1H), 7.47 (dd, J 9.2, 2.8, 1H), 3.91-3.80 (m, 2H), 3.70-3.49 (m, 6H), 2.05-1.95 (m, 1H), 0.80-0.68 (m, 4H).

中間物 55 (4-(6- 胺基吡啶 -3- ) 六氫吡嗪 -1- )( 環丙基 ) 甲酮 將中間物54 (1.5 g, 5.43 mmol)置於高壓釜中且溶解於甲醇(12 ml)與乙醇(12 ml)之混合物中,且添加碳載5%鈀(600 mg)。將此混合物在室溫下在4 kg氫壓下攪拌5 h。在反應完成後,經由矽藻土床過濾反應混合物,且用MeOH與DCM之混合物(1:9, 170 ml)洗滌該床。使合併的濾液及洗滌液蒸發,獲得固體。將固體與二乙醚一起濕磨,獲得呈粉色固體之標題化合物(1.1 g)。產率:82%。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 7.63 (d, J 2.4, 1H), 7.20 (dd, J 8.8, 2.4, 1H), 6.41 (d, J 8.8, 1H), 5.45 (s, 2H), 3.78 (bs, 2H), 3.57 (bs, 2H), 3.00-2.80 (m, 4H), 2.05-2.97 (m, 1H), 0.80-0.65 (m, 4H)。 Intermediate 55 : (4-(6 -aminopyridin- 3 -yl ) hexahydropyrazin- 1 -yl )( cyclopropyl ) methanone : Intermediate 54 (1.5 g, 5.43 mmol) was placed in autoclave and dissolved in a mixture of methanol (12 ml) and ethanol (12 ml), and 5% palladium on carbon (600 mg) was added. This mixture was stirred at room temperature under 4 kg hydrogen pressure for 5 h. After the reaction was complete, the reaction mixture was filtered through a bed of celite, and the bed was washed with a mixture of MeOH and DCM (1:9, 170 ml). The combined filtrate and washings were evaporated to give a solid. The solid was triturated with diethyl ether to afford the title compound (1.1 g) as a pink solid. Yield: 82%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 7.63 (d, J 2.4, 1H), 7.20 (dd, J 8.8, 2.4, 1H), 6.41 (d, J 8.8, 1H), 5.45 (s, 2H), 3.78 (bs, 2H), 3.57 (bs, 2H), 3.00-2.80 (m, 4H), 2.05-2.97 (m, 1H), 0.80-0.65 (m, 4H).

中間物 56 7-(6- 硝基吡啶 -3- )-3-( 三氟甲基 )-5,6,7,8- 四氫 -[1,2,4] 三唑并 [4,3-a] 吡嗪 使5-氟-2-硝基吡啶(4.04 g, 19.9 mmol)、3-(三氟甲基)-5,6,7,8-四氫-[1,2,4]三唑并[4,3-a]吡嗪(5 g, 26 mmol)及DIPEA (10.1 g, 78.1 mmol)懸浮於DMF (37 ml)中,且在120℃下攪拌16 h。用水(100 ml)淬滅反應混合物。用MeOH:DCM (1:9) (3*100 ml)萃取水層。蒸餾出合併的有機層,獲得粗製物。藉由combi-flash使用MeOH及DCM (2.2:97.8)作為溶析液純化粗製物,獲得呈黃色固體之標題化合物(2.7 g)。產率:33%。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 8.43 (d, J 3.0, 1H), 8.21 (d, J 9.2, 1H), 7.70 (dd, J 9.2, 3.0, 1H), 5.04 (s, 2H), 4.33 (t, J 5.2, 2H), 4.09 (t, J 5.2, 2H)。 Intermediate 56 : 7-(6 -nitropyridin- 3 -yl )-3-( trifluoromethyl )-5,6,7,8- tetrahydro- [1,2,4] triazolo [4 ,3-a] pyrazine : make 5-fluoro-2-nitropyridine (4.04 g, 19.9 mmol), 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2 ,4] Triazolo[4,3-a]pyrazine (5 g, 26 mmol) and DIPEA (10.1 g, 78.1 mmol) were suspended in DMF (37 ml) and stirred at 120°C for 16 h. The reaction mixture was quenched with water (100 ml). The aqueous layer was extracted with MeOH:DCM (1:9) (3*100 ml). The combined organic layers were distilled off to obtain a crude product. The crude was purified by combi-flash using MeOH and DCM (2.2:97.8) as eluents to obtain the title compound (2.7 g) as a yellow solid. Yield: 33%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 8.43 (d, J 3.0, 1H), 8.21 (d, J 9.2, 1H), 7.70 (dd, J 9.2, 3.0, 1H), 5.04 (s, 2H), 4.33 (t, J 5.2, 2H), 4.09 (t, J 5.2, 2H).

中間物 57 5-(3-( 三氟甲基 )-5,6- 二氫 -[1,2,4] 三唑并 [4,3-a] 吡嗪 -7(8H)- ) 吡啶 -2- 將中間物56 (1.1 g, 4.16 mmol)置於高壓釜中且溶解於甲醇(9 ml)與乙醇(9 ml)之混合物中,且添加碳載5%鈀(440 mg)。將此混合物在室溫下在4 kg氫壓下攪拌5 h。在反應完成後,經由矽藻土床過濾反應混合物,且用MeOH與DCM之混合物(1:9, 170 ml)洗滌該床。使合併的濾液及洗滌液蒸發,獲得固體。將固體與二乙醚一起濕磨,獲得呈褐色固體之標題化合物(840 mg)。產率:86%。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 7.75 (d, J 2.8, 1H), 7.31 (dd, J 9.2, 2.8, 1H), 6.43 (d, J 9.2, 1H), 5.57 (s, 2H), 4.42 (s, 2H), 4.22 (t, J 5.2, 2H), 3.51 (t, J 5.2, 2H)。 Intermediate 57 : 5-(3-( trifluoromethyl )-5,6 -dihydro- [1,2,4] triazolo [4,3-a] pyrazin -7(8H) -yl ) Pyridin -2- amine : Intermediate 56 (1.1 g, 4.16 mmol) was placed in an autoclave and dissolved in a mixture of methanol (9 ml) and ethanol (9 ml), and 5% palladium on carbon (440 mg ). This mixture was stirred at room temperature under 4 kg hydrogen pressure for 5 h. After the reaction was complete, the reaction mixture was filtered through a bed of celite, and the bed was washed with a mixture of MeOH and DCM (1:9, 170 ml). The combined filtrate and washings were evaporated to give a solid. The solid was triturated with diethyl ether to afford the title compound (840 mg) as a tan solid. Yield: 86%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 7.75 (d, J 2.8, 1H), 7.31 (dd, J 9.2, 2.8, 1H), 6.43 (d, J 9.2, 1H), 5.57 (s, 2H), 4.42 (s, 2H), 4.22 (t, J 5.2, 2H), 3.51 (t, J 5.2, 2H).

中間物 58 4- 甲基 -1-(6- 硝基吡啶 -3- ) 六氫吡啶 -4- 使5-溴-2-硝基吡啶(2.18 g, 12.9 mmol)、4-甲基嘧啶-4-醇(1.48 g, 12.9 mmol)及碳酸鉀(2.23 g, 16.1 mmol)懸浮於DMSO (14 ml)中,且在90℃下攪拌16 h。用水(200 ml)稀釋反應混合物,用DCM (2*200 ml)萃取,且將合併的有機層用鹽水(100 ml)及水(100 ml)洗滌,經無水硫酸鈉乾燥且在真空下蒸餾,獲得粗產物。藉由combi-flash使用甲醇及DCM (2.5:97.5)作為溶析液進行純化,得到呈黃色固體之標題化合物(1.1 g)。產率:51%。 1H-NMR (δ ppm, CDCl 3, 400 MHz): 8.23 (d, J 2.8, 1H), 8.10 (d, J 9.6, 1H), 7.44 (dd, J 9.6, 2.8, 1H), 4.47 (s, 1H), 3.79-3.70 (m, 2H), 3.41-3.31 (m, 2H), 1.59-1.48 (m, 4H), 1.14 (s, 3H)。MS (m/z):238.16 (M+H);[C 11H 15N 3O 3+H]計算值:238.11。 Intermediate 58 : 4- methyl- 1-(6 -nitropyridin- 3 -yl ) hexahydropyridin- 4 - ol : 5-bromo-2-nitropyridine (2.18 g, 12.9 mmol), 4- Methylpyrimidin-4-ol (1.48 g, 12.9 mmol) and potassium carbonate (2.23 g, 16.1 mmol) were suspended in DMSO (14 ml) and stirred at 90°C for 16 h. The reaction mixture was diluted with water (200 ml), extracted with DCM (2*200 ml), and the combined organic layer was washed with brine (100 ml) and water (100 ml), dried over anhydrous sodium sulfate and distilled under vacuum, A crude product is obtained. Purification by combi-flash using methanol and DCM (2.5:97.5) as eluents afforded the title compound (1.1 g) as a yellow solid. Yield: 51%. 1 H-NMR (δ ppm, CDCl 3 , 400 MHz): 8.23 (d, J 2.8, 1H), 8.10 (d, J 9.6, 1H), 7.44 (dd, J 9.6, 2.8, 1H), 4.47 (s , 1H), 3.79-3.70 (m, 2H), 3.41-3.31 (m, 2H), 1.59-1.48 (m, 4H), 1.14 (s, 3H). MS (m/z): 238.16 ( M +H); Calcd. for [ C11H15N3O3 +H]: 238.11 .

中間物 59 1-(6- 胺基吡啶 -3- )-4- 甲基六氫吡啶 -4- 醇:將中間物58 (900 mg, 3.79 mmol)置於高壓釜中且溶解於甲醇(10 ml)與乙醇(10 ml)之混合物中,且添加碳載5%鈀(440 mg)。將此混合物在室溫下在4 kg氫壓下攪拌5 h。在反應完成後,經由矽藻土床過濾反應混合物,且用MeOH與DCM之混合物(1:9, 2000 ml)洗滌該床。使合併的濾液及洗滌液蒸發,獲得固體。將固體與二乙醚一起濕磨,獲得呈褐色固體之標題化合物(700 mg)。產率:89%。 1H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 7.59 (d, J 2.8, 1H), 7.14 (dd, J 9.6, 3.0, 1H), 6.36 (d, J 8.8, 1H), 5.31 (s, 2H), 4.20 (s, 1H), 2.96-2.85 (m, 4H), 1.57-1.50 (m, 4H), 1.12 (s, 3H)。MS (m/z):208.16 (M+H);[C 11H 17N 3O+H]計算值:208.28。 Intermediate 59 : 1-(6 -Aminopyridin- 3 -yl )-4 - methylhexahydropyridin- 4- ol: Intermediate 58 (900 mg, 3.79 mmol) was placed in autoclave and dissolved in methanol (10 ml) and ethanol (10 ml), and 5% palladium on carbon (440 mg) was added. This mixture was stirred at room temperature under 4 kg hydrogen pressure for 5 h. After completion of the reaction, the reaction mixture was filtered through a bed of celite, and the bed was washed with a mixture of MeOH and DCM (1 :9, 2000 ml). The combined filtrate and washings were evaporated to give a solid. The solid was triturated with diethyl ether to afford the title compound (700 mg) as a tan solid. Yield: 89%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 7.59 (d, J 2.8, 1H), 7.14 (dd, J 9.6, 3.0, 1H), 6.36 (d, J 8.8, 1H), 5.31 (s, 2H), 4.20 (s, 1H), 2.96-2.85 (m, 4H), 1.57-1.50 (m, 4H), 1.12 (s, 3H). MS (m/z): 208.16 (M+H); Calcd. for [ C11H17N3O +H]: 208.28 .

中間物 60 (±)-1-(6- -8- -2- 甲基喹啉 -4- ) -1- 胺:使中間物15 (200 g, 0.708 mol)懸浮於2 M甲醇氨(1.88 lt,3.75 mol)中。向此混合物中添加異丙醇鈦(IV) (403 g, 1.42 mol),且在室溫下攪拌16 h。16 h後,使反應混合物冷卻至0℃且添加硼氫化鈉(40.23 g, 1.06 mol),升溫至室溫並在室溫下攪拌5 h。5 h後,用氨水(2 lt)及EtOAc (2 lt)淬滅反應混合物,獲得固體。過濾固體且用EtOAc (10 lt)洗滌固體。用水(3 lt)及鹽水(2.5 lt)洗滌合併的濾液。用EtOAc (8 lt)萃取水層。蒸餾出合併的EtOAc層,獲得粗製物。將粗製物與(3*100 ml)甲苯一起共蒸餾,獲得固體。將固體與二乙醚(1 lt)一起攪拌並過濾固體。在真空下乾燥固體,獲得呈褐色固體之標題化合物(120.5 g)。產率:60%。 1H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 8.22 (s, 1H), 7.81 (dd, J 10.4, 4, 1H), 7.73 (s, 1H), 4.70 (t, J 6.8, 1H), 2.66 (s, 3H), 2.09 (bs, 2H), 1.34 (d, J 6.8, 3H)。MS (m/z):283.17 (M+H);[C 12H 12BrFN 2+H]計算值:284.02。 Intermediate 60 : (±)-1-(6- bromo -8- fluoro -2 -methylquinolin- 4 -yl ) ethan - 1 -amine: Intermediate 15 (200 g, 0.708 mol) was suspended in 2 M methanolic ammonia (1.88 lt, 3.75 mol). To this mixture was added titanium(IV) isopropoxide (403 g, 1.42 mol) and stirred at room temperature for 16 h. After 16 h, the reaction mixture was cooled to 0 °C and sodium borohydride (40.23 g, 1.06 mol) was added, warmed to room temperature and stirred at room temperature for 5 h. After 5 h, the reaction mixture was quenched with ammonia (2 lt) and EtOAc (2 lt) to obtain a solid. The solid was filtered and washed with EtOAc (10 lt). The combined filtrates were washed with water (3 lt) and brine (2.5 lt). The aqueous layer was extracted with EtOAc (8 lt). The combined EtOAc layers were distilled off to obtain crude. The crude was co-distilled with (3*100 ml) toluene to obtain a solid. The solid was stirred with diethyl ether (1 lt) and the solid was filtered. The solid was dried under vacuum to obtain the title compound (120.5 g) as a tan solid. Yield: 60%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 8.22 (s, 1H), 7.81 (dd, J 10.4, 4, 1H), 7.73 (s, 1H), 4.70 (t, J 6.8, 1H), 2.66 (s, 3H), 2.09 (bs, 2H), 1.34 (d, J 6.8, 3H). MS (m/z): 283.17 (M+H); Calcd. for [ C12H12BrFN2 + H]: 284.02.

中間物 61 (±)-(1-(6- -8- -2- 甲基喹啉 -4- ) 乙基 ) 胺基甲酸第三丁基酯:將中間物60 (16 g, 56.5 mmol)溶解於DCM (160 ml)中且冷卻至0℃。向此溶液中添加三乙胺(8.58 g, 84.76 mmol)。將Boc酸酐(14.8 g, 67.8 mmol)添加至此混合物中且在室溫下攪拌2 h。2 h後,用水(900 ml)稀釋反應混合物且分離有機層。用 MeOH與DCM之混合物(1:9) (3*500 ml)再次萃取水層。將合併的有機層用水(2*500 ml)及碳酸氫鈉水溶液(3*500 ml)洗滌。使有機層經無水Na 2SO 4乾燥並蒸餾,獲得呈灰白色固體之標題化合物(20.8 g)。其不經進一步純化即可用於下一步驟中。產率:96%。 1H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 8.22 (s, 1H), 7.86 (dd, J 10.4, 2, 1H), 7.71 (d, J 7.6, 1H), 7.47 (s, 1H), 5.31 (t, J 7.2, 1H), 2.65 (s, 3H), 1.40 (d, J 7.2, 1H), 1.37 (s, 9H)。MS (m/z):383.18 (M+H);[C 17H 20BrFN 2O 2+H]計算值:383.07。 Intermediate 61 : tert-butyl (±)-(1-(6- bromo -8- fluoro -2 -methylquinolin- 4 -yl ) ethyl ) carbamate: Intermediate 60 (16 g , 56.5 mmol) was dissolved in DCM (160 ml) and cooled to 0 °C. To this solution was added triethylamine (8.58 g, 84.76 mmol). Boc anhydride (14.8 g, 67.8 mmol) was added to this mixture and stirred at room temperature for 2 h. After 2 h, the reaction mixture was diluted with water (900 ml) and the organic layer was separated. The aqueous layer was extracted again with a mixture of MeOH and DCM (1:9) (3*500 ml). The combined organic layers were washed with water (2*500 ml) and aqueous sodium bicarbonate (3*500 ml). The organic layer was dried over anhydrous Na2SO4 and distilled to obtain the title compound (20.8 g) as an off-white solid. It was used in the next step without further purification. Yield: 96%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 8.22 (s, 1H), 7.86 (dd, J 10.4, 2, 1H), 7.71 (d, J 7.6, 1H), 7.47 (s, 1H), 5.31 (t, J 7.2, 1H), 2.65 (s, 3H), 1.40 (d, J 7.2, 1H), 1.37 (s, 9H). MS (m/z): 383.18 ( M + H); Calcd. for [ C17H20BrFN2O2 + H]: 383.07.

中間物 62 (±)-(1-(8- -2- 甲基 -6-(4,4,5,5- 四甲基 -1,3,2- 二氧雜硼雜環戊烷 -2- ) 喹啉 -4- ) 乙基 ) 胺基甲酸第三丁基酯:遵循一般程序-1,自中間物61 (18 g, 47 mmol)合成標題化合物。在後處理後,藉由combi-flash使用EtOAc及石油醚(20:80)作為溶析液純化粗產物,獲得呈淡黃色固體之標題化合物(15.2 g)。產率:75.2%。 1H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 8.22 (s, 1H), 7.74 (d, J 7.6, 1H), 7.58 (d, J 10.8, 1H), 7.50 (s, 1H), 5.38 (t, J 6.8, 1H), 2.68 (s, 3H), 1.41 (d, J 6.8, 3H), 1.37 (s, 12 H), 1.15 (s, 9H)。MS (m/z):431.30 (M+H);[C 23H 32BFN 2O 4+H]計算值:431.33。 Intermediate 62 : (±)-(1-(8- fluoro -2- methyl -6-(4,4,5,5 -tetramethyl- 1,3,2- dioxaborolane -2- yl ) quinolin- 4 -yl ) ethyl ) carbamate tert-butyl ester: The title compound was synthesized from Intermediate 61 (18 g, 47 mmol) following General Procedure-1. After work-up, the crude product was purified by combi-flash using EtOAc and petroleum ether (20:80) as eluents to obtain the title compound (15.2 g) as a light yellow solid. Yield: 75.2%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 8.22 (s, 1H), 7.74 (d, J 7.6, 1H), 7.58 (d, J 10.8, 1H), 7.50 (s, 1H) , 5.38 (t, J 6.8, 1H), 2.68 (s, 3H), 1.41 (d, J 6.8, 3H), 1.37 (s, 12 H), 1.15 (s, 9H). MS (m/z): 431.30 (M + H); Calcd. for [ C23H32BFN2O4 + H]: 431.33 .

中間物 63 (±)-(1-(6-(2- -5- 氟嘧啶 -4- )-8- -2- 甲基喹啉 -4- ) 乙基 ) 胺基甲酸第三丁基酯:遵循一般程序-2,自中間物62 (15 g, 34.86 mmol)及2,4-二氯-5-氟嘧啶(6.98 g, 41.83 mmol)合成標題化合物。在反應完成後,使反應混合物冷卻至室溫並攪拌16 h ,獲得固體。過濾固體,用二噁烷與水之混合物(1:1) (50 ml)及石油醚(100 ml)洗滌。在旋轉蒸發儀上使固體與甲苯(2*100 ml)一起在65℃下共蒸餾。將固體與二乙醚及石油醚之混合物(1:1) (100 ml)一起攪拌30 min。過濾固體,且用石油醚與二乙醚混合物(1:1) (50 ml)洗滌。在真空下乾燥固體,獲得呈白色固體之標題化合物(10 g)。產率:67%。 1H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.07 (d, J 3.2, 1H), 8.62 (s, 1H), 8.06 (d, J 11.2, 1H), 7.79 (d, J 3.2, 1H), 7.58 (s, 1H), 5.41 (t, J 6.8, 1H), 2.73 (s, 3H), 1.46 (d, J 6.8, 3H), 1.37 (s, 9H)。MS (m/z):435.24 (M+H);[C 21H 21ClF 2N 4O 2+H]計算值:435.13。 Intermediate 63 : (±)-(1-(6-(2- chloro -5- fluoropyrimidin - 4 -yl )-8- fluoro -2 -methylquinolin- 4 -yl ) ethyl ) carbamate Tert-butyl ester: The title compound was synthesized from Intermediate 62 (15 g, 34.86 mmol) and 2,4-dichloro-5-fluoropyrimidine (6.98 g, 41.83 mmol) following General Procedure-2. After the reaction was complete, the reaction mixture was cooled to room temperature and stirred for 16 h to obtain a solid. The solid was filtered, washed with a mixture of dioxane and water (1:1) (50 ml) and petroleum ether (100 ml). The solid was co-distilled with toluene (2*100 ml) at 65°C on a rotary evaporator. The solid was stirred with a mixture of diethyl ether and petroleum ether (1:1) (100 ml) for 30 min. The solid was filtered and washed with petroleum ether and diethyl ether mixture (1 :1 ) (50 ml). The solid was dried under vacuum to obtain the title compound (10 g) as a white solid. Yield: 67%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.07 (d, J 3.2, 1H), 8.62 (s, 1H), 8.06 (d, J 11.2, 1H), 7.79 (d, J 3.2 , 1H), 7.58 (s, 1H), 5.41 (t, J 6.8, 1H), 2.73 (s, 3H), 1.46 (d, J 6.8, 3H), 1.37 (s, 9H). MS (m/z): 435.24 (M + H); Calcd. for [ C21H21ClF2N4O2 + H]: 435.13 .

中間物 64 6- -8- 氟喹啉 -2,4- 二甲酸:使中間物12 (1 g, 4.10 mmol)懸浮於氫氧化鉀(10 g, 40.98 mmol)於水(360 ml)中之溶液中,且添加丙酮酸鈉(6.76 mg, 61.5 mmol)。將此混合物在50℃下攪拌16 h。使反應混合物冷卻至25℃且使用6 N HCl將pH調整至約3,獲得固體。過濾固體並用水(200 ml)洗滌,且於烘箱中在70℃下乾燥6 h,獲得呈褐色固體之標題化合物(8.2 g)。產率:64%。 1H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 14.01 (bs, 2H), 8.89 (s, 1H), 8.57 (s, 1H), 8.11 (dd, J 10, 1.6, 1H)。MS (m/z):314.08 (M+H);[C 11H 5BrFNO 4+H]計算值:313.94。 Intermediate 64 : 6- Bromo -8- fluoroquinoline- 2,4- dicarboxylic acid: Intermediate 12 (1 g, 4.10 mmol) was suspended in potassium hydroxide (10 g, 40.98 mmol) in water (360 ml) solution in , and sodium pyruvate (6.76 mg, 61.5 mmol) was added. This mixture was stirred at 50 °C for 16 h. The reaction mixture was cooled to 25 °C and the pH was adjusted to about 3 using 6 N HCl to obtain a solid. The solid was filtered and washed with water (200 ml) and dried in an oven at 70 °C for 6 h to obtain the title compound (8.2 g) as a tan solid. Yield: 64%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 14.01 (bs, 2H), 8.89 (s, 1H), 8.57 (s, 1H), 8.11 (dd, J 10, 1.6, 1H). MS (m/z): 314.08 (M+H); Calcd. for [ C11H5BrFNO4 + H]: 313.94 .

中間物 65 6- -8- 氟喹啉 -4- 甲酸:使中間物64 (8 g, 25.5 mmol)懸浮於硝基苯(80 ml)中且加熱至220℃持續5 h。5 h後,使反應混合物冷卻至室溫並用石油醚(320 ml)稀釋,獲得固體。將此混合物攪拌1 h且過濾固體。用石油醚(80 ml)洗滌固體。使固體在真空下乾燥1 h,獲得呈淡褐色固體之標題化合物(6.1 g)。產率:89%。 1H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 14.21 (s, 1H), 9.12 (d, J 4.4, 1H), 8.81 (s, 1H), 8.10 (d, J 4.4, 1H), 8.00 (dd, J 10, 2, 1H)。 Intermediate 65 : 6- Bromo -8- fluoroquinoline- 4 - carboxylic acid: Intermediate 64 (8 g, 25.5 mmol) was suspended in nitrobenzene (80 ml) and heated to 220 °C for 5 h. After 5 h, the reaction mixture was cooled to room temperature and diluted with petroleum ether (320 ml) to obtain a solid. This mixture was stirred for 1 h and the solid was filtered. The solid was washed with petroleum ether (80 ml). The solid was dried under vacuum for 1 h to obtain the title compound (6.1 g) as a light brown solid. Yield: 89%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 14.21 (s, 1H), 9.12 (d, J 4.4, 1H), 8.81 (s, 1H), 8.10 (d, J 4.4, 1H) , 8.00 (dd, J 10, 2, 1H).

中間物 66 6- -8- -N- 甲氧基 -N- 甲基喹啉 -4- 甲醯胺 將中間物65 (3 g, 11.1 mmol)、HATU (6.34 g, 16.7 mmol)及DIPEA (5.74 g, 44.4, mmol)溶解於DMF (30 ml)中。將N,O-二甲基羥胺鹽酸鹽(2.17 g, 22.2 mmol)添加至反應混合物中且在室溫下攪拌16 h。16 h後,用水(150 ml)稀釋反應混合物並用EtOAc (3*70 ml)萃取。將合併的有機層用NaHCO 3水溶液(3*100 ml)及鹽水(100 ml)洗滌。蒸餾有機層,獲得粗製物。使粗製物懸浮於二乙醚與石油醚之混合物(1:1) (40 ml)中且攪拌30 min,獲得固體。過濾固體,且用二乙醚與石油醚(1:1) (20 ml)洗滌。在真空下乾燥固體,獲得呈淡褐色固體之標題化合物(2.5 g)。產率:72%。 1H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.06 (d, J 4, 1H), 8.00 (dd, J 10, 1, 1H), 7.81 (t, J 1.6, 1H), 7.77 (d, J 4, 1H), 3.41 (bs, 6H)。MS (m/z):313.15 (M+H);[C 12H 10BrFN 2O 2+H]計算值:312.99。 Intermediate 66 : 6- Bromo -8- fluoro -N- methoxy- N -methylquinoline- 4 -formamide : Intermediate 65 (3 g, 11.1 mmol), HATU (6.34 g, 16.7 mmol ) and DIPEA (5.74 g, 44.4, mmol) were dissolved in DMF (30 ml). N,O-Dimethylhydroxylamine hydrochloride (2.17 g, 22.2 mmol) was added to the reaction mixture and stirred at room temperature for 16 h. After 16 h, the reaction mixture was diluted with water (150 ml) and extracted with EtOAc (3*70 ml). The combined organic layers were washed with aqueous NaHCO 3 (3*100 ml) and brine (100 ml). The organic layer was distilled to obtain a crude product. The crude was suspended in a mixture of diethyl ether and petroleum ether (1 :1 ) (40 ml) and stirred for 30 min to obtain a solid. The solid was filtered and washed with diethyl ether and petroleum ether (1:1) (20 ml). The solid was dried under vacuum to obtain the title compound (2.5 g) as a light brown solid. Yield: 72%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.06 (d, J 4, 1H), 8.00 (dd, J 10, 1, 1H), 7.81 (t, J 1.6, 1H), 7.77 (d, J 4, 1H), 3.41 (bs, 6H). MS (m/z): 313.15 (M + H); Calcd. for [ C12H10BrFN2O2 + H]: 312.99 .

中間物 67 1-(6- -8- 氟喹啉 -4- ) -1- 酮:將中間物66 (2.5 g, 7.98 mmol)溶解於THF (25 ml)中且冷卻至0℃。緩慢添加甲基氯化鎂(3 M於THF中,24.53 ml, 12 mmol)。將混合物在室溫下攪拌3 h。用NH 4Cl水溶液淬滅反應混合物並用EtOAc (2*25 ml)萃取。相繼用水(25 ml)及鹽水溶液(25 ml)洗滌有機層,經無水Na 2SO 4乾燥並蒸餾,獲得粗產物。藉由combi-flash使用EtOAc及石油醚(14:86)作為溶析液進行純化,得到呈灰白色固體之標題化合物(900 mg)。 1H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.17 (d, J 4.4, 1H), 8.46 (s, 1H), 8.15 (d, J 4.4, 1H),8.01 (dd, J 10。 1.6, 1H), 2.76 (s, 3H)。MS (m/z):268.15 (M+H);[C 11H 7BrFNO+H]計算值:267.97。 Intermediate 67 : 1-(6- Bromo -8- fluoroquinolin- 4 -yl ) ethan - 1 -one: Intermediate 66 (2.5 g, 7.98 mmol) was dissolved in THF (25 ml) and cooled to 0 ℃. Methylmagnesium chloride (3 M in THF, 24.53 ml, 12 mmol) was added slowly. The mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with aqueous NH 4 Cl and extracted with EtOAc (2*25 ml). The organic layer was washed successively with water (25 ml) and brine solution (25 ml), dried over anhydrous Na2SO4 and distilled to obtain crude product. Purification by combi-flash using EtOAc and petroleum ether (14:86) as eluents afforded the title compound (900 mg) as an off-white solid. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.17 (d, J 4.4, 1H), 8.46 (s, 1H), 8.15 (d, J 4.4, 1H), 8.01 (dd, J 10 .1.6, 1H), 2.76 (s, 3H). MS (m/z): 268.15 (M+H); Calcd. for [ C11H7BrFNO +H]: 267.97 .

中間物 68 (±)-1-(6- -8- 氟喹啉 -4- ) -1- 使中間物67 (900 mg, 3.4 mmol)懸浮於2 M甲醇氨(8.4 ml, 17mol)中。向此混合物中添加異丙醇鈦(IV) (1.9 g, 6.7 mol),且在室溫下攪拌16 h。16 h後,使反應混合物冷卻至0℃且添加硼氫化鈉(190 mg, 5.03 mol),升溫至室溫並在室溫下攪拌5 h。5 h後,用氨水(9 ml)及EtOAc (25 ml)淬滅反應混合物,獲得固體。過濾固體且用EtOAc (25 ml)洗滌固體。用水(100 ml)及鹽水(100 ml)洗滌合併的濾液。用EtOAc (2*30 ml)萃取水層。蒸餾出合併的EtOAc層,獲得粗製物。藉由combi-flash使用MeOH及DCM (3:97)作為溶析液純化粗製物,獲得呈灰白色固體之標題化合物(500 mg)。產率:55%。 1H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 8.94 (d, J 4.4, 1H), 8.30 (s, 1H), 7.88 (dd, J 10, 1.6, 1H), 7.85 (d, J 4.4, 1H), 4.76 (q, J 6.4, 1H), 1.34 (d, J 6.8, 3H)。MS (m/z):269.16 (M+H);[C 11H 10BrFN 2+H]計算值:270.12。 Intermediate 68 : (±)-1-(6- bromo -8- fluoroquinolin- 4 -yl ) ethan - 1 -amine : Intermediate 67 (900 mg, 3.4 mmol) was suspended in 2 M methanolic ammonia (8.4 ml, 17mol). To this mixture was added titanium(IV) isopropoxide (1.9 g, 6.7 mol) and stirred at room temperature for 16 h. After 16 h, the reaction mixture was cooled to 0 °C and sodium borohydride (190 mg, 5.03 mol) was added, warmed to room temperature and stirred at room temperature for 5 h. After 5 h, the reaction mixture was quenched with ammonia (9 ml) and EtOAc (25 ml) to obtain a solid. The solid was filtered and washed with EtOAc (25 ml). The combined filtrates were washed with water (100 ml) and brine (100 ml). The aqueous layer was extracted with EtOAc (2*30 ml). The combined EtOAc layers were distilled off to obtain crude. The crude was purified by combi-flash using MeOH and DCM (3:97) as eluents to afford the title compound (500 mg) as an off-white solid. Yield: 55%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 8.94 (d, J 4.4, 1H), 8.30 (s, 1H), 7.88 (dd, J 10, 1.6, 1H), 7.85 (d, J 4.4, 1H), 4.76 (q, J 6.4, 1H), 1.34 (d, J 6.8, 3H). MS (m/z): 269.16 (M+H); Calcd. for [ C11H10BrFN2 + H]: 270.12 .

中間物 69 (±)-(1-(6- -8- 氟喹啉 -4- ) 乙基 ) 胺基甲酸第三丁基酯:將中間物68 (2.1 g, 7.8 mmol)溶解於DCM (21 ml)中且冷卻至0℃。向此溶液中添加三乙胺(1.18 g, 11.7 mmol)。將Boc酸酐(2.04 g, 9.36 mmol)添加至此混合物中且在室溫下攪拌2 h。2 h後,用水(100 ml)稀釋反應混合物且分離有機層。用DCM (3*70 ml)再次萃取水層。將合併的有機層用水(100 ml)及碳酸氫鈉水溶液(3*100 ml)洗滌。使有機層經無水Na 2SO 4乾燥並蒸餾,獲得呈灰白色固體之標題化合物(2.8 g)。其不經進一步純化即可用於下一步驟中。產率:97%。 1H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 8.96 (d, J 4.4, 1H), 8.31 (s, 1H), 7.92 (dd, J 10, 1.6, 1H), 7.78 (d, J 7.6, 1H), 7.61 (d, J 4.4, 1H), 5.36 (t, J 6.8, 1H), 1.40 (d, J 6.8, 3H), 1.37 (s, 9H)。MS (m/z):369.12 (M+H);[C 16H 18BrFN 2O 2+H]計算值:369.05。 Intermediate 69 : tert-butyl (±)-(1-(6- bromo -8- fluoroquinolin- 4 -yl ) ethyl ) carbamate: Intermediate 68 (2.1 g, 7.8 mmol) was dissolved in DCM (21 ml) and cooled to 0 °C. To this solution was added triethylamine (1.18 g, 11.7 mmol). Boc anhydride (2.04 g, 9.36 mmol) was added to this mixture and stirred at room temperature for 2 h. After 2 h, the reaction mixture was diluted with water (100 ml) and the organic layer was separated. The aqueous layer was extracted again with DCM (3*70 ml). The combined organic layers were washed with water (100 ml) and aqueous sodium bicarbonate (3*100 ml). The organic layer was dried over anhydrous Na2SO4 and distilled to obtain the title compound (2.8 g) as an off-white solid. It was used in the next step without further purification. Yield: 97%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 8.96 (d, J 4.4, 1H), 8.31 (s, 1H), 7.92 (dd, J 10, 1.6, 1H), 7.78 (d, J 7.6, 1H), 7.61 (d, J 4.4, 1H), 5.36 (t, J 6.8, 1H), 1.40 (d, J 6.8, 3H), 1.37 (s, 9H). MS (m/z): 369.12 (M + H); Calcd. for [ C16H18BrFN2O2 + H]: 369.05 .

中間物 70 (±)-(1-(8- -6-(4,4,5,5- 四甲基 -1,3,2- 二氧雜硼雜環戊烷 -2- ) 喹啉 -4- ) 乙基 ) 胺基甲酸第三丁基酯:遵循一般程序-1,自中間物69 (2.8 g, 7.58 mmol)合成標題化合物。在後處理後,藉由combi-flash使用EtOAc及石油醚(23:77)作為溶析液純化粗產物,獲得呈淡黃色固體之標題化合物(1.7 g)。產率:94%。 1H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 8.99 (d, J 4.4, 1H), 8.29 (s, 1H), 7.81 (d, J 7.6, 1H), 7.64 (d, J 7.2, 1H), 7.62 (s, 1H), 5.42-5.33 (m, 1H), 1.43 (d, J 6.8, 3H), 1.37 (s, 12 H), 1.35 (s, 9H)。MS (m/z):417.32 (M+H);[C 22H 30BFN 2O 4+H]計算值:417.23。 Intermediate 70 : (±)-(1-(8- fluoro -6-(4,4,5,5 -tetramethyl- 1,3,2-dioxaborolan - 2- yl ) Quinolin- 4 -yl ) ethyl ) carbamate tert-butyl: The title compound was synthesized from Intermediate 69 (2.8 g, 7.58 mmol) following General Procedure-1. After work-up, the crude product was purified by combi-flash using EtOAc and petroleum ether (23:77) as eluents to obtain the title compound (1.7 g) as a pale yellow solid. Yield: 94%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 8.99 (d, J 4.4, 1H), 8.29 (s, 1H), 7.81 (d, J 7.6, 1H), 7.64 (d, J 7.2 , 1H), 7.62 (s, 1H), 5.42-5.33 (m, 1H), 1.43 (d, J 6.8, 3H), 1.37 (s, 12 H), 1.35 (s, 9H). MS (m/z): 417.32 (M + H); Calcd. for [ C22H30BFN2O4 + H]: 417.23 .

中間物 71 (±)-(1-(6-(2- -5- 氟嘧啶 -4- )-8- 氟喹啉 -4- ) 乙基 ) 胺基甲酸第三丁基酯:遵循一般程序-2,自中間物70 (1.7 g, 4.08 mmol)及2,4-二氯-5-氟嘧啶(818 mg, 4.9 mmol)合成標題化合物。在反應完成後,向反應混合物中添加水(100 ml)並用DCM (3*70 ml)萃取。用水(100 ml)洗滌有機層並蒸餾,獲得粗製物。藉由combi-flash使用EtOAc及石油醚(27:63)作為溶析液純化粗製物,獲得呈灰白色固體之標題化合物(600 mg)。產率:30%。 1H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.09 (d, J 3.2, 1H), 9.07 (d, J 4.4, 1H), 8.68 (s, 1H), 8.11 (d, J 11.2, 1H), 7.84 (d, J 7.6, 1H), 7.70 (d, J 4.4, 1H), 5.49-5.38 (m, 1H), 1.47 (d, J 7, 3H), 1.36 (s, 9H)。MS (m/z):421.11 (M+H);[C 20H 19ClF 2N 4O 2+H]計算值:421.12。 Intermediate 71 : (±)-tert-butyl(1-(6-(2- chloro -5- fluoropyrimidin - 4 -yl )-8- fluoroquinolin- 4 -yl ) ethyl ) carbamate : The title compound was synthesized from Intermediate 70 (1.7 g, 4.08 mmol) and 2,4-dichloro-5-fluoropyrimidine (818 mg, 4.9 mmol) following General Procedure-2. After completion of the reaction, water (100 ml) was added to the reaction mixture and extracted with DCM (3*70 ml). The organic layer was washed with water (100 ml) and distilled to obtain a crude material. The crude was purified by combi-flash using EtOAc and petroleum ether (27:63) as eluents to afford the title compound (600 mg) as an off-white solid. Yield: 30%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.09 (d, J 3.2, 1H), 9.07 (d, J 4.4, 1H), 8.68 (s, 1H), 8.11 (d, J 11.2 , 1H), 7.84 (d, J 7.6, 1H), 7.70 (d, J 4.4, 1H), 5.49-5.38 (m, 1H), 1.47 (d, J 7, 3H), 1.36 (s, 9H). MS (m/z): 421.11 (M + H) ; Calcd. for [ C20H19ClF2N4O2 + H]: 421.12 .

中間物 72 (±)-1-(6- -8- 氟喹啉 -4- ) 乙醇:將中間物67 (10 g, 37.3 mmol)溶解於MeOH (100 ml)與THF (100 ml)之混合物中。向此混合物中添加NaBH 4(7.05 g, 186.5 mmol),且使此混合物回流3 h。3 h後,使反應混合物冷卻至室溫且添加水(500 ml)。用EtOAc (3*300 ml)萃取水層。用水(100 ml)及鹽水(100 ml)洗滌合併的有機層。在減壓下蒸餾有機層,獲得固體。使固體懸浮於二乙醚(50 ml)中且攪拌30 min。30 min後,過濾固體且用二乙醚(20 ml)洗滌。在真空下乾燥固體,獲得呈黃色固體之標題化合物(9 g)。產率:89%。 1H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 8.96 (d, J 4.4, 1H), 8.28 (s, 1H), 7.89 (d, J 10, 1H), 7.74 (d, J 4.4, 1H), 5.69 (d, J 4.4, 1H), 5.50-5.43 (m, 1H), 1.45 (d, J 6.4, 3H)。MS (m/z):270.21 (M+H);[C 11H 9BrFNO+H]計算值:269.99。 Intermediate 72 : (±)-1-(6- bromo -8- fluoroquinolin- 4 -yl ) ethanol: Intermediate 67 (10 g, 37.3 mmol) was dissolved in MeOH (100 ml) and THF (100 ml ) in the mixture. To this mixture was added NaBH4 ( 7.05 g, 186.5 mmol), and this mixture was refluxed for 3 h. After 3 h, the reaction mixture was cooled to room temperature and water (500 ml) was added. The aqueous layer was extracted with EtOAc (3*300 ml). The combined organic layers were washed with water (100 ml) and brine (100 ml). The organic layer was distilled under reduced pressure to obtain a solid. The solid was suspended in diethyl ether (50 ml) and stirred for 30 min. After 30 min, the solid was filtered and washed with diethyl ether (20 ml). The solid was dried under vacuum to obtain the title compound (9 g) as a yellow solid. Yield: 89%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 8.96 (d, J 4.4, 1H), 8.28 (s, 1H), 7.89 (d, J 10, 1H), 7.74 (d, J 4.4 , 1H), 5.69 (d, J 4.4, 1H), 5.50-5.43 (m, 1H), 1.45 (d, J 6.4, 3H). MS (m/z): 270.21 (M+H); Calcd. for [ C11H9BrFNO +H]: 269.99 .

中間物 73 (±)-1-(8- -6-(4,4,5,5- 四甲基 -1,3,2- 二氧雜硼雜環戊烷 -2- ) 喹啉 -4- ) 乙醇:遵循一般程序-1,自中間物72 (3.6 g, 13.3 mmol)合成標題化合物。在後處理後,藉由combi-flash使用EtOAc及石油醚(35:65)作為溶析液純化粗產物,獲得呈灰白色固體之標題化合物(900 mg)。產率:21%。 1H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 8.98 (d, J 4.8, 1H), 8.34 (s, 1H), 7.73 (d, J 4.8, 1H), 7.61 (d, J 10, 1H), 5.68 (d, J 4.8, 1H), 5.50-5.42 (m, 1H), 1.49 (d, J 6.4, 3H), 1.35 (s, 12H)。MS (m/z):318.40 (M+H);[C 17H 21BFNO 3+H]計算值:318.16。 Intermediate 73 : (±)-1-(8- fluoro -6-(4,4,5,5 -tetramethyl- 1,3,2-dioxaborolan - 2- yl ) quinone Phenyl- 4 -yl ) ethanol : The title compound was synthesized from Intermediate 72 (3.6 g, 13.3 mmol) following General Procedure-1. After work-up, the crude product was purified by combi-flash using EtOAc and petroleum ether (35:65) as eluents to obtain the title compound (900 mg) as an off-white solid. Yield: 21%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 8.98 (d, J 4.8, 1H), 8.34 (s, 1H), 7.73 (d, J 4.8, 1H), 7.61 (d, J 10 , 1H), 5.68 (d, J 4.8, 1H), 5.50-5.42 (m, 1H), 1.49 (d, J 6.4, 3H), 1.35 (s, 12H). MS (m/z): 318.40 ( M +H); Calcd. for [ C17H21BFNO3 +H]: 318.16 .

中間物 74 (±)-1-(6-(2- -5- 氟嘧啶 -4- )-8- 氟喹啉 -4- ) 乙醇:遵循一般程序-2,自中間物73 (900 mg, 2.84 mmol)及2,4-二氯-5-氟嘧啶(474 mg, 2.84 mmol)合成標題化合物。在反應完成後,將反應混合物在室溫下攪拌16 h,獲得固體。過濾固體,且用二噁烷與水之混合物(1:1) (17 ml)及石油醚(100 ml)洗滌。將固體與甲苯一起在65℃下共蒸餾 。使固體懸浮於二乙醚(20 ml)中且攪拌30 min。30 min後,過濾固體且用二乙醚(20 ml)洗滌。在真空下乾燥固體,獲得呈灰白色固體之標題化合物(600 mg)。產率:66%。 1H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.07 (d, J 3.2, 1H), 9.06 (d, J 4.4, 1H), 8.76 (s, 1H), 8.09 (d, J 11.6, 1H), 7.82 (d, J 4.4, 1H), 5.79 (d, J 4, 1H), 5.53-5.45 (m, 1H), 1.53 (d, J 6.4, 3H)。MS (m/z):322.25 (M+H);[C 15H 10ClF 2N 3O+H]計算值:322.05。 Intermediate 74 : (±)-1-(6-(2- Chloro -5- fluoropyrimidin - 4 -yl )-8- fluoroquinolin- 4 -yl ) ethanol: following General Procedure-2, from Intermediate 73 (900 mg, 2.84 mmol) and 2,4-dichloro-5-fluoropyrimidine (474 mg, 2.84 mmol) to synthesize the title compound. After completion of the reaction, the reaction mixture was stirred at room temperature for 16 h to obtain a solid. The solid was filtered and washed with a mixture of dioxane and water (1 :1 ) (17 ml) and petroleum ether (100 ml). The solid was co-distilled with toluene at 65 °C. The solid was suspended in diethyl ether (20 ml) and stirred for 30 min. After 30 min, the solid was filtered and washed with diethyl ether (20 ml). The solid was dried under vacuum to afford the title compound (600 mg) as an off-white solid. Yield: 66%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.07 (d, J 3.2, 1H), 9.06 (d, J 4.4, 1H), 8.76 (s, 1H), 8.09 (d, J 11.6 , 1H), 7.82 (d, J 4.4, 1H), 5.79 (d, J 4, 1H), 5.53-5.45 (m, 1H), 1.53 (d, J 6.4, 3H). MS (m/z): 322.25 ( M + H) ; Calcd. for [C15H10ClF2N3O+H]: 322.05.

中間物 75 (±)-1-(6- -8- -2- 甲基喹啉 -4- ) -1- 醇:向中間物15 (2.7 g, 9.57 mmol)於甲醇(27 ml)與THF (27 ml)之混合物中之溶液中分多次添加硼氫化鈉(50.8, 1.34 mol)。將反應混合物在80℃下攪拌3 h。使混合物冷卻至25℃,用水(150 ml)稀釋且用EtOAc (3*80 ml)萃取水層。用水(100 ml)及鹽水(100 ml)洗滌合併的有機層。蒸餾有機層,獲得粗製物。將粗製物與石油醚(40 ml)一起攪拌30 min,獲得固體。過濾固體且用石油醚(20 ml)洗滌。在真空下乾燥固體,獲得呈灰白色固體之標題化合物(2.3 g)。產率:85%。 1H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 8.20 (s, 1H), 7.83 (dd, J 10.4, 2, 1H), 7.61 (s, 1H), 5.65 (d, J 4.4, 1H), 5.43-5.35 (m, 1H), 2.66 (s, 3H), 1.43 (d, J 6.4, 3H)。MS (m/z):284.20 (M+H);[C 12H 11BrFNO+H]計算值:285.13。 Intermediate 75 : (±)-1-(6- bromo -8- fluoro -2 -methylquinolin- 4 -yl ) ethan - 1 - ol: To Intermediate 15 (2.7 g, 9.57 mmol) in methanol ( 27 ml) in a mixture of THF (27 ml) was added portionwise with sodium borohydride (50.8, 1.34 mol). The reaction mixture was stirred at 80 °C for 3 h. The mixture was cooled to 25 °C, diluted with water (150 ml) and the aqueous layer was extracted with EtOAc (3*80 ml). The combined organic layers were washed with water (100 ml) and brine (100 ml). The organic layer was distilled to obtain a crude product. The crude was stirred with petroleum ether (40 ml) for 30 min to obtain a solid. The solid was filtered and washed with petroleum ether (20 ml). The solid was dried under vacuum to afford the title compound (2.3 g) as an off-white solid. Yield: 85%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 8.20 (s, 1H), 7.83 (dd, J 10.4, 2, 1H), 7.61 (s, 1H), 5.65 (d, J 4.4, 1H), 5.43-5.35 (m, 1H), 2.66 (s, 3H), 1.43 (d, J 6.4, 3H). MS (m/z): 284.20 (M+H); Calcd. for [ C12H11BrFNO +H]: 285.13 .

中間物 76 (±)-1-(8- -2- 甲基 -6-(4,4,5,5- 四甲基 -1,3,2- 二氧雜硼雜環戊烷 -2- ) 喹啉 -4- ) -1- 醇:遵循一般程序-1,自中間物75 (2.3 g, 8.10 mmol)合成標題化合物。在後處理後,藉由combi-flash使用EtOAc及石油醚(35:65)作為溶析液純化粗產物,獲得呈灰白色固體之標題化合物(1 g)。產率:37%。 1H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 8.27 (s, 1H), 7.60 (s, 1H), 7.56 (d, J 10.8, 1H), 5.64 (bs, 1H), 5.43-5.41 (m, 1H), 2.69 (s, 3H), 1.47 (d, J 6.4, 3H), 1.34 (s, 12 H)。MS (m/z):332.36 (M+H);[C 18H 23BFNO 3+H]計算值:332.19。 Intermediate 76 : (±)-1-(8- fluoro -2- methyl -6-(4,4,5,5 -tetramethyl- 1,3,2 - dioxaborolane- 2- yl ) quinolin- 4 -yl ) ethan - 1 - ol: The title compound was synthesized from Intermediate 75 (2.3 g, 8.10 mmol) following General Procedure-1. After work-up, the crude product was purified by combi-flash using EtOAc and petroleum ether (35:65) as eluents to obtain the title compound (1 g) as an off-white solid. Yield: 37%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 8.27 (s, 1H), 7.60 (s, 1H), 7.56 (d, J 10.8, 1H), 5.64 (bs, 1H), 5.43- 5.41 (m, 1H), 2.69 (s, 3H), 1.47 (d, J 6.4, 3H), 1.34 (s, 12H). MS (m/z): 332.36 ( M +H); Calcd. for [ C18H23BFNO3 +H]: 332.19 .

中間物 77 (±)-1-(6-(2- -5- 氟嘧啶 -4- )-8- -2- 甲基喹啉 -4- ) -1- 醇:遵循一般程序-2,自中間物76 (950 mg, 2.9 mmol)及2,4-二氯-5-氟嘧啶(570 mg, 3.4 mmol)合成標題化合物。在反應完成後,使反應混合物冷卻至室溫且添加水,獲得固體。過濾固體,且用二噁烷與水之混合物(1:1) (10 ml)洗滌。用石油醚(20 ml)進一步洗滌固體。將固體與二乙醚(20 ml)一起攪拌。過濾固體且用二乙醚洗滌。將固體與二乙醚(20 ml)一起再攪拌30 min且過濾固體。乾燥固體,獲得呈灰白色固體之標題化合物(670 mg)。產率:70%。 1H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.05 (s, 1H), 8.69 (s, 1H), 8.04 (d, J 10, 1H), 7.69 (s, 1H), 5.76 (s, 1H), 5.50-5.40- (m, 1H), 2.73 (s, 3H), 1.51 (d, J 6.4, 3H)。MS (m/z):336.27 (M+H);[C 16H 12ClF 2N 3O+H]計算值:336.74。 Intermediate 77 : (±)-1-(6-(2- chloro -5- fluoropyrimidin - 4 -yl )-8- fluoro -2 -methylquinolin- 4 -yl ) ethan - 1 - ol: follow General Procedure-2, The title compound was synthesized from Intermediate 76 (950 mg, 2.9 mmol) and 2,4-dichloro-5-fluoropyrimidine (570 mg, 3.4 mmol). After the reaction was complete, the reaction mixture was cooled to room temperature and water was added to obtain a solid. The solid was filtered and washed with a mixture of dioxane and water (1 :1 ) (10 ml). The solid was further washed with petroleum ether (20 ml). The solid was stirred with diethyl ether (20 ml). The solid was filtered and washed with diethyl ether. The solid was stirred with diethyl ether (20 ml) for another 30 min and the solid was filtered. The solid was dried to obtain the title compound (670 mg) as an off-white solid. Yield: 70%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.05 (s, 1H), 8.69 (s, 1H), 8.04 (d, J 10, 1H), 7.69 (s, 1H), 5.76 ( s, 1H), 5.50-5.40- (m, 1H), 2.73 (s, 3H), 1.51 (d, J 6.4, 3H). MS (m/z): 336.27 (M+H); Calcd. for [ C16H12ClF2N3O + H]: 336.74 .

中間物 78 8- -4- 異丙基 -2- 甲基 -6-(4,4,5,5- 四甲基 -1,3,2- 二氧雜硼雜環戊烷 -2- ) 喹啉:將中間物17 (1.8 g, 5.5 mmol)溶解於MeOH (90 ml)及EtOH (90 ml)中。向此混合物中添加5% Pd/C (720 mg),且於高壓釜反應器中在1 KG氫氣氣氛下攪拌2 h。2 h後,在矽藻土床上過濾反應混合物,且用MeOH與DCM之混合物(1:9) (200 ml)洗滌床。蒸餾合併的濾液,獲得粗製物。藉由combi-flash使用EtOAc及石油醚(8:92)作為溶析液純化粗製物,獲得呈灰白色固體之標題化合物(1.35 g)。產率:75%。 1H-NMR (δ ppm, CDCl 3, 400 MHz): 8.29 (s, 1H), 7.70 (d, J 10.8, 1H), 7.25 (d, J 5.2, 1H), 3.81 (七重峰,J 6.4, 1H), 2.77 (s, 3H), 1.39 (s, 6H), 1.37 (s, 12 H)。 Intermediate 78 : 8- fluoro - 4 - isopropyl- 2- methyl -6-(4,4,5,5 -tetramethyl- 1,3,2-dioxaborolane - 2 -yl ) quinoline: Intermediate 17 (1.8 g, 5.5 mmol ) was dissolved in MeOH (90 ml) and EtOH (90 ml). To this mixture was added 5% Pd/C (720 mg) and stirred in an autoclave reactor under 1 KG hydrogen atmosphere for 2 h. After 2 h, the reaction mixture was filtered on a bed of celite, and the bed was washed with a mixture of MeOH and DCM (1:9) (200 ml). The combined filtrates were distilled to obtain a crude material. The crude was purified by combi-flash using EtOAc and petroleum ether (8:92) as eluents to afford the title compound (1.35 g) as an off-white solid. Yield: 75%. 1 H-NMR (δ ppm, CDCl 3 , 400 MHz): 8.29 (s, 1H), 7.70 (d, J 10.8, 1H), 7.25 (d, J 5.2, 1H), 3.81 (septet, J 6.4, 1H), 2.77 (s, 3H), 1.39 (s, 6H), 1.37 (s, 12H).

中間物 79 6-(2- -5- 氟嘧啶 -4- )-8- -4- 異丙基 -2- 甲基喹啉:遵循一般程序-2,自中間物78 (1.3 g, 3.95 mmol)及2,4-二氯-5-氟嘧啶(791 mg, 4.74 mmol)合成標題化合物。在反應完成後,過濾反應物料中之沈澱產物。使固體在真空下乾燥2 h,獲得呈灰白色固體之標題化合物(1.1 g)。產率:83%。 1H-NMR (δ ppm, CDCl 3, 400 MHz): 8.70 (s, 1H), 8.59 (d, J 2.8, 1H), 8.16 (d, J 12.4, 1H), 7.33 (s, 1H), 3.76 (七重峰,J 6.8, 1H), 2.81 (s, 3H), 1.43 (s, 6H)。 Intermediate 79 : 6-(2- Chloro -5- fluoropyrimidin - 4 -yl )-8- fluoro - 4 - isopropyl- 2 -methylquinoline: following general procedure-2, from Intermediate 78 (1.3 g, 3.95 mmol) and 2,4-dichloro-5-fluoropyrimidine (791 mg, 4.74 mmol) to synthesize the title compound. After the reaction was completed, the precipitated product in the reaction mass was filtered. The solid was dried under vacuum for 2 h to obtain the title compound (1.1 g) as an off-white solid. Yield: 83%. 1 H-NMR (δ ppm, CDCl 3 , 400 MHz): 8.70 (s, 1H), 8.59 (d, J 2.8, 1H), 8.16 (d, J 12.4, 1H), 7.33 (s, 1H), 3.76 (Septet, J 6.8, 1H), 2.81 (s, 3H), 1.43 (s, 6H).

中間物 80 6- -8- 氟喹啉 -4- 甲酸甲基酯將硫酸(6 mL, 0.1 mmol)添加至中間物65 (6 g, 22.2 mmol)於甲醇(6 ml)中之溶液中,且使混合物回流16 h。藉由蒸餾去除甲醇,且將殘餘物溶解於水(600 ml)中。用EtOAc (3*300 ml)萃取水層,且用飽和NaHCO 3水溶液(300 ml)、之後水(200 ml)及鹽水(200 ml)洗滌有機層。蒸餾有機層,獲得粗製物。藉由combi-flash使用EtOAc及石油醚(5:95)作為溶析液純化粗產物,獲得呈黃色固體之標題化合物(4.5 g)。產率:71%。 1H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.08 (d, J 4.4, 1H), 8.60 (t, J 1.6, 1H), 8.03 (d, J 4.4, 1H), 7.63 (dd, J 9.2, 2, 1H), 4.06 (s, 3H)。MS (m/z):284.15 (M+H);[C 11H 7BrFNO 2+H]計算值:283.96。 Intermediate 80 : methyl 6- bromo -8- fluoroquinoline- 4 -carboxylate Add sulfuric acid (6 mL, 0.1 mmol) to a solution of intermediate 65 (6 g, 22.2 mmol) in methanol (6 ml) , and the mixture was refluxed for 16 h. Methanol was removed by distillation, and the residue was dissolved in water (600 ml). The aqueous layer was extracted with EtOAc (3*300 ml), and the organic layer was washed with saturated aqueous NaHCO 3 (300 ml), then water (200 ml) and brine (200 ml). The organic layer was distilled to obtain a crude product. The crude product was purified by combi-flash using EtOAc and petroleum ether (5:95) as eluents to obtain the title compound (4.5 g) as a yellow solid. Yield: 71%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.08 (d, J 4.4, 1H), 8.60 (t, J 1.6, 1H), 8.03 (d, J 4.4, 1H), 7.63 (dd , J 9.2, 2, 1H), 4.06 (s, 3H). MS (m/z): 284.15 (M+H); Calcd. for [ C11H7BrFNO2 + H]: 283.96 .

中間物 81 2-(6- -8- 氟喹啉 -4- ) -2- 醇:在0℃下將2 M甲基溴化鎂於THF中之溶液(46 mL, 93 mmol)緩慢添加至中間物80 (3.3 g, 12 mmol)於THF (51.2 mL)中之溶液中,且在相同溫度下攪拌2 h。將飽和氯化銨水溶液(50 mL)添加至混合物中且萃取至乙酸乙酯(200 mL)中。相繼用水(100 mL)及鹽水(200 mL)洗滌有機層,經硫酸鈉乾燥並蒸發,得到殘餘物,藉由矽膠管柱層析在combi-flash系統上利用乙酸乙酯-己烷(15:85)溶析來純化該殘餘物,得到呈灰白色固體之標題化合物(1.5 g)。產率:46%。 1H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 8.98 (s, 1H), 8.89 (d, J 4.4, 1H), 7.86 (dd, J 10, 2, 1H), 7.61 (d, J 4.4, 1H), 5.72 (s,1 H), 1.65 (s, 6H)。MS (m/z):284.25 (M+H);[C 12H 11BrFNO+H]計算值:284.00。 Intermediate 81 : 2-(6- Bromo -8- fluoroquinolin- 4 -yl ) propan -2- ol: 2 M methylmagnesium bromide in THF at 0 °C (46 mL, 93 mmol ) was slowly added to a solution of Intermediate 80 (3.3 g, 12 mmol) in THF (51.2 mL) and stirred at the same temperature for 2 h. Saturated aqueous ammonium chloride (50 mL) was added to the mixture and extracted into ethyl acetate (200 mL). The organic layer was washed successively with water (100 mL) and brine (200 mL), dried over sodium sulfate and evaporated to give a residue, which was purified by silica gel column chromatography on a combi-flash system using ethyl acetate-hexane (15: 85) The residue was purified by elution to give the title compound (1.5 g) as an off-white solid. Yield: 46%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 8.98 (s, 1H), 8.89 (d, J 4.4, 1H), 7.86 (dd, J 10, 2, 1H), 7.61 (d, J 4.4, 1H), 5.72 (s, 1H), 1.65 (s, 6H). MS (m/z): 284.25 (M+H); Calcd. for [ C12H11BrFNO +H]: 284.00.

中間物 82 (8- -4-(2- 羥基丙 -2- ) 喹啉 -6- ) 硼酸:在-78℃下在氮氣氣氛下將硼酸三異丙酯(8.1 mL, 35.0 mmol)逐滴添加至2-(6-溴-8-氟-2-甲基喹啉-4-基)丙-2-醇(中間物81,5.1 g, 17 mmol)於無水THF (176 mL)中之溶液。將2.5 M n-Buli於己烷中之溶液(8.1 mL, 35 mmol)逐滴添加至上述混合物中且在相同溫度下攪拌2小時。使混合物升溫至室溫且用2 N HCl酸化,攪拌30 min,藉由添加10% NaOH水溶液中和,攪拌20 min,且萃取至乙酸乙酯(2*100 mL)中。相繼用水(100 mL)及鹽水(100 mL)洗滌合併的有機層,經硫酸鈉乾燥並濃縮。將殘餘物與石油醚(10 mL)一起攪拌20 min,且過濾所形成之固體並乾燥。灰白色固體(3.0 g)。產率:68%。 1H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 8.94 (s, 1H), 8.86 (d, J 4.4, 1H), 8.37 (s, 2H), 7.80 (d, J 11.6, 1H), 7.67 (d, J 4.4, 1H), 5.54 (s, 1H), 1.70 (s, 6H)。MS (m/z):249.90 (M+H);[C 12H 13BFNO 3+H]計算值:250.10。 Intermediate 82 : (8- Fluoro - 4-(2 -hydroxypropan- 2- yl ) quinolin -6- yl ) boronic acid: Triisopropyl borate (8.1 mL, 35.0 mmol) was added dropwise to 2-(6-bromo-8-fluoro-2-methylquinolin-4-yl)propan-2-ol (Intermediate 81, 5.1 g, 17 mmol) in anhydrous THF (176 mL ) solution. A solution of 2.5 M n -Buli in hexane (8.1 mL, 35 mmol) was added dropwise to the above mixture and stirred at the same temperature for 2 hours. The mixture was allowed to warm to room temperature and acidified with 2 N HCl, stirred for 30 min, neutralized by addition of 10% aqueous NaOH, stirred for 20 min, and extracted into ethyl acetate (2*100 mL). The combined organic layers were washed successively with water (100 mL) and brine (100 mL), dried over sodium sulfate and concentrated. The residue was stirred with petroleum ether (10 mL) for 20 min, and the solid formed was filtered and dried. Off-white solid (3.0 g). Yield: 68%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 8.94 (s, 1H), 8.86 (d, J 4.4, 1H), 8.37 (s, 2H), 7.80 (d, J 11.6, 1H) , 7.67 (d, J 4.4, 1H), 5.54 (s, 1H), 1.70 (s, 6H). MS (m/z): 249.90 ( M +H); Calcd. for [ C12H13BFNO3 +H]: 250.10 .

中間物 83 2-(6-(2- -5- 氟嘧啶 -4- )-8- 氟喹啉 -4- ) -2- 醇:遵循一般程序-2,自中間物82 (400 mg, 1.61 mmol)及2,4-二氯-5-氟嘧啶(322 mg, 3.85 mmol)合成標題化合物。在後處理後,藉由combi-flash使用EtOAc及石油醚(1:1)作為溶析液純化粗產物,獲得呈灰白色固體之標題化合物(260 mg)。產率:48%。 1H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.55 (s, 1H), 9.04 (d, J 3.2, 1H), 8.99 (d, J 4.4, 1H), 8.06 (d, J 11.6, 1H), 7.72 (d, J 4.4, 1H), 5.78 (s, 1H), 1.71 (s, 6H)。MS (m/z):336.22 (M+H);[C 16H 12ClF 2N 3O+H]計算值:336.06。 Intermediate 83 : 2-(6-(2- Chloro -5- fluoropyrimidin - 4 -yl )-8- fluoroquinolin- 4 -yl ) propan -2- ol: following General Procedure-2, from Intermediate 82 (400 mg, 1.61 mmol) and 2,4-dichloro-5-fluoropyrimidine (322 mg, 3.85 mmol) to synthesize the title compound. After work-up, the crude product was purified by combi-flash using EtOAc and petroleum ether (1:1) as eluents to obtain the title compound (260 mg) as an off-white solid. Yield: 48%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.55 (s, 1H), 9.04 (d, J 3.2, 1H), 8.99 (d, J 4.4, 1H), 8.06 (d, J 11.6 , 1H), 7.72 (d, J 4.4, 1H), 5.78 (s, 1H), 1.71 (s, 6H). MS (m/z): 336.22 (M+H); Calcd. for [ C16H12ClF2N3O + H]: 336.06 .

中間物 84 4-((( 三氟甲基 ) 磺醯基 ) 氧基 )-5,6- 二氫吡啶 -1(2H)- 甲酸第三丁基酯:將二異丙胺(8.5 ml, 60.23 mmol)及無水THF (300 ml)置於RBF中。使此混合物冷卻至-78℃且緩慢添加n-BuLi (24.03 ml, 60.23 mmol)並在-78℃下攪拌40 min。40 min後,將溶解於THF (60 ml)中之4-側氧基六氫吡啶-1-甲酸第三丁基酯(10 g, 50.2 mmol)逐滴添加至上述混合物中持續30 min。將溶解於THF (57 ml)中之1,1,1-三氟-N-苯基-N-((三氟甲基)磺醯基)甲烷磺醯胺(19.72 g, 55.2 mmol)逐滴添加至上述反應混合物中持續30 min。使此反應混合物升溫至室溫且在室溫下攪拌2 h。2 h後,用NaHCO 3水溶液(260 ml)淬滅反應混合物,攪拌1 h且萃取至EtOAc (2* 300 ml)中。將合併的EtOAc層用鹽水洗滌。在真空下蒸餾EtOAc層,獲得粗製物。藉由管柱層析在60-120目矽膠上使用EtOAc及石油醚(8:92)作為溶析液純化粗製物,獲得呈黃色液體之標題化合物 (12 g)。產率:72.17%。 1H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 5.76 (bs, 1H), 4.09-4.01 (m, 2H), 3.68-3.59 (m, 2H), 2.48-2.40 (m, 2H), 1.47 (s, 9H)。 Intermediate 84 : tert-butyl 4-((( trifluoromethyl ) sulfonyl ) oxy )-5,6 -dihydropyridine- 1(2H) -carboxylate: diisopropylamine (8.5 ml, 60.23 mmol) and anhydrous THF (300 ml) were placed in RBF. This mixture was cooled to -78°C and n-BuLi (24.03 ml, 60.23 mmol) was added slowly and stirred at -78°C for 40 min. After 40 min, tert-butyl 4-oxyhexahydropyridine-1-carboxylate (10 g, 50.2 mmol) dissolved in THF (60 ml) was added dropwise to the above mixture for 30 min. 1,1,1-Trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (19.72 g, 55.2 mmol) dissolved in THF (57 ml) was added dropwise Added to the above reaction mixture for 30 min. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 2 h. After 2 h, the reaction mixture was quenched with aqueous NaHCO 3 (260 ml), stirred for 1 h and extracted into EtOAc (2*300 ml). The combined EtOAc layers were washed with brine. The EtOAc layer was distilled under vacuum to obtain crude. The crude was purified by column chromatography on 60-120 mesh silica gel using EtOAc and petroleum ether (8:92) as eluents to obtain the title compound (12 g) as a yellow liquid. Yield: 72.17%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 5.76 (bs, 1H), 4.09-4.01 (m, 2H), 3.68-3.59 (m, 2H), 2.48-2.40 (m, 2H) , 1.47 (s, 9H).

中間物 85 2- 硝基 -5-(4,4,5,5- 四甲基 -1,3,2- 二氧雜硼雜環戊烷 -2- ) 吡啶:遵循一般程序-1,自2-硝基-5-溴吡啶(20.0 g, 99 mmol)合成標題化合物。在後處理後,藉由管柱層析在60-120目矽膠上使用EtOAc及石油醚(3:7)作為溶析液純化粗產物,獲得呈褐色固體之標題化合物(4.5 g)。產率:18%。 1H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 8.81 (d, J 1.6, 1H), 8.42 (dd, J 8.0, 1.6, 1H), 8.30 (d, J 8, 1H),1.34 (s, 12 H)。 MS (m/z):251.24 (M+H);[C 11H 15BN 2O 4+H]計算值:251.11。 Intermediate 85 : 2- nitro -5-(4,4,5,5 -tetramethyl- 1,3,2-dioxaborolan - 2- yl ) pyridine: following general procedure-1 , the title compound was synthesized from 2-nitro-5-bromopyridine (20.0 g, 99 mmol). After work-up, the crude product was purified by column chromatography on 60-120 mesh silica gel using EtOAc and petroleum ether (3:7) as eluents to obtain the title compound (4.5 g) as a brown solid. Yield: 18%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 8.81 (d, J 1.6, 1H), 8.42 (dd, J 8.0, 1.6, 1H), 8.30 (d, J 8, 1H), 1.34 (s, 12 H). MS (m/z): 251.24 (M + H); Calcd. for [ C11H15BN2O4 + H]: 251.11 .

中間物 86 6- 硝基 -5',6'- 二氫 -[3,4'- 聯吡啶 ]-1'(2'H)- 甲酸第三丁基酯 遵循一般程序-2,自中間物85 (1.5 g, 6 mmol)及中間物84 (2.38 g, 7.2 mmol)合成標題化合物。在反應完成後,進行後處理,之後進行管柱純化,得到呈淡褐色固體之標題化合物(1.4 g)。產率:76%。 1H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 8.77 (d, J 2, 1H), 8.30 (d, J 8.4, 1H), 8.24 (dd, J 8.8, 2.4, 1H), 6.56 (bs, 1H), 4.11-4.05 (m, 2H), 3.60-3.52 (m, 2H), 2.58-2.52 (m, 2H), 1.43 (s, 9H)。MS (m/z):306.17 (M+H);[C 15H 19N 3O 4+H]計算值:306.14。 Intermediate 86 : tert-butyl 6- nitro- 5',6' -dihydro- [3,4' -bipyridine ]-1'(2'H) -carboxylate : following general procedure-2, from The title compound was synthesized from intermediate 85 (1.5 g, 6 mmol) and intermediate 84 (2.38 g, 7.2 mmol). After completion of the reaction, work-up followed by column purification afforded the title compound (1.4 g) as a light brown solid. Yield: 76%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 8.77 (d, J 2, 1H), 8.30 (d, J 8.4, 1H), 8.24 (dd, J 8.8, 2.4, 1H), 6.56 (bs, 1H), 4.11-4.05 (m, 2H), 3.60-3.52 (m, 2H), 2.58-2.52 (m, 2H), 1.43 (s, 9H). MS (m/z): 306.17 ( M +H); Calcd. for [ C15H19N3O4 + H]: 306.14.

