TW202421628A - Methods for treating cancer - Google Patents
Methods for treating cancer Download PDFInfo
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- TW202421628A TW202421628A TW112140291A TW112140291A TW202421628A TW 202421628 A TW202421628 A TW 202421628A TW 112140291 A TW112140291 A TW 112140291A TW 112140291 A TW112140291 A TW 112140291A TW 202421628 A TW202421628 A TW 202421628A
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Abstract
Description
本揭露提供了恢復p53功能之式(I)化合物及其醫藥學上可接受之鹽。此等化合物可用於例如治療p53功能降低造成個體(例如,人類)之疾病(例如,癌症)的病變及/或症狀及/或進展的疾病。The present disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof that restore p53 function. These compounds can be used, for example, to treat diseases (e.g., cancer) in which reduced p53 function causes pathological changes and/or symptoms and/or progression in individuals (e.g., humans).
由TP53基因編碼之腫瘤抑制因子p53為調控DNA修復、細胞週期停滯、衰老及細胞凋亡所需要之基因表現的轉錄因子,並且p53在介導此等過程中之各者中發揮關鍵作用(Alvarado-Ortiz等人, Frontiers in Cell and Developmental Biology (2021) 8, Article 607670;Vousden等人, Cell (2009) 137, 413-431;Bieging等人, Nat. Rev. Cancer (2014) 14, 359-370)。TP53在超過50%之所有人類癌症中改變,使其成為致癌基因及腫瘤抑制基因中之最常突變的基因(Hainaut等人, Adv Cancer Res (2000) 77, 81-137;Joerger等人, Cold Spring Harb. Perspect. Biol. (2010) 2(6), Article a000919)。TP53之突變導致其正常功能喪失,使得細胞不能對各種細胞應激諸如DNA損傷或致癌基因活化作出反應,使得易於形成腫瘤(Joerger等人, Oncogene (2007) 26, 2226-2242)。大部分TP53突變為位於其DNA結合域內或附近的誤義突變(Baugh等人, Cell Death & Differentiation (2018) 25, 154-160)。導致p53功能喪失之突變可分類為兩個主要類型:(1) DNA接觸突變,其中突變蛋白失去其結合DNA之能力;(2)結構突變,其使得p53蛋白不穩定(Brosh等人, Nat. Rev. Cancer (2009) 9, 701-713;Hollstein等人, Science (1991) 253, 49-53)。兩種類別之突變防止p53驅動之轉錄活化,由此消除p53介導之腫瘤抑制(Zhu等人, Frontiers in Oncology (2020) 10, Article 595187)。The tumor suppressor p53, encoded by the TP53 gene, is a transcription factor that regulates the expression of genes required for DNA repair, cell cycle arrest, senescence, and cell apoptosis, and p53 plays a key role in mediating each of these processes (Alvarado-Ortiz et al., Frontiers in Cell and Developmental Biology (2021) 8, Article 607670; Vousden et al., Cell (2009) 137, 413-431; Bieging et al., Nat. Rev. Cancer (2014) 14, 359-370). TP53 is altered in more than 50% of all human cancers, making it the most commonly mutated gene among oncogenes and tumor suppressor genes (Hainaut et al., Adv Cancer Res (2000) 77, 81-137; Joerger et al., Cold Spring Harb. Perspect. Biol. (2010) 2(6), Article a000919). Mutations in TP53 result in the loss of its normal function, rendering cells unable to respond to various cellular stresses such as DNA damage or oncogene activation, making them susceptible to tumor formation (Joerger et al., Oncogene (2007) 26, 2226-2242). Most TP53 mutations are missense mutations located within or near its DNA binding domain (Baugh et al., Cell Death & Differentiation (2018) 25, 154-160). Mutations that cause p53 loss of function can be classified into two main types: (1) DNA-binding mutations, in which the mutant protein loses its ability to bind DNA; (2) structural mutations, which destabilize the p53 protein (Brosh et al., Nat. Rev. Cancer (2009) 9, 701-713; Hollstein et al., Science (1991) 253, 49-53). Both types of mutations prevent p53-driven transcriptional activation, thereby eliminating p53-mediated tumor suppression (Zhu et al., Frontiers in Oncology (2020) 10, Article 595187).
突變p53蛋白之再活化作為治療TP53突變癌症之有吸引力的方法出現(Degtjarik等人, Nature Communications (2021) 12, Article 7057;Bykov等人, FEBS Letters (2014) 588, 2622-2627)。理論上,突變p53再活化會恢復其腫瘤抑制功能,刺激p53依賴性停滯或細胞凋亡並且導致腫瘤細胞之有效消除(Selivanova等人, Oncogene (2007) 26, 2243-2254)。p53 Y220C突變發生於約1%之人類癌症中;每年在世界範圍內發生約100,000個新癌症病例(Joerger等人, Annu. Rev. Biochem. (2016) 85, 375-404;Bouaoun等人, Hum. Mutat. (2016) 37, 865-876)。突變蛋白之穩定化可恢復及/或保持蛋白質之功能性構形(Baud等人, Eur J Med Chem. (2018) 25, 101-114;Rauf等人, Protein J (2013) 32, 68-74)。在諸如Y200C突變之一些情況下,存在遠離p53與DNA之間的結合界面的小分子結合袋,使得在此袋處之小分子接合並不破壞DNA結合(Bauer等人, Future Med. Chem. (2019) 11, 2491-2504)。 Reactivation of mutant p53 protein has emerged as an attractive approach to treat TP53 mutant cancers (Degtjarik et al., Nature Communications (2021) 12, Article 7057; Bykov et al., FEBS Letters (2014) 588, 2622-2627). In theory, mutant p53 reactivation would restore its tumor suppressor function, stimulate p53-dependent arrest or apoptosis and lead to effective elimination of tumor cells (Selivanova et al., Oncogene (2007) 26, 2243-2254). The p53 Y220C mutation occurs in approximately 1% of human cancers; approximately 100,000 new cancer cases occur worldwide each year (Joerger et al., Annu. Rev. Biochem. (2016) 85, 375-404; Bouaoun et al., Hum. Mutat. (2016) 37, 865-876). Stabilization of the mutant protein can restore and/or maintain the functional conformation of the protein (Baud et al., Eur J Med Chem. (2018) 25, 101-114; Rauf et al., Protein J (2013) 32, 68-74). In some cases, such as the Y200C mutation, there is a small molecule binding pocket distal to the binding interface between p53 and DNA, such that small molecule binding at this pocket does not disrupt DNA binding (Bauer et al., Future Med. Chem. (2019) 11, 2491-2504).
一些實施例提供了式(I)化合物: (I) 或其醫藥學上可接受之鹽,其中: X 1為CR 1或N; R 1為氫、鹵素、氰基、–OR 4、-NR 4R 5、-C(=O)R 4、-OC(=O)R 4、–C(=O)OR 4、–C(=O)NR 4R 5、–SR 4、–S(=O)R 4、–S(O 2)R 4、-NR 4C(=O)R 5、–R 4C(=O)R 5、視情況經取代之C1-C6烷基、視情況經取代之C2-C6烯基、視情況經取代之C2-C6炔基、視情況經取代之C3-C10環烷基、視情況經取代之苯基、視情況經取代之4-12員雜環基或視情況經取代之5-10員雜芳基; X 2、X 3、X 4及X 5中之各者為CH、N、CR 2或CR 3,其中X 2、X 3、X 4及X 5中之兩者或更多者獨立地為CH、CR 2或CR 3; Y 1、Y 2及Y 3中之各者為C或N,其中Y 1、Y 2及Y 3中之一者為N; R A為氫、–OR 6、-NR 6R 7、-C(=O)R 6、-R 6C(=O)R 7、-OC(=O)R 6、-OC(=O)NR 6、–C(=O)OR 6、–NR 6C(=O)OR 7、–C(=O)NR 6R 7、–SR 6、–S(=O)R 6、–S(O 2)R 6、–S(O 2)NR 6、–NR 6S(O 2)R 7、-NR 6C(=O)R 7、-NR 6C(=O)NR 7、-SiR 6R 7R 8、視情況經取代之C1-C6烷基、視情況經取代之C2-C6烯基、視情況經取代之C2-C6炔基、視情況經取代之C3-C10環烷基、視情況經取代之苯基、視情況經取代之4-12員雜環基或視情況經取代之5-10員雜芳基; R B為鹵素、氰基、羥基、–NR 8R 9、-OR 8、–C(=O)NR 8R 9、–C(=O)R 8、-C(=O)OR 8、-NR 8C(=O)OR 9、–OC(=O)R 8、–OC(=O)NR 8、–C(=O)NR 8R 9、–NR 8C(=O)R 9、–NR 8C(=O)NR 9、–SR 8、–S(=O)R 8、–S(O 2)R 8、–S(O 2)NR 8、–NR 8S(O 2)R 9、-R 8C(=O)R 9、-NR 8C(=O)R 9、-NR 8C(=O)NR 9、視情況經取代之C1-C6烷基、C1-C6鹵烷基、視情況經取代之C2-C6烯基、視情況經取代之C2-C6炔基、視情況經取代之C3-C10環烷基、視情況經取代之苯基、視情況經取代之3-12員雜環基或視情況經取代之5-10員雜芳基; 各R 2為 ; Z 1為一鍵、-C=O-、-S(O 2)-視情況經取代之C1-C6伸烷基、視情況經取代之C2-C6伸烯基、視情況經取代之C2-C6伸炔基或視情況經取代之C3-C4伸環烷基; Z 2為CR 2C、N、O或一鍵;其中當Z 2為O時,R 2B不存在,並且當Z 1為一鍵並且Z 2為一鍵時,R 2B不存在並且R 2A經由Z 1直接連接至式(I); R 2A及R 2B獨立地為氫、–C(=O)R 10、–C(=O)OR 10、–C(=O)NR 10R 11、–S(=O)R 10、–S(O 2)R 10、視情況經取代之C1-C6烷基、視情況經取代之C2-C6烯基、視情況經取代之C2-C6炔基、視情況經取代之C3-C10環烷基、視情況經取代之苯基、視情況經取代之4-12員雜環基、視情況經取代之5-10員雜芳基;或 R 2A及R 2B與其一起附接之原子一起形成視情況經取代之4-10員環烷基、視情況經取代之苯基、視情況經取代之5-10員雜芳基或視情況經取代之4-12員雜環基;或Z 2為O並且R 2B不存在; R 2C為氫、鹵素或C1-C6烷基; 各R 3獨立地為鹵素、氰基、–NR 12R 13、-OR 12、–C(=O)NR 12R 13、–C(=O)R 12、-C(=O)OR 12、–OC(=O)R 12、–NR 12(C=O)NR 13R 14、–SR 12、–S(=O)R 12、–S(O 2)R 12、–S(O 2)NR 12R 13、–NR 12S(O 2)NR 13R 14、-R 12C(=O)R 13、-NR 12C(=O)R 13、視情況經取代之C1-C6烷基、視情況經取代之C2-C6烯基、視情況經取代之C2-C6炔基、視情況經取代之C3-C6環烷基、視情況經取代之苯基、視情況經取代之4-6員雜環基或視情況經取代之5-6員雜芳基; L為視情況經取代之C2-C6伸炔基; m為0、1或2;且 各R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13及R 14獨立地為氫、視情況經取代之C1-C6烷基、視情況經取代之C2-C6烯基、視情況經取代之C2-C6炔基、視情況經取代之C3-C10環烷基、視情況經取代之苯基、視情況經取代之4-12員雜環基或視情況經取代之5-10員雜芳基。 Some embodiments provide compounds of formula (I): (I) or a pharmaceutically acceptable salt thereof, wherein: X 1 is CR 1 or N; R 1 is hydrogen, halogen, cyano, –OR 4 , –NR 4 R 5 , –C(=O)R 4 , –OC(=O)R 4 , –C(=O)OR 4 , –C(=O)NR 4 R 5 , –SR 4 , –S(=O)R 4 , –S(O 2 )R 4 , –NR 4 C(=O)R 5 , –R 4 C(=O)R 5 , an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C10 cycloalkyl, an optionally substituted phenyl, an optionally substituted 4-12 membered heterocyclic group or an optionally substituted 5-10 membered heteroaryl; each of X2 , X3 , X4 and X5 is CH, N, CR2 or CR3 , wherein two or more of X2 , X3 , X4 and X5 are independently CH, CR2 or CR3 ; each of Y1 , Y2 and Y3 is C or N, wherein one of Y1 , Y2 and Y3 is N; RA is hydrogen, –OR6 、-NR 6 R 7 、-C(=O)R 6 、-R 6 C(=O)R 7 、-OC(=O)R 6 、-OC(=O)NR 6 、–C(=O)OR 6 、–NR 6 C(=O)OR 7 、–C(=O)NR 6 R 7 、–SR 6 、–S(=O)R 6 、–S(O 2 )R 6 、–S(O 2 )NR 6 、–NR 6 S(O 2 )R 7 、-NR 6 C(=O)R 7 、-NR 6 C(=O)NR 7 、-SiR 6 R 7 R 8 , an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C10 cycloalkyl, an optionally substituted phenyl, an optionally substituted 4-12 membered heterocycloyl, or an optionally substituted 5-10 membered heteroaryl; RB is halogen, cyano, hydroxyl, –NR8R9 , –OR8 , –C (=O) NR8R9 , –C(=O) R8 , –C(=O) OR8 , –NR8C(=O) OR9 , –OC(=O) R8 , –OC (=O) NR8 , –C(=O) NR8R9, –NR8C (=O)R 9 , –NR 8 C(═O)NR 9 , –SR 8 , –S(═O)R 8 , –S(O 2 )R 8 , –S(O 2 )NR 8 , –NR 8 S(O 2 )R 9 , –R 8 C(═O)R 9 , –NR 8 C(═O)R 9 , –NR 8 C(═O)NR 9 , optionally substituted C1-C6 alkyl, C1-C6 halogenalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 3-12 membered heterocyclo or optionally substituted 5-10 membered heteroaryl; Each R2 is ; Z 1 is a bond, -C=O-, -S(O 2 )-, optionally substituted C1-C6 alkylene, optionally substituted C2-C6 alkenylene, optionally substituted C2-C6 alkynylene or optionally substituted C3-C4 cycloalkylene; Z 2 is CR 2C , N, O or a bond; wherein when Z 2 is O, R 2B is absent, and when Z 1 is a bond and Z 2 is a bond, R 2B is absent and R 2A is directly connected to formula (I) via Z 1 ; R 2A and R 2B are independently hydrogen, -C(=O)R 10 , -C(=O)OR 10 , -C(=O)NR 10 R 11 , -S(=O)R 10 , -S(O 2 )R 10 , optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclic group, optionally substituted 5-10 membered heteroaryl; or R 2A and R 2B together with the atoms to which they are attached form an optionally substituted 4-10 membered cycloalkyl, an optionally substituted phenyl, an optionally substituted 5-10 membered heteroaryl or an optionally substituted 4-12 membered heterocyclic group; or Z 2 is O and R 2B is absent; R R 2C is hydrogen, halogen or C1-C6 alkyl; each R 3 is independently halogen, cyano, –NR 12 R 13 , –OR 12 , –C(=O)NR 12 R 13 , –C(=O)R 12 , –C(=O)OR 12 , –OC(=O)R 12 , –NR 12 (C=O)NR 13 R 14 , –SR 12 , –S(=O)R 12 , –S(O 2 )R 12 , –S(O 2 )NR 12 R 13 , –NR 12 S(O 2 )NR 13 R 14 , -R 12 C(=O)R 13 , -NR 12 C(=O)R 13 , an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C6 cycloalkyl, an optionally substituted phenyl, an optionally substituted 4-6 membered heterocycloyl or an optionally substituted 5-6 membered heteroaryl; L is an optionally substituted C2-C6 alkynylene; m is 0, 1 or 2; and each of R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 is independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclic group or optionally substituted 5-10 membered heteroaryl.
本文亦提供了醫藥組合物,其包含式(I)化合物或其醫藥學上可接受之鹽,及一或多種醫藥學上可接受之賦形劑。Also provided herein are pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
本文提供了治療有需要之個體之癌症的方法,該方法包含向個體投與治療有效量的如本文所提供之式(I)化合物或其醫藥學上可接受之鹽或醫藥組合物。Provided herein are methods for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as provided herein.
本文亦提供了治療有需要之個體之癌症的方法,該方法包含(a)確定癌症與 TP53基因、p53蛋白或其中任一者之活性之失調相關;及(b)向個體投與治療有效量的如本文所提供之式(I)化合物或其醫藥學上可接受之鹽或醫藥組合物。 Also provided herein is a method for treating cancer in a subject in need thereof, the method comprising (a) determining that the cancer is associated with dysregulation of the TP53 gene, p53 protein, or the activity of either thereof; and (b) administering to the subject a therapeutically effective amount of a compound of formula (I) as provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
本文提供了治療個體之p53相關癌症之方法,該方法包含向經鑑別或診斷患有p53相關癌症之個體投與治療有效量的如本文所提供之式(I)化合物或其醫藥學上可接受之鹽或醫藥組合物。Provided herein are methods for treating a p53-related cancer in an individual, the method comprising administering to the individual identified or diagnosed as having a p53-related cancer a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as provided herein.
本揭露亦提供了治療個體之p53相關癌症之方法,該方法包含:確定個體之癌症為p53相關癌症;及向個體投與治療有效量的如本文所提供之式(I)化合物或其醫藥學上可接受之鹽或醫藥組合物。The present disclosure also provides a method for treating a p53-related cancer in an individual, the method comprising: determining that the individual's cancer is a p53-related cancer; and administering to the individual a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition provided herein.
本文進一步提供了治療個體之p53相關癌症之方法,該方法包含向經鑑別或診斷患有p53相關癌症之個體投與治療有效量的如本文所提供之式(I)化合物或其醫藥學上可接受之鹽或醫藥組合物。Further provided herein is a method for treating a p53-related cancer in an individual, the method comprising administering to the individual identified or diagnosed as having a p53-related cancer a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as provided herein.
本揭露亦提供了治療個體之p53相關癌症之方法,該方法包含:確定個體之癌症為p53相關癌症;及向個體投與治療有效量的如本文所提供之式(I)化合物或其醫藥學上可接受之鹽或醫藥組合物。The present disclosure also provides a method for treating a p53-related cancer in an individual, the method comprising: determining that the individual's cancer is a p53-related cancer; and administering to the individual a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition provided herein.
本文提供了治療個體之方法,該方法包含向具有指示個體具有 TP53基因、p53蛋白或其中任一者之活性之失調的臨床記錄的個體投與治療有效量的如本文所提供之式(I)化合物或其醫藥學上可接受之鹽或醫藥組合物。 Provided herein are methods of treating an individual comprising administering to an individual having a clinical record indicating that the individual has a disorder of the activity of the TP53 gene, p53 protein, or either thereof, a therapeutically effective amount of a compound of formula (I) as provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
本揭露亦提供了用於恢復哺乳動物細胞之p53功能的方法,該方法包含使哺乳動物細胞與有效量之式(I)化合物或其醫藥學上可接受之鹽接觸。The present disclosure also provides a method for restoring p53 function in mammalian cells, the method comprising contacting the mammalian cells with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
其他實施例包括實施方式及/或申請專利範圍中所描述之彼等。 額外定義 Other embodiments include those described in the embodiments and/or claims. Additional Definitions
為了促進對本文所闡述之本揭露的理解,下文定義了許多額外術語。大體上,本文所用之命名法及本文所描述之有機化學、醫藥化學及藥理學中之實驗室程序為此項技術中熟知的且通常使用的。除非另有定義,否則本文所用之所有技術及科學術語大體上具有與一般熟習本揭露所屬技術者通常所理解的相同含義。在整個說明書及附錄中提及之專利、申請案、公佈的申請案及其他公開案中之各者以全文引用之方式併入本文。To facilitate understanding of the disclosure described herein, a number of additional terms are defined below. In general, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are well known and commonly used in the art. Unless otherwise defined, all technical and scientific terms used herein generally have the same meanings as those generally understood by those skilled in the art to which the disclosure belongs. Each of the patents, applications, published applications, and other publications mentioned throughout the specification and appendix is incorporated herein by reference in its entirety.
術語「約」在提及數字或數值範圍時意謂所提及數字或數值範圍為例如在實驗可變性及/或統計實驗誤差內之近似值,且因此數字或數值範圍可在指定數字或數值範圍之多達±10%內變化。The term "about" when referring to a number or a numerical range means that the referenced number or numerical range is an approximation, for example, within experimental variability and/or statistical experimental error, and thus the number or numerical range may vary by as much as ±10% of the specified number or numerical range.
如本文所用,相對於調配物、組合物或成分之術語「可接受」意謂對於所治療個體之一般健康狀況無持續有害的效應。As used herein, the term "acceptable" with respect to a formulation, composition or ingredient means having no persistent detrimental effect on the general health of the treated individual.
片語「治療有效量」意謂在投與需要此治療之個體時,足以(i)治療p53蛋白相關癌症,(ii) 減弱、改善或消除特定癌症之一或多種症狀或(iii)延遲本文所描述之特定癌症之一或多種症狀之發作的化合物之量。The phrase "therapeutically effective amount" means an amount of a compound that, when administered to a subject in need of such treatment, is sufficient to (i) treat p53 protein-related cancer, (ii) attenuate, ameliorate or eliminate one or more symptoms of a specific cancer, or (iii) delay the onset of one or more symptoms of a specific cancer described herein.
術語「醫藥學上可接受之賦形劑」意謂醫藥學上可接受之材料、組合物或媒劑,諸如液體或固體填充劑、稀釋劑、載劑、溶劑或囊封材料。在一個實施例中,各組分在與醫藥調配物之其他成分相容,並且適合於與人類及動物之組織或器官接觸而無過量毒性、刺激、過敏性反應、免疫原性或其他問題或併發症,與合理效益/風險比相稱的含義上為「醫藥學上可接受的」。 參見例如Remington: The Science and Practice of Pharmacy, 第21版;Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 第6版;Rowe 等人編;The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 第3版;Ash及Ash編; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 第2版; Gibson編; CRC Press LLC: Boca Raton, FL, 2009。 The term "pharmaceutically acceptable formulation" means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, carrier, solvent or encapsulating material. In one embodiment, each component is "pharmaceutically acceptable" in the sense that it is compatible with the other ingredients of the pharmaceutical formulation and is suitable for contact with human and animal tissues or organs without excessive toxicity, irritation, allergic reaction, immunogenicity or other problems or complications, commensurate with a reasonable benefit/risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed .; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed .; Rowe et al., eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed .; Ash and Ash, eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed .; Gibson, ed.; CRC Press LLC: Boca Raton, FL, 2009.
術語「醫藥學上可接受之鹽」係指並不導致投與其之生物體之顯著刺激並且不消除化合物之生物活性及特性的化合物之調配物。在某些情況下,醫藥學上可接受之鹽係藉由使本文所描述之化合物與酸諸如鹽酸、氫溴酸、硫酸、硝酸、磷酸、甲磺酸、乙磺酸、對甲苯磺酸、水楊酸及其類似酸反應來獲得。在一些情況下,醫藥學上可接受之鹽係藉由使本文所描述的具有酸性基團之化合物與鹼反應以便形成鹽諸如銨鹽,鹼金屬鹽諸如鈉或鉀鹽,鹼土金屬鹽諸如鈣或鎂鹽,有機鹼諸如二環己基胺、 N-甲基-D-葡糖胺、參(羥甲基)甲胺之鹽,及具有胺基酸諸如精胺酸、離胺酸及其類似酸之鹽,或藉由先前確定之其他方法來獲得。藥理學上可接受之鹽並不特別受到限制,只要其可用於藥劑中。本文所描述之化合物與鹼形成之鹽之實例包括以下:其與無機鹼諸如鈉、鉀、鎂、鈣及鋁之鹽;其與有機鹼諸如甲胺、乙胺及乙醇胺之鹽;其與鹼性胺基酸諸如離胺酸及鳥胺酸之鹽;及銨鹽。鹽可為酸加成鹽,其藉由具有以下之酸加成鹽來具體例示:礦物酸諸如鹽酸、氫溴酸、氫碘酸、硫酸、硝酸及磷酸;有機酸諸如甲酸、乙酸、丙酸、草酸、丙二酸、丁二酸、反丁烯二酸、順丁烯二酸、乳酸、蘋果酸、酒石酸、檸檬酸、甲磺酸及乙磺酸;酸性胺基酸諸如天冬胺酸及麩胺酸。 The term "pharmaceutically acceptable salt" refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In certain instances, pharmaceutically acceptable salts are obtained by reacting the compounds described herein with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. In some cases, the pharmaceutically acceptable salt is obtained by reacting the compound having an acidic group described herein with a base to form a salt such as an ammonium salt, an alkali metal salt such as a sodium or potassium salt, an alkali earth metal salt such as a calcium or magnesium salt, an organic base such as a salt of dicyclohexylamine, N- methyl-D-glucosamine, tris(hydroxymethyl)methylamine, and a salt having an amino acid such as arginine, lysine and the like, or by other methods previously determined. The pharmacologically acceptable salt is not particularly limited as long as it can be used in a medicament. Examples of salts of the compounds described herein with bases include the following: salts thereof with inorganic bases such as sodium, potassium, magnesium, calcium and aluminum; salts thereof with organic bases such as methylamine, ethylamine and ethanolamine; salts thereof with basic amino acids such as lysine and ornithine; and ammonium salts. The salt may be an acid addition salt, which is specifically exemplified by having the following acid addition salts: mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid and ethanesulfonic acid; acidic amino acids such as aspartic acid and glutamine.
如本文所用,「個體」係指任何動物,包括哺乳動物諸如靈長類動物(例如,人類)、小鼠、大鼠、其他齧齒動物、兔、犬、貓、豬、牛、綿羊、馬、靈長類動物及人類。在一些實施例中,個體為人類。在一些實施例中,個體經歷及/或展現出待治療之癌症之至少一個症狀。As used herein, "subject" refers to any animal, including mammals such as primates (e.g., humans), mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, primates, and humans. In some embodiments, the subject is a human. In some embodiments, the subject experiences and/or exhibits at least one symptom of the cancer to be treated.
如本文所用,術語「治療(treat/treatment)」係指治療性或姑息性措施。不論可偵測或不可偵測,有益或所需臨床結果包括但不限於完全或部分地減輕與癌症相關之症狀、減小癌症程度、穩定(亦即,不惡化)疾病狀態、延遲或減緩癌症進展、改善或緩解疾病狀態(例如,癌症之一或多種症狀)及緩解(不論部分或全部)。「治療」亦可意謂如與若未接受治療之預期存活期相比,延長存活期。As used herein, the terms "treat" and "treatment" refer to curative or palliative measures. Whether detectable or undetectable, beneficial or desired clinical results include, but are not limited to, complete or partial relief of cancer-related symptoms, reduction in the extent of cancer, stabilization (i.e., not worsening) of the disease state, delay or slowing of cancer progression, improvement or relief of the disease state (e.g., one or more symptoms of cancer), and remission (whether partial or complete). "Treatment" can also mean prolonging survival, such as compared to the expected survival if not receiving treatment.
當基團被描述為「視情況經取代」時,彼基團可未經取代或經所指示取代基中之一或多者取代。同樣地,當基團被描述為「經取代」時,取代基可選自一或多個所指示取代基。若未指示取代基,則意謂所指示「視情況經取代」或「經取代」基團可藉由穩定並且對於經取代之基團而言化學上可接受的一或多種個別地且獨立地選擇之基團來取代。視情況選用之取代基之非限制性實例為鹵素、氰基、羥基、硝基、亞硝基、疊氮基、硫氫基、醯基、烷基、羥烷基、胺基烷基、烷氧基胺基、鹵烷基、烯基、鹵烯基、炔基、鹵炔基、烷氧基、羥基烷氧基、烷氧基烷氧基、烯氧基、炔氧基、鹵烷氧基、鹵烯氧基、鹵炔氧基、環烷基、鹵環烷基、環烷氧基、芳基、芳氧基、雜芳基、雜芳氧基、雜環基、雜環基氧基、芳烷基、環烷基烷基、雜芳烷基、烷氧基烷基、雜環基烷基、硫羰基、O-胺甲醯基、N-胺甲醯基、O-硫胺甲醯基、N-硫胺甲醯基、烷氧基羰基、C-醯胺基、N-醯胺基、S-磺醯胺基、N-磺醯胺基、烴硫基、鹵烴硫基、磺醯基、亞磺醯基、磺醯亞胺基(sulfoximino)、磺醯亞胺醯胺基(sulfonimidamido)、氧化膦、C-羧基、O-羧基、芳基烷氧基、環烷基烷氧基、甲醛、亞胺基、三鹵甲磺醯基、三鹵甲磺醯胺基、亞磷基(phosphityl)、亞膦醯基(phosphonityl)、硫磷醯基(phosphorothioityl)、磷醯胺基(phophoamidityl)、膦醯胺基(phosphonamidityl)、次磷酸基(phosphinityl)、膦醯基(phosphinyl)、硫膦基(phosphonothioityl)、磷醯基二醯胺基(phosphorodiamidityl)、磷醯胺基(phosphinamidityl)、磷醯基二硫基(phosphorodithioityl)、膦二醯胺基(phosphonodiamidityl)、磷醯基三醯胺基(phosphorotriamidityl)、磷酸基(phosphatyl)、次膦酸基(phosphinatyl)、膦醯基(phosphonatyl)、磷醯基醯胺基(phosphoroamidatyl)、磷醯基二醯胺基(phosphorodiamidatyl)、膦醯二醯胺基(phosphonodiamidatyl)、膦醯胺基(phosphonamidatyl)、磷醯基醯胺基(phosphinamidatyl)、磷醯基三醯胺基(phosphorotriamidatyl)、硫磷醯基(phosphorothiatyl)、二硫次膦酸基(dithiophosphinatyl)、二硫磷醯基(phosphorodithioatyl)、硫磷酸基(phosphonothioatyl)、硫次膦醯基(thiophosphatyl)、硫次膦酸基(thiophosphinatyl)、二硫磷醯基(phosphorodithiatyl)、硫膦醯基(thiophosphonatyl)、氟化磷醯基(phosphorofluoridatyl)、雙膦醯基(bisphosphonatyl)、三磷酸基(triphosphatyl)、焦磷酸基(pyrophosphatyl)、四磷酸基(tetraphosphatyl)及脲基(ureido)。When a group is described as "optionally substituted," that group may be unsubstituted or substituted with one or more of the indicated substituents. Likewise, when a group is described as "substituted," the substituent may be selected from one or more of the indicated substituents. If no substituents are indicated, it is meant that the indicated "optionally substituted" or "substituted" group may be substituted with one or more individually and independently selected groups that are stable and chemically acceptable to the group being substituted. Non-limiting examples of the optional substituents are halogen, cyano, hydroxyl, nitro, nitroso, azido, sulfhydryl, acyl, alkyl, hydroxyalkyl, aminoalkyl, alkoxyamino, halogenalkyl, alkenyl, halogenalkenyl, alkynyl, halogenalkynyl, alkoxy, hydroxyalkoxy, alkoxyalkoxy, alkenyloxy, alkynyloxy, halogenalkoxy, halogenalkenyloxy, halogenalkynyloxy, cycloalkyl, halogencycloalkyl, cycloalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy , heterocyclic group, heterocyclic groupoxy, aralkyl, cycloalkylalkyl, heteroaralkyl, alkoxyalkyl, heterocyclic groupalkyl, thiocarbonyl, O-aminoformyl, N-aminoformyl, O-thiaminoformyl, N-thiaminoformyl, alkoxycarbonyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, alkylthio, halogenthio, sulfonyl, sulfinyl, sulfoximino, sulfonimideamide (s ulfonimidamido), phosphine oxide, C-carboxyl, O-carboxyl, arylalkoxy, cycloalkylalkoxy, formaldehyde, imino, trihalomethanesulfonyl, trihalomethanesulfonamido, phosphityl, phosphonityl, phosphorothioityl, phophoamidityl, phosphonamidityl, phosphinityl, phosphinyl, phosphonothioityl, phosphorodiamidityl, phosphinamidityl, phosphorodithi oityl), phosphonodiamidityl, phosphorotriamidityl, phosphatyl, phosphinatyl, phosphonatyl, phosphoroamidatyl, phosphorodiamidatyl, phosphonodiamidatyl, phosphonamidatyl, phosphinamidatyl, phosphorotriamidatyl, phosphorothiatyl ), dithiophosphinatyl, phosphorodithioatyl, phosphonothioatyl, thiophosphatyl, thiophosphinatyl, phosphorodithiatyl, thiophosphonatyl, phosphorofluoridatyl, bisphosphonatyl, triphosphatyl, pyrophosphatyl, tetraphosphatyl and ureido.
術語「鹵素」係指氟(F)、氯(Cl)、溴(Br)或碘(I)。The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
術語「側氧基」係指二價雙鍵結的氧原子(亦即,「=O」)。如本文所用,側氧基基團附接至碳原子以形成羰基。The term "oxo" refers to a divalent, doubly-bonded oxygen atom (ie, "=0"). As used herein, an oxo group is attached to a carbon atom to form a carbonyl group.
術語「羥基」係指-OH基團。The term "hydroxy" refers to an -OH group.
術語「硫氫基」係指–SH基團。The term "sulfhydryl" refers to a -SH group.
術語「氰基」係指-CN基團。The term "cyano" refers to a -CN group.
術語「疊氮基」係指–N 3基團。 The term "azido" refers to a -N 3 group.
術語「硝基」係指–NO 2基團。 The term "nitro" refers to the -NO2 group.
術語「亞硝基」係指–N=O基團。The term "nitroso" refers to a -N=O group.
術語「烷基」係指可為直鏈或分支鏈之飽和無環烴基團,其含有所指示數目之碳原子。例如,C1-C10指示該基團可在其中具有1至10個(包括端點)碳原子。非限制性實例包括甲基、乙基、 異丙基、 三級丁基、 正己基。如在此上下文中使用之術語「飽和」意謂僅單一鍵存在於構成碳原子之間及由氫及/或如本文所定義之其他取代基來佔據其他可利用的化合價。 The term "alkyl" refers to a saturated acyclic hydrocarbon group which may be straight or branched, containing the indicated number of carbon atoms. For example, C1-C10 indicates that the group may have from 1 to 10 (including the end points) carbon atoms therein. Non-limiting examples include methyl, ethyl, isopropyl , tertiary butyl, n- hexyl. The term "saturated" as used in this context means that only a single bond exists between the constituent carbon atoms and the other available valencies are occupied by hydrogen and/or other substituents as defined herein.
術語「醯基」係指–C(=O)烷基基團(例如,乙醯基),或–C(=O)烯基基團(例如,-C(=O)-CH=CH 2),或–C(=O)炔基基團(例如, )。醯基基團可經氰基或1-3個獨立選擇之鹵素取代。如本文所用,「烯基」係指在直鏈或分支烴鏈中含有一或多個雙鍵的烷基。 The term "acyl" refers to a -C(=O)alkyl group (eg, acetyl), or a -C(=O)alkenyl group (eg, -C(=O)-CH=CH 2 ), or a -C(=O)alkynyl group (eg, ). The acyl group may be substituted with cyano or 1-3 independently selected halogens. As used herein, "alkenyl" refers to an alkyl group containing one or more double bonds in a straight or branched hydrocarbon chain.
如本文所用,「炔基」係指在直鏈或分支烴鏈中含有一或多個三鍵之烷基。As used herein, "alkynyl" refers to an alkyl group containing one or more triple bonds in the straight or branched hydrocarbon chain.
術語「芳基」係指6-20碳單環、雙環、三環或多環基團,其中系統中之至少一個環為芳香族的(例如,6碳單環、10碳雙環或14碳三環芳香族環系統);並且其中各環之0、1、2、3或4個原子可經取代基取代。芳基基團之實例包括苯基、萘基、四氫萘基及其類似基團。The term "aryl" refers to a 6-20 carbon monocyclic, bicyclic, tricyclic or polycyclic group, wherein at least one ring in the system is aromatic (e.g., a 6-carbon monocyclic, 10-carbon bicyclic or 14-carbon tricyclic aromatic ring system); and wherein 0, 1, 2, 3 or 4 atoms of each ring may be substituted with substituents. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl and the like.
如本文所用,術語「環烷基」係指具有例如3至20個環碳,較佳3至16個環碳,且更佳3至12個環碳或3-10個環碳或3-6個環碳之環狀飽和或部分不飽和的烴基團,其中環烷基可視情況經取代。環烷基之實例包括但不限於環丙基、環丁基、環戊基、環戊烯基、環己基、環己烯基、環庚基及環辛基。環烷基可包括多個稠合環及/或橋接環。稠合/橋接環烷基之非限制性實例包括:雙環[1.1.0]丁烷、雙環[2.1.0]戊烷、雙環[1.1.1]戊烷、雙環[3.1.0]己烷、雙環[2.1.1]己烷、雙環[3.2.0]庚烷、雙環[4.1.0]庚烷、雙環[2.2.1]庚烷、雙環[3.1.1]庚烷、雙環[4.2.0]辛烷、雙環[3.2.1]辛烷、雙環[2.2.2]辛烷及其類似基團。環烷基亦包括螺環(例如,螺雙環,其中兩個環僅經由一個原子來連接)。螺環烷基之非限制性實例包括螺[2.2]戊烷、螺[2.5]辛烷、螺[3.5]壬烷、螺[3.5]壬烷、螺[3.5]壬烷、螺[4.4]壬烷、螺[2.6]壬烷、螺[4.5]癸烷、螺[3.6]癸烷、螺[5.5]十一烷及其類似基團。如在此上下文中使用之術語「飽和」意謂僅單一鍵存在於構成碳原子之間。As used herein, the term "cycloalkyl" refers to a cyclic saturated or partially unsaturated alkyl group having, for example, 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons, or 3-10 ring carbons, or 3-6 ring carbons, wherein the cycloalkyl may be substituted as appropriate. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. The cycloalkyl may include multiple fused rings and/or bridged rings. Non-limiting examples of fused/bridged cycloalkyl groups include bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[1.1.1]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[4.2.0]octane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, and the like. Cycloalkyl groups also include spirocycles (e.g., spirobicycles, in which the two rings are connected via only one atom). Non-limiting examples of spirocycloalkyl groups include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane, and the like. The term "saturated" as used in this context means that only a single bond exists between the constituent carbon atoms.
如本文所用,術語「雜芳基」意謂具有5至20個環原子,或者5、6、9、10或14個環原子之單環、雙環、三環或多環基團;其中系統中之至少一個環含有一或多個獨立地選自由N、O、S、P、B及Si組成之群的雜原子並且系統中之至少一個環為芳香族的(但不必為含有雜原子之環,例如四氫異喹啉基,例如,四氫喹啉基)。雜芳基之實例包括噻吩基、吡啶基、呋喃基、噁唑基、噁二唑基、吡咯基、咪唑基、三唑基、噻二唑基、吡唑基、異噁唑基、噻二唑基、吡喃基、吡嗪基、嘧啶基、噠嗪基、三嗪基、噻唑基苯并噻吩基、苯并噁二唑基、苯并呋喃基、苯并咪唑基、苯并三唑基、噌啉基、吲唑基、吲哚基、異喹啉基、異噻唑基、萘啶基、嘌呤基、噻吩并吡啶基、吡啶并[2,3- d]嘧啶基、吡咯并[2,3- b]吡啶基、喹唑啉基、喹啉基、噻吩并[2,3- c]吡啶基、吡唑并[3,4- b]吡啶基、吡唑并[3,4- c]吡啶基、吡唑并[4,3- c]吡啶、吡唑并[4,3- b]吡啶基、四唑基、色烷、2,3-二氫苯并[ b][1,4]二噁英、苯并[ d][1,3]二氧雜環戊烯、2,3-二氫苯并呋喃、四氫喹啉、2,3-二氫苯并[ b][1,4]氧硫雜環己二烯、異吲哚啉及其他基團。在一些實施例中,雜芳基選自噻吩基、吡啶基、呋喃基、吡唑基、咪唑基、異吲哚啉基、吡喃基、吡嗪基及嘧啶基。出於澄清目的,雜芳基亦包括芳香族內醯胺、芳香族環狀脲或其間乙烯類似物,其中與羰基相鄰之各環氮為三級的(亦即,所有三個化合價由非氫取代基佔據),諸如吡啶酮(例如, 、 、 或 )、嘧啶酮(例如, 或 )、噠嗪酮(例如, 或 )、吡嗪酮(例如, 或 )及咪唑酮(例如, )中之一或多者,其中與羰基相鄰之各環氮為三級的(亦即,本文中之側氧基基團(亦即,「=O」)為雜芳基環之構成部分)。 As used herein, the term "heteroaryl" means a monocyclic, bicyclic, tricyclic or polycyclic group having 5 to 20 ring atoms, or 5, 6, 9, 10 or 14 ring atoms; wherein at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, S, P, B and Si and at least one ring in the system is aromatic (but not necessarily a heteroatom-containing ring, such as tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl). Examples of heteroaryl groups include thienyl, pyridyl, furanyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiadiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, oxazinyl, triazinyl, thiazolylbenzothiophenyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridyl, pyrido[2,3- d ]pyrimidinyl, pyrrolo[2,3- b ]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3- c ]pyridinyl, pyrazolo[3,4- b ]pyridinyl, pyrazolo[3,4- c ] pyridinyl ]pyridinyl, pyrazolo[4,3- c ]pyridine, pyrazolo[4,3- b ]pyridinyl, tetrazolyl, chromane, 2,3-dihydrobenzo[ b ][1,4]dioxin, benzo[ d ][1,3]dioxol, 2,3-dihydrobenzofuran, tetrahydroquinoline, 2,3-dihydrobenzo[ b ][1,4]oxathiophene, isoindolyl and other groups. In some embodiments, the heteroaryl group is selected from thienyl, pyridinyl, furanyl, pyrazolyl, imidazolyl, isoindolyl, pyranyl, pyrazinyl and pyrimidinyl. For the purpose of clarification, heteroaryl also includes aromatic lactams, aromatic cyclic ureas or their metaethylene analogs in which each ring nitrogen adjacent to the carbonyl group is tertiary (i.e., all three valences are occupied by non-hydrogen substituents), such as pyridones (e.g., , , or ), pyrimidone (e.g., or ), oxazolidinone (e.g., or ), pyrazinones (e.g. or ) and imidazolones (e.g., ), wherein each ring nitrogen adjacent to the carbonyl group is tertiary (i.e., the pendoxy group (i.e., "=0") herein is part of a heteroaryl ring).
術語「雜環基」係指具有3-16個環原子之單環、雙環、三環或多環飽和或部分不飽和環系統(例如,5-8員單環、8-12員雙環或11-14員三環系統),若其為單環,則具有1-3個雜原子,若其為雙環,則具有1-6個雜原子,或若其為三環或多環,則具有1-9個雜原子,該等雜原子選自O、N、P、S、B或Si (例如,碳原子及若其為單環、雙環或三環,則分別具有1-3個、1-6個或1-9個N、O、P、S、B或Si雜原子),其中若化合價允許,一或多個環原子可經1-3個側氧基(形成例如內醯胺或磷雜環環己烷氧化物(phosphinane oxide))取代並且一或多個N或S原子可經1-2個氧負離子基(形成例如N-氧化物、S-氧化物或S,S-二氧化物)取代;並且其中各環之0、1、2或3個原子可經1-2個取代基取代。雜環基基團之實例包括哌嗪基、吡咯啶基、二噁烷基、嗎啉基、四氫呋喃基、四氫吡啶基、二氫吡嗪基、二氫吡啶基、二氫吡咯基、二氫呋喃基、二氫噻吩基、氧雜磷雜環己基氧化物、氮雜磷雜環己基氧化物及其類似基團。雜環基可包括多個稠合環及橋接環。稠合/橋接雜環基之非限制性實例包括:2-氮雜雙環[1.1.0]丁烷、2-氮雜雙環[2.1.0]戊烷、2-氮雜雙環[1.1.1]戊烷、3-氮雜雙環[3.1.0]己烷、5-氮雜雙環[2.1.1]己烷、3-氮雜雙環[3.2.0]庚烷、八氫環戊[c]吡咯、3-氮雜雙環[4.1.0]庚烷、7-氮雜雙環[2.2.1]庚烷、6-氮雜雙環[3.1.1]庚烷、7-氮雜雙環[4.2.0]辛烷、2-氮雜雙環[2.2.2]辛烷、3-氮雜雙環[3.2.1]辛烷、2-氧雜雙環[1.1.0]丁烷、2-氧雜雙環[2.1.0]戊烷、2-氧雜雙環[1.1.1]戊烷、3-氧雜雙環[3.1.0]己烷、5-氧雜雙環[2.1.1]己烷、3-氧雜雙環[3.2.0]庚烷、3-氧雜雙環[4.1.0]庚烷、7-氧雜雙環[2.2.1]庚烷、6-氧雜雙環[3.1.1]庚烷、7-氧雜雙環[4.2.0]辛烷、2-氧雜雙環[2.2.2]辛烷、3-氧雜雙環[3.2.1]辛烷及其類似基團。雜環基亦包括螺環(例如,螺雙環,其中兩個環僅經由一個原子來連接)。螺環雜環基之非限制性實例包括2-氮雜螺[2.2]戊烷、4-氮雜螺[2.5]辛烷、1-氮雜螺[3.5]壬烷、2-氮雜螺[3.5]壬烷、7-氮雜螺[3.5]壬烷、2-氮雜螺[4.4]壬烷、6-氮雜螺[2.6]壬烷、1,7-二氮雜螺[4.5]癸烷、7-氮雜螺[4.5]癸烷、2,5-二氮雜螺[3.6]癸烷、3-氮雜螺[5.5]十一烷、2-氧雜螺[2.2]戊烷、4-氧雜螺[2.5]辛烷、1-氧雜螺[3.5]壬烷、2-氧雜螺[3.5]壬烷、7-氧雜螺[3.5]壬烷、2-氧雜螺[4.4]壬烷、6-氧雜螺[2.6]壬烷、1,7-二氧雜螺[4.5]癸烷、2,5-二氧雜螺[3.6]癸烷、1-氧雜螺[5.5]十一烷、3-氧雜螺[5.5]十一烷、3-氧雜-9-氮雜螺[5.5]十一烷 及其類似基團。The term "heterocyclic group" refers to a monocyclic, bicyclic, tricyclic or polycyclic saturated or partially unsaturated ring system having 3-16 ring atoms (e.g., a 5-8 membered monocyclic, 8-12 membered bicyclic or 11-14 membered tricyclic system), if it is monocyclic, it has 1-3 heteroatoms, if it is bicyclic, it has 1-6 heteroatoms, or if it is tricyclic or polycyclic, it has 1-9 heteroatoms, wherein the heteroatoms are selected from O, N, P, S, B or Si. (e.g., carbon atoms and, if it is monocyclic, bicyclic or tricyclic, 1-3, 1-6 or 1-9 N, O, P, S, B or Si atoms, respectively), wherein one or more ring atoms may be substituted with 1-3 pendoxy groups (forming, for example, lactam or phosphinane oxide) and one or more N or S atoms may be substituted with 1-2 oxo groups (forming, for example, N-oxide, S-oxide or S,S-dioxide) if valence permits; and wherein 0, 1, 2 or 3 atoms of each ring may be substituted with 1-2 substituents. Examples of heterocyclic groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, tetrahydropyridinyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrrolyl, dihydrofuranyl, dihydrothienyl, oxadiazin ... Non-limiting examples of fused/bridged heterocyclic groups include: 2-azabicyclo[1.1.0]butane, 2-azabicyclo[2.1.0]pentane, 2-azabicyclo[1.1.1]pentane, 3-azabicyclo[3.1.0]hexane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[3.1.0] [3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptane, 7-azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane, 7-azabicyclo[4.2.0]octane, 2-azabicyclo[2.2.2]octane, 3-azabicyclo[4.1.0]heptane, 7-azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane, 7-azabicyclo[4.2.0]octane, 2-azabicyclo[2.2.2]octane, Cyclo[3.2.1]octane, 2-oxacyclo[1.1.0]butane, 2-oxacyclo[2.1.0]pentane, 2-oxacyclo[1.1.1]pentane, 3-oxacyclo[3.1.0]hexane, 5-oxacyclo[2.1.1]hexane, 3-oxacyclo[3.2.0] heptane, 3-oxabicyclo[4.1.0]heptane, 7-oxabicyclo[2.2.1]heptane, 6-oxabicyclo[3.1.1]heptane, 7-oxabicyclo[4.2.0]octane, 2-oxabicyclo[2.2.2]octane, 3-oxabicyclo[3.2.1]octane and the like. Heterocyclic groups also include spirocycles (e.g., spirobicycles in which the two rings are connected via only one atom). Non-limiting examples of spirocycloheterocyclic groups include 2-azaspiro[2.2]pentane, 4-azaspiro[2.5]octane, 1-azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, 1,7-diazaspiro[4.5]decane, 7-azaspiro[4.5]decane, 2,5-diazaspiro[3.6]decane, 3-azaspiro[5.5]undecane, 2- Oxaspiro[2.2]pentane, 4-oxaspiro[2.5]octane, 1-oxaspiro[3.5]nonane, 2-oxaspiro[3.5]nonane, 7-oxaspiro[3.5]nonane, 2-oxaspiro[4.4]nonane, 6-oxaspiro[2.6]nonane, 1,7-dioxaspiro[4.5]decane, 2,5-dioxaspiro[3.6]decane, 1-oxaspiro[5.5]undecane, 3-oxaspiro[5.5]undecane, 3-oxa-9-azaspiro[5.5]undecane and similar groups.
如本文所用,芳香族環之實例包括:苯、吡啶、嘧啶、吡嗪、噠嗪、吡啶酮、吡咯、吡唑、噁唑、噻唑、異噁唑、異噻唑及其類似基團。As used herein, examples of aromatic rings include benzene, pyridine, pyrimidine, pyrazine, oxazine, pyridone, pyrrole, pyrazole, oxazole, thiazole, isoxazole, isothiazole, and the like.
術語「鹵烷基」係指其中一或多個氫原子經獨立選擇之鹵素置換的烷基。The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced with independently selected halogens.
術語「鹵環烷基」係指其中一或多個氫原子經獨立選擇之鹵素置換的環烷基。The term "halocycloalkyl" refers to a cycloalkyl group in which one or more hydrogen atoms are replaced with independently selected halogens.
術語「羥烷基」係指其中一或多個氫原子經羥基置換的烷基。The term "hydroxyalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a hydroxy group.
術語「鹵烯基」係指其中一或多個氫原子經獨立選擇之鹵素置換的烯基。The term "haloalkenyl" refers to an alkenyl group in which one or more hydrogen atoms are replaced with independently selected halogens.
術語「鹵炔基」係指其中一或多個氫原子經獨立選擇之鹵素置換的炔基。The term "haloalkynyl" refers to an alkynyl group in which one or more hydrogen atoms are replaced with independently selected halogens.
術語「烷氧基」係指-O-烷基基團(例如,-OCH 3)。 The term "alkoxy" refers to an -O-alkyl group (eg, -OCH 3 ).
術語「烷氧基烷基」係指其中一個或兩個氫原子經獨立選擇之烷氧基置換的烷基(例如,甲氧基乙基)。The term "alkoxyalkyl" refers to an alkyl group in which one or both hydrogen atoms are replaced by independently selected alkoxy groups (eg, methoxyethyl).
術語「羥基烷氧基」係指其中一個或兩個氫原子經羥基置換的烷氧基。The term "hydroxyalkoxy" refers to an alkoxy group in which one or both hydrogen atoms are replaced by hydroxy groups.
術語「烷氧基烷氧基」係指其中一個或兩個氫原子經獨立選擇之烷氧基置換的烷氧基。The term "alkoxyalkoxy" refers to an alkoxy group in which one or both hydrogen atoms are replaced by independently selected alkoxy groups.
術語「烷氧基胺基」係指–O-胺基基團(例如,-OCH 2CH 2N(CH 3) 2)。 The term " alkoxyamino " refers to an -O-amino group (eg, -OCH2CH2N ( CH3 ) 2 ).
術語「鹵烷氧基」係指-O-鹵烷基基團(例如,-OCF 3)。 The term "haloalkoxy" refers to an -O-haloalkyl group (eg, -OCF 3 ).
術語「烯氧基」係指-O-烯基基團(例如,-O-烯丙基)。The term "alkenyloxy" refers to an -O-alkenyl group (eg, -O-allyl).
術語「鹵烯氧基」係指-O-鹵烯基基團。The term "haloalkenyloxy" refers to an -O-haloalkenyl group.
術語「炔氧基」係指-O-炔基基團(例如,-O-炔丙基)。The term "alkynyloxy" refers to an -O-alkynyl group (eg, -O-propargyl).
術語「鹵炔氧基」係指-O-鹵炔基基團。The term "haloalkynyloxy" refers to an -O-haloalkynyl group.
術語「環烷氧基」係指-O-環烷基基團(例如,-O-環丙基)。The term "cycloalkoxy" refers to an -O-cycloalkyl group (eg, -O-cyclopropyl).
術語「芳氧基」係指-O-芳基基團(例如,苯氧基)。The term "aryloxy" refers to an -O-aryl group (eg, phenoxy).
術語「雜芳基氧基」係指-O-雜芳基基團(例如,吡啶氧基)。The term "heteroaryloxy" refers to an -O-heteroaryl group (eg, pyridyloxy).
術語「雜環基氧基」係指-O-雜環基基團(例如,-O-吡咯啶基或–O-氧雜環丁基)。The term "heterocyclooxy" refers to an -O-heterocycloyl group (eg, -O-pyrrolidinyl or -O-oxacyclobutyl).
術語「芳烷基」係指經由烷基基團連接的作為取代基之芳基基團(例如,苄基)。The term "aralkyl" refers to an aryl group as a substituent attached through an alkyl group (eg, benzyl).
術語「環烷基烷基」係指經由烷基基團連接的作為取代基之環烷基基團(例如,乙基環丁基)。The term "cycloalkylalkyl" refers to a cycloalkyl group as a substituent attached through an alkyl group (eg, ethylcyclobutyl).
術語「雜芳烷基」係指經由烷基基團連接的作為取代基之雜芳基基團(例如,甲基嘧啶基)。The term "heteroaralkyl" refers to a heteroaryl group as a substituent attached via an alkyl group (eg, methylpyrimidinyl).
術語「雜環基烷基」係指經由烷基基團連接的作為取代基之雜環基基團(例如,甲基氧雜環丁基)。The term "heterocycloalkyl" refers to a heterocyclo group as a substituent attached through an alkyl group (eg, methyloxyheterocyclobutyl).
術語「芳烷氧基」係指經由烷氧基基團連接的作為取代基之芳基基團(例如,苄氧基)。The term "aralkoxy" refers to an aryl group as a substituent attached through an alkoxy group (eg, benzyloxy).
術語「環烷基烷氧基」係指經由烷氧基基團連接的作為取代基之環烷基(例如,甲氧基環丙基)。The term "cycloalkylalkoxy" refers to a cycloalkyl group as a substituent attached through an alkoxy group (eg, methoxycyclopropyl).
術語「胺基烷基」係指經由烷基基團連接的作為取代基之胺基基團(例如,甲基(二甲基胺基))。The term "aminoalkyl" refers to an amino group as a substituent attached through an alkyl group (eg, methyl(dimethylamino)).
「烴硫基」基團係指-SR基團,其中R可為氫、烷基、烯基、炔基、環烷基、環烯基、芳基、雜芳基、雜環基、芳烷基雜芳烷基、雜環基烷基或環烷基烷基。A "thioalkyl" group refers to a -SR group, where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclo, aralkylheteroaralkyl, heterocycloalkyl, or cycloalkylalkyl.
「鹵烴硫基」基團係指其中一或多個氫原子經獨立選擇之鹵素置換的烴硫基(例如,-S(CF 3)或–S(CHF 2))。 A "halosulfanyl" group refers to a sulfhydryl group in which one or more hydrogen atoms are replaced with independently selected halogens (eg, -S(CF 3 ) or -S(CHF 2 )).
「亞磺醯基」基團係指-S(=O)R基團,其中R可與關於烴硫基定義相同。A "sulfinyl" group refers to a -S(=O)R group, where R is as defined for a sulfhydryl group.
「磺醯基」基團係指-SO 2R基團,其中R可與關於烴硫基定義相同。 A "sulfonyl" group refers to a -SO2R group, where R is as defined for a sulfhydryl group.
「磺醯亞胺(sulfoximine)」基團係指–S(=O)(=NR)R’,其中R為氫、烷基、鹵烷基、羥烷基、胺基烷基、烯基、炔基、環烷基、環烯基、芳基、雜芳基、雜環基、芳烷基雜芳烷基、雜環基烷基或環烷基烷基;並且其中R’為烷基、鹵烷基、羥烷基、胺基烷基、烯基、炔基、環烷基、環烯基、芳基、雜芳基、雜環基、芳烷基雜芳烷基、雜環基烷基或環烷基烷基。A “sulfoximine” group refers to —S(═O)(═NR)R’, where R is hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclo, aralkylheteroaralkyl, heterocycloalkyl, or cycloalkylalkyl; and where R’ is alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclo, aralkylheteroaralkyl, heterocycloalkyl, or cycloalkylalkyl.
「磺醯亞胺醯胺基(sulfonimidamido)」基團係指–S(=O)(=NR)NR’R”,其中R、R’及R”獨立地為氫、烷基、鹵烷基、羥烷基、胺基烷基、烯基、炔基、環烷基、環烯基、芳基、雜芳基、雜環基、芳烷基雜芳烷基、雜環基烷基或環烷基烷基;並且其中R’為烷基、鹵烷基、羥烷基、胺基烷基、烯基、炔基、環烷基、環烯基、芳基、雜芳基、雜環基、芳烷基雜芳烷基、雜環基烷基或環烷基烷基。A “sulfonimidamido” group refers to —S(═O)(═NR)NR′R″, wherein R, R′ and R″ are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclo, aralkylheteroaralkyl, heterocycloalkyl or cycloalkylalkyl; and wherein R′ is alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclo, aralkylheteroaralkyl, heterocycloalkyl or cycloalkylalkyl.
「O-羧基」基團係指RC(=O)O-基團,其中R可為氫、烷基、烷氧基、羥烷基、胺基烷基、烯基、炔基、環烷基、環烯基、芳基、雜芳基、雜環基、芳烷基雜芳烷基、雜環基烷基或環烷基烷基。An "O-carboxy" group refers to a RC(=O)O- group, where R can be hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclo, aralkylheteroaralkyl, heterocycloalkyl, or cycloalkylalkyl.
術語「酯」及「C-羧基」係指-C(=O)OR基團,其中R可與關於O-羧基定義相同。The terms "ester" and "C-carboxy" refer to a -C(=O)OR group, where R is the same as defined for O-carboxy.
「硫羰基」基團係指-C(=S)R基團,其中R可與關於O-羧基定義相同。A "thiocarbonyl" group refers to a -C(=S)R group, where R is as defined for O-carboxyl.
「三鹵甲磺醯基」基團係指X 3CSO 2-基團,其中各X為鹵素。 A " trihalomethanesulfonyl " group refers to an X3CSO2- group, wherein each X is a halogen.
「三鹵甲磺醯胺基」基團係指X 3CS(O) 2N(R’)-基團,其中各X為鹵素,並且R’為氫、烷基、烯基、炔基、環烷基、環烯基、芳基、雜芳基、雜環基、芳烷基雜芳烷基、雜環基烷基或環烷基烷基。 A "trihalomethanesulfonamido" group refers to a X 3 CS(O) 2 N(R')- group, wherein each X is a halogen and R' is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclo, aralkylheteroaralkyl, heterocycloalkyl, or cycloalkylalkyl.
「S-磺醯胺基」基團係指-SO 2N(RR’)基團,其中R及R’獨立地為氫、烷基、烷氧基、羥烷基、胺基烷基、烯基、炔基、環烷基、環烯基、芳基、雜芳基、雜環基、芳烷基雜芳烷基、雜環基烷基或環烷基烷基。 An "S-sulfonamido" group refers to a -SO2N (RR') group, where R and R' are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclo, aralkylheteroaralkyl, heterocycloalkyl, or cycloalkylalkyl.
「N-磺醯胺基」基團係指RSO 2N(R’)-基團,其中R及R’獨立地為氫、烷基、烷氧基、羥烷基、胺基烷基、烯基、炔基、環烷基、環烯基、芳基、雜芳基、雜環基、芳烷基雜芳烷基、雜環基烷基或環烷基烷基。 An "N-sulfonamido" group refers to a RSO2N (R')- group, where R and R' are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclo, aralkylheteroaralkyl, heterocycloalkyl, or cycloalkylalkyl.
「O-胺甲醯基」基團係指-OC(=O)N(RR’)基團,其中R及R’獨立地為氫、烷基、烷氧基、羥烷基、胺基烷基、烯基、炔基、環烷基、環烯基、芳基、雜芳基、雜環基、芳烷基雜芳烷基、雜環基烷基或環烷基烷基。An "O-aminoformyl" group refers to a -OC(=O)N(RR') group, where R and R' are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclo, aralkylheteroaralkyl, heterocycloalkyl, or cycloalkylalkyl.
「N-胺甲醯基」基團係指ROC(=O)N(R’)-基團,其中R及R’獨立地為氫、烷基、烷氧基、羥烷基、胺基烷基、烯基、炔基、環烷基、環烯基、芳基、雜芳基、雜環基、芳烷基雜芳烷基、雜環基烷基或環烷基烷基。An "N-aminoformyl" group refers to a ROC(=O)N(R')- group, wherein R and R' are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclo, aralkylheteroaralkyl, heterocycloalkyl, or cycloalkylalkyl.
「O-硫胺甲醯基」基團係指-OC(=S)N(RR’)基團,其中R及R’獨立地為氫、烷基、烷氧基、羥烷基、胺基烷基、烯基、炔基、環烷基、環烯基、芳基、雜芳基、雜環基、芳烷基雜芳烷基、雜環基烷基或環烷基烷基。An "O-thiaminocarboxyl" group refers to a -OC(=S)N(RR') group, where R and R' are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclo, aralkylheteroaralkyl, heterocycloalkyl, or cycloalkylalkyl.
「N-硫胺甲醯基」基團係指ROC(=S)N(R’)—基團,其中R及R’獨立地為氫、烷基、烷氧基、羥烷基、胺基烷基、烯基、炔基、環烷基、環烯基、芳基、雜芳基、雜環基、芳烷基雜芳烷基、雜環基烷基或環烷基烷基。An "N-thiaminocarboxyl" group refers to a ROC(=S)N(R')- group, wherein R and R' are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclo, aralkylheteroaralkyl, heterocycloalkyl, or cycloalkylalkyl.
「C-醯胺基」基團係指-C(=O)N(RR’)基團,其中R及R’獨立地為氫、烷基、烷氧基、烷氧基烷基、羥烷基、胺基烷基、烯基、炔基、環烷基、環烯基、芳基、雜芳基、雜環基、芳烷基雜芳烷基、雜環基烷基或環烷基烷基。A "C-amido" group refers to a -C(=O)N(RR') group, where R and R' are independently hydrogen, alkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclo, aralkylheteroaralkyl, heterocycloalkyl, or cycloalkylalkyl.
「N-醯胺基」基團係指RC(=O)N(R’)基團,其中R及R’獨立地為氫、烷基、烷氧基、羥烷基、胺基烷基、烯基、炔基、環烷基、環烯基、芳基、雜芳基、雜環基、芳烷基雜芳烷基、雜環基烷基或環烷基烷基。An "N-amido" group refers to a RC(=O)N(R') group, where R and R' are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclo, aralkylheteroaralkyl, heterocycloalkyl, or cycloalkylalkyl.
術語「脲基」或「脲」係指–NR(C=O)NR’R”基團,其中R、R’及R”獨立地為氫、羥基、烷基、鹵烷基、羥烷基、胺基烷基、烯基、炔基、環烷基、環烯基、芳基、雜芳基、雜環基、芳烷基雜芳烷基、雜環基烷基或環烷基烷基。The term "urea" or "urea" refers to a -NR(C=O)NR'R" radical, wherein R, R' and R" are independently hydrogen, hydroxyl, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclo, aralkylheteroaralkyl, heterocycloalkyl or cycloalkylalkyl.
術語「甲醛」係指–C(=O)H基團。The term "formaldehyde" refers to the -C(=O)H group.
術語「亞胺」或「亞胺基」係指–N=R基團,其中R為氫、羥基、烷基、鹵烷基、烯基、炔基、環烷基、環烯基、芳基、雜芳基、雜環基、芳烷基雜芳烷基、雜環基烷基或環烷基烷基。The term "imine" or "imino" refers to a -N=R radical, where R is hydrogen, hydroxyl, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclo, aralkylheteroaralkyl, heterocycloalkyl, or cycloalkylalkyl.
術語「胺基」係指–NRR’基團,其中R及R’獨立地為氫、烷基、鹵烷基、羥烷基、烯基、炔基、環烷基、環烯基、芳基、雜芳基、雜環基、芳烷基雜芳烷基、雜環基烷基或環烷基烷基。在一些情況下,胺基基團為–NH 2、單烷基胺(R為氫並且R’為烷基)或二烷基胺(R及R’為獨立選擇之烷基)。 The term "amino" refers to a -NRR' group, where R and R' are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclo, aralkylheteroaralkyl, heterocycloalkyl, or cycloalkylalkyl. In some cases, the amino group is -NH2 , a monoalkylamine (R is hydrogen and R' is an alkyl), or a dialkylamine (R and R' are independently selected alkyl groups).
術語「氧化膦(phosphine oxide)」係指–P(=O)RR’基團,其中R及R’獨立地為烷基、鹵烷基、羥烷基、胺基烷基、烯基、炔基、環烷基、環烯基、芳基、雜芳基、雜環基、芳烷基雜芳烷基、雜環基烷基或環烷基烷基。如本文所用,當環被描述為「部分不飽和」時,其意謂該環具有一或多個額外不飽和度(除了歸因於環本身之不飽和度;例如,介於構成環原子之間的一或多個雙或三鍵之外),條件係該環不為芳香族的。此等環之實例包括:環戊烯、環己烯、環庚烯、二氫吡啶、四氫吡啶、二氫吡咯、二氫呋喃、二氫噻吩及其類似基團。The term "phosphine oxide" refers to a -P(=O)RR' group, where R and R' are independently alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclo, aralkyl heteroaralkyl, heterocycloalkyl or cycloalkylalkyl. As used herein, when a ring is described as "partially unsaturated", it means that the ring has one or more additional unsaturations (in addition to the unsaturation due to the ring itself; for example, one or more double or triple bonds between the atoms constituting the ring), provided that the ring is not aromatic. Examples of such rings include cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene and the like.
為避免疑問,並且除非另有規定,否則對於含有足夠數目之環原子以形成雙環或更高階環系統(例如,三環、多環系統)的環及環狀基團(例如,本文所描述之芳基、雜芳基、雜環基、環烷基及其類似基團),應理解此等環及環狀基團涵蓋具有稠合環之彼等環及環狀基團,包括其中稠合點位於(i)相鄰環原子(例如,[x.x.0]環系統,其中0代表零原子橋(例如, ));(ii) 單一環原子(螺接-稠合環系統) (例如, 、 或 ),或(iii)鄰接環原子陣列(具有>0之所有橋長度的橋接環系統) (例如, 、 或 )上的彼等環及環狀基團。 For the avoidance of doubt, and unless otherwise specified, with respect to rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclo, cycloalkyl, and the like described herein) containing a sufficient number of ring atoms to form a bicyclic or higher order ring system (e.g., tricyclic, polycyclic system), it is understood that such rings and cyclic groups include those having fused rings, including those wherein the fusion points are located at (i) adjacent ring atoms (e.g., [xx0] ring system, where 0 represents a zero atom bridge (e.g., )); (ii) single ring atom (spiro-fused ring system) (e.g. , or ), or (iii) an array of adjacent ring atoms (a bridged ring system with all bridge lengths > 0) (e.g., , or ) on the rings and cyclic groups.
另外,構成本發明實施例之化合物之原子意欲包括此等原子之所有同位素形式。如本文所用,同位素包括具有相同原子序但不同質量數之彼等原子。藉助於一般實例且非限制性地,氫之同位素包括氚及氘,並且碳之同位素包括 13C及 14C。 In addition, the atoms making up the compounds of the embodiments of the present invention are intended to include all isotopic forms of such atoms. As used herein, isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include 13 C and 14 C.
另外,本文一般地或特定地揭示之化合物意欲包括所有互變異構形式。因此,舉例而言,含有部分 之化合物涵蓋含有部分 之互變異構形式。類似地,被描述為視情況經羥基取代之吡啶基或嘧啶基部分涵蓋吡啶酮或嘧啶酮互變異構形式。 In addition, compounds disclosed generally or specifically herein are intended to include all tautomeric isomeric forms. Thus, for example, a compound containing part The compounds include some Similarly, pyridinyl or pyrimidinyl moieties described as optionally substituted with hydroxy encompass pyridone or pyrimidone tautomeric forms.
本文所提供之化合物可涵蓋各種立體化學形式。化合物亦涵蓋鏡像異構物(例如,R及S異構物),非鏡像異構物,以及鏡像異構物(例如,R及S異構物)之混合物,包括外消旋混合物及非鏡像異構物之混合物,以及個別鏡像異構物及非鏡像異構物,其由於某些化合物中之結構不對稱性而出現。除非另有指示,否則當所揭示化合物藉由不指定立體化學之結構(例如,「平坦」結構)來命名或描述且具有一或多個掌性中心時,其應理解為代表化合物之所有可能的立體異構物。同樣地,除非另有指示,否則當所揭示化合物藉由指定立體化學之結構(例如,具有「楔形」及/或「虛(dashed)」鍵之結構)來命名或描述且具有一或多個掌性中心時,其應理解為代表化合物之所指示立體異構物。The compounds provided herein may encompass various stereochemical forms. The compounds also encompass mirror image isomers (e.g., R and S isomers), non-mirror image isomers, and mixtures of mirror image isomers (e.g., R and S isomers), including racemic mixtures and mixtures of non-mirror image isomers, as well as individual mirror image isomers and non-mirror image isomers that occur due to structural asymmetry in certain compounds. Unless otherwise indicated, when a disclosed compound is named or described by a structure that does not specify stereochemistry (e.g., a "planar" structure) and has one or more chiral centers, it should be understood to represent all possible stereoisomers of the compound. Likewise, unless otherwise indicated, when a disclosed compound is named or described by a designated stereochemical structure (e.g., a structure with "wedge-shaped" and/or "dashed" bonds) and has one or more chiral centers, it is understood to represent the indicated stereoisomers of the compound.
本揭露之一或多個實施例之詳情在附圖及以下描述中闡述。本揭露之其他特徵及優勢自描述及附圖,以及申請專利範圍中顯而易知。The details of one or more embodiments of the present disclosure are set forth in the accompanying drawings and the following description. Other features and advantages of the present disclosure are apparent from the description and the accompanying drawings, as well as from the scope of the claims.
相關申請案之交叉引用Cross-references to related applications
本申請案主張2022年10月21日提交之美國臨時申請案系列第63/418,089號、2023年2月7日提交之63/443,877及2023年5月26日提交之63/469,252之權益;該等美國臨時申請案以全文引用之方式併入本文。 序列表 This application claims the benefit of U.S. Provisional Application Serial Nos. 63/418,089 filed October 21, 2022, 63/443,877 filed February 7, 2023, and 63/469,252 filed May 26, 2023; each of which is incorporated herein by reference in its entirety.
本申請案含有命名為「50006-0107WO1_ST26_SL.XML」之作為XML檔案以電子方式提交之序列表。2023年10月19日創建之XML檔案之大小為2,257個位元組。XML檔案中之材料特此以全文引用之方式併入。This application contains a sequence listing submitted electronically as an XML file named "50006-0107WO1_ST26_SL.XML". The size of the XML file created on October 19, 2023 is 2,257 bytes. The material in the XML file is hereby incorporated by reference in its entirety.
本揭露提供了恢復p53功能之式(I)化合物及其醫藥學上可接受之鹽。此等化合物可用於例如治療p53功能降低造成個體(例如,人類)之疾病(例如,癌症)的病變及/或症狀及/或進展的疾病。 式(I)化合物 The present disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof that restore p53 function. These compounds can be used, for example, to treat the pathological changes and/or symptoms and/or progression of diseases (e.g., cancer) in individuals (e.g., humans) caused by reduced p53 function.
一些實施例提供了式(I)化合物: (I) 或其醫藥學上可接受之鹽,其中: X 1為CR 1或N; R 1為氫、鹵素、氰基、–OR 4、-NR 4R 5、-C(=O)R 4、-OC(=O)R 4、–C(=O)OR 4、–C(=O)NR 4R 5、–SR 4、–S(=O)R 4、–S(O 2)R 4、-NR 4C(=O)R 5、–R 4C(=O)R 5、視情況經取代之C1-C6烷基、視情況經取代之C2-C6烯基、視情況經取代之C2-C6炔基、視情況經取代之C3-C10環烷基、視情況經取代之苯基、視情況經取代之4-12員雜環基或視情況經取代之5-10員雜芳基; X 2、X 3、X 4及X 5中之各者為CH、N、CR 2或CR 3,其中X 2、X 3、X 4及X 5中之兩者或更多者獨立地為CH、CR 2或CR 3; Y 1、Y 2及Y 3中之各者為C或N,其中Y 1、Y 2及Y 3中之一者為N; R A為氫、–OR 6、-NR 6R 7、-C(=O)R 6、-R 6C(=O)R 7、-OC(=O)R 6、-OC(=O)NR 6、–C(=O)OR 6、–NR 6C(=O)OR 7、–C(=O)NR 6R 7、–SR 6、–S(=O)R 6、–S(O 2)R 6、–S(O 2)NR 6、–NR 6S(O 2)R 7、-NR 6C(=O)R 7、-NR 6C(=O)NR 7、-SiR 6R 7R 8、視情況經取代之C1-C6烷基、視情況經取代之C2-C6烯基、視情況經取代之C2-C6炔基、視情況經取代之C3-C10環烷基、視情況經取代之苯基、視情況經取代之4-12員雜環基或視情況經取代之5-10員雜芳基; R B為鹵素、氰基、羥基、–NR 8R 9、-OR 8、–C(=O)NR 8R 9、–C(=O)R 8、-C(=O)OR 8、-NR 8C(=O)OR 9、–OC(=O)R 8、–OC(=O)NR 8、–C(=O)NR 8R 9、–NR 8C(=O)R 9、–NR 8C(=O)NR 9、–SR 8、–S(=O)R 8、–S(O 2)R 8、–S(O 2)NR 8、–NR 8S(O 2)R 9、-R 8C(=O)R 9、-NR 8C(=O)R 9、-NR 8C(=O)NR 9、視情況經取代之C1-C6烷基、C1-C6鹵烷基、視情況經取代之C2-C6烯基、視情況經取代之C2-C6炔基、視情況經取代之C3-C10環烷基、視情況經取代之苯基、視情況經取代之3-12員雜環基或視情況經取代之5-10員雜芳基; 各R 2為 ; Z 1為一鍵、-C=O-、-S(O 2)-視情況經取代之C1-C6伸烷基、視情況經取代之C2-C6伸烯基、視情況經取代之C2-C6伸炔基或視情況經取代之C3-C4伸環烷基; Z 2為CR 2C、N、O或一鍵;其中當Z 2為O時,R 2B不存在,並且當Z 1為一鍵並且Z 2為一鍵時,R 2B不存在並且R 2A經由Z 1直接連接至式(I); R 2A及R 2B獨立地為氫、–C(=O)R 10、–C(=O)OR 10、–C(=O)NR 10R 11、–S(=O)R 10、–S(O 2)R 10、視情況經取代之C1-C6烷基、視情況經取代之C2-C6烯基、視情況經取代之C2-C6炔基、視情況經取代之C3-C10環烷基、視情況經取代之苯基、視情況經取代之4-12員雜環基、視情況經取代之5-10員雜芳基;或 R 2A及R 2B與其一起附接之原子一起形成視情況經取代之4-10員環烷基、視情況經取代之苯基、視情況經取代之5-10員雜芳基或視情況經取代之4-12員雜環基;或Z 2為O並且R 2B不存在; R 2C為氫、鹵素或C1-C6烷基; 各R 3獨立地為鹵素、氰基、–NR 12R 13、-OR 12、–C(=O)NR 12R 13、–C(=O)R 12、-C(=O)OR 12、–OC(=O)R 12、–NR 12(C=O)NR 13R 14、–SR 12、–S(=O)R 12、–S(O 2)R 12、–S(O 2)NR 12R 13、–NR 12S(O 2)NR 13R 14、-R 12C(=O)R 13、-NR 12C(=O)R 13、視情況經取代之C1-C6烷基、視情況經取代之C2-C6烯基、視情況經取代之C2-C6炔基、視情況經取代之C3-C6環烷基、視情況經取代之苯基、視情況經取代之4-6員雜環基或視情況經取代之5-6員雜芳基; L為視情況經取代之C2-C6伸炔基; m為0、1或2;且 各R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13及R 14獨立地為氫、視情況經取代之C1-C6烷基、視情況經取代之C2-C6烯基、視情況經取代之C2-C6炔基、視情況經取代之C3-C10環烷基、視情況經取代之苯基、視情況經取代之4-12員雜環基或視情況經取代之5-10員雜芳基。 Some embodiments provide compounds of formula (I): (I) or a pharmaceutically acceptable salt thereof, wherein: X 1 is CR 1 or N; R 1 is hydrogen, halogen, cyano, –OR 4 , –NR 4 R 5 , –C(=O)R 4 , –OC(=O)R 4 , –C(=O)OR 4 , –C(=O)NR 4 R 5 , –SR 4 , –S(=O)R 4 , –S(O 2 )R 4 , –NR 4 C(=O)R 5 , –R 4 C(=O)R 5 , an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C10 cycloalkyl, an optionally substituted phenyl, an optionally substituted 4-12 membered heterocyclic group or an optionally substituted 5-10 membered heteroaryl; each of X2 , X3 , X4 and X5 is CH, N, CR2 or CR3 , wherein two or more of X2 , X3 , X4 and X5 are independently CH, CR2 or CR3 ; each of Y1 , Y2 and Y3 is C or N, wherein one of Y1 , Y2 and Y3 is N; RA is hydrogen, –OR6 、-NR 6 R 7 、-C(=O)R 6 、-R 6 C(=O)R 7 、-OC(=O)R 6 、-OC(=O)NR 6 、–C(=O)OR 6 、–NR 6 C(=O)OR 7 、–C(=O)NR 6 R 7 、–SR 6 、–S(=O)R 6 、–S(O 2 )R 6 、–S(O 2 )NR 6 、–NR 6 S(O 2 )R 7 、-NR 6 C(=O)R 7 、-NR 6 C(=O)NR 7 、-SiR 6 R 7 R 8 , an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C10 cycloalkyl, an optionally substituted phenyl, an optionally substituted 4-12 membered heterocycloyl, or an optionally substituted 5-10 membered heteroaryl; RB is halogen, cyano, hydroxyl, –NR8R9 , –OR8 , –C (=O) NR8R9 , –C(=O) R8 , –C(=O) OR8 , –NR8C(=O) OR9 , –OC(=O) R8 , –OC (=O) NR8 , –C(=O) NR8R9, –NR8C (=O)R 9 , –NR 8 C(═O)NR 9 , –SR 8 , –S(═O)R 8 , –S(O 2 )R 8 , –S(O 2 )NR 8 , –NR 8 S(O 2 )R 9 , –R 8 C(═O)R 9 , –NR 8 C(═O)R 9 , –NR 8 C(═O)NR 9 , optionally substituted C1-C6 alkyl, C1-C6 halogenalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 3-12 membered heterocyclo or optionally substituted 5-10 membered heteroaryl; Each R2 is ; Z 1 is a bond, -C=O-, -S(O 2 )-, optionally substituted C1-C6 alkylene, optionally substituted C2-C6 alkenylene, optionally substituted C2-C6 alkynylene or optionally substituted C3-C4 cycloalkylene; Z 2 is CR 2C , N, O or a bond; wherein when Z 2 is O, R 2B is absent, and when Z 1 is a bond and Z 2 is a bond, R 2B is absent and R 2A is directly connected to formula (I) via Z 1 ; R 2A and R 2B are independently hydrogen, -C(=O)R 10 , -C(=O)OR 10 , -C(=O)NR 10 R 11 , -S(=O)R 10 , -S(O 2 )R 10 , optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclic group, optionally substituted 5-10 membered heteroaryl; or R 2A and R 2B together with the atoms to which they are attached form optionally substituted 4-10 membered cycloalkyl, optionally substituted phenyl, optionally substituted 5-10 membered heteroaryl or optionally substituted 4-12 membered heterocyclic group; or Z 2 is O and R 2B is absent; R R 2C is hydrogen, halogen or C1-C6 alkyl; each R 3 is independently halogen, cyano, –NR 12 R 13 , –OR 12 , –C(=O)NR 12 R 13 , –C(=O)R 12 , –C(=O)OR 12 , –OC(=O)R 12 , –NR 12 (C=O)NR 13 R 14 , –SR 12 , –S(=O)R 12 , –S(O 2 )R 12 , –S(O 2 )NR 12 R 13 , –NR 12 S(O 2 )NR 13 R 14 , -R 12 C(=O)R 13 , -NR 12 C(=O)R 13 , an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C6 cycloalkyl, an optionally substituted phenyl, an optionally substituted 4-6 membered heterocycloyl or an optionally substituted 5-6 membered heteroaryl; L is an optionally substituted C2-C6 alkynylene; m is 0, 1 or 2; and each of R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 is independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclic group or optionally substituted 5-10 membered heteroaryl.
在一些實施例中,式(I)化合物或其醫藥學上可接受之鹽選自由以下組成之群: (I-A)、 (I-B)及 (I-C),或前述化合物中之任一者之醫藥學上可接受之鹽。 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of: (IA) (IB) and (IC), or a pharmaceutically acceptable salt of any of the aforementioned compounds.
在一些實施例中,式(I)化合物或其醫藥學上可接受之鹽選自由以下組成之群: (I-D)、 (I-E)、 (I-F)、 (I-G)、 (I-H)及 (I-I),或前述化合物中之任一者之醫藥學上可接受之鹽。 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of: (ID), (IE), (IF), (IG), (IH) and (II), or a pharmaceutically acceptable salt of any of the aforementioned compounds.
在一些實施例中,X 2、X 3、X 4及X 5中之一者為N。 In some embodiments, one of X 2 , X 3 , X 4 and X 5 is N.
在一些實施例中,X 2、X 3、X 4及X 5中之兩者為N。 In some embodiments, two of X 2 , X 3 , X 4 and X 5 are N.
在一些實施例中,X 1為CR 1。 In some embodiments, X 1 is CR 1 .
在一些實施例中,R 1為氫。 In some embodiments, R 1 is hydrogen.
在一些實施例中,R 1為鹵素。 In some embodiments, R 1 is halogen.
在一些實施例中,R 1為氰基。 In some embodiments, R 1 is cyano.
在一些實施例中,R 1為–OR 4。 In some embodiments, R 1 is -OR 4 .
在一些實施例中,R 1為-NR 4R 5。 In some embodiments, R 1 is -NR 4 R 5 .
在一些實施例中,R 1為-C(=O)R 4。 In some embodiments, R 1 is -C(=O)R 4 .
在一些實施例中,R 1為-OC(=O)R 4。 In some embodiments, R 1 is -OC(=O)R 4 .
在一些實施例中,R 1為–C(=O)OR 4。 In some embodiments, R 1 is —C(═O)OR 4 .
在一些實施例中,R 1為–C(=O)NR 4R 5。 In some embodiments, R 1 is —C(═O)NR 4 R 5 .
在一些實施例中,R 1為–SR 4。 In some embodiments, R 1 is -SR 4 .
在一些實施例中,R 1為–S(=O)R 4。 In some embodiments, R 1 is —S(═O)R 4 .
在一些實施例中,R 1為–S(O 2)R 4。 In some embodiments, R 1 is —S(O 2 )R 4 .
在一些實施例中,R 1為-NR 4C(=O)R 5。 In some embodiments, R 1 is -NR 4 C(=O)R 5 .
在一些實施例中,R 1為–R 4C(=O)R 5。 In some embodiments, R 1 is -R 4 C(=O)R 5 .
在一些實施例中,R 4為氫、視情況經取代之C1-C6烷基、視情況經取代之C2-C6烯基、視情況經取代之C2-C6炔基、視情況經取代之C3-C10環烷基、視情況經取代之苯基、視情況經取代之4-12員雜環基或視情況經取代之5-10員雜芳基。 In some embodiments, R 4 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocycloyl, or optionally substituted 5-10 membered heteroaryl.
在一些實施例中,R 4為氫、視情況經取代之C1-C3烷基、視情況經取代之C2-C3烯基、視情況經取代之C2-C3炔基、視情況經取代之C3-C6環烷基、視情況經取代之苯基、視情況經取代之4-8員雜環基或視情況經取代之5-6員雜芳基。 In some embodiments, R 4 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclo, or optionally substituted 5-6 membered heteroaryl.
在一些實施例中,R 4為氫、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10環烷基、苯基、4-12員雜環基或5-10員雜芳基。 In some embodiments, R 4 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-12 membered heterocyclic group or 5-10 membered heteroaryl group.
在一些實施例中,R 4為氫、C1-C3烷基、C2-C3烯基、C2-C3炔基、C3-C6環烷基、苯基、4-8員雜環基或5-6員雜芳基。 In some embodiments, R 4 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C6 cycloalkyl, phenyl, 4-8 membered heterocyclic group or 5-6 membered heteroaryl group.
在一些實施例中,R 4為氫、C1-C6烷基、C3-C10環烷基或4-12員雜環基。在一些實施例中,R 4為氫、C1-C3烷基、C3-C6環烷基或4-8員雜環基。 In some embodiments, R4 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl or 4-12 membered heterocyclic group. In some embodiments, R4 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl or 4-8 membered heterocyclic group.
在一些實施例中,R 5為氫、視情況經取代之C1-C6烷基、視情況經取代之C2-C6烯基、視情況經取代之C2-C6炔基、視情況經取代之C3-C10環烷基、視情況經取代之苯基、視情況經取代之4-12員雜環基或視情況經取代之5-10員雜芳基。 In some embodiments, R 5 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocycloyl, or optionally substituted 5-10 membered heteroaryl.
在一些實施例中,R 5為氫、視情況經取代之C1-C3烷基、視情況經取代之C2-C3烯基、視情況經取代之C2-C3炔基、視情況經取代之C3-C6環烷基、視情況經取代之苯基、視情況經取代之4-8員雜環基或視情況經取代之5-6員雜芳基。 In some embodiments, R 5 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocycloyl, or optionally substituted 5-6 membered heteroaryl.
在一些實施例中,R 5為氫、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10環烷基、苯基、4-12員雜環基或5-10員雜芳基。 In some embodiments, R 5 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-12 membered heterocyclic group or 5-10 membered heteroaryl group.
在一些實施例中,R 5為氫、C1-C3烷基、C2-C3烯基、C2-C3炔基、C3-C6環烷基、苯基、4-8員雜環基或5-6員雜芳基。 In some embodiments, R 5 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C6 cycloalkyl, phenyl, 4-8 membered heterocyclic group or 5-6 membered heteroaryl group.