中間物 87 4-(6- 胺基吡啶 -3- ) 六氫吡啶 -1- 甲酸第三丁基酯將中間物86 (1.8 g, 5.9 mmol)溶解於MeOH (125 ml)與THF (125 ml)之混合物中。將碳載5%鈀(1.8 g)添加至上述溶液中,且在室溫下在H 2氣氛下攪拌44 h。44 h後,在矽藻土床上過濾反應混合物且用EtOAc洗滌床。將合併的濾液蒸餾,獲得呈黃色黏性液體之標題化合物(1.6 g)。產率:98%。 1H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 7.76 (d, J 2.4, 1H), 7.25 (dd, J 8.4, 2.4, 1H), 6.38 (d, J 8.4, 1H), 5.65 (s, 2H), 4.10-4.00 (m, 2H), 2.88-2.70 (m, 2H), 2.50-2.43 (m, 1H), 1.80-1.71 (m, 2H), 1.45-1.35 (m, 11H)。MS (m/z):278.18 (M+H);[C 15H 23N 3O 2+H]計算值:278.18。 Intermediate 87 : tert-butyl 4-(6 -aminopyridin- 3 -yl ) hexahydropyridine- 1 -carboxylate Intermediate 86 (1.8 g, 5.9 mmol) was dissolved in MeOH (125 ml) and THF ( 125 ml) in the mixture. 5% palladium on carbon (1.8 g) was added to the above solution and stirred at room temperature under H2 atmosphere for 44 h. After 44 h, the reaction mixture was filtered on a bed of celite and the bed was washed with EtOAc. The combined filtrates were distilled to obtain the title compound (1.6 g) as a yellow viscous liquid. Yield: 98%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 7.76 (d, J 2.4, 1H), 7.25 (dd, J 8.4, 2.4, 1H), 6.38 (d, J 8.4, 1H), 5.65 (s, 2H), 4.10-4.00 (m, 2H), 2.88-2.70 (m, 2H), 2.50-2.43 (m, 1H), 1.80-1.71 (m, 2H), 1.45-1.35 (m, 11H) . MS (m/z): 278.18 (M+H); Calcd. for [ C15H23N3O2 + H]: 278.18 .

中間物 88 4-(4,4,5,5- 四甲基 -1,3,2- 二氧雜硼雜環戊烷 -2- )-5,6- 二氫吡啶 -1(2H)- 甲酸第三丁基酯:遵循一般程序-1,自中間物84 (20.0 g, 99 mmol)合成標題化合物。在此反應中,使用PdCl 2(dppf).CH 2Cl 2作為觸媒且使用1,4-二噁烷作為溶劑。在後處理後,藉由combi-flash使用EtOAc及石油醚(5:95)作為溶析液純化粗產物,獲得呈灰白色固體之標題化合物(600 mg)。產率:64%。 1H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 6.38 (s, 1H), 3.86 (s, 2H), 3.35-3.30 (m, 2H), 2.10-2.04 (m, 2H), 1.39 (s, 9H), 1.20 (s, 12 H)。MS (m/z):210.24 (M+H-C 5H 9O 2);[C 16H 28BNO 4+H-C 5H 9O 2]計算值:210.21。 Intermediate 88 : 4-(4,4,5,5 -Tetramethyl -1,3,2-dioxaborolan - 2- yl )-5,6 -dihydropyridine- 1(2H ) -tert-butyl formate: The title compound was synthesized from Intermediate 84 (20.0 g, 99 mmol) following General Procedure-1. In this reaction, PdCl 2 (dppf).CH 2 Cl 2 was used as catalyst and 1,4-dioxane was used as solvent. After work-up, the crude product was purified by combi-flash using EtOAc and petroleum ether (5:95) as eluents to obtain the title compound (600 mg) as an off-white solid. Yield: 64%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 6.38 (s, 1H), 3.86 (s, 2H), 3.35-3.30 (m, 2H), 2.10-2.04 (m, 2H), 1.39 (s, 9H), 1.20 (s, 12H). MS (m/z): 210.24 (M + HC5H9O2 ) ; Calcd . for [ C16H28BNO4 + HC5H9O2 ]: 210.21 .

中間物 89 4-(2- 胺基嘧啶 -5- )-5,6- 二氫吡啶 -1(2H)- 甲酸第三丁基酯:遵循一般程序-2,自2-胺基-5-溴嘧啶(270 mg, 1.6 mmol)及中間物88 (580 mg, 1.9 mmol)合成標題化合物。在反應完成後,進行後處理,之後進行管柱純化,得到呈淡褐色固體之標題化合物(190 mg)。產率:44%。 1H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 8.32 (s, 2H), 6.65 (s, 2H), 6.02 (s, 1H), 3.98-3.92 (m, 2H), 3.54-3.47 (m, 2H), 2.41-2.34 (m, 2H), 1.41 (s, 9H)。MS (m/z):277.15 (M+H);[C 14H 20N 4O 2+H]計算值:277.16。 Intermediate 89 : tert-butyl 4-(2 -aminopyrimidin -5- yl )-5,6 -dihydropyridine- 1(2H) -carboxylate: following general procedure-2, from 2-amino- The title compound was synthesized from 5-bromopyrimidine (270 mg, 1.6 mmol) and intermediate 88 (580 mg, 1.9 mmol). After completion of the reaction, work-up followed by column purification afforded the title compound (190 mg) as a light brown solid. Yield: 44%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 8.32 (s, 2H), 6.65 (s, 2H), 6.02 (s, 1H), 3.98-3.92 (m, 2H), 3.54-3.47 (m, 2H), 2.41-2.34 (m, 2H), 1.41 (s, 9H). MS (m/z): 277.15 (M + H); Calcd. for [ C14H20N4O2 + H]: 277.16 .

中間物 90 4-(2- 胺基嘧啶 -5- ) 六氫吡啶 -1- 甲酸第三丁基酯:將中間物89 (180 mg, 0.65 mmol)溶解於MeOH (6 ml)與THF (6 ml)之混合物中。將碳載5%鈀(180 mg)添加至上述溶液中,且在室溫下在H 2氣氛下攪拌44 h。44 h後,在矽藻土床上過濾反應混合物,且用DCM與MeOH之混合物(9:1) (100 ml)洗滌床。將合併的濾液蒸餾,獲得呈褐色黏性固體之標題化合物(180 mg)。產率:99%。 1H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 8.12 (s, 2H), 6.39 (s, 2H), 4.10-4.00 (m, 2H), 2.82-2.68 (m, 2H), 1.74-1.65 (m, 2H), 1.50-1.35 (m, 2H), 1.40 (s, 9H)。MS (m/z):179.25 (M+H- C 5H 9O 2);[C 14H 22N 4O 2+H- C 5H 9O 2]計算值:179.17。 Intermediate 90 : tert-butyl 4-(2 -aminopyrimidin -5- yl ) hexahydropyridine- 1 -carboxylate: Intermediate 89 (180 mg, 0.65 mmol) was dissolved in MeOH (6 ml) and THF (6 ml) in the mixture. 5% palladium on carbon (180 mg) was added to the above solution and stirred at room temperature under H2 atmosphere for 44 h. After 44 h, the reaction mixture was filtered on a bed of celite, and the bed was washed with a mixture of DCM and MeOH (9:1 ) (100 ml). The combined filtrates were distilled to give the title compound (180 mg) as a brown sticky solid. Yield: 99%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 8.12 (s, 2H), 6.39 (s, 2H), 4.10-4.00 (m, 2H), 2.82-2.68 (m, 2H), 1.74 -1.65 (m, 2H), 1.50-1.35 (m, 2H), 1.40 (s, 9H). MS (m/z): 179.25 (M + H - C5H9O2 ); Calcd . for [ C14H22N4O2 + H - C5H9O2 ]: 179.17 .

中間物 91 :三氟甲烷磺酸 1- 甲基 -1,2,3,6- 四氫吡啶 -4- 基酯:將二異丙胺(15 ml, 106 mmol)及無水THF (300 ml)置於RBF中。使此混合物冷卻至-78℃且緩慢添加n-BuLi (2 M於己烷中) (42.42 ml, 106 mmol)並在-78℃下攪拌40 min。40 min後,將溶解於THF (60 ml)中之1-甲基六氫吡啶-4-酮(10 g, 88.4 mmol)逐滴添加至上述混合物中持續30 min。將溶解於THF (100 ml)中之1,1,1-三氟-N-苯基-N-((三氟甲基)磺醯基)甲烷磺醯胺(34.72 g, 97.2 mmol)逐滴添加至上述反應混合物中持續30 min。使此反應混合物升溫至室溫且在室溫下攪拌2.5 h。2.5 h後,用NaHCO 3水溶液(260 ml)淬滅反應混合物,攪拌1 h且萃取至EtOAc (2* 300 ml)中。將合併的EtOAc層用鹽水洗滌。在真空下蒸餾EtOAc層,獲得粗製物。藉由管柱層析在60-120目矽膠上使用EtOAc及石油醚(1:1)作為溶析液純化粗製物,獲得呈褐色液體之標題化合物(19 g)。產率:88%。 1H-NMR (δ ppm, CDCl 3, 400 MHz): 5.76-5.71 (m, 1H), 3.14-3.09 (m, 2H), 2.74-2.68 (m, 2H), 2.51-2.44 (m, 2H), 2.41 (s, 3H)。MS (m/z):246.10 (M+H);[C 7H 10F 3NO 3S+H]計算值:246.03。 Intermediate 91 : 1 -Methyl -1,2,3,6 -tetrahydropyridin- 4 -yl trifluoromethanesulfonate: Diisopropylamine (15 ml, 106 mmol) and anhydrous THF (300 ml) were dissolved in in RBF. This mixture was cooled to -78°C and n-BuLi (2 M in hexane) (42.42 ml, 106 mmol) was added slowly and stirred at -78°C for 40 min. After 40 min, 1-methylhexahydropyridin-4-one (10 g, 88.4 mmol) dissolved in THF (60 ml) was added dropwise to the above mixture for 30 min. 1,1,1-Trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (34.72 g, 97.2 mmol) dissolved in THF (100 ml) was added dropwise Added to the above reaction mixture for 30 min. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 2.5 h. After 2.5 h, the reaction mixture was quenched with aqueous NaHCO 3 (260 ml), stirred for 1 h and extracted into EtOAc (2*300 ml). The combined EtOAc layers were washed with brine. The EtOAc layer was distilled under vacuum to obtain crude. The crude was purified by column chromatography on 60-120 mesh silica gel using EtOAc and petroleum ether (1:1) as eluents to obtain the title compound (19 g) as a brown liquid. Yield: 88%. 1 H-NMR (δ ppm, CDCl 3 , 400 MHz): 5.76-5.71 (m, 1H), 3.14-3.09 (m, 2H), 2.74-2.68 (m, 2H), 2.51-2.44 (m, 2H) , 2.41 (s, 3H). MS (m/z): 246.10 ( M +H); Calcd. for [ C7H10F3NO3S +H]: 246.03 .

中間物 92 1'- 甲基 -6- 硝基 -1',2',3',6'- 四氫 -3,4'- 聯吡啶:遵循一般程序-2,自中間物85 (2 g, 8 mmol)及中間物91 (2.35 g, 9.6 mmol)合成標題化合物。在反應完成後,進行後處理,之後進行管柱純化,得到呈褐色固體之標題化合物(580 mg)。產率:33%。 1H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 8.77 (d, J 2.4, 1H), 8.27 (d, J 8.8, 1H), 8.23 (dd, J 8.8, 2.4, 1H), 6.61-6.57 (m, 1H), 3.12-3.07 (m, 2H), 2.63-2.59 (m, 2H), 2.57-2.52 (m, 2H), 2.30 (s, 3H)。 MS (m/z):220.20 (M+H);[C 11H 13N 3O 2+H]計算值:220.10。 Intermediate 92 : 1' -Methyl -6- nitro- 1',2',3',6' -tetrahydro- 3,4' -bipyridine: following general procedure-2, from Intermediate 85 (2 g, 8 mmol) and intermediate 91 (2.35 g, 9.6 mmol) to synthesize the title compound. After the reaction was completed, work-up followed by column purification gave the title compound (580 mg) as a brown solid. Yield: 33%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 8.77 (d, J 2.4, 1H), 8.27 (d, J 8.8, 1H), 8.23 (dd, J 8.8, 2.4, 1H), 6.61 -6.57 (m, 1H), 3.12-3.07 (m, 2H), 2.63-2.59 (m, 2H), 2.57-2.52 (m, 2H), 2.30 (s, 3H). MS (m/z): 220.20 (M+H); Calcd. for [ C11H13N3O2 + H]: 220.10 .

中間物 93 5-(1- 甲基六氫吡啶 -4- ) 吡啶 -2- 將中間物92 (580 mg, 2.6 mmol)溶解於MeOH (30 ml)與THF (30 ml)之混合物中。將碳載5%鈀(1.16 g)添加至上述溶液中,且在室溫下在H 2氣氛下攪拌45 h。45 h後,在矽藻土床上過濾反應混合物且用EtOAc (200 ml)洗滌床。將合併的濾液蒸餾,獲得呈褐色黏性固體之標題化合物(460 mg)。產率:91%。 1H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 7.75 (d, J 2.4, 1H), 7.25 (dd, J 8.4, 2.4, 1H), 6.38 (d, J 8.4, 1H), 5.63 (s, 2H), 2.86-2.78 (m, 2H), 2.30-2.21 (m, 1H), 2.16 (s, 3H), 1.95-1.85 (m, 2H), 1.68-1.50 (m, 4H)。MS (m/z):192.22 (M+H);[C 11H 17N 3+H]計算值:192.14。 實例 1 4-(6-((5- -4-( 喹啉 -6- ) 嘧啶 -2- ) 胺基 ) 吡啶 -3- ) 六氫吡嗪 -1- 甲酸第三丁基酯 Intermediate 93 : 5-(1 -Methylhexahydropyridin- 4 -yl ) pyridin -2- amine : Intermediate 92 (580 mg, 2.6 mmol) was dissolved in MeOH (30 ml) and THF (30 ml) in the mixture. 5% palladium on carbon (1.16 g) was added to the above solution and stirred at room temperature under H2 atmosphere for 45 h. After 45 h, the reaction mixture was filtered on a bed of celite and the bed was washed with EtOAc (200 ml). The combined filtrates were distilled to afford the title compound (460 mg) as a brown sticky solid. Yield: 91%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 7.75 (d, J 2.4, 1H), 7.25 (dd, J 8.4, 2.4, 1H), 6.38 (d, J 8.4, 1H), 5.63 (s, 2H), 2.86-2.78 (m, 2H), 2.30-2.21 (m, 1H), 2.16 (s, 3H), 1.95-1.85 (m, 2H), 1.68-1.50 (m, 4H). MS (m/z): 192.22 ( M +H); Calcd. for [ C11H17N3 +H]: 192.14 . Example 1 4-(6-((5- fluoro - 4-( quinolin -6- yl ) pyrimidin -2- yl ) amino ) pyridin - 3 -yl ) hexahydropyrazine- 1 -carboxylic acid tert-butyl ester

遵循一般程序-3,自中間物2 (500 mg, 1.93 mmol)及中間物5 (590 mg, 2.1 mmol)合成標題化合物。在後處理(EtOAc/鹽水,接著H 2O)後,藉由combi-flash使用甲醇及DCM (2.7:97.3)作為溶析液純化粗產物,獲得呈黃色固體之標題化合物(120 mg)。產率:12.4%。熔點:223℃-225℃。 1H-NMR (δ ppm, CDCl 3, 400 MHz): 9.02-8.99 (m, 1H), 8.62 (br. s, 1H), 8.49-8.44 (m, 2H), 8.36-8.23 (m, 3H), 8.15 (br. s, 1H), 8.05 (d, J  2.8, 1H), 7.50 (dd, J  8.4, 4.4, 1H), 7.38 (dd, J  9.2, 2.8, 1H), 3.61 (t, J  4.8, 4H), 3.10 (t, J  4.8, 4H), 1.49 (s, 9H)。MS (m/z):502.33 (M+H);[C 27H 28FN 7O 2+H]計算值:502.24。 實例 1A 5- -N-(5-( 六氫吡嗪 -1- ) 吡啶 -2- )-4-( 喹啉 -6- ) 嘧啶 -2- The title compound was synthesized from Intermediate 2 (500 mg, 1.93 mmol) and Intermediate 5 (590 mg, 2.1 mmol) following General Procedure-3. After work-up (EtOAc/brine, then H2O ), the crude product was purified by combi-flash using methanol and DCM (2.7:97.3) as eluents to obtain the title compound (120 mg) as a yellow solid. Yield: 12.4%. Melting point: 223°C-225°C. 1 H-NMR (δ ppm, CDCl 3 , 400 MHz): 9.02-8.99 (m, 1H), 8.62 (br. s, 1H), 8.49-8.44 (m, 2H), 8.36-8.23 (m, 3H) , 8.15 (br. s, 1H), 8.05 (d, J 2.8, 1H), 7.50 (dd, J 8.4, 4.4, 1H), 7.38 (dd, J 9.2, 2.8, 1H), 3.61 (t, J 4.8 , 4H), 3.10 (t, J 4.8, 4H), 1.49 (s, 9H). MS (m/z): 502.33 (M+H); Calcd. for [ C27H28FN7O2 + H]: 502.24 . Example 1A 5- fluoro -N-(5-( hexahydropyrazin- 1 -yl ) pyridin -2- yl )-4-( quinolin -6- yl ) pyrimidin -2- amine

遵循一般程序-4,自4-(6-((5-氟-4-(喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-1-甲酸第三丁基酯(實例1) (110 mg, 0.22 mmol)合成呈淡黃色固體之標題化合物(35 mg)。產率:40%。 1H-NMR (δ ppm, DMSO- d 6+ CDCl 3, 400 MHz): 9.70 (s, 1H), 9.02-8.95 (m, 1H), 8.70-8.65 (m, 2H), 8.53 (d, J  8.4, 1H), 8.40 (d, J  9.2, 1H), 8.17 (d, J  8.8, 1H), 8.09 (d, J  9.2, 1H), 7.97 (br. s, 1H), 7.60 (dd, J  8.4, 4.4, 1H), 7.38-7.45 (m, 1H), 3.01 (br. s, 4H), 2.85 (br. s, 4H)。 實例 1B 5- -N-(5-( 六氫吡嗪 -1- ) 吡啶 -2- )-4-( 喹啉 -6- ) 嘧啶 -2- 胺鹽酸鹽 Following general procedure-4, from 4-(6-((5-fluoro-4-(quinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazine-1- tert-Butyl formate (Example 1) (110 mg, 0.22 mmol) The title compound (35 mg) was synthesized as a pale yellow solid. Yield: 40%. 1 H-NMR (δ ppm, DMSO- d 6 + CDCl 3 , 400 MHz): 9.70 (s, 1H), 9.02-8.95 (m, 1H), 8.70-8.65 (m, 2H), 8.53 (d, J 8.4, 1H), 8.40 (d, J 9.2, 1H), 8.17 (d, J 8.8, 1H), 8.09 (d, J 9.2, 1H), 7.97 (br. s, 1H), 7.60 (dd, J 8.4 , 4.4, 1H), 7.38-7.45 (m, 1H), 3.01 (br. s, 4H), 2.85 (br. s, 4H). Example 1B 5- fluoro -N-(5-( hexahydropyrazin- 1 -yl ) pyridin -2- yl )-4-( quinolin -6- yl ) pyrimidin -2- amine hydrochloride

將5-氟-N-(5-(六氫吡嗪-1-基)吡啶-2-基)-4-(喹啉-6-基)嘧啶-2-胺(實例1A) (27 mg, 0.067 mmol)溶解於甲醇(2.7 ml)中且添加HCl (25 mg, 0.67 mmol),獲得澄清溶液。 將此溶液在室溫下攪拌30 min。30 min後,蒸餾出甲醇,獲得殘餘物。將殘餘物與甲苯(5 ml)一起共蒸餾,獲得呈黃色固體之標題化合物。熔點:220℃-222℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 11.74 (br. s, 1H) 9.50 (br. s, 2H), 9.19 (br. s, 1H), 9.00-8.80 (m, 3H), 8.51 (br. s, 1H), 8.39 (t, J  8.4, 1H), 8.16 (br. s, 1H), 8.02 (s, 1H), 7.90-7.80 (m, 2H), 3.50-3.40 (br. s, 4H), 3.30-3.20 (br. s, 4H)。MS (m/z):402.1 (M+H);[C 22H 20FN 7+H]計算值:402.1。 實例 2 4-(6-((5- -4-(8- 氟喹啉 -6- ) 嘧啶 -2- ) 胺基 ) 吡啶 -3- ) 六氫吡嗪 -1- 甲酸第三丁基酯 5-fluoro-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)-4-(quinolin-6-yl)pyrimidin-2-amine (Example 1A) (27 mg, 0.067 mmol) was dissolved in methanol (2.7 ml) and HCl (25 mg, 0.67 mmol) was added to obtain a clear solution. The solution was stirred at room temperature for 30 min. After 30 min, methanol was distilled off to obtain a residue. The residue was co-distilled with toluene (5 ml) to obtain the title compound as a yellow solid. Melting point: 220°C-222°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 11.74 (br. s, 1H) 9.50 (br. s, 2H), 9.19 (br. s, 1H), 9.00-8.80 (m, 3H ), 8.51 (br. s, 1H), 8.39 (t, J 8.4, 1H), 8.16 (br. s, 1H), 8.02 (s, 1H), 7.90-7.80 (m, 2H), 3.50-3.40 ( br. s, 4H), 3.30-3.20 (br. s, 4H). MS (m/z): 402.1 ( M +H) ; Calcd. for [ C22H20FN7 +H]: 402.1. Example 2 4-(6-((5- fluoro - 4-(8- fluoroquinolin- 6- yl ) pyrimidin -2- yl ) amino ) pyridin - 3 -yl ) hexahydropyrazine- 1 - carboxylic acid tributyl ester

遵循一般程序-3,自中間物7 (500 mg, 1.80 mmol)及中間物5 (551 mg, 1.98 mmol)合成標題化合物。在後處理後,藉由combi-flash使用甲醇及DCM (2.5:97.5)作為溶析液純化粗產物,獲得呈黃色固體之標題化合物(130 mg)。產率:14%。熔點:227℃-229℃。 1H-NMR (δ ppm, CDCl 3, 400 MHz): 9.08-9.04 (m, 1H), 8.49 (d, J = 3.6, 1H), 8.36-8.19 (m, 4H), 8.07 (d, J  2.4, 1H), 7.57 (dd, J  8.0, 4.0, 1H), 7.40 (dd, J  9.2, 2.8, 1H), 3.61 (t, J = 4.8, 4H), 3.11 (t, J = 4.8, 4H), 1.50 (s, 9H)。MS (m/z):520.32 (M+H);[C 27H 27F 2N 7O 2+H]計算值:520.23。 實例 2A 5- -4-(8- 氟喹啉 -6- )-N-(5-( 六氫吡嗪 -1- ) 吡啶 -2- ) 嘧啶 -2- The title compound was synthesized from Intermediate 7 (500 mg, 1.80 mmol) and Intermediate 5 (551 mg, 1.98 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (2.5:97.5) as eluents to obtain the title compound (130 mg) as a yellow solid. Yield: 14%. Melting point: 227°C-229°C. 1 H-NMR (δ ppm, CDCl 3 , 400 MHz): 9.08-9.04 (m, 1H), 8.49 (d, J = 3.6, 1H), 8.36-8.19 (m, 4H), 8.07 (d, J 2.4 , 1H), 7.57 (dd, J 8.0, 4.0, 1H), 7.40 (dd, J 9.2, 2.8, 1H), 3.61 (t, J = 4.8, 4H), 3.11 (t, J = 4.8, 4H), 1.50 (s, 9H). MS (m/z): 520.32 (M + H); Calcd. for [ C27H27F2N7O2 + H]: 520.23 . Example 2A 5- fluoro - 4-(8- fluoroquinolin- 6- yl )-N-(5-( hexahydropyrazin- 1 -yl ) pyridin -2- yl ) pyrimidin -2- amine

遵循一般程序-4,自4-(6-((5-氟-4-(8-氟喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-1-甲酸第三丁基酯(實例2) (120 mg, 0.23 mmol)合成呈淡黃色固體之標題化合物(55 mg)。產率:57%。1H-NMR (δ ppm, DMSO- d6, 400 MHz): 9.82 (s, 1H), 9.06 (br. s, 1H), 8.72 (d, J  3.2, 1H), 8.67 (d, J  8.0, 1H), 8.56 (s, 1H), 8.21 (d, J = 12.4, 1H), 8.06-7.96 (m, 2H), 7.74 (dd, J  8.4, 4.0, 1H), 7.44 (d, J = 8.8, 1H), 3.02 (br. s, 4H), 2.84 (br. s, 4H)。 實例 2B 5- -4-(8- 氟喹啉 -6- )-N-(5-( 六氫吡嗪 -1- ) 吡啶 -2- ) 嘧啶 -2- 胺鹽酸鹽 Following General Procedure-4, from 4-(6-((5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazine - tert-butyl 1-carboxylate (Example 2) (120 mg, 0.23 mmol) The title compound (55 mg) was synthesized as a pale yellow solid. Yield: 57%. 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 9.82 (s, 1H), 9.06 (br. s, 1H), 8.72 (d, J 3.2, 1H), 8.67 (d, J 8.0, 1H ), 8.56 (s, 1H), 8.21 (d, J = 12.4, 1H), 8.06-7.96 (m, 2H), 7.74 (dd, J 8.4, 4.0, 1H), 7.44 (d, J = 8.8, 1H ), 3.02 (br. s, 4H), 2.84 (br. s, 4H). Example 2B 5- fluoro - 4-(8- fluoroquinolin- 6- yl )-N-(5-( hexahydropyrazin- 1 -yl ) pyridin -2- yl ) pyrimidin -2- amine hydrochloride

將5-氟-4-(8-氟喹啉-6-基)-N-(5-(六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺(實例2A) (50 mg, 0.12 mmol)溶解於甲醇(2.5 ml)中且添加HCl (43 mg, 1.2 mmol),獲得澄清溶液。 將此溶液在室溫下攪拌30 min。30 min後,蒸餾出甲醇,獲得殘餘物。將殘餘物與甲苯(5 ml)一起共蒸餾,獲得呈黃色固體之標題化合物(45 mg)。產率:83% 熔點:220℃-222℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz):熔點:262℃-264℃。 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 11.78 (br. s, 1H), 9.56 (br. s, 2H), 9.08 (br. s, 1H), 8.94 (br. s, 1H), 8.70 (d, J  8.4, 1H), 8.61 (s, 1H), 8.12-8.23 (m, 2H), 8.01 (s, 1H), 7.84 (d, J  8.8, 1H), 7.77 (dd, J  8.4, 4.0, 1H), 3.49-3.41(m, 4H), 3.28-3.20 (m, 4H)。MS (m/z):420.39 (M+H-HCl);[C 22H 19F 2N 7.HCl+H-HCl]計算值:420.17。 實例 3 N-(5-((4- 乙基六氫吡嗪 -1- ) 甲基 ) 吡啶 -2- )-5- -4-(8- 氟喹啉 -6- ) 嘧啶 -2- 5-fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine (Example 2A) ( 50 mg, 0.12 mmol) was dissolved in methanol (2.5 ml) and HCl (43 mg, 1.2 mmol) was added to obtain a clear solution. The solution was stirred at room temperature for 30 min. After 30 min, methanol was distilled off to obtain a residue. The residue was co-distilled with toluene (5 ml) to obtain the title compound (45 mg) as a yellow solid. Yield: 83% Melting point: 220°C-222°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): melting point: 262°C-264°C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 11.78 (br. s, 1H), 9.56 (br. s, 2H), 9.08 (br. s, 1H), 8.94 (br. s, 1H) , 8.70 (d, J 8.4, 1H), 8.61 (s, 1H), 8.12-8.23 (m, 2H), 8.01 (s, 1H), 7.84 (d, J 8.8, 1H), 7.77 (dd, J 8.4 , 4.0, 1H), 3.49-3.41(m, 4H), 3.28-3.20 (m, 4H). MS (m/z): 420.39 (M+H-HCl); Calcd. for [ C22H19F2N7.HCl + H - HCl]: 420.17 . Example 3 N-(5-((4- ethylhexahydropyrazin- 1 -yl ) methyl ) pyridin -2- yl )-5- fluoro - 4-(8- fluoroquinolin- 6- yl ) pyrimidine -2- amine

遵循一般程序-3,自中間物7 (500 mg, 1.8 mmol)及中間物9 (400 mg, 1.8 mmol)合成標題化合物。在後處理後,藉由combi-flash使用甲醇及DCM (11.5:88.5)作為溶析液純化粗產物,獲得呈黃色固體之標題化合物(280 mg)。產率:34%。熔點:246℃-248℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 10.12 (s, 1H), 9.08 (d, J  3.6, 1H), 8.81 (d, J  3.2, 1H), 8.69 (d, J  8.0, 1H), 8.60 (s, 1H), 8.30-8.20 (m, 3H), 7.80-7.70 (m, 1H), 7.40-7.30 (m, 1H), 3.47 (br. s, 2H) 2.70-2.20 (m, 10H), 1.00 (br. s, 3H)。MS (m/z):462.29 (M+H);[C 25H 25F 2N 7+H]計算值:462.22。 實例 3A N-(5-((4- 乙基六氫吡嗪 -1- ) 甲基 ) 吡啶 -2- )-5- -4-(8- 氟喹啉 -6- ) 嘧啶 -2- 胺鹽酸鹽 The title compound was synthesized from Intermediate 7 (500 mg, 1.8 mmol) and Intermediate 9 (400 mg, 1.8 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (11.5:88.5) as eluents to obtain the title compound (280 mg) as a yellow solid. Yield: 34%. Melting point: 246°C-248°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 10.12 (s, 1H), 9.08 (d, J 3.6, 1H), 8.81 (d, J 3.2, 1H), 8.69 (d, J 8.0 , 1H), 8.60 (s, 1H), 8.30-8.20 (m, 3H), 7.80-7.70 (m, 1H), 7.40-7.30 (m, 1H), 3.47 (br. s, 2H) 2.70-2.20 ( m, 10H), 1.00 (br. s, 3H). MS (m/z): 462.29 (M+H); Calcd. for [ C25H25F2N7 + H]: 462.22 . Example 3A N-(5-((4- ethylhexahydropyrazin- 1 -yl ) methyl ) pyridin -2- yl )-5- fluoro - 4-(8- fluoroquinolin- 6- yl ) pyrimidine -2- amine hydrochloride

使N-(5-((4-乙基六氫吡嗪-1-基)甲基)吡啶-2-基)-5-氟-4-(8-氟喹啉-6-基)嘧啶-2-胺(實例3) (250 mg, 0.54 mmol)懸浮於甲醇(6 ml)中且添加35%鹽酸水溶液(197 mg, 5.4 mmol),獲得澄清溶液。 將此混合物在室溫下攪拌30 min。添加甲基第三丁基醚(18 ml)且攪拌1小時,獲得固體,過濾該固體,用甲基第三丁基醚(20 ml)洗滌並乾燥,獲得呈褐色固體之標題化合物(230 mg)。產率:85%。熔點:289℃-291℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz):熔點:289℃-291℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 11.89 (br. s, 1H), 11.40 (br. s, 1H), 9.08-9.13 (br. s, 1H), 8.92-8.97 (br. s, 1H), 8.72 (d, J = 8.4, 1H), 8.60-8.70 (m, 2H), 8.25-8.40 (m, 2H), 8.12 (d, J = 8.8, 1H), 7.75-8.15 (m, 1H), 4.45 (br. s, 2H), 3.15-3.82 (m, 10H), 1.27 (t, J = 7.2, 3H)。MS (m/z):461.8 (M+H-HCl);[C 25H 25F 2N 7.HCl+H-HCl]計算值:462.2。 實例 4 N-(5-((4- 乙基六氫吡嗪 -1- ) 甲基 ) 吡啶 -2- )-5- -4-( 喹啉 -6- ) 嘧啶 -2- Make N-(5-((4-ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidine- 2-Amine (Example 3) (250 mg, 0.54 mmol) was suspended in methanol (6 ml) and 35% aqueous hydrochloric acid (197 mg, 5.4 mmol) was added to obtain a clear solution. This mixture was stirred at room temperature for 30 min. Addition of methyl tert-butyl ether (18 ml) and stirring for 1 hour gave a solid which was filtered, washed with methyl tert-butyl ether (20 ml) and dried to give the title compound as a brown solid (230 mg ). Yield: 85%. Melting point: 289°C-291°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): Melting point: 289°C-291°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 11.89 (br. s, 1H), 11.40 (br. s, 1H), 9.08-9.13 (br. s, 1H), 8.92-8.97 ( br. s, 1H), 8.72 (d, J = 8.4, 1H), 8.60-8.70 (m, 2H), 8.25-8.40 (m, 2H), 8.12 (d, J = 8.8, 1H), 7.75-8.15 (m, 1H), 4.45 (br. s, 2H), 3.15-3.82 (m, 10H), 1.27 (t, J = 7.2, 3H). MS (m/z): 461.8 (M+H-HCl); Calcd. for [ C25H25F2N7.HCl + H - HCl]: 462.2. Example 4 N-(5-((4- ethylhexahydropyrazin- 1 -yl ) methyl ) pyridin -2- yl )-5- fluoro - 4-( quinolin -6- yl ) pyrimidine -2- amine

遵循一般程序-3,自中間物2 (500 mg, 1.9 mmol)及中間物9 (420 mg, 1.9 mmol)合成標題化合物。在後處理後,藉由combi-flash使用甲醇及DCM (13:87)作為溶析液純化粗產物,獲得呈黃色固體之標題化合物(200 mg)。產率:23%。熔點:289℃-291℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 10.07 (s, 1H), 9.04 (s, 1H), 8. 80-8. 70 (m, 2H), 8.60 (d, J  8.0, 1H), 8.45 (d, J  8.0, 1H), 8. 30-8. 20 (m, 3H), 7. 80-7. 60 (m, 1H), 7.55-7.40 (m, 1H), 3.42 (s, 2H), 2. 80-2. 10 (m, 10H), 1.24 (br. s, 3H)。MS (m/z):444.32 (M+H);[C 25H 26FN 7+H]計算值:444.23。 實例 4A N-(5-((4- 乙基六氫吡嗪 -1- ) 甲基 ) 吡啶 -2- )-5- -4-( 喹啉 -6- ) 嘧啶 -2- 胺鹽酸鹽 The title compound was synthesized from Intermediate 2 (500 mg, 1.9 mmol) and Intermediate 9 (420 mg, 1.9 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (13:87) as eluents to obtain the title compound (200 mg) as a yellow solid. Yield: 23%. Melting point: 289°C-291°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 10.07 (s, 1H), 9.04 (s, 1H), 8. 80-8. 70 (m, 2H), 8.60 (d, J 8.0 , 1H), 8.45 (d, J 8.0, 1H), 8. 30-8. 20 (m, 3H), 7. 80-7. 60 (m, 1H), 7.55-7.40 (m, 1H), 3.42 (s, 2H), 2. 80-2. 10 (m, 10H), 1.24 (br. s, 3H). MS (m/z): 444.32 (M+H) ; Calcd. for [ C25H26FN7 +H]: 444.23. Example 4A N-(5-((4- ethylhexahydropyrazin- 1 -yl ) methyl ) pyridin -2- yl )-5- fluoro - 4-( quinolin -6- yl ) pyrimidine -2- Amine hydrochloride

使N-(5-((4-乙基六氫吡嗪-1-基)甲基)吡啶-2-基)-5-氟-4-(喹啉-6-基)嘧啶-2-胺(實例4) (190 mg, 0.43 mmol)懸浮於甲醇(5 ml)中且添加35%鹽酸水溶液(160 mg, 4.4 mmol),獲得澄清溶液。 將此溶液在室溫下攪拌30 min。添加甲基第三丁基醚(15 ml)且攪拌1小時,獲得固體,過濾該固體,用甲基第三丁基醚(20 ml)洗滌並乾燥,獲得呈褐色固體之標題化合物(60 mg)。產率:85%。熔點:255℃-257℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 11.99 (br. s, 1H), 11.32 (br. s, 1H), 9.21 (d, J = 4.4, 1H), 9.05-8.90 (m, 3H), 8.52-8.51 (m, 2H), 8.42 (d, J  8.8, 1H), 8.30 (d, J  8.8, 1H), 8.14 (d, J  8.8, 1H), 7.90 (dd, J  8.0, 4.8, 1H), 4.44 (br. s, 2H), 3.80-3.00 (m, 10H), 1.27 (t, J = 7.2, 3H)。MS (m/z):443.8 (M+H-HCl);[C 25H 26FN 7.HCl+H-HCl]計算值:444.2。 實例 5 4-(6-((5- -4-(8- -2- 甲基 -4-( -1- -2- ) 喹啉 -6- ) 嘧啶 -2- ) 胺基 ) 吡啶 -3- ) 六氫吡嗪 -1- 甲酸第三丁基酯 Make N-(5-((4-ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(quinolin-6-yl)pyrimidin-2-amine (Example 4) (190 mg, 0.43 mmol) was suspended in methanol (5 ml) and 35% aqueous hydrochloric acid (160 mg, 4.4 mmol) was added to obtain a clear solution. The solution was stirred at room temperature for 30 min. Addition of methyl tert-butyl ether (15 ml) and stirring for 1 hour gave a solid which was filtered, washed with methyl tert-butyl ether (20 ml) and dried to give the title compound as a brown solid (60 mg ). Yield: 85%. Melting point: 255°C-257°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 11.99 (br. s, 1H), 11.32 (br. s, 1H), 9.21 (d, J = 4.4, 1H), 9.05-8.90 ( m, 3H), 8.52-8.51 (m, 2H), 8.42 (d, J 8.8, 1H), 8.30 (d, J 8.8, 1H), 8.14 (d, J 8.8, 1H), 7.90 (dd, J 8.0 , 4.8, 1H), 4.44 (br. s, 2H), 3.80-3.00 (m, 10H), 1.27 (t, J = 7.2, 3H). MS (m/z): 443.8 (M+H-HCl); Calcd. for [ C25H26FN7.HCl +H - HCl]: 444.2 . Example 5 4-(6-((5- fluoro - 4-(8- fluoro -2- methyl- 4-( prop- 1 -en -2- yl ) quinolin -6- yl ) pyrimidin -2- yl ) amino ) pyridin - 3 -yl ) hexahydropyrazine- 1 -carboxylic acid tert-butyl ester

遵循一般程序-3,自中間物18 (500 mg, 1.51 mmol)及中間物5 (420 mg, 1.51 mmol)合成標題化合物。在後處理後,藉由combi-flash使用甲醇及DCM (1.8:98.2)作為溶析液純化粗產物,獲得呈黃色固體之標題化合物(180 mg)。產率:21%。熔點:150℃-152℃。 1H-NMR (δ ppm, CDCl3, 400 MHz): 8.66 (s, 1H), 8.45 (d, J  3.6, 1H), 8.30 (d, J  9.2, 1H), 8.16 (d, J  12.0, 1H), 8.10 (s, 1H), 8.05 (d, J  2.8, 1H), 7.37 (dd, J  9.2, 3.2, 1H), 5.56 (s, 1H), 5.20 (s, 1H), 3.66-3.59(m, 4H), 3.14-3.08(m , 4H), 2.26 (s, 3H), 1.62 (s, 3H), 1.50 (s, 9H)。MS (m/z):574.35 (M+H);[C 31H 33F 2N 7O 2+ H]計算值:574.28。 實例 5A 5- -4-(8- -2- 甲基 -4-( -1- -2- ) 喹啉 -6- )-N-(5-( 六氫吡嗪 -1- ) 吡啶 -2- ) 嘧啶 -2- The title compound was synthesized from Intermediate 18 (500 mg, 1.51 mmol) and Intermediate 5 (420 mg, 1.51 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (1.8:98.2) as eluents to obtain the title compound (180 mg) as a yellow solid. Yield: 21%. Melting point: 150°C-152°C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 8.66 (s, 1H), 8.45 (d, J 3.6, 1H), 8.30 (d, J 9.2, 1H), 8.16 (d, J 12.0, 1H), 8.10 (s, 1H), 8.05 (d, J 2.8, 1H), 7.37 (dd, J 9.2, 3.2, 1H), 5.56 (s, 1H), 5.20 (s, 1H), 3.66-3.59(m, 4H ), 3.14-3.08(m , 4H), 2.26 (s, 3H), 1.62 (s, 3H), 1.50 (s, 9H). MS (m/z): 574.35 (M + H); Calcd. for [ C31H33F2N7O2 + H]: 574.28 . Example 5A 5- fluoro - 4-(8- fluoro -2- methyl- 4-( prop- 1 -en -2- yl ) quinolin -6- yl ) -N-(5-( hexahydropyrazine- 1- yl ) pyridin -2- yl ) pyrimidin -2- amine

遵循一般程序-4,自4-(6-((5-氟-4-(8-氟-2-甲基-4-(丙-1-烯-2-基)喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-1-甲酸第三丁基酯(實例5) (150 mg, 0.26 mmol)合成呈黃色固體之標題化合物(110 mg)。產率:89%。熔點:165℃-167℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 9.82 (s, 1H), 8.67 (d, J  2.4, 1H), 8.61 (s, 1H), 8.14 (d, J  11.6, 1H), 8.10-7.95 (m, 2H), 7.49 (s, 1H), 7.40 (d, J  8.0, 1H), 5.61 (s, 1H), 5.19 (s, 1H), 3.10-3.00 (m, 4H), 2.90-2.82 (m, 4H), 2.72 (s, 3H), 2.23 (s, 3H)。MS (m/z):474.53 (M+H);[C 26H 25F 2N 7+ H]計算值:474.2。 實例 5B 5- -4-(8- -2- 甲基 -4-( -1- -2- ) 喹啉 -6- )-N-(5-( 六氫吡嗪 -1- ) 吡啶 -2- ) 嘧啶 -2- 胺鹽酸鹽: Following general procedure-4, from 4-(6-((5-fluoro-4-(8-fluoro-2-methyl-4-(prop-1-en-2-yl)quinolin-6-yl) The title compound (110 mg) was synthesized as a yellow solid . Yield: 89%. Melting point: 165°C-167°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.82 (s, 1H), 8.67 (d, J 2.4, 1H), 8.61 (s, 1H), 8.14 (d, J 11.6, 1H) , 8.10-7.95 (m, 2H), 7.49 (s, 1H), 7.40 (d, J 8.0, 1H), 5.61 (s, 1H), 5.19 (s, 1H), 3.10-3.00 (m, 4H), 2.90-2.82 (m, 4H), 2.72 (s, 3H), 2.23 (s, 3H). MS (m/z): 474.53 (M+H); Calcd. for [ C26H25F2N7 + H]: 474.2 . Example 5B 5- fluoro - 4-(8- fluoro -2- methyl- 4-( prop- 1 -en -2- yl ) quinolin -6- yl ) -N-(5-( hexahydropyrazine- 1- yl ) pyridin -2- yl ) pyrimidin -2- amine hydrochloride:

使5-氟-4-(8-氟-2-甲基-4-(丙-1-烯-2-基)喹啉-6-基)-N-(5-(六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺(實例5A) (100 mg, 0.21 mmol)懸浮於甲醇(2 ml)中且添加35%鹽酸水溶液(221 mg, 2.1 mmol),獲得澄清溶液。 將此混合物在室溫下攪拌30 min。添加甲基第三丁基醚(6 ml)且攪拌1小時,獲得固體,過濾該固體,用甲基第三丁基醚(2 ml)洗滌並乾燥,獲得呈黃色固體之標題化合物(95 mg)。產率:80%。熔點:213℃-215℃。 熔點:213℃-215℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 11.74 (br. s, 1H), 9.53 (br. s, 2H), 8.88 (s, 1H), 8.58 (s, 1H), 8.20-8.10 (m, 2H), 7.98 (s, 1H), 7.83 (d, J  9.6, 1H), 7.54 (s, 1H), 5.63 (s, 1H), 5.21 (s, 1H), 3.49-3.41 (m, 4H), 3.30-3.19 (m, 4H), 2.73 (s, 3H), 2.23 (s, 3H)。MS (m/z):474.5 (M+H);[C 26H 25F 2N 7+ H]計算值:474.2。 實例 6 5- -N-(5-(4- 甲基六氫吡嗪 -1- ) 吡啶 -2- )-4-( 喹啉 -6- ) 嘧啶 -2- Make 5-fluoro-4-(8-fluoro-2-methyl-4-(prop-1-en-2-yl)quinolin-6-yl)-N-(5-(hexahydropyrazine-1 -yl)pyridin-2-yl)pyrimidin-2-amine (Example 5A) (100 mg, 0.21 mmol) was suspended in methanol (2 ml) and 35% aqueous hydrochloric acid (221 mg, 2.1 mmol) was added to obtain a clear solution . This mixture was stirred at room temperature for 30 min. Addition of methyl tert-butyl ether (6 ml) and stirring for 1 hour gave a solid which was filtered, washed with methyl tert-butyl ether (2 ml) and dried to give the title compound as a yellow solid (95 mg ). Yield: 80%. Melting point: 213°C-215°C. Melting point: 213°C-215°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 11.74 (br. s, 1H), 9.53 (br. s, 2H), 8.88 (s, 1H), 8.58 (s, 1H), 8.20 -8.10 (m, 2H), 7.98 (s, 1H), 7.83 (d, J 9.6, 1H), 7.54 (s, 1H), 5.63 (s, 1H), 5.21 (s, 1H), 3.49-3.41 ( m, 4H), 3.30-3.19 (m, 4H), 2.73 (s, 3H), 2.23 (s, 3H). MS (m/z): 474.5 (M+H); Calcd. for [ C26H25F2N7 + H]: 474.2 . Example 6 5- fluoro -N-(5-(4- methylhexahydropyrazin- 1 -yl ) pyridin -2- yl )-4-( quinolin -6- yl ) pyrimidin -2- amine

遵循一般程序-3,自中間物2 (400 mg, 1.54 mmol)及中間物11 (296 mg, 1.54 mmol)合成標題化合物。在後處理後,藉由combi-flash使用甲醇及DCM (8:92)作為溶析液純化粗產物,在用二乙醚(5 mL)洗滌後獲得呈黃色固體之標題化合物(150 mg)。產率:23%。熔點:255℃-258℃。 1H-NMR (δ ppm, DMSO- d6, 400 MHz): 9.69 (s, 1H), 9.00 (dd, J  4.0, 2.8, 1H), 8.70 (s, 1H), 8.67 (d, J  3.6, 1H), 8.55 (d, J  8.8, 1H), 8.43 (d, J  8.8, 1H), 8.19 (d, J  9.2, 1H), 8.12 (d, J  9.2, 1H), 8.01 (d, J  2.8, 1H), 7.62 (dd, J  8.4, 4.0, 1H), 7.45 (dd, J  9.2, 2.8, 1H), 3.30-3.22 (m, 4H), 3.15-3.10(m, 4H), 2.25 (s, 3H)。MS (m/z):416.44 (M+H);[C 23H 22FN 7+H]計算值:416.20。 實例 6A 5- -N-(5-(4- 甲基六氫吡嗪 -1- ) 吡啶 -2- )-4-( 喹啉 -6- ) 嘧啶 -2- 胺鹽酸鹽: The title compound was synthesized from Intermediate 2 (400 mg, 1.54 mmol) and Intermediate 11 (296 mg, 1.54 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (8:92) as eluents to afford the title compound (150 mg) as a yellow solid after washing with diethyl ether (5 mL). Yield: 23%. Melting point: 255°C-258°C. 1 H-NMR (δ ppm, DMSO- d 6, 400 MHz): 9.69 (s, 1H), 9.00 (dd, J 4.0, 2.8, 1H), 8.70 (s, 1H), 8.67 (d, J 3.6, 1H), 8.55 (d, J 8.8, 1H), 8.43 (d, J 8.8, 1H), 8.19 (d, J 9.2, 1H), 8.12 (d, J 9.2, 1H), 8.01 (d, J 2.8, 1H), 7.62 (dd, J 8.4, 4.0, 1H), 7.45 (dd, J 9.2, 2.8, 1H), 3.30-3.22 (m, 4H), 3.15-3.10(m, 4H), 2.25 (s, 3H ). MS (m/z): 416.44 (M+H) ; Calcd. for [ C23H22FN7 +H]: 416.20 . Example 6A 5- fluoro -N-(5-(4- methylhexahydropyrazin- 1 -yl ) pyridin -2- yl )-4-( quinolin -6- yl ) pyrimidin -2- amine hydrochloride :

使5-氟-N-(5-(4-甲基六氫吡嗪-1-基)吡啶-2-基)-4-(喹啉-6-基)嘧啶-2-胺(實例6) (120 mg, 0.29 mmol)懸浮於甲醇(2.5 ml)中且添加35%鹽酸水溶液(105 mg, 2.9 mmol),短暫獲得澄清溶液,之後固體沈澱。 將此混合物在室溫下攪拌30 min。過濾固體,用甲醇(2 ml)洗滌並乾燥,獲得呈黃色固體之標題化合物(80 mg)。產率:61%。熔點:272℃-274℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 11.76 (br. s, 1H), 11.47 (br. s, 1H), 9.19 (br. s, 1H), 8.98-8.82 (m, 3H), 8.54 (d, J  8.4, 1H), 8.18 (d, J  9.2, 1H), 8.04 (s, 1H), 8.04 (s, 1H), 7.86-7.81 (m, 2H), 3.85 (d, J  11.6, 2H), 3.52 (d, J  10.4, 1H), 3.32-3.10 (m, 4H), 2.80 (s, 3H)。MS (m/z):416.46 (M+H);[C 23H 22FN 7+H]計算值:416.20。 實例 7 5- -4-(8- 氟喹啉 -6- )-N-(5-(4- 甲基六氫吡嗪 -1- ) 吡啶 -2- ) 嘧啶 -2- Make 5-fluoro-N-(5-(4-methylhexahydropyrazin-1-yl)pyridin-2-yl)-4-(quinolin-6-yl)pyrimidin-2-amine (example 6) (120 mg, 0.29 mmol) was suspended in methanol (2.5 ml) and 35% aqueous hydrochloric acid (105 mg, 2.9 mmol) was added, briefly obtaining a clear solution before a solid precipitated. This mixture was stirred at room temperature for 30 min. The solid was filtered, washed with methanol (2 ml) and dried to give the title compound (80 mg) as a yellow solid. Yield: 61%. Melting point: 272°C-274°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 11.76 (br. s, 1H), 11.47 (br. s, 1H), 9.19 (br. s, 1H), 8.98-8.82 (m, 3H), 8.54 (d, J 8.4, 1H), 8.18 (d, J 9.2, 1H), 8.04 (s, 1H), 8.04 (s, 1H), 7.86-7.81 (m, 2H), 3.85 (d, J 11.6, 2H), 3.52 (d, J 10.4, 1H), 3.32-3.10 (m, 4H), 2.80 (s, 3H). MS (m/z): 416.46 (M+H); Calcd. for [ C23H22FN7 +H]: 416.20 . Example 7 5- fluoro - 4-(8- fluoroquinolin- 6- yl )-N-(5-(4- methylhexahydropyrazin- 1 -yl ) pyridin -2- yl ) pyrimidin -2- amine

遵循一般程序-3,自中間物7 (500 mg, 1.8 mmol)及中間物11 (350 mg, 1.8 mmol)合成標題化合物。在後處理後,藉由combi-flash使用甲醇及DCM (9:91)作為溶析液純化粗產物,在用二乙醚(5 mL)洗滌後獲得呈黃色固體之標題化合物(290 mg)。產率:34%。熔點:244℃-246℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 9.83 (s, 1H), 9.06 (d, J  2.8, 1H), 8.72 (d, J  3.6, 1H), 8.67 (d, J  8.4, 1H), 8.56 (s, 1H), 8.20 (d, J  8.0, 1H), 8.07-8.00 (m, 2H), 7.74 (dd, J  8.4, 4.4, 1H), 7.47 (dd, J  9.2, 2.8, 1H), 3.18-3.09 (m, 4H), 2.40-2.55 (m, 4H), 2.23 (s, 3H)。MS (m/z):434.43 (M+H);[C 23H 22F 2N 7+H]計算值:434.19。 實例 7A 5- -4-(8- 氟喹啉 -6- )-N-(5-(4- 甲基六氫吡嗪 -1- ) 吡啶 -2- ) 嘧啶 -2- 胺鹽酸鹽: The title compound was synthesized from Intermediate 7 (500 mg, 1.8 mmol) and Intermediate 11 (350 mg, 1.8 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (9:91 ) as eluents to afford the title compound (290 mg) as a yellow solid after washing with diethyl ether (5 mL). Yield: 34%. Melting point: 244°C-246°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.83 (s, 1H), 9.06 (d, J 2.8, 1H), 8.72 (d, J 3.6, 1H), 8.67 (d, J 8.4 , 1H), 8.56 (s, 1H), 8.20 (d, J 8.0, 1H), 8.07-8.00 (m, 2H), 7.74 (dd, J 8.4, 4.4, 1H), 7.47 (dd, J 9.2, 2.8 , 1H), 3.18-3.09 (m, 4H), 2.40-2.55 (m, 4H), 2.23 (s, 3H). MS (m/z): 434.43 (M+H); Calcd. for [ C23H22F2N7 + H]: 434.19 . Example 7A 5- fluoro - 4-(8- fluoroquinolin- 6- yl )-N-(5-(4- methylhexahydropyrazin- 1 -yl ) pyridin -2- yl ) pyrimidin -2- amine Hydrochloride:

使5-氟-4-(8-氟喹啉-6-基)-N-(5-(4-甲基六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺(實例7) (280 mg, 0.65 mmol)懸浮於甲醇(7.3 ml)中且添加35%鹽酸水溶液(240 mg, 6.5 mmol),在此期間混合物短暫變成澄清溶液且立即形成沈澱物。將異質混合物在室溫下攪拌30 min。過濾固體,相繼用甲醇(3 ml)及二乙醚(15 ml)洗滌並乾燥,獲得呈黃色固體之標題化合物(240 mg)。產率:79%。熔點:286℃-288℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 11.83 (br. s, 1H), 11.44 (br. s, 1H), 9.09 (d, J  4.0, 1H), 8.95 (d, J  3.2, 1H), 8.71 (d, J  8.0, 1H), 8.61 (s, 1H), 8.24-8.17 (m, 2H), 8.01 (d, J  2.0, 1H), 7.84 (d, J  9.6, 1H), 7.78 (dd, J  8.4, 4.0, 1H), 3.90-3.82 (m, 2H), 3.54-3.49 (m, 2H), 3.30-3.10 (m, 4H), 2.80 (d, J  4.0, 3H)。MS (m/z):434.42 (M+H-HCl);[C 23H 21F 2N 7.HCl+H-HCl]計算值:434.19。 實例 8 N-(5-(4- 乙基六氫吡嗪 -1- ) 吡啶 -2- )-5- -4-(8- 氟喹啉 -6- ) 嘧啶 -2- Make 5-fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(4-methylhexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine ( Example 7) (280 mg, 0.65 mmol) was suspended in methanol (7.3 ml) and 35% aqueous hydrochloric acid (240 mg, 6.5 mmol) was added, during which time the mixture became a clear solution briefly and a precipitate formed immediately. The heterogeneous mixture was stirred at room temperature for 30 min. The solid was filtered, washed successively with methanol (3 ml) and diethyl ether (15 ml) and dried to give the title compound (240 mg) as a yellow solid. Yield: 79%. Melting point: 286°C-288°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 11.83 (br. s, 1H), 11.44 (br. s, 1H), 9.09 (d, J 4.0, 1H), 8.95 (d, J 3.2, 1H), 8.71 (d, J 8.0, 1H), 8.61 (s, 1H), 8.24-8.17 (m, 2H), 8.01 (d, J 2.0, 1H), 7.84 (d, J 9.6, 1H) , 7.78 (dd, J 8.4, 4.0, 1H), 3.90-3.82 (m, 2H), 3.54-3.49 (m, 2H), 3.30-3.10 (m, 4H), 2.80 (d, J 4.0, 3H). MS (m/z): 434.42 (M+H-HCl); Calcd. for [ C23H21F2N7.HCl + H-HCl]: 434.19 . Example 8 N-(5-(4- ethylhexahydropyrazin- 1 -yl ) pyridin -2- yl )-5- fluoro - 4-(8- fluoroquinolin- 6- yl ) pyrimidin -2- amine

遵循一般程序-3,自中間物7 (400 mg, 1.4 mmol)及中間物20 (300 mg, 1.5 mmol)合成標題化合物。在後處理後,藉由combi-flash使用甲醇及DCM (7:93)作為溶析液純化粗產物,在用二乙醚(5 mL)洗滌後獲得呈黃色固體之標題化合物(350 mg)。產率:54%。熔點:254℃-256℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 9.06 (d, J  2.8, 1H), 8.70 (d, J  3.6, 1H), 8.64 (d, J  8.4, 1H), 8.55 (s, 1H), 8.20 (d, J  11.6, 1H), 8.05 (d, J  9.2, 1H), 8.01 (d, J  2.4, 2H), 7.72 (dd, J  8.4, 4.4, 1H), 7.46 (dd, J  9.2, 3.2, 1H), 4.04 (s, 4H), 3.15-3.08 (m, 4H), 2.38 (q, J  7.2, 2H), 1.03 (t, J  7.2, 2H)。MS (m/z):448.43 (M+H);[C 23H 21F 2N 7+H]計算值:448.21。 實例 8A N-(5-(4- 乙基六氫吡嗪 -1- ) 吡啶 -2- )-5- -4-(8- 氟喹啉 -6- ) 嘧啶 -2- 胺鹽酸鹽: The title compound was synthesized from Intermediate 7 (400 mg, 1.4 mmol) and Intermediate 20 (300 mg, 1.5 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (7:93) as eluents to afford the title compound (350 mg) as a yellow solid after washing with diethyl ether (5 mL). Yield: 54%. Melting point: 254°C-256°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.06 (d, J 2.8, 1H), 8.70 (d, J 3.6, 1H), 8.64 (d, J 8.4, 1H), 8.55 (s , 1H), 8.20 (d, J 11.6, 1H), 8.05 (d, J 9.2, 1H), 8.01 (d, J 2.4, 2H), 7.72 (dd, J 8.4, 4.4, 1H), 7.46 (dd, J 9.2, 3.2, 1H), 4.04 (s, 4H), 3.15-3.08 (m, 4H), 2.38 (q, J 7.2, 2H), 1.03 (t, J 7.2, 2H). MS (m/z): 448.43 (M+H); Calcd. for [ C23H21F2N7 + H]: 448.21 . Example 8A N-(5-(4- ethylhexahydropyrazin- 1 -yl ) pyridin -2- yl )-5- fluoro - 4-(8- fluoroquinolin- 6- yl ) pyrimidin -2- amine Hydrochloride:

使N-(5-(4-乙基六氫吡嗪-1-基)吡啶-2-基)-5-氟-4-(8-氟喹啉-6-基)嘧啶-2-胺(實例8) (210 mg, 0.47 mmol)懸浮於甲醇(5.3 ml)中且添加35%鹽酸水溶液(170 mg, 4.7 mmol),在此期間混合物變成澄清溶液。將混合物在室溫下攪拌30 min。添加甲基第三丁基醚(24 ml)且在室溫下攪拌1 h。過濾沈澱固體,用甲基第三丁基醚(15 ml)洗滌並乾燥,獲得呈黃色固體之標題化合物(165 mg)。產率:79%。熔點:273℃-275℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 11.87 (s, 1H), 11.40 (br. s, 1H), 9.09 (br. s, 1H), 8.95 (s, 1H), 8.70 (d, J  7.2, 1H), 8.61 (s, 1H), 8.27-8.06 (m, 2H), 8.02 (s, 1H), 7.84 (d, J  9.2, 1H), 7.78 (dd, J  8.4, 4.4, 1H), 3.90-3.80 (m,  2H), 3.62-3.55 (m, 2H), 3.34-3.22 (m, 2H), 3.20-3.02 (m, 4H), 1.30 (t, J  7.2, 3H)。MS (m/z):448.43 (M+H-HCl);[C 24H 23F 2N 7.HCl+H-HCl]計算值:448.21。 實例 9 N-(5-((4- 乙基六氫吡嗪 -1- ) 甲基 ) 吡啶 -2- )-5- -4-(8- -2- 甲基喹啉 -6- ) 嘧啶 -2- Make N-(5-(4-ethylhexahydropyrazin-1-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-amine ( Example 8) (210 mg, 0.47 mmol) was suspended in methanol (5.3 ml) and 35% aqueous hydrochloric acid (170 mg, 4.7 mmol) was added during which time the mixture became a clear solution. The mixture was stirred at room temperature for 30 min. Methyl tert-butyl ether (24 ml) was added and stirred at room temperature for 1 h. The precipitated solid was filtered, washed with methyl tert-butyl ether (15 ml) and dried to give the title compound (165 mg) as a yellow solid. Yield: 79%. Melting point: 273°C-275°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 11.87 (s, 1H), 11.40 (br. s, 1H), 9.09 (br. s, 1H), 8.95 (s, 1H), 8.70 (d, J 7.2, 1H), 8.61 (s, 1H), 8.27-8.06 (m, 2H), 8.02 (s, 1H), 7.84 (d, J 9.2, 1H), 7.78 (dd, J 8.4, 4.4 , 1H), 3.90-3.80 (m, 2H), 3.62-3.55 (m, 2H), 3.34-3.22 (m, 2H), 3.20-3.02 (m, 4H), 1.30 (t, J 7.2, 3H). MS (m/z): 448.43 (M+H-HCl); Calcd. for [ C24H23F2N7.HCl + H - HCl]: 448.21 . Example 9 N-(5-((4- ethylhexahydropyrazin- 1 -yl ) methyl ) pyridin -2- yl )-5- fluoro - 4-(8- fluoro -2 - methylquinoline- 6- yl ) pyrimidin -2- amine

遵循一般程序-3,自中間物23 (400 mg, 1.4 mmol)及中間物9 (300 mg, 1.4 mmol)合成標題化合物。在後處理後,藉由combi-flash使用甲醇及DCM (7.4:92.6)作為溶析液純化粗產物,獲得呈黃色固體之標題化合物(120 mg)。產率:18%。熔點:203℃-205℃。1H-NMR (δ ppm, DMSO- d6, 400 MHz): 10.10 (s, 1H), 8.77 (d, J  3.6, 1H), 8.56-8.51 (m, 2H), 8.22-8.16 (m, 3H), 7.72 (dd, J  8.4, 2.0, 1H), 7.62 (d, J  8.8, 1H), 3.44 (s, 2H), 2.73 (s, 3H), 2.30-2.60 (m, 10H), 0.98 (t, J  7.2, 3H)。MS (m/z):476.22 (M+H);[C 26H 27F 2N 7+ H]計算值:476.23。 實例 9A N-(5-((4- 乙基六氫吡嗪 -1- ) 甲基 ) 吡啶 -2- )-5- -4-(8- -2- 甲基喹啉 -6- ) 嘧啶 -2- 胺鹽酸鹽 The title compound was synthesized from Intermediate 23 (400 mg, 1.4 mmol) and Intermediate 9 (300 mg, 1.4 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (7.4:92.6) as eluents to obtain the title compound (120 mg) as a yellow solid. Yield: 18%. Melting point: 203°C-205°C. 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 10.10 (s, 1H), 8.77 (d, J 3.6, 1H), 8.56-8.51 (m, 2H), 8.22-8.16 (m, 3H) , 7.72 (dd, J 8.4, 2.0, 1H), 7.62 (d, J 8.8, 1H), 3.44 (s, 2H), 2.73 (s, 3H), 2.30-2.60 (m, 10H), 0.98 (t, J 7.2, 3H). MS (m/z): 476.22 (M+H); Calcd. for [ C26H27F2N7 + H]: 476.23 . Example 9A N-(5-((4- ethylhexahydropyrazin- 1 -yl ) methyl ) pyridin -2- yl )-5- fluoro - 4-(8- fluoro -2 - methylquinoline- 6- yl ) pyrimidin -2- amine hydrochloride

使N-(5-((4-乙基六氫吡嗪-1-基)甲基)吡啶-2-基)-5-氟-4-(8-氟-2-甲基喹啉-6-基)嘧啶-2-胺(實例9,120 mg, 0.25 mmol)懸浮於甲醇(3 ml)中且添加35%鹽酸水溶液(92 mg, 2.5 mmol),獲得澄清溶液。將此混合物在室溫下攪拌30 min。濃縮該混合物,將殘餘物溶解於水(20 ml)中且用DCM-MeOH 9:1 (3*50 ml)洗滌。使水層蒸發,且使殘餘固體與水一起共蒸發,獲得呈黃色固體之標題化合物(15 mg)。產率:12%。熔點:257℃-259℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 12.02 (br. s, 1H), 11.51 (br. s, 1H), 8.91 (d, J  2.4, 1H), 8.67-8.54 (m, 3H), 8.40-8.30 (m, 1H), 8.20 (d, J  12.0, 1H), 8.40-8.12 (m, 1H), 7.65 (d, J  8.8, 1H), 4.47 (br. s, 2H), 3.80-3.35 (m, 8H), 3.17 (br. s, 2H), 2.74 (s, 3H), 1.25 (t, J  7.2, 3H)。MS (m/z):475.3 (M+H);[C 26H 27F 2N 7+ H]計算值:476.2。 實例 10 4-(6-((5- -4-(8- -2- 甲基喹啉 -6- ) 嘧啶 -2- ) 胺基 ) 吡啶 -3- ) 六氫吡嗪 -1- 甲酸第三丁基酯 Make N-(5-((4-ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-2-methylquinoline-6 -yl)pyrimidin-2-amine (Example 9, 120 mg, 0.25 mmol) was suspended in methanol (3 ml) and 35% aqueous hydrochloric acid (92 mg, 2.5 mmol) was added to obtain a clear solution. This mixture was stirred at room temperature for 30 min. The mixture was concentrated, the residue was dissolved in water (20 ml) and washed with DCM-MeOH 9:1 (3*50 ml). The aqueous layer was evaporated and the residual solid was co-evaporated with water to give the title compound (15 mg) as a yellow solid. Yield: 12%. Melting point: 257°C-259°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 12.02 (br. s, 1H), 11.51 (br. s, 1H), 8.91 (d, J 2.4, 1H), 8.67-8.54 (m , 3H), 8.40-8.30 (m, 1H), 8.20 (d, J 12.0, 1H), 8.40-8.12 (m, 1H), 7.65 (d, J 8.8, 1H), 4.47 (br. s, 2H) , 3.80-3.35 (m, 8H), 3.17 (br. s, 2H), 2.74 (s, 3H), 1.25 (t, J 7.2, 3H). MS (m/z): 475.3 (M+H) ; Calcd. for [ C26H27F2N7 + H]: 476.2 . Example 10 4-(6-((5- fluoro - 4-(8- fluoro -2 -methylquinolin -6- yl ) pyrimidin -2- yl ) amino ) pyridin - 3 -yl ) hexahydropyrazine -3 -Butyl 1-carboxylate

遵循一般程序-3,自中間物23 (500 mg, 1.7 mmol)及中間物5 (480 mg, 1.7 mmol)合成標題化合物。在後處理後,藉由combi-flash使用甲醇及DCM (7.8:92.2)作為溶析液純化粗產物,獲得呈黃色固體之標題化合物(100 mg)。產率:11%。 1H-NMR (δ ppm, CDCl 3, 400 MHz): 8.46 (d, J  3.6, 1H), 8.41 (br. s, 1H), 8.29 (d, J  8.8, 1H), 8.23-8.20 (m, 1H), 8.10 (s, 1H), 8.18 (d, J  1.6, 1H), 8.12 (br. s., 1H), 8.07-8.04 (m, 1H), 7.44 (d, J  8.4, 1H), 7.40 (dd, J  8.8, 2.8, 1H), 3.61 (t, J  4.8, 4H), 3.12 (t, J  4.8, 4H), 2.85 (s, 3H), 1.50 (s, 9H)。 實例 10A 5- -4-(8- -2- 甲基喹啉 -6- )-N-(5-( 六氫吡嗪 -1- ) 吡啶 -2- ) 嘧啶 -2- The title compound was synthesized from Intermediate 23 (500 mg, 1.7 mmol) and Intermediate 5 (480 mg, 1.7 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (7.8:92.2) as eluents to obtain the title compound (100 mg) as a yellow solid. Yield: 11%. 1 H-NMR (δ ppm, CDCl 3 , 400 MHz): 8.46 (d, J 3.6, 1H), 8.41 (br. s, 1H), 8.29 (d, J 8.8, 1H), 8.23-8.20 (m, 1H), 8.10 (s, 1H), 8.18 (d, J 1.6, 1H), 8.12 (br. s., 1H), 8.07-8.04 (m, 1H), 7.44 (d, J 8.4, 1H), 7.40 (dd, J 8.8, 2.8, 1H), 3.61 (t, J 4.8, 4H), 3.12 (t, J 4.8, 4H), 2.85 (s, 3H), 1.50 (s, 9H). Example 10A 5- fluoro - 4-(8- fluoro -2 -methylquinolin -6- yl )-N-(5-( hexahydropyrazin- 1 -yl ) pyridin -2- yl ) pyrimidine -2- amine

遵循一般程序-4,自4-(6-((5-氟-4-(8-氟-2-甲基喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-1-甲酸第三丁基酯(實例10,90 mg, 0.17 mmol)合成呈褐色固體之標題化合物(55 mg)。產率:75%。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 9.78 (s, 1H), 8.70 (d, J  3.6, 1H), 8.55-8.48 (m, 2H),  8.16 (d, J  11.6, 1H), 8.03 (d, J  9.2, 1H), 7.99 (d, J  2.4, 1H), 7.62 (d, J  8.4, 1H), 7.45 (dd, J  8.8, 2.8, 1H), 3.08-3.02(m, 4H), 2.88-2.81 (m, 4H), 2.79 (s, 3H)。 實例 10B 5- -4-(8- -2- 甲基喹啉 -6- )-N-(5-( 六氫吡嗪 -1- ) 吡啶 -2- ) 嘧啶 -2- 胺鹽酸鹽: Following general procedure-4, from 4-(6-((5-fluoro-4-(8-fluoro-2-methylquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl ) tert-butyl hexahydropyrazine-1-carboxylate (Example 10, 90 mg, 0.17 mmol) The title compound (55 mg) was synthesized as a brown solid. Yield: 75%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.78 (s, 1H), 8.70 (d, J 3.6, 1H), 8.55-8.48 (m, 2H), 8.16 (d, J 11.6, 1H), 8.03 (d, J 9.2, 1H), 7.99 (d, J 2.4, 1H), 7.62 (d, J 8.4, 1H), 7.45 (dd, J 8.8, 2.8, 1H), 3.08-3.02(m , 4H), 2.88-2.81 (m, 4H), 2.79 (s, 3H). Example 10B 5- fluoro - 4-(8- fluoro -2 -methylquinolin -6- yl )-N-(5-( hexahydropyrazin- 1 -yl ) pyridin -2- yl ) pyrimidine -2- Amine hydrochloride:

使5-氟-4-(8-氟-2-甲基喹啉-6-基)-N-(5-(六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺(實例10A,42 mg, 0.097 mmol)懸浮於甲醇(2 ml)中且添加35%鹽酸水溶液(35 mg, 0.97 mmol),獲得澄清溶液。 將此混合物在室溫下攪拌30 min。在真空下去除溶劑,之後與甲苯一起共蒸發,得到呈黃色固體之標題化合物(25 mg)。產率:85%。熔點:220℃-222℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 11.78 (br. s, 1H), 9.56 (br. s, 2H), 8.91 (s, 1H), 8.61-8.51 (m, 2H), 8.22-8.12 (m, 2H), 8.00 (s, 1H), 7.83 (d, J  9.6, 1H), 7.65 (d, J  8.4, 1H), 3.50-3.40 (m, 4H), 3.29-3.20 (m, 4H), 2.74 (s, 3H)。MS (m/z):434.46 (M+H);[C 23H 21F 2N 7+ H]計算值:434.19。 實例 11 4-(6-((5- -4-(8- -4- 異丙基 -2- 甲基喹啉 -6- ) 嘧啶 -2- ) 胺基 ) 吡啶 -3- ) 六氫吡嗪 -1- 甲酸第三丁基酯 Make 5-fluoro-4-(8-fluoro-2-methylquinolin-6-yl)-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine (Example 10A, 42 mg, 0.097 mmol) was suspended in methanol (2 ml) and 35% aqueous hydrochloric acid (35 mg, 0.97 mmol) was added to obtain a clear solution. This mixture was stirred at room temperature for 30 min. The solvent was removed in vacuo followed by co-evaporation with toluene to give the title compound (25 mg) as a yellow solid. Yield: 85%. Melting point: 220°C-222°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 11.78 (br. s, 1H), 9.56 (br. s, 2H), 8.91 (s, 1H), 8.61-8.51 (m, 2H) , 8.22-8.12 (m, 2H), 8.00 (s, 1H), 7.83 (d, J 9.6, 1H), 7.65 (d, J 8.4, 1H), 3.50-3.40 (m, 4H), 3.29-3.20 ( m, 4H), 2.74 (s, 3H). MS (m/z): 434.46 (M+H); Calcd. for [ C23H21F2N7 + H]: 434.19 . Example 11 4-(6-((5- fluoro - 4-(8- fluoro - 4 - isopropyl- 2 -methylquinolin -6- yl ) pyrimidin -2- yl ) amino ) pyridine - 3- base ) tert-butyl hexahydropyrazine- 1 -carboxylate

向4-(6-((5-氟-4-(8-氟-2-甲基-4-(丙-1-烯-2-基)喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-1-甲酸第三丁基酯(實例5,160 mg, 0.261 mmol)於甲醇與EtOAc之3:2混合物(15 ml)中之溶液中添加 碳載20%氫氧化鈀,且使混合物在 8 kg/cm 2之氫壓下在室溫下氫化64 h。 用DCM-甲醇(9:1, 50 ml)稀釋該混合物且經由矽藻土床過濾,用DCM-甲醇(9:1, 150 ml)洗滌該床。使合併的濾液蒸發,得到粗產物。 藉由combi-flash層析系統使用甲醇及DCM (1.8:98.2)作為溶析液進行純化,得到呈綠色固體之標題化合物(100 mg)。產率:66%。熔點:178℃-180℃。 1H-NMR (δ ppm, CDCl 3, 400 MHz): 8.72 (s, 1H), 8.46 (d, J  3.6, 1H), 8.31 (d, J  9.2, 1H), 8.15 (d, J  12.8, 1H), 8.08-8.03 (m, 2H), 7.37 (dd, J  9.2, 2.8, 1H), 7.33 (s, 1H), 3.77 (七重峰,J = 6.8, 1H), 3.67-3.59 (m, 4H), 3.15-3.08 (m, 4H), 2.82 (s, 3H), 1.50 (s, 9H), 1.46 (d, J  6.8, 6H)。MS (m/z):576.29 (M+H);[C 31H 35F 2N 7O 2+ H]計算值:576.29。 實例 11A 5- -4-(8- -4- 異丙基 -2- 甲基喹啉 -6- )-N-(5-( 六氫吡嗪 -1- ) 吡啶 -2- ) 嘧啶 -2- To 4-(6-((5-fluoro-4-(8-fluoro-2-methyl-4-(prop-1-en-2-yl) quinoline-6-yl)pyrimidin-2-yl) To a solution of amino)pyridin-3-yl)hexahydropyrazine-1-carboxylic acid tert-butyl ester (Example 5, 160 mg, 0.261 mmol) in a 3:2 mixture of methanol and EtOAc (15 ml) was added 20% palladium hydroxide was supported on carbon, and the mixture was hydrogenated under a hydrogen pressure of 8 kg/ cm2 at room temperature for 64 h. The mixture was diluted with DCM-methanol (9:1, 50 ml) and filtered through a bed of Celite, washing the bed with DCM-methanol (9:1, 150 ml). The combined filtrates were evaporated to give crude product. Purification by combi-flash chromatography system using methanol and DCM (1.8:98.2) as eluent gave the title compound (100 mg) as a green solid. Yield: 66%. Melting point: 178°C-180°C. 1 H-NMR (δ ppm, CDCl 3 , 400 MHz): 8.72 (s, 1H), 8.46 (d, J 3.6, 1H), 8.31 (d, J 9.2, 1H), 8.15 (d, J 12.8, 1H ), 8.08-8.03 (m, 2H), 7.37 (dd, J 9.2, 2.8, 1H), 7.33 (s, 1H), 3.77 (septet, J = 6.8, 1H), 3.67-3.59 (m, 4H) , 3.15-3.08 (m, 4H), 2.82 (s, 3H), 1.50 (s, 9H), 1.46 (d, J 6.8, 6H). MS (m/z): 576.29 (M + H); Calcd. for [ C31H35F2N7O2 + H]: 576.29 . Example 11A 5- fluoro - 4-(8- fluoro - 4 - isopropyl- 2 -methylquinolin -6- yl )-N-(5-( hexahydropyrazin- 1 -yl ) pyridine -2- base ) pyrimidin -2- amine

遵循一般程序-4,自4-(6-((5-氟-4-(8-氟-4-異丙基-2-甲基喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-1-甲酸第三丁基酯(實例11,100 mg, 0.174 mmol)合成呈黃色固體之標題化合物(60 mg)。產率:83%。熔點:217℃-219℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 9.84 (s, 1H), 8.72-8.67 (m, 2H), 8.10 (d, J  11.6, 1H), 8.07-7.97 (m, 2H), 7.53 (s, 1H), 7.40 (dd, J  9.2, 2.4, 1H), 3.75 (七重峰,J = 6.8, 1H), 3.08-3.00 (m, 4H), 2.89-2.82(m, 4H), 2.71 (s, 3H), 1.38 (d, J  6.8, 6H)。 實例 11B 5- -4-(8- -4- 異丙基 -2- 甲基喹啉 -6- )-N-(5-( 六氫吡嗪 -1- ) 吡啶 -2- ) 嘧啶 -2- 胺鹽酸鹽 Following general procedure-4, from 4-(6-((5-fluoro-4-(8-fluoro-4-isopropyl-2-methylquinolin-6-yl)pyrimidin-2-yl)amino )pyridin-3-yl)pyrazine-1-carboxylic acid tert-butyl ester (Example 11, 100 mg, 0.174 mmol) The title compound (60 mg) was synthesized as a yellow solid. Yield: 83%. Melting point: 217°C-219°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.84 (s, 1H), 8.72-8.67 (m, 2H), 8.10 (d, J 11.6, 1H), 8.07-7.97 (m, 2H ), 7.53 (s, 1H), 7.40 (dd, J 9.2, 2.4, 1H), 3.75 (septet, J = 6.8, 1H), 3.08-3.00 (m, 4H), 2.89-2.82(m, 4H) , 2.71 (s, 3H), 1.38 (d, J 6.8, 6H). Example 11B 5- fluoro - 4-(8- fluoro - 4 - isopropyl- 2 -methylquinolin -6- yl )-N-(5-( hexahydropyrazin- 1 -yl ) pyridine -2- base ) pyrimidin -2- amine hydrochloride :

使5-氟-4-(8-氟-4-異丙基-2-甲基喹啉-6-基)-N-(5-(六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺(實例11A) (55 mg, 0.12 mmol)懸浮於甲醇(1.1 ml)中且添加35%鹽酸水溶液(42 mg, 1.2 mmol),獲得澄清溶液。 將此混合物在室溫下攪拌30 min。在真空下去除溶劑且與甲苯一起共蒸發,得到呈淡綠色固體之標題化合物(40 mg)。產率:67%。熔點:245℃-247℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 11.77 (br. s, 1H), 9.54 (br. s, 2H), 8.91 (d, J  2.4, 1H), 8.70 (s, 1H), 8.20-8.10 (m, 2H), 7.99 (s, 1H), 7.85 (d, J  9.6, 1H), 7.59 (s, 1H), 3.76 (七重峰,J  6.8, 1H), 3.25 (br. s, 4H), 3.15 (br. s, 4H), 2.73 (s, 3H), 1.38 (d, J = 6.8, 3H)。MS (m/z):476.3 (M+H);[C 26H 27F 2N 7+ H]計算值:476.2。 實例 12 N-(5-(4- 乙基六氫吡嗪 -1- ) 吡啶 -2- )-5- -4-( 喹啉 -6- ) 嘧啶 -2- Make 5-fluoro-4-(8-fluoro-4-isopropyl-2-methylquinolin-6-yl)-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl ) pyrimidin-2-amine (Example 11A) (55 mg, 0.12 mmol) was suspended in methanol (1.1 ml) and 35% aqueous hydrochloric acid (42 mg, 1.2 mmol) was added to obtain a clear solution. This mixture was stirred at room temperature for 30 min. The solvent was removed in vacuo and co-evaporated with toluene to give the title compound (40 mg) as a light green solid. Yield: 67%. Melting point: 245°C-247°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 11.77 (br. s, 1H), 9.54 (br. s, 2H), 8.91 (d, J 2.4, 1H), 8.70 (s, 1H ), 8.20-8.10 (m, 2H), 7.99 (s, 1H), 7.85 (d, J 9.6, 1H), 7.59 (s, 1H), 3.76 (septet, J 6.8, 1H), 3.25 (br. s, 4H), 3.15 (br. s, 4H), 2.73 (s, 3H), 1.38 (d, J = 6.8, 3H). MS (m/z): 476.3 (M+H); Calcd. for [ C26H27F2N7 + H]: 476.2 . Example 12 N-(5-(4- ethylhexahydropyrazin- 1 -yl ) pyridin -2- yl )-5- fluoro - 4-( quinolin -6- yl ) pyrimidin -2- amine

遵循一般程序-3,自中間物2 (500 mg, 1.93 mmol)及中間物20 (397 mg, 1.93 mmol)合成標題化合物。在後處理後,藉由combi-flash使用甲醇及DCM (5.6:94.4)作為溶析液純化粗產物。使彙集之溶離份蒸發,且將殘餘物與二乙醚(10 mL)一起攪拌30 min,過濾,用二乙醚(5 mL)洗滌並乾燥,獲得呈黃色固體之標題化合物(45 mg)。產率:5.4%。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 9.78 (s, 1H), 9.01 (dd, J 4.0, 2.0, 1H), 8.72-8.68 (m, 2H), 8.57 (d, J 8.4, 1H), 8.41 (d, J 8.8, 1H), 8.19 (d, J 9.2, 1H), 8.08 (d, J 9.2, 1H), 8.01 (d, J 2.8, 1H), 7.63 (dd, J 8.4, 4.0, 1H), 7.47 (dd, J 8.8, 3.2, 1H), 3.18-3.10 (m, 4H), 2.60-2.35 (m, 10H), 1.04 (t, J 7.2, 3H)。MS (m/z):430.44 (M+H);[C 24H 24FN 7+ H]計算值:430.22。 實例 12A N-(5-(4- 乙基六氫吡嗪 -1- ) 吡啶 -2- )-5- -4-( 喹啉 -6- ) 嘧啶 -2- 胺鹽酸鹽 The title compound was synthesized from Intermediate 2 (500 mg, 1.93 mmol) and Intermediate 20 (397 mg, 1.93 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (5.6:94.4) as eluents. The pooled fractions were evaporated and the residue was stirred with diethyl ether (10 mL) for 30 min, filtered, washed with diethyl ether (5 mL) and dried to give the title compound (45 mg) as a yellow solid. Yield: 5.4%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.78 (s, 1H), 9.01 (dd, J 4.0, 2.0, 1H), 8.72-8.68 (m, 2H), 8.57 (d, J 8.4, 1H), 8.41 (d, J 8.8, 1H), 8.19 (d, J 9.2, 1H), 8.08 (d, J 9.2, 1H), 8.01 (d, J 2.8, 1H), 7.63 (dd, J 8.4, 4.0, 1H), 7.47 (dd, J 8.8, 3.2, 1H), 3.18-3.10 (m, 4H), 2.60-2.35 (m, 10H), 1.04 (t, J 7.2, 3H). MS (m/z): 430.44 (M+H); Calcd. for [ C24H24FN7 +H]: 430.22 . Example 12A N-(5-(4- ethylhexahydropyrazin- 1 -yl ) pyridin -2- yl )-5- fluoro - 4-( quinolin -6- yl ) pyrimidin -2- amine hydrochloride

向5-氟-N-(5-(六氫吡嗪-1-基)吡啶-2-基)-4-(喹啉-3-基)嘧啶-2-胺(實例12,35 mg, 0.08 mmol)於甲醇(2 mL)中之混合物中添加35%鹽酸水溶液(30 mg, 0.81 mmol),且將混合物在室溫下攪拌30 min。過濾所形成之固體,用二乙醚(5 mL)洗滌且在真空下乾燥,得到呈黃色固體之標題化合物(17 mg)。產率:44%。熔點:291℃-294℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 11.65 (bs, 1H), 11.20 (bs, 1H), 9.15 (bs, 1H), 8.93 (d, J 3.2, 1H), 8.83 (bs, 2H), 8.50 (d, J 9.2, 1H), 8.35 (d, J 9.2, 1H), 8.15 (d, J 8.4, 1H), 8.03 (d, J 2.8, 1H), 7.88-7.78 (m, 2H), 3.85 (d, J 12.4, 2H), 3.59 (d, J 12.0, 2H), 3.32-3.05 (m, 6H), 1.30 (t, J 7.2, 3H)。MS (m/z):430.44 (M+H);[C 24H 24FN 7+H]計算值:430.22。 實例 13 5- -4-(8- 氟喹啉 -6- )-N-(5-(4- 異丙基六氫吡嗪 -1- ) 吡啶 -2- ) 嘧啶 -2- To 5-fluoro-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)-4-(quinolin-3-yl)pyrimidin-2-amine (Example 12, 35 mg, 0.08 mmol) in methanol (2 mL) was added 35% aqueous hydrochloric acid (30 mg, 0.81 mmol), and the mixture was stirred at room temperature for 30 min. The solid formed was filtered, washed with diethyl ether (5 mL) and dried under vacuum to give the title compound (17 mg) as a yellow solid. Yield: 44%. Melting point: 291°C-294°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 11.65 (bs, 1H), 11.20 (bs, 1H), 9.15 (bs, 1H), 8.93 (d, J 3.2, 1H), 8.83 ( bs, 2H), 8.50 (d, J 9.2, 1H), 8.35 (d, J 9.2, 1H), 8.15 (d, J 8.4, 1H), 8.03 (d, J 2.8, 1H), 7.88-7.78 (m , 2H), 3.85 (d, J 12.4, 2H), 3.59 (d, J 12.0, 2H), 3.32-3.05 (m, 6H), 1.30 (t, J 7.2, 3H). MS (m/z): 430.44 (M+H); Calcd. for [ C24H24FN7 +H]: 430.22 . Example 13 5- fluoro - 4-(8- fluoroquinolin- 6- yl )-N-(5-(4- isopropylhexahydropyrazin- 1 -yl ) pyridin -2- yl ) pyrimidine -2- amine

遵循一般程序-3,自中間物7 (500 mg, 1.80 mmol)及中間物25 (397 mg, 1.80 mmol)合成標題化合物。在後處理後,藉由combi-flash使用甲醇及DCM (8:92)作為溶析液純化粗產物。使彙集之溶離份蒸發,且將殘餘物與二乙醚(10 mL)一起攪拌30 min,過濾並乾燥,獲得呈黃色固體之標題化合物(80 mg)。產率:9.6%。熔點:258℃-261℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 9.83 (s, 1H), 9.05, (dd, J 4, 1.8, 1H), 8.72 (d, J 3.6, 1H), 8.66 (d, J 8.4, 1H), 8.56 (s, 1H), 8.20 (d, J 11.6, 1H), 8.03 (d, J 8.8, 1H), 8.01 (d, J 2.8, 1H), 7.74 (dd, J 8.4, 4, 1H), 7.46 (dd, J 9.2, 2.8, 1H), 3.15-3.05 (m, 4H), 2.70-2.66 (m, 1H), 2.61-2.54 (m, 4H), 1.00 (d, J 6.4, 6H)。MS (m/z):462.44 (M+H);[C 25H 25F 2N 7+ H]計算值:462.22。 實例 13A 5- -4-(8- 氟喹啉 -6- )-N-(5-(4- 異丙基六氫吡嗪 -1- ) 吡啶 -2- ) 嘧啶 -2- 胺鹽酸鹽 The title compound was synthesized from Intermediate 7 (500 mg, 1.80 mmol) and Intermediate 25 (397 mg, 1.80 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (8:92) as eluents. The pooled fractions were evaporated and the residue was stirred with diethyl ether (10 mL) for 30 min, filtered and dried to afford the title compound (80 mg) as a yellow solid. Yield: 9.6%. Melting point: 258°C-261°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.83 (s, 1H), 9.05, (dd, J 4, 1.8, 1H), 8.72 (d, J 3.6, 1H), 8.66 (d , J 8.4, 1H), 8.56 (s, 1H), 8.20 (d, J 11.6, 1H), 8.03 (d, J 8.8, 1H), 8.01 (d, J 2.8, 1H), 7.74 (dd, J 8.4 , 4, 1H), 7.46 (dd, J 9.2, 2.8, 1H), 3.15-3.05 (m, 4H), 2.70-2.66 (m, 1H), 2.61-2.54 (m, 4H), 1.00 (d, J 6.4, 6H). MS (m/z): 462.44 (M+H); Calcd. for [ C25H25F2N7 + H]: 462.22 . Example 13A 5- fluoro - 4-(8- fluoroquinolin- 6- yl )-N-(5-(4- isopropylhexahydropyrazin- 1 -yl ) pyridin -2- yl ) pyrimidine -2- Amine hydrochloride

向5-氟-4-(8-氟喹啉-6-基)-N-(5-(4-異丙基六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺(實例13,80 mg, 0.17 mmol)於甲醇(2 mL)中之混合物中添加35%鹽酸水溶液(63 mg, 1.7 mmol)。添加10 min後,獲得澄清溶液且將混合物在室溫下攪拌30 min。在攪拌期間形成固體。將混合物用甲基第三丁基醚(5 mL)稀釋且過濾固體,用甲基第三丁基醚(10 mL)洗滌且在真空下乾燥,得到呈黃色固體之標題化合物(50 mg)。產率:58%。熔點:295℃-297℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 11.76 (s, 1H), 11.25 (s, 1H), 9.09 (dd, J 4.0, 1.6, 1H), 8.94 (d, J 3.2, 1H), 8.70 (d, J 8.4, 1H), 8.61 (s, 1H), 8.23-8.17 (m, 2H), 8.01 (d, J 2.8, 1H), 7.83 (d, J 11.2, 1H), 7.78 (dd, J 8.4, 4, 1H), 3.85 (d, J 12.4。 2H), 3.58-3.48 (m, 3H), 3.35 (t, J 11.6, 2H), 3.20-3.10 (m, 2H), 1.32 (d, J 6.4, 6H)。MS (m/z):462.2 (M+H);[C 25H 25F 2N 7+ H]計算值:462.22。 實例 14 5- -N-(5-(4- 異丙基六氫吡嗪 -1- ) 吡啶 -2- )-4-( 喹啉 -6- ) 嘧啶 -2- To 5-fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(4-isopropylhexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine (Example 13, 80 mg, 0.17 mmol) in methanol (2 mL) was added 35% aqueous hydrochloric acid (63 mg, 1.7 mmol). After 10 min of addition, a clear solution was obtained and the mixture was stirred at room temperature for 30 min. A solid formed during stirring. The mixture was diluted with methyl tert-butyl ether (5 mL) and the solid was filtered, washed with methyl tert-butyl ether (10 mL) and dried under vacuum to give the title compound (50 mg) as a yellow solid. Yield: 58%. Melting point: 295°C-297°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 11.76 (s, 1H), 11.25 (s, 1H), 9.09 (dd, J 4.0, 1.6, 1H), 8.94 (d, J 3.2, 1H), 8.70 (d, J 8.4, 1H), 8.61 (s, 1H), 8.23-8.17 (m, 2H), 8.01 (d, J 2.8, 1H), 7.83 (d, J 11.2, 1H), 7.78 (dd, J 8.4, 4, 1H), 3.85 (d, J 12.4. 2H), 3.58-3.48 (m, 3H), 3.35 (t, J 11.6, 2H), 3.20-3.10 (m, 2H), 1.32 (d, J 6.4, 6H). MS (m/z): 462.2 (M+H); Calcd. for [ C25H25F2N7 + H]: 462.22 . Example 14 5- fluoro -N-(5-(4- isopropylhexahydropyrazin- 1 -yl ) pyridin -2- yl )-4-( quinolin -6- yl ) pyrimidin -2- amine

遵循一般程序-3,自中間物2 (500 mg, 1.93 mmol)及中間物25 (424 mg, 1.93 mmol)合成標題化合物。在後處理後,藉由combi-flash使用甲醇及DCM (10:90)作為溶析液純化粗產物。使彙集之溶離份蒸發,且將殘餘物與二乙醚(10 mL)一起攪拌30 min,過濾,用二乙醚(5 mL)洗滌並乾燥,獲得呈黃色固體之標題化合物(200 mg)。產率:23.4%。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 9.72 (s, 1H), 9.04-8.93 (m, 1H), 8.68-8.64 (m, 2H), 8.53 (d, J 8, 1H), 8.40 (d, J 8.8, 1H), 8.18 (d, J 9.2, 1H), 8.10 (d, J 9.2, 1H), 8.00 (d, J 2.8, 1H), 7.61 (dd, J 8.4, 3.6, 1H), 3.18-3.05 (m, 4H), 2.71-2.55 (m, 5H), 1.02 (d, J 6.4, 6H)。MS (m/z):444.48 (M+H);[C 25H 26FN 7+ H]計算值:444.23。 實例 14A 5- -N-(5-(4- 異丙基六氫吡嗪 -1- ) 吡啶 -2- )-4-( 喹啉 -6- ) 嘧啶 -2- 胺鹽酸鹽 The title compound was synthesized from Intermediate 2 (500 mg, 1.93 mmol) and Intermediate 25 (424 mg, 1.93 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (10:90) as eluents. The pooled fractions were evaporated and the residue was stirred with diethyl ether (10 mL) for 30 min, filtered, washed with diethyl ether (5 mL) and dried to give the title compound (200 mg) as a yellow solid. Yield: 23.4%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.72 (s, 1H), 9.04-8.93 (m, 1H), 8.68-8.64 (m, 2H), 8.53 (d, J 8, 1H ), 8.40 (d, J 8.8, 1H), 8.18 (d, J 9.2, 1H), 8.10 (d, J 9.2, 1H), 8.00 (d, J 2.8, 1H), 7.61 (dd, J 8.4, 3.6 , 1H), 3.18-3.05 (m, 4H), 2.71-2.55 (m, 5H), 1.02 (d, J 6.4, 6H). MS (m/z): 444.48 (M+H) ; Calcd. for [ C25H26FN7 +H]: 444.23. Example 14A 5- fluoro -N-(5-(4- isopropylhexahydropyrazin- 1 -yl ) pyridin -2- yl )-4-( quinolin -6- yl ) pyrimidin -2- amine hydrochloride Salt

向5-氟-N-(5-(4-異丙基六氫吡嗪-1-基)吡啶-2-基)-4-(喹啉-6-基)嘧啶-2-胺(實例14,200 mg, 0.45 mmol)於甲醇(2 mL)中之混合物中添加35%鹽酸水溶液(164 mg, 4.5 mmol)。溶液在一段時間內變得澄清,且接著在攪拌期間形成固體。將混合物攪拌30 min且過濾固體,相繼用甲醇(5 mL)及二乙醚(10 mL)洗滌並在真空下乾燥,得到呈黃色固體之標題化合物(90 mg)。產率:41%。熔點:278℃-280℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 11.78 (s, 1H), 11.35 (s, 1H), 9.19 (dd, J 4.8, 1.6, 1H), 8.95 (d, J 3.2, 1H), 8.92 (d, J 8.4, 1H), 8.86 (s, 1H), 8.54 (d, J 9.2, 1H), 8.41 (d, J 9.2, 1H), 8.19 (dd, J 9.6, 2.4, 1H), 8.04 (d, J 2.4, 1H), 7.90-7.82 (m, 2H), 3.85 (d, J 13.2, 2H), 3.57-3.48 (m, 3H), 3.37 (d, J 13.2, 2H), 3.20-3.09 (m, 2H)。MS (m/z):444.47 (M+H);[C 25H 26FN 7+ H]計算值:444.23。 實例 15 5- -4-(8- 氟喹啉 -6- )-N-(5-((4- 甲基六氫吡嗪 -1- ) 甲基 ) 吡啶 -2- ) 嘧啶 -2- To 5-fluoro-N-(5-(4-isopropylhexahydropyrazin-1-yl)pyridin-2-yl)-4-(quinolin-6-yl)pyrimidin-2-amine (Example 14 , 200 mg, 0.45 mmol) in methanol (2 mL) was added 35% aqueous hydrochloric acid (164 mg, 4.5 mmol). The solution became clear over a period of time and then a solid formed during stirring. The mixture was stirred for 30 min and the solid was filtered, washed sequentially with methanol (5 mL) and diethyl ether (10 mL) and dried under vacuum to give the title compound (90 mg) as a yellow solid. Yield: 41%. Melting point: 278°C-280°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 11.78 (s, 1H), 11.35 (s, 1H), 9.19 (dd, J 4.8, 1.6, 1H), 8.95 (d, J 3.2, 1H), 8.92 (d, J 8.4, 1H), 8.86 (s, 1H), 8.54 (d, J 9.2, 1H), 8.41 (d, J 9.2, 1H), 8.19 (dd, J 9.6, 2.4, 1H ), 8.04 (d, J 2.4, 1H), 7.90-7.82 (m, 2H), 3.85 (d, J 13.2, 2H), 3.57-3.48 (m, 3H), 3.37 (d, J 13.2, 2H), 3.20-3.09 (m, 2H). MS (m/z): 444.47 (M+H) ; Calcd. for [ C25H26FN7 +H]: 444.23. Example 15 5- fluoro - 4-(8- fluoroquinolin- 6- yl )-N-(5-((4- methylhexahydropyrazin- 1 -yl ) methyl ) pyridin -2- yl ) pyrimidine -2- amine

遵循一般程序-3,自中間物7 (500 mg, 1.80 mmol)及中間物27 (371 mg, 1.80 mmol)合成標題化合物。在後處理後,藉由combi-flash使用甲醇及DCM (10:90)作為溶析液純化粗產物。使彙集之溶離份蒸發,且將殘餘物與二乙醚(10 mL)一起攪拌30 min,過濾,用二乙醚(5 mL)洗滌並乾燥,獲得呈淡綠色固體之標題化合物(150 mg)。產率:17.4%。熔點:250℃-252℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 10.17 (s, 1H), 9.06 (d, J 4, 1H), 8.80 (d, J 3.2, 1H), 8.67 (d, J 8.4, 1H), 8.58 (s, 1H), 8.22 (t, J 10.8, 1H), 7.75 (dd, J 8, 4, 1H), 3.52 (s, 2H), 3.00-2.90 (m, 4H), 2.61-2.52 (m, 4H)。MS (m/z):448.3 (M+H);[C 24H 23F 2N 7+ H]計算值:448.21 實例 15A 5- -4-(8- 氟喹啉 -6- )-N-(5-((4- 甲基六氫吡嗪 -1- ) 甲基 ) 吡啶 -2- ) 嘧啶 -2- 胺鹽酸鹽 The title compound was synthesized from Intermediate 7 (500 mg, 1.80 mmol) and Intermediate 27 (371 mg, 1.80 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (10:90) as eluents. The pooled fractions were evaporated and the residue was stirred with diethyl ether (10 mL) for 30 min, filtered, washed with diethyl ether (5 mL) and dried to give the title compound (150 mg) as a light green solid. Yield: 17.4%. Melting point: 250°C-252°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 10.17 (s, 1H), 9.06 (d, J 4, 1H), 8.80 (d, J 3.2, 1H), 8.67 (d, J 8.4 , 1H), 8.58 (s, 1H), 8.22 (t, J 10.8, 1H), 7.75 (dd, J 8, 4, 1H), 3.52 (s, 2H), 3.00-2.90 (m, 4H), 2.61 -2.52 (m, 4H). MS (m/z): 448.3 (M+H); Calcd. for [ C24H23F2N7 + H]: 448.21 Example 15A 5 - Fluoro - 4-(8- fluoroquinolin- 6- yl )- N-(5-((4- methylhexahydropyrazin- 1 -yl ) methyl ) pyridin -2- yl ) pyrimidin -2- amine hydrochloride

向5-氟-4-(8-氟喹啉-6-基)-N-(5-((4-甲基六氫吡嗪-1-基)甲基)吡啶-2-基)嘧啶-2-胺(實例15,500 mg, 0.34 mmol)於甲醇(3 mL)中之混合物中添加35%鹽酸水溶液(122 mg, 3.4 mmol)。溶液在一段時間內變得澄清,且接著在攪拌期間形成固體。將混合物攪拌30 min且過濾固體,相繼用甲醇(5 mL)及二乙醚(10 mL)洗滌並在真空下乾燥,得到呈黃色固體之標題化合物(130 mg)。產率:80%。熔點:250℃-253℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 11.98 (s, 1H), 11.69 (s, 1H), 9.08 (dd, J 4, 1.2, 1H), 8.95-8.91 (m, m, 1H), 8.70 (d, J 8.4, 1H), 8.66-8.59 (m, 2H), 8.42-8.31 (m, 1H), 8.24 (d, J 12, 1H), 8.11-8.04 (m, 1H), 7.77 (dd, J 8.4, 4, 1H), 4.45 (s, 2H), 3.75-3.60 (m, 4H), 3.45-3.30 (m, 4H), 2.80 (s, 3H)。MS (m/z):448.26 (M+H);[C 24H 23F 2N 7+ H]計算值:448.21。 實例 16 2-(6-(2-((5-((4- 乙基六氫吡嗪 -1- ) 甲基 ) 吡啶 -2- ) 胺基 )-5- 氟嘧啶 -4- )-8- -2- 甲基喹啉 -4- ) -2- To 5-fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-((4-methylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)pyrimidine- To a mixture of 2-amine (Example 15, 500 mg, 0.34 mmol) in methanol (3 mL) was added 35% aqueous hydrochloric acid (122 mg, 3.4 mmol). The solution became clear over a period of time and then a solid formed during stirring. The mixture was stirred for 30 min and the solid was filtered, washed sequentially with methanol (5 mL) and diethyl ether (10 mL) and dried under vacuum to give the title compound (130 mg) as a yellow solid. Yield: 80%. Melting point: 250°C-253°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 11.98 (s, 1H), 11.69 (s, 1H), 9.08 (dd, J 4, 1.2, 1H), 8.95-8.91 (m, m , 1H), 8.70 (d, J 8.4, 1H), 8.66-8.59 (m, 2H), 8.42-8.31 (m, 1H), 8.24 (d, J 12, 1H), 8.11-8.04 (m, 1H) , 7.77 (dd, J 8.4, 4, 1H), 4.45 (s, 2H), 3.75-3.60 (m, 4H), 3.45-3.30 (m, 4H), 2.80 (s, 3H). MS (m/z): 448.26 (M+H); Calcd. for [ C24H23F2N7 + H]: 448.21 . Example 16 2-(6-(2-((5-((4- ethylhexahydropyrazin- 1 -yl ) methyl ) pyridin -2- yl ) amino )-5- fluoropyrimidin - 4 -yl )-8- fluoro -2 -methylquinolin- 4 -yl ) propan -2- ol

遵循一般程序-3,自中間物31 (500 mg, 1.43 mmol)及中間物9 (315 mg, 1.43 mmol)合成標題化合物。在後處理後,藉由combi-flash使用甲醇及DCM (12:88)作為溶析液純化粗產物。使彙集之溶離份蒸發,且將殘餘物與石油醚(10 mL)一起攪拌20 min,過濾並乾燥,獲得呈黃色固體之標題化合物(180 mg)。產率:23.6%。熔點:253℃-256℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 10.09 (s, 1H), 9.51 (s, 1H), 8.75 (d, J 7.6, 1H), 8.27 (d, J 8.8, 1H), 8.18 (d, J 2, 1H), 8.10 (d, J 12, 1H), 7.71 (dd, J 8.8, 2, 1H), 7.60 (s, 1H), 3.43 (s, 2H), 2.71 (s, 3H), 2.50-2.20 (m, 10H), 0.96 (t, J 6.8, 3H)。MS (m/z):534.35 (M+H);[C 29H 33F 2N 7O + H]計算值:534.28。 實例 16A 2-(6-(2-((5-((4- 乙基六氫吡嗪 -1- ) 甲基 ) 吡啶 -2- ) 胺基 )-5- 氟嘧啶 -4- )-8- -2- 甲基喹啉 -4- ) -2- 醇鹽酸鹽 The title compound was synthesized from Intermediate 31 (500 mg, 1.43 mmol) and Intermediate 9 (315 mg, 1.43 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (12:88) as eluents. The pooled fractions were evaporated and the residue was stirred with petroleum ether (10 mL) for 20 min, filtered and dried to afford the title compound (180 mg) as a yellow solid. Yield: 23.6%. Melting point: 253°C-256°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 10.09 (s, 1H), 9.51 (s, 1H), 8.75 (d, J 7.6, 1H), 8.27 (d, J 8.8, 1H) , 8.18 (d, J 2, 1H), 8.10 (d, J 12, 1H), 7.71 (dd, J 8.8, 2, 1H), 7.60 (s, 1H), 3.43 (s, 2H), 2.71 (s , 3H), 2.50-2.20 (m, 10H), 0.96 (t, J 6.8, 3H). MS (m/z): 534.35 (M+H); Calcd. for [ C29H33F2N7O + H]: 534.28 . Example 16A 2-(6-(2-((5-((4- ethylhexahydropyrazin- 1 -yl ) methyl ) pyridin -2- yl ) amino )-5- fluoropyrimidin - 4 -yl )-8- fluoro -2 -methylquinolin- 4 -yl ) propan -2- ol hydrochloride

向2-(6-(2-((5-((4-乙基六氫吡嗪-1-基)甲基)吡啶-2-基)胺基)-5-氟嘧啶-4-基)-8-氟-2-甲基喹啉-4-基)丙-2-醇(實例16,180 mg, 0.34 mmol)於甲醇(3 mL)中之混合物中添加35%鹽酸水溶液(123 mg, 3.4 mmol)。溶液在一段時間內變得澄清,且接著在攪拌期間形成固體。將混合物攪拌30 min且過濾固體,用二乙醚(10 mL)洗滌並在真空下乾燥,得到呈黃色固體之標題化合物(110 mg)。產率:57.2%。熔點:275℃-278℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 11.92 (bs, 1H), 11.44 (bs, 1H), 9.53 (s, 1H), 8.89 (d, J 3.6, 1H), 8.61 (d, J 1.2, 1H), 8.37-8.32 (m, 1H), 8.20-8.12 (m, 2H), 7.64 (s, 1H), 4.47 (s, 2H), 3.75-3.55 (m, 4H), 3.50-3.38 (m, 6H), 2.74 (s, 3H), 1.74 (s, 6H), 1.25 9t, J 7.2, 3H)。MS (m/z):534.37 (M+H);[C 29H 33F 2N 7O+H]計算值:534.28。 實例 17 4-(6-((5- -4-(8- -4-(2- 羥基丙 -2- )-2- 甲基喹啉 -6- ) 嘧啶 -2- ) 胺基 ) 吡啶 -3- ) 六氫吡嗪 -1- 甲酸第三丁基酯 To 2-(6-(2-((5-((4-ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl) To a mixture of -8-fluoro-2-methylquinolin-4-yl)propan-2-ol (Example 16, 180 mg, 0.34 mmol) in methanol (3 mL) was added 35% aqueous hydrochloric acid (123 mg, 3.4 mmol). The solution became clear over a period of time and then a solid formed during stirring. The mixture was stirred for 30 min and the solid was filtered, washed with diethyl ether (10 mL) and dried under vacuum to give the title compound (110 mg) as a yellow solid. Yield: 57.2%. Melting point: 275°C-278°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 11.92 (bs, 1H), 11.44 (bs, 1H), 9.53 (s, 1H), 8.89 (d, J 3.6, 1H), 8.61 ( d, J 1.2, 1H), 8.37-8.32 (m, 1H), 8.20-8.12 (m, 2H), 7.64 (s, 1H), 4.47 (s, 2H), 3.75-3.55 (m, 4H), 3.50 -3.38 (m, 6H), 2.74 (s, 3H), 1.74 (s, 6H), 1.25 9t, J 7.2, 3H). MS (m/z): 534.37 (M+H); Calcd. for [ C29H33F2N7O + H]: 534.28 . Example 17 4-(6-((5- fluoro - 4-(8- fluoro - 4-(2 -hydroxyprop- 2- yl )-2 -methylquinolin -6- yl ) pyrimidin -2- yl ) Amino ) pyridin - 3 -yl ) hexahydropyrazine- 1 -carboxylic acid tert-butyl ester

遵循一般程序-3,自中間物31 (500 mg, 1.43 mmol)及中間物5 (398 mg, 1.43 mmol)合成標題化合物。在後處理後,藉由combi-flash使用甲醇及DCM (3.5:96.5)作為溶析液純化粗產物。使彙集之溶離份蒸發,且將殘餘物與二乙醚(10 mL)一起攪拌20 min,過濾並乾燥,獲得呈淡黃色固體之標題化合物(145 mg)。產率:17.1%。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 9.83 (s, 1H), 9.47 (s, 1H), 8.70 (d, J 3.6, 1H), 8.14 (d, J 8.8, 1H), 8.08 (d, J 12.4, 1H), 8.04 (d, J 3.6, 1H), 7.60 (s, 1H), 7.48-7.44 (m, 1H), 5.69 (s, 1H), 3.50-3.44 (m, 4H), 3.10-3.05 (m, 4H), 2.71 (s, 3H), 1.72 (s, 6H), 1.41 (s, 9H)。MS (m/z):592.44 (M+H);[C 31H 35F 2N 7O 3+H]計算值:592.29。 實例 17A 2-(8- -6-(5- -2-((5-( 六氫吡嗪 -1- ) 吡啶 -2- ) 胺基 ) 嘧啶 -4- )-2- 甲基喹啉 -4- ) -2- The title compound was synthesized from Intermediate 31 (500 mg, 1.43 mmol) and Intermediate 5 (398 mg, 1.43 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (3.5:96.5) as eluents. The pooled fractions were evaporated and the residue was stirred with diethyl ether (10 mL) for 20 min, filtered and dried to afford the title compound (145 mg) as a light yellow solid. Yield: 17.1%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.83 (s, 1H), 9.47 (s, 1H), 8.70 (d, J 3.6, 1H), 8.14 (d, J 8.8, 1H) , 8.08 (d, J 12.4, 1H), 8.04 (d, J 3.6, 1H), 7.60 (s, 1H), 7.48-7.44 (m, 1H), 5.69 (s, 1H), 3.50-3.44 (m, 4H), 3.10-3.05 (m, 4H), 2.71 (s, 3H), 1.72 (s, 6H), 1.41 (s, 9H). MS (m/z): 592.44 ( M +H); Calcd. for [ C31H35F2N7O3 + H]: 592.29 . Example 17A 2-(8- fluoro -6-(5- fluoro -2-((5-( hexahydropyrazin- 1 -yl ) pyridin -2- yl ) amino ) pyrimidin - 4 -yl )-2- Methylquinolin- 4 -yl ) propan -2- ol

遵循一般程序-4,自4-(6-((5-氟-4-(8-氟-4-(2-羥基丙-2-基)-2-甲基喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-1-甲酸第三丁基酯(實例17,140 mg, 0.28 mmol)合成呈淡黃色固體之標題化合物(60 mg)。產率:54%。熔點:258℃-261℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 9.79 (s, 1H), 9.47 (s, 1H), 8.69 (d, J 3.6, 1H), 8.11 (d, J 9.2, 1H), 8.07 (d, J 11.6, 1H), 8.00 (d, J 2.8, 1H), 7.60 (s, 1H), 7.42 (dd, J 8.8, 2.8, 1H), 5.69 (s, 1H), 3.05-2.99 (m, 4H), 2.88-2.81 (m, 4H), 2.71 (s, 3H), 1.72 (s, 6H)。MS (m/z):492.49 (M+H);[C 26H 27F 2N 7O + H]計算值:492.23。 實例 17B 2-(8- -6-(5- -2-((5-( 六氫吡嗪 -1- ) 吡啶 -2- ) 胺基 ) 嘧啶 -4- )-2- 甲基喹啉 -4- ) -2- 醇鹽酸鹽 Following general procedure-4, from 4-(6-((5-fluoro-4-(8-fluoro-4-(2-hydroxypropan-2-yl)-2-methylquinolin-6-yl)pyrimidine -2-yl)amino)pyridin-3-yl)tert-butyl hexahydropyrazine-1-carboxylate (Example 17, 140 mg, 0.28 mmol) The title compound (60 mg) was synthesized as a pale yellow solid. Yield: 54%. Melting point: 258°C-261°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.79 (s, 1H), 9.47 (s, 1H), 8.69 (d, J 3.6, 1H), 8.11 (d, J 9.2, 1H) , 8.07 (d, J 11.6, 1H), 8.00 (d, J 2.8, 1H), 7.60 (s, 1H), 7.42 (dd, J 8.8, 2.8, 1H), 5.69 (s, 1H), 3.05-2.99 (m, 4H), 2.88-2.81 (m, 4H), 2.71 (s, 3H), 1.72 (s, 6H). MS (m/z): 492.49 (M+H); Calcd. for [ C26H27F2N7O + H]: 492.23 . Example 17B 2-(8- fluoro -6-(5- fluoro -2-((5-( hexahydropyrazin- 1 -yl ) pyridin -2- yl ) amino ) pyrimidin - 4 -yl )-2- Methylquinolin- 4 -yl ) propan -2- ol hydrochloride

向2-(8-氟-6-(5-氟-2-((5-(六氫吡嗪-1-基)吡啶-2-基)胺基)嘧啶-4-基)-2-甲基喹啉-4-基)丙-2-醇(實例17A,70 mg, 0.14 mmol)於甲醇(2 mL)中之混合物中添加35%鹽酸水溶液(52 mg, 3.4 mmol)。溶液在一段時間內變得澄清,且接著在攪拌期間形成固體。將混合物攪拌30 min,用甲基第三丁基醚(5 mL)稀釋且過濾固體,用甲基第三丁基醚(10 mL)洗滌且在真空下乾燥,得到呈黃色固體之標題化合物(37 mg)。產率:49%。熔點:278℃-280℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 11.74 (s, 1H), 9.55-9.45 (m, 3H), 8.91 (d, J  3.6, 1H), 8.17 (d, J  12.8, 1H),  8.00 (d, J  2.4, 1H), 7.88 (d, J  9.6, 1H), 7.63 (s, 1H), 3.49-3.42 (m, 4H), 3.29-3.20(m, 4H), 2.73 (s, 3H), 1.72(s, 6H)。MS (m/z):492.49 (M+H-HCl);[C 26H 27F 2N 7O.HCl + H-HCl]計算值:492.23。 實例 18 2-(6-(2-((5-(4- 乙基六氫吡嗪 -1- ) 吡啶 -2- ) 胺基 )-5- 氟嘧啶 -4- )-8- -2- 甲基喹啉 -4- ) -2- To 2-(8-fluoro-6-(5-fluoro-2-((5-(hexahydropyrazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methyl To a mixture of (quinolin-4-yl)propan-2-ol (Example 17A, 70 mg, 0.14 mmol) in methanol (2 mL) was added 35% aqueous hydrochloric acid (52 mg, 3.4 mmol). The solution became clear over a period of time and then a solid formed during stirring. The mixture was stirred for 30 min, diluted with methyl tert-butyl ether (5 mL) and the solid was filtered, washed with methyl tert-butyl ether (10 mL) and dried under vacuum to give the title compound as a yellow solid ( 37 mg). Yield: 49%. Melting point: 278°C-280°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 11.74 (s, 1H), 9.55-9.45 (m, 3H), 8.91 (d, J 3.6, 1H), 8.17 (d, J 12.8, 1H), 8.00 (d, J 2.4, 1H), 7.88 (d, J 9.6, 1H), 7.63 (s, 1H), 3.49-3.42 (m, 4H), 3.29-3.20(m, 4H), 2.73 ( s, 3H), 1.72(s, 6H). MS (m/z): 492.49 (M+H-HCl); Calcd. for [ C26H27F2N7O.HCl + H - HCl]: 492.23 . Example 18 2-(6-(2-((5-(4- ethylhexahydropyrazin- 1 -yl ) pyridin -2- yl ) amino )-5- fluoropyrimidin - 4 -yl )-8- Fluoro -2 -methylquinolin- 4 -yl ) propan -2- ol

遵循一般程序-3,自中間物31 (500 mg, 1.43 mmol)及中間物20 (295 mg, 1.43 mmol)合成標題化合物。在後處理後,藉由combi-flash使用甲醇及DCM (10:90)作為溶析液純化粗產物。使彙集之溶離份蒸發,且將殘餘物與二乙醚(10 mL)一起攪拌30 min,過濾,用二乙醚(5 mL)洗滌並乾燥,獲得呈淡黃色固體之標題化合物(110 mg)。產率:14.8%。熔點:206℃-208℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 9.80 (s, 1H), 9.47 (s, 1H), 8.69 (d, J = 3.6, 1H), 8.12 (d, J = 8.8, 1H), 8.08 (d, J = 12.0, 1H), 8.01 (d, J = 2.8, 1H), 7.60 (s, 1H), 7.44 (dd, J = 8.8, 2.8, 1H), 5.70 (s, 1H), 3.12 (br. s, 4H), 2.72 (s, 3H), 2.42-2.51 (m,4H,在DMSO信號下), 2.37 (q, J = 7.2, 2H), 1.72 (s, 6H), 1.03 (t, J = 7.2, 3H)。MS (m/z):520.52 (M+H);[C 28H 31F 2N 7O + H]計算值:520.27。 實例 18A 2-(6-(2-((5-(4- 乙基六氫吡嗪 -1- ) 吡啶 -2- ) 胺基 )-5- 氟嘧啶 -4- )-8- -2- 甲基喹啉 -4- ) -2- 醇鹽酸鹽 The title compound was synthesized from Intermediate 31 (500 mg, 1.43 mmol) and Intermediate 20 (295 mg, 1.43 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (10:90) as eluents. The pooled fractions were evaporated and the residue was stirred with diethyl ether (10 mL) for 30 min, filtered, washed with diethyl ether (5 mL) and dried to afford the title compound (110 mg) as a light yellow solid. Yield: 14.8%. Melting point: 206°C-208°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.80 (s, 1H), 9.47 (s, 1H), 8.69 (d, J = 3.6, 1H), 8.12 (d, J = 8.8, 1H), 8.08 (d, J = 12.0, 1H), 8.01 (d, J = 2.8, 1H), 7.60 (s, 1H), 7.44 (dd, J = 8.8, 2.8, 1H), 5.70 (s, 1H ), 3.12 (br. s, 4H), 2.72 (s, 3H), 2.42-2.51 (m, 4H, under DMSO signal), 2.37 (q, J = 7.2, 2H), 1.72 (s, 6H), 1.03 (t, J = 7.2, 3H). MS (m/z): 520.52 (M+H); Calcd. for [ C28H31F2N7O + H]: 520.27 . Example 18A 2-(6-(2-((5-(4- ethylhexahydropyrazin- 1 -yl ) pyridin -2- yl ) amino )-5- fluoropyrimidin - 4 -yl )-8- Fluoro -2 -methylquinolin- 4 -yl ) propan -2- ol hydrochloride

向2-(6-(2-((5-(4-乙基六氫吡嗪-1-基)吡啶-2-基)胺基)-5-氟嘧啶-4-基)-8-氟-2-甲基喹啉-4-基)丙-2-醇(實例18,100 mg, 0.19 mmol)於甲醇(2.5 mL)中之混合物中添加35%鹽酸水溶液(70 mg, 1.9 mmol)。將所得澄清溶液攪拌30 min,用二乙醚(5 mL)稀釋且過濾所形成之固體,用二乙醚(10 mL)洗滌且在真空下乾燥,得到呈黃色固體之標題化合物(25 mg)。產率:37%。熔點:215℃-220℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 11.69 (s, 1H), 11.27 (s, 1H), 9.50 (s, 1H), 8.90 (d, J  3.2, 1H), 8.18 (br. s, 1H), 8.10 (d, J  12.4, 1H), 8.02 (d, J  2.8, 1H), 7.89 (d, J  9.6, 1H), 7.63 (s, 1H), 3.85 (d, J  12.8, 2H), 3.59 (d, J  11.6, 2H), 3.27 (t, J  12.8, 2H), 3.23-3.05 (m, 4H), 2.73 (s, 1H), 1.73 (s, 6H), 1.30 (t, J  7.2, 3H)。MS (m/z):520.51 (M+H);[C 28H 31F 2N 7O + H]計算值:520.27。 實例 19 4-(4-( 二氟甲基 )-8- -2- 甲基喹啉 -6- )-N-(5-(4- 乙基六氫吡嗪 -1- ) 吡啶 -2- )-5- 氟嘧啶 -2- To 2-(6-(2-((5-(4-ethylhexahydropyrazin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-8-fluoro - To a mixture of 2-methylquinolin-4-yl)propan-2-ol (Example 18, 100 mg, 0.19 mmol) in methanol (2.5 mL) was added 35% aqueous hydrochloric acid (70 mg, 1.9 mmol). The resulting clear solution was stirred for 30 min, diluted with diethyl ether (5 mL) and the solid formed was filtered, washed with diethyl ether (10 mL) and dried under vacuum to give the title compound (25 mg) as a yellow solid. Yield: 37%. Melting point: 215°C-220°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 11.69 (s, 1H), 11.27 (s, 1H), 9.50 (s, 1H), 8.90 (d, J 3.2, 1H), 8.18 ( br. s, 1H), 8.10 (d, J 12.4, 1H), 8.02 (d, J 2.8, 1H), 7.89 (d, J 9.6, 1H), 7.63 (s, 1H), 3.85 (d, J 12.8 , 2H), 3.59 (d, J 11.6, 2H), 3.27 (t, J 12.8, 2H), 3.23-3.05 (m, 4H), 2.73 (s, 1H), 1.73 (s, 6H), 1.30 (t , J 7.2, 3H). MS (m/z): 520.51 (M+H); Calcd. for [ C28H31F2N7O + H]: 520.27 . Example 19 4-(4-( Difluoromethyl )-8- fluoro -2 -methylquinolin -6- yl )-N-(5-(4- ethylhexahydropyrazin- 1 -yl ) pyridine -2- yl )-5- fluoropyrimidin -2- amine

遵循一般程序-3,自中間物36 (500 mg, 1.46 mmol)及中間物20 (302 mg, 1.46 mmol)合成標題化合物。在後處理後,藉由combi-flash使用甲醇及DCM (4.6:95.4)作為溶析液純化粗產物。使彙集之溶離份蒸發,且將殘餘物與二乙醚(10 mL)一起攪拌30 min,過濾固體,用二乙醚(5 mL)洗滌並乾燥,獲得呈黃色固體之標題化合物(50 mg)。產率:6.7%。熔點:237℃-238℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 9.87 (s, 1H), 8.73 (d, J  3.6, 1H), 8.71 (br. s, 1H), 8.24 (d, J  9.0, 1H), 8.10-8.02 (m, 2H), 7.86 (s, 1H), 7.68 (t, J  53.6, 1H), 7.43 (dd, J  9.2, 3.2, 1H), 3.14 (br. s, 4H), 2.80 (s, 3H), 2.54 (br (s, 4H), 2.45-2.32 (m, 2H), 1.04 (t, J  7.2, 3H)。MS (m/z):512.46 (M+H);[C 26H 25F 4N 7+ H]計算值:512.22。 實例 19A 4-(4-( 二氟甲基 )-8- -2- 甲基喹啉 -6- )-N-(5-(4- 乙基六氫吡嗪 -1- ) 吡啶 -2- )-5- 氟嘧啶 -2- 胺鹽酸鹽 The title compound was synthesized from Intermediate 36 (500 mg, 1.46 mmol) and Intermediate 20 (302 mg, 1.46 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (4.6:95.4) as eluents. The pooled fractions were evaporated and the residue was stirred with diethyl ether (10 mL) for 30 min, the solid was filtered, washed with diethyl ether (5 mL) and dried to give the title compound (50 mg) as a yellow solid. Yield: 6.7%. Melting point: 237°C-238°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.87 (s, 1H), 8.73 (d, J 3.6, 1H), 8.71 (br. s, 1H), 8.24 (d, J 9.0, 1H), 8.10-8.02 (m, 2H), 7.86 (s, 1H), 7.68 (t, J 53.6, 1H), 7.43 (dd, J 9.2, 3.2, 1H), 3.14 (br. s, 4H), 2.80 (s, 3H), 2.54 (br (s, 4H), 2.45-2.32 (m, 2H), 1.04 (t, J 7.2, 3H). MS (m/z): 512.46 (M+H); [ Calcd for C 26 H 25 F 4 N 7 + H]: 512.22. Example 19A 4-(4-( difluoromethyl )-8- fluoro -2 -methylquinolin -6- yl )-N-(5 -(4- Ethylhexahydropyrazin- 1 -yl ) pyridin -2- yl )-5- fluoropyrimidin -2- amine hydrochloride

向4-(4-(二氟甲基)-8-氟-2-甲基喹啉-6-基)-N-(5-(4-乙基六氫吡嗪-1-基)吡啶-2-基)-5-氟嘧啶-2-胺(實例19,40 mg, 0.08 mmol)於甲醇(1 mL)中之混合物中添加35%鹽酸水溶液(29 mg, 0.8 mmol)。將所得澄清溶液攪拌30 min,用二乙醚(4 mL)稀釋且過濾所形成之固體,用二乙醚(2 mL)洗滌且在真空下乾燥,得到呈黃色固體之標題化合物(35 mg)。產率:79%。熔點:195℃-197℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 11.36 (s, 1H), 10.95 (s, 1H), 8.91 (d, J  3.2, 1H), 8.68 (s, 1H), 8.25 (d, J  11.6, 1H), 8.10-7.97 (m, 2H), 7.86-7.92 (m, 2H), 7.69 (t, J  53.2, 1H), 3.84 (d, J  10.8, 2H), 3.59 (d, J  11.6, 2H), 3.30-3.05 (m, 6H), 2.81 (s, 3H), 1.29 (t, J  7.2, 3H)。MS (m/z):512.52 (M+H);[C 26H 25F 4N 7+ H]計算值:512.22。 實例 20 4-(6-((4-(4-( 二氟甲基 )-8- -2- 甲基喹啉 -6- )-5- 氟嘧啶 -2- ) 胺基 ) 吡啶 -3- ) 六氫吡嗪 -1- 甲酸第三丁基酯 To 4-(4-(difluoromethyl)-8-fluoro-2-methylquinolin-6-yl)-N-(5-(4-ethylhexahydropyrazin-1-yl)pyridine- To a mixture of 2-yl)-5-fluoropyrimidin-2-amine (Example 19, 40 mg, 0.08 mmol) in methanol (1 mL) was added 35% aqueous hydrochloric acid (29 mg, 0.8 mmol). The resulting clear solution was stirred for 30 min, diluted with diethyl ether (4 mL) and the solid formed was filtered, washed with diethyl ether (2 mL) and dried under vacuum to give the title compound (35 mg) as a yellow solid. Yield: 79%. Melting point: 195°C-197°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 11.36 (s, 1H), 10.95 (s, 1H), 8.91 (d, J 3.2, 1H), 8.68 (s, 1H), 8.25 ( d, J 11.6, 1H), 8.10-7.97 (m, 2H), 7.86-7.92 (m, 2H), 7.69 (t, J 53.2, 1H), 3.84 (d, J 10.8, 2H), 3.59 (d, J 11.6, 2H), 3.30-3.05 (m, 6H), 2.81 (s, 3H), 1.29 (t, J 7.2, 3H). MS (m/z): 512.52 (M+H); Calcd. for [ C26H25F4N7 + H]: 512.22 . Example 20 4-(6-((4-(4-( difluoromethyl )-8- fluoro -2 -methylquinolin -6- yl )-5- fluoropyrimidin -2- yl ) amino ) pyridine -3 -yl ) hexahydropyrazine- 1 -carboxylic acid tert-butyl ester

遵循一般程序-3,自中間物36 (500 mg, 1.46 mmol)及中間物5 (407 mg, 1.46 mmol)合成標題化合物。在後處理後,藉由combi-flash使用甲醇及DCM (3.5:96.5)作為溶析液純化粗產物。使彙集之溶離份蒸發,且將殘餘物與二乙醚(10 mL)一起攪拌30 min,過濾固體並乾燥,獲得呈黃色固體之標題化合物(110 mg)。產率:12.9%。熔點:224℃-227℃。 1H-NMR (δ ppm, CDCl 3, 400 MHz): 8.77 (s, 1H), 8.51 (d, J  3.6, 1H), 8.34 (d, J  9.2, 1H), 8.31-8.17 (m, 2H), 8.08 (s, 1H), 7.64 (s, 1H), 7.42 (dd, J  9.2, 3.2, 1H), 7.19 (t, J  54.4, 1H), 3.68-3.61 (m, 4H), 3.18-3.10 (m, 4H), 1.52 (s, 9H)。MS (m/z):584.23 (M+H);[C 29H 29F 4N 7O 2+ H]計算值:584.24。 實例 20A 4-(4-( 二氟甲基 )-8- -2- 甲基喹啉 -6- )-5- -N-(5-( 六氫吡嗪 -1- ) 吡啶 -2- ) 嘧啶 -2- The title compound was synthesized from Intermediate 36 (500 mg, 1.46 mmol) and Intermediate 5 (407 mg, 1.46 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (3.5:96.5) as eluents. The pooled fractions were evaporated and the residue was stirred with diethyl ether (10 mL) for 30 min, the solid was filtered and dried to afford the title compound (110 mg) as a yellow solid. Yield: 12.9%. Melting point: 224°C-227°C. 1 H-NMR (δ ppm, CDCl 3 , 400 MHz): 8.77 (s, 1H), 8.51 (d, J 3.6, 1H), 8.34 (d, J 9.2, 1H), 8.31-8.17 (m, 2H) , 8.08 (s, 1H), 7.64 (s, 1H), 7.42 (dd, J 9.2, 3.2, 1H), 7.19 (t, J 54.4, 1H), 3.68-3.61 (m, 4H), 3.18-3.10 ( m, 4H), 1.52 (s, 9H). MS (m/z): 584.23 (M + H); Calcd. for [ C29H29F4N7O2 + H]: 584.24 . Example 20A 4-(4-( difluoromethyl )-8- fluoro -2 -methylquinolin -6- yl )-5- fluoro -N-(5-( hexahydropyrazin- 1 -yl ) pyridine -2- yl ) pyrimidin -2- amine

遵循一般程序-4,自4-(6-((4-(4-(二氟甲基)-8-氟-2-甲基喹啉-6-基)-5-氟嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-1-甲酸第三丁基酯(實例20,100 mg, 0.17 mmol)合成呈黃色固體之標題化合物(50 mg)。產率:60%。熔點:262℃-264℃。 1H-NMR (δ ppm, CDCl 3, 400 MHz): 9.86 (s, 1H), 8.72 (d, J  8.36, 1H), 8.70 (br. s, 1H), 8.23 (d, J  11.6, 1H), 8.05 (d, J  8.8, 1H), 8.01 (d, J  3.2, 1H), 7.86 (s, 1H), 7.68 (t, J  53.6, 1H), 7.40 (dd, J  9.2, 3.2, 1H), 3.08-3.03 (m, 4H), 2.91-2.85 (m, 4H), 2.79 (s, 3H)。MS (m/z):484.45 (M+H);[C 24H 21F 4N 7+ H]計算值:484.19。 實例 20B 4-(4-( 二氟甲基 )-8- -2- 甲基喹啉 -6- )-5- -N-(5-( 六氫吡嗪 -1- ) 吡啶 -2- ) 嘧啶 -2- 胺鹽酸鹽 Following general procedure-4, from 4-(6-((4-(4-(difluoromethyl)-8-fluoro-2-methylquinolin-6-yl)-5-fluoropyrimidin-2-yl )amino)pyridin-3-yl)tert-butyl hexahydropyrazine-1-carboxylate (Example 20, 100 mg, 0.17 mmol) The title compound (50 mg) was synthesized as a yellow solid. Yield: 60%. Melting point: 262°C-264°C. 1 H-NMR (δ ppm, CDCl 3 , 400 MHz): 9.86 (s, 1H), 8.72 (d, J 8.36, 1H), 8.70 (br. s, 1H), 8.23 (d, J 11.6, 1H) , 8.05 (d, J 8.8, 1H), 8.01 (d, J 3.2, 1H), 7.86 (s, 1H), 7.68 (t, J 53.6, 1H), 7.40 (dd, J 9.2, 3.2, 1H), 3.08-3.03 (m, 4H), 2.91-2.85 (m, 4H), 2.79 (s, 3H). MS (m/z): 484.45 (M+H); Calcd. for [ C24H21F4N7 + H]: 484.19 . Example 20B 4-(4-( difluoromethyl )-8- fluoro -2 -methylquinolin -6- yl )-5- fluoro -N-(5-( hexahydropyrazin- 1 -yl ) pyridine -2- yl ) pyrimidin -2- amine hydrochloride

向4-(4-(二氟甲基)-8-氟-2-甲基喹啉-6-基)-5-氟-N-(5-(六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺(實例20A,40 mg, 0.08 mmol)於甲醇(1 mL)中之混合物中添加35%鹽酸水溶液(30 mg, 0.8 mmol)。將所得澄清溶液攪拌30 min,用二乙醚(4 mL)稀釋且過濾所形成之固體,用二乙醚(2 mL)洗滌並乾燥。將所獲得之固體溶解於甲醇-二氯甲烷1:4 (20 mL)中,過濾並將濾液在真空下濃縮,且使殘餘物與甲苯(5.0 mL)一起共蒸餾,得到呈黃色固體之標題化合物(25 mg)。產率:67%。熔點:263℃-265℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 10.76 (br. s, 1H), 9.06 (br. s, 2H), 8.84 (d, J  3.2, 1H), 8.69 (s, 1H), 8.25 (d, J  12.0, 1H), 8.03 (d, J  2.8, 1H), 7.97 (d, J  9.2, 1H), 7.89 (s, 1H), 7.80 (br. s, 1H), 7.69 (t, J  54, 1H), 3.41-3.35 (m, 4H), 3.30-3.22 (m, 4H), 2.80 (s, 3H)。MS (m/z):484.49 (M+H);[C 24H 21F 4N 7+ H]計算值:484.19。 實例 21 4-(4-( 二氟甲基 )-8- -2- 甲基喹啉 -6- )-N-(5-((4- 乙基六氫吡嗪 -1- ) 甲基 ) 吡啶 -2- )-5- 氟嘧啶 -2- To 4-(4-(difluoromethyl)-8-fluoro-2-methylquinolin-6-yl)-5-fluoro-N-(5-(hexahydropyrazin-1-yl)pyridine- To a mixture of 2-yl)pyrimidin-2-amine (Example 20A, 40 mg, 0.08 mmol) in methanol (1 mL) was added 35% aqueous hydrochloric acid (30 mg, 0.8 mmol). The resulting clear solution was stirred for 30 min, diluted with diethyl ether (4 mL) and the solid formed was filtered, washed with diethyl ether (2 mL) and dried. The obtained solid was dissolved in methanol-dichloromethane 1:4 (20 mL), filtered and the filtrate was concentrated in vacuo, and the residue was co-distilled with toluene (5.0 mL) to give the title as a yellow solid compound (25 mg). Yield: 67%. Melting point: 263°C-265°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 10.76 (br. s, 1H), 9.06 (br. s, 2H), 8.84 (d, J 3.2, 1H), 8.69 (s, 1H ), 8.25 (d, J 12.0, 1H), 8.03 (d, J 2.8, 1H), 7.97 (d, J 9.2, 1H), 7.89 (s, 1H), 7.80 (br. s, 1H), 7.69 ( t, J 54, 1H), 3.41-3.35 (m, 4H), 3.30-3.22 (m, 4H), 2.80 (s, 3H). MS (m/z): 484.49 (M+H); Calcd. for [ C24H21F4N7 + H]: 484.19 . Example 21 4-(4-( Difluoromethyl )-8- fluoro -2 -methylquinolin -6- yl )-N-(5-((4- ethylhexahydropyrazin- 1 -yl ) Methyl ) pyridin -2- yl )-5- fluoropyrimidin -2- amine

遵循一般程序-3,自中間物36 (500 mg, 1.46 mmol)及中間物9 (322 mg, 1.46 mmol)合成標題化合物。在後處理後,藉由combi-flash使用甲醇及DCM (12:88)作為溶析液純化粗產物。使彙集之溶離份蒸發,且將殘餘物與二乙醚(10 mL)一起攪拌30 min,過濾固體並乾燥,獲得呈黃色固體之標題化合物(140 mg)。產率:18.2%。熔點:219℃-222℃。MS (m/z):526.3 (M+H);[C 27H 27F 4N 7+ H]計算值:526.24。 實例 21A 4-(4-( 二氟甲基 )-8- -2- 甲基喹啉 -6- )-N-(5-((4- 乙基六氫吡嗪 -1- ) 甲基 ) 吡啶 -2- )-5- 氟嘧啶 -2- 胺鹽酸鹽 The title compound was synthesized from Intermediate 36 (500 mg, 1.46 mmol) and Intermediate 9 (322 mg, 1.46 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (12:88) as eluents. The pooled fractions were evaporated and the residue was stirred with diethyl ether (10 mL) for 30 min, the solid was filtered and dried to afford the title compound (140 mg) as a yellow solid. Yield: 18.2%. Melting point: 219°C-222°C. MS (m/z): 526.3 (M+H) ; Calcd. for [ C27H27F4N7 + H]: 526.24 . Example 21A 4-(4-( Difluoromethyl )-8- fluoro -2 -methylquinolin -6- yl )-N-(5-((4- ethylhexahydropyrazin- 1 -yl ) Methyl ) pyridin -2- yl )-5- fluoropyrimidin -2- amine hydrochloride

向4-(4-(二氟甲基)-8-氟-2-甲基喹啉-6-基)-N-(5-((4-乙基六氫吡嗪-1-基)甲基)吡啶-2-基)-5-氟嘧啶-2-胺(實例21,100 mg, 0.19 mmol)於甲醇(2.5 mL)中之混合物中添加35%鹽酸水溶液(69 mg, 1.9 mmol)。將所得澄清溶液攪拌30 min,用二乙醚(4 mL)稀釋且過濾所形成之固體,用二乙醚(2 mL)洗滌並乾燥。將所獲得之固體溶解於甲醇-二氯甲烷1:4 (20 mL)中,過濾並將濾液在真空下濃縮,且使殘餘物與甲苯(5.0 mL)一起共蒸餾,得到呈褐色固體之標題化合物(53 mg)。產率:50%。熔點:218℃-220℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 11.82 (br. s, 1H), 11.19 (br. s, 1H), 8.90 (d, J  3.2, 1H), 8.72 (s, 1H), 8.58 (s, 1H), 8.30-8.13 (m, 3H), 7.89 (s, 1H), 7.70 (t, J  53.6, 1H), 5.0-4.6 (m, 7H), 3.80-3.10 (m, 9H), 1.25 (t, J = 7.2, 3H)。MS (m/z):526.25 (M+H-HCl);[C 27H 27F 4N 7.HCl + H-HCl]計算值:526.24。 實例 22 N-(5-((4- 乙基六氫吡嗪 -1- ) 甲基 ) 吡啶 -2- )-5- -4-(8- -4-(2- 氟丙 -2- )-2- 甲基喹啉 -6- ) 嘧啶 -2- To 4-(4-(difluoromethyl)-8-fluoro-2-methylquinolin-6-yl)-N-(5-((4-ethylhexahydropyrazin-1-yl)methyl yl)pyridin-2-yl)-5-fluoropyrimidin-2-amine (Example 21, 100 mg, 0.19 mmol) in methanol (2.5 mL) was added 35% aqueous hydrochloric acid (69 mg, 1.9 mmol). The resulting clear solution was stirred for 30 min, diluted with diethyl ether (4 mL) and the solid formed was filtered, washed with diethyl ether (2 mL) and dried. The obtained solid was dissolved in methanol-dichloromethane 1:4 (20 mL), filtered and the filtrate was concentrated in vacuo, and the residue was co-distilled with toluene (5.0 mL) to afford the title as a tan solid. Compound (53 mg). Yield: 50%. Melting point: 218°C-220°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 11.82 (br. s, 1H), 11.19 (br. s, 1H), 8.90 (d, J 3.2, 1H), 8.72 (s, 1H ), 8.58 (s, 1H), 8.30-8.13 (m, 3H), 7.89 (s, 1H), 7.70 (t, J 53.6, 1H), 5.0-4.6 (m, 7H), 3.80-3.10 (m, 9H), 1.25 (t, J = 7.2, 3H). MS (m/z): 526.25 (M+H-HCl); Calcd. for [ C27H27F4N7.HCl + H - HCl]: 526.24 . Example 22 N-(5-((4- ethylhexahydropyrazin- 1 -yl ) methyl ) pyridin -2- yl )-5- fluoro - 4-(8- fluoro - 4-(2- fluoropropane -2- yl )-2 -methylquinolin -6- yl ) pyrimidin -2- amine