在一些實施例中,R 5為氫、C1-C6烷基、C3-C10環烷基或4-12員雜環基。在一些實施例中,R 5為氫、C1-C3烷基、C3-C6環烷基或4-8員雜環基。 In some embodiments, R 5 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl or 4-12 membered heterocyclic group. In some embodiments, R 5 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl or 4-8 membered heterocyclic group.
在一些實施例中,當R 4及R 5附接至同一氮原子時,R 4及R 5為相同的。在一些實施例中,當R 4及R 5附接至同一氮原子時,R 4及R 5為不同的。在一些實施例中,當R 4及R 5附接至同一氮原子時,R 4及R 5各自為氫。在一些實施例中,當R 4及R 5附接至同一氮原子時,R 4及R 5各自為獨立選擇之C1-C6烷基。 In some embodiments, when R4 and R5 are attached to the same nitrogen atom, R4 and R5 are the same. In some embodiments, when R4 and R5 are attached to the same nitrogen atom, R4 and R5 are different. In some embodiments, when R4 and R5 are attached to the same nitrogen atom, R4 and R5 are each hydrogen. In some embodiments, when R4 and R5 are attached to the same nitrogen atom, R4 and R5 are each independently selected C1-C6 alkyl.
在一些實施例中,當R 4及R 5附接至同一氮原子時,R 4及R 5中之一者為氫且R 4及R 5中之另一者為視情況經取代之C1-C6烷基、視情況經取代之C2-C6烯基、視情況經取代之C2-C6炔基、視情況經取代之C3-C10環烷基、視情況經取代之苯基、視情況經取代之4-12員雜環基或視情況經取代之5-10員雜芳基。 In some embodiments, when R4 and R5 are attached to the same nitrogen atom, one of R4 and R5 is hydrogen and the other of R4 and R5 is an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C10 cycloalkyl, an optionally substituted phenyl, an optionally substituted 4-12 membered heterocycloyl, or an optionally substituted 5-10 membered heteroaryl.
在一些實施例中,當R 4及R 5附接至同一氮原子時,R 4及R 5中之一者為氫且R 4及R 5中之另一者為C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10環烷基、苯基、4-12員雜環基或5-10員雜芳基。 In some embodiments, when R4 and R5 are attached to the same nitrogen atom, one of R4 and R5 is hydrogen and the other of R4 and R5 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-12 membered heterocyclic group, or 5-10 membered heteroaryl.
在一些實施例中,R 1為視情況經取代之C1-C6烷基。在一些實施例中,R 1為C1-C6烷基。在一些實施例中,R 1為甲基或乙基。 In some embodiments, R 1 is optionally substituted C1-C6 alkyl. In some embodiments, R 1 is C1-C6 alkyl. In some embodiments, R 1 is methyl or ethyl.
在一些實施例中,R 1為視情況經取代之C2-C6烯基。在一些實施例中,R 1為C2-C6烯基。在一些實施例中,R 1為視情況經取代之C2-C3烯基。在一些實施例中,R 1為C2-C3烯基。 In some embodiments, R 1 is an optionally substituted C2-C6 alkenyl. In some embodiments, R 1 is an optionally substituted C2-C6 alkenyl. In some embodiments, R 1 is an optionally substituted C2-C3 alkenyl. In some embodiments, R 1 is a C2-C3 alkenyl.
在一些實施例中,R 1為視情況經取代之C2-C6炔基。在一些實施例中,R 1為C2-C6炔基。在一些實施例中,R 1為視情況經取代之C2-C3炔基。在一些實施例中,R 1為C2-C3炔基。 In some embodiments, R 1 is an optionally substituted C2-C6 alkynyl. In some embodiments, R 1 is an optionally substituted C2-C6 alkynyl. In some embodiments, R 1 is an optionally substituted C2-C3 alkynyl. In some embodiments, R 1 is a C2-C3 alkynyl.
在一些實施例中,R 1為視情況經取代之C3-C6環烷基。在一些實施例中,R 1為C3-C6環烷基。 In some embodiments, R 1 is an optionally substituted C3-C6 cycloalkyl. In some embodiments, R 1 is a C3-C6 cycloalkyl.
在一些實施例中,R 1為視情況經取代之苯基。在一些實施例中,R 1為苯基。 In some embodiments, R 1 is optionally substituted phenyl. In some embodiments, R 1 is phenyl.
在一些實施例中,R 1為視情況經取代之4-6員雜環基。在一些實施例中,R 1為4-6員雜環基。 In some embodiments, R 1 is an optionally substituted 4-6 membered heterocyclic group. In some embodiments, R 1 is an optionally substituted 4-6 membered heterocyclic group.
在一些實施例中,R 1為視情況經取代之5-6員雜芳基。在一些實施例中,R 1為5-6員雜芳基。 In some embodiments, R 1 is an optionally substituted 5-6 membered heteroaryl. In some embodiments, R 1 is an optionally substituted 5-6 membered heteroaryl.
在一些實施例中,X 1為N。 In some embodiments, X1 is N.
在一些實施例中,式(I)化合物或其醫藥學上可接受之鹽選自由以下組成之群: (I-J)、 (I-K)、 (I-L)、 (I-M)、 (I-N)、 (I-O)、 (I-P)、 (I-Q)、 (I-R)、 (I-S)、 (I-T)及 (I-U),或前述化合物中之任一者之醫藥學上可接受之鹽。 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of: (IJ), (IK), (IL), (IM), (IN), (IO), (IP), (IQ), (IR), (IS), (IT) and (IU), or a pharmaceutically acceptable salt of any of the aforementioned compounds.
在一些實施例中,式(I)化合物或其醫藥學上可接受之鹽選自由以下組成之群: (I-V)、 (I-W)、 (I-X)、 (I-Y)、 (I-Z)及 (I-AA),或前述化合物中之任一者之醫藥學上可接受之鹽。 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of: (IV) (IW), (IX) (IY), (IZ) and (I-AA), or a pharmaceutically acceptable salt of any one of the foregoing compounds.
在一些實施例中,式(I)化合物或其醫藥學上可接受之鹽選自由以下組成之群: (I-Va)、 (I-Wa)、 (I-Xa)、 (I-Ya)、 (I-Za)、 (I-AAa)、 (I-ABa)、 (I-ACa)、 (I-ADa)及 (I-AEa),或前述化合物中之任一者之醫藥學上可接受之鹽。 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of: (I-Va), (I-Wa), (I-Xa), (I-Ya), (I-Za), (I-AAa), (I-ABa), (I-ACa), (I-ADa) and (I-AEa), or a pharmaceutically acceptable salt of any one of the aforementioned compounds.
在一些實施例中,式(I)化合物或其醫藥學上可接受之鹽選自由以下組成之群: (I-V1)、 (I-W1)、 (I-X1)、 (I-Y1)、 (I-Z1)及 (I-AA1),或前述化合物中之任一者之醫藥學上可接受之鹽。 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of: (I-V1), (I-W1), (I-X1), (I-Y1), (I-Z1) and (I-AA1), or a pharmaceutically acceptable salt of any of the aforementioned compounds.
在一些實施例中,式(I)化合物或其醫藥學上可接受之鹽選自由以下組成之群: (I-V2)、 (I-W2)、 (I-X2)、 (I-Y2)、 (I-Z2)及 (I-AA2),或前述化合物中之任一者之醫藥學上可接受之鹽。 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of: (I-V2), (I-W2), (I-X2), (I-Y2), (I-Z2) and (I-AA2), or a pharmaceutically acceptable salt of any of the aforementioned compounds.
在一些實施例中,式(I)化合物或其醫藥學上可接受之鹽選自由以下組成之群: (I-V11)、 (I-W11)、 (I-X11)、 (I-Y11)、 (I-Z11)、 (I-AA11)、 (I-AB11)、 (I-AC11)、 (I-AD11)及 (I-AE11),或前述化合物中之任一者之醫藥學上可接受之鹽。 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of: (I-V11), (I-W11), (I-X11), (I-Y11), (I-Z11), (I-AA11), (I-AB11), (I-AC11), (I-AD11) and (I-AE11), or a pharmaceutically acceptable salt of any one of the aforementioned compounds.
在一些實施例中,式(I)化合物或其醫藥學上可接受之鹽選自由以下組成之群: (I-V21)、 (I-W21)、 (I-X21)、 (I-Y21)、 (I-Z21)、 (I-AA21)、 (I-AB21)、 (I-AC21)、 (I-AD21)、 (I-AE21),或前述化合物中之任一者之醫藥學上可接受之鹽。在一些實施例中,式(I)化合物或其醫藥學上可接受之鹽為 (I-V21)。在一些實施例中,式(I)化合物或其醫藥學上可接受之鹽為 (I-W21)。在一些實施例中,式(I)化合物或其醫藥學上可接受之鹽為 (I-X21)。在一些實施例中,式(I)化合物或其醫藥學上可接受之鹽為 (I-Y21)。在一些實施例中,式(I)化合物或其醫藥學上可接受之鹽為 (I-Z21)。在一些實施例中,式(I)化合物或其醫藥學上可接受之鹽為 (I-AA21)。在一些實施例中,式(I)化合物或其醫藥學上可接受之鹽為 (I-AB21)。在一些實施例中,式(I)化合物或其醫藥學上可接受之鹽為 (I-AC21)。在一些實施例中,式(I)化合物或其醫藥學上可接受之鹽為 (I-AD21)。在一些實施例中,式(I)化合物或其醫藥學上可接受之鹽為 (I-AE21)。 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of: (I-V21), (I-W21), (I-X21), (I-Y21), (I-Z21), (I-AA21), (I-AB21), (I-AC21), (I-AD21), (I-AE21), or a pharmaceutically acceptable salt of any of the aforementioned compounds. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is (I-V21). In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is (I-W21). In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is (I-X21). In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is (I-Y21). In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is (I-Z21). In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is (I-AA21). In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is (I-AB21). In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is (I-AC21). In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is (I-AD21). In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is (I-AE21).
在一些實施例中,式(I)化合物或其醫藥學上可接受之鹽選自由以下組成之群: (I-V3)、 (I-W3)、 (I-X3)、 (I-Y3)、 (I-Z3)、 (I-AA3)、 (I-V4)、 (I-W4)、 (I-X4)、 (I-Y4)、 (I-Z4)及 (I-AA4),或前述化合物中之任一者之醫藥學上可接受之鹽。 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of: (I-V3), (I-W3), (I-X3), (I-Y3), (I-Z3), (I-AA3), (I-V4), (I-W4), (I-X4), (I-Y4), (I-Z4) and (I-AA4), or a pharmaceutically acceptable salt of any of the aforementioned compounds.
在一些實施例中,式(I)化合物或其醫藥學上可接受之鹽選自由以下組成之群: (I-V5)、 (I-W5)、 (I-X5)、 (I-Y5)、 (I-Z5)及 (I-AA5),或前述化合物中之任一者之醫藥學上可接受之鹽,其中R 2B ’為氫或視情況經取代之C1-C6烷基。 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of: (I-V5), (I-W5), (I-X5), (I-Y5), (I-Z5) and (I-AA5), or a pharmaceutically acceptable salt of any one of the aforementioned compounds, wherein R 2B ' is hydrogen or an optionally substituted C1-C6 alkyl.
在一些實施例中,式(I)化合物或其醫藥學上可接受之鹽選自由以下組成之群: (I-V6)、 (I-W6)、 (I-X6)、 (I-Y6)、 (I-Z6)及 (I-AA6),或前述化合物中之任一者之醫藥學上可接受之鹽,其中R 2B ’為氫或視情況經取代之C1-C6烷基。 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of: (I-V6), (I-W6), (I-X6), (I-Y6), (I-Z6) and (I-AA6), or a pharmaceutically acceptable salt of any one of the aforementioned compounds, wherein R 2B ' is hydrogen or an optionally substituted C1-C6 alkyl.
在一些實施例中,式(I)化合物或其醫藥學上可接受之鹽選自由以下組成之群: (I-V7)、 (I-W7)、 (I-X7)、 (I-Y7)、 (I-Z7)及 (I-AA7),或前述化合物中之任一者之醫藥學上可接受之鹽。 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of: (I-V7), (I-W7), (I-X7), (I-Y7), (I-Z7) and (I-AA7), or a pharmaceutically acceptable salt of any of the aforementioned compounds.
在一些實施例中,式(I)化合物或其醫藥學上可接受之鹽選自由以下組成之群: (I-V8)、 (I-W8)、 (I-X8)、 (I-Y8)、 (I-Z8)、 (I-AA8)、 (I-AB8)、 (I-AC8)、 (I-AD8)、 (I-AE8),或前述化合物中之任一者之醫藥學上可接受之鹽,其中R 2B ’為氫或視情況經取代之C1-C6烷基。 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of: (I-V8), (I-W8), (I-X8), (I-Y8), (I-Z8), (I-AA8), (I-AB8), (I-AC8), (I-AD8), (I-AE8), or a pharmaceutically acceptable salt of any one of the aforementioned compounds, wherein R 2B ' is hydrogen or an optionally substituted C1-C6 alkyl.
在一些實施例中,R A為氫。 In some embodiments, RA is hydrogen.
在一些實施例中,R A為–OR 6。 In some embodiments, RA is -OR 6 .
在一些實施例中,R A為-NR 6R 7。 In some embodiments, RA is -NR6R7 .
在一些實施例中,R A為-C(=O)R 6。 In some embodiments, RA is -C(=O) R6 .
在一些實施例中,R A為-R 6C(=O)R 7。 In some embodiments, RA is -R6C (=O) R7 .
在一些實施例中,R A為-OC(=O)R 6。 In some embodiments, RA is -OC(=O) R6 .
在一些實施例中,R A為-OC(=O)NR 6。 In some embodiments, RA is -OC(=O) NR6 .
在一些實施例中,R A為–C(=O)OR 6。 In some embodiments, RA is -C(=O)OR 6 .
在一些實施例中,R A為–NR 6C(=O)OR 7。 In some embodiments, RA is -NR 6 C(=O)OR 7 .
在一些實施例中,R A為–C(=O)NR 6R 7。 In some embodiments, RA is -C(=O)NR 6 R 7 .
在一些實施例中,R A為–SR 6。 In some embodiments, RA is -SR6 .
在一些實施例中,R A為–S(=O)R 6。 In some embodiments, RA is -S(=O) R6 .
在一些實施例中,R A為–S(O 2)R 6。 In some embodiments, RA is -S(O 2 )R 6 .
在一些實施例中,R A為–S(O 2)NR 6。 In some embodiments, RA is -S(O 2 )NR 6 .
在一些實施例中,R A為–NR 6S(O 2)R 7。 In some embodiments, RA is -NR 6 S(O 2 )R 7 .
在一些實施例中,R A為-NR 6C(=O)R 7。 In some embodiments, RA is -NR6C (=O) R7 .
在一些實施例中,R A為-NR 6C(=O)NR 7。 In some embodiments, RA is -NR6C (=O) NR7 .
在一些實施例中,R A為-SiR 6R 7R 8。 In some embodiments , RA is -SiR6R7R8 .
在一些實施例中,R 6為氫、視情況經取代之C1-C6烷基、視情況經取代之C2-C6烯基、視情況經取代之C2-C6炔基、視情況經取代之C3-C10環烷基、視情況經取代之苯基、視情況經取代之4-12員雜環基或視情況經取代之5-10員雜芳基。 In some embodiments, R6 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocycloyl, or optionally substituted 5-10 membered heteroaryl.
在一些實施例中,R 6為氫、視情況經取代之C1-C3烷基、視情況經取代之C2-C3烯基、視情況經取代之C2-C3炔基、視情況經取代之C3-C6環烷基、視情況經取代之苯基、視情況經取代之4-8員雜環基或視情況經取代之5-6員雜芳基。 In some embodiments, R6 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclo, or optionally substituted 5-6 membered heteroaryl.
在一些實施例中,R 6為氫、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10環烷基、苯基、4-12員雜環基或5-10員雜芳基。 In some embodiments, R 6 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-12 membered heterocyclic group or 5-10 membered heteroaryl group.
在一些實施例中,R 6為氫、C1-C3烷基、C2-C3烯基、C2-C3炔基、C3-C6環烷基、苯基、4-8員雜環基或5-6員雜芳基。 In some embodiments, R 6 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C6 cycloalkyl, phenyl, 4-8 membered heterocyclic group or 5-6 membered heteroaryl group.
在一些實施例中,R 6為氫、C1-C6烷基、C3-C10環烷基或4-12員雜環基。在一些實施例中,R 6為氫、C1-C3烷基、C3-C6環烷基或4-8員雜環基。 In some embodiments, R 6 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl or 4-12 membered heterocyclic group. In some embodiments, R 6 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl or 4-8 membered heterocyclic group.
在一些實施例中,R 7為氫、視情況經取代之C1-C6烷基、視情況經取代之C2-C6烯基、視情況經取代之C2-C6炔基、視情況經取代之C3-C10環烷基、視情況經取代之苯基、視情況經取代之4-12員雜環基或視情況經取代之5-10員雜芳基。 In some embodiments, R 7 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocycloyl, or optionally substituted 5-10 membered heteroaryl.
在一些實施例中,R 7為氫、視情況經取代之C1-C3烷基、視情況經取代之C2-C3烯基、視情況經取代之C2-C3炔基、視情況經取代之C3-C6環烷基、視情況經取代之苯基、視情況經取代之4-8員雜環基或視情況經取代之5-6員雜芳基。 In some embodiments, R7 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocycloyl, or optionally substituted 5-6 membered heteroaryl.
在一些實施例中,R 7為氫、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10環烷基、苯基、4-12員雜環基或5-10員雜芳基。 In some embodiments, R 7 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-12 membered heterocyclic group or 5-10 membered heteroaryl group.
在一些實施例中,R 7為氫、C1-C3烷基、C2-C3烯基、C2-C3炔基、C3-C6環烷基、苯基、4-8員雜環基或5-6員雜芳基。 In some embodiments, R 7 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C6 cycloalkyl, phenyl, 4-8 membered heterocyclic group or 5-6 membered heteroaryl group.
在一些實施例中,R 7為氫、C1-C6烷基、C3-C10環烷基或4-12員雜環基。在一些實施例中,R 7為氫、C1-C3烷基、C3-C6環烷基或4-8員雜環基。 In some embodiments, R 7 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl or 4-12 membered heterocyclic group. In some embodiments, R 7 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl or 4-8 membered heterocyclic group.
在一些實施例中,當R 6及R 7附接至同一氮原子時,R 6及R 7為相同的。在一些實施例中,當R 6及R 7附接至同一氮原子時,R 6及R 7為不同的。在一些實施例中,當R 6及R 7附接至同一氮原子時,R 6及R 7各自為氫。在一些實施例中,當R 6及R 7附接至同一氮原子時,R 6及R 7各自為獨立選擇之C1-C6烷基。 In some embodiments, when R 6 and R 7 are attached to the same nitrogen atom, R 6 and R 7 are the same. In some embodiments, when R 6 and R 7 are attached to the same nitrogen atom, R 6 and R 7 are different. In some embodiments, when R 6 and R 7 are attached to the same nitrogen atom, R 6 and R 7 are each hydrogen. In some embodiments, when R 6 and R 7 are attached to the same nitrogen atom, R 6 and R 7 are each independently selected C1-C6 alkyl.
在一些實施例中,當R 6及R 7附接至同一氮原子時,R 6及R 7中之一者為氫且R 6及R 7中之另一者為視情況經取代之C1-C6烷基、視情況經取代之C2-C6烯基、視情況經取代之C2-C6炔基、視情況經取代之C3-C10環烷基、視情況經取代之苯基、視情況經取代之4-12員雜環基或視情況經取代之5-10員雜芳基。 In some embodiments, when R and R are attached to the same nitrogen atom, one of R and R is hydrogen and the other of R and R is an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C10 cycloalkyl, an optionally substituted phenyl, an optionally substituted 4-12 membered heterocyclo, or an optionally substituted 5-10 membered heteroaryl.
在一些實施例中,當R 6及R 7附接至同一氮原子時,R 6及R 7中之一者為氫且R 6及R 7中之另一者為視情況經取代之苯基或視情況經取代之5-10員雜芳基。在一些實施例中,當R 6及R 7附接至同一氮原子時,R 6及R 7中之一者為氫且R 6及R 7中之另一者為經取代之苯基或視情況為5-10員雜芳基。 In some embodiments, when R 6 and R 7 are attached to the same nitrogen atom, one of R 6 and R 7 is hydrogen and the other of R 6 and R 7 is optionally substituted phenyl or optionally substituted 5-10 membered heteroaryl. In some embodiments, when R 6 and R 7 are attached to the same nitrogen atom, one of R 6 and R 7 is hydrogen and the other of R 6 and R 7 is optionally substituted phenyl or optionally substituted 5-10 membered heteroaryl.
在一些實施例中,當R 6及R 7附接至同一氮原子時,R 6及R 7中之一者為氫且R 6及R 7中之另一者為C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10環烷基、苯基、4-12員雜環基或5-10員雜芳基。 In some embodiments, when R 6 and R 7 are attached to the same nitrogen atom, one of R 6 and R 7 is hydrogen and the other of R 6 and R 7 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-12 membered heterocyclic group, or 5-10 membered heteroaryl.
在一些實施例中,R 8為氫、視情況經取代之C1-C6烷基、視情況經取代之C2-C6烯基、視情況經取代之C2-C6炔基、視情況經取代之C3-C10環烷基、視情況經取代之苯基、視情況經取代之4-12員雜環基或視情況經取代之5-10員雜芳基。 In some embodiments, R 8 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocycloyl, or optionally substituted 5-10 membered heteroaryl.
在一些實施例中,R 8為氫、視情況經取代之C1-C3烷基、視情況經取代之C2-C3烯基、視情況經取代之C2-C3炔基、視情況經取代之C3-C6環烷基、視情況經取代之苯基、視情況經取代之4-8員雜環基或視情況經取代之5-6員雜芳基。 In some embodiments, R 8 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocycloyl, or optionally substituted 5-6 membered heteroaryl.
在一些實施例中,R 8為氫、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10環烷基、苯基、4-12員雜環基或5-10員雜芳基。 In some embodiments, R 8 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-12 membered heterocyclic group or 5-10 membered heteroaryl group.
在一些實施例中,R 8為氫、C1-C3烷基、C2-C3烯基、C2-C3炔基、C3-C6環烷基、苯基、4-8員雜環基或5-6員雜芳基。 In some embodiments, R 8 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C6 cycloalkyl, phenyl, 4-8 membered heterocyclic group or 5-6 membered heteroaryl group.
在一些實施例中,R 8為氫、C1-C6烷基、C3-C10環烷基或8-12員雜環基。在一些實施例中,R 8為氫、C1-C3烷基、C3-C6環烷基或4-8員雜環基。 In some embodiments, R 8 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 8-12 membered heterocyclic group. In some embodiments, R 8 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclic group.
在一些實施例中,R A為視情況經取代之C1-C6烷基。在一些實施例中,R A為C1-C6烷基。在一些實施例中,R A為甲基、乙基或正丙基。 In some embodiments, RA is optionally substituted C1-C6 alkyl. In some embodiments, RA is C1-C6 alkyl. In some embodiments, RA is methyl, ethyl, or n-propyl.
在一些實施例中,R A為C1-C6鹵烷基。在一些實施例中,R A為C1-C3鹵烷基。在一些實施例中,R A為三氟甲基。 In some embodiments, RA is C1-C6 haloalkyl. In some embodiments, RA is C1-C3 haloalkyl. In some embodiments, RA is trifluoromethyl.
在一些實施例中,R A為視情況經取代之C2-C6烯基。在一些實施例中,R A為C2-C6烯基。在一些實施例中,R A為視情況經取代之C2-C3烯基。在一些實施例中,R A為C2-C3烯基。 In some embodiments, RA is an optionally substituted C2-C6 alkenyl. In some embodiments, RA is a C2-C6 alkenyl. In some embodiments, RA is an optionally substituted C2-C3 alkenyl. In some embodiments, RA is a C2-C3 alkenyl.
在一些實施例中,R A為視情況經取代之C2-C6炔基。在一些實施例中,R A為C2-C6炔基。在一些實施例中,R A為視情況經取代之C2-C3炔基。在一些實施例中,R A為C2-C3炔基。 In some embodiments, RA is an optionally substituted C2-C6 alkynyl. In some embodiments, RA is a C2-C6 alkynyl. In some embodiments, RA is an optionally substituted C2-C3 alkynyl. In some embodiments, RA is a C2-C3 alkynyl.
在一些實施例中,R A為視情況經取代之C3-C10環烷基。在一些實施例中,R A為視情況經取代之C3-C6環烷基。在一些實施例中,R A為C3-C10環烷基。在一些實施例中,R A為C3-C6環烷基。 In some embodiments, RA is an optionally substituted C3-C10 cycloalkyl. In some embodiments, RA is an optionally substituted C3-C6 cycloalkyl. In some embodiments, RA is a C3-C10 cycloalkyl. In some embodiments, RA is a C3-C6 cycloalkyl.
在一些實施例中,R A為視情況經取代之苯基。在一些實施例中,R A為苯基。 In some embodiments, RA is optionally substituted phenyl. In some embodiments, RA is phenyl.
在一些實施例中,R A為視情況經取代之3-12員雜環基。在一些實施例中,R A為視情況經取代之4-8員雜環基。在一些實施例中,R A為3-12員雜環基。在一些實施例中,R A為4-8員雜環基。 In some embodiments, RA is an optionally substituted 3-12 membered heterocyclic group. In some embodiments, RA is an optionally substituted 4-8 membered heterocyclic group. In some embodiments, RA is a 3-12 membered heterocyclic group. In some embodiments, RA is a 4-8 membered heterocyclic group.
在一些實施例中,R A為視情況經取代之5-10員雜芳基。在一些實施例中,R A為視情況經取代之5-6員雜芳基。在一些實施例中,R A為5-10員雜芳基。在一些實施例中,R A為5-6員雜芳基。在一些實施例中,R A為視情況經取代之9-10員雜芳基。在一些實施例中,R A為9-10員雜芳基。 In some embodiments, RA is an optionally substituted 5-10 membered heteroaryl. In some embodiments, RA is an optionally substituted 5-6 membered heteroaryl. In some embodiments, RA is a 5-10 membered heteroaryl. In some embodiments, RA is a 5-6 membered heteroaryl. In some embodiments, RA is an optionally substituted 9-10 membered heteroaryl. In some embodiments, RA is a 9-10 membered heteroaryl.
在一些實施例中,R A為視情況經1-3個獨立選擇之R A1取代的苯基。在一些實施例中,R A為吡啶基、嘧啶基、噠嗪基或吡嗪基,各自視情況經1-3個獨立選擇之R A2取代。在一些實施例中,R A為視情況經1-3個獨立選擇之R A3取代的9員雜芳基。 In some embodiments, RA is phenyl optionally substituted with 1-3 independently selected RA1 . In some embodiments, RA is pyridyl, pyrimidinyl, oxazinyl or pyrazinyl, each optionally substituted with 1-3 independently selected RA2 . In some embodiments, RA is 9-membered heteroaryl optionally substituted with 1-3 independently selected RA3 .
在一些實施例中,各R A1獨立地選自鹵素、氰基、胺基、羥基、硫氫基、C1-C3烷基、C1-C3烷氧基、(C1-C3烷氧基)C1-C3烷基、(羥基)C1-C3烷氧基、(C1-C3烷氧基)C1-C3烷氧基、(C1-C3烷氧基)C1-C3胺基、4-5員雜環基氧基、C-醯胺基、S-磺醯胺基、烴硫基、磺醯基、亞磺醯基、磺醯亞胺、磺醯亞胺醯胺基、磷氧化物及C-羧基。 In some embodiments, each RA1 is independently selected from halogen, cyano, amine, hydroxyl, sulfhydryl, C1-C3 alkyl, C1-C3 alkoxy, (C1-C3 alkoxy)C1-C3 alkyl, (hydroxy)C1-C3 alkoxy, (C1-C3 alkoxy)C1-C3 alkoxy, (C1-C3 alkoxy)C1-C3 amine, 4-5 membered heterocyclic oxy, C-amide, S-sulfonamide, alkylthio, sulfonyl, sulfinyl, sulfonimide, sulfonimide amide, phosphorus oxide and C-carboxyl.
在一些實施例中,各R A2獨立地選自鹵素、氰基、胺基、羥基、硫氫基、C1-C3烷基、C1-C3烷氧基、(C1-C3烷氧基)C1-C3烷基、(羥基)C1-C3烷氧基、(C1-C3烷氧基)C1-C3烷氧基、4-5員雜環基氧基、C-醯胺基、S-磺醯胺基、烴硫基、磺醯基、亞磺醯基、磺醯亞胺、磺醯亞胺醯胺基、氧化膦及C-羧基。 In some embodiments, each RA is independently selected from halogen, cyano, amine, hydroxyl, sulfhydryl, C1-C3 alkyl, C1-C3 alkoxy, (C1-C3 alkoxy)C1-C3 alkyl, (hydroxy)C1-C3 alkoxy, (C1-C3 alkoxy)C1-C3 alkoxy, 4-5 membered heterocyclic oxy, C-amido, S-sulfonamido, alkylthio, sulfonyl, sulfinyl, sulfonimide, sulfonimideamide, phosphine oxide and C-carboxyl.
在一些實施例中,各R A3獨立地選自鹵素、氰基、胺基、羥基、硫氫基、C1-C3烷基、C1-C3烷氧基、(C1-C3烷氧基)C1-C3烷基、(羥基)C1-C3烷氧基、(C1-C3烷氧基)C1-C3烷氧基、4-5員雜環基氧基、C-醯胺基、S-磺醯胺基、烴硫基、磺醯基、亞磺醯基、磺醯亞胺、磺醯亞胺醯胺基、氧化膦及C-羧基。 In some embodiments, each RA3 is independently selected from halogen, cyano, amine, hydroxyl, sulfhydryl, C1-C3 alkyl, C1-C3 alkoxy, (C1-C3 alkoxy)C1-C3 alkyl, (hydroxy)C1-C3 alkoxy, (C1-C3 alkoxy)C1-C3 alkoxy, 4-5 membered heterocyclic oxy, C-amide, S-sulfonamide, alkylthio, sulfonyl, sulfinyl, sulfonimide, sulfonimide amide, phosphine oxide and C-carboxyl.
在一些實施例中,各R A1、R A2及R A3獨立地選自鹵素、氰基、羥基、C1-C3烷基、C1-C3烷氧基、(C1-C3烷氧基)C1-C3烷基、(羥基)C1-C3烷氧基、(C1-C3烷氧基)C1-C3烷氧基、(C1-C3烷氧基)C1-C3胺基、4-5員雜環基氧基、-C(=O)NRR’、-CO 2H、-SO 2(C1-C3烷基)、-S(=O)C1-C3烷基、-SO 2NRR’、-S(=O)(=NR)NRR’或-P(=O)(C1-C3烷基) 2,其中各R及R’獨立地為氫或C1-C3烷基。 In some embodiments, each of RA1 , RA2 and RA3 is independently selected from halogen, cyano, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, (C1-C3 alkoxy)C1-C3 alkyl, (hydroxyl)C1-C3 alkoxy, (C1-C3 alkoxy)C1-C3 alkoxy, (C1-C3 alkoxy)C1-C3 amine, 4-5 membered heterocyclooxy, -C(=O)NRR', -CO2H, -SO2 (C1-C3 alkyl), -S(=O)C1-C3 alkyl, -SO2NRR ', -S(=O)(=NR)NRR', or -P(=O)(C1-C3 alkyl) 2 , wherein each R and R' is independently hydrogen or C1-C3 alkyl.
在一些實施例中,各R A1獨立地選自鹵素、氰基、C1-C3烷基、C1-C3烷氧基、4-5員雜環基氧基、-SO 2(C1-C3烷基)、-SO 2NRR’或-P(=O)(C1-C3烷基) 2,其中R及R’獨立地為氫或C1-C3烷基。 In some embodiments, each RA1 is independently selected from halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy, 4-5 membered heterocyclooxy, -SO2 (C1-C3 alkyl), -SO2NRR ', or -P(=O)(C1-C3 alkyl) 2 , wherein R and R' are independently hydrogen or C1-C3 alkyl.
在一些實施例中,R A為 、 、 、 或 。在一些實施例中,R A為 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 或 。 In some embodiments, RA is , , , or In some embodiments, RA is , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .
在一些實施例中,R A為 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 或 。 In some embodiments, RA is , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .
在一些實施例中,R A為 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 或 。 In some embodiments, RA is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .
在一些實施例中,R A為 、 、 、 、 、 、 、 、 或 。 In some embodiments, RA is , , , , , , , , or .
在一些實施例中,R A為 、 或 。 In some embodiments, RA is , or .
在一些實施例中,R A為 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 或 。 In some embodiments, RA is , , , , , , , , , , , , , , , , , , , , , , , , , or .
在一些實施例中,R B為鹵素。在一些實施例中,R B為氟或氯。 In some embodiments, RB is halogen. In some embodiments, RB is fluorine or chlorine.
在一些實施例中,R B為氰基。 In some embodiments, RB is cyano.
在一些實施例中,R B為羥基。 In some embodiments, RB is hydroxy.
在一些實施例中,R B為–NR 8R 9。 In some embodiments, RB is -NR8R9 .
在一些實施例中,R B為-OR 8。 In some embodiments, RB is -OR8 .
在一些實施例中,R B為–C(=O)NR 8R 9。 In some embodiments, RB is -C (=O) NR8R9 .
在一些實施例中,R B為–C(=O)R 8。 In some embodiments, RB is -C(=O) R8 .
在一些實施例中,R B為-C(=O)OR 8。 In some embodiments, RB is -C(=O) OR8 .
在一些實施例中,R B為-NR 8C(=O)OR 9 In some embodiments, RB is -NR8C (=O) OR9
在一些實施例中,R B為–OC(=O)R 8。 In some embodiments, RB is -OC(=O) R8 .
在一些實施例中,R B為–OC(=O)NR 8。 In some embodiments, RB is -OC(=O) NR8 .
在一些實施例中,R B為–C(=O)NR 8R 9。 In some embodiments, RB is -C (=O) NR8R9 .
在一些實施例中,R B為–NR 8C(=O)R 9。 In some embodiments, RB is -NR8C (=O) R9 .
在一些實施例中,R B為–NR 8C(=O)NR 9。 In some embodiments, RB is -NR8C (=O) NR9 .
在一些實施例中,R B為–SR 8。 In some embodiments, RB is -SR8 .
在一些實施例中,R B為–S(=O)R 8。 In some embodiments, RB is -S(=O) R8 .
在一些實施例中,R B為–S(O 2)R 8。 In some embodiments, RB is -S( O2 ) R8 .
在一些實施例中,R B為–S(O 2)NR 8。 In some embodiments, RB is -S( O2 ) NR8 .
在一些實施例中,R B為–NR 8S(O 2)R 9。 In some embodiments, RB is -NR8S ( O2 ) R9 .
在一些實施例中,R B為-R 8C(=O)R 9。 In some embodiments, RB is -R8C (=O) R9 .
在一些實施例中,R B為-NR 8C(=O)R 9。 In some embodiments, RB is -NR8C (=O) R9 .
在一些實施例中,R B為-NR 8C(=O)NR 9。 In some embodiments, RB is -NR8C (=O) NR9 .
在一些實施例中,R 8為氫、視情況經取代之C1-C6烷基、視情況經取代之C2-C6烯基、視情況經取代之C2-C6炔基、視情況經取代之C3-C10環烷基、視情況經取代之苯基、視情況經取代之4-12員雜環基或視情況經取代之5-10員雜芳基。在一些實施例中,R 8之視情況經取代之C1-C6烷基為C1-C6鹵烷基。 In some embodiments, R 8 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclic group or optionally substituted 5-10 membered heteroaryl. In some embodiments, the optionally substituted C1-C6 alkyl of R 8 is C1-C6 halogenalkyl.
在一些實施例中,R 8為氫、視情況經取代之C1-C3烷基、視情況經取代之C2-C3烯基、視情況經取代之C2-C3炔基、視情況經取代之C3-C6環烷基、視情況經取代之苯基、視情況經取代之4-8員雜環基或視情況經取代之5-6員雜芳基。在一些實施例中,R 8之視情況經取代之C1-C3烷基為C1-C3鹵烷基。在一些實施例中,R 8為經取代之C1-C3烷基,其中C1-C3烷基經鹵素取代。在一些實施例中,R 8為經取代之C1烷基,其中C1烷基經鹵素取代。在一些實施例中,R 8為經取代之C1烷基,其中C1烷基經1、2或3個鹵素(例如,氟或氯)取代。在一些實施例中,R 8為經取代之C1烷基,其中C1烷基經1個鹵素取代。在一些實施例中,R 8為經取代之C1烷基,其中C1烷基經2個鹵素取代。在一些實施例中,R 8為經取代之C1烷基,其中C1烷基經3個鹵素取代。 In some embodiments, R 8 is hydrogen, an optionally substituted C1-C3 alkyl, an optionally substituted C2-C3 alkenyl, an optionally substituted C2-C3 alkynyl, an optionally substituted C3-C6 cycloalkyl, an optionally substituted phenyl, an optionally substituted 4-8 membered heterocyclic group, or an optionally substituted 5-6 membered heteroaryl. In some embodiments, the optionally substituted C1-C3 alkyl of R 8 is a C1-C3 haloalkyl. In some embodiments, R 8 is a substituted C1-C3 alkyl, wherein the C1-C3 alkyl is substituted with a halogen. In some embodiments, R 8 is a substituted C1 alkyl, wherein the C1 alkyl is substituted with a halogen. In some embodiments, R 8 is a substituted C1 alkyl, wherein the C1 alkyl is substituted with 1, 2 or 3 halogens (e.g., fluorine or chlorine). In some embodiments, R 8 is a substituted C1 alkyl, wherein the C1 alkyl is substituted with 1 halogen. In some embodiments, R 8 is a substituted C1 alkyl, wherein the C1 alkyl is substituted with 2 halogens. In some embodiments, R 8 is a substituted C1 alkyl, wherein the C1 alkyl is substituted with 3 halogens.
在一些實施例中,R 8為氫、C1-C6烷基、C1-C6鹵烷基、C2-C6烯基、C2-C6炔基、C3-C10環烷基、苯基、4-12員雜環基或5-10員雜芳基。 In some embodiments, R 8 is hydrogen, C1-C6 alkyl, C1-C6 halogenalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-12 membered heterocyclic group or 5-10 membered heteroaryl group.
在一些實施例中,R 8為氫、C1-C3烷基、C2-C3烯基、C2-C3炔基、C3-C6環烷基、苯基、4-8員雜環基或5-6員雜芳基。 In some embodiments, R 8 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C6 cycloalkyl, phenyl, 4-8 membered heterocyclic group or 5-6 membered heteroaryl group.
在一些實施例中,R 8為氫、C1-C6烷基、C3-C10環烷基或8-12員雜環基。在一些實施例中,R 8為氫、C1-C3烷基、C3-C6環烷基或4-8員雜環基。 In some embodiments, R 8 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 8-12 membered heterocyclic group. In some embodiments, R 8 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclic group.
在一些實施例中,R 9為氫、視情況經取代之C1-C6烷基、視情況經取代之C2-C6烯基、視情況經取代之C2-C6炔基、視情況經取代之C3-C10環烷基、視情況經取代之苯基、視情況經取代之4-12員雜環基或視情況經取代之5-10員雜芳基。 In some embodiments, R 9 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocycloyl, or optionally substituted 5-10 membered heteroaryl.
在一些實施例中,R 9為氫、視情況經取代之C1-C3烷基、視情況經取代之C2-C3烯基、視情況經取代之C2-C3炔基、視情況經取代之C3-C6環烷基、視情況經取代之苯基、視情況經取代之4-8員雜環基或視情況經取代之5-6員雜芳基。 In some embodiments, R 9 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocycloyl, or optionally substituted 5-6 membered heteroaryl.
在一些實施例中,R 9為氫、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10環烷基、苯基、4-12員雜環基或5-10員雜芳基。 In some embodiments, R 9 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-12 membered heterocyclic group or 5-10 membered heteroaryl group.
在一些實施例中,R 9為氫、C1-C3烷基、C2-C3烯基、C2-C3炔基、C3-C6環烷基、苯基、4-8員雜環基或5-6員雜芳基。 In some embodiments, R 9 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C6 cycloalkyl, phenyl, 4-8 membered heterocyclic group or 5-6 membered heteroaryl group.
在一些實施例中,R 9為氫、C1-C6烷基、C3-C10環烷基或4-12員雜環基。在一些實施例中,R 9為氫、C1-C3烷基、C3-C6環烷基或4-8員雜環基。 In some embodiments, R 9 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclic group. In some embodiments, R 9 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclic group.
在一些實施例中,當R 8及R 9附接至同一氮原子時,R 8及R 9為相同的。在一些實施例中,當R 8及R 9附接至同一氮原子時,R 8及R 9為不同的。在一些實施例中,當R 8及R 9附接至同一氮原子時,R 8及R 9各自為氫。在一些實施例中,當R 8及R 9附接至同一氮原子時,R 8及R 9各自為獨立選擇之C1-C6烷基。 In some embodiments, when R 8 and R 9 are attached to the same nitrogen atom, R 8 and R 9 are the same. In some embodiments, when R 8 and R 9 are attached to the same nitrogen atom, R 8 and R 9 are different. In some embodiments, when R 8 and R 9 are attached to the same nitrogen atom, R 8 and R 9 are each hydrogen. In some embodiments, when R 8 and R 9 are attached to the same nitrogen atom, R 8 and R 9 are each independently selected C1-C6 alkyl.
在一些實施例中,當R 8及R 9附接至同一氮原子時,R 8及R 9中之一者為氫且R 8及R 9中之另一者為視情況經取代之C1-C6烷基、視情況經取代之C2-C6烯基、視情況經取代之C2-C6炔基、視情況經取代之C3-C10環烷基、視情況經取代之苯基、視情況經取代之4-12員雜環基或視情況經取代之5-10員雜芳基。 In some embodiments, when R and R are attached to the same nitrogen atom, one of R and R is hydrogen and the other of R and R is an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C10 cycloalkyl, an optionally substituted phenyl, an optionally substituted 4-12 membered heterocyclo, or an optionally substituted 5-10 membered heteroaryl.
在一些實施例中,當R 8及R 9附接至同一氮原子時,R 8及R 9中之一者為氫且R 8及R 9中之另一者為C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10環烷基、苯基、4-12員雜環基或5-10員雜芳基。 In some embodiments, when R 8 and R 9 are attached to the same nitrogen atom, one of R 8 and R 9 is hydrogen and the other of R 8 and R 9 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-12 membered heterocyclic group, or 5-10 membered heteroaryl.
在一些實施例中,R B為視情況經取代之C1-C6烷基。在一些實施例中,R B為C1-C6烷基。在一些實施例中,R B為甲基、乙基或正丙基。 In some embodiments, RB is optionally substituted C1-C6 alkyl. In some embodiments, RB is C1-C6 alkyl. In some embodiments, RB is methyl, ethyl or n-propyl.
在一些實施例中,R B為C1-C6鹵烷基。在一些實施例中,R B為C1-C3鹵烷基。在一些實施例中,R B為C1-C3氟烷基。在一些實施例中,R B為三氟甲基或2,2,2-三氟乙基。在一些實施例中,R B為2,2,2-三氟乙基。 In some embodiments, RB is C1-C6 haloalkyl. In some embodiments, RB is C1-C3 haloalkyl. In some embodiments, RB is C1-C3 fluoroalkyl. In some embodiments, RB is trifluoromethyl or 2,2,2-trifluoroethyl. In some embodiments, RB is 2,2,2-trifluoroethyl.
在一些實施例中,R B為視情況經取代之C2-C6烯基。在一些實施例中,R B為C2-C6烯基。在一些實施例中,R B為視情況經取代之C2-C3烯基。在一些實施例中,R B為C2-C3烯基。 In some embodiments, RB is an optionally substituted C2-C6 alkenyl. In some embodiments, RB is an optionally substituted C2-C6 alkenyl. In some embodiments, RB is an optionally substituted C2-C3 alkenyl. In some embodiments, RB is a C2-C3 alkenyl.
在一些實施例中,R B為視情況經取代之C2-C6炔基。在一些實施例中,R B為C2-C6炔基。在一些實施例中,R B為視情況經取代之C2-C3炔基。在一些實施例中,R B為C2-C3炔基。 In some embodiments, RB is an optionally substituted C2-C6 alkynyl. In some embodiments, RB is a C2-C6 alkynyl. In some embodiments, RB is an optionally substituted C2-C3 alkynyl. In some embodiments, RB is a C2-C3 alkynyl.
在一些實施例中,R B為視情況經取代之C3-C10環烷基。在一些實施例中,R B為視情況經取代之C3-C6環烷基。在一些實施例中,R B為C3-C10環烷基。在一些實施例中,R B為C3-C6環烷基。 In some embodiments, RB is an optionally substituted C3-C10 cycloalkyl. In some embodiments, RB is an optionally substituted C3-C6 cycloalkyl. In some embodiments, RB is a C3-C10 cycloalkyl. In some embodiments, RB is a C3-C6 cycloalkyl.
在一些實施例中,R B為視情況經取代之苯基。在一些實施例中,R B為苯基。 In some embodiments, RB is optionally substituted phenyl. In some embodiments, RB is phenyl.
在一些實施例中,R B為視情況經取代之3-12員雜環基。在一些實施例中,R B為視情況經取代之4-8員雜環基。在一些實施例中,R B為3-12員雜環基。在一些實施例中,R B為4-8員雜環基。 In some embodiments, RB is an optionally substituted 3-12 membered heterocyclic group. In some embodiments, RB is an optionally substituted 4-8 membered heterocyclic group. In some embodiments, RB is a 3-12 membered heterocyclic group. In some embodiments, RB is a 4-8 membered heterocyclic group.
在一些實施例中,R B為視情況經取代之5-10員雜芳基。在一些實施例中,R B為視情況經取代之5-6員雜芳基。在一些實施例中,R B為5-10員雜芳基。在一些實施例中,R B為5-6員雜芳基。 In some embodiments, RB is an optionally substituted 5-10 membered heteroaryl. In some embodiments, RB is an optionally substituted 5-6 membered heteroaryl. In some embodiments, RB is an optionally substituted 5-10 membered heteroaryl. In some embodiments, RB is an optionally substituted 5-6 membered heteroaryl.
在一些實施例中,R B為甲基、乙基或正丙基。 In some embodiments, RB is methyl, ethyl, or n-propyl.
在一些實施例中,R B為羥基、 或 。 In some embodiments, R B is hydroxyl, or .
在一些實施例中,R B為 或 。在一些實施例中,R B為 、 或 。 In some embodiments, RB is or In some embodiments, RB is , or .
在一些實施例中,R B為 、 。在一些實施例中,R B為 、 、 或 。 In some embodiments, RB is , In some embodiments, RB is , , or .
在一些實施例中,R B為 、 、 、 。在一些實施例中,R B為 、 、 、 或 。在一些實施例中,R B為 、 或 。 In some embodiments, RB is , , , In some embodiments, RB is , , , or In some embodiments, RB is , or .
在一些實施例中,R B為–SR 8,其中R 8為視情況經取代之C1-C6烷基。在一些實施例中,R B為–SR 8,其中R 8為C1-C6鹵烷基。在一些實施例中,R B為–SCF 3。 In some embodiments, RB is -SR 8 , wherein R 8 is optionally substituted C1-C6 alkyl. In some embodiments, RB is -SR 8 , wherein R 8 is C1-C6 halogenalkyl. In some embodiments, RB is -SCF 3 .
在一些實施例中,各R 2為 。 In some embodiments, each R 2 is .
在一些實施例中,X 2、X 3、X 4及X 5中之一者為CR 2並且其餘X 2、X 3、X 4及X 5為CH、N或CR 3。 In some embodiments, one of X 2 , X 3 , X 4 and X 5 is CR 2 and the rest of X 2 , X 3 , X 4 and X 5 are CH, N or CR 3 .
在一些實施例中,Z 1為一鍵。 In some embodiments, Z1 is a key.
在一些實施例中,Z 1為-C=O-。 In some embodiments, Z 1 is -C=O-.
在一些實施例中,Z 1為-S(O 2)-。 In some embodiments, Z 1 is -S(O 2 )-.
在一些實施例中,Z 1為視情況經取代之C1-C6伸烷基。在一些實施例中,Z 1為視情況經取代之C1-C3伸烷基。在一些實施例中,Z 1為C1-C6伸烷基。在一些實施例中,Z 1為C1-C3伸烷基。在一些實施例中,Z 1為亞甲基或伸乙基。 In some embodiments, Z 1 is an optionally substituted C1-C6 alkylene group. In some embodiments, Z 1 is an optionally substituted C1-C3 alkylene group. In some embodiments, Z 1 is a C1-C6 alkylene group. In some embodiments, Z 1 is a C1-C3 alkylene group. In some embodiments, Z 1 is a methylene group or an ethylene group.
在一些實施例中,Z 1為視情況經取代之C2-C6伸烯基。在一些實施例中,Z 1為視情況經取代之C2-C3伸烯基。在一些實施例中,Z 1為C2-C6伸烯基。在一些實施例中,Z 1為C2-C3伸烯基。 In some embodiments, Z 1 is an optionally substituted C2-C6 alkenylene. In some embodiments, Z 1 is an optionally substituted C2-C3 alkenylene. In some embodiments, Z 1 is a C2-C6 alkenylene. In some embodiments, Z 1 is a C2-C3 alkenylene.
在一些實施例中,Z 1為視情況經取代之C2-C6伸炔基。在一些實施例中,Z 1為視情況經取代之C2-C3伸炔基。在一些實施例中,Z 1為C2-C6伸炔基。在一些實施例中,Z 1為C2-C3伸炔基。 In some embodiments, Z 1 is an optionally substituted C2-C6 alkynylene. In some embodiments, Z 1 is an optionally substituted C2-C3 alkynylene. In some embodiments, Z 1 is a C2-C6 alkynylene. In some embodiments, Z 1 is a C2-C3 alkynylene.
在一些實施例中,Z 1為視情況經取代之C3-C4伸環烷基。在一些實施例中,Z 1為C3-C4伸環烷基。 In some embodiments, Z 1 is an optionally substituted C 3 -C 4 cycloalkylene group. In some embodiments, Z 1 is a C 3 -C 4 cycloalkylene group.
在一些實施例中,Z 2為N。 In some embodiments, Z2 is N.
在一些實施例中,Z 2為O並且R 2B不存在。 In some embodiments, Z 2 is O and R 2B is absent.
在一些實施例中,Z 2為一鍵。 In some embodiments, Z 2 is a key.
在一些實施例中,Z 2為CR 2C。 In some embodiments, Z 2 is CR 2C .
在一些實施例中,R 2C為氫。 In some embodiments, R 2C is hydrogen.
在一些實施例中,R 2C為鹵素。在一些實施例中,R 2C為氟或氯。 In some embodiments, R 2C is halogen. In some embodiments, R 2C is fluoro or chloro.
在一些實施例中,R 2C為C1-C6烷基。在一些實施例中,R 2C為C1-C3烷基。在一些實施例中,R 2C為甲基。 In some embodiments, R 2C is C1-C6 alkyl. In some embodiments, R 2C is C1-C3 alkyl. In some embodiments, R 2C is methyl.
在一些實施例中,當Z 1為一鍵並且Z 2為一鍵時,R 2B不存在並且R 2A經由Z 1直接連接至式(I)。在一些實施例中,當Z 2為一鍵時,R 2B不存在並且R 2A直接連接至Z 1。在一些實施例中,Z 2為O並且R 2B不存在。 In some embodiments, when Z 1 is a bond and Z 2 is a bond, R 2B is absent and R 2A is directly linked to Formula (I) via Z 1. In some embodiments, when Z 2 is a bond, R 2B is absent and R 2A is directly linked to Z 1. In some embodiments, Z 2 is O and R 2B is absent.
在一些實施例中,R 2為–NR 2AR 2B,亦即,Z 1為一鍵並且Z 2為N。在一些實施例中,R 2為R 2B,亦即,Z 1及Z 2均為一鍵,R 2A不存在並且R 2B經由Z 1直接連接至式(I)。 In some embodiments, R 2 is -NR 2A R 2B , that is, Z 1 is a bond and Z 2 is N. In some embodiments, R 2 is R 2B , that is, Z 1 and Z 2 are both a bond, R 2A is absent and R 2B is directly linked to Formula (I) via Z 1 .
在一些實施例中,在Z 1不為一鍵並且Z 2為一鍵時,R 2B不存在並且R 2A直接連接至Z 1。 In some embodiments, when Z 1 is not a bond and Z 2 is a bond, R 2B is absent and R 2A is directly linked to Z 1 .
在一些實施例中,R 2A為氫。 In some embodiments, R 2A is hydrogen.
在一些實施例中,R 2A為-C(=O)R 10。 In some embodiments, R 2A is -C(=O)R 10 .
在一些實施例中,R 2A為–C(=O)OR 10。 In some embodiments, R 2A is —C(═O)OR 10 .
在一些實施例中,R 2A為–C(=O)NR 10R 11。 In some embodiments, R 2A is —C(═O)NR 10 R 11 .
在一些實施例中,R 2A為–S(=O)R 10。 In some embodiments, R 2A is —S(═O)R 10 .
在一些實施例中,R 2A為–S(O 2)R 10。 In some embodiments, R 2A is —S(O 2 )R 10 .
在一些實施例中,R 10為氫、視情況經取代之C1-C6烷基、視情況經取代之C2-C6烯基、視情況經取代之C2-C6炔基、視情況經取代之C3-C10環烷基、視情況經取代之苯基、視情況經取代之4-12員雜環基或視情況經取代之5-10員雜芳基。 In some embodiments, R 10 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocycloyl, or optionally substituted 5-10 membered heteroaryl.
在一些實施例中,R 10為氫、視情況經取代之C1-C3烷基、視情況經取代之C2-C3烯基、視情況經取代之C2-C3炔基、視情況經取代之C3-C6環烷基、視情況經取代之苯基、視情況經取代之4-10員雜環基或視情況經取代之5-6員雜芳基。 In some embodiments, R 10 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-10 membered heterocycloyl, or optionally substituted 5-6 membered heteroaryl.
在一些實施例中,R 10為氫、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10環烷基、苯基、4-12員雜環基或5-10員雜芳基。 In some embodiments, R 10 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-12 membered heterocyclic group or 5-10 membered heteroaryl group.
在一些實施例中,R 10為氫、C1-C3烷基、C2-C3烯基、C2-C3炔基、C3-C6環烷基、苯基、4-8員雜環基或5-6員雜芳基。 In some embodiments, R 10 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C6 cycloalkyl, phenyl, 4-8 membered heterocyclic group or 5-6 membered heteroaryl group.
在一些實施例中,R 10為氫、C1-C6烷基、C3-C10環烷基或4-8員雜環基。在一些實施例中,R 10為氫、C1-C3烷基、C3-C6環烷基或4-10員雜環基。 In some embodiments, R 10 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl or 4-8 membered heterocyclic group. In some embodiments, R 10 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl or 4-10 membered heterocyclic group.
在一些實施例中,R 11為氫、視情況經取代之C1-C6烷基、視情況經取代之C2-C6烯基、視情況經取代之C2-C6炔基、視情況經取代之C3-C10環烷基、視情況經取代之苯基、視情況經取代之4-12員雜環基或視情況經取代之5-10員雜芳基。 In some embodiments, R 11 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocycloyl, or optionally substituted 5-10 membered heteroaryl.
在一些實施例中,R 11為氫、視情況經取代之C1-C3烷基、視情況經取代之C2-C3烯基、視情況經取代之C2-C3炔基、視情況經取代之C3-C6環烷基、視情況經取代之苯基、視情況經取代之4-8員雜環基或視情況經取代之5-6員雜芳基。 In some embodiments, R 11 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocycloyl, or optionally substituted 5-6 membered heteroaryl.
在一些實施例中,R 11為氫、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10環烷基、苯基、4-8員雜環基或5-10員雜芳基。 In some embodiments, R 11 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-8 membered heterocyclic group or 5-10 membered heteroaryl group.
在一些實施例中,R 11為氫、C1-C3烷基、C2-C3烯基、C2-C3炔基、C3-C6環烷基、苯基、4-8員雜環基或5-6員雜芳基。 In some embodiments, R 11 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C6 cycloalkyl, phenyl, 4-8 membered heterocyclic group or 5-6 membered heteroaryl group.
在一些實施例中,R 11為氫、C1-C6烷基、C3-C10環烷基或4-12員雜環基。在一些實施例中,R 11為氫、C1-C3烷基、C3-C6環烷基或4-8員雜環基。 In some embodiments, R 11 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclic group. In some embodiments, R 11 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclic group.
在一些實施例中,當R 10及R 11附接至同一氮原子時,R 10及R 11為相同的。在一些實施例中,當R 10及R 11附接至同一氮原子時,R 10及R 11為不同的。在一些實施例中,當R 10及R 11附接至同一氮原子時,R 10及R 11各自為氫。在一些實施例中,當R 10及R 11附接至同一氮原子時,R 10及R 11各自為獨立選擇之C1-C6烷基。 In some embodiments, when R 10 and R 11 are attached to the same nitrogen atom, R 10 and R 11 are the same. In some embodiments, when R 10 and R 11 are attached to the same nitrogen atom, R 10 and R 11 are different. In some embodiments, when R 10 and R 11 are attached to the same nitrogen atom, R 10 and R 11 are each hydrogen. In some embodiments, when R 10 and R 11 are attached to the same nitrogen atom, R 10 and R 11 are each independently selected C1-C6 alkyl.
在一些實施例中,當R 10及R 11附接至同一氮原子時,R 10及R 11中之一者為氫且R 10及R 11中之另一者為視情況經取代之C1-C6烷基、視情況經取代之C2-C6烯基、視情況經取代之C2-C6炔基、視情況經取代之C3-C10環烷基、視情況經取代之苯基、視情況經取代之4-8員雜環基或視情況經取代之5-10員雜芳基。 In some embodiments, when R 10 and R 11 are attached to the same nitrogen atom, one of R 10 and R 11 is hydrogen and the other of R 10 and R 11 is an optionally substituted C1-C6 alkyl group, an optionally substituted C2-C6 alkenyl group, an optionally substituted C2-C6 alkynyl group, an optionally substituted C3-C10 cycloalkyl group, an optionally substituted phenyl group, an optionally substituted 4-8 membered heterocyclo group, or an optionally substituted 5-10 membered heteroaryl group.
在一些實施例中,當R 10及R 11附接至同一氮原子時,R 10及R 11中之一者為氫且R 10及R 11中之另一者為C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10環烷基、苯基、4-8員雜環基或5-10員雜芳基。 In some embodiments, when R 10 and R 11 are attached to the same nitrogen atom, one of R 10 and R 11 is hydrogen and the other of R 10 and R 11 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-8 membered heterocyclic group, or 5-10 membered heteroaryl.
在一些實施例中,R 2A為視情況經取代之C1-C6烷基。在一些實施例中,R 2A為C1-C6烷基。在一些實施例中,R 2A為甲基或乙基。 In some embodiments, R 2A is optionally substituted C1-C6 alkyl. In some embodiments, R 2A is C1-C6 alkyl. In some embodiments, R 2A is methyl or ethyl.
在一些實施例中,R 2A為C1-C6鹵烷基。在一些實施例中,R 2A為C1-C3鹵烷基。在一些實施例中,R 2A為三氟甲基。 In some embodiments, R 2A is C1-C6 haloalkyl. In some embodiments, R 2A is C1-C3 haloalkyl. In some embodiments, R 2A is trifluoromethyl.
在一些實施例中,R 2A為視情況經取代之C2-C6烯基。在一些實施例中,R 2A為C2-C6烯基。在一些實施例中,R 2A為視情況經取代之C2-C3烯基。在一些實施例中,R 2A為C2-C3烯基。 In some embodiments, R 2A is an optionally substituted C2-C6 alkenyl. In some embodiments, R 2A is an optionally substituted C2-C6 alkenyl. In some embodiments, R 2A is an optionally substituted C2-C3 alkenyl. In some embodiments, R 2A is a C2-C3 alkenyl.
在一些實施例中,R 2A為視情況經取代之C2-C6炔基。在一些實施例中,R 2A為C2-C6炔基。在一些實施例中,R 2A為視情況經取代之C2-C3炔基。在一些實施例中,R 2A為C2-C3炔基。 In some embodiments, R 2A is an optionally substituted C2-C6 alkynyl. In some embodiments, R 2A is a C2-C6 alkynyl. In some embodiments, R 2A is an optionally substituted C2-C3 alkynyl. In some embodiments, R 2A is a C2-C3 alkynyl.
在一些實施例中,R 2A為視情況經取代之C3-C10環烷基。在一些實施例中,R 2A為視情況經取代之C3-C6環烷基。在一些實施例中,R 2A為C3-C10環烷基。在一些實施例中,R 2A為C3-C6環烷基。 In some embodiments, R 2A is an optionally substituted C3-C10 cycloalkyl. In some embodiments, R 2A is an optionally substituted C3-C6 cycloalkyl. In some embodiments, R 2A is a C3-C10 cycloalkyl. In some embodiments, R 2A is a C3-C6 cycloalkyl.
在一些實施例中,R 2A為視情況經取代之苯基。在一些實施例中,R 2A為苯基。 In some embodiments, R 2A is optionally substituted phenyl. In some embodiments, R 2A is phenyl.
在一些實施例中,R 2A為視情況經取代之3-12員雜環基。在一些實施例中,R 2A為視情況經取代之4-8員雜環基。在一些實施例中,R 2A為3-12員雜環基。在一些實施例中,R 2A為4-8員雜環基。 In some embodiments, R 2A is an optionally substituted 3-12 membered heterocyclic group. In some embodiments, R 2A is an optionally substituted 4-8 membered heterocyclic group. In some embodiments, R 2A is a 3-12 membered heterocyclic group. In some embodiments, R 2A is a 4-8 membered heterocyclic group.
在一些實施例中,R 2A為視情況經取代之5-10員雜芳基。在一些實施例中,R 2A為視情況經取代之5-6員雜芳基。在一些實施例中,R 2A為5-10員雜芳基。在一些實施例中,R 2A為5-6員雜芳基。 In some embodiments, R 2A is an optionally substituted 5-10 membered heteroaryl. In some embodiments, R 2A is an optionally substituted 5-6 membered heteroaryl. In some embodiments, R 2A is a 5-10 membered heteroaryl. In some embodiments, R 2A is a 5-6 membered heteroaryl.
在一些實施例中,R 2B為氫。 In some embodiments, R 2B is hydrogen.
在一些實施例中,R 2B為-C(=O)R 10。 In some embodiments, R 2B is -C(=O)R 10 .
在一些實施例中,R 2B為–C(=O)OR 10。 In some embodiments, R 2B is —C(═O)OR 10 .
在一些實施例中,R 2B為–C(=O)NR 10R 11。 In some embodiments, R 2B is —C(═O)NR 10 R 11 .
在一些實施例中,R 2B為–S(=O)R 10。 In some embodiments, R 2B is —S(═O)R 10 .
在一些實施例中,R 2B為–S(O 2)R 10。 In some embodiments, R 2B is —S(O 2 )R 10 .
在一些實施例中,R 2B為視情況經取代之C1-C6烷基。在一些實施例中,R 2B為C1-C6烷基。在一些實施例中,R 2B為甲基或乙基。 In some embodiments, R 2B is optionally substituted C1-C6 alkyl. In some embodiments, R 2B is C1-C6 alkyl. In some embodiments, R 2B is methyl or ethyl.
在一些實施例中,R 2B為C1-C6鹵烷基。在一些實施例中,R 2B為C1-C3鹵烷基。在一些實施例中,R 2B為三氟甲基。 In some embodiments, R 2B is C1-C6 haloalkyl. In some embodiments, R 2B is C1-C3 haloalkyl. In some embodiments, R 2B is trifluoromethyl.
在一些實施例中,R 2B為視情況經取代之C2-C6烯基。在一些實施例中,R 2B為C2-C6烯基。在一些實施例中,R 2B為視情況經取代之C2-C3烯基。在一些實施例中,R 2B為C2-C3烯基。 In some embodiments, R 2B is an optionally substituted C2-C6 alkenyl. In some embodiments, R 2B is an optionally substituted C2-C6 alkenyl. In some embodiments, R 2B is an optionally substituted C2-C3 alkenyl. In some embodiments, R 2B is a C2-C3 alkenyl.
在一些實施例中,R 2B為視情況經取代之C2-C6炔基。在一些實施例中,R 2B為C2-C6炔基。在一些實施例中,R 2B為視情況經取代之C2-C3炔基。在一些實施例中,R 2B為C2-C3炔基。 In some embodiments, R 2B is an optionally substituted C2-C6 alkynyl. In some embodiments, R 2B is an optionally substituted C2-C6 alkynyl. In some embodiments, R 2B is an optionally substituted C2-C3 alkynyl. In some embodiments, R 2B is a C2-C3 alkynyl.
在一些實施例中,R 2B為視情況經取代之C3-C10環烷基。在一些實施例中,R 2B為視情況經取代之C3-C6環烷基。在一些實施例中,R 2B為C3-C10環烷基。在一些實施例中,R 2B為C3-C6環烷基。 In some embodiments, R 2B is an optionally substituted C3-C10 cycloalkyl. In some embodiments, R 2B is an optionally substituted C3-C6 cycloalkyl. In some embodiments, R 2B is a C3-C10 cycloalkyl. In some embodiments, R 2B is a C3-C6 cycloalkyl.
在一些實施例中,R 2B為視情況經取代之苯基。在一些實施例中,R 2B為苯基。 In some embodiments, R 2B is optionally substituted phenyl. In some embodiments, R 2B is phenyl.
在一些實施例中,R 2B為視情況經取代之3-12員雜環基。在一些實施例中,R 2B為視情況經取代之4-8員雜環基。在一些實施例中,R 2B為3-12員雜環基。在一些實施例中,R 2B為4-8員雜環基。 In some embodiments, R 2B is an optionally substituted 3-12 membered heterocyclic group. In some embodiments, R 2B is an optionally substituted 4-8 membered heterocyclic group. In some embodiments, R 2B is a 3-12 membered heterocyclic group. In some embodiments, R 2B is a 4-8 membered heterocyclic group.
在一些實施例中,R 2B為視情況經取代之5-10員雜芳基。在一些實施例中,R 2B為視情況經取代之5-6員雜芳基。在一些實施例中,R 2B為5-10員雜芳基。在一些實施例中,R 2B為5-6員雜芳基。 In some embodiments, R 2B is an optionally substituted 5-10 membered heteroaryl. In some embodiments, R 2B is an optionally substituted 5-6 membered heteroaryl. In some embodiments, R 2B is an optionally substituted 5-10 membered heteroaryl. In some embodiments, R 2B is an optionally substituted 5-6 membered heteroaryl.
在一些實施例中,R 2B為–C(=O)R 10、–C(=O)OR 10、–C(=O)NR 10R 11、–S(=O)R 10、–S(O 2)R 10、視情況經取代之C1-C6烷基、視情況經取代之C2-C6烯基、視情況經取代之C2-C6炔基、視情況經取代之C3-C10環烷基、視情況經取代之苯基、視情況經取代之4-12員雜環基、視情況經取代之5-10員雜芳基;並且R 2B為氫。 In some embodiments, R 2B is —C(═O)R 10 , —C(═O)OR 10 , —C(═O)NR 10 R 11 , —S(═O)R 10 , —S(O 2 )R 10 , optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocycloyl, optionally substituted 5-10 membered heteroaryl; and R 2B is hydrogen.
在一些實施例中,R 2A及R 2B中之一者為氫、C1-C6烷基或C3-C10環烷基,且R 2A及R 2B中之另一者為氫、–C(=O)R 10、–C(=O)OR 10、–C(=O)NR 10R 11、–S(=O)R 10、–S(O 2)R 10、視情況經取代之C1-C6烷基、視情況經取代之C2-C6烯基、視情況經取代之C2-C6炔基、視情況經取代之C3-C10環烷基、視情況經取代之苯基、視情況經取代之4-12員雜環基、視情況經取代之5-10員雜芳基。 In some embodiments, one of R 2A and R 2B is hydrogen, C1-C6 alkyl or C3-C10 cycloalkyl, and the other of R 2A and R 2B is hydrogen, —C(═O)R 10 , —C(═O)OR 10 , —C(═O)NR 10 R 11 , —S(═O)R 10 , —S(O 2 )R 10 , optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocycloyl, optionally substituted 5-10 membered heteroaryl.
在一些實施例中,R 2A及R 2B中之一者為氫且R 2A及R 2B中之另一者為視情況經取代之4-12員雜環基或視情況經取代之5-6員雜芳基。在一些實施例中,R 2A及R 2B中之一者為氫且R 2A及R 2B中之另一者為視情況經取代之4-12員雜環基。在一些實施例中,R 2A及R 2B中之一者為氫且R 2A及R 2B中之另一者為經取代之4-12員雜環基。 In some embodiments, one of R 2A and R 2B is hydrogen and the other of R 2A and R 2B is an optionally substituted 4-12 membered heterocyclic group or an optionally substituted 5-6 membered heteroaryl group. In some embodiments, one of R 2A and R 2B is hydrogen and the other of R 2A and R 2B is an optionally substituted 4-12 membered heterocyclic group. In some embodiments, one of R 2A and R 2B is hydrogen and the other of R 2A and R 2B is a substituted 4-12 membered heterocyclic group.
在一些實施例中,R 2A及R 2B與其一起附接之原子一起形成視情況經取代之4-10員環烷基、視情況經取代之苯基、視情況經取代之5-10員雜芳基或視情況經取代之4-12員雜環基。 In some embodiments, R 2A and R 2B together with the atoms to which they are attached together form an optionally substituted 4-10 membered cycloalkyl, an optionally substituted phenyl, an optionally substituted 5-10 membered heteroaryl, or an optionally substituted 4-12 membered heterocyclo.
在一些實施例中,R 2為 、 或 ,亦即,Z 1為視情況經取代之伸烷基並且Z 2為N。在一些實施例中,R 2為 、 、 、 、 或 。在一些實施例中,R 2為 、 或 ,亦即,Z 1為視情況經取代之伸烷基,Z 2為一鍵,並且R 2A不存在。在一些實施例中,R 2為 、 、 、 、 或 。 In some embodiments, R2 is , or , that is, Z 1 is optionally substituted alkylene and Z 2 is N. In some embodiments, R 2 is , , , , or In some embodiments, R2 is , or , that is, Z 1 is an optionally substituted alkylene group, Z 2 is a bond, and R 2A is absent. In some embodiments, R 2 is , , , , or .
在一些實施例中,R 2A為氫。 In some embodiments, R 2A is hydrogen.
在一些實施例中,R 2B為 、 或 。在一些實施例中,R 2B為 、 、 或 。 In some embodiments, R 2B is , or In some embodiments, R 2B is , , or .
在一些實施例中,R 2B為 、 、 、 、 、 、 、 、 、 或 。在一些實施例中,R 2B為 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 或 。 In some embodiments, R 2B is , , , , , , , , , or In some embodiments, R 2B is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .
在一些實施例中,R 2B為 、 、 、 、 、 、 、 、 、 或 。 In some embodiments, R 2B is , , , , , , , , , or .
在一些實施例中,R 2B為 、 、 、 、 、 、 、 、 、 、 、 、 或 。 In some embodiments, R 2B is , , , , , , , , , , , , or .
在一些實施例中,R 2B為 、 、 、 、 、 、 、 、 、 、 , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 或 。 In some embodiments, R 2B is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .
在一些實施例中,R 2B為 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 或 。 In some embodiments, R 2B is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .
在一些實施例中,R 2B為 、 、 、 、 、 、 、 、 、 、 、 、 、 、 或 。 In some embodiments, R 2B is , , , , , , , , , , , , , , or .
在一些實施例中,R 2B為 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 或 。 In some embodiments, R 2B is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .
在一些實施例中,R 2B為 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 或 。 In some embodiments, R 2B is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .
在一些實施例中,R 2B為 、 、 、 、 、 、 、 、 、 、 、 、 、 或 。 In some embodiments, R 2B is , , , , , , , , , , , , , or .
在一些實施例中,R 2B為 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 或 。 In some embodiments, R 2B is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .
在一些實施例中,如本文所定義之R 2包含α,β-不飽和系統或親電子基團。 In some embodiments, R2 as defined herein comprises an α,β-unsaturated system or an electrophilic group.
在一些實施例中,R 2選自由以下組成之群: (例如, 或 )、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 及 。 In some embodiments, R is selected from the group consisting of: (For example, or ), , , , , , , , , , , , , , , , and .
在一些實施例中,X 3為CR 2並且如本文所定義之R 2包含如本文所描述之α,β-不飽和系統或親電子基團。 In some embodiments, X 3 is CR 2 and R 2 as defined herein comprises an α,β-unsaturated system or an electrophilic group as described herein.
在一些實施例中,X 2、X 3、X 4及X 5中之一者為CR 2,X 2、X 3、X 4及X 5中之一者為CR 3,並且其餘X 2、X 3、X 4及X 5為CH或N。 In some embodiments, one of X 2 , X 3 , X 4 and X 5 is CR 2 , one of X 2 , X 3 , X 4 and X 5 is CR 3 , and the rest of X 2 , X 3 , X 4 and X 5 are CH or N.
在一些實施例中,X 2、X 3、X 4及X 5中之一者為CR 2,X 2、X 3、X 4及X 5中之一者為CR 3,並且其餘X 2、X 3、X 4及X 5為CH。 In some embodiments, one of X 2 , X 3 , X 4 and X 5 is CR 2 , one of X 2 , X 3 , X 4 and X 5 is CR 3 , and the rest of X 2 , X 3 , X 4 and X 5 are CH.
在一些實施例中,R 3為鹵素。在一些實施例中,R 3為氟。在一些實施例中,R 3為氯。 In some embodiments, R 3 is halogen. In some embodiments, R 3 is fluorine. In some embodiments, R 3 is chlorine.
在一些實施例中,R 3為氰基。 In some embodiments, R 3 is cyano.
在一些實施例中,R 3為–NR 12R 13。 In some embodiments, R 3 is -NR 12 R 13 .
在一些實施例中,R 3為-OR 12。 In some embodiments, R 3 is -OR 12 .
在一些實施例中,R 3為–C(=O)NR 12R 13。 In some embodiments, R 3 is —C(═O)NR 12 R 13 .
在一些實施例中,R 3為–C(=O)R 12。 In some embodiments, R 3 is -C(=O)R 12 .
在一些實施例中,R 3為-C(=O)OR 12。 In some embodiments, R 3 is -C(=O)OR 12 .
在一些實施例中,R 3為–OC(=O)R 12。 In some embodiments, R 3 is -OC(=O)R 12 .
在一些實施例中,R 3為–NR 12(C=O)NR 12R 13。 In some embodiments, R 3 is —NR 12 (C═O)NR 12 R 13 .
在一些實施例中,R 3為–SR 12。 In some embodiments, R 3 is -SR 12 .
在一些實施例中,R 3為–S(=O)R 12。 In some embodiments, R 3 is -S(=O)R 12 .
在一些實施例中,R 3為–S(O 2)R 12。 In some embodiments, R 3 is -S(O 2 )R 12 .
在一些實施例中,R 3為–S(O 2)NR 12R 13。 In some embodiments, R 3 is —S(O 2 )NR 12 R 13 .
在一些實施例中,R 3為–NR 12S(O 2)NR 13R 14。 In some embodiments, R 3 is —NR 12 S(O 2 )NR 13 R 14 .
在一些實施例中,R 3為-R 12C(=O)R 13。 In some embodiments, R 3 is -R 12 C(=O)R 13 .
在一些實施例中,R 3為-NR 12C(=O)R 13。 In some embodiments, R 3 is -NR 12 C(=O)R 13 .
在一些實施例中,R 12為氫、視情況經取代之C1-C6烷基、視情況經取代之C2-C6烯基、視情況經取代之C2-C6炔基、視情況經取代之C3-C10環烷基、視情況經取代之苯基、視情況經取代之4-12員雜環基或視情況經取代之5-10員雜芳基。 In some embodiments, R 12 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocycloyl, or optionally substituted 5-10 membered heteroaryl.
在一些實施例中,R 12為氫、視情況經取代之C1-C3烷基、視情況經取代之C2-C3烯基、視情況經取代之C2-C3炔基、視情況經取代之C3-C6環烷基、視情況經取代之苯基、視情況經取代之4-8員雜環基或視情況經取代之5-6員雜芳基。 In some embodiments, R 12 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocycloyl, or optionally substituted 5-6 membered heteroaryl.
在一些實施例中,R 12為氫、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10環烷基、苯基、4-12員雜環基或5-10員雜芳基。 In some embodiments, R 12 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-12 membered heterocyclic group or 5-10 membered heteroaryl group.
在一些實施例中,R 12為氫、C1-C3烷基、C2-C3烯基、C2-C3炔基、C3-C6環烷基、苯基、4-8員雜環基或5-6員雜芳基。 In some embodiments, R 12 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C6 cycloalkyl, phenyl, 4-8 membered heterocyclic group or 5-6 membered heteroaryl group.
在一些實施例中,R 12為氫、C1-C6烷基、C3-C10環烷基或4-12員雜環基。在一些實施例中,R 12為氫、C1-C3烷基、C3-C6環烷基或4-8員雜環基。 In some embodiments, R 12 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclic group. In some embodiments, R 12 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclic group.
在一些實施例中,R 13為氫、視情況經取代之C1-C6烷基、視情況經取代之C2-C6烯基、視情況經取代之C2-C6炔基、視情況經取代之C3-C10環烷基、視情況經取代之苯基、視情況經取代之4-12員雜環基或視情況經取代之5-10員雜芳基。 In some embodiments, R 13 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocycloyl, or optionally substituted 5-10 membered heteroaryl.
在一些實施例中,R 13為氫、視情況經取代之C1-C3烷基、視情況經取代之C2-C3烯基、視情況經取代之C2-C3炔基、視情況經取代之C3-C6環烷基、視情況經取代之苯基、視情況經取代之4-8員雜環基或視情況經取代之5-6員雜芳基。 In some embodiments, R 13 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocycloyl, or optionally substituted 5-6 membered heteroaryl.
在一些實施例中,R 13為氫、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10環烷基、苯基、4-12員雜環基或5-10員雜芳基。 In some embodiments, R 13 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-12 membered heterocyclic group or 5-10 membered heteroaryl group.
在一些實施例中,R 13為氫、C1-C3烷基、C2-C3烯基、C2-C3炔基、C3-C6環烷基、苯基、4-8員雜環基或5-6員雜芳基。 In some embodiments, R 13 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C6 cycloalkyl, phenyl, 4-8 membered heterocyclic group or 5-6 membered heteroaryl group.
在一些實施例中,R 13為氫、C1-C6烷基、C3-C10環烷基或4-12員雜環基。在一些實施例中,R 13為氫、C1-C3烷基、C3-C6環烷基或4-8員雜環基。 In some embodiments, R 13 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclic group. In some embodiments, R 13 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclic group.
在一些實施例中,R 14為氫、視情況經取代之C1-C6烷基、視情況經取代之C2-C6烯基、視情況經取代之C2-C6炔基、視情況經取代之C3-C10環烷基、視情況經取代之苯基、視情況經取代之4-12員雜環基或視情況經取代之5-10員雜芳基。 In some embodiments, R 14 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocycloyl, or optionally substituted 5-10 membered heteroaryl.
在一些實施例中,R 14為氫、視情況經取代之C1-C3烷基、視情況經取代之C2-C3烯基、視情況經取代之C2-C3炔基、視情況經取代之C3-C6環烷基、視情況經取代之苯基、視情況經取代之4-8員雜環基或視情況經取代之5-6員雜芳基。 In some embodiments, R 14 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocycloyl, or optionally substituted 5-6 membered heteroaryl.
在一些實施例中,R 14為氫、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10環烷基、苯基、4-12員雜環基或5-10員雜芳基。 In some embodiments, R 14 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-12 membered heterocyclic group or 5-10 membered heteroaryl group.
在一些實施例中,R 14為氫、C1-C3烷基、C2-C3烯基、C2-C3炔基、C3-C6環烷基、苯基、4-8員雜環基或5-6員雜芳基。 In some embodiments, R 14 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C6 cycloalkyl, phenyl, 4-8 membered heterocyclic group or 5-6 membered heteroaryl group.
在一些實施例中,R 14為氫、C1-C6烷基、C3-C10環烷基或4-12員雜環基。在一些實施例中,R 14為氫、C1-C3烷基、C3-C6環烷基或4-8員雜環基。 In some embodiments, R 14 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclic group. In some embodiments, R 14 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclic group.
在一些實施例中,當R 12及R 13附接至同一氮原子時,R 12及R 13為相同的。在一些實施例中,當R 12及R 13附接至同一氮原子時,R 12及R 13為不同的。在一些實施例中,當R 12及R 13附接至同一氮原子時,R 12及R 13各自為氫。在一些實施例中,當R 12及R 13附接至同一氮原子時,R 12及R 13各自為獨立選擇之C1-C6烷基。 In some embodiments, when R 12 and R 13 are attached to the same nitrogen atom, R 12 and R 13 are the same. In some embodiments, when R 12 and R 13 are attached to the same nitrogen atom, R 12 and R 13 are different. In some embodiments, when R 12 and R 13 are attached to the same nitrogen atom, R 12 and R 13 are each hydrogen. In some embodiments, when R 12 and R 13 are attached to the same nitrogen atom, R 12 and R 13 are each independently selected C1-C6 alkyl.
在一些實施例中,當R 12及R 13附接至同一氮原子時,R 12及R 13中之一者為氫且R 12及R 13中之另一者為視情況經取代之C1-C6烷基、視情況經取代之C2-C6烯基、視情況經取代之C2-C6炔基、視情況經取代之C3-C10環烷基、視情況經取代之苯基、視情況經取代之4-12員雜環基或視情況經取代之5-10員雜芳基。 In some embodiments, when R 12 and R 13 are attached to the same nitrogen atom, one of R 12 and R 13 is hydrogen and the other of R 12 and R 13 is an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C10 cycloalkyl, an optionally substituted phenyl, an optionally substituted 4-12 membered heterocycloyl, or an optionally substituted 5-10 membered heteroaryl.
在一些實施例中,當R 12及R 13附接至同一氮原子時,R 12及R 13中之一者為氫且R 12及R 13中之另一者為C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10環烷基、苯基、4-12員雜環基或5-10員雜芳基。 In some embodiments, when R 12 and R 13 are attached to the same nitrogen atom, one of R 12 and R 13 is hydrogen and the other of R 12 and R 13 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-12 membered heterocyclo, or 5-10 membered heteroaryl.
在一些實施例中,當R 13及R 14附接至同一氮原子時,R 13及R 14為相同的。在一些實施例中,當R 13及R 14附接至同一氮原子時,R 13及R 14為不同的。在一些實施例中,當R 13及R 14附接至同一氮原子時,R 13及R 14各自為氫。在一些實施例中,當R 13及R 14附接至同一氮原子時,R 13及R 14各自為獨立選擇之C1-C6烷基。 In some embodiments, when R 13 and R 14 are attached to the same nitrogen atom, R 13 and R 14 are the same. In some embodiments, when R 13 and R 14 are attached to the same nitrogen atom, R 13 and R 14 are different. In some embodiments, when R 13 and R 14 are attached to the same nitrogen atom, R 13 and R 14 are each hydrogen. In some embodiments, when R 13 and R 14 are attached to the same nitrogen atom, R 13 and R 14 are each independently selected C1-C6 alkyl.
在一些實施例中,當R 13及R 14附接至同一氮原子時,R 13及R 14中之一者為氫且R 13及R 14中之另一者為視情況經取代之C1-C6烷基、視情況經取代之C2-C6烯基、視情況經取代之C2-C6炔基、視情況經取代之C3-C10環烷基、視情況經取代之苯基、視情況經取代之4-12員雜環基或視情況經取代之5-10員雜芳基。 In some embodiments, when R 13 and R 14 are attached to the same nitrogen atom, one of R 13 and R 14 is hydrogen and the other of R 13 and R 14 is an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C10 cycloalkyl, an optionally substituted phenyl, an optionally substituted 4-12 membered heterocycloyl, or an optionally substituted 5-10 membered heteroaryl.
在一些實施例中,當R 13及R 14附接至同一氮原子時,R 13及R 14中之一者為氫且R 13及R 14中之另一者為C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10環烷基、苯基、4-12員雜環基或5-10員雜芳基。 In some embodiments, when R 13 and R 14 are attached to the same nitrogen atom, one of R 13 and R 14 is hydrogen and the other of R 13 and R 14 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-12 membered heterocyclo, or 5-10 membered heteroaryl.
在一些實施例中,R 3為視情況經取代之C1-C6烷基。在一些實施例中,R 3為C1-C6烷基。在一些實施例中,R 3為甲基或乙基。 In some embodiments, R 3 is optionally substituted C1-C6 alkyl. In some embodiments, R 3 is C1-C6 alkyl. In some embodiments, R 3 is methyl or ethyl.
在一些實施例中,R 3為視情況經取代之C2-C6烯基。在一些實施例中,R 3為C2-C6烯基。在一些實施例中,R 3為視情況經取代之C2-C3烯基。在一些實施例中,R 3為C2-C3烯基。 In some embodiments, R 3 is an optionally substituted C2-C6 alkenyl. In some embodiments, R 3 is an optionally substituted C2-C6 alkenyl. In some embodiments, R 3 is an optionally substituted C2-C3 alkenyl. In some embodiments, R 3 is a C2-C3 alkenyl.
在一些實施例中,R 3為視情況經取代之C2-C6炔基。在一些實施例中,R 3為C2-C6炔基。在一些實施例中,R 3為視情況經取代之C2-C3炔基。在一些實施例中,R 3為C2-C3炔基。 In some embodiments, R 3 is an optionally substituted C2-C6 alkynyl. In some embodiments, R 3 is an optionally substituted C2-C6 alkynyl. In some embodiments, R 3 is an optionally substituted C2-C3 alkynyl. In some embodiments, R 3 is a C2-C3 alkynyl.
在一些實施例中,R 3為視情況經取代之C3-C6環烷基。在一些實施例中,R 3為C3-C6環烷基。 In some embodiments, R 3 is optionally substituted C 3 -C 6 cycloalkyl. In some embodiments, R 3 is C 3 -C 6 cycloalkyl.
在一些實施例中,R 3為視情況經取代之苯基。在一些實施例中,R 3為苯基。 In some embodiments, R 3 is an optionally substituted phenyl group. In some embodiments, R 3 is a phenyl group.
在一些實施例中,R 3為視情況經取代之4-6員雜環基。在一些實施例中,R 3為4-6員雜環基。 In some embodiments, R 3 is an optionally substituted 4-6 membered heterocyclic group. In some embodiments, R 3 is an optionally substituted 4-6 membered heterocyclic group.
在一些實施例中,R 3為視情況經取代之5-6員雜芳基。在一些實施例中,R 3為5-6員雜芳基。 In some embodiments, R 3 is an optionally substituted 5-6 membered heteroaryl. In some embodiments, R 3 is an optionally substituted 5-6 membered heteroaryl.
在一些實施例中,m為0。在一些實施例中,m為1。在一些實施例中,m為2。In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.