遵循一般程序-3,自中間物39 (500 mg, 1.42 mmol)及中間物9 (313 mg, 1.42 mmol)合成標題化合物。在後處理後,藉由combi-flash使用甲醇及DCM (6.7:93.3)作為溶析液純化粗產物。使彙集之溶離份蒸發,且將殘餘物與二乙醚(10 mL)一起攪拌30 min,過濾固體,用二乙醚(5 mL)洗滌並乾燥,獲得呈淡褐色固體之標題化合物(170 mg)。產率:22.3%。熔點:207℃-209℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 10.14 (s, 1H), 8.99 (s, 1H), 8.76 (d, J  3.6, 1H), 8.28 (m, 3H), 7.68 (dd, J  8.8, 2.4, 1H),  7.64 (s, 1H), 3.45 (s, 2H), 2.75 (s, 3H), 2.60-2.20 (m, 10H), 1.95 (d, J  22.8, 6H), 0.98 (t, J  7.2, 3H)。MS (m/z):536.33 (M+H);[C 29H 32F 3N 7+ H]計算值:536.27。 實例 22A N-(5-((4- 乙基六氫吡嗪 -1- ) 甲基 ) 吡啶 -2- )-5- -4-(8- -4-(2- 氟丙 -2- )-2- 甲基喹啉 -6- ) 嘧啶 -2- 胺鹽酸鹽 The title compound was synthesized from Intermediate 39 (500 mg, 1.42 mmol) and Intermediate 9 (313 mg, 1.42 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (6.7:93.3) as eluents. The pooled fractions were evaporated and the residue was stirred with diethyl ether (10 mL) for 30 min, the solid was filtered, washed with diethyl ether (5 mL) and dried to afford the title compound (170 mg) as a light brown solid. Yield: 22.3%. Melting point: 207°C-209°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 10.14 (s, 1H), 8.99 (s, 1H), 8.76 (d, J 3.6, 1H), 8.28 (m, 3H), 7.68 ( dd, J 8.8, 2.4, 1H), 7.64 (s, 1H), 3.45 (s, 2H), 2.75 (s, 3H), 2.60-2.20 (m, 10H), 1.95 (d, J 22.8, 6H), 0.98 (t, J 7.2, 3H). MS (m/z): 536.33 (M+H); Calcd. for [ C29H32F3N7 +H]: 536.27 . Example 22A N-(5-((4- ethylhexahydropyrazin- 1 -yl ) methyl ) pyridin -2- yl )-5- fluoro - 4-(8- fluoro - 4-(2- fluoropropane -2- yl )-2 -methylquinolin -6- yl ) pyrimidin -2- amine hydrochloride

向N-(5-((4-乙基六氫吡嗪-1-基)甲基)吡啶-2-基)-5-氟-4-(8-氟-4-(2-氟丙-2-基)-2-甲基喹啉-6-基)嘧啶-2-胺(實例22,150 mg, 0.28 mmol)於甲醇(3 mL)中之混合物中添加35%鹽酸水溶液(102 mg, 2.8 mmol)。將所得澄清溶液攪拌30 min,用甲基第三丁基醚(6 mL)稀釋並攪拌30 min。過濾所形成之固體,用甲基第三丁基醚(5 mL)洗滌並乾燥,得到呈淡黃色固體之標題化合物(60 mg)。產率:37%。熔點:250℃-253℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 11.56 (br. s, 1H), 10.95 (br. s, 1H), 8.64 (s, 1H), 8.54 (d, J  3.2, 1H), 8.25 (s, 1H), 7.96 (d, J  8.8, 1H), 7.88-7.80 (m, 2H), 7.32 (s, 3H), 4.10 (br. s, 2H), 3.40-2.70 (m, 10H), 2.41 (s, 3H), 2.20-2.00 (m, 2H), 1.63 (d, J  22.8, 6H), 0.91 (t, J  7.2, 3H)。MS (m/z):536.39 (M+H-HCl);[C 29H 32F 3N 7.HCl + H]計算值:536.27。 實例 23 4-(6-((5- -4-(8- -4-(2- 氟丙 -2- )-2- 甲基喹啉 -6- ) 嘧啶 -2- ) 胺基 ) 吡啶 -3- ) 六氫吡嗪 -1- 甲酸第三丁基酯 To N-(5-((4-ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-4-(2-fluoropropane- 2-yl)-2-methylquinolin-6-yl)pyrimidin-2-amine (Example 22, 150 mg, 0.28 mmol) in methanol (3 mL) was added 35% aqueous hydrochloric acid (102 mg, 2.8 mmol). The resulting clear solution was stirred for 30 min, diluted with methyl tert-butyl ether (6 mL) and stirred for 30 min. The solid formed was filtered, washed with methyl tert-butyl ether (5 mL) and dried to give the title compound (60 mg) as a light yellow solid. Yield: 37%. Melting point: 250°C-253°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 11.56 (br. s, 1H), 10.95 (br. s, 1H), 8.64 (s, 1H), 8.54 (d, J 3.2, 1H ), 8.25 (s, 1H), 7.96 (d, J 8.8, 1H), 7.88-7.80 (m, 2H), 7.32 (s, 3H), 4.10 (br. s, 2H), 3.40-2.70 (m, 10H), 2.41 (s, 3H), 2.20-2.00 (m, 2H), 1.63 (d, J 22.8, 6H), 0.91 (t, J 7.2, 3H). MS (m/z): 536.39 (M+H-HCl); Calcd. for [ C29H32F3N7.HCl +H]: 536.27 . Example 23 4-(6-((5- fluoro - 4-(8- fluoro - 4-(2- fluoroprop- 2- yl )-2 -methylquinolin -6- yl ) pyrimidin -2- yl ) Amino ) pyridin - 3 -yl ) hexahydropyrazine- 1 -carboxylic acid tert-butyl ester

遵循一般程序-3,自中間物39 (500 mg, 1.42 mmol)及中間物5 (396 mg, 1.42 mmol)合成標題化合物。在後處理後,藉由combi-flash使用甲醇及DCM (6.5:93.5)作為溶析液純化粗產物。使彙集之溶離份蒸發,且將殘餘物與二乙醚(10 mL)一起攪拌30 min,過濾固體,用二乙醚(5 mL)洗滌並乾燥,獲得呈黃色固體之標題化合物(220 mg)。產率:26.1%。熔點:224℃-226℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 8.94 (s, 1H), 8.47 (d, J  3.6, 1H), 8.33 (d, J  8.8, 1H), 8.20-8.14 (m, 2H), 8.06 (d, J  2.8, 1H), 7.48 (s, 1H), 7.37 (dd, J  8.8, 2.8, 1H), 3.62 (t, J  4.8, 4H), 3.11 (t, J  4.8, 4H), 2.85 (s, 3H), 2.00 (d, J  22.4, 6H), 1.50 (s, 9H)。MS (m/z):594.34 (M+H);[C 31H 34F 3N 7O 2+ H]計算值:594.28。 實例 23A 5- -4-(8- -4-(2- 氟丙 -2- )-2- 甲基喹啉 -6- )-N-(5-( 六氫吡嗪 -1- ) 吡啶 -2- ) 嘧啶 -2- The title compound was synthesized from Intermediate 39 (500 mg, 1.42 mmol) and Intermediate 5 (396 mg, 1.42 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (6.5:93.5) as eluents. The pooled fractions were evaporated and the residue was stirred with diethyl ether (10 mL) for 30 min, the solid was filtered, washed with diethyl ether (5 mL) and dried to give the title compound (220 mg) as a yellow solid. Yield: 26.1%. Melting point: 224°C-226°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 8.94 (s, 1H), 8.47 (d, J 3.6, 1H), 8.33 (d, J 8.8, 1H), 8.20-8.14 (m, 2H), 8.06 (d, J 2.8, 1H), 7.48 (s, 1H), 7.37 (dd, J 8.8, 2.8, 1H), 3.62 (t, J 4.8, 4H), 3.11 (t, J 4.8, 4H ), 2.85 (s, 3H), 2.00 (d, J 22.4, 6H), 1.50 (s, 9H). MS (m/z): 594.34 (M+H); Calcd. for [ C31H34F3N7O2 + H]: 594.28 . Example 23A 5- fluoro - 4-(8- fluoro - 4-(2- fluoroprop- 2- yl )-2 -methylquinolin -6- yl )-N-(5-( hexahydropyrazine -1 -yl ) pyridin -2- yl ) pyrimidin - 2- amine

遵循一般程序-4,自4-(6-((5-氟-4-(8-氟-4-(2-氟丙-2-基)-2-甲基喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-1-甲酸第三丁基酯(實例23,200 mg, 0.34 mmol)合成呈黃色固體之標題化合物(120 mg)。產率:72%。熔點:204℃-206℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 9.88 (s, 1H), 8.94 (s, 1H), 8.71 (d, J  3.6, 1H), 8.14 (d, J  11.6, 1H), 8.07 (d, J  8.8, 1H), 8.03 (d, J  3.2, 1H), 7.64 (s, 1H), 7.42 (dd, J  9.2, 3.2, 1H), 3.14 (t, J  5.2, 4H), 2.99 (t, J  5.2, 4H), 2.74 (s, 3H), 1.95 (d, J  22.8, 6H)。MS (m/z):494.49 (M+H);[C 27H 27F 4N 7+ H]計算值:494.23。 實例 23B 5- -4-(8- -4-(2- 氟丙 -2- )-2- 甲基喹啉 -6- )-N-(5-( 六氫吡嗪 -1- ) 吡啶 -2- ) 嘧啶 -2- 胺鹽酸鹽 Following general procedure-4, from 4-(6-((5-fluoro-4-(8-fluoro-4-(2-fluoroprop-2-yl)-2-methylquinolin-6-yl)pyrimidine -2-yl)amino)pyridin-3-yl)tert-butyl hexahydropyrazine-1-carboxylate (Example 23, 200 mg, 0.34 mmol) The title compound (120 mg) was synthesized as a yellow solid. Yield: 72%. Melting point: 204°C-206°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.88 (s, 1H), 8.94 (s, 1H), 8.71 (d, J 3.6, 1H), 8.14 (d, J 11.6, 1H) , 8.07 (d, J 8.8, 1H), 8.03 (d, J 3.2, 1H), 7.64 (s, 1H), 7.42 (dd, J 9.2, 3.2, 1H), 3.14 (t, J 5.2, 4H), 2.99 (t, J 5.2, 4H), 2.74 (s, 3H), 1.95 (d, J 22.8, 6H). MS (m/z): 494.49 (M+H); Calcd. for [ C27H27F4N7 + H]: 494.23 . Example 23B 5- fluoro - 4-(8- fluoro - 4-(2- fluoroprop- 2- yl )-2 -methylquinolin -6- yl )-N-(5-( hexahydropyrazine -1 -yl ) pyridin -2- yl ) pyrimidin - 2- amine hydrochloride

向5-氟-4-(8-氟-4-(2-氟丙-2-基)-2-甲基喹啉-6-基)-N-(5-(六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺(實例23A,80 mg, 0.16 mmol)於甲醇(2 mL)中之混合物中添加35%鹽酸水溶液(59 mg, 1.6 mmol)。將所得澄清溶液攪拌30 min,用甲基第三丁基醚(6 mL)稀釋並攪拌30 min。過濾所形成之固體,用甲基第三丁基醚(5 mL)洗滌並乾燥,得到呈淡黃色固體之標題化合物(60 mg)。產率:68%。熔點:240℃-243℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 11.77 (br. s, 1H), 9.53 (br. s, 2H), 8.95-8.89 (m, 2H), 8.22-8.12 (m, 2H), 7.97 (d, J  2.8, 1H), 7.86 (d, J  9.2, 1H), 7.67 (s, 1H), 3.46 (br. s, 4H), 3.25 (br. s, 4H), 2.75 (s, 3H), 1.95 (d, J  22.4, 6H)。MS (m/z):494.47 (M+H-HCl);[C 27H 27F 4N 7.HCl + H-HCl]計算值:494.23。 實例 24 5- -N-(5-((4- 甲基六氫吡嗪 -1- ) 甲基 ) 吡啶 -2- )-4-( 喹啉 -6- ) 嘧啶 -2- To 5-fluoro-4-(8-fluoro-4-(2-fluoroprop-2-yl)-2-methylquinolin-6-yl)-N-(5-(hexahydropyrazine-1- yl)pyridin-2-yl)pyrimidin-2-amine (Example 23A, 80 mg, 0.16 mmol) in methanol (2 mL) was added 35% aqueous hydrochloric acid (59 mg, 1.6 mmol). The resulting clear solution was stirred for 30 min, diluted with methyl tert-butyl ether (6 mL) and stirred for 30 min. The solid formed was filtered, washed with methyl tert-butyl ether (5 mL) and dried to give the title compound (60 mg) as a light yellow solid. Yield: 68%. Melting point: 240°C-243°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 11.77 (br. s, 1H), 9.53 (br. s, 2H), 8.95-8.89 (m, 2H), 8.22-8.12 (m, 2H), 7.97 (d, J 2.8, 1H), 7.86 (d, J 9.2, 1H), 7.67 (s, 1H), 3.46 (br. s, 4H), 3.25 (br. s, 4H), 2.75 ( s, 3H), 1.95 (d, J 22.4, 6H). MS (m/z): 494.47 (M+H-HCl); Calcd. for [ C27H27F4N7.HCl + H - HCl]: 494.23 . Example 24 5- fluoro -N-(5-((4- methylhexahydropyrazin- 1 -yl ) methyl ) pyridin -2- yl )-4-( quinolin -6- yl ) pyrimidine -2- amine

遵循一般程序3,自中間物2 (500 mg, 1.93 mmol)及中間物27 (397 mg, 1.93 mmol)合成標題化合物。在後處理後,藉由combi-flash使用甲醇及DCM (11.5:89.5)作為溶析液純化粗產物。使彙集之溶離份蒸發,且將殘餘物與二乙醚(10 mL)一起攪拌30 min,過濾固體,用二乙醚(5 mL)洗滌並乾燥,獲得呈黃色固體之標題化合物(320 mg)。產率:38.7%。熔點:196℃-198℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 10.08 (s, 1H), 9.01 (dd, J  4.4, 1.2, 1H), 8.77 (d, J  3.2, 1H), 8.71 (s, 1H), 8.59 (d, J  7.6, 1H), 8.42 (d, J  9.2, 1H), 8.27-8.16 (m, 3H), 7.72 (dd, J  8.4, 2.4, 1H), 7.64 (dd, J  8.0, 4.0, 1H), 3.42 (s, 2H), 2.56-2.24 (m, 8H,), 2.15 (s, 3H)。MS (m/z):430.29 (M+H);[C 24H 24FN 7+ H]計算值:430.22。 實例 24A 5- -N-(5-((4- 甲基六氫吡嗪 -1- ) 甲基 ) 吡啶 -2- )-4-( 喹啉 -6- ) 嘧啶 -2- 胺鹽酸鹽 The title compound was synthesized from Intermediate 2 (500 mg, 1.93 mmol) and Intermediate 27 (397 mg, 1.93 mmol) following general procedure 3. After work-up, the crude product was purified by combi-flash using methanol and DCM (11.5:89.5) as eluents. The pooled fractions were evaporated and the residue was stirred with diethyl ether (10 mL) for 30 min, the solid was filtered, washed with diethyl ether (5 mL) and dried to afford the title compound (320 mg) as a yellow solid. Yield: 38.7%. Melting point: 196°C-198°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 10.08 (s, 1H), 9.01 (dd, J 4.4, 1.2, 1H), 8.77 (d, J 3.2, 1H), 8.71 (s, 1H), 8.59 (d, J 7.6, 1H), 8.42 (d, J 9.2, 1H), 8.27-8.16 (m, 3H), 7.72 (dd, J 8.4, 2.4, 1H), 7.64 (dd, J 8.0 , 4.0, 1H), 3.42 (s, 2H), 2.56-2.24 (m, 8H,), 2.15 (s, 3H). MS (m/z): 430.29 (M+H); Calcd. for [ C24H24FN7 +H]: 430.22 . Example 24A 5- fluoro -N-(5-((4- methylhexahydropyrazin- 1 -yl ) methyl ) pyridin -2- yl )-4-( quinolin -6- yl ) pyrimidine -2- Amine hydrochloride

向5-氟-N-(5-((4-甲基六氫吡嗪-1-基)甲基)吡啶-2-基)-4-(喹啉-6-基)嘧啶-2-胺(實例24,300 mg, 0.70 mmol)於甲醇(7.5 mL)中之混合物中添加35%鹽酸水溶液(260 mg, 7.1 mmol)。將所得澄清溶液攪拌30 min,用甲基第三丁基醚(15 mL)稀釋並攪拌1 h。過濾所形成之固體,用甲基第三丁基醚(15 mL)洗滌並乾燥,得到呈淡褐色固體之標題化合物(60 mg)。產率:68%。熔點:235℃-238℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 12.00 (br. s, 1H), 11.47 (br. s, 1H), 9.23 (dd, J  4.8, 1.2, 1H), 9.01 (d, J  8.4, 1H), 8.94 (d, J  2.8, 1H), 8.91 (s, 1H), 8.64-8.57 (m, 2H), 8.44 (d, J  9.2, 1H), 8.33 (d, J  9.2, 1H), 8.10 (d, J  9.2, 1H), 8.10 (d, J  9.2, 1H), 8.10 (d, J  9.2, 1H), 7.92 (dd, J  8.4, 4.8, 1H), 4.44 (br. s, 2H), 3.70-3.55 (m, 4H), 3.50-3.30 (m, 4H), 2.80 (s, 3H)。MS (m/z):430.33 (M+H-HCl);[C 24H 24FN 7.HCl+ H-HCl]計算值:430.22。 實例 25 N-(5-((4- 乙基六氫吡嗪 -1- ) 甲基 ) 吡啶 -2- )-5- -4-(7- 氟喹啉 -6- ) 嘧啶 -2- To 5-fluoro-N-(5-((4-methylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-4-(quinolin-6-yl)pyrimidin-2-amine (Example 24, 300 mg, 0.70 mmol) in methanol (7.5 mL) was added 35% aqueous hydrochloric acid (260 mg, 7.1 mmol). The resulting clear solution was stirred for 30 min, diluted with methyl tert-butyl ether (15 mL) and stirred for 1 h. The resulting solid was filtered, washed with methyl tert-butyl ether (15 mL) and dried to give the title compound (60 mg) as a light brown solid. Yield: 68%. Melting point: 235°C-238°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 12.00 (br. s, 1H), 11.47 (br. s, 1H), 9.23 (dd, J 4.8, 1.2, 1H), 9.01 (d , J 8.4, 1H), 8.94 (d, J 2.8, 1H), 8.91 (s, 1H), 8.64-8.57 (m, 2H), 8.44 (d, J 9.2, 1H), 8.33 (d, J 9.2, 1H), 8.10 (d, J 9.2, 1H), 8.10 (d, J 9.2, 1H), 8.10 (d, J 9.2, 1H), 7.92 (dd, J 8.4, 4.8, 1H), 4.44 (br.s , 2H), 3.70-3.55 (m, 4H), 3.50-3.30 (m, 4H), 2.80 (s, 3H). MS (m/z): 430.33 (M+H-HCl); Calcd. for [ C24H24FN7.HCl +H - HCl]: 430.22 . Example 25 N-(5-((4- ethylhexahydropyrazin- 1 -yl ) methyl ) pyridin -2- yl )-5- fluoro - 4-(7- fluoroquinolin- 6- yl ) pyrimidine -2- amine

遵循一般程序-3,自中間物41 (500 mg, 1.80 mmol)及中間物9 (400 mg, 1.80 mmol)合成標題化合物。在後處理後,藉由combi-flash使用甲醇及DCM (8.7:91.3)作為溶析液純化粗產物。使彙集之溶離份蒸發,且將殘餘物與二乙醚(10 mL)一起攪拌30 min,過濾固體,用二乙醚(5 mL)洗滌並乾燥,獲得呈淡黃色固體之標題化合物(370 mg)。產率:44.5%。熔點:198℃-200℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 10.19 (s, 1H), 9.03 (br. d, J  3.2, 1H), 8.00 (d, J  1.6, 1H), 8.59 (d, J  8.0, 1H), 8.47 (d, J  8.0, 1H), 8.21-8.15 (m, 2H), 7.99 (d, J  11.2, 1H), 7.68-7.60 (m, 2H), 3.39 (s, 2H), 2.40-2.20 (m, 10H), 0.96 (t, J = 10.8, 3H)。MS (m/z):462.34 (M+H);[C 25H 25F 2N 7+ H]計算值:462.22。 實例 25A N-(5-((4- 乙基六氫吡嗪 -1- ) 甲基 ) 吡啶 -2- )-5- -4-(7- 氟喹啉 -6- ) 嘧啶 -2- 胺鹽酸鹽 The title compound was synthesized from Intermediate 41 (500 mg, 1.80 mmol) and Intermediate 9 (400 mg, 1.80 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (8.7:91.3) as eluents. The pooled fractions were evaporated and the residue was stirred with diethyl ether (10 mL) for 30 min, the solid was filtered, washed with diethyl ether (5 mL) and dried to afford the title compound (370 mg) as a light yellow solid. Yield: 44.5%. Melting point: 198°C-200°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 10.19 (s, 1H), 9.03 (br. d, J 3.2, 1H), 8.00 (d, J 1.6, 1H), 8.59 (d, J 8.0, 1H), 8.47 (d, J 8.0, 1H), 8.21-8.15 (m, 2H), 7.99 (d, J 11.2, 1H), 7.68-7.60 (m, 2H), 3.39 (s, 2H) , 2.40-2.20 (m, 10H), 0.96 (t, J = 10.8, 3H). MS (m/z): 462.34 (M+H); Calcd. for [ C25H25F2N7 + H]: 462.22 . Example 25A N-(5-((4- ethylhexahydropyrazin- 1 -yl ) methyl ) pyridin -2- yl )-5- fluoro - 4-(7- fluoroquinolin- 6- yl ) pyrimidine -2- amine hydrochloride

向N-(5-((4-乙基六氫吡嗪-1-基)甲基)吡啶-2-基)-5-氟-4-(7-氟喹啉-6-基)嘧啶-2-胺(實例25,330 mg, 0.72 mmol)於甲醇(8.25 mL)中之混合物中添加35%鹽酸水溶液(260 mg, 7.1 mmol)。將所得澄清溶液攪拌30 min,用甲基第三丁基醚(24.7 mL)稀釋並攪拌1 h。過濾所形成之固體,用甲基第三丁基醚(20 mL)洗滌並乾燥,得到呈淡黃色固體之標題化合物(290 mg)。產率:81%。熔點:255℃-257℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 11.94 (br. s, 1H), 11.51 (br. s, 1H), 9.12 (dd, J = 4.4, 1.6, 1H), 8.96 (d, J = 1.6, 1H), 8.74 (d, J = 7.4, 1H), 8.62-8.56 (m, 2H), 8.28 (d, J = 9.2, 1H), 8.14-8.04 (m, 2H), 7.74 (dd, J = 8.4, 4.8, 1H), 4.43 (br. s, 2H), 3.80-3.10 (m, 10H), 1.24 (t, J = 7.2, 3H)。MS (m/z):462.35 (M+H-HCl);[C 25H 25F 2N 7.HCl + H-HCl]計算值:462.22。 實例 26 4-(6-((5- -4-(7- 氟喹啉 -6- ) 嘧啶 -2- ) 胺基 ) 吡啶 -3- ) 六氫吡嗪 -1- 甲酸第三丁基酯 To N-(5-((4-ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(7-fluoroquinolin-6-yl)pyrimidine- To a mixture of 2-amine (Example 25, 330 mg, 0.72 mmol) in methanol (8.25 mL) was added 35% aqueous hydrochloric acid (260 mg, 7.1 mmol). The resulting clear solution was stirred for 30 min, diluted with methyl tert-butyl ether (24.7 mL) and stirred for 1 h. The resulting solid was filtered, washed with methyl tert-butyl ether (20 mL) and dried to give the title compound (290 mg) as a light yellow solid. Yield: 81%. Melting point: 255°C-257°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 11.94 (br. s, 1H), 11.51 (br. s, 1H), 9.12 (dd, J = 4.4, 1.6, 1H), 8.96 ( d, J = 1.6, 1H), 8.74 (d, J = 7.4, 1H), 8.62-8.56 (m, 2H), 8.28 (d, J = 9.2, 1H), 8.14-8.04 (m, 2H), 7.74 (dd, J = 8.4, 4.8, 1H), 4.43 (br. s, 2H), 3.80-3.10 (m, 10H), 1.24 (t, J = 7.2, 3H). MS (m/z): 462.35 (M+H-HCl); Calcd. for [ C25H25F2N7.HCl + H - HCl]: 462.22. Example 26 4-(6-((5- fluoro - 4-(7- fluoroquinolin- 6- yl ) pyrimidin -2- yl ) amino ) pyridin - 3 -yl ) hexahydropyrazine- 1 - carboxylic acid tributyl ester

遵循一般程序-3,自中間物41 (500 mg, 1.80 mmol)及中間物5 (500 mg, 1.80 mmol)合成標題化合物。在後處理後,藉由combi-flash使用甲醇及DCM (2.3:97.7)作為溶析液純化粗產物。使彙集之溶離份蒸發,且將殘餘物與二乙醚(10 mL)一起攪拌30 min,過濾固體,用二乙醚(5 mL)洗滌並乾燥,獲得呈黃色固體之標題化合物(360 mg)。產率:38.5%。熔點:248℃-250℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 9.93 (s, 1H), 9.03 (dd, J  4.0, 1.6, 1H), 8.74 (d, J  1.6, 1H), 8.58 (d, J  7.6, 1H), 8.06-7.95 (m, 3H), 7.63 (dd, J  8.4, 4.4, 1H), 7.42 (dd, J  9.2, 3.2, 1H), 3.48-3.42 (m, 4H), 3.08-3.02 (m, 4H), 1.41 (s, 9H)。MS (m/z):520.31 (M+H);[C 27H 27F 2N 7O 2+ H]計算值:520.22。 實例 26A 5- -4-(7- 氟喹啉 -6- )-N-(5-( 六氫吡嗪 -1- ) 吡啶 -2- ) 嘧啶 -2- The title compound was synthesized from Intermediate 41 (500 mg, 1.80 mmol) and Intermediate 5 (500 mg, 1.80 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (2.3:97.7) as eluents. The pooled fractions were evaporated and the residue was stirred with diethyl ether (10 mL) for 30 min, the solid was filtered, washed with diethyl ether (5 mL) and dried to afford the title compound (360 mg) as a yellow solid. Yield: 38.5%. Melting point: 248°C-250°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.93 (s, 1H), 9.03 (dd, J 4.0, 1.6, 1H), 8.74 (d, J 1.6, 1H), 8.58 (d, J 7.6, 1H), 8.06-7.95 (m, 3H), 7.63 (dd, J 8.4, 4.4, 1H), 7.42 (dd, J 9.2, 3.2, 1H), 3.48-3.42 (m, 4H), 3.08- 3.02 (m, 4H), 1.41 (s, 9H). MS (m/z): 520.31 (M + H); Calcd. for [ C27H27F2N7O2 + H]: 520.22 . Example 26A 5- fluoro - 4-(7- fluoroquinolin- 6- yl )-N-(5-( hexahydropyrazin- 1 -yl ) pyridin -2- yl ) pyrimidin -2- amine

遵循一般程序-4,自4-(6-((5-氟-4-(7-氟喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-1-甲酸第三丁基酯(實例26,330 mg, 0.64 mmol)合成呈黃色固體之標題化合物(250 mg)。產率:93%。熔點:228℃-230℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 9.89 (s, 1H), 9.05-9.00 (m, 1H), 9.03 (s, 1H), 8.58 (d, J  7.6, 1H), 8.45 (d, J  7.6, 1H), 8.02-7.87 (m, 3H), 7.63 (dd, J  8.4, 4.0, 1H), 7.37 (d, J  8.8, 1H), 3.02-2.94 (m, 4H), 2.84-2.78 (m, 4H)。MS (m/z):420.47 (M+H);[C 22H 19F 2N 7+ H]計算值:420.17。 實例 26B 5- -4-(7- 氟喹啉 -6- )-N-(5-( 六氫吡嗪 -1- ) 吡啶 -2- ) 嘧啶 -2- 胺鹽酸鹽 Following General Procedure-4, from 4-(6-((5-fluoro-4-(7-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazine - tert-butyl 1-carboxylate (Example 26, 330 mg, 0.64 mmol) The title compound (250 mg) was synthesized as a yellow solid. Yield: 93%. Melting point: 228°C-230°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.89 (s, 1H), 9.05-9.00 (m, 1H), 9.03 (s, 1H), 8.58 (d, J 7.6, 1H), 8.45 (d, J 7.6, 1H), 8.02-7.87 (m, 3H), 7.63 (dd, J 8.4, 4.0, 1H), 7.37 (d, J 8.8, 1H), 3.02-2.94 (m, 4H), 2.84-2.78 (m, 4H). MS (m/z): 420.47 (M+H); Calcd. for [ C22H19F2N7 + H]: 420.17 . Example 26B 5- fluoro - 4-(7- fluoroquinolin- 6- yl )-N-(5-( hexahydropyrazin- 1 -yl ) pyridin -2- yl ) pyrimidin -2- amine hydrochloride

向5-氟-4-(7-氟喹啉-6-基)-N-(5-(六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺(實例26A,230 mg, 0.55 mmol)於甲醇(5.75 mL)中之混合物中添加35%鹽酸水溶液(200 mg, 5.48 mmol)。將所得澄清溶液攪拌30 min,用甲基第三丁基醚(17.3 mL)稀釋並攪拌1 h。過濾所形成之固體,用甲基第三丁基醚(20 mL)洗滌並乾燥,得到呈褐色固體之標題化合物(190 mg)。產率:76%。熔點:259℃-262℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 11.87 (br. s, 1H), 9.66 (br. s, 2H), 9.08-9.13 (m, 1H), 8.98 (d, J = 2.0, 1H), 8.72 (d, J = 8.4, 1H), 8.59 (d, J = 7.6, 1H), 8.16 (d, J = 9.2, 1H), 8.10 (d, J = 11.6, 1H), 7.99 (d, J = 2.8, 1H), 7.84 (d, J = 9.6, 1H), 7.72 (dd, J = 8.0, 4.4, 1H), 3.42 (bs, 4H), 3.22 (bs, 4H)。MS (m/z):420.48 (M+H);[C 22H 19F 2N 7.HCl + H-HCl]計算值:420.17。 實例 27 N-(5-(4- 乙基六氫吡嗪 -1- ) 吡啶 -2- )-5- -4-(7- 氟喹啉 -6- ) 嘧啶 -2- To 5-fluoro-4-(7-fluoroquinolin-6-yl)-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine (example 26A, 230 mg, 0.55 mmol) in methanol (5.75 mL) was added 35% aqueous hydrochloric acid (200 mg, 5.48 mmol). The resulting clear solution was stirred for 30 min, diluted with methyl tert-butyl ether (17.3 mL) and stirred for 1 h. The solid formed was filtered, washed with methyl tert-butyl ether (20 mL) and dried to give the title compound (190 mg) as a tan solid. Yield: 76%. Melting point: 259°C-262°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 11.87 (br. s, 1H), 9.66 (br. s, 2H), 9.08-9.13 (m, 1H), 8.98 (d, J = 2.0, 1H), 8.72 (d, J = 8.4, 1H), 8.59 (d, J = 7.6, 1H), 8.16 (d, J = 9.2, 1H), 8.10 (d, J = 11.6, 1H), 7.99 (d, J = 2.8, 1H), 7.84 (d, J = 9.6, 1H), 7.72 (dd, J = 8.0, 4.4, 1H), 3.42 (bs, 4H), 3.22 (bs, 4H). MS (m/z): 420.48 (M+H); Calcd. for [ C22H19F2N7.HCl + H - HCl]: 420.17 . Example 27 N-(5-(4- ethylhexahydropyrazin- 1 -yl ) pyridin -2- yl )-5- fluoro - 4-(7- fluoroquinolin- 6- yl ) pyrimidin -2- amine

遵循一般程序-3,自中間物41 (500 mg, 1.80 mmol)及中間物20 (371 mg, 1.80 mmol)合成標題化合物。在後處理後,藉由combi-flash使用甲醇及DCM (5.8:94.2)作為溶析液純化粗產物。使彙集之溶離份蒸發,且將殘餘物與二乙醚(10 mL)一起攪拌30 min,過濾固體,用二乙醚(5 mL)洗滌並乾燥,獲得呈黃色固體之標題化合物(200 mg)。產率:24.8%。熔點:258℃-260℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 9.88 (s, 1H), 9.03-9.01 (m, 1H), 8.73 (bs, 1H), 8.58 (d, J 7.6, 1H), 8.45 (d, J 7.6, 1H), 8.02-7.88 (m, 3H), 7.63 (dd, J 8.4, 4.4 1H), 7.42-7.38 (m, 1H), 3.03 (bs, 4H), 2.60-2.40 (m, 4H), 2.40-2.30 (m, 2H), 1.02 (t, J = 6.8, 3H)。MS (m/z):448.47. (M+H);[C 24H 23F 2N 7+ H]計算值:448.20。 實例 27A N-(5-(4- 乙基六氫吡嗪 -1- ) 吡啶 -2- )-5- -4-(7- 氟喹啉 -6- ) 嘧啶 -2- 胺鹽酸鹽 The title compound was synthesized from Intermediate 41 (500 mg, 1.80 mmol) and Intermediate 20 (371 mg, 1.80 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (5.8:94.2) as eluents. The pooled fractions were evaporated and the residue was stirred with diethyl ether (10 mL) for 30 min, the solid was filtered, washed with diethyl ether (5 mL) and dried to give the title compound (200 mg) as a yellow solid. Yield: 24.8%. Melting point: 258°C-260°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.88 (s, 1H), 9.03-9.01 (m, 1H), 8.73 (bs, 1H), 8.58 (d, J 7.6, 1H), 8.45 (d, J 7.6, 1H), 8.02-7.88 (m, 3H), 7.63 (dd, J 8.4, 4.4 1H), 7.42-7.38 (m, 1H), 3.03 (bs, 4H), 2.60-2.40 ( m, 4H), 2.40-2.30 (m, 2H), 1.02 (t, J = 6.8, 3H). MS (m/z): 448.47 . (M+H); Calcd. for [ C24H23F2N7 + H]: 448.20 . Example 27A N-(5-(4- ethylhexahydropyrazin- 1 -yl ) pyridin -2- yl )-5- fluoro - 4-(7- fluoroquinolin- 6- yl ) pyrimidin -2- amine Hydrochloride

向N-(5-(4-乙基六氫吡嗪-1-基)吡啶-2-基)-5-氟-4-(7-氟喹啉-6-基)嘧啶-2-胺(實例27,180 mg, 0.40 mmol)於甲醇(4.5 mL)中之混合物中添加35%鹽酸水溶液(147 mg, 4.02 mmol)。將所得澄清溶液攪拌30 min,用甲基第三丁基醚(13.5 mL)稀釋並攪拌1 h。過濾所形成之固體,用甲基第三丁基醚(20 mL)洗滌並乾燥,得到呈黃色固體之標題化合物(160 mg)。產率:82.5%。熔點:240℃-242℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 11.91 (bs, 1H), 11.42 (bs, 1H), 9.11 (dd, J 4.4, 1.2, 1H), 8.99(d, J 1.6, 1H), 8.72 (d, J 8.4, 1H), 8.59 (d, J 8.0, 1H), 8.20 (dd, J 9.6, 2.4, 1H), 8.10 (d, J 11.6, 1H), 8.00 (d, J 2.4, 1H), 7.82 (d, J 9.6, 1H), 7.73 (d, J 8.0, 4.4, 1H), 3.84 (d, J 12.8, 2H), 3.57 (d, J 11.6, 2H), 3.27 (d, J 12.0, 2H), 3.04-3.00 (m, 4H), 1.29 (t, J 7.2, 3H)。MS (m/z):448.46. (M+H);[C 24H 23F 2N 7.HCl + H-HCl]計算值:448.20。 實例 28 N-(5-(4-( 二甲基胺基 ) 六氫吡啶 -1- ) 吡啶 -2- )-5- -4-(8- 氟喹啉 -6- ) 嘧啶 -2- To N-(5-(4-ethylhexahydropyrazin-1-yl)pyridin-2-yl)-5-fluoro-4-(7-fluoroquinolin-6-yl)pyrimidin-2-amine ( To a mixture of Example 27, 180 mg, 0.40 mmol) in methanol (4.5 mL) was added 35% aqueous hydrochloric acid (147 mg, 4.02 mmol). The resulting clear solution was stirred for 30 min, diluted with methyl tert-butyl ether (13.5 mL) and stirred for 1 h. The resulting solid was filtered, washed with methyl tert-butyl ether (20 mL) and dried to give the title compound (160 mg) as a yellow solid. Yield: 82.5%. Melting point: 240°C-242°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 11.91 (bs, 1H), 11.42 (bs, 1H), 9.11 (dd, J 4.4, 1.2, 1H), 8.99(d, J 1.6, 1H), 8.72 (d, J 8.4, 1H), 8.59 (d, J 8.0, 1H), 8.20 (dd, J 9.6, 2.4, 1H), 8.10 (d, J 11.6, 1H), 8.00 (d, J 2.4, 1H), 7.82 (d, J 9.6, 1H), 7.73 (d, J 8.0, 4.4, 1H), 3.84 (d, J 12.8, 2H), 3.57 (d, J 11.6, 2H), 3.27 (d , J 12.0, 2H), 3.04-3.00 (m, 4H), 1.29 (t, J 7.2, 3H). MS (m/z): 448.46. (M+H); Calcd. for [ C24H23F2N7.HCl + H - HCl]: 448.20 . Example 28 N-(5-(4-( dimethylamino ) hexahydropyridin- 1 -yl ) pyridin -2- yl )-5- fluoro - 4-(8- fluoroquinolin- 6- yl ) pyrimidine -2- amine

遵循一般程序-3,自中間物7 (500 mg, 1.80 mmol)及中間物43 (400 mg, 1.80 mmol)合成標題化合物。在後處理後,藉由combi-flash使用甲醇及DCM (16:84)作為溶析液純化粗產物。使彙集之溶離份蒸發,且將殘餘物與二乙醚(20 mL)一起攪拌30 min,過濾固體,用二乙醚(20 mL)洗滌並乾燥,獲得呈黃色固體之標題化合物(270 mg)。產率:32%。熔點:238℃-240℃。熔點:238℃-240℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 9.48 (s, 1H), 9.06 (d, J 2.8, 1H), 8.73 (d, J 4, 1H), 8.66 (d, J 8.4, 1H), 8.56 (s, 1H), 8.20 (d, J 12, 1H), 8.07-8.01 (m, 2H), 7.74 (dd, J 8.4, 4, 1H), 7.50 (dd, J 9.2, 2.8, 1H), 3.76 (d, J 12, 2H), 2.72-2.64 (m, 2H), 2.61-2.50 (m, 7H), 1.99 (d, J 12, 2H), 1.72-1.60 (m, 2H)。MS (m/z):462.40. (M+H);[C 25H 25F 2N 7+ H]計算值:462.21。 實例 28A N-(5-(4-( 二甲基胺基 ) 六氫吡啶 -1- ) 吡啶 -2- )-5- -4-(8- 氟喹啉 -6- ) 嘧啶 -2- 胺鹽酸鹽 The title compound was synthesized from Intermediate 7 (500 mg, 1.80 mmol) and Intermediate 43 (400 mg, 1.80 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (16:84) as eluents. The pooled fractions were evaporated and the residue was stirred with diethyl ether (20 mL) for 30 min, the solid was filtered, washed with diethyl ether (20 mL) and dried to give the title compound (270 mg) as a yellow solid. Yield: 32%. Melting point: 238°C-240°C. Melting point: 238°C-240°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.48 (s, 1H), 9.06 (d, J 2.8, 1H), 8.73 (d, J 4, 1H), 8.66 (d, J 8.4 , 1H), 8.56 (s, 1H), 8.20 (d, J 12, 1H), 8.07-8.01 (m, 2H), 7.74 (dd, J 8.4, 4, 1H), 7.50 (dd, J 9.2, 2.8 , 1H), 3.76 (d, J 12, 2H), 2.72-2.64 (m, 2H), 2.61-2.50 (m, 7H), 1.99 (d, J 12, 2H), 1.72-1.60 (m, 2H) . MS (m/z): 462.40 . (M+H); Calcd. for [ C25H25F2N7 + H]: 462.21 . Example 28A N-(5-(4-( dimethylamino ) hexahydropyridin- 1 -yl ) pyridin -2- yl )-5- fluoro - 4-(8- fluoroquinolin- 6- yl ) pyrimidine -2- amine hydrochloride

向N-(5-(4-(二甲基胺基)六氫吡啶-1-基)吡啶-2-基)-5-氟-4-(8-氟喹啉-6-基)嘧啶-2-胺(實例28,250 mg, 0.54 mmol)於甲醇(6.25 mL)中之混合物中添加35%鹽酸水溶液(20 mg, 5.4 mmol)。將所得澄清溶液攪拌30 min,用甲基第三丁基醚(18.75 mL)稀釋並攪拌1 h。過濾所形成之固體,用甲基第三丁基醚(20 mL)洗滌並乾燥,得到呈褐色固體之標題化合物(230 mg)。產率:85%。熔點:292℃-294℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 11.87 (bs, 1H), 11.14 (bs, 1H), 9.08 (dd, J 4, 1.6, 1H), 8.95 (d, J 4, 1H), 8.70 (dd, J 8.8, 1.6, 1H), 8.61 (s, 1H), 8.25 (d, J 9.6, 1H), 8.21 (dd, J 12, 1.2, 1H), 7.97 (d, J 2.4, 1H), 7.82-7.76 (m, 2H), 3.86 (d, J 12, 2H), 3.38-3.28 (m, 1H), 2.81 (t, J 12, 2H), 2.71 (s, 3H), 2.70 (s, 3H), 2.17 (d, J 12, 2H), 1.85-1.72 (m, 2H)。MS (m/z):462.40. (M+H);[C 25H 25F 2N 7.HCl + H-HCl]計算值:462.21。 實例 29 4-(6-((5- -4-(8- 氟喹啉 -6- ) 嘧啶 -2- ) 胺基 ) 吡啶 -3- ) 六氫吡嗪 -2- To N-(5-(4-(dimethylamino)hexahydropyridin-1-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidine- To a mixture of 2-amine (Example 28, 250 mg, 0.54 mmol) in methanol (6.25 mL) was added 35% aqueous hydrochloric acid (20 mg, 5.4 mmol). The resulting clear solution was stirred for 30 min, diluted with methyl tert-butyl ether (18.75 mL) and stirred for 1 h. The resulting solid was filtered, washed with methyl tert-butyl ether (20 mL) and dried to give the title compound (230 mg) as a tan solid. Yield: 85%. Melting point: 292°C-294°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 11.87 (bs, 1H), 11.14 (bs, 1H), 9.08 (dd, J 4, 1.6, 1H), 8.95 (d, J 4, 1H), 8.70 (dd, J 8.8, 1.6, 1H), 8.61 (s, 1H), 8.25 (d, J 9.6, 1H), 8.21 (dd, J 12, 1.2, 1H), 7.97 (d, J 2.4 , 1H), 7.82-7.76 (m, 2H), 3.86 (d, J 12, 2H), 3.38-3.28 (m, 1H), 2.81 (t, J 12, 2H), 2.71 (s, 3H), 2.70 (s, 3H), 2.17 (d, J 12, 2H), 1.85-1.72 (m, 2H). MS (m/z): 462.40. (M+H); Calcd. for [ C25H25F2N7.HCl + H - HCl]: 462.21 . Example 29 4-(6-((5- fluoro - 4-(8- fluoroquinolin- 6- yl ) pyrimidin -2- yl ) amino ) pyridin - 3 -yl ) hexahydropyrazin -2- one

遵循一般程序-3,自中間物7 (500 mg, 1.80 mmol)及中間物45 (350 mg, 1.80 mmol)合成標題化合物。在後處理後,藉由combi-flash使用甲醇及DCM (5.7:94.3)作為溶析液純化粗產物。使彙集之溶離份蒸發,且將殘餘物與二乙醚(20 mL)一起攪拌30 min,過濾固體,用二乙醚(20 mL)洗滌並乾燥,獲得呈黃色固體之標題化合物(180 mg)。產率:23%。熔點:205℃-207℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 9.87 (s, 1H), 9.06 (dd, J 4, 1.6, 1H), 8.73 (d, J 3.2, 1H), 8.66 (d, J 8.8, 1H), 8.56 (s, 1H), 8.20 (d, J 12, 1H), 8.06 (d, J 9.2, 2H), 8.03 (d, J 2.8, 1H), 7.74 (dd, J 8.8, 4.4, 1H), 3.71 (s, 2H), 3.42-3.37 (m, 2H), 3.40-3.30 (m, 2H)。MS (m/z):434.42. (M+H);[C 22H 17F 2N 7O + H]計算值:434.15。 實例 29A 4-(6-((5- -4-(8- 氟喹啉 -6- ) 嘧啶 -2- ) 胺基 ) 吡啶 -3- ) 六氫吡嗪 -2- 酮鹽酸鹽 The title compound was synthesized from Intermediate 7 (500 mg, 1.80 mmol) and Intermediate 45 (350 mg, 1.80 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (5.7:94.3) as eluents. The pooled fractions were evaporated and the residue was stirred with diethyl ether (20 mL) for 30 min, the solid was filtered, washed with diethyl ether (20 mL) and dried to give the title compound (180 mg) as a yellow solid. Yield: 23%. Melting point: 205°C-207°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.87 (s, 1H), 9.06 (dd, J 4, 1.6, 1H), 8.73 (d, J 3.2, 1H), 8.66 (d, J 8.8, 1H), 8.56 (s, 1H), 8.20 (d, J 12, 1H), 8.06 (d, J 9.2, 2H), 8.03 (d, J 2.8, 1H), 7.74 (dd, J 8.8, 4.4, 1H), 3.71 (s, 2H), 3.42-3.37 (m, 2H), 3.40-3.30 (m, 2H). MS (m/z): 434.42 . (M+H); Calcd. for [ C22H17F2N7O + H]: 434.15 . Example 29A 4-(6-((5- fluoro - 4-(8- fluoroquinolin- 6- yl ) pyrimidin -2- yl ) amino ) pyridin - 3 -yl ) hexahydropyrazin -2- one salt salt

向4-(6-((5-氟-4-(8-氟喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-2-酮(實例29,150 mg, 0.35 mmol)於甲醇(3.75 mL)中之混合物中添加35%鹽酸水溶液(13 mg, 3.5 mmol)。將所得澄清溶液攪拌30 min,用甲基第三丁基醚(11.25 mL)稀釋並攪拌1 h。過濾所形成之固體,用甲基第三丁基醚(20 mL)洗滌並乾燥,得到呈褐色固體之標題化合物(125 mg)。產率:77%。熔點:236℃-238℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 11.91 (s, 1H), 9.08 (d, J 4, 1H), 8.94 (d, J 2.4, 1H), 8.70 (d, J 8, 1H), 8.59 (s, 1H), 8.25-8.17 (m, 3H), 7.89 (d, J 2.8, 1H), 7.77 (dd, J 8, 3.6, 2H), 3.81 (s, 2H), 3.50-3.45 (m, 2H), 3.38-3.32 (m, 2H)。MS (m/z):434.38. (M+H);[C 22H 17F 2N 7O.HCl + H-HCl]計算值:434.15 實例 30 N-(5-(4- 環丙基六氫吡嗪 -1- ) 吡啶 -2- )-5- -4-(8- 氟喹啉 -6- ) 嘧啶 -2- To 4-(6-((5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazin-2-one (example 29, 150 mg, 0.35 mmol) in methanol (3.75 mL) was added 35% aqueous hydrochloric acid (13 mg, 3.5 mmol). The resulting clear solution was stirred for 30 min, diluted with methyl tert-butyl ether (11.25 mL) and stirred for 1 h. The resulting solid was filtered, washed with methyl tert-butyl ether (20 mL) and dried to give the title compound (125 mg) as a tan solid. Yield: 77%. Melting point: 236°C-238°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 11.91 (s, 1H), 9.08 (d, J 4, 1H), 8.94 (d, J 2.4, 1H), 8.70 (d, J 8 , 1H), 8.59 (s, 1H), 8.25-8.17 (m, 3H), 7.89 (d, J 2.8, 1H), 7.77 (dd, J 8, 3.6, 2H), 3.81 (s, 2H), 3.50 -3.45 (m, 2H), 3.38-3.32 (m, 2H). MS (m/z): 434.38. (M+H); Calculated for [C 22 H 17 F 2 N 7 O.HCl + H-HCl]: 434.15 Example 30 N-(5-(4 -cyclopropylhexa Hydropyrazin - 1 -yl ) pyridin -2- yl )-5- fluoro - 4-(8- fluoroquinolin- 6- yl ) pyrimidin -2- amine

遵循一般程序-3,自中間物7 (500 mg, 1.80 mmol)及中間物47 (390 mg, 1.80 mmol)合成標題化合物。在後處理後,藉由combi-flash使用甲醇及DCM (6.8:93.2)作為溶析液純化粗產物。使彙集之溶離份蒸發,且將殘餘物與二乙醚(10 mL)一起攪拌30 min以獲得固體,過濾固體,用二乙醚(5 mL)洗滌並乾燥,獲得呈黃色固體之標題化合物(180 mg)。產率:27%。熔點:246℃-248℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 9.83 (s, 1H), 9.06 (dd, J 4, 1.6, 1H), 8.72 (d, J 4, 1H), 8.67 (d, J 8.4, 1H), 8.56 (s, 1H), 8.21 (d, J 12.8, 1H), 8.03 (d, J 9.2, 1H), 8.00 (d, J 3.2, 1H), 7.75 (dd, J 8.4, 4, 1H), 7.47 (dd, J 8.8, 2.8, 1H), 3.11-3.05 (m, 4H), 2.71-2.65 (m, 4H), 1.65 (quintet, J 3.6, 1H), 0.46-0.41 (m, 2H), 0.36-0.31 (m, 2H)。MS (m/z):460.40. (M+H);[C 25H 23F 2N 7+ H]計算值:460.20。 實例 30A N-(5-(4- 環丙基六氫吡嗪 -1- ) 吡啶 -2- )-5- -4-(8- 氟喹啉 -6- ) 嘧啶 -2- 胺鹽酸鹽 The title compound was synthesized from Intermediate 7 (500 mg, 1.80 mmol) and Intermediate 47 (390 mg, 1.80 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (6.8:93.2) as eluents. The pooled fractions were evaporated and the residue was stirred with diethyl ether (10 mL) for 30 min to obtain a solid which was filtered, washed with diethyl ether (5 mL) and dried to afford the title compound (180 mg ). Yield: 27%. Melting point: 246°C-248°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.83 (s, 1H), 9.06 (dd, J 4, 1.6, 1H), 8.72 (d, J 4, 1H), 8.67 (d, J 8.4, 1H), 8.56 (s, 1H), 8.21 (d, J 12.8, 1H), 8.03 (d, J 9.2, 1H), 8.00 (d, J 3.2, 1H), 7.75 (dd, J 8.4, 4, 1H), 7.47 (dd, J 8.8, 2.8, 1H), 3.11-3.05 (m, 4H), 2.71-2.65 (m, 4H), 1.65 (quintet, J 3.6, 1H), 0.46-0.41 (m , 2H), 0.36-0.31 (m, 2H). MS (m/z): 460.40 . (M+H); Calcd. for [ C25H23F2N7 + H]: 460.20 . Example 30A N-(5-(4 -cyclopropylhexahydropyrazin- 1 -yl ) pyridin -2- yl )-5- fluoro - 4-(8- fluoroquinolin- 6- yl ) pyrimidine -2- Amine hydrochloride

向N-(5-(4-環丙基六氫吡嗪-1-基)吡啶-2-基)-5-氟-4-(8-氟喹啉-6-基)嘧啶-2-胺(實例30,200 mg, 0.435 mmol)於甲醇(4 mL)中之混合物中添加35%鹽酸水溶液(159 mg, 4.35 mmol)。將所得澄清溶液攪拌30 min,用甲基第三丁基醚(12 mL)稀釋並攪拌1 h。過濾所形成之固體,用甲基第三丁基醚(15 mL)洗滌並乾燥,得到呈褐色固體之標題化合物(200 mg)。產率:91%。熔點:296℃-298℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 11.64 (s, 1H), 9.09 (dd, J 4, 1.6, 1H), 8.98-8.92 (m, 1H), 8.20 (d, J 8.4, 1H), 8.61 (s, 1H), 8.20 (dd, J 12, 1.6, 1H), 8.18-8.12 (m, 1H), 8.00 (d, J 2.8, 1H), 7.84-7.75 (m, 2H), 3.84 (d, J 12, 2H), 3.59 (d, J 10, 2H), 3.39-3.22 (m,4H), 2.95-2.87 (m, 1H), 1.22-1.14 9m, 2H), 0.85-0.78 (m, 2H)。MS (m/z):460.40. (M+H);[C 25H 23F 2N 7.HCl + H-HCl]計算值:459.50。 實例 31 1-(4-(6-((5- -4-(8- 氟喹啉 -6- ) 嘧啶 -2- ) 胺基 ) 吡啶 -3- ) 六氫吡嗪 -1- ) -1- To N-(5-(4-cyclopropylhexahydropyrazin-1-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-amine (Example 30, 200 mg, 0.435 mmol) in methanol (4 mL) was added 35% aqueous hydrochloric acid (159 mg, 4.35 mmol). The resulting clear solution was stirred for 30 min, diluted with methyl tert-butyl ether (12 mL) and stirred for 1 h. The resulting solid was filtered, washed with methyl tert-butyl ether (15 mL) and dried to give the title compound (200 mg) as a tan solid. Yield: 91%. Melting point: 296°C-298°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 11.64 (s, 1H), 9.09 (dd, J 4, 1.6, 1H), 8.98-8.92 (m, 1H), 8.20 (d, J 8.4, 1H), 8.61 (s, 1H), 8.20 (dd, J 12, 1.6, 1H), 8.18-8.12 (m, 1H), 8.00 (d, J 2.8, 1H), 7.84-7.75 (m, 2H ), 3.84 (d, J 12, 2H), 3.59 (d, J 10, 2H), 3.39-3.22 (m, 4H), 2.95-2.87 (m, 1H), 1.22-1.14 9m, 2H), 0.85- 0.78 (m, 2H). MS (m/z): 460.40. (M+H); Calcd. for [ C25H23F2N7.HCl + H - HCl]: 459.50 . Example 31 1-(4-(6-((5- fluoro - 4-(8- fluoroquinolin- 6- yl ) pyrimidin -2- yl ) amino ) pyridin - 3 -yl ) hexahydropyrazine -1 -yl ) ethan - 1 -one

遵循一般程序-3,自中間物7 (500 mg, 1.80 mmol)及中間物49 (400 mg, 1.80 mmol)合成標題化合物。在後處理後,藉由combi-flash使用甲醇及DCM (4.8:95.2)作為溶析液純化粗產物。使彙集之溶離份蒸發,且將殘餘物與二乙醚(20 mL)一起攪拌30 min以獲得固體,過濾固體,用二乙醚(20 mL)洗滌並乾燥,獲得呈黃色固體之標題化合物(300 mg)。產率:40%。熔點:240℃-242℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 9.87 (s, 1H), 9.06 (dd, J 4, 1.6, 1H), 8.73 (d, J 4, 1H), 8.67 (d, J 8.8, 1H), 8.56 (s, 1H), 8.21 (d, J 13.2, 1H), 8.06 (d, J 9.2, 1H), 8.04 (d, J 3.2, 1H), 7.75 (dd, J 8.8, 4, 1H), 7.51 (dd, J 9.2, 3.2, 1H), 3.62-3.56 (m, 4H), 3.18-3.12 (m, 2H), 3.10-3.05 (m, 2H), 2.03 (s, 3H)。MS (m/z):462.49. (M+H);[C 24H 21F 2N 7O + H]計算值:462.18 實例 31A 1-(4-(6-((5- -4-(8- 氟喹啉 -6- ) 嘧啶 -2- ) 胺基 ) 吡啶 -3- ) 六氫吡嗪 -1- ) -1- 酮鹽酸鹽 The title compound was synthesized from Intermediate 7 (500 mg, 1.80 mmol) and Intermediate 49 (400 mg, 1.80 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (4.8:95.2) as eluents. The pooled fractions were evaporated and the residue was stirred with diethyl ether (20 mL) for 30 min to obtain a solid which was filtered, washed with diethyl ether (20 mL) and dried to afford the title compound (300 mg ). Yield: 40%. Melting point: 240°C-242°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.87 (s, 1H), 9.06 (dd, J 4, 1.6, 1H), 8.73 (d, J 4, 1H), 8.67 (d, J 8.8, 1H), 8.56 (s, 1H), 8.21 (d, J 13.2, 1H), 8.06 (d, J 9.2, 1H), 8.04 (d, J 3.2, 1H), 7.75 (dd, J 8.8, 4, 1H), 7.51 (dd, J 9.2, 3.2, 1H), 3.62-3.56 (m, 4H), 3.18-3.12 (m, 2H), 3.10-3.05 (m, 2H), 2.03 (s, 3H) . MS (m/z): 462.49. (M+H); Calcd. for [ C24H21F2N7O + H]: 462.18 Example 31A 1-(4-(6-((5- fluoro - 4- (8- fluoroquinolin- 6- yl ) pyrimidin -2- yl ) amino ) pyridin - 3 -yl ) hexahydropyrazin- 1 -yl ) ethan - 1 -one hydrochloride

向1-(4-(6-((5-氟-4-(8-氟喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-1-基)乙-1-酮(實例31,260 mg, 0.56 mmol)於甲醇(6.5 mL)中之混合物中添加35%鹽酸水溶液(210 mg, 5.6 mmol)。將所得澄清溶液攪拌30 min,用甲基第三丁基醚(20 mL)稀釋並攪拌1 h。過濾所形成之固體,用甲基第三丁基醚(20 mL)洗滌並乾燥,得到呈褐色固體之標題化合物(200 mg)。產率:96%。熔點:228℃-230℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 11.97 (s, 1H), 9.09 (dd, J 4, 1.2, 1H), 8.95 (d, J 3.2, 1H), 8.71 (d, J 8, 1H), 8.61 (s, 1H), 8.27 (dd, J 9.2, 3.5, 1H), 8.19 (d, J 11.6, 1H), 7.92 (d, J 3.5, 1H), 7.80-7.74 (m, 2H), 3.62 (t, J 4.8, 4H), 3.24 (t, J 4.8, 2H), 3.17 (t, J 4.8, 2H), 2.05 (s, 3H)。MS (m/z):462.49. (M+H);[C 24H 21F 2N 7O.HCl + H-HCl]計算值:462.18 實例 32 5- -4-(8- 氟喹啉 -6- )-N-(5-(4-(2,2,2- 三氟乙基 ) 六氫吡嗪 -1- ) 吡啶 -2- ) 嘧啶 -2- To 1-(4-(6-((5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazine-1- To a mixture of ethyl)ethan-1-one (Example 31, 260 mg, 0.56 mmol) in methanol (6.5 mL) was added 35% aqueous hydrochloric acid (210 mg, 5.6 mmol). The resulting clear solution was stirred for 30 min, diluted with methyl tert-butyl ether (20 mL) and stirred for 1 h. The resulting solid was filtered, washed with methyl tert-butyl ether (20 mL) and dried to give the title compound (200 mg) as a tan solid. Yield: 96%. Melting point: 228°C-230°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 11.97 (s, 1H), 9.09 (dd, J 4, 1.2, 1H), 8.95 (d, J 3.2, 1H), 8.71 (d, J 8, 1H), 8.61 (s, 1H), 8.27 (dd, J 9.2, 3.5, 1H), 8.19 (d, J 11.6, 1H), 7.92 (d, J 3.5, 1H), 7.80-7.74 (m , 2H), 3.62 (t, J 4.8, 4H), 3.24 (t, J 4.8, 2H), 3.17 (t, J 4.8, 2H), 2.05 (s, 3H). MS (m/z): 462.49. (M+H); Calculated for [C 24 H 21 F 2 N 7 O.HCl + H-HCl]: 462.18 Example 32 5- Fluoro - 4-(8- fluoroquinoline -6- yl )-N-(5-(4-(2,2,2- trifluoroethyl ) hexahydropyrazin- 1 -yl ) pyridin -2- yl ) pyrimidin -2- amine

遵循一般程序-3,自中間物7 (500 mg, 1.80 mmol)及中間物51 (469 mg, 1.80 mmol)合成標題化合物。在後處理後,使粗產物懸浮於MeOH (50 ml)及DCM (50 ml)中,攪拌30 min,獲得固體。過濾固體且在真空下乾燥,獲得呈黃色固體之標題化合物(280 mg)。產率:31%。熔點:260℃-262℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 9.86 (s, 1H), 9.05 (dd, J 4, 2.8, 1H), 8.72 (d, J 3.2, 1H), 8.66 (d, J 8.4, 1H), 8.55 (s, 1H), 8.11 (d, J 12, 1H), 8.04 (d, J 9.2, 1H), 8.02 (d, J 2.8, 1H), 7.74 (dd, J 8.4, 4, 1H), 7.48 (dd, J 8.4, 2.8, 1H), 3.25 (q, J 10.4, 2H), 3.17-3.11 (m, 4H), 2.80-2.73 (m, 4H)。MS (m/z):502.52 (M+H);[C 24H 20F 5N 7+ H]計算值:502.17 實例 32A 5- -4-(8- 氟喹啉 -6- )-N-(5-(4-(2,2,2- 三氟乙基 ) 六氫吡嗪 -1- ) 吡啶 -2- ) 嘧啶 -2- 胺鹽酸鹽 The title compound was synthesized from Intermediate 7 (500 mg, 1.80 mmol) and Intermediate 51 (469 mg, 1.80 mmol) following General Procedure-3. After working up, the crude product was suspended in MeOH (50 ml) and DCM (50 ml) and stirred for 30 min to obtain a solid. The solid was filtered and dried under vacuum to obtain the title compound (280 mg) as a yellow solid. Yield: 31%. Melting point: 260°C-262°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.86 (s, 1H), 9.05 (dd, J 4, 2.8, 1H), 8.72 (d, J 3.2, 1H), 8.66 (d, J 8.4, 1H), 8.55 (s, 1H), 8.11 (d, J 12, 1H), 8.04 (d, J 9.2, 1H), 8.02 (d, J 2.8, 1H), 7.74 (dd, J 8.4, 4, 1H), 7.48 (dd, J 8.4, 2.8, 1H), 3.25 (q, J 10.4, 2H), 3.17-3.11 (m, 4H), 2.80-2.73 (m, 4H). MS (m/z): 502.52 (M+H); Calcd. for [ C24H20F5N7 +H]: 502.17 Example 32A 5 - Fluoro - 4-(8- fluoroquinolin - 6- yl )- N-(5-(4-(2,2,2- trifluoroethyl ) hexahydropyrazin- 1 -yl ) pyridin -2- yl ) pyrimidin -2- amine hydrochloride

向5-氟-4-(8-氟喹啉-6-基)-N-(5-(4-(2,2,2-三氟乙基)六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺(實例32,250 mg, 0.50 mmol)於甲醇(5 mL)中之混合物中添加35%鹽酸水溶液(182 mg, 5.0 mmol)。將所得澄清溶液攪拌30 min,用甲基第三丁基醚(15 mL)稀釋並攪拌1 h。過濾所形成之固體,用甲基第三丁基醚(10 mL)洗滌並乾燥,得到呈褐色固體之標題化合物(200 mg)。產率:75%。熔點:238℃-240℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 11.89 (s, 1H), 9.09 (dd, J 4, 1.2, 1H), 8.95 (d, J 3.2, 1H), 8.70 (d, J 8.4, 1H), 8.61 (s, 1H), 8.24-8.18 (m, 2H), 7.90 (bs, 1H), 7.78 (dd, J 8.4, 4.0, 1H), 7.22 (d, J 9.6, 1H), 3.45-3.31 (m, 2H), 3.29-3.23 (m, 4H), 2.90-2.82 (m, 4H)。MS (m/z):502.50 (M+H);[C 24H 20F 5N 7.HCl + H-HCl]計算值:502.17。 實例 33 5- -4-(8- 氟喹啉 -6- )-N-(5-(4-( 甲基磺醯基 ) 六氫吡嗪 -1- ) 吡啶 -2- ) 嘧啶 -2- To 5-fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(4-(2,2,2-trifluoroethyl)hexahydropyrazin-1-yl)pyridine- To a mixture of 2-yl)pyrimidin-2-amine (Example 32, 250 mg, 0.50 mmol) in methanol (5 mL) was added 35% aqueous hydrochloric acid (182 mg, 5.0 mmol). The resulting clear solution was stirred for 30 min, diluted with methyl tert-butyl ether (15 mL) and stirred for 1 h. The resulting solid was filtered, washed with methyl tert-butyl ether (10 mL) and dried to give the title compound (200 mg) as a tan solid. Yield: 75%. Melting point: 238°C-240°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 11.89 (s, 1H), 9.09 (dd, J 4, 1.2, 1H), 8.95 (d, J 3.2, 1H), 8.70 (d, J 8.4, 1H), 8.61 (s, 1H), 8.24-8.18 (m, 2H), 7.90 (bs, 1H), 7.78 (dd, J 8.4, 4.0, 1H), 7.22 (d, J 9.6, 1H) , 3.45-3.31 (m, 2H), 3.29-3.23 (m, 4H), 2.90-2.82 (m, 4H). MS (m/z): 502.50 ( M +H); Calcd. for [ C24H20F5N7.HCl +H-HCl]: 502.17 . Example 33 5- fluoro - 4-(8- fluoroquinolin- 6- yl )-N-(5-(4-( methylsulfonyl ) hexahydropyrazin- 1 -yl ) pyridin -2- yl ) Pyrimidin -2- amine

遵循一般程序-3,自中間物7 (500 mg, 1.80 mmol)及中間物53 (469 mg, 1.80 mmol)合成標題化合物。在後處理後,使粗產物懸浮於MeOH (1 ml)及DCM (9 ml)中,攪拌30 min,獲得固體。過濾固體,用二乙醚(20 ml)洗滌且在真空下乾燥,獲得呈黃色固體之標題化合物(220 mg)。產率:25%。熔點:295℃-297℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 9.90 (s, 1H), 9.06 (d, J 2.8, 1H), 8.74 (d, J 2.8, 1H), 8.67 (d, J 8.4, 1H), 8.57 (s, 1H), 8.21 (d, J 12.4, 2H), 8.10-8.05 (m, 1H), 7.75 (d, J 8.4, 1H), 7.53 (d, J 12.4, 1H), 3.28-3.20 (m, 4H), 2.93 (s, 3H), 2.60-2.50 (m, 4H)。 實例 33A 5- -4-(8- 氟喹啉 -6- )-N-(5-(4-( 甲基磺醯基 ) 六氫吡嗪 -1- ) 吡啶 -2- ) 嘧啶 -2- 胺鹽酸鹽 The title compound was synthesized from Intermediate 7 (500 mg, 1.80 mmol) and Intermediate 53 (469 mg, 1.80 mmol) following General Procedure-3. After working up, the crude product was suspended in MeOH (1 ml) and DCM (9 ml) and stirred for 30 min to obtain a solid. The solid was filtered, washed with diethyl ether (20 ml) and dried under vacuum to obtain the title compound (220 mg) as a yellow solid. Yield: 25%. Melting point: 295°C-297°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.90 (s, 1H), 9.06 (d, J 2.8, 1H), 8.74 (d, J 2.8, 1H), 8.67 (d, J 8.4 , 1H), 8.57 (s, 1H), 8.21 (d, J 12.4, 2H), 8.10-8.05 (m, 1H), 7.75 (d, J 8.4, 1H), 7.53 (d, J 12.4, 1H), 3.28-3.20 (m, 4H), 2.93 (s, 3H), 2.60-2.50 (m, 4H). Example 33A 5- fluoro - 4-(8- fluoroquinolin- 6- yl )-N-(5-(4-( methylsulfonyl ) hexahydropyrazin- 1 -yl ) pyridin -2- yl ) Pyrimidin -2- amine hydrochloride

向5-氟-4-(8-氟喹啉-6-基)-N-(5-(4-(甲基磺醯基)六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺(實例33,200 mg, 0.40 mmol)於甲醇(5 mL)中之混合物中添加35%鹽酸水溶液(150 mg, 4.0 mmol)。將所得澄清溶液攪拌30 min,用甲基第三丁基醚(15 mL)稀釋並攪拌1 h。過濾所形成之固體,用甲基第三丁基醚(20 mL)洗滌並乾燥,得到呈黃色固體之標題化合物(210 mg)。產率:98%。熔點:258℃-260℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 12.01 (s, 1H), 9.08 (dd, J 4, 1.2, 1H), 8.94 (t, J 3.2, 1H), 8.70 (d, J 8.4, 1H), 8.59 (s, 1H), 8.27 (d, J 9.6, 1H), 8.00 (d, J 11.6, 1H), 7.95 (d, J 2.4, 1H), 7.84-7.74 (m, 2H), 3.34-3.25 (m, 8H), 2.95 (s, 3H)。MS (m/z):497.80. (M+H);[C 23H 21F 2N 7O 2S.HCl + H-HCl]計算值:498.14。 實例 34 環丙基 (4-(6-((5- -4-(8- 氟喹啉 -6- ) 嘧啶 -2- ) 胺基 ) 吡啶 -3- ) 六氫吡嗪 -1- ) 甲酮 To 5-fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(4-(methylsulfonyl)hexahydropyrazin-1-yl)pyridin-2-yl)pyrimidine - To a mixture of 2-amine (Example 33, 200 mg, 0.40 mmol) in methanol (5 mL) was added 35% aqueous hydrochloric acid (150 mg, 4.0 mmol). The resulting clear solution was stirred for 30 min, diluted with methyl tert-butyl ether (15 mL) and stirred for 1 h. The resulting solid was filtered, washed with methyl tert-butyl ether (20 mL) and dried to give the title compound (210 mg) as a yellow solid. Yield: 98%. Melting point: 258°C-260°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 12.01 (s, 1H), 9.08 (dd, J 4, 1.2, 1H), 8.94 (t, J 3.2, 1H), 8.70 (d, J 8.4, 1H), 8.59 (s, 1H), 8.27 (d, J 9.6, 1H), 8.00 (d, J 11.6, 1H), 7.95 (d, J 2.4, 1H), 7.84-7.74 (m, 2H ), 3.34-3.25 (m, 8H), 2.95 (s, 3H). MS (m/z): 497.80. (M + H); Calcd. for [ C23H21F2N7O2S.HCl + H - HCl]: 498.14 . Example 34 cyclopropyl (4-(6-((5- fluoro - 4-(8- fluoroquinolin- 6- yl ) pyrimidin -2- yl ) amino ) pyridin - 3 - yl ) hexahydropyrazine- 1- yl ) methanone

遵循一般程序-3,自中間物7 (500 mg, 1.80 mmol)及中間物55 (440 mg, 1.80 mmol)合成標題化合物。在後處理後,藉由combi-flash使用甲醇及DCM (4.7:95.3)作為溶析液純化粗產物。使彙集之溶離份蒸發,且將殘餘物與二乙醚(20 mL)一起攪拌30 min,過濾固體,用二乙醚(20 mL)洗滌並乾燥,獲得呈黃色固體之標題化合物(300 mg)。產率:34%。熔點:236℃-238℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 9.89 (s, 1H), 9.06 (d, J 3, 1H), 8.73 (d, J 3, 1H), 8.67 (d, J 7.6, 1H), 8.56 (s, 1H), 8.21 (d, J 12.8, 1H), 8.10-8.03 (m, 2H), 7.74 (dd, J 8.4, 4.4, 1H), 7.53 (dd, J 8.4, 2.4, 1H), 3.88-3.80 (m, 2H), 3.67-3.58 (m, 2H), 3.20-3.03 (m, 4H), 2.07-1.98 (m, 1H), 0.78-0.65 (m, 4H)。MS (m/z):488.47. (M+H);[C 26H 23F 2N 7O + H]計算值:488.19。 實例 34A 環丙基 (4-(6-((5- -4-(8- 氟喹啉 -6- ) 嘧啶 -2- ) 胺基 ) 吡啶 -3- ) 六氫吡嗪 -1- ) 甲酮鹽酸鹽 The title compound was synthesized from Intermediate 7 (500 mg, 1.80 mmol) and Intermediate 55 (440 mg, 1.80 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (4.7:95.3) as eluents. The pooled fractions were evaporated and the residue was stirred with diethyl ether (20 mL) for 30 min, the solid was filtered, washed with diethyl ether (20 mL) and dried to give the title compound (300 mg) as a yellow solid. Yield: 34%. Melting point: 236°C-238°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.89 (s, 1H), 9.06 (d, J 3, 1H), 8.73 (d, J 3, 1H), 8.67 (d, J 7.6 , 1H), 8.56 (s, 1H), 8.21 (d, J 12.8, 1H), 8.10-8.03 (m, 2H), 7.74 (dd, J 8.4, 4.4, 1H), 7.53 (dd, J 8.4, 2.4 , 1H), 3.88-3.80 (m, 2H), 3.67-3.58 (m, 2H), 3.20-3.03 (m, 4H), 2.07-1.98 (m, 1H), 0.78-0.65 (m, 4H). MS (m/z): 488.47 . (M+H); Calcd. for [ C26H23F2N7O + H]: 488.19 . Example 34A Cyclopropyl (4-(6-((5- fluoro - 4-(8- fluoroquinolin- 6- yl ) pyrimidin -2- yl ) amino ) pyridin - 3 - yl ) hexahydropyrazine- 1- yl ) methanone hydrochloride

向環丙基(4-(6-((5-氟-4-(8-氟喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-1-基)甲酮(實例34,260 mg, 0.53 mmol)於甲醇(5 mL)中之混合物中添加35%鹽酸水溶液(150 mg, 4.0 mmol)。將所得澄清溶液攪拌30 min,用甲基第三丁基醚(20 mL)稀釋並攪拌1 h。過濾所形成之固體,用甲基第三丁基醚(20 mL)洗滌並乾燥,得到呈黃色固體之標題化合物(280 mg)。產率:100%。熔點:228℃-230℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 11.98 (s, 1H), 9.08 (dd, J 4, 1.2, 1H), 8.95-8.92 (m, 1H), 8.70 (d, J 8.4, 1H), 8.60 (s, 1H), 8.27 (dd, J 9.6, 2.8, 1H), 8.20 (d, J 12, 1H), 7.93 (d, J 2.8, 1H), 7.82-7.74 (m, 2H), 3.87 (bs, 2H), 3.65 (bs, 2H), 3.27 (bs, 2H), 3.19 (bs, 2H), 2.09-2.01 (m, 1H), 0.79-0.70 (m, 4H)。MS (m/z):488.0. (M+H);[C 26H 23F 2N 7O.HCl + H-HCl]計算值:488.19。 實例 35 5- -4-(8- 氟喹啉 -6- )-N-(5-(3-( 三氟甲基 )-5,6- 二氫 -[1,2,4] 三唑并 [4,3-a] 吡嗪 -7(8H)- ) 吡啶 -2- ) 嘧啶 -2- Cyclopropyl(4-(6-((5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazine-1 To a mixture of -yl)methanone (Example 34, 260 mg, 0.53 mmol) in methanol (5 mL) was added 35% aqueous hydrochloric acid (150 mg, 4.0 mmol). The resulting clear solution was stirred for 30 min, diluted with methyl tert-butyl ether (20 mL) and stirred for 1 h. The resulting solid was filtered, washed with methyl tert-butyl ether (20 mL) and dried to give the title compound (280 mg) as a yellow solid. Yield: 100%. Melting point: 228°C-230°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 11.98 (s, 1H), 9.08 (dd, J 4, 1.2, 1H), 8.95-8.92 (m, 1H), 8.70 (d, J 8.4, 1H), 8.60 (s, 1H), 8.27 (dd, J 9.6, 2.8, 1H), 8.20 (d, J 12, 1H), 7.93 (d, J 2.8, 1H), 7.82-7.74 (m, 2H), 3.87 (bs, 2H), 3.65 (bs, 2H), 3.27 (bs, 2H), 3.19 (bs, 2H), 2.09-2.01 (m, 1H), 0.79-0.70 (m, 4H). MS (m/z): 488.0. (M+H); Calcd. for [ C26H23F2N7O.HCl + H - HCl]: 488.19 . Example 35 5- fluoro - 4-(8- fluoroquinolin- 6- yl )-N-(5-(3-( trifluoromethyl )-5,6 -dihydro- [1,2,4] tri Azolo [4,3-a] pyrazin -7(8H) -yl ) pyridin -2- yl ) pyrimidin -2- amine

遵循一般程序-3,自中間物7 (500 mg, 1.80 mmol)及中間物57 (510 mg, 1.80 mmol)合成標題化合物。在後處理後,使粗產物懸浮於MeOH (2 ml)與DCM (18 ml)之混合物中且攪拌30 min,獲得固體。過濾固體,用二乙醚(20 ml)洗滌且在真空下乾燥,獲得呈淡黃色固體之標題化合物(90 mg)。產率:10%。熔點:288℃-290℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 9.97 (s, 1H), 9.07 (d, J 4.4, 1H), 8.75 (d, J 3.6, 1H), 8.67 (d, J 7.6, 1H), 8.57 (s, 1H), 8.25-8.19 (m, 2H), 8.13 (d, J 9.2, 1H), 7.75 (dd, J 8.4, 4, 1H), 7.68 (d, J 9.2, 1H), 4.68 (s, 2H), 4.29 (d, J 5.6, 2H), 3.77 (t, J 5.6, 2H)。MS (m/z):526.48. (M+H);[C 24H 16F 5N 9+ H]計算值:526.14。 實例 35A 5- -4-(8- 氟喹啉 -6- )-N-(5-(3-( 三氟甲基 )-5,6- 二氫 -[1,2,4] 三唑并 [4,3-a] 吡嗪 -7(8H)- ) 吡啶 -2- ) 嘧啶 -2- 胺鹽酸鹽 The title compound was synthesized from Intermediate 7 (500 mg, 1.80 mmol) and Intermediate 57 (510 mg, 1.80 mmol) following General Procedure-3. After working up, the crude product was suspended in a mixture of MeOH (2 ml) and DCM (18 ml) and stirred for 30 min to obtain a solid. The solid was filtered, washed with diethyl ether (20 ml) and dried under vacuum to obtain the title compound (90 mg) as a light yellow solid. Yield: 10%. Melting point: 288°C-290°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.97 (s, 1H), 9.07 (d, J 4.4, 1H), 8.75 (d, J 3.6, 1H), 8.67 (d, J 7.6 , 1H), 8.57 (s, 1H), 8.25-8.19 (m, 2H), 8.13 (d, J 9.2, 1H), 7.75 (dd, J 8.4, 4, 1H), 7.68 (d, J 9.2, 1H ), 4.68 (s, 2H), 4.29 (d, J 5.6, 2H), 3.77 (t, J 5.6, 2H). MS (m/z): 526.48 . (M+H); Calcd . for [ C24H16F5N9 +H]: 526.14 . Example 35A 5- fluoro - 4-(8- fluoroquinolin- 6- yl )-N-(5-(3-( trifluoromethyl )-5,6 -dihydro- [1,2,4] tri Azolo [4,3-a] pyrazin -7(8H) -yl ) pyridin -2- yl ) pyrimidin -2- amine hydrochloride

向5-氟-4-(8-氟喹啉-6-基)-N-(5-(3-(三氟甲基)-5,6-二氫-[1,2,4]三唑并[4,3-a]吡嗪-7(8H)-基)吡啶-2-基)嘧啶-2-胺(實例35,70 mg, 0.1 mmol)於甲醇(1.75 mL)中之混合物中添加35%鹽酸水溶液(50 mg, 1 mmol)。將所得澄清溶液攪拌30 min,用甲基第三丁基醚(5.25 mL)稀釋並攪拌1 h。過濾所形成之固體,用甲基第三丁基醚(10 mL)洗滌並乾燥,得到呈黃色固體之標題化合物(60 mg)。產率:80%。熔點:270℃-272℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 11.80 (s, 1H), 9.08 (dd, J 4, 1.2, 1H), 8.94 (d, J 3.2, 1H), 8.70 (d, J 8.4, 1H), 8.60 (s, 1H), 8.32 (dd, J 9.6, 2.8, 1H), 8.10 (d, J 11.6, 1H), 8.11 (d, J 2.8, 1H), 7.87 (d, J 9.6, 1H), 7.77 (dd, J 8.4, 4, 1H), 4.80 (s, 2H), 4.32 (t, J 5.2, 2H), 3.87 (t, J 5.2, 2H)。MS (m/z):524.54. (M-H);[C 24H 16F 5N 9- H]計算值:524.45。 實例 36 N-(5-((4- 乙基六氫吡嗪 -1- ) 甲基 ) 吡啶 -2- )-5- -4-(8- -4- 異丙基 -2- 甲基喹啉 -6- ) 嘧啶 -2- To 5-fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazole To a mixture of [4,3-a]pyrazin-7(8H)-yl)pyridin-2-yl)pyrimidin-2-amine (Example 35, 70 mg, 0.1 mmol) in methanol (1.75 mL) was added 35% aqueous hydrochloric acid (50 mg, 1 mmol). The resulting clear solution was stirred for 30 min, diluted with methyl tert-butyl ether (5.25 mL) and stirred for 1 h. The solid formed was filtered, washed with methyl tert-butyl ether (10 mL) and dried to give the title compound (60 mg) as a yellow solid. Yield: 80%. Melting point: 270°C-272°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 11.80 (s, 1H), 9.08 (dd, J 4, 1.2, 1H), 8.94 (d, J 3.2, 1H), 8.70 (d, J 8.4, 1H), 8.60 (s, 1H), 8.32 (dd, J 9.6, 2.8, 1H), 8.10 (d, J 11.6, 1H), 8.11 (d, J 2.8, 1H), 7.87 (d, J 9.6, 1H), 7.77 (dd, J 8.4, 4, 1H), 4.80 (s, 2H), 4.32 (t, J 5.2, 2H), 3.87 (t, J 5.2, 2H). MS (m/z): 524.54 . (MH); Calcd. for [ C24H16F5N9 - H]: 524.45 . Example 36 N-(5-((4- ethylhexahydropyrazin- 1 -yl ) methyl ) pyridin -2- yl )-5- fluoro - 4-(8- fluoro - 4 - isopropyl- 2 -Methylquinolin - 6- yl ) pyrimidin -2- amine

遵循一般程序-3,自中間物79 (400 mg, 1.20 mmol)及中間物9 (264 mg, 1.20 mmol)合成標題化合物。在後處理後,藉由combi-flash使用甲醇及DCM (7.5:92.5)作為溶析液純化粗產物。使彙集之溶離份蒸發,且將殘餘物與二乙醚(10 mL)一起攪拌30 min以獲得固體,過濾固體,用二乙醚(5 mL)洗滌並乾燥,獲得呈黃色固體之標題化合物(300 mg)。產率:24%。熔點:182℃-184℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 10.14 (s, 1H), 8.75 (d, J 3.6, 1H), 8.74 (s, 1H), 8.20 (d, J 4.4, 1H), 8.18 (s, 1H), 8.11 (d, J 12, 1H), 7.68 (dd, J 8.4, 1.6, 1H), 7.52 (s, 1H), 3.76 (七重峰,J 6.8, 1H), 3.43 (s, 2H), 3.45-3.35 (m, 2H), 2.70 (s, 3H), 2.45-2.25 (m, 8H), 1.39 (d, J 6.8, 6H), 0.96 (t, J 7.2, 3H)。MS (m/z):518.39. (M+H);[C 29H 33F 2N 7+ H]計算值:518.28 實例 36A N-(5-((4- 乙基六氫吡嗪 -1- ) 甲基 ) 吡啶 -2- )-5- -4-(8- -4- 異丙基 -2- 甲基喹啉 -6- ) 嘧啶 -2- 胺鹽酸鹽 The title compound was synthesized from Intermediate 79 (400 mg, 1.20 mmol) and Intermediate 9 (264 mg, 1.20 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (7.5:92.5) as eluents. The pooled fractions were evaporated and the residue was stirred with diethyl ether (10 mL) for 30 min to obtain a solid which was filtered, washed with diethyl ether (5 mL) and dried to afford the title compound (300 mg ). Yield: 24%. Melting point: 182°C-184°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 10.14 (s, 1H), 8.75 (d, J 3.6, 1H), 8.74 (s, 1H), 8.20 (d, J 4.4, 1H) , 8.18 (s, 1H), 8.11 (d, J 12, 1H), 7.68 (dd, J 8.4, 1.6, 1H), 7.52 (s, 1H), 3.76 (septet, J 6.8, 1H), 3.43 ( s, 2H), 3.45-3.35 (m, 2H), 2.70 (s, 3H), 2.45-2.25 (m, 8H), 1.39 (d, J 6.8, 6H), 0.96 (t, J 7.2, 3H). MS (m/z): 518.39. (M+H); Calcd. for [ C29H33F2N7 + H]: 518.28 Example 36A N-(5-((4- ethylhexahydropyrazine - 1 -yl ) methyl ) pyridin -2- yl ) -5- fluoro - 4-(8- fluoro - 4 - isopropyl- 2 -methylquinolin -6- yl ) pyrimidin -2- amine hydrochloride

向N-(5-((4-乙基六氫吡嗪-1-基)甲基)吡啶-2-基)-5-氟-4-(8-氟-4-異丙基-2-甲基喹啉-6-基)嘧啶-2-胺(實例36,140 mg, 0.27 mmol)於甲醇(1.75 mL)中之混合物中添加35%鹽酸水溶液(98.6 mg, 2.70 mmol)。將所得澄清溶液攪拌30 min,用甲基第三丁基醚(12 mL)稀釋並攪拌1 h。過濾所形成之固體,用甲基第三丁基醚(15 mL)洗滌並乾燥,得到呈淡黃色固體之標題化合物(100 mg)。產率:66%。熔點:208℃-210℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 12.05 (bs, 1H), 11.56 (bs, 1H), 8.90 (d, J 3.2, 1H), 8.74 (s, 1H), 8.65-8.59 (m, 1H), 8.40-8.30 (m, 1H), 8.17 (d, J 11.6, 1H), 8.11 (d, J 8.8, 1H), 7.61 (s, 1H), 4.48 (bs, 2H), 3.78 (七重峰,J 6.8, 1H), 3.70-3.60 (m, 4H), 3.50-3.38 (m, 4H), 3.72-3.10 (m, 2H), 2.74 (s, 3H), 1.40 (d, J 6.8, 6H), 1.25 (t, J 7.2, 3H)。MS (m/z):518.35. (M+H);[C 29H 33F 2N 7.HCl + H-HCl]計算值:518.28。 實例 37 N-(5-(4- 乙基六氫吡嗪 -1- ) 吡啶 -2- )-5- -4-(8- -4- 異丙基 -2- 甲基喹啉 -6- ) 嘧啶 -2- To N-(5-((4-ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-4-isopropyl-2- To a mixture of methylquinolin-6-yl)pyrimidin-2-amine (Example 36, 140 mg, 0.27 mmol) in methanol (1.75 mL) was added 35% aqueous hydrochloric acid (98.6 mg, 2.70 mmol). The resulting clear solution was stirred for 30 min, diluted with methyl tert-butyl ether (12 mL) and stirred for 1 h. The resulting solid was filtered, washed with methyl tert-butyl ether (15 mL) and dried to give the title compound (100 mg) as a light yellow solid. Yield: 66%. Melting point: 208°C-210°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 12.05 (bs, 1H), 11.56 (bs, 1H), 8.90 (d, J 3.2, 1H), 8.74 (s, 1H), 8.65- 8.59 (m, 1H), 8.40-8.30 (m, 1H), 8.17 (d, J 11.6, 1H), 8.11 (d, J 8.8, 1H), 7.61 (s, 1H), 4.48 (bs, 2H), 3.78 (Septet, J 6.8, 1H), 3.70-3.60 (m, 4H), 3.50-3.38 (m, 4H), 3.72-3.10 (m, 2H), 2.74 (s, 3H), 1.40 (d, J 6.8, 6H), 1.25 (t, J 7.2, 3H). MS (m/z): 518.35. (M+H); Calcd. for [ C29H33F2N7.HCl + H - HCl]: 518.28 . Example 37 N-(5-(4- ethylhexahydropyrazin- 1 -yl ) pyridin -2- yl )-5- fluoro - 4-(8- fluoro - 4 - isopropyl- 2 -methylquine Lin -6- yl ) pyrimidin - 2- amine

遵循一般程序-3,自中間物79 (400 mg, 1.20 mmol)及中間物20 (247 mg, 1.20 mmol)合成標題化合物。在後處理後,藉由combi-flash使用甲醇及DCM (7.8:92.2)作為溶析液純化粗產物。使彙集之溶離份蒸發,且將殘餘物與二乙醚(10 mL)一起攪拌30 min以獲得固體,過濾固體,用二乙醚(5 mL)洗滌並乾燥,獲得呈淡黃色固體之標題化合物(150 mg)。產率:24%。熔點:211℃-213℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 9.84 (s, 1H), 8.71 (s, 1H), 8.69 (d, J 3.6, 1H), 8.10 (d, J 11.6, 1H), 8.03 (d, J 8.8, 1H), 8.02 (s, 1H), 7.52 (s, 1H), 7.42 (dd, J 9.2, 3.2, 1H), 3.74 (七重峰,J 6.8, 1H), 3.15-3.09 (m, 4H), 2.70 (s, 3H), 2.55-2.45 (m, 4H), 2.37 (q, J 6.8, 2H), 1.38 (d, J 6.8, 6H), 1.02 (t, J 6.8, 3H)。MS (m/z):504.55. (M+H);[C 28H 31F 2N 7+ H]計算值:504.26。 實例 37A N-(5-(4- 乙基六氫吡嗪 -1- ) 吡啶 -2- )-5- -4-(8- -4- 異丙基 -2- 甲基喹啉 -6- ) 嘧啶 -2- 胺鹽酸鹽 The title compound was synthesized from Intermediate 79 (400 mg, 1.20 mmol) and Intermediate 20 (247 mg, 1.20 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (7.8:92.2) as eluents. The pooled fractions were evaporated and the residue was stirred with diethyl ether (10 mL) for 30 min to obtain a solid which was filtered, washed with diethyl ether (5 mL) and dried to afford the title compound (150 mg). Yield: 24%. Melting point: 211°C-213°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.84 (s, 1H), 8.71 (s, 1H), 8.69 (d, J 3.6, 1H), 8.10 (d, J 11.6, 1H) , 8.03 (d, J 8.8, 1H), 8.02 (s, 1H), 7.52 (s, 1H), 7.42 (dd, J 9.2, 3.2, 1H), 3.74 (septet, J 6.8, 1H), 3.15- 3.09 (m, 4H), 2.70 (s, 3H), 2.55-2.45 (m, 4H), 2.37 (q, J 6.8, 2H), 1.38 (d, J 6.8, 6H), 1.02 (t, J 6.8, 3H). MS (m/z): 504.55 . (M+H); Calcd. for [ C28H31F2N7 + H]: 504.26 . Example 37A N-(5-(4- ethylhexahydropyrazin- 1 -yl ) pyridin -2- yl )-5- fluoro - 4-(8- fluoro - 4 - isopropyl- 2 -methylquine ( Pyrimin -6- yl ) pyrimidin -2- amine hydrochloride

向N-(5-(4-乙基六氫吡嗪-1-基)吡啶-2-基)-5-氟-4-(8-氟-4-異丙基-2-甲基喹啉-6-基)嘧啶-2-胺(實例37,140 mg, 0.278 mmol)於甲醇(2.8 mL)中之混合物中添加35%鹽酸水溶液(101 mg, 2.78 mmol)。將所得澄清溶液攪拌30 min,用甲基第三丁基醚(8.4 mL)稀釋並攪拌1 h。過濾所形成之固體,用甲基第三丁基醚(15 mL)洗滌並乾燥,得到呈淡黃色固體之標題化合物(110 mg)。產率:71%。熔點:228℃-230℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 11.84 (s, 1H), 11.42 (bs, 1H), 8.92 (d, J 3.2, 1H), 8.70 (s, 1H), 8.22 (d, J 9.6, 2.8, 1H), 8.13 (d, J 11.6, 1H), 8.00 (d, J 2.8, 1H), 7.85 (d, J 9.6, 1H), 7.60 (s, 1H), 3.85 (d, J 12.8, 2H), 3.76 (七重峰,J 7.0, 1H), 3.59 (d, J 11.6, 2H), 3.29 (t, J 11.6, 2H), 3.20-3.05 (m, 4H), 2.73 (s, 3H), 1.38 (d, J 7, 6H), 1.30 (t, J 7.2, 3H)。MS (m/z):504.61. (M+H);[C 28H 31F 2N 7.HCl + H-HCl]計算值:504.26。 實例 38 1-(6-((5- -4-(8- 氟喹啉 -6- ) 嘧啶 -2- ) 胺基 ) 吡啶 -3- )-4- 甲基六氫吡啶 -4- To N-(5-(4-ethylhexahydropyrazin-1-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-4-isopropyl-2-methylquinoline To a mixture of -6-yl)pyrimidin-2-amine (Example 37, 140 mg, 0.278 mmol) in methanol (2.8 mL) was added 35% aqueous hydrochloric acid (101 mg, 2.78 mmol). The resulting clear solution was stirred for 30 min, diluted with methyl tert-butyl ether (8.4 mL) and stirred for 1 h. The resulting solid was filtered, washed with methyl tert-butyl ether (15 mL) and dried to give the title compound (110 mg) as a light yellow solid. Yield: 71%. Melting point: 228°C-230°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 11.84 (s, 1H), 11.42 (bs, 1H), 8.92 (d, J 3.2, 1H), 8.70 (s, 1H), 8.22 ( d, J 9.6, 2.8, 1H), 8.13 (d, J 11.6, 1H), 8.00 (d, J 2.8, 1H), 7.85 (d, J 9.6, 1H), 7.60 (s, 1H), 3.85 (d , J 12.8, 2H), 3.76 (septet, J 7.0, 1H), 3.59 (d, J 11.6, 2H), 3.29 (t, J 11.6, 2H), 3.20-3.05 (m, 4H), 2.73 (s , 3H), 1.38 (d, J 7, 6H), 1.30 (t, J 7.2, 3H). MS (m/z): 504.61. (M+H); Calcd. for [ C28H31F2N7.HCl + H - HCl]: 504.26 . Example 38 1-(6-((5- fluoro - 4-(8- fluoroquinolin- 6- yl ) pyrimidin -2- yl ) amino ) pyridin - 3 -yl )-4 -methylhexahydropyridine- 4- ol

遵循一般程序-3,自中間物7 (500 mg, 1.80 mmol)及中間物59 (373 mg, 1.80 mmol)合成標題化合物。在後處理後,將粗產物與DCM (50 ml)與MeOH (50 ml)之混合物一起攪拌45 min,獲得固體。過濾固體且用DCM (20 ml)洗滌。將固體與二乙醚(10 ml)一起濕磨且過濾固體。用二乙醚(5 ml)洗滌固體並乾燥,獲得呈黃色固體之標題化合物(210 mg)。產率:26%。熔點:198℃-200℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 9.79 (s, 1H), 9.05 (d, J 4, 1H), 8.71 (d, J 3.2, 1H), 8.66 (d, J 8.4, 1H), 8.55 (s, 1H), 8.20 (d, J 12, 1H), 8.02 (s, 1H), 8.01 (d, J 5.2, 1H), 7.74 (dd, J 8.4, 3.2, 1H), 7.46 (dd, J 9.2, 2.8, 1H), 4.29 (s, 1H), 3.29-3.21 (m, 2H), 3.13-3.06 (m, 2H), 1.60-1.55 (m, 4H), 1.14 (s, 3H)。MS (m/z):449.44 (M+H);[C 24H 22F 2N 6O+ H]計算值:449.18。 實例 38A 1-(6-((5- -4-(8- 氟喹啉 -6- ) 嘧啶 -2- ) 胺基 ) 吡啶 -3- )-4- 甲基六氫吡啶 -4- 醇鹽酸鹽 The title compound was synthesized from Intermediate 7 (500 mg, 1.80 mmol) and Intermediate 59 (373 mg, 1.80 mmol) following General Procedure-3. After working up, the crude product was stirred with a mixture of DCM (50 ml) and MeOH (50 ml) for 45 min to obtain a solid. The solid was filtered and washed with DCM (20 ml). The solid was triturated with diethyl ether (10 ml) and the solid was filtered. The solid was washed with diethyl ether (5 ml) and dried to obtain the title compound (210 mg) as a yellow solid. Yield: 26%. Melting point: 198°C-200°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.79 (s, 1H), 9.05 (d, J 4, 1H), 8.71 (d, J 3.2, 1H), 8.66 (d, J 8.4 , 1H), 8.55 (s, 1H), 8.20 (d, J 12, 1H), 8.02 (s, 1H), 8.01 (d, J 5.2, 1H), 7.74 (dd, J 8.4, 3.2, 1H), 7.46 (dd, J 9.2, 2.8, 1H), 4.29 (s, 1H), 3.29-3.21 (m, 2H), 3.13-3.06 (m, 2H), 1.60-1.55 (m, 4H), 1.14 (s, 3H). MS (m/z): 449.44 (M+H); Calcd. for [ C24H22F2N6O + H]: 449.18 . Example 38A 1-(6-((5- fluoro - 4-(8- fluoroquinolin- 6- yl ) pyrimidin -2- yl ) amino ) pyridin - 3 -yl )-4 -methylhexahydropyridine- 4- alcohol hydrochloride

向1-(6-((5-氟-4-(8-氟喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)-4-甲基六氫吡啶-4-醇(實例38,200 mg, 0.446 mmol)於甲醇(4 mL)中之混合物中添加35%鹽酸水溶液(163 mg, 4.46 mmol)。將所得澄清溶液攪拌30 min,用甲基第三丁基醚(12 mL)稀釋並攪拌1 h。過濾所形成之固體,用甲基第三丁基醚(15 mL)洗滌並乾燥,得到呈紅色固體之標題化合物(195 mg)。產率:71%。熔點:249℃-251℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 11.67 (s, 1H), 9.08 (dd, J 4.4, 1.6, 1H), 8.92 (d, J 2.8, 1H), 8.70 (d, J 8.4, 1H), 8.60 (s, 1H), 8.29 (dd, J 9.2, 2.4, 1H), 8.21 (d, J 11.6, 1H), 7.90 (bs, 1H), 7.77 (dd, J 8.4, 4, 1H), 5.33 (bs、-OH), 3.43-3.36 (m, 2H), 3.35-3.25 (m, 2H), 1.81-1.70 (m, 2H), 1.69-1.60 (m, 2H), 1.18 (s, 3H)。MS (m/z):449.46 (M+H);[C 24H 22F 2N 6O+ H]計算值:449.48。 實例 39 (±)-4-(6-((4-(4-(1-(( 第三丁氧基羰基 ) 胺基 ) 乙基 )-8- -2- 甲基喹啉 -6- )-5- 氟嘧啶 -2- ) 胺基 ) 吡啶 -3- ) 六氫吡嗪 -1- 甲酸第三丁基酯 To 1-(6-((5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)-4-methylhexahydropyridine-4 - To a mixture of alcohol (Example 38, 200 mg, 0.446 mmol) in methanol (4 mL) was added 35% aqueous hydrochloric acid (163 mg, 4.46 mmol). The resulting clear solution was stirred for 30 min, diluted with methyl tert-butyl ether (12 mL) and stirred for 1 h. The resulting solid was filtered, washed with methyl tert-butyl ether (15 mL) and dried to give the title compound (195 mg) as a red solid. Yield: 71%. Melting point: 249°C-251°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 11.67 (s, 1H), 9.08 (dd, J 4.4, 1.6, 1H), 8.92 (d, J 2.8, 1H), 8.70 (d, J 8.4, 1H), 8.60 (s, 1H), 8.29 (dd, J 9.2, 2.4, 1H), 8.21 (d, J 11.6, 1H), 7.90 (bs, 1H), 7.77 (dd, J 8.4, 4 , 1H), 5.33 (bs, -OH), 3.43-3.36 (m, 2H), 3.35-3.25 (m, 2H), 1.81-1.70 (m, 2H), 1.69-1.60 (m, 2H), 1.18 ( s, 3H). MS (m/z): 449.46 (M+H); Calcd. for [ C24H22F2N6O + H]: 449.48. Example 39 (±)-4-(6-((4-(4-(1-(( tertiary butoxycarbonyl ) amino ) ethyl )-8- fluoro -2 -methylquinoline -6- Base )-5- fluoropyrimidin -2- yl ) amino ) pyridin - 3 -yl ) hexahydropyrazine- 1 -carboxylic acid tert-butyl ester

遵循一般程序-3,自中間物63 (500 mg, 1.15 mmol)及中間物5 (320 mg, 1.15 mmol)合成標題化合物。在後處理後,藉由combi-flash使用MeOH及DCM (2:98)作為溶析液純化粗產物。蒸餾來自管柱之合併純淨溶離份,獲得固體。將固體與二乙醚(10 ml)一起濕磨。過濾固體且用二乙醚(5 ml)洗滌,獲得呈黃色固體之標題化合物(210 mg)。產率:32.1%。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz):9.93 (s, 1H), 8.73 (s, 1H), 8.72 (s, 1H), 8.18-8.10 (m, 2H), 8.06 (d, J 3.6, 1H), 7.86 (d, J 7.6, 1H), 7.56 (s, 1H), 7.50 (d, J 6, 1H), 5.50-5.43 (m, 1H), 3.51-3.45 (m, 4H), 3.11-3.05 (m, 4H), 2.27 (s, 3H), 1.45 (d, J 7.2, 3H), 1.42 (s, 9H), 1.38 (s, 9H)。MS (m/z):677.44 (M+H);[C 35H 42F 2N 8O 4+H]計算值:677.33。 實例 39A (±)-4-(4-(1- 胺基乙基 )-8- -2- 甲基喹啉 -6- )-5- -N-(5-( 六氫吡嗪 -1- ) 吡啶 -2- ) 嘧啶 -2- The title compound was synthesized from Intermediate 63 (500 mg, 1.15 mmol) and Intermediate 5 (320 mg, 1.15 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using MeOH and DCM (2:98) as eluents. Distillation of the combined clean fractions from the column afforded a solid. The solid was triturated with diethyl ether (10 ml). The solid was filtered and washed with diethyl ether (5 ml) to obtain the title compound (210 mg) as a yellow solid. Yield: 32.1%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.93 (s, 1H), 8.73 (s, 1H), 8.72 (s, 1H), 8.18-8.10 (m, 2H), 8.06 (d , J 3.6, 1H), 7.86 (d, J 7.6, 1H), 7.56 (s, 1H), 7.50 (d, J 6, 1H), 5.50-5.43 (m, 1H), 3.51-3.45 (m, 4H ), 3.11-3.05 (m, 4H), 2.27 (s, 3H), 1.45 (d, J 7.2, 3H), 1.42 (s, 9H), 1.38 (s, 9H). MS (m/z): 677.44 (M + H); Calcd. for [ C35H42F2N8O4 + H]: 677.33 . Example 39A (±)-4-(4-(1 -aminoethyl )-8- fluoro -2 -methylquinolin -6- yl )-5- fluoro -N-(5-( hexahydropyrazine -1 -yl ) pyridin -2- yl ) pyrimidin -2- amine

遵循一般程序-4,自4-(6-((4-(4-(1-((第三丁氧基羰基)胺基)乙基)-8-氟-2-甲基喹啉-6-基)-5-氟嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-1-甲酸第三丁基酯(實例39,250 mg, 0.37 mmol)合成呈灰白色固體之標題化合物(80 mg)。產率:45%。熔點:241℃-243℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 9.86 (s, 1H), 8.77 (s, 1H), 8.71 (d, J 4, 1H), 8.11 (d, J 12.4, 1H), 8.07 (d, J 8.8, 1H), 8.01 (d, J 2.8, 1H), 7.81 (s, 1H), 7.43 (dd, J 9.2, 2.8, 1H), 4.86-4.79 (m, 1H), 3.07-3.01 (m, 4H), 2.88-2.82 (m, 4H), 2.72 (s, 3H), 1.43 (d, J 6.8, 3H)。MS (m/z):477.54 (M+H);[C 25H 26F 2N 8+H]計算值:477.22。 實例 39B (±)-4-(4-(1- 胺基乙基 )-8- -2- 甲基喹啉 -6- )-5- -N-(5-( 六氫吡嗪 -1- ) 吡啶 -2- ) 嘧啶 -2- 胺鹽酸鹽 Following general procedure-4, from 4-(6-((4-(4-(1-((tert-butoxycarbonyl)amino)ethyl)-8-fluoro-2-methylquinoline-6 -yl)-5-fluoropyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazine-1-carboxylic acid tert-butyl ester (Example 39, 250 mg, 0.37 mmol) was synthesized as an off-white solid Title compound (80 mg). Yield: 45%. Melting point: 241°C-243°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.86 (s, 1H), 8.77 (s, 1H), 8.71 (d, J 4, 1H), 8.11 (d, J 12.4, 1H) , 8.07 (d, J 8.8, 1H), 8.01 (d, J 2.8, 1H), 7.81 (s, 1H), 7.43 (dd, J 9.2, 2.8, 1H), 4.86-4.79 (m, 1H), 3.07 -3.01 (m, 4H), 2.88-2.82 (m, 4H), 2.72 (s, 3H), 1.43 (d, J 6.8, 3H). MS (m/z): 477.54 (M+H); Calcd. for [ C25H26F2N8 + H]: 477.22 . Example 39B (±)-4-(4-(1 -aminoethyl )-8- fluoro -2 -methylquinolin -6- yl )-5- fluoro -N-(5-( hexahydropyrazine -1 -yl ) pyridin -2- yl ) pyrimidin -2- amine hydrochloride

向4-(4-(1-胺基乙基)-8-氟-2-甲基喹啉-6-基)-5-氟-N-(5-(六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺(實例39A,60 mg, 0.13 mmol)於甲醇(1.2 mL)中之混合物中添加35%鹽酸水溶液(46 mg, 1.3 mmol)。將所得澄清溶液攪拌30 min,用甲基第三丁基醚(3.6 mL)稀釋並攪拌1 h。在真空下蒸餾反應混合物,得到固體。向固體中添加二乙醚(12 ml)。過濾固體且用二乙醚(5 mL)洗滌並乾燥,得到呈黃色固體之標題化合物(35 mg)。產率:54%。熔點:253℃-256℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 11.77 (bs, 1H), 9.60-9.45 (m, 2H), 9.17 (bs, 3H), 8.96 (s, 1H), 8.69 (s, 1H), 8.23-8.15 (m, 2H), 8.06 (s, 1H), 7.99 (s, 1H), 7.88 (d, J 8.8, 1H), 5.35-5.25 (m, 1H), 3.55-3.45 (m, 4H), 3.30-3.20 (m, 4H), 2.76 (s, 3H), 1.69 (d, J 6.8, 3H)。MS (m/z):477.53 (M+H);[C 25H 26F 2N 8+H-HCl]計算值:477.22。 實例 40 (±)-4-(6-((4-(4-(1-(( 第三丁氧基羰基 ) 胺基 ) 乙基 )-8- 氟喹啉 -6- )-5- 氟嘧啶 -2- ) 胺基 ) 吡啶 -3- ) 六氫吡嗪 -1- 甲酸第三丁基酯 To 4-(4-(1-aminoethyl)-8-fluoro-2-methylquinolin-6-yl)-5-fluoro-N-(5-(hexahydropyrazin-1-yl) To a mixture of pyridin-2-yl)pyrimidin-2-amine (Example 39A, 60 mg, 0.13 mmol) in methanol (1.2 mL) was added 35% aqueous hydrochloric acid (46 mg, 1.3 mmol). The resulting clear solution was stirred for 30 min, diluted with methyl tert-butyl ether (3.6 mL) and stirred for 1 h. The reaction mixture was distilled under vacuum to give a solid. Diethyl ether (12 ml) was added to the solid. The solid was filtered and washed with diethyl ether (5 mL) and dried to give the title compound (35 mg) as a yellow solid. Yield: 54%. Melting point: 253°C-256°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 11.77 (bs, 1H), 9.60-9.45 (m, 2H), 9.17 (bs, 3H), 8.96 (s, 1H), 8.69 (s , 1H), 8.23-8.15 (m, 2H), 8.06 (s, 1H), 7.99 (s, 1H), 7.88 (d, J 8.8, 1H), 5.35-5.25 (m, 1H), 3.55-3.45 ( m, 4H), 3.30-3.20 (m, 4H), 2.76 (s, 3H), 1.69 (d, J 6.8, 3H). MS (m/z): 477.53 (M+H); Calcd. for [ C25H26F2N8 + H-HCl]: 477.22 . Example 40 (±)-4-(6-((4-(4-(1-(( tertiary butoxycarbonyl ) amino ) ethyl )-8- fluoroquinolin- 6- yl )-5- Fluoropyrimidin -2- yl ) amino ) pyridin - 3 -yl ) hexahydropyrazine- 1 -carboxylic acid tert-butyl ester

遵循一般程序-3,自中間物71 (500 mg, 1.15 mmol)及中間物5 (320 mg, 1.15 mmol)合成標題化合物。在後處理後,藉由combi-flash使用MeOH及DCM (2:98)作為溶析液純化粗產物。蒸餾來自管柱之合併純淨溶離份,獲得固體。將固體與二乙醚(10 ml)一起濕磨。過濾固體且用二乙醚(5 ml)洗滌,獲得呈黃色固體之標題化合物(210 mg)。產率:32.1%。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 9.93 (s, 1H), 9.04 (d, J 4.4, 1H), 8.78 (s, 1H), 8.74 (d, J 3.6, 1H), 8.17 (d, J 12, 1H), 8.11 (d, J 8.8, 1H), 8.07 (d, J 3.2, 1H), 7.92 (d, J 7.2, 1H), 7.69 (d, J 4.4, 1H), 7.48 (dd, J 9.2, 2.8, 1H), 5.55-5.45 (m, 1H), 3.52-3.45 (m, 4H), 3.11-3.05 (m, 4H), 1.46 (d, J 6.8, 3H), 1.43 (s, 9H), 1.38 (s, 9H)。MS (m/z):663.51 (M+H);[C 34H 40F 2N 8O 4+H]計算值:663.31。 實例 40A (±)-4-(4-(1- 胺基乙基 )-8- 氟喹啉 -6- )-5- -N-(5-( 六氫吡嗪 -1- ) 吡啶 -2- ) 嘧啶 -2- The title compound was synthesized from Intermediate 71 (500 mg, 1.15 mmol) and Intermediate 5 (320 mg, 1.15 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using MeOH and DCM (2:98) as eluents. Distillation of the combined clean fractions from the column afforded a solid. The solid was triturated with diethyl ether (10 ml). The solid was filtered and washed with diethyl ether (5 ml) to obtain the title compound (210 mg) as a yellow solid. Yield: 32.1%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.93 (s, 1H), 9.04 (d, J 4.4, 1H), 8.78 (s, 1H), 8.74 (d, J 3.6, 1H) , 8.17 (d, J 12, 1H), 8.11 (d, J 8.8, 1H), 8.07 (d, J 3.2, 1H), 7.92 (d, J 7.2, 1H), 7.69 (d, J 4.4, 1H) , 7.48 (dd, J 9.2, 2.8, 1H), 5.55-5.45 (m, 1H), 3.52-3.45 (m, 4H), 3.11-3.05 (m, 4H), 1.46 (d, J 6.8, 3H), 1.43 (s, 9H), 1.38 (s, 9H). MS (m/z): 663.51 (M + H); Calcd. for [ C34H40F2N8O4 + H]: 663.31 . Example 40A (±)-4-(4-(1 -aminoethyl )-8- fluoroquinolin- 6- yl )-5- fluoro -N-(5-( hexahydropyrazin- 1 -yl ) Pyridin -2- yl ) pyrimidin -2- amine

遵循一般程序-4,自4-(6-((4-(4-(1-((第三丁氧基羰基)胺基)乙基)-8-氟喹啉-6-基)-5-氟嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-1-甲酸第三丁基酯(實例40,850 mg, 1.28 mmol)合成呈灰白色固體之標題化合物(325 mg)。產率:55%。熔點:>270℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 9.84 (s, 1H), 9.02 (d, J 4.4, 1H), 8.84 (s, 1H), 8.72 (d, J 3.6, 1H), 8.15 (d, J 11.6, 1H), 8.07 (d, J 9.2, 1H), 8.01 (d, J 2.8, 1H), 7.92 (d, J 4.4, 1H), 7.43 (dd, J 9.2, 2.8, 1H), 4.90-4.82 (m, 1H), 3.07-3.01 (m, 4H), 2.88-2.82 (m, 4H), 2.20 (bs, 3H), 1.44 (d, J 6.4, 3H)。MS (m/z):463.55 (M+H);[C 24H 24F 2N 8+H]計算值:463.21 實例 40B (±)-4-(4-(1- 胺基乙基 )-8- 氟喹啉 -6- )-5- -N-(5-( 六氫吡嗪 -1- ) 吡啶 -2- ) 嘧啶 -2- 胺二鹽酸鹽 Following general procedure-4, from 4-(6-((4-(4-(1-((tert-butoxycarbonyl)amino)ethyl)-8-fluoroquinolin-6-yl)-5 -Fluoropyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazine-1-carboxylic acid tert-butyl ester (Example 40, 850 mg, 1.28 mmol) synthesized the title compound as an off-white solid (325 mg ). Yield: 55%. Melting point: >270°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.84 (s, 1H), 9.02 (d, J 4.4, 1H), 8.84 (s, 1H), 8.72 (d, J 3.6, 1H) , 8.15 (d, J 11.6, 1H), 8.07 (d, J 9.2, 1H), 8.01 (d, J 2.8, 1H), 7.92 (d, J 4.4, 1H), 7.43 (dd, J 9.2, 2.8, 1H), 4.90-4.82 (m, 1H), 3.07-3.01 (m, 4H), 2.88-2.82 (m, 4H), 2.20 (bs, 3H), 1.44 (d, J 6.4, 3H). MS (m/z): 463.55 ( M +H); Calcd. for [ C24H24F2N8 + H]: 463.21 Example 40B (±)-4-(4-(1 -aminoethyl )- 8- fluoroquinolin- 6- yl )-5- fluoro -N-(5-( hexahydropyrazin- 1 -yl ) pyridin -2- yl ) pyrimidin -2- amine dihydrochloride

向4-(4-(1-胺基乙基)-8-氟喹啉-6-基)-5-氟-N-(5-(六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺(實例40A,60 mg, 0.13 mmol)於甲醇(1.2 mL)中之混合物中添加35%鹽酸水溶液(46 mg, 1.3 mmol)。將所得澄清溶液攪拌30 min,用甲基第三丁基醚(3.6 mL)稀釋並攪拌1 h。在真空下蒸餾反應混合物,得到固體。向固體中添加二乙醚(12 ml)。過濾固體且用二乙醚(5 mL)洗滌並乾燥,得到呈黃色固體之標題化合物(35 mg)。產率:54%。熔點:253℃-256℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 11.37 (bs, 1H), 9.55-9.50 (m, 2H), 9.27 (bs, 3H), 9.17 (d, J 4.4, 1H), 8.92 (s, 1H), 8.75 (s, 1H), 8.21 (d, J 11.2, 1H), 8.10-8.00 (m, 3H), 7.96 (d, J 7.2, 1H), 5.40-5.30 (m, 1H), 3.51-3.45 (m, 4H), 3.29-3.20 (m, 4H), 1.71 (d, J 6.8, 3H)。MS (m/z):463.47 (M+H-2HCl);[C 24H 24F 2N 8.2HCl+H-2HCl]計算值:463.21。 實例 41 (±)-4-(6-((5- -4-(8- -4-(1- 羥基乙基 ) 喹啉 -6- ) 嘧啶 -2- ) 胺基 ) 吡啶 -3- ) 六氫吡嗪 -1- 甲酸第三丁基酯 To 4-(4-(1-aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl ) pyrimidin-2-amine (Example 40A, 60 mg, 0.13 mmol) in methanol (1.2 mL) was added 35% aqueous hydrochloric acid (46 mg, 1.3 mmol). The resulting clear solution was stirred for 30 min, diluted with methyl tert-butyl ether (3.6 mL) and stirred for 1 h. The reaction mixture was distilled under vacuum to give a solid. Diethyl ether (12 ml) was added to the solid. The solid was filtered and washed with diethyl ether (5 mL) and dried to give the title compound (35 mg) as a yellow solid. Yield: 54%. Melting point: 253°C-256°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 11.37 (bs, 1H), 9.55-9.50 (m, 2H), 9.27 (bs, 3H), 9.17 (d, J 4.4, 1H), 8.92 (s, 1H), 8.75 (s, 1H), 8.21 (d, J 11.2, 1H), 8.10-8.00 (m, 3H), 7.96 (d, J 7.2, 1H), 5.40-5.30 (m, 1H ), 3.51-3.45 (m, 4H), 3.29-3.20 (m, 4H), 1.71 (d, J 6.8, 3H). MS (m/z): 463.47 ( M +H-2HCl); Calcd. for [ C24H24F2N8.2HCl + H-2HCl]: 463.21 . Example 41 (±)-4-(6-((5- fluoro - 4-(8- fluoro - 4-(1- hydroxyethyl ) quinolin -6- yl ) pyrimidin -2- yl ) amino ) pyridine -3 -yl ) hexahydropyrazine- 1 -carboxylic acid tert-butyl ester

遵循一般程序-3,自中間物74 (500 mg, 1.6 mmol)及中間物5 (430 mg, 1.6 mmol)合成標題化合物。在後處理後,藉由combi-flash使用MeOH及DCM (4:96)作為溶析液純化粗產物。蒸餾來自管柱之合併純淨溶離份,獲得固體。將固體與二乙醚(20 ml)一起濕磨。過濾固體且用二乙醚(20 ml)洗滌,獲得呈黃色固體之標題化合物(70 mg)。產率:8%。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 9.90 (s, 1H), 9.03 (d, J 4.4, 1H), 8.81 (s, 1H), 8.73 (d, J 3.6, 1H), 8.16 (d, J 11.6, 1H), 8.10 (d, J 8.8, 1H), 8.06 (d, J 2.8, 1H), 7.81 (d, J 4.4, 1H), 7.47 (d, J 9.2, 3.2, 1H), 5.78 (d, J 4, 1H), 5.58-5.50 (m, 1H), 3.52-3.44 (m, 4H), 3.12-3.05 (m, 4H), 1.54 (d, J 6.8, 3H), 1.42 (s, 9H)。MS (m/z):564.49 [M+H];[C 29H 31F 2N 7O 3+H]計算值:564.25。 實例 41A (±)-1-(8- -6-(5- -2-((5-( 六氫吡嗪 -1- ) 吡啶 -2- ) 胺基 ) 嘧啶 -4- ) 喹啉 -4- ) 乙醇 The title compound was synthesized from Intermediate 74 (500 mg, 1.6 mmol) and Intermediate 5 (430 mg, 1.6 mmol) following General Procedure-3. After workup, the crude product was purified by combi-flash using MeOH and DCM (4:96) as eluents. Distillation of the combined clean fractions from the column afforded a solid. The solid was triturated with diethyl ether (20 ml). The solid was filtered and washed with diethyl ether (20 ml) to obtain the title compound (70 mg) as a yellow solid. Yield: 8%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.90 (s, 1H), 9.03 (d, J 4.4, 1H), 8.81 (s, 1H), 8.73 (d, J 3.6, 1H) , 8.16 (d, J 11.6, 1H), 8.10 (d, J 8.8, 1H), 8.06 (d, J 2.8, 1H), 7.81 (d, J 4.4, 1H), 7.47 (d, J 9.2, 3.2, 1H), 5.78 (d, J 4, 1H), 5.58-5.50 (m, 1H), 3.52-3.44 (m, 4H), 3.12-3.05 (m, 4H), 1.54 (d, J 6.8, 3H), 1.42 (s, 9H). MS (m/z): 564.49 [ M +H]; Calcd. for [ C29H31F2N7O3 + H]: 564.25 . Example 41A (±)-1-(8- fluoro -6-(5- fluoro -2-((5-( hexahydropyrazin- 1 -yl ) pyridin -2- yl ) amino ) pyrimidin - 4 -yl ) quinolin- 4 -yl ) ethanol

遵循一般程序-4,自4-(6-((5-氟-4-(8-氟-4-(1-羥基乙基)喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-1-甲酸第三丁基酯(實例41,310 mg, 0.55 mmol)合成呈黃色固體之標題化合物(120 mg)。產率:47%。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 9.86 (s, 1H), 9.03 (d, J 4.4, 1H), 8.81 (s, 1H), 8.72 (d, J 3.2, 1H), 8.15 (d, J 12, 1H), 8.08 (d, J 8.8, 1H), 8.02 (d, J 2.8, 1H), 7.81 (d, J 4.4, 1H), 7.43 (d, J 8.8, 2.8, 1H), 5.85-5.80 (m, 1H), 5.60-5.50 (m, 1H), 3.08-3.00 (m, 4H), 2.90-2.80 (m, 4H), 1.54 (d, J 6.4, 3H)。MS (m/z):464.59 [M+H];[C 24H 23F 2N 7O+H]計算值:464.19。 實例 41B (±)-1-(8- -6-(5- -2-((5-( 六氫吡嗪 -1- ) 吡啶 -2- ) 胺基 ) 嘧啶 -4- ) 喹啉 -4- ) 乙醇三甲磺酸鹽 Following general procedure-4, from 4-(6-((5-fluoro-4-(8-fluoro-4-(1-hydroxyethyl)quinolin-6-yl)pyrimidin-2-yl)amino) Pyridin-3-yl)tert-butyl hexahydropyrazine-1-carboxylate (Example 41, 310 mg, 0.55 mmol) The title compound (120 mg) was synthesized as a yellow solid. Yield: 47%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.86 (s, 1H), 9.03 (d, J 4.4, 1H), 8.81 (s, 1H), 8.72 (d, J 3.2, 1H) , 8.15 (d, J 12, 1H), 8.08 (d, J 8.8, 1H), 8.02 (d, J 2.8, 1H), 7.81 (d, J 4.4, 1H), 7.43 (d, J 8.8, 2.8, 1H), 5.85-5.80 (m, 1H), 5.60-5.50 (m, 1H), 3.08-3.00 (m, 4H), 2.90-2.80 (m, 4H), 1.54 (d, J 6.4, 3H). MS (m/z): 464.59 [ M + H]; Calcd. for [ C24H23F2N7O +H]: 464.19. Example 41B (±)-1-(8- fluoro -6-(5- fluoro -2-((5-( hexahydropyrazin- 1 -yl ) pyridin -2- yl ) amino ) pyrimidin - 4 -yl ) quinoline- 4 -yl ) ethanol trimesylate

向1-(8-氟-6-(5-氟-2-((5-(六氫吡嗪-1-基)吡啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)乙醇(實例41A,50 mg, 0.108 mmol)於甲醇(1 mL)中之混合物中添加CH 3SO 3H (15.6 mg, 0.162 mmol)。將所得澄清溶液攪拌30 min,用甲基第三丁基醚(5 mL)稀釋並攪拌1 h。在真空下蒸餾反應混合物,得到固體。向固體中添加二乙醚(10 ml)。過濾固體且用二乙醚(10 mL)洗滌並乾燥,得到呈黃色固體之標題化合物(35 mg)。產率:58 %。熔點:吸濕性 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 11.56 (s, 1H), 9.07 (d, J 3.6, 1H), 8.94 (d, J 2.4, 1H), 8.89 (bs, 2H), 8.80 (s, 1H), 8.17 (d, J 11.6, 1H), 8.12 (d, J 9.6, 1H), 8.00 (s, 1H), 7.83 (d, J 4.4, 1H), 7.80 (d, J 9.6, 1H), 5.57-5.50 (m, 1H), 3.48-3.40 (m, 4H), 3.35-3.25 (m, 4H), 2.35 (s, 9H), 1.55 (d, J 6.4, 3H)。MS (m/z):464.10 [M+H-3CH 3SO 3H];[C 24H 23F 2N 7O.(3CH 3SO 3H)+H-3CH 3SO 3H]計算值:464.19。 實例 42 (±)-(1-(8- -6-(5- -2-((5-(4- 甲基六氫吡嗪 -1- ) 吡啶 -2- ) 胺基 ) 嘧啶 -4- ) 喹啉 -4- ) 乙基 ) 胺基甲酸第三丁基酯 To 1-(8-fluoro-6-(5-fluoro-2-((5-(hexahydropyrazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinoline-4 To a mixture of -yl)ethanol (Example 41A, 50 mg, 0.108 mmol) in methanol ( 1 mL) was added CH3SO3H (15.6 mg, 0.162 mmol). The resulting clear solution was stirred for 30 min, diluted with methyl tert-butyl ether (5 mL) and stirred for 1 h. The reaction mixture was distilled under vacuum to give a solid. Diethyl ether (10 ml) was added to the solid. The solid was filtered and washed with diethyl ether (10 mL) and dried to give the title compound (35 mg) as a yellow solid. Yield: 58%. Melting point: Hygroscopic 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 11.56 (s, 1H), 9.07 (d, J 3.6, 1H), 8.94 (d, J 2.4, 1H), 8.89 (bs, 2H), 8.80 (s, 1H), 8.17 (d, J 11.6, 1H), 8.12 (d, J 9.6, 1H), 8.00 (s, 1H), 7.83 (d, J 4.4, 1H), 7.80 (d, J 9.6, 1H), 5.57-5.50 (m, 1H), 3.48-3.40 (m, 4H), 3.35-3.25 (m, 4H), 2.35 (s, 9H), 1.55 (d, J 6.4 , 3H). MS (m/z): 464.10 [ M + H - 3CH3SO3H ]; Calcd for [ C24H23F2N7O .( 3CH3SO3H )+H - 3CH3SO3H ]: 464.19. Example 42 (±)-(1-(8- fluoro -6-(5- fluoro -2-((5-(4- methylhexahydropyrazin- 1 -yl ) pyridin -2- yl ) amino ) Pyrimidin - 4 -yl ) quinolin- 4 -yl ) ethyl ) carbamate tert-butyl ester

遵循一般程序-3,自中間物71 (1 g, 2.38 mmol)及中間物11 (457 mg, 2.38 mmol)合成標題化合物。在後處理後,藉由combi-flash使用MeOH及DCM (9:91)作為溶析液純化粗產物。蒸餾來自管柱之合併純淨溶離份,獲得固體。將固體與二乙醚(10 ml)一起濕磨。過濾固體且用二乙醚(5 ml)洗滌,獲得呈黃色固體之標題化合物(310 mg)。產率:23%。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 9.88 (s, 1H), 9.04 (d, J 4.4, 1H), 8.78 (s, 1H), 8.74 (d, J 3.6, 1H), 8.17 (d, J 11.6, 1H), 8.10 (d, J 9.2, 1H), 8.04 (d, J 2.8, 1H), 7.91 (d, J 7.2, 1H), 7.69 (d, J 4.8, 1H), 7.48 (dd, J 9.2, 2.8, 1H), 5.55-5.45 (m, 1H), 3.18-3.10 (m, 4H), 2.50-2.44 (m, 4H), 2.24 (s, 3H), 1.47 (d, J 7.6, 3H), 1.37 (s, 9H)。MS (m/z):577.48 (M+H);[C 30H 34F 2N 8O 2+H]計算值:577.28。 實例 42A (±)-4-(4-(1- 胺基乙基 )-8- 氟喹啉 -6- )-5- -N-(5-(4- 甲基六氫吡嗪 -1- ) 吡啶 -2- ) 嘧啶 -2- The title compound was synthesized from Intermediate 71 (1 g, 2.38 mmol) and Intermediate 11 (457 mg, 2.38 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using MeOH and DCM (9:91 ) as eluents. Distillation of the combined clean fractions from the column afforded a solid. The solid was triturated with diethyl ether (10 ml). The solid was filtered and washed with diethyl ether (5 ml) to obtain the title compound (310 mg) as a yellow solid. Yield: 23%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.88 (s, 1H), 9.04 (d, J 4.4, 1H), 8.78 (s, 1H), 8.74 (d, J 3.6, 1H) , 8.17 (d, J 11.6, 1H), 8.10 (d, J 9.2, 1H), 8.04 (d, J 2.8, 1H), 7.91 (d, J 7.2, 1H), 7.69 (d, J 4.8, 1H) , 7.48 (dd, J 9.2, 2.8, 1H), 5.55-5.45 (m, 1H), 3.18-3.10 (m, 4H), 2.50-2.44 (m, 4H), 2.24 (s, 3H), 1.47 (d , J 7.6, 3H), 1.37 (s, 9H). MS (m/z): 577.48 (M + H); Calcd. for [ C30H34F2N8O2 + H]: 577.28 . Example 42A (±)-4-(4-(1 -aminoethyl )-8- fluoroquinolin- 6- yl )-5- fluoro -N-(5-(4 - methylhexahydropyrazine- 1- yl ) pyridin -2- yl ) pyrimidin -2- amine

遵循一般程序-4,自(±)-(1-(8-氟-6-(5-氟-2-((5-(4-甲基六氫吡嗪-1-基)吡啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)乙基)胺基甲酸第三丁基酯(實例42,300 mg, 0.52 mmol)合成呈黃色固體之標題化合物(190 mg)。產率:77%。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 9.86 (s, 1H), 9.02 (d, J 4.4, 1H), 8.83 (s, 1H), 8.72 (d, J 3.6, 1H), 8.15 (d, J 11.6, 1H), 8.07 (d, J 9.2, 1H), 8.03 (d, J 4.8, 1H), 7.92 (d, J 3.6, 1H), 7.45 (dd, J 9.2, 3, 1H), 4.90-4.82 (m, 1H), 3.20-3.09 (m, 4H), 2.52-2.45 (m, 4H), 2.25 (bs, 2H), 2.23 (s, 3H), 1.44 (d, J 6.4, 3H)。MS (m/z):476.61 (M+H);[C 25H 26F 2N 8+H]計算值:477.22。 實例 42B (±)-4-(4-(1- 胺基乙基 )-8- 氟喹啉 -6- )-5- -N-(5-(4- 甲基六氫吡嗪 -1- ) 吡啶 -2- ) 嘧啶 -2- 胺三鹽酸鹽 Following general procedure-4, from (±)-(1-(8-fluoro-6-(5-fluoro-2-((5-(4-methylhexahydropyrazin-1-yl)pyridine-2- Base) amino) pyrimidin-4-yl) quinolin-4-yl) ethyl) tert-butyl carbamate (Example 42, 300 mg, 0.52 mmol) The title compound (190 mg) was synthesized as a yellow solid . Yield: 77%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.86 (s, 1H), 9.02 (d, J 4.4, 1H), 8.83 (s, 1H), 8.72 (d, J 3.6, 1H) , 8.15 (d, J 11.6, 1H), 8.07 (d, J 9.2, 1H), 8.03 (d, J 4.8, 1H), 7.92 (d, J 3.6, 1H), 7.45 (dd, J 9.2, 3, 1H), 4.90-4.82 (m, 1H), 3.20-3.09 (m, 4H), 2.52-2.45 (m, 4H), 2.25 (bs, 2H), 2.23 (s, 3H), 1.44 (d, J 6.4 , 3H). MS (m/z): 476.61 (M+H); Calcd. for [ C25H26F2N8 + H]: 477.22 . Example 42B (±)-4-(4-(1 -aminoethyl )-8- fluoroquinolin- 6- yl )-5- fluoro -N-(5-(4 - methylhexahydropyrazine- 1- yl ) pyridin -2- yl ) pyrimidin -2- amine trihydrochloride

藉由溶解於MeOH (1 ml)中,向4-(4-(1-胺基乙基)-8-氟喹啉-6-基)-5-氟-N-(5-(4-甲基六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺(實例42A,180 mg, 0.378 mmol)於甲醇(2.6 mL)中之混合物中添加35%鹽酸水溶液(138 mg, 3.78 mmol)。將所得澄清溶液攪拌30 min,用甲基第三丁基醚(10.8 mL)稀釋並攪拌1 h。過濾固體且在真空下乾燥固體,獲得呈黃色固體之標題化合物(170 mg)。產率:87%。熔點:260℃-262℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 11.41 (bs, 1H), 11.10 (bs, 1H), 9.19 (d, J 4.4, 1H), 9.17-9.10 (m, 3H), 8.95 (d, J 3.2, 1H), 8.74 (s, 1H), 8.21 (d, J 11.2, 1H), 8.12-8.04 (m, 2H), 8.01 (d, J 4.8, 1H), 7.92 (d, J 10, 1H), 5.41-5.32 (m, 1H), 3.90-3.80 (m, 3H), 3.55-3.49 (m, 3H), 3.22-3.15 (m, 2H), 2.82 (d, J 4.4, 3H), 1.70 (d, J 6.4, 3H)。MS (m/z):477.4 (M+H-3HCl);[C 25H 26F 2N 8.3HCl+H-3HCl]計算值:477.22。 實例 43 (±)-1-(6-(2-((5-(4- 乙基六氫吡嗪 -1- ) 吡啶 -2- ) 胺基 )-5- 氟嘧啶 -4- )-8- 氟喹啉 -4- ) 乙醇 4-(4-(1-Aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-(4-methyl 35% aqueous hydrochloric acid (138 mg, 3.78 mmol). The resulting clear solution was stirred for 30 min, diluted with methyl tert-butyl ether (10.8 mL) and stirred for 1 h. The solid was filtered and dried under vacuum to obtain the title compound (170 mg) as a yellow solid. Yield: 87%. Melting point: 260°C-262°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 11.41 (bs, 1H), 11.10 (bs, 1H), 9.19 (d, J 4.4, 1H), 9.17-9.10 (m, 3H), 8.95 (d, J 3.2, 1H), 8.74 (s, 1H), 8.21 (d, J 11.2, 1H), 8.12-8.04 (m, 2H), 8.01 (d, J 4.8, 1H), 7.92 (d, J 10, 1H), 5.41-5.32 (m, 1H), 3.90-3.80 (m, 3H), 3.55-3.49 (m, 3H), 3.22-3.15 (m, 2H), 2.82 (d, J 4.4, 3H ), 1.70 (d, J 6.4, 3H). MS (m/z): 477.4 (M+H-3HCl); Calcd. for [ C25H26F2N8.3HCl + H- 3HCl ]: 477.22 . Example 43 (±)-1-(6-(2-((5-(4- ethylhexahydropyrazin- 1 -yl ) pyridin -2- yl ) amino )-5- fluoropyrimidin - 4 -yl )-8- fluoroquinolin- 4 -yl ) ethanol

遵循一般程序-3,自中間物74 (500 mg, 1.55 mmol)及中間物20 (321 mg, 1.55 mmol)合成標題化合物。在後處理後,將粗產物與DCM及MeOH之混合物(9:1) (10 ml)一起濕磨,獲得固體。過濾固體且用DCM (5 ml)洗滌固體。在旋轉蒸發儀上在55℃下真空乾燥固體,獲得呈黃色固體之標題化合物(100 mg)。產率:13%。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 9.86 (s, 1H), 9.03 (d, J 4.4, 1H), 8.81 (s, 1H), 8.73 (d, J 3.6, 1H), 8.15 (d, J 12, 1H), 8.08 (d, J 8.8, 1H), 8.03 (d, J 2.8, 1H), 7.80 (d, J 4.4, 1H), 7.45 (dd, J 9.2, 3.2, 1H), 5.81 (d, J 4.4, 1H), 5.57-5.50 (m, 1H), 3.18-3.10 (m, 4H), 2.55-2.48 (m, 4H), 2.38 (q, J 7.2, 2H), 1.54 (d, J 6.4, 3H), 1.03 (t, J 7.2, 3H)。MS (m/z):492.54 (M+H);[C 26H 27F 2N 7O+H]計算值:492.22。 實例 43A (±)-1-(6-(2-((5-(4- 乙基六氫吡嗪 -1- ) 吡啶 -2- ) 胺基 )-5- 氟嘧啶 -4- )-8- 氟喹啉 -4- ) 乙醇三鹽酸鹽 The title compound was synthesized from Intermediate 74 (500 mg, 1.55 mmol) and Intermediate 20 (321 mg, 1.55 mmol) following General Procedure-3. After work-up, the crude product was triturated with a mixture of DCM and MeOH (9:1 ) (10 ml) to obtain a solid. The solid was filtered and washed with DCM (5 ml). The solid was dried under vacuum on a rotary evaporator at 55°C to obtain the title compound (100 mg) as a yellow solid. Yield: 13%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.86 (s, 1H), 9.03 (d, J 4.4, 1H), 8.81 (s, 1H), 8.73 (d, J 3.6, 1H) , 8.15 (d, J 12, 1H), 8.08 (d, J 8.8, 1H), 8.03 (d, J 2.8, 1H), 7.80 (d, J 4.4, 1H), 7.45 (dd, J 9.2, 3.2, 1H), 5.81 (d, J 4.4, 1H), 5.57-5.50 (m, 1H), 3.18-3.10 (m, 4H), 2.55-2.48 (m, 4H), 2.38 (q, J 7.2, 2H), 1.54 (d, J 6.4, 3H), 1.03 (t, J 7.2, 3H). MS (m/z): 492.54 (M+H); Calcd. for [ C26H27F2N7O + H]: 492.22 . Example 43A (±)-1-(6-(2-((5-(4- ethylhexahydropyrazin- 1 -yl ) pyridin -2- yl ) amino )-5- fluoropyrimidin - 4 -yl )-8- fluoroquinolin- 4 -yl ) ethanol trihydrochloride

藉由溶解於MeOH (0.9 ml)中,向4-(4-(1-胺基乙基)-8-氟喹啉-6-基)-5-氟-N-(5-(4-甲基六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺(實例43,95 mg, 0.19 mmol)於甲醇(1 mL)中之混合物中添加35%鹽酸水溶液(138 mg, 3.78 mmol)。將所得澄清溶液攪拌30 min。30 min後,用甲基第三丁基醚(5.7 mL)稀釋並攪拌1 h,獲得固體。過濾固體且在真空下乾燥固體,獲得呈黃色固體之標題化合物(80 mg)。產率:76%。熔點:249℃-251℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 11.75 (s, 1H), 11.51 (s, 1H), 9.06 (d, J 4.4, 1H), 8.93 (d, J 3.2, 1H), 8.82 (s, 1H), 8.25-8.14 (m, 2H), 8.04 (d, J 2.8, 1H), 7.93 (d, J 9.6, 1H), 7.83 (d, J 4.4, 1H), 5.58-5.50 (m, 1H), 3.90-3.83 (m, 2H), 3.63-3.56 (m, 2H), 3.39-3.28 (m, 2H), 3.20-3.08 (m, 4H), 1.54 (d, J 6.8, 3H), 1.31 (t, J 7.2, 3H)。MS (m/z):492.58 (M+H-3HCl);[C 26H 27F 2N 7O.3HCl+H-3HCl]計算值:492.22。 實例 44 (±)-1-(8- -6-(5- -2-((5-(4- 異丙基六氫吡嗪 -1- ) 吡啶 -2- ) 胺基 ) 嘧啶 -4- ) 喹啉 -4- ) 乙醇 4-(4-(1-Aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-(4-methyl 35% aqueous hydrochloric acid (138 mg, 3.78 mmol). The resulting clear solution was stirred for 30 min. After 30 min, dilute with methyl tert-butyl ether (5.7 mL) and stir for 1 h to obtain a solid. The solid was filtered and dried under vacuum to obtain the title compound (80 mg) as a yellow solid. Yield: 76%. Melting point: 249°C-251°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 11.75 (s, 1H), 11.51 (s, 1H), 9.06 (d, J 4.4, 1H), 8.93 (d, J 3.2, 1H) , 8.82 (s, 1H), 8.25-8.14 (m, 2H), 8.04 (d, J 2.8, 1H), 7.93 (d, J 9.6, 1H), 7.83 (d, J 4.4, 1H), 5.58-5.50 (m, 1H), 3.90-3.83 (m, 2H), 3.63-3.56 (m, 2H), 3.39-3.28 (m, 2H), 3.20-3.08 (m, 4H), 1.54 (d, J 6.8, 3H ), 1.31 (t, J 7.2, 3H). MS (m/z): 492.58 (M+H-3HCl); Calcd. for [ C26H27F2N7O.3HCl + H - 3HCl]: 492.22 . Example 44 (±)-1-(8- fluoro -6-(5- fluoro -2-((5-(4- isopropylhexahydropyrazin- 1 -yl ) pyridin -2- yl ) amino ) Pyrimidin - 4 -yl ) quinolin- 4 -yl ) ethanol