在一些實施例中,L為視情況經取代之C2-C6伸炔基。在一些實施例中,L為C2-C6伸炔基。在一些實施例中,L為C2-C3伸炔基。在一些實施例中,L為C2伸炔基。 非限制性例示性化合物 In some embodiments, L is an optionally substituted C2-C6 alkynylene. In some embodiments, L is a C2-C6 alkynylene. In some embodiments, L is a C2-C3 alkynylene. In some embodiments, L is a C2 alkynylene. Non-limiting exemplary compounds
在一些實施例中,化合物選自由列表1中所描述之化合物或其醫藥學上可接受之鹽組成之群。 列表1 In some embodiments, the compound is selected from the group consisting of compounds described in Table 1 or pharmaceutically acceptable salts thereof. Table 1
N-((3S,4R)-3-氟-1-甲基哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-乙烯基-2H-吲唑-7-胺;N-((3S,4R)-3-氟-1-甲基哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(3,3,3-三氟丙-1-烯-2-基)-2H-吲唑-7-胺;N-((3S,4R)-3-氟-1-甲基哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(丙-1-烯-2-基)-2H-吲唑-7-胺;N-((3S,4R)-3-氟-1-甲基哌啶-4-基)-3-(1-氟乙烯基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-2H-吲唑-7-胺;N-((3S,4R)-3-氟-1-甲基哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-((Z)-丙-1-烯-1-基)-2H-吲唑-7-胺;3-乙炔基-N-((3S,4R)-3-氟-1-甲基哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-2H-吲唑-7-胺;N-((3S,4R)-3-氟-1-甲基哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(丙-1-炔-1-基)-2H-吲唑-7-胺;N-((3S,4R)-3-氟-1-甲基哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-乙烯基咪唑并[1,2-a]吡啶-8-胺;N-((3S,4R)-3-氟-1-甲基哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-乙烯基吡唑并[1,5-a]吡啶-7-胺;N7-((3S,4R)-3-氟-1-甲基哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-乙烯基吡唑并[1,5-a]吡啶-5,7-二胺;N8-((3S,4R)-3-氟-1-甲基哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-乙烯基咪唑并[1,2-a]吡啶-6,8-二胺;N7-((3S,4R)-3-氟-1-甲基哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-乙烯基-2H-吲唑-5,7-二胺;N-((3S,4R)-3-氟-1-甲基哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-乙烯基吡唑并[1,5-c]嘧啶-7-胺;N-((3S,4R)-3-氟-1-甲基哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-乙烯基咪唑并[1,2-a]吡嗪-8-胺;N-((3S,4R)-3-氟-1-甲基哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-乙烯基-2H-吡唑并[3,4-c]吡啶-7-胺;N-((3S,4R)-3-氟-1-甲基哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-乙烯基吡唑并[1,5-a]吡嗪-7-胺;N-((3S,4R)-3-氟-1-甲基哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-乙烯基咪唑并[1,2-c]嘧啶-8-胺;N-((3S,4R)-3-氟-1-甲基哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-乙烯基-2H-吡唑并[4,3-c]吡啶-7-胺;N-((3S,4R)-3-氟-1-甲基哌啶-4-基)-3-(1-氟乙烯基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)吡唑并[1,5-a]吡啶-7-胺;N-((3S,4R)-3-氟-1-甲基哌啶-4-基)-3-(1-氟乙烯基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)咪唑并[1,2-a]吡啶-8-胺;N-((3S,4R)-3-氟-1-甲基哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(丙-1-烯-2-基)吡唑并[1,5-a]吡啶-7-胺;N-((3S,4R)-3-氟-1-甲基哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(丙-1-烯-2-基)咪唑并[1,2-a]吡啶-8-胺;N-((3S,4R)-3-氟-1-甲基哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(3,3,3-三氟丙-1-烯-2-基)吡唑并[1,5-a]吡啶-7-胺;N-((3S,4R)-3-氟-1-甲基哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(3,3,3-三氟丙-1-烯-2-基)咪唑并[1,2-a]吡啶-8-胺;N-((3S,4R)-3-氟-1-甲基哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(1,2,2-三氟乙烯基)吡唑并[1,5-a]吡啶-7-胺;N-((3S,4R)-3-氟-1-甲基哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(1,2,2-三氟乙烯基)咪唑并[1,2-a]吡啶-8-胺;N-((3S,4R)-3-氟-1-甲基哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(1,2,2-三氟乙烯基)-2H-吲唑-7-胺;N-((3S,4R)-3-氟-1-甲基哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-((E)-丙-1-烯-1-基)吡唑并[1,5-a]吡啶-7-胺;N-((3S,4R)-3-氟-1-甲基哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-((E)-丙-1-烯-1-基)咪唑并[1,2-a]吡啶-8-胺;N-((3S,4R)-3-氟-1-甲基哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-((E)-丙-1-烯-1-基)-2H-吲唑-7-胺;3-乙炔基-N-((3S,4R)-3-氟-1-甲基哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)吡唑并[1,5-a]吡啶-7-胺;3-乙炔基-N-((3S,4R)-3-氟-1-甲基哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)咪唑并[1,2-a]吡啶-8-胺;N-((3S,4R)-3-氟-1-甲基哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(丙-1-炔-1-基)吡唑并[1,5-a]吡啶-7-胺;N-((3S,4R)-3-氟-1-甲基哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(丙-1-炔-1-基)咪唑并[1,2-a]吡啶-8-胺;N-((3S,4R)-3-氟-1-甲基哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-((Z)-丙-1-烯-1-基)吡唑并[1,5-a]吡啶-7-胺;N-((3S,4R)-3-氟-1-甲基哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-((Z)-丙-1-烯-1-基)咪唑并[1,2-a]吡啶-8-胺;N-((3S,4R)-3-氟-1-甲基哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-((E)-3,3,3-三氟丙-1-烯-1-基)吡唑并[1,5-a]吡啶-7-胺;N-((3S,4R)-3-氟-1-甲基哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-((E)-3,3,3-三氟丙-1-烯-1-基)咪唑并[1,2-a]吡啶-8-胺;N-((3S,4R)-3-氟-1-甲基哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-((E)-3,3,3-三氟丙-1-烯-1-基)-2H-吲唑-7-胺;3-(2,2-二氟乙烯基)-N-((3S,4R)-3-氟-1-甲基哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)吡唑并[1,5-a]吡啶-7-胺;3-(2,2-二氟乙烯基)-N-((3S,4R)-3-氟-1-甲基哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)咪唑并[1,2-a]吡啶-8-胺;3-(2,2-二氟乙烯基)-N-((3S,4R)-3-氟-1-甲基哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-2H-吲唑-7-胺;4-((3-(7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-乙烯基吡唑并[1,5-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基苯甲醯胺;4-((3-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-乙烯基咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基苯甲醯胺;4-((3-(7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-乙烯基-2H-吲唑-2-基)丙-2-炔-1-基)胺基)-3-甲氧基苯甲醯胺;4-((3-(7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-乙烯基吡唑并[1,5-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;4-((3-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-乙烯基咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;4-((3-(7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-乙烯基-2H-吲唑-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;4-((3-(7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-乙烯基吡唑并[1,5-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N,N-二甲基苯甲醯胺;4-((3-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-乙烯基咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N,N-二甲基苯甲醯胺;4-((3-(7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-乙烯基-2H-吲唑-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N,N-二甲基苯甲醯胺;N-乙基-4-((3-(7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-乙烯基吡唑并[1,5-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;N-乙基-4-((3-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-乙烯基咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;N-乙基-4-((3-(7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-乙烯基-2H-吲唑-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;4-((3-(7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-乙烯基吡唑并[1,5-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-(2-甲氧基乙基)-N-甲基苯甲醯胺;4-((3-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-乙烯基咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-(2-甲氧基乙基)-N-甲基苯甲醯胺;4-((3-(7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-乙烯基-2H-吲唑-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-(2-甲氧基乙基)-N-甲基苯甲醯胺;N-(2-(二甲基胺基)乙基)-4-((3-(7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-乙烯基吡唑并[1,5-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;N-(2-(二甲基胺基)乙基)-4-((3-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-乙烯基咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;N-(2-(二甲基胺基)乙基)-4-((3-(7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-乙烯基-2H-吲唑-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;4-((3-(7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-乙烯基吡唑并[1,5-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基苯磺醯胺;4-((3-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-乙烯基咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基苯磺醯胺;4-((3-(7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-乙烯基-2H-吲唑-2-基)丙-2-炔-1-基)胺基)-3-甲氧基苯磺醯胺;4-((3-(7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-乙烯基吡唑并[1,5-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯磺醯胺;4-((3-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-乙烯基咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯磺醯胺;4-((3-(7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-乙烯基-2H-吲唑-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯磺醯胺;4-((3-(7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-乙烯基吡唑并[1,5-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N,N-二甲基苯磺醯胺;4-((3-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-乙烯基咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N,N-二甲基苯磺醯胺;4-((3-(7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-乙烯基-2H-吲唑-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N,N-二甲基苯磺醯胺;N-((3S,4R)-3-氟哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-乙烯基吡唑并[1,5-a]吡啶-7-胺;N-((3S,4R)-3-氟哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-乙烯基咪唑并[1,2-a]吡啶-8-胺;N-((3S,4R)-3-氟哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-乙烯基-2H-吲唑-7-胺;N-((3S,4R)-1-乙基-3-氟哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-乙烯基吡唑并[1,5-a]吡啶-7-胺;N-((3S,4R)-1-乙基-3-氟哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-乙烯基咪唑并[1,2-a]吡啶-8-胺;N-((3S,4R)-1-乙基-3-氟哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-乙烯基-2H-吲唑-7-胺;2-((3S,4R)-3-氟-4-((2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-乙烯基吡唑并[1,5-a]吡啶-7-基)胺基)哌啶-1-基)乙-1-醇;2-((3S,4R)-3-氟-4-((2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-乙烯基咪唑并[1,2-a]吡啶-8-基)胺基)哌啶-1-基)乙-1-醇;2-((3S,4R)-3-氟-4-((2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-乙烯基-2H-吲唑-7-基)胺基)哌啶-1-基)乙-1-醇;N-((3S,4R)-3-氟-1-(2-甲氧基乙基)哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-乙烯基吡唑并[1,5-a]吡啶-7-胺;N-((3S,4R)-3-氟-1-(2-甲氧基乙基)哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-乙烯基咪唑并[1,2-a]吡啶-8-胺;N-((3S,4R)-3-氟-1-(2-甲氧基乙基)哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-乙烯基-2H-吲唑-7-胺;N-((3S,4R)-3-氟-1-異丙基哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-乙烯基吡唑并[1,5-a]吡啶-7-胺;N-((3S,4R)-3-氟-1-異丙基哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-乙烯基咪唑并[1,2-a]吡啶-8-胺;N-((3S,4R)-3-氟-1-異丙基哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-乙烯基-2H-吲唑-7-胺;1-((3S,4R)-3-氟-4-((2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-乙烯基吡唑并[1,5-a]吡啶-7-基)胺基)哌啶-1-基)乙-1-酮;1-((3S,4R)-3-氟-4-((2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-乙烯基咪唑并[1,2-a]吡啶-8-基)胺基)哌啶-1-基)乙-1-酮;1-((3S,4R)-3-氟-4-((2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-乙烯基-2H-吲唑-7-基)胺基)哌啶-1-基)乙-1-酮;(3S,4R)-3-氟-4-((2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-乙烯基吡唑并[1,5-a]吡啶-7-基)胺基)-N-甲基哌啶-1-甲醯胺;(3S,4R)-3-氟-4-((2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-乙烯基咪唑并[1,2-a]吡啶-8-基)胺基)-N-甲基哌啶-1-甲醯胺;(3S,4R)-3-氟-4-((2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-乙烯基-2H-吲唑-7-基)胺基)-N-甲基哌啶-1-甲醯胺;(3S,4R)-3-氟-4-((2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-乙烯基吡唑并[1,5-a]吡啶-7-基)胺基)哌啶-1-甲酸甲酯;(3S,4R)-3-氟-4-((2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-乙烯基咪唑并[1,2-a]吡啶-8-基)胺基)哌啶-1-甲酸甲酯;(3S,4R)-3-氟-4-((2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-乙烯基-2H-吲唑-7-基)胺基)哌啶-1-甲酸甲酯;2-胺基-1-((3S,4R)-3-氟-4-((2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-乙烯基吡唑并[1,5-a]吡啶-7-基)胺基)哌啶-1-基)乙-1-酮;2-胺基-1-((3S,4R)-3-氟-4-((2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-乙烯基咪唑并[1,2-a]吡啶-8-基)胺基)哌啶-1-基)乙-1-酮;2-胺基-1-((3S,4R)-3-氟-4-((2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-乙烯基-2H-吲唑-7-基)胺基)哌啶-1-基)乙-1-酮;2-(二甲基胺基)-1-((3S,4R)-3-氟-4-((2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-乙烯基吡唑并[1,5-a]吡啶-7-基)胺基)哌啶-1-基)乙-1-酮;2-(二甲基胺基)-1-((3S,4R)-3-氟-4-((2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-乙烯基咪唑并[1,2-a]吡啶-8-基)胺基)哌啶-1-基)乙-1-酮;2-(二甲基胺基)-1-((3S,4R)-3-氟-4-((2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-乙烯基-2H-吲唑-7-基)胺基)哌啶-1-基)乙-1-酮;4-((3-(7-(((3S,4R)-1-乙基-3-氟哌啶-4-基)胺基)-3-乙烯基吡唑并[1,5-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;4-((3-(8-(((3S,4R)-1-乙基-3-氟哌啶-4-基)胺基)-3-乙烯基咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;4-((3-(7-(((3S,4R)-1-乙基-3-氟哌啶-4-基)胺基)-3-乙烯基-2H-吲唑-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;4-((3-(7-(((3S,4R)-3-氟-1-異丙基哌啶-4-基)胺基)-3-乙烯基吡唑并[1,5-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;4-((3-(8-(((3S,4R)-3-氟-1-異丙基哌啶-4-基)胺基)-3-乙烯基咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;4-((3-(7-(((3S,4R)-3-氟-1-異丙基哌啶-4-基)胺基)-3-乙烯基-2H-吲唑-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;N7-((3S,4R)-3-氟-1-甲基哌啶-4-基)-2-(3-((2-甲氧基-4-甲基苯基)胺基)丙-1-炔-1-基)-3-乙烯基吡唑并[1,5-a]吡啶-5,7-二胺;N8-((3S,4R)-3-氟-1-甲基哌啶-4-基)-2-(3-((2-甲氧基-4-甲基苯基)胺基)丙-1-炔-1-基)-3-乙烯基咪唑并[1,2-a]吡啶-6,8-二胺;N7-((3S,4R)-3-氟-1-甲基哌啶-4-基)-2-(3-((2-甲氧基-4-甲基苯基)胺基)丙-1-炔-1-基)-3-乙烯基-2H-吲唑-5,7-二胺;4-((3-(7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(1-氟乙烯基)吡唑并[1,5-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;4-((3-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(1-氟乙烯基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;4-((3-(7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(1-氟乙烯基)-2H-吲唑-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;4-((3-(7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(丙-1-烯-2-基)吡唑并[1,5-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;4-((3-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(丙-1-烯-2-基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;4-((3-(7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(丙-1-烯-2-基)-2H-吲唑-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;4-((3-(7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(3,3,3-三氟丙-1-烯-2-基)吡唑并[1,5-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;4-((3-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(3,3,3-三氟丙-1-烯-2-基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;4-((3-(7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(3,3,3-三氟丙-1-烯-2-基)-2H-吲唑-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;4-((3-(7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(1,2,2-三氟乙烯基)吡唑并[1,5-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;4-((3-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(1,2,2-三氟乙烯基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;4-((3-(7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(1,2,2-三氟乙烯基)-2H-吲唑-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;4-((3-(7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-((E)-丙-1-烯-1-基)吡唑并[1,5-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;4-((3-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-((E)-丙-1-烯-1-基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;4-((3-(7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-((E)-丙-1-烯-1-基)-2H-吲唑-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;4-((3-(3-乙炔基-7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)吡唑并[1,5-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;4-((3-(3-乙炔基-8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;4-((3-(3-乙炔基-7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-2H-吲唑-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;4-((3-(7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(丙-1-炔-1-基)吡唑并[1,5-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;4-((3-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(丙-1-炔-1-基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;4-((3-(7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(丙-1-炔-1-基)-2H-吲唑-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;4-((3-(7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-((Z)-丙-1-烯-1-基)吡唑并[1,5-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;4-((3-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-((Z)-丙-1-烯-1-基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;4-((3-(7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-((Z)-丙-1-烯-1-基)-2H-吲唑-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;4-((3-(7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-((E)-3,3,3-三氟丙-1-烯-1-基)吡唑并[1,5-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;4-((3-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-((E)-3,3,3-三氟丙-1-烯-1-基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;4-((3-(7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-((E)-3,3,3-三氟丙-1-烯-1-基)-2H-吲唑-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;4-((3-(3-(2,2-二氟乙烯基)-7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)吡唑并[1,5-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;4-((3-(3-(2,2-二氟乙烯基)-8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;4-((3-(3-(2,2-二氟乙烯基)-7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-2H-吲唑-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;5-氟-N-((3S,4R)-3-氟-1-甲基哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-乙烯基吡唑并[1,5-a]吡啶-7-胺;6-氟-N-((3S,4R)-3-氟-1-甲基哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-乙烯基咪唑并[1,2-a]吡啶-8-胺;5-氟-N-((3S,4R)-3-氟-1-甲基哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-乙烯基-2H-吲唑-7-胺;N-((3S,4R)-3-氟-1-甲基哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-((R)-環氧乙-2-基)吡唑并[1,5-a]吡啶-7-胺;N-((3S,4R)-3-氟-1-甲基哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-((R)-環氧乙-2-基)咪唑并[1,2-a]吡啶-8-胺;N-((3S,4R)-3-氟-1-甲基哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-((R)-環氧乙-2-基)-2H-吲唑-7-胺;N-((3S,4R)-3-氟-1-甲基哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-((S)-環氧乙-2-基)吡唑并[1,5-a]吡啶-7-胺;N-((3S,4R)-3-氟-1-甲基哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-((S)-環氧乙-2-基)咪唑并[1,2-a]吡啶-8-胺;N-((3S,4R)-3-氟-1-甲基哌啶-4-基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-((S)-環氧乙-2-基)-2H-吲唑-7-胺;N-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-6-基)丙烯醯胺;N-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-6-基)甲基丙烯醯胺;(E)-N-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-6-基)丁-2-烯醯胺;(E)-4-(二甲基胺基)-N-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-6-基)丁-2-烯醯胺;(E)-N-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-6-基)-4-(甲基胺基)丁-2-烯醯胺;N-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-6-基)丁-2-炔醯胺;4-(二甲基胺基)-N-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-6-基)丁-2-炔醯胺;1-(3-((8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-6-基)胺基)氮雜環丁-1-基)丙-2-烯-1-酮;1-((S)-3-((8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-6-基)胺基)吡咯啶-1-基)丙-2-烯-1-酮;1-((R)-3-((8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-6-基)胺基)吡咯啶-1-基)丙-2-烯-1-酮;1-(4-((8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-6-基)胺基)哌啶-1-基)丙-2-烯-1-酮;1-(3-((8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-6-基)氧基)氮雜環丁-1-基)丙-2-烯-1-酮;2-氟-N-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-6-基)丙烯醯胺;N-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-6-基)丙炔醯胺;(E)-4-(3,3-二氟氮雜環丁-1-基)-N-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-6-基)丁-2-烯醯胺;(E)-N-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-6-基)-4-(4-甲基哌嗪-1-基)丁-2-烯醯胺;(E)-N-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-6-基)-4-嗎啉基丁-2-烯醯胺;N-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-6-基)-4-(甲基胺基)丁-2-炔醯胺;1-(3-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-6-基)氮雜環丁-1-基)丙-2-烯-1-酮;2-氟-1-(3-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-6-基)氮雜環丁-1-基)丙-2-烯-1-酮;(E)-4-(二甲基胺基)-1-(3-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-6-基)氮雜環丁-1-基)丁-2-烯-1-酮;1-((2S)-4-((8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-6-基)胺基)-2-甲基哌啶-1-基)丙-2-烯-1-酮;1-((2R)-4-((8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-6-基)胺基)-2-甲基哌啶-1-基)丙-2-烯-1-酮;2-氟-1-(3-((8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-6-基)胺基)氮雜環丁-1-基)丙-2-烯-1-酮;(E)-4-(二甲基胺基)-1-(3-((8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-6-基)胺基)氮雜環丁-1-基)丁-2-烯-1-酮;1-(3-((8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-6-基)硫代)氮雜環丁-1-基)丙-2-烯-1-酮;N-((3-(7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(2,2,2-三氟乙基)-2H-吲唑-2-基)-1,2,4-噁二唑-5-基)甲基)環丙烷甲醯胺;N-((3-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)-1,2,4-噁二唑-5-基)甲基)環丙烷甲醯胺;N-((3-(7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(2,2,2-三氟乙基)吡唑并[1,5-a]吡啶-2-基)-1,2,4-噁二唑-5-基)甲基)環丙烷甲醯胺;1-(三級丁基)-N-((3-(7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(2,2,2-三氟乙基)-2H-吲唑-2-基)-1,2,4-噁二唑-5-基)甲基)-1H-吡唑-4-甲醯胺;1-(三級丁基)-N-((3-(7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(2,2,2-三氟乙基)-2H-吲唑-2-基)-1,2,4-噁二唑-5-基)甲基)-1H-吡咯-3-甲醯胺;1-(三級丁基)-N-((3-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)-1,2,4-噁二唑-5-基)甲基)-1H-吡唑-4-甲醯胺;1-(三級丁基)-N-((3-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)-1,2,4-噁二唑-5-基)甲基)-1H-吡咯-3-甲醯胺;1-(三級丁基)-N-((3-(7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(2,2,2-三氟乙基)吡唑并[1,5-a]吡啶-2-基)-1,2,4-噁二唑-5-基)甲基)-1H-吡唑-4-甲醯胺;1-(三級丁基)-N-((3-(7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(2,2,2-三氟乙基)吡唑并[1,5-a]吡啶-2-基)-1,2,4-噁二唑-5-基)甲基)-1H-吡咯-3-甲醯胺;N-((5-(7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(2,2,2-三氟乙基)-2H-吲唑-2-基)-1,3,4-噻二唑-2-基)甲基)環丙烷甲醯胺;1-(三級丁基)-N-((5-(7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(2,2,2-三氟乙基)-2H-吲唑-2-基)-1,3,4-噻二唑-2-基)甲基)-1H-吡唑-4-甲醯胺;1-(三級丁基)-N-((5-(7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(2,2,2-三氟乙基)-2H-吲唑-2-基)-1,3,4-噻二唑-2-基)甲基)-1H-吡咯-3-甲醯胺;N-((5-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)-1,3,4-噻二唑-2-基)甲基)環丙烷甲醯胺;1-(三級丁基)-N-((5-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)-1,3,4-噻二唑-2-基)甲基)-1H-吡唑-4-甲醯胺;1-(三級丁基)-N-((5-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)-1,3,4-噻二唑-2-基)甲基)-1H-吡咯-3-甲醯胺;N-((5-(7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(2,2,2-三氟乙基)吡唑并[1,5-a]吡啶-2-基)-1,3,4-噻二唑-2-基)甲基)環丙烷甲醯胺;1-(三級丁基)-N-((5-(7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(2,2,2-三氟乙基)吡唑并[1,5-a]吡啶-2-基)-1,3,4-噻二唑-2-基)甲基)-1H-吡唑-4-甲醯胺;1-(三級丁基)-N-((5-(7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(2,2,2-三氟乙基)吡唑并[1,5-a]吡啶-2-基)-1,3,4-噻二唑-2-基)甲基)-1H-吡咯-3-甲醯胺;N-((3-(5-胺基-7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(2,2,2-三氟乙基)-2H-吲唑-2-基)-1,2,4-噁二唑-5-基)甲基)環丙烷甲醯胺;N-((3-(5-胺基-7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(2,2,2-三氟乙基)-2H-吲唑-2-基)-1,2,4-噁二唑-5-基)甲基)-1-(三級丁基)-1H-吡唑-4-甲醯胺;N-((3-(5-胺基-7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(2,2,2-三氟乙基)-2H-吲唑-2-基)-1,2,4-噁二唑-5-基)甲基)-1-(三級丁基)-1H-吡咯-3-甲醯胺;N-((3-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡嗪-2-基)-1,2,4-噁二唑-5-基)甲基)環丙烷甲醯胺;1-(三級丁基)-N-((3-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡嗪-2-基)-1,2,4-噁二唑-5-基)甲基)-1H-吡唑-4-甲醯胺;1-(三級丁基)-N-((3-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡嗪-2-基)-1,2,4-噁二唑-5-基)甲基)-1H-吡咯-3-甲醯胺;N-((3-(7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(2,2,2-三氟乙基)吡唑并[1,5-a]吡嗪-2-基)-1,2,4-噁二唑-5-基)甲基)環丙烷甲醯胺;1-(三級丁基)-N-((3-(7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(2,2,2-三氟乙基)吡唑并[1,5-a]吡嗪-2-基)-1,2,4-噁二唑-5-基)甲基)-1H-吡唑-4-甲醯胺;1-(三級丁基)-N-((3-(7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(2,2,2-三氟乙基)吡唑并[1,5-a]吡嗪-2-基)-1,2,4-噁二唑-5-基)甲基)-1H-吡咯-3-甲醯胺;N-((5-(5-胺基-7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(2,2,2-三氟乙基)-2H-吲唑-2-基)-1,3,4-噻二唑-2-基)甲基)環丙烷甲醯胺;N-((5-(5-胺基-7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(2,2,2-三氟乙基)-2H-吲唑-2-基)-1,3,4-噻二唑-2-基)甲基)-1-(三級丁基)-1H-吡咯-3-甲醯胺;N-((5-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡嗪-2-基)-1,3,4-噻二唑-2-基)甲基)環丙烷甲醯胺;1-(三級丁基)-N-((5-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡嗪-2-基)-1,3,4-噻二唑-2-基)甲基)-1H-吡唑-4-甲醯胺;1-(三級丁基)-N-((5-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡嗪-2-基)-1,3,4-噻二唑-2-基)甲基)-1H-吡咯-3-甲醯胺;N-((5-(7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(2,2,2-三氟乙基)吡唑并[1,5-a]吡嗪-2-基)-1,3,4-噻二唑-2-基)甲基)環丙烷甲醯胺;N-((5-(5-胺基-7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(2,2,2-三氟乙基)-2H-吲唑-2-基)-1,3,4-噻二唑-2-基)甲基)-1-(三級丁基)-1H-吡唑-4-甲醯胺;1-(三級丁基)-N-((5-(7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(2,2,2-三氟乙基)吡唑并[1,5-a]吡嗪-2-基)-1,3,4-噻二唑-2-基)甲基)-1H-吡唑-4-甲醯胺;1-(三級丁基)-N-((5-(7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(2,2,2-三氟乙基)吡唑并[1,5-a]吡嗪-2-基)-1,3,4-噻二唑-2-基)甲基)-1H-吡咯-3-甲醯胺;N-((3-(5-氟-7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(2,2,2-三氟乙基)-2H-吲唑-2-基)-1,2,4-噁二唑-5-基)甲基)環丙烷甲醯胺;1-(三級丁基)-N-((3-(5-氟-7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(2,2,2-三氟乙基)-2H-吲唑-2-基)-1,2,4-噁二唑-5-基)甲基)-1H-吡唑-4-甲醯胺;1-(三級丁基)-N-((3-(5-氟-7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(2,2,2-三氟乙基)-2H-吲唑-2-基)-1,2,4-噁二唑-5-基)甲基)-1H-吡咯-3-甲醯胺;N-((5-(5-氟-7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(2,2,2-三氟乙基)-2H-吲唑-2-基)-1,3,4-噻二唑-2-基)甲基)環丙烷甲醯胺;1-(三級丁基)-N-((5-(5-氟-7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(2,2,2-三氟乙基)-2H-吲唑-2-基)-1,3,4-噻二唑-2-基)甲基)-1H-吡唑-4-甲醯胺;1-(三級丁基)-N-((5-(5-氟-7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(2,2,2-三氟乙基)-2H-吲唑-2-基)-1,3,4-噻二唑-2-基)甲基)-1H-吡咯-3-甲醯胺;N-((3-(7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(全氟乙基)-2H-吲唑-2-基)-1,2,4-噁二唑-5-基)甲基)環丙烷甲醯胺;1-(三級丁基)-N-((3-(7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(全氟乙基)-2H-吲唑-2-基)-1,2,4-噁二唑-5-基)甲基)-1H-吡唑-4-甲醯胺;1-(三級丁基)-N-((3-(7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(全氟乙基)-2H-吲唑-2-基)-1,2,4-噁二唑-5-基)甲基)-1H-吡咯-3-甲醯胺;N-((5-(7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(全氟乙基)吡唑并[1,5-a]吡啶-2-基)-1,3,4-噻二唑-2-基)甲基)環丙烷甲醯胺;1-(三級丁基)-N-((5-(7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(全氟乙基)吡唑并[1,5-a]吡啶-2-基)-1,3,4-噻二唑-2-基)甲基)-1H-吡唑-4-甲醯胺;1-(三級丁基)-N-((5-(7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-(全氟乙基)吡唑并[1,5-a]吡啶-2-基)-1,3,4-噻二唑-2-基)甲基)-1H-吡咯-3-甲醯胺;(S)-2-甲氧基-4-甲基-N-(3-(8-(4-甲基哌嗪-2-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)苯胺;2-甲氧基-N-(3-(8-(4-甲基哌嗪-2-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-4-(甲基磺醯基)苯胺;(S)-6-(2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)-4-甲基哌嗪-2-酮;6-(2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)-4-甲基哌嗪-2-酮;(R)-2-甲氧基-N-(3-(8-(6-甲基-1,6-二氮雜螺[3.3]庚-2-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-4-(甲基磺醯基)苯胺;(S)-2-甲氧基-N-(3-(8-(6-甲基-1,6-二氮雜螺[3.3]庚-2-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-4-(甲基磺醯基)苯胺;(R)-2-甲氧基-N-(3-(8-(6-甲基-2,6-二氮雜螺[3.3]庚-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-4-(甲基磺醯基)苯胺;(S)-2-甲氧基-N-(3-(8-(6-甲基-2,6-二氮雜螺[3.3]庚-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-4-(甲基磺醯基)苯胺;(S)-N-(3-(8-(2-氧雜-6-氮雜螺[3.3]庚-5-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-(甲基磺醯基)苯胺;(R)-N-(3-(8-(2-氧雜-6-氮雜螺[3.3]庚-5-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-(甲基磺醯基)苯胺;N-(3-(8-((2R,5R)-5-((二甲基胺基)甲基)吡咯啶-2-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-(甲基磺醯基)苯胺;N-(3-(8-((2R,5S)-5-((二甲基胺基)甲基)吡咯啶-2-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-(甲基磺醯基)苯胺;N-(3-(8-((2S,5R)-5-((二甲基胺基)甲基)吡咯啶-2-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-(甲基磺醯基)苯胺;N-(3-(8-((2S,5S)-5-((二甲基胺基)甲基)吡咯啶-2-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-(甲基磺醯基)苯胺;2-甲氧基-N-(3-(8-((2R,3aS,6aS)-5-甲基八氫吡咯并[3,4-b]吡咯-2-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-4-(甲基磺醯基)苯胺;2-甲氧基-N-(3-(8-((2R,3aR,6aR)-5-甲基八氫吡咯并[3,4-b]吡咯-2-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-4-(甲基磺醯基)苯胺;2-甲氧基-N-(3-(8-((2S,3aS,6aS)-5-甲基八氫吡咯并[3,4-b]吡咯-2-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-4-(甲基磺醯基)苯胺;2-甲氧基-N-(3-(8-((2S,3aR,6aR)-5-甲基八氫吡咯并[3,4-b]吡咯-2-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-4-(甲基磺醯基)苯胺;2-甲氧基-N-(3-(8-((2R,5S)-7-甲基-1,7-二氮雜螺[4.4]壬-2-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-4-(甲基磺醯基)苯胺;2-甲氧基-N-(3-(8-((2R,5R)-7-甲基-1,7-二氮雜螺[4.4]壬-2-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-4-(甲基磺醯基)苯胺;2-甲氧基-N-(3-(8-((2S,5S)-7-甲基-1,7-二氮雜螺[4.4]壬-2-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-4-(甲基磺醯基)苯胺;2-甲氧基-N-(3-(8-((5R)-7-甲基-1,7-二氮雜螺[4.4]壬-2-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-4-(甲基磺醯基)苯胺;N-(3-(8-((2R,5S)-7-氧雜-1-氮雜螺[4.4]壬-2-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-(甲基磺醯基)苯胺;N-(3-(8-((2R,5R)-7-氧雜-1-氮雜螺[4.4]壬-2-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-(甲基磺醯基)苯胺;N-(3-(8-((2S,5S)-7-氧雜-1-氮雜螺[4.4]壬-2-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-(甲基磺醯基)苯胺;N-(3-(8-((5R)-7-氧雜-1-氮雜螺[4.4]壬-2-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-(甲基磺醯基)苯胺;N-(3-(8-((2R,3aR,6aR)-3a-氟-5-甲基八氫吡咯并[3,4-b]吡咯-2-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-(甲基磺醯基)苯胺;N-(3-(8-((2R,3aS,6aS)-3a-氟-5-甲基八氫吡咯并[3,4-b]吡咯-2-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-(甲基磺醯基)苯胺;N-(3-(8-((2S,3aR,6aR)-3a-氟-5-甲基八氫吡咯并[3,4-b]吡咯-2-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-(甲基磺醯基)苯胺;N-(3-(8-((2S,3aS,6aS)-3a-氟-5-甲基八氫吡咯并[3,4-b]吡咯-2-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-(甲基磺醯基)苯胺;N-(3-(8-((2R,6S)-6-((二甲基胺基)甲基)哌啶-2-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-(甲基磺醯基)苯胺;N-(3-(8-((2R,6R)-6-((二甲基胺基)甲基)哌啶-2-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-(甲基磺醯基)苯胺;N-(3-(8-((2S,6R)-6-((二甲基胺基)甲基)哌啶-2-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-(甲基磺醯基)苯胺;N-(3-(8-((6S)-6-((二甲基胺基)甲基)哌啶-2-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-(甲基磺醯基)苯胺;N-(3-(8-((3S,5R)-5-((二甲基胺基)甲基)嗎啉-3-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-(甲基磺醯基)苯胺;N-(3-(8-((3S,5S)-5-((二甲基胺基)甲基)嗎啉-3-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-(甲基磺醯基)苯胺;N-(3-(8-((3R,5S)-5-((二甲基胺基)甲基)嗎啉-3-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-(甲基磺醯基)苯胺;N-(3-(8-((5R)-5-((二甲基胺基)甲基)嗎啉-3-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-(甲基磺醯基)苯胺;N-(3-(8-((2R,6S)-6-((二甲基胺基)甲基)-4,4-二氟哌啶-2-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-(甲基磺醯基)苯胺;N-(3-(8-((2R,6R)-6-((二甲基胺基)甲基)-4,4-二氟哌啶-2-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-(甲基磺醯基)苯胺;N-(3-(8-((2S,6R)-6-((二甲基胺基)甲基)-4,4-二氟哌啶-2-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-(甲基磺醯基)苯胺;N-(3-(8-((6S)-6-((二甲基胺基)甲基)-4,4-二氟哌啶-2-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-(甲基磺醯基)苯胺;(R)-2-甲氧基-N-(3-(8-(1-甲基-1,4-二氮雜環庚-5-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-4-(甲基磺醯基)苯胺;(S)-2-甲氧基-N-(3-(8-(1-甲基-1,4-二氮雜環庚-5-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-4-(甲基磺醯基)苯胺;(S)-N-(3-(8-(6,6-二氟-1-甲基-1,4-二氮雜環庚-5-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-(甲基磺醯基)苯胺;(R)-N-(3-(8-(6,6-二氟-1-甲基-1,4-二氮雜環庚-5-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-(甲基磺醯基)苯胺;N-(3-(8-((5S,6R)-6-氟-1-甲基-1,4-二氮雜環庚-5-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-(甲基磺醯基)苯胺;N-(3-(8-((5R,6R)-6-氟-1-甲基-1,4-二氮雜環庚-5-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-(甲基磺醯基)苯胺;N-(3-(8-((5S,6S)-6-氟-1-甲基-1,4-二氮雜環庚-5-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-(甲基磺醯基)苯胺;N-(3-(8-((5R,6S)-6-氟-1-甲基-1,4-二氮雜環庚-5-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-(甲基磺醯基)苯胺;N-(3-(8-((5S,6S)-6-氟-1,4-氧雜氮雜環庚-5-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-(甲基磺醯基)苯胺;N-(3-(8-((5R,6S)-6-氟-1,4-氧雜氮雜環庚-5-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-甲基苯胺;N-(3-(8-((5S,6R)-6-氟-1,4-氧雜氮雜環庚-5-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-(甲基磺醯基)苯胺;N-(3-(8-((5R,6R)-6-氟-1,4-氧雜氮雜環庚-5-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-(甲基磺醯基)苯胺;(R)-N-(3-(8-(1,4-氧雜氮雜環庚-5-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-(甲基磺醯基)苯胺;(S)-N-(3-(8-(1,4-氧雜氮雜環庚-5-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-(甲基磺醯基)苯胺;(S)-N-(3-(8-(6,6-二氟-1,4-氧雜氮雜環庚-5-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-(甲基磺醯基)苯胺;(R)-N-(3-(8-(6,6-二氟-1,4-氧雜氮雜環庚-5-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-(甲基磺醯基)苯胺;2-甲氧基-N-(3-(8-((1S,5R,7R)-3-甲基-3,6-二氮雜雙環[3.2.1]辛-7-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-4-(甲基磺醯基)苯胺;2-甲氧基-N-(3-(8-((1R,5S,7S)-3-甲基-3,6-二氮雜雙環[3.2.1]辛-7-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-4-(甲基磺醯基)苯胺;2-甲氧基-N-(3-(8-((1S,5R,7S)-3-甲基-3,6-二氮雜雙環[3.2.1]辛-7-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-4-(甲基磺醯基)苯胺;2-甲氧基-N-(3-(8-((1R,5S,7R)-3-甲基-3,6-二氮雜雙環[3.2.1]辛-7-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-4-(甲基磺醯基)苯胺;N-(3-(8-((2R,4S)-4-((二甲基胺基)甲基)氮雜環丁-2-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-(甲基磺醯基)苯胺;N-(3-(8-((2R,4R)-4-((二甲基胺基)甲基)氮雜環丁-2-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-(甲基磺醯基)苯胺;N-(3-(8-((2S,4S)-4-((二甲基胺基)甲基)氮雜環丁-2-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-(甲基磺醯基)苯胺;N-(3-(8-((2S,4R)-4-((二甲基胺基)甲基)氮雜環丁-2-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-(甲基磺醯基)苯胺;(3R)-3-((二甲基胺基)甲基)-5-(2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)吡咯啶-2-酮;(3S)-3-((二甲基胺基)甲基)-5-(2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)吡咯啶-2-酮;(2R)-2-((二甲基胺基)甲基)-5-(2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)嗎啉-3-酮;(2S)-2-((二甲基胺基)甲基)-5-(2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)嗎啉-3-酮;3-((二甲基胺基)甲基)-6-(2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)吡啶-2(1H)-酮;3-(二甲基胺基)-6-(2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)吡啶-2(1H)-酮;3-(二甲基胺基)-6-(2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)吡嗪-2(1H)-酮;2-(二甲基胺基)-6-(2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)吡啶-4(1H)-酮;(S)-2-(1-(二甲基胺基)乙基)-6-(2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)吡啶-4(1H)-酮;(R)-2-(1-(二甲基胺基)乙基)-6-(2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)吡啶-4(1H)-酮;N-(3-(8-(3-((二甲基胺基)甲基)-1H-吡唑-5-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-(甲基磺醯基)苯胺;N-(3-(8-(3-((二甲基胺基)甲基)-1H-1,2,4-三唑-5-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-(甲基磺醯基)苯胺;N-(3-(8-(4-((二甲基胺基)甲基)-1H-咪唑-2-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-(甲基磺醯基)苯胺;2-甲氧基-N-(3-(8-(6-甲基-4,5,6,7-四氫-2H-吡唑并[3,4-c]吡啶-3-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-4-(甲基磺醯基)苯胺;2-甲氧基-N-(3-(8-(4-甲基-4,5,6,7-四氫-2H-吡唑并[4,3-b]吡啶-3-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-4-(甲基磺醯基)苯胺;2-甲氧基-N-(3-(8-(5-甲基-4,5,6,7-四氫-2H-吡唑并[4,3-c]吡啶-3-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-4-(甲基磺醯基)苯胺;2-甲氧基-N-(3-(8-(7-甲基-4,5,6,7-四氫-2H-吡唑并[3,4-b]吡啶-3-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-4-(甲基磺醯基)苯胺;2-甲氧基-N-(3-(8-(7-甲基-2,5,6,7-四氫吡唑并[4,3-b][1,4]噁嗪-3-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-4-(甲基磺醯基)苯胺;2-甲氧基-N-(3-(8-(4-甲基-2,4,5,6-四氫吡唑并[3,4-b][1,4]噁嗪-3-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-4-(甲基磺醯基)苯胺;2-甲氧基-N-(3-(8-(5-甲基-4,5,6,7-四氫-3H-咪唑并[4,5-c]吡啶-2-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-4-(甲基磺醯基)苯胺;N-(3-(8-(7,7-二氟-5-甲基-4,5,6,7-四氫-3H-咪唑并[4,5-c]吡啶-2-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-(甲基磺醯基)苯胺;N-(3-(8-(4,4-二氟-6-甲基-4,5,6,7-四氫-2H-吡唑并[3,4-c]吡啶-3-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-(甲基磺醯基)苯胺;(R)-3-(2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)-N,N-二甲基-2,4,5,6-四氫環戊[c]吡唑-6-胺;(S)-3-(2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)-N,N-二甲基-2,4,5,6-四氫環戊[c]吡唑-6-胺;(R)-2-甲氧基-4-(甲基磺醯基)-N-(3-(8-(5,6,7,8-四氫-4H-吡唑并[1,5-a][1,3]二氮呯-5-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)苯胺;(S)-2-甲氧基-4-(甲基磺醯基)-N-(3-(8-(5,6,7,8-四氫-4H-吡唑并[1,5-a][1,3]二氮呯-5-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)苯胺;(R)-2-甲氧基-4-(甲基磺醯基)-N-(3-(8-(2,3,4,5-四氫-1H-咪唑并[1,5-a][1,3]二氮呯-2-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)苯胺;(S)-2-甲氧基-4-(甲基磺醯基)-N-(3-(8-(2,3,4,5-四氫-1H-咪唑并[1,5-a][1,3]二氮呯-2-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)苯胺;(R)-2-甲氧基-4-(甲基磺醯基)-N-(3-(8-(4,5,6,7-四氫吡唑并[1,5-a]嘧啶-5-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)苯胺;(S)-2-甲氧基-4-(甲基磺醯基)-N-(3-(8-(4,5,6,7-四氫吡唑并[1,5-a]嘧啶-5-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)苯胺;(R)-N-(1-(2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)乙基)-1-甲基-1H-吡唑-5-胺;(S)-N-(1-(2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)乙基)-1-甲基-1H-吡唑-5-胺;(S)-N-(2,2-二氟-1-(2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)乙基)-1-甲基-1H-吡唑-5-胺;(R)-N-(2,2-二氟-1-(2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)乙基)-1-甲基-1H-吡唑-5-胺;(S)-1-甲基-N-(2,2,2-三氟-1-(2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)乙基)-1H-吡唑-5-胺;(R)-1-甲基-N-(2,2,2-三氟-1-(2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)乙基)-1H-吡唑-5-胺;N-(3-(8-((S)-胺基((3R,4S)-3-氟-1-甲基哌啶-4-基)甲基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-(甲基磺醯基)苯胺;N-(3-(8-((S)-((3R,4S)-3-氟-1-甲基哌啶-4-基)(甲基胺基)甲基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-(甲基磺醯基)苯胺;N-((S)-((3R,4S)-3-氟-1-甲基哌啶-4-基)(2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)甲基)乙醯胺;N-(3-(8-((S)-胺基((3S,4S)-3-氟-1-甲基哌啶-4-基)甲基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-(甲基磺醯基)苯胺;N-(3-(8-((S)-((3S,4S)-3-氟-1-甲基哌啶-4-基)(甲基胺基)甲基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-(甲基磺醯基)苯胺;N-((S)-((3S,4S)-3-氟-1-甲基哌啶-4-基)(2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)甲基)乙醯胺;N-(3-(8-((S)-胺基((3R,4R)-3-氟-1-甲基哌啶-4-基)甲基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-(甲基磺醯基)苯胺;N-(3-(8-((S)-((3R,4R)-3-氟-1-甲基哌啶-4-基)(甲基胺基)甲基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-(甲基磺醯基)苯胺;N-((S)-((3R,4R)-3-氟-1-甲基哌啶-4-基)(2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)甲基)乙醯胺;N-(3-(8-((R)-胺基((3R,4R)-3-氟-1-甲基哌啶-4-基)甲基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-(甲基磺醯基)苯胺;N-(3-(8-((R)-((3R,4R)-3-氟-1-甲基哌啶-4-基)(甲基胺基)甲基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-(甲基磺醯基)苯胺;N-((R)-((3R,4R)-3-氟-1-甲基哌啶-4-基)(2-(3-((2-甲氧基-4-(甲基磺醯基)苯基)胺基)丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)甲基)乙醯胺;(R)-N-(3-(8-(4-氟-6-甲基-4,5,6,7-四氫-2H-吡唑并[3,4-c]吡啶-3-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-(甲基磺醯基)苯胺;及(S)-N-(3-(8-(4-氟-6-甲基-4,5,6,7-四氫-2H-吡唑并[3,4-c]吡啶-3-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)-2-甲氧基-4-(甲基磺醯基)苯胺。N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinyl-2H-indazol-7-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinyl-2H-indazol-7-amine N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(prop-1-en-2-yl)-2H-indazol-7-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(prop-1-en-2-yl)-2H -indazol-7-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(1-fluorovinyl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-2H-indazol-7-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-2H-indazol-7-amine methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-((Z)-prop-1-en-1-yl)-2H-indazol-7-amine; 3-ethynyl-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-2H -indazol-7-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(prop-1-yn-1-yl)-2H-indazol-7-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-( (2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylimidazo[1,2-a]pyridin-8-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylpyrazolo[1 ,5-a]pyridin-7-amine; N7-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylpyrazolo[1,5-a]pyridine-5,7-diamine; N8-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl) -2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylimidazo[1,2-a]pyridine-6,8-diamine; N7-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)- 3-vinyl-2H-indazole-5,7-diamine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylpyrazolo[1,5-c]pyrimidin-7-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylpyrazolo[1,5-c]pyrimidin-7-amine N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylimidazo[1,2-a]pyrazin-8-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3 -vinyl-2H-pyrazolo[3,4-c]pyridin-7-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylpyrazolo[1,5-a]pyrazin-7-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylpyrazolo[1,5-a]pyrazin-7-amine 2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylimidazo[1,2-c]pyrimidin-8-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylimidazo[1,2-c]pyrimidin-8-amine -yl)-3-vinyl-2H-pyrazolo[4,3-c]pyridin-7-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-3-(1-fluorovinyl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)pyrazolo[1,5-a]pyridin-7-amine; N-((3S,4 R)-3-fluoro-1-methylpiperidin-4-yl)-3-(1-fluorovinyl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)imidazo[1,2-a]pyridin-8-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)imidazo[1,2-a]pyridin-8-amine 1-yn-1-yl)-3-(prop-1-en-2-yl)imidazo[1,5-a]pyridin-7-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(prop-1-en-2-yl)imidazo[1,5-a]pyridin-7-amine [1,2-a]pyridin-8-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(3,3,3-trifluoroprop-1-en-2-yl)pyrazolo[1,5-a]pyridin-7-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(3,3,3-trifluoroprop-1-en-2-yl)pyrazolo[1,5-a]pyridin-7-amine -1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(3,3,3-trifluoroprop-1-en-2-yl)imidazo[1,2-a]pyridin-8-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(3,3,3-trifluoroprop-1-en-2-yl)imidazo[1,2-a]pyridin-8-amine -(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(1,2,2-trifluorovinyl)pyrazolo[1,5-a]pyridin-7-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(1,2,2 -trifluorovinyl)imidazo[1,2-a]pyridin-8-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(1,2,2-trifluorovinyl)-2H-indazol-7-amine; N-((3S,4R)-3-fluoro- 1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-((E)-prop-1-en-1-yl)pyrazolo[1,5-a]pyridin-7-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-((E)-prop-1-en-1-yl)pyrazolo[1,5-a]pyridin-7-amine 1-yn-1-yl)-3-((E)-prop-1-en-1-yl)imidazo[1,2-a]pyridin-8-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-((E)-prop-1-en-1-yl)imidazo[1,2-a]pyridin-8-amine -1-yl)-2H-indazol-7-amine; 3-ethynyl-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)pyrazolo[1,5-a]pyridin-7-amine; 3-ethynyl-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)pyrazolo[1,5-a]pyridin-7-amine -4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)imidazo[1,2-a]pyridin-8-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(prop- -1-yn-1-yl)pyrazolo[1,5-a]pyridin-7-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(prop-1-yn-1-yl)imidazo[1,2-a]pyridin-8-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(prop-1-yn-1-yl)imidazo[1,2-a]pyridin-8-amine -3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-((Z)-prop-1-en-1-yl)pyrazolo[1,5-a]pyridin-7-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-((Z)-prop-1-en-1-yl)pyrazolo[1,5-a]pyridin-7-amine -(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-((Z)-prop-1-en-1-yl)imidazo[1,2-a]pyridin-8-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-((E) -3,3,3-trifluoroprop-1-en-1-yl)pyrazolo[1,5-a]pyridin-7-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-((E)-3,3,3-trifluoroprop-1-en-1-yl)imidazo[ 1,2-a]pyridin-8-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-((E)-3,3,3-trifluoroprop-1-en-1-yl)-2H-indazol-7-amine; 3-(2,2-difluorovinyl)-N-( (3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)pyrazolo[1,5-a]pyridin-7-amine; 3-(2,2-difluorovinyl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)pyrazolo[1,5-a]pyridin-7-amine 3-(2,2-difluorovinyl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-2H-indazole-7-yl)- Amine; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-vinylpyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxybenzamide; 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-vinylimidazole 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-vinyl-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3-methoxybenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-vinyl-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3-methoxybenzamide; 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-vinylpyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-vinylimidazo[1,2-a]pyridine-2 -yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-vinyl-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(7-(((3S,4 R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-vinylpyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N,N-dimethylbenzamide; 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-vinylimidazo[1,2-a]pyridine -2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N,N-dimethylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-vinyl-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N,N-dimethylbenzamide; N-ethyl-4-(( 3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-vinylpyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; N-ethyl-4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-ethyl N-ethyl-4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-vinyl-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; N-ethyl-4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-vinyl-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methyl Benzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-vinylpyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-(2-methoxyethyl)-N-methylbenzamide; 4-((3-(8-(((3S,4R)-3-fluoro-1- 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-vinyl-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-(2-methoxyethyl)-N-methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-vinyl-2H-indazol-2-yl)prop- N-(2-(dimethylamino)ethyl)-4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-vinylpyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-(2-methoxyethyl)-N-methylbenzamide; N-(2-(dimethylamino)ethyl)-4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-vinylpyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- Methoxy-N-methylbenzamide; N-(2-(dimethylamino)ethyl)-4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-vinylimidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; N-(2-(dimethylamino)ethyl 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-vinyl-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-vinylpyrazole 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-vinylimidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxybenzenesulfonamide; 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-vinylimidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxybenzenesulfonamide; (((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-vinyl-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3-methoxybenzenesulfonamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-vinylpyrazolo[1,5-a]pyridin-2-yl)prop- 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-vinylimidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzenesulfonamide; 4-((3-(7-(((3S,4 R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-vinyl-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzenesulfonamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-vinylpyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzenesulfonamide 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-vinylimidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N,N-dimethylbenzenesulfonamide; 4-((3-(7-((( N-((3S,4R)-3-fluoropiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)amino)-3-methoxy-N,N-dimethylbenzenesulfonamide; N-((3S,4R)-3-fluoropiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1 -yl)-3-vinylpyrazolo[1,5-a]pyridin-7-amine; N-((3S,4R)-3-fluoropiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylimidazo[1,2-a]pyridin-8-amine; N-((3S,4R)-3-fluoropiperidin-4-yl)- 2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinyl-2H-indazol-7-amine; N-((3S,4R)-1-ethyl-3-fluoropiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylpyrazolo[1 ,5-a]pyridin-7-amine; N-((3S,4R)-1-ethyl-3-fluoropiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylimidazo[1,2-a]pyridin-8-amine; N-((3S,4R)-1-ethyl-3-fluoropiperidin-4-yl)-2-(3- ((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinyl-2H-indazol-7-amine; 2-((3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylpyrazolo[1,5-a]pyridin-7-yl)amine 2-((3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylimidazo[1,2-a]pyridin-8-yl)amino)piperidin-1-yl)ethan-1-ol; 2-((3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylimidazo[1,2-a]pyridin-8-yl)amino)piperidin-1-yl)ethan-1-ol; (3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinyl-2H-indazol-7-yl)amino)piperidin-1-yl)ethan-1-ol; N-((3S,4R)-3-fluoro-1-(2-methoxyethyl)piperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino) prop-1-yn-1-yl)-3-vinylpyrazolo[1,5-a]pyridin-7-amine; N-((3S,4R)-3-fluoro-1-(2-methoxyethyl)piperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylimidazo[1,2-a]pyridin-8-amine; N-(( 3S,4R)-3-fluoro-1-(2-methoxyethyl)piperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinyl-2H-indazol-7-amine; N-((3S,4R)-3-fluoro-1-isopropylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinyl-2H-indazol-7-amine N-((3S,4R)-3-fluoro-1-isopropylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylimidazo[1,2-a]pyridin-8-amine ; N-((3S,4R)-3-fluoro-1-isopropylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinyl-2H-indazol-7-amine; 1-((3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino) 1-((3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylimidazo[1,2-a]pyridin-8-yl)amino)- ... 1-((3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinyl-2H-indazol-7-yl)amino)piperidin-1-yl)ethan-1-one; (3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinyl-2H-indazol-7-yl)amino)piperidin-1-yl)ethan-1-one; -4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylpyrazolo[1,5-a]pyridin-7-yl)amino)-N-methylpiperidin-1-carboxamide; (3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylimidazo[1,5-a]pyridin-7-yl)amino)-N-methylpiperidin-1-carboxamide; (3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylimidazo[1,5-a]pyridin-7-yl)amino)-N-methylpiperidin-1-carboxamide (2-a]pyridin-8-yl)amino)-N-methylpiperidine-1-carboxamide; (3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinyl-2H-indazol-7-yl)amino)-N-methylpiperidine-1-carboxamide; (3S,4R)-3-fluoro-4-( (2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylpyrazolo[1,5-a]pyridin-7-yl)amino)piperidine-1-carboxylic acid methyl ester; (3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3- Methyl (vinyl imidazo[1,2-a]pyridin-8-yl)amino)piperidine-1-carboxylate; Methyl (3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinyl-2H-indazol-7-yl)amino)piperidine-1-carboxylate; 2-amino-1-((3S,4R )-3-fluoro-4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylpyrazolo[1,5-a]pyridin-7-yl)amino)piperidin-1-yl)ethan-1-one; 2-amino-1-((3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylpyrazolo[1,5-a]pyridin-7-yl)amino)piperidin-1-yl)ethan-1-one 2-Amino-1-((3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinyl-2H-indazole 2-(dimethylamino)-1-((3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylpyrazolo[1,5-a]pyridin-7-yl)amino)piperidin-1-yl)ethan-1-one; 2-(dimethylamino)-1-((3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylpyrazolo[1,5-a]pyridin-7-yl)amino)piperidin-1-yl)ethan-1-one; 2-(dimethylamino)-1-((3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylimidazo[1,2-a]pyridin-8-yl)amino)piperidin-1-yl)ethan-1-one; 2-(dimethylamino)-1-((3S,4R)-3-fluoro-4-((2 -(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinyl-2H-indazol-7-yl)amino)piperidin-1-yl)ethan-1-one; 4-((3-(7-(((3S,4R)-1-ethyl-3-fluoropiperidin-4-yl)amino)-3-vinylpyrazolo[1,5-a]pyridin-2-yl)prop-1-yn-1-yl)-3-vinyl-2H-indazol-7-yl)amino)piperidin-1-yl)ethan-1-one -2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(8-(((3S,4R)-1-ethyl-3-fluoropiperidin-4-yl)amino)-3-vinylimidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(7-(((3S 4-((3-(7-(((3S,4R)-3-fluoro-1-isopropylpiperidin-4-yl)amino)-3-vinylpyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-isopropylpiperidin-4-yl)amino)-3-vinylpyrazolo[1,5-a]pyridin-2-yl)prop- 4-((3-(8-(((3S,4R)-3-fluoro-1-isopropylpiperidin-4-yl)amino)-3-vinylimidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(7-(((3S N7-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-methylphenyl)amino)prop-1-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; N7-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-methylphenyl)amino)prop-1-yn-1-yl) -3-vinylpyrazolo[1,5-a]pyridine-5,7-diamine; N8-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-methylphenyl)amino)prop-1-yn-1-yl)-3-vinylimidazo[1,2-a]pyridine-6,8-diamine; N7-((3S,4R)-3-fluoro-1- 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(1-fluorovinyl)pyrazolo[1,5-a]pyridin-2-yl)propan-2-yl)-3-vinyl-2H-indazole-5,7-diamine; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(1-fluorovinyl)pyrazolo[1,5-a]pyridin-2-yl)propan-2-yl)-3-vinyl-2H-indazole-5,7-diamine 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(1-fluorovinyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(7-((( 3-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(1-fluorovinyl)-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(prop-1-en-2-yl)pyrazolo[1 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(prop-1-en-2-yl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(prop-1-en-2-yl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- Methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(prop-1-en-2-yl)-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl) 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(3,3,3-trifluoroprop-1-en-2-yl)amido)-3-(3,3,3-trifluoroprop-1-en-2-yl)amido)-3-methoxy-N-methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(3,3,3-trifluoroprop-1-en-2-yl)-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(3,3,3-trifluoroprop-1-en-2-yl)-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3- Methoxy-N-methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(1,2,2-trifluorovinyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(8-(((3S,4R)- 3-(((3-fluoro-1-methylpiperidin-4-yl)amino)-3-(1,2,2-trifluorovinyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(1,2,2-trifluorovinyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((E)-prop-1-en-1-yl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((E)-prop-1-en-1-yl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(7-(((3S,4R)- 3-((E)-prop-1-en-1-yl)-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(3-ethynyl-7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)pyrazolo[1,5-a]pyridine -2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(3-ethynyl-8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(3-ethynyl-8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide Ethynyl-7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(prop-1-yn-1-yl)pyrazolo[1, 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(prop-1-yn-1-yl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; Benzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(prop-1-yn-1-yl)-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(prop-1-yn-1-yl)-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((Z)-prop-1-en-1-yl)imidazo[1,2-a] 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((Z)-prop-1-en-1-yl)-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((E)-3,3,3-trifluoroprop-1-en-1-yl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(8-(((3S,4R)-3-fluoro- 1-methylpiperidin-4-yl)amino)-3-((E)-3,3,3-trifluoroprop-1-en-1-yl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((E)- 3-((3-(3-(2,2-difluorovinyl)-7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(3-(2,2-difluorovinyl)-7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide 1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(3-(2,2-difluorovinyl)-8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(3-(2 ,2-difluorovinyl)-7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2H-indazol-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 5-fluoro-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl) 6-Fluoro-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinylimidazo[1,2-a]pyridine-8-yl)- amine; 5-fluoro-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinyl-2H-indazol-7-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-vinyl-2H-indazol-7-amine 2-(((R)-epoxyeth-2-yl)pyrazolo[1,5-a]pyridin-7-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-((R)-epoxyeth-2-yl)pyrazolo[1,5-a]pyridin-7-amine 2-yl)imidazo[1,2-a]pyridin-8-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-((R)-oxiran-2-yl)-2H-indazol-7-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-((R)-oxiran-2-yl)-2H-indazol-7-amine 4-(2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-((S)-epoxyeth-2-yl)pyrazolo[1,5-a]pyridin-7-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-((S)-epoxyeth-2-yl)pyrazolo[1,5-a]pyridin-7-amine )amino)prop-1-yn-1-yl)-3-((S)-oxiran-2-yl)imidazo[1,2-a]pyridin-8-amine; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-((S)-oxiran-2-yl)-2H- Indazol-7-amine; N-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)acrylamide; N-(8-(((3S,4R)- (E)-N-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)methacrylamide; (E)-N-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amine (E)-4-(dimethylamino)-N-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)but-2-enamide; (E)-4-(dimethylamino)-N-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2- (3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)but-2-enamide; (E)-N-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)but-2-enamide N-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)-4-(methylamino)but-2-enamide; N-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino) 4-(dimethylamino)-N-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl) -3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)but-2-ynamide; 1-(3-((8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl) imidazo[1,2-a]pyridin-6-yl)amino)azidocyclobut-1-yl)prop-2-en-1-one; 1-((S)-3-((8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl) 1-((R)-3-((8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-triazine)-1-one; 1-(4-((8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one; 1-(4-((8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one 1-(3-((8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazole oxazolo[1,2-a]pyridin-6-yl)oxy)azidocyclobut-1-yl)prop-2-en-1-one; 2-fluoro-N-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo ... [1,2-a]pyridin-6-yl)acrylamide; N-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)propynamide; (E) -4-(3,3-difluoroazacyclobutan-1-yl)-N-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)but-2-enamide; (E)-N-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)-4-(4-methylpiperazin-1-yl)but-2-enamide; (E)-N-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)-4-oxolinylbut-2-enamide; N-(8-(((3S ,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)-4-(methylamino)but-2-ynamide; 1-(3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)-4-(methylamino)but-2-ynamide; 2-Fluoro-1-(3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)azinecyclobut-1-yl)prop-2-en-1-one; 2-Fluoro-1-(3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)azinecyclobut-1-yl)prop-2-en-1-one -1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)azepinecyclobut-1-yl)prop-2-en-1-one; (E)-4-(dimethylamino)-1-(3-(8-(((3 1-((2S)-4-((8-((3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)azinecyclobut-1-yl)but-2-en-1-one; 1-((2S)-4-((8-((3 S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one; 1-((2R)-4-( (8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one; 2-fluoro-1 -(3-((8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)amino)azinecyclobut-1-yl)prop-2-en-1-one; (E )-4-(dimethylamino)-1-(3-((8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)amino)azepan-1-yl) But-2-en-1-one; 1-(3-((8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)thio)azepinecyclobut-1-yl)propane -2-en-1-one; N-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,2,4-oxadiazol-5-yl)methyl)cyclopropanecarboxamide; N-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl) N-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)-1,2,4-oxadiazol-5-yl)methyl)cyclopropanecarboxamide; N-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)-1 1-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-1H-pyrazole-4-carboxamide 1-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-1H-pyrrole-3-carboxamide; 1-(tert-butyl)-N-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-1H-pyrrole-3-carboxamide 1-(Tributyl)-N-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(tributyl)-N-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-1H-pyrazole-4-carboxamide 1-(Tri-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-1H-pyrrole-3-carboxamide; 1-(tri-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl) -1,2,4-oxadiazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(tributyl)-N-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-1H-pyrazole-4-carboxamide N-((5-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,3,4-thiadiazol-2-yl)methyl)cyclopropanecarboxamide; 1-(tert-butyl)-N-((5-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,3,4-thiadiazol-2-yl)methyl)cyclopropanecarboxamide 1-(Tributyl)-N-((5-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,3,4-thiadiazol-2-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(tributyl)-N-((5-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2 N-((5-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)-1,3,4-thiadiazol-2-yl)methyl)cyclopropanecarboxamide Amide; 1-(tert-butyl)-N-((5-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)-1,3,4-thiadiazol-2-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(tert-butyl)-N-((5-(8-(( ((5-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)-1,3,4-thiadiazol-2-yl)methyl)-1H-pyrrole-3-carboxamide; N-((5-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2 1-(Tributyl)-N-((5-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)-1,3,4-thiadiazol-2-yl)methyl)cyclopropanecarboxamide; 1-(Tributyl)-N-((5-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)-1 1-(Tributyl)-N-((5-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)-1,3,4-thiadiazol-2-yl)methyl)-1H-pyrrole-4-carboxamide; 1-(Tributyl)-N-((5-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)-1,3,4-thiadiazol-2-yl)methyl)-1H-pyrrole -3-carboxamide; N-((3-(5-amino-7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,2,4-oxadiazol-5-yl)methyl)cyclopropanecarboxamide; N-((3-(5-amino-7-(((3S,4R)-3-fluoro-1-methyl Piperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-1-(tert-butyl)-1H-pyrazole-4-carboxamide; N-((3-(5-amino-7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-1-(tert-butyl)-1H-pyrazole-4-carboxamide N-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyrazin-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-1-(tributyl)-1H-pyrrole-3-carboxamide; N-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyrazin-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-1-(tributyl)-1H-pyrrole-3-carboxamide 1-(tert-butyl)-N-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyrazin-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(tert-butyl)-N-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyrazin-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-1H-pyrazole-4-carboxamide N-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyrazin-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-1H-pyrrole-3-carboxamide; N-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyrazin-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-1H-pyrrole-3-carboxamide 1-(Tributyl)-N-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyrazin-2-yl)-1,2,4-oxadiazol-5-yl)methyl)cyclopropanecarboxamide; 1-(Tributyl)-N-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo[1 1-(Tri-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyrazin-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(Tri-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyrazin-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-1H-pyrazole-4-carboxamide -5-yl)methyl)-1H-pyrrole-3-carboxamide; N-((5-(5-amino-7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,3,4-thiadiazol-2-yl)methyl)cyclopropanecarboxamide; N-((5-(5-amino-7-((( ((5-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,3,4-thiadiazol-2-yl)methyl)-1-(tert-butyl)-1H-pyrrole-3-carboxamide; N-((5-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-( 1-(Tri-butyl)-N-((5-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyrazin-2-yl)-1,3,4-thiadiazol-2-yl)methyl)cyclopropanecarboxamide; 1-(tert-butyl)-N-((5-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyrazin-2-yl) -1,3,4-thiadiazol-2-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(tert-butyl)-N-((5-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyrazin-2-yl)-1,3,4-thiadiazol-2-yl)methyl)-1H- Pyrrole-3-carboxamide; N-((5-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyrazin-2-yl)-1,3,4-thiadiazol-2-yl)methyl)cyclopropanecarboxamide; N-((5-(5-amino-7-(((3S,4R)-3-fluoro- 1-(tert-butyl)-N-((5-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,3,4-thiadiazol-2-yl)methyl)-1-(tert-butyl)-1H-pyrazole-4-carboxamide; 1-(tert-butyl)-N-((5-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2, 1-(Tri-butyl)-N-((5-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyrazine-2-yl)-1,3,4-thiadiazol-2-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(Tri-butyl)-N-((5-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyrazine- N-((3-(5-fluoro-7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,2,4-oxadiazol-5-yl)methyl)cyclopropanecarboxamide; 1-(tertiary 1-(3-(5-fluoro-7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(tert-butyl)-N-((3-(5-fluoro-7-(((3S,4 N-((5-(5-fluoro-7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-1H-pyrrole-3-carboxamide; N-((5-(5-fluoro-7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-1H-pyrrole-3-carboxamide 1-(Tributyl)-N-((5-(5-fluoro-7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,3,4-thiadiazol-2-yl)methyl)cyclopropanecarboxamide; 1-(Tributyl)-N-((5-(5-fluoro-7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,3,4-thiadiazol-2-yl)methyl )-1H-pyrazole-4-carboxamide; 1-(tert-butyl)-N-((5-(5-fluoro-7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-1,3,4-thiadiazol-2-yl)methyl)-1H-pyrrole-3-carboxamide; N-((3-(7-( ((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(perfluoroethyl)-2H-indazol-2-yl)-1,2,4-oxadiazol-5-yl)methyl)cyclopropanecarboxamide; 1-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(perfluoroethyl)-2H-indazol-2-yl)-1,2,4-oxadiazol-5-yl)methyl)cyclopropanecarboxamide 1-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(perfluoroethyl)-2H-indazol-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-1H-pyrrol-3-carboxamide; 1-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(perfluoroethyl)-2H-indazol-2-yl)-1,2,4-oxadiazol-5-yl)methyl)-1H-pyrrol-3-carboxamide N-((5-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(perfluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)-1,3,4-thiadiazol-2-yl)methyl)cyclopropanecarboxamide; 1-(tert-butyl)-N-((5-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4 -yl)amino)-3-(perfluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)-1,3,4-thiadiazol-2-yl)methyl)-1H-pyrazole-4-carboxamide; 1-(tert-butyl)-N-((5-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(perfluoroethyl)pyrazolo[1,5-a]pyridin-2-yl)-1,3,4-thiadiazol-2-yl)methyl)-1H-pyrazole-4-carboxamide; (S)-2-methoxy-4-methyl-N-(3-(8-(4-methylpiperazin-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)aniline; 2-methoxy-N-(3-(8-(4 (S)-6-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline; (S)-6-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2 -a]pyridin-8-yl)-4-methylpiperazin-2-one; 6-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-4-methylpiperazin-2-one; (R)-2-methoxy-N-(3-(8-(6-methyl- (S)-2-methoxy-N-(3-(8-(6-methyl-1,6-diazaspiro[3.3]hept-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline; (S)-2-methoxy-N-(3-(8-(6-methyl-1,6-diazaspiro[3.3]hept-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline (R)-2-methoxy-N-(3-(8-(6-methyl-2,6-diazaspiro[3.3]hept-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline; (R)-2-methoxy-N-(3-(8-(6-methyl-2,6-diazaspiro[3.3]hept-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline (S)-2-methoxy-N-(3-(8-(6-methyl-2,6-diazaspiro[3.3]hept-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline; (S)-N-(3-(8-(2-oxa-6-azaspiro[3.3]hept-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline 3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; (R)-N-(3-(8-(2-oxa-6-azaspiro[3.3]hept-5-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline N-(3-(8-((2R,5R)-5-((dimethylamino)methyl)pyrrolidin-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((2R,5R)-5-((dimethylamino)methyl)pyrrolidin-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((2R,5S)-5-((dimethylamino)methyl)pyrrolidin-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((2S,5R)-5-((dimethylamino)methyl)pyrrolidin-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline pyridine-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((2S,5S)-5-((dimethylamino)methyl)pyrrolidin-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine -2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; 2-methoxy-N-(3-(8-((2R,3aS,6aS)-5-methyloctahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4-( 2-Methoxy-N-(3-(8-((2R,3aR,6aR)-5-methyloctahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline; 2-Methoxy-N-(3-(8-(( 2-Methoxy-N-(3-(8-((2S,3aS,6aS)-5-methyloctahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline; 2-methoxy-N-(3-(8-((2S,3aR,6aR)-5-methyloctahydropyrrolo[3,4 -b]pyrrol-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline; 2-methoxy-N-(3-(8-((2R,5S)-7-methyl-1,7-diazaspiro[4.4]nonan-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1 ,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline; 2-methoxy-N-(3-(8-((2R,5R)-7-methyl-1,7-diazaspiro[4.4]non-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline 2-Methoxy-N-(3-(8-((2S,5S)-7-methyl-1,7-diazaspiro[4.4]non-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline; 2-Methoxy-N-(3-(8-((5R)-7-methyl-1,7-diazaspiro[4.4]non-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline -1,7-diazaspiro[4.4]non-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline; N-(3-(8-((2R,5S)-7-oxa-1-azaspiro[4.4]non-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline [1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((2R,5R)-7-oxa-1-azaspiro[4.4]non-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline (Methylsulfonyl)aniline; N-(3-(8-((2S,5S)-7-oxa-1-azaspiro[4.4]non-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((5R)-7-oxa-1-azaspiro[4.4]non-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline Heterospiro[4.4]nonan-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((2R,3aR,6aR)-3a-fluoro-5-methyloctahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(2,2 ,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((2R,3aS,6aS)-3a-fluoro-5-methyloctahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine -2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((2S,3aR,6aR)-3a-fluoro-5-methyloctahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline -4-(methylsulfonyl)aniline; N-(3-(8-((2S,3aS,6aS)-3a-fluoro-5-methyloctahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8 -((2R,6S)-6-((dimethylamino)methyl)piperidin-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((2R,6R)-6-((dimethylamino)methyl)piperidin-2-yl)-3-( 2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((2S,6R)-6-((dimethylamino)methyl)piperidin-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline -1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((6S)-6-((dimethylamino)methyl)piperidin-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((3S, 5R)-5-((dimethylamino)methyl)morpholin-3-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((3S,5S)-5-((dimethylamino)methyl)morpholin-3-yl)-3-(2,2,2 -(((dimethylamino)methyl)oxazolin-3-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((3R,5S)-5-((dimethylamino)methyl)oxazolin-3-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl) -2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((5R)-5-((dimethylamino)methyl)oxolin-3-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((2R,6S)- 6-((dimethylamino)methyl)-4,4-difluoropiperidin-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((2R,6R)-6-((dimethylamino)methyl)-4,4-difluoropiperidin-2-yl) -3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((2S,6R)-6-((dimethylamino)methyl)-4,4-difluoropiperidin-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline 4-(methylsulfonyl)aniline; N-(3-(8-((6S)-6-((dimethylamino)methyl)-4,4-difluoropiperidin-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline (R)-2-methoxy-N-(3-(8-(1-methyl-1,4-diazocyclohept-5-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline; (S)-2-methoxy-N-(3-(8-(1-methyl-1,4-diazocyclohept-5-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline (S)-N-(3-(8-(6,6-difluoro-1-methyl-1,4-diazocycloheptan-5-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline; (S)-N-(3-(8-(6,6-difluoro-1-methyl-1,4-diazocycloheptan-5-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl) (R)-N-(3-(8-(6,6-difluoro-1-methyl-1,4-diazocyclohept-5-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N- (3-(8-((5S,6R)-6-fluoro-1-methyl-1,4-diazocyclohept-5-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((5R,6R)-6-fluoro-1-methyl-1,4-diazocyclohept-5-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline ((5S,6S)-6-fluoro-1-methyl-1,4-diazacycloheptan-5-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((5S,6S)-6-fluoro-1-methyl-1,4-diazacycloheptan-5-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2 -a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((5R,6S)-6-fluoro-1-methyl-1,4-diazocyclohept-5-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline N-(3-(8-((5S,6S)-6-fluoro-1,4-oxazolidinone)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((5R,6S)-6-fluoro-1,4-oxazolidinone)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline N-(3-(8-((5S,6R)-6-fluoro-1,4-oxazocyclohept-5-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine-2-yl)prop-2-yn-1-yl)-2-methoxy-4-methylaniline; N-(3-(8-((5S,6R)-6-fluoro-1,4-oxazocyclohept-5-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine-2-yl)prop-2-yn-1-yl)-2-methoxy-4-methylaniline N-(3-(8-((5R,6R)-6-fluoro-1,4-oxazolidinone)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; (R) -N-(3-(8-(1,4-oxadiazinecyclohept-5-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; (S)-N-(3-(8-(1,4-oxadiazinecyclohept-5-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline [1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; (S)-N-(3-(8-(6,6-difluoro-1,4-oxazolidin-5-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline (R)-N-(3-(8-(6,6-difluoro-1,4-oxazolidinone)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; 2-methoxy-N-(3-(8-((1S,5R,7R)-3 -methyl-3,6-diazabicyclo[3.2.1]oct-7-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline; 2-methoxy-N-(3-(8-((1R,5S,7S)-3-methyl-3,6-diazabicyclo[3.2.1]oct-7 -yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline; 2-methoxy-N-(3-(8-((1S,5R,7S)-3-methyl-3,6-diazabicyclo[3.2.1]octan-7-yl)-3-(2,2,2-trifluoroethyl)imidazo[1, 2-methoxy-N-(3-(8-((1R,5S,7R)-3-methyl-3,6-diazabicyclo[3.2.1]octan-7-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline; 2-methoxy-N-(3-(8-((1R,5S,7R)-3-methyl-3,6-diazabicyclo[3.2.1]octan-7-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline -(methylsulfonyl)aniline; N-(3-(8-((2R,4S)-4-((dimethylamino)methyl)azinecyclobut-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((2R,4R)-4-( ((dimethylamino)methyl)azidocyclobutan-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((2S,4S)-4-((dimethylamino)methyl)azidocyclobutan-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline N-(3-(8-((2S,4R)-4-((dimethylamino)methyl)azinecyclobutan-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((2S,4R)-4-((dimethylamino)methyl)azinecyclobutan-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2 -methoxy-4-(methylsulfonyl)aniline; (3R)-3-((dimethylamino)methyl)-5-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)pyrrolidin-2-one; (3S)-3-((dimethylamino)methyl (2R)-2-((dimethylamino)methyl)-5-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)pyrrolidin-2-one; (2R)-2-((dimethylamino)methyl)-5-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)pyrrolidin-2-one (2S)-2-((dimethylamino)methyl)-5-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazole imidazo[1,2-a]pyridin-8-yl)pyridin-3-one; 3-((dimethylamino)methyl)-6-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)pyridin-2(1H)-one; 3-(dimethylamino)-6- (2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)pyridin-2(1H)-one; 3-(dimethylamino)-6-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)- 2-(dimethylamino)-6-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)pyrazin-2(1H)-one; 2-(dimethylamino)-6-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)pyridin-4 (1H)-one; (S)-2-(1-(dimethylamino)ethyl)-6-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)pyridin-4(1H)-one; (R)-2-(1-(dimethylamino)ethyl)- 6-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)pyridin-4(1H)-one; N-(3-(8-(3-((dimethylamino)methyl)-1H-pyrazol-5-yl)-3-(2,2,2-trifluoroethyl) imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-(3-((dimethylamino)methyl)-1H-1,2,4-triazol-5-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline Oxy-4-(methylsulfonyl)aniline; N-(3-(8-(4-((dimethylamino)methyl)-1H-imidazol-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; 2-methoxy-N-(3-(8-(6-methyl-4, 5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-3-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline; 2-methoxy-N-(3-(8-(4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-b]pyridin- 2-Methoxy-N-(3-(8-(5-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline; 2-methoxy-N-(3-(8-(5-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2 -a]pyridin-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline; 2-methoxy-N-(3-(8-(7-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline 2-Methoxy-N-(3-(8-(7-methyl-2,5,6,7-tetrahydropyrazolo[4,3-b][1,4]oxazin-3-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline; 2-Methoxy-N-(3-(8-(4 2-Methoxy-N-(3-(8-(5-methyl-4,5,6,7-tetrahydro-3H-imidazo[4, 5-c]pyridin-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline; N-(3-(8-(7,7-difluoro-5-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)aniline )imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-(4,4-difluoro-6-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-3-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl) (R)-3-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-N,N-dimethyl-2,4,5,6-tetrahydrocyclopenta[c]pyridine oxazol-6-amine; (S)-3-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-N,N-dimethyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-6-amine; (R)-2-methoxy-4-(methylsulfonyl)phenyl (S)-2-methoxy-4-(methylsulfonyl)-N-(3-(8-(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazin-5-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)aniline; (S)-2-methoxy-4-(methylsulfonyl)-N-(3-(8-(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazin-5-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)aniline (R)-2-methoxy-4-(methylsulfonyl)-N-(3-(8-(2,3,4,5-tetrahydro-1H-imidazo[1,5-a][1,3]pyridin-2-yl)imidazo[1,2-a][1,3]diazol-5-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)aniline; (R)-2-methoxy-4-(methylsulfonyl)-N-(3-(8-(2,3,4,5-tetrahydro-1H-imidazo[1,5-a][1,3] (S)-2-methoxy-4-(methylsulfonyl)-N-(3-(8-(2,3,4,5-tetrahydro-1H-imidazo[1,5-a][1,3]diazopen-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)aniline; (S)-2-methoxy-4-(methylsulfonyl)-N-(3-(8-(2,3,4,5-tetrahydro-1H-imidazo[1,5-a][1,3]diazopen-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)aniline (R)-2-methoxy-4-(methylsulfonyl)-N-(3-(8-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-5-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)benzene Amine; (S)-2-methoxy-4-(methylsulfonyl)-N-(3-(8-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-5-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)aniline; (R)-N-(1-(2-(3-((2-methoxy-4-(methylsulfonyl)- (S)-N-(1-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)ethyl)-1-methyl-1H-pyrazol-5-amine; (S)-N-(1-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)ethyl)-1-methyl-1H-pyrazol-5-amine (S)-N-(2,2-difluoro-1-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)ethyl)-1-methyl-1H-pyrazol-5-amine; (S)-N-(2,2-difluoro-1-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)ethyl)-1-methyl-1H-pyrazol-5-amine Methyl-1H-pyrazol-5-amine; (R)-N-(2,2-difluoro-1-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)ethyl)-1-methyl-1H-pyrazol-5-amine; (S)-1-methyl-N-( 2,2,2-trifluoro-1-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)ethyl)-1H-pyrazol-5-amine; (R)-1-methyl-N-(2,2,2-trifluoro-1-(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)ethyl)-1H-pyrazol-5-amine -4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)ethyl)-1H-pyrazol-5-amine; N-(3-(8-((S)-amino((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)methyl)-3-(2,2,2-trifluoroethyl)imidazole imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((S)-((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)(methylamino)methyl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl) -2-methoxy-4-(methylsulfonyl)aniline; N-((S)-((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)methyl)acetamide; N-( 3-(8-((S)-amino((3S,4S)-3-fluoro-1-methylpiperidin-4-yl)methyl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((S)-((3S,4S)-3-fluoro-1-methylpiperidin -4-yl)(methylamino)methyl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-((S)-((3S,4S)-3-fluoro-1-methylpiperidin-4-yl)(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl N-(3-(8-((S)-amino((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)methyl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)propan-2-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)methyl)acetamide; N-(3-(8-((S)-amino((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)methyl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)propan-2-yl) N-(3-(8-((S)-((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)(methylamino)methyl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline ; N-((S)-((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)methyl)acetamide; N-(3-(8-((R)-amino((3R,4R )-3-fluoro-1-methylpiperidin-4-yl)methyl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-(3-(8-((R)-((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)(methylamino)methyl)-3-( 2-((2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline; N-((R)-((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)(2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-(2 (R)-N-(3-(8-(4-fluoro-6-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-3-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2 -methoxy-4-(methylsulfonyl)aniline; and (S)-N-(3-(8-(4-fluoro-6-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-3-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline.
在一些實施例中,化合物選自由列表2中所描述之化合物或其醫藥學上可接受之鹽組成之群。 列表2 In some embodiments, the compound is selected from the group consisting of compounds described in Table 2 or pharmaceutically acceptable salts thereof. Table 2
3-((3-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-N-異丙基-4-甲氧基苯甲醯胺;氮雜環丁-1-基(3-((3-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-4-甲氧基苯基)甲酮;3-((3-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-4-甲氧基-N,N-二甲基苯甲醯胺;5-((3-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-N-甲基菸鹼醯胺;5-((3-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-6-甲氧基-N-甲基菸鹼醯胺;3-((3-(4-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-1-(2,2,2-三氟乙基)-1H-吲哚-2-基)丙-2-炔-1-基)胺基)-4-甲氧基-N-甲基苯甲醯胺;3-((3-(8-(((3R,4S)-4-氟-1-甲基吡咯啶-3-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-4-甲氧基-N-甲基苯甲醯胺;3-((3-(8-(((3R,4S)-4-氟吡咯啶-3-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-4-甲氧基-N-甲基苯甲醯胺;6-((3-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-N-甲基菸鹼醯胺;6-((3-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-5-甲氧基-N-甲基菸鹼醯胺;2-((3-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-N-甲基-1H-咪唑-5-甲醯胺;2-((3-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-N,1-二甲基-1H-咪唑-5-甲醯胺;4-((3-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-5-甲氧基-N-甲基嘧啶-2-甲醯胺;4-((3-(8-(((3S,4S)-4-氟-1-甲基哌啶-3-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;4-((3-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡嗪-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;3-((3-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-4-甲氧基苯甲醯胺;4-((3-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基苯甲醯胺;4-((3-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)嘧啶-2(1H)-酮;6-((3-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-N-甲基吡啶醯胺;3-((3-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-N-甲基苯甲醯胺;4-((3-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-N-甲基苯甲醯胺;5-((3-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-6-甲氧基吡啶醯胺;3-((3-(3-((二氟甲基)硫代)-8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-4-甲氧基-N-甲基苯甲醯胺;2-((3-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-N-甲基-1H-吡咯并[3,2-b]吡啶-3-甲醯胺;6-((3-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-5-甲氧基-N-甲基吡啶醯胺;6-((3-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-5-甲氧基-N-甲基吡嗪-2-甲醯胺;6-((3-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-5-甲氧基吡啶醯胺;6-((3-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-5-甲氧基異吲哚啉-1-酮;4-((3-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-5-甲氧基吡啶-2(1H)-酮;4-((3-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-5-甲氧基-N-甲基吡啶醯胺;4-((3-(8-(((3S,4R)-3-氟-1-(2-羥基-2-甲基丙基)哌啶-4-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;4-((3-(8-(((3R,4S)-4-氟-1-甲基哌啶-3-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;4-((3-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-c]嘧啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;(S)-3-甲氧基-N-甲基-4-((3-(8-((1-甲基-2-側氧基哌啶-4-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)苯甲醯胺;(R)-3-甲氧基-N-甲基-4-((3-(8-((1-甲基-2-側氧基哌啶-4-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)苯甲醯胺;2-氟-5-((3-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-4-甲氧基-N-甲基苯甲醯胺;6-((3-(8-(((3R,4S)-4-氟-1-甲基吡咯啶-3-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-5-甲氧基-N-甲基吡啶醯胺;6-((3-(8-(((3R,4S)-4-氟吡咯啶-3-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-5-甲氧基-N-甲基吡啶醯胺;4-((3-(6-氟-8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;(S)-3-甲氧基-N-甲基-4-((3-(8-((1-甲基-6-側氧基哌啶-3-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)苯甲醯胺;(R)-3-甲氧基-N-甲基-4-((3-(8-((1-甲基-6-側氧基哌啶-3-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)苯甲醯胺;4-((3-(8-(((3-氟-1-甲基氮雜環丁-3-基)甲基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;3-((3-(8-(((1S,5S,6S)-1-氟-3-甲基-3-氮雜雙環[3.1.0]己-6-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-4-甲氧基-N-甲基苯甲醯胺;4-((3-(8-(((1S,5S,6S)-1-氟-3-甲基-3-氮雜雙環[3.1.0]己-6-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;(S)-3-甲氧基-N-甲基-4-((3-(8-((4,5,6,7-四氫吡唑并[1,5-a]吡啶-5-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)苯甲醯胺;(R)-3-甲氧基-N-甲基-4-((3-(8-((4,5,6,7-四氫吡唑并[1,5-a]吡啶-5-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)苯甲醯胺;(S)-4-((3-(8-((6,7-二氫-5H-吡咯并[1,2-c]咪唑-7-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;(S)-4-((3-(8-((6,7-二氫-5H-吡咯并[1,2-c]咪唑-6-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;(R)-4-((3-(8-((6,7-二氫-5H-吡咯并[1,2-c]咪唑-6-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;(R)-3-甲氧基-N-甲基-4-((3-(8-((5,6,7,8-四氫咪唑并[1,5-a]吡啶-7-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)苯甲醯胺;(S)-3-甲氧基-N-甲基-4-((3-(8-((5,6,7,8-四氫咪唑并[1,5-a]吡啶-7-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)苯甲醯胺;6-((3-(3-((二氟甲基)硫代)-8-(((3R,4S)-4-氟-1-甲基吡咯啶-3-基)胺基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-5-甲氧基-N-甲基吡啶醯胺;3-((3-(3-((二氟甲基)硫代)-8-(((3R,4S)-4-氟-1-甲基吡咯啶-3-基)胺基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-4-甲氧基-N-甲基苯甲醯胺;4-((3-(3-((二氟甲基)硫代)-8-(((3R,4S)-4-氟-1-甲基吡咯啶-3-基)胺基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;4-((3-(8-(((3-氟氮雜環丁-3-基)甲基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;6-((3-(3-((二氟甲基)硫代)-8-(((3R,4S)-4-氟吡咯啶-3-基)胺基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-5-甲氧基-N-甲基吡啶醯胺;3-((3-(3-((二氟甲基)硫代)-8-(((3R,4S)-4-氟吡咯啶-3-基)胺基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-4-甲氧基-N-甲基苯甲醯胺;4-((3-(3-((二氟甲基)硫代)-8-(((3R,4S)-4-氟吡咯啶-3-基)胺基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;3-((3-(3-((二氟甲基)硫代)-7-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)吡唑并[1,5-a]吡啶-2-基)丙-2-炔-1-基)胺基)-4-甲氧基-N-甲基苯甲醯胺;6-((3-(3-((二氟甲基)硫代)-8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-5-甲氧基-N-甲基吡啶醯胺;4-((3-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-N-甲基-1H-咪唑-5-甲醯胺;3-((3-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-N-甲基-1H-吡唑-4-甲醯胺;3-((3-(6-氟-8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-4-甲氧基-N-甲基苯甲醯胺;3-((3-(3-((二氟甲基)硫代)-7-(((3S,4R)-3-氟哌啶-4-基)胺基)吡唑并[1,5-a]吡啶-2-基)丙-2-炔-1-基)胺基)-4-甲氧基-N-甲基苯甲醯胺;3-((3-(3-((二氟甲基)硫代)-8-(((3S,4R)-3-氟哌啶-4-基)胺基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-4-甲氧基-N-甲基苯甲醯胺;6-((3-(3-((二氟甲基)硫代)-8-(((3S,4R)-3-氟哌啶-4-基)胺基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-5-甲氧基-N-甲基吡啶醯胺;3-((3-(8-(((1S,2R,3R,5R)-2-氟-8-甲基-8-氮雜雙環[3.2.1]辛-3-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-4-甲氧基-N-甲基苯甲醯胺;3-((3-(8-(((1R,2S,3S,5S)-2-氟-8-甲基-8-氮雜雙環[3.2.1]辛-3-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-4-甲氧基-N-甲基苯甲醯胺;4-((3-(8-(((1R,2S,3S,5S)-2-氟-8-甲基-8-氮雜雙環[3.2.1]辛-3-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;(S)-3-甲氧基-N-甲基-4-((3-(8-((2-側氧基哌啶-4-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)苯甲醯胺;(R)-3-甲氧基-N-甲基-4-((3-(8-((2-側氧基哌啶-4-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)苯甲醯胺;(R)-3-甲氧基-N-甲基-4-((3-(8-((6-側氧基哌啶-3-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)苯甲醯胺;(S)-3-甲氧基-N-甲基-4-((3-(8-((6-側氧基哌啶-3-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)苯甲醯胺;(R)-3-甲氧基-N-甲基-4-((3-(8-((5,6,7,8-四氫-[1,2,4]三唑并[1,5-a]吡啶-6-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)苯甲醯胺;(S)-3-甲氧基-N-甲基-4-((3-(8-((5,6,7,8-四氫-[1,2,4]三唑并[1,5-a]吡啶-6-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)苯甲醯胺;(S)-3-甲氧基-N-甲基-4-((3-(8-((5,6,7,8-四氫-[1,2,4]三唑并[4,3-a]吡啶-6-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)苯甲醯胺;(R)-3-甲氧基-N-甲基-4-((3-(8-((5,6,7,8-四氫-[1,2,4]三唑并[4,3-a]吡啶-6-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)苯甲醯胺;4-((3-(8-(((1R,2R,3S,5S)-2-氟-8-氮雜雙環[3.2.1]辛-3-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;3-((3-(8-(((1S,2S,3R,5R)-2-氟-8-氮雜雙環[3.2.1]辛-3-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-4-甲氧基-N-甲基苯甲醯胺;3-((3-(8-(((1R,2R,3S,5S)-2-氟-8-氮雜雙環[3.2.1]辛-3-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-4-甲氧基-N-甲基苯甲醯胺;4-((3-(1-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-6-((三氟甲基)硫代)吡咯并[1,2-a]吡嗪-7-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;(R)-4-((3-(8-((6,7-二氫-5H-吡咯并[1,2-c]咪唑-7-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;3-((3-(8-((2-(2,2-二氟乙基)-2-氮雜螺[3.3]庚-6-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-4-甲氧基-N-甲基苯甲醯胺;4-((3-(8-((2-(2,2-二氟乙基)-2-氮雜螺[3.3]庚-6-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺;6-((3-(3-((二氟甲基)硫代)-8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-7-甲氧基-3,4-二氫異喹啉-1(2H)-酮;6-((3-(8-(((3R,4S)-4-氟-1-甲基吡咯啶-3-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-7-甲氧基-3,4-二氫異喹啉-1(2H)-酮;及6-((3-(8-(((3R,4S)-4-氟吡咯啶-3-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-7-甲氧基-3,4-二氫異喹啉-1(2H)-酮。3-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-isopropyl-4-methoxybenzamide; 3-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-isopropyl-4-methoxybenzamide 3-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxyphenyl)methanone; 3-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxyphenyl)methanone -alkyn-1-yl)amino)-4-methoxy-N,N-dimethylbenzamide; 5-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-methylnicotinamide; 5-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-methylnicotinamide; 4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-6-methoxy-N-methylnicotinamide; 3-((3-(4-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)- 1H-indol-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide; 3-((3-(8-(((3R,4S)-4-fluoro-1-methylpyrrolidin-3-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide Amine; 3-((3-(8-(((3R,4S)-4-fluoropyrrolidin-3-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide; 6-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((Trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-methylnicotinamide; 6-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-5-methyl Oxy-N-methylnicotinamide; 2-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-methyl-1H-imidazole-5-carboxamide; 2-((3-(8-(((3S,4R)-3-fluoro-1 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N,1-dimethyl-1H-imidazole-5-carboxamide; 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2 -a]pyridin-2-yl)prop-2-yn-1-yl)amino)-5-methoxy-N-methylpyrimidine-2-carboxamide; 4-((3-(8-(((3S,4S)-4-fluoro-1-methylpiperidin-3-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methyl Benzamide; 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyrazin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 3-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyrazin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxybenzamide; 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxybenzamide )amino)-3-methoxybenzamide; 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)pyrimidin-2(1H)-one; 6-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)pyrimidin-2(1H)-one 3-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-methylpyridinamide; 3-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-methylpyridinamide -1-yl)amino)-N-methylbenzamide; 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-methylbenzamide; 5-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-methylbenzamide 3-((3-((difluoromethyl)thio)-8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-6-methoxypyridinamide; 3-((3-(3-((difluoromethyl)thio)-8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)imidazo[1,2-a]pyridin-2-yl)prop- 2-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide ; 6-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-5-methoxy-N-methylpyridinamide; 6-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino) -3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-5-methoxy-N-methylpyrazine-2-carboxamide; 6-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-5-methoxy-N-methylpyrazine-2-carboxamide 6-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-5-methoxyisoindolin-1-one; 4-((3-(8-(((3S,4R)- 3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-5-methoxypyridin-2(1H)-one; 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-5-methoxypyridin-2(1H)-one 2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-5-methoxy-N-methylpyridinamide; 4-((3-(8-(((3S,4R)-3-fluoro-1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- Methoxy-N-methylbenzamide; 4-((3-(8-(((3R,4S)-4-fluoro-1-methylpiperidin-3-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-3-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide (S)-3-methoxy-N-methyl-4-((3-(8-((1-methyl-2-oxo-piperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-c]pyrimidin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; (S)-3-methoxy-N-methyl-4-((3-(8-((1-methyl-2-oxo-piperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-c]pyrimidin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide (R)-3-methoxy-N-methyl-4-((3-(8-((1-methyl-2-oxo-piperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide; 2-fluoro-5-((3 -(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide; 6-((3-(8-(((3R,4S)-4-fluoro-1-methylpyrrolidin-3-yl)amino)-3-(( 6-((3-(8-(((3R,4S)-4-fluoropyrrolidin-3-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-5-methoxy-N-methylpyridinamide; 6-((3-(8-(((3R,4S)-4-fluoropyrrolidin-3-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-5-methoxy-N-methylpyridinamide Oxy-N-methylpyridinamide; 4-((3-(6-fluoro-8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; (S)-3-methoxy-N-methyl-4-((3-( 8-((1-methyl-6-oxopiperidin-3-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide; (R)-3-methoxy-N-methyl-4-((3-(8-((1-methyl-6-oxopiperidin-3-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide [1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide; 4-((3-(8-(((3-fluoro-1-methylazinocyclobutan-3-yl)methyl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 3-((3-(8 -(((1S,5S,6S)-1-fluoro-3-methyl-3-azabicyclo[3.1.0]hex-6-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide; 4-((3-(8-(((1S,5S,6S)-1-fluoro-3-methyl -3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; (S)-3-methoxy-N-methyl-4-((3-(8-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-5-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide (R)-3-methoxy-N-methyl-4-((3-(8-((4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-5-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide; (R)-3-methoxy-N-methyl-4-((3-(8-((4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-5-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin- (S)-4-((3-(8-((6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; (S)-4-(( 3-(8-((6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-6-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; (R)-4-((3-(8-((6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-6-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide (R)-3-methoxy-N-methyl-4-((3-(8-((5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-7-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; (R)-3-methoxy-N-methyl-4-((3-(8-((5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-7-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide (S)-3-methoxy-N-methyl-4-((3-(8-((5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-7-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide; (S)-3-methoxy-N-methyl-4-((3-(8-((5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-7-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino )benzamide; 6-((3-(3-((difluoromethyl)thio)-8-(((3R,4S)-4-fluoro-1-methylpyrrolidin-3-yl)amino)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-5-methoxy-N-methylpyridinamide; 3-((3-(3-((difluoromethyl)thio)-8-(((3R,4S) -4-fluoro-1-methylpyrrolidin-3-yl)amino)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide; 4-((3-(3-((difluoromethyl)thio)-8-(((3R,4S)-4-fluoro-1-methylpyrrolidin-3-yl)amino)imidazo[1,2-a]pyridin-2-yl) 4-((3-(8-(((3-fluoroazolobutyl-3-yl)methyl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 6-((3-(3-((difluoromethyl) 3-((3-(3-((difluoromethyl)thio)-8-(((3R,4S)-4-fluoropyrrolidin-3-yl)amino)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-5-methoxy-N-methylpyridinamide; 3-((3-(3-((difluoromethyl)thio)-8-(((3R,4S)-4-fluoropyrrolidin-3-yl)amino)imidazo[1,2-a]pyridinamide -2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide; 4-((3-(3-((difluoromethyl)thio)-8-(((3R,4S)-4-fluoropyrrolidin-3-yl)amino)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 3-((3-(3-(3-(difluoromethyl)thio)-8-(((3R,4S)-4-fluoropyrrolidin-3-yl)amino)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide -((difluoromethyl)thio)-7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide; 6-((3-(3-((difluoromethyl)thio)-8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-5-methoxy-N-methylpyridinamide; 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-methyl 3-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-methyl-1H-pyrazole-4-carboxamide; 3-((3-(6-fluoro-8-(((3S,4R) -3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide; 3-((3-(3-((difluoromethyl)thio)-7-(((3S,4R)-3-fluoropiperidin-4-yl)amino)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide 3-((3-(3-((difluoromethyl)thio)-8-(((3S,4R)-3-fluoropiperidin-4-yl)amino)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide; 6-((3-(3-(difluoromethyl)thio)-8-(((3S,4R)-3-fluoropiperidin-4-yl)amino)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide -((difluoromethyl)thio)-8-(((3S,4R)-3-fluoropiperidin-4-yl)amino)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-5-methoxy-N-methylpyridinamide; 3-((3-(8-(((1S,2R,3R,5R)-2-fluoro-8-methyl-8-azabicyclo[3.2.1]octane-3- 3-((3-(8-(((1R,2S,3S,5S)-2-fluoro-8-methyl-8-azabicyclo[3.2.1]oct-3-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide; 3-((3-(8-(((1R,2S,3S,5S)-2-fluoro-8-methyl-8-azabicyclo[3.2.1]oct-3-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide; 4-((3-(8-(((1R,2S,3S,5S)-2-fluoro-8-methyl-8-azabicyclo[3.2.1]oct-3-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide (S)-3-methoxy-N-methyl-4-((3-(8-((2-oxopiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide; (R)-3-methoxy-N-methyl-4-(( 3-(8-((2-oxopiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide; (R)-3-methoxy-N-methyl-4-((3-(8-((6-oxopiperidin-3-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide (S)-3-methoxy-N-methyl-4-((3-(8-((6-oxopiperidin-3-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide; (R)-3-methoxy-N-methyl-4-((3 -(8-((5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide; (S)-3-methoxy-N-methyl-4-((3-(8-((5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide (S)-3-methoxy-N-methyl-4-((3-(8-((5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide; (S)-3-methoxy-N-methyl-4-((3-(8-((5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)amino) -3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide; (R)-3-methoxy-N-methyl-4-((3-(8-((5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a ]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide; 4-((3-(8-(((1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]oct-3-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide Amine; 3-((3-(8-(((1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]oct-3-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide; 3-((3-(8-(((1R,2R,3S,5 S)-2-fluoro-8-azabicyclo[3.2.1]oct-3-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide; 4-((3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide (R)-4-((3-(8-((6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; (R)-4-((3-(8-((6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide )amino)-3-methoxy-N-methylbenzamide; 3-((3-(8-((2-(2,2-difluoroethyl)-2-azaspiro[3.3]hept-6-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide; 4-((3-(8-((2 -(2,2-difluoroethyl)-2-azaspiro[3.3]hept-6-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; 6-((3-(3-((difluoromethyl)thio)-8-(((3S,4R)-3-fluoro-1-methylpiperidin-4 -yl)amino)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-7-methoxy-3,4-dihydroisoquinolin-1(2H)-one; 6-((3-(8-(((3R,4S)-4-fluoro-1-methylpyrrolidin-3-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-7-methoxy-3,4-dihydroisoquinolin-1(2H)-one -1-yl)amino)-7-methoxy-3,4-dihydroisoquinolin-1(2H)-one; and 6-((3-(8-(((3R,4S)-4-fluoropyrrolidin-3-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-7-methoxy-3,4-dihydroisoquinolin-1(2H)-one.
在一些實施例中,化合物選自由列表1及/或列表2中所描述之化合物或其醫藥學上可接受之鹽組成之群。在一些實施例中,化合物選自由表A中所描述之化合物或其醫藥學上可接受之鹽組成之群。
表A
一些實施例提供了醫藥組合物,其包含式(I)化合物或其醫藥學上可接受之鹽及一或多種醫藥學上可接受之賦形劑。 治療方法 Some embodiments provide pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
本文提供了恢復由 TP53基因編碼之p53功能的方法。例如,本文提供了恢復p53功能之化合物,該等化合物可用於治療或預防與 TP53基因、p53蛋白或其中任一者之活性之失調相關的疾病(亦即,p53相關疾病),諸如癌症(例如,p53相關癌症)。 Provided herein are methods for restoring p53 function encoded by the TP53 gene. For example, provided herein are compounds that restore p53 function, which can be used to treat or prevent diseases associated with dysregulation of the TP53 gene, p53 protein, or the activity of either thereof (i.e., p53-related diseases), such as cancer (e.g., p53-related cancer).
術語「恢復(restore/restoration of)」意謂藉由可量測量來增加指定靶標之活性及/或功能。例如,用式(I)化合物來恢復突變p53係指在化合物存在下,將突變p53之功能增加至比在化合物不存在下,突變p53之功能更高的水準。The term "restore" or "restoration of" means to increase the activity and/or function of a specified target by a measurable amount. For example, restoring mutant p53 with a compound of formula (I) means increasing the function of mutant p53 in the presence of the compound to a level higher than the function of mutant p53 in the absence of the compound.
測試化合物充當p53恢復劑之能力可藉由此項技術中已知之檢定來證明。本文提供的作為p53恢復劑之化合物及組合物之活性可 活體外、 活體內或在細胞株中檢定。 活體外檢定包括確定蛋白質之活化及/或其構形之變化的檢定。如本文所提供之p53恢復劑之效能可藉由EC 50值來確定。相對於具有更高EC 50值之化合物,如在實質上類似條件下確定的具有更低EC 50值之化合物為更有效的p53恢復劑。 適應症 The ability of a test compound to act as a p53 restorer can be demonstrated by assays known in the art. The activity of the compounds and compositions provided herein as p53 restorers can be assayed in vitro , in vivo , or in a cell line. In vitro assays include assays that determine activation of the protein and/or changes in its conformation. The potency of a p53 restorer as provided herein can be determined by an EC 50 value. A compound having a lower EC 50 value, as determined under substantially similar conditions, is a more effective p53 restorer relative to a compound having a higher EC 50 value. Indications
式(I)化合物或其醫藥學上可接受之鹽可用於治療可用p53恢復劑治療的疾病,諸如p53相關疾病,例如,增殖性病症諸如癌症,包括血液癌症及實體腫瘤(例如,晚期或轉移性實體腫瘤)。在一些實施例中,p53相關疾病或病症為李-佛美尼症候群(Li-Fraumeni syndrome)。The compound of formula (I) or a pharmaceutically acceptable salt thereof can be used to treat diseases treatable by p53 restorers, such as p53-related diseases, for example, proliferative disorders such as cancer, including blood cancers and solid tumors (e.g., advanced or metastatic solid tumors). In some embodiments, the p53-related disease or disorder is Li-Fraumeni syndrome.
一些實施例提供了治療有需要之個體之癌症的方法,其包含向個體投與治療有效量的式(I)化合物或其醫藥學上可接受之鹽。在一些實施例中,癌症為p53相關癌症。Some embodiments provide a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer is a p53-related cancer.
一些實施例提供了治療有需要之個體之p53相關癌症的方法,其包含向個體投與治療有效量的式(I)化合物或其醫藥學上可接受之鹽。在一些實施例中,p53相關癌症攜帶Y220C突變。Some embodiments provide a method of treating a p53-related cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the p53-related cancer carries a Y220C mutation.
一些實施例提供了治療有需要之個體之p53相關癌症的方法,其包含向個體投與治療有效量的實例1-510之化合物中之任一者或其醫藥學上可接受之鹽。在一些實施例中,p53相關癌症攜帶Y220C突變。Some embodiments provide a method of treating a p53-related cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of any one of the compounds of Examples 1-510 or a pharmaceutically acceptable salt thereof. In some embodiments, the p53-related cancer carries a Y220C mutation.
一些實施例提供了治療經鑑別或診斷患有p53相關癌症之個體之癌症的方法,其包含向個體投與治療有效量的式(I)化合物或其醫藥學上可接受之鹽。Some embodiments provide a method of treating cancer in a subject identified or diagnosed as having a p53-related cancer, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
一些實施例提供了治療有需要之個體之癌症的方法,其包含(a)確定個體患有p53相關癌症,及(b)向個體投與治療有效量的式(I)化合物或其醫藥學上可接受之鹽。Some embodiments provide a method of treating cancer in a subject in need thereof, comprising (a) determining that the subject has a p53-related cancer, and (b) administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
一些實施例提供了治療有需要之個體之李-佛美尼症候群的方法,其包含向個體投與治療有效量的式(I)化合物或其醫藥學上可接受之鹽。Some embodiments provide a method of treating Li-Fraumeni syndrome in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
一些實施例提供了治療經鑑別或診斷患有李-佛美尼症候群之個體之李-佛美尼症候群的方法,其包含向個體投與治療有效量的式(I)化合物或其醫藥學上可接受之鹽。Some embodiments provide a method of treating Li-Fraumeni syndrome in a subject identified or diagnosed as having Li-Fraumeni syndrome, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
一些實施例提供了治療有需要之個體之李-佛美尼症候群的方法,其包含(a)確定個體患有李-佛美尼症候群,及(b)向個體投與治療有效量的式(I)化合物或其醫藥學上可接受之鹽。Some embodiments provide a method of treating Li-Fraumeni syndrome in a subject in need thereof, comprising (a) determining that the subject has Li-Fraumeni syndrome, and (b) administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
在一些實施例中,將式(I)化合物或其醫藥學上可接受之鹽預防性地投與至患有李-佛美尼症候群之個體。在一些實施例中,將治療有效量之式(I)或其醫藥學上可接受之鹽預防性地投與至患有李-佛美尼症候群之個體。In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered prophylactically to a subject suffering from Li-Fraumeni syndrome. In some embodiments, a therapeutically effective amount of formula (I) or a pharmaceutically acceptable salt thereof is administered prophylactically to a subject suffering from Li-Fraumeni syndrome.
如本文所用,術語「p53相關疾病」係指與 TP53基因、p53蛋白或其中任一者(例如,一或多者)之活性之失調(例如,任何類型的本文所描述之 TP53基因或p53蛋白或其中任一者之活性之失調)相關或具有該失調的疾病。p53相關疾病之非限制性實例包括,例如,癌症(例如,p53相關癌症)。 As used herein, the term "p53-related disease" refers to a disease associated with or having a dysregulation of the activity of a TP53 gene, a p53 protein, or any of them (e.g., one or more) (e.g., any type of dysregulation of the activity of a TP53 gene or a p53 protein or any of them described herein). Non-limiting examples of p53-related diseases include, for example, cancer (e.g., p53-related cancer).
如本文所用,術語「p53相關癌症」係指與 TP53基因、p53蛋白或其中任一者之活性之失調相關或具有該失調的癌症。本文描述了p53相關癌症之非限制性實例。 As used herein, the term "p53-associated cancer" refers to a cancer associated with or having a dysregulation of the TP53 gene, p53 protein, or the activity of either. Non-limiting examples of p53-associated cancers are described herein.
術語「野生型(wild type/wild-type)」描述通常存在於不具有與參考核酸或蛋白質相關之癌症的個體中的核酸(例如, TP53基因或p53 mRNA)或蛋白質(例如,p53)序列。 The term "wild type" or "wild-type" describes a nucleic acid (eg, TP53 gene or p53 mRNA) or protein (eg, p53) sequence that is typically present in an individual who does not have a cancer associated with a reference nucleic acid or protein.
本文提供了治療需要此治療之個體之癌症(例如,p53相關癌症)的方法,該方法包含向個體投與治療有效量的式(I)化合物或其醫藥學上可接受之鹽或其醫藥組合物。例如,本文提供了用於治療需要此治療之個體之p53相關癌症的方法,該方法包含a)偵測來自個體之樣品中的 TP53基因、p53蛋白或其中任一者之活性之失調;及b)投與治療有效量的式(I)化合物或其醫藥學上可接受之鹽。在一些實施例中, TP53基因、p53蛋白或其中任一者之活性之失調包括一或多個p53蛋白取代/點突變/插入。p53蛋白取代/插入/缺失之非限制性實例描述於表1中。 Provided herein are methods for treating cancer (e.g., p53-related cancer) in an individual in need of such treatment, the method comprising administering to the individual a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. For example, provided herein are methods for treating p53-related cancer in an individual in need of such treatment, the method comprising a) detecting a disorder of the activity of a TP53 gene, a p53 protein, or any of them in a sample from the individual; and b) administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the disorder of the activity of a TP53 gene, a p53 protein, or any of them comprises one or more p53 protein substitutions/point mutations/insertions. Non-limiting examples of p53 protein substitutions/insertions/deletions are described in Table 1.
在一些實施例中,p53蛋白取代/插入/缺失為Y220X,其中X為不同於Y之任何胺基酸。在一些實施例中,p53蛋白取代/插入/缺失選自由Y220C、Y220S、Y220N、Y220D及其組合組成之群。在一些實施例中,p53蛋白取代/插入/缺失選自由Y220C或Y220S或其組合組成之群。在一些實施例中,p53蛋白取代/插入/缺失為Y220C。在一些實施例中,p53蛋白取代/插入/缺失為Y220S。In some embodiments, the p53 protein substitution/insertion/deletion is Y220X, wherein X is any amino acid different from Y. In some embodiments, the p53 protein substitution/insertion/deletion is selected from the group consisting of Y220C, Y220S, Y220N, Y220D and a combination thereof. In some embodiments, the p53 protein substitution/insertion/deletion is selected from the group consisting of Y220C or Y220S or a combination thereof. In some embodiments, the p53 protein substitution/insertion/deletion is Y220C. In some embodiments, the p53 protein substitution/insertion/deletion is Y220S.
在一些實施例中,如與野生型p53蛋白相比, TP53基因、p53蛋白或其中任一者之活性之失調包括導致產生具有一或多個胺基酸取代或插入或缺失之p53蛋白的 TP53基因中之至少一個點突變,導致產生具有一或多個胺基酸插入或移除之p53蛋白的 TP53基因中之至少一個點突變。在一些情況下,如與野生型p53蛋白或不包括相同突變之p53蛋白相比,所得突變的p53蛋白具有減少的功能。在一些實施例中,相對於在本文所描述之化合物不存在下之突變的p53蛋白功能,本文所描述之化合物例如藉由將突變蛋白穩定化至活性構形來恢復所得突變的p53蛋白功能。 人類p53 (UniProtKB條目P04637-1)之例示性序列(SEQ ID NO: 1) MEEPQSDPSVEPPLSQETFSDLWKLLPENNVLSPLPSQAMDDLMLSPDDIEQWFTEDPGPDEAPRMPEAAPPVAPAPAAPTPAAPAPAPSWPLSSSVPSQKTYQGSYGFRLGFLHSGTAKSVTCTYSPALNKMFCQLAKTCPVQLWVDSTPPPGTRVRAMAIYKQSQHMTEVVRRCPHHERCSDSDGLAPPQHLIRVEGNLRVEYLDDRNTFRHSVVVPYEPPEVGSDCTTIHYNYMCNSSCMGGMNRRPILTIITLEDSSGNLLGRNSFEVRVCACPGRDRRTEEENLRKKGEPHHELPPGSTKRALPNNTSSSPQPKKKPLDGEYFTLQIRGRERFEMFRELNEALELKDAQAGKEPGGSRAHSSHLKSKKGQSTSRHKKLMFKTEGPDSD In some embodiments, the dysregulation of the activity of the TP53 gene, p53 protein, or any of them includes at least one point mutation in the TP53 gene resulting in a p53 protein having one or more amino acid substitutions or insertions or deletions, resulting in at least one point mutation in the TP53 gene resulting in a p53 protein having one or more amino acid insertions or removals, as compared to a wild-type p53 protein. In some cases, the resulting mutant p53 protein has reduced function, as compared to a wild-type p53 protein or a p53 protein that does not include the same mutation. In some embodiments, the compounds described herein, for example, restore the resulting mutant p53 protein function by stabilizing the mutant protein to an active conformation, relative to the mutant p53 protein function in the absence of the compounds described herein. Exemplary sequence of human p53 (UniProtKB entry P04637-1) (SEQ ID NO: 1) MEEPQSDPSVEPPLSQETFSDLWKLLPENNVLSPLPSQAMDDLMLSPDDIEQWFTEDPGPDEAPRMPEAAPPVAPAPAAPTPAAPAPAPSWPLSSSVPSQKTYQGSYGFRLGFLHSGTAKSVTCTYSPALNKMFCQLAKTCPVQLWVDSTPPPGTRVRAMAIYKQSQHMTEVVRRCPHHERCSDSDGLAPPQHLIRVEGNLRVEYLDDRNTFRHSVVVPYEPPEVGSDCTTIHYNYMCNSSCMGGMNRRPILTIITLEDSSGNLLGRNSFEVRVCACPGRDRRTEEENLRKKGEPHHELPPGSTKRALPNNTSSSPQPKKKPLDGEYFTLQIRGRERFEMFRELNEALELKDAQAGKEPGGSRAHSSHLKSKKGQSTSRHKKLMFKTEGPDSD
在一些實施例中,式(I)化合物或其醫藥學上可接受之鹽可用於治療鑑別為具有一或多個p53突變之癌症。因此,本文提供了治療診斷患有(或經鑑別患有)癌症之個體的方法,其包含向個體投與治療有效量的式(I)化合物或其醫藥學上可接受之鹽。In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof can be used to treat cancers identified as having one or more p53 mutations. Thus, provided herein is a method for treating an individual diagnosed with (or identified as having) cancer, comprising administering to the individual a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
本文亦提供了治療經鑑別或診斷患有p53相關癌症之個體的方法,其包含向個體投與治療有效量的式(I)化合物或其醫藥學上可接受之鹽或其醫藥組合物。在一些實施例中,經由使用監管機構批准,例如,FDA批准的鑑別個體或來自個體之生檢樣品中之 TP53基因、p53蛋白或其中任一者之活性之失調的測試或檢定,或藉由執行本文所描述之檢定之非限制性實例中之任一者,將個體鑑別或診斷為患有p53相關癌症。在一些實施例中,測試或檢定作為套組提供。在一些實施例中,癌症為p53相關癌症。 Also provided herein are methods for treating an individual identified or diagnosed with a p53-related cancer, comprising administering to the individual a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. In some embodiments, the individual is identified or diagnosed as having a p53-related cancer by using a test or assay for dysregulation of the activity of the TP53 gene, p53 protein, or either of them in a biopsy sample approved by a regulatory agency, such as the FDA, or by performing any of the non-limiting examples of the assays described herein. In some embodiments, the test or assay is provided as a kit. In some embodiments, the cancer is a p53-related cancer.
亦提供了治療有需要之個體之癌症的方法,該方法包含:(a) 偵測個體之p53相關癌症;及(b)向個體投與治療有效量的式(I)化合物或其醫藥學上可接受之鹽或其醫藥組合物。此等方法之一些實施例進一步包括向個體投與另一抗癌劑(例如,免疫療法)。在一些實施例中,個體先前用另一抗癌治療,例如,腫瘤之至少部分切除或放射療法來治療。在一些實施例中,經由使用監管機構批准,例如,FDA批准的鑑別個體或來自個體之生檢樣品中之 TP53基因、p53蛋白或其中任一者之活性之失調的測試或檢定,或藉由執行本文所描述之檢定之非限制性實例中之任一者,將個體確定為患有p53相關癌症。在一些實施例中,測試或檢定作為套組提供。在一些實施例中,癌症為p53相關癌症。 Also provided are methods of treating cancer in a subject in need thereof, the methods comprising: (a) detecting a p53-related cancer in the subject; and (b) administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. Some embodiments of these methods further comprise administering to the subject another anticancer agent (e.g., immunotherapy). In some embodiments, the subject was previously treated with another anticancer therapy, e.g., at least partial resection of a tumor or radiation therapy. In some embodiments, an individual is determined to have a p53-related cancer by using a test or assay approved by a regulatory agency, e.g., FDA, to identify dysregulation of the TP53 gene, p53 protein, or activity of either in an individual or in a biopsy sample from an individual, or by performing any of the non-limiting examples of assays described herein. In some embodiments, the test or assay is provided as a kit. In some embodiments, the cancer is a p53-related cancer.
亦提供了式(I)化合物或其醫藥學上可接受之鹽或其醫藥組合物,其用於經由對自個體獲得之樣品執行檢定(例如, 活體外檢定)以確定個體是否具有 TP53基因、p53蛋白或其中任一者之活性之失調的步驟,治療經鑑別或診斷患有p53相關癌症之個體之p53相關癌症,其中 TP53基因、p53蛋白或其中任一者之活性之失調之存在鑑別個體患有p53相關癌症。 Also provided is a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for use in treating a p53-related cancer in an individual identified or diagnosed as having a p53-related cancer by performing an assay (e.g., an in vitro assay) on a sample obtained from the individual to determine whether the individual has a disorder of the TP53 gene, p53 protein, or the activity of any of them, wherein the presence of a disorder of the TP53 gene, p53 protein, or the activity of any of them identifies the individual as having a p53-related cancer.
亦提供了式(I)化合物或其醫藥學上可接受之鹽,其用於治療有需要之個體或經鑑別或診斷患有p53相關癌症之個體之癌症。亦提供了式(I)化合物或其醫藥學上可接受之鹽用於製造藥劑之用途,該藥劑用於治療經鑑別或診斷患有p53相關癌症之個體之癌症。在一些實施例中,經由使用監管機構批准,例如,FDA批准的鑑別個體或來自個體之生檢樣品中之 TP53基因、p53蛋白或其中任一者之活性之失調的套組,將個體鑑別或診斷為患有p53相關癌症。如本文提供,p53相關癌症包括本文所描述及此項技術中已知的彼等癌症。 Also provided is a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating cancer in an individual in need thereof or an individual identified or diagnosed as having a p53-related cancer. Also provided is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating cancer in an individual identified or diagnosed as having a p53-related cancer. In some embodiments, an individual is identified or diagnosed as having a p53-related cancer using a kit approved by a regulatory agency, e.g., FDA, for identifying a disorder of the activity of the TP53 gene, p53 protein, or either in an individual or in a biopsy sample from an individual. As provided herein, p53-related cancers include those cancers described herein and known in the art.
在本文所描述之方法或用途中之任一者之一些實施例中,個體經鑑別或診斷患有具有 TP53基因、p53蛋白或其中任一者之活性之失調的癌症。在本文所描述之方法或用途中之任一者之一些實施例中,個體患有對於 TP53基因、p53蛋白或其中任一者之活性之失調呈陽性之腫瘤。在本文所描述之方法或用途中之任一者之一些實施例中,個體可為患有對於 TP53基因、p53蛋白或其中任一者之活性之失調呈陽性之腫瘤的個體。在本文所描述之方法或用途中之任一者之一些實施例中,個體可為其腫瘤具有 TP53基因、p53蛋白或其中任一者之活性之失調的個體。在本文所描述之方法或用途中之任一者之一些實施例中,個體疑似患有p53相關癌症。在一些實施例中,本文提供了用於治療需要此治療之個體之p53相關癌症的方法,該方法包含a)偵測來自個體之樣品中之 TP53基因、p53蛋白或其中任一者之活性之失調;及b)投與治療有效量的式(I)化合物或其醫藥學上可接受之鹽。在一些實施例中, TP53基因、p53蛋白或其中任一者之活性之失調包括一或多個如本文所描述之p53蛋白點突變/插入/缺失。在一些實施例中,具有 TP53基因、p53蛋白或其中任一者之活性之失調的癌症使用監管機構批准,例如,FDA批准之檢定或套組來確定。在一些實施例中,具有 TP53基因、p53蛋白或其中任一者之活性之失調的腫瘤使用監管機構批准,例如,FDA批准之檢定或套組來確定。 In some embodiments of any of the methods or uses described herein, the individual is identified or diagnosed as having a cancer having a disorder of the activity of the TP53 gene, p53 protein, or either thereof. In some embodiments of any of the methods or uses described herein, the individual has a tumor that is positive for a disorder of the activity of the TP53 gene, p53 protein, or either thereof. In some embodiments of any of the methods or uses described herein, the individual may be an individual having a tumor that is positive for a disorder of the activity of the TP53 gene, p53 protein, or either thereof. In some embodiments of any of the methods or uses described herein, the individual may be an individual whose tumor has a disorder of the activity of the TP53 gene, p53 protein, or either thereof. In some embodiments of any of the methods or uses described herein, the individual is suspected of having a p53-related cancer. In some embodiments, provided herein is a method for treating a p53-related cancer in an individual in need of such treatment, the method comprising a) detecting a disorder of the activity of the TP53 gene, p53 protein, or any of them in a sample from the individual; and b) administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the disorder of the activity of the TP53 gene, p53 protein, or any of them comprises one or more p53 protein point mutations/insertions/deletions as described herein. In some embodiments, a cancer with a disorder of the activity of the TP53 gene, p53 protein, or any of them is determined using an assay or kit approved by a regulatory agency, e.g., FDA. In some embodiments, a tumor having a dysregulation of the TP53 gene, p53 protein, or the activity of either is identified using a regulatory agency approved, e.g., FDA approved, assay or kit.
在本文所描述之方法或用途中之任一者之一些實施例中,個體具有指示個體患有具有 TP53基因、p53蛋白或其中任一者之活性之失調之腫瘤的臨床記錄。亦提供了治療個體之方法,該等方法包括向具有指示個體具有 TP53基因、p53蛋白或其中任一者之活性之失調之臨床記錄的個體投與治療有效量的式(I)化合物或其醫藥學上可接受之鹽。 In some embodiments of any of the methods or uses described herein, the subject has a clinical record indicating that the subject has a tumor with a disorder of the activity of the TP53 gene, p53 protein, or any thereof. Also provided are methods of treating a subject, comprising administering to a subject having a clinical record indicating that the subject has a disorder of the activity of the TP53 gene, p53 protein, or any thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
亦提供了用於恢復細胞中之p53功能的方法,其包含使細胞與式(I)化合物或其醫藥學上可接受之鹽接觸。在一些實施例中,接觸為活體外的。在一些實施例中,接觸為 活體內的。在一些實施例中,接觸為 活體內的,其中該方法包含向具有具備異常p53功能之細胞之個體投與有效量的式(I)化合物或其醫藥學上可接受之鹽。在一些實施例中,細胞為癌細胞。在一些實施例中,癌細胞為如本文所描述之任何癌症。在一些實施例中,癌細胞為p53相關癌細胞。如本文所用,術語「接觸」係指在 活體外系統或 活體內系統中,將所指示部分聚集在一起。例如,使p53蛋白與本文所提供之化合物「接觸」包括向具有p53蛋白之個體(individual)或個體(subject),諸如人類,投與本文所提供之化合物,以及例如將本文所提供之化合物引入含有含p53蛋白之細胞或純化的製劑的樣品中。 Also provided is a method for restoring p53 function in a cell, comprising contacting the cell with a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the contact is in vitro. In some embodiments, the contact is in vivo . In some embodiments, the contact is in vivo , wherein the method comprises administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to an individual having cells with abnormal p53 function. In some embodiments, the cell is a cancer cell. In some embodiments, the cancer cell is any cancer as described herein. In some embodiments, the cancer cell is a p53-related cancer cell. As used herein, the term "contact" refers to bringing together the indicated moieties in an in vitro system or an in vivo system. For example, "contacting" a p53 protein with a compound provided herein includes administering a compound provided herein to an individual or subject, such as a human, having a p53 protein, as well as, for example, introducing a compound provided herein into a sample containing cells or purified preparations containing a p53 protein.
本文亦提供了 活體外或 活體內抑制細胞增殖之方法,該方法包含使細胞與有效量的如本文所定義之式(I)化合物或其醫藥學上可接受之鹽或其醫藥組合物接觸。 Also provided herein is a method for inhibiting cell proliferation in vitro or in vivo , which method comprises contacting the cells with an effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
本文進一步提供了 活體外或 活體內增加細胞死亡之方法,該方法包含使細胞與有效量的如本文所定義之式(I)化合物或其醫藥學上可接受之鹽或其醫藥組合物接觸。本文亦提供了增加個體中之腫瘤細胞死亡的方法。該方法包含以有效增加腫瘤細胞死亡之量,向個體投與有效的式(I)化合物或其醫藥學上可接受之鹽。 Further provided herein is a method of increasing cell death in vitro or in vivo , the method comprising contacting the cell with an effective amount of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. Also provided herein is a method of increasing tumor cell death in an individual. The method comprises administering to the individual an effective compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount effective to increase tumor cell death.
在本文所描述之方法或用途中之任一者之一些實施例中,癌症(例如,p53相關癌症)選自血液癌症及實體腫瘤。In some embodiments of any of the methods or uses described herein, the cancer (e.g., a p53-related cancer) is selected from a hematological cancer and a solid tumor.
在本文所描述之方法或用途中之任一者之一些實施例中,癌症(例如,p53相關癌症)為血液癌症。在一些實施例中,血液癌症為白血病。在一些實施例中,血液癌症為淋巴瘤。在一些實施例中,血液癌症為急性骨髓性白血病(AML)、慢性淋巴球性白血病(CLL)或毛細胞白血病(HCL)。在一些實施例中,血液癌症為急性骨髓性白血病(AML)。In some embodiments of any of the methods or uses described herein, the cancer (e.g., a p53-related cancer) is a blood cancer. In some embodiments, the blood cancer is a leukemia. In some embodiments, the blood cancer is a lymphoma. In some embodiments, the blood cancer is acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), or hairy cell leukemia (HCL). In some embodiments, the blood cancer is acute myeloid leukemia (AML).
在本文所描述之方法或用途中之任一者之一些實施例中,癌症(例如,p53相關癌症)為實體腫瘤。In some embodiments of any of the methods or uses described herein, the cancer (eg, p53-associated cancer) is a solid tumor.
在本文所描述之方法或用途中之任一者之一些實施例中,癌症(例如,p53相關癌症)選自腦癌、膀胱癌、乳癌、結腸直腸癌、皮膚癌、食管癌、肺癌、胃癌、腎癌、子宮癌、卵巢癌、肝癌、胰臟癌、前列腺癌、平滑肌肉瘤及頭頸部鱗狀細胞癌。In some embodiments of any of the methods or uses described herein, the cancer (e.g., a p53-related cancer) is selected from brain cancer, bladder cancer, breast cancer, colorectal cancer, skin cancer, esophageal cancer, lung cancer, stomach cancer, kidney cancer, uterine cancer, ovarian cancer, liver cancer, pancreatic cancer, prostate cancer, leiomyosarcoma, and head and neck squamous cell carcinoma.
在本文所描述之方法或用途中之任一者之一些實施例中,癌症(例如,p53相關癌症)選自結腸直腸癌、卵巢癌、胰臟癌、乳癌、非小細胞肺癌、小細胞肺癌、子宮內膜癌及膀胱癌。In some embodiments of any of the methods or uses described herein, the cancer (e.g., a p53-related cancer) is selected from colorectal cancer, ovarian cancer, pancreatic cancer, breast cancer, non-small cell lung cancer, small cell lung cancer, endometrial cancer, and bladder cancer.
在一些實施例中,腦癌為星細胞瘤、寡星細胞瘤、寡樹突神經膠細胞瘤或多形性神經膠母細胞瘤。In some embodiments, the brain cancer is astrocytoma, oligoastrocytoma, oligodendritic neuroglioma, or multiforme neuroglioma.
在一些實施例中,膀胱癌為膀胱尿路上皮癌。In some embodiments, the bladder cancer is bladder urothelial carcinoma.
在一些實施例中,食管癌為食管腺癌或食管鱗狀細胞癌。In some embodiments, the esophageal cancer is esophageal adenocarcinoma or esophageal squamous cell carcinoma.
在一些實施例中,皮膚癌為皮膚黑色素瘤。In some embodiments, the skin cancer is cutaneous melanoma.
在一些實施例中,肺癌為小細胞肺癌(SCLC)或非小細胞肺癌(NSCLC)。在一些實施例中,肺癌為小細胞肺癌(SCLC)。在一些實施例中,肺癌為非小細胞肺癌(NSCLC)。在一些實施例中,肺癌為肺腺癌或肺鱗狀細胞癌。In some embodiments, the lung cancer is small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC). In some embodiments, the lung cancer is small cell lung cancer (SCLC). In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, the lung cancer is lung adenocarcinoma or lung squamous cell carcinoma.
在一些實施例中,胃癌為黏液性胃腺癌或腸型胃腺癌。In some embodiments, the gastric cancer is mucinous gastric adenocarcinoma or intestinal type gastric adenocarcinoma.
在一些實施例中,乳癌為乳房侵襲性導管癌。In some embodiments, the breast cancer is invasive ductal carcinoma of the breast.
在一些實施例中,子宮癌為子宮混合性子宮內膜癌、子宮內膜樣癌、子宮漿液性癌或子宮乳頭狀漿液性癌。In some embodiments, the uterine cancer is mixed endometrial carcinoma, endometrioid carcinoma, serous carcinoma, or papillary serous carcinoma.
在一些實施例中,卵巢癌為漿液性卵巢癌。In some embodiments, the ovarian cancer is serous ovarian cancer.
在一些實施例中,腎癌為難染性腎細胞癌。In some embodiments, the kidney cancer is refractory renal cell carcinoma.
在一些實施例中,結腸直腸癌為結腸腺癌。In some embodiments, colorectal cancer is colon adenocarcinoma.
在一些實施例中,肝癌為肝細胞癌。In some embodiments, the liver cancer is hepatocellular carcinoma.
在一些實施例中,胰臟癌為胰臟腺癌。In some embodiments, the pancreatic cancer is pancreatic adenocarcinoma.
在一些實施例中,癌症為前列腺癌。In some embodiments, the cancer is prostate cancer.
在本文所描述之方法或用途中之任一者之一些實施例中,p53相關癌症為乳癌。在本文所描述之方法或用途中之任一者之一些實施例中,p53相關癌症為結腸直腸癌。在本文所描述之方法或用途中之任一者之一些實施例中,p53相關癌症為子宮內膜癌。在本文所描述之方法或用途中之任一者之一些實施例中,p53相關癌症為肺癌。In some embodiments of any of the methods or uses described herein, the p53-related cancer is breast cancer. In some embodiments of any of the methods or uses described herein, the p53-related cancer is colorectal cancer. In some embodiments of any of the methods or uses described herein, the p53-related cancer is endometrial cancer. In some embodiments of any of the methods or uses described herein, the p53-related cancer is lung cancer.
在本文所描述之方法或用途中之任一者之一些實施例中,p53相關癌症選自表1中所描述之癌症。
表1. p53蛋白胺基酸取代/插入/缺失
A
A除非另有提及,否則表1之突變見於源自Cerami等人 The cBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics Data.Cancer Discovery. 2012年5月2日; 401;及Gao等人 Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal.Sci. Signal. 6, pl1 (2013)之cBioPortal資料庫中。 組合 A Unless otherwise mentioned, the mutations in Table 1 are found in the cBioPortal database from Cerami et al . The cBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics Data. Cancer Discovery. May 2, 2012; 401; and Gao et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal. 6, pl1 (2013).
在腫瘤醫學領域中,使用不同治療形式之組合來治療患有癌症之各個體為通常實踐。在腫瘤醫學中,除了本文所提供之組合物以外的此聯合治療或療法之其他組分可為例如手術、放射療法及化學治療劑,諸如激酶抑制劑、信號轉導抑制劑及/或單株抗體或前述手段中之任一者之組合。例如,手術可為開放性手術或微創手術。因此,式(I)化合物或其醫藥學上可接受之鹽亦可適合用作癌症治療之佐劑,亦即其可與一或多種額外療法或治療劑,例如,藉由不同作用機制起作用之化學治療劑組合使用。在一些實施例中,式(I)化合物或其醫藥學上可接受之鹽可在投與額外治療劑或額外療法之前使用。例如,可向有需要之個體投與一或多個劑量之式(I)化合物或其醫藥學上可接受之鹽持續一段時間,然後經歷腫瘤之至少部分切除。在一些實施例中,在腫瘤之至少部分切除之前,用一或多個劑量之式(I)化合物或其醫藥學上可接受之鹽來治療減小腫瘤之大小(例如,腫瘤負荷)。在一些實施例中,可向有需要之個體投與式(I)化合物或其醫藥學上可接受之鹽持續一段時間並且處於一或多輪放射療法下。在一些實施例中,在一或多輪放射療法之前,用式(I)化合物或其醫藥學上可接受之鹽來治療減小腫瘤之大小(例如,腫瘤負荷)。In the field of oncology medicine, it is common practice to treat individuals suffering from cancer using a combination of different treatment modalities. In oncology medicine, other components of this combined therapy or treatment other than the compositions provided herein may be, for example, surgery, radiotherapy and chemotherapy, such as kinase inhibitors, signal transduction inhibitors and/or monoclonal antibodies or a combination of any of the foregoing means. For example, surgery may be open surgery or minimally invasive surgery. Therefore, the compound of formula (I) or a pharmaceutically acceptable salt thereof may also be suitable for use as an adjuvant for cancer treatment, i.e., it may be used in combination with one or more additional therapies or treatments, for example, chemotherapeutic agents acting by different mechanisms of action. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof may be used prior to administration of an additional therapeutic agent or additional therapy. For example, a subject in need thereof may be administered one or more doses of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time and then undergo at least partial resection of the tumor. In some embodiments, prior to at least partial resection of the tumor, treatment with one or more doses of a compound of formula (I) or a pharmaceutically acceptable salt thereof reduces the size of the tumor (e.g., tumor burden). In some embodiments, a subject in need thereof may be administered a compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time and under one or more rounds of radiation therapy. In some embodiments, treatment with a compound of Formula (I) or a pharmaceutically acceptable salt thereof reduces the size of a tumor (e.g., tumor burden) prior to one or more rounds of radiation therapy.
在一些實施例中,個體患有對於標準療法(例如,投與化學治療劑諸如多激酶抑制劑、免疫療法或放射(例如,放射性碘))難治或不耐受的癌症(例如,局部晚期或轉移性腫瘤)。在一些實施例中,個體患有對於先前療法(例如,投與化學治療劑諸如多激酶抑制劑、免疫療法或放射(例如,放射性碘))難治或不耐受的癌症(例如,局部晚期或轉移性腫瘤)。在一些實施例中,個體患有無標準療法之癌症(例如,局部晚期或轉移性腫瘤)。在一些實施例中,個體已經歷先前療法。在一些實施例中,個體對於p53恢復療法為初始的。在一些實施例中,個體對於p53恢復療法不為初始的。在一些實施例中,個體為激酶抑制劑初始的。在一些實施例中,個體不為激酶抑制劑初始的。In some embodiments, the individual has a cancer (e.g., a locally advanced or metastatic tumor) that is refractory or intolerant to standard therapy (e.g., administration of chemotherapeutics such as multi-kinase inhibitors, immunotherapy, or radiation (e.g., radioactive iodine). In some embodiments, the individual has a cancer (e.g., a locally advanced or metastatic tumor) that is refractory or intolerant to a prior therapy (e.g., administration of chemotherapeutics such as multi-kinase inhibitors, immunotherapy, or radiation (e.g., radioactive iodine). In some embodiments, the individual has a cancer (e.g., a locally advanced or metastatic tumor) for which there is no standard therapy. In some embodiments, the individual has undergone prior therapy. In some embodiments, the individual is naive to p53 restoration therapy. In some embodiments, the subject is not naive for p53 restoration therapy. In some embodiments, the subject is kinase inhibitor naive. In some embodiments, the subject is not kinase inhibitor naive.
在本文所描述之任何方法之一些實施例中,式(I)化合物(或其醫藥學上可接受之鹽)與治療有效量的選自一或多種本文所描述之額外療法或治療(例如,化學治療)劑之至少一種額外治療劑組合投與。例如,在一些實施例中,式(I)化合物(或其醫藥學上可接受之鹽)與一種、兩種或三種獨立選擇之如本文所描述之額外治療劑組合投與。In some embodiments of any of the methods described herein, a compound of formula (I) (or a pharmaceutically acceptable salt thereof) is administered in combination with a therapeutically effective amount of at least one additional therapeutic agent selected from one or more additional therapeutic agents or treatments (e.g., chemotherapeutic agents) described herein. For example, in some embodiments, a compound of formula (I) (or a pharmaceutically acceptable salt thereof) is administered in combination with one, two, or three independently selected additional therapeutic agents as described herein.
額外治療劑之非限制性實例包括小分子、抗體及抗體-藥物偶聯物諸如EGFR抑制劑、HER2抑制劑、RAS路徑靶向治療劑(如本文描述的)、PARP抑制劑、CDK4/6抑制劑、FGFR抑制劑、ALK抑制劑、NTRK/ROS抑制劑、MET抑制劑、RET抑制劑、其他激酶抑制劑(例如,受體酪胺酸激酶靶向治療劑(例如,多激酶抑制劑))、選擇性雌激素受體調節劑或降解劑(SERM/SERD)、抗雄激素、檢查點抑制劑;細胞毒性化學治療劑、血管生成靶向療法、免疫靶向劑包括免疫療法及放射療法。Non-limiting examples of additional therapeutic agents include small molecules, antibodies and antibody-drug conjugates such as EGFR inhibitors, HER2 inhibitors, RAS pathway targeted therapies (as described herein), PARP inhibitors, CDK4/6 inhibitors, FGFR inhibitors, ALK inhibitors, NTRK/ROS inhibitors, MET inhibitors, RET inhibitors, other kinase inhibitors (e.g., receptor tyrosine kinase targeted therapies (e.g., multi-kinase inhibitors)), selective estrogen receptor modulators or degraders (SERM/SERD), anti-androgens, checkpoint inhibitors; cytotoxic chemotherapeutics, angiogenesis targeted therapies, immune targeted agents including immunotherapy and radiation therapy.
在一些實施例中,CDK4/6抑制劑為帕博西尼(palbociclib) (IBRANCE®, PD-0332991)、瑞博西尼(ribociclib) (KISQALI®, LEE-011)、玻瑪西尼(abemaciclib) (VERZENIO®, LY-2835219)、曲拉西尼(triraciclib) (COSELA™, G1T28)、來羅西尼(lerociclib) (G1T38)、達爾西尼(dalpiciclib) (SHR-6390)或BPI-16350。In some embodiments, the CDK4/6 inhibitor is palbociclib (IBRANCE®, PD-0332991), ribociclib (KISQALI®, LEE-011), abemaciclib (VERZENIO®, LY-2835219), triraciclib (COSELA™, G1T28), lerociclib (G1T38), dalpiciclib (SHR-6390), or BPI-16350.
在一些實施例中,FGFR抑制劑為培米替尼(pemigatinib) (PEMAZYRE®,INCB-054828)、英菲替尼(infigratinib) (TRUSELTIQ®,BGJ-398,NVP-BGJ398)、福巴替尼(futibatinib) (LYTGOBI®,TAS-120)、厄達替尼(erdafitinib) (BALVERSA®,JNJ-42756493)、AZD4547、德拉替尼(derazantinib) (ARQ-087)、AZD4547、阿魏酸-13C3、FGFR-IN-7、PP58、FGFR3-IN-1、ENMD-2076酒石酸鹽、R1530、FGFR3-IN-3、酪胺酸激酶-IN-1、SU4984、羅布替尼(roblitinib) (FGF-401)、PD173074、FGFR4-IN-8、德立他尼(lucitanib) (E-3810)、馬西替尼(masitinib) (AB1010)、唑來替尼(zoligratinib) (debio 1347,CH5183284)、FGFR4-IN-4、BLU9931、SM1-71、TG 100801、FGFR1抑制劑-6或TG 100572。In some embodiments, the FGFR inhibitor is pemigatinib (PEMAZYRE®, INCB-054828), infigratinib (TRUSELTIQ®, BGJ-398, NVP-BGJ398), futibatinib (LYTGOBI®, TAS-120), erdafitinib (BALVERSA®, JNJ-42756493), AZD4547, derazantinib ( (ARQ-087), AZD4547, ferulic acid-13C3, FGFR-IN-7, PP58, FGFR3-IN-1, ENMD-2076 tartrate, R1530, FGFR3-IN-3, tyrosine kinase-IN-1, SU4984, roblitinib (FGF-401), PD173074, FGFR4-IN-8, lucitanib (E-3810), masitinib (AB1010), zoligratinib (debio 1347, CH5183284), FGFR4-IN-4, BLU9931, SM1-71, TG 100801, FGFR1 inhibitor-6, or TG 100572.
在一些實施例中,ALK抑制劑為克唑替尼(crizotinib) (XALKORI®,PF-02341066)、色瑞替尼(ceritinib) (ZYKADIA®,LDK-378)、艾樂替尼(alectinib) (ALECENSA®,CH5424802,RO5424802,AF802)、布加替尼(brigatinib) (ALUNBRIG®,AP-26113)、洛拉替尼(lorlatinib) (LORBRENA®,PF-06463922)、恩曲替尼(entrectinib) (NMS-E628,RXDX-101,ROZLYTREK®)、ASP3026、TSR-011、PF-06463922、恩沙替尼(ensartinib) (X-396)或CEP-37440。In some embodiments, the ALK inhibitor is crizotinib (XALKORI®, PF-02341066), ceritinib (ZYKADIA®, LDK-378), alectinib (ALECENSA®, CH5424802, RO5424802, AF802), brigatinib (ALUNBRIG®, AP-26113), lorlatinib (LORBRENA®, PF-06463922), entrectinib (NMS-E628, RXDX-101, ROZLYTREK®), ASP3026, TSR-011, PF-06463922, ensartinib (X-396), or CEP-37440.
在一些實施例中,NTRK/ROS抑制劑為恩曲替尼(NMS-E628,RXDX-101,ROZLYTREK®)、他雷替尼(taletrectinib) (DS-6051b,AB-106)或瑞波替尼(repotrectinib) (TPX-0005), 在一些實施例中,MET抑制劑為卡普替尼(capmatinib) (TABRECTA®,INC280;INCB28060)、特潑替尼(tepotinib) (TEPMETKO®)、提瓦替尼(tivantinib) (ARQ197)、薩沃利替尼(savolitinib) (ORPATHYS®,沃利替尼(Volitinib),HMPL-504,AZD-6094)、弗雷替尼(foretinib) (XL880,GSK1363089,GSK089,EXEL-2880)、帕莫替尼(pamufetinib) (TAS-115)、c-Met-IN-2、PHA-665752、SU11274、SYN1143或阿姆替尼鹽酸鹽(amuvatinib hydrochloride) (MP470鹽酸鹽,HPK 56鹽酸鹽)。 In some embodiments, the NTRK/ROS inhibitor is entrectinib (NMS-E628, RXDX-101, ROZLYTREK®), taletrectinib (DS-6051b, AB-106) or repotrectinib (TPX-0005), In some embodiments, the MET inhibitor is capmatinib (TABRECTA®, INC280; INCB28060), tepotinib (TEPMETKO®), tivantinib (ARQ197), savolitinib (ORPATHYS®, Volitinib, HMPL-504, AZD-6094), foretinib (XL880, GSK1363089, GSK089, EXEL-2880), pamufetinib (TAS-115), c-Met-IN-2, PHA-665752, SU11274, SYN1143 or amuvatinib hydrochloride (MP470 hydrochloride, HPK 56 hydrochloride).
在一些實施例中,RET抑制劑為塞爾帕替尼(selpercatinib) (RETEVMO®,LOXO-292)、澤布替尼(zeteletinib) (BOS-172738,DS-5010)、GSK3179106、阿姆替尼鹽酸鹽(MP470鹽酸鹽,HPK 56鹽酸鹽)、TPX-0046或普拉替尼(pralsetinib) (GAVRETO®,BLU-667)。In some embodiments, the RET inhibitor is selpercatinib (RETEVMO®, LOXO-292), zeteletinib (BOS-172738, DS-5010), GSK3179106, amoxicillin hydrochloride (MP470 hydrochloride, HPK 56 hydrochloride), TPX-0046, or pralsetinib (GAVRETO®, BLU-667).
在一些實施例中,EGFR抑制劑為奧希替尼(osimertinib) (AZD9291,默來替尼(merelectinib),TAGRISSOTM)、厄洛替尼(erlotinib) (TARCEVA®)、吉非替尼(gefitinib) (IRESSA®)、西妥昔單抗(cetuximab) (ERBITUX®)、奈昔妥珠單抗(necitumumab) (PORTRAZZATM、IMC-11F8)、來那替尼(neratinib) (HKI-272、NERLYNX®)、拉帕替尼(lapatinib) (TYKERB®)、帕尼單抗(panitumumab) (ABX-EGF、VECTIBIX®)、凡德他尼(vandetanib) (CAPRELSA®)、羅西替尼(rociletinib) (CO-1686)、奧莫替尼(olmutinib) (OLITATM、HM61713、BI-1482694)、納奎替尼(naquotinib) (ASP8273)、納扎替尼(nazartinib) (EGF816、NVS-816)、瑪韋替尼(mavelertinib) (PF-06747775)、埃克替尼(icotinib) (BPI-2009H)、阿法替尼(afatinib) (BIBW 2992、GILOTRIF®)、達克替尼(dacomitinib) (PF-00299804、PF-804、PF-299、PF-299804)、阿維替尼(avitinib) (AC0010)、AC0010MA EAI045、馬妥珠單抗(matuzumab) (EMD-7200)、尼妥珠單抗(nimotuzumab) (h-R3、BIOMAb EGFR®)、扎魯木單抗(zalutumab)、MDX447、達妥昔珠單抗(depatuxizumab) (人類化mAb 806, ABT-806)、達妥昔珠單抗馬佛多坦(depatuxizumab mafodotin) (ABT-414)、ABT-806、mAb 806、卡奈替尼(canertinib) (CI-1033)、紫草素(shikonin)、紫草素衍生物(例如,去氧紫草素、異丁醯基紫草素、乙醯紫草素、β,β-二甲基丙烯紫草素及乙醯阿卡寧(acetylalkannin))、波齊替尼(poziotinib) (NOV120101,HM781-36B)、AV-412、依魯替尼(ibrutinib)、WZ4002、布加替尼(AP26113 ALUNBRIG®)、培利替尼(pelitinib) (EKB-569)、他洛替尼(tarloxotinib) (TH-4000,PR610)、BPI-15086、Hemay022、ZN-e4、特西伐替尼(tesevatinib) (KD019,XL647)、YH25448、伊匹替尼(epitinib) (HMPL-813)、CK-101、MM-151、AZD3759、ZD6474、PF-06459988、瓦利替尼(varlintinib) (ASLAN001,ARRY-334543)、AP32788、HLX07、D-0316、AEE788、HS-10296、阿維替尼、GW572016、吡咯替尼(pyrotinib) (SHR1258)、SCT200、CPGJ602、Sym004、MAb-425、莫多西單抗(Modotuximab) (TAB-H49)、弗妥昔單抗(futuximab) (992 DS)、扎魯木單抗(zalutumumab)、KL-140、RO5083945、IMGN289、JNJ-61186372、LY3164530、Sym013、AMG 595、BDTX-189、阿伐替尼(avatinib)、破壞蛋白(Disruptin)、CL-387785、配備EGFRBi之自體T細胞及EGFR CAR-T療法。在一些實施例中,EGFR靶向治療劑選自奧希替尼、吉非替尼、厄洛替尼、阿法替尼、拉帕替尼、來那替尼、AZD-9291、CL-387785、CO-1686或WZ4002。In some embodiments, the EGFR inhibitor is osimertinib (AZD9291, merelectinib, TAGRISSO™), erlotinib (TARCEVA®), gefitinib (IRESSA®), cetuximab (ERBITUX®), necitumumab (PORTRAZZA™, IMC-11F8), neratinib (HKI-272, NERLYNX®), lapatinib (TYKERB®), panitumumab (ABX-EGF, VECTIBIX®), vandetanib (CAPRELSA®), rociletinib (CO-1686), olmutinib ( (OLITATM, HM61713, BI-1482694), naquotinib (ASP8273), nazartinib (EGF816, NVS-816), mavelertinib (PF-06747775), icotinib (BPI-2009H), afatinib (BIBW 2992, GILOTRIF®), dacomitinib (PF-00299804, PF-804, PF-299, PF-299804), avitinib (AC0010), AC0010MA EAI045, matuzumab (EMD-7200), nimotuzumab (h-R3, BIOMAb EGFR®), zalutumab, MDX447, depatuxizumab (humanized mAb 806, ABT-806), depatuxizumab mafodotin (ABT-414), ABT-806, mAb 806, canertinib (CI-1033), shikonin, shikonin derivatives (e.g., deoxyshikonin, isobutylshikonin, acetylshikonin, β,β-dimethylallylshikonin, and acetylalkannin), poziotinib (NOV120101, HM781-36B), AV-412, ibrutinib, WZ4002, brigatinib (AP26113 ALUNBRIG®), pelitinib (EKB-569), tarloxotinib (TH-4000, PR610), BPI-15086, Hemay022, ZN-e4, tesevatinib (KD019, XL647), YH25448, epitinib (HMPL-813), CK-101, MM-151, AZD3759, ZD6474, PF-06459988, varlintinib (ASLAN001, ARRY-334543), AP32788, HLX07, D-0316, AEE788, HS-10296, avitinib, GW572016, pyrotinib (SHR1258), SCT200, CPGJ602, Sym004, MAb-425, Modotuximab (TAB-H49), futuximab (992 DS), zalutumumab, KL-140, RO5083945, IMGN289, JNJ-61186372, LY3164530, Sym013, AMG 595, BDTX-189, avatinib, disruptin, CL-387785, autologous T cells equipped with EGFRBi and EGFR CAR-T therapy. In some embodiments, the EGFR targeted therapeutic agent is selected from osimertinib, gefitinib, erlotinib, afatinib, lapatinib, neratinib, AZD-9291, CL-387785, CO-1686 or WZ4002.
例示性HER2抑制劑包括曲妥珠單抗(trastuzumab) (例如,TRAZIMERA™,HERCEPTIN®)、帕妥珠單抗(pertuzumab) (例如,PERJETA®)、曲妥珠單抗艾坦辛(trastuzumab emtansine) (T-DM1或阿多曲妥珠單抗艾坦辛(ado-trastuzumab emtansine),例如,KADCYLA®)、拉帕替尼、KU004、來那替尼(例如,NERLYNX®)、達克替尼(例如,VIZIMPRO®)、阿法替尼(GILOTRIF®)、妥卡替尼(tucatinib) (例如,TUKYSA™)、厄洛替尼(例如,TARCEVA®)、吡咯替尼、波齊替尼、CP-724714、CUDC-101、沙皮替尼(sapitinib) (AZD8931)、坦螺旋黴素(tanespimycin) (17-AAG)、IPI-504、PF299、培利替尼、S-22261 1及AEE-788。Exemplary HER2 inhibitors include trastuzumab (e.g., TRAZIMERA™, HERCEPTIN®), pertuzumab (e.g., PERJETA®), trastuzumab emtansine (T-DM1 or ado-trastuzumab emtansine, e.g., KADCYLA®), lapatinib, KU004, neratinib (e.g., NERLYNX®), dacomitinib (e.g., VIZIMPRO®), afatinib (GILOTRIF®), tucatinib (e.g., TUKYSA™), erlotinib (e.g., TARCEVA®), pyrotinib, pozitinib, CP-724714, CUDC-101, sapitinib (AZD8931), tanespimycin (17-AAG), IPI-504, PF299, pelitinib, S-22261 1 and AEE-788.
如本文所用,「RAS路徑靶向治療劑」包括展現RAS路徑中之任何蛋白質之鈍化活性(例如,激酶抑制、別位抑制、二聚化之抑制及降解之誘導)的任何化合物。RAS路徑中之蛋白之非限制性實例包括RAS-RAF-MAPK路徑或PI3K/AKT路徑中之蛋白質中之任一者,諸如RAS (例如,KRAS、HRAS及NRAS)、RAF (ARAF、BRAF、CRAF)、MEK、ERK、PI3K、AKT及mTOR。在一些實施例中,RAS路徑調節劑可對RAS路徑中之蛋白質具有選擇性,例如,RAS路徑調節劑可對RAS具有選擇性(亦稱為RAS調節劑)。在一些實施例中,RAS調節劑為共價抑制劑。在一些實施例中,RAS路徑靶向治療劑為「KRAS路徑調節劑」。KRAS路徑調節劑包括展現KRAS路徑中之任何蛋白質之鈍化活性(例如,激酶抑制、別位抑制、二聚化之抑制及降解之誘導)的任何化合物。KRAS路徑中之蛋白質之非限制性實例包括KRAS-RAF-MAPK路徑或PI3K/AKT路徑中之蛋白質中之任一者,諸如KRAS、RAF、BRAF、MEK、ERK、PI3K、AKT及mTOR。在一些實施例中,KRAS路徑調節劑可對RAS路徑中之蛋白質具有選擇性,例如,KRAS路徑調節劑可對KRAS具有選擇性(亦稱為KRAS調節劑)。在一些實施例中,KRAS調節劑為共價抑制劑。As used herein, "RAS pathway targeted therapeutics" include any compound that exhibits blunting activity (e.g., kinase inhibition, allosteric inhibition, inhibition of dimerization, and induction of degradation) of any protein in the RAS pathway. Non-limiting examples of proteins in the RAS pathway include any of the proteins in the RAS-RAF-MAPK pathway or the PI3K/AKT pathway, such as RAS (e.g., KRAS, HRAS, and NRAS), RAF (ARAF, BRAF, CRAF), MEK, ERK, PI3K, AKT, and mTOR. In some embodiments, a RAS pathway modulator may be selective for a protein in the RAS pathway, for example, a RAS pathway modulator may be selective for RAS (also referred to as a RAS modulator). In some embodiments, the RAS modulator is a covalent inhibitor. In some embodiments, the RAS pathway targeted therapeutic is a "KRAS pathway modulator". KRAS pathway modulators include any compound that exhibits blunting activity (e.g., kinase inhibition, allosteric inhibition, inhibition of dimerization, and induction of degradation) of any protein in the KRAS pathway. Non-limiting examples of proteins in the KRAS pathway include any of the proteins in the KRAS-RAF-MAPK pathway or the PI3K/AKT pathway, such as KRAS, RAF, BRAF, MEK, ERK, PI3K, AKT, and mTOR. In some embodiments, a KRAS pathway modulator can be selective for a protein in the RAS pathway, for example, a KRAS pathway modulator can be selective for KRAS (also referred to as a KRAS modulator). In some embodiments, a KRAS modulator is a covalent inhibitor.
KRAS靶向治療劑(例如,KRAS抑制劑)之非限制性實例包括索托拉西布(sotorasib) (AMG510,LUMAKRAS®)、BI 1701963、BI 1823911、ARS-853、ARS-3248、ARS-1620、AZD4785、SML-8-73-1、SML-10-70-1、VSA9、GDC-6036、D-1553、AA12、JDQ443及阿達格拉西布(adagrasib) (MRTX-849)。Non-limiting examples of KRAS targeted therapeutics (e.g., KRAS inhibitors) include sotorasib (AMG510, LUMAKRAS®), BI 1701963, BI 1823911, ARS-853, ARS-3248, ARS-1620, AZD4785, SML-8-73-1, SML-10-70-1, VSA9, GDC-6036, D-1553, AA12, JDQ443, and adagrasib (MRTX-849).
RAS靶向治療劑之進一步非限制性實例包括BRAF抑制劑、MEK抑制劑、ERK抑制劑、PI3K抑制劑、AKT抑制劑及mTOR抑制劑。在一些實施例中,BRAF抑制劑為威羅菲尼(vemurafenib) (ZELBORAF®)、達拉菲尼(dabrafenib) (TAFINLAR®)及恩拉菲尼(encorafenib) (BRAFTOVI®)、BMS-908662 (XL281)、索拉菲尼(sorafenib)、PLX3603、RAF265、RO5185426、GSK2118436、ARQ 736、GDC-0879、PLX-4720、AZ304、PLX-8394、HM95573、RO5126766、LXH254或其組合。Further non-limiting examples of RAS targeted therapeutics include BRAF inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, AKT inhibitors, and mTOR inhibitors. In some embodiments, the BRAF inhibitor is vemurafenib (ZELBORAF®), dabrafenib (TAFINLAR®), and encorafenib (BRAFTOVI®), BMS-908662 (XL281), sorafenib, PLX3603, RAF265, RO5185426, GSK2118436, ARQ 736, GDC-0879, PLX-4720, AZ304, PLX-8394, HM95573, RO5126766, LXH254, or a combination thereof.
在一些實施例中,MEK抑制劑為曲美替尼(trametinib) (MEKINIST®,GSK1120212)、考比替尼(cobimetinib) (COTELLIC®)、畢尼替尼(binimetinib) (MEKTOVI®,MEK162)、司美替尼(selumetinib) (AZD6244)、PD0325901、MSC1936369B、SHR7390、TAK-733、RO5126766、CS3006、WX-554、PD98059、CI1040 (PD184352)、寄端黴素(hypothemycin)或其組合。In some embodiments, the MEK inhibitor is trametinib (MEKINIST®, GSK1120212), cobimetinib (COTELLIC®), binimetinib (MEKTOVI®, MEK162), selumetinib (AZD6244), PD0325901, MSC1936369B, SHR7390, TAK-733, RO5126766, CS3006, WX-554, PD98059, CI1040 (PD184352), hypothemycin, or a combination thereof.
在一些實施例中,ERK抑制劑為FRI-20 (ON-01060)、VTX-11e、25-OH-D3-3-BE (B3CD,溴乙醯氧基骨化二醇)、FR-180204、AEZ-131 (AEZS-131)、AEZS-136、AZ-13767370、BL-EI-001、LY-3214996、LTT-462、KO-947、KO-947、MK-8353 (SCH900353)、SCH772984、優立替尼(ulixertinib) (BVD-523)、CC-90003、GDC-0994 (RG-7482)、ASN007、FR148083、5-7-側氧基玉米赤黴醇(Oxozeaenol)、5-碘殺結核菌素(iodotubercidin)、GDC0994、ONC201或其組合。In some embodiments, the ERK inhibitor is FRI-20 (ON-01060), VTX-11e, 25-OH-D3-3-BE (B3CD, bromoacetyloxycalcifediol), FR-180204, AEZ-131 (AEZS-131), AEZS-136, AZ-13767370, BL-EI-001, LY-3214996, LTT-462, KO-947, KO-947, MK-8353 (SCH900353), SCH772984, ulixertinib (BVD-523), CC-90003, GDC-0994 (RG-7482), ASN007, FR148083, 5-7-oxozeaenol, 5-iodotubercidin, GDC0994, ONC201, or a combination thereof.
在一些實施例中,PI3K抑制劑選自布帕昔布(buparlisib) (BKM120)、艾培昔布(alpelisib) (BYL719)、WX-037、考班昔布(copanlisib) (ALIQOPATM,BAY80-6946)、達妥昔布(dactolisib) (NVP-BEZ235,BEZ-235)、泰尼西布(taselisib) (GDC-0032,RG7604)、索諾昔布(sonolisib) (PX-866)、CUDC-907、PQR309、ZSTK474、SF1126、AZD8835、GDC-0077、ASN003、皮克昔布(pictilisib) (GDC-0941)、皮拉昔布(pilaralisib) (XL147,SAR245408)、吉達昔布(gedatolisib) (PF-05212384,PKI-587)、塞拉貝昔布(serabelisib) (TAK-117,MLN1117,INK 1117)、BGT-226 (NVP-BGT226)、PF-04691502、阿匹昔布(apitolisib) (GDC-0980)、奧米昔布(omipalisib) (GSK2126458,GSK458)、沃塔昔布(voxtalisib) (XL756,SAR245409)、AMG 511、CH5132799、GSK1059615、GDC-0084 (RG7666)、VS-5584 (SB2343)、PKI-402、渥曼青黴素(wortmannin)、LY294002、PI-103、瑞戈替布(rigosertib)、XL-765、LY2023414、SAR260301、KIN-193 (AZD-6428)、GS-9820、AMG319、GSK2636771或其組合。In some embodiments, the PI3K inhibitor is selected from buparlisib (BKM120), alpelisib (BYL719), WX-037, copanlisib (ALIQOPATM, BAY80-6946), dactolisib (NVP-BEZ235, BEZ-235), taselisib (GDC-0032, RG7604), sonolisib (PX-866), CUDC-907, PQR309, ZSTK474, SF1126, AZD8835, GDC-0077, ASN003, pictilisib (GDC-0941), pilaralisib (XL147, SAR245408), gedatolisib (PF-05212384, PKI-587), serabelisib (TAK-117, MLN1117, INK 1117), BGT-226 (NVP-BGT226), PF-04691502, apitolisib (GDC-0980), omipalisib (GSK2126458, GSK458), voxtalisib (XL756, SAR245409), AMG 511, CH5132799, GSK1059615, GDC-0084 (RG7666), VS-5584 (SB2343), PKI-402, wortmannin, LY294002, PI-103, rigosertib, XL-765, LY2023414, SAR260301, KIN-193 (AZD-6428), GS-9820, AMG319, GSK2636771, or a combination thereof.
在一些實施例中,AKT抑制劑選自米替福新(miltefosine) (IMPADIVO®)、渥曼青黴素、NL-71-101、H-89、GSK690693、CCT128930、AZD5363、伊巴替布(ipatasertib) (GDC-0068,RG7440)、A-674563、A-443654、AT7867、AT13148、烏普替布(uprosertib)、阿福舍替布(afuresertib)、DC120、2-[4-(2-胺基丙-2-基)苯基]-3-苯基喹噁啉、MK-2206、依地福新(edelfosine)、米替福新(miltefosine)、哌立福新(perifosine)、瓢兒菜基磷酸膽鹼(erucylphophocholine)、依羅福新(erufosine)、SR13668、OSU-A9、PH-316、PHT-427、PIT-1、DM-PIT-1、曲西立濱(triciribine) (曲西立濱磷酸酯一水合物)、API-1、N-(4-(5-(3-乙醯胺基苯基)-2-(2-胺基吡啶-3-基)-3H-咪唑并[4,5-b]吡啶-3-基)苄基)-3-氟苯醯胺、ARQ092、BAY 1125976、3-側氧基-甘遂酸、乳醌黴素(lactoquinomycin)、boc-Phe-乙烯基酮、哌立福新(D-21266)、TCN、TCN-P、GSK2141795、ONC201或其組合。In some embodiments, the AKT inhibitor is selected from miltefosine (IMPADIVO®), wortmannin, NL-71-101, H-89, GSK690693, CCT128930, AZD5363, ipatasertib, (GDC-0068, RG7440), A-674563, A-443654, AT7867, AT13148, uprosertib, afuresertib, DC120, 2-[4-(2-aminopropyl-2-yl)phenyl]-3-phenylquinoxaline, MK-2206, edelfosine, miltefosine, perifosine, erucylphophocholine, erufosine, SR13668, OSU-A9, PH-316, PHT-427, PIT-1, DM-PIT-1, triciribine (tricilibrin phosphate monohydrate), API-1, N-(4-(5-(3-acetamidophenyl)-2-(2-aminopyridin-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl)benzyl)-3-fluorobenzamide, ARQ092, BAY 1125976, 3-hydroxy-glucosidic acid, lactoquinomycin, boc-Phe-vinyl ketone, perifosine (D-21266), TCN, TCN-P, GSK2141795, ONC201, or a combination thereof.
在一些實施例中,mTOR抑制劑選自MLN0128、維蘇替布(visusertib) (AZD-2014)、安踏替布(onatasertib) (CC-223)、CC-115、依維莫司(everolimus) (RAD001)、替西羅莫司(temsirolimus) (CCI-779)、地磷莫司(ridaforolimus) (AP-23573)、西羅莫司(sirolimus) (雷帕黴素(rapamycin))、地磷莫司(MK-8669)或其組合。In some embodiments, the mTOR inhibitor is selected from MLN0128, visusertib (AZD-2014), onatasertib (CC-223), CC-115, everolimus (RAD001), temsirolimus (CCI-779), ridaforolimus (AP-23573), sirolimus (rapamycin), ridaforolimus (MK-8669), or a combination thereof.
在一些實施例中,化學治療劑包括蒽環黴素、拓撲異構酶抑制劑、抗代謝物、烷化劑、紫杉烷、鉑基劑、絲裂黴素、埃雷布林(eribulin) (HALAVEN TM)或其組合。 In some embodiments, the chemotherapeutic agent comprises an anthracycline, a topoisomerase inhibitor, an anti-metabolite, an alkylating agent, a taxane, a platinum-based agent, a mitomycin, eribulin (HALAVEN ™ ), or a combination thereof.
在一些實施例中,拓撲異構酶抑制劑為伊立替康(irinotecan) (CAMPTOSAR®)、喜樹鹼、托泊替康(topotecan)、依託泊苷(etoposide)或替尼泊苷(teniposide)。In some embodiments, the topoisomerase inhibitor is irinotecan (CAMPTOSAR®), camptothecin, topotecan, etoposide, or teniposide.
在一些實施例中,烷化劑為環磷醯胺、美法侖(Melphalan)、氮芥苯丁酸、異環磷醯胺、苯達莫司汀(bendamustine)、卡莫司汀(carmustine)、洛莫司汀(lomustine)或白消安(busulfan)。在一些實施例中,烷化劑為環磷醯胺。In some embodiments, the alkylating agent is cyclophosphamide, melphalan, mechlorethamine, isocyclophosphamide, bendamustine, carmustine, lomustine, or busulfan. In some embodiments, the alkylating agent is cyclophosphamide.
在一些實施例中,抗代謝物為胺甲蝶呤(methotrexate)、培美曲塞(pemetrexed) (ALIMTA®)、5-氟尿嘧啶(5-FU)、6-巰基嘌呤(6-MP)、卡培他濱(capecitabine) (XELODA®)、阿糖胞苷(cytarabine) (Ara-C®)、氟尿苷、氟達拉濱(fludarabine)、吉西他濱(gemcitabine) (GEMZAR®)、羥基脲、光胺蝶呤(phototrexate)或前述中之任一者之組合。在一些實施例中,抗代謝物為胺甲蝶呤、培美曲塞或5-FU。In some embodiments, the anti-metabolite is methotrexate, pemetrexed (ALIMTA®), 5-fluorouracil (5-FU), 6-hydroxypurine (6-MP), capecitabine (XELODA®), cytarabine (Ara-C®), floxuridine, fludarabine, gemcitabine (GEMZAR®), hydroxyurea, phototrexate, or a combination of any of the foregoing. In some embodiments, the anti-metabolite is methotrexate, pemetrexed, or 5-FU.
紫杉烷之非限制性實例包括太平洋紫杉醇、多西他賽(docetaxel)、亞伯杉烷(abraxane)及剋癌易(taxotere)。Non-limiting examples of taxanes include paclitaxel, docetaxel, abraxane, and taxotere.
在一些實施例中,蒽環黴素選自道諾黴素(daunorubicin)、多柔比星(doxorubicin)、表柔比星(epirubicin)、伊達比星(idarubicin)、阿柔比星(aclarubicin)及其組合。In some embodiments, the anthracycline is selected from daunorubicin, doxorubicin, epirubicin, idarubicin, aclarubicin, and combinations thereof.
在一些實施例中,鉑基劑選自卡鉑、順鉑、奧沙利鉑(oxaliplatin)、奈達鉑(nedplatin)、四硝酸三鉑、菲鉑(phenanthriplatin)、吡鉑(picoplatin)、沙鉑(satraplatin)及其組合。In some embodiments, the platinum-based agent is selected from carboplatin, cisplatin, oxaliplatin, nedplatin, triplatinum tetranitrate, phenanthriplatin, picoplatin, satraplatin, and combinations thereof.
PARP抑制劑之非限制性實例包括奧拉帕尼(olaparib) (LYNPARZA®)、他拉唑帕尼(talazoparib)、卡帕尼(rucaparib)、尼拉帕尼(niraparib)、維利帕尼(veliparib)、BGB-290 (帕米帕尼(pamiparib))、CEP 9722、E7016、伊尼帕尼(iniparib)、IMP4297、NOV1401、2X-121、ABT-767、RBN-2397、BMN 673、KU-0059436 (AZD2281)、BSI-201、PF-01367338、INO-1001及JPI-289。Non-limiting examples of PARP inhibitors include olaparib (LYNPARZA®), talazoparib, rucaparib, niraparib, veliparib, BGB-290 (pamiparib), CEP 9722, E7016, iniparib, IMP4297, NOV1401, 2X-121, ABT-767, RBN-2397, BMN 673, KU-0059436 (AZD2281), BSI-201, PF-01367338, INO-1001, and JPI-289.
選擇性雌激素受體調節劑或降解劑(SERM / SERD)之非限制性實例包括他莫昔芬(tamoxifen)、氟維司群(fulvestrant)、布瑞司群(brilanestrant)、埃拉司群(elacestrant)、吉瑞司群(giredestrant)、安賽司群(amcenestant) (SAR439859)、AZD9833、林特司群(rintodestrant)、LSZ102、LY3484356、ZN-c5、D-0502及SHR9549。Non-limiting examples of selective estrogen receptor modulators or degraders (SERMs/SERDs) include tamoxifen, fulvestrant, brilanestrant, elacestrant, giredestrant, amcenestrant (SAR439859), AZD9833, rintodestrant, LSZ102, LY3484356, ZN-c5, D-0502, and SHR9549.
抗雄激素之非限制性實例包括恩雜魯胺(enzalutamide) (XTANDI®)、柳培林(leuprolide) (LUPRON®、ELIGARD®)、戈舍瑞林(goserelin) (ZOLDEX®)、曲普瑞林(triptorelin) (TRELSTAR®)、甲磺酸柳培林(CAMCEVI®)、氟他胺(flutamide) (EULEXIN®)、比卡魯胺(bicalutamide) (CASXODEX®)、尼魯米特(nilutamide) (NILANDRON®)、地加瑞克(degarelix) (FIRMAGON®)、瑞盧戈利(relugolix) (ORGOVYX®)及阿比特龍(abiraterone) (ZYTIGA®)。Non-limiting examples of anti-androgens include enzalutamide (XTANDI®), leuprolide (LUPRON®, ELIGARD®), goserelin (ZOLDEX®), triptorelin (TRELSTAR®), leuprolide mesylate (CAMCEVI®), flutamide (EULEXIN®), bicalutamide (CASXODEX®), nilutamide (NILANDRON®), degarelix (FIRMAGON®), relugolix (ORGOVYX®), and abiraterone (ZYTIGA®).