遵循一般程序-3,自中間物74 (500 mg, 1.55 mmol)及中間物25 (342 mg, 1.55 mmol)合成標題化合物。在後處理後,將粗產物與二乙醚(10 ml)一起濕磨,獲得固體。過濾固體且在旋轉蒸發儀上在55℃下真空乾燥固體,獲得呈黃色固體之標題化合物(320 mg)。產率:41%。熔點:238℃-240℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 9.84 (s, 1H), 9.03 (d, J 4.4, 1H), 8.81 (s, 1H), 8.72 (d, J 3.6, 1H), 8.15 (d, J 12, 1H), 8.07 (d, J 9.2, 1H), 8.03 (d, J 2.8, 1H), 7.80 (d, J 4.4,1H), 7.44 (dd, J 9.2, 3.2, 1H), 5.78 (d, J 4.4,1H), 5.58-5.50 (m, 1H), 3.17-3.09 (m, 4H), 2.72-2.63 (m, 1H), 2.62-2.55 (m, 4H), 1.54 (d, J 6.4, 3H), 1.01 (d, J 6.4, 6H)。MS (m/z):506.64 (M+H);[C 27H 29F 2N 7O+H]計算值:506.24。 實例 44A (±)-1-(8- -6-(5- -2-((5-(4- 異丙基六氫吡嗪 -1- ) 吡啶 -2- ) 胺基 ) 嘧啶 -4- ) 喹啉 -4- ) 乙醇三鹽酸鹽 The title compound was synthesized from Intermediate 74 (500 mg, 1.55 mmol) and Intermediate 25 (342 mg, 1.55 mmol) following General Procedure-3. After work-up, the crude product was triturated with diethyl ether (10 ml) to obtain a solid. The solid was filtered and dried under vacuum on a rotary evaporator at 55 °C to obtain the title compound (320 mg) as a yellow solid. Yield: 41%. Melting point: 238°C-240°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.84 (s, 1H), 9.03 (d, J 4.4, 1H), 8.81 (s, 1H), 8.72 (d, J 3.6, 1H) , 8.15 (d, J 12, 1H), 8.07 (d, J 9.2, 1H), 8.03 (d, J 2.8, 1H), 7.80 (d, J 4.4,1H), 7.44 (dd, J 9.2, 3.2, 1H), 5.78 (d, J 4.4,1H), 5.58-5.50 (m, 1H), 3.17-3.09 (m, 4H), 2.72-2.63 (m, 1H), 2.62-2.55 (m, 4H), 1.54 (d, J 6.4, 3H), 1.01 (d, J 6.4, 6H). MS (m/z): 506.64 (M+H); Calcd. for [ C27H29F2N7O + H]: 506.24 . Example 44A (±)-1-(8- fluoro -6-(5- fluoro -2-((5-(4- isopropylhexahydropyrazin- 1 -yl ) pyridin -2- yl ) amino ) Pyrimidin - 4 -yl ) quinolin- 4 -yl ) ethanol trihydrochloride

藉由溶解於MeOH (1 ml)中,向(±)-1-(8-氟-6-(5-氟-2-((5-(4-異丙基六氫吡嗪-1-基)吡啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)乙醇(實例44,300 mg, 0.593 mmol)於甲醇(5 mL)中之混合物中添加35%鹽酸水溶液(216 mg, 5.93 mmol) 將所得澄清溶液攪拌30 min。30 min後,用甲基第三丁基醚(18 mL)稀釋並攪拌1 h,獲得固體。過濾固體且在旋轉蒸發儀上在55℃下真空乾燥固體,獲得呈黃色固體之標題化合物(290 mg)。熔點:245℃-247℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 11.74 (s, 1H), 11.32 (s, 1H), 9.06 (d, J 4.4, 1H), 8.94 (d, J 3.2, 1H), 8.81 (s, 1H), 8.22-8.15 (m, 2H), 8.03 (d, J 2.8, 1H), 7.89 (d, J 9.6, 1H), 7.83 (, J 4.8, 1H), 5.58-5.50 (m, 1H), 3.91-3.83 (m, 2H), 3.60-3.50 (m, 3H), 3.41-3.32 (m, 2H), 3.22-3.10 (m, 2H), 1.54 (d, J 6.8, 3H), 1.34 (d, J 6.8, 6H)。MS (m/z):506.65 (M+H-3HCl);[C 27H 29F 2N 7O+H-3HCl]計算值:506.24。 實例 45 N-(5-(4- 乙基六氫吡嗪 -1- ) 吡啶 -2- )-5- -4-(8- -2- 甲基喹啉 -6- ) 嘧啶 -2- To (±)-1-(8-fluoro-6-(5-fluoro-2-((5-(4-isopropylhexahydropyrazin-1-yl) )pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl)ethanol (Example 44, 300 mg, 0.593 mmol) in methanol (5 mL) was added 35% aqueous hydrochloric acid ( 216 mg, 5.93 mmol) The resulting clear solution was stirred for 30 min. After 30 min, dilute with methyl tert-butyl ether (18 mL) and stir for 1 h to obtain a solid. The solid was filtered and dried under vacuum on a rotary evaporator at 55 °C to obtain the title compound (290 mg) as a yellow solid. Melting point: 245°C-247°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 11.74 (s, 1H), 11.32 (s, 1H), 9.06 (d, J 4.4, 1H), 8.94 (d, J 3.2, 1H) , 8.81 (s, 1H), 8.22-8.15 (m, 2H), 8.03 (d, J 2.8, 1H), 7.89 (d, J 9.6, 1H), 7.83 (, J 4.8, 1H), 5.58-5.50 ( m, 1H), 3.91-3.83 (m, 2H), 3.60-3.50 (m, 3H), 3.41-3.32 (m, 2H), 3.22-3.10 (m, 2H), 1.54 (d, J 6.8, 3H) , 1.34 (d, J 6.8, 6H). MS (m/z): 506.65 (M+H-3HCl); Calcd. for [ C27H29F2N7O + H - 3HCl]: 506.24 . Example 45 N-(5-(4- ethylhexahydropyrazin- 1 -yl ) pyridin -2- yl )-5- fluoro - 4-(8- fluoro -2 -methylquinolin -6- yl ) Pyrimidin -2- amine

遵循一般程序-3,自中間物23 (500 mg, 1.55 mmol)及中間物20 (342 mg, 1.55 mmol)合成標題化合物。在後處理後,藉由combi-flash使用MeOH及DCM (6:94)作為溶析液純化粗產物。使來自管柱層析之純淨化合物懸浮於二乙醚(20 ml)中且攪拌30 min,獲得固體。過濾固體且用二乙醚洗滌。在真空下乾燥固體, 獲得呈黃色固體之標題化合物(200 mg)。產率: %。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 9.81 (s, 1H), 8.70 (d, J 3.6, 1H), 8.52 (d, J 8.8, 1H), 8.49 (s, 1H), 8.15 (d, J 12。 1H), 8.03 (d, J 9.2, 1H), 8.01 (d, J 2.4, 1H), 7.61 (d, J 8.8, 1H), 7.47 (dd, J 8.8, 2.4, 1H), 3.18-3.10 (m, 4H), 2.72 (s, 3H), 2.60-2.50 (m, 4H), 2.42-2.36 (m, 2H), 1.03 (t, J 6.8, 3H)。MS (m/z):462.45 (M+H);[C 25H 25F 2N 7+H]計算值:462.21。 實例 45A N -(5-(4- 乙基六氫吡嗪 -1- ) 吡啶 -2- )-5- -4-(8- -2- 甲基喹啉 -6- ) 嘧啶 -2- 胺鹽酸鹽 The title compound was synthesized from Intermediate 23 (500 mg, 1.55 mmol) and Intermediate 20 (342 mg, 1.55 mmol) following General Procedure-3. After workup, the crude product was purified by combi-flash using MeOH and DCM (6:94) as eluents. The pure compound from column chromatography was suspended in diethyl ether (20 ml) and stirred for 30 min to obtain a solid. The solid was filtered and washed with diethyl ether. The solid was dried under vacuum to afford the title compound (200 mg) as a yellow solid. Yield: %. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.81 (s, 1H), 8.70 (d, J 3.6, 1H), 8.52 (d, J 8.8, 1H), 8.49 (s, 1H) , 8.15 (d, J 12. 1H), 8.03 (d, J 9.2, 1H), 8.01 (d, J 2.4, 1H), 7.61 (d, J 8.8, 1H), 7.47 (dd, J 8.8, 2.4, 1H), 3.18-3.10 (m, 4H), 2.72 (s, 3H), 2.60-2.50 (m, 4H), 2.42-2.36 (m, 2H), 1.03 (t, J 6.8, 3H). MS (m/z): 462.45 (M+H); Calcd. for [ C25H25F2N7 + H]: 462.21 . Example 45A N- (5-(4- ethylhexahydropyrazin- 1 -yl ) pyridin -2- yl )-5- fluoro - 4-(8- fluoro -2 -methylquinolin -6- yl ) Pyrimidin -2- amine hydrochloride

N-(5-(4-乙基六氫吡嗪-1-基)吡啶-2-基)-5-氟-4-(8-氟-2-甲基喹啉-6-基)嘧啶-2-胺(實例45,180 mg, 0.39 mmol)於甲醇(4.5 mL)中之混合物中添加35%鹽酸水溶液(216 mg, 5.93 mmol)。將所得澄清溶液攪拌30 min。30 min後,用甲基第三丁基醚(13.5 mL)稀釋並攪拌1 h,獲得固體。過濾固體且在旋轉蒸發儀上在55℃下真空乾燥固體,獲得呈黃色固體之標題化合物(150 mg)。熔點:265℃-267℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 11.82 (bs, 1H), 11.33 (bs, 1H), 8.93 (d, J 3.2, 1H),  8.57 (d, J 9.2, 1H), 8.55 (s, 1H), 8.23 (dd, J 9.2, 2.4, 1H), 8.17 (d, J 11.6, 1H), 8.01 (d, J 2.4, 1H), 7.82 (d, J 9.2, 1H), 7.65 (d, J 8.4, 1H), 3.90-3.80 (m, 2H), 3.63-3.55 (m, 2H), 3.33-3.24 (m, 2H), 3.20-3.05 (m, 4H), 2.74 (s, 3H), 1.29 (t, J 7.2, 3H)。MS (m/z):462.49 (M+H-HCl);[C 25H 25F 2N 7.HCl+H-HCl]計算值:462.21。 實例 46 (±)-4-(6-((5- -4-(8- -4-(1- 羥基乙基 )-2- 甲基喹啉 -6- ) 嘧啶 -2- ) 胺基 ) 吡啶 -3- ) 六氫吡嗪 -1- 甲酸第三丁基酯 To N- (5-(4-ethylhexahydropyrazin-1-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-2-methylquinolin-6-yl)pyrimidine - To a mixture of 2-amine (Example 45, 180 mg, 0.39 mmol) in methanol (4.5 mL) was added 35% aqueous hydrochloric acid (216 mg, 5.93 mmol). The resulting clear solution was stirred for 30 min. After 30 min, dilute with methyl tert-butyl ether (13.5 mL) and stir for 1 h to obtain a solid. The solid was filtered and dried under vacuum on a rotary evaporator at 55 °C to obtain the title compound (150 mg) as a yellow solid. Melting point: 265°C-267°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 11.82 (bs, 1H), 11.33 (bs, 1H), 8.93 (d, J 3.2, 1H), 8.57 (d, J 9.2, 1H) , 8.55 (s, 1H), 8.23 (dd, J 9.2, 2.4, 1H), 8.17 (d, J 11.6, 1H), 8.01 (d, J 2.4, 1H), 7.82 (d, J 9.2, 1H), 7.65 (d, J 8.4, 1H), 3.90-3.80 (m, 2H), 3.63-3.55 (m, 2H), 3.33-3.24 (m, 2H), 3.20-3.05 (m, 4H), 2.74 (s, 3H), 1.29 (t, J 7.2, 3H). MS (m/z): 462.49 (M+H-HCl); Calcd. for [ C25H25F2N7.HCl + H - HCl]: 462.21 . Example 46 (±)-4-(6-((5- fluoro - 4-(8- fluoro - 4-(1- hydroxyethyl )-2 -methylquinolin -6- yl ) pyrimidin -2- yl ) amino ) pyridin - 3 -yl ) hexahydropyrazine- 1 -carboxylic acid tert-butyl ester

遵循一般程序-3,自中間物77 (500 mg, 1.55 mmol)及中間物5 (342 mg, 1.55 mmol)合成標題化合物。在後處理後,藉由combi-flash使用MeOH及DCM (3:97)作為溶析液純化粗產物。使來自管柱層析之純淨化合物懸浮於二乙醚(20 ml)中且攪拌30 min,獲得固體。過濾固體且用二乙醚(20 ml)洗滌。在真空下乾燥固體, 獲得呈黃色固體之標題化合物(200 mg)。產率:12%。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 9.89 (s, 1H), 8.75 (s, 1H), 8.72 (d, J 3.5, 1H), 8.15-8.03 (m, 3H), 7.68 (s, 1H), 7.46 (dd, J 9.0, 2.4, 1H),  5.75 (d, J 4.0, 1H), 5.50-5.42 (m, 1H), 3.52-3.44 (m, 4H), 3.11-3.05 (m, 4H), 2.73 (s, 3H), 1.53 (d, J 6.5, 3H), 1.42 (s, 9H)。MS (m/z):578.38 (M+H);[C 30H 33F 2N 7O 3+H]計算值:578.26。 實例 46A (±)-1-(8- -6-(5- -2-((5-( 六氫吡嗪 -1- ) 吡啶 -2- ) 胺基 ) 嘧啶 -4- )-2- 甲基喹啉 -4- ) 乙醇 The title compound was synthesized from Intermediate 77 (500 mg, 1.55 mmol) and Intermediate 5 (342 mg, 1.55 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using MeOH and DCM (3:97) as eluents. The pure compound from column chromatography was suspended in diethyl ether (20 ml) and stirred for 30 min to obtain a solid. The solid was filtered and washed with diethyl ether (20 ml). The solid was dried under vacuum to afford the title compound (200 mg) as a yellow solid. Yield: 12%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.89 (s, 1H), 8.75 (s, 1H), 8.72 (d, J 3.5, 1H), 8.15-8.03 (m, 3H), 7.68 (s, 1H), 7.46 (dd, J 9.0, 2.4, 1H), 5.75 (d, J 4.0, 1H), 5.50-5.42 (m, 1H), 3.52-3.44 (m, 4H), 3.11-3.05 (m, 4H), 2.73 (s, 3H), 1.53 (d, J 6.5, 3H), 1.42 (s, 9H). MS (m/z): 578.38 ( M +H); Calcd. for [ C30H33F2N7O3 + H]: 578.26 . Example 46A (±)-1-(8- fluoro -6-(5- fluoro -2-((5-( hexahydropyrazin- 1 -yl ) pyridin -2- yl ) amino ) pyrimidin - 4 -yl )-2 -methylquinolin- 4 -yl ) ethanol

遵循一般程序-4,自(±)-4-(6-((5-氟-4-(8-氟-4-(1-羥基乙基)-2-甲基喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-1-甲酸第三丁基酯(實例46,190 mg, 0.33 mmol)合成呈黃色固體之標題化合物(90 mg)。產率:60%。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 9.82 (s, 1H), 8.80-8.69 (m, 2H), 8.20-8.00 (m, 3H), 7.68 (s, 1H), 7.43 (d, J 8.6, 1H), 5.80-5.70 (m, 1H), 5.51-5.44 (m, 1H), 3.45-3.35 (m, 4H), 3.10-3.00 (m, 2H), 2.90-2.82 (m, 2H), 2.73 (s, 3H), 1.53 (d, J 6.3, 3H)。MS (m/z):478.50 (M+H);[C 25H 25F 2N 7O+H]計算值:478.21。 實例 46B (±)-1-(8- -6-(5- -2-((5-( 六氫吡嗪 -1- ) 吡啶 -2- ) 胺基 ) 嘧啶 -4- )-2- 甲基喹啉 -4- ) -1- 醇鹽酸鹽 Following general procedure-4, from (±)-4-(6-((5-fluoro-4-(8-fluoro-4-(1-hydroxyethyl)-2-methylquinolin-6-yl) Pyrimidin-2-yl)amino)pyridin-3-yl)tert-butyl hexahydropyrazine-1-carboxylate (Example 46, 190 mg, 0.33 mmol) The title compound (90 mg) was synthesized as a yellow solid. Yield: 60%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.82 (s, 1H), 8.80-8.69 (m, 2H), 8.20-8.00 (m, 3H), 7.68 (s, 1H), 7.43 (d, J 8.6, 1H), 5.80-5.70 (m, 1H), 5.51-5.44 (m, 1H), 3.45-3.35 (m, 4H), 3.10-3.00 (m, 2H), 2.90-2.82 (m , 2H), 2.73 (s, 3H), 1.53 (d, J 6.3, 3H). MS (m/z): 478.50 (M+H); Calcd. for [ C25H25F2N7O + H]: 478.21 . Example 46B (±)-1-(8- fluoro -6-(5- fluoro -2-((5-( hexahydropyrazin- 1 -yl ) pyridin -2- yl ) amino ) pyrimidin - 4 -yl )-2 -methylquinolin- 4 -yl ) ethan - 1 - ol hydrochloride

藉由溶解於MeOH (0.1 ml)中,向1-(8-氟-6-(5-氟-2-((5-(六氫吡嗪-1-基)吡啶-2-基)胺基)嘧啶-4-基)-2-甲基喹啉-4-基)乙-1-醇(實例46A,90 mg, 0.2 mmol)於甲醇(4.5 mL)中之混合物中添加35%鹽酸水溶液(30 mg, 0.8 mmol) 。將所得澄清溶液攪拌30 min。30 min後,用甲基第三丁基醚(5.4 mL)稀釋並攪拌1 h,獲得固體。過濾固體且用甲基第三丁基醚(20 mL)洗滌。在旋轉蒸發儀上在55℃下真空乾燥固體,獲得呈黃色固體之標題化合物(75 mg)。熔點:238℃-240℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 11.92 (s, 1H), 9.60 (bs, 2H), 8.95-8.90 (m, 1H), 8.79-8.72 (m, 1H), 8.25-8.18 (m, 1H), 8.14 (dd, J 11.2, 4, 1H), 8.00 (s, 1H), 7.88 (dd, J 9.2, 4.8, 1H), 7.73 (d, J 4.8, 1H), 5.51-5.40 (m, 1H), 3.50-3.42 (m, 4H), 3.30-3.20 (m, 4H), 2.75 (d, J 4.4, 3H), 1.11 (d, J 4.8, 3H)。MS (m/z):478.50 (M+H-HCl);[C 25H 25F 2N 7O+H-HCl]計算值:478.21。 實例 47 (±)-1-(8- -6-(5- -2-((5-(4- 甲基六氫吡嗪 -1- ) 吡啶 -2- ) 胺基 ) 嘧啶 -4- ) 喹啉 -4- ) 乙醇 1-(8-Fluoro-6-(5-fluoro-2-((5-(hexahydropyrazin-1-yl)pyridin-2-yl)amino) by dissolving in MeOH (0.1 ml) )pyrimidin-4-yl)-2-methylquinolin-4-yl)ethan-1-ol (Example 46A, 90 mg, 0.2 mmol) in methanol (4.5 mL) was added 35% aqueous hydrochloric acid ( 30 mg, 0.8 mmol). The resulting clear solution was stirred for 30 min. After 30 min, dilute with methyl tert-butyl ether (5.4 mL) and stir for 1 h to obtain a solid. The solid was filtered and washed with methyl tert-butyl ether (20 mL). The solid was dried under vacuum on a rotary evaporator at 55°C to obtain the title compound (75 mg) as a yellow solid. Melting point: 238°C-240°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 11.92 (s, 1H), 9.60 (bs, 2H), 8.95-8.90 (m, 1H), 8.79-8.72 (m, 1H), 8.25 -8.18 (m, 1H), 8.14 (dd, J 11.2, 4, 1H), 8.00 (s, 1H), 7.88 (dd, J 9.2, 4.8, 1H), 7.73 (d, J 4.8, 1H), 5.51 -5.40 (m, 1H), 3.50-3.42 (m, 4H), 3.30-3.20 (m, 4H), 2.75 (d, J 4.4, 3H), 1.11 (d, J 4.8, 3H). MS (m/z): 478.50 (M+H-HCl); Calcd. for [ C25H25F2N7O + H - HCl]: 478.21 . Example 47 (±)-1-(8- fluoro -6-(5- fluoro -2-((5-(4- methylhexahydropyrazin- 1 -yl ) pyridin -2- yl ) amino ) pyrimidine -4 -yl ) quinolin- 4 -yl ) ethanol

遵循一般程序-3,自中間物74 (500 mg, 1.55 mmol)及中間物11 (299 mg, 1.55 mmol)合成標題化合物。在後處理後,藉由combi-flash使用MeOH及DCM (13:87)作為溶析液純化粗產物。蒸餾來自管柱之純淨溶離份,獲得殘餘物。將殘餘物與二乙醚(20 ml)一起濕磨,獲得固體。過濾固體且用二乙醚(10 ml)洗滌固體。在旋轉蒸發儀上在55℃下真空乾燥固體,獲得呈黃色固體之標題化合物(330 mg)。產率:45%。熔點:235℃-237℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 9.84 (s, 1H), 9.03 (d, J 4.8, 1H), 8.81 (s, 1H), 8.72 (d, J 3.6, 1H), 8.14 (d, J 12, 1H), 8.08 (d, J 9.2, 1H), 8.03 (d, J 2.8, 1H), 7.80 (d, J 4.8, 1H), 7.45 (dd, J 9.2, 3.2, 1H), 5.78 (d, J 4.4, 1H), 5.56-5.48 (m, 1H), 3.18-3.10- (m, 4H), 2.50-2.42 (m, 4H), 2.23 (s, 3H), 1.54 (d, J 6.4, 3H)。MS (m/z):478.50 (M+H);[C 25H 25F 2N 7O+H]計算值:478.21。 實例 47A (±)-1-(8- -6-(5- -2-((5-(4- 甲基六氫吡嗪 -1- ) 吡啶 -2- ) 胺基 ) 嘧啶 -4- ) 喹啉 -4- ) 乙醇三鹽酸鹽 The title compound was synthesized from Intermediate 74 (500 mg, 1.55 mmol) and Intermediate 11 (299 mg, 1.55 mmol) following General Procedure-3. After workup, the crude product was purified by combi-flash using MeOH and DCM (13:87) as eluents. The pure fraction from the column was distilled to obtain a residue. The residue was triturated with diethyl ether (20 ml) to obtain a solid. The solid was filtered and washed with diethyl ether (10 ml). The solid was dried under vacuum on a rotary evaporator at 55°C to obtain the title compound (330 mg) as a yellow solid. Yield: 45%. Melting point: 235°C-237°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.84 (s, 1H), 9.03 (d, J 4.8, 1H), 8.81 (s, 1H), 8.72 (d, J 3.6, 1H) , 8.14 (d, J 12, 1H), 8.08 (d, J 9.2, 1H), 8.03 (d, J 2.8, 1H), 7.80 (d, J 4.8, 1H), 7.45 (dd, J 9.2, 3.2, 1H), 5.78 (d, J 4.4, 1H), 5.56-5.48 (m, 1H), 3.18-3.10- (m, 4H), 2.50-2.42 (m, 4H), 2.23 (s, 3H), 1.54 ( d, J 6.4, 3H). MS (m/z): 478.50 (M+H); Calcd. for [ C25H25F2N7O + H]: 478.21 . Example 47A (±)-1-(8- fluoro -6-(5- fluoro -2-((5-(4- methylhexahydropyrazin- 1 -yl ) pyridin -2- yl ) amino ) pyrimidine -4 -yl ) quinolin- 4 -yl ) ethanol trihydrochloride

藉由溶解於MeOH (1 ml)中,向(±)-1-(8-氟-6-(5-氟-2-((5-(4-甲基六氫吡嗪-1-基)吡啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)乙醇(實例47,300 mg, 0.63 mmol)於甲醇(5 mL)中之混合物中添加35%鹽酸水溶液(229 mg, 6.3 mmol)。將所得澄清溶液攪拌30 min。30 min後,用甲基第三丁基醚(18 mL)稀釋並攪拌1 h,獲得固體。過濾固體且在旋轉蒸發儀上在55℃下真空乾燥固體,獲得呈黃色固體之標題化合物(270 mg)。熔點:268℃-270℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 11.66 (s, 1H), 11.33 (s, 1H), 9.06 (d, J 4.4, 1H), 8.93 (d, J 2.8, 1H), 8.81 (s, 1H), 8.20-8.13 (m, 2H), 8.02 (d, J 2.8, 1H), 7.89 (d, J 9.2, 1H), 7.83 (d, J 4.8, 1H), 5.58-5.50 (m, 1H), 3.90-3.82 (m, 2H), 3.59-3.50 (m, 2H), 3.30-3.12 (m, 4H), 2.83 (s, 3H), 1.55 (d, J 6.8, 3H)。MS (m/z):478.50 (M+H-3HCl);[C 25H 25F 2N 7O+H-3HCl]計算值:478.21。 實例 48 4-(6-((5- -4-(8- -4-(2- 羥基丙 -2- ) 喹啉 -6- ) 嘧啶 -2- ) 胺基 ) 吡啶 -3- ) 六氫吡嗪 -1- 甲酸第三丁基酯 To (±)-1-(8-fluoro-6-(5-fluoro-2-((5-(4-methylhexahydropyrazin-1-yl) To a mixture of pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl)ethanol (Example 47, 300 mg, 0.63 mmol) in methanol (5 mL) was added 35% aqueous hydrochloric acid (229 mg, 6.3 mmol). The resulting clear solution was stirred for 30 min. After 30 min, dilute with methyl tert-butyl ether (18 mL) and stir for 1 h to obtain a solid. The solid was filtered and dried under vacuum on a rotary evaporator at 55 °C to obtain the title compound (270 mg) as a yellow solid. Melting point: 268°C-270°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 11.66 (s, 1H), 11.33 (s, 1H), 9.06 (d, J 4.4, 1H), 8.93 (d, J 2.8, 1H) , 8.81 (s, 1H), 8.20-8.13 (m, 2H), 8.02 (d, J 2.8, 1H), 7.89 (d, J 9.2, 1H), 7.83 (d, J 4.8, 1H), 5.58-5.50 (m, 1H), 3.90-3.82 (m, 2H), 3.59-3.50 (m, 2H), 3.30-3.12 (m, 4H), 2.83 (s, 3H), 1.55 (d, J 6.8, 3H). MS (m/z): 478.50 (M+H-3HCl); Calcd. for [ C25H25F2N7O + H - 3HCl]: 478.21 . Example 48 4-(6-((5- fluoro - 4-(8- fluoro - 4-(2 -hydroxyprop- 2- yl ) quinolin -6- yl ) pyrimidin -2 - yl ) amino ) pyridine- 3- yl ) Hexahydropyrazine- 1 -carboxylic acid tert-butyl ester

遵循一般程序-3,自中間物83 (810 mg, 2.5 mmol)及中間物5 (700 mg, 2.5 mmol)合成標題化合物。在後處理後,藉由combi-flash使用MeOH及DCM (3:97)作為溶析液純化粗產物。使來自管柱層析之純淨化合物懸浮於二乙醚(50 ml)中且攪拌30 min,獲得固體。過濾固體且用二乙醚(50 ml)洗滌。在真空下乾燥固體, 獲得呈淡綠色固體之標題化合物(760 mg)。產率:54%。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 9.86 (bs, 1H), 9.53 (s, 1H), 8.97 (d, J 4.4, 1H), 8.67 (bs, 1H), 8.13 (d, J 12.4, 1H), 8.12-8.05 (m, 1H), 8.03 (d, J 2.8, 1H), 7.73 (d, J 4.4, 1H), 7.45 (dd, J 9.2, 2.8, 1H), 5.88 (bs, 1H), 3.51-3.44 (m, 4H), 3.11-3.04 (m, 4H), 1.74 (s, 6H), 1.42 (s, 9H)。MS (m/z):578.63 (M+H);[C 30H 33F 2N 7O 3+H]計算值:578.26。 實例 48A 2-(8- -6-(5- -2-((5-( 六氫吡嗪 -1- ) 吡啶 -2- ) 胺基 ) 嘧啶 -4- ) 喹啉 -4- ) -2- The title compound was synthesized from Intermediate 83 (810 mg, 2.5 mmol) and Intermediate 5 (700 mg, 2.5 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using MeOH and DCM (3:97) as eluents. The pure compound from column chromatography was suspended in diethyl ether (50 ml) and stirred for 30 min to obtain a solid. The solid was filtered and washed with diethyl ether (50 ml). The solid was dried under vacuum to afford the title compound (760 mg) as a light green solid. Yield: 54%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.86 (bs, 1H), 9.53 (s, 1H), 8.97 (d, J 4.4, 1H), 8.67 (bs, 1H), 8.13 ( d, J 12.4, 1H), 8.12-8.05 (m, 1H), 8.03 (d, J 2.8, 1H), 7.73 (d, J 4.4, 1H), 7.45 (dd, J 9.2, 2.8, 1H), 5.88 (bs, 1H), 3.51-3.44 (m, 4H), 3.11-3.04 (m, 4H), 1.74 (s, 6H), 1.42 (s, 9H). MS (m/z): 578.63 ( M +H); Calcd. for [ C30H33F2N7O3 + H]: 578.26 . Example 48A 2-(8- fluoro -6-(5- fluoro -2-((5-( hexahydropyrazin- 1 -yl ) pyridin -2- yl ) amino ) pyrimidin - 4 - yl ) quinoline- 4- yl ) propan -2- ol

遵循一般程序-4,自4-(6-((5-氟-4-(8-氟-4-(2-羥基丙-2-基)喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-1-甲酸第三丁基酯(實例48,490 mg, 0.87 mmol)合成呈黃色固體之標題化合物(370 mg)。產率:77%。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 9.81 (s, 1H), 9.55 (s, 1H), 8.98 (d, J 4.8, 1H), 8.72 (d, J 3.6, 1H), 8.17-8.10 (m, 2H), 8.01 (d, J 3.2, 1H), 7.81 (d, J 4.4, 1H), 7.43 (dd, J 9.2, 3.2, 1H), 5.83 (bs, 1H), 5.59-5.50 (m, 1H), 3.08-3.01 (m, 4H), 2.88-2.81 (m, 4H), 1.75 (s, 6H)。MS (m/z):478.67 (M+H);[C 25H 25F 2N 7O+H]計算值:478.21。 實例 48B 2-(8- -6-(5- -2-((5-( 六氫吡嗪 -1- ) 吡啶 -2- ) 胺基 ) 嘧啶 -4- ) 喹啉 -4- ) -2- Following general procedure-4, from 4-(6-((5-fluoro-4-(8-fluoro-4-(2-hydroxypropan-2-yl)quinolin-6-yl)pyrimidin-2-yl) Amino)pyridin-3-yl)pyrazine-1-carboxylic acid tert-butyl ester (Example 48, 490 mg, 0.87 mmol) The title compound (370 mg) was synthesized as a yellow solid. Yield: 77%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.81 (s, 1H), 9.55 (s, 1H), 8.98 (d, J 4.8, 1H), 8.72 (d, J 3.6, 1H) , 8.17-8.10 (m, 2H), 8.01 (d, J 3.2, 1H), 7.81 (d, J 4.4, 1H), 7.43 (dd, J 9.2, 3.2, 1H), 5.83 (bs, 1H), 5.59 -5.50 (m, 1H), 3.08-3.01 (m, 4H), 2.88-2.81 (m, 4H), 1.75 (s, 6H). MS (m/z): 478.67 (M+H); Calcd. for [ C25H25F2N7O + H]: 478.21 . Example 48B 2-(8- fluoro -6-(5- fluoro -2-((5-( hexahydropyrazin- 1 -yl ) pyridin -2- yl ) amino ) pyrimidin - 4 - yl ) quinoline- 4- yl ) propan -2- ol

藉由溶解於MeOH (1 ml)中,向1-(8-氟-6-(5-氟-2-((5-(4-甲基六氫吡嗪-1-基)吡啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)乙醇(實例48A,300 mg, 0.63 mmol)於甲醇(5 mL)中之混合物中添加35%鹽酸水溶液(229 mg, 6.3 mmol)。將所得澄清溶液攪拌30 min。30 min後,用甲基第三丁基醚(18 mL)稀釋並攪拌1 h,獲得固體。過濾固體且在旋轉蒸發儀上在55℃下真空乾燥固體,獲得呈黃色固體之標題化合物(270 mg)。熔點:268℃-270℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 11.81 (s, 1H), 9.60 (bs, 1H), 9.57 (s, 1H), 9.01 (d, J 4.8, 1H), 8.94 (d, J 3.2, 1H), 8.21 (d, J 9.6, 1H), 8.16 (d, J 12.4, 1H), 8.02 (d, J 2.8, 1H), 7.91 (d, J 9.6, 1H), 7.75 (d, J 4.8, 1H), 3.52-3.44 (m, 4H), 3.30-3.21 (m, 4H), 1.75 (s, 6H)。MS (m/z):478.65 (M+H-3HCl);[C 25H 25F 2N 7O.3HCl+H-3HCl]計算值:478.21。 實例 49 (±)-4-(6-((5- -4-(8- -4-(1- 羥基乙基 ) 喹啉 -6- ) 嘧啶 -2- ) 胺基 ) 吡啶 -3- ) 六氫吡嗪 -1- 甲酸第三丁基酯 1-(8-Fluoro-6-(5-fluoro-2-((5-(4-methylhexahydropyrazin-1-yl)pyridine-2-yl)pyridine-2- yl)amino)pyrimidin-4-yl)quinolin-4-yl)ethanol (Example 48A, 300 mg, 0.63 mmol) in methanol (5 mL) was added 35% aqueous hydrochloric acid (229 mg, 6.3 mmol ). The resulting clear solution was stirred for 30 min. After 30 min, dilute with methyl tert-butyl ether (18 mL) and stir for 1 h to obtain a solid. The solid was filtered and dried under vacuum on a rotary evaporator at 55 °C to obtain the title compound (270 mg) as a yellow solid. Melting point: 268°C-270°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 11.81 (s, 1H), 9.60 (bs, 1H), 9.57 (s, 1H), 9.01 (d, J 4.8, 1H), 8.94 ( d, J 3.2, 1H), 8.21 (d, J 9.6, 1H), 8.16 (d, J 12.4, 1H), 8.02 (d, J 2.8, 1H), 7.91 (d, J 9.6, 1H), 7.75 ( d, J 4.8, 1H), 3.52-3.44 (m, 4H), 3.30-3.21 (m, 4H), 1.75 (s, 6H). MS (m/z): 478.65 (M+H-3HCl); Calcd. for [ C25H25F2N7O.3HCl + H - 3HCl]: 478.21 . Example 49 (±)-4-(6-((5- fluoro - 4-(8- fluoro - 4-(1- hydroxyethyl ) quinolin -6- yl ) pyrimidin -2- yl ) amino ) pyridine -3 -yl ) hexahydropyrazine- 1 -carboxylic acid tert-butyl ester

遵循一般程序-3,自中間物74 (1.8 g, 5.6 mmol)及中間物5 (1.56 g, 5.6 mmol)合成標題化合物。在後處理後,藉由combi-flash使用MeOH及DCM (3:97)作為溶析液純化粗產物。使來自管柱層析之純淨化合物懸浮於二乙醚(50 ml)中且攪拌30 min,獲得固體。過濾固體且用二乙醚(50 ml)洗滌。在真空下乾燥固體,獲得呈淡綠色固體之標題化合物(1.8 g)。產率:57%。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 9.90 (s, 1H), 9.03 (d, J 4.4, 1H), 8.81 (s, 1H), 8.73 (d, J 3.6, 1H), 8.16 (d, J 11.6, 1H), 8.10 (d, J 8.8, 1H), 8.06 (d, J 2.8, 1H), 7.81 (d, J 4.4, 1H), 7.47 (dd, J 9.2, 3.2, 1H), 5.78 (d, J 4, 1H), 5.57-5.50 (m, 1H), 3.52-3.44 (m, 4H), 3.12-3.05 (m, 4H), 1.54 (d, J 6.8, 3H), 1.43 (s, 9H)。MS (m/z):564.49 (M+H);[C 29H 31F 2N 7O 3+H]計算值:564.25。 實例 49A (±)-1-(8- -6-(5- -2-((5-( 六氫吡嗪 -1- ) 吡啶 -2- ) 胺基 ) 嘧啶 -4- ) 喹啉 -4- ) 乙醇 The title compound was synthesized from Intermediate 74 (1.8 g, 5.6 mmol) and Intermediate 5 (1.56 g, 5.6 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using MeOH and DCM (3:97) as eluents. The pure compound from column chromatography was suspended in diethyl ether (50 ml) and stirred for 30 min to obtain a solid. The solid was filtered and washed with diethyl ether (50 ml). The solid was dried under vacuum to afford the title compound (1.8 g) as a pale green solid. Yield: 57%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.90 (s, 1H), 9.03 (d, J 4.4, 1H), 8.81 (s, 1H), 8.73 (d, J 3.6, 1H) , 8.16 (d, J 11.6, 1H), 8.10 (d, J 8.8, 1H), 8.06 (d, J 2.8, 1H), 7.81 (d, J 4.4, 1H), 7.47 (dd, J 9.2, 3.2, 1H), 5.78 (d, J 4, 1H), 5.57-5.50 (m, 1H), 3.52-3.44 (m, 4H), 3.12-3.05 (m, 4H), 1.54 (d, J 6.8, 3H), 1.43 (s, 9H). MS (m/z): 564.49 ( M +H); Calcd. for [ C29H31F2N7O3 + H]: 564.25 . Example 49A (±)-1-(8- fluoro -6-(5- fluoro -2-((5-( hexahydropyrazin- 1 -yl ) pyridin -2- yl ) amino ) pyrimidin - 4 -yl ) quinoline- 4 -yl ) ethanol

遵循一般程序-4,自(±)-4-(6-((5-氟-4-(8-氟-4-(1-羥基乙基)喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-1-甲酸第三丁基酯(實例49,1.0 g, 1.77 mmol)合成呈黃色固體之標題化合物(650 mg)。產率:79%。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 9.86 (s, 1H), 9.03 (d, J 4.4, 1H), 8.82 (s, 1H), 8.73 (d, J 3.6, 1H), 8.15 (d, J 12, 1H), 8.08 (d, J 9.2, 1H), 8.02 (d, J 2.8, 1H), 7.80 (d, J 4.4, 1H), 7.43 (dd, J 9.2, 2.8, 1H), 5.79 (d, J 4, 1H), 5.57-5.49 (m, 1H), 3.09-3.01 (m, 4H), 2.90-2.83 (m, 4H), 1.54 (d, J 6.4, 3H)。MS (m/z):464.54 (M+H);[C 24H 23F 2N 7O+H]計算值:464.19。 實例 49B (±)-1-(8- -6-(5- -2-((5-( 六氫吡嗪 -1- ) 吡啶 -2- ) 胺基 ) 嘧啶 -4- ) 喹啉 -4- ) 乙醇三鹽酸鹽 Following general procedure-4, from (±)-4-(6-((5-fluoro-4-(8-fluoro-4-(1-hydroxyethyl)quinolin-6-yl)pyrimidin-2-yl )amino)pyridin-3-yl)hexahydropyrazine-1-carboxylic acid tert-butyl ester (Example 49, 1.0 g, 1.77 mmol) The title compound (650 mg) was synthesized as a yellow solid. Yield: 79%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.86 (s, 1H), 9.03 (d, J 4.4, 1H), 8.82 (s, 1H), 8.73 (d, J 3.6, 1H) , 8.15 (d, J 12, 1H), 8.08 (d, J 9.2, 1H), 8.02 (d, J 2.8, 1H), 7.80 (d, J 4.4, 1H), 7.43 (dd, J 9.2, 2.8, 1H), 5.79 (d, J 4, 1H), 5.57-5.49 (m, 1H), 3.09-3.01 (m, 4H), 2.90-2.83 (m, 4H), 1.54 (d, J 6.4, 3H). MS (m/z): 464.54 (M+H); Calcd. for [ C24H23F2N7O + H]: 464.19 . Example 49B (±)-1-(8- fluoro -6-(5- fluoro -2-((5-( hexahydropyrazin- 1 -yl ) pyridin -2- yl ) amino ) pyrimidin - 4 -yl ) quinolin- 4 -yl ) ethanol trihydrochloride

藉由溶解於MeOH (1 ml)中,向 (±)-1-(8-氟-6-(5-氟-2-((5-(六氫吡嗪-1-基)吡啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)乙醇(實例49A,300 mg, 0.65 mmol)於甲醇(6 mL)中之混合物中添加35%鹽酸水溶液(229 mg, 6.3 mmol)。將所得澄清溶液攪拌30 min。30 min後,用甲基第三丁基醚(18 mL)稀釋並攪拌1 h,獲得固體。過濾固體且在旋轉蒸發儀上在55℃下真空乾燥固體,獲得呈黃色固體之標題化合物(320 mg)。產率:93%。熔點:236℃-238℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 11.88 (s, 1H), 9.63 (bs, 2H), 9.07 (d, J 4.4, 1H), 8.95 (d, J 3.2, 1H), 8.81 (s, 1H), 8.22 (d, J 9.6, 1H), 8.18 (d, J 11.6, 1H), 8.01 (d, J 2.8, 1H), 7.888 (d, J 9.6, 1H), 7.84 (d, J 4.4, 1H), 5.56-5.49 (m, 1H), 3.52-3.44 (m, 4H), 3.30-3.20 (m, 4H), 1.54 (d, J 6.8, 3H)。MS (m/z):464.63 (M+H-3HCl);[C 24H 23F 2N 7O+H-3HCl]計算值:464.19。 實例 50 (±)-4-(6-((5- -4-(8- -4-(1- 羥基乙基 ) 喹啉 -6- ) 嘧啶 -2- ) 胺基 ) 吡啶 -3- ) 六氫吡啶 -1- 甲酸第三丁基酯 (±) -1-(8-Fluoro-6-(5-fluoro-2-((5-(hexahydropyrazin-1-yl)pyridine-2- yl)amino)pyrimidin-4-yl)quinolin-4-yl)ethanol (Example 49A, 300 mg, 0.65 mmol) in methanol (6 mL) was added 35% aqueous hydrochloric acid (229 mg, 6.3 mmol ). The resulting clear solution was stirred for 30 min. After 30 min, dilute with methyl tert-butyl ether (18 mL) and stir for 1 h to obtain a solid. The solid was filtered and dried under vacuum on a rotary evaporator at 55 °C to obtain the title compound (320 mg) as a yellow solid. Yield: 93%. Melting point: 236°C-238°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 11.88 (s, 1H), 9.63 (bs, 2H), 9.07 (d, J 4.4, 1H), 8.95 (d, J 3.2, 1H) , 8.81 (s, 1H), 8.22 (d, J 9.6, 1H), 8.18 (d, J 11.6, 1H), 8.01 (d, J 2.8, 1H), 7.888 (d, J 9.6, 1H), 7.84 ( d, J 4.4, 1H), 5.56-5.49 (m, 1H), 3.52-3.44 (m, 4H), 3.30-3.20 (m, 4H), 1.54 (d, J 6.8, 3H). MS (m/z): 464.63 (M+H-3HCl); Calcd. for [ C24H23F2N7O + H - 3HCl]: 464.19 . Example 50 (±)-4-(6-((5- fluoro - 4-(8- fluoro - 4-(1- hydroxyethyl ) quinolin -6- yl ) pyrimidin -2- yl ) amino ) pyridine -3 -yl ) tert-butyl hexahydropyridine- 1 -carboxylate

遵循一般程序-3,自中間物74 (810 mg, 2.5 mmol)及中間物87 (700 mg, 2.5 mmol)合成標題化合物。在後處理後,藉由combi-flash使用MeOH及DCM (3:97)作為溶析液純化粗產物。使來自管柱層析之純淨化合物懸浮於二乙醚(50 ml)中且攪拌30 min,獲得固體。過濾固體且用二乙醚(50 ml)洗滌。在真空下乾燥固體, 獲得呈淡綠色固體之標題化合物(760 mg)。產率:54%。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 10.09 (s, 1H), 9.04 (d, J 4.4, 1H), 8.83 (s, 1H), 8.78 (d, J 3.6, 1H), 8.22 (d, J 2.4, 1H), 8.21-8.14 (m, 2H), 7.81 (d, J 4.4, 1H), 7.70 (dd, J 8.8, 2.4, 1H), 5.79 (d, J 4.4, 1H), 5.58-5.50 (m, 1H), 4.12-4.05 (m, 2H), 2.90-2.75 (m, 2H), 2.74-2.65 (m, 1H), 1.81-1.74 (m, 2H), 1.60-1.50 (m, 5H), 1.42 (s, 9H)。MS (m/z):563.45 (M+H);[C 30H 32F 2N 6O 3+H]計算值:563.25。 實例 50A (±)-1-(8- -6-(5- -2-((5-( 六氫吡啶 -4- ) 吡啶 -2- ) 胺基 ) 嘧啶 -4- ) 喹啉 -4- ) 乙醇 The title compound was synthesized from Intermediate 74 (810 mg, 2.5 mmol) and Intermediate 87 (700 mg, 2.5 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using MeOH and DCM (3:97) as eluents. The pure compound from column chromatography was suspended in diethyl ether (50 ml) and stirred for 30 min to obtain a solid. The solid was filtered and washed with diethyl ether (50 ml). The solid was dried under vacuum to afford the title compound (760 mg) as a light green solid. Yield: 54%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 10.09 (s, 1H), 9.04 (d, J 4.4, 1H), 8.83 (s, 1H), 8.78 (d, J 3.6, 1H) , 8.22 (d, J 2.4, 1H), 8.21-8.14 (m, 2H), 7.81 (d, J 4.4, 1H), 7.70 (dd, J 8.8, 2.4, 1H), 5.79 (d, J 4.4, 1H ), 5.58-5.50 (m, 1H), 4.12-4.05 (m, 2H), 2.90-2.75 (m, 2H), 2.74-2.65 (m, 1H), 1.81-1.74 (m, 2H), 1.60-1.50 (m, 5H), 1.42 (s, 9H). MS (m/z): 563.45 ( M +H); Calcd. for [ C30H32F2N6O3 + H]: 563.25 . Example 50A (±)-1-(8- fluoro -6-(5- fluoro -2-((5-( hexahydropyridin- 4 -yl ) pyridin -2- yl ) amino ) pyrimidin - 4 -yl ) Quinolin- 4 -yl ) ethanol

遵循一般程序-4,自(±)-4-(6-((5-氟-4-(8-氟-4-(1-羥基乙基)喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡啶-1-甲酸第三丁基酯(實例50,490 mg, 0.87 mmol)合成呈黃色固體之標題化合物(310 mg)。產率:77%。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 10.07 (s, 1H), 9.04 (d, J 4.4, 1H), 8.83 (s, 1H), 8.77 (d, J 3.2, 1H), 8.22-8.12 (m, 3H), 7.81 (d, J 4.4, 1H), 7.66 (dd, J 8.8, 2.5, 1H), 5.83 (bs, 1H), 5.58-5.50 (m, 1H), 3.08-2.99 (m, 2H), 2.62-.2.54 (m, 3H), 1.72-1.64 (m, 2H), 1.55 (d, J 6.4, 3H), 1.55-1.45 (m, 2H)。MS (m/z):463.19 (M+H);[C 25H 24F 2N 6O+H]計算值:463.67。 實例 50B (±)-1-(8- -6-(5- -2-((5-( 六氫吡啶 -4- ) 吡啶 -2- ) 胺基 ) 嘧啶 -4- ) 喹啉 -4- ) 乙醇三鹽酸鹽 Following general procedure-4, from (±)-4-(6-((5-fluoro-4-(8-fluoro-4-(1-hydroxyethyl)quinolin-6-yl)pyrimidin-2-yl )amino)pyridin-3-yl)tert-butyl hexahydropyridine-1-carboxylate (Example 50, 490 mg, 0.87 mmol) The title compound (310 mg) was synthesized as a yellow solid. Yield: 77%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 10.07 (s, 1H), 9.04 (d, J 4.4, 1H), 8.83 (s, 1H), 8.77 (d, J 3.2, 1H) , 8.22-8.12 (m, 3H), 7.81 (d, J 4.4, 1H), 7.66 (dd, J 8.8, 2.5, 1H), 5.83 (bs, 1H), 5.58-5.50 (m, 1H), 3.08- 2.99 (m, 2H), 2.62-.2.54 (m, 3H), 1.72-1.64 (m, 2H), 1.55 (d, J 6.4, 3H), 1.55-1.45 (m, 2H). MS (m/z): 463.19 (M+H); Calcd. for [ C25H24F2N6O + H]: 463.67 . Example 50B (±)-1-(8- fluoro -6-(5- fluoro -2-((5-( hexahydropyridin- 4 -yl ) pyridin -2- yl ) amino ) pyrimidin - 4 -yl ) Quinolin- 4 -yl ) ethanol trihydrochloride

藉由溶解於MeOH (1 ml)中,向 (±)-1-(8-氟-6-(5-氟-2-((5-(六氫吡啶-4-基)吡啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)乙醇(實例50A,190 mg, 0.41 mmol)於甲醇(2.8 mL)中之混合物中添加35%鹽酸水溶液(150 mg, 4.1 mmol)。將所得澄清溶液攪拌30 min。30 min後,用甲基第三丁基醚(19 mL)稀釋並攪拌1 h,獲得固體。過濾固體且在旋轉蒸發儀上在55℃下真空乾燥固體,獲得呈黃色固體之標題化合物(190 mg)。產率:59%。熔點:250℃-252℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 11.98 (s, 1H), 9.31-9.22 (m, 2H), 9.06 (d, J 4.4, 1H), 8.96 (d, J 2.8, 1H), 8.83 (s, 1H), 8.31 (d, J 2.5, 1H), 8.19 (d, J 11.2, 1H), 7.97 (d, J 8.8, 1H), 7.84 (d, J 4.8, 1H), 5.58-5.50 (m, 1H), 3.41-3.35 (m, 2H), 3.08-2.95 (m, 3H), 2.05-1.90 (m, 4H), 1.55 (d, J 6.4, 3H)。MS (m/z):463.58 (M+H-3HCl);[C 25H 24F 2N 6O.3HCl+H-3HCl]計算值:463.67。 實例 51 4-(6-((5- -4-(8- -4-(2- 羥基丙 -2- ) 喹啉 -6- ) 嘧啶 -2- ) 胺基 ) 吡啶 -3- ) 六氫吡啶 -1- 甲酸第三丁基酯 (±) -1-(8-fluoro-6-(5-fluoro-2-((5-(hexahydropyridin-4-yl)pyridin-2-yl) )amino)pyrimidin-4-yl)quinolin-4-yl)ethanol (Example 50A, 190 mg, 0.41 mmol) in methanol (2.8 mL) was added 35% aqueous hydrochloric acid (150 mg, 4.1 mmol) . The resulting clear solution was stirred for 30 min. After 30 min, dilute with methyl tert-butyl ether (19 mL) and stir for 1 h to obtain a solid. The solid was filtered and dried under vacuum on a rotary evaporator at 55 °C to obtain the title compound (190 mg) as a yellow solid. Yield: 59%. Melting point: 250°C-252°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 11.98 (s, 1H), 9.31-9.22 (m, 2H), 9.06 (d, J 4.4, 1H), 8.96 (d, J 2.8, 1H), 8.83 (s, 1H), 8.31 (d, J 2.5, 1H), 8.19 (d, J 11.2, 1H), 7.97 (d, J 8.8, 1H), 7.84 (d, J 4.8, 1H), 5.58-5.50 (m, 1H), 3.41-3.35 (m, 2H), 3.08-2.95 (m, 3H), 2.05-1.90 (m, 4H), 1.55 (d, J 6.4, 3H). MS (m/z): 463.58 (M+H-3HCl); Calcd. for [ C25H24F2N6O.3HCl + H-3HCl]: 463.67 . Example 51 4-(6-((5- fluoro - 4-(8- fluoro - 4-(2 -hydroxyprop- 2- yl ) quinolin -6- yl ) pyrimidin -2 - yl ) amino ) pyridine- 3- yl ) tert-butyl hexahydropyridine- 1 -carboxylate

遵循一般程序-3,自中間物83 (540 mg, 1.6 mmol)及中間物87 (450 mg, 1.6 mmol)合成標題化合物。在後處理後,藉由combi-flash使用MeOH及DCM (2.5:97.5)作為溶析液純化粗產物。使來自管柱層析之純淨化合物懸浮於二乙醚(30 ml)中且攪拌30 min,獲得固體。過濾固體且用二乙醚(30 ml)洗滌。在真空下乾燥固體, 獲得呈淡綠色固體之標題化合物(400 mg)。產率:43%。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 10.04 (s, 1H), 9.57 (s, 1H), 8.98 (d, J 4.4, 1H), 8.77 (d, J 3.6, 1H), 8.25 (d, J 8.8, 1H), 8.21 (d, J 2.4, 1H), 8.15 (d, J 12, 1H), 7.73 (d, J 4.4, 1H), 7.70 (dd, J 8.8, 2.4, 1H), 5.76 (s, 1H), 4.12-4.03 (m, 2H), 2.90-2.78 (m, 2H), 2.75-2.65 (m, 1H), 1.82-1.73 (m, 8H), 1.60-1.50 (m, 2H), 1.42 (s, 9H)。MS (m/z):577.48 (M+H);[C 31H 34F 2N 6O 3+H]計算值:577.27。 實例 51A 2-(8- -6-(5- -2-((5-( 六氫吡啶 -4- ) 吡啶 -2- ) 胺基 ) 嘧啶 -4- ) 喹啉 -4- ) -2- The title compound was synthesized from Intermediate 83 (540 mg, 1.6 mmol) and Intermediate 87 (450 mg, 1.6 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using MeOH and DCM (2.5:97.5) as eluents. The pure compound from column chromatography was suspended in diethyl ether (30 ml) and stirred for 30 min to obtain a solid. The solid was filtered and washed with diethyl ether (30 ml). The solid was dried under vacuum to afford the title compound (400 mg) as a pale green solid. Yield: 43%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 10.04 (s, 1H), 9.57 (s, 1H), 8.98 (d, J 4.4, 1H), 8.77 (d, J 3.6, 1H) , 8.25 (d, J 8.8, 1H), 8.21 (d, J 2.4, 1H), 8.15 (d, J 12, 1H), 7.73 (d, J 4.4, 1H), 7.70 (dd, J 8.8, 2.4, 1H), 5.76 (s, 1H), 4.12-4.03 (m, 2H), 2.90-2.78 (m, 2H), 2.75-2.65 (m, 1H), 1.82-1.73 (m, 8H), 1.60-1.50 ( m, 2H), 1.42 (s, 9H). MS (m/z): 577.48 ( M +H); Calcd. for [ C31H34F2N6O3 + H]: 577.27 . Example 51A 2-(8- fluoro -6-(5- fluoro -2-((5-( hexahydropyridin- 4 -yl ) pyridin -2- yl ) amino ) pyrimidin - 4 -yl ) quinoline- 4 -yl ) propan - 2- ol

遵循一般程序-4,自4-(6-((5-氟-4-(8-氟-4-(2-羥基丙-2-基)喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡啶-1-甲酸第三丁基酯(實例51,370 mg, 0.64 mmol)合成呈黃色固體之標題化合物(290 mg)。產率:95%。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 10.02 (s, 1H), 9.57 (s, 1H), 8.99 (d, J 4.8, 1H), 8.77 (d, J 3.6, 1H), 8.24 (d, J 8.8, 1H), 8.19 (d, J 2.5, 1H), 8.16 (d, J 12.4, 1H), 7.73 (d, J 4.8, 1H), 7.67 (d, J 8.4, 2.5, 1H), 5.78 (s, 1H), 3.05-2.98 (m, 2H), 2.62-2.52 (m, 3H), 2.00 (bs, NH), 1.79 (s, 6H), 1.72-1.65 (m, 2H), 1.57-1.48 (m, 2H)。MS (m/z):477.60 (M+H);[C 26H 26F 2N 6O+H]計算值:477.21。 實例 51B 2-(8- -6-(5- -2-((5-( 六氫吡啶 -4- ) 吡啶 -2- ) 胺基 ) 嘧啶 -4- ) 喹啉 -4- ) -2- 醇三鹽酸鹽 Following general procedure-4, from 4-(6-((5-fluoro-4-(8-fluoro-4-(2-hydroxypropan-2-yl)quinolin-6-yl)pyrimidin-2-yl) Amino)pyridin-3-yl)tert-butylhexahydropyridine-1-carboxylate (Example 51, 370 mg, 0.64 mmol) The title compound (290 mg) was synthesized as a yellow solid. Yield: 95%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 10.02 (s, 1H), 9.57 (s, 1H), 8.99 (d, J 4.8, 1H), 8.77 (d, J 3.6, 1H) , 8.24 (d, J 8.8, 1H), 8.19 (d, J 2.5, 1H), 8.16 (d, J 12.4, 1H), 7.73 (d, J 4.8, 1H), 7.67 (d, J 8.4, 2.5, 1H), 5.78 (s, 1H), 3.05-2.98 (m, 2H), 2.62-2.52 (m, 3H), 2.00 (bs, NH), 1.79 (s, 6H), 1.72-1.65 (m, 2H) , 1.57-1.48 (m, 2H). MS (m/z): 477.60 (M+H); Calcd. for [ C26H26F2N6O + H]: 477.21 . Example 51B 2-(8- fluoro -6-(5- fluoro -2-((5-( hexahydropyridin- 4 -yl ) pyridin -2- yl ) amino ) pyrimidin - 4 -yl ) quinoline- 4 -yl ) propan - 2- ol trihydrochloride

藉由溶解於MeOH (1 ml)中,向2-(8-氟-6-(5-氟-2-((5-(六氫吡啶-4-基)吡啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)丙-2-醇(實例51A,240 mg, 0.5 mmol)於甲醇(2.8 mL)中之混合物中添加35%鹽酸水溶液(180 mg, 5 mmol)。將所得澄清溶液攪拌30 min。30 min後,用甲基第三丁基醚(14.4 mL)稀釋並攪拌1 h,獲得固體。過濾固體且在旋轉蒸發儀上在55℃下真空乾燥固體,獲得呈灰白色固體之標題化合物(250 mg)。產率:78%。熔點:223℃-225℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 12.30-12.10 (m, 1H), 9.59 (s, 1H), 9.40-9.28 (m, 2H), 9.02 (d, J 4.8, 1H), 8.98 (d, J 3.2, 1H), 8.32 (bs, 1H), 8.30-8.22 (m, 1H), 8.19 (d, J 11.6, 1H), 7.97 (d, J 8.8, 1H), 7.76 (d, J 4.8, 1H), 5.94 (bs, 1H), 3.42-3.33 (m, 2H), 3.09-2.92 (m, 3H), 2.05-1.90 (m, 4H), 1.76 (s, 6H)。MS (m/z):477.56 (M+H-3HCl);[C 26H 26F 2N 6O.3HCl +H-3HCl]計算值:477.21。 實例 52 4-(6-((5- -4-(8- -4-(2- 羥基丙 -2- )-2- 甲基喹啉 -6- ) 嘧啶 -2- ) 胺基 ) 吡啶 -3- ) 六氫吡啶 -1- 甲酸第三丁基酯 2-(8-Fluoro-6-(5-fluoro-2-((5-(hexahydropyridin-4-yl)pyridin-2-yl)amino) To a mixture of pyrimidin-4-yl)quinolin-4-yl)propan-2-ol (Example 51A, 240 mg, 0.5 mmol) in methanol (2.8 mL) was added 35% aqueous hydrochloric acid (180 mg, 5 mmol) . The resulting clear solution was stirred for 30 min. After 30 min, dilute with methyl tert-butyl ether (14.4 mL) and stir for 1 h to obtain a solid. The solid was filtered and dried under vacuum on a rotary evaporator at 55°C to afford the title compound (250 mg) as an off-white solid. Yield: 78%. Melting point: 223°C-225°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 12.30-12.10 (m, 1H), 9.59 (s, 1H), 9.40-9.28 (m, 2H), 9.02 (d, J 4.8, 1H ), 8.98 (d, J 3.2, 1H), 8.32 (bs, 1H), 8.30-8.22 (m, 1H), 8.19 (d, J 11.6, 1H), 7.97 (d, J 8.8, 1H), 7.76 ( d, J 4.8, 1H), 5.94 (bs, 1H), 3.42-3.33 (m, 2H), 3.09-2.92 (m, 3H), 2.05-1.90 (m, 4H), 1.76 (s, 6H). MS (m/z): 477.56 (M+H-3HCl); Calcd. for [ C26H26F2N6O.3HCl + H-3HCl]: 477.21 . Example 52 4-(6-((5- fluoro - 4-(8- fluoro - 4-(2 -hydroxypropan- 2- yl )-2 -methylquinolin -6- yl ) pyrimidin -2- yl ) Amino ) pyridin - 3 -yl ) hexahydropyridine- 1 -carboxylic acid tert-butyl ester

遵循一般程序-3,自中間物31 (530 mg, 1.5 mmol)及中間物87 (420 mg, 1.5 mmol)合成標題化合物。在後處理後,藉由combi-flash使用MeOH及DCM (2.5:97.5)作為溶析液純化粗產物。使來自管柱層析之純淨化合物懸浮於二乙醚(30 ml)中且攪拌30 min,獲得固體。過濾固體且用二乙醚(30 ml)洗滌。在真空下乾燥固體, 獲得呈淡綠色固體之標題化合物(380 mg)。產率:42%。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 10.01 (s, 1H), 9.50 (s, 1H), 8.75 (d, J 3.6, 1H), 8.25 (d, J 8.4, 1H), 8.21 (d, J 2.4, 1H), 8.10 (d, J 11.6, 1H), 7.70 (dd, J 8.8, 2.4, 1H), 7.61 (s, 1H), 5.70 (s, 1H), 4.12-4.06 (m, 2H), 2.90-2.75 (m, 2H), 2.74-2.65 (m, 4H), 1.81-1.70 (m, 8H), 1.60-1.45 (m, 2H), 1.42 (s, 9H)。MS (m/z):591.52 (M+H);[C 32H 36F 2N 6O 3+H]計算值:591.28。 實例 52A 2-(8- -6-(5- -2-((5-( 六氫吡啶 -4- ) 吡啶 -2- ) 胺基 ) 嘧啶 -4- )-2- 甲基喹啉 -4- ) -2- The title compound was synthesized from Intermediate 31 (530 mg, 1.5 mmol) and Intermediate 87 (420 mg, 1.5 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using MeOH and DCM (2.5:97.5) as eluents. The pure compound from column chromatography was suspended in diethyl ether (30 ml) and stirred for 30 min to obtain a solid. The solid was filtered and washed with diethyl ether (30 ml). The solid was dried under vacuum to afford the title compound (380 mg) as a pale green solid. Yield: 42%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 10.01 (s, 1H), 9.50 (s, 1H), 8.75 (d, J 3.6, 1H), 8.25 (d, J 8.4, 1H) , 8.21 (d, J 2.4, 1H), 8.10 (d, J 11.6, 1H), 7.70 (dd, J 8.8, 2.4, 1H), 7.61 (s, 1H), 5.70 (s, 1H), 4.12-4.06 (m, 2H), 2.90-2.75 (m, 2H), 2.74-2.65 (m, 4H), 1.81-1.70 (m, 8H), 1.60-1.45 (m, 2H), 1.42 (s, 9H). MS (m/z): 591.52 ( M +H); Calcd. for [ C32H36F2N6O3 + H]: 591.28 . Example 52A 2-(8- fluoro -6-(5- fluoro -2-((5-( hexahydropyridin- 4 -yl ) pyridin -2- yl ) amino ) pyrimidin - 4 -yl )-2- methyl ylquinolin- 4 -yl ) propan -2- ol

遵循一般程序-4,自4-(6-((5-氟-4-(8-氟-4-(2-羥基丙-2-基)-2-甲基喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡啶-1-甲酸第三丁基酯(實例52,360 mg, 0.61 mmol)合成呈灰白色固體之標題化合物(260 mg)。產率:87%。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 9.99 (s, 1H), 9.50 (s, 1H), 8.75 (d, J 3.6, 1H), 8.25 (d, J 8.8, 1H), 8.19 (d, J 2.4, 1H), 8.11 (d, J 12, 1H), 7.67 (dd, J 8.4, 2.4, 1H), 7.62 (s, 1H), 5.71 (s, 1H), 3.08-3.00 (m, 2H), 2.73 (s, 3H), 2.62-2.52 (m, 3H), 2.00 (bs, 1H, NH), 1.78-1.68 (m, 8H), 1.60-1.48 (m, 2H)。MS (m/z):491.62 (M+H);[C 27H 28F 2N 6O+H]計算值:491.23。 實例 52B 2-(8- -6-(5- -2-((5-( 六氫吡啶 -4- ) 吡啶 -2- ) 胺基 ) 嘧啶 -4- )-2- 甲基喹啉 -4- ) -2- 醇三鹽酸鹽 Following general procedure-4, from 4-(6-((5-fluoro-4-(8-fluoro-4-(2-hydroxypropan-2-yl)-2-methylquinolin-6-yl)pyrimidine -2-yl)amino)pyridin-3-yl)tert-butyl hexahydropyridine-1-carboxylate (Example 52, 360 mg, 0.61 mmol) The title compound (260 mg) was synthesized as an off-white solid. Yield: 87%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 9.99 (s, 1H), 9.50 (s, 1H), 8.75 (d, J 3.6, 1H), 8.25 (d, J 8.8, 1H) , 8.19 (d, J 2.4, 1H), 8.11 (d, J 12, 1H), 7.67 (dd, J 8.4, 2.4, 1H), 7.62 (s, 1H), 5.71 (s, 1H), 3.08-3.00 (m, 2H), 2.73 (s, 3H), 2.62-2.52 (m, 3H), 2.00 (bs, 1H, NH), 1.78-1.68 (m, 8H), 1.60-1.48 (m, 2H). MS (m/z): 491.62 (M+H); Calcd. for [ C27H28F2N6O + H]: 491.23 . Example 52B 2-(8- fluoro -6-(5- fluoro -2-((5-( hexahydropyridin- 4 -yl ) pyridin -2- yl ) amino ) pyrimidin - 4 -yl )-2- methyl Quinolin- 4 -yl ) propan -2- ol trihydrochloride

藉由溶解於MeOH (1 ml)中,向2-(8-氟-6-(5-氟-2-((5-(六氫吡啶-4-基)吡啶-2-基)胺基)嘧啶-4-基)-2-甲基喹啉-4-基)丙-2-醇(實例52A,230 mg, 0.47 mmol)於甲醇(3.6 mL)中之混合物中添加35%鹽酸水溶液(170 mg, 4.7 mmol)。將所得澄清溶液攪拌30 min。30 min後,用甲基第三丁基醚(13.8 mL)稀釋並攪拌1 h,獲得固體。過濾固體且在旋轉蒸發儀上在55℃下真空乾燥固體,獲得呈灰白色固體之標題化合物(250 mg)。產率:78%。熔點:221℃-223℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 12.17 (s, 1H), 9.53 (s, 1H), 9.27 (bs, 2H), 8.96 (d, J 3.2, 1H), 8.32 (s, 1H), 8.26 (d, J 8.8, 1H), 8.15 (d, J 11.6, 1H), 7.96 (d, J 8.8, 1H), 7.65 (s, 1H), 5.23 (bs, 1H), 3.43-3.34 (m, 2H), 3.10-2.95 (m, 3H), 2.75 (s, 3H), 2.05-1.88 (m, 4H), 1.74 (s, 6H)。MS (m/z):491.61 (M+H-3HCl);[C 27H 28F 2N 6O.3HCl +H-3HCl]計算值:491.61。 實例 53 (±)-4-(6-((5- -4-(8- -4-(1- 羥基乙基 )-2- 甲基喹啉 -6- ) 嘧啶 -2- ) 胺基 ) 吡啶 -3- ) 六氫吡啶 -1- 甲酸第三丁基酯 2-(8-Fluoro-6-(5-fluoro-2-((5-(hexahydropyridin-4-yl)pyridin-2-yl)amino) To a mixture of pyrimidin-4-yl)-2-methylquinolin-4-yl)propan-2-ol (Example 52A, 230 mg, 0.47 mmol) in methanol (3.6 mL) was added 35% aqueous hydrochloric acid (170 mg, 4.7 mmol). The resulting clear solution was stirred for 30 min. After 30 min, dilute with methyl tert-butyl ether (13.8 mL) and stir for 1 h to obtain a solid. The solid was filtered and dried under vacuum on a rotary evaporator at 55°C to afford the title compound (250 mg) as an off-white solid. Yield: 78%. Melting point: 221°C-223°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 12.17 (s, 1H), 9.53 (s, 1H), 9.27 (bs, 2H), 8.96 (d, J 3.2, 1H), 8.32 ( s, 1H), 8.26 (d, J 8.8, 1H), 8.15 (d, J 11.6, 1H), 7.96 (d, J 8.8, 1H), 7.65 (s, 1H), 5.23 (bs, 1H), 3.43 -3.34 (m, 2H), 3.10-2.95 (m, 3H), 2.75 (s, 3H), 2.05-1.88 (m, 4H), 1.74 (s, 6H). MS (m/z): 491.61 (M+H-3HCl); Calcd. for [ C27H28F2N6O.3HCl + H-3HCl]: 491.61 . Example 53 (±)-4-(6-((5- fluoro - 4-(8- fluoro - 4-(1- hydroxyethyl )-2 -methylquinolin -6- yl ) pyrimidin -2- yl ) amino ) pyridin - 3 -yl ) hexahydropyridine- 1 -carboxylic acid tert-butyl ester

遵循一般程序-3,自中間物77 (540 mg, 1.6 mmol)及中間物87 (450 mg, 1.6 mmol)合成標題化合物。在後處理後,藉由combi-flash使用MeOH及DCM (2.5:97.5)作為溶析液純化粗產物。使來自管柱層析之純淨化合物懸浮於二乙醚(20 ml)中且攪拌30 min,獲得固體。過濾固體且用二乙醚(20 ml)洗滌。在真空下乾燥固體, 獲得呈黃色固體之標題化合物(300 mg)。產率:32%。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 10.05 (s, 1H), 8.77 (s, 1H), 8.76 (d, J 3.6, 1H), 8.22 (d, J 2.4, 1H), 8.20 (d, J 8.8, 1H), 8.12 (d, J 12, 1H), 7.71-7.66 (m, 2H), 5.75 (d, J 4, 1H), 5.52-5.44 (m, 1H), 4.12-4.05 (m, 2H), 2.90-2.76 (m, 2H), 2.73 (s, 3H), 2.75-2.65 (m, 1H), 1.81-1.72 (m, 2H), 1.60-1.45 (m, 2H), 1.54 (d, J 6.4, 3H), 1.42 (s, 9H)。MS (m/z):577.43 (M+H);[C 31H 34F 2N 6O 3+H]計算值:577.27。 實例 53A (±)-1-(8- -6-(5- -2-((5-( 六氫吡啶 -4- ) 吡啶 -2- ) 胺基 ) 嘧啶 -4- )-2- 甲基喹啉 -4- ) 乙醇 The title compound was synthesized from Intermediate 77 (540 mg, 1.6 mmol) and Intermediate 87 (450 mg, 1.6 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using MeOH and DCM (2.5:97.5) as eluents. The pure compound from column chromatography was suspended in diethyl ether (20 ml) and stirred for 30 min to obtain a solid. The solid was filtered and washed with diethyl ether (20 ml). The solid was dried under vacuum to obtain the title compound (300 mg) as a yellow solid. Yield: 32%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 10.05 (s, 1H), 8.77 (s, 1H), 8.76 (d, J 3.6, 1H), 8.22 (d, J 2.4, 1H) , 8.20 (d, J 8.8, 1H), 8.12 (d, J 12, 1H), 7.71-7.66 (m, 2H), 5.75 (d, J 4, 1H), 5.52-5.44 (m, 1H), 4.12 -4.05 (m, 2H), 2.90-2.76 (m, 2H), 2.73 (s, 3H), 2.75-2.65 (m, 1H), 1.81-1.72 (m, 2H), 1.60-1.45 (m, 2H) , 1.54 (d, J 6.4, 3H), 1.42 (s, 9H). MS (m/z): 577.43 ( M +H); Calcd. for [ C31H34F2N6O3 + H]: 577.27 . Example 53A (±)-1-(8- fluoro -6-(5- fluoro -2-((5-( hexahydropyridin- 4 -yl ) pyridin -2- yl ) amino ) pyrimidin - 4 -yl ) -2 -methylquinolin- 4 -yl ) ethanol

遵循一般程序-4,自4-(6-((5-氟-4-(8-氟-4-(1-羥基乙基)-2-甲基喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡啶-1-甲酸第三丁基酯(實例53,280 mg, 0.49 mmol)合成呈灰白色固體之標題化合物(180 mg)。產率:78%。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 10.03 (s, 1H), 8.77 (s, 1H), 8.75 (d, J 3.6, 1H), 8.20 (d, J 2.0, 1H), 8.19 (d, J 3.6, 1H), 8.12 (d, J 12, 1H), 7.68 (s, 1H), 7.66 (d, J 8.8, 2, 1H), 5.75 (s, 1H), 5.53-5.45 (m, 1H), 3.08-3.00 (m, 2H), 2.73 (s, 3H), 2.63-2.56 (m, 3H), 1.74-1.68 (m, 2H), 1.60-1.45 (m, 2H), 1.54 (d, J 6.8, 3H)。MS (m/z):477.62 (M+H);[C 26H 26F 2N 6O+H]計算值:477.21。 實例 53B (±)-1-(8- -6-(5- -2-((5-( 六氫吡啶 -4- ) 吡啶 -2- ) 胺基 ) 嘧啶 -4- )-2- 甲基喹啉 -4- ) 乙醇三鹽酸鹽 Following general procedure-4, from 4-(6-((5-fluoro-4-(8-fluoro-4-(1-hydroxyethyl)-2-methylquinolin-6-yl)pyrimidine-2- yl)amino)pyridin-3-yl)tert-butyl hexahydropyridine-1-carboxylate (Example 53, 280 mg, 0.49 mmol) The title compound (180 mg) was synthesized as an off-white solid. Yield: 78%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 10.03 (s, 1H), 8.77 (s, 1H), 8.75 (d, J 3.6, 1H), 8.20 (d, J 2.0, 1H) , 8.19 (d, J 3.6, 1H), 8.12 (d, J 12, 1H), 7.68 (s, 1H), 7.66 (d, J 8.8, 2, 1H), 5.75 (s, 1H), 5.53-5.45 (m, 1H), 3.08-3.00 (m, 2H), 2.73 (s, 3H), 2.63-2.56 (m, 3H), 1.74-1.68 (m, 2H), 1.60-1.45 (m, 2H), 1.54 (d, J 6.8, 3H). MS (m/z): 477.62 (M+H); Calcd. for [ C26H26F2N6O + H]: 477.21 . Example 53B (±)-1-(8- fluoro -6-(5- fluoro -2-((5-( hexahydropyridin- 4 -yl ) pyridin -2- yl ) amino ) pyrimidin - 4 -yl ) -2 -Methylquinolin- 4 -yl ) ethanol trihydrochloride

藉由溶解於MeOH (1 ml)中,向1-(8-氟-6-(5-氟-2-((5-(六氫吡啶-4-基)吡啶-2-基)胺基)嘧啶-4-基)-2-甲基喹啉-4-基)乙醇(實例53A,160 mg, 0.34 mmol)於甲醇(2.2 mL)中之混合物中添加35%鹽酸水溶液(120 mg, 3.4 mmol)。將所得澄清溶液攪拌30 min。30 min後,用甲基第三丁基醚(16 mL)稀釋並攪拌1 h,獲得固體。過濾固體且在旋轉蒸發儀上在55℃下真空乾燥固體,獲得呈灰白色固體之標題化合物(180 mg)。產率:56%。熔點:220℃-222℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 12.17 (s, 1H), 9.26 (bs, 2H), 8.96 (d, J 3.2, 1H), 8.78 (s, 1H), 8.31 (s, 1H), 8.24 (d, J 8.8, 1H), 8.15 (d, J 12, 1H), 7.93 (d, J 8.8, 1H), 7.73 (s, 1H), 5.52-5.45 (m, 1H), 3.42-3.33 (m, 2H), 3.10-2.92 (m, 3H), 2.76 (s, 3H), 2.05-1.89 (m, 4H), 1.54 (d, J 6.4, 3H)。MS (m/z):477.56 (M+H-3HCl);[C 26H 26F 2N 6O.3HCl +H-3HCl]計算值:477.21。 實例 54 4-(2-((5- -4-(8- -4-(2- 羥基丙 -2- ) 喹啉 -6- ) 嘧啶 -2- ) 胺基 ) 嘧啶 -5- ) 六氫吡啶 -1- 甲酸第三丁基酯 1-(8-Fluoro-6-(5-fluoro-2-((5-(hexahydropyridin-4-yl)pyridin-2-yl)amino) To a mixture of pyrimidin-4-yl)-2-methylquinolin-4-yl)ethanol (Example 53A, 160 mg, 0.34 mmol) in methanol (2.2 mL) was added 35% aqueous hydrochloric acid (120 mg, 3.4 mmol ). The resulting clear solution was stirred for 30 min. After 30 min, dilute with methyl tert-butyl ether (16 mL) and stir for 1 h to obtain a solid. The solid was filtered and dried under vacuum on a rotary evaporator at 55°C to afford the title compound (180 mg) as an off-white solid. Yield: 56%. Melting point: 220°C-222°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 12.17 (s, 1H), 9.26 (bs, 2H), 8.96 (d, J 3.2, 1H), 8.78 (s, 1H), 8.31 ( s, 1H), 8.24 (d, J 8.8, 1H), 8.15 (d, J 12, 1H), 7.93 (d, J 8.8, 1H), 7.73 (s, 1H), 5.52-5.45 (m, 1H) , 3.42-3.33 (m, 2H), 3.10-2.92 (m, 3H), 2.76 (s, 3H), 2.05-1.89 (m, 4H), 1.54 (d, J 6.4, 3H). MS (m/z): 477.56 (M+H-3HCl); Calcd. for [ C26H26F2N6O.3HCl + H-3HCl]: 477.21 . Example 54 4-(2-((5- fluoro - 4-(8- fluoro - 4-(2 -hydroxyprop- 2- yl ) quinolin -6- yl ) pyrimidin -2 - yl ) amino ) pyrimidine- 5- yl ) tert-butyl hexahydropyridine- 1 -carboxylate

遵循一般程序-3,自中間物83 (217 mg, 0.65 mmol)及中間物90 (180 mg, 0.65 mmol)合成標題化合物。在後處理後,藉由combi-flash使用MeOH及DCM (4:96)作為溶析液純化粗產物。使來自管柱層析之純淨化合物懸浮於二乙醚(20 ml)中且攪拌30 min,獲得固體。過濾固體且用二乙醚(5 ml)洗滌。在真空下乾燥固體, 獲得呈灰白色固體之標題化合物(65 mg)。產率:17%。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 10.47 (s, 1H), 9.53 (s, 1H), 8.97 (d, J 4.4, 1H), 8.79 (d, J 3.6, 1H), 8.56 (s, 2H), 8.21 (d, J 12, 1H), 7.74 (d, J 4.8, 1H), 5.71 (s, 1H), 4.14-4.05 (m, 2H), 2.90-2.62 (m, 3H), 1.84-1.77 (m, 2H), 1.74 (s, 6H), 1.62-1.51 (m, 2H), 1.42 (s, 9H)。MS (m/z):578.48 (M+H);[C 30H 33F 2N 7O 3+H]計算值:578.26。 實例 54A 2-(8- -6-(5- -2-((5-( 六氫吡啶 -4- ) 嘧啶 -2- ) 胺基 ) 嘧啶 -4- ) 喹啉 -4- ) -2- The title compound was synthesized from Intermediate 83 (217 mg, 0.65 mmol) and Intermediate 90 (180 mg, 0.65 mmol) following General Procedure-3. After workup, the crude product was purified by combi-flash using MeOH and DCM (4:96) as eluents. The pure compound from column chromatography was suspended in diethyl ether (20 ml) and stirred for 30 min to obtain a solid. The solid was filtered and washed with diethyl ether (5 ml). The solid was dried under vacuum to afford the title compound (65 mg) as an off-white solid. Yield: 17%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 10.47 (s, 1H), 9.53 (s, 1H), 8.97 (d, J 4.4, 1H), 8.79 (d, J 3.6, 1H) , 8.56 (s, 2H), 8.21 (d, J 12, 1H), 7.74 (d, J 4.8, 1H), 5.71 (s, 1H), 4.14-4.05 (m, 2H), 2.90-2.62 (m, 3H), 1.84-1.77 (m, 2H), 1.74 (s, 6H), 1.62-1.51 (m, 2H), 1.42 (s, 9H). MS (m/z): 578.48 ( M +H); Calcd. for [ C30H33F2N7O3 + H]: 578.26 . Example 54A 2-(8- fluoro -6-(5- fluoro -2-((5-( hexahydropyridin- 4 -yl ) pyrimidin -2- yl ) amino ) pyrimidin - 4 -yl ) quinoline- 4 -yl ) propan - 2- ol

遵循一般程序-4,自4-(2-((5-氟-4-(8-氟-4-(2-羥基丙-2-基)喹啉-6-基)嘧啶-2-基)胺基)嘧啶-5-基)六氫吡啶-1-甲酸第三丁基酯(實例54,300 mg, 0.52 mmol)合成呈灰白色固體之標題化合物(215 mg)。產率:87%。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 10.45 (bs, 1H), 9.52 (s, 1H), 8.98 (d, J 3.2, 1H), 8.79 (d, J 3.6, 1H), 8.52 (s, 2H), 8.21 (d, J 12, 1H), 7.75 (d, J 4.8, 1H), 5.73 (s, 1H), 3.08-2.99 (m, 2H), 2.70-2.52 (m, 4H), 2.10 (bs, 1H, NH), 1.74 (s, 8H), 1.61-1.49 (m, 2H)。MS (m/z):478.50 (M+H);[C 25H 25F 2N 7O+H]計算值:478.21。 實例 54B 2-(8- -6-(5- -2-((5-( 六氫吡啶 -4- ) 嘧啶 -2- ) 胺基 ) 嘧啶 -4- ) 喹啉 -4- ) -2- 醇三鹽酸鹽 Following general procedure-4, from 4-(2-((5-fluoro-4-(8-fluoro-4-(2-hydroxypropan-2-yl)quinolin-6-yl)pyrimidin-2-yl) Amino)pyrimidin-5-yl)tert-butylhexahydropyridine-1-carboxylate (Example 54, 300 mg, 0.52 mmol) The title compound (215 mg) was synthesized as an off-white solid. Yield: 87%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 10.45 (bs, 1H), 9.52 (s, 1H), 8.98 (d, J 3.2, 1H), 8.79 (d, J 3.6, 1H) , 8.52 (s, 2H), 8.21 (d, J 12, 1H), 7.75 (d, J 4.8, 1H), 5.73 (s, 1H), 3.08-2.99 (m, 2H), 2.70-2.52 (m, 4H), 2.10 (bs, 1H, NH), 1.74 (s, 8H), 1.61-1.49 (m, 2H). MS (m/z): 478.50 (M+H); Calcd. for [ C25H25F2N7O + H]: 478.21 . Example 54B 2-(8- fluoro -6-(5- fluoro -2-((5-( hexahydropyridin- 4 -yl ) pyrimidin -2- yl ) amino ) pyrimidin - 4 -yl ) quinoline- 4 -yl ) propan - 2- ol trihydrochloride

藉由溶解於MeOH (1 ml)中,向2-(8-氟-6-(5-氟-2-((5-(六氫吡啶-4-基)嘧啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)丙-2-醇(實例54A,200 mg, 0.42 mmol)於甲醇(3 mL)中之混合物中添加35%鹽酸水溶液(153 mg, 4.2 mmol)。將所得澄清溶液攪拌30 min。30 min後,用甲基第三丁基醚(20 mL)稀釋並攪拌1 h,獲得固體。過濾固體且在旋轉蒸發儀上在55℃下真空乾燥固體,獲得呈灰白色固體之標題化合物(180 mg)。產率:56%。熔點:257℃-259℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 11.08 (bs, 1H), 9.55 (s, 1H), 9.23 (bs, 1H), 9.08 (bs, 1H), 9.00 (d, J 4.4, 1H), 8.63 (d, J 3.2, 1H), 8.22 (d, J 12, 1H), 7.77 (d, J 4.8, 1H), 3.41-3.34 (m, 2H), 3.07-2.90 (m, 3H), 2.07-1.90 (m, 4H), 1.75 (s, 6H)。MS (m/z):478.48 (M+H-3HCl);[C 25H 25F 2N 7O.3HCl +H-3HCl]計算值:478.51。 實例 55 (±)-4-(2-((5- -4-(8- -4-(1- 羥基乙基 ) 喹啉 -6- ) 嘧啶 -2- ) 胺基 ) 嘧啶 -5- ) 六氫吡啶 -1- 甲酸第三丁基酯 2-(8-Fluoro-6-(5-fluoro-2-((5-(hexahydropyridin-4-yl)pyrimidin-2-yl)amino) To a mixture of pyrimidin-4-yl)quinolin-4-yl)propan-2-ol (Example 54A, 200 mg, 0.42 mmol) in methanol (3 mL) was added 35% aqueous hydrochloric acid (153 mg, 4.2 mmol) . The resulting clear solution was stirred for 30 min. After 30 min, dilute with methyl tert-butyl ether (20 mL) and stir for 1 h to obtain a solid. The solid was filtered and dried under vacuum on a rotary evaporator at 55°C to afford the title compound (180 mg) as an off-white solid. Yield: 56%. Melting point: 257°C-259°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 11.08 (bs, 1H), 9.55 (s, 1H), 9.23 (bs, 1H), 9.08 (bs, 1H), 9.00 (d, J 4.4, 1H), 8.63 (d, J 3.2, 1H), 8.22 (d, J 12, 1H), 7.77 (d, J 4.8, 1H), 3.41-3.34 (m, 2H), 3.07-2.90 (m, 3H), 2.07-1.90 (m, 4H), 1.75 (s, 6H). MS (m/z): 478.48 (M+H-3HCl); Calcd. for [ C25H25F2N7O.3HCl + H - 3HCl]: 478.51 . Example 55 (±)-4-(2-((5- fluoro - 4-(8- fluoro - 4-(1- hydroxyethyl ) quinolin -6- yl ) pyrimidin -2- yl ) amino ) pyrimidine -5- yl ) tert-butyl hexahydropyridine- 1 -carboxylate

遵循一般程序-3,自中間物77 (500 mg, 1.55 mmol)及中間物90 (433 mg, 1.55 mmol)合成標題化合物。在後處理後,藉由combi-flash使用MeOH及DCM (4:96)作為溶析液純化粗產物。使來自管柱層析之純淨化合物懸浮於二乙醚(20 ml)中且攪拌30 min,獲得固體。過濾固體且用二乙醚(15 ml)洗滌。在真空下乾燥固體, 獲得呈淡褐色固體之標題化合物(270 mg)。產率:31%。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 10.50 (s, 1H), 9.03 (d, J 4.4, 1H), 8.84 (s, 1H), 8.80 (d, J 3.6, 1H), 8.56 (s, 2H), 8.21 (d, J 12, 1H), 7.81 (d, J 4.4, 1H), 5.76 (d, J 4.4, 1H), 5.57-5.49 (m, 1H), 4.14-4.06 (m, 2H), 2.90-2.78 (m, 2H), 2.77-2.65 (m, 1H), 1.85-1.78 (m, 2H), 1.64-1.55 (m, 2H), 1.53 (d, J 6.4, 3H), 1.42 (s, 9H)。MS (m/z):564.37 (M+H);[C 29H 31F 2N 7O 3+H]計算值:564.25。 實例 55A (±)-1-(8- -6-(5- -2-((5-( 六氫吡啶 -4- ) 嘧啶 -2- ) 胺基 ) 嘧啶 -4- ) 喹啉 -4- ) 乙醇 The title compound was synthesized from Intermediate 77 (500 mg, 1.55 mmol) and Intermediate 90 (433 mg, 1.55 mmol) following General Procedure-3. After workup, the crude product was purified by combi-flash using MeOH and DCM (4:96) as eluents. The pure compound from column chromatography was suspended in diethyl ether (20 ml) and stirred for 30 min to obtain a solid. The solid was filtered and washed with diethyl ether (15 ml). The solid was dried under vacuum to afford the title compound (270 mg) as a light brown solid. Yield: 31%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 10.50 (s, 1H), 9.03 (d, J 4.4, 1H), 8.84 (s, 1H), 8.80 (d, J 3.6, 1H) , 8.56 (s, 2H), 8.21 (d, J 12, 1H), 7.81 (d, J 4.4, 1H), 5.76 (d, J 4.4, 1H), 5.57-5.49 (m, 1H), 4.14-4.06 (m, 2H), 2.90-2.78 (m, 2H), 2.77-2.65 (m, 1H), 1.85-1.78 (m, 2H), 1.64-1.55 (m, 2H), 1.53 (d, J 6.4, 3H ), 1.42 (s, 9H). MS (m/z): 564.37 ( M +H); Calcd. for [ C29H31F2N7O3 + H]: 564.25 . Example 55A (±)-1-(8- fluoro -6-(5- fluoro -2-((5-( hexahydropyridin- 4 -yl ) pyrimidin -2- yl ) amino ) pyrimidin - 4 -yl ) Quinolin- 4 -yl ) ethanol

遵循一般程序-4,自4-(2-((5-氟-4-(8-氟-4-(1-羥基乙基)喹啉-6-基)嘧啶-2-基)胺基)嘧啶-5-基)六氫吡啶-1-甲酸第三丁基酯(實例55,250 mg, 0.44 mmol)合成呈灰白色固體之標題化合物(200 mg)。產率:97%。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 10.50 (s, 1H), 9.03 (d, J 4.4, 1H), 8.85 (s, 1H), 8.80 (d, J 3.6, 1H), 8.53 (s, 2H), 8.21 (d, J 12, 1H), 7.81 (d, J 4.4, 1H), 5.77 (s, 1H), 5.58-5.49 (m, 1H), 3.08-3.00 (m, 2H), 2.68-2.53 (m, 3H), 1.78-1.70 (m, 2H), 1.62-1.53 (m, 2H), 1.53 (d, J 6.8, 3H)。MS (m/z):464.46 (M+H);[C 24H 23F 2N 7O+H]計算值:464.19。 實例 55B (±)-1-(8- -6-(5- -2-((5-( 六氫吡啶 -4- ) 嘧啶 -2- ) 胺基 ) 嘧啶 -4- ) 喹啉 -4- ) 乙醇三鹽酸鹽 Following general procedure-4, from 4-(2-((5-fluoro-4-(8-fluoro-4-(1-hydroxyethyl)quinolin-6-yl)pyrimidin-2-yl)amino) Pyrimidin-5-yl) tert-butyl hexahydropyridine-1-carboxylate (Example 55, 250 mg, 0.44 mmol) The title compound (200 mg) was synthesized as an off-white solid. Yield: 97%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 10.50 (s, 1H), 9.03 (d, J 4.4, 1H), 8.85 (s, 1H), 8.80 (d, J 3.6, 1H) , 8.53 (s, 2H), 8.21 (d, J 12, 1H), 7.81 (d, J 4.4, 1H), 5.77 (s, 1H), 5.58-5.49 (m, 1H), 3.08-3.00 (m, 2H), 2.68-2.53 (m, 3H), 1.78-1.70 (m, 2H), 1.62-1.53 (m, 2H), 1.53 (d, J 6.8, 3H). MS (m/z): 464.46 (M+H); Calcd. for [ C24H23F2N7O + H]: 464.19 . Example 55B (±)-1-(8- fluoro -6-(5- fluoro -2-((5-( hexahydropyridin- 4 -yl ) pyrimidin -2- yl ) amino ) pyrimidin - 4 -yl ) Quinolin- 4 -yl ) ethanol trihydrochloride

藉由溶解於MeOH (1 ml)中,向1-(8-氟-6-(5-氟-2-((5-(六氫吡啶-4-基)嘧啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)乙醇(實例55A,200 mg, 0.43 mmol)於甲醇(3 mL)中之混合物中添加35%鹽酸水溶液(157 mg, 4.3 mmol)。將所得澄清溶液攪拌30 min。30 min後,用甲基第三丁基醚(20 mL)稀釋並攪拌1 h,獲得固體。過濾固體且在旋轉蒸發儀上在55℃下真空乾燥固體,獲得呈灰白色固體之標題化合物(200 mg)。產率:59%。熔點:220℃-222℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 11.08 (s, 1H), 9.28-9.20 (m, 1H), 9.15-9.08 (m, 1H), 9.05 (d, J 4.4, 1H), 8.87 (d, J 3.2, 2H), 8.63 (s, 2H), 8.23 (d, J 12, 1H), 7.84 (d, J 4.4, 1H), 5.58-5.51 (m, 1H), 3.42-3.34 (m, 2H), 3.06-2.92 (m, 3H), 2.07-1.90 (m, 4H), 1.55 (d, J 6.4, 3H)。MS (m/z):464.43 (M+H);[C 24H 23F 2N 7O.3HCl+H-3HCl]計算值:464.19。 實例 56 2-(8- -6-(5- -2-((5-(1- 甲基六氫吡啶 -4- ) 吡啶 -2- ) 胺基 ) 嘧啶 -4- ) 喹啉 -4- ) -2- 1-(8-fluoro-6-(5-fluoro-2-((5-(hexahydropyridin-4-yl)pyrimidin-2-yl)amino) To a mixture of pyrimidin-4-yl)quinolin-4-yl)ethanol (Example 55A, 200 mg, 0.43 mmol) in methanol (3 mL) was added 35% aqueous hydrochloric acid (157 mg, 4.3 mmol). The resulting clear solution was stirred for 30 min. After 30 min, dilute with methyl tert-butyl ether (20 mL) and stir for 1 h to obtain a solid. The solid was filtered and dried under vacuum on a rotary evaporator at 55 °C to afford the title compound (200 mg) as an off-white solid. Yield: 59%. Melting point: 220°C-222°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 11.08 (s, 1H), 9.28-9.20 (m, 1H), 9.15-9.08 (m, 1H), 9.05 (d, J 4.4, 1H ), 8.87 (d, J 3.2, 2H), 8.63 (s, 2H), 8.23 (d, J 12, 1H), 7.84 (d, J 4.4, 1H), 5.58-5.51 (m, 1H), 3.42- 3.34 (m, 2H), 3.06-2.92 (m, 3H), 2.07-1.90 (m, 4H), 1.55 (d, J 6.4, 3H). MS (m/z): 464.43 (M+H); Calcd. for [ C24H23F2N7O.3HCl + H - 3HCl]: 464.19 . Example 56 2-(8- fluoro -6-(5- fluoro -2-((5-(1 -methylhexahydropyridin- 4 -yl ) pyridin -2- yl ) amino ) pyrimidin - 4 -yl ) Quinolin- 4 -yl ) propan -2- ol

遵循一般程序-3,自中間物83 (700 mg, 2.1 mmol)及中間物93 (400 mg, 2.1 mmol)合成標題化合物。在後處理後,使粗產物懸浮於Et 2O與EtOAc之混合物(1:1) (20 ml)中且攪拌30 min,獲得固體。過濾固體,且用Et 2O與EtOAc之混合物(1:1) (10 ml)洗滌。在真空下乾燥固體,獲得呈灰白色固體之標題化合物(200 mg)。產率:20%。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 10.03 (s, 1H), 9.57 (s, 1H), 8.98 (d, J 4.4, 1H), 8.77 (d, J 3.6, 1H), 8.25 (d, J 8.4, 1H), 8.21 (d, J 2, 1H), 8.15 (d, J 12, 1H), 7.73 (d, J 4.4, 1H), 7.69 (d, J 8.4, 2, 1H), 5.77 (s, 1H), 2.95-2.86 (m, 2H), 2.55-2.49 (m, 1H), 2.24 (s, 3H), 2.09-1.99 (m, 2H), 1.80-1.65 (m, 4H), 1.75 (s, 6H)。MS (m/z):491.57 (M+H);[C 27H 28F 2N 6O+H]計算值:491.23。 實例 56A 2-(8- -6-(5- -2-((5-(1- 甲基六氫吡啶 -4- ) 吡啶 -2- ) 胺基 ) 嘧啶 -4- ) 喹啉 -4- ) -2- 醇三鹽酸鹽 The title compound was synthesized from Intermediate 83 (700 mg, 2.1 mmol) and Intermediate 93 (400 mg, 2.1 mmol) following General Procedure-3. After work-up, the crude product was suspended in a mixture of Et2O and EtOAc (1 :1 ) (20 ml) and stirred for 30 min to obtain a solid. The solid was filtered and washed with a mixture of Et2O and EtOAc (1:1) (10 ml). The solid was dried under vacuum to obtain the title compound (200 mg) as an off-white solid. Yield: 20%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 10.03 (s, 1H), 9.57 (s, 1H), 8.98 (d, J 4.4, 1H), 8.77 (d, J 3.6, 1H) , 8.25 (d, J 8.4, 1H), 8.21 (d, J 2, 1H), 8.15 (d, J 12, 1H), 7.73 (d, J 4.4, 1H), 7.69 (d, J 8.4, 2, 1H), 5.77 (s, 1H), 2.95-2.86 (m, 2H), 2.55-2.49 (m, 1H), 2.24 (s, 3H), 2.09-1.99 (m, 2H), 1.80-1.65 (m, 4H), 1.75 (s, 6H). MS (m/z): 491.57 (M+H); Calcd. for [ C27H28F2N6O + H]: 491.23 . Example 56A 2-(8- fluoro -6-(5- fluoro -2-((5-(1 -methylhexahydropyridin- 4 -yl ) pyridin -2- yl ) amino ) pyrimidin - 4 -yl ) Quinolin- 4 -yl ) propan -2- ol trihydrochloride

藉由溶解於MeOH (1 ml)中,向2-(8-氟-6-(5-氟-2-((5-(1-甲基六氫吡啶-4-基)吡啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)丙-2-醇(實例56,200 mg, 0.41 mmol)於甲醇(3 mL)中之混合物中添加35%鹽酸水溶液(150 mg, 4.1 mmol)。將所得澄清溶液攪拌30 min。30 min後,用甲基第三丁基醚(12 mL)稀釋並攪拌1 h,獲得固體。過濾固體且在旋轉蒸發儀上在55℃下真空乾燥固體,獲得呈灰白色固體之標題化合物(200 mg)。產率:59%。熔點:238℃-240℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 12.11 (s, 1H), 11.12 (s, 1H), 9.59 (s, 1H), 9.02 (d, J 4.8, 1H), 8.97 (d, J 3.2, 1H), 8.33 (d, J 2.5, 1H), 8.25 (dd, J 9.2, 2.5, 1H), 8.18 (d, J 12, 1H), 7.97 (d, J 9.2, 1H), 7.75 (d, J 4.8, 1H), 3.55-3.47 (m, 2H), 3.12-3.03 (m, 2H), 3.02-2.94 (m, 1H), 2.76 (d, J 4.8, 3H), 2.13-2.04 (m, 4H), 1.76 (s, 6H)。MS (m/z):491.52 (M+H-3HCl);[C 27H 28F 2N 6O.3HCl+H-3HCl]計算值:491.23。 實例 57 (±)-1-(8- -6-(5- -2-((5-(1- 甲基六氫吡啶 -4- ) 吡啶 -2- ) 胺基 ) 嘧啶 -4- ) 喹啉 -4- ) 乙醇 2-(8-fluoro-6-(5-fluoro-2-((5-(1-methylhexahydropyridin-4-yl)pyridin-2-yl) )amino)pyrimidin-4-yl)quinolin-4-yl)propan-2-ol (Example 56, 200 mg, 0.41 mmol) in methanol (3 mL) was added 35% aqueous hydrochloric acid (150 mg , 4.1 mmol). The resulting clear solution was stirred for 30 min. After 30 min, dilute with methyl tert-butyl ether (12 mL) and stir for 1 h to obtain a solid. The solid was filtered and dried under vacuum on a rotary evaporator at 55 °C to afford the title compound (200 mg) as an off-white solid. Yield: 59%. Melting point: 238°C-240°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 12.11 (s, 1H), 11.12 (s, 1H), 9.59 (s, 1H), 9.02 (d, J 4.8, 1H), 8.97 ( d, J 3.2, 1H), 8.33 (d, J 2.5, 1H), 8.25 (dd, J 9.2, 2.5, 1H), 8.18 (d, J 12, 1H), 7.97 (d, J 9.2, 1H), 7.75 (d, J 4.8, 1H), 3.55-3.47 (m, 2H), 3.12-3.03 (m, 2H), 3.02-2.94 (m, 1H), 2.76 (d, J 4.8, 3H), 2.13-2.04 (m, 4H), 1.76 (s, 6H). MS (m/z): 491.52 (M+H-3HCl); Calcd. for [ C27H28F2N6O.3HCl + H-3HCl]: 491.23 . Example 57 (±)-1-(8- fluoro -6-(5- fluoro -2-((5-(1 -methylhexahydropyridin- 4 -yl ) pyridin -2 - yl ) amino ) pyrimidine- 4- yl ) quinolin- 4 -yl ) ethanol

遵循一般程序-3,自中間物77 (780 mg, 2.4 mmol)及中間物93 (460 mg, 2.4 mmol)合成標題化合物。在後處理後,使粗產物懸浮於Et 2O與MeOH之混合物(1:1) (20 ml)中且攪拌30 min,獲得固體。過濾固體,且用Et 2O與MeOH之混合物(1:1) (10 ml)洗滌。使固體懸浮於Et2O中且攪拌30 min。過濾固體且在真空下乾燥,獲得呈黃色固體之標題化合物(230 mg)。產率:20%。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 10.08 (s, 1H), 9.04 (d, J 4.4, 1H), 8.83 (s, 1H), 8.77 (d, J 3.6, 1H), 8.23-8.12 (m, 3H), 7.81 (d, J 4.4, 1H), 7.69 (dd, J 8.8, 2.5, 1H), 5.80 (d, J 4.4, 1H), 5.58-5.49 (m, 1H), 2.91-2.84 (m, 2H), 2.50-2.43 (m, 1H), 2.21 (s, 3H), 2.03-1.94 (m, 2H), 1.79-1.62 (m, 4H), 1.55 (d, J 6.4, 3H)。MS (m/z):477.57 (M+H);[C 26H 26F 2N 6O+H]計算值:477.21。 實例 57A (±)-1-(8- -6-(5- -2-((5-(1- 甲基六氫吡啶 -4- ) 吡啶 -2- ) 胺基 ) 嘧啶 -4- ) 喹啉 -4- ) 乙醇三鹽酸鹽 The title compound was synthesized from Intermediate 77 (780 mg, 2.4 mmol) and Intermediate 93 (460 mg, 2.4 mmol) following General Procedure-3. After work-up, the crude product was suspended in a mixture of Et2O and MeOH (1 :1 ) (20 ml) and stirred for 30 min to obtain a solid. The solid was filtered and washed with a mixture of Et2O and MeOH (1:1) (10 ml). The solid was suspended in Et2O and stirred for 30 min. The solid was filtered and dried under vacuum to obtain the title compound (230 mg) as a yellow solid. Yield: 20%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 10.08 (s, 1H), 9.04 (d, J 4.4, 1H), 8.83 (s, 1H), 8.77 (d, J 3.6, 1H) , 8.23-8.12 (m, 3H), 7.81 (d, J 4.4, 1H), 7.69 (dd, J 8.8, 2.5, 1H), 5.80 (d, J 4.4, 1H), 5.58-5.49 (m, 1H) , 2.91-2.84 (m, 2H), 2.50-2.43 (m, 1H), 2.21 (s, 3H), 2.03-1.94 (m, 2H), 1.79-1.62 (m, 4H), 1.55 (d, J 6.4 , 3H). MS (m/z): 477.57 (M+H); Calcd. for [ C26H26F2N6O + H]: 477.21 . Example 57A (±)-1-(8- fluoro -6-(5- fluoro -2-((5-(1 -methylhexahydropyridin- 4 -yl ) pyridin -2 - yl ) amino ) pyrimidine- 4- yl ) quinolin- 4 -yl ) ethanol trihydrochloride

藉由溶解於MeOH (1 ml)中,向1-(8-氟-6-(5-氟-2-((5-(1-甲基六氫吡啶-4-基)吡啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)乙醇(實例57,200 mg, 0.42 mmol)於甲醇(3 mL)中之混合物中添加35%鹽酸水溶液(150 mg, 4.2 mmol)。將所得澄清溶液攪拌30 min。30 min後,用甲基第三丁基醚(20 mL)稀釋並攪拌1 h,獲得固體。過濾固體且在旋轉蒸發儀上在55℃下真空乾燥固體,獲得呈灰白色固體之標題化合物(200 mg)。產率:44%。熔點:238℃-240℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 12.22 (bs, 1H), 11.13 (s, 1H), 9.07 (d, J 4.4, 1H), 8.99 (d, J 3.2, 1H), 8.83 (s, 1H), 8.33 (d, J 2.4, 1H), 8.27 (dd, J 8.8, 2.4, 1H), 8.19 (d, J 12, 1H), 7.93 (d, J 9.2, 1H), 7.84 (d, J 4.4, 1H), 5.58-5.50 (m, 1H), 3.55-3.46 (m, 2H), 3.12-3.03 (m, 2H), 3.02-2.93 (m, 1H), 2.76 (d, J 4.8, 3H), 2.18-2.05 (m, 4H), 1.56 (d, J 6.8, 3H)。MS (m/z):477.57 (M+H-3HCl);[C 26H 26F 2N 6O.3HCl+H-3HCl]計算值:477.53。 實例 58 (±)-4-(6-((4-(4-(1-(( 第三丁氧基羰基 ) 胺基 ) 乙基 )-8- 氟喹啉 -6- )-5- 氟嘧啶 -2- ) 胺基 ) 吡啶 -3- ) 六氫吡啶 -1- 甲酸第三丁基酯 1-(8-fluoro-6-(5-fluoro-2-((5-(1-methylhexahydropyridin-4-yl)pyridin-2-yl) )amino)pyrimidin-4-yl)quinolin-4-yl)ethanol (Example 57, 200 mg, 0.42 mmol) in methanol (3 mL) was added 35% aqueous hydrochloric acid (150 mg, 4.2 mmol) . The resulting clear solution was stirred for 30 min. After 30 min, dilute with methyl tert-butyl ether (20 mL) and stir for 1 h to obtain a solid. The solid was filtered and dried under vacuum on a rotary evaporator at 55 °C to afford the title compound (200 mg) as an off-white solid. Yield: 44%. Melting point: 238°C-240°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 12.22 (bs, 1H), 11.13 (s, 1H), 9.07 (d, J 4.4, 1H), 8.99 (d, J 3.2, 1H) , 8.83 (s, 1H), 8.33 (d, J 2.4, 1H), 8.27 (dd, J 8.8, 2.4, 1H), 8.19 (d, J 12, 1H), 7.93 (d, J 9.2, 1H), 7.84 (d, J 4.4, 1H), 5.58-5.50 (m, 1H), 3.55-3.46 (m, 2H), 3.12-3.03 (m, 2H), 3.02-2.93 (m, 1H), 2.76 (d, J 4.8, 3H), 2.18-2.05 (m, 4H), 1.56 (d, J 6.8, 3H). MS (m/z): 477.57 (M+H-3HCl); Calcd. for [ C26H26F2N6O.3HCl + H-3HCl]: 477.53 . Example 58 (±)-4-(6-((4-(4-(1-(( tertiary butoxycarbonyl ) amino ) ethyl )-8- fluoroquinolin- 6- yl )-5- Fluoropyrimidin -2- yl ) amino ) pyridin - 3 -yl ) tert-butyl hexahydropyridine- 1 -carboxylate

遵循一般程序-3,自中間物71 (600 mg, 1.43 mmol)及中間物87 (395 mg, 1.43 mmol)合成標題化合物。在後處理後,藉由combi-flash使用MeOH及DCM (3:97)作為溶析液純化粗產物。使來自管柱層析之純淨化合物懸浮於二乙醚(20 ml)中且攪拌30 min,獲得固體。過濾固體且用二乙醚(10 ml)洗滌。在真空下乾燥固體, 獲得呈淡黃色固體之標題化合物(370 mg)。產率:39%。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 10.11 (s, 1H), 9.05 (d, J 4.4, 1H), 8.81 (s, 1H), 8.79 (d, J 3.2, 1H), 8.25-8.15 (m, 3H), 7.98-7.89 (m, 1H), 7.74-7.65 (m, 2H), 5.57-5.49 (m, 1H), 4.14-4.05 (m, 2H), 2.88-2.78 (m, 2H), 2.72-2.65 (m, 1H), 1.81-1.74 (m, 2H), 1.59-1.47 (m, 2H), 1.46 (d, J 6.8, 3H), 1.42 (s, 9H), 1.38 (s, 9H)。MS (m/z):662.36 (M+H);[C 35H 41F 2N 7O 4+H]計算值:662.32。 實例 58A (±)-4-(4-(1- 胺基乙基 )-8- 氟喹啉 -6- )-5- -N-(5-( 六氫吡啶 -4- ) 吡啶 -2- ) 嘧啶 -2- The title compound was synthesized from Intermediate 71 (600 mg, 1.43 mmol) and Intermediate 87 (395 mg, 1.43 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using MeOH and DCM (3:97) as eluents. The pure compound from column chromatography was suspended in diethyl ether (20 ml) and stirred for 30 min to obtain a solid. The solid was filtered and washed with diethyl ether (10 ml). The solid was dried under vacuum to obtain the title compound (370 mg) as a light yellow solid. Yield: 39%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 10.11 (s, 1H), 9.05 (d, J 4.4, 1H), 8.81 (s, 1H), 8.79 (d, J 3.2, 1H) , 8.25-8.15 (m, 3H), 7.98-7.89 (m, 1H), 7.74-7.65 (m, 2H), 5.57-5.49 (m, 1H), 4.14-4.05 (m, 2H), 2.88-2.78 ( m, 2H), 2.72-2.65 (m, 1H), 1.81-1.74 (m, 2H), 1.59-1.47 (m, 2H), 1.46 (d, J 6.8, 3H), 1.42 (s, 9H), 1.38 (s, 9H). MS (m/z): 662.36 (M + H); Calcd. for [ C35H41F2N7O4 + H]: 662.32 . Example 58A (±)-4-(4-(1 -aminoethyl )-8- fluoroquinolin- 6- yl )-5- fluoro -N-(5-( hexahydropyridin- 4 -yl ) pyridine -2- yl ) pyrimidin -2- amine

遵循一般程序-4,自(±)-4-(6-((4-(4-(1-((第三丁氧基羰基)胺基)乙基)-8-氟喹啉-6-基)-5-氟嘧啶-2-基)胺基)吡啶-3-基)六氫吡啶-1-甲酸第三丁基酯(實例58,350 mg, 0.53 mmol)合成呈黃色固體之標題化合物(37 mg)。產率:97%。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 10.08 (s, 1H), 9.03 (d, J 4.4, 1H), 8.85 (s, 1H), 8.77 (d, J 3.6, 1H), 8.21-8.14 (m, 3H), 7.92 (d, J 4.4, 1H), 7.67 (d, J 8.8, 2.4, 1H), 4.91-4.83 (m, 1H), 3.10-3.00 (m, 2H), 2.69-2.55 (m, 3H), 1.76-1.68 (m, 2H), 1.62-1.49 (m, 2H), 1.45 (d, J 6.4, 3H)。MS (m/z):462.49 (M+H);[C 25H 25F 2N 7+H]計算值:462.21。 實例 58B (±)-4-(4-(1- 胺基乙基 )-8- 氟喹啉 -6- )-5- -N-(5-( 六氫吡啶 -4- ) 吡啶 -2- ) 嘧啶 -2- 胺三鹽酸鹽 Following general procedure-4, from (±)-4-(6-((4-(4-(1-((tert-butoxycarbonyl)amino)ethyl)-8-fluoroquinoline-6- The title compound was synthesized as a yellow solid (37 mg). Yield: 97%. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 10.08 (s, 1H), 9.03 (d, J 4.4, 1H), 8.85 (s, 1H), 8.77 (d, J 3.6, 1H) , 8.21-8.14 (m, 3H), 7.92 (d, J 4.4, 1H), 7.67 (d, J 8.8, 2.4, 1H), 4.91-4.83 (m, 1H), 3.10-3.00 (m, 2H), 2.69-2.55 (m, 3H), 1.76-1.68 (m, 2H), 1.62-1.49 (m, 2H), 1.45 (d, J 6.4, 3H). MS (m/z): 462.49 (M+H); Calcd. for [ C25H25F2N7 + H]: 462.21 . Example 58B (±)-4-(4-(1 -aminoethyl )-8- fluoroquinolin- 6- yl )-5- fluoro -N-(5-( hexahydropyridin- 4 -yl ) pyridine -2- yl ) pyrimidin -2- amine trihydrochloride

藉由溶解於MeOH (1 ml)中,向(±)-4-(4-(1-胺基乙基)-8-氟喹啉-6-基)-5-氟-N-(5-(六氫吡啶-4-基)吡啶-2-基)嘧啶-2-胺(實例58A,80 mg, 0.17 mmol)於甲醇(2 mL)中之混合物中添加35%鹽酸水溶液(63 mg, 1.7 mmol)。將所得澄清溶液攪拌30 min。30 min後,用甲基第三丁基醚(10 mL)稀釋並攪拌1 h,獲得固體。過濾固體且在旋轉蒸發儀上在55℃下真空乾燥固體,獲得呈灰白色固體之標題化合物(70 mg)。產率:87%。熔點:246℃-248℃。 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 11.59 (s, 1H), 9.35-9.20 (m, 4H), 9.18 (d, J 4.4, 1H), 8.76 (s, 1H), 8.32 (d, J 2, 1H), 8.24 (d, J 12, 1H), 8.11 (d, J 8.4, 1H), 8.07 (d, J 4.4, 1H), 8.03 (d, J 8.8, 1H), 5.41-5.32 (m, 1H), 3.40-3.32 (m 2H), 3.08-2.94 (m, 3H), 2.05-1.90 (m, 4H), 1.72 (d, J 6.8, 3H)。MS (m/z):462.48 (M+H-3HCl);[C 25H 25F 2N 7.3HCl+H-3HCl]計算值:462.21。 生物分析 To (±)-4-(4-(1-aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5- To a mixture of (hexahydropyridin-4-yl)pyridin-2-yl)pyrimidin-2-amine (Example 58A, 80 mg, 0.17 mmol) in methanol (2 mL) was added 35% aqueous hydrochloric acid (63 mg, 1.7 mmol). The resulting clear solution was stirred for 30 min. After 30 min, dilute with methyl tert-butyl ether (10 mL) and stir for 1 h to obtain a solid. The solid was filtered and dried under vacuum on a rotary evaporator at 55°C to afford the title compound (70 mg) as an off-white solid. Yield: 87%. Melting point: 246°C-248°C. 1 H-NMR (δ ppm, DMSO- d 6 , 400 MHz): 11.59 (s, 1H), 9.35-9.20 (m, 4H), 9.18 (d, J 4.4, 1H), 8.76 (s, 1H), 8.32 (d, J 2, 1H), 8.24 (d, J 12, 1H), 8.11 (d, J 8.4, 1H), 8.07 (d, J 4.4, 1H), 8.03 (d, J 8.8, 1H), 5.41-5.32 (m, 1H), 3.40-3.32 (m 2H), 3.08-2.94 (m, 3H), 2.05-1.90 (m, 4H), 1.72 (d, J 6.8, 3H). MS (m/z): 462.48 (M+H-3HCl); Calcd. for [ C25H25F2N7.3HCl + H - 3HCl]: 462.21 . biological analysis

本發明化合物之藥理學性質可藉由若干藥理學分析來證實。本發明化合物及/或其醫藥學上可接受之鹽可進行之藥理學分析例示於下文中。 實例 -A 用於篩選式 (I) 化合物或測定式 (I) 化合物之 IC 50 CDK1 酶分析方案 目標 The pharmacological properties of the compounds of the invention can be confirmed by several pharmacological assays. Examples of pharmacological assays that can be performed on the compounds of the present invention and/or their pharmaceutically acceptable salts are shown below. EXAMPLE -A CDK1 Enzyme Assay Protocol Target for Screening Compounds of Formula (I ) or Determining the IC50 of Compounds of Formula (I)

使用ADP-Glo激酶分析,篩選本發明化合物對CDK1酶之抑制%或測定本發明化合物抵抗CDK1酶之活性之IC 50套組 Using the ADP-Glo kinase assay, the compounds of the invention were screened for % inhibition of the CDK1 enzyme or the IC50 of the activity of the compounds of the invention against the CDK1 enzyme was determined. set

使用ADP-glow激酶套組進行CDK1酶分析。 ADP-Glo 激酶分析方案 CDK1 enzyme assays were performed using the ADP-glow kinase kit. ADP-Glo Kinase Assay Protocol

激酶分析具有3步:a)酶促反應,b) ATP耗竭,c)激酶偵測。以下方案針對384孔板設計,3個步驟分別使用1:1:2比率。 a) 酶促反應: l激酶促反應之總體積為5 µL。1 μL DMSO/藥物(稀釋於激酶緩衝液中作為5X)且孔中之最終濃度為1X。2 μL酶(在激酶緩衝液中製備為1 ng/ μL)。添加2 μL ATP/受質(組織蛋白)混合物(2.5 x,在激酶緩衝液中製備),使得ATP/孔之最終濃度為50 µM且每孔之組織蛋白為125 ng。 l 向每一孔中添加1 µL 5X濃度之測試化合物。對於對照孔(空白孔及酶空白孔),添加1 µL在1X緩衝液中製備之DMSO。將所有孔中之最終DMSO濃度維持在0.5%。 l 將2 µL (1 ng/µl) CDK1/週期蛋白A2酶添加至酶空白孔及藥物處理孔中。將2 µL 1X激酶促反應緩衝液添加至對照(空白)孔中。 l 使板離心10秒且在室溫下培育15分鐘。 l 向每一孔中添加2 µL ATP (2.5X) +受質(組織蛋白)溶液(ATP/孔之最終濃度為50 µM且組織蛋白為125 ng/孔)。 l 使板離心10秒且在室溫下培育60分鐘。 b) ATP 耗竭: l 在使用前,使ADP-glo試劑解凍至室溫。 l 添加5 µL ADP-Glo試劑以終止激酶促反應,以耗竭未消耗之ATP。 l 使板離心10秒且在室溫下培育40分鐘。 c) 激酶偵測: l 在使用前,使激酶偵測緩衝液解凍至室溫。 l 添加10 µL激酶偵測試劑以使ADP轉化成ATP,且引入螢光素酶及螢光素以偵測ATP。 l 使板在室溫下培育30分鐘。 l 使用BMG Labtech, FLUOstar Omega記錄發光。 The kinase assay has 3 steps: a) enzymatic reaction, b) ATP depletion, c) kinase detection. The protocol below is designed for a 384-well plate, using a 1:1:2 ratio for each of the 3 steps. a) Enzymatic reaction : l The total volume of the kinase-catalyzed reaction is 5 µL. 1 μL DMSO/drug (diluted in Kinase Buffer as 5X) and the final concentration in the wells is 1X. 2 µL of enzyme (prepared at 1 ng/µL in kinase buffer). Add 2 μL of ATP/substrate (histone) mix (2.5x, prepared in kinase buffer) so that the final concentration of ATP/well is 50 μM and histone is 125 ng per well. l Add 1 µL of test compound at 5X concentration to each well. For control wells (blank and enzyme blank), add 1 µL of DMSO prepared in 1X buffer. The final DMSO concentration in all wells was maintained at 0.5%. l Add 2 µL (1 ng/µl) of CDK1/Cyclin A2 enzyme to enzyme blank and drug-treated wells. Add 2 µL of 1X Kinase Reaction Buffer to control (blank) wells. l Centrifuge the plate for 10 seconds and incubate at room temperature for 15 minutes. l Add 2 µL of ATP (2.5X) + substrate (histone) solution to each well (final concentration of ATP/well is 50 µM and histone is 125 ng/well). l Centrifuge the plate for 10 seconds and incubate at room temperature for 60 minutes. b) ATP depletion : l Thaw ADP-glo reagent to room temperature before use. l Add 5 µL of ADP-Glo Reagent to terminate the kinase-catalyzed reaction to deplete unconsumed ATP. l Centrifuge the plate for 10 seconds and incubate at room temperature for 40 minutes. c) Kinase detection : l Thaw the kinase detection buffer to room temperature before use. l Add 10 µL Kinase Detection Reagent to convert ADP to ATP, and introduce luciferase and luciferin to detect ATP. l Incubate the plate at room temperature for 30 minutes. l Use BMG Labtech, FLUOstar Omega to record luminescence.

篩選計算: 1)   計算每一孔之平均值。 2)   自每一酶空白孔及處理孔之平均值減去空白孔之平均值。 3)   計算空白扣除孔之平均值 4)   基於以下公式計算抑制% 100 - (空白扣除處理孔之平均值* 100) / (空白扣除酶空白孔之平均值) 5)   對於IC 50計算,使用GraphPad Prism,使用平均空白扣除值繪製IC 50曲線。 實例 -B 用於篩選式 (I) 化合物或測定式 (I) 化合物之 IC 50 CDK2 酶分析方案 目標 Screening calculation : 1) Calculate the average value of each well. 2) Subtract the average value of the blank wells from the average value of each enzyme blank well and treated wells. 3) Calculate the average value of blank subtracted wells 4) Calculate the inhibition % based on the following formula 100 - (average value of blank subtracted treated wells * 100) / (average value of blank subtracted enzyme blank wells) 5) For IC 50 calculation, use GraphPad Prism, IC50 curves were plotted using mean blank subtracted values. Example - B CDK2 Enzyme Assay Protocol Objectives for Screening or Determining the IC 50 of Compounds of Formula (I )

使用ADP-Glo激酶分析,篩選本發明化合物對CDK2酶之抑制%或測定本發明化合物抵抗CDK2酶之活性之IC 50套組: Using the ADP-Glo kinase assay, the compounds of the invention were screened for % inhibition of the CDK2 enzyme or the IC50 of the activity of the compounds of the invention against the CDK2 enzyme was determined. Set:

使用ADP-glow激酶套組進行CDK2酶分析。 ADP-Glo 激酶分析方案 CDK2 enzyme assays were performed using the ADP-glow kinase kit. ADP-Glo Kinase Assay Protocol

激酶分析具有3步:a)酶促反應,b) ATP耗竭,c)激酶偵測。以下方案針對384孔板設計,3個步驟分別使用1:1:2比率。 a) 酶促反應: l 激酶促反應之總體積為5 µL。1 μL DMSO/藥物(稀釋於激酶緩衝液中作為5X)且孔中之最終濃度為1X。2 μL酶(在激酶緩衝液中製備為1 ng/ μL)。添加2 μL ATP/受質(組織蛋白)混合物(2.5 x,在激酶緩衝液中製備),使得ATP/孔之最終濃度為50 µM且每孔之組織蛋白為125 ng。 l 向每一孔中添加1 µL 5X濃度之測試化合物。對於對照孔(空白孔及酶空白孔),添加1 µL在1X緩衝液中製備之DMSO。將所有孔中之最終DMSO濃度維持在0.5%。 l 將2 µL (1 ng/µl) CDK2/週期蛋白A2酶添加至酶空白孔及藥物處理孔中。將2 µL 1X激酶促反應緩衝液添加至對照(空白)孔中。 l 使板離心10秒且在室溫下培育15分鐘。 l 向每一孔中添加2 µL ATP (2.5X) +受質(組織蛋白)溶液(ATP/孔之最終濃度為50 µM且組織蛋白為125 ng/孔)。 l 使板離心10秒且在室溫下培育20分鐘。 b) ATP- 耗竭: l 在使用前,使ADP-glo試劑解凍至室溫。 l 添加5 µL ADP-Glo試劑以終止激酶促反應,以耗竭未消耗之ATP。 l 使板離心10秒且在室溫下培育40分鐘。 c) 激酶偵測: l 在使用前,使激酶偵測緩衝液解凍至室溫。 l 添加10 µL激酶偵測試劑以使ADP轉化成ATP,且引入螢光素酶及螢光素以偵測ATP。 l 使板在室溫下培育30分鐘。 l 使用BMG Labtech, FLUOstar Omega記錄發光。 The kinase assay has 3 steps: a) enzymatic reaction, b) ATP depletion, c) kinase detection. The protocol below is designed for a 384-well plate, using a 1:1:2 ratio for each of the 3 steps. a) Enzymatic reaction : l The total volume of the kinase-catalyzed reaction is 5 µL. 1 μL DMSO/drug (diluted in Kinase Buffer as 5X) and the final concentration in the wells is 1X. 2 µL of enzyme (prepared at 1 ng/µL in kinase buffer). Add 2 μL of ATP/substrate (histone) mix (2.5x, prepared in kinase buffer) so that the final concentration of ATP/well is 50 μM and histone is 125 ng per well. l Add 1 µL of test compound at 5X concentration to each well. For control wells (blank and enzyme blank), add 1 µL of DMSO prepared in 1X buffer. The final DMSO concentration in all wells was maintained at 0.5%. l Add 2 µL (1 ng/µl) of CDK2/Cyclin A2 enzyme to enzyme blank and drug-treated wells. Add 2 µL of 1X Kinase Reaction Buffer to control (blank) wells. l Centrifuge the plate for 10 seconds and incubate at room temperature for 15 minutes. l Add 2 µL of ATP (2.5X) + substrate (histone) solution to each well (final concentration of ATP/well is 50 µM and histone is 125 ng/well). l Centrifuge the plate for 10 seconds and incubate at room temperature for 20 minutes. b ) ATP- depletion : l Thaw ADP-glo reagent to room temperature before use. l Add 5 µL of ADP-Glo Reagent to terminate the kinase-catalyzed reaction to deplete unconsumed ATP. l Centrifuge the plate for 10 seconds and incubate at room temperature for 40 minutes. c) Kinase detection : l Thaw the kinase detection buffer to room temperature before use. l Add 10 µL Kinase Detection Reagent to convert ADP to ATP, and introduce luciferase and luciferin to detect ATP. l Incubate the plate at room temperature for 30 minutes. l Use BMG Labtech, FLUOstar Omega to record luminescence.

篩選計算: 1)   計算每一孔之平均值 2)   自每一酶空白孔及處理孔之平均值減去空白孔之平均值。 3)   計算空白扣除孔之平均值 4)   基於以下公式計算抑制% 100 - (空白扣除處理孔之平均值* 100) / (空白扣除酶空白孔之平均值) 5)   對於IC 50計算,使用GraphPad Prism,使用平均空白扣除值繪製IC 50曲線。 實例 -C 用於篩選式 (I) 化合物或測定式 (I) 化合物之 IC 50 CDK4 酶分析方案 目標 Screening calculations : 1) Calculate the mean value for each well 2) Subtract the mean value of the blank wells from the mean values of each enzyme blank well and treated wells. 3) Calculate the average value of blank subtracted wells 4) Calculate the inhibition % based on the following formula 100 - (average value of blank subtracted treated wells * 100) / (average value of blank subtracted enzyme blank wells) 5) For IC 50 calculation, use GraphPad Prism, IC50 curves were plotted using mean blank subtracted values. Example - C CDK4 Enzyme Assay Protocol Objectives for Screening Compounds of Formula (I ) or Determining the IC 50 of Compounds of Formula (I)

使用ADP-Glo激酶分析,篩選本發明化合物對CDK4酶之抑制%及/或測定本發明化合物抵抗CDK4酶之IC 50套組: Using the ADP-Glo kinase assay, compounds of the invention are screened for % inhibition of CDK4 enzyme and/or IC50 of compounds of the invention against CDK4 enzyme are determined. Set:

使用ADP-glow激酶套組進行CDK4酶分析。 ADP-Glo 激酶分析方案 CDK4 enzyme assays were performed using the ADP-glow kinase kit. ADP-Glo Kinase Assay Protocol

激酶分析具有3步:a)酶促反應,b) ATP耗竭,c)激酶偵測。以下方案針對384孔板設計,3個步驟分別使用1:1:2比率。 a) 酶促反應: l 激酶促反應之總體積為5 µL。1 μL DMSO/藥物(稀釋於激酶緩衝液中作為5X)且孔中之最終濃度為1X。2 μL酶(在激酶緩衝液中製備為20 ng/ μL)。2 μL ATP (2.5 x,在激酶緩衝液中製備)/受質(Rb蛋白),使得ATP/孔之最終濃度為100 µM且每孔之Rb蛋白為0.005 μg。 l 向每一孔中添加1 µL 5X濃度之測試化合物。對於對照孔(空白孔及酶空白孔),添加1 µL在1X緩衝液中製備之DMSO。將所有孔中之最終DMSO濃度維持在0.5%。 l 將2 µL (20 ng/µl) CDK4/週期蛋白D3酶添加至酶空白孔及藥物處理孔中。將2 µL 1X激酶促反應緩衝液添加至對照(空白)孔中。使板離心10秒且在室溫下培育15分鐘。 l 向每一孔中添加2 µL ATP (2.5X) +受質(Rb蛋白)溶液(ATP/孔之最終濃度為100 µM且Rb蛋白為0.005 µg)。 l 使板離心10秒且在室溫下培育60分鐘。 b) ATP 耗竭: l 在使用前,使ADP-glo試劑解凍至室溫。 l 添加5 µL ADP-Glo試劑以終止激酶促反應,以耗竭未消耗之ATP。使板離心10秒且在室溫下培育40分鐘。 c) 激酶偵測: l 在使用前,使激酶偵測緩衝液解凍至室溫。 l 添加10 µL激酶偵測試劑以使ADP轉化成ATP,且引入螢光素酶及螢光素以偵測ATP。 l 使板在室溫下培育30分鐘。 l 使用BMG Labtech, FLUOstar Omega記錄發光。 The kinase assay has 3 steps: a) enzymatic reaction, b) ATP depletion, c) kinase detection. The protocol below is designed for a 384-well plate, using a 1:1:2 ratio for each of the 3 steps. a) Enzymatic reaction : l The total volume of the kinase-catalyzed reaction is 5 µL. 1 μL DMSO/drug (diluted in Kinase Buffer as 5X) and the final concentration in the wells is 1X. 2 µL of enzyme (prepared at 20 ng/µL in kinase buffer). 2 μL of ATP (2.5x, prepared in Kinase Buffer)/substrate (Rb protein) for a final concentration of ATP/well of 100 μM and 0.005 μg of Rb protein per well. l Add 1 µL of test compound at 5X concentration to each well. For control wells (blank and enzyme blank), add 1 µL of DMSO prepared in 1X buffer. The final DMSO concentration in all wells was maintained at 0.5%. l Add 2 µL (20 ng/µl) of CDK4/cyclin D3 enzyme to enzyme blank and drug-treated wells. Add 2 µL of 1X Kinase Reaction Buffer to control (blank) wells. Plates were centrifuged for 10 seconds and incubated at room temperature for 15 minutes. l Add 2 µL of ATP (2.5X) + substrate (Rb protein) solution to each well (final concentration of ATP/well is 100 µM and Rb protein is 0.005 µg). l Centrifuge the plate for 10 seconds and incubate at room temperature for 60 minutes. b) ATP depletion : l Thaw ADP-glo reagent to room temperature before use. l Add 5 µL of ADP-Glo Reagent to terminate the kinase-catalyzed reaction to deplete unconsumed ATP. Plates were centrifuged for 10 seconds and incubated at room temperature for 40 minutes. c) Kinase detection : l Thaw the kinase detection buffer to room temperature before use. l Add 10 µL Kinase Detection Reagent to convert ADP to ATP, and introduce luciferase and luciferin to detect ATP. l Incubate the plate at room temperature for 30 minutes. l Use BMG Labtech, FLUOstar Omega to record luminescence.

篩選計算: 1)   計算每一孔之平均值 2)   自每一酶空白孔及處理孔之平均值減去空白孔之平均值。 3)   計算空白扣除孔之平均值 4)   基於以下公式計算抑制% :100 - (空白扣除處理孔之平均值* 100) / (空白扣除酶空白孔之平均值) 5) 對於IC 50計算,使用GraphPad Prism,使用平均空白扣除值繪製IC 50曲線。 實例 -D 用於篩選式 (I) 化合物或測定式 (I) 化合物之 IC 50 CDK6 酶分析方案 目標 Screening calculations : 1) Calculate the mean value for each well 2) Subtract the mean value of the blank wells from the mean values of each enzyme blank well and treated wells. 3) Calculate the average value of blank subtracted wells 4) Calculate the % inhibition based on the following formula: 100 - (average value of blank subtracted treated wells * 100) / (average value of blank subtracted enzyme blank wells) 5) For IC50 calculation, use GraphPad Prism, plotting IC50 curves using mean blank subtracted values. Example - D CDK6 Enzyme Assay Protocol Objectives for Screening Compounds of Formula (I ) or Determining the IC 50 of Compounds of Formula (I)

使用ADP-Glo激酶分析,篩選本發明化合物對CDK6酶之抑制%及/或測定本發明化合物抵抗CDK6酶之IC 50套組 Using the ADP-Glo kinase assay, the compounds of the invention are screened for % inhibition of the CDK6 enzyme and/or the IC50 of the compounds of the invention against the CDK6 enzyme is determined. set

使用ADP-glow激酶套組進行CDK6酶分析。套組組分包括激酶偵測試劑、ADP-glo試劑、ATP、受質(組織蛋白)及CDK6酶。所有該等試劑均根據製造商說明書製備並儲存。 ADP-Glo 激酶分析方案 CDK6 enzyme assays were performed using the ADP-glow kinase kit. The kit components include kinase detection reagent, ADP-glo reagent, ATP, substrate (histone) and CDK6 enzyme. All such reagents were prepared and stored according to the manufacturer's instructions. ADP-Glo Kinase Assay Protocol

激酶分析具有3步:a)酶促反應,b) ATP耗竭,c)激酶偵測。以下方案針對384孔板設計,3個步驟分別使用1:1:2比率。 a) 酶促反應:l 激酶促反應之總體積為5 µL。1 μL DMSO/藥物(稀釋於激酶緩衝液中作為5X)且孔中之最終濃度為1X。2 μL酶(在激酶緩衝液中製備為10 ng/ μL)。2 μL ATP (2.5 x,在激酶緩衝液中製備)/受質(組織蛋白),使得ATP/孔之最終濃度為250 µM且每孔之組織蛋白為0.025 μg l 向每一孔中添加1 µL 5X濃度之測試化合物。對於對照孔(空白孔及酶空白孔),添加1 µL在1X緩衝液中製備之DMSO。將所有孔中之最終DMSO濃度維持在0.5%。 l 將2 µL (10 ng/µl) CDK6/週期蛋白D3酶添加至酶空白孔及藥物處理孔中。將2 µL 1X激酶促反應緩衝液添加至對照(空白)孔中。 l 使板離心10秒且在室溫下培育15分鐘。 l 向每一孔中添加2 µL ATP (2.5X) +受質溶液(ATP/孔之最終濃度為250 µM且組織蛋白為0.025 µg。 l 使板離心10秒且在室溫下培育60分鐘。 b) ATP 耗竭: l 在使用前,使ADP-glo試劑解凍至室溫。 l 添加5 µL ADP-Glo試劑以終止激酶促反應,以耗竭未消耗之ATP。 l 使板離心10秒且在室溫下培育40分鐘。 c) 激酶偵測: l 在使用前,使激酶偵測緩衝液解凍至室溫。 l 添加10 µL激酶偵測試劑以使ADP轉化成ATP,且引入螢光素酶及螢光素以偵測ATP。 l 使板在室溫下培育30分鐘。 l 使用BMG Labtech, FLUOstar Omega記錄發光。 The kinase assay has 3 steps: a) enzymatic reaction, b) ATP depletion, c) kinase detection. The protocol below is designed for a 384-well plate, using a 1:1:2 ratio for each of the 3 steps. a) Enzymatic reaction: l The total volume of the kinase-catalyzed reaction is 5 µL. 1 μL DMSO/drug (diluted in Kinase Buffer as 5X) and the final concentration in the wells is 1X. 2 µL of enzyme (prepared at 10 ng/µL in kinase buffer). 2 μL ATP (2.5x, prepared in Kinase Buffer)/substrate (histone) so that the final concentration of ATP/well is 250 μM and histone is 0.025 μg l per well Add 1 μL to each well 5X concentration of test compound. For control wells (blank and enzyme blank), add 1 µL of DMSO prepared in 1X buffer. The final DMSO concentration in all wells was maintained at 0.5%. l Add 2 µL (10 ng/µl) of CDK6/cyclin D3 enzyme to enzyme blank and drug-treated wells. Add 2 µL of 1X Kinase Reaction Buffer to control (blank) wells. l Centrifuge the plate for 10 seconds and incubate at room temperature for 15 minutes. l Add 2 µL of ATP (2.5X) + substrate solution to each well (final concentration of ATP/well is 250 µM and histone is 0.025 µg. l Centrifuge the plate for 10 seconds and incubate at room temperature for 60 minutes. b) ATP depletion : l Thaw ADP-glo reagent to room temperature before use. l Add 5 µL of ADP-Glo Reagent to terminate the kinase-catalyzed reaction to deplete unconsumed ATP. l Centrifuge the plate for 10 seconds and incubate at room temperature for 40 minutes. c) Kinase detection : l Thaw the kinase detection buffer to room temperature before use. l Add 10 µL Kinase Detection Reagent to convert ADP to ATP, and introduce luciferase and luciferin to detect ATP. l Incubate the plate at room temperature for 30 minutes. l Use BMG Labtech, FLUOstar Omega to record luminescence.

篩選計算: 1)   計算每一孔之平均值 2)   自每一酶空白孔及處理孔之平均值減去空白孔之平均值。 3)   計算空白扣除孔之平均值 4)   基於以下公式計算抑制% :100 - (空白扣除處理孔之平均值* 100) / (空白扣除酶空白孔之平均值) 5)   對於IC 50計算,使用GraphPad Prism,使用平均空白扣除值繪製IC 50曲線。 結果:抑制%值於下表-2及表-3中給出,且IC 50值於下表-4中給出: 實例 -E 用於篩選所選式 (I) 化合物之 GI 50 之乳癌細胞株中的細胞增殖分析方案 目標: Screening calculations : 1) Calculate the mean value for each well 2) Subtract the mean value of the blank wells from the mean values of each enzyme blank well and treated wells. 3) Calculate the average value of blank subtracted wells 4) Calculate the % inhibition based on the following formula: 100 - (average value of blank subtracted treated wells * 100) / (average value of blank subtracted enzyme blank wells) 5) For IC50 calculation, use GraphPad Prism, plotting IC50 curves using mean blank subtracted values. Results : Inhibition % values are given in Table-2 and Table-3 below, and IC50 values are given in Table-4 below: Example - E is used to screen breast cancer cells for GI 50 of selected formula (I) compounds Cell Proliferation Assay in Strains Protocol Goals:

在乳癌細胞株(ZR.75.1、MCF-7及MDA-MB-231)中實施細胞增殖分析,以使用MTT分析來測定所選本發明化合物之GI 50方法:MTT分析(3--2,5-二苯基四唑鎓溴化物) Cell proliferation assays were performed in breast cancer cell lines ( ZR.75.1 , MCF-7 and MDA-MB-231) to determine the GI50 of selected compounds of the invention using the MTT assay. Method : MTT analysis (3--2,5-diphenyltetrazolium bromide)

程序: 處理細胞,團粒化並計數。於96孔板中使細胞以100 µl/孔以期望密度一式三份平鋪於完全培養基中,且使板在37℃及5% CO 2下培育。將每一孔中之細胞用在完全培養基中製備之抑制劑稀釋液以一式三份處理,且使板在37℃及5% CO 2下培育144 h。 144 h後,將15 µL 5 mg/mL (最終濃度為1X)之MTT添加至測試孔中且充分混合。使板在37℃及5% CO 2下培育3.5小時。培育後,使細胞在4000 rpm下團粒化沈降10 min。吸出培養基,且每孔添加150 µL DMSO。藉由反復吸量管抽吸使晶體溶解。在A560 nm及A640 nm下讀取吸光度。使用GraphPad Prism計算GI 50值。 Procedure : Cells are processed, pelleted and counted. Cells were plated in triplicate at 100 μl/well in complete medium at the desired density in 96-well plates and the plates were incubated at 37°C and 5% CO 2 . Cells in each well were treated in triplicate with inhibitor dilutions prepared in complete medium, and plates were incubated at 37°C and 5% CO2 for 144 h. After 144 h, 15 µL of 5 mg/mL (1X final concentration) of MTT was added to the test wells and mixed well. Plates were incubated for 3.5 hours at 37°C and 5% CO2 . After incubation, the cells were pelleted and sedimented at 4000 rpm for 10 min. Aspirate the medium and add 150 µL DMSO per well. The crystals were dissolved by repeated pipetting. Absorbance was read at A560 nm and A640 nm. GI 50 values were calculated using GraphPad Prism.