免疫療法之非限制性實例包括免疫檢查點療法,諸如靶向CTLA-4、PD-1、PD-L1、BTLA、LAG-3、A2AR、TIM-3、B7-H3、VISTA、IDO及其組合之抑制劑。在一些實施例中,CTLA-4抑制劑為依匹單抗(ipilimumab) (YERVOY®)。在一些實施例中,PD-1抑制劑選自派姆單抗(pembrolizumab) (KEYTRUDA®)、尼沃魯單抗(nivolumab) (OPDIVO®)、測米匹單抗(cemiplimab) (LIBTAYO®)、多塔利單抗(dostarlimab) (JEMPERLI®)、沃普利單抗(vopratelimab) (JTX-4014)、斯巴達珠單抗(spartalizumab) (PDR001)、卡瑞利珠單抗(camrelizumab) (SHR1210)、信迪利單抗(sintilimab) (IBI308)、替雷利珠單抗(tislelizumab) (BGB-A317)、特瑞普利單抗(toripalimab) (JS 001)、INCMGA00012、AMP-224、AMP-514 (MEDI0680)或其組合。在一些實施例中,PD-L1抑制劑選自阿替珠單抗(atezolizumab) (TECENTRIQ®)、阿維魯單抗(avelumab) (BAVENCIO®)、德瓦魯單抗(durvalumab) (IMFINZI®)、KN035、柯希利單抗(cosibelimab) (CK-301)、AUNP12、CA-170、BMS-986189或其組合。在一些實施例中,LAG-3抑制劑為IMP701 (LAG525)。在一些實施例中,A2AR抑制劑為CPI-444。在一些實施例中,TIM-3抑制劑為MBG453。在一些實施例中,B7-H3抑制劑為恩利珠單抗(enoblituzumab)。在一些實施例中,VISTA抑制劑為JNJ-61610588。在一些實施例中,IDO抑制劑為因多昔莫(indoximod)。參見例如Marin-Acevedo等人, J Hematol Oncol. 11: 39 (2018)。 Non-limiting examples of immunotherapy include immune checkpoint therapy, such as inhibitors targeting CTLA-4, PD-1, PD-L1, BTLA, LAG-3, A2AR, TIM-3, B7-H3, VISTA, IDO, and combinations thereof. In some embodiments, the CTLA-4 inhibitor is ipilimumab (YERVOY®). In some embodiments, the PD-1 inhibitor is selected from pembrolizumab (KEYTRUDA®), nivolumab (OPDIVO®), cemiplimab (LIBTAYO®), dostarlimab (JEMPERLI®), vopratelimab (JTX-4014), spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), INCMGA00012, AMP-224, AMP-514 (MEDI0680) or a combination thereof. In some embodiments, the PD-L1 inhibitor is selected from atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®), durvalumab (IMFINZI®), KN035, cosibelimab (CK-301), AUNP12, CA-170, BMS-986189 or a combination thereof. In some embodiments, the LAG-3 inhibitor is IMP701 (LAG525). In some embodiments, the A2AR inhibitor is CPI-444. In some embodiments, the TIM-3 inhibitor is MBG453. In some embodiments, the B7-H3 inhibitor is enoblituzumab. In some embodiments, the VISTA inhibitor is JNJ-61610588. In some embodiments, the IDO inhibitor is indoximod. See, e.g., Marin-Acevedo et al., J Hematol Oncol . 11: 39 (2018).
在一些實施例中,額外療法或治療劑選自5-FU、伊立替康、順鉑、卡鉑、奧沙利鉑、多柔比星、表柔比星、吉西他濱、胺甲蝶呤、培美曲塞、環磷醯胺、奧拉帕尼、卡帕尼、尼拉帕尼、派姆單抗(KEYTRUDA®)、尼沃魯單抗(OPDIVO®)、測米匹單抗(LIBTAYO®)、多塔利單抗(JEMPERLI®)、阿替珠單抗(TECENTRIQ®)、阿維魯單抗(BAVENCIO®)、德瓦魯單抗(IMFINZI®)、放射療法及前述中之任一者之組合。In some embodiments, the additional therapy or treatment is selected from 5-FU, irinotecan, cisplatin, carboplatin, oxaliplatin, doxorubicin, epirubicin, gemcitabine, methotrexate, pemetrexed, cyclophosphamide, olaparib, capanib, niraparib, pembrolizumab (KEYTRUDA®), nivolumab (OPDIVO®), selumetumab (LIBTAYO®), dotalimumab (JEMPERLI®), atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®), durvalumab (IMFINZI®), radiation therapy, and a combination of any of the foregoing.
在一些實施例中,亦可投與額外治療劑以治療特定抗癌療法之潛在副作用及/或作為姑息性療法,例如,類鴉片及皮質類固醇。 實例 化合物製備 In some embodiments, additional therapeutic agents may also be administered to treat potential side effects of specific anticancer therapies and/or as palliative treatments, for example, opioids and corticosteroids .
藉由使用熟習此項技術者已知或鑒於本文中之教導的標準合成方法及程序,本文所揭示之化合物可以各種方法使用商購的起始材料、文獻中已知之化合物或自容易製備的中間物來製備。本文所揭示之化合物之合成可藉由大體上遵循本文所提供之方案並且修改特定所需取代基來達成。By using standard synthetic methods and procedures known to those skilled in the art or in light of the teachings herein, the compounds disclosed herein can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates. The synthesis of the compounds disclosed herein can be achieved by generally following the schemes provided herein and modifying the specific desired substituents.
製備有機分子以及官能基轉化及操作之標準合成方法及程序可自相關科技文獻或此領域之標準教科書獲得。雖然不限於任何一或多個來源,但經典教科書諸如R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989);L. Fieser及M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994);Smith, M. B., March, J., March' s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 第5版, John Wiley & Sons: New York, 2001;及Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 第3版, John Wiley & Sons: New York, 1999為熟習此項技術者已知的有機合成之適用及公認參考教科書。合成方法之以下描述被設計來示出,但並不限制用於製備本揭露之化合物的一般程序。Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant technical literature or standard textbooks in this field. Although not limited to any one or more sources, classic textbooks such as R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); Smith, M. B., March, J., March' s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition, John Wiley & Sons: New York, 2001; and Greene, T. W., Wuts, P. G. M., Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999 are applicable and recognized reference textbooks for organic synthesis known to those skilled in the art. The following descriptions of synthetic methods are designed to illustrate, but not to limit, the general procedures for preparing the compounds of the present disclosure.
本文所揭示之合成過程可容許多種官能基;因此,可使用各種經取代之起始材料。該等過程大體上在整個過程結束時或接近結束時提供所需最終化合物,但在某些情況下可能需要進一步將化合物轉化為其醫藥學上可接受之鹽。The synthetic processes disclosed herein can tolerate a variety of functional groups; therefore, various substituted starting materials can be used. These processes generally provide the desired final compound at or near the end of the entire process, but in some cases it may be necessary to further convert the compound into its pharmaceutically acceptable salt.
本文所描述之化合物可例如使用以下程序、使用來自以下方案中之可多樣化中間物8的不同偶合搭配物來合成。 The compounds described herein can be synthesized, for example, using the following procedures, using different coupling partners from the diversifiable intermediate 8 in the following scheme.
本文所描述之化合物亦可例如使用以下程序、使用來自以下方案中之可多樣化中間物8的不同偶合搭配物來合成。 中間物 中間物1. 8-溴-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶之合成 步驟1. 8-溴-3-(羥甲基)咪唑并[1,2-a]吡啶-2-甲酸乙酯之合成: The compounds described herein can also be synthesized, for example, using the following procedures, using different coupling partners from the diversifiable intermediate 8 in the following scheme. Intermediate 1. Synthesis of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine Step 1. Synthesis of 8-bromo-3-(hydroxymethyl)imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester:
將8-溴咪唑并[1,2-a]吡啶-2-甲酸乙酯(10 g,37.16 mmol,1當量)、乙酸鈉(16.0 g,195.09 mmol,5.2當量)及甲醛(28 mL,282.93 mmol,7.6當量,37%溶液)於AcOH (60 mL)中之混合物在110℃及氮氣氛圍下攪拌8 h。混合物用水(200 mL)稀釋,用飽和NaOH及NaHCO 3鹼化至pH 8,且用CH 2Cl 2萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。藉由與EtOAc (100 mL)一起濕磨來純化殘餘物。藉由過濾收集固體且用EtOAc (3*10 mL)洗滌,以得到呈黃色固體之8-溴-3-(羥甲基)咪唑并[1,2-a]吡啶-2-甲酸乙酯(5.7 g,51.28%)。LC-MS:(M+H) +實測值299.0。 步驟2.8-溴-3-甲醯基咪唑并[1,2-a]吡啶-2-甲酸乙酯之合成: A mixture of ethyl 8-bromoimidazo[1,2-a]pyridine-2-carboxylate (10 g, 37.16 mmol, 1 eq.), sodium acetate (16.0 g, 195.09 mmol, 5.2 eq.) and formaldehyde (28 mL, 282.93 mmol, 7.6 eq., 37% solution) in AcOH (60 mL) was stirred at 110 °C under nitrogen atmosphere for 8 h. The mixture was diluted with water (200 mL), basified to pH 8 with saturated NaOH and NaHCO 3 , and extracted with CH 2 Cl 2. The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with EtOAc (100 mL). The solid was collected by filtration and washed with EtOAc (3*10 mL) to give 8-bromo-3-(hydroxymethyl)imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (5.7 g, 51.28%) as a yellow solid. LC-MS: (M+H) + found 299.0. Step 2. Synthesis of 8-bromo-3-formylimidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester:
將8-溴-3-(羥甲基)咪唑并[1,2-a]吡啶-2-甲酸乙酯(5.7 g,19.06 mmol,1當量)及MnO 2(11.60 g,133.39 mmol,7當量)於DCM (50 mL)中之混合物在室溫下攪拌隔夜。過濾所得混合物且濾餅用DCM (3*3 mL)洗滌。將濾液在減壓下濃縮,以得到呈淺黃色固體之8-溴-3-甲醯基咪唑并[1,2-a]吡啶-2-甲酸乙酯(5.8 g)。LC-MS:(M+H) +實測值296.9。 步驟3. 8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-甲酸乙酯之合成: A mixture of ethyl 8-bromo-3-(hydroxymethyl)imidazo[1,2-a]pyridine-2-carboxylate (5.7 g, 19.06 mmol, 1 eq.) and MnO 2 (11.60 g, 133.39 mmol, 7 eq.) in DCM (50 mL) was stirred at room temperature overnight. The resulting mixture was filtered and the filter cake was washed with DCM (3*3 mL). The filtrate was concentrated under reduced pressure to give ethyl 8-bromo-3-formylimidazo[1,2-a]pyridine-2-carboxylate (5.8 g) as a light yellow solid. LC-MS: (M+H) + found 296.9. Step 3. Synthesis of 8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester:
將8-溴-3-甲醯基咪唑并[1,2-a]吡啶-2-甲酸乙酯(5.8 g,19.52 mmol,1當量)及二氟(三苯基膦鎓基)乙酸酯(13.91 g,39.044 mmol,2當量)於DMF (58 mL)中之溶液在60℃及氮氣氛圍下攪拌1 h。然後將反應冷卻至室溫且添加於THF中之1 M TBAF (58.56 mL,58.57 mmol,3當量)。將所得溶液在60℃及氮氣氛圍下攪拌1 h,然後用水(300 mL)稀釋。水層用DCM (3*300 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用PE / EA (1:1)溶析,以得到呈淺黃色固體之8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-甲酸乙酯(2.9 g,42.31%)。LC-MS:(M+H) +實測值352.9。 中間物2. 8-溴-3-乙基-2-碘咪唑并[1,2-a]吡啶之合成 A solution of ethyl 8-bromo-3-formylimidazo[1,2-a]pyridine-2-carboxylate (5.8 g, 19.52 mmol, 1 eq) and difluoro(triphenylphosphinium)acetate (13.91 g, 39.044 mmol, 2 eq) in DMF (58 mL) was stirred at 60 °C under nitrogen atmosphere for 1 h. The reaction was then cooled to room temperature and 1 M TBAF (58.56 mL, 58.57 mmol, 3 eq) in THF was added. The resulting solution was stirred at 60 °C under nitrogen atmosphere for 1 h and then diluted with water (300 mL). The aqueous layer was extracted with DCM (3*300 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (1:1) to obtain 8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (2.9 g, 42.31%) as a light yellow solid. LC-MS: (M+H) + found 352.9. Intermediate 2. Synthesis of 8-bromo-3-ethyl-2-iodoimidazo[1,2-a]pyridine
將丁-1-炔-1-基三甲基矽烷(569.3 mg,4.50 mmol,1.30當量)及AgF (879.9 mg,4.62 mmol,2當量)於1,2-二氯苯(10 mL)中之混合物在室溫下攪拌16 h。過濾所得混合物。向濾液中添加3-溴吡啶-2-胺(600.0 mg,2.30 mmol,1當量)、I 2(586.8 mg,2.30 mmol,1當量)及Cu(OAc) 2 .H 2O (419.9 mg,2.30 mmol,1當量)。將反應混合物在120℃下攪拌6 h。所得溶液使用具有以下條件(移動相A:水,移動相B:ACN;流動速率:80 mL/min;梯度:在30 min內0% B至100% B;254/220 nm)之C18層析純化。此產生呈黃色固體之8-溴-3-乙基-2-碘咪唑并[1,2-a]吡啶(200.0 mg,16.4%)。LC-MS:(M+H) +實測值350.9。 中間物3. 8-溴-3-乙氧基-2-碘咪唑并[1,2-a]吡啶之合成 步驟1:乙氧基(碘)乙炔之合成: A mixture of but-1-yn-1-yltrimethylsilane (569.3 mg, 4.50 mmol, 1.30 equiv) and AgF (879.9 mg, 4.62 mmol, 2 equiv) in 1,2-dichlorobenzene (10 mL) was stirred at room temperature for 16 h. The resulting mixture was filtered. 3-Bromopyridin-2-amine (600.0 mg, 2.30 mmol, 1 equiv), I 2 (586.8 mg, 2.30 mmol, 1 equiv) and Cu(OAc) 2 . H 2 O (419.9 mg, 2.30 mmol, 1 equiv) were added to the filtrate. The reaction mixture was stirred at 120 °C for 6 h. The resulting solution was purified using C18 chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 80 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm). This yielded 8-bromo-3-ethyl-2-iodoimidazo[1,2-a]pyridine (200.0 mg, 16.4%) as a yellow solid. LC-MS: (M+H) + found 350.9. Intermediate 3. Synthesis of 8-bromo-3-ethoxy-2-iodoimidazo[1,2-a]pyridine Step 1: Synthesis of ethoxy(iodo)acetylene:
在-78℃及氮氣氛圍下,向乙氧基-乙炔(2.0 g,28.53 mmol,1當量)於THF(20 mL)中之攪拌溶液中逐滴添加n-BuLi (2.5 M於己烷中,11.4 mL,28.53 mmol,1當量)。攪拌1 h後,添加I 2(8.33 g,32.81 mmol,1.15當量)於THF (20 mL)中之溶液且將反應溫熱至r.t.。攪拌15 min後,用EA (100 mL)稀釋反應。有機層用飽和硫代硫酸鈉溶液(2*70 mL)、鹽水(2*70 mL)洗滌且經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。此產生呈黑色油狀物之乙氧基(碘)乙炔(2.50 g,44.70%)。LC-MS:(M+H) +實測值196.0。 步驟2:8-溴-3-乙氧基-2-碘咪唑并[1,2-a]吡啶 之合成 To a stirred solution of ethoxy-acetylene (2.0 g, 28.53 mmol, 1 eq) in THF (20 mL) was added n-BuLi (2.5 M in hexanes, 11.4 mL, 28.53 mmol, 1 eq) dropwise at -78 °C under nitrogen atmosphere. After stirring for 1 h, a solution of I2 (8.33 g, 32.81 mmol, 1.15 eq) in THF (20 mL) was added and the reaction was warmed to rt. After stirring for 15 min, the reaction was diluted with EA (100 mL). The organic layer was washed with saturated sodium thiosulfate solution (2*70 mL), brine (2*70 mL) and dried over anhydrous Na2SO4 . After filtration, the filtrate was concentrated under reduced pressure. This produced ethoxy(iodo)acetylene (2.50 g, 44.70%) as a black oil. LC-MS: (M+H) + found 196.0. Step 2: Synthesis of 8-bromo-3-ethoxy-2-iodoimidazo[1,2-a]pyridine
在室溫下,向3-溴吡啶-2-胺(926.9 mg,5.36 mmol,1.40當量)於ACN (20 mL)中之攪拌溶液中添加乙氧基(碘)乙炔(2.50g,12.76 mmol,1當量)及Cu(OAc) 2(463.4 mg,2.55 mmol,0.20當量)。將所得混合物在60℃下攪拌8 h。移除溶劑。殘餘物藉由矽膠管柱層析純化,用PE / EA (20:1)溶析,以得到呈黑色油狀物之8-溴-3-乙氧基-2-碘咪唑并[1,2-a]吡啶(1.50g,32.04%)。LC-MS:(M+H) +實測值367.0。 中間物4. 8-溴-2-(丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶之合成 步驟1:8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-甲醛 之合成 To a stirred solution of 3-bromopyridin-2-amine (926.9 mg, 5.36 mmol, 1.40 equiv) in ACN (20 mL) was added ethoxy(iodo)acetylene (2.50 g, 12.76 mmol, 1 equiv) and Cu(OAc) 2 (463.4 mg, 2.55 mmol, 0.20 equiv) at room temperature. The resulting mixture was stirred at 60 °C for 8 h. The solvent was removed. The residue was purified by silica gel column chromatography eluting with PE/EA (20:1) to give 8-bromo-3-ethoxy-2-iodoimidazo[1,2-a]pyridine (1.50 g, 32.04%) as a black oil. LC-MS: (M+H) + found 367.0. Intermediate 4. Synthesis of 8-bromo-2-(prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine Step 1: Synthesis of 8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine-2-carbaldehyde
在-40℃及氮氣氛圍下,向8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-甲酸乙酯(1 g,2.84 mmol,1當量)於DCM (5 mL)中之攪拌溶液中添加DIBAL-H (1M於己烷中,3.42 mL,3.42 mmol,1.2當量)。將所得混合物在-40℃下攪拌4 h。藉由在-40℃下添加飽和NH 4Cl (水溶液)來淬滅反應。所得混合物用水稀釋且用EA萃取。有機層用鹽水洗滌,經Na 2SO 4乾燥且在減壓下濃縮。殘餘物使用具有以下條件(移動相A:水,移動相B:ACN;流動速率:60 mL/min;梯度:在30 min內0% B至100% B;254/220 nm)之C18急速層析純化。此產生呈白色固體之8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-甲醛(400 mg,45.7%)。LC-MS:(M+H) +實測值307.2。 步驟2:8-溴-2-乙炔基-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶之合成 To a stirred solution of ethyl 8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine-2-carboxylate (1 g, 2.84 mmol, 1 eq) in DCM (5 mL) at -40 °C under nitrogen atmosphere was added DIBAL-H (1 M in hexanes, 3.42 mL, 3.42 mmol, 1.2 eq). The resulting mixture was stirred at -40 °C for 4 h. The reaction was quenched by the addition of saturated NH 4 Cl (aq) at -40 °C. The resulting mixture was diluted with water and extracted with EA. The organic layer was washed with brine, dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by C18 flash chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm). This yielded 8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine-2-carbaldehyde (400 mg, 45.7%) as a white solid. LC-MS: (M+H) + found 307.2. Step 2: Synthesis of 8-bromo-2-ethynyl-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine
在0℃下,向8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-甲醛(390 mg,1.27 mmol,1當量)於MeOH (3 mL)中之攪拌溶液中添加(1-重氮基-2-側氧基丙基)膦酸二甲酯(488 mg,2.54 mmol,2當量)及K 2CO 3(526.6 mg,3.81 mmol,3當量)。將所得混合物在室溫及氮氣氛圍下攪拌3 h。所得溶液使用具有以下條件(移動相A:水,移動相B:ACN;流動速率:60 mL/min;梯度:在30 min內0% B至100% B;254/220 nm)之C18急速層析純化。此產生呈白色固體之8-溴-2-乙炔基-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶(340 mg,88.33%)。LC-MS:(M+H) +實測值302.8。 步驟3. 8-溴-2-(丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶之合成 To a stirred solution of 8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine-2-carbaldehyde (390 mg, 1.27 mmol, 1 eq.) in MeOH (3 mL) at 0°C, dimethyl (1-diazo-2-oxopropyl)phosphonate (488 mg, 2.54 mmol, 2 eq.) and K 2 CO 3 (526.6 mg, 3.81 mmol, 3 eq.) were added. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 3 h. The resulting solution was purified using C18 flash chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm). This resulted in 8-bromo-2-ethynyl-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (340 mg, 88.33%) as a white solid. LC-MS: (M+H) + found 302.8. Step 3. Synthesis of 8-bromo-2-(prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine
8-溴-2-乙炔基-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶(240 mg,0.79 mmol,1當量)於二乙醚(4 mL)中之攪拌溶液中添加1,3-雙(金剛烷-1-基)-1λ5-咪唑-1-基鎓四氟硼酸鹽(33.6 mg,0.07 mmol,0.1當量)、CuI (30.2 mg,0.15 mmol,0.2當量)、Cs 2CO 3(335.4 mg,1.03 mmol,1.3當量)、[PdCl(allyl)] 2(29 mg,0.07 mmol,0.1當量)、MeI (134.9 mg,0.95 mmol,1.2當量)及DMF (2 mL)。將所得混合物在40℃及氮氣氛圍下攪拌3 h。在真空下移除溶劑。殘餘物使用具有以下條件(移動相A:水(10 mmol/L NH 4HCO 3),移動相B:ACN;流動速率:60 mL/min;梯度:在30 min內0% B至100% B;254/220 nm)之C18急速層析純化。此產生呈黃色固體之8-溴-2-(丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶(120 mg,47.79%)。LC-MS:(M+H) +實測值317.3。 中間物5. 7-溴-2-(丙-1-炔-1-基)-3-(2,2,2-三氟乙基)吡唑并[1,5-a]吡啶之合成 步驟1. [7-溴-3-(2,2,2-三氟乙基)吡唑并[1,5-a]吡啶-2-基]甲醇之合成 To a stirred solution of 8-bromo-2-ethynyl-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (240 mg, 0.79 mmol, 1 eq.) in diethyl ether (4 mL) were added 1,3-bis(adamantan-1-yl)-1λ5-imidazol-1-ylium tetrafluoroborate (33.6 mg, 0.07 mmol, 0.1 eq.), CuI (30.2 mg, 0.15 mmol, 0.2 eq.), Cs 2 CO 3 (335.4 mg, 1.03 mmol, 1.3 eq.), [PdCl(allyl)] 2 (29 mg, 0.07 mmol, 0.1 eq.), MeI (134.9 mg, 0.95 mmol, 1.2 eq.) and DMF (2 mL). The resulting mixture was stirred at 40 °C under nitrogen atmosphere for 3 h. The solvent was removed under vacuum. The residue was purified using C18 flash chromatography with the following conditions (mobile phase A: water (10 mmol/L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm). This resulted in 8-bromo-2-(prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (120 mg, 47.79%) as a yellow solid. LC-MS: (M+H) + found 317.3. Intermediate 5. Synthesis of 7-bromo-2-(prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine Step 1. Synthesis of [7-bromo-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl]methanol
在-45℃及氮氣氛圍下,向7-溴-3-(2,2,2-三氟乙基)吡唑并[1,5-a]吡啶-2-甲酸甲酯(1.3 g,3.85 mmol,1當量)於DCM (3 mL)中之攪拌溶液中添加DIBAL-H (1 M於己烷中,7.71 mL)。將所得混合物在-30℃及氮氣氛圍下攪拌4 h。藉由在-20℃下添加飽和NH 4Cl (水溶液)來淬滅反應。將所得混合物倒入水中且用DCM萃取。有機層用鹽水洗滌,經Na 2SO 4乾燥且蒸發。殘餘物使用具有以下條件(移動相A:水,移動相B:ACN;流動速率:60 mL/min;梯度:在30 min內0% B至100% B;254/220 nm)之C18急速層析純化。此產生呈黃色固體之[7-溴-3-(2,2,2-三氟乙基)吡唑并[1,5-a]吡啶-2-基]甲醇(730 mg,61.24%)。LC-MS:(M+H) +實測值308.9。 步驟2. 7-溴-3-(2,2,2-三氟乙基)吡唑并[1,5-a]吡啶-2-甲醛之合成 To a stirred solution of methyl 7-bromo-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-carboxylate (1.3 g, 3.85 mmol, 1 eq.) in DCM (3 mL) at -45 °C under nitrogen atmosphere was added DIBAL-H (1 M in hexanes, 7.71 mL). The resulting mixture was stirred at -30 °C under nitrogen atmosphere for 4 h. The reaction was quenched by the addition of saturated NH 4 Cl (aq.) at -20 °C. The resulting mixture was poured into water and extracted with DCM. The organic layer was washed with brine, dried over Na 2 SO 4 and evaporated. The residue was purified by C18 flash chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm). This yielded [7-bromo-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl]methanol (730 mg, 61.24%) as a yellow solid. LC-MS: (M+H) + found 308.9. Step 2. Synthesis of 7-bromo-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-carbaldehyde
向[7-溴-3-(2,2,2-三氟乙基)吡唑并[1,5-a]吡啶-2-基]甲醇(700 mg,2.26 mmol,1當量)於DCM (3 mL)中之攪拌溶液中添加二氧化錳(1.38 g,15.85 mmol,7當量)。將所得混合物在50℃下攪拌隔夜。過濾所得混合物且濾餅用DCM洗滌。將濾液在減壓下濃縮。此產生呈白色固體之7-溴-3-(2,2,2-三氟乙基)吡唑并[1,5-a]吡啶-2-甲醛(560 mg,80.53%)。LC-MS:(M+H) +實測值306.9。 步驟3. 7-溴-2-乙炔基-3-(2,2,2-三氟乙基)吡唑并[1,5-a]吡啶之合成 To a stirred solution of [7-bromo-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-2-yl]methanol (700 mg, 2.26 mmol, 1 eq) in DCM (3 mL) was added manganese dioxide (1.38 g, 15.85 mmol, 7 eq). The resulting mixture was stirred at 50 °C overnight. The resulting mixture was filtered and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. This resulted in 7-bromo-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-carbaldehyde (560 mg, 80.53%) as a white solid. LC-MS: (M+H) + found 306.9. Step 3. Synthesis of 7-bromo-2-ethynyl-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine
在0℃下,向7-溴-3-(2,2,2-三氟乙基)吡唑并[1,5-a]吡啶-2-甲醛(540 mg,1.75 mmol,1當量)於MeOH (3 mL)中之攪拌溶液中添加塞費特-吉爾伯特同系物(seyferth-gilbert homologation) (675.7 mg,3.51 mmol,2當量)及K 2CO 3(729.1 mg,5.27 mmol,3當量)。將所得混合物在室溫及氮氣氛圍下攪拌2 h。所得溶液使用具有以下條件(移動相A:水,移動相B:ACN;流動速率:60 mL/min;梯度:在30 min內0% B至100% B;254/220 nm)之C18急速層析純化。此產生呈白色固體之7-溴-2-乙炔基-3-(2,2,2-三氟乙基)吡唑并[1,5-a]吡啶(320 mg,60.04%)。LC-MS:(M+H) +實測值302.9。 步驟4. 7-溴-2-(丙-1-炔-1-基)-3-(2,2,2-三氟乙基)吡唑并[1,5-a]吡啶之合成 To a stirred solution of 7-bromo-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine-2-carbaldehyde (540 mg, 1.75 mmol, 1 eq.) in MeOH (3 mL) at 0°C was added Seyferth-Gilbert homologation (675.7 mg, 3.51 mmol, 2 eq.) and K 2 CO 3 (729.1 mg, 5.27 mmol, 3 eq.). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 h. The resulting solution was purified using C18 flash chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm). This resulted in 7-bromo-2-ethynyl-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine (320 mg, 60.04%) as a white solid. LC-MS: (M+H) + found 302.9. Step 4. Synthesis of 7-bromo-2-(prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine
向7-溴-2-乙炔基-3-(2,2,2-三氟乙基)吡唑并[1,5-a]吡啶(310 mg,1.02 mmol,1當量)於Et 2O (3 mL)中之攪拌溶液中添加碘甲烷(174.2 mg,1.22 mmol,1.2當量)、CuI (39.0 mg,0.20 mmol,0.2當量)、Cs 2CO 3(433.2 mg,1.33 mmol,1.3當量)、rac-1,3-雙[(3R,5S,7s)-金剛烷-1-基]-3H-1λ5-咪唑-1-基鎓-四氟硼氫化物(43.4 mg,0.10 mmol,0.1當量)、[PdCl(allyl)] 2(37.4 mg,0.10 mmol,0.1當量)及DMF (3 mL)。將所得混合物在40℃及氮氣氛圍下攪拌3 h。在真空下移除溶劑。殘餘物使用具有以下條件(移動相A:水,移動相B:ACN;流動速率:60 mL/min;梯度:在30 min內0% B至100% B;254/220 nm)之C18急速層析純化。此產生呈白色固體之7-溴-2-(丙-1-炔-1-基)-3-(2,2,2-三氟乙基)吡唑并[1,5-a]吡啶(170 mg,52.41%)。LC-MS:(M+H) +實測值316.8。 中間物6. 8-溴-3-乙烯基-2-(丙-1-炔-1-基)咪唑并[1,2-a]吡啶之合成 步驟1. 8-溴-3-乙烯基咪唑并[1,2-a]吡啶-2-甲酸乙酯之合成 To a stirred solution of 7-bromo-2-ethynyl-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine (310 mg, 1.02 mmol, 1 eq) in Et2O (3 mL) were added iodomethane (174.2 mg, 1.22 mmol, 1.2 eq), CuI (39.0 mg, 0.20 mmol, 0.2 eq), Cs2CO3 (433.2 mg , 1.33 mmol, 1.3 eq), rac-1,3-bis[(3R,5S,7s)-adamantan-1-yl]-3H-1λ5-imidazol-1-ylium-tetrafluoroborohydride (43.4 mg, 0.10 mmol, 0.1 eq), [PdCl(allyl)] 2 (37.4 mg, 0.10 mmol, 0.1 eq) and DMF (3 mL). The resulting mixture was stirred at 40 °C under nitrogen atmosphere for 3 h. The solvent was removed under vacuum. The residue was purified using C18 flash chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm). This produced 7-bromo-2-(prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine (170 mg, 52.41%) as a white solid. LC-MS: (M+H) + found 316.8. Intermediate 6. Synthesis of 8-bromo-3-vinyl-2-(prop-1-yn-1-yl)imidazo[1,2-a]pyridine Step 1. Synthesis of 8-bromo-3-vinylimidazolo[1,2-a]pyridine-2-carboxylic acid ethyl ester
將8-溴-3-碘咪唑并[1,2-a]吡啶-2-甲酸乙酯(4 g,10.12 mmol,1當量)、2-乙烯基-4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷(1.56 g,10.13 mmol,1當量)、Na 2CO 3(3.22 g,30.38 mmol,3當量)及Pd(dppf)Cl 2 .CH 2Cl 2(824.9 mg,1.01 mmol,0.1當量)於二噁烷(20 mL)/H 2O (20 mL)中之溶液在95℃及氮氣氛圍下攪拌1 h。使混合物冷卻至室溫且用水(200 mL)稀釋。所得混合物用CH 2Cl 2(3* 200mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用PE / EA (3:1)溶析,以得到呈淺粉紅色固體之8-溴-3-乙烯基咪唑并[1,2-a]吡啶-2-甲酸乙酯(2.34 g,78.29%)。LC-MS:(M+H) +實測值295.0。 步驟2. (8-溴-3-乙烯基咪唑并[1,2-a]吡啶-2-基)甲醇之合成 A solution of ethyl 8-bromo-3-iodoimidazo[1,2-a]pyridine-2-carboxylate (4 g, 10.12 mmol, 1 eq), 2-vinyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.56 g, 10.13 mmol, 1 eq), Na 2 CO 3 (3.22 g, 30.38 mmol, 3 eq) and Pd(dppf)Cl 2 .CH 2 Cl 2 (824.9 mg, 1.01 mmol, 0.1 eq) in dioxane (20 mL)/H 2 O (20 mL) was stirred at 95 °C under nitrogen atmosphere for 1 h. The mixture was cooled to room temperature and diluted with water (200 mL). The resulting mixture was extracted with CH 2 Cl 2 (3*200 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (3:1) to give 8-bromo-3-vinylimidazolo[1,2-a]pyridine-2-carboxylic acid ethyl ester (2.34 g, 78.29%) as a light pink solid. LC-MS: (M+H) + found 295.0. Step 2. Synthesis of (8-bromo-3-vinylimidazolo[1,2-a]pyridin-2-yl)methanol
在-40℃及氮氣氛圍下,向8-溴-3-乙烯基咪唑并[1,2-a]吡啶-2-甲酸乙酯(2.34 g,7.93 mmol,1當量)於DCM (20 mL)中之攪拌溶液中逐滴添加於DCM中之1M DIBAl-H (15.86 mL,15.86 mmol,2當量)。將所得混合物在-40℃下攪拌1h,然後藉由在0℃下添加飽和NH 4Cl來淬滅。所得混合物用CH 2Cl 2(4*100mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用PE / EA (5:1)溶析,以得到呈淺黃色固體之(8-溴-3-乙烯基咪唑并[1,2-a]吡啶-2-基)甲醇(1.5 g,75.35%)。LC-MS:(M+H) +實測值253.1。 步驟3. 8-溴-3-乙烯基咪唑并[1,2-a]吡啶-2-甲醛之合成 To a stirred solution of ethyl 8-bromo-3-vinylimidazolo[1,2-a]pyridine-2-carboxylate (2.34 g, 7.93 mmol, 1 eq.) in DCM (20 mL) was added 1 M DIBAl-H in DCM (15.86 mL, 15.86 mmol, 2 eq.) dropwise at -40 °C under nitrogen atmosphere. The resulting mixture was stirred at -40 °C for 1 h and then quenched by adding saturated NH 4 Cl at 0 °C. The resulting mixture was extracted with CH 2 Cl 2 (4*100 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (5:1) to give (8-bromo-3-vinylimidazolo[1,2-a]pyridin-2-yl)methanol (1.5 g, 75.35%) as a light yellow solid. LC-MS: (M+H) + found 253.1. Step 3. Synthesis of 8-bromo-3-vinylimidazolo[1,2-a]pyridine-2-carbaldehyde
將(8-溴-3-乙烯基咪唑并[1,2-a]吡啶-2-基)甲醇(1.5 g,5.08 mmol,1當量)及MnO 2(3.09 g,35.54 mmol,6.99當量)於DCM (10 mL)中之混合物在室溫及氮氣氛圍下攪拌隔夜。過濾所得混合物,濾餅用CH 2Cl 2洗滌。將濾液在減壓下濃縮,以得到呈淺黃色固體之8-溴-3-乙烯基咪唑并[1,2-a]吡啶-2-甲醛(970 mg,76.01%)。LC-MS:(M+H) +實測值253.0。 步驟4. 8-溴-3-乙烯基-2-乙炔基咪唑并[1,2-a]吡啶之合成 A mixture of (8-bromo-3-vinylimidazolo[1,2-a]pyridin-2-yl)methanol (1.5 g, 5.08 mmol, 1 eq) and MnO 2 (3.09 g, 35.54 mmol, 6.99 eq) in DCM (10 mL) was stirred at room temperature under nitrogen atmosphere overnight. The resulting mixture was filtered and the filter cake was washed with CH 2 Cl 2. The filtrate was concentrated under reduced pressure to give 8-bromo-3-vinylimidazolo[1,2-a]pyridine-2-carbaldehyde (970 mg, 76.01%) as a light yellow solid. LC-MS: (M+H) + found 253.0. Step 4. Synthesis of 8-bromo-3-vinyl-2-ethynylimidazo[1,2-a]pyridine
在0℃及氮氣氛圍下,向8-溴-3-乙烯基咪唑并[1,2-a]吡啶-2-甲醛(940 mg,3.74 mmol,1當量)及K 2CO 3(1.55 g,11.23 mmol,3當量)於MeOH (10 mL)中之攪拌混合物中逐滴添加塞費特-吉爾伯特同系物(1.44 g,7.49 mmol,2當量)。將所得混合物在室溫下攪拌3h。所得混合物用水(100 mL)稀釋。所得混合物用CH 2Cl 2(3 *100 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用PE / EA (4:1)溶析,以得到呈灰白色固體之8-溴-3-乙烯基-2-乙炔基咪唑并[1,2-a]吡啶(740 mg,79.99%)。LC-MS:(M+H) +實測值246.9。 步驟5. 8-溴-3-乙烯基-2-(丙-1-炔-1-基)咪唑并[1,2-a]吡啶之合成 To a stirred mixture of 8-bromo-3-vinylimidazolo[1,2-a]pyridine-2-carbaldehyde (940 mg, 3.74 mmol, 1 eq.) and K 2 CO 3 (1.55 g, 11.23 mmol, 3 eq.) in MeOH (10 mL) was added Seyfert-Gilbert homolog (1.44 g, 7.49 mmol, 2 eq.) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 3 h. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with CH 2 Cl 2 (3 * 100 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (4:1) to give 8-bromo-3-vinyl-2-ethynylimidazo[1,2-a]pyridine (740 mg, 79.99%) as an off-white solid. LC-MS: (M+H) + found 246.9. Step 5. Synthesis of 8-bromo-3-vinyl-2-(prop-1-yn-1-yl)imidazo[1,2-a]pyridine
將8-溴-3-乙烯基-2-乙炔基咪唑并[1,2-a]吡啶(720 mg,2.91 mmol,1當量)、碘甲烷(537.7 mg,3.79 mmol,1.3當量)、CuI (111.0 mg,0.58 mmol,0.2當量)、Cs 2CO 3(1.42 g,4.37 mmol,1.5當量)、1,3-雙(1-金剛烷基)咪唑鎓四氟硼酸鹽(123.6 mg,0.29 mmol,0.1當量)及雙(氯(丙-2-烯-1-基)鈀) (106.6 mg,0.29 mmol,0.1當量)於Et 2O (5 mL)/DMF (5 mL)中之混合物在40℃及氮氣氛圍下攪拌3 h。所得混合物用水(100 mL)稀釋且用CH 2Cl 2(3*100 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用PE / EA (3:1)溶析,以得到呈棕色油狀物之8-溴-3-乙烯基-2-(丙-1-炔-1-基)咪唑并[1,2-a]吡啶(480 mg,63.09%)。LC-MS:(M+H) +實測值262.9。 中間物7. N-{8-溴-2-碘咪唑并[1,2-a]吡啶-3-基}胺基甲酸三級丁酯之合成 步驟1. 8-溴-2-碘咪唑并[1,2-a]吡啶-3-甲酸 之合成 A mixture of 8-bromo-3-vinyl-2-ethynylimidazo[1,2-a]pyridine (720 mg, 2.91 mmol, 1 eq), iodomethane (537.7 mg, 3.79 mmol, 1.3 eq), CuI (111.0 mg, 0.58 mmol, 0.2 eq), Cs 2 CO 3 (1.42 g, 4.37 mmol, 1.5 eq), 1,3-bis(1-adamantyl)imidazolium tetrafluoroborate (123.6 mg, 0.29 mmol, 0.1 eq) and bis(chloro(prop-2-en-1-yl)palladium) (106.6 mg, 0.29 mmol, 0.1 eq) in Et 2 O (5 mL)/DMF (5 mL) was stirred at 40 °C under nitrogen atmosphere for 3 h. The resulting mixture was diluted with water (100 mL) and extracted with CH 2 Cl 2 (3*100 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (3:1) to give 8-bromo-3-vinyl-2-(prop-1-yn-1-yl)imidazo[1,2-a]pyridine (480 mg, 63.09%) as a brown oil. LC-MS: (M+H) + found 262.9. Intermediate 7. Synthesis of tributyl N-{8-bromo-2-iodoimidazo[1,2-a]pyridin-3-yl}carbamate Step 1. Synthesis of 8-bromo-2-iodoimidazo[1,2-a]pyridine-3-carboxylic acid
在0℃下,向8-溴-2-碘咪唑并[1,2-a]吡啶-3-甲醛(3 g,8.55 mmol,1當量)、2-甲基-2-丁烯(9 g,128.22 mmol,15當量)、t-BuOH (14.6 mL)及KH 2PO 4(6.96 g,51.11 mmol,5.98當量)於THF (146 mL)中之攪拌混合物中逐滴添加 NaClO 2(7.74 g,85.56 mmol,10當量)於H 2O (36 mL)中之溶液。將所得混合物在室溫下攪拌3 h。混合物變成透明溶液。將溶液用1M HCl酸化至pH 3~4且用CH 2Cl 2(3 * 300 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。所得混合物用DCM/正己烷(10:1)洗滌3次。沉澱的固體藉由過濾來收集,以得到呈灰白色固體之8-溴-2-碘咪唑并[1,2-a]吡啶-3-甲酸(3.8 g)。LC-MS:(M+H) +實測值368.7。 步驟2. N-{8-溴-2-碘咪唑并[1,2-a]吡啶-3-基}胺基甲酸三級丁酯之合成 To a stirred mixture of 8-bromo-2-iodoimidazo[1,2-a]pyridine-3-carbaldehyde (3 g, 8.55 mmol, 1 eq), 2-methyl-2-butene (9 g, 128.22 mmol, 15 eq), t-BuOH (14.6 mL) and KH 2 PO 4 (6.96 g, 51.11 mmol, 5.98 eq) in THF (146 mL) was added dropwise a solution of NaClO 2 (7.74 g, 85.56 mmol, 10 eq) in H 2 O (36 mL) at 0° C. The resulting mixture was stirred at room temperature for 3 h. The mixture became a clear solution. The solution was acidified to pH 3~4 with 1M HCl and extracted with CH 2 Cl 2 (3*300 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was washed 3 times with DCM/n-hexane (10:1). The precipitated solid was collected by filtration to give 8-bromo-2-iodoimidazo[1,2-a]pyridine-3-carboxylic acid (3.8 g) as an off-white solid. LC-MS: (M+H) + found 368.7. Step 2. Synthesis of tributyl N-{8-bromo-2-iodoimidazo[1,2-a]pyridin-3-yl}carbamate
將8-溴-2-碘咪唑并[1,2-a]吡啶-3-甲酸(3.8 g,10.35 mmol,1當量)、TEA (3.14 g,31.068 mmol,3當量)及DPPA (7.12 g,25.89 mmol,2.5當量)於t-BuOH (50 mL) 中之混合物在80℃下攪拌2 h。所得混合物用水(50 mL)稀釋且用CH 2Cl 2(3*50 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由具有以下條件(管柱,C18矽膠;移動相,於水中之MeOH (10 mmol/L NH 4HCO 3),在25 min內0%至100%梯度;偵測器,UV 254 nm)之反相急速層析純化,以得到呈棕黃色固體之N-{8-溴-2-碘咪唑并[1,2-a]吡啶-3-基}胺基甲酸三級丁酯(1.6 g,35.27%)。LC-MS:(M+H) +實測值439.8。 中間物8. 8-溴-2-碘-6-(甲氧基甲氧基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶之合成 步驟1. 3-溴-5-甲氧基吡啶-2-胺之合成 A mixture of 8-bromo-2-iodoimidazo[1,2-a]pyridine-3-carboxylic acid (3.8 g, 10.35 mmol, 1 eq.), TEA (3.14 g, 31.068 mmol, 3 eq.) and DPPA (7.12 g, 25.89 mmol, 2.5 eq.) in t-BuOH (50 mL) was stirred at 80 °C for 2 h. The resulting mixture was diluted with water (50 mL) and extracted with CH 2 Cl 2 (3*50 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeOH (10 mmol/L NH 4 HCO 3 ) in water, gradient from 0% to 100% in 25 min; detector, UV 254 nm) to give tributyl N-{8-bromo-2-iodoimidazo[1,2-a]pyridin-3-yl}carbamate (1.6 g, 35.27%) as a brownish yellow solid. LC-MS: (M+H) + found 439.8. Intermediate 8. Synthesis of 8-bromo-2-iodo-6-(methoxymethoxy)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine Step 1. Synthesis of 3-bromo-5-methoxypyridin-2-amine
在0℃下,向5-甲氧基吡啶-2-胺(10 g,80.55 mmol,1當量)於AcOH (70 mL,488.6 mmol)中之攪拌溶液中逐滴添加Br 2(12.87 g,80.55 mmol,1當量)。將所得混合物在室溫下攪拌2 h。將反應在0℃下用飽和次亞硫酸鈉(sodium hyposulfite) (水溶液)淬滅。所得混合物用CH 2Cl 2(5*50 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用PE / EA (1:2)溶析,以得到呈深紅色固體之3-溴-5-甲氧基吡啶-2-胺(6.0 g,36.69%)。LC-MS:(M+H) +實測值:202.9。 步驟2. 8-溴-3-{[(三級丁基二甲基矽基)氧基]甲基}-2-碘-6-甲氧基咪唑并[1,2-a]吡啶之合成 To a stirred solution of 5-methoxypyridin-2-amine (10 g, 80.55 mmol, 1 eq.) in AcOH (70 mL, 488.6 mmol) at 0 °C, Br 2 (12.87 g, 80.55 mmol, 1 eq.) was added dropwise. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with saturated sodium hyposulfite (aq.) at 0 °C. The resulting mixture was extracted with CH 2 Cl 2 (5*50 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (1:2) to give 3-bromo-5-methoxypyridin-2-amine (6.0 g, 36.69%) as a dark red solid. LC-MS: (M+H) + found: 202.9. Step 2. Synthesis of 8-bromo-3-{[(tributyldimethylsilyl)oxy]methyl}-2-iodo-6-methoxyimidazo[1,2-a]pyridine
在室溫下,向3-溴-5-甲氧基吡啶-2-胺(6.50 g,32.01 mmol,1當量)及三級丁基[(3-碘丙-2-炔-1-基)氧基]二甲基矽烷(9.96 g,33.61 mmol,1.05當量)於1,2-二氯苯(100 mL)中之攪拌溶液中逐份添加Cu(OAc) 2(6.98 g,38.41 mmol,1.20當量)。將反應在120℃下攪拌2 h。過濾所得混合物,濾餅用EtOAc洗滌。將濾液在減壓下濃縮。殘餘物藉由具有以下條件(管柱,C18矽膠;移動相,於水中之MeCN (0.1% FA),在30 min內60%至90%梯度;偵測器,UV 254 nm)之反相急速層析純化,以得到呈白色固體之8-溴-3-{[(三級丁基二甲基矽基)氧基]甲基}-2-碘-6-甲氧基咪唑并[1,2-a]吡啶(5.96 g,37.44%)。LC-MS:(M+H) +實測值:496.8。 步驟3. {8-溴-2-碘-6-甲氧基咪唑并[1,2-a]吡啶-3-基}甲醇之合成 To a stirred solution of 3-bromo-5-methoxypyridin-2-amine (6.50 g, 32.01 mmol, 1 eq) and tributyl[(3-iodoprop-2-yn-1-yl)oxy]dimethylsilane (9.96 g, 33.61 mmol, 1.05 eq) in 1,2-dichlorobenzene (100 mL) was added Cu(OAc) 2 (6.98 g, 38.41 mmol, 1.20 eq) portionwise at room temperature. The reaction was stirred at 120 °C for 2 h. The resulting mixture was filtered and the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient 60% to 90% in 30 min; detector, UV 254 nm) to give 8-bromo-3-{[(tributyldimethylsilyl)oxy]methyl}-2-iodo-6-methoxyimidazo[1,2-a]pyridine (5.96 g, 37.44%) as a white solid. LC-MS: (M+H) + found: 496.8. Step 3. Synthesis of {8-bromo-2-iodo-6-methoxyimidazo[1,2-a]pyridin-3-yl}methanol
在室溫下,向8-溴-3-{[(三級丁基二甲基矽基)氧基]甲基}-2-碘-6-甲氧基咪唑并[1,2-a]吡啶(1.6 g,3.22 mmol,1當量)於THF (15 mL)中之攪拌溶液中添加Et 3N .3HF (3.63 g,22.52 mmol,7當量)。將所得混合物在室溫下攪拌1 h。將反應在0℃下用飽和NaHCO 3淬滅。所得混合物用CH 2Cl 2/MeOH (10/1) (10*20 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由具有以下條件之反相急速層析純化:管柱,C18矽膠;移動相,於水中之MeCN (0.1% TFA),在10 min內10%至50%梯度;偵測器,UV 254 nm。此產生呈深紅色固體之{8-溴-2-碘-6-甲氧基咪唑并[1,2-a]吡啶-3-基}甲醇(700 mg,56.80%)。LC-MS:(M+H) +實測值:384.7。 步驟4. 8-溴-2-碘-6-甲氧基咪唑并[1,2-a]吡啶-3-甲醛之合成 To a stirred solution of 8-bromo-3-{[(tributyldimethylsilyl)oxy]methyl}-2-iodo-6-methoxyimidazo[1,2-a]pyridine (1.6 g, 3.22 mmol, 1 eq.) in THF (15 mL) was added Et 3 N . 3HF (3.63 g, 22.52 mmol, 7 eq.) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with saturated NaHCO 3 at 0°C. The resulting mixture was extracted with CH 2 Cl 2 /MeOH (10/1) (10*20 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% TFA) in water, gradient 10% to 50% in 10 min; detector, UV 254 nm. This yielded {8-bromo-2-iodo-6-methoxyimidazo[1,2-a]pyridin-3-yl}methanol (700 mg, 56.80%) as a dark red solid. LC-MS: (M+H) + found: 384.7. Step 4. Synthesis of 8-bromo-2-iodo-6-methoxyimidazo[1,2-a]pyridine-3-carbaldehyde
在室溫下,向{8-溴-2-碘-6-甲氧基咪唑并[1,2-a]吡啶-3-基}甲醇(500 mg,1.30 mmol,1當量)於DCM (30 mL)中之攪拌溶液中添加MnO 2(2.27 g,26.12 mmol,20當量)。將所得混合物回流隔夜。過濾所得混合物,濾餅用DCM洗滌。將濾液在減壓下濃縮。殘餘物藉由具有以下條件之反相急速層析純化:管柱,C18矽膠;移動相,於水中之MeCN (10 mmol/L NH 4HCO 3),在10 min內10%至50%梯度;偵測器,UV 254 nm。此產生呈棕色固體之8-溴-2-碘-6-甲氧基咪唑并[1,2-a]吡啶-3-甲醛(200 mg,40.21%)。LC-MS:(M+H) +實測值:382.9。 步驟5. 8-溴-2-碘-6-甲氧基-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶之合成 To a stirred solution of {8-bromo-2-iodo-6-methoxyimidazo[1,2-a]pyridin-3-yl}methanol (500 mg, 1.30 mmol, 1 eq.) in DCM (30 mL) at room temperature was added MnO 2 (2.27 g, 26.12 mmol, 20 eq.). The resulting mixture was refluxed overnight. The resulting mixture was filtered and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH 4 HCO 3 ) in water, gradient from 10% to 50% in 10 min; detector, UV 254 nm. This produced 8-bromo-2-iodo-6-methoxyimidazo[1,2-a]pyridine-3-carbaldehyde (200 mg, 40.21%) as a brown solid. LC-MS: (M+H) + found: 382.9. Step 5. Synthesis of 8-bromo-2-iodo-6-methoxy-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine
在室溫及氮氣氛圍下,向8-溴-2-碘-6-甲氧基咪唑并[1,2-a]吡啶-3-甲醛(3.0 g,7.87 mmol,1當量) 於DMF (30 mL)中之攪拌溶液中添加2,2-二氟-2-(三苯基膦鎓基)乙酸酯(7.01 g,19.68 mmol,2.50當量)。將所得混合物在60℃及氮氣氛圍下攪拌2 h。在室溫下向上述混合物中添加TBAF (23.60 mL,23.60 mmol,3當量)。將所得混合物在60℃下再攪拌20 min。將反應在室溫下用水淬滅且用EtOAc (3* 50 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由具有以下條件之反相急速層析純化:管柱,C18矽膠;移動相,於水中之MeCN (0.1% TFA),在10 min內10%至50%梯度;偵測器,UV 254 nm。此產生呈棕色固體之8-溴-2-碘-6-甲氧基-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶(2.5 g,粗物質)。粗物質藉由矽膠管柱層析純化,用PE / EA (10:1)溶析,以得到呈淺黃色固體之8-溴-2-碘-6-甲氧基-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶(1.5 g,43.79%)。LC-MS:(M+H) +實測值:434.9。 步驟6. 8-溴-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-6-醇之合成 To a stirred solution of 8-bromo-2-iodo-6-methoxyimidazo[1,2-a]pyridine-3-carbaldehyde (3.0 g, 7.87 mmol, 1 eq.) in DMF (30 mL) at room temperature under nitrogen atmosphere was added 2,2-difluoro-2-(triphenylphosphinium)acetate (7.01 g, 19.68 mmol, 2.50 eq.). The resulting mixture was stirred at 60 °C under nitrogen atmosphere for 2 h. To the above mixture was added TBAF (23.60 mL, 23.60 mmol, 3 eq.) at room temperature. The resulting mixture was stirred at 60 °C for another 20 min. The reaction was quenched with water at room temperature and extracted with EtOAc (3*50 mL). The combined organic layers were dried over anhydrous Na2SO4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% TFA) in water, gradient 10% to 50% in 10 min; detector, UV 254 nm. This yielded 8-bromo-2-iodo-6-methoxy-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (2.5 g, crude) as a brown solid. The crude material was purified by silica gel column chromatography and eluted with PE/EA (10:1) to give 8-bromo-2-iodo-6-methoxy-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (1.5 g, 43.79%) as a light yellow solid. LC-MS: (M+H) + found: 434.9. Step 6. Synthesis of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine-6-ol
在0℃下,向8-溴-2-碘-6-甲氧基-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶(1.1 g,2.53 mmol,1當量)於DCM (10 mL)中之溶液中逐滴添加BBr 3(12.64 mL,12.64 mmol,5當量)。將混合物在0℃下攪拌4 h。將混合物用飽和NaHCO 3鹼化至pH 8且用EtOAc (3*10 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。此產生呈黃色固體之8-溴-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-6-醇(1.0 g,93.94%)。LC-MS:(M+H) +實測值:420.9。 步驟7. 8-溴-2-碘-6-(甲氧基甲氧基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶之合成 To a solution of 8-bromo-2-iodo-6-methoxy-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (1.1 g, 2.53 mmol, 1 eq) in DCM (10 mL) was added BBr 3 (12.64 mL, 12.64 mmol, 5 eq) dropwise at 0°C. The mixture was stirred at 0°C for 4 h. The mixture was basified to pH 8 with saturated NaHCO 3 and extracted with EtOAc (3*10 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. This produced 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-ol (1.0 g, 93.94%) as a yellow solid. LC-MS: (M+H) + found: 420.9. Step 7. Synthesis of 8-bromo-2-iodo-6-(methoxymethoxy)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine
在0℃下,向8-溴-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-6-醇(1 g,2.37 mmol,1當量)及Cs 2CO 3(1.93 g,5.94 mmol,2.5當量)於DMF (15 mL)中之溶液中逐滴添加溴甲氧基-甲烷(445 mg,3.56 mmol,1.5當量)。將反應混合物在0℃下攪拌2 h,之後用水(20 mL)淬滅。所得混合物用EtOAc (3*10 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由具有以下條件之反相急速層析純化:管柱,C18矽膠;移動相,於水中之MeCN (0.1% TFA),在5 min內50%至50%梯度;偵測器,UV 254 nm。此產生呈黃色固體之8-溴-2-碘-6-(甲氧基甲氧基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶(760 mg,68.80%)。LC-MS:(M+H) +實測值:465.0。 中間物9. 8-溴-2-碘-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶之合成 步驟1. 8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-甲酸乙酯之合成 To a solution of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-ol (1 g, 2.37 mmol, 1 eq.) and Cs 2 CO 3 (1.93 g, 5.94 mmol, 2.5 eq.) in DMF (15 mL) at 0°C was added bromomethoxy-methane (445 mg, 3.56 mmol, 1.5 eq.) dropwise. The reaction mixture was stirred at 0°C for 2 h, and then quenched with water (20 mL). The resulting mixture was extracted with EtOAc (3*10 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% TFA) in water, gradient 50% to 50% in 5 min; detector, UV 254 nm. This yielded 8-bromo-2-iodo-6-(methoxymethoxy)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (760 mg, 68.80%) as a yellow solid. LC-MS: (M+H) + found: 465.0. Intermediate 9. Synthesis of 8-bromo-2-iodo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine Step 1. Synthesis of 8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester
在室溫下,向8-溴-3-碘咪唑并[1,2-a]吡啶-2-甲酸乙酯(1.50 g,3.80 mmol,1當量)於DMF (15 mL)中之攪拌溶液中添加[(三氟甲基)硫基]銅(937.7 mg,5.70 mmol,1.50當量)及1,10-啡啉(68.4 mg,0.38 mmol,0.10當量)。將所得混合物在60℃及氮氣氛圍下攪拌16 h,然後藉由具有以下條件之C18反相急速層析純化:移動相,於水中之MeCN (5mmol/L NH 4HCO 3),在30 min內0%至70%梯度;偵測器,UV 254 nm。此產生呈白色固體之8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-甲酸乙酯(1.0 g,71.33%)。LC-MS:(M+H) +實測值369.2。 步驟2. 8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-甲酸之合成 To a stirred solution of ethyl 8-bromo-3-iodoimidazo[1,2-a]pyridine-2-carboxylate (1.50 g, 3.80 mmol, 1 eq) in DMF (15 mL) was added [(trifluoromethyl)thio]copper (937.7 mg, 5.70 mmol, 1.50 eq) and 1,10-phenanthroline (68.4 mg, 0.38 mmol, 0.10 eq) at room temperature. The resulting mixture was stirred at 60 °C under nitrogen atmosphere for 16 h and then purified by C18 reverse phase flash chromatography with the following conditions: mobile phase, MeCN (5 mmol/L NH 4 HCO 3 ) in water, gradient from 0% to 70% in 30 min; detector, UV 254 nm. This produced 8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (1.0 g, 71.33%) as a white solid. LC-MS: (M+H) + found 369.2. Step 2. Synthesis of 8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine-2-carboxylic acid
將8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-甲酸乙酯(1.0 g,2.71 mmol,1當量)及LiOH.H 2O (170.5 mg,4.06 mmol,1.50當量)於THF (8 mL)/H 2O (8 mL) 中之溶液在室溫下攪拌1 h。用HCl (水溶液)將混合物酸化至pH 5。將所得混合物在減壓下濃縮。殘餘物藉由具有以下條件之C18反相急速層析純化:移動相,於水中之MeCN (0.1% FA),在20 min內0%至80%梯度;偵測器,UV 254 nm。此產生呈淺灰色固體之8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-甲酸(800 mg,86.58%)。LC-MS:(M+H) +實測值341.1。 步驟3. N-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}胺基甲酸三級丁酯之合成 A solution of ethyl 8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine-2-carboxylate (1.0 g, 2.71 mmol, 1 eq) and LiOH.H 2 O (170.5 mg, 4.06 mmol, 1.50 eq) in THF (8 mL)/H 2 O (8 mL) was stirred at room temperature for 1 h. The mixture was acidified to pH 5 with HCl (aq). The resulting mixture was concentrated under reduced pressure. The residue was purified by C18 reverse phase flash chromatography with the following conditions: mobile phase, MeCN (0.1% FA) in water, gradient 0% to 80% in 20 min; detector, UV 254 nm. This gave 8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine-2-carboxylic acid (800 mg, 86.58%) as a light grey solid. LC-MS: (M+H) + found 341.1. Step 3. Synthesis of tributyl N-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}carbamate
在室溫下,向8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-甲酸(750.0 mg,2.20 mmol,1當量)於t-BuOH (6 mL)中之攪拌溶液中逐滴添加DPPA (1.21 g,4.40 mmol,2當量)及Et 3N (445.0 mg,4.40 mmol,2當量)。將所得混合物在80℃及氮氣氛圍下攪拌1 h,然後藉由具有以下條件之C18反相急速層析純化:移動相,於水中之MeCN (0.1% FA),在30 min內0%至70%梯度;偵測器,UV 254 nm。此產生呈淺棕色固體之N-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}胺基甲酸三級丁酯(600.0 mg,66.20%)。LC-MS:(M+H) +實測值412.2。 步驟4. 8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-胺之合成 To a stirred solution of 8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine-2-carboxylic acid (750.0 mg, 2.20 mmol, 1 eq) in t-BuOH (6 mL) was added DPPA (1.21 g, 4.40 mmol, 2 eq) and Et3N (445.0 mg, 4.40 mmol, 2 eq) dropwise at room temperature. The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 1 h and then purified by C18 reverse phase flash chromatography with the following conditions: mobile phase, MeCN (0.1% FA) in water, gradient from 0% to 70% in 30 min; detector, UV 254 nm. This produced tributyl N-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}carbamate (600.0 mg, 66.20%) as a light brown solid. LC-MS: (M+H) + found 412.2. Step 4. Synthesis of 8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-amine
將N-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}胺基甲酸三級丁酯(600.0 mg,1.46 mmol,1當量)於DCM (6 mL)及TFA (2 mL)中之溶液在室溫下攪拌1 h。將所得混合物在減壓下濃縮。殘餘物藉由具有以下條件之C18反相急速層析純化:移動相,於水中之MeCN (10mmol/L NH 4HCO 3),在20 min內0%至60%梯度;偵測器,UV 254 nm。此產生呈淺黃色固體之8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-胺(300.0 mg,66.04%)。LC-MS:(M+H) +實測值312.1。 步驟5. 8-溴-2-碘-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶之合成 A solution of tributyl N-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}carbamate (600.0 mg, 1.46 mmol, 1 eq) in DCM (6 mL) and TFA (2 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by C18 reverse phase flash chromatography with the following conditions: mobile phase, MeCN (10 mmol/L NH 4 HCO 3 ) in water, gradient 0% to 60% in 20 min; detector, UV 254 nm. This produced 8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-amine (300.0 mg, 66.04%) as a light yellow solid. LC-MS: (M+H) + found 312.1. Step 5. Synthesis of 8-bromo-2-iodo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine
在室溫下,向8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-胺(230.0 mg,0.74 mmol,1當量)於ACN (3 mL)中之攪拌溶液中添加CuI (280.7 mg,1.47 mmol,2當量)、亞硝酸3-甲基丁酯(129.5 mg,1.11 mmol,1.50當量)。將所得混合物在50℃及氮氣氛圍下攪拌4 h,然後藉由具有以下條件之C18反相急速層析純化:移動相,於水中之MeCN,在20 min內0%至60%梯度;偵測器,UV 254 nm。此產生呈棕色固體之8-溴-2-碘-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶(180.0 mg,57.75%)。LC-MS:(M+H) +實測值423.0。 中間物10. 8-溴-3-環丙基-2-碘咪唑并[1,2-a]吡啶之合成 步驟1:(2-碘乙炔基)環丙烷之合成 To a stirred solution of 8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-amine (230.0 mg, 0.74 mmol, 1 eq) in ACN (3 mL) was added CuI (280.7 mg, 1.47 mmol, 2 eq), 3-methylbutyl nitrite (129.5 mg, 1.11 mmol, 1.50 eq) at room temperature. The resulting mixture was stirred at 50 °C under nitrogen atmosphere for 4 h, then purified by C18 reverse phase flash chromatography with the following conditions: mobile phase, MeCN in water, gradient from 0% to 60% in 20 min; detector, UV 254 nm. This gave 8-bromo-2-iodo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine (180.0 mg, 57.75%) as a brown solid. LC-MS: (M+H) + found 423.0. Intermediate 10. Synthesis of 8-bromo-3-cyclopropyl-2-iodoimidazo[1,2-a]pyridine Step 1: Synthesis of (2-iodoethynyl)cyclopropane
在-78℃及氮氣氛圍下,向乙炔基環丙烷(2.0 g,30.26 mmol,1當量)於THF (30 mL)中之攪拌溶液中逐滴添加n-BuLi (2.5 M於己烷中,12.10 mL,30.26 mmol,1當量)。攪拌1 h後,添加I 2(8.83 g,34.79 mmol,1.15當量)之THF溶液且將反應溫熱至r.t.。攪拌1 h後,反應用EA (50 mL)稀釋且用飽和硫代硫酸鈉溶液(2*50 mL)及鹽水(2*50 mL)洗滌。有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。此產生呈黃色油狀物之(2-碘乙炔基)環丙烷(4.18 g,71.96%)。 步驟2. 8-溴-3-環丙基-2-碘咪唑并[1,2-a]吡啶之合成 To a stirred solution of ethynylcyclopropane (2.0 g, 30.26 mmol, 1 eq) in THF (30 mL) was added n-BuLi (2.5 M in hexanes, 12.10 mL, 30.26 mmol, 1 eq) dropwise at -78 °C under nitrogen atmosphere. After stirring for 1 h, a solution of I2 (8.83 g, 34.79 mmol, 1.15 eq) in THF was added and the reaction was warmed to rt. After stirring for 1 h, the reaction was diluted with EA (50 mL) and washed with saturated sodium thiosulfate solution (2*50 mL) and brine (2*50 mL). The organic layer was dried over anhydrous Na2SO4 . After filtration, the filtrate was concentrated under reduced pressure. This produced (2-iodoethynyl)cyclopropane (4.18 g, 71.96%) as a yellow oil. Step 2. Synthesis of 8-bromo-3-cyclopropyl-2-iodoimidazo[1,2-a]pyridine
在室溫下,向3-溴吡啶-2-胺(2.70 g,15.63 mmol,1.50當量)於ACN (20 mL)中之攪拌溶液中添加(2-碘乙炔基)環丙烷(2.0 g,10.42 mmol,1當量)及Cu(OAc) 2(470.0 mg,2.60 mmol,0.25當量)。將所得混合物在70℃及空氣氛圍下攪拌16 h,然後藉由具有以下條件之反相急速層析純化:管柱,C18;移動相,於水中之MeCN (0.1% FA),在20 min內0%至90%梯度;偵測器,UV 254 nm。此產生呈淺棕色固體之8-溴-3-環丙基-2-碘咪唑并[1,2-a]吡啶(1.30 g,34.38%)。LC-MS:(M+H) +實測值363.0。 中間物11. 8-溴-2-碘-3-(1,1,2,2,2-五氟乙基)咪唑并[1,2-a]吡啶之合成 步驟1. 8-溴-3-(1,1,2,2,2-五氟乙基)咪唑并[1,2-a]吡啶-2-甲酸乙酯之合成 To a stirred solution of 3-bromopyridin-2-amine (2.70 g, 15.63 mmol, 1.50 equiv) in ACN (20 mL) was added (2-iodoethynyl)cyclopropane (2.0 g, 10.42 mmol, 1 equiv) and Cu(OAc) 2 (470.0 mg, 2.60 mmol, 0.25 equiv) at room temperature. The resulting mixture was stirred at 70 °C under air atmosphere for 16 h and then purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN (0.1% FA) in water, gradient from 0% to 90% in 20 min; detector, UV 254 nm. This produced 8-bromo-3-cyclopropyl-2-iodoimidazo[1,2-a]pyridine (1.30 g, 34.38%) as a light brown solid. LC-MS: (M+H) + found 363.0. Intermediate 11. Synthesis of 8-bromo-2-iodo-3-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]pyridine Step 1. Synthesis of 8-bromo-3-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester
向8-溴咪唑并[1,2-a]吡啶-2-甲酸乙酯(1.50 g,5.57 mmol,1當量)於ACN (30 mL)中之溶液中添加CsF (3.39 g,22.29 mmol,4當量)、乙酸(乙醯基氧基)(苯基)-λ3-碘烷基酯(iodanyl) (3.59 g,11.15 mmol,2當量)及三甲基(1,1,2,2,2-五氟乙基)矽烷(4.29 g,22.30 mmol,4當量)。將反應混合物在30℃及氮氣氛圍下攪拌4 h,然後使用具有以下條件之C18急速層析純化:移動相A:水,移動相B:ACN;流動速率:80 mL/min;梯度:在30 min內0% B至100% B;254/220 nm。此產生呈黃色固體之8-溴-3-(1,1,2,2,2-五氟乙基)咪唑并[1,2-a]吡啶-2-甲酸乙酯(630.0 mg,31.40%)。LC-MS:(M+H) +實測值387.1。 步驟2. 8-溴-3-(1,1,2,2,2-五氟乙基)咪唑并[1,2-a]吡啶-2-甲酸之合成 To a solution of ethyl 8-bromoimidazo[1,2-a]pyridine-2-carboxylate (1.50 g, 5.57 mmol, 1 eq) in ACN (30 mL) were added CsF (3.39 g, 22.29 mmol, 4 eq), (acetyloxy)(phenyl)-λ3-iodoalkyl acetate (3.59 g, 11.15 mmol, 2 eq) and trimethyl(1,1,2,2,2-pentafluoroethyl)silane (4.29 g, 22.30 mmol, 4 eq). The reaction mixture was stirred at 30 °C under nitrogen atmosphere for 4 h and then purified using C18 flash chromatography with the following conditions: mobile phase A: water, mobile phase B: ACN; flow rate: 80 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm. This produced ethyl 8-bromo-3-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]pyridine-2-carboxylate (630.0 mg, 31.40%) as a yellow solid. LC-MS: (M+H) + found 387.1. Step 2. Synthesis of 8-bromo-3-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]pyridine-2-carboxylic acid
向8-溴-3-(1,1,2,2,2 五氟乙基)咪唑并[1,2-a]吡啶-2-甲酸乙酯(630.0 mg,1.63 mmol,1當量)於MeOH (5 mL)中之溶液中添加NaOH (260.4 mg,6.51 mmol,4當量,於3 mL水中)。將所得混合物在室溫下攪拌1h,然後用HCl (水溶液)將pH值調整至3。所得溶液使用具有以下條件之C18急速層析純化:移動相A:水(0.1% FA),移動相B:ACN;流動速率:60 mL/min;梯度:在15 min內0% B至100% B;波長:254 nm;220 nm。此產生呈黃色固體之8-溴-3-(1,1,2,2,2-五氟乙基)咪唑并[1,2-a]吡啶-2-甲酸(420.0 mg,68.60%)。LC-MS:(M+H) +實測值360.9。 步驟3. 8-溴-2-碘-3-(1,1,2,2,2-五氟乙基)咪唑并[1,2-a]吡啶之合成 To a solution of ethyl 8-bromo-3-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]pyridine-2-carboxylate (630.0 mg, 1.63 mmol, 1 eq) in MeOH (5 mL) was added NaOH (260.4 mg, 6.51 mmol, 4 eq in 3 mL water). The resulting mixture was stirred at room temperature for 1 h, and then the pH was adjusted to 3 with HCl (aq). The resulting solution was purified using C18 flash chromatography with the following conditions: mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 15 min; wavelength: 254 nm; 220 nm. This produced 8-bromo-3-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]pyridine-2-carboxylic acid (420.0 mg, 68.60%) as a yellow solid. LC-MS: (M+H) + found 360.9. Step 3. Synthesis of 8-bromo-2-iodo-3-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]pyridine
將8-溴-3-(1,1,2,2,2-五氟乙基)咪唑并[1,2-a]吡啶-2-甲酸(350.0 mg,0.98 mmol,1當量)於1,2-二氯苯(5 mL)中之溶液用I 2(742.2 mg,2.93mmol,3當量)及K 3PO 4(206.9 mg,0.98 mmol,1當量)處理。將所得混合物在120℃下攪拌2 h,然後冷卻至r.t.且使用具有以下條件之C18快速層析純化:移動相A:水,移動相B:ACN;流動速率:60 mL/min;梯度:在15 min內0% B至100% B;波長:254 nm;220 nm。此產生呈白色固體之8-溴-2-碘-3-(1,1,2,2,2-五氟乙基)咪唑并[1,2-a]吡啶(230.0 mg,48.2%)。LC-MS:(M+H) +實測值449.8。 中間物12. 6-溴-8-氟-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶之合成 步驟1. 6-溴-3-{[(三級丁基二甲基矽烷基)氧基]甲基}-8-氟-2-碘咪唑并[1,2-a]吡啶之合成 A solution of 8-bromo-3-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]pyridine-2-carboxylic acid (350.0 mg, 0.98 mmol, 1 eq) in 1,2-dichlorobenzene (5 mL) was treated with I 2 (742.2 mg, 2.93 mmol, 3 eq) and K 3 PO 4 (206.9 mg, 0.98 mmol, 1 eq). The resulting mixture was stirred at 120 °C for 2 h, then cooled to rt and purified using C18 flash chromatography with the following conditions: mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 15 min; wavelength: 254 nm; 220 nm. This gave 8-bromo-2-iodo-3-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]pyridine (230.0 mg, 48.2%) as a white solid. LC-MS: (M+H) + found 449.8. Intermediate 12. Synthesis of 6-bromo-8-fluoro-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine Step 1. Synthesis of 6-bromo-3-{[(tributyldimethylsilyl)oxy]methyl}-8-fluoro-2-iodoimidazo[1,2-a]pyridine
在室溫及空氣氛圍下,向5-溴-3-氟吡啶-2-胺(1 g,5.24 mmol,1當量)及三級丁基[(3-碘丙-2-炔-1-基)氧基]二甲基矽烷(2.33 g,7.85 mmol,1.5當量)於甲苯(5 mL)中之攪拌溶液中逐份添加Cu(OAc) 2(190 mg,1.05 mmol,0.2當量)。將所得混合物在120℃及空氣氛圍下攪拌隔夜。反應混合物用水(50 mL)稀釋且用EtOAc (3*50 mL)萃取。合併的有機層經硫酸鈉乾燥,過濾且真空濃縮。殘餘物藉由矽膠管柱層析純化,用PE/EtOAc (20:1)溶析,以得到呈灰白色固體之6-溴-3-{[(三級丁基二甲基矽烷基)氧基]甲基}-8-氟-2-碘咪唑并[1,2-a]吡啶(1.2 g,47.24%)。 步驟2. {6-溴-8-氟-2-碘咪唑并[1,2-a]吡啶-3-基}甲醇之合成 To a stirred solution of 5-bromo-3-fluoropyridin-2-amine (1 g, 5.24 mmol, 1 eq.) and tert-butyl[(3-iodoprop-2-yn-1-yl)oxy]dimethylsilane (2.33 g, 7.85 mmol, 1.5 eq.) in toluene (5 mL) was added Cu(OAc) 2 (190 mg, 1.05 mmol, 0.2 eq.) portionwise at room temperature under air atmosphere. The resulting mixture was stirred at 120 °C under air atmosphere overnight. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3*50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography and eluted with PE/EtOAc (20:1) to obtain 6-bromo-3-{[(tributyldimethylsilyl)oxy]methyl}-8-fluoro-2-iodoimidazo[1,2-a]pyridine (1.2 g, 47.24%) as an off-white solid. Step 2. Synthesis of {6-bromo-8-fluoro-2-iodoimidazo[1,2-a]pyridin-3-yl}methanol
在0℃下,向6-溴-3-{[(三級丁基二甲基矽烷基)氧基]甲基}-8-氟-2-碘咪唑并[1,2-a]吡啶(5 g,10.30 mmol,1當量)於THF (50 mL)中之混合物中逐滴添加Et 3N .3HF (4.98 g,30.92 mmol,3當量)。將所得混合物在室溫下攪拌3 h,然後過濾。濾餅用DCM (3*50 mL)洗滌。此產生呈灰白色固體之{6-溴-8-氟-2-碘咪唑并[1,2-a]吡啶-3-基}甲醇(3.32 g,87%)。LC-MS:(M+H) +實測值:371.0。 步驟3. 6-溴-8-氟-2-碘咪唑并[1,2-a]吡啶-3-甲醛之合成 To a mixture of 6-bromo-3-{[(tributyldimethylsilyl)oxy]methyl}-8-fluoro-2-iodoimidazo[1,2-a]pyridine (5 g, 10.30 mmol, 1 eq.) in THF (50 mL) at 0°C was added Et3N.3HF (4.98 g, 30.92 mmol, 3 eq.) dropwise . The resulting mixture was stirred at room temperature for 3 h and then filtered. The filter cake was washed with DCM (3*50 mL). This resulted in {6-bromo-8-fluoro-2-iodoimidazo[1,2-a]pyridin-3-yl}methanol (3.32 g, 87%) as an off-white solid. LC-MS: (M+H) + found: 371.0. Step 3. Synthesis of 6-bromo-8-fluoro-2-iodoimidazo[1,2-a]pyridine-3-carbaldehyde
在0℃下,向{6-溴-8-氟-2-碘咪唑并[1,2-a]吡啶-3-基}甲醇(1 g,2.70 mmol,1當量)、TEMPO (8.42 mg,0.05 mmol,0.02當量)、KBr (32 mg,0.27 mmol,0.1當量)及NaHCO 3(29 mg,0.35 mmol,0.13當量)於DCM (7 mL)/H 2O (1 mL)中之溶液中逐滴添加NaOCl (4.26 mL,4.04 mmol,1.5當量)。將混合物在0℃下攪拌1 h。藉由過濾收集沉澱的固體且用水洗滌。此產生呈灰白色固體之6-溴-8-氟-2-碘咪唑并[1,2-a]吡啶-3-甲醛(900 mg,90.49%)。 To a solution of {6-bromo-8-fluoro-2-iodoimidazo[1,2-a]pyridin-3-yl}methanol (1 g, 2.70 mmol, 1 eq), TEMPO (8.42 mg, 0.05 mmol, 0.02 eq), KBr (32 mg, 0.27 mmol, 0.1 eq) and NaHCO 3 (29 mg, 0.35 mmol, 0.13 eq) in DCM (7 mL)/H 2 O (1 mL) was added NaOCl (4.26 mL, 4.04 mmol, 1.5 eq) dropwise at 0° C. The mixture was stirred at 0° C. for 1 h. The precipitated solid was collected by filtration and washed with water. This resulted in 6-bromo-8-fluoro-2-iodoimidazo[1,2-a]pyridine-3-carbaldehyde (900 mg, 90.49%) as an off-white solid.
LC-MS:(M+H +)實測值:369.0。 步驟4. 6-溴-8-氟-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶之合成 LC-MS: (M+H + ) found: 369.0. Step 4. Synthesis of 6-bromo-8-fluoro-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine
將6-溴-8-氟-2-碘咪唑并[1,2-a]吡啶-3-甲醛(9 g,24.40 mmol,1當量)及2,2-二氟-2-(三苯基膦鎓基)乙酸酯(17.38 g,48.79 mmol,2當量)於DMF (90 mL)中之混合物在60℃及氮氣氛圍下再攪拌1 h。在室溫下向上述混合物中逐份添加TBAF (73.18 mL,73.19 mmol,3當量)。將所得混合物在室溫下再攪拌15 min。反應混合物用水(500 mL)稀釋且用EtOAc (3*500 mL)萃取。合併的有機層經硫酸鈉乾燥,過濾且真空濃縮。殘餘物藉由矽膠管柱層析純化,用PE/ EtOAc (10:1)溶析,以得到呈淺黃色固體之6-溴-8-氟-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶(12 g,116.31%)。LC-MS:(M+H) +實測值:422.7。 中間物13.N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺 之合成 A mixture of 6-bromo-8-fluoro-2-iodoimidazo[1,2-a]pyridine-3-carbaldehyde (9 g, 24.40 mmol, 1 eq.) and 2,2-difluoro-2-(triphenylphosphinium)acetate (17.38 g, 48.79 mmol, 2 eq.) in DMF (90 mL) was stirred at 60 °C under nitrogen atmosphere for another 1 h. TBAF (73.18 mL, 73.19 mmol, 3 eq.) was added portionwise to the above mixture at room temperature. The resulting mixture was stirred at room temperature for another 15 min. The reaction mixture was diluted with water (500 mL) and extracted with EtOAc (3*500 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography and eluted with PE/EtOAc (10:1) to obtain 6-bromo-8-fluoro-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (12 g, 116.31%) as a light yellow solid. LC-MS: (M+H) + found: 422.7. Intermediate 13. Synthesis of N-methyl-4-(prop-2-yn-1-ylamino)benzamide
將4-胺基-N-苯甲醯胺(1 g,6.66 mmol,1當量)、炔丙基溴(1.2 mL,13.32 mmol,2當量)及DIEA (5.8 mL,33.30 mmol,5當量)於CHCl 3(10 mL)中之混合物在70℃下攪拌3 h。將混合物冷卻至室溫且在減壓下濃縮。殘餘物藉由具有以下條件(管柱,C18矽膠;移動相,於水中之MeCN (10mmol/L NH 4HCO 3),在20 min內10%至50%梯度;偵測器,UV 254 nm)之反相急速層析純化,以得到呈棕黃色油狀物之N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺(963 mg,76.83%)。LC-MS:(M+H) +實測值189.1。 中間物14. 3-甲氧基-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺之合成 步驟1. 3-甲氧基-N-甲基-4-硝基苯甲醯胺 之合成 A mixture of 4-amino-N-benzamide (1 g, 6.66 mmol, 1 eq), propargyl bromide (1.2 mL, 13.32 mmol, 2 eq) and DIEA (5.8 mL, 33.30 mmol, 5 eq) in CHCl 3 (10 mL) was stirred at 70 °C for 3 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH 4 HCO 3 ) in water, gradient from 10% to 50% in 20 min; detector, UV 254 nm) to give N-methyl-4-(prop-2-yn-1-ylamino)benzamide (963 mg, 76.83%) as a brown oil. LC-MS: (M+H) + found 189.1. Intermediate 14. Synthesis of 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide Step 1. Synthesis of 3-methoxy-N-methyl-4-nitrobenzamide
在0℃下,向3-甲氧基-4-硝基苯甲酸(50 g,253.62 mmol,1當量)於DCM (500 mL)中之攪拌溶液中添加HATU (144.65 g,380.43 mmol,1.50當量)。將所得混合物在室溫下攪拌1 h。在室溫下向上述混合物中添加甲胺鹽酸鹽(18.83 g,278.98 mmol,1.10當量)及Et 3N (76.99 g,760.86 mmol,3當量)。將所得混合物在室溫下攪拌隔夜。所得混合物用水稀釋且用DCM (500 mL*2)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由矽膠管柱純化,用PE / EA (1:1)溶析,以得到呈白色固體之3-甲氧基-N-甲基-4-硝基苯甲醯胺(50 g,93.79%)。LC-MS:(M+H) +實測值211.1。 步驟2. 4-胺基-3-甲氧基-N-甲基苯甲醯胺之合成 To a stirred solution of 3-methoxy-4-nitrobenzoic acid (50 g, 253.62 mmol, 1 eq.) in DCM (500 mL) at 0°C was added HATU (144.65 g, 380.43 mmol, 1.50 eq.). The resulting mixture was stirred at room temperature for 1 h. Methylamine hydrochloride (18.83 g, 278.98 mmol, 1.10 eq.) and Et 3 N (76.99 g, 760.86 mmol, 3 eq.) were added to the above mixture at room temperature. The resulting mixture was stirred at room temperature overnight. The resulting mixture was diluted with water and extracted with DCM (500 mL*2). The combined organic layers were dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column and eluted with PE/EA (1:1) to obtain 3-methoxy-N-methyl-4-nitrobenzamide (50 g, 93.79%) as a white solid. LC-MS: (M+H) + found 211.1. Step 2. Synthesis of 4-amino-3-methoxy-N-methylbenzamide
在室溫及氮氣氛圍下,向3-甲氧基-N-甲基-4-硝基苯甲醯胺(45 g,214.09 mmol,1當量)於THF (250 mL)中之攪拌混合物中逐份添加Pd/C (5 g)。將所得混合物在室溫及氫氣氛圍下攪拌8 h。過濾所得混合物,濾餅用DCM (3*100 mL)洗滌。將濾液在減壓下濃縮。此產生白色固體之4-胺基-3-甲氧基-N-甲基苯甲醯胺(36 g,93.31%)。LC-MS:(M+H) +實測值181.1。 步驟3. 3-甲氧基-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺之合成 To a stirred mixture of 3-methoxy-N-methyl-4-nitrobenzamide (45 g, 214.09 mmol, 1 eq.) in THF (250 mL) was added Pd/C (5 g) portionwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature under hydrogen atmosphere for 8 h. The resulting mixture was filtered and the filter cake was washed with DCM (3*100 mL). The filtrate was concentrated under reduced pressure. This gave 4-amino-3-methoxy-N-methylbenzamide (36 g, 93.31%) as a white solid. LC-MS: (M+H) + found 181.1. Step 3. Synthesis of 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide
在室溫及氮氣氛圍下,向4-胺基-3-甲氧基-N-甲基苯甲醯胺(15 g,83.24 mmol,1當量)及DIPEA (32.27 g,249.71 mmol,3當量)於DMF (30 mL)中之攪拌混合物中添加炔丙基溴(9.90 g,83.24 mmol,1當量)。將所得混合物在70℃及氮氣氛圍下攪拌12 h。將所得溶液在減壓下濃縮。殘餘物藉由具有以下條件(移動相A:水,移動相B:ACN;流動速率:60 mL/min;梯度:在15 min內0% B至100% B;波長:254 nm;220 nm)之反向急速層析純化,以得到呈紅色固體之3-甲氧基-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺(9 g,49.54%)。LC-MS:(M+H) +實測值219.1。 中間物15. 3-甲氧基-N,N-二甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺之合成 步驟1. 3-甲氧基-N,N-二甲基-4-硝基苯甲醯胺之合成 To a stirred mixture of 4-amino-3-methoxy-N-methylbenzamide (15 g, 83.24 mmol, 1 eq) and DIPEA (32.27 g, 249.71 mmol, 3 eq) in DMF (30 mL) at room temperature under nitrogen atmosphere was added propargyl bromide (9.90 g, 83.24 mmol, 1 eq). The resulting mixture was stirred at 70 °C under nitrogen atmosphere for 12 h. The resulting solution was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 15 min; wavelength: 254 nm; 220 nm) to give 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (9 g, 49.54%) as a red solid. LC-MS: (M+H) + found 219.1. Intermediate 15. Synthesis of 3-methoxy-N,N-dimethyl-4-(prop-2-yn-1-ylamino)benzamide Step 1. Synthesis of 3-methoxy-N,N-dimethyl-4-nitrobenzamide
在室溫下,向3-甲氧基-4-硝基苯甲酸(2 g,10.14 mmol,1當量)於DCM (20 mL)中之攪拌混合物中逐份添加HATU (5.79 g,15.22 mmol,1.50當量)。將所得混合物在室溫下攪拌1 h。在室溫下向上述混合物中添加二甲胺鹽酸鹽(1.24 g,15.22 mmol,1.50當量)及TEA (3.08 g,30.44 mmol,3當量)。在室溫下攪拌2 h後,用水洗滌所得溶液。有機層經Na 2SO 4乾燥且在減壓下濃縮。殘餘物使用具有以下條件(移動相A:水,移動相B:ACN;流動速率:100 mL/min;梯度:在30 min內0% B至100% B;254/220 nm)之C18急速層析純化。此產生呈淺黃色油狀物之3-甲氧基-N,N-二甲基-4-硝基苯甲醯胺(2.20 g,96.72%)。LC-MS:(M+H) +實測值225.1。 步驟2.4-胺基-3-甲氧基-N,N-二甲基苯甲醯胺之合成 To a stirred mixture of 3-methoxy-4-nitrobenzoic acid (2 g, 10.14 mmol, 1 eq.) in DCM (20 mL) was added HATU (5.79 g, 15.22 mmol, 1.50 eq.) portionwise at room temperature. The resulting mixture was stirred at room temperature for 1 h. To the above mixture was added dimethylamine hydrochloride (1.24 g, 15.22 mmol, 1.50 eq.) and TEA (3.08 g, 30.44 mmol, 3 eq.) at room temperature. After stirring at room temperature for 2 h, the resulting solution was washed with water. The organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by C18 flash chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 100 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm). This yielded 3-methoxy-N,N-dimethyl-4-nitrobenzamide (2.20 g, 96.72%) as a light yellow oil. LC-MS: (M+H) + found 225.1. Step 2. Synthesis of 4-amino-3-methoxy-N,N-dimethylbenzamide
在室溫及氮氣氛圍下,向3-甲氧基-N,N-二甲基-4-硝基苯甲醯胺(2.20 g,9.81 mmol,1當量)於THF (15 mL)中之攪拌溶液中逐份添加Pd/C (250.0 mg)。將所得混合物在室溫及氫氣氛圍下攪拌16 h。過濾後,濾餅用THF洗滌。將濾液在減壓下濃縮。此產生呈無色油狀物之4-胺基-3-甲氧基-N,N-二甲基苯甲醯胺(1.50 g,78.71%)。LC-MS:(M+H) +實測值195.1。 步驟3.3-甲氧基-N,N-二甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺之合成 To a stirred solution of 3-methoxy-N,N-dimethyl-4-nitrobenzamide (2.20 g, 9.81 mmol, 1 eq.) in THF (15 mL) was added Pd/C (250.0 mg) portionwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature under hydrogen atmosphere for 16 h. After filtration, the filter cake was washed with THF. The filtrate was concentrated under reduced pressure. This gave 4-amino-3-methoxy-N,N-dimethylbenzamide (1.50 g, 78.71%) as a colorless oil. LC-MS: (M+H) + found 195.1. Step 3. Synthesis of 3-methoxy-N,N-dimethyl-4-(prop-2-yn-1-ylamino)benzamide
在室溫下,向4-胺基-3-甲氧基-N,N-二甲基苯甲醯胺(1.50 g,7.72 mmol,1當量)於DMF (10 mL)中之攪拌混合物中逐滴添加炔丙基溴(1.38 g,11.59 mmol,1.50當量)及DIPEA (2.99 g,23.17 mmol,3當量)。將所得混合物在70℃下攪拌12 h。所得溶液使用具有以下條件(移動相A:水,移動相B:ACN;流動速率:100 mL/min;梯度:在30 min內0% B至100% B;254/220 nm)之C18急速層析純化。此產生呈淺黃色油狀物之3-甲氧基-N,N-二甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺(1.20 g,66.70%)。LC-MS:(M+H) +實測值233.1。 中間物16. N-乙基-3-甲氧基-4-(丙-2-炔-1-基胺基)苯甲醯胺之合成 步驟1.N-乙基-3-甲氧基-4-硝基苯甲醯胺之合成 To a stirred mixture of 4-amino-3-methoxy-N,N-dimethylbenzamide (1.50 g, 7.72 mmol, 1 eq.) in DMF (10 mL) was added propargyl bromide (1.38 g, 11.59 mmol, 1.50 eq.) and DIPEA (2.99 g, 23.17 mmol, 3 eq.) dropwise at room temperature. The resulting mixture was stirred at 70 °C for 12 h. The resulting solution was purified using C18 flash chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 100 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm). This gave 3-methoxy-N,N-dimethyl-4-(prop-2-yn-1-ylamino)benzamide (1.20 g, 66.70%) as a light yellow oil. LC-MS: (M+H) + found 233.1. Intermediate 16. Synthesis of N-ethyl-3-methoxy-4-(prop-2-yn-1-ylamino)benzamide Step 1. Synthesis of N-ethyl-3-methoxy-4-nitrobenzamide
在室溫下,向3-甲氧基-4-硝基苯甲醯基鋞(2 g,10.14 mmol,1當量)於DCM (10 mL)中之攪拌溶液中添加HATU (5.79 g,15.22 mmol,1.50當量)。將混合物在室溫下攪拌1 h。在室溫下向上述混合物中逐滴添加乙胺(2.00 M於THF中,7 mL,14 mmol,1.40當量)及Et 3N (3.08 g,30.44 mmol,3當量)。將所得混合物在室溫下攪拌隔夜,然後用CH 2Cl 2稀釋且用鹽水洗滌。將有機層在減壓下濃縮。殘餘物使用具有以下條件(移動相A:水,移動相B:ACN;流動速率:80 mL/min;梯度:在30 min內0% B至100% B;254/220 nm)之C18急速層析純化。此產生呈紅棕色油狀物之N-乙基-3-甲氧基-4-硝基苯甲醯胺(2.25 g,98.9%)。LC-MS:(M+H) +實測值225.1 步驟2. 4-胺基-N-乙基-3-甲氧基苯甲醯胺之合成 To a stirred solution of 3-methoxy-4-nitrobenzylphosphonium (2 g, 10.14 mmol, 1 eq) in DCM (10 mL) at room temperature was added HATU (5.79 g, 15.22 mmol, 1.50 eq). The mixture was stirred at room temperature for 1 h. To the above mixture was added ethylamine (2.00 M in THF, 7 mL, 14 mmol, 1.40 eq) and Et3N (3.08 g, 30.44 mmol, 3 eq) dropwise at room temperature. The resulting mixture was stirred at room temperature overnight and then diluted with CH2Cl2 and washed with brine . The organic layer was concentrated under reduced pressure. The residue was purified by C18 flash chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 80 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm). This yielded N-ethyl-3-methoxy-4-nitrobenzamide (2.25 g, 98.9%) as a reddish brown oil. LC-MS: (M+H) + found 225.1 Step 2. Synthesis of 4-amino-N-ethyl-3-methoxybenzamide
在氮氣氛圍下,向N-乙基-3-甲氧基-4-硝基苯甲醯胺(2.25 g,10.04 mmol,1當量)於THF (15 mL)中之溶液中添加Pd/C (230.0 mg)。將反應混合物在室溫及氫氣氛圍下攪拌隔夜。過濾所得混合物且濾餅用THF洗滌。將濾液在減壓下濃縮。此產生呈棕色油狀物之4-胺基-N-乙基-3-甲氧基苯甲醯胺(1.90 g,97.5%)。 LC-MS:(M+H) +實測值195.1 步驟3. N-乙基-3-甲氧基-4-(丙-2-炔-1-基胺基)苯甲醯胺之合成 To a solution of N-ethyl-3-methoxy-4-nitrobenzamide (2.25 g, 10.04 mmol, 1 eq.) in THF (15 mL) was added Pd/C (230.0 mg) under nitrogen atmosphere. The reaction mixture was stirred overnight at room temperature under hydrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with THF. The filtrate was concentrated under reduced pressure. This gave 4-amino-N-ethyl-3-methoxybenzamide (1.90 g, 97.5%) as a brown oil. LC-MS: (M+H) + found 195.1 Step 3. Synthesis of N-ethyl-3-methoxy-4-(prop-2-yn-1-ylamino)benzamide
將4-胺基-N-乙基-3-甲氧基苯甲醯胺(1.90 g,9.78 mmol,1當量)、炔丙基溴(1.75 g,14.67 mmol,1.50當量)及DIPEA (3.79 g,29.35 mmol,3當量)於DMF (10 mL)中之溶液在70℃下攪拌隔夜。所得混合物用水稀釋且用CH 2Cl 2萃取。將有機層在減壓下濃縮。殘餘物使用具有以下條件之C18急速層析純化:移動相A:水,移動相B:ACN;流動速率:80 mL/min;梯度:在30 min內0% B至100% B;254/220 nm。此產生呈棕色油狀物之N-乙基-3-甲氧基-4-(丙-2-炔-1-基胺基)苯甲醯胺(1.37 g,60.3%)。LC-MS:(M+H) +實測值233.1。 中間物17. N-異丙基-3-甲氧基-4-(丙-2-炔-1-基胺基)苯甲醯胺之合成 步驟1. N-異丙基-3-甲氧基-4-硝基苯甲醯胺之合成 A solution of 4-amino-N-ethyl-3-methoxybenzamide (1.90 g, 9.78 mmol, 1 eq.), propargyl bromide (1.75 g, 14.67 mmol, 1.50 eq.) and DIPEA (3.79 g, 29.35 mmol, 3 eq.) in DMF (10 mL) was stirred at 70 °C overnight. The resulting mixture was diluted with water and extracted with CH2Cl2 . The organic layer was concentrated under reduced pressure. The residue was purified using C18 flash chromatography with the following conditions: mobile phase A: water, mobile phase B: ACN; flow rate: 80 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm. This gave N-ethyl-3-methoxy-4-(prop-2-yn-1-ylamino)benzamide (1.37 g, 60.3%) as a brown oil. LC-MS: (M+H) + found 233.1. Intermediate 17. Synthesis of N-isopropyl-3-methoxy-4-(prop-2-yn-1-ylamino)benzamide Step 1. Synthesis of N-isopropyl-3-methoxy-4-nitrobenzamide
在0℃下,向3-甲氧基-4-硝基苯甲酸(3 g,15.22 mmol,1當量)於DMF (20 mL)中之攪拌溶液中添加Et 3N (4.62 g,45.65 mmol,3當量)、異丙胺(1.35 g,22.83 mmol,1.50當量)及HATU (8.68 g,22.83 mmol,1.50當量)。將所得混合物在室溫下攪拌2 h,然後藉由具有以下條件之反向急速層析純化:管柱,C18;移動相,於水中之MeCN,在20 min內0%至60%梯度;偵測器,UV 254 nm。此產生呈黃色固體之N-異丙基-3-甲氧基-4-硝基苯甲醯胺(3.46 g,95.44%)。LC-MS:(M+H) +實測值238.2。 步驟2. 4-胺基-N-異丙基-3-甲氧基苯甲醯胺之合成 To a stirred solution of 3-methoxy-4-nitrobenzoic acid (3 g, 15.22 mmol, 1 eq) in DMF (20 mL) at 0° C. were added Et 3 N (4.62 g, 45.65 mmol, 3 eq), isopropylamine (1.35 g, 22.83 mmol, 1.50 eq) and HATU (8.68 g, 22.83 mmol, 1.50 eq). The resulting mixture was stirred at room temperature for 2 h and then purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in water, gradient 0% to 60% in 20 min; detector, UV 254 nm. This gave N-isopropyl-3-methoxy-4-nitrobenzamide (3.46 g, 95.44%) as a yellow solid. LC-MS: (M+H) + found 238.2. Step 2. Synthesis of 4-amino-N-isopropyl-3-methoxybenzamide
在室溫及氮氣氛圍下,向N-異丙基-3-甲氧基-4-硝基苯甲醯胺(3.46 g,14.52 mmol,1當量)於異丙醇(30 mL)中之攪拌溶液中添加Pd/C (350.0 mg)。將所得混合物在室溫及氫氣氛圍下攪拌3 h。過濾所得混合物且濾餅用MeOH洗滌。將濾液在減壓下濃縮。此產生呈黃色固體之4-胺基-N-異丙基-3-甲氧基苯甲醯胺(2.78 g,91.91%)。LC-MS:(M+H) +實測值208.3。 步驟3. N-異丙基-3-甲氧基-4-(丙-2-炔-1-基胺基)苯甲醯胺之合成 To a stirred solution of N-isopropyl-3-methoxy-4-nitrobenzamide (3.46 g, 14.52 mmol, 1 eq.) in isopropanol (30 mL) was added Pd/C (350.0 mg) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature under hydrogen atmosphere for 3 h. The resulting mixture was filtered and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure. This gave 4-amino-N-isopropyl-3-methoxybenzamide (2.78 g, 91.91%) as a yellow solid. LC-MS: (M+H) + found 208.3. Step 3. Synthesis of N-isopropyl-3-methoxy-4-(prop-2-yn-1-ylamino)benzamide
在室溫下,向4-胺基-N-異丙基-3-甲氧基苯甲醯胺(1 g,4.80 mmol,1當量)及DIPEA (1.86 g,14.41 mmol,3當量)於DMF (15 mL)中之攪拌溶液中添加炔丙基溴(628.3 mg,5.28 mmol,1.10當量)。將所得混合物在70℃下攪拌6 h,然後冷卻至室溫且藉由具有以下條件之反相急速層析純化:管柱,C18;移動相,於水中之MeCN,在20 min內0%至60%梯度;偵測器,UV 254 nm。此產生呈黃色固體之N-異丙基-3-甲氧基-4-(丙-2-炔-1-基胺基)苯甲醯胺(800.0 mg,67.64%)。LC-MS:(M+H) +實測值246.3。 中間物18. N-環丙基-3-甲氧基-4-(丙-2-炔-1-基胺基)苯甲醯胺之合成 步驟1. N-環丙基-3-甲氧基-4-硝基苯甲醯胺之合成 To a stirred solution of 4-amino-N-isopropyl-3-methoxybenzamide (1 g, 4.80 mmol, 1 eq) and DIPEA (1.86 g, 14.41 mmol, 3 eq) in DMF (15 mL) at room temperature was added propargyl bromide (628.3 mg, 5.28 mmol, 1.10 eq). The resulting mixture was stirred at 70 °C for 6 h, then cooled to room temperature and purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in water, gradient 0% to 60% in 20 min; detector, UV 254 nm. This gave N-isopropyl-3-methoxy-4-(prop-2-yn-1-ylamino)benzamide (800.0 mg, 67.64%) as a yellow solid. LC-MS: (M+H) + found 246.3. Intermediate 18. Synthesis of N-cyclopropyl-3-methoxy-4-(prop-2-yn-1-ylamino)benzamide Step 1. Synthesis of N-cyclopropyl-3-methoxy-4-nitrobenzamide
在室溫下,向3-甲氧基-4-硝基苯甲酸(2 g,10.15 mmol,1當量)於DCM (10 mL)中之攪拌溶液中添加HATU (5.79 g,15.22 mmol,1.50當量)。將混合物在室溫下攪拌1 h。在室溫下向上述混合物中逐滴添加胺基環丙烷(0.87 g,15.22 mmol,1.50當量)及Et 3N (3.08 g,30.44 mmol,3當量)。將所得混合物在室溫下再攪拌12 h,然後用CH 2Cl 2(30 mL)稀釋。合併的有機層用水(3*20 mL)洗滌且經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物使用具有以下條件(移動相A:水,移動相B:ACN;流動速率:80 mL/min;梯度:在15 min內0% B至60% B;254/220 nm)之C18急速層析純化。此產生呈白色固體之N-環丙基-3-甲氧基-4-硝基苯甲醯胺(2.10 g,87.6%)。LC-MS:(M+H) +實測值237.1。 步驟2. 4-胺基-N-環丙基-3-甲氧基苯甲醯胺之合成 To a stirred solution of 3-methoxy-4-nitrobenzoic acid (2 g, 10.15 mmol, 1 eq.) in DCM (10 mL) was added HATU (5.79 g, 15.22 mmol, 1.50 eq.) at room temperature. The mixture was stirred at room temperature for 1 h. To the above mixture were added aminocyclopropane (0.87 g, 15.22 mmol, 1.50 eq.) and Et 3 N (3.08 g, 30.44 mmol, 3 eq.) dropwise at room temperature. The resulting mixture was stirred at room temperature for another 12 h and then diluted with CH 2 Cl 2 (30 mL). The combined organic layers were washed with water (3*20 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified using C18 flash chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 80 mL/min; gradient: 0% B to 60% B in 15 min; 254/220 nm). This produced N-cyclopropyl-3-methoxy-4-nitrobenzamide (2.10 g, 87.6%) as a white solid. LC-MS: (M+H) + found 237.1. Step 2. Synthesis of 4-amino-N-cyclopropyl-3-methoxybenzamide
在氮氣氛圍下,向N-環丙基-3-甲氧基-4-硝基苯甲醯胺(2.0 g,8.47 mmol,1當量)於THF (15 mL)中之溶液中添加Pd/C (200.0 mg)。將反應混合物在室溫及氫氣氛圍下攪拌隔夜。過濾所得混合物且濾餅用THF洗滌。將濾液在減壓下濃縮。此產生呈白色固體之4-胺基-N-環丙基-3-甲氧基苯甲醯胺(1.40 g,80.1%)。LC-MS:(M+H) +實測值207.1。 步驟3. N-環丙基-3-甲氧基-4-(丙-2-炔-1-基胺基)苯甲醯胺之合成 To a solution of N-cyclopropyl-3-methoxy-4-nitrobenzamide (2.0 g, 8.47 mmol, 1 eq.) in THF (15 mL) was added Pd/C (200.0 mg) under a nitrogen atmosphere. The reaction mixture was stirred overnight at room temperature under a hydrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with THF. The filtrate was concentrated under reduced pressure. This gave 4-amino-N-cyclopropyl-3-methoxybenzamide (1.40 g, 80.1%) as a white solid. LC-MS: (M+H) + found 207.1. Step 3. Synthesis of N-cyclopropyl-3-methoxy-4-(prop-2-yn-1-ylamino)benzamide
在室溫下,向4-胺基-N-環丙基-3-甲氧基苯甲醯胺(1.30 g,6.30 mmol,1當量)於DMF (10 mL)中之攪拌溶液中逐滴添加炔丙基溴(1.12 g,9.45 mmol,1.50當量)及DIPEA (2.44 g,18.91 mmol,3當量)。將所得混合物在70℃下攪拌12 h。將所得溶液在減壓下濃縮。殘餘物使用具有以下條件之C18急速層析純化:管柱,C18;移動相,於水中之MeCN (0.1% TFA),在10 min內10%至60%梯度;偵測器,UV 254 nm。此產生呈黑色油狀物之N-環丙基-3-甲氧基-4-(丙-2-炔-1-基胺基)苯甲醯胺(1.0 g,64.9%)。LC-MS:(M+H) +實測值245.1。 中間物19. 2-甲氧基-N-(丙-2-炔-1-基)-4-(吡咯啶-1-羰基)苯胺之合成 步驟1. 1-(3-甲氧基-4-硝基苯甲醯基)吡咯啶之合成 To a stirred solution of 4-amino-N-cyclopropyl-3-methoxybenzamide (1.30 g, 6.30 mmol, 1 eq.) in DMF (10 mL) was added propargyl bromide (1.12 g, 9.45 mmol, 1.50 eq.) and DIPEA (2.44 g, 18.91 mmol, 3 eq.) dropwise at room temperature. The resulting mixture was stirred at 70 °C for 12 h. The resulting solution was concentrated under reduced pressure. The residue was purified using C18 flash chromatography with the following conditions: column, C18; mobile phase, MeCN (0.1% TFA) in water, gradient 10% to 60% in 10 min; detector, UV 254 nm. This gave N-cyclopropyl-3-methoxy-4-(prop-2-yn-1-ylamino)benzamide (1.0 g, 64.9%) as a black oil. LC-MS: (M+H) + found 245.1. Intermediate 19. Synthesis of 2-methoxy-N-(prop-2-yn-1-yl)-4-(pyrrolidine-1-carbonyl)aniline Step 1. Synthesis of 1-(3-methoxy-4-nitrobenzyl)pyrrolidine
向3-甲氧基-4-硝基苯甲酸(3.0 g,15.22 mmol,1當量)於DMF (30 mL)中之攪拌溶液中添加吡咯啶(1.08 g,15.22 mmol,1當量)、DIEA (4.92 g,38.04 mmol,2.5當量)及HATU (9.26 g,24.35 mmol,1.6當量)。將反應溶液在室溫下攪拌3 h,然後使用具有以下條件(移動相A:水,移動相B:ACN;流動速率:60 mL/min;梯度:在30 min內0% B至100% B;254/220 nm)之C18層析純化,以得到呈棕色油狀物之1-(3-甲氧基-4-硝基苯甲醯基)吡咯啶(3.57 g,93.7%)。LC-MS:(M+H) +實測值251.1。 步驟2. 2-甲氧基-4-(吡咯啶-1-羰基)苯胺之合成 To a stirred solution of 3-methoxy-4-nitrobenzoic acid (3.0 g, 15.22 mmol, 1 eq) in DMF (30 mL) were added pyrrolidine (1.08 g, 15.22 mmol, 1 eq), DIEA (4.92 g, 38.04 mmol, 2.5 eq) and HATU (9.26 g, 24.35 mmol, 1.6 eq). The reaction solution was stirred at room temperature for 3 h and then purified using C18 chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm) to give 1-(3-methoxy-4-nitrobenzyl)pyrrolidine (3.57 g, 93.7%) as a brown oil. LC-MS: (M+H) + found 251.1. Step 2. Synthesis of 2-methoxy-4-(pyrrolidine-1-carbonyl)aniline
在氮氣氛圍下,向1-(3-甲氧基-4-硝基苯甲醯基)吡咯啶(3.57 g,14.27 mmol,1當量)於MeOH (30 mL)中之溶液中添加Pd/C (360.0 mg)。將所得混合物在室溫及氫氣氛圍下攪拌3 h。將所得混合物通過矽藻土墊過濾且濾餅用MeOH洗滌。將濾液在減壓下濃縮。殘餘物使用具有以下條件(移動相A:水(10 mmol/L NH 4HCO 3),移動相B:ACN;流動速率:65 mL/min;梯度:在25 min內0% B至100% B;254/220 nm)之C18層析純化,以得到呈淺綠色固體之2-甲氧基-4-(吡咯啶-1-羰基)苯胺(3.03 g,96.4%)。LC-MS:(M+H) +實測值221.1。 步驟3. 2-甲氧基-N-(丙-2-炔-1-基)-4-(吡咯啶-1-羰基)苯胺之合成 To a solution of 1-(3-methoxy-4-nitrobenzyl)pyrrolidine (3.57 g, 14.27 mmol, 1 eq.) in MeOH (30 mL) was added Pd/C (360.0 mg) under nitrogen atmosphere. The resulting mixture was stirred at room temperature under hydrogen atmosphere for 3 h. The resulting mixture was filtered through a celite pad and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure. The residue was purified using C18 chromatography with the following conditions (mobile phase A: water (10 mmol/L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 65 mL/min; gradient: 0% B to 100% B in 25 min; 254/220 nm) to give 2-methoxy-4-(pyrrolidine-1-carbonyl)aniline (3.03 g, 96.4%) as a light green solid. LC-MS: (M+H) + found 221.1. Step 3. Synthesis of 2-methoxy-N-(prop-2-yn-1-yl)-4-(pyrrolidine-1-carbonyl)aniline
向2-甲氧基-4-(吡咯啶-1-羰基)苯胺(1.0 g,4.54 mmol,1當量)於DMF (8 mL)中之攪拌溶液中添加炔丙基溴(810.0 mg,6.81 mmol,1.5當量)及DIEA (1.76 g,13.62 mmol,3當量)。將反應混合物在70℃下攪拌12 h,然後冷卻至室溫且使用具有以下條件(移動相A:水,移動相B:ACN;流動速率:60 mL/min;梯度:在30 min內0% B至100% B;254/220 nm)之C18層析純化,以得到呈黃色油狀物之2-甲氧基-N-(丙-2-炔-1-基)-4-(吡咯啶-1-羰基)苯胺(800 mg,68.22%)。LC-MS:(M+H) +實測值259.1。 中間物20. 4-(氮雜環丁烷-1-羰基)-2-甲氧基-N-(丙-2-炔-1-基)苯胺之合成 步驟1. 1-(3-甲氧基-4-硝基苯甲醯基)氮雜環丁烷之合成 To a stirred solution of 2-methoxy-4-(pyrrolidine-1-carbonyl)aniline (1.0 g, 4.54 mmol, 1 eq) in DMF (8 mL) were added propargyl bromide (810.0 mg, 6.81 mmol, 1.5 eq) and DIEA (1.76 g, 13.62 mmol, 3 eq). The reaction mixture was stirred at 70 °C for 12 h, then cooled to room temperature and purified using C18 chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm) to give 2-methoxy-N-(prop-2-yn-1-yl)-4-(pyrrolidine-1-carbonyl)aniline (800 mg, 68.22%) as a yellow oil. LC-MS: (M+H) + found 259.1. Intermediate 20. Synthesis of 4-(Azocyclobutane-1-carbonyl)-2-methoxy-N-(prop-2-yn-1-yl)aniline Step 1. Synthesis of 1-(3-methoxy-4-nitrobenzoyl)azinecyclobutane
將3-甲氧基-4-硝基苯甲酸(2.70 g,13.69 mmol,1當量)於DCM (30 mL)中之溶液在0℃下用(COCl) 2(2.61 g,20.54 mmol,1.50當量)及DMF (0.10 mL)處理。將所得混合物在室溫下攪拌1 h。在0℃下向上述混合物中添加氮雜環丁烷鹽酸鹽(1.67 g,17.80 mmol,1.30當量)及TEA (6.91 g,68.45 mmol,5當量)。將所得混合物在室溫下再攪拌1 h。移除溶劑後,殘餘物使用具有以下條件之C18急速層析純化:移動相A:水,移動相B:ACN;流動速率:80 mL/min;梯度:在30 min內0% B至100% B;254/220 nm。此產生呈黃色油狀物之1-(3-甲氧基-4-硝基苯甲醯基)氮雜環丁烷(3.20 g,96.0%)。LC-MS:(M+H) +實測值237.1。 步驟2. 4-(氮雜環丁烷-1-羰基)-2-甲氧基苯胺之合成 A solution of 3-methoxy-4-nitrobenzoic acid (2.70 g, 13.69 mmol, 1 eq) in DCM (30 mL) was treated with (COCl) 2 (2.61 g, 20.54 mmol, 1.50 eq) and DMF (0.10 mL) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. To the above mixture was added azocyclobutane hydrochloride (1.67 g, 17.80 mmol, 1.30 eq) and TEA (6.91 g, 68.45 mmol, 5 eq) at 0 °C. The resulting mixture was stirred at room temperature for another 1 h. After removal of the solvent, the residue was purified using C18 flash chromatography with the following conditions: mobile phase A: water, mobile phase B: ACN; flow rate: 80 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm. This produced 1-(3-methoxy-4-nitrobenzyl)azinecyclobutane (3.20 g, 96.0%) as a yellow oil. LC-MS: (M+H) + found 237.1. Step 2. Synthesis of 4-(azinecyclobutane-1-carbonyl)-2-methoxyaniline
將1-(3-甲氧基-4-硝基苯甲醯基)氮雜環丁烷(3.20 g,14.82 mmol,1當量)於IPA (100 mL)中之溶液在氮氣氛圍下用Pd/C (350.0 mg)處理。將所得混合物在室溫及氫氣氛圍下攪拌6 h。過濾後,濾餅用IPA洗滌。將濾液在減壓下濃縮。此產生呈黃色固體之4-(氮雜環丁烷-1-羰基)-2-甲氧基苯胺(2.1 mg,78.0%)。LC-MS:(M+H) +實測值207.0。 步驟3. 氮雜環丁-1-基(3-甲氧基-4-(丙-2-炔-1-基胺基)苯基)甲酮之合成 A solution of 1-(3-methoxy-4-nitrobenzyl)azinecyclobutane (3.20 g, 14.82 mmol, 1 eq.) in IPA (100 mL) was treated with Pd/C (350.0 mg) under nitrogen atmosphere. The resulting mixture was stirred at room temperature under hydrogen atmosphere for 6 h. After filtration, the filter cake was washed with IPA. The filtrate was concentrated under reduced pressure. This gave 4-(azinecyclobutane-1-carbonyl)-2-methoxyaniline (2.1 mg, 78.0%) as a yellow solid. LC-MS: (M+H) + found 207.0. Step 3. Synthesis of azacyclobut-1-yl(3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)methanone
在室溫下,向4-(氮雜環丁烷-1-羰基)-2-甲氧基苯胺(1.0 g,4.85 mmol,1當量)於DMF (15 mL)中之攪拌混合物中添加炔丙基溴(576.8 mg,4.85 mmol,1當量)及DIPEA (1.88 g,14.55 mmol,3當量)。將所得混合物在70℃下攪拌4h,然後冷卻至室溫且使用具有以下條件之C18快速層析純化:移動相A:水,移動相B:ACN;流動速率:60 mL/min;梯度:在15 min內0% B至100% B;波長:254 nm;220 nm。此產生呈黃色固體之氮雜環丁-1-基(3-甲氧基-4-(丙-2-炔-1-基胺基)苯基)甲酮(424.0 mg,30.0%)。LC-MS:(M+H) +實測值245.1。 中間物21. N-甲基-5-(丙-2-炔-1-基胺基)吡啶-2-甲醯胺之合成 步驟1. N-甲基-5-硝基吡啶-2-甲醯胺之合成 To a stirred mixture of 4-(azacyclobutane-1-carbonyl)-2-methoxyaniline (1.0 g, 4.85 mmol, 1 eq) in DMF (15 mL) at room temperature, propargyl bromide (576.8 mg, 4.85 mmol, 1 eq) and DIPEA (1.88 g, 14.55 mmol, 3 eq) were added. The resulting mixture was stirred at 70 °C for 4 h, then cooled to room temperature and purified using C18 flash chromatography with the following conditions: mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 15 min; wavelength: 254 nm; 220 nm. This gave a yellow solid azacyclobut-1-yl(3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)methanone (424.0 mg, 30.0%). LC-MS: (M+H) + found 245.1. Intermediate 21. Synthesis of N-methyl-5-(prop-2-yn-1-ylamino)pyridine-2-carboxamide Step 1. Synthesis of N-methyl-5-nitropyridine-2-carboxamide
在0℃下,向5-硝基吡啶-2-甲酸(5 g,29.74 mmol,1當量)、甲胺鹽酸鹽(2.21 g,32.72 mmol,1.1當量)及DIPEA (15.38 g,118.97 mmol,4當量)於DMF (50 mL)中之攪拌溶液中添加HATU (12.44 g,32.72 mmol,1.1當量)。將所得溶液在室溫下攪拌隔夜,然後用EA (500 mL)稀釋且用鹽水(3*500 mL)洗滌。有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用PE / EA (1:1)溶析,以得到呈黃色固體之N-甲基-5-硝基吡啶-2-甲醯胺(6.73 g)。LC-MS:(M+H) +實測值182.0。 步驟2. 5-胺基-N-甲基吡啶-2-甲醯胺之合成 To a stirred solution of 5-nitropyridine-2-carboxylic acid (5 g, 29.74 mmol, 1 eq.), methylamine hydrochloride (2.21 g, 32.72 mmol, 1.1 eq.) and DIPEA (15.38 g, 118.97 mmol, 4 eq.) in DMF (50 mL) at 0°C was added HATU (12.44 g, 32.72 mmol, 1.1 eq.). The resulting solution was stirred at room temperature overnight, then diluted with EA (500 mL) and washed with brine (3*500 mL). The organic layer was dried over anhydrous Na2SO4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (1:1) to obtain N-methyl-5-nitropyridine-2-carboxamide (6.73 g) as a yellow solid. LC-MS: (M+H) + found 182.0. Step 2. Synthesis of 5-amino-N-methylpyridine-2-carboxamide
將N-甲基-5-硝基吡啶-2-甲醯胺(6.5 g,35.88 mmol,1當量)及Fe (10.02 g,179.41 mmol,5當量)於EtOH (52 mL)/飽和NH 4Cl (13 mL)中之混合物在70℃下攪拌1 h。過濾所得混合物且濾餅用EtOH洗滌。將濾液在減壓下濃縮。所得混合物用DCM (5*50 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮,以得到呈紅色固體之5-胺基-N-甲基吡啶-2-甲醯胺(4.5 g,82.96%)。LC-MS:(M+H) +實測值152.0。 步驟3. N-甲基-5-(丙-2-炔-1-基胺基)吡啶-2-甲醯胺之合成 A mixture of N-methyl-5-nitropyridine-2-carboxamide (6.5 g, 35.88 mmol, 1 eq.) and Fe (10.02 g, 179.41 mmol, 5 eq.) in EtOH (52 mL)/saturated NH 4 Cl (13 mL) was stirred at 70 °C for 1 h. The resulting mixture was filtered and the filter cake was washed with EtOH. The filtrate was concentrated under reduced pressure. The resulting mixture was extracted with DCM (5*50 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to obtain 5-amino-N-methylpyridine-2-carboxamide (4.5 g, 82.96%) as a red solid. LC-MS: (M+H) + found 152.0. Step 3. Synthesis of N-methyl-5-(prop-2-yn-1-ylamino)pyridine-2-carboxamide
將5-胺基-N-甲基吡啶-2-甲醯胺(4.5 g,29.77 mmol,1當量)、K 2CO 3(8.23 g,59.54 mmol,2當量)及炔丙基溴(17.71 g,148.84 mmol,5當量)於DMF (50 mL)中之混合物在70℃下攪拌3 h。過濾所得混合物且濾餅用DCM洗滌。將濾液在減壓下濃縮。殘餘物藉由具有以下條件(管柱,C18矽膠;移動相,於水中之MeOH,在20 min內0%至100%梯度;偵測器,UV 254 nm)之反相急速層析純化,以得到呈棕色固體之N-甲基-5-(丙-2-炔-1-基胺基)吡啶-2-甲醯胺(1.98 g,35.21%)。LC-MS:(M+H) +實測值190.0。 中間物22. N-甲基-4-(丙-2-炔-1-基胺基)-3-(三氟甲氧基)苯甲醯胺之合成 步驟1. 4-(丙-2-炔-1-基胺基)-3-(三氟甲氧基)苯甲酸甲酯之合成 A mixture of 5-amino-N-methylpyridine-2-carboxamide (4.5 g, 29.77 mmol, 1 eq.), K 2 CO 3 (8.23 g, 59.54 mmol, 2 eq.) and propargyl bromide (17.71 g, 148.84 mmol, 5 eq.) in DMF (50 mL) was stirred at 70° C. for 3 h. The resulting mixture was filtered and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeOH in water, gradient 0% to 100% in 20 min; detector, UV 254 nm) to give N-methyl-5-(prop-2-yn-1-ylamino)pyridine-2-carboxamide (1.98 g, 35.21%) as a brown solid. LC-MS: (M+H) + found 190.0. Intermediate 22. Synthesis of N-methyl-4-(prop-2-yn-1-ylamino)-3-(trifluoromethoxy)benzamide Step 1. Synthesis of methyl 4-(prop-2-yn-1-ylamino)-3-(trifluoromethoxy)benzoate
將4-胺基-3-(三氟甲氧基)苯甲酸甲酯(2.0 g,8.50 mmol,1當量)、炔丙基溴(1.52 g,12.75 mmol,1.50當量)及K 2CO 3(3.53 g,25.51 mmol,3當量)於DMF (20 mL)中之混合物在90℃下攪拌隔夜。將反應在室溫下用水淬滅且用EtOAc (3*100 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由具有以下條件之反相急速層析純化:管柱,C18矽膠;移動相,於水中之MeCN (10 mmol/L NH 4HCO 3),在10 min內55%至60%梯度;偵測器,UV 254 nm。此產生呈白色固體之4-(丙-2-炔-1-基胺基)-3-(三氟甲氧基)苯甲酸甲酯(600 mg,25.54%)。LC-MS:(M+H) +實測值274.0。 步驟2. 4-(丙-2-炔-1-基胺基)-3-(三氟甲氧基)苯甲酸之合成 A mixture of methyl 4-amino-3-(trifluoromethoxy)benzoate (2.0 g, 8.50 mmol, 1 eq.), propargyl bromide (1.52 g, 12.75 mmol, 1.50 eq.) and K 2 CO 3 (3.53 g, 25.51 mmol, 3 eq.) in DMF (20 mL) was stirred at 90 °C overnight. The reaction was quenched with water at room temperature and extracted with EtOAc (3*100 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH 4 HCO 3 ) in water, gradient 55% to 60% in 10 min; detector, UV 254 nm. This yielded methyl 4-(prop-2-yn-1-ylamino)-3-(trifluoromethoxy)benzoate (600 mg, 25.54%) as a white solid. LC-MS: (M+H) + found 274.0. Step 2. Synthesis of 4-(prop-2-yn-1-ylamino)-3-(trifluoromethoxy)benzoic acid
在室溫下,向4-(丙-2-炔-1-基胺基)-3-(三氟甲氧基)苯甲酸甲酯(630 mg,2.30 mmol,1當量)於MeOH (5 mL)及THF (5 mL)中之攪拌混合物中逐滴添加NaOH (277 mg,6.91 mmol,3當量)於H 2O (5 mL)中之溶液。將混合物在60℃下攪拌1 h。使混合物冷卻至室溫,然後用2N HCl酸化至pH 6。藉由過濾收集沉澱的固體且用水洗滌。此產生呈白色固體之4-(丙-2-炔-1-基胺基)-3-(三氟甲氧基)苯甲酸(850 mg,粗物質)。LC-MS:(M+H) +實測值260.0。 步驟3. N-甲基-4-(丙-2-炔-1-基胺基)-3-(三氟甲氧基)苯甲醯胺之合成 To a stirred mixture of methyl 4-(prop-2-yn-1-ylamino)-3-(trifluoromethoxy)benzoate (630 mg, 2.30 mmol, 1 eq) in MeOH (5 mL) and THF (5 mL) was added dropwise a solution of NaOH (277 mg, 6.91 mmol, 3 eq) in H 2 O (5 mL) at room temperature. The mixture was stirred at 60 °C for 1 h. The mixture was cooled to room temperature and then acidified to pH 6 with 2N HCl. The precipitated solid was collected by filtration and washed with water. This resulted in 4-(prop-2-yn-1-ylamino)-3-(trifluoromethoxy)benzoic acid (850 mg, crude) as a white solid. LC-MS: (M+H) + found 260.0. Step 3. Synthesis of N-methyl-4-(prop-2-yn-1-ylamino)-3-(trifluoromethoxy)benzamide
在0℃下,向4-(丙-2-炔-1-基胺基)-3-(三氟甲氧基)苯甲酸(845 mg,3.26 mmol,1當量)、甲胺鹽酸鹽(441 mg,6.52 mmol,2當量)及NaHCO 3(1.37 g,16.30 mmol,5當量)於DMF (10 mL)中之攪拌混合物中逐份添加HATU (1.49 g,3.91 mmol,1.20當量)。將混合物在室溫下攪拌1h,然後在室溫下用水淬滅。所得混合物用EtOAc (3*20 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。此產生呈黃色固體之N-甲基-4-(丙-2-炔-1-基胺基)-3-(三氟甲氧基)苯甲醯胺(540 mg,57.31%)。LC-MS:(M+H) +實測值273.0。 中間物23. N-甲基-4-(丙-2-炔-1-基胺基)-3-(三氟甲基)苯甲醯胺之合成 步驟1. N-甲基-4-硝基-3-(三氟甲基)苯甲醯胺之合成 To a stirred mixture of 4-(prop-2-yn-1-ylamino)-3-(trifluoromethoxy)benzoic acid (845 mg, 3.26 mmol, 1 eq), methylamine hydrochloride (441 mg, 6.52 mmol, 2 eq) and NaHCO 3 (1.37 g, 16.30 mmol, 5 eq) in DMF (10 mL) at 0° C. was added HATU (1.49 g, 3.91 mmol, 1.20 eq) portionwise. The mixture was stirred at room temperature for 1 h and then quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3*20 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. This gave N-methyl-4-(prop-2-yn-1-ylamino)-3-(trifluoromethoxy)benzamide (540 mg, 57.31%) as a yellow solid. LC-MS: (M+H) + found 273.0. Intermediate 23. Synthesis of N-methyl-4-(prop-2-yn-1-ylamino)-3-(trifluoromethyl)benzamide Step 1. Synthesis of N-methyl-4-nitro-3-(trifluoromethyl)benzamide
在0℃下,向4-硝基-3-(三氟甲基)苯甲酸(5 g,21.26 mmol,1當量)、甲胺鹽酸鹽(1.58 g,23.39 mmol,1.1當量)及DIPEA (10.99 g,85.06 mmol,4當量)於DMF (50 mL)中之攪拌溶液中逐份添加HATU (8.89 g,23.39 mmol,1.1當量)。將所得溶液在室溫下攪拌隔夜,然後用水(200mL)稀釋。所得混合物用CH 2Cl 2(3*200 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由具有以下條件(管柱,C18矽膠;移動相,於水中之MeOH,在20 min內0%至100%梯度;偵測器,UV 254 nm)之反相急速層析純化,以得到呈黃色固體之N-甲基-4-硝基-3-(三氟甲基)苯甲醯胺(4.65 g,88.11%)。LC-MS:(M-H) -實測值246.9。 步驟2. 4-胺基-N-甲基-3-(三氟甲基)苯甲醯胺之合成 To a stirred solution of 4-nitro-3-(trifluoromethyl)benzoic acid (5 g, 21.26 mmol, 1 eq.), methylamine hydrochloride (1.58 g, 23.39 mmol, 1.1 eq.) and DIPEA (10.99 g, 85.06 mmol, 4 eq.) in DMF (50 mL) at 0°C was added HATU (8.89 g, 23.39 mmol, 1.1 eq.) portionwise. The resulting solution was stirred at room temperature overnight and then diluted with water (200 mL). The resulting mixture was extracted with CH 2 Cl 2 (3*200 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeOH in water, gradient from 0% to 100% in 20 min; detector, UV 254 nm) to give N-methyl-4-nitro-3-(trifluoromethyl)benzamide (4.65 g, 88.11%) as a yellow solid. LC-MS: (MH) - found 246.9. Step 2. Synthesis of 4-amino-N-methyl-3-(trifluoromethyl)benzamide
將N-甲基-4-硝基-3-(三氟甲基)苯甲醯胺(4.65 g,18.74 mmol,1當量)及Fe (5.23 g,93.69 mmol,5當量)於EtOH (40 mL) /飽和NH 4Cl (10 mL)中之溶液在70℃下攪拌1 h。使混合物冷卻至室溫且過濾。濾餅用EtOH洗滌。將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用PE / EA (3:7)溶析,以得到呈灰白色油狀物之4-胺基-N-甲基-3-(三氟甲基)苯甲醯胺(4.1 g)。LC-MS:(M+H) +實測值219.0。 步驟3. N-甲基-4-(丙-2-炔-1-基胺基)-3-(三氟甲基)苯甲醯胺之合成 A solution of N-methyl-4-nitro-3-(trifluoromethyl)benzamide (4.65 g, 18.74 mmol, 1 eq.) and Fe (5.23 g, 93.69 mmol, 5 eq.) in EtOH (40 mL)/saturated NH 4 Cl (10 mL) was stirred at 70 °C for 1 h. The mixture was cooled to room temperature and filtered. The filter cake was washed with EtOH. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (3:7) to give 4-amino-N-methyl-3-(trifluoromethyl)benzamide (4.1 g) as an off-white oil. LC-MS: (M+H) + found 219.0. Step 3. Synthesis of N-methyl-4-(prop-2-yn-1-ylamino)-3-(trifluoromethyl)benzamide
將4-胺基-N-甲基-3-(三氟甲基)苯甲醯胺(4 g,18.33 mmol,1當量)、K 2CO 3(12.67 g,91.67 mmol,5當量)及炔丙基溴(10.90 g,91.67 mmol,5當量)於DMF (40 mL)中之溶液在70℃下攪拌5 h。使混合物冷卻至室溫且過濾。濾餅用DCM洗滌。將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用PE / EA (7:3)溶析,以得到呈棕黃色固體之N-甲基-4-(丙-2-炔-1-基胺基)-3-(三氟甲基)苯甲醯胺(930 mg,79.19%)。LC-MS:(M+H) +實測值257.1。 中間物24. 3-氯-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺之合成 步驟1. 3-氯-N-甲基-4-硝基苯甲醯胺之合成 A solution of 4-amino-N-methyl-3-(trifluoromethyl)benzamide (4 g, 18.33 mmol, 1 eq.), K 2 CO 3 (12.67 g, 91.67 mmol, 5 eq.) and propargyl bromide (10.90 g, 91.67 mmol, 5 eq.) in DMF (40 mL) was stirred at 70 °C for 5 h. The mixture was cooled to room temperature and filtered. The filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (7:3) to give N-methyl-4-(prop-2-yn-1-ylamino)-3-(trifluoromethyl)benzamide (930 mg, 79.19%) as a brown solid. LC-MS: (M+H) + found 257.1. Intermediate 24. Synthesis of 3-chloro-N-methyl-4-(prop-2-yn-1-ylamino)benzamide Step 1. Synthesis of 3-chloro-N-methyl-4-nitrobenzamide
在0℃下,向3-氯-4-硝基苯甲酸(10 g,49.61 mmol,1當量)、甲胺鹽酸鹽(3.68 g,54.57 mmol,1.1當量)及DIPEA (25.65 g,198.45 mmol,4當量)於DMF (100 mL)中之攪拌溶液中添加HATU (20.75 g,54.57 mmol,1.1當量)。將所得溶液在室溫下攪拌2 h。所得混合物用水稀釋且用EtOAc (2*150 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用PE / EA (1:1)溶析,以得到呈黃色油狀物之3-氯-N-甲基-4-硝基苯甲醯胺(9.9 g,92.98%)。LC-MS:(M+H) +實測值215.4。 步驟2. 4-胺基-3-氯-N-甲基苯甲醯胺之合成 To a stirred solution of 3-chloro-4-nitrobenzoic acid (10 g, 49.61 mmol, 1 eq.), methylamine hydrochloride (3.68 g, 54.57 mmol, 1.1 eq.) and DIPEA (25.65 g, 198.45 mmol, 4 eq.) in DMF (100 mL) at 0 °C was added HATU (20.75 g, 54.57 mmol, 1.1 eq.). The resulting solution was stirred at room temperature for 2 h. The resulting mixture was diluted with water and extracted with EtOAc (2*150 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (1:1) to obtain 3-chloro-N-methyl-4-nitrobenzamide (9.9 g, 92.98%) as a yellow oil. LC-MS: (M+H) + found 215.4. Step 2. Synthesis of 4-amino-3-chloro-N-methylbenzamide
將3-氯-N-甲基-4-硝基苯甲醯胺(5 g,23.30 mmol,1當量)及Fe (7.81 g,139.79 mmol,6當量)於飽和NH 4Cl (25 mL)/EtOH (25 mL)中之混合物在70℃下攪拌1 h。過濾所得混合物,濾餅用EtOH洗滌。將濾液在減壓下濃縮。殘餘物用DCM洗滌且過濾。將濾液在減壓下濃縮,以得到呈黃色固體之4-胺基-3-氯-N-甲基苯甲醯胺(4 g,93.0%)。LC-MS:(M+H) +實測值185.1。 步驟3. 3-氯-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺之合成 A mixture of 3-chloro-N-methyl-4-nitrobenzamide (5 g, 23.30 mmol, 1 eq.) and Fe (7.81 g, 139.79 mmol, 6 eq.) in saturated NH 4 Cl (25 mL)/EtOH (25 mL) was stirred at 70 °C for 1 h. The resulting mixture was filtered and the filter cake was washed with EtOH. The filtrate was concentrated under reduced pressure. The residue was washed with DCM and filtered. The filtrate was concentrated under reduced pressure to give 4-amino-3-chloro-N-methylbenzamide (4 g, 93.0%) as a yellow solid. LC-MS: (M+H) + found 185.1. Step 3. Synthesis of 3-chloro-N-methyl-4-(prop-2-yn-1-ylamino)benzamide
將4-胺基-3-氯-N-甲基苯甲醯胺(700 mg,3.79 mmol,1當量)、炔丙基溴(902.1 mg,7.58 mmol,2當量)及K 2CO 3(1.57 g,11.38 mmol,3當量)於DMF (2 mL)中之混合物在70℃下攪拌1 h。過濾所得混合物。將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用PE / EA (1:1)溶析,以得到呈黃色油狀物之3-氯-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺(520 mg,61.59%)。LC-MS:(M+H) +實測值223.1。 中間物25. N-[2-氰基-4-(甲基胺甲醯基)苯基]-N-(丙-2-炔-1-基)胺基甲酸三級丁酯之合成 步驟1. 4-[(三級丁氧基羰基)胺基]-3-氰基苯甲酸甲酯之合成 A mixture of 4-amino-3-chloro-N-methylbenzamide (700 mg, 3.79 mmol, 1 eq.), propargyl bromide (902.1 mg, 7.58 mmol, 2 eq.) and K 2 CO 3 (1.57 g, 11.38 mmol, 3 eq.) in DMF (2 mL) was stirred at 70 °C for 1 h. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (1:1) to give 3-chloro-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (520 mg, 61.59%) as a yellow oil. LC-MS: (M+H) + found 223.1. Intermediate 25. Synthesis of tert-butyl N-[2-cyano-4-(methylaminoformyl)phenyl]-N-(prop-2-yn-1-yl)carbamate Step 1. Synthesis of methyl 4-[(tert-butyloxycarbonyl)amino]-3-cyanobenzoate
將4-胺基-3-氰基苯甲酸甲酯(2 g,11.35 mmol,1當量)、DMAP (1.39 g,11.35 mmol,1當量)及Boc 2O (2.9 g,13.29 mmol,1.17當量)於二噁烷(3 mL)中之溶液在100℃下攪拌隔夜。所得溶液用EtOAc (100 mL)稀釋且用水(3*100 mL)洗滌。有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用PE / EA (3:1)溶析,以得到呈黃色固體之4-[(三級丁氧基羰基)胺基]-3-氰基苯甲酸甲酯(2.7 g,96.66%)。LC-MS:(M+H) +實測值377.2。 步驟2. 4-[(三級丁氧基羰基)胺基]-3-氰基苯甲酸甲酯之合成 A solution of methyl 4-amino-3-cyanobenzoate (2 g, 11.35 mmol, 1 eq.), DMAP (1.39 g, 11.35 mmol, 1 eq.) and Boc 2 O (2.9 g, 13.29 mmol, 1.17 eq.) in dioxane (3 mL) was stirred at 100 °C overnight. The resulting solution was diluted with EtOAc (100 mL) and washed with water (3*100 mL). The organic layer was dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (3:1) to obtain methyl 4-[(tert-butyloxycarbonyl)amino]-3-cyanobenzoate (2.7 g, 96.66%) as a yellow solid. LC-MS: (M+H) + found 377.2. Step 2. Synthesis of methyl 4-[(tert-butyloxycarbonyl)amino]-3-cyanobenzoate
將4-[雙(三級丁氧基羰基)胺基]-3-氰基苯甲酸甲酯(2.7 g,7.17 mmol,1當量)及K 2CO 3(2.97 g,21.52 mmol,3當量)於MeOH (27 mL)中之混合物在室溫下攪拌1 h。所得混合物用水稀釋且用DCM (2*150 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用PE / EA (2:1)溶析,以得到呈黃色固體之4-[(三級丁氧基羰基)胺基]-3-氰基苯甲酸甲酯(1.1 g,55.50%)。LC-MS:(M+H) +實測值277.1。 步驟3. 4-[(三級丁氧基羰基)(丙-2-炔-1-基)胺基]-3-氰基苯甲酸甲酯之合成 A mixture of methyl 4-[bis(tert-butyloxycarbonyl)amino]-3-cyanobenzoate (2.7 g, 7.17 mmol, 1 eq.) and K 2 CO 3 (2.97 g, 21.52 mmol, 3 eq.) in MeOH (27 mL) was stirred at room temperature for 1 h. The resulting mixture was diluted with water and extracted with DCM (2*150 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (2:1) to give methyl 4-[(tert-butyloxycarbonyl)amino]-3-cyanobenzoate (1.1 g, 55.50%) as a yellow solid. LC-MS: (M+H) + found 277.1. Step 3. Synthesis of methyl 4-[(tert-butyloxycarbonyl)(prop-2-yn-1-yl)amino]-3-cyanobenzoate
將4-[(三級丁氧基羰基)胺基]-3-氰基苯甲酸甲酯(200 mg,0.72 mmol,1當量)、Cs 2CO 3(707.6mg,2.17 mmol,3當量)及3-溴丙-1-炔(238 mg,2.08mmol,2當量)於DMF (2 mL)中之混合物在70℃下攪拌4 h,然後過濾。將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析(PE/EA=5:1)純化,以得到呈黃色油狀物之4-[(三級丁氧基羰基)(丙-2-炔-1-基)胺基]-3-氰基苯甲酸甲酯(186 mg,81.74%)。LC-MS:(M+H) +實測值315.1。 步驟4. 4-[(三級丁氧基羰基)(丙-2-炔-1-基)胺基]-3-氰基苯甲酸之合成 A mixture of methyl 4-[(tert-butyloxycarbonyl)amino]-3-cyanobenzoate (200 mg, 0.72 mmol, 1 eq.), Cs 2 CO 3 (707.6 mg, 2.17 mmol, 3 eq.) and 3-bromoprop-1-yne (238 mg, 2.08 mmol, 2 eq.) in DMF (2 mL) was stirred at 70° C. for 4 h, and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA=5:1) to give methyl 4-[(tert-butyloxycarbonyl)(prop-2-yn-1-yl)amino]-3-cyanobenzoate (186 mg, 81.74%) as a yellow oil. LC-MS: (M+H) + found 315.1. Step 4. Synthesis of 4-[(tert-butyloxycarbonyl)(prop-2-yn-1-yl)amino]-3-cyanobenzoic acid
將4-[(三級丁氧基羰基)(丙-2-炔-1-基)胺基]-3-氰基苯甲酸甲酯(200 mg,0.64 mmol,1當量)及NaOH (76.3 mg,1.91 mmol,3當量)於H 2O (1 mL)/MeOH (3 mL)中之混合物在室溫下攪拌1h。將混合物用HCl (水溶液)酸化至pH 5且用DCM (3*50 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。將殘餘物在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用PE / EA (1:1)溶析,以得到呈黃色油狀物之4-[(三級丁氧基羰基)(丙-2-炔-1-基)胺基]-3-氰基苯甲酸(196 mg,102.58%)。LC-MS:(M+H) +實測值301.1。 步驟5. N-[2-氰基-4-(甲基胺甲醯基)苯基]-N-(丙-2-炔-1-基)胺基甲酸三級丁酯之合成 A mixture of methyl 4-[(tert-butyloxycarbonyl)(prop-2-yn-1-yl)amino]-3-cyanobenzoate (200 mg, 0.64 mmol, 1 eq) and NaOH (76.3 mg, 1.91 mmol, 3 eq) in H 2 O (1 mL)/MeOH (3 mL) was stirred at room temperature for 1 h. The mixture was acidified to pH 5 with HCl (aq) and extracted with DCM (3*50 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (1:1) to give 4-[(tert-butyloxycarbonyl)(prop-2-yn-1-yl)amino]-3-cyanobenzoic acid (196 mg, 102.58%) as a yellow oil. LC-MS: (M+H) + found 301.1. Step 5. Synthesis of tert-butyl N-[2-cyano-4-(methylaminocarbonyl)phenyl]-N-(prop-2-yn-1-yl)carbamate
在0℃下,向4-[(三級丁氧基羰基)(丙-2-炔-1-基)胺基]-3-氰基苯甲酸(200 mg,0.67 mmol,1當量)、DIPEA (344.3 mg,2.66 mmol,4當量)及甲胺鹽酸鹽(67.5 mg,1.00 mmol,1.5當量)於DMF (2 mL)中之攪拌溶液中添加HATU (379.8 mg,1.00 mmol,1.5當量)。將所得溶液在室溫下攪拌1 h,然後用EtOAc (50 mL)稀釋且用鹽水(2*50 mL)洗滌。有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用PE / EA (1:1)溶析,以得到呈黃色油狀物之N-[2-氰基-4-(甲基胺甲醯基)苯基]-N-(丙-2-炔-1-基)胺基甲酸三級丁酯(192 mg,92.0%)。LC-MS:(M+H) +實測值314.1。 中間物26. 3-環丙基-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺之合成 步驟1. 4-胺基-3-環丙基苯甲酸甲酯之合成 To a stirred solution of 4-[(tert-butyloxycarbonyl)(prop-2-yn-1-yl)amino]-3-cyanobenzoic acid (200 mg, 0.67 mmol, 1 eq), DIPEA (344.3 mg, 2.66 mmol, 4 eq) and methylamine hydrochloride (67.5 mg, 1.00 mmol, 1.5 eq) in DMF (2 mL) at 0°C was added HATU (379.8 mg, 1.00 mmol, 1.5 eq). The resulting solution was stirred at room temperature for 1 h, then diluted with EtOAc (50 mL) and washed with brine (2*50 mL). The organic layer was dried over anhydrous Na2SO4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (1:1) to give tributyl N-[2-cyano-4-(methylaminocarbonyl)phenyl]-N-(prop-2-yn-1-yl)carbamate (192 mg, 92.0%) as a yellow oil. LC-MS: (M+H) + found 314.1. Intermediate 26. Synthesis of 3-cyclopropyl-N-methyl-4-(prop-2-yn-1-ylamino)benzamide Step 1. Synthesis of methyl 4-amino-3-cyclopropylbenzoate
將4-胺基-3-溴苯甲酸甲酯(10 g,43.47 mmol,1當量)、環丙基硼酸(5.60 g,65.20 mmol,1.5當量)、K 2CO 3(18.02 g,130.40 mmol,3當量)及Pd(dppf)Cl 2 .CH 2Cl 2(1.77 g,2.17 mmol,0.05當量)於1,4-二噁烷(80 mL) / H 2O (20 mL)中之混合物在95℃及氮氣氛圍下攪拌1 h。將所得混合物在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用PE / EA (1:1)溶析,以得到呈黃色固體之4-胺基-3-環丙基苯甲酸甲酯(8 g,96.24%)。LC-MS:(M+H) +實測值192.1。 步驟2. 3-環丙基-4-(丙-2-炔-1-基胺基)苯甲酸甲酯之合成 A mixture of methyl 4-amino-3-bromobenzoate (10 g, 43.47 mmol, 1 eq.), cyclopropylboronic acid (5.60 g, 65.20 mmol, 1.5 eq.), K 2 CO 3 (18.02 g, 130.40 mmol, 3 eq.) and Pd(dppf)Cl 2 . CH 2 Cl 2 (1.77 g, 2.17 mmol, 0.05 eq.) in 1,4-dioxane (80 mL) / H 2 O (20 mL) was stirred at 95 °C under nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (1:1) to obtain methyl 4-amino-3-cyclopropylbenzoate (8 g, 96.24%) as a yellow solid. LC-MS: (M+H) + found 192.1. Step 2. Synthesis of methyl 3-cyclopropyl-4-(prop-2-yn-1-ylamino)benzoate
將4-胺基-3-環丙基苯甲酸甲酯(8 g,41.83 mmol,1當量)、炔丙基溴(9.95 g,83.67 mmol,2當量)及K 2CO 3(17.35 g,125.502 mmol,3當量)於DMF (30 mL)中之混合物在70℃下攪拌4 h。過濾所得混合物。濾餅用DCM洗滌。濾液用水(700 mL)稀釋且用DCM (3*300 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用PE / EA (5:1)溶析,以得到呈棕色固體之3-環丙基-4-(丙-2-炔-1-基胺基)苯甲酸甲酯(4 g,41.70%)。LC-MS:(M+H) +實測值230.1。 步驟3. 3-環丙基-4-(丙-2-炔-1-基胺基)苯甲酸之合成 A mixture of methyl 4-amino-3-cyclopropylbenzoate (8 g, 41.83 mmol, 1 eq.), propargyl bromide (9.95 g, 83.67 mmol, 2 eq.) and K 2 CO 3 (17.35 g, 125.502 mmol, 3 eq.) in DMF (30 mL) was stirred at 70 °C for 4 h. The resulting mixture was filtered. The filter cake was washed with DCM. The filtrate was diluted with water (700 mL) and extracted with DCM (3*300 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (5:1) to give methyl 3-cyclopropyl-4-(prop-2-yn-1-ylamino)benzoate (4 g, 41.70%) as a brown solid. LC-MS: (M+H) + found 230.1. Step 3. Synthesis of 3-cyclopropyl-4-(prop-2-yn-1-ylamino)benzoic acid
將3-環丙基-4-(丙-2-炔-1-基胺基)苯甲酸甲酯(4.3 g,18.75 mmol,1當量)及NaOH (3.75 g,93.77 mmol,5當量)於MeOH (20 mL) / H 2O (20 mL)中之混合物在60℃下攪拌3 h。將混合物殘餘物用1 M HCl酸化至pH 5,然後用DCM (3*300 mL)萃取。合併的層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮,以得到呈灰白色固體之3-環丙基-4-(丙-2-炔-1-基胺基)苯甲酸(4 g,99.09%)。LC-MS:(M+H) +實測值216.1。 步驟4. 3-環丙基-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺之合成 A mixture of methyl 3-cyclopropyl-4-(prop-2-yn-1-ylamino)benzoate (4.3 g, 18.75 mmol, 1 eq.) and NaOH (3.75 g, 93.77 mmol, 5 eq.) in MeOH (20 mL) / H 2 O (20 mL) was stirred at 60 °C for 3 h. The mixture residue was acidified to pH 5 with 1 M HCl, and then extracted with DCM (3*300 mL). The combined layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure to give 3-cyclopropyl-4-(prop-2-yn-1-ylamino)benzoic acid (4 g, 99.09%) as an off-white solid. LC-MS: (M+H) + found 216.1. Step 4. Synthesis of 3-cyclopropyl-N-methyl-4-(prop-2-yn-1-ylamino)benzamide
在0℃下,向3-環丙基-4-(丙-2-炔-1-基胺基)苯甲酸(2 g,9.29 mmol,1當量)、甲胺鹽酸鹽(0.94 g,13.94 mmol,1.5當量)及DIEA (4.80 g,37.16 mmol,4當量)於DMF (20 mL)中之攪拌溶液中添加HATU (5.30 g,13.94 mmol,1.5當量)。將所得溶液在室溫下攪拌1 h,然後用水(100mL)稀釋且用DCM (3*100 mL)萃取。合併的層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用CH 2Cl 2/ MeOH (10:1)溶析,以得到呈黃色固體之3-環丙基-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺(2 g,94.29%)。LC-MS:(M+H) +實測值229.1。 中間物27. 3-乙基-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺之合成 步驟1. 4-胺基-3-溴-N-甲基苯甲醯胺之合成 To a stirred solution of 3-cyclopropyl-4-(prop-2-yn-1-ylamino)benzoic acid (2 g, 9.29 mmol, 1 eq.), methylamine hydrochloride (0.94 g, 13.94 mmol, 1.5 eq.) and DIEA (4.80 g, 37.16 mmol, 4 eq.) in DMF (20 mL) at 0 °C was added HATU (5.30 g, 13.94 mmol, 1.5 eq.). The resulting solution was stirred at room temperature for 1 h, then diluted with water (100 mL) and extracted with DCM (3*100 mL). The combined layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with CH 2 Cl 2 / MeOH (10:1) to give 3-cyclopropyl-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (2 g, 94.29%) as a yellow solid. LC-MS: (M+H) + found 229.1. Intermediate 27. Synthesis of 3-ethyl-N-methyl-4-(prop-2-yn-1-ylamino)benzamide Step 1. Synthesis of 4-amino-3-bromo-N-methylbenzamide
在0℃下,向甲胺鹽酸鹽(3.61 g,53.46 mmol,3當量)、4-胺基-3-溴苯甲酸(3.85 g,17.82 mmol,1當量)於DMF (30 mL)中之攪拌溶液中逐份添加DIPEA (13.82 g,106.93 mmol,6當量)及HATU (20.33 g,53.46 mmol,3當量)。將所得溶液在室溫下攪拌1 h。所得溶液藉由具有以下條件(管柱,C18矽膠;移動相,於水中之MeOH,在30 min內0%至100%梯度;偵測器,UV 254 nm)之反相急速層析直接純化,以得到呈白色固體之4-胺基-3-溴-N-甲基苯甲醯胺(3 g,73.49%)。LC-MS:(M+H) +實測值229.0。 步驟2. 4-胺基-3-乙烯基-N-甲基苯甲醯胺之合成 To a stirred solution of methylamine hydrochloride (3.61 g, 53.46 mmol, 3 eq.), 4-amino-3-bromobenzoic acid (3.85 g, 17.82 mmol, 1 eq.) in DMF (30 mL) was added DIPEA (13.82 g, 106.93 mmol, 6 eq.) and HATU (20.33 g, 53.46 mmol, 3 eq.) portionwise at 0° C. The resulting solution was stirred at room temperature for 1 h. The resulting solution was directly purified by reverse phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeOH in water, gradient from 0% to 100% in 30 min; detector, UV 254 nm) to give 4-amino-3-bromo-N-methylbenzamide (3 g, 73.49%) as a white solid. LC-MS: (M+H) + found 229.0. Step 2. Synthesis of 4-amino-3-vinyl-N-methylbenzamide
將4-胺基-3-溴-N-甲基苯甲醯胺(3 g,13.2 mmol,1當量)、2-乙烯基-4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷(3.63 g,23.70 mmol,1.8當量)、Na 2CO 3(4.14 g,39.6 mmol,3當量)及Pd(dppf)Cl 2(956.7 mg,1.32 mmol,0.1當量)於二噁烷(45 mL) / H 2O (4.5 mL)中之混合物在95℃下攪拌3 h。過濾所得混合物,濾餅用DCM洗滌。將濾液在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/於MeOH中之7M NH 3= 20:1)純化,以得到呈白色固體之4-胺基-3-乙烯基-N-甲基苯甲醯胺(3.13 g)。LC-MS:(M+H) +實測值176.2 步驟3. 4-胺基-3-乙基-N-甲基苯甲醯胺之合成 A mixture of 4-amino-3-bromo-N-methylbenzamide (3 g, 13.2 mmol, 1 eq.), 2-vinyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.63 g, 23.70 mmol, 1.8 eq.), Na 2 CO 3 (4.14 g, 39.6 mmol, 3 eq.) and Pd(dppf)Cl 2 (956.7 mg, 1.32 mmol, 0.1 eq.) in dioxane (45 mL)/H 2 O (4.5 mL) was stirred at 95 °C for 3 h. The resulting mixture was filtered and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 /7M NH 3 in MeOH = 20:1) to give 4-amino-3-vinyl-N-methylbenzamide (3.13 g) as a white solid. LC-MS: (M+H) + found 176.2 Step 3. Synthesis of 4-amino-3-ethyl-N-methylbenzamide
將4-胺基-3-乙烯基-N-甲基苯甲醯胺(3.13 g)及10%濕Pd/C (1 g)於MeOH (30 mL)中之混合物在室溫及氫氣氛圍下攪拌1 h。過濾所得混合物,濾餅用DCM洗滌。將濾液在減壓下濃縮。殘餘物藉由具有以下條件(管柱,C18矽膠;移動相,於水中之MeOH,在20 min內0%至100%梯度;偵測器,UV 254 nm)之反相急速層析純化,以得到呈棕色油狀物之4-胺基-3-乙基-N-甲基苯甲醯胺(1.5 g)。LC-MS:(M+H) +實測值178.2。 步驟4. 3-乙基-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺之合成 A mixture of 4-amino-3-vinyl-N-methylbenzamide (3.13 g) and 10% wet Pd/C (1 g) in MeOH (30 mL) was stirred at room temperature under hydrogen atmosphere for 1 h. The resulting mixture was filtered and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeOH in water, gradient from 0% to 100% in 20 min; detector, UV 254 nm) to give 4-amino-3-ethyl-N-methylbenzamide (1.5 g) as a brown oil. LC-MS: (M+H) + found 178.2. Step 4. Synthesis of 3-ethyl-N-methyl-4-(prop-2-yn-1-ylamino)benzamide
將4-胺基-3-乙基-N-甲基苯甲醯胺(1.5 g,8.42 mmol,1當量)、炔丙基溴(3.0 g,25.25 mmol,3當量)及K 2CO 3(2.33 g,16.83 mmol,2當量)於DMF (20 mL)中之混合物在70℃下攪拌隔夜。過濾所得混合物,濾餅用DCM洗滌。將濾液在減壓下濃縮。殘餘物藉由具有以下條件(管柱,C18矽膠;移動相,於水中之MeOH,在20 min內0%至100%梯度;偵測器,UV 254 nm)之反相急速層析純化,以得到呈棕色油狀物之3-乙基-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺(1.3 g,71.42%)。LC-MS:(M+H) +實測值216.1。 中間物28. 3-乙氧基-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺之合成 步驟1. 3-羥基-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺之合成 A mixture of 4-amino-3-ethyl-N-methylbenzamide (1.5 g, 8.42 mmol, 1 eq.), propargyl bromide (3.0 g, 25.25 mmol, 3 eq.) and K 2 CO 3 (2.33 g, 16.83 mmol, 2 eq.) in DMF (20 mL) was stirred at 70° C. overnight. The resulting mixture was filtered and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeOH in water, gradient 0% to 100% in 20 min; detector, UV 254 nm) to give 3-ethyl-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (1.3 g, 71.42%) as a brown oil. LC-MS: (M+H) + found 216.1. Intermediate 28. Synthesis of 3-ethoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide Step 1. Synthesis of 3-hydroxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide
在0℃及氮氣氛圍下,向3-甲氧基-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺( 中間物14;1.9 g,8.70 mmol,1當量) 於DCM (50 mL) 中之攪拌溶液中逐滴添加BBr 3(7.63 g,30.47 mmol,3.5當量,1.0 M於DCM中)。在0℃下攪拌2 h後,用NaOH (水溶液)將混合物鹼化至pH 11。所得混合物用DCM (3*50 mL)洗滌。將濃HCl添加至水相中直至pH為8,然後用EtOAc (3*50 mL)萃取。合併的有機層(EtOAc)經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。粗產物(1.2 g)無需進一步純化即直接使用。LC-MS:(M+H) +實測值:371.0。 步驟2. 3-乙氧基-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺之合成 To a stirred solution of 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide ( intermediate 14 ; 1.9 g, 8.70 mmol, 1 eq) in DCM (50 mL) was added BBr 3 (7.63 g, 30.47 mmol, 3.5 eq, 1.0 M in DCM) dropwise at 0°C under nitrogen atmosphere. After stirring at 0°C for 2 h, the mixture was basified to pH 11 with NaOH (aq). The resulting mixture was washed with DCM (3*50 mL). Concentrated HCl was added to the aqueous phase until pH 8, and then extracted with EtOAc (3*50 mL). The combined organic layers (EtOAc) were dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The crude product (1.2 g) was used directly without further purification. LC-MS: (M+H) + found: 371.0. Step 2. Synthesis of 3-ethoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide
將3-羥基-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺(1.2 g,5.87 mmol,1當量)、碘乙烷(1.37 g,8.81 mmol,1.5當量)及K 2CO 3(2.44 g,17.63 mmol,3當量)於DMF (15 mL)中之混合物在50℃下攪拌1 h。用水(50 mL)淬滅反應混合物且水相用EtOAc (2*100 mL)萃取。合併的有機層經硫酸鈉乾燥,過濾且真空濃縮。殘餘物藉由具有以下條件(管柱,C18矽膠;移動相,於0.1%NH 4HCO 3中之MeOH,在10 min內30%至60%梯度;偵測器,UV 220 nm)之反相急速層析純化,以得到呈黃色固體之3-乙氧基-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺(1 g,73.27%)。 A mixture of 3-hydroxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (1.2 g, 5.87 mmol, 1 eq.), iodoethane (1.37 g, 8.81 mmol, 1.5 eq.) and K 2 CO 3 (2.44 g, 17.63 mmol, 3 eq.) in DMF (15 mL) was stirred at 50 °C for 1 h. The reaction mixture was quenched with water (50 mL) and the aqueous phase was extracted with EtOAc (2*100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeOH in 0.1% NH4HCO3 , gradient 30% to 60% in 10 min; detector, UV 220 nm) to give 3-ethoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (1 g, 73.27%) as a yellow solid.
LC-MS:(M+H) +實測值:233.1。 中間物29. 3-(二氟甲氧基)-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺之合成 步驟1. 3-羥基-4-硝基苯甲醯胺之合成 LC-MS: (M+H) + found: 233.1. Intermediate 29. Synthesis of 3-(difluoromethoxy)-N-methyl-4-(prop-2-yn-1-ylamino)benzamide Step 1. Synthesis of 3-hydroxy-4-nitrobenzamide
在0℃下,向3-羥基-4-硝基苯甲酸(5 g,27.3 mmol,1當量)及HATU (12.5 g,32.8 mmol,1.2當量)於DMF (50 mL)中之攪拌溶液中逐滴添加NH 2Me.HCl (2.76 g,40.9 mmol,1.5當量)及DIEA (10.6 g,81.9 mmol,3當量)。將所得混合物在室溫下再攪拌隔夜。所得混合物用水(100 mL)稀釋且用EtOAc (3*100 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用PE / EA (1:1)溶析,以得到呈黃色固體之3-羥基-4-硝基苯甲醯胺(5.3 g,99.05%)。LC-MS:(M+H) +實測值197.1。 步驟2. 3-(二氟甲氧基)-N-甲基-4-硝基苯甲醯胺之合成 To a stirred solution of 3-hydroxy-4-nitrobenzoic acid (5 g, 27.3 mmol, 1 eq.) and HATU (12.5 g, 32.8 mmol, 1.2 eq.) in DMF (50 mL) at 0°C, NH2Me.HCl (2.76 g, 40.9 mmol, 1.5 eq.) and DIEA (10.6 g, 81.9 mmol, 3 eq.) were added dropwise. The resulting mixture was stirred at room temperature overnight. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (3*100 mL). The combined organic layers were dried over anhydrous Na2SO4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (1:1) to obtain 3-hydroxy-4-nitrobenzamide (5.3 g, 99.05%) as a yellow solid. LC-MS: (M+H) + found 197.1. Step 2. Synthesis of 3-(difluoromethoxy)-N-methyl-4-nitrobenzamide
在室溫下,向3-羥基-N-甲基-4-硝基苯甲醯胺(1 g,5.10 mmol,1當量)及K 2CO 3(1.06 g,7.60 mmol,1.5當量)於DMF (20 mL)中之攪拌溶液中逐滴添加二氟碘甲烷(1.09 g,6.10 mmol,1.2當量)。將所得混合物在室溫及氮氣氛圍下攪拌3 h。所得混合物用水(50 mL)稀釋且用EtOAc (3*50 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用PE / EA (4:1)溶析,以得到呈黃色固體之3-(二氟甲氧基)-N-甲基-4-硝基苯甲醯胺(790 mg,62.95%)。LC-MS:(M+H) +實測值247.1。 步驟3. 4-胺基-3-(二氟甲氧基)-N-甲基苯甲醯胺之合成 To a stirred solution of 3-hydroxy-N-methyl-4-nitrobenzamide (1 g, 5.10 mmol, 1 eq.) and K 2 CO 3 (1.06 g, 7.60 mmol, 1.5 eq.) in DMF (20 mL) was added difluoroiodomethane (1.09 g, 6.10 mmol, 1.2 eq.) dropwise at room temperature. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 3 h. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (3*50 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (4:1) to give 3-(difluoromethoxy)-N-methyl-4-nitrobenzamide (790 mg, 62.95%) as a yellow solid. LC-MS: (M+H) + found 247.1. Step 3. Synthesis of 4-amino-3-(difluoromethoxy)-N-methylbenzamide
將3-(二氟甲氧基)-N-甲基-4-硝基苯甲醯胺(790 mg,3.21 mmol,1當量)、Fe (1.79 g,32.1 mmol,10當量)及NH 4Cl (1.72 g,32.1 mmol,10當量)於EtOH (15 mL)及H 2O (3 mL)中之混合物在70℃下攪拌1.5 h。過濾所得混合物,濾餅用MeOH洗滌。將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用CH 2Cl 2/ MeOH (50:1)溶析,以得到呈黃色固體之4-胺基-3-(二氟甲氧基)-N-甲基苯甲醯胺(670 mg,96.57%)。LC-MS:(M+H) +實測值217.1。 步驟4. 3-(二氟甲氧基)-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺之合成 A mixture of 3-(difluoromethoxy)-N-methyl-4-nitrobenzamide (790 mg, 3.21 mmol, 1 eq.), Fe (1.79 g, 32.1 mmol, 10 eq.) and NH 4 Cl (1.72 g, 32.1 mmol, 10 eq.) in EtOH (15 mL) and H 2 O (3 mL) was stirred at 70° C. for 1.5 h. The resulting mixture was filtered and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with CH 2 Cl 2 / MeOH (50:1) to give 4-amino-3-(difluoromethoxy)-N-methylbenzamide (670 mg, 96.57%) as a yellow solid. LC-MS: (M+H) + found 217.1. Step 4. Synthesis of 3-(difluoromethoxy)-N-methyl-4-(prop-2-yn-1-ylamino)benzamide
將4-胺基-3-(二氟甲氧基)-N-甲基苯甲醯胺(620 mg,2.9 mmol,1當量)、K 2CO 3(1.2 g,8.6 mmol,3當量)及炔丙基溴(682 mg,5.7 mmol,2當量)於DMF (6 mL)中之混合物在70℃下攪拌隔夜。過濾之後,將濾液在減壓下濃縮。殘餘物藉由具有以下條件(管柱,C18矽膠;移動相,於水中之MeCN (10mmol/L NH 4HCO 3),在20 min內10%至50%梯度;偵測器,UV 254 nm)之反相急速層析純化,以得到呈淺黃色固體之3-(二氟甲氧基)-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺(340 mg,46.63%)。LC-MS:(M+H) +實測值255.05。 中間物30. N-甲基-4-(丙-2-炔-1-基胺基)-3-(2,2,2-三氟乙氧基)苯甲醯胺之合成 A mixture of 4-amino-3-(difluoromethoxy)-N-methylbenzamide (620 mg, 2.9 mmol, 1 eq.), K 2 CO 3 (1.2 g, 8.6 mmol, 3 eq.) and propargyl bromide (682 mg, 5.7 mmol, 2 eq.) in DMF (6 mL) was stirred at 70° C. overnight. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH 4 HCO 3 ) in water, gradient 10% to 50% in 20 min; detector, UV 254 nm) to give 3-(difluoromethoxy)-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (340 mg, 46.63%) as a light yellow solid. LC-MS: (M+H) + found 255.05. Intermediate 30. Synthesis of N-methyl-4-(prop-2-yn-1-ylamino)-3-(2,2,2-trifluoroethoxy)benzamide
將3-羥基-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺(200 mg,0.98 mmol,1當量),2-溴乙腈(118 mg,0.98 mmol,2當量)及K 2CO 3(271 mg,1.96 mmol,2當量)於DMF (2 mL)中之混合物在50℃下攪拌1 h。所得混合物用水淬滅且用EtOAc (3*10 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用PE / EA (1:1)溶析,以得到呈白色固體之N-甲基-4-(丙-2-炔-1-基胺基)-3-(2,2,2-三氟乙氧基)苯甲醯胺(214 mg,67.79%)。LC-MS:(M+H) +實測值287.0。 中間物31. 3-(2-甲氧基乙氧基)-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺之合成 A mixture of 3-hydroxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (200 mg, 0.98 mmol, 1 eq), 2-bromoacetonitrile (118 mg, 0.98 mmol, 2 eq) and K 2 CO 3 (271 mg, 1.96 mmol, 2 eq) in DMF (2 mL) was stirred at 50 °C for 1 h. The resulting mixture was quenched with water and extracted with EtOAc (3*10 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (1:1) to give N-methyl-4-(prop-2-yn-1-ylamino)-3-(2,2,2-trifluoroethoxy)benzamide (214 mg, 67.79%) as a white solid. LC-MS: (M+H) + found 287.0. Intermediate 31. Synthesis of 3-(2-methoxyethoxy)-N-methyl-4-(prop-2-yn-1-ylamino)benzamide
4-胺基-3-(2-甲氧基乙氧基)-N-甲基苯甲醯胺(654 mg,2.92 mmol,1當量)、炔丙基溴(694 mg,5.83 mmol,2當量)及DIEA (2.54 mL,14.58 mmol,5當量)於CHCl 3(10 mL)中之混合物在70℃下攪拌隔夜。將所得混合物在減壓下濃縮。殘餘物藉由具有以下條件(管柱,C18矽膠;移動相,於水中之MeCN (0.1% NH 4HCO 3),在25 min內0%至100%梯度;偵測器,UV 254 nm)之反相急速層析純化,以得到呈黃色固體之3-(2-甲氧基乙氧基)-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺(435 mg,54.42%)。LC-MS:(M+H) +實測值263.1。 中間物32. 3-甲氧基-4-(丙-2-炔-1-基胺基)-N,N-雙({[2-(三甲基矽烷基)乙氧基]甲基})苯磺醯胺之合成 步驟1. 3-甲氧基-4-硝基苯磺醯胺之合成 A mixture of 4-amino-3-(2-methoxyethoxy)-N-methylbenzamide (654 mg, 2.92 mmol, 1 eq), propargyl bromide (694 mg, 5.83 mmol, 2 eq) and DIEA (2.54 mL, 14.58 mmol, 5 eq) in CHCl 3 (10 mL) was stirred at 70° C. overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeCN (0.1% NH 4 HCO 3 ) in water, gradient from 0% to 100% in 25 min; detector, UV 254 nm) to give 3-(2-methoxyethoxy)-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (435 mg, 54.42%) as a yellow solid. LC-MS: (M+H) + found 263.1. Intermediate 32. Synthesis of 3-methoxy-4-(prop-2-yn-1-ylamino)-N,N-bis({[2-(trimethylsilyl)ethoxy]methyl})benzenesulfonamide Step 1. Synthesis of 3-methoxy-4-nitrobenzenesulfonamide
在0℃下,向NH 3 .H 2O (80 mL,25%)及THF (80 mL)之攪拌混合物中逐滴添加3-甲氧基-4-硝基苯磺醯氯(900 mg,3.58 mmol,1當量)於THF (5 mL)中之溶液。將所得混合物在0℃下攪拌5 min,然後在室溫下攪拌1 h。將所得混合物在真空下濃縮。殘餘物藉由矽膠管柱層析純化,用PE / EA (1:1)溶析,以得到呈黃色固體之3-甲氧基-4-硝基苯磺醯胺(800 mg,96.33%)。LC-MS:(M+H)+實測值233.0。 步驟2. 3-甲氧基-4-硝基-N,N-雙((2-(三甲基矽烷基)乙氧基)甲基)-苯磺醯胺之合成 To a stirred mixture of NH 3 .H 2 O (80 mL, 25%) and THF (80 mL ) was added dropwise a solution of 3-methoxy-4-nitrobenzenesulfonyl chloride (900 mg, 3.58 mmol, 1 eq) in THF (5 mL) at 0°C. The resulting mixture was stirred at 0°C for 5 min and then at room temperature for 1 h. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with PE/EA (1:1) to give 3-methoxy-4-nitrobenzenesulfonylamine (800 mg, 96.33%) as a yellow solid. LC-MS: (M+H)+ found 233.0. Step 2. Synthesis of 3-methoxy-4-nitro-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)-benzenesulfonamide
將3-甲氧基-4-硝基苯磺醯胺(600 mg,2.58 mmol,1當量)於THF (6 mL)中之溶液在0℃及氮氣氛圍下用NaH (516.7 mg,12.92 mmol,5當量,60%)處理30min,接著在室溫下逐滴添加[2-(氯甲氧基)乙基]三甲基矽烷(1.29 g,7.75 mmol,3當量)。將混合物在室溫及氮氣氛圍下攪拌1h。用水/冰淬滅反應。所得混合物用DCM (3*50 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。粗產物無需進一步純化直接用於下一步驟中。LC-MS:(M+H) +實測值493.2。 步驟3. 4-胺基-3-甲氧基-N,N-雙({[2-(三甲基矽烷基)乙氧基]甲基})-苯磺醯胺之合成 A solution of 3-methoxy-4-nitrobenzenesulfonamide (600 mg, 2.58 mmol, 1 eq.) in THF (6 mL) was treated with NaH (516.7 mg, 12.92 mmol, 5 eq., 60%) at 0 °C under nitrogen atmosphere for 30 min, followed by the dropwise addition of [2-(chloromethoxy)ethyl]trimethylsilane (1.29 g, 7.75 mmol, 3 eq.) at room temperature. The mixture was stirred at room temperature under nitrogen atmosphere for 1 h. The reaction was quenched with water/ice. The resulting mixture was extracted with DCM (3*50 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LC-MS: (M+H) + found 493.2. Step 3. Synthesis of 4-amino-3-methoxy-N,N-bis({[2-(trimethylsilyl)ethoxy]methyl})-benzenesulfonamide
將3-甲氧基-4-硝基-N,N-雙({[2-(三甲基矽烷基)乙氧基]甲基})-苯磺醯胺(60 mg,0.12 mmol,1當量)及Fe (34.0 mg,0.61 mmol,5當量)於乙醇(0.8 mL)及飽和NH 4Cl (0.2 mL)中之溶液在70℃及氮氣氛圍下攪拌1h。使混合物冷卻至室溫且在真空下濃縮。將殘餘物溶解於乙酸乙酯(10 mL)中,然後用3*10 mL之鹽水洗滌。將有機層用無水硫酸鈉乾燥且在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用CH 2Cl 2/ MeOH (10:1)溶析,以得到呈白色固體之4-胺基-3-甲氧基-N,N-雙({[2-(三甲基矽烷基)乙氧基]甲基})苯磺醯胺(40 mg,70.99%)。LC-MS:(M+H) +實測值463.2。 步驟4. 3-甲氧基-4-(丙-2-炔-1-基胺基)-N,N-雙({[2-(三甲基矽烷基)-乙氧基]甲基})苯磺醯胺之合成 A solution of 3-methoxy-4-nitro-N,N-bis({[2-(trimethylsilyl)ethoxy]methyl})-benzenesulfonamide (60 mg, 0.12 mmol, 1 eq.) and Fe (34.0 mg, 0.61 mmol, 5 eq.) in ethanol (0.8 mL) and saturated NH 4 Cl (0.2 mL) was stirred at 70° C. under nitrogen atmosphere for 1 h. The mixture was cooled to room temperature and concentrated under vacuum. The residue was dissolved in ethyl acetate (10 mL), and then washed with 3*10 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with CH2Cl2 /MeOH (10:1) to give 4-amino-3-methoxy-N,N-bis({[2-(trimethylsilyl)ethoxy]methyl})benzenesulfonamide (40 mg, 70.99%) as a white solid. LC-MS: (M+H) + found 463.2. Step 4. Synthesis of 3-methoxy-4-(prop-2-yn-1-ylamino)-N,N-bis({[2-(trimethylsilyl)ethoxy]methyl})benzenesulfonamide
將4-胺基-3-甲氧基-N,N-雙({[2-(三甲基矽烷基)乙氧基]甲基})苯-磺醯胺(1.5 g,3.24 mmol,1當量)、炔丙基溴(1.93 g,16.21 mmol,5當量)、DIPEA (2.09 g,16.21 mmol,5當量)及CHCl 3(15 mL)之混合物在70℃下攪拌隔夜。將所得混合物在減壓下濃縮。殘餘物藉由具有以下條件(管柱,C18矽膠;移動相,於水中之ACN,在30min內0%至100%梯度;偵測器,UV 254 nm)之反向急速層析純化,以得到呈黃色油狀物之3-甲氧基-4-(丙-2-炔-1-基胺基)-N,N-雙({[2-(三甲基矽烷基)乙氧基]甲基})苯磺醯胺(700 mg,43.12%)。 A mixture of 4-amino-3-methoxy-N,N-bis({[2-(trimethylsilyl)ethoxy]methyl})benzene-sulfonamide (1.5 g, 3.24 mmol, 1 eq), propargyl bromide (1.93 g, 16.21 mmol, 5 eq), DIPEA (2.09 g, 16.21 mmol, 5 eq) and CHCl 3 (15 mL) was stirred at 70° C. overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, ACN in water, gradient from 0% to 100% in 30 min; detector, UV 254 nm) to give 3-methoxy-4-(prop-2-yn-1-ylamino)-N,N-bis({[2-(trimethylsilyl)ethoxy]methyl})benzenesulfonamide (700 mg, 43.12%) as a yellow oil.