結果:下表4中測定所選本發明化合物之GI 50值。 -2 實例編號 抑制 % CDK1 CDK2 CDK4 CDK6 100 nM 1000 nM 100 nM 1000 nM 100 nM 1000 nM 100 nM 1000 nM 1B B A B A 2B D D D C A A B A 3A D D D D A A C B 4A A A C B 5B B A B A 6A B A D B 7A A A C B 8A D D D C A A B A 9A B A C B 10B B A B A 11B A A A A 12A B A C B 13A B A C B 14A B A C B 15A B A C B 17B D B B A             -3 實例編號 抑制 % CDK1 CDK2 CDK4 CDK6 30 nM 100 nM 30 nM 100 nM 30 nM 100 nM 30 nM 100 nM 16A B A D C 17B             C A C B 18A C A C B 19A D D D D 20B D B D C 21A D C D D 22A D C D D 23B D B D C 24A D C D D 25A D D D D 26B D C D D 27A D C D D 28A C B D C 29A D B D D 30A D D D D 31A D D D C D B D D 32A D D D D 33A D C D D 34A D C D D 35A D C D D 36A D B D D 37A C C D C 38A D C D D D D D D 39B D D D D C B D C 40B D D C C B A A A 41B C B B A A A B A 42B D D D D C A C B 43A D D C C B A B A 44A D C D C C A C A 45A D D D D C C D D 46B C A B A 47A D C C B B B B A 48B C A A A B B A A 49B D C D B B B B B 50B D D C B B B C B 51B C B B A B A B A 52B D D D C B A C B 53B D C B A C B 54B C B B A D B 55B D D C B D D 56A C B A A B A A A 58B       D C C A C C Results: GI 50 values for selected compounds of the invention were determined in Table 4 below. Table -2 instance number Inhibition % CDK1 CDK2 CDK4 CDK6 100nM 1000 nM 100nM 1000nM 100nM 1000nM 100nM 1000nM 1B B A B A 2B D. D. D. C A A B A 3A D. D. D. D. A A C B 4A A A C B 5B B A B A 6A B A D. B 7A A A C B 8A D. D. D. C A A B A 9A B A C B 10B B A B A 11B A A A A 12A B A C B 13A B A C B 14A B A C B 15A B A C B 17B D. B B A Table -3 instance number Inhibition % CDK1 CDK2 CDK4 CDK6 30nM 100nM 30nM 100nM 30nM 100nM 30nM 100nM 16A B A D. C 17B C A C B 18A C A C B 19A D. D. D. D. 20B D. B D. C 21A D. C D. D. 22A D. C D. D. 23B D. B D. C 24A D. C D. D. 25A D. D. D. D. 26B D. C D. D. 27A D. C D. D. 28A C B D. C 29A D. B D. D. 30A D. D. D. D. 31A D. D. D. C D. B D. D. 32A D. D. D. D. 33A D. C D. D. 34A D. C D. D. 35A D. C D. D. 36A D. B D. D. 37A C C D. C 38A D. C D. D. D. D. D. D. 39B D. D. D. D. C B D. C 40B D. D. C C B A A A 41B C B B A A A B A 42B D. D. D. D. C A C B 43A D. D. C C B A B A 44A D. C D. C C A C A 45A D. D. D. D. C C D. D. 46B C A B A 47A D. C C B B B B A 48B C A A A B B A A 49B D. C D. B B B B B 50B D. D. C B B B C B 51B C B B A B A B A 52B D. D. D. C B A C B 53B D. C B A C B 54B C B B A D. B 55B D. D. C B D. D. 56A C B A A B A A A 58B D. C C A C C

抑制%:A代表>75%至100%;B代表>50%至≤75%;C代表>25%至≤50%且D代表≤25%; -4 實例編號 IC50 GI50 (nM) CDK1 CDK2 CDK4 CDK6 MCF-7 ZR-75.1 MDA-MB-231 1B ++++ ++ b 2B +++ +++ b 3A +++++ + d 5B +++++ ++++ a 7A +++++ ++ b 8A +++++ ++ b 9A ++ + e 10B ++++ +++ b 11B ++++ +++ b 16A ++++ ++ 17B +++ +++ ++++ a b b 18A ++++ +++ a 41B +++ +++ +++++ ++++ c c IC50:「+++++」代表1 nM至≤25 nM;「++++」代表>25 nM至≤50 nM;「+++」代表>50 nM至≤100 nM;「++」代表>100 nM至≤200nM,「+」代表>200 nM; GI50:「a」代表100 nM至≤200 nM;「b」代表>200 nM至≤500 nM;「c」代表>500 nM至≤1000nM;「d」代表>1000 nM至≤10000 nM,「e」代表>10000 nM; Inhibition %: A stands for >75% to 100%; B stands for >50% to ≤75%; C stands for >25% to ≤50% and D stands for ≤25%; Table -4 instance number IC50 GI50 (nM) CDK1 CDK2 CDK4 CDK6 MCF-7 ZR-75.1 MDA-MB-231 1B ++++ ++ b 2B +++ +++ b 3A +++++ + d 5B +++++ ++++ a 7A +++++ ++ b 8A +++++ ++ b 9A ++ + e 10B ++++ +++ b 11B ++++ +++ b 16A ++++ ++ 17B +++ +++ ++++ a b b 18A ++++ +++ a 41B +++ +++ +++++ ++++ c c IC50: "++++" stands for 1 nM to ≤25 nM; "++++" stands for >25 nM to ≤50 nM; "+++" stands for >50 nM to ≤100 nM; "++" Represents >100 nM to ≤200 nM, "+" represents >200 nM; GI50: "a" represents 100 nM to ≤200 nM; "b" represents >200 nM to ≤500 nM; "c" represents >500 nM to ≤ 1000nM; "d" stands for >1000 nM to ≤10000 nM, "e" stands for >10000 nM;

儘管在本文中已參照實施例對本發明予以闡述,但應理解,該等實施例僅僅為對本發明之原理及應用之闡釋。因此,應理解,在不背離如上文所闡述之本發明精神及範圍之情形下,可對闡釋性實施例作出諸多修改且可設計出其他配置。隨附申請專利範圍意欲界定本發明之範圍,且由此涵蓋該等申請專利範圍及其等效內容範圍內之方法及結構。Although the present invention has been described herein with reference to the embodiments, it should be understood that these embodiments are merely illustrative of the principles and applications of the invention. It will therefore be understood that various modifications may be made and other configurations may be devised in the illustrative embodiments without departing from the spirit and scope of the invention as set forth above. The accompanying claims are intended to define the scope of the invention and to thereby cover methods and structures within the scope of these claims and their equivalents.

本申請案中所引用之所有公開案及專利及/或專利申請案均係以引用的方式併入本文中,其併入程度如同每一個別公開案或專利申請案明確且個別地指示為以引用的方式併入本文中一般。All publications and patents and/or patent applications cited in this application are hereby incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be Incorporated herein generally by way of reference.

Figure 110144250-A0101-11-0003-3
Figure 110144250-A0101-11-0003-3

Claims (32)

一種式 (I)化合物,
Figure 03_image001
(I)或其互變異構物、其前藥、其N-氧化物、其立體異構物、其醫藥學上可接受之酯或其醫藥學上可接受之鹽, 其中 Y 1選自CR a或N; Y 2選自CR b或N;條件係Y 1及Y 2中之至少一者為N; R a、R b、R c、R d、R e、R f及R g在每次出現時獨立地選自氫、鹵素、羥基、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之鹵烷基、經取代或未經取代之烷氧基、經取代或未經取代之胺基烷基、經取代或未經取代之羥基烷基、經取代或未經取代之環烷基、經取代或未經取代之環烷基烷基、經取代或未經取代之雜環基或經取代或未經取代之雜環基烷基; Y選自CR h或N; Z選自CR i或N;條件係Y及Z中之至少一者為N; R h及R i在每次出現時獨立地選自氫、鹵素、經取代或未經取代之C (1-3)烷基或經取代或未經取代之C (1-3)鹵烷基; X 1選自CR 1或N; X 2選自CR 2或N; X 3選自CR 3或N; X 4選自CR 4或N; R 1、R 2、R 3、R 4、R 5及R 6在每次出現時獨立地選自氫、鹵素、羥基、經取代或未經取代之烷基或經取代或未經取代之鹵烷基、經取代或未經取代之烷氧基、經取代或未經取代之環烷基、經取代或未經取代之環烷基烷基、經取代或未經取代之雜環基或經取代或未經取代之雜環基烷基; L為不存在、NH、O、S-、-SO-、-SO 2-、-C(=O)-或經取代或未經取代之烷基; 環A為經取代或未經取代之雜環基環; R 7在每次出現時獨立地選自氫、羥基、鹵素、經取代或未經取代之烷基、經取代或未經取代之烷氧基、經取代或未經取代之烯基、經取代或未經取代之炔基、經取代或未經取代之環烷基、經取代或未經取代之環烯基、經取代或未經取代之環烷基烷基、經取代或未經取代之環烯基烷基、經取代或未經取代之雜環基、經取代或未經取代之雜環基烷基、經取代或未經取代之芳基、經取代或未經取代之芳基烷基、經取代或未經取代之雜芳基、經取代或未經取代之雜芳基烷基、側氧基(=O)、-C(=O)OR z、-C(=O)R z、-C(=S)R z、-C(=O)NR zR z、-C(=O)ONR zR z、-NR zR z、-NR zC(=O)NR zR z、-NR zS(=O)R z、-NR zS(=O) 2R z、 -N=NR z、-NR zC(=O)OR z、-NR zC(=O)R z、-NR xC(=S)R y-NR zC(=S)NR zR z、-SONR zR z、-SO 2NR zR z、-OR z、-OC(=O)NR zR z、-OC(=O)OR z、-OC(=O)R z、-OC(=O)NR zR z、-CR xR y-NR zC(=O)R z、-CR xR y-OR z、-CR xR y-C(=O)OR z、-CR xR y-C(=O)NR zR z、 -CR xR y-OC(=O)R z、SR z、-SOR z、-SO 2R z、-CR xR yC(=O)R z或-CR xR yC(=S)R z; R z選自氫、經取代或未經取代之烷基、經取代或未經取代之烷氧基、經取代或未經取代之烯基、經取代或未經取代之炔基、經取代或未經取代之芳基、經取代或未經取代之芳基烷基、經取代或未經取代之雜芳基、經取代或未經取代之雜芳基烷基、經取代或未經取代之環烷基、經取代或未經取代之環烷基烷基、經取代或未經取代之環烯基、經取代或未經取代之雜環基、經取代之雜環基烷基或經取代或未經取代之胺基,或任兩個R z在結合至共用原子時可連結以形成(i)經取代或未經取代之飽和或不飽和3員至14員環,其可視情況包括一或多個雜原子,該(等)雜原子可相同或不同且選自O、NR za及S,或(ii) 側氧基(=O)、硫基(=S)或亞胺基(=NR za);其中R za、R x及R y在每次出現時獨立地選自氫、鹵基、羥基、胺基、烷氧基、C 1-5烷基、C 3-7環烷基、C 5-7芳基、 C 5-7雜芳基或C 3-7雜環烷基;且 n為選自0、1、2、3及4之整數。
A compound of formula (I) ,
Figure 03_image001
(I) or its tautomer, its prodrug, its N - oxide, its stereoisomer, its pharmaceutically acceptable ester or its pharmaceutically acceptable salt, wherein Y is selected from CR a or N; Y 2 is selected from CR b or N; proviso that at least one of Y 1 and Y 2 is N; R a , R b , R c , R d , Re , R f and R g are in each The second occurrence is independently selected from hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted Alkoxy, substituted or unsubstituted aminoalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkane group, substituted or unsubstituted heterocyclyl or substituted or unsubstituted heterocyclylalkyl; Y is selected from CR h or N; Z is selected from CR i or N; the proviso is that at least one of Y and Z One is N; R h and R i are independently selected from each occurrence of hydrogen, halogen, substituted or unsubstituted C (1-3) alkyl or substituted or unsubstituted C ( 1-3) 3) Haloalkyl; X 1 is selected from CR 1 or N; X 2 is selected from CR 2 or N; X 3 is selected from CR 3 or N; X 4 is selected from CR 4 or N; R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen, halogen, hydroxyl, substituted or unsubstituted alkyl or substituted or unsubstituted haloalkyl, substituted or unsubstituted Substituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heterocyclic L is absent, NH, O, S-, -SO-, -SO 2 -, -C(=O)-, or substituted or unsubstituted alkyl; Ring A is substituted or unsubstituted Substituted heterocyclyl ring ; each occurrence of R is independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted Substituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl , substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, side oxy (=O), -C(=O)OR z , -C(=O)R z , -C(=S)R z , -C(=O)NR z R z , -C(=O)ONR z R z , -NR z R z , -NR z C(=O)NR z R z , -NR z S(=O)R z , -NR z S(=O) 2 R z , -N=N R z , -NR z C(=O)OR z , -NR z C(=O)R z , -NR x C(=S)R y -NR z C(=S)NR z R z , -SONR z R z , -SO 2 NR z R z , -OR z , -OC(=O)NR z R z , -OC(=O)OR z , -OC(=O)R z , -OC(=O )NR z R z , -CR x R y -NR z C(=O)R z , -CR x R y -OR z , -CR x R y -C(=O)OR z , -CR x R y -C(=O)NR z R z , -CR x R y -OC(=O)R z , SR z , -SOR z , -SO 2 R z , -CR x R y C(=O)R z or -CR x R y C(=S) R z ; R z is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl , substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted Heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted hetero Cyclic, substituted heterocyclylalkyl or substituted or unsubstituted amino, or any two R z when bound to a common atom may be linked to form (i) substituted or unsubstituted saturated or An unsaturated 3- to 14-membered ring, which optionally includes one or more heteroatoms, which (the) heteroatoms may be the same or different and are selected from O, NR za and S, or (ii) pendant oxy (=O ), thio (=S) or imino (=NR za ); wherein R za , R x and R y are each independently selected from hydrogen, halo, hydroxyl, amino, alkoxy, C 1-5 alkyl, C 3-7 cycloalkyl, C 5-7 aryl, C 5-7 heteroaryl or C 3-7 heterocycloalkyl; and n is selected from 0, 1, 2, Integer of 3 and 4.
如請求項1之化合物,其中X 1、X 2、X 3及X 4獨立地選自CH或N。 The compound according to claim 1, wherein X 1 , X 2 , X 3 and X 4 are independently selected from CH or N. 如請求項2之化合物,其中X 1及X 2為N。 The compound as claimed in item 2, wherein X 1 and X 2 are N. 如請求項2之化合物,其中X 1為N。 The compound as claimed in item 2, wherein X 1 is N. 如請求項2之化合物,其中X 2、X 3及X 4獨立地選自CH。 The compound according to claim 2, wherein X 2 , X 3 and X 4 are independently selected from CH. 如請求項1之化合物,其中Y及Z獨立地選自CH或N。 The compound of claim 1, wherein Y and Z are independently selected from CH or N. 如請求項6之化合物,其中Y為N。 The compound as claimed in item 6, wherein Y is N. 如請求項6之化合物,其中Z為N。 The compound as claimed in item 6, wherein Z is N. 如請求項1之化合物,其中該式 (IA)(IB)(IC)(ID)化合物:
Figure 03_image004
Figure 03_image006
(IA)                                                                   (IB)
Figure 03_image008
Figure 03_image010
(IC)                                                                   (ID)或其互變異構物、其前藥、其N-氧化物、其立體異構物、其醫藥學上可接受之酯或其醫藥學上可接受之鹽, 其中所有變數(包括環A、L、R 5、R 6、R 7、R c、R d、R e、R f、R g、Y 1、Y 2及n)係如式 (I)中所定義。
As the compound of claim 1, wherein the formula (IA) , (IB) , (IC) or (ID) compound:
Figure 03_image004
Figure 03_image006
(IA) (IB)
Figure 03_image008
Figure 03_image010
(IC) (ID) or its tautomers, its prodrugs, its N-oxides, its stereoisomers, its pharmaceutically acceptable esters or its pharmaceutically acceptable salts, wherein all variables (including rings A, L, R 5 , R 6 , R 7 , R c , R d , Re , R f , R g , Y 1 , Y 2 and n) are as defined in formula (I) .
如請求項1至9中任一項之化合物,其中環A選自
Figure 03_image358
Figure 03_image359
The compound according to any one of claims 1 to 9, wherein ring A is selected from
Figure 03_image358
Figure 03_image359
.
如請求項1至10中任一項之化合物,其中L為不存在或CH 2The compound according to any one of claims 1 to 10, wherein L is absent or CH 2 . 如請求項11之化合物,其中L為不存在。 The compound as claimed in item 11, wherein L is absent. 如請求項11之化合物,其中L為CH 2The compound according to claim 11, wherein L is CH 2 . 如請求項1至13中任一項之化合物,其中R 5為氫或鹵素。 The compound according to any one of claims 1 to 13, wherein R 5 is hydrogen or halogen. 如請求項14之化合物,其中R 5為氫或氟。 The compound as claimed in claim 14, wherein R 5 is hydrogen or fluorine. 如請求項1至15中任一項之化合物,其中R 6為氫。 The compound as claimed in any one of items 1 to 15, wherein R 6 is hydrogen. 如請求項1至16中任一項之化合物,其中Y 1為N。 The compound as claimed in any one of items 1 to 16, wherein Y 1 is N. 如請求項1至17中任一項之化合物,其中環
Figure 03_image015
選自
Figure 03_image362
The compound according to any one of claims 1 to 17, wherein ring
Figure 03_image015
selected from
Figure 03_image362
.
一種化合物,其選自: 4-(6-((5-氟-4-(喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-1-甲酸第三丁基酯; 5-氟-N-(5-(六氫吡嗪-1-基)吡啶-2-基)-4-(喹啉-6-基)嘧啶-2-胺; 5-氟-N-(5-(六氫吡嗪-1-基)吡啶-2-基)-4-(喹啉-6-基)嘧啶-2-胺鹽酸鹽; 4-(6-((5-氟-4-(8-氟喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-1-甲酸第三丁基酯; 5-氟-4-(8-氟喹啉-6-基)-N-(5-(六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺; 5-氟-4-(8-氟喹啉-6-基)-N-(5-(六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺鹽酸鹽; N-(5-((4-乙基六氫吡嗪-1-基)甲基)吡啶-2-基)-5-氟-4-(8-氟喹啉-6-基)嘧啶-2-胺; N-(5-((4-乙基六氫吡嗪-1-基)甲基)吡啶-2-基)-5-氟-4-(8-氟喹啉-6-基)嘧啶-2-胺鹽酸鹽; N-(5-((4-乙基六氫吡嗪-1-基)甲基)吡啶-2-基)-5-氟-4-(喹啉-6-基)嘧啶-2-胺; N-(5-((4-乙基六氫吡嗪-1-基)甲基)吡啶-2-基)-5-氟-4-(喹啉-6-基)嘧啶-2-胺鹽酸鹽; 4-(6-((5-氟-4-(8-氟-2-甲基-4-(丙-1-烯-2-基)喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-1-甲酸第三丁基酯; 5-氟-4-(8-氟-2-甲基-4-(丙-1-烯-2-基)喹啉-6-基)-N-(5-(六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺; 5-氟-4-(8-氟-2-甲基-4-(丙-1-烯-2-基)喹啉-6-基)-N-(5-(六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺鹽酸鹽; 5-氟-N-(5-(4-甲基六氫吡嗪-1-基)吡啶-2-基)-4-(喹啉-6-基)嘧啶-2-胺; 5-氟-N-(5-(4-甲基六氫吡嗪-1-基)吡啶-2-基)-4-(喹啉-6-基)嘧啶-2-胺鹽酸鹽; 5-氟-4-(8-氟喹啉-6-基)-N-(5-(4-甲基六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺; 5-氟-4-(8-氟喹啉-6-基)-N-(5-(4-甲基六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺鹽酸鹽; N-(5-(4-乙基六氫吡嗪-1-基)吡啶-2-基)-5-氟-4-(8-氟喹啉-6-基)嘧啶-2-胺; N-(5-(4-乙基六氫吡嗪-1-基)吡啶-2-基)-5-氟-4-(8-氟喹啉-6-基)嘧啶-2-胺鹽酸鹽; N-(5-((4-乙基六氫吡嗪-1-基)甲基)吡啶-2-基)-5-氟-4-(8-氟-2-甲基喹啉-6-基)嘧啶-2-胺; N-(5-((4-乙基六氫吡嗪-1-基)甲基)吡啶-2-基)-5-氟-4-(8-氟-2-甲基喹啉-6-基)嘧啶-2-胺鹽酸鹽; 4-(6-((5-氟-4-(8-氟-2-甲基喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-1-甲酸第三丁基酯; 5-氟-4-(8-氟-2-甲基喹啉-6-基)-N-(5-(六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺; 5-氟-4-(8-氟-2-甲基喹啉-6-基)-N-(5-(六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺鹽酸鹽; 4-(6-((5-氟-4-(8-氟-4-異丙基-2-甲基喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-1-甲酸第三丁基酯; 5-氟-4-(8-氟-4-異丙基-2-甲基喹啉-6-基)-N-(5-(六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺; 5-氟-4-(8-氟-4-異丙基-2-甲基喹啉-6-基)-N-(5-(六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺鹽酸鹽; N-(5-(4-乙基六氫吡嗪-1-基)吡啶-2-基)-5-氟-4-(喹啉-6-基)嘧啶-2-胺; N-(5-(4-乙基六氫吡嗪-1-基)吡啶-2-基)-5-氟-4-(喹啉-6-基)嘧啶-2-胺鹽酸鹽; 5-氟-4-(8-氟喹啉-6-基)-N-(5-(4-異丙基六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺; 5-氟-4-(8-氟喹啉-6-基)-N-(5-(4-異丙基六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺鹽酸鹽; 5-氟-N-(5-(4-異丙基六氫吡嗪-1-基)吡啶-2-基)-4-(喹啉-6-基)嘧啶-2-胺; 5-氟-N-(5-(4-異丙基六氫吡嗪-1-基)吡啶-2-基)-4-(喹啉-6-基)嘧啶-2-胺鹽酸鹽; 5-氟-4-(8-氟喹啉-6-基)-N-(5-((4-甲基六氫吡嗪-1-基)甲基)吡啶-2-基)嘧啶-2-胺; 5-氟-4-(8-氟喹啉-6-基)-N-(5-((4-甲基六氫吡嗪-1-基)甲基)吡啶-2-基)嘧啶-2-胺鹽酸鹽; 2-(6-(2-((5-((4-乙基六氫吡嗪-1-基)甲基)吡啶-2-基)胺基)-5-氟嘧啶-4-基)-8-氟-2-甲基喹啉-4-基)丙-2-醇; 2-(6-(2-((5-((4-乙基六氫吡嗪-1-基)甲基)吡啶-2-基)胺基)-5-氟嘧啶-4-基)-8-氟-2-甲基喹啉-4-基)丙-2-醇鹽酸鹽; 4-(6-((5-氟-4-(8-氟-4-(2-羥基丙-2-基)-2-甲基喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-1-甲酸第三丁基酯; 2-(8-氟-6-(5-氟-2-((5-(六氫吡嗪-1-基)吡啶-2-基)胺基)嘧啶-4-基)-2-甲基喹啉-4-基)丙-2-醇; 2-(8-氟-6-(5-氟-2-((5-(六氫吡嗪-1-基)吡啶-2-基)胺基)嘧啶-4-基)-2-甲基喹啉-4-基)丙-2-醇鹽酸鹽; 2-(6-(2-((5-(4-乙基六氫吡嗪-1-基)吡啶-2-基)胺基)-5-氟嘧啶-4-基)-8-氟-2-甲基喹啉-4-基)丙-2-醇; 2-(6-(2-((5-(4-乙基六氫吡嗪-1-基)吡啶-2-基)胺基)-5-氟嘧啶-4-基)-8-氟-2-甲基喹啉-4-基)丙-2-醇鹽酸鹽; 4-(4-(二氟甲基)-8-氟-2-甲基喹啉-6-基)-N-(5-(4-乙基六氫吡嗪-1-基)吡啶-2-基)-5-氟嘧啶-2-胺; 4-(4-(二氟甲基)-8-氟-2-甲基喹啉-6-基)-N-(5-(4-乙基六氫吡嗪-1-基)吡啶-2-基)-5-氟嘧啶-2-胺鹽酸鹽; 4-(6-((4-(4-(二氟甲基)-8-氟-2-甲基喹啉-6-基)-5-氟嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-1-甲酸第三丁基酯; 4-(4-(二氟甲基)-8-氟-2-甲基喹啉-6-基)-5-氟-N-(5-(六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺; 4-(4-(二氟甲基)-8-氟-2-甲基喹啉-6-基)-5-氟-N-(5-(六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺鹽酸鹽; 4-(4-(二氟甲基)-8-氟-2-甲基喹啉-6-基)-N-(5-((4-乙基六氫吡嗪-1-基)甲基)吡啶-2-基)-5-氟嘧啶-2-胺; 4-(4-(二氟甲基)-8-氟-2-甲基喹啉-6-基)-N-(5-((4-乙基六氫吡嗪-1-基)甲基)吡啶-2-基)-5-氟嘧啶-2-胺鹽酸鹽; N-(5-((4-乙基六氫吡嗪-1-基)甲基)吡啶-2-基)-5-氟-4-(8-氟-4-(2-氟丙-2-基)-2-甲基喹啉-6-基)嘧啶-2-胺; N-(5-((4-乙基六氫吡嗪-1-基)甲基)吡啶-2-基)-5-氟-4-(8-氟-4-(2-氟丙-2-基)-2-甲基喹啉-6-基)嘧啶-2-胺鹽酸鹽; 4-(6-((5-氟-4-(8-氟-4-(2-氟丙-2-基)-2-甲基喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-1-甲酸第三丁基酯; 5-氟-4-(8-氟-4-(2-氟丙-2-基)-2-甲基喹啉-6-基)-N-(5-(六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺; 5-氟-4-(8-氟-4-(2-氟丙-2-基)-2-甲基喹啉-6-基)-N-(5-(六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺鹽酸鹽; 5-氟-N-(5-((4-甲基六氫吡嗪-1-基)甲基)吡啶-2-基)-4-(喹啉-6-基)嘧啶-2-胺; 5-氟-N-(5-((4-甲基六氫吡嗪-1-基)甲基)吡啶-2-基)-4-(喹啉-6-基)嘧啶-2-胺鹽酸鹽; N-(5-((4-乙基六氫吡嗪-1-基)甲基)吡啶-2-基)-5-氟-4-(7-氟喹啉-6-基)嘧啶-2-胺; N-(5-((4-乙基六氫吡嗪-1-基)甲基)吡啶-2-基)-5-氟-4-(7-氟喹啉-6-基)嘧啶-2-胺鹽酸鹽; 4-(6-((5-氟-4-(7-氟喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-1-甲酸第三丁基酯; 5-氟-4-(7-氟喹啉-6-基)-N-(5-(六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺; 5-氟-4-(7-氟喹啉-6-基)-N-(5-(六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺鹽酸鹽; N-(5-(4-乙基六氫吡嗪-1-基)吡啶-2-基)-5-氟-4-(7-氟喹啉-6-基)嘧啶-2-胺; N-(5-(4-乙基六氫吡嗪-1-基)吡啶-2-基)-5-氟-4-(7-氟喹啉-6-基)嘧啶-2-胺鹽酸鹽; N-(5-(4-(二甲基胺基)六氫吡啶-1-基)吡啶-2-基)-5-氟-4-(8-氟喹啉-6-基)嘧啶-2-胺; N-(5-(4-(二甲基胺基)六氫吡啶-1-基)吡啶-2-基)-5-氟-4-(8-氟喹啉-6-基)嘧啶-2-胺鹽酸鹽; 4-(6-((5-氟-4-(8-氟喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-2-酮; 4-(6-((5-氟-4-(8-氟喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-2-酮鹽酸鹽; N-(5-(4-環丙基六氫吡嗪-1-基)吡啶-2-基)-5-氟-4-(8-氟喹啉-6-基)嘧啶-2-胺; N-(5-(4-環丙基六氫吡嗪-1-基)吡啶-2-基)-5-氟-4-(8-氟喹啉-6-基)嘧啶-2-胺鹽酸鹽; 1-(4-(6-((5-氟-4-(8-氟喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-1-基)乙-1-酮; 1-(4-(6-((5-氟-4-(8-氟喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-1-基)乙-1-酮鹽酸鹽; 5-氟-4-(8-氟喹啉-6-基)-N-(5-(4-(2,2,2-三氟乙基)六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺; 5-氟-4-(8-氟喹啉-6-基)-N-(5-(4-(2,2,2-三氟乙基)六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺鹽酸鹽; 5-氟-4-(8-氟喹啉-6-基)-N-(5-(4-(甲基磺醯基)六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺; 5-氟-4-(8-氟喹啉-6-基)-N-(5-(4-(甲基磺醯基)六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺鹽酸鹽; 環丙基(4-(6-((5-氟-4-(8-氟喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-1-基)甲酮; 環丙基(4-(6-((5-氟-4-(8-氟喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-1-基)甲酮鹽酸鹽; 5-氟-4-(8-氟喹啉-6-基)-N-(5-(3-(三氟甲基)-5,6-二氫-[1,2,4]三唑并[4,3-a]吡嗪-7(8H)-基)吡啶-2-基)嘧啶-2-胺; 5-氟-4-(8-氟喹啉-6-基)-N-(5-(3-(三氟甲基)-5,6-二氫-[1,2,4]三唑并[4,3-a]吡嗪-7(8H)-基)吡啶-2-基)嘧啶-2-胺鹽酸鹽; N-(5-((4-乙基六氫吡嗪-1-基)甲基)吡啶-2-基)-5-氟-4-(8-氟-4-異丙基-2-甲基喹啉-6-基)嘧啶-2-胺; N-(5-((4-乙基六氫吡嗪-1-基)甲基)吡啶-2-基)-5-氟-4-(8-氟-4-異丙基-2-甲基喹啉-6-基)嘧啶-2-胺鹽酸鹽; N-(5-(4-乙基六氫吡嗪-1-基)吡啶-2-基)-5-氟-4-(8-氟-4-異丙基-2-甲基喹啉-6-基)嘧啶-2-胺; N-(5-(4-乙基六氫吡嗪-1-基)吡啶-2-基)-5-氟-4-(8-氟-4-異丙基-2-甲基喹啉-6-基)嘧啶-2-胺鹽酸鹽; 1-(6-((5-氟-4-(8-氟喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)-4-甲基六氫吡啶-4-醇; 1-(6-((5-氟-4-(8-氟喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)-4-甲基六氫吡啶-4-醇鹽酸鹽; (±)-4-(6-((4-(4-(1-((第三丁氧基羰基)胺基)乙基)-8-氟-2-甲基喹啉-6-基)-5-氟嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-1-甲酸第三丁基酯; (±)-4-(4-(1-胺基乙基)-8-氟-2-甲基喹啉-6-基)-5-氟-N-(5-(六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺; (±)-4-(4-(1-胺基乙基)-8-氟-2-甲基喹啉-6-基)-5-氟-N-(5-(六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺鹽酸鹽; (±)-4-(6-((4-(4-(1-((第三丁氧基羰基)胺基)乙基)-8-氟喹啉-6-基)-5-氟嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-1-甲酸第三丁基酯; (±)-4-(4-(1-胺基乙基)-8-氟喹啉-6-基)-5-氟-N-(5-(六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺; (±)-4-(4-(1-胺基乙基)-8-氟喹啉-6-基)-5-氟-N-(5-(六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺二鹽酸鹽; (±)-4-(6-((5-氟-4-(8-氟-4-(1-羥基乙基)喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-1-甲酸第三丁基酯; (±)-1-(8-氟-6-(5-氟-2-((5-(六氫吡嗪-1-基)吡啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)乙醇; (±)-1-(8-氟-6-(5-氟-2-((5-(六氫吡嗪-1-基)吡啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)乙醇三甲磺酸鹽; (±)-(1-(8-氟-6-(5-氟-2-((5-(4-甲基六氫吡嗪-1-基)吡啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)乙基)胺基甲酸第三丁基酯; (±)-4-(4-(1-胺基乙基)-8-氟喹啉-6-基)-5-氟-N-(5-(4-甲基六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺; (±)-4-(4-(1-胺基乙基)-8-氟喹啉-6-基)-5-氟-N-(5-(4-甲基六氫吡嗪-1-基)吡啶-2-基)嘧啶-2-胺三鹽酸鹽; (±)-1-(6-(2-((5-(4-乙基六氫吡嗪-1-基)吡啶-2-基)胺基)-5-氟嘧啶-4-基)-8-氟喹啉-4-基)乙醇; (±)-1-(6-(2-((5-(4-乙基六氫吡嗪-1-基)吡啶-2-基)胺基)-5-氟嘧啶-4-基)-8-氟喹啉-4-基)乙醇三鹽酸鹽; (±)-1-(8-氟-6-(5-氟-2-((5-(4-異丙基六氫吡嗪-1-基)吡啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)乙醇; (±)-1-(8-氟-6-(5-氟-2-((5-(4-異丙基六氫吡嗪-1-基)吡啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)乙醇三鹽酸鹽; N-(5-(4-乙基六氫吡嗪-1-基)吡啶-2-基)-5-氟-4-(8-氟-2-甲基喹啉-6-基)嘧啶-2-胺; N-(5-(4-乙基六氫吡嗪-1-基)吡啶-2-基)-5-氟-4-(8-氟-2-甲基喹啉-6-基)嘧啶-2-胺鹽酸鹽; (±)-4-(6-((5-氟-4-(8-氟-4-(1-羥基乙基)-2-甲基喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-1-甲酸第三丁基酯; (±)-1-(8-氟-6-(5-氟-2-((5-(六氫吡嗪-1-基)吡啶-2-基)胺基)嘧啶-4-基)-2-甲基喹啉-4-基)乙醇; (±)-1-(8-氟-6-(5-氟-2-((5-(六氫吡嗪-1-基)吡啶-2-基)胺基)嘧啶-4-基)-2-甲基喹啉-4-基)乙-1-醇鹽酸鹽; (±)-1-(8-氟-6-(5-氟-2-((5-(4-甲基六氫吡嗪-1-基)吡啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)乙醇; (±)-1-(8-氟-6-(5-氟-2-((5-(4-甲基六氫吡嗪-1-基)吡啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)乙醇三鹽酸鹽; 4-(6-((5-氟-4-(8-氟-4-(2-羥基丙-2-基)喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-1-甲酸第三丁基酯; 2-(8-氟-6-(5-氟-2-((5-(六氫吡嗪-1-基)吡啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)丙-2-醇; 2-(8-氟-6-(5-氟-2-((5-(六氫吡嗪-1-基)吡啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)丙-2-醇; (±)-4-(6-((5-氟-4-(8-氟-4-(1-羥基乙基)喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡嗪-1-甲酸第三丁基酯; (±)-1-(8-氟-6-(5-氟-2-((5-(六氫吡嗪-1-基)吡啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)乙醇; (±)-1-(8-氟-6-(5-氟-2-((5-(六氫吡嗪-1-基)吡啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)乙醇三鹽酸鹽; (±)-4-(6-((5-氟-4-(8-氟-4-(1-羥基乙基)喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡啶-1-甲酸第三丁基酯; (±)-1-(8-氟-6-(5-氟-2-((5-(六氫吡啶-4-基)吡啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)乙醇; (±)-1-(8-氟-6-(5-氟-2-((5-(六氫吡啶-4-基)吡啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)乙醇三鹽酸鹽; 4-(6-((5-氟-4-(8-氟-4-(2-羥基丙-2-基)喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡啶-1-甲酸第三丁基酯; 2-(8-氟-6-(5-氟-2-((5-(六氫吡啶-4-基)吡啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)丙-2-醇; 2-(8-氟-6-(5-氟-2-((5-(六氫吡啶-4-基)吡啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)丙-2-醇三鹽酸鹽; 4-(6-((5-氟-4-(8-氟-4-(2-羥基丙-2-基)-2-甲基喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡啶-1-甲酸第三丁基酯; 2-(8-氟-6-(5-氟-2-((5-(六氫吡啶-4-基)吡啶-2-基)胺基)嘧啶-4-基)-2-甲基喹啉-4-基)丙-2-醇; 2-(8-氟-6-(5-氟-2-((5-(六氫吡啶-4-基)吡啶-2-基)胺基)嘧啶-4-基)-2-甲基喹啉-4-基)丙-2-醇三鹽酸鹽; (±)-4-(6-((5-氟-4-(8-氟-4-(1-羥基乙基)-2-甲基喹啉-6-基)嘧啶-2-基)胺基)吡啶-3-基)六氫吡啶-1-甲酸第三丁基酯; (±)-1-(8-氟-6-(5-氟-2-((5-(六氫吡啶-4-基)吡啶-2-基)胺基)嘧啶-4-基)-2-甲基喹啉-4-基)乙醇; (±)-1-(8-氟-6-(5-氟-2-((5-(六氫吡啶-4-基)吡啶-2-基)胺基)嘧啶-4-基)-2-甲基喹啉-4-基)乙醇三鹽酸鹽; 4-(2-((5-氟-4-(8-氟-4-(2-羥基丙-2-基)喹啉-6-基)嘧啶-2-基)胺基)嘧啶-5-基)六氫吡啶-1-甲酸第三丁基酯; 2-(8-氟-6-(5-氟-2-((5-(六氫吡啶-4-基)嘧啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)丙-2-醇; 2-(8-氟-6-(5-氟-2-((5-(六氫吡啶-4-基)嘧啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)丙-2-醇三鹽酸鹽; (±)-4-(2-((5-氟-4-(8-氟-4-(1-羥基乙基)喹啉-6-基)嘧啶-2-基)胺基)嘧啶-5-基)六氫吡啶-1-甲酸第三丁基酯; (±)-1-(8-氟-6-(5-氟-2-((5-(六氫吡啶-4-基)嘧啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)乙醇; (±)-1-(8-氟-6-(5-氟-2-((5-(六氫吡啶-4-基)嘧啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)乙醇三鹽酸鹽; 2-(8-氟-6-(5-氟-2-((5-(1-甲基六氫吡啶-4-基)吡啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)丙-2-醇; 2-(8-氟-6-(5-氟-2-((5-(1-甲基六氫吡啶-4-基)吡啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)丙-2-醇三鹽酸鹽; (±)-1-(8-氟-6-(5-氟-2-((5-(1-甲基六氫吡啶-4-基)吡啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)乙醇; (±)-1-(8-氟-6-(5-氟-2-((5-(1-甲基六氫吡啶-4-基)吡啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)乙醇三鹽酸鹽; (±)-4-(6-((4-(4-(1-((第三丁氧基羰基)胺基)乙基)-8-氟喹啉-6-基)-5-氟嘧啶-2-基)胺基)吡啶-3-基)六氫吡啶-1-甲酸第三丁基酯; (±)-4-(4-(1-胺基乙基)-8-氟喹啉-6-基)-5-氟-N-(5-(六氫吡啶-4-基)吡啶-2-基)嘧啶-2-胺; (±)-4-(4-(1-胺基乙基)-8-氟喹啉-6-基)-5-氟-N-(5-(六氫吡啶-4-基)吡啶-2-基)嘧啶-2-胺三鹽酸鹽; 及其醫藥學上可接受之鹽。 A compound selected from the group consisting of: 4-(6-((5-fluoro-4-(quinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazine-1- tert-butyl formate; 5-fluoro-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)-4-(quinolin-6-yl)pyrimidin-2-amine; 5 -Fluoro-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)-4-(quinolin-6-yl)pyrimidin-2-amine hydrochloride; 4-(6-( (5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazine-1-carboxylic acid tert-butyl ester; 5-fluoro -4-(8-fluoroquinolin-6-yl)-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine; 5-fluoro-4-(8 -Fluoroquinolin-6-yl)-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine hydrochloride; N-(5-((4-ethyl N-(5-(( 4-Ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-amine hydrochloride; N -(5-((4-ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(quinolin-6-yl)pyrimidin-2-amine; N -(5-((4-Ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(quinolin-6-yl)pyrimidin-2-amine hydrochloride Salt; 4-(6-((5-fluoro-4-(8-fluoro-2-methyl-4-(prop-1-en-2-yl)quinolin-6-yl)pyrimidin-2-yl )amino)pyridin-3-yl)hexahydropyrazine-1-carboxylic acid tert-butyl ester; 5-fluoro-4-(8-fluoro-2-methyl-4-(prop-1-ene-2 -yl) quinoline-6-yl)-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine; 5-fluoro-4-(8-fluoro-2 -Methyl-4-(prop-1-en-2-yl)quinolin-6-yl)-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)pyrimidine-2- Amine hydrochloride; 5-fluoro-N-(5-(4-methylhexahydropyrazin-1-yl)pyridin-2-yl)-4-(quinolin-6-yl)pyrimidin-2-amine ; 5-fluoro-N-(5-(4-methylhexahydropyrazin-1-yl)pyridin-2-yl)-4-(quinolin-6-yl)pyrimidin-2-amine hydrochloride; 5-fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(4-methylhexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine; 5 -Fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(4-methylhexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine hydrochloride ; N-(5-(4-ethylhexahydropyrazin-1-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoroquinoline-6 -yl)pyrimidin-2-amine; N-(5-(4-ethylhexahydropyrazin-1-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoroquinoline-6- Base) pyrimidin-2-amine hydrochloride; N-(5-((4-ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(8- Fluoro-2-methylquinolin-6-yl)pyrimidin-2-amine; N-(5-((4-ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-5 -Fluoro-4-(8-fluoro-2-methylquinolin-6-yl)pyrimidin-2-amine hydrochloride; 4-(6-((5-fluoro-4-(8-fluoro-2- Methylquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazine-1-carboxylic acid tert-butyl ester; 5-fluoro-4-(8-fluoro-2 -Methylquinolin-6-yl)-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine; 5-fluoro-4-(8-fluoro-2 -Methylquinolin-6-yl)-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine hydrochloride; 4-(6-((5- Fluoro-4-(8-fluoro-4-isopropyl-2-methylquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazine-1-carboxylic acid Tributyl ester; 5-fluoro-4-(8-fluoro-4-isopropyl-2-methylquinolin-6-yl)-N-(5-(hexahydropyrazin-1-yl)pyridine -2-yl)pyrimidin-2-amine; 5-fluoro-4-(8-fluoro-4-isopropyl-2-methylquinolin-6-yl)-N-(5-(hexahydropyrazine -1-yl)pyridin-2-yl)pyrimidin-2-amine hydrochloride; N-(5-(4-ethylhexahydropyrazin-1-yl)pyridin-2-yl)-5-fluoro- 4-(quinolin-6-yl)pyrimidin-2-amine; N-(5-(4-ethylhexahydropyrazin-1-yl)pyridin-2-yl)-5-fluoro-4-(quinolin Lin-6-yl)pyrimidin-2-amine hydrochloride; 5-fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(4-isopropylhexahydropyrazine-1 -yl)pyridin-2-yl)pyrimidin-2-amine; 5-fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(4-isopropylhexahydropyrazine-1 -yl)pyridin-2-yl)pyrimidin-2-amine hydrochloride; 5-fluoro-N-(5-(4-isopropylhexahydropyrazin-1-yl)pyridin-2-yl)-4 -(quinolin-6-yl)pyrimidin-2-amine; 5-fluoro-N-(5-(4-isopropylhexahydropyrazin-1-yl)pyridin-2-yl)-4-(quinolin Lin-6-yl)pyrimidin-2-amine hydrochloride; 5-fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-((4-methylhexahydropyrazine-1 -yl)methyl)pyridin-2-yl)pyrimidin-2-amine; 5-fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-((4-methylhexahydropyridine oxazin-1-yl)methyl)pyridin-2-yl)pyrimidin-2-amine hydrochloride; 2-(6-(2-((5-((4-ethylhexahydropyridine oxazin-1-yl)methyl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-8-fluoro-2-methylquinolin-4-yl)propan-2-ol; 2-(6-(2-((5-((4-ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)- 8-fluoro-2-methylquinolin-4-yl)propan-2-ol hydrochloride; 4-(6-((5-fluoro-4-(8-fluoro-4-(2-hydroxypropan- 2-yl)-2-methylquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazine-1-carboxylic acid tert-butyl ester; 2-(8- Fluoro-6-(5-fluoro-2-((5-(hexahydropyrazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylquinoline-4- Base) propan-2-ol; 2-(8-fluoro-6-(5-fluoro-2-((5-(hexahydropyrazin-1-yl)pyridin-2-yl)amino)pyrimidine-4 -yl)-2-methylquinolin-4-yl)propan-2-ol hydrochloride; 2-(6-(2-((5-(4-ethylhexahydropyrazin-1-yl) Pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-8-fluoro-2-methylquinolin-4-yl)propan-2-ol; 2-(6-(2-( (5-(4-Ethylhexahydropyrazin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-8-fluoro-2-methylquinoline-4- base) propan-2-ol hydrochloride; 4-(4-(difluoromethyl)-8-fluoro-2-methylquinolin-6-yl)-N-(5-(4-ethylhexa Hydropyrazin-1-yl)pyridin-2-yl)-5-fluoropyrimidin-2-amine; 4-(4-(difluoromethyl)-8-fluoro-2-methylquinolin-6-yl )-N-(5-(4-ethylhexahydropyrazin-1-yl)pyridin-2-yl)-5-fluoropyrimidin-2-amine hydrochloride; 4-(6-((4-( 4-(Difluoromethyl)-8-fluoro-2-methylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazine-1- tert-butyl formate; 4-(4-(difluoromethyl)-8-fluoro-2-methylquinolin-6-yl)-5-fluoro-N-(5-(hexahydropyrazine- 1-yl)pyridin-2-yl)pyrimidin-2-amine; 4-(4-(difluoromethyl)-8-fluoro-2-methylquinolin-6-yl)-5-fluoro-N- (5-(Hexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine hydrochloride; 4-(4-(Difluoromethyl)-8-fluoro-2-methylquinoline -6-yl)-N-(5-((4-ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-5-fluoropyrimidin-2-amine; 4-(4- (Difluoromethyl)-8-fluoro-2-methylquinolin-6-yl)-N-(5-((4-ethylhexahydropyrazin-1-yl)methyl)pyridine-2- N-(5-((4-ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4 -(8- Fluoro-4-(2-fluoroprop-2-yl)-2-methylquinolin-6-yl)pyrimidin-2-amine; N-(5-((4-ethylhexahydropyrazine-1- Base) methyl) pyridin-2-yl)-5-fluoro-4-(8-fluoro-4-(2-fluoroprop-2-yl)-2-methylquinolin-6-yl)pyrimidine-2 -Amine hydrochloride; 4-(6-((5-fluoro-4-(8-fluoro-4-(2-fluoroprop-2-yl)-2-methylquinolin-6-yl)pyrimidine- 2-yl)amino)pyridin-3-yl)hexahydropyrazine-1-carboxylic acid tert-butyl ester; 5-fluoro-4-(8-fluoro-4-(2-fluoroprop-2-yl) -2-methylquinolin-6-yl)-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine; 5-fluoro-4-(8-fluoro -4-(2-fluoroprop-2-yl)-2-methylquinolin-6-yl)-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)pyrimidine-2 -Amine hydrochloride; 5-fluoro-N-(5-((4-methylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-4-(quinolin-6-yl) Pyrimidin-2-amine; 5-fluoro-N-(5-((4-methylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-4-(quinolin-6-yl) Pyrimidin-2-amine hydrochloride; N-(5-((4-ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(7-fluoroquine Lin-6-yl)pyrimidin-2-amine; N-(5-((4-ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(7 -Fluoroquinolin-6-yl)pyrimidin-2-amine hydrochloride; 4-(6-((5-fluoro-4-(7-fluoroquinolin-6-yl)pyrimidin-2-yl)amino )pyridin-3-yl)hexahydropyrazine-1-carboxylic acid tert-butyl ester; 5-fluoro-4-(7-fluoroquinolin-6-yl)-N-(5-(hexahydropyrazine- 1-yl)pyridin-2-yl)pyrimidin-2-amine; 5-fluoro-4-(7-fluoroquinolin-6-yl)-N-(5-(hexahydropyrazin-1-yl)pyridine -2-yl)pyrimidin-2-amine hydrochloride; N-(5-(4-ethylhexahydropyrazin-1-yl)pyridin-2-yl)-5-fluoro-4-(7-fluoro Quinolin-6-yl)pyrimidin-2-amine; N-(5-(4-ethylhexahydropyrazin-1-yl)pyridin-2-yl)-5-fluoro-4-(7-fluoroquine Pyrimin-6-yl)pyrimidin-2-amine hydrochloride; N-(5-(4-(dimethylamino)hexahydropyridin-1-yl)pyridin-2-yl)-5-fluoro-4 -(8-fluoroquinolin-6-yl)pyrimidin-2-amine; N-(5-(4-(dimethylamino)hexahydropyridin-1-yl)pyridin-2-yl)-5- Fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-amine hydrochloride; 4-(6-((5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidine- 2-yl)amino)pyridin-3-yl)hexahydropyrazin-2-one; 4-(6-((5-fluoro-4-(8-fluoroquinolin-6-yl) Pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazin-2-one hydrochloride; N-(5-(4-cyclopropylhexahydropyrazin-1-yl)pyridine-2 -yl)-5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-amine; N-(5-(4-cyclopropylhexahydropyrazin-1-yl)pyridine-2 -yl)-5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-amine hydrochloride; 1-(4-(6-((5-fluoro-4-(8-fluoro Quinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazin-1-yl)ethan-1-one; 1-(4-(6-((5-fluoro -4-(8-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazin-1-yl)ethan-1-one hydrochloride; 5-fluoro -4-(8-fluoroquinolin-6-yl)-N-(5-(4-(2,2,2-trifluoroethyl)hexahydropyrazin-1-yl)pyridin-2-yl) Pyrimidin-2-amine; 5-fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(4-(2,2,2-trifluoroethyl)hexahydropyrazine-1 -yl)pyridin-2-yl)pyrimidin-2-amine hydrochloride; 5-fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(4-(methylsulfonyl ) Hexahydropyrazin-1-yl) pyridin-2-yl) pyrimidin-2-amine; 5-fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(4-(methyl Cyclopropyl (4-(6-((5-fluoro-4-(8-fluoro Quinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazin-1-yl)methanone; cyclopropyl (4-(6-((5-fluoro-4 -(8-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazin-1-yl)methanone hydrochloride; 5-fluoro-4-(8 -Fluoroquinolin-6-yl)-N-(5-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyridine Azin-7(8H)-yl)pyridin-2-yl)pyrimidin-2-amine; 5-fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(3-(trifluoro Methyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)pyridin-2-yl)pyrimidin-2-amine salt acid salt; N-(5-((4-ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-4-isopropyl- 2-methylquinolin-6-yl)pyrimidin-2-amine; N-(5-((4-ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-5-fluoro -4-(8-fluoro-4-isopropyl-2-methylquinolin-6-yl)pyrimidin-2-amine hydrochloride; N-(5-(4-ethylhexahydropyrazine-1 -yl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-4-isopropyl-2-methylquinolin-6-yl)pyrimidin-2-amine; N-(5-( 4-Ethylhexahydropyrazin-1-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-4-isopropyl-2-methylquinolin-6-yl)pyrimidine- 2-amine hydrochloride; 1-(6-((5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)-4-methyl ylhexahydropyridin-4-ol; 1-(6-((5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)-4 -Methylhexahydropyridin-4-ol hydrochloride; (±)-4-(6-((4-(4-(1-((tertiary butoxycarbonyl)amino)ethyl)-8 -Fluoro-2-methylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazine-1-carboxylic acid tert-butyl ester; (±) -4-(4-(1-aminoethyl)-8-fluoro-2-methylquinolin-6-yl)-5-fluoro-N-(5-(hexahydropyrazin-1-yl) Pyridin-2-yl)pyrimidin-2-amine; (±)-4-(4-(1-aminoethyl)-8-fluoro-2-methylquinolin-6-yl)-5-fluoro- N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine hydrochloride; (±)-4-(6-((4-(4-(1-( (Third butoxycarbonyl)amino)ethyl)-8-fluoroquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazine-1 - tert-butyl formate; (±)-4-(4-(1-aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-(hexahydropyridine Azin-1-yl)pyridin-2-yl)pyrimidin-2-amine; (±)-4-(4-(1-aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoro -N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine dihydrochloride; (±)-4-(6-((5-fluoro-4-( ( ±)-1-(8-fluoro-6-(5-fluoro-2-((5-(hexahydropyrazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinoline -4-yl)ethanol; (±)-1-(8-fluoro-6-(5-fluoro-2-((5-(hexahydropyrazin-1-yl)pyridin-2-yl)amino) Pyrimidin-4-yl)quinolin-4-yl)ethanol trimesylate; (±)-(1-(8-fluoro-6-(5-fluoro-2-((5-(4-methylhexa Hydropyrazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl)ethyl)tert-butyl carbamate; (±)-4-(4 -(1-aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-(4-methylhexahydropyrazin-1-yl)pyridin-2-yl) Pyrimidin-2-amine; (±)-4-(4-(1-aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-(4 -Methylhexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine trihydrochloride; (±)-1-(6-(2-((5-(4-ethylhexa Hydropyrazin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-8-fluoroquinolin-4-yl)ethanol; (±)-1-(6-( 2-((5-(4-Ethylhexahydropyrazin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-8-fluoroquinolin-4-yl) Ethanol trihydrochloride; (±)-1-(8-fluoro-6-(5-fluoro-2-((5-(4-isopropylhexahydropyrazin-1-yl)pyridin-2-yl ) amino) pyrimidin-4-yl) quinoline-4-yl) ethanol; (±)-1-(8-fluoro-6-(5-fluoro-2-((5-(4-isopropylhexa Hydropyrazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl)ethanol trihydrochloride; N-(5-(4-ethylhexahydropyrazine -1-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-2-methylquinolin-6-yl)pyrimidin-2-amine; N-(5-(4-ethyl Hexahydropyrazin-1-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-2-methylquinolin-6-yl)pyrimidin-2-amine hydrochloride; (±) -4-(6-((5-fluoro-4-(8-fluoro-4-(1-hydroxyethyl)-2-methylquinolin-6-yl)pyrimidin-2-yl)amino)pyridine -3-yl) tert-butyl hexahydropyrazine-1-carboxylate; (±)-1-(8-fluoro-6-(5-fluoro-2-((5-(hexahydropyrazine-1 -yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylquinolin-4-yl)ethanol; (±)-1-(8-fluoro-6-(5-fluoro- 2-((5-(Hexahydropyrazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylquinolin-4-yl)ethan-1-ol hydrochloride Salt; (±)-1-(8-fluoro-6-(5-fluoro-2-((5-(4-methylhexahydropyrazin-1-yl)pyridin-2-yl)amino)pyrimidine -4-yl)quinolin-4-yl)ethanol; (±)-1-(8-fluoro-6-(5-fluoro-2-((5-(4-methylhexahydropyrazine-1- yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl)ethanol trihydrochloride; 4-(6-((5-fluoro-4-(8-fluoro-4- (2-hydroxypropan-2-yl)quinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazine-1-carboxylic acid tert-butyl ester; 2-(8 -Fluoro-6-(5-fluoro-2-((5-(hexahydropyrazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl)propane- 2-alcohol; 2-(8-fluoro-6-(5-fluoro-2-((5-(hexahydropyrazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinoline (±)-4-(6-((5-fluoro-4-(8-fluoro-4-(1-hydroxyethyl) Quinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazine-1-carboxylic acid tert-butyl ester; (±)-1-(8-fluoro-6-( 5-fluoro-2-((5-(hexahydropyrazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl)ethanol; (±)-1- (8-fluoro-6-(5-fluoro-2-((5-(hexahydropyrazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl) Ethanol trihydrochloride; (±)-4-(6-((5-fluoro-4-(8-fluoro-4-(1-hydroxyethyl)quinolin-6-yl)pyrimidin-2-yl) Amino)pyridin-3-yl)hexahydropyridine-1-carboxylic acid tert-butyl ester; (±)-1-(8-fluoro-6-(5-fluoro-2-((5-(hexahydropyridine -4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl)ethanol; (±)-1-(8-fluoro-6-(5-fluoro-2-( (5-(Hexahydropyridin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl)ethanol trihydrochloride; 4-(6-((5-fluoro -4-(8-fluoro-4-(2-hydroxyprop-2-yl)quinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyridine-1-carboxylic acid Tributyl ester; 2-(8-fluoro-6-(5-fluoro-2-((5-(hexahydropyridin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinoline phen-4-yl)propan-2-ol; 2-(8-fluoro-6-(5-fluoro-2-((5-(hexahydropyridin-4-yl)pyridin-2-yl)amino) Pyrimidin-4-yl)quinolin-4-yl)propan-2-ol trihydrochloride; 4-(6-((5-fluoro-4-(8-fluoro-4-(2-hydroxypropan-2 -yl)-2-methylquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyridine-1-carboxylic acid tert-butyl ester; 2-(8-fluoro- 6-(5-fluoro-2-((5-(hexahydropyridin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylquinolin-4-yl)propane -2-alcohol; 2-(8-fluoro-6-(5-fluoro-2-((5-(hexahydropyridin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)- 2-methylquinolin-4-yl)propan-2-ol trihydrochloride; (±)-4-(6-((5-fluoro-4-(8-fluoro-4-(1-hydroxyethyl Base)-2-methylquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyridine-1-carboxylic acid tert-butyl ester; (±)-1-(8 -Fluoro-6-(5-fluoro-2-((5-(hexahydropyridin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylquinoline-4- base) ethanol; (±)-1-(8-fluoro-6-(5-fluoro-2-((5-(hexahydropyridin-4-yl)pyridin-2-yl)amino)pyrimidine-4- Base)-2-methylquinolin-4-yl)ethanol trihydrochloride; 4-(2-((5 -Fluoro-4-(8-fluoro-4-(2-hydroxyprop-2-yl)quinolin-6-yl)pyrimidin-2-yl)amino)pyrimidin-5-yl)hexahydropyridine-1- tert-butyl formate; 2-(8-fluoro-6-(5-fluoro-2-((5-(hexahydropyridin-4-yl)pyrimidin-2-yl)amino)pyrimidin-4-yl )quinolin-4-yl)propan-2-ol; 2-(8-fluoro-6-(5-fluoro-2-((5-(hexahydropyridin-4-yl)pyrimidin-2-yl)amine Base) pyrimidin-4-yl) quinolin-4-yl) propan-2-ol trihydrochloride; (±)-4-(2-((5-fluoro-4-(8-fluoro-4-( 1-hydroxyethyl) quinoline-6-yl) pyrimidin-2-yl) amino) pyrimidin-5-yl) tert-butyl hexahydropyridine-1-carboxylate; (±)-1-(8- Fluoro-6-(5-fluoro-2-((5-(hexahydropyridin-4-yl)pyrimidin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl)ethanol; (± )-1-(8-fluoro-6-(5-fluoro-2-((5-(hexahydropyridin-4-yl)pyrimidin-2-yl)amino)pyrimidin-4-yl)quinoline-4 -yl)ethanol trihydrochloride; 2-(8-fluoro-6-(5-fluoro-2-((5-(1-methylhexahydropyridin-4-yl)pyridin-2-yl)amino ) pyrimidin-4-yl) quinoline-4-yl) propan-2-ol; 2-(8-fluoro-6-(5-fluoro-2-((5-(1-methylhexahydropyridine-4 -yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl)propan-2-ol trihydrochloride; (±)-1-(8-fluoro-6-(5 -Fluoro-2-((5-(1-methylhexahydropyridin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl)ethanol; (±)- 1-(8-fluoro-6-(5-fluoro-2-((5-(1-methylhexahydropyridin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinoline -4-yl)ethanol trihydrochloride; (±)-4-(6-((4-(4-(1-((tertiary butoxycarbonyl)amino)ethyl)-8-fluoroquine (Pyridine-6-yl)-5-fluoropyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyridine-1-carboxylic acid tert-butyl ester; (±)-4-(4-(1- Aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-(hexahydropyridin-4-yl)pyridin-2-yl)pyrimidin-2-amine; (±) -4-(4-(1-aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-(hexahydropyridin-4-yl)pyridin-2-yl) pyrimidin-2-amine trihydrochloride; and pharmaceutically acceptable salts thereof. 一種醫藥組合物,其包含如請求項1至19中任一項之化合物以及醫藥學上可接受之載劑。A pharmaceutical composition comprising the compound according to any one of claims 1 to 19 and a pharmaceutically acceptable carrier. 如請求項20之醫藥組合物,其進一步包含一或多種額外治療劑。The pharmaceutical composition according to claim 20, further comprising one or more additional therapeutic agents. 如請求項21之醫藥組合物,其中該一或多種額外治療劑為抗癌劑、抗發炎劑、免疫抑制劑、類固醇、非類固醇抗發炎劑、抗組織胺、止痛劑或上述中任一者之任一組合。The pharmaceutical composition of claim 21, wherein the one or more additional therapeutic agents are anticancer agents, anti-inflammatory agents, immunosuppressants, steroids, non-steroidal anti-inflammatory agents, antihistamines, analgesics or any of the above any combination. 一種抑制存在於細胞中的選自CDK1、CDK2、CDK4、CDK6及上述中任一者之任一組合之CDK酶的催化活性之方法,其包括使該細胞與有效量之如請求項1至19中任一項之化合物接觸。A method for inhibiting the catalytic activity of a CDK enzyme present in a cell selected from CDK1, CDK2, CDK4, CDK6, and any combination of any of the above, which includes making the cell an effective amount of the following claims 1 to 19 any one of the compounds in contact. 如請求項23之方法,其中該抑制發生在患有如下疾病或病症之個體中:癌症、骨病症、發炎性疾病、免疫疾病、神經系統疾病、代謝疾病、呼吸疾病、血栓形成或心臟疾病。The method of claim 23, wherein the inhibition occurs in an individual suffering from the following diseases or conditions: cancer, bone disorder, inflammatory disease, immune disease, nervous system disease, metabolic disease, respiratory disease, thrombosis or cardiac disease. 一種如請求項1至19中任一項之化合物之用途,其用於製造用以治療將受益於抑制CDK酶之催化活性之疾病、病症或疾患之藥劑,該CDK酶選自CDK1、CDK2、CDK4、CDK6及上述中任一者之任一組合。A use of a compound according to any one of claims 1 to 19 for the manufacture of a medicament for the treatment of a disease, disorder or condition which would benefit from inhibition of the catalytic activity of a CDK enzyme selected from the group consisting of CDK1, CDK2, CDK4, CDK6, and any combination of any of the above. 一種治療與CDK1、CDK2、CDK4、CDK6或上述中任一者之任一組合相關之疾病、病症或疾患之方法,其包括向有需要之個體投與有效量之如請求項1至19中任一項之化合物。A method of treating a disease, disorder or disorder associated with CDK1, CDK2, CDK4, CDK6, or any combination of any of the above, comprising administering to an individual in need thereof an effective amount of any of claims 1 to 19 One of the compounds. 如請求項26之方法,其進一步包括如下步驟:向該個體同時或依序投與至少一種其他抗癌劑、抗發炎劑、免疫抑制劑、類固醇、非類固醇抗發炎劑、抗組織胺、止痛劑或上述中任一者之任一組合。The method of claim 26, further comprising the step of simultaneously or sequentially administering to the individual at least one other anticancer agent, anti-inflammatory agent, immunosuppressant, steroid, non-steroidal anti-inflammatory agent, antihistamine, analgesic agent or any combination of any of the above. 如請求項26或27之方法,其中該疾病、病症或疾患為免疫系統相關之疾病、涉及發炎之疾病或病症、癌症或其他增殖性疾病、肝臟疾病或病症或腎臟疾病或病症。The method of claim 26 or 27, wherein the disease, disorder or disorder is an immune system related disease, a disease or disorder involving inflammation, cancer or other proliferative disease, liver disease or disorder or kidney disease or disorder. 如請求項26或27之方法,其中該疾病、病症或疾患選自發炎、腎小球性腎炎、眼色素層炎、肝臟疾病或病症、腎臟疾病或病症、慢性阻塞性肺病、類風濕性關節炎、發炎性腸病、血管炎、皮膚炎、骨關節炎、發炎性肌病、過敏性鼻炎、陰道炎、間質性膀胱炎、硬皮症、骨質疏鬆症、濕疹、同種異體或異種移植、移植物排斥、移植物抗宿主病、紅斑狼瘡、肺纖維化、皮肌炎、甲狀腺炎、重症肌無力、自體免疫溶血性貧血、囊性纖維化、慢性復發性肝炎、原發性膽汁性肝硬化、過敏性結膜炎、肝炎、異位性皮膚炎、氣喘、薛格連氏症候群(Sjogren's syndrome)、器官移植排斥、多發性硬化、格林-巴利症候群(Guillain-Barre)、自體免疫性眼色素層炎、自體免疫溶血性貧血、惡性貧血、自體免疫性血小板減少症、顳動脈炎、抗磷脂症候群、血管炎、韋格納氏肉芽腫病(Wegener's granulomatosis)、貝賽特氏病(Behcet's disease)、牛皮癬、疱疹樣皮膚炎、尋常天疱瘡、白斑病、克隆氏病(Crohn's disease)、結腸炎、潰瘍性結腸炎、原發性膽汁性肝硬化、自體免疫肝炎、1型糖尿病或免疫介導之糖尿病、格雷夫斯氏病(Grave's disease)、橋本氏甲狀腺炎(Hashimoto's thyroiditis)、自體免疫性卵巢炎及睪丸炎、腎上腺之自體免疫病症、全身性紅斑狼瘡、多發性肌炎、皮肌炎、關節黏連性脊椎炎、移植排斥、皮膚移植物排斥、關節炎、與骨吸收增加相關之骨病、迴腸炎、巴雷特氏症候群(Barrett's syndrome)、成人呼吸窘迫症候群、慢性阻塞性氣道疾病;角膜營養不良、沙眼、蟠尾絲蟲病、交感性眼炎、眼內炎、牙齦炎、齒根骨膜炎、結核病、麻風病、尿毒症併發症、腎病、硬化性皮膚炎、牛皮癬、神經系統之慢性脫髓鞘病、AIDS相關之神經退化、阿茲海默氏病(Alzheimer's disease)、感染性腦膜炎、腦脊髓炎、帕金森氏病(Parkinson's disease)、亨廷頓氏病(Huntington's disease)、肌萎縮性脊髓側索硬化症、病毒性或自體免疫性腦炎、自體免疫病症、免疫複合物血管炎、全身性紅斑狼瘡(systemic lupus and erythematodes、systemic lupus erythematosus,SLE)、心肌病變、缺血性心臟病、高膽固醇血症、動脈粥樣硬化、子癇前症、慢性肝衰竭、腦及脊髓創傷以及癌症。The method of claim 26 or 27, wherein the disease, condition or condition is selected from inflammation, glomerulonephritis, uveitis, liver disease or condition, kidney disease or condition, chronic obstructive pulmonary disease, rheumatoid arthritis Inflammatory bowel disease, vasculitis, dermatitis, osteoarthritis, inflammatory myopathy, allergic rhinitis, vaginitis, interstitial cystitis, scleroderma, osteoporosis, eczema, allogeneic or xenogeneic Transplantation, graft rejection, graft versus host disease, lupus erythematosus, pulmonary fibrosis, dermatomyositis, thyroiditis, myasthenia gravis, autoimmune hemolytic anemia, cystic fibrosis, chronic relapsing hepatitis, primary Biliary cirrhosis, allergic conjunctivitis, hepatitis, atopic dermatitis, asthma, Sjogren's syndrome, organ transplant rejection, multiple sclerosis, Guillain-Barre syndrome, autoimmunity Uveitis, autoimmune hemolytic anemia, pernicious anemia, autoimmune thrombocytopenia, temporal arteritis, antiphospholipid syndrome, vasculitis, Wegener's granulomatosis, Behcet's disease (Behcet's disease), psoriasis, dermatitis herpetiformis, pemphigus vulgaris, leukoplakia, Crohn's disease, colitis, ulcerative colitis, primary biliary cirrhosis, autoimmune hepatitis, type 1 Diabetes or immune-mediated diabetes, Grave's disease, Hashimoto's thyroiditis, autoimmune oophoritis and orchitis, adrenal autoimmune disorders, systemic lupus erythematosus, multiple Myositis, dermatomyositis, adhesive spondylitis, graft rejection, skin graft rejection, arthritis, osteopathy associated with increased bone resorption, ileitis, Barrett's syndrome, adult respiratory Distress syndrome, chronic obstructive airway disease; corneal dystrophy, trachoma, onchocerciasis, sympathetic ophthalmia, endophthalmitis, gingivitis, root periostitis, tuberculosis, leprosy, uremia complications, nephropathy, Sclerosing dermatitis, psoriasis, chronic demyelinating diseases of the nervous system, AIDS-related neurodegeneration, Alzheimer's disease, infectious meningitis, encephalomyelitis, Parkinson's disease , Huntington's disease, amyotrophic lateral sclerosis, viral or autoimmune encephalitis, autoimmune disorders, immune complex vasculitis, systemic lupus and erythematodes, systemic lupus erythematosus lupus erythematosus, SLE), cardiomyopathy, ischemic heart disease, high cholesterol Alcoholemia, atherosclerosis, preeclampsia, chronic liver failure, brain and spinal cord trauma, and cancer. 如請求項26或27之方法,其中該疾病、病症或疾患選自淋巴譜系之造血腫瘤:白血病、急性淋巴球性白血病、急性淋巴母細胞性白血病、B細胞淋巴瘤、T細胞淋巴瘤、霍奇金氏淋巴瘤(Hodgkin's lymphoma)、非霍奇金氏淋巴瘤、毛細胞淋巴瘤及柏基特氏淋巴瘤(Burkett's lymphoma);骨髓譜系之造血腫瘤:急性骨髓性白血病、慢性骨髓性白血病、骨髓發育不良症候群、前骨髓細胞性白血病、膀胱癌、乳癌、結腸癌、腎癌、肝癌、肺癌、小細胞肺癌、食管癌、膽囊癌、卵巢癌、胰臟癌、胃癌、子宮頸癌、甲狀腺癌、前列腺癌、皮膚癌、鱗狀細胞癌;間質起源之腫瘤:纖維肉瘤、橫紋肌肉瘤;中樞及周圍神經系統之腫瘤:星細胞瘤、神經母細胞瘤、神經膠質瘤、神經鞘瘤;黑色素瘤、精原細胞瘤、畸形癌、骨肉瘤、著色性乾皮病、角化棘皮瘤、甲狀腺濾泡癌、腦癌及卡波西氏肉瘤(Kaposi's sarcoma)。The method of claim 26 or 27, wherein the disease, disease or disease is selected from hematopoietic tumors of the lymphoid lineage: leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, cholangiocarcinoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, pilocytic lymphoma and Burkett's lymphoma; hematopoietic tumors of the myeloid lineage: acute myelogenous leukemia, chronic myelogenous leukemia, Myelodysplastic syndrome, promyelocytic leukemia, bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, esophagus cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer Carcinoma, prostate cancer, skin cancer, squamous cell carcinoma; tumors of mesenchymal origin: fibrosarcoma, rhabdomyosarcoma; tumors of the central and peripheral nervous system: astrocytoma, neuroblastoma, glioma, schwannoma; Melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosa, keratoacanthoma, follicular carcinoma of the thyroid, brain cancer, and Kaposi's sarcoma. 如請求項26或27之方法,其中該疾病、病症或疾患選自乳癌、卵巢癌、肝癌、肺癌、小細胞肺癌、食管癌、膽囊癌、胰臟癌、腦癌或胃癌。The method according to claim 26 or 27, wherein the disease, disease or condition is selected from breast cancer, ovarian cancer, liver cancer, lung cancer, small cell lung cancer, esophageal cancer, gallbladder cancer, pancreatic cancer, brain cancer or gastric cancer. 如請求項26或27之方法,其中該疾病、病症或疾患為乳癌或卵巢癌。The method according to claim 26 or 27, wherein the disease, disorder or condition is breast cancer or ovarian cancer.
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