LC-MS:(M+H) +實測值501.2。 中間物33. 3-甲氧基-N-甲基-4-(丙-2-炔-1-基胺基)-N-{[2-(三甲基矽烷基)乙氧基]甲基}苯磺醯胺之合成 步驟1. 3-甲氧基-N-甲基-4-硝基苯磺醯胺之合成 LC-MS: (M+H) + found 501.2. Intermediate 33. Synthesis of 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide Step 1. Synthesis of 3-methoxy-N-methyl-4-nitrobenzenesulfonamide
在0℃及氮氣氛圍下,向3-甲氧基-4-硝基苯磺醯氯(1 g,3.97 mmol,1當量)於DCM (10 mL)中之攪拌溶液中逐滴添加甲胺(2.98 mL,5.96 mmol,1.5當量,2M於THF中)及TEA (1.21 g,11.92 mmol,3當量)。將所得 混合物在室溫下攪拌1h,然後用水(100 mL)稀釋。所得混合物用CH 2Cl 2(3*100 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮,以得到呈紅色油狀物之3-甲氧基-N-甲基-4-硝基苯磺醯胺(1.03 g),其直接用於下一步驟中。LC-MS:(M+H)+實測值247.0。 2. 3- 甲氧基-N-甲基-4-硝基-N-{[2-(三甲基矽烷基)乙氧基]甲基}苯-磺醯胺之合成 To a stirred solution of 3-methoxy-4-nitrobenzenesulfonyl chloride (1 g, 3.97 mmol, 1 eq) in DCM (10 mL) at 0 °C under nitrogen atmosphere, methylamine (2.98 mL, 5.96 mmol, 1.5 eq, 2M in THF) and TEA (1.21 g, 11.92 mmol, 3 eq) were added dropwise. The resulting mixture was stirred at room temperature for 1 h and then diluted with water (100 mL). The resulting mixture was extracted with CH 2 Cl 2 (3*100 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to obtain 3-methoxy-N-methyl-4-nitrobenzenesulfonamide (1.03 g) as a red oil, which was used directly in the next step. LC-MS: (M+H)+ found 247.0. 2. Synthesis of 3-methoxy-N-methyl-4-nitro-N-{[2-(trimethylsilyl)ethoxy]methyl}benzene-sulfonamide
將3-甲氧基-N-甲基-4-硝基苯磺醯胺(100 mg,0.41 mmol,1當量)於THF (1 mL)中之溶液在0℃及氮氣氛圍下用NaH (32.5 mg,0.81 mmol,2當量,60%)處理30 min,接著在0℃下逐滴添加[2-(氯甲氧基)乙基]三甲基矽烷(101.6 mg,0.61 mmol,1.5當量)。將所得混合物在室溫及氮氣氛圍下攪拌1h。用水/冰淬滅反應。所得混合物用CH 2Cl 2萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮,以得到呈棕色油狀物之3-甲氧基-N-甲基-4-硝基-N-{[2-(三甲基矽烷基)乙氧基]甲基}苯磺醯胺(137 mg,89.60%)。LC-MS:(M+H) +實測值377.1。 步驟3. 4-胺基-3-甲氧基-N-甲基-N-{[2-(三甲基矽烷基)乙氧基]甲基}苯-磺醯胺之合成 A solution of 3-methoxy-N-methyl-4-nitrobenzenesulfonamide (100 mg, 0.41 mmol, 1 eq) in THF (1 mL) was treated with NaH (32.5 mg, 0.81 mmol, 2 eq, 60%) at 0 °C under nitrogen atmosphere for 30 min, followed by the dropwise addition of [2-(chloromethoxy)ethyl]trimethylsilane (101.6 mg, 0.61 mmol, 1.5 eq) at 0 °C. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 h. The reaction was quenched with water/ice. The resulting mixture was extracted with CH 2 Cl 2. The combined organic layers were dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to give 3-methoxy-N-methyl-4-nitro-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide (137 mg, 89.60%) as a brown oil. LC-MS: (M+H) + found 377.1. Step 3. Synthesis of 4-amino-3-methoxy-N-methyl-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide
將3-甲氧基-N-甲基-4-硝基-N-{[2-(三甲基矽烷基)乙氧基]甲基}苯磺醯胺(710 mg,1.89 mmol,1當量)及Fe (44.5 mg,0.80 mmol,5當量)於EtOH (8 mL)及飽和NH 4Cl (2 mL)中之混合物在70℃下攪拌1h。過濾所得混合物,濾餅用CH 2Cl 2洗滌。濾液用水(30 mL)稀釋且用CH 2Cl 2(2*30 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮,以得到呈淺黃色油狀物之4-胺基-3-甲氧基-N-甲基-N-{[2-(三甲基矽烷基)乙氧基]甲基}苯磺醯胺(650 mg,99.47%)。LC-MS:(M+H) +實測值347.1。 步驟4. 3-甲氧基-N-甲基-4-(丙-2-炔-1-基胺基)-N-{[2-(三甲基矽烷基)乙氧基]甲基}苯磺醯胺之合成 A mixture of 3-methoxy-N-methyl-4-nitro-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide (710 mg, 1.89 mmol, 1 eq) and Fe (44.5 mg, 0.80 mmol, 5 eq) in EtOH (8 mL) and saturated NH 4 Cl (2 mL) was stirred at 70 °C for 1 h. The resulting mixture was filtered and the filter cake was washed with CH 2 Cl 2. The filtrate was diluted with water (30 mL) and extracted with CH 2 Cl 2 (2*30 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to obtain 4-amino-3-methoxy-N-methyl-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide (650 mg, 99.47%) as a light yellow oil. LC-MS: (M+H) + found 347.1. Step 4. Synthesis of 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide
將4-胺基-3-甲氧基-N-甲基-N-{[2-(三甲基矽烷基)乙氧基]甲基}苯磺醯胺(600 mg,1.73 mmol,1當量)、DIPEA (1.12 g,8.66 mmol,5當量)及炔丙基溴(1.03 g,8.66 mmol,5當量)於CHCl 3(8 mL)中之混合物在70℃下攪拌隔夜。將混合物冷卻至室溫且在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用PE / EA (5:1)溶析,以得到呈黃色油狀物之3-甲氧基-N-甲基-4-(丙-2-炔-1-基胺基)-N-{[2-(三甲基矽烷基)乙氧基]甲基}苯磺醯胺(400 mg,60.07%)。LC-MS:(M+H) +實測值385.2。 中間物34. 3-甲氧基-N,N-二甲基-4-(丙-2-炔-1-基胺基)苯磺醯胺之合成 步驟1. 3-甲氧基-N,N-二甲基-4-硝基苯磺醯胺之合成 A mixture of 4-amino-3-methoxy-N-methyl-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide (600 mg, 1.73 mmol, 1 eq.), DIPEA (1.12 g, 8.66 mmol, 5 eq.) and propargyl bromide (1.03 g, 8.66 mmol, 5 eq.) in CHCl 3 (8 mL) was stirred at 70° C. overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (5:1) to give 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide (400 mg, 60.07%) as a yellow oil. LC-MS: (M+H) + found 385.2. Intermediate 34. Synthesis of 3-methoxy-N,N-dimethyl-4-(prop-2-yn-1-ylamino)benzenesulfonamide Step 1. Synthesis of 3-methoxy-N,N-dimethyl-4-nitrobenzenesulfonamide
在0℃下,向二甲胺(2 M於THF中) (2.98 mL,5.96 mmol,1.5當量)及Et 3N (2.01 g,19.86 mmol,5當量)於DCM (20 mL)中之攪拌溶液中逐滴添加3-甲氧基-4-硝基苯磺醯氯(1 g,3.97 mmol,1當量)。將所得溶液在室溫下攪拌2 h。將所得溶液在減壓下濃縮,以得到呈黃色固體之3-甲氧基-N,N-二甲基-4-硝基苯磺醯胺(1.7 g)。 步驟2. 4-胺基-3-甲氧基-N,N-二甲基苯磺醯胺之合成 To a stirred solution of dimethylamine (2 M in THF) (2.98 mL, 5.96 mmol, 1.5 eq.) and Et3N (2.01 g, 19.86 mmol, 5 eq.) in DCM (20 mL) at 0°C was added 3-methoxy-4-nitrobenzenesulfonyl chloride (1 g, 3.97 mmol, 1 eq.) dropwise. The resulting solution was stirred at room temperature for 2 h. The resulting solution was concentrated under reduced pressure to give 3-methoxy-N,N-dimethyl-4-nitrobenzenesulfonamide (1.7 g) as a yellow solid. Step 2. Synthesis of 4-amino-3-methoxy-N,N-dimethylbenzenesulfonamide
將3-甲氧基-N,N-二甲基-4-硝基苯磺醯胺(1.7 g,粗物質)及Fe (1.82 g,32.66 mmol)於EtOH (20 mL)/飽和NH 4Cl (5 mL)中之混合物在70℃下攪拌1 h。過濾所得混合物。濾餅用EtOH洗滌。將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用EA溶析,以得到呈黃色固體之4-胺基-3-甲氧基-N,N-二甲基苯磺醯胺(730 mg)。LC-MS:(M+H) +實測值231.05。 步驟3. 3-甲氧基-N,N-二甲基-4-(丙-2-炔-1-基胺基)苯磺醯胺之合成 A mixture of 3-methoxy-N,N-dimethyl-4-nitrobenzenesulfonamide (1.7 g, crude) and Fe (1.82 g, 32.66 mmol) in EtOH (20 mL)/saturated NH 4 Cl (5 mL) was stirred at 70° C. for 1 h. The resulting mixture was filtered. The filter cake was washed with EtOH. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EA to give 4-amino-3-methoxy-N,N-dimethylbenzenesulfonamide (730 mg) as a yellow solid. LC-MS: (M+H) + found 231.05. Step 3. Synthesis of 3-methoxy-N,N-dimethyl-4-(prop-2-yn-1-ylamino)benzenesulfonamide
將4-胺基-3-甲氧基-N,N-二甲基苯磺醯胺(630 mg,2.73 mmol,1當量)、炔丙基溴(1.63 g,13.68 mmol,5當量)及DIEA (1.77 g,13.68 mmol,5當量)於CHCl 3(15 mL)中之混合物在70℃下攪拌隔夜。將所得溶液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用CH 2Cl 2/MeOH (40:1)溶析,以得到呈白色固體之3-甲氧基-N,N-二甲基-4-(丙-2-炔-1-基胺基)苯磺醯胺(230 mg,31.33%)。LC-MS:(M+H) +實測值269.05。 中間物35. 1-(2-甲磺醯基乙基)哌啶-4-胺之合成 步驟1. N-[1-(2-甲磺醯基乙基)哌啶-4-基]胺基甲酸三級丁酯之合成 A mixture of 4-amino-3-methoxy-N,N-dimethylbenzenesulfonamide (630 mg, 2.73 mmol, 1 eq.), propargyl bromide (1.63 g, 13.68 mmol, 5 eq.) and DIEA (1.77 g, 13.68 mmol, 5 eq.) in CHCl 3 (15 mL) was stirred at 70° C. overnight. The resulting solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH 2 Cl 2 /MeOH (40:1) to give 3-methoxy-N,N-dimethyl-4-(prop-2-yn-1-ylamino)benzenesulfonamide (230 mg, 31.33%) as a white solid. LC-MS: (M+H) + found 269.05. Intermediate 35. Synthesis of 1-(2-methylsulfonylethyl)piperidin-4-amine Step 1. Synthesis of tert-butyl N-[1-(2-methylsulfonylethyl)piperidin-4-yl]carbamate
在室溫下,向N-(哌啶-4-基)胺基甲酸三級丁酯(4.3 g,21.47 mmol,1當量)及TEA (10.3 g,101.79 mmol,4.74當量)於EtOH (50 mL)中之攪拌溶液中逐份添加甲基乙烯碸(5.4 g,50.88 mmol,2.37當量)。將所得混合物在 室溫下攪拌4 h,然後在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用CH 2Cl 2/ MeOH (1:20)溶析,以得到呈白色固體之N-[1-(2-甲磺醯基乙基)哌啶-4-基]胺基甲酸三級丁酯(5 g,76.0%)。LC-MS:(M+H) +實測值306.4。 步驟2. 1-(2-甲磺醯基乙基)哌啶-4-胺鹽酸鹽之合成 To a stirred solution of tert-butyl N-(piperidin-4-yl)carbamate (4.3 g, 21.47 mmol, 1 eq.) and TEA (10.3 g, 101.79 mmol, 4.74 eq.) in EtOH (50 mL) was added methylvinyl sulfide (5.4 g, 50.88 mmol, 2.37 eq.) portionwise at room temperature. The resulting mixture was stirred at room temperature for 4 h and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 /MeOH (1:20) to give tert-butyl N-[1-( 2 -methylsulfonylethyl)piperidin-4-yl]carbamate (5 g, 76.0%) as a white solid. LC-MS: (M+H) + found 306.4. Step 2. Synthesis of 1-(2-methylsulfonylethyl)piperidin-4-amine hydrochloride
在室溫下,向N-[1-(2-甲磺醯基乙基)哌啶-4-基]胺基甲酸三級丁酯(1 g,21.21 mmol,1當量) 於DCM (10 mL) 中之攪拌溶液中添加TFA (10 mL)。將所得溶液在室溫下攪拌1 h,然後在減壓下濃縮。將殘餘物用DCM溶解且用TEA鹼化。將所得溶液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用CH 2Cl 2/ MeOH (1:20)溶析,以得到呈白色固體之1-(2-甲磺醯基乙基)哌啶-4-胺(800 mg,53.87%)。LC-MS:(M+H) +實測值206.4。 中間物36. 4-(乙磺醯基)-2-甲氧基-N-(丙-2-炔-1-基)苯胺之合成 步驟1. 4-(乙基硫基)-2-甲氧基-1-硝基苯之合成 To a stirred solution of tributyl N-[1-(2-methylsulfonylethyl)piperidin-4-yl]carbamate (1 g, 21.21 mmol, 1 eq.) in DCM (10 mL) was added TFA (10 mL) at room temperature. The resulting solution was stirred at room temperature for 1 h and then concentrated under reduced pressure. The residue was dissolved with DCM and basified with TEA. The resulting solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 /MeOH (1:20) to give 1-(2-methylsulfonylethyl)piperidin-4-amine (800 mg, 53.87%) as a white solid. LC-MS: (M+H) + found 206.4. Intermediate 36. Synthesis of 4-(ethylsulfonyl)-2-methoxy-N-(prop-2-yn-1-yl)aniline Step 1. Synthesis of 4-(ethylthio)-2-methoxy-1-nitrobenzene
在0℃下,向4-氟-2-甲氧基-1-硝基苯(3 g,17.53 mmol,1當量)於DMF (30 mL)中之攪拌溶液中逐份添加(乙基硫基)鈉(1.92 g,22.79 mmol,1.3當量)。將所得混合物在室溫下攪拌隔夜。在0℃下用飽和NH 4Cl淬滅反應。水層用EtOAc (3*200 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用PE / EA (3:1)溶析,以得到呈黃色固體之4-(乙基硫基)-2-甲氧基-1-硝基苯(2.9 g,77.57%)。LC-MS:(M+H) +實測值213.9。 步驟2. 4-(乙基磺醯基)-2-甲氧基-1-硝基苯之合成 To a stirred solution of 4-fluoro-2-methoxy-1-nitrobenzene (3 g, 17.53 mmol, 1 eq.) in DMF (30 mL) at 0°C was added (ethylthio)sodium (1.92 g, 22.79 mmol, 1.3 eq.) portionwise. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with saturated NH 4 Cl at 0°C. The aqueous layer was extracted with EtOAc (3*200 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (3:1) to give 4-(ethylsulfanyl)-2-methoxy-1-nitrobenzene (2.9 g, 77.57%) as a yellow solid. LC-MS: (M+H) + found 213.9. Step 2. Synthesis of 4-(ethylsulfonyl)-2-methoxy-1-nitrobenzene
將4-(乙基硫基)-2-甲氧基-1-硝基苯(2.9 g,13.60 mmol,1當量)及過硫酸氫鉀(14.13 g,40.797 mmol,3當量)於丙酮(10 mL)/MeOH (1 mL)/H 2O (10 mL)中之混合物在室溫下攪拌3 h。將反應在0℃下用飽和次亞硫酸鈉淬滅。水層用EtOAc (3*100 mL)萃取。將所得混合物在減壓下濃縮。粗產物無需進一步純化直接用於下一步驟中。 步驟3. 4-(乙基磺醯基)-2-甲氧基苯胺之合成 A mixture of 4-(ethylsulfanyl)-2-methoxy-1-nitrobenzene (2.9 g, 13.60 mmol, 1 eq.) and potassium persulfate (14.13 g, 40.797 mmol, 3 eq.) in acetone (10 mL)/MeOH (1 mL)/H 2 O (10 mL) was stirred at room temperature for 3 h. The reaction was quenched with saturated sodium hyposulfite at 0°C. The aqueous layer was extracted with EtOAc (3*100 mL). The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. Step 3. Synthesis of 4-(ethylsulfonyl)-2-methoxyaniline
將4-(乙磺醯基)-2-甲氧基-1-硝基苯(3.1 g,12.64 mmol,1當量)及Fe (3.53 g,63.20 mmol,5當量)於EtOH (20 mL)/飽和NH 4Cl (5 mL)中之混合物在70℃下攪拌1 h。過濾所得混合物,濾餅用EtOH洗滌。將濾液在減壓下濃縮。所得混合物用EtOAc (3*100mL)萃取。有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。粗產物(2.6g)無需進一步純化直接用於下一步驟中。LC-MS:(M+H) +實測值216.0。 步驟4. 4-(乙磺醯基)-2-甲氧基-N-(丙-2-炔-1-基)苯胺之合成 A mixture of 4-(ethylsulfonyl)-2-methoxy-1-nitrobenzene (3.1 g, 12.64 mmol, 1 eq.) and Fe (3.53 g, 63.20 mmol, 5 eq.) in EtOH (20 mL)/saturated NH 4 Cl (5 mL) was stirred at 70° C. for 1 h. The resulting mixture was filtered and the filter cake was washed with EtOH. The filtrate was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (3*100 mL). The organic layer was dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (2.6 g) was used directly in the next step without further purification. LC-MS: (M+H) + found 216.0. Step 4. Synthesis of 4-(ethylsulfonyl)-2-methoxy-N-(prop-2-yn-1-yl)aniline
將4-(乙磺醯基)-2-甲氧基苯胺(1 g,4.65 mmol,1當量)、K 2CO 3(1.93 g,13.93 mmol,3當量)及炔丙基溴(552.6 mg,4.64 mmol,1當量)於DMF (10 mL)中之混合物在70℃下攪拌隔夜。過濾所得混合物。濾餅用DCM洗滌。將濾液在減壓下濃縮。殘餘物藉由具有以下條件(管柱,C18矽膠;移動相,於水中之MeOH (10mmol/L NH 4HCO 3),在30 min內0%至80%梯度;偵測器,UV 254 nm)之反相急速層析純化,以得到呈白色固體之4-(乙磺醯基)-2-甲氧基-N-(丙-2-炔-1-基)苯胺(400 mg,34%)。LC-MS:(M+H) +實測值254.2。 中間物37. 4-(環丙烷磺醯基)-2-甲氧基-N-(丙-2-炔-1-基)苯胺之合成 步驟1. 4-(環丙烷磺醯基)-2-甲氧基苯胺之合成 A mixture of 4-(ethylsulfonyl)-2-methoxyaniline (1 g, 4.65 mmol, 1 eq.), K 2 CO 3 (1.93 g, 13.93 mmol, 3 eq.) and propargyl bromide (552.6 mg, 4.64 mmol, 1 eq.) in DMF (10 mL) was stirred at 70° C. overnight. The resulting mixture was filtered. The filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeOH (10 mmol/L NH 4 HCO 3 ) in water, gradient 0% to 80% in 30 min; detector, UV 254 nm) to give 4-(ethylsulfonyl)-2-methoxy-N-(prop-2-yn-1-yl)aniline (400 mg, 34%) as a white solid. LC-MS: (M+H) + found 254.2. Intermediate 37. Synthesis of 4-(cyclopropanesulfonyl)-2-methoxy-N-(prop-2-yn-1-yl)aniline Step 1. Synthesis of 4-(cyclopropanesulfonyl)-2-methoxyaniline
將4-溴-2-甲氧基苯胺(2 g,9.90 mmol,1當量)、環丙烷亞磺酸鈉(2.54 g,19.80 mmol,2當量)、CuI (1.89 g,9.90 mmol,1當量)、NaOH (395.9 mg,9.90 mmol,1當量)及吡咯啶-2-甲酸(569.8 mg,4.95 mmol,0.50當量)於DMSO (20 mL)中之溶液在90℃及氮氣氛圍下攪拌隔夜。使混合物冷卻至室溫。過濾所得混合物,濾餅用EtOAc洗滌。濾液用水(200 mL)稀釋且用EtOAc (3*100 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用PE / EA (1:1)溶析,以得到呈黃色固體之4-(環丙烷磺醯基)-2-甲氧基苯胺(1.63 g,72.45%)。LC-MS:(M-H) -實測值228.1。 步驟2. 4-(環丙烷磺醯基)-2-甲氧基-N-(丙-2-炔-1-基)苯胺之合成 A solution of 4-bromo-2-methoxyaniline (2 g, 9.90 mmol, 1 eq.), sodium cyclopropanesulfinate (2.54 g, 19.80 mmol, 2 eq.), CuI (1.89 g, 9.90 mmol, 1 eq.), NaOH (395.9 mg, 9.90 mmol, 1 eq.) and pyrrolidine-2-carboxylic acid (569.8 mg, 4.95 mmol, 0.50 eq.) in DMSO (20 mL) was stirred at 90 °C under nitrogen atmosphere overnight. The mixture was cooled to room temperature. The resulting mixture was filtered and the filter cake was washed with EtOAc. The filtrate was diluted with water (200 mL) and extracted with EtOAc (3*100 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (1:1) to obtain 4-(cyclopropanesulfonyl)-2-methoxyaniline (1.63 g, 72.45%) as a yellow solid. LC-MS: (MH) - found 228.1. Step 2. Synthesis of 4-(cyclopropanesulfonyl)-2-methoxy-N-(prop-2-yn-1-yl)aniline
將4-(環丙烷磺醯基)-2-甲氧基苯胺(1.5 g,6.60 mmol,1當量)、K 2CO 3(2.74 g,19.80 mmol,3當量)及炔丙基溴(3.93 g,33.00 mmol,5當量)於DMF (15 mL)中之混合物在70℃下攪拌隔夜。使混合物冷卻至室溫。過濾所得混合物,濾餅用DCM洗滌。將濾液在減壓下濃縮。殘餘物藉由具有以下條件(管柱,C18矽膠;移動相,於水中之MeOH,在20 min內0%至100%梯度;偵測器,UV 254 nm)之反相急速層析純化,以得到呈黃色固體之4-(環丙烷磺醯基)-2-甲氧基-N-(丙-2-炔-1-基)苯胺(955 mg,54.54%)。LC-MS:(M+H) +實測值266.0。 中間物38. 2-氟-4-甲磺醯基-N-(丙-2-炔-1-基)苯胺之合成 A mixture of 4-(cyclopropanesulfonyl)-2-methoxyaniline (1.5 g, 6.60 mmol, 1 eq.), K 2 CO 3 (2.74 g, 19.80 mmol, 3 eq.) and propargyl bromide (3.93 g, 33.00 mmol, 5 eq.) in DMF (15 mL) was stirred at 70 °C overnight. The mixture was cooled to room temperature. The resulting mixture was filtered and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeOH in water, gradient 0% to 100% in 20 min; detector, UV 254 nm) to give 4-(cyclopropanesulfonyl)-2-methoxy-N-(prop-2-yn-1-yl)aniline (955 mg, 54.54%) as a yellow solid. LC-MS: (M+H) + found 266.0. Intermediate 38. Synthesis of 2-fluoro-4-methylsulfonyl-N-(prop-2-yn-1-yl)aniline
將2-氟-4-甲磺醯基苯胺(1 g,5.29 mmol,1當量)、K 2CO 3(2.21 g,15.86 mmol,3當量)及炔丙基溴(3.14 g,26.43 mmol,5當量)於DMF (10 mL) 中之混合物在70℃下攪拌隔夜。過濾所得混合物,濾餅用DCM洗滌。將濾液在減壓下濃縮。殘餘物藉由具有以下條件(管柱,C18矽膠;移動相,於水中之MeOH (10mmol/L NH 4HCO 3),在30min內0%至100%梯度;偵測器,UV 254 nm)之反相急速層析純化,以得到呈白色固體之2-氟-4-甲磺醯基-N-(丙-2-炔-1-基)苯胺(360 mg,29.97%)。LC-MS:(M-H) -實測值226.1。 中間物39. 4-甲磺醯基-2-甲氧基-N-(丙-2-炔-1-基)苯胺之合成 A mixture of 2-fluoro-4-methanesulfonylaniline (1 g, 5.29 mmol, 1 eq.), K 2 CO 3 (2.21 g, 15.86 mmol, 3 eq.) and propargyl bromide (3.14 g, 26.43 mmol, 5 eq.) in DMF (10 mL) was stirred at 70° C. overnight. The resulting mixture was filtered and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeOH (10 mmol/L NH 4 HCO 3 ) in water, gradient from 0% to 100% in 30 min; detector, UV 254 nm) to give 2-fluoro-4-methylsulfonyl-N-(prop-2-yn-1-yl)aniline (360 mg, 29.97%) as a white solid. LC-MS: (MH) - found 226.1. Intermediate 39. Synthesis of 4-methylsulfonyl-2-methoxy-N-(prop-2-yn-1-yl)aniline
在室溫下,向4-甲磺醯基-2-甲氧基苯胺(5.0 g,24.87 mmol,1當量)及炔丙基溴(2.94 g,24.87 mmol,1當量)於DMF (50 mL)中之攪拌混合物中逐份添加K 2CO 3(6.86 g,49.74 mmol,2當量)。將所得混合物在70℃及氮氣氛圍下攪拌隔夜。可藉由LCMS偵測所需產物。濾出固體,並且將濾液用水稀釋且用EtOAc (3 x 50mL)萃取。合併的有機層用鹽水(50 mL)洗滌、經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由反相層析純化,用MeOH/H 2O溶析,以得到呈淺黃色固體之4-甲磺醯基-2-甲氧基-N-(丙-2-炔-1-基)苯胺(2.4 g,40.38%)。LC-MS:(M+H) +實測值240.0。 中間物40. 4-甲磺醯基-N-(丙-2-炔-1-基)苯胺之合成 To a stirred mixture of 4-methanesulfonyl-2-methoxyaniline (5.0 g, 24.87 mmol, 1 eq.) and propargyl bromide (2.94 g, 24.87 mmol, 1 eq.) in DMF (50 mL) was added K 2 CO 3 (6.86 g, 49.74 mmol, 2 eq.) portionwise at room temperature. The resulting mixture was stirred at 70 °C under nitrogen atmosphere overnight. The desired product could be detected by LCMS. The solid was filtered off, and the filtrate was diluted with water and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography and eluted with MeOH/H 2 O to give 4-methanesulfonyl-2-methoxy-N-(prop-2-yn-1-yl)aniline (2.4 g, 40.38%) as a light yellow solid. LC-MS: (M+H) + found 240.0. Intermediate 40. Synthesis of 4-methanesulfonyl-N-(prop-2-yn-1-yl)aniline
將4-甲基磺醯基苯胺(1 g,5.84 mmol,1當量)、炔丙基溴(4.86 g,40.89 mmol,7當量)及K 2CO 3(4.04 g,29.20 mmol,5當量)於DMF (10 mL)中之混合物在70℃下攪拌3 h。過濾所得混合物,濾餅用CH 2Cl 2洗滌。將濾液在減壓下濃縮。殘餘物藉由反相急速層析(管柱,C18矽膠;移動相,於水中之MeCN (10mmol/L NH 4HCO 3),在20 min內0%至100%梯度;偵測器,UV 254 nm)純化,以得到呈黃色固體之4-甲磺醯基-N-(丙-2-炔-1-基)苯胺(790 mg,64.64%)。LC-MS:(M-H) -實測值208.0。 中間物41. 2-甲氧基-N-(丙-2-炔-1-基)-4-(丙烷-2-磺醯基)苯胺之合成 步驟1. 異丙基(3-甲氧基-4-硝基苯基)硫烷之合成 A mixture of 4-methylsulfonylaniline (1 g, 5.84 mmol, 1 eq.), propargyl bromide (4.86 g, 40.89 mmol, 7 eq.) and K 2 CO 3 (4.04 g, 29.20 mmol, 5 eq.) in DMF (10 mL) was stirred at 70 °C for 3 h. The resulting mixture was filtered and the filter cake was washed with CH 2 Cl 2. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH 4 HCO 3 ) in water, gradient from 0% to 100% in 20 min; detector, UV 254 nm) to give 4-methylsulfonyl-N-(prop-2-yn-1-yl)aniline (790 mg, 64.64%) as a yellow solid. LC-MS: (MH) - found 208.0. Intermediate 41. Synthesis of 2-methoxy-N-(prop-2-yn-1-yl)-4-(propane-2-sulfonyl)aniline Step 1. Synthesis of isopropyl (3-methoxy-4-nitrophenyl) sulfane
在0℃下,向4-氟-2-甲氧基-1-硝基苯(10 g,58.44 mmol,1當量)於DMF (100 mL)中之攪拌溶液中逐份添加(異丙基硫基)鈉(7.46 g,75.97 mmol,1.3當量)。將所得混合物在室溫下攪拌3 h,然後用水淬滅。所得溶液用DCM (3*700 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮,以得到呈灰色油狀物之異丙基(3-甲氧基-4-硝基苯基)硫烷(21 g)。 步驟2. 2-甲氧基-1-硝基-4-(丙烷-2-磺醯基)苯之合成 To a stirred solution of 4-fluoro-2-methoxy-1-nitrobenzene (10 g, 58.44 mmol, 1 eq.) in DMF (100 mL) at 0 °C was added sodium (isopropylsulfanyl) (7.46 g, 75.97 mmol, 1.3 eq.) portionwise. The resulting mixture was stirred at room temperature for 3 h and then quenched with water. The resulting solution was extracted with DCM (3*700 mL). The combined organic layers were dried over anhydrous Na2SO4 . After filtration, the filtrate was concentrated under reduced pressure to give isopropyl (3-methoxy-4-nitrophenyl) sulfane (21 g) as a grey oil. Step 2. Synthesis of 2-methoxy-1-nitro-4-(propane-2-sulfonyl)benzene
在室溫下,向4-(異丙基硫基)-2-甲氧基-1-硝基苯(21 g)於丙酮(100 mL)/H 2O (100 mL)/MeOH (10 mL)中之攪拌溶液中逐份添加過硫酸氫鉀(103.58 g)。將所得混合物在室溫下攪拌2 h,然後過濾。濾餅用MeOH洗滌。用 飽和NaS 2O 3淬滅濾液。所得溶液用EtOAc (3*700 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮,以得到呈白色固體之2-甲氧基-1-硝基-4-(丙烷-2-磺醯基)苯(7 g,21.91%)。 步驟3. 2-甲氧基-4-(丙烷-2-磺醯基)苯胺之合成 To a stirred solution of 4-(isopropylthio)-2-methoxy-1-nitrobenzene (21 g) in acetone (100 mL)/H 2 O (100 mL)/MeOH (10 mL) was added potassium persulfate (103.58 g) portionwise at room temperature. The resulting mixture was stirred at room temperature for 2 h and then filtered. The filter cake was washed with MeOH. The filtrate was quenched with saturated NaS 2 O 3. The resulting solution was extracted with EtOAc (3*700 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to obtain 2-methoxy-1-nitro-4-(propane-2-sulfonyl)benzene (7 g, 21.91%) as a white solid. Step 3. Synthesis of 2-methoxy-4-(propane-2-sulfonyl)aniline
將2-甲氧基-1-硝基-4-(丙烷-2-磺醯基)苯(4 g,15.43 mmol,1當量)及Pd/C (1 g,0.94 mmol,0.06當量,10 wt%)於MeOH (40 mL)中之混合物在室溫及氫氣氛圍下攪拌隔夜。過濾所得混合物,濾餅用MeOH洗滌。將濾液在減壓下濃縮,以得到呈黃色固體之2-甲氧基-4-(丙烷-2-磺醯基)苯胺(3.1 g,87.64%)。LC-MS:(M+H) +實測值230.1。 步驟4. 2-甲氧基-N-(丙-2-炔-1-基)-4-(丙烷-2-磺醯基)苯胺之合成 A mixture of 2-methoxy-1-nitro-4-(propane-2-sulfonyl)benzene (4 g, 15.43 mmol, 1 eq.) and Pd/C (1 g, 0.94 mmol, 0.06 eq., 10 wt%) in MeOH (40 mL) was stirred at room temperature under hydrogen atmosphere overnight. The resulting mixture was filtered and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure to give 2-methoxy-4-(propane-2-sulfonyl)aniline (3.1 g, 87.64%) as a yellow solid. LC-MS: (M+H) + found 230.1. Step 4. Synthesis of 2-methoxy-N-(prop-2-yn-1-yl)-4-(propane-2-sulfonyl)aniline
將2-甲氧基-4-(丙烷-2-磺醯基)苯胺(1.5 g,6.54 mmol,1當量)、炔丙基溴(2.34 g,19.69 mmol,3.01當量)及K 2CO 3(2.70 g,19.56 mmol,2.99當量)於DMF (15 mL)中之混合物在70℃下攪拌隔夜。過濾所得混合物,濾餅用DCM洗滌。將濾液在減壓下濃縮。殘餘物藉由反相急速層析(管柱,C18矽膠;移動相,於水中之MeOH,在20 min內0%至100%梯度;偵測器,UV 254 nm)純化,以得到呈黃色固體之2-甲氧基-N-(丙-2-炔-1-基)-4-(丙烷-2-磺醯基)苯胺(800 mg,45.74%)。LC-MS:(M-H) -實測值266.1。 中間物42. 5-甲磺醯基-2-甲氧基-N-(丙-2-炔-1-基)苯胺之合成 A mixture of 2-methoxy-4-(propane-2-sulfonyl)aniline (1.5 g, 6.54 mmol, 1 eq.), propargyl bromide (2.34 g, 19.69 mmol, 3.01 eq.) and K 2 CO 3 (2.70 g, 19.56 mmol, 2.99 eq.) in DMF (15 mL) was stirred at 70° C. overnight. The resulting mixture was filtered and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeOH in water, gradient 0% to 100% in 20 min; detector, UV 254 nm) to give 2-methoxy-N-(prop-2-yn-1-yl)-4-(propane-2-sulfonyl)aniline (800 mg, 45.74%) as a yellow solid. LC-MS: (MH) - found 266.1. Intermediate 42. Synthesis of 5-methanesulfonyl-2-methoxy-N-(prop-2-yn-1-yl)aniline
將5-甲磺醯基-2-甲氧基苯胺(1 g,4.97 mmol,1當量)、炔丙基溴(591.1 mg,4.97 mmol,1當量)及K 2CO 3(2.06 g,14.91 mmol,3當量)於DMF (10 mL)中之混合物在70℃下攪拌16 h。反應混合物用水(200 mL)淬滅且用EtOAc (2*200 mL)萃取。合併的有機層經硫酸鈉乾燥,過濾且真空濃縮。殘餘物藉由反相急速層析(管柱,C18矽膠;移動相,於水中之MeOH (0.1%NH 4HCO 3),在10 min內25%至30%梯度;偵測器,UV 220 nm)純化,以得到呈灰白色固體之5-甲磺醯基-2-甲氧基-N-(丙-2-炔-1-基)苯胺(600 mg,50.46%)。LC-MS:(M+H) +實測值:240.0。 中間物43. 6-甲氧基-N-甲基-5-(丙-2-炔-1-基胺基)吡啶-2-甲醯胺之合成 步驟1. 6-甲氧基-N-甲基-5-硝基吡啶-2-甲醯胺之合成 A mixture of 5-methanesulfonyl-2-methoxyaniline (1 g, 4.97 mmol, 1 eq), propargyl bromide (591.1 mg, 4.97 mmol, 1 eq) and K 2 CO 3 (2.06 g, 14.91 mmol, 3 eq) in DMF (10 mL) was stirred at 70 °C for 16 h. The reaction mixture was quenched with water (200 mL) and extracted with EtOAc (2*200 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeOH (0.1% NH 4 HCO 3 ) in water, gradient 25% to 30% in 10 min; detector, UV 220 nm) to give 5-methylsulfonyl-2-methoxy-N-(prop-2-yn-1-yl)aniline (600 mg, 50.46%) as an off-white solid. LC-MS: (M+H) + found: 240.0. Intermediate 43. Synthesis of 6-methoxy-N-methyl-5-(prop-2-yn-1-ylamino)pyridine-2-carboxamide Step 1. Synthesis of 6-methoxy-N-methyl-5-nitropyridine-2-carboxamide
在0℃下,向6-甲氧基-5-硝基吡啶-2-甲酸(3 g,15.14 mmol,1當量)、甲胺鹽酸鹽(1.53 g,22.71 mmol,1.5當量)及DIPEA (9.78 g,75.70 mmol,5當量)於DMF (20 mL)中之攪拌溶液中添加HATU (8.64 g,22.71 mmol,1.5當量)。將所得溶液在室溫下攪拌2 h,然後藉由反相急速層析(管柱,C18矽膠;移動相,於水中之MeOH (0.1% FA),在30 min內0至100%梯度;偵測器,UV 254 nm)純化,以得到呈黃色固體之6-甲氧基-N-甲基-5-硝基吡啶-2-甲醯胺(3 g,93.82%)。LC-MS:(M+H) +實測值212.1。 步驟2. 5-胺基-6-甲氧基-N-甲基吡啶-2-甲醯胺之合成 To a stirred solution of 6-methoxy-5-nitropyridine-2-carboxylic acid (3 g, 15.14 mmol, 1 eq), methylamine hydrochloride (1.53 g, 22.71 mmol, 1.5 eq) and DIPEA (9.78 g, 75.70 mmol, 5 eq) in DMF (20 mL) at 0 °C was added HATU (8.64 g, 22.71 mmol, 1.5 eq). The resulting solution was stirred at room temperature for 2 h and then purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeOH (0.1% FA) in water, gradient 0 to 100% in 30 min; detector, UV 254 nm) to give 6-methoxy-N-methyl-5-nitropyridine-2-carboxamide (3 g, 93.82%) as a yellow solid. LC-MS: (M+H) + found 212.1. Step 2. Synthesis of 5-amino-6-methoxy-N-methylpyridine-2-carboxamide
將6-甲氧基-N-甲基-5-硝基吡啶-2-甲醯胺(3 g,14.21 mmol,1當量)及Pd/C (3.02 g,28.41 mmol,2當量)於MeOH (25 mL)中之混合物在室溫及氫氣氛圍下攪拌3 h。過濾所得混合物且濾餅用MeOH洗滌。將濾液在減壓下濃縮,以得到呈白色固體之5-胺基-6-甲氧基-N-甲基吡啶-2-甲醯胺(2.5 g,97.12%)。LC-MS:(M+H) +實測值182.2。 步驟3. 6-甲氧基-N-甲基-5-(丙-2-炔-1-基胺基)吡啶-2-甲醯胺之合成 A mixture of 6-methoxy-N-methyl-5-nitropyridine-2-carboxamide (3 g, 14.21 mmol, 1 eq.) and Pd/C (3.02 g, 28.41 mmol, 2 eq.) in MeOH (25 mL) was stirred at room temperature under hydrogen atmosphere for 3 h. The resulting mixture was filtered and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure to give 5-amino-6-methoxy-N-methylpyridine-2-carboxamide (2.5 g, 97.12%) as a white solid. LC-MS: (M+H) + found 182.2. Step 3. Synthesis of 6-methoxy-N-methyl-5-(prop-2-yn-1-ylamino)pyridine-2-carboxamide
將5-胺基-6-甲氧基-N-甲基吡啶-2-甲醯胺(1 g,5.52 mmol,1當量)、炔丙基溴(1.31 g,11.04 mmol,2當量)及K 2CO 3(2.29 g,16.56 mmol,3當量)於DMF (20 mL)中之混合物在65℃下攪拌隔夜。 過濾所得混合物,濾餅用EtOAc洗滌。將濾液在減壓下濃縮。殘餘物藉由反相急速層析(管柱,C18矽膠;移動相,於水中之MeCN (10mmol/L NH 4HCO 3),在20 min內0%至100%梯度;偵測器,UV 254 nm)純化,以得到呈黃色固體之6-甲氧基-N-甲基-5-(丙-2-炔-1-基胺基)吡啶-2-甲醯胺(500 mg,41.32%)。LC-MS:(M+H) +實測值220.1。 中間物44. 6-甲氧基-5-(丙-2-炔-1-基胺基)-2,3-二氫異吲哚-1-酮之合成 步驟1. 6-甲氧基-5-硝基-2,3-二氫異吲哚-1-酮之合成 A mixture of 5-amino-6-methoxy-N-methylpyridine-2-carboxamide (1 g, 5.52 mmol, 1 eq.), propargyl bromide (1.31 g, 11.04 mmol, 2 eq.) and K 2 CO 3 (2.29 g, 16.56 mmol, 3 eq.) in DMF (20 mL) was stirred at 65° C. overnight. The resulting mixture was filtered and the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH 4 HCO 3 ) in water, gradient 0% to 100% in 20 min; detector, UV 254 nm) to give 6-methoxy-N-methyl-5-(prop-2-yn-1-ylamino)pyridine-2-carboxamide (500 mg, 41.32%) as a yellow solid. LC-MS: (M+H) + found 220.1. Intermediate 44. Synthesis of 6-methoxy-5-(prop-2-yn-1-ylamino)-2,3-dihydroisoindol-1-one Step 1. Synthesis of 6-methoxy-5-nitro-2,3-dihydroisoindol-1-one
在0℃下,向6-甲氧基-2,3-二氫異吲哚-1-酮(10 g,61.28 mmol,1當量)於TFAA (50 mL)/ACN (50 mL)中之攪拌溶液中逐滴添加HNO 3(3.90 g,61.90 mmol,1.01當量)。將所得混合物在0℃下攪拌1 h,然後用水稀釋。用飽和NaHCO 3(水溶液)將溶液鹼化至pH 8。過濾所得混合物,濾餅用DCM洗滌。濾液用CH 2Cl 2(3*200 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮,以得到呈灰白色固體之6-甲氧基-5-硝基-2,3-二氫異吲哚-1-酮(8 g,62.71%)。LC-MS:(M+H) +實測值209.0。 步驟2. 5-胺基-6-甲氧基-2,3-二氫異吲哚-1-酮之合成 To a stirred solution of 6-methoxy-2,3-dihydroisoindol-1-one (10 g, 61.28 mmol, 1 eq.) in TFAA (50 mL)/ACN (50 mL) was added HNO 3 (3.90 g, 61.90 mmol, 1.01 eq.) dropwise at 0°C. The resulting mixture was stirred at 0°C for 1 h and then diluted with water. The solution was basified to pH 8 with saturated NaHCO 3 (aq.). The resulting mixture was filtered and the filter cake was washed with DCM. The filtrate was extracted with CH 2 Cl 2 (3*200 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to obtain 6-methoxy-5-nitro-2,3-dihydroisoindol-1-one (8 g, 62.71%) as an off-white solid. LC-MS: (M+H) + found 209.0. Step 2. Synthesis of 5-amino-6-methoxy-2,3-dihydroisoindol-1-one
將6-甲氧基-5-硝基-2,3-二氫異吲哚-1-酮(8 g,38.43 mmol,1當量)及Pd/C (2.0 g,1.88 mmol,0.05當量,10wt%)於MeOH (80 mL)中之混合物在室溫及氫氣氛圍下攪拌隔夜。過濾所得混合物,濾餅用MeOH洗滌。將濾液在減壓下濃縮,以得到呈灰白色固體之5-胺基-6-甲氧基-2,3-二氫異吲哚-1-酮(1.35 g,19.71%)。LC-MS:(M+H) +實測值179.0。 A mixture of 6-methoxy-5-nitro-2,3-dihydroisoindol-1-one (8 g, 38.43 mmol, 1 eq.) and Pd/C (2.0 g, 1.88 mmol, 0.05 eq., 10 wt%) in MeOH (80 mL) was stirred at room temperature under hydrogen atmosphere overnight. The resulting mixture was filtered and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure to give 5-amino-6-methoxy-2,3-dihydroisoindol-1-one (1.35 g, 19.71%) as an off-white solid. LC-MS: (M+H) + found 179.0.
1H NMR (400 MHz, DMSO-d6) δ 7.92 (d, J= 4.7 Hz, 1H), 6.98 (d, J= 3.1 Hz, 1H), 6.70 (d, J= 2.2 Hz, 1H), 5.38 (s, 2H), 4.14 (s, 2H), 3.81 (s, 3H)。 步驟3. 6-甲氧基-5-(丙-2-炔-1-基胺基)-2,3-二氫異吲哚-1-酮之合成 1 H NMR (400 MHz, DMSO-d6) δ 7.92 (d, J = 4.7 Hz, 1H), 6.98 (d, J = 3.1 Hz, 1H), 6.70 (d, J = 2.2 Hz, 1H), 5.38 (s, 2H), 4.14 (s, 2H), 3.81 (s, 3H). Step 3. Synthesis of 6-methoxy-5-(prop-2-yn-1-ylamino)-2,3-dihydroisoindol-1-one
將5-胺基-6-甲氧基-2,3-二氫異吲哚-1-酮(1.35 g,7.58 mmol,1當量)、炔丙基溴(919.3 mg,7.73 mmol,1.02當量)及K 2CO 3(3.13 g,22.65 mmol,2.99當量)於DMF (13 mL)中之混合物在70℃下攪拌隔夜。過濾所得混合物,濾餅用CH 2Cl 2洗滌。將濾液在減壓下濃縮。殘餘物藉由反相急速層析(管柱,C18矽膠;移動相,於水中之MeOH,在25 min內0%至100%梯度;偵測器,UV 254 nm)純化,以得到呈灰白色固體之6-甲氧基-5-(丙-2-炔-1-基胺基)-2,3-二氫異吲哚-1-酮(400 mg,24.42%)。LC-MS:(M+H) +實測值217.1。 中間物45. 8-溴-2-碘-3-(三氟甲基)咪唑并[1,2-a]吡啶之合成 步驟1. 8-溴-3-碘咪唑并[1,2-a]吡啶-2-甲酸酯 之合成 A mixture of 5-amino-6-methoxy-2,3-dihydroisoindol-1-one (1.35 g, 7.58 mmol, 1 eq.), propargyl bromide (919.3 mg, 7.73 mmol, 1.02 eq.) and K 2 CO 3 (3.13 g, 22.65 mmol, 2.99 eq.) in DMF (13 mL) was stirred at 70° C. overnight. The resulting mixture was filtered and the filter cake was washed with CH 2 Cl 2. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeOH in water, gradient 0% to 100% in 25 min; detector, UV 254 nm) to give 6-methoxy-5-(prop-2-yn-1-ylamino)-2,3-dihydroisoindol-1-one (400 mg, 24.42%) as an off-white solid. LC-MS: (M+H) + found 217.1. Intermediate 45. Synthesis of 8-bromo-2-iodo-3-(trifluoromethyl)imidazo[1,2-a]pyridine Step 1. Synthesis of 8-bromo-3-iodoimidazo[1,2-a]pyridine-2-carboxylate
將8-溴咪唑并[1,2-a]吡啶-2-甲酸乙酯(10.0 g,37.16 mmol,1當量)及NIS (12.79 g,56.86 mmol,1.53當量)於ACN (100 mL)中之溶液在50℃下攪拌2 h。將所得混合物在真空下濃縮。殘餘物用乙酸乙酯(200 mL)稀釋且用鹽水(3 *100 mL)洗滌。有機層經無水Na 2SO 4乾燥且在真空下濃縮。殘餘物藉由矽膠管柱層析純化,用PE / EA (7:1)溶析,以得到呈黃色固體之8-溴-3-碘咪唑并[1,2-a]吡啶-2-甲酸乙酯(7.90 g,53.82%)。LC-MS:(M+H) +實測值395.0。 步驟2. 8-溴-3-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲酸乙酯之合成 A solution of ethyl 8-bromoimidazo[1,2-a]pyridine-2-carboxylate (10.0 g, 37.16 mmol, 1 eq.) and NIS (12.79 g, 56.86 mmol, 1.53 eq.) in ACN (100 mL) was stirred at 50 °C for 2 h. The resulting mixture was concentrated under vacuum. The residue was diluted with ethyl acetate (200 mL) and washed with brine (3*100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with PE/EA (7:1) to give 8-bromo-3-iodoimidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (7.90 g, 53.82%) as a yellow solid. LC-MS: (M+H) + found 395.0. Step 2. Synthesis of 8-bromo-3-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester
將8-溴-3-碘咪唑并[1,2-a]吡啶-2-甲酸乙酯(4.0 g,10.13 mmol,1當量)及(三氟甲基)銅-1,10-啡啉(4.75 g,15.19 mmol,1.50當量)於DMF (40 mL)中之溶液在室溫及氮氣氛圍下攪拌2 h。所得混合物用乙酸乙酯(200 mL)稀釋且用鹽水(3*100 mL)洗滌。有機層經無水Na 2SO 4乾燥且在真空下濃縮。 殘餘物藉由反相急速層析(管柱,C18;移動相,於水中之MeCN (0.1% TFA),在20 min內0%至60%梯度;偵測器,UV 254 nm)純化,以得到呈深綠色固體之8-溴-3-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲酸乙酯(2.03 g,59.47%)。LC-MS:(M+H) +實測值337.1。 步驟3. 8-溴-3-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲酸之合成 A solution of ethyl 8-bromo-3-iodoimidazo[1,2-a]pyridine-2-carboxylate (4.0 g, 10.13 mmol, 1 eq.) and (trifluoromethyl)copper-1,10-phenanthroline (4.75 g, 15.19 mmol, 1.50 eq.) in DMF (40 mL) was stirred at room temperature under nitrogen atmosphere for 2 h. The resulting mixture was diluted with ethyl acetate (200 mL) and washed with brine (3*100 mL). The organic layer was dried over anhydrous Na 2 SO 4 and concentrated under vacuum. The residue was purified by reverse phase flash chromatography (column, C18; mobile phase, MeCN (0.1% TFA) in water, gradient 0% to 60% in 20 min; detector, UV 254 nm) to give ethyl 8-bromo-3-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylate (2.03 g, 59.47%) as a dark green solid. LC-MS: (M+H) + found 337.1. Step 3. Synthesis of 8-bromo-3-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylic acid
向8-溴-3-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲酸乙酯(2.03 g,6.02 mmol,1當量)於THF (10 mL) /水(10 mL)中之溶液中添加LiOH (379.0 mg,9.03 mmol,1.50當量,10 mL水)。將所得溶液在室溫下攪拌1 h。移除THF之後,用HCl (水溶液)將所得混合物酸化至pH 3,然後過濾且濾餅用水洗滌。粗物質藉由反相急速層析(管柱,C18;移動相,於水中之MeCN (0.1% FA),在20 min內0%至50%梯度;偵測器,UV 254 nm)純化,以得到呈白色固體之8-溴-3-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲酸(1.48 g,79.52%)。LC-MS:(M+H) +實測值309.0。 步驟4. N-[8-溴-3-(三氟甲基)咪唑并[1,2-a]吡啶-2-基]胺基甲酸三級丁酯之合成 To a solution of ethyl 8-bromo-3-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylate (2.03 g, 6.02 mmol, 1 eq) in THF (10 mL)/water (10 mL) was added LiOH (379.0 mg, 9.03 mmol, 1.50 eq, 10 mL water). The resulting solution was stirred at room temperature for 1 h. After removal of THF, the resulting mixture was acidified to pH 3 with HCl (aq) and then filtered and the filter cake washed with water. The crude material was purified by reverse phase flash chromatography (column, C18; mobile phase, MeCN (0.1% FA) in water, gradient 0% to 50% in 20 min; detector, UV 254 nm) to give 8-bromo-3-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylic acid (1.48 g, 79.52%) as a white solid. LC-MS: (M+H) + found 309.0. Step 4. Synthesis of tributyl N-[8-bromo-3-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]carbamate
將8-溴-3-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲酸(1.40 g,4.53 mmol,1當量)、DPPA (2.49 g,9.06 mmol,2當量)及Et 3N (916.8 mg,9.06 mmol,2當量)於t-BuOH (15 mL)中之混合物在80℃及氮氣氛圍下攪拌1 h。所得混合物藉由反相急速層析(管柱,C18;移動相,於水中之MeCN,在20 min內0%至70%梯度;偵測器,UV 254 nm)純化,以得到呈黃色固體之N-[8-溴-3-(三氟甲基)咪唑并[1,2-a]吡啶-2-基]胺基甲酸三級丁酯(1.60 g,92.90%)。LC-MS:(M+H) +實測值380.2。 步驟5. 8-溴-3-(三氟甲基)咪唑并[1,2-a]吡啶-2-胺之合成 A mixture of 8-bromo-3-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylic acid (1.40 g, 4.53 mmol, 1 eq.), DPPA (2.49 g, 9.06 mmol, 2 eq.) and Et 3 N (916.8 mg, 9.06 mmol, 2 eq.) in t-BuOH (15 mL) was stirred at 80° C. under nitrogen atmosphere for 1 h. The resulting mixture was purified by reverse phase flash chromatography (column, C18; mobile phase, MeCN in water, gradient 0% to 70% in 20 min; detector, UV 254 nm) to give tributyl N-[8-bromo-3-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]carbamate (1.60 g, 92.90%) as a yellow solid. LC-MS: (M+H) + found 380.2. Step 5. Synthesis of 8-bromo-3-(trifluoromethyl)imidazo[1,2-a]pyridin-2-amine
將N-[8-溴-3-(三氟甲基)咪唑并[1,2-a]吡啶-2-基]胺基甲酸三級丁酯(1.60 g,4.21 mmol,1當量)於DCM(13.50 mL) / TFA (4.50 mL)中之溶液在室溫下攪拌1 h。移除溶劑。用飽和NH 4HCO 3將殘餘物鹼化至pH 8且用CH 2Cl 2(3*10 mL)萃取。有機層經無水Na 2SO 4乾燥且在真空下濃縮,以得到呈淺黃色固體之8-溴-3-(三氟甲基)咪唑并[1,2-a]吡啶-2-胺(1.2 g,粗物質)。LC-MS:(M+H) +實測值280.0。 步驟6. 8-溴-2-碘-3-(三氟甲基)咪唑并[1,2-a]吡啶之合成 A solution of tributyl N-[8-bromo-3-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]carbamate (1.60 g, 4.21 mmol, 1 eq.) in DCM (13.50 mL) / TFA (4.50 mL) was stirred at room temperature for 1 h. The solvent was removed. The residue was basified to pH 8 with saturated NH 4 HCO 3 and extracted with CH 2 Cl 2 (3*10 mL). The organic layer was dried over anhydrous Na 2 SO 4 and concentrated under vacuum to give 8-bromo-3-(trifluoromethyl)imidazo[1,2-a]pyridin-2-amine (1.2 g, crude) as a light yellow solid. LC-MS: (M+H) + found 280.0. Step 6. Synthesis of 8-bromo-2-iodo-3-(trifluoromethyl)imidazo[1,2-a]pyridine
向8-溴-3-(三氟甲基)咪唑并[1,2-a]吡啶-2-胺(500 mg,1.79 mmol,1當量)於ACN (5 mL)中之攪拌溶液中添加亞硝酸異戊酯(313.7 mg,2.68 mmol,1.50當量)及CuI (680.1 mg,3.57 mmol,2當量)。將所得混合物在50℃及氮氣氛圍下攪拌4 h。所得溶液藉由反相急速層析(管柱,C18;移動相,於水中之MeCN,在20 min內0%至60%梯度;偵測器,UV 254 nm)純化,以得到呈淺黃色固體之8-溴-2-碘-3-(三氟甲基)咪唑并[1,2-a]吡啶(495.0 mg,70.92%)。LC-MS:(M+H) +實測值390.9。 中間物46. 8-溴-7-氟-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶之合成 步驟1. 8-溴-3-{[(三級丁基二甲基矽烷基)氧基]甲基}-7-氟-2-碘咪唑并[1,2-a]吡啶之合成 To a stirred solution of 8-bromo-3-(trifluoromethyl)imidazo[1,2-a]pyridin-2-amine (500 mg, 1.79 mmol, 1 eq) in ACN (5 mL) was added isoamyl nitrite (313.7 mg, 2.68 mmol, 1.50 eq) and CuI (680.1 mg, 3.57 mmol, 2 eq). The resulting mixture was stirred at 50 °C under nitrogen atmosphere for 4 h. The resulting solution was purified by reverse phase flash chromatography (column, C18; mobile phase, MeCN in water, gradient 0% to 60% in 20 min; detector, UV 254 nm) to give 8-bromo-2-iodo-3-(trifluoromethyl)imidazo[1,2-a]pyridine (495.0 mg, 70.92%) as a light yellow solid. LC-MS: (M+H) + found 390.9. Intermediate 46. Synthesis of 8-bromo-7-fluoro-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine Step 1. Synthesis of 8-bromo-3-{[(tributyldimethylsilyl)oxy]methyl}-7-fluoro-2-iodoimidazo[1,2-a]pyridine
在120℃下,向3-溴-4-氟吡啶-2-胺(4.50 g,23.56 mmol,1當量)及Cu(OAc) 2(855 mg,4.71 mmol,0.20當量)於甲苯(35 mL)中之攪拌溶液中逐滴添加三級丁基[(3-碘丙-2-炔-1-基)氧基]二甲基矽烷(10.46 g,35.34 mmol,1.50當量)。將所得混合物在120℃下攪拌3 h,然後冷卻至室溫且用乙酸乙酯(200 mL)稀釋。過濾所得混合物,濾餅用乙酸乙酯洗滌。濾液用水洗滌,然後在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用PE / EA (20:1)溶析,以得到呈淺黃色固體之8-溴-3-{[(三級丁基二甲基矽烷基)氧基]甲基}-7-氟-2-碘咪唑并[1,2-a]吡啶(4.0 g,34.99%)。LC-MS:(M+H) +實測值:486.9。 步驟2. {8-溴-7-氟-2-碘咪唑并[1,2-a]吡啶-3-基}甲醇之合成 To a stirred solution of 3-bromo-4-fluoropyridin-2-amine (4.50 g, 23.56 mmol, 1 eq.) and Cu(OAc) 2 (855 mg, 4.71 mmol, 0.20 eq.) in toluene (35 mL) at 120 °C was added tert-butyl[(3-iodoprop-2-yn-1-yl)oxy]dimethylsilane (10.46 g, 35.34 mmol, 1.50 eq.) dropwise. The resulting mixture was stirred at 120 °C for 3 h, then cooled to room temperature and diluted with ethyl acetate (200 mL). The resulting mixture was filtered, and the filter cake was washed with ethyl acetate. The filtrate was washed with water, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (20:1) to obtain 8-bromo-3-{[(tributyldimethylsilyl)oxy]methyl}-7-fluoro-2-iodoimidazo[1,2-a]pyridine (4.0 g, 34.99%) as a light yellow solid. LC-MS: (M+H) + found: 486.9. Step 2. Synthesis of {8-bromo-7-fluoro-2-iodoimidazo[1,2-a]pyridin-3-yl}methanol
在室溫下,向8-溴-3-{[(三級丁基二甲基矽烷基)氧基]甲基}-7-氟-2-碘咪唑并[1,2-a]吡啶(4.15 g,8.55 mmol,1當量)於THF (40 mL)中之之攪拌溶液中逐滴添加Et 3N .3HF (4.14 g,25.65 mmol,3當量)。將所得混合物在室溫下攪拌3 h,然後在減壓下濃縮至1/3體積。藉由過濾收集沉澱的固體且用DCM洗滌,以得到呈白色固體之{8-溴-7-氟-2-碘咪唑并[1,2-a]吡啶-3-基}甲醇(2.70 g,85.10%)。LC-MS:(M+H) +實測值:372.6。 步驟3. 8-溴-7-氟-2-碘咪唑并[1,2-a]吡啶-3-甲醛之合成 To a stirred solution of 8-bromo-3-{[(tributyldimethylsilyl)oxy]methyl}-7-fluoro-2-iodoimidazo[1,2-a]pyridine (4.15 g, 8.55 mmol, 1 eq.) in THF (40 mL) was added Et 3 N .3HF (4.14 g, 25.65 mmol, 3 eq.) dropwise at room temperature. The resulting mixture was stirred at room temperature for 3 h and then concentrated to 1/3 volume under reduced pressure. The precipitated solid was collected by filtration and washed with DCM to give {8-bromo-7-fluoro-2-iodoimidazo[1,2-a]pyridin-3-yl}methanol (2.70 g, 85.10%) as a white solid. LC-MS: (M+H) + found: 372.6. Step 3. Synthesis of 8-bromo-7-fluoro-2-iodoimidazo[1,2-a]pyridine-3-carbaldehyde
將{8-溴-7-氟-2-碘咪唑并[1,2-a]吡啶-3-基}甲醇(2.40 g,6.47 mmol,1當量)及MnO 2(11.24 g,129.40 mmol,20當量)於DCM (100 mL)中之混合物在45℃下攪拌隔夜。過濾所得混合物,濾餅用DCM洗滌。將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用PE / EA (10:1)溶析,以得到呈白色固體之8-溴-7-氟-2-碘咪唑并[1,2-a]吡啶-3-甲醛(1.90 g,79.60%)。LC-MS:(M+H) +實測值:370.7。 步驟4. 8-溴-7-氟-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶之合成 A mixture of {8-bromo-7-fluoro-2-iodoimidazo[1,2-a]pyridin-3-yl}methanol (2.40 g, 6.47 mmol, 1 eq.) and MnO 2 (11.24 g, 129.40 mmol, 20 eq.) in DCM (100 mL) was stirred at 45° C. overnight. The resulting mixture was filtered and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (10:1) to give 8-bromo-7-fluoro-2-iodoimidazo[1,2-a]pyridine-3-carbaldehyde (1.90 g, 79.60%) as a white solid. LC-MS: (M+H) + found: 370.7. Step 4. Synthesis of 8-bromo-7-fluoro-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine
將8-溴-7-氟-2-碘咪唑并[1,2-a]吡啶-3-甲醛(2.0 g,5.42 mmol,1當量)及2,2-二氟-2-(三苯基膦鎓基)乙酸酯(4.83 g,13.55 mmol,2.50當量)於DMF (20 mL)中之溶液在80℃及氮氣氛圍下攪拌,然後在25℃及氮氣下添加四丁基氟化銨(16.2 mL,16.26 mmol,3當量)。將所得混合物在60℃及氮氣氛圍下攪拌1h。所得混合物用水(80 mL)稀釋且用EtOAc (3*80 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用PE / EA (5:1)溶析,以得到呈黃色固體之8-溴-7-氟-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶(1.3 g,56.70%)。LC-MS:(M+H) +實測值:423.0。 中間物47. 8-溴-6-氟-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶之合成 步驟1. 8-溴-3-{[(三級丁基二甲基矽烷基)氧基]甲基}-6-氟-2-碘咪唑并[1,2-a]吡啶之合成 A solution of 8-bromo-7-fluoro-2-iodoimidazo[1,2-a]pyridine-3-carbaldehyde (2.0 g, 5.42 mmol, 1 eq.) and 2,2-difluoro-2-(triphenylphosphinium)acetate (4.83 g, 13.55 mmol, 2.50 eq.) in DMF (20 mL) was stirred at 80 °C under nitrogen atmosphere, and then tetrabutylammonium fluoride (16.2 mL, 16.26 mmol, 3 eq.) was added at 25 °C under nitrogen atmosphere. The resulting mixture was stirred at 60 °C under nitrogen atmosphere for 1 h. The resulting mixture was diluted with water (80 mL) and extracted with EtOAc (3*80 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (5:1) to obtain 8-bromo-7-fluoro-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (1.3 g, 56.70%) as a yellow solid. LC-MS: (M+H) + found: 423.0. Intermediate 47. Synthesis of 8-bromo-6-fluoro-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine Step 1. Synthesis of 8-bromo-3-{[(tributyldimethylsilyl)oxy]methyl}-6-fluoro-2-iodoimidazo[1,2-a]pyridine
向3-溴-5-氟吡啶-2-胺(5.0 g,26.18 mmol,1當量)於甲苯(25 mL)中之攪拌溶液中添加三級丁基[(3-碘丙-2-炔-1-基)氧基]二甲基矽烷(11.63 g,39.27 mmol,1.50當量)及Cu(OAc) 2(0.95 g,5.24 mmol,0.20當量)。將所得混合物在120℃及空氣氛圍下攪拌隔夜。反應混合物用水(50 mL)淬滅且用EtOAc (3*50 mL)萃取。合併的有機層經硫酸鈉乾燥,過濾且真空濃縮。殘餘物藉由矽膠管柱層析純化,用PE / EtOAc (25:1)溶析,以得到呈黃色固體之8-溴-3-{[(三級丁基二甲基矽烷基)氧基]甲基}-6-氟-2-碘咪唑并[1,2-a]吡啶(7.0 g,55.11%)。LC-MS:(M+H) +實測值:485.2。 步驟2. {8-溴-6-氟-2-碘咪唑并[1,2-a]吡啶-3-基}甲醇之合成 To a stirred solution of 3-bromo-5-fluoropyridin-2-amine (5.0 g, 26.18 mmol, 1 eq) in toluene (25 mL) was added tert-butyl[(3-iodoprop-2-yn-1-yl)oxy]dimethylsilane (11.63 g, 39.27 mmol, 1.50 eq) and Cu(OAc) 2 (0.95 g, 5.24 mmol, 0.20 eq). The resulting mixture was stirred at 120 °C under air atmosphere overnight. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (3*50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography and eluted with PE/EtOAc (25:1) to give 8-bromo-3-{[(tributyldimethylsilyl)oxy]methyl}-6-fluoro-2-iodoimidazo[1,2-a]pyridine (7.0 g, 55.11%) as a yellow solid. LC-MS: (M+H) + found: 485.2. Step 2. Synthesis of {8-bromo-6-fluoro-2-iodoimidazo[1,2-a]pyridin-3-yl}methanol
向8-溴-3-{[(三級丁基二甲基矽烷基)氧基]甲基}-6-氟-2-碘咪唑并[1,2-a]吡啶(7.0 g,14.43 mmol,1當量)於THF (35 mL)中之攪拌溶液中添加Et 3N .3HF (6.98 g,43.28 mmol,3當量)。將所得混合物在0℃下攪拌3 h。過濾所得混合物,濾餅用DCM洗滌,以得到呈白色固體之{8-溴-6-氟-2-碘咪唑并[1,2-a]吡啶-3-基}甲醇(4.80 g,89.69%)。LC-MS:(M+H) +實測值:370.9。 步驟3. 8-溴-6-氟-2-碘咪唑并[1,2-a]吡啶-3-甲醛之合成 To a stirred solution of 8-bromo-3-{[(tributyldimethylsilyl)oxy]methyl}-6-fluoro-2-iodoimidazo[1,2-a]pyridine (7.0 g, 14.43 mmol, 1 eq) in THF (35 mL) was added Et 3 N . 3HF (6.98 g, 43.28 mmol, 3 eq). The resulting mixture was stirred at 0° C. for 3 h. The resulting mixture was filtered and the filter cake was washed with DCM to give {8-bromo-6-fluoro-2-iodoimidazo[1,2-a]pyridin-3-yl}methanol (4.80 g, 89.69%) as a white solid. LC-MS: (M+H) + found: 370.9. Step 3. Synthesis of 8-bromo-6-fluoro-2-iodoimidazo[1,2-a]pyridine-3-carbaldehyde
在0℃下,向{8-溴-6-氟-2-碘咪唑并[1,2-a]吡啶-3-基}甲醇(4.80 g,12.94 mmol,1當量)、tempo (40.44 mg,0.26 mmol,0.02當量)、KBr (154 mg,1.29 mmol,0.10當量)及NaHCO 3(163 mg,1.94 mmol,0.15 當量)於DCM (40 mL)中之攪拌溶液中逐滴添加NaClO (20 mL)。將所得混合物在0℃下攪拌3 h。藉由過濾收集沉澱的固體且用水洗滌,以得到呈黃色固體之8-溴-6-氟-2-碘咪唑并[1,2-a]吡啶-3-甲醛(2.80 g,58.65%)。LC-MS:(M+H +)實測值:368.9。 步驟4. 8-溴-6-氟-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶之合成 To a stirred solution of {8-bromo-6-fluoro-2-iodoimidazo[1,2-a]pyridin-3-yl}methanol (4.80 g, 12.94 mmol, 1 eq.), tempo (40.44 mg, 0.26 mmol, 0.02 eq.), KBr (154 mg, 1.29 mmol, 0.10 eq.) and NaHCO 3 (163 mg, 1.94 mmol, 0.15 eq .) in DCM (40 mL) was added NaClO (20 mL) dropwise at 0° C. The resulting mixture was stirred at 0° C. for 3 h. The precipitated solid was collected by filtration and washed with water to give 8-bromo-6-fluoro-2-iodoimidazo[1,2-a]pyridine-3-carbaldehyde (2.80 g, 58.65%) as a yellow solid. LC-MS: (M+H + ) found: 368.9. Step 4. Synthesis of 8-bromo-6-fluoro-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine
在氮氣氛圍下,向8-溴-6-氟-2-碘咪唑并[1,2-a]吡啶-3-甲醛(2.80 g,7. 59mmol,1當量)於DMF (15 mL)中之攪拌溶液中添加2,2-二氟-2-(三苯基膦鎓基)乙酸酯(3.24 g,9.11 mmol,1.20當量)。將所得混合物在60℃下攪拌1 h。使混合物冷卻至室溫,且添加TBAF (9.11 mL,9.11 mmol,1.20當量)之溶液。將所得溶液在60℃下攪拌1 h,然後冷卻至室溫且用水(50 mL)淬滅,用EtOAc (3*150 mL)萃取。合併的有機層經硫酸鈉乾燥,過濾且真空濃縮。殘餘物藉由矽膠管柱層析純化,用PE/ EtOAc (10:1)溶析,以得到呈白色固體之8-溴-6-氟-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶(650.0 mg,20.25%)。LC-MS:(M+H) +實測值:422.9。 中間物48. 8-溴-3-[(二氟甲基)硫基]-2-碘咪唑并[1,2-a]吡啶之合成 步驟1. 8-溴-3-[(二氟甲基)硫基]咪唑并[1,2-a]吡啶-2-甲酸酯之合成 To a stirred solution of 8-bromo-6-fluoro-2-iodoimidazo[1,2-a]pyridine-3-carbaldehyde (2.80 g, 7.59 mmol, 1 eq) in DMF (15 mL) under nitrogen atmosphere was added 2,2-difluoro-2-(triphenylphosphinium)acetate (3.24 g, 9.11 mmol, 1.20 eq). The resulting mixture was stirred at 60 °C for 1 h. The mixture was cooled to room temperature, and a solution of TBAF (9.11 mL, 9.11 mmol, 1.20 eq) was added. The resulting solution was stirred at 60 °C for 1 h, then cooled to room temperature and quenched with water (50 mL), extracted with EtOAc (3*150 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography and eluted with PE/EtOAc (10:1) to give 8-bromo-6-fluoro-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (650.0 mg, 20.25%) as a white solid. LC-MS: (M+H) + found: 422.9. Intermediate 48. Synthesis of 8-bromo-3-[(difluoromethyl)thio]-2-iodoimidazo[1,2-a]pyridine Step 1. Synthesis of 8-bromo-3-[(difluoromethyl)thio]imidazo[1,2-a]pyridine-2-carboxylate
向8-溴咪唑并[1,2-a]吡啶-2-甲酸乙酯(1 g,3.72 mmol,1當量)及2-[(二氟甲基)硫基]異吲哚-1,3-二酮(1.02 g,4.46 mmol,1.2當量)於DCE (22 mL)中之攪拌溶液中添加TMSCl (0.71 mL,5.57 mmol,1.5當量)。將所得混合物在90℃及氮氣氛圍下攪拌隔夜,然後冷卻至室溫。將所得混合物在真空下濃縮。殘餘物藉由矽膠管柱層析純化,用MeOH / CH 2Cl 2= 1:19溶析,以得到呈白色固體之8-溴-3-[(二氟甲基)硫基]咪唑并[1,2-a]吡啶-2-甲酸乙酯(855 mg,65.52%)。LC-MS:(M+H) +實測值351.0。 步驟2. 8-溴-3-[(二氟甲基)硫基]咪唑并[1,2-a]吡啶-2-甲酸之合成 To a stirred solution of ethyl 8-bromoimidazo[1,2-a]pyridine-2-carboxylate (1 g, 3.72 mmol, 1 eq) and 2-[(difluoromethyl)thio]isoindole-1,3-dione (1.02 g, 4.46 mmol, 1.2 eq) in DCE (22 mL) was added TMSCl (0.71 mL, 5.57 mmol, 1.5 eq). The resulting mixture was stirred at 90 °C under nitrogen atmosphere overnight and then cooled to room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with MeOH/ CH2Cl2 = 1:19 to give 8-bromo-3-[(difluoromethyl)thio]imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (855 mg, 65.52%) as a white solid. LC-MS: (M+H) + found 351.0. Step 2. Synthesis of 8-bromo-3-[(difluoromethyl)thio]imidazo[1,2-a]pyridine-2-carboxylic acid
將8-溴-3-[(二氟甲基)硫基]咪唑并[1,2-a]吡啶-2-甲酸乙酯(855 mg,2.43 mmol,1當量)於H 2O (8 mL)/THF (2 mL)中之溶液在0℃下用LiOH (87 mg,3.65 mmol,1.5當量)處理。將所得混合物在室溫下攪拌1 h。用1M HCl將混合物酸化至pH 6~7。藉由過濾收集沉澱的固體且用冷水洗滌,然後在真空下乾燥,以得到呈白色固體之8-溴-3-[(二氟甲基)硫基]咪唑并[1,2-a]吡啶-2-甲酸(531 mg,67.50%)。LC-MS:(M+H) +實測值323.0。 步驟3. 8-溴-3-[(二氟甲基)硫基]-2-碘咪唑并[1,2-a]吡啶之合成 A solution of ethyl 8-bromo-3-[(difluoromethyl)thio]imidazo[1,2-a]pyridine-2-carboxylate (855 mg, 2.43 mmol, 1 eq) in H 2 O (8 mL)/THF (2 mL) was treated with LiOH (87 mg, 3.65 mmol, 1.5 eq) at 0°C. The resulting mixture was stirred at room temperature for 1 h. The mixture was acidified to pH 6~7 with 1M HCl. The precipitated solid was collected by filtration and washed with cold water, then dried under vacuum to give 8-bromo-3-[(difluoromethyl)thio]imidazo[1,2-a]pyridine-2-carboxylic acid (531 mg, 67.50%) as a white solid. LC-MS: (M+H) + found 323.0. Step 3. Synthesis of 8-bromo-3-[(difluoromethyl)thio]-2-iodoimidazo[1,2-a]pyridine
在室溫下,向8-溴-3-[(二氟甲基)硫基]咪唑并[1,2-a]吡啶-2-甲酸(479 mg,1.48 mmol,1當量)於DMSO (5 mL)中之攪拌溶液中逐份添加I 2(1.51 g,5.92 mmol,4當量)及K 3PO 4(377 mg,1.78 mmol,1.2當量)。將所得混合物在120℃及氮氣氛圍下攪拌隔夜,然後冷卻至室溫。藉由在0℃下添加50% Na 2S 2O 8(30 mL)淬滅反應。在0℃下,向上述混合物中逐份添加Na 2CO 3(10 mL),然後用CH 2Cl 2(3*20 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用EA / PE = 1:4溶析,以得到呈白色固體之8-溴-3-[(二氟甲基)硫基]-2-碘咪唑并[1,2-a]吡啶(203 mg,33.81%)。LC-MS:(M+H) +實測值405.1。 中間物49. 4-甲氧基-N-甲基-3-(丙-2-炔-1-基胺基)苯甲醯胺之合成 步驟1. 4-甲氧基-3-(丙-2-炔-1-基胺基)苯甲酸甲酯之合成 To a stirred solution of 8-bromo-3-[(difluoromethyl)thio]imidazo[1,2-a]pyridine-2-carboxylic acid (479 mg, 1.48 mmol, 1 eq) in DMSO (5 mL) was added I 2 (1.51 g, 5.92 mmol, 4 eq) and K 3 PO 4 (377 mg, 1.78 mmol, 1.2 eq) portionwise at room temperature. The resulting mixture was stirred at 120 °C under nitrogen atmosphere overnight and then cooled to room temperature. The reaction was quenched by adding 50% Na 2 S 2 O 8 (30 mL) at 0 °C. Na 2 CO 3 (10 mL) was added portionwise to the above mixture at 0 °C and then extracted with CH 2 Cl 2 (3*20 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with EA / PE = 1:4 to give 8-bromo-3-[(difluoromethyl)thio]-2-iodoimidazo[1,2-a]pyridine (203 mg, 33.81%) as a white solid. LC-MS: (M+H) + found 405.1. Intermediate 49. Synthesis of 4-methoxy-N-methyl-3-(prop-2-yn-1-ylamino)benzamide Step 1. Synthesis of methyl 4-methoxy-3-(prop-2-yn-1-ylamino)benzoate
將3-胺基-4-甲氧基苯甲酸甲酯(5.0 g,27.59 mmol,1當量)、炔丙基溴(4.92 g,41.39 mmol,1.50當量)及K 2CO 3(11.44 g,82.78 mmol,3當量)於DMF (50 mL)中之混合物在70℃下攪拌隔夜。混合物用水(100 mL)淬滅且用EtOAc (3*100 mL)萃取。合併的有機層經硫酸鈉乾燥,過濾且真空濃縮。殘餘物藉由反相急速層析(管柱,C18矽膠;移動相,於0.1% TFA中之MeCN,在10 min內52%至54%梯度;偵測器,UV 254 nm)純化,以得到呈黃色固體之4-甲氧基-3-(丙-2-炔-1-基胺基)苯甲酸甲酯(3.3 g,54.55%)。LC-MS:(M+H) +實測值:220.0。 步驟2. 4-甲氧基-3-(丙-2-炔-1-基胺基)苯甲酸之合成 A mixture of methyl 3-amino-4-methoxybenzoate (5.0 g, 27.59 mmol, 1 eq.), propargyl bromide (4.92 g, 41.39 mmol, 1.50 eq.) and K 2 CO 3 (11.44 g, 82.78 mmol, 3 eq.) in DMF (50 mL) was stirred at 70 °C overnight. The mixture was quenched with water (100 mL) and extracted with EtOAc (3*100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in 0.1% TFA, gradient from 52% to 54% in 10 min; detector, UV 254 nm) to give methyl 4-methoxy-3-(prop-2-yn-1-ylamino)benzoate (3.3 g, 54.55%) as a yellow solid. LC-MS: (M+H) + found: 220.0. Step 2. Synthesis of 4-methoxy-3-(prop-2-yn-1-ylamino)benzoic acid
將4-甲氧基-3-(丙-2-炔-1-基胺基)苯甲酸甲酯(3.30 g,15.05 mmol,1當量)於MeOH (10 mL)、H 2O (10 mL)及THF (10 mL)中之混合物在室溫下用LiOH (3.79 g,90.31 mmol,6當量)處理。將所得混合物在60℃下攪拌2 h。用HCl (水溶液)將混合物中和至pH 6。藉由過濾收集沉澱的固體且用EtOAc洗滌。將所得固體在真空下乾燥,以得到呈棕色固體之4-甲氧基-3-(丙-2-炔-1-基胺基)苯甲酸(3.30 g)。產物無需進一步純化直接用於下一步驟中。LC-MS:(M+H) +實測值:205.9。 步驟3. 4-甲氧基-N-甲基-3-(丙-2-炔-1-基胺基)苯甲醯胺之合成 A mixture of methyl 4-methoxy-3-(prop-2-yn-1-ylamino)benzoate (3.30 g, 15.05 mmol, 1 eq) in MeOH (10 mL), H 2 O (10 mL) and THF (10 mL) was treated with LiOH (3.79 g, 90.31 mmol, 6 eq) at room temperature. The resulting mixture was stirred at 60 °C for 2 h. The mixture was neutralized to pH 6 with HCl (aq). The precipitated solid was collected by filtration and washed with EtOAc. The resulting solid was dried under vacuum to give 4-methoxy-3-(prop-2-yn-1-ylamino)benzoic acid (3.30 g) as a brown solid. The product was used directly in the next step without further purification. LC-MS: (M+H) + found: 205.9. Step 3. Synthesis of 4-methoxy-N-methyl-3-(prop-2-yn-1-ylamino)benzamide
在0℃下,向4-甲氧基-3-(丙-2-炔-1-基胺基)苯甲酸(500 mg,2.43 mmol,1當量)、甲胺鹽酸鹽(197 mg,2.92 mmol,1.20當量)及DIEA (1.57 g,12.18 mmol,5當量)於DMF (5 mL)中之攪拌混合物中逐份添加HATU (1.11 g,2.92 mmol,1.20當量)。將所得混合物在室溫下再攪拌1 h。混合物用水(20 mL)淬滅且用EtOAc (3*20 mL)萃取。合併的有機層經硫酸鈉乾燥,過濾且真空濃縮。殘餘物藉由反相急速層析(管柱,C18矽膠;移動相,於水中之MeCN (10mmol/L NH 4HCO 3),在10 min內40%至50%梯度;偵測器,UV 254 nm)純化,以得到呈黃色油狀物之4-甲氧基-N-甲基-3-(丙-2-炔-1-基胺基)苯甲醯胺(480 mg,90.26%)。LC-MS:(M+H) +實測值:218.9。 中間物50. N-乙基-4-甲氧基-3-(丙-2-炔-1-基胺基)苯甲醯胺之合成 To a stirred mixture of 4-methoxy-3-(prop-2-yn-1-ylamino)benzoic acid (500 mg, 2.43 mmol, 1 eq), methylamine hydrochloride (197 mg, 2.92 mmol, 1.20 eq) and DIEA (1.57 g, 12.18 mmol, 5 eq) in DMF (5 mL) at 0 °C was added HATU (1.11 g, 2.92 mmol, 1.20 eq) portionwise. The resulting mixture was stirred at room temperature for another 1 h. The mixture was quenched with water (20 mL) and extracted with EtOAc (3*20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH 4 HCO 3 ) in water, gradient 40% to 50% in 10 min; detector, UV 254 nm) to give 4-methoxy-N-methyl-3-(prop-2-yn-1-ylamino)benzamide (480 mg, 90.26%) as a yellow oil. LC-MS: (M+H) + found: 218.9. Intermediate 50. Synthesis of N-ethyl-4-methoxy-3-(prop-2-yn-1-ylamino)benzamide
在室溫下,向4-甲氧基-3-(丙-2-炔-1-基胺基)苯甲酸(300 mg,1.46 mmol,1當量)、乙胺鹽酸鹽(119 mg,1.46 mmol,1當量)及DIEA (756 mg,5.85 mmol,4當量)於DMF (1 mL)中之攪拌混合物中添加HATU (1.11 g,2.92 mmol,2當量)。將所得混合物在室溫下攪拌1 h。反應用水淬滅且用乙酸乙酯(3*50 mL)萃取。將合併的有機層在減壓下濃縮。殘餘物藉由反相急速層析(管柱,C18矽膠;移動相,於水中之MeCN (10 mmol/L NH 4HCO 3),在10 min內40%至60%梯度;偵測器,UV 254 nm)純化,以得到呈灰白色固體之N-乙基-4-甲氧基-3-(丙-2-炔-1-基胺基)苯甲醯胺(200 mg,58.90%)。LC-MS:(M+H +)實測值:233.2。 中間物51. N-環丙基-4-甲氧基-3-(丙-2-炔-1-基胺基)苯甲醯胺之合成 To a stirred mixture of 4-methoxy-3-(prop-2-yn-1-ylamino)benzoic acid (300 mg, 1.46 mmol, 1 eq), ethylamine hydrochloride (119 mg, 1.46 mmol, 1 eq) and DIEA (756 mg, 5.85 mmol, 4 eq) in DMF (1 mL) at room temperature was added HATU (1.11 g, 2.92 mmol, 2 eq). The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with water and extracted with ethyl acetate (3*50 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH 4 HCO 3 ) in water, gradient 40% to 60% in 10 min; detector, UV 254 nm) to give N-ethyl-4-methoxy-3-(prop-2-yn-1-ylamino)benzamide (200 mg, 58.90%) as an off-white solid. LC-MS: (M+H + ) found: 233.2. Intermediate 51. Synthesis of N-cyclopropyl-4-methoxy-3-(prop-2-yn-1-ylamino)benzamide
在0℃下,向4-甲氧基-3-(丙-2-炔-1-基胺基)苯甲酸(300 mg,1.46 mmol,1當量)、胺基環丙烷(125.2 mg,2.19 mmol,1.50當量)及DIEA (566.8 mg,4.39 mmol,3當量)於DMF (3 mL)中之攪拌溶液中添加HATU (667.0 mg,1.75 mmol,1.20當量)。將所得混合物在室溫下攪拌1h。反應用水(10 mL)淬滅且用EtOAc (3*20 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由反相急速層析(管柱,C18矽膠;移動相,於水中之MeCN (10mmol/L NH 4HCO 3),在10 min內30%至70%梯度;偵測器,UV 254 nm)純化,以得到呈白色固體之N-環丙基-4-甲氧基-3-(丙-2-炔-1-基胺基)苯甲醯胺(294 mg,82.32%)。LC-MS:(M+H) +實測值245.0。 中間物52. 7-甲氧基-6-(丙-2-炔-1-基胺基)-3,4-二氫-2H-異喹啉-1-酮之合成 步驟1. 7-甲氧基-6-硝基-3,4-二氫-2H-異喹啉-1-酮之合成 To a stirred solution of 4-methoxy-3-(prop-2-yn-1-ylamino)benzoic acid (300 mg, 1.46 mmol, 1 eq.), aminocyclopropane (125.2 mg, 2.19 mmol, 1.50 eq.) and DIEA (566.8 mg, 4.39 mmol, 3 eq.) in DMF (3 mL) at 0°C was added HATU (667.0 mg, 1.75 mmol, 1.20 eq.). The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with water (10 mL) and extracted with EtOAc (3*20 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH 4 HCO 3 ) in water, gradient 30% to 70% in 10 min; detector, UV 254 nm) to give N-cyclopropyl-4-methoxy-3-(prop-2-yn-1-ylamino)benzamide (294 mg, 82.32%) as a white solid. LC-MS: (M+H) + found 245.0. Intermediate 52. Synthesis of 7-methoxy-6-(prop-2-yn-1-ylamino)-3,4-dihydro-2H-isoquinolin-1-one Step 1. Synthesis of 7-methoxy-6-nitro-3,4-dihydro-2H-isoquinolin-1-one
在0℃及氮氣氛圍下,向7-甲氧基-3,4-二氫-2H-異喹啉-1-酮(2 g,11.28 mmol,1當量)於ACN (8 mL)及TFAA (8 mL)中之攪拌溶液中逐滴添加HNO 3(0.69 mL,10.157 mmol,0.9當量)。將所得混合物在0℃及氮氣氛圍下攪拌1 h。用飽和NaHCO 3將混合物鹼化至pH 8且用EtOAc (3*50 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用EA溶析,以得到呈淺黃色固體之7-甲氧基-6-硝基-3,4-二氫-2H-異喹啉-1-酮(2.2 g,87.72%)。LC-MS:(M+H) +實測值223.1。 步驟2. 6-胺基-7-甲氧基-3,4-二氫-2H-異喹啉-1-酮之合成 To a stirred solution of 7-methoxy-3,4-dihydro-2H-isoquinolin-1-one (2 g, 11.28 mmol, 1 eq.) in ACN (8 mL) and TFAA (8 mL) was added HNO 3 (0.69 mL, 10.157 mmol, 0.9 eq.) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 0°C under nitrogen atmosphere for 1 h. The mixture was basified to pH 8 with saturated NaHCO 3 and extracted with EtOAc (3*50 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with EA to give 7-methoxy-6-nitro-3,4-dihydro-2H-isoquinolin-1-one (2.2 g, 87.72%) as a light yellow solid. LC-MS: (M+H) + found 223.1. Step 2. Synthesis of 6-amino-7-methoxy-3,4-dihydro-2H-isoquinolin-1-one
將7-甲氧基-6-硝基-3,4-二氫-2H-異喹啉-1-酮(2.2 g,9.90 mmol,1當量)、NH 4Cl (2.65 g,49.51 mmol,5當量)及Fe (2.76 g,49.51 mmol,5當量)於EtOH (20 mL)/H 2O (4 mL)中之混合物在70℃下攪拌1 h。過濾所得混合物,濾餅用MeOH洗滌。將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用CH 2Cl 2/ MeOH (10:1) 溶析,以得到呈淺黃色固體之6-胺基-7-甲氧基-3,4-二氫-2H-異喹啉-1-酮(580 mg,30.47%)。LC-MS:(M+H) +實測值193.0。 步驟3. 7-甲氧基-6-(丙-2-炔-1-基胺基)-3,4-二氫-2H-異喹啉-1-酮之合成 A mixture of 7-methoxy-6-nitro-3,4-dihydro-2H-isoquinolin-1-one (2.2 g, 9.90 mmol, 1 eq.), NH 4 Cl (2.65 g, 49.51 mmol, 5 eq.) and Fe (2.76 g, 49.51 mmol, 5 eq.) in EtOH (20 mL)/H 2 O (4 mL) was stirred at 70° C. for 1 h. The resulting mixture was filtered and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with CH 2 Cl 2 / MeOH (10:1) to give 6-amino-7-methoxy-3,4-dihydro-2H-isoquinolin-1-one (580 mg, 30.47%) as a light yellow solid. LC-MS: (M+H) + found 193.0. Step 3. Synthesis of 7-methoxy-6-(prop-2-yn-1-ylamino)-3,4-dihydro-2H-isoquinolin-1-one
將6-胺基-7-甲氧基-3,4-二氫-2H-異喹啉-1-酮(580 mg,3.02 mmol,1當量)、炔丙基溴(718 mg,6.03 mmol,2當量)及DIEA (1.17 g,9.05 mmol,3當量)於CHCl 3(6 mL)中之混合物在70℃下攪拌隔夜。將所得混合物在減壓下濃縮。殘餘物藉由反相急速層析(管柱,C18矽膠;移動相,於水中之MeCN (10mmol/L NH 4HCO 3),在20 min內10%至50%梯度;偵測器,UV 254 nm)純化,以得到呈黃色固體之7-甲氧基-6-(丙-2-炔-1-基胺基)-3,4-二氫-2H-異喹啉-1-酮(520 mg,74.84%)。LC-MS:(M+H) +實測值231.2。 中間物53. 2-氯-5-甲氧基-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺之合成 步驟1. 4-胺基-2-氯-5-甲氧基苯甲酸之合成 A mixture of 6-amino-7-methoxy-3,4-dihydro-2H-isoquinolin-1-one (580 mg, 3.02 mmol, 1 eq.), propargyl bromide (718 mg, 6.03 mmol, 2 eq.) and DIEA (1.17 g, 9.05 mmol, 3 eq.) in CHCl 3 (6 mL) was stirred at 70° C. overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH 4 HCO 3 ) in water, gradient 10% to 50% in 20 min; detector, UV 254 nm) to give 7-methoxy-6-(prop-2-yn-1-ylamino)-3,4-dihydro-2H-isoquinolin-1-one (520 mg, 74.84%) as a yellow solid. LC-MS: (M+H) + found 231.2. Intermediate 53. Synthesis of 2-chloro-5-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide Step 1. Synthesis of 4-amino-2-chloro-5-methoxybenzoic acid
將4-胺基-2-氯-5-甲氧基苯甲酸甲酯(500 mg,2.32 mmol,1當量)及LiOH (67 mg,2.78 mmol,1.2當量)於THF (6.5 mL)/H 2O (2 mL)中之混合物在35℃下攪拌3天。用1 M HCl將混合物中和至pH 7且用DCM (3*20 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮,以得到呈黃色固體之4-胺基-2-氯-5-甲氧基苯甲酸(450 mg,96.26%)。LC-MS:(M+H) +實測值202.0。 步驟2. 4-胺基-2-氯-5-甲氧基-N-甲基苯甲醯胺之合成 A mixture of methyl 4-amino-2-chloro-5-methoxybenzoate (500 mg, 2.32 mmol, 1 eq.) and LiOH (67 mg, 2.78 mmol, 1.2 eq.) in THF (6.5 mL)/H 2 O (2 mL) was stirred at 35 °C for 3 days. The mixture was neutralized to pH 7 with 1 M HCl and extracted with DCM (3*20 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure to give 4-amino-2-chloro-5-methoxybenzoic acid (450 mg, 96.26%) as a yellow solid. LC-MS: (M+H) + found 202.0. Step 2. Synthesis of 4-amino-2-chloro-5-methoxy-N-methylbenzamide
將4-胺基-2-氯-5-甲氧基苯甲酸(450 mg,2.23 mmol,1當量)、HATU (1.27 g,3.35 mmol,1.5當量)、DIEA (1.17 mL,6.72 mmol,3當量)及甲胺鹽酸鹽(181 mg,2.68 mmol,1.2當量)於DMF (5 mL)中之溶液在室溫下攪拌2 h。所得溶液藉由反相急速層析(管柱,C18矽膠;移動相,於水中之MeCN (0.1% FA),在25 min內0%至50%梯度;偵測器,UV 254 nm)純化,以得到呈淺黃色固體之4-胺基-2-氯-5-甲氧基-N-甲基苯甲醯胺(400 mg,83.49%)。LC-MS:(M+H) +實測值215.1。 步驟3. 2-氯-5-甲氧基-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺之合成 A solution of 4-amino-2-chloro-5-methoxybenzoic acid (450 mg, 2.23 mmol, 1 eq), HATU (1.27 g, 3.35 mmol, 1.5 eq), DIEA (1.17 mL, 6.72 mmol, 3 eq) and methylamine hydrochloride (181 mg, 2.68 mmol, 1.2 eq) in DMF (5 mL) was stirred at room temperature for 2 h. The resulting solution was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient 0% to 50% in 25 min; detector, UV 254 nm) to give 4-amino-2-chloro-5-methoxy-N-methylbenzamide (400 mg, 83.49%) as a light yellow solid. LC-MS: (M+H) + found 215.1. Step 3. Synthesis of 2-chloro-5-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide
將4-胺基-2-氯-5-甲氧基-N-甲基苯甲醯胺(400 mg,1.86 mmol,1當量)、炔丙基溴(665 mg,5.59 mmol,3當量)及K 2CO 3(515 mg,3.73 mmol,2當量)於DMF (5 mL)中之混合物在40℃下攪拌隔夜。過濾所得混合物,濾餅用DCM洗滌。將濾液在減壓下濃縮。殘餘物藉由反相急速層析(管柱,C18矽膠;移動相,於水中之MeCN (0.1% FA),在30 min內0%至50%梯度;偵測器,UV 254 nm)純化,以得到呈棕色固體之2-氯-5-甲氧基-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺(240 mg,50.97%)。LC-MS:(M+H) +實測值352.9。 中間物54. N-(丙-2-炔-1-基)苯胺之合成 A mixture of 4-amino-2-chloro-5-methoxy-N-methylbenzamide (400 mg, 1.86 mmol, 1 eq.), propargyl bromide (665 mg, 5.59 mmol, 3 eq.) and K 2 CO 3 (515 mg, 3.73 mmol, 2 eq.) in DMF (5 mL) was stirred at 40° C. overnight. The resulting mixture was filtered and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient 0% to 50% in 30 min; detector, UV 254 nm) to give 2-chloro-5-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (240 mg, 50.97%) as a brown solid. LC-MS: (M+H) + found 352.9. Intermediate 54. Synthesis of N-(prop-2-yn-1-yl)aniline
將苯胺(1 g,10.74 mmol,1當量)、K 2CO 3(4.45 g,32.21 mmol,3當量)及炔丙基溴(2.55 g,21.48 mmol,2當量)於DMF (10 mL)中之混合物在30℃下攪拌2 h。過濾所得混合物,濾餅用DCM洗滌。將濾液在減壓下濃縮。殘餘物藉由反相急速層析(管柱,C18矽膠;移動相,於水中之ACN (10mmol/L NH 4HCO 3),在20 min內50%至100%梯度;偵測器,UV 254 nm)純化,以得到呈黃色油狀物之N-(丙-2-炔-1-基)苯胺(380 mg,21.37%)。LC-MS:(M+H) +實測值132.2。 中間物 55. 8- 溴吲嗪 -2- 甲酸乙酯之合成 步驟1. 2-[(3-溴吡啶-2-基)(羥基)甲基]丙-2-烯酸乙酯之合成 A mixture of aniline (1 g, 10.74 mmol, 1 eq.), K 2 CO 3 (4.45 g, 32.21 mmol, 3 eq.) and propargyl bromide (2.55 g, 21.48 mmol, 2 eq.) in DMF (10 mL) was stirred at 30° C. for 2 h. The resulting mixture was filtered and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, ACN (10 mmol/L NH 4 HCO 3 ) in water, gradient 50% to 100% in 20 min; detector, UV 254 nm) to give N-(prop-2-yn-1-yl)aniline (380 mg, 21.37%) as a yellow oil. LC-MS: (M+H) + found 132.2. Intermediate 55. Synthesis of 8- bromoindolizine -2- carboxylic acid ethyl ester Step 1. Synthesis of ethyl 2-[(3-bromopyridin-2-yl)(hydroxy)methyl]prop-2-enoate
向3-溴吡啶甲醛(15.00 g,123.82 mmol,1.00當量)及2-乙氧基丁-1,3-二烯(15.83 g,161.28 mmol,2.00當量)於1,4-二噁烷/ H 2O (1:1,400.00 mL)中之溶液中逐份添加DABCO (9.05 g,80.64 mmol,1.00當量)。將反應混合物在25℃下攪拌1 h。所得混合物用DCM (3x100 mL)萃取。有機層經無水Na 2SO 4乾燥且在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用PE / EA (4:1)溶析,以得到呈黃色油狀物之2-[(3-溴吡啶-2-基)(羥基)甲基]丙-2-烯酸乙酯(22.00 g,95.35%)。LC-MS:(M+H) +實測值286.10。 步驟 2. 8- 溴吲嗪 -2- 甲酸乙酯之合成 To a solution of 3-bromopicolinaldehyde (15.00 g, 123.82 mmol, 1.00 equiv) and 2-ethoxybuta-1,3-diene (15.83 g, 161.28 mmol, 2.00 equiv) in 1,4-dioxane/H 2 O (1:1, 400.00 mL) was added DABCO (9.05 g, 80.64 mmol, 1.00 equiv) portionwise. The reaction mixture was stirred at 25 °C for 1 h. The resulting mixture was extracted with DCM (3x100 mL). The organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (4:1) to give ethyl 2-[(3-bromopyridin-2-yl)(hydroxy)methyl]prop-2-enoate (22.00 g, 95.35%) as a yellow oil. LC-MS: (M+H) + found 286.10. Step 2. Synthesis of ethyl 8- bromoindolizine -2- carboxylate
將2-[(3-溴吡啶-2-基)(羥基)甲基]丙-2-烯酸乙酯(20.00 g,69.90 mmol,1.00當量)於乙酸酐(300.00 mL)中之溶液在140℃下攪拌16 h。所得混合物用DCM (3 x 100 mL)萃取。有機層經無水Na 2SO 4乾燥且在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用PE / EA (30:1)溶析,以得到呈白色固體之8-溴吲嗪-2-甲酸乙酯(14.00 g,74.70%)。LC-MS:(M+H) +實測值268.05。 中間物 56. 8- 溴 -3-[( 三氟甲基 ) 硫基 ] 吲嗪 -2- 甲醛之合成 步驟 1. {8- 溴 -3-[( 三氟甲基 ) 硫基 ] 吲嗪 -2- 基 } 甲醇之合成 A solution of ethyl 2-[(3-bromopyridin-2-yl)(hydroxy)methyl]prop-2-enoate (20.00 g, 69.90 mmol, 1.00 equiv) in acetic anhydride (300.00 mL) was stirred at 140 °C for 16 h. The resulting mixture was extracted with DCM (3 x 100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (30:1) to give ethyl 8-bromoindolizine-2-carboxylate (14.00 g, 74.70%) as a white solid. LC-MS: (M+H) + found 268.05. Intermediate 56. Synthesis of 8- bromo -3-[( trifluoromethyl ) thio ] indolizine -2- carbaldehyde Step 1. Synthesis of {8- bromo -3-[( trifluoromethyl ) thio ] indolizin -2- yl } methanol
在-40℃及氮氣氛圍下,向8-溴-3-[(三氟甲基)硫基]吲嗪-2-甲酸乙酯(5.10 g,13.85 mmol,1.00當量)於DCM (80.00 mL)中之攪拌溶液中逐滴添加DIBAL-H (1M於甲苯中,27.70 mL,27.70 mmol,2.00當量)。將所得混合物在-20℃及氮氣氛圍下攪拌1 h。在室溫下用Na 2SO 4 .10H 2O淬滅反應。過濾混合物。濾餅用DCM (3x100 mL)洗滌。將濾液在減壓下濃縮。此產生呈白色固體之{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}甲醇(5.00 g,110.71%)。LC-MS:(M+H) +實測值326.10。 步驟 2. 8- 溴 -3-[( 三氟甲基 ) 硫基 ] 吲嗪 -2- 甲醛之合成 To a stirred solution of ethyl 8-bromo-3-[(trifluoromethyl)thio]indolizine-2-carboxylate (5.10 g, 13.85 mmol, 1.00 equiv) in DCM (80.00 mL) at -40 °C under nitrogen atmosphere was added DIBAL-H (1M in toluene, 27.70 mL, 27.70 mmol, 2.00 equiv) dropwise. The resulting mixture was stirred at -20 °C under nitrogen atmosphere for 1 h. The reaction was quenched with Na 2 SO 4 .10H 2 O at room temperature. The mixture was filtered. The filter cake was washed with DCM (3x100 mL). The filtrate was concentrated under reduced pressure. This produced {8-bromo-3-[(trifluoromethyl)thio]indolizine-2-yl}methanol (5.00 g, 110.71%) as a white solid. LC-MS: (M+H) + found 326.10. Step 2. Synthesis of 8- bromo -3-[( trifluoromethyl ) thio ] indolizine -2- carbaldehyde
將{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}甲醇(5.00 g,15.64 mmol,1.00當量)及IBX (10.95 g,39.09 mmol,2.50當量)於EA (60.00 mL)中之溶液在80℃下攪拌2 h。過濾混合物。濾餅用EA (3 x 100 mL)洗滌。將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用DCM / PE (1:5)溶析,以得到呈淺黃色固體之8-溴-3-[(三氟甲基)硫基]吲嗪-2-甲醛(4.00 g,78.93%)。LC-MS:(M+H) +實測值325.90。 中間物 57. 8- 溴 -2-(3- 溴丙 -1- 炔 -1- 基 )-3-[( 三氟甲基 ) 硫基 ] 吲嗪之合成 步驟 1. 8- 溴 -2- 乙炔基 -3-[( 三氟甲基 ) 硫基 ] 吲嗪之合成 A solution of {8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}methanol (5.00 g, 15.64 mmol, 1.00 equiv) and IBX (10.95 g, 39.09 mmol, 2.50 equiv) in EA (60.00 mL) was stirred at 80 °C for 2 h. The mixture was filtered. The filter cake was washed with EA (3 x 100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / PE (1:5) to give 8-bromo-3-[(trifluoromethyl)thio]indolizine-2-carbaldehyde (4.00 g, 78.93%) as a light yellow solid. LC-MS: (M+H) + found 325.90. Intermediate 57. Synthesis of 8- bromo -2-(3- bromoprop -1- yn -1- yl )-3-[( trifluoromethyl ) thio ] indolizine Step 1. Synthesis of 8- bromo -2- ethynyl -3-[( trifluoromethyl ) thio ] indolizine
將8-溴-3-[(三氟甲基)硫基]吲嗪-2-甲醛(4.00 g,12.34 mmol,1.00當量)、(1-重氮基-2-側氧基丙基)膦酸二甲酯(4.74 g,24.68 mmol,2.00當量)及K 2CO 3(5.12 g,37.02 mmol,3.00當量)於MeOH (15.00mL)中之溶液在0℃及氮氣氛圍下攪拌2 h。所得溶液藉由具有以下條件之反相急速層析純化:管柱,C18;移動相,於水中之MeCN,在20 min內0%至90%梯度;偵測器,UV 254 nm。此產生呈淺黃色固體之8-溴-2-乙炔基-3-[(三氟甲基)硫基]吲嗪(3.16 g,79.98%)。LC-MS:(M+H) +實測值320.10。 步驟 2. 3-{8- 溴 -3-[( 三氟甲基 ) 硫基 ] 吲嗪 -2- 基 } 丙 -2- 炔 -1- 醇之合成 A solution of 8-bromo-3-[(trifluoromethyl)thio]indolizine-2-carbaldehyde (4.00 g, 12.34 mmol, 1.00 equiv), dimethyl (1-diazo-2-oxopropyl)phosphonate (4.74 g, 24.68 mmol, 2.00 equiv) and K 2 CO 3 (5.12 g, 37.02 mmol, 3.00 equiv) in MeOH (15.00 mL) was stirred at 0° C. under nitrogen atmosphere for 2 h. The resulting solution was purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in water, gradient from 0% to 90% in 20 min; detector, UV 254 nm. This produced 8-bromo-2-ethynyl-3-[(trifluoromethyl)thio]indolizine (3.16 g, 79.98%) as a light yellow solid. LC-MS: (M+H) + found 320.10. Step 2. Synthesis of 3-{8- bromo -3-[( trifluoromethyl ) thio ] indolizine -2- yl } prop -2- yn -1- ol
在室溫下,向雙三氟甲磺酸鋅(2+) (7.89 g,21.72 mmol,2.20當量)及TMEDA (2.52 g,21.72 mmol,2.20當量)於甲苯(30.00 mL)中之溶液中添加Et 3N (2.20 g,21.72 mmol,2.20當量)。將反應混合物在室溫及氮氣氛圍下攪拌2 h,接著在室溫下逐滴添加於甲苯(1.00 mL)中之8-溴-2-乙炔基-3-[(三氟甲基)硫基]吲嗪(3.16 g,9.87 mmol,1.00當量)。將混合物在60℃及氮氣氛圍下攪拌1 h。在室溫下向上述混合物中添加POM (1.96 g,21.72 mmol,2.20當量)。將所得混合物在60℃及氮氣氛圍下再攪拌16 h。將所得混合物在減壓下濃縮。殘餘物藉由具有以下條件之反相急速層析純化:管柱,C18;移動相,於水中之MeCN,在20 min內0%至80%梯度;偵測器,UV 254 nm。此產生呈白色固體之3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-醇(2.50 g,72.33%)。LC-MS:(M+H) +實測值350.20。 步驟 3. 8- 溴 -2-(3- 溴丙 -1- 炔 -1- 基 )-3-[( 三氟甲基 ) 硫基 ] 吲嗪之合成 To a solution of zinc(2+) bistrifluoromethanesulfonate (7.89 g, 21.72 mmol, 2.20 equiv) and TMEDA (2.52 g, 21.72 mmol, 2.20 equiv) in toluene (30.00 mL) was added Et3N (2.20 g, 21.72 mmol, 2.20 equiv) at room temperature. The reaction mixture was stirred at room temperature under nitrogen atmosphere for 2 h, and then 8-bromo-2-ethynyl-3-[(trifluoromethyl)thio]indolizine (3.16 g, 9.87 mmol, 1.00 equiv) in toluene (1.00 mL) was added dropwise at room temperature. The mixture was stirred at 60 °C under nitrogen atmosphere for 1 h. POM (1.96 g, 21.72 mmol, 2.20 equiv) was added to the above mixture at room temperature. The resulting mixture was stirred at 60 °C under nitrogen atmosphere for another 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in water, 0% to 80% gradient in 20 min; detector, UV 254 nm. This resulted in 3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-ol (2.50 g, 72.33%) as a white solid. LC-MS: (M+H) + found 350.20. Step 3. Synthesis of 8- bromo -2-(3- bromoprop -1- yn -1- yl )-3-[( trifluoromethyl ) thio ] indolizine
將3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-醇(2.50 g,7.14 mmol,1.00當量)及PPh 3Br 2(3.92 g,9.28 mmol,1.30當量)於DCM (25.00 mL)中之溶液在室溫及氮氣氛圍下攪拌1.5 h。將所得混合物在減壓下濃縮。殘餘物藉由具有以下條件之反相急速層析純化:管柱,C18;移動相,於水中之MeCN,在20 min內0%至80%梯度;偵測器,UV 254 nm。此產生呈淺黃色油狀物之8-溴-2-(3-溴丙-1-炔-1-基)-3-[(三氟甲基)硫基]吲嗪(2.25 g,76.29%)。LC-MS:(M+H) +實測值413.80。 中間物 58. 4-[(3-{8- 溴 -3-[( 三氟甲基 ) 硫基 ] 吲嗪 -2- 基 } 丙 -2- 炔 -1- 基 ) 胺基 ]-3- 甲氧基 -N- 甲基苯甲醯胺之合成 A solution of 3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-ol (2.50 g, 7.14 mmol, 1.00 equiv) and PPh 3 Br 2 (3.92 g, 9.28 mmol, 1.30 equiv) in DCM (25.00 mL) was stirred at room temperature under nitrogen atmosphere for 1.5 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in water, gradient 0% to 80% in 20 min; detector, UV 254 nm. This gave 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizine (2.25 g, 76.29%) as a light yellow oil. LC-MS: (M+H) + found 413.80. Intermediate 58. Synthesis of 4-[(3-{8- bromo -3-[( trifluoromethyl ) thio ] indolizine -2- yl } prop -2- yn -1- yl ) amino ]-3- methoxy - N- methylbenzamide
將8-溴-2-(3-溴丙-1-炔-1-基)-3-[(三氟甲基)硫基]吲嗪( 中間物57,300.00 mg,0.73 mmol,1.00當量)、4-胺基-3-甲氧基-N-甲基苯甲醯胺(143.97 mg,0.80 mmol,1.10當量)及K 2CO 3(301.14 mg,2.18 mmol,3.00當量)於DMF (3.00 mL)中之混合物在70℃下攪拌16 h。所得溶液藉由具有以下條件之反相急速層析純化:管柱,C18;移動相,於水中之MeCN,在20 min內0%至70%梯度;偵測器,UV 254 nm。此產生呈白色固體之4-[(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺(160.00 mg,43.00%)。LC-MS:(M+H) +實測值512.0。 中間物 59. 5-[(3-{8- 溴 -3-[( 三氟甲基 ) 硫基 ] 吲嗪 -2- 基 } 丙 -2- 炔 -1- 基 ) 胺基 ]-6- 甲氧基吡啶 -3- 甲酸酯之合成 A mixture of 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizine ( intermediate 57 , 300.00 mg, 0.73 mmol, 1.00 equiv), 4-amino-3-methoxy-N-methylbenzamide (143.97 mg, 0.80 mmol , 1.10 equiv) and K2CO3 (301.14 mg, 2.18 mmol, 3.00 equiv) in DMF (3.00 mL) was stirred at 70 °C for 16 h. The resulting solution was purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in water, gradient 0% to 70% in 20 min; detector, UV 254 nm. This resulted in 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (160.00 mg, 43.00%) as a white solid. LC-MS: (M+H) + found 512.0. Intermediate 59. Synthesis of 5-[(3-{8- bromo -3-[( trifluoromethyl ) thio ] indolizin -2- yl } prop -2- yn -1- yl ) amino ]-6 - methoxypyridine -3- carboxylate
將8-溴-2-(3-溴丙-1-炔-1-基)-3-[(三氟甲基)硫基]吲嗪( 中間物57,300.00 mg,0.72 mmol,1.00當量)、5-胺基-6-甲氧基吡啶-3-甲酸甲酯(138.93 mg,0.76 mmol,1.05當量)及K 2CO 3(301.14 mg,2.17 mmol,3.00當量)於DMF (3.00 mL)中之溶液在70℃下攪拌2 h。溶液藉由具有以下條件之反相急速層析純化:管柱,C18;移動相,於水中之MeCN (10 mmol/L NH 4HCO 3),在20 min內0%至100%梯度;偵測器,UV 254 nm。此產生呈淺黃色固體之5-[(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)胺基]-6-甲氧基吡啶-3-甲酸甲酯(170.00 mg,45.51%)。LC-MS:(M+H) +實測值514.3。 中間物60. N-{2-甲氧基-5-[甲基({[2-(三甲基矽烷基)乙氧基]甲基})胺磺醯基]苯基}胺基甲酸酯之合成 步驟1. 4-甲氧基-N-甲基-3-硝基苯磺醯胺之合成 A solution of 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizine ( Intermediate 57 , 300.00 mg, 0.72 mmol, 1.00 equiv), methyl 5-amino-6 - methoxypicolinate (138.93 mg, 0.76 mmol, 1.05 equiv) and K2CO3 (301.14 mg, 2.17 mmol, 3.00 equiv) in DMF ( 3.00 mL) was stirred at 70°C for 2 h. The solution was purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN (10 mmol/L NH4HCO3 ) in water, gradient from 0% to 100% in 20 min; detector, UV 254 nm. This gave methyl 5-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-6-methoxypyridine-3-carboxylate (170.00 mg, 45.51%) as a light yellow solid. LC-MS: (M+H) + found 514.3. Intermediate 60. Synthesis of N-{2-methoxy-5-[methyl({[2-(trimethylsilyl)ethoxy]methyl})sulfamoyl]phenyl}carbamate Step 1. Synthesis of 4-methoxy-N-methyl-3-nitrobenzenesulfonamide
在室溫下,向4-甲氧基-3-硝基苯磺醯氯(800.00 mg,3.18 mmol,1.00當量)及CH 3NH 2.HCl (429.31 mg,6.36 mmol,2.00當量)於DCM (10.00 mL)中之攪拌混合物中逐份添加Et 3N (965.12 mg,9.54 mmol,3.00當量)。將所得混合物在室溫及空氣氛圍下攪拌2 h。所得混合物用DCM (50.00 mL)稀釋。合併的有機層用鹽水(3 x 10.00 mL)洗滌且經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物使用具有以下條件(移動相A:水,移動相B:ACN;流動速率:60 mL/min;梯度:在15 min內0% B至100% B;波長:254 nm;220 nm)之C18急速層析純化。此產生呈黃色油狀物之4-甲氧基-N-甲基-3-硝基苯磺醯胺(750.00 mg,95.6%)。LC-MS:(M+H) +實測值247.03。 步驟2.4-甲氧基-N-甲基-3-硝基-N-{[2-(三甲基矽烷基)乙氧基]甲基}苯磺醯胺 之合成 To a stirred mixture of 4-methoxy-3-nitrobenzenesulfonyl chloride (800.00 mg, 3.18 mmol, 1.00 equiv) and CH 3 NH 2. HCl (429.31 mg, 6.36 mmol, 2.00 equiv) in DCM (10.00 mL) was added Et 3 N (965.12 mg, 9.54 mmol, 3.00 equiv) portionwise at room temperature. The resulting mixture was stirred at room temperature under air atmosphere for 2 h. The resulting mixture was diluted with DCM (50.00 mL). The combined organic layers were washed with brine (3 x 10.00 mL) and dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by C18 flash chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 15 min; wavelength: 254 nm; 220 nm). This produced 4-methoxy-N-methyl-3-nitrobenzenesulfonamide (750.00 mg, 95.6%) as a yellow oil. LC-MS: (M+H) + found 247.03. Step 2. Synthesis of 4-methoxy-N-methyl-3-nitro-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide
在0℃及氮氣氛圍下,向4-甲氧基-N-甲基-3-硝基苯磺醯胺(600.00 mg,2.44 mmol,1.00當量)於THF (10.00 mL)中之攪拌混合物中逐份添加NaH (60%,195.20 mg,4.88 mmol,2.00當量)。將混合物在室溫及氮氣氛圍下攪拌1 h。在0℃下向上述混合物中逐滴添加SEM-Cl (812.48 mg,4.87 mmol,2.00當量)。將所得混合物在室溫下攪拌1 h。在0℃下用水淬滅反應。將所得混合物在減壓下濃縮。殘餘物使用具有以下條件(移動相A:水,移動相B:ACN;流動速率:60 mL/min;梯度:在15 min內0% B至100% B;波長:254 nm;220 nm)之C18急速層析純化。此產生呈黃色油狀物之4-甲氧基-N-甲基-3-硝基-N-{[2-(三甲基矽烷基)乙氧基]甲基}苯磺醯胺(700.00 mg,76.3%)。LC-MS:(M+H) +實測值377.11。 步驟3. 3-胺基-4-甲氧基-N-甲基-N-{[2-(三甲基矽烷基)乙氧基]甲基}苯磺醯胺之合成 To a stirred mixture of 4-methoxy-N-methyl-3-nitrobenzenesulfonamide (600.00 mg, 2.44 mmol, 1.00 equiv) in THF (10.00 mL) at 0°C under nitrogen atmosphere was added NaH (60%, 195.20 mg, 4.88 mmol, 2.00 equiv) portionwise. The mixture was stirred at room temperature under nitrogen atmosphere for 1 h. To the above mixture was added SEM-Cl (812.48 mg, 4.87 mmol, 2.00 equiv) dropwise at 0°C. The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with water at 0°C. The resulting mixture was concentrated under reduced pressure. The residue was purified by C18 flash chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 15 min; wavelength: 254 nm; 220 nm). This produced 4-methoxy-N-methyl-3-nitro-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide (700.00 mg, 76.3%) as a yellow oil. LC-MS: (M+H) + found 377.11. Step 3. Synthesis of 3-amino-4-methoxy-N-methyl-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide
在室溫及氮氣氛圍下,向4-甲氧基-N-甲基-3-硝基-N-{[2-(三甲基矽烷基)乙氧基]甲基}苯磺醯胺(700.00 mg,1.86 mmol,1.00當量)於i-PrOH (10.00 mL)中之攪拌混合物中逐份添加Pd/C (100.00 mg)。將所得混合物在室溫及氫氣氛圍下攪拌8 h。過濾所得混合物且濾餅用CH 2Cl 2(3 x 20.00 mL)洗滌。將濾液在減壓下濃縮。此產生呈黃色油狀物之3-胺基-4-甲氧基-N-甲基-N-{[2-(三甲基矽烷基)乙氧基]甲基}苯磺醯胺(500 mg,77.6%)。LC-MS:(M+H) +實測值347.14。 步驟4. N-{2-甲氧基-5-[甲基({[2-(三甲基矽烷基)乙氧基]甲基})胺磺醯基]苯基}胺基甲酸三級丁酯之合成 To a stirred mixture of 4-methoxy-N-methyl-3-nitro-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide (700.00 mg, 1.86 mmol, 1.00 equiv) in i-PrOH (10.00 mL) at room temperature under nitrogen atmosphere was added Pd/C (100.00 mg) portionwise. The resulting mixture was stirred at room temperature under hydrogen atmosphere for 8 h. The resulting mixture was filtered and the filter cake was washed with CH 2 Cl 2 (3 x 20.00 mL). The filtrate was concentrated under reduced pressure. This produced 3-amino-4-methoxy-N-methyl-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide (500 mg, 77.6%) as a yellow oil. LC-MS: (M+H) + found 347.14. Step 4. Synthesis of tributyl N-{2-methoxy-5-[methyl({[2-(trimethylsilyl)ethoxy]methyl})sulfonylamine]phenyl}carbamate
在室溫及氮氣氛圍下,向3-胺基-4-甲氧基-N-甲基-N-{[2-(三甲基矽烷基)乙氧基]甲基}苯磺醯胺(450.00 mg,1.30 mmol,1.00當量)及(Boc) 2O (283.42 mg,1.30 mmol,1.00當量)於二噁烷(5.00 mL)中之攪拌溶液中逐份添加DMAP (158.65 mg,1.30 mmol,1.00當量)。將所得混合物在100℃及氮氣氛圍下攪拌8 h。將所得混合物在減壓下濃縮。殘餘物使用具有以下條件(移動相A:水,移動相B:ACN;流動速率:60 mL/min;梯度:在15 min內0% B至100% B;波長:254 nm;220 nm)之C18急速層析純化。此產生呈黃色油狀物之N-{2-甲氧基-5-[甲基({[2-(三甲基矽烷基)乙氧基]甲基})胺磺醯基]苯基}胺基甲酸三級丁酯(350.00 mg,60.3%)。LC-MS:(M+H) +實測值447.19。 中間物61. 6-胺基-5-甲氧基-N-甲基吡啶-2-甲醯胺之合成 步驟1. 6-胺基-5-甲氧基-N-甲基吡啶-2-甲醯胺之合成 To a stirred solution of 3-amino-4-methoxy-N-methyl-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide (450.00 mg, 1.30 mmol, 1.00 equiv) and (Boc) 2O (283.42 mg, 1.30 mmol, 1.00 equiv) in dioxane (5.00 mL) was added DMAP (158.65 mg, 1.30 mmol, 1.00 equiv) portionwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 °C under nitrogen atmosphere for 8 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by C18 flash chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 15 min; wavelength: 254 nm; 220 nm). This yielded tributyl N-{2-methoxy-5-[methyl({[2-(trimethylsilyl)ethoxy]methyl})sulfonamido]phenyl}carbamate (350.00 mg, 60.3%) as a yellow oil. LC-MS: (M+H) + found 447.19. Intermediate 61. Synthesis of 6-amino-5-methoxy-N-methylpyridine-2-carboxamide Step 1. Synthesis of 6-amino-5-methoxy-N-methylpyridine-2-carboxamide
在室溫下,向5-甲氧基-6-硝基吡啶-2-甲酸(400.00 mg,2.02 mmol,1.00當量)及HATU (1.15 g,3.03 mmol,1.50當量)於DMF (5.00 mL)中之攪拌混合物中逐份添加DIEA (782.79 mg,6.06 mmol,3.00當量)及CH 3NH 2HCl (204.47 mg,3.03 mmol,1.50當量)。將所得混合物在室溫下攪拌1 h。所得溶液藉由具有以下條件之反相急速層析純化:管柱,C18;移動相,於水中之MeCN,在20 min內10%至100%梯度;偵測器,UV 254 nm。此產生呈白色固體之5-甲氧基-N-甲基-6-硝基吡啶-2-甲醯胺(310 mg,72.71%)。LC-MS:(M+H) +實測值:212.15。 步驟2. 6-胺基-5-甲氧基-N-甲基吡啶-2-甲醯胺之合成 To a stirred mixture of 5-methoxy-6-nitropyridine-2-carboxylic acid (400.00 mg, 2.02 mmol, 1.00 equiv) and HATU (1.15 g, 3.03 mmol, 1.50 equiv) in DMF (5.00 mL) was added DIEA ( 782.79 mg, 6.06 mmol, 3.00 equiv) and CH3NH2HCl ( 204.47 mg, 3.03 mmol, 1.50 equiv) portionwise at room temperature. The resulting mixture was stirred at room temperature for 1 h. The resulting solution was purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in water, gradient from 10% to 100% in 20 min; detector, UV 254 nm. This gave 5-methoxy-N-methyl-6-nitropyridine-2-carboxamide (310 mg, 72.71%) as a white solid. LC-MS: (M+H) + found: 212.15. Step 2. Synthesis of 6-amino-5-methoxy-N-methylpyridine-2-carboxamide
在室溫及氮氣氛圍下,向5-甲氧基-N-甲基-6-硝基吡啶-2-甲醯胺(310.00 mg,1.47 mmol,1.00當量)於IPA (6.00 mL)中之攪拌溶液中逐份添加Pd/C (31.00 mg)。將所得混合物在室溫及氫氣氛圍下攪拌16 h。過濾所得混合物且濾餅用CH 2Cl 2(5x10 mL)洗滌。將濾液在減壓下濃縮,以得到呈白色固體之6-胺基-5-甲氧基-N-甲基吡啶-2-甲醯胺(240 mg,90.23%)。LC-MS:(M+H) +實測值:182.15。 中間物62. 6-胺基-5-甲氧基-N-甲基吡啶-2-甲醯胺之合成 步驟 1. 8- 溴 -3-[( 二氟甲基 ) 硫基 ] 吲嗪 -2- 甲酸甲酯之合成 To a stirred solution of 5-methoxy-N-methyl-6-nitropyridine-2-carboxamide (310.00 mg, 1.47 mmol, 1.00 equiv) in IPA (6.00 mL) was added Pd/C (31.00 mg) portionwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature under hydrogen atmosphere for 16 h. The resulting mixture was filtered and the filter cake was washed with CH 2 Cl 2 (5×10 mL). The filtrate was concentrated under reduced pressure to give 6-amino-5-methoxy-N-methylpyridine-2-carboxamide (240 mg, 90.23%) as a white solid. LC-MS: (M+H) + found: 182.15. Intermediate 62. Synthesis of 6-amino-5-methoxy-N-methylpyridine-2-carboxamide Step 1. Synthesis of 8- bromo -3-[( difluoromethyl ) thio ] indolizine -2- carboxylic acid methyl ester
向8-溴吲嗪-2-甲酸甲酯(2.00 g,4.72 mmol,1.00當量,60%)於DCE (30.00 mL)中之攪拌溶液中添加2-[(二氟甲基)硫基]異吲哚-1,3-二酮(1.30 g,5.67 mmol,1.20當量)及TMSCl (769.64 mg,7.09 mmol,1.50當量)。將所得混合物在90℃及氮氣氛圍下攪拌5 h。將所得混合物在減壓下濃縮。殘餘物藉由具有以下條件之反相急速層析純化:管柱,C18;移動相,於水中之MeCN,在20 min內0%至70%梯度;偵測器,UV 254 nm。此產生呈淺黃色固體之8-溴-3-[(二氟甲基)硫基]吲嗪-2-甲酸甲酯(1.50 g,94.48%)。LC-MS:(M+H) +實測值336.05。 步驟 2. {8- 溴 -3-[( 二氟甲基 ) 硫基 ] 吲嗪 -2- 基 } 甲醇之合成 To a stirred solution of methyl 8-bromoindolizine-2-carboxylate (2.00 g, 4.72 mmol, 1.00 equiv, 60%) in DCE (30.00 mL) were added 2-[(difluoromethyl)thio]isoindole-1,3-dione (1.30 g, 5.67 mmol, 1.20 equiv) and TMSCl (769.64 mg, 7.09 mmol, 1.50 equiv). The resulting mixture was stirred at 90 °C under nitrogen atmosphere for 5 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in water, gradient from 0% to 70% in 20 min; detector, UV 254 nm. This produced methyl 8-bromo-3-[(difluoromethyl)thio]indolizine-2-carboxylate (1.50 g, 94.48%) as a light yellow solid. LC-MS: (M+H) + found 336.05. Step 2. Synthesis of {8- bromo -3-[( difluoromethyl ) thio ] indolizine -2- yl } methanol
在-30℃及氮氣氛圍下,向8-溴-3-[(二氟甲基)硫基]吲嗪-2-甲酸甲酯(1.50 g,4.46 mmol,1.00當量)於DCM (20.00 mL)中之攪拌溶液中逐滴添加DIBAL-H (1M於甲苯中,8.92 mL,8.92 mmol,2.00當量)。將所得混合物在-20℃及氮氣氛圍下攪拌1 h。在0℃下用Na 2SO 4 .10H 2O淬滅反應。過濾所得混合物。濾餅用EA洗滌。將濾液在減壓下濃縮。此產生呈深灰色固體之{8-溴-3-[(二氟甲基)硫基]吲嗪-2-基}甲醇(1.4 g,粗物質)。LC-MS:(M+H) +實測值308.00。 中間物 63. 8- 溴 -3-[( 二氟甲基 ) 硫基 ]-2- 乙炔基吲嗪之合成 步驟 1. 8- 溴 -3-[( 二氟甲基 ) 硫基 ] 吲嗪 -2- 甲醛之合成 To a stirred solution of methyl 8-bromo-3-[(difluoromethyl)thio]indolizine-2-carboxylate (1.50 g, 4.46 mmol, 1.00 equiv) in DCM (20.00 mL) was added DIBAL-H (1M in toluene, 8.92 mL, 8.92 mmol, 2.00 equiv) dropwise at -30 °C under nitrogen atmosphere. The resulting mixture was stirred at -20 °C under nitrogen atmosphere for 1 h. The reaction was quenched with Na 2 SO 4 .10H 2 O at 0 °C. The resulting mixture was filtered. The filter cake was washed with EA. The filtrate was concentrated under reduced pressure. This resulted in {8-bromo-3-[(difluoromethyl)thio]indolizin-2-yl}methanol (1.4 g, crude) as a dark grey solid. LC-MS: (M+H) + found 308.00. Intermediate 63. Synthesis of 8- bromo -3-[( difluoromethyl ) thio ]-2- ethynylindolizine Step 1. Synthesis of 8- bromo -3-[( difluoromethyl ) thio ] indolizine -2- carbaldehyde
向{8-溴-3-[(二氟甲基)硫基]吲嗪-2-基}甲醇(1.40 g,4.54 mmol,1.00當量)於EtOAc (20.00 mL)中之攪拌溶液中添加IBX (3.18 g,11.36 mmol,2.50當量)。將所得混合物在80℃下攪拌2 h。過濾所得混合物。濾餅用乙酸乙酯洗滌。將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用PE / EA (5:1)溶析,以得到呈黃色固體之8-溴-3-[(二氟甲基)硫基]吲嗪-2-甲醛(1.38 g,99.22%)。LC-MS:(M+H) +實測值305.95。 步驟 2. 8- 溴 -3-[( 二氟甲基 ) 硫基 ]-2- 乙炔基吲嗪之合成 To a stirred solution of {8-bromo-3-[(difluoromethyl)thio]indolizin-2-yl}methanol (1.40 g, 4.54 mmol, 1.00 equiv) in EtOAc (20.00 mL) was added IBX (3.18 g, 11.36 mmol, 2.50 equiv). The resulting mixture was stirred at 80 °C for 2 h. The resulting mixture was filtered. The filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (5:1) to give 8-bromo-3-[(difluoromethyl)thio]indolizine-2-carbaldehyde (1.38 g, 99.22%) as a yellow solid. LC-MS: (M+H) + found 305.95. Step 2. Synthesis of 8- bromo -3-[( difluoromethyl ) thio ]-2- ethynylindolizine
在0℃下,向8-溴-3-[(二氟甲基)硫基]吲嗪-2-甲醛(1.30 g,4.25 mmol,1.00當量)於MeOH (20.00 mL)中之攪拌溶液中添加(1-重氮基-2-側氧基丙基)膦酸二甲酯(1.63g,8.50 mmol,2當量)及K 2CO 3(1.76 g,12.74 mmol,3.00當量)。將所得混合物在0℃及氮氣氛圍下攪拌2 h。所得溶液藉由具有以下條件之反相急速層析純化:管柱,C18;移動相,於水中之MeCN,在20 min內0%至80%梯度;偵測器,UV 254 nm。此產生呈淺黃色固體之8-溴-3-[(二氟甲基)硫基]-2-乙炔基吲嗪(1.23 g,95.86%)。LC-MS:(M+H) +實測值302.00。 中間物 64. 8- 溴 -2-(3- 溴丙 -1- 炔 -1- 基 )-3-[( 二氟甲基 ) 硫基 ] 吲嗪之合成 步驟 1. 3-{8- 溴 -3-[( 二氟甲基 ) 硫基 ] 吲嗪 -2- 基 } 丙 -2- 炔 -1- 醇之合成 To a stirred solution of 8-bromo-3-[(difluoromethyl)thio]indolizine-2-carbaldehyde (1.30 g, 4.25 mmol, 1.00 equiv) in MeOH (20.00 mL) at 0°C was added dimethyl (1-diazo-2-oxopropyl)phosphonate (1.63 g, 8.50 mmol, 2 equiv) and K 2 CO 3 (1.76 g, 12.74 mmol, 3.00 equiv). The resulting mixture was stirred at 0°C under nitrogen atmosphere for 2 h. The resulting solution was purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in water, gradient from 0% to 80% in 20 min; detector, UV 254 nm. This produced 8-bromo-3-[(difluoromethyl)thio]-2-ethynylindolizine (1.23 g, 95.86%) as a light yellow solid. LC-MS: (M+H) + found 302.00. Intermediate 64. Synthesis of 8- bromo -2-(3- bromoprop -1- yn -1- yl )-3-[( difluoromethyl ) thio ] indolizine Step 1. Synthesis of 3-{8- bromo -3-[( difluoromethyl ) thio ] indolizin -2- yl } prop -2- yn-1 - ol
向雙三氟甲磺酸鋅(2+) (3.18g,8.73 mmol,2.20當量)於甲苯(30.00 mL)中之攪拌溶液中添加TMEDA (1.02 g,8.73 mmol,2.20當量)及Et 3N (884.20 mg,8.73 mmol,2.20當量)。將所得混合物在室溫及氮氣氛圍下攪拌2 h。在室溫下向上述混合物中添加8-溴-3-[(二氟甲基)硫基]-2-乙炔基吲嗪(1.20 g,3.97 mmol,1.00當量)。將所得混合物在60℃下再攪拌1 h。在室溫下向上述混合物中以一份添加POM (1.07 g,11.91 mmol,3.00當量)。將所得混合物在60℃下再攪拌1 h。將所得混合物在減壓下濃縮。殘餘物藉由具有以下條件之反相急速層析純化:管柱,C18;移動相,於水中之MeCN,在20 min內0%至65%梯度;偵測器,UV 254 nm。此產生呈淺灰色固體之3-{8-溴-3-[(二氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-醇(1.16 g,87.93%)。LC-MS:(M+H) +實測值331.95。 步驟 2. 8- 溴 -2-(3- 溴丙 -1- 炔 -1- 基 )-3-[( 二氟甲基 ) 硫基 ] 吲嗪之合成 To a stirred solution of zinc(2+) bistrifluoromethanesulfonate (3.18 g, 8.73 mmol, 2.20 equiv) in toluene (30.00 mL) were added TMEDA (1.02 g, 8.73 mmol, 2.20 equiv) and Et3N (884.20 mg, 8.73 mmol, 2.20 equiv). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 h. To the above mixture was added 8-bromo-3-[(difluoromethyl)thio]-2-ethynylindolizine (1.20 g, 3.97 mmol, 1.00 equiv) at room temperature. The resulting mixture was stirred at 60 °C for another 1 h. To the above mixture was added POM (1.07 g, 11.91 mmol, 3.00 equiv) in one portion at room temperature. The resulting mixture was stirred at 60 °C for another 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in water, gradient 0% to 65% in 20 min; detector, UV 254 nm. This produced 3-{8-bromo-3-[(difluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-ol (1.16 g, 87.93%) as a light grey solid. LC-MS: (M+H) + found 331.95. Step 2. Synthesis of 8- bromo -2-(3- bromoprop -1- yn -1- yl )-3-[( difluoromethyl ) thio ] indolizine
向3-{8-溴-3-[(二氟甲基)s硫基]吲嗪-2-基}丙-2-炔-1-醇(1.17 g,3.52 mmol,1.00當量)於DCM (15.00 mL)中之攪拌溶液中添加PPh 3Br 2(1.93 g,4.58 mmol,1.30當量)。將反應混合物在室溫下攪拌1 h。將所得混合物在減壓下濃縮。殘餘物藉由具有以下條件之反相急速層析純化:管柱,C18;移動相,於水中之MeCN,在20 min內0%至80%梯度;偵測器,UV 254 nm。此產生呈淺黃色固體之8-溴-2-(3-溴丙-1-炔-1-基)-3-[(二氟甲基)硫基]吲嗪(880.00 mg,63.24%)。LC-MS:(M+H) +實測值393.95。 中間物 65. 5- 氯吲嗪 -2- 甲酸甲酯之合成 步驟1. 2-[(6-氯吡啶-2-基)(羥基)甲基]丙-2-烯酸甲酯之合成 To a stirred solution of 3-{8-bromo-3-[(difluoromethyl)sulfanyl]indolizin-2-yl}prop-2-yn-1-ol (1.17 g, 3.52 mmol, 1.00 equiv) in DCM (15.00 mL) was added PPh 3 Br 2 (1.93 g, 4.58 mmol, 1.30 equiv). The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in water, gradient 0% to 80% in 20 min; detector, UV 254 nm. This produced 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(difluoromethyl)thio]indolizine (880.00 mg, 63.24%) as a light yellow solid. LC-MS: (M+H) + found 393.95. Intermediate 65. Synthesis of methyl 5- chloroindolizine -2- carboxylate Step 1. Synthesis of methyl 2-[(6-chloropyridin-2-yl)(hydroxy)methyl]prop-2-enoate
將6-氯吡啶-2-甲醛(6 g,42.388 mmol,1當量)及丙烯酸甲酯(4.38 g,50.866 mmol,1.2當量)、1,4-二氮雜雙環[2.2.2]辛烷(290 mg,2.543 mmol,0.06當量) 於二噁烷(45 mL)、H 2O (15 mL)中之混合物在室溫及氮氣氛圍下攪拌3h。將所得混合物在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用PE / EA (5:1)溶析,以得到呈黃色固體之2-[(6-氯吡啶-2-基)(羥基)甲基]丙-2-烯酸甲酯(6.5 g,63.05%)。LC-MS:(M+H) +實測值228。 步驟 2. 8- 溴 -2-(3- 溴丙 -1- 炔 -1- 基 )-3-[( 二氟甲基 ) 硫基 ] 吲嗪之合成 A mixture of 6-chloropyridine-2-carbaldehyde (6 g, 42.388 mmol, 1 eq.), methyl acrylate (4.38 g, 50.866 mmol, 1.2 eq.), 1,4-diazabicyclo[2.2.2]octane (290 mg, 2.543 mmol, 0.06 eq.) in dioxane (45 mL) and H 2 O (15 mL) was stirred at room temperature under nitrogen atmosphere for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (5:1) to give methyl 2-[(6-chloropyridin-2-yl)(hydroxy)methyl]prop-2-enoate (6.5 g, 63.05%) as a yellow solid. LC-MS: (M+H) + found 228. Step 2. Synthesis of 8- bromo -2-(3- bromoprop -1- yn -1- yl )-3-[( difluoromethyl ) thio ] indolizine
將2-[(6-氯吡啶-2-基)(羥基)甲基]丙-2-烯酸甲酯(3 g,13.179 mmol,1當量) 於AC 2O (58.80 mL)中之混合物在100℃及氮氣氛圍下攪拌6h。可藉由LCMS偵測所需產物。所得混合物無需進一步純化直接用於下一步驟中。LC-MS:(M+H) +實測值270。 步驟 3. 5- 氯吲嗪 -2- 甲酸甲酯之合成 A mixture of methyl 2-[(6-chloropyridin-2-yl)(hydroxy)methyl]prop-2-enoate (3 g, 13.179 mmol, 1 eq.) in AC 2 O (58.80 mL) was stirred at 100° C. under nitrogen atmosphere for 6 h. The desired product was detected by LCMS. The resulting mixture was used directly in the next step without further purification. LC-MS: (M+H) + found 270. Step 3. Synthesis of methyl 5- chloroindolizine -2- carboxylate
將步驟2之所得混合物在160℃及氮氣氛圍下攪拌10h。可藉由LCMS偵測所需產物。使混合物冷卻至室溫。當倒入冰及飽和碳酸氫鈉水溶液之混合物中時,攪拌1小時,用EtOAc (3x10 mL)萃取水層。將所得混合物在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用PE / EA (5:1)溶析,以得到呈白色固體之5-氯吲嗪-2-甲酸甲酯(3 g)。LC-MS:(M+H) +實測值210。 中間物 66. 5- 氯 -1-[( 三氟甲基 ) 硫基 ] 吲嗪 -2- 甲酸甲酯之合成 步驟 1. 1- 溴 -5- 氯吲嗪 -2- 甲酸甲酯之合成 The resulting mixture of step 2 was stirred at 160° C. under nitrogen atmosphere for 10 h. The desired product can be detected by LCMS. The mixture was cooled to room temperature. When poured into a mixture of ice and saturated aqueous sodium bicarbonate solution, stirred for 1 hour, the aqueous layer was extracted with EtOAc (3×10 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (5:1) to give 5-chloroindolizine-2-carboxylic acid methyl ester (3 g) as a white solid. LC-MS: (M+H) + found 210. Intermediate 66. Synthesis of 5- chloro -1-[( trifluoromethyl ) thio ] indolizine -2- carboxylic acid methyl ester Step 1. Synthesis of 1- bromo -5- chloroindolizine -2- carboxylic acid methyl ester
在-78℃及氮氣氛圍下,向5-氯吲嗪-2-甲酸甲酯(2 g,9.541 mmol,1當量)於DCM (20 mL)中之攪拌混合物中逐滴添加於DCM (0.5 mL)中之Br 2(0.4 mL,8.587 mmol,0.90當量)。將所得混合物在-78℃及氮氣氛圍下攪拌0.5h。可藉由LCMS偵測所需產物。用水淬滅反應,分離有機相,用10%硫代硫酸鈉水溶液(20 mL)洗滌,經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由具有以下條件之反相急速層析純化:管柱,C18矽膠;移動相,於水中之MeCN (10 mmol/L NH 4HCO 3),在30 min內60%至100%梯度;偵測器,UV 254 nm。此產生呈白色固體之1-溴-5-氯吲嗪-2-甲酸甲酯(1 g,34.51%)。LC-MS:(M+H) +實測值288。 步驟 2. 5- 氯 -1- 碘吲嗪 -2- 甲酸甲酯之合成 To a stirred mixture of methyl 5-chloroindolizine-2-carboxylate (2 g, 9.541 mmol, 1 eq.) in DCM (20 mL) at -78 °C under nitrogen atmosphere was added Br 2 (0.4 mL, 8.587 mmol, 0.90 eq.) in DCM (0.5 mL) dropwise. The resulting mixture was stirred at -78 °C under nitrogen atmosphere for 0.5 h. The desired product could be detected by LCMS. The reaction was quenched with water, and the organic phase was separated, washed with 10% aqueous sodium thiosulfate solution (20 mL), and dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH 4 HCO 3 ) in water, gradient 60% to 100% in 30 min; detector, UV 254 nm. This yielded methyl 1-bromo-5-chloroindolizine-2-carboxylate (1 g, 34.51%) as a white solid. LC-MS: (M+H) + found 288. Step 2. Synthesis of methyl 5 - chloro -1- iodoindolizine -2- carboxylate
將1-溴-5-氯吲嗪-2-甲酸甲酯(1 g,3.466 mmol,1當量)及KI (1.73 g,10.398 mmol,3當量)、CuI (1.98 g,10.398 mmol,3當量)於DMF (10 mL)中之混合物在130℃及氮氣氛圍下攪拌隔夜。可藉由LCMS偵測所需產物。使混合物冷卻至室溫。殘餘物藉由具有以下條件之反相急速層析純化:管柱,C18矽膠;移動相,於水中之MeCN (0.1% FA),在30 min內10%至100%梯度;偵測器,UV 254 nm,以得到呈棕色固體之5-氯-1-碘吲嗪-2-甲酸甲酯(1.07 g,91.55%)。LC-MS:(M+H) +實測值336。 步驟 3. 5- 氯 -1-[( 三氟甲基 ) 硫基 ] 吲嗪 -2- 甲酸甲酯之合成 A mixture of methyl 1-bromo-5-chloroindolizine-2-carboxylate (1 g, 3.466 mmol, 1 eq.) and KI (1.73 g, 10.398 mmol, 3 eq.), CuI (1.98 g, 10.398 mmol, 3 eq.) in DMF (10 mL) was stirred at 130 °C under nitrogen atmosphere overnight. The desired product could be detected by LCMS. The mixture was cooled to room temperature. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient from 10% to 100% in 30 min; detector, UV 254 nm to give methyl 5-chloro-1-iodoindolizine-2-carboxylate (1.07 g, 91.55%) as a brown solid. LC-MS: (M+H) + found 336. Step 3. Synthesis of methyl 5- chloro -1-[( trifluoromethyl ) thio ] indolizine -2- carboxylate
將5-氯-1-碘吲嗪-2-甲酸甲酯(2.3 g,6.855 mmol,1當量)、CuI (2.61 g,13.710 mmol,2當量)、(三氟甲基)硫化銀(1+) (4.30 g,20.565 mmol,3當量)及2,2'-聯吡啶(2.14 g,13.710 mmol,2當量)於ACN (23 mL)中之混合物在90℃及氮氣氛圍下攪拌隔夜。可藉由LCMS偵測所需產物。使混合物冷卻至室溫。藉由在0℃下添加飽和NH 4Cl(水溶液) (10mL)來淬滅反應。過濾所得混合物,濾餅用CH 2Cl 2(3x10 mL)洗滌。將濾液在減壓下濃縮。所得混合物用CH 2Cl 2(3 x 10 mL)萃取。合併的有機層用鹽水(3x10 mL)洗滌、經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由具有以下條件之反相急速層析純化:管柱,C18矽膠;移動相,於水中之MeCN (0.1% FA),在35 min內20%至100%梯度;偵測器,UV 254 nm(85%)。此產生呈棕色固體之5-氯-1-[(三氟甲基)硫基]吲嗪-2-甲酸甲酯(1.05 g,49.46%)。LC-MS:(M+H) +實測值310。 中間物 67. 5- 氯 -2- 乙炔基 -1-[( 三氟甲基 ) 硫基 ] 吲嗪之合成 步驟 1. {5- 氯 -1-[( 三氟甲基 ) 硫基 ] 吲嗪 -2- 基 } 甲醇之合成 A mixture of methyl 5-chloro-1-iodoindolizine-2-carboxylate (2.3 g, 6.855 mmol, 1 eq.), CuI (2.61 g, 13.710 mmol, 2 eq.), (trifluoromethyl)silver(1+) sulfide (4.30 g, 20.565 mmol, 3 eq.) and 2,2'-bipyridine (2.14 g, 13.710 mmol, 2 eq.) in ACN (23 mL) was stirred at 90 °C under nitrogen atmosphere overnight. The desired product could be detected by LCMS. The mixture was cooled to room temperature. The reaction was quenched by the addition of saturated NH4Cl (aq.) (10 mL) at 0 °C. The resulting mixture was filtered and the filter cake was washed with CH2Cl2 ( 3x10 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was extracted with CH 2 Cl 2 (3 x 10 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient from 20% to 100% in 35 min; detector, UV 254 nm (85%). This gave methyl 5-chloro-1-[(trifluoromethyl)thio]indolizine-2-carboxylate (1.05 g, 49.46%) as a brown solid. LC-MS: (M+H) + found 310. Intermediate 67. Synthesis of 5- chloro -2- ethynyl -1-[( trifluoromethyl ) thio ] indolizine Step 1. Synthesis of {5- chloro -1-[( trifluoromethyl ) thio ] indolizine -2- yl } methanol
將5-氯-1-[(三氟甲基)硫基]吲嗪-2-甲酸甲酯(1.2 g,3.875 mmol,1當量)於DCM (12 mL)中之溶液保持在室溫及氮氣氛圍下,接著在-20℃下逐滴添加DIBAl-H/1M DCM (1.65 g,12 mL,11.625 mmol,3當量)。將所得混合物在-20℃及氮氣氛圍下攪拌1h。藉由在-20℃下添加Na2SO4.10H2O來淬滅反應。過濾所得混合物,濾餅用CH2Cl2 (3x10 mL)洗滌。將濾液在減壓下濃縮。此產生呈棕色固體之{5-氯-1-[(三氟甲基)硫基]吲嗪-2-基}甲醇(975 mg,89.33%)。粗產物無需進一步純化直接用於下一步驟中。LC-MS:(M+H) +實測值282。 步驟 2. 5- 氯 -1-[( 三氟甲基 ) 硫基 ] 吲嗪 -2- 甲醛之合成 A solution of methyl 5-chloro-1-[(trifluoromethyl)thio]indolizine-2-carboxylate (1.2 g, 3.875 mmol, 1 eq) in DCM (12 mL) was kept at room temperature under nitrogen atmosphere, and then DIBAl-H/1M DCM (1.65 g, 12 mL, 11.625 mmol, 3 eq) was added dropwise at -20 °C. The resulting mixture was stirred at -20 °C under nitrogen atmosphere for 1 h. The reaction was quenched by adding Na2SO4.10H2O at -20 °C. The resulting mixture was filtered and the filter cake was washed with CH2Cl2 (3x10 mL). The filtrate was concentrated under reduced pressure. This gave {5-chloro-1-[(trifluoromethyl)thio]indolizine-2-yl}methanol (975 mg, 89.33%) as a brown solid. The crude product was used directly in the next step without further purification. LC-MS: (M+H) + found 282. Step 2. Synthesis of 5- chloro -1-[( trifluoromethyl ) thio ] indolizine -2- carbaldehyde
將{5-氯-1-[(三氟甲基)硫基]吲嗪-2-基}甲醇(975 mg,3.461 mmol,1當量)於EA (10 mL)中之溶液保持在室溫及氮氣氛圍下,接著在室溫下逐份添加IBX (2.91 g,10.383 mmol,3當量)。將所得混合物在80℃及氮氣氛圍下攪拌4h。藉由LCMS監測反應。可藉由LCMS偵測所需產物。使混合物冷卻至室溫。過濾所得混合物,濾餅用EtOAc (3x8 mL)洗滌。將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用PE / EA (10:1)溶析,以得到呈黑色固體之5-氯-1-[(三氟甲基)硫基]吲嗪-2-甲醛(824 mg,85.12%)。LC-MS:(M+H) +實測值280。 步驟 3. 5- 氯 -2- 乙炔基 -1-[( 三氟甲基 ) 硫基 ] 吲嗪之合成 A solution of {5-chloro-1-[(trifluoromethyl)thio]indolizin-2-yl}methanol (975 mg, 3.461 mmol, 1 eq.) in EA (10 mL) was kept at room temperature under nitrogen atmosphere, and then IBX (2.91 g, 10.383 mmol, 3 eq.) was added portionwise at room temperature. The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 4 h. The reaction was monitored by LCMS. The desired product could be detected by LCMS. The mixture was cooled to room temperature. The resulting mixture was filtered and the filter cake was washed with EtOAc (3x8 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (10:1) to give 5-chloro-1-[(trifluoromethyl)thio]indolizine-2-carbaldehyde (824 mg, 85.12%) as a black solid. LC-MS: (M+H) + found 280. Step 3. Synthesis of 5- chloro -2- ethynyl -1-[( trifluoromethyl ) thio ] indolizine
在0℃及氮氣氛圍下,向5-氯-1-[(三氟甲基)硫基]吲嗪-2-甲醛(709 mg,2.535 mmol,1當量)於MeOH (7 mL)中之攪拌混合物中逐滴添加塞費特-吉爾伯特同系物(0.8 mL,5.070 mmol,2當量)及K 2CO 3(1.05 g,7.605 mmol,3當量)。將所得混合物在0℃及氮氣氛圍下攪拌2h。藉由LCMS監測反應。可藉由LCMS偵測所需產物。藉由在0℃下添加酒石酸鉀鈉(10 mL)來淬滅反應。過濾所得混合物,濾餅用EtOAc (3x10 mL)洗滌。殘餘物藉由矽膠管柱層析純化,用PE / EA (10:1)溶析,以得到呈黃色固體之5-氯-2-乙炔基-1-[(三氟甲基)硫基]吲嗪(420 mg,60.10%)。LC-MS:(M+H) +實測值276。 中間物 68. 2-(3- 溴丙 -1- 炔 -1- 基 )-5- 氯 -1-[( 三氟甲基 ) 硫基 ] 吲嗪之合成 步驟 1. 3-{5- 氯 -1-[( 三氟甲基 ) 硫基 ] 吲嗪 -2- 基 } 丙 -2- 炔 -1- 醇之合成 To a stirred mixture of 5-chloro-1-[(trifluoromethyl)thio]indolizine-2-carbaldehyde (709 mg, 2.535 mmol, 1 eq) in MeOH (7 mL) at 0°C under nitrogen atmosphere was added Seyfert-Gilbert homolog (0.8 mL, 5.070 mmol, 2 eq) and K 2 CO 3 (1.05 g, 7.605 mmol, 3 eq) dropwise. The resulting mixture was stirred at 0°C under nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The desired product could be detected by LCMS. The reaction was quenched by the addition of sodium potassium tartrate (10 mL) at 0°C. The resulting mixture was filtered and the filter cake was washed with EtOAc (3×10 mL). The residue was purified by silica gel column chromatography and eluted with PE/EA (10:1) to give 5-chloro-2-ethynyl-1-[(trifluoromethyl)thio]indolizine (420 mg, 60.10%) as a yellow solid. LC-MS: (M+H) + found 276. Intermediate 68. Synthesis of 2-(3- bromoprop -1- yn -1- yl )-5- chloro -1-[( trifluoromethyl ) thio ] indolizine Step 1. Synthesis of 3-{5- chloro -1-[( trifluoromethyl ) thio ] indolizin -2- yl } prop -2- yn -1 -ol
在室溫及氮氣氛圍下,向Zn(OTf) 2(1.22 g,3.353 mmol,2.2當量)及TMEDA (0.5 mL,3.353 mmol,2.2當量)於甲苯(2 mL)中之攪拌混合物中逐滴添加TEA (0.5 mL,3.353 mmol,2.2當量)。將所得混合物在室溫及氮氣氛圍下攪拌2h。向上述混合物中逐滴添加於甲苯(1 mL)中之5-氯-2-乙炔基-1-[(三氟甲基)硫基]吲嗪(420 mg,1.524 mmol,1當量)。將所得混合物在60℃下再攪拌1h。向上述混合物中逐滴添加於甲苯(1 mL)中之POM (301 mg,3.353 mmol,2.2當量)。將所得混合物在60℃下再攪拌1h。藉由LCMS監測反應。可藉由LCMS偵測所需產物。使混合物冷卻至室溫。將所得混合物在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用PE / EA (10:1)溶析,以得到呈棕色固體之3-{5-氯-1-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-醇(330 mg,70.85%)。LC-MS:(M+H) +實測值306。 步驟 2. 2-(3- 溴丙 -1- 炔 -1- 基 )-5- 氯 -1-[( 三氟甲基 ) 硫基 ] 吲嗪之合成 To a stirred mixture of Zn(OTf) 2 (1.22 g, 3.353 mmol, 2.2 equiv) and TMEDA (0.5 mL, 3.353 mmol, 2.2 equiv) in toluene (2 mL) was added TEA (0.5 mL, 3.353 mmol, 2.2 equiv) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. To the above mixture was added 5-chloro-2-ethynyl-1-[(trifluoromethyl)thio]indolizine (420 mg, 1.524 mmol, 1 equiv) in toluene (1 mL) dropwise. The resulting mixture was stirred at 60 °C for another 1 h. To the above mixture was added POM (301 mg, 3.353 mmol, 2.2 equiv) in toluene (1 mL) dropwise. The resulting mixture was stirred at 60°C for another 1 h. The reaction was monitored by LCMS. The desired product could be detected by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (10:1) to give 3-{5-chloro-1-[(trifluoromethyl)thio]indolizine-2-yl}prop-2-yn-1-ol (330 mg, 70.85%) as a brown solid. LC-MS: (M+H) + found 306. Step 2. Synthesis of 2-(3- bromoprop -1- yn -1- yl )-5- chloro -1-[( trifluoromethyl ) thio ] indolizine
將3-{5-氯-1-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-醇(300 mg,0.981 mmol,1當量)於DCM (3 mL)中之溶液保持在室溫及氮氣氛圍下,接著在室溫下逐份添加PPh 3Br 2(538 mg,1.275 mmol,1.3當量)。將所得混合物在室溫及氮氣氛圍下攪拌2h。藉由LCMS監測反應。可藉由LCMS偵測所需產物。將所得混合物在減壓下濃縮。殘餘物藉由具有以下條件之反相急速層析純化:管柱,C18矽膠;移動相,於水中之MeCN (0.1% FA),在35 min內0%至100%梯度;偵測器,UV 254 nm(80%)。此產生呈黑色油狀物之2-(3-溴丙-1-炔-1-基)-5-氯-1-[(三氟甲基)硫基]吲嗪(130 mg,35.94%)。LC-MS:(M+H) +實測值368。 中間物69. 8-溴-3-[(二氟甲基)硫基]-2-碘咪唑并[1,2-a]吡啶之合成 步驟1. 8-溴-3-[(二氟甲基)硫基]咪唑并[1,2-a]吡啶-2-甲酸酯之合成 A solution of 3-{5-chloro-1-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-ol (300 mg, 0.981 mmol, 1 eq) in DCM (3 mL) was kept at room temperature under nitrogen atmosphere, and then PPh 3 Br 2 (538 mg, 1.275 mmol, 1.3 eq) was added portionwise at room temperature. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient 0% to 100% in 35 min; detector, UV 254 nm (80%). This yielded 2-(3-bromoprop-1-yn-1-yl)-5-chloro-1-[(trifluoromethyl)thio]indolizine (130 mg, 35.94%) as a black oil. LC-MS: (M+H) + found 368. Intermediate 69. Synthesis of 8-bromo-3-[(difluoromethyl)thio]-2-iodoimidazo[1,2-a]pyridine Step 1. Synthesis of 8-bromo-3-[(difluoromethyl)thio]imidazo[1,2-a]pyridine-2-carboxylate
向8-溴咪唑并[1,2-a]吡啶-2-甲酸乙酯(1 g,3.716 mmol,1當量)及2-[(二氟甲基)硫基]異吲哚-1,3-二酮(1.02 g,4.459 mmol,1.2當量)於DCE (22 mL)中之攪拌溶液中添加TMSCl (0.71 mL,5.574 mmol,1.5當量)。將所得混合物在90℃及氮氣氛圍下攪拌隔夜。藉由LCMS監測反應。使混合物冷卻至室溫。將所得混合物在真空下濃縮。殘餘物藉由矽膠管柱層析純化,用MeOH / CH 2Cl 2(5%)溶析,以得到呈白色固體之8-溴-3-[(二氟甲基)硫基]咪唑并[1,2-a]吡啶-2-甲酸乙酯(855 mg,65.52%)。LC-MS:(M+H) +實測值351;353。 步驟2. 8-溴-3-[(二氟甲基)硫基]咪唑并[1,2-a]吡啶-2-甲酸之合成 To a stirred solution of ethyl 8-bromoimidazo[1,2-a]pyridine-2-carboxylate (1 g, 3.716 mmol, 1 eq) and 2-[(difluoromethyl)thio]isoindole-1,3-dione (1.02 g, 4.459 mmol, 1.2 eq) in DCE (22 mL) was added TMSCl (0.71 mL, 5.574 mmol, 1.5 eq). The resulting mixture was stirred at 90 °C under nitrogen atmosphere overnight. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with MeOH/ CH2Cl2 (5%) to give 8-bromo-3-[(difluoromethyl)thio]imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (855 mg, 65.52%) as a white solid. LC-MS: (M+H) + found 351; 353. Step 2. Synthesis of 8-bromo-3-[(difluoromethyl)thio]imidazo[1,2-a]pyridine-2-carboxylic acid
將8-溴-3-[(二氟甲基)硫基]咪唑并[1,2-a]吡啶-2-甲酸乙酯(855 mg,2.43 mmol,1當量)於H 2O (2 mL)及THF (8 mL)中之溶液在0℃下逐份用LiOH (87 mg,3.65 mmol,1.5當量)處理。將所得混合物在室溫及氮氣氛圍下攪拌1h。用HCl (1N)將混合物酸化至pH 6~7。然後沉澱產物。藉由過濾收集沉澱的固體且用冷水(3x5 mL)洗滌。將所得混合物在真空下濃縮。此產生呈白色固體之8-溴-3-[(二氟甲基)硫基]咪唑并[1,2-a]吡啶-2-甲酸(531 mg,67.50%)。LC-MS:(M+H) +實測值323;325。 步驟3. 8-溴-3-[(二氟甲基)硫基]-2-碘咪唑并[1,2-a]吡啶之合成 A solution of ethyl 8-bromo-3-[(difluoromethyl)thio]imidazo[1,2-a]pyridine-2-carboxylate (855 mg, 2.43 mmol, 1 eq.) in H 2 O (2 mL) and THF (8 mL) was treated portionwise with LiOH (87 mg, 3.65 mmol, 1.5 eq.) at 0° C. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 h. The mixture was acidified to pH 6~7 with HCl (1N). The product was then precipitated. The precipitated solid was collected by filtration and washed with cold water (3×5 mL). The resulting mixture was concentrated under vacuum. This resulted in 8-bromo-3-[(difluoromethyl)thio]imidazo[1,2-a]pyridine-2-carboxylic acid (531 mg, 67.50%) as a white solid. LC-MS: (M+H) + found 323; 325. Step 3. Synthesis of 8-bromo-3-[(difluoromethyl)thio]-2-iodoimidazo[1,2-a]pyridine
在室溫及氮氣氛圍下,向8-溴-3-[(二氟甲基)硫基]咪唑并[1,2-a]吡啶-2-甲酸(479 mg,1.48 mmol,1當量)於DMSO (5 mL)中之攪拌溶液中逐份添加I 2(1.51 g,5.92 mmol,4當量)及K 3PO 4(377 mg,1.78 mmol,1.2當量)。將所得混合物在120℃及氮氣氛圍下攪拌隔夜。藉由LCMS監測反應。使混合物冷卻至室溫。藉由在0℃下添加50% Na 2S 2O 8(30 mL)淬滅反應。在0℃下向上述混合物中逐份添加Na 2CO 3(10 mL)。所得混合物用CH 2Cl 2(3 x 20mL)萃取。合併的有機層用鹽水(3x10 mL)洗滌、經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用EA / PE (20%)溶析,以得到呈白色固體之8-溴-3-[(二氟甲基)硫基]-2-碘咪唑并[1,2-a]吡啶(203 mg,33.81%)。LC-MS:(M+H) +實測值405;407。 化合物 實例1. (3S,4R)-3-氟-N-(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)-1-甲基哌啶-4-胺之合成 步驟1. N-{3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}-4-甲磺醯基-2-甲氧基苯胺之合成 To a stirred solution of 8-bromo-3-[(difluoromethyl)thio]imidazo[1,2-a]pyridine-2-carboxylic acid (479 mg, 1.48 mmol, 1 eq) in DMSO (5 mL) was added I 2 (1.51 g, 5.92 mmol, 4 eq) and K 3 PO 4 (377 mg, 1.78 mmol, 1.2 eq) portionwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 120 °C under nitrogen atmosphere overnight. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The reaction was quenched by the addition of 50% Na 2 S 2 O 8 (30 mL) at 0 °C. To the above mixture was added Na 2 CO 3 (10 mL) portionwise at 0 °C. The resulting mixture was extracted with CH 2 Cl 2 (3 x 20 mL). The combined organic layers were washed with brine (3x10 mL) and dried over anhydrous Na2SO4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with EA/PE (20%) to give 8-bromo-3-[(difluoromethyl)thio]-2-iodoimidazo[1,2-a]pyridine (203 mg, 33.81%) as a white solid. LC-MS: (M+H) + found 405; 407. Compound Example 1. Synthesis of (3S,4R)-3-fluoro-N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine Step 1. Synthesis of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-4-methanesulfonyl-2-methoxyaniline
在室溫下,在5 mL密封管中添加8-溴-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶( 中間物1;110 mg,0.27 mmol,1當量)、DMSO (4 mL)、4-甲磺醯基-2-甲氧基-N-(丙-2-炔-1-基)苯胺( 中間物39;130 mg,0.54 mmol,2當量)、Pd(PPh 3) 4(63 mg,0.05 mmol,0.2當量)、CuI (52 mg,0.27 mmol,1當量)及i-Pr 2NH (275 mg,2.72 mmol,10當量)。將所得混合物在室溫及氮氣氛圍下攪拌隔夜,然後用水(10 mL)稀釋且用EtOAc (3*10 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型TLC (PE/EA=1:2)純化,以得到呈黃色固體之N-{3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}-4-甲磺醯基-2-甲氧基苯胺(140 mg,83.85%)。LC-MS:(M+H) +實測值516.0。 步驟2. (3S,4R)-3-氟-N-(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)-1-甲基哌啶-4-胺之合成 8-Bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( Intermediate 1 ; 110 mg, 0.27 mmol, 1 eq), DMSO (4 mL), 4-methanesulfonyl-2-methoxy-N-(prop-2-yn-1-yl)aniline ( Intermediate 39 ; 130 mg, 0.54 mmol, 2 eq), Pd( PPh3 ) 4 (63 mg, 0.05 mmol, 0.2 eq), CuI (52 mg, 0.27 mmol, 1 eq) and i- Pr2NH (275 mg, 2.72 mmol, 10 eq) were added to a 5 mL sealed tube at room temperature. The resulting mixture was stirred at room temperature under nitrogen atmosphere overnight, then diluted with water (10 mL) and extracted with EtOAc (3*10 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE/EA=1:2) to give N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-4-methanesulfonyl-2-methoxyaniline (140 mg, 83.85%) as a yellow solid. LC-MS: (M+H) + found 516.0. Step 2. Synthesis of (3S,4R)-3-fluoro-N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine
在室溫下,在10 mL密封管中添加N-{3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}-4-甲磺醯基-2-甲氧基苯胺(100 mg,0.19 mmol,1當量)、二噁烷(4 mL)、RuPhos (90 mg,0.19 mmol,1當量)、Cs 2CO 3(315 mg,0.970 mmol,5當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(119 mg,0.58 mmol,3當量)及BrettPhos Pd G4 (149 mg,0.097 mmol,0.5當量)。將所得混合物在100℃及氮氣氛圍下攪拌1 h,然後用水(30 mL)稀釋且用EtOAc (3*20 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/ MeOH 10:1)純化,以得到70 mg粗產物。粗產物藉由具有以下條件(管柱,C18矽膠;移動相,於水中之MeCN (10mmol/L NH 4HCO 3),在30 min內0%至100%梯度;偵測器,UV 254 nm)之反相急速層析純化,以得到呈白色固體之(3S,4R)-3-氟-N-(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)-1-甲基哌啶-4-胺(5.9 mg,5.24%)。LC-MS:(M+H) +實測值568.05。 1H NMR (400 MHz, DMSO- d 6) δ 7.79 (d, J= 6.8 Hz, 1H), 7.39 (dd, J= 8.4, 2.0 Hz, 1H), 7.25 (d, J= 2.0 Hz, 1H), 6.87 (d, J= 8.4 Hz, 1H), 6.83 (t, J= 7.2 Hz, 1H), 6.48 (t, J= 6.2 Hz, 1H), 6.39 (d, J= 7.6 Hz, 1H), 5.37 (d, J= 9.2 Hz, 1H), 4.82 (d, J= 49.2 Hz, 1H), 4.31 (d, J= 6.2 Hz, 2H), 4.03 (q, J= 10.7 Hz, 2H), 3.90 (s, 3H), 3.79 – 3.59 (m, 1H), 3.09 (s, 3H), 3.03 (t, J= 13.5 Hz, 1H), 2.76 (d, J= 11.3 Hz, 1H), 2.33 – 2.27 (m, 1H), 2.19 (s, 3H), 2.15 – 2.02 (m, 1H), 1.82 – 1.75 (m, 2H)。 實例2. N-(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)-1-甲基哌啶-4-胺之合成 In a 10 mL sealed tube at room temperature, N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-4-methanesulfonyl-2-methoxyaniline (100 mg, 0.19 mmol, 1 eq), dioxane (4 mL), RuPhos (90 mg, 0.19 mmol, 1 eq), Cs2CO3 ( 315 mg, 0.970 mmol, 5 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (119 mg, 0.58 mmol, 3 eq) and BrettPhos Pd G4 (149 mg, 0.097 mmol, 0.5 eq) were added. The resulting mixture was stirred at 100 °C under nitrogen atmosphere for 1 h, then diluted with water (30 mL) and extracted with EtOAc (3*20 mL). The combined organic layers were dried over anhydrous Na2SO4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC ( CH2Cl2 /MeOH 10:1) to give 70 mg of crude product. The crude product was purified by reverse phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH 4 HCO 3 ) in water, gradient from 0% to 100% in 30 min; detector, UV 254 nm) to give (3S,4R)-3-fluoro-N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine (5.9 mg, 5.24%) as a white solid. LC-MS: (M+H) + found 568.05. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.79 (d, J = 6.8 Hz, 1H), 7.39 (dd, J = 8.4, 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 6.83 (t, J = 7.2 Hz, 1H), 6.48 (t, J = 6.2 Hz, 1H), 6.39 (d, J = 7.6 Hz, 1H), 5.37 (d, J = 9.2 Hz, 1H), 4.82 (d, J = 49.2 Hz, 1H), 4.31 (d, J = 6.2 Hz, 2H), 4.03 (q, J = 10.7 Hz, 2H), 3.90 (s, 3H), 3.79 – 3.59 (m, 1H), 3.09 (s, 3H), 3.03 (t, J = 13.5 Hz, 1H), 2.76 (d, J = 11.3 Hz, 1H), 2.33 – 2.27 (m, 1H), 2.19 (s, 3H), 2.15 – 2.02 (m, 1H), 1.82 – 1.75 (m, 2H). Example 2. Synthesis of N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine
在室溫下,在10 mL密封管中添加N-{3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}-4-甲磺醯基-2-甲氧基苯胺(70 mg,0.14 mmol,1當量)、二噁烷(2 mL)、RuPhos (13 mg,0.03 mmol,0.2當量)、Cs 2CO 3(133 mg,0.41 mmol,3當量)、1-甲基哌啶-4-胺(46 mg,0.41 mmol,3當量)及BrettPhos Pd G4 (21 mg,0.014 mmol,0.1當量)。將所得混合物在100℃及氮氣氛圍下攪拌3 h,然後用水(10 mL)稀釋且用EtOAc (3*10 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型TLC (DCM/MeOH 10:1,+0.1% NH 3 ·H 2O)純化,以得到呈黃色固體之N-(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)-1-甲基哌啶-4-胺(8.7 mg,11.68%)。LC-MS:(M+H) +實測值550.40。 1H NMR (400 MHz, DMSO- d 6) δ 7.72 (d, J= 6.8 Hz, 1H), 7.39 (dd, J= 8.4, 2.0 Hz, 1H), 7.25 (d, J= 2.0 Hz, 1H), 6.86 (d, J= 8.4 Hz, 1H), 6.80 (t, J= 7.2 Hz, 1H), 6.48 (t, J= 6.3 Hz, 1H), 6.22 (d, J= 7.5 Hz, 1H), 5.73 (d, J= 8.3 Hz, 1H), 4.31 (d, J= 6.2 Hz, 2H), 4.03 – 4.01 (m, 2H), 3.90 (s, 3H), 3.37 (s, 1H), 3.10 (s, 3H), 2.77 (s, 2H), 2.21 (s, 3H), 2.09 (s, 2H), 1.88 (d, J= 11.7 Hz, 2H), 1.57 (d, J= 11.4 Hz, 2H)。 實例3. 2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-N-(氧雜環己-4-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-胺之合成 In a 10 mL sealed tube at room temperature, N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-4-methanesulfonyl-2-methoxyaniline (70 mg, 0.14 mmol, 1 eq), dioxane (2 mL), RuPhos (13 mg, 0.03 mmol, 0.2 eq), Cs2CO3 (133 mg, 0.41 mmol, 3 eq), 1-methylpiperidin-4-amine (46 mg, 0.41 mmol , 3 eq) and BrettPhos Pd G4 (21 mg, 0.014 mmol, 0.1 eq) were added. The resulting mixture was stirred at 100 °C under nitrogen atmosphere for 3 h, then diluted with water (10 mL) and extracted with EtOAc (3*10 mL). The combined organic layers were dried over anhydrous Na2SO4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM/MeOH 10:1, +0.1% NH3 · H2O ) to give N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine (8.7 mg, 11.68%) as a yellow solid. LC-MS: (M+H) + found 550.40. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.72 (d, J = 6.8 Hz, 1H), 7.39 (dd, J = 8.4, 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.80 (t, J = 7.2 Hz, 1H), 6.48 (t, J = 6.3 Hz, 1H), 6.22 (d, J = 7.5 Hz, 1H), 5.73 (d, J = 8.3 Hz, 1H), 4.31 (d, J = 6.2 Hz, 2H), 4.03 – 4.01 (m, 2H), 3.91 (s, 3H), 3.37 (s, 1H), 3.10 (s, 3H), 2.77 (s, 2H), 2.21 (s, 3H), 2.09 (s, 2H), 1.88 (d, J = 11.7 Hz, 2H), 1.57 (d, J = 11.4 Hz, 2H). Example 3. Synthesis of 2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-N-(oxacyclohexyl-4-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-amine
將N-{3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}-4-甲磺醯基-2-甲氧基苯胺(200 mg,0.39 mmol,1當量)、氧雜環己-4-胺(58.8 mg,0.58 mmol,1.5當量)、t-BuONa (74.5 mg,0.77 mmol,2當量)及tBuXPhos Pd G3 (153.9 mg,0.19 mmol,0.50當量)於THF (3 mL)中之混合物在65℃及氮氣氛圍下攪拌1 h。將所得混合物在減壓下濃縮。所得混合物藉由製備型TLC (CH 2Cl 2/於MeOH中之7M NH 3= 20:1),及製備型HPLC (管柱:XBridge Shield RP18 OBD管柱,19*250 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3+0.05%NH 3 .H 2O),移動相B:ACN(1% 2mM NH 3-MEOH);流動速率:25 mL/min mL/min;梯度:在10min內51% B至77% B;波長:254nm/220nm nm;RT1(min):9.75;運行次數:4)純化,以得到呈灰白色固體之2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-N-(氧雜環己-4-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-胺(32.5 mg,15.61%)。LC-MS:(M+H) +實測值537.15。 1H NMR (400 MHz, DMSO- d 6) δ 7.77 – 7.65 (d, J= 6.8 Hz, 1H), 7.44 – 7.36 (dd, J= 2.0, 8.4 Hz, 1H), 7.30 – 7.21 (d, J= 2.0 Hz, 1H), 6.94 – 6.85 (d, J= 8.4 Hz, 1H), 6.83 – 6.73 (t, J= 7.1 Hz, 1H), 6.51 – 6.42 (t, J= 6.3 Hz, 1H), 6.32 – 6.22 (d, J= 7.5 Hz, 1H), 5.87 – 5.77 (d, J= 8.5 Hz, 1H), 4.37 – 4.26 (d, J= 6.3 Hz, 2H), 4.10 – 3.94 (m, 2H), 3.92 – 3.81 (m, 5H), 3.67 – 3.54 (s, 1H), 3.47 – 3.36 (td, J= 2.1, 11.6 Hz, 2H), 3.13 – 3.04 (s, 3H), 1.94 – 1.76 (m, 2H), 1.70 – 1.43 (m, 2H)。 實例113. N-(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)-1-(2-甲氧基乙基)哌啶-4-胺之合成 A mixture of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-4-methanesulfonyl-2-methoxyaniline (200 mg, 0.39 mmol, 1 eq.), oxadiazine (58.8 mg, 0.58 mmol, 1.5 eq.), t-BuONa (74.5 mg, 0.77 mmol, 2 eq.) and tBuXPhos Pd G3 (153.9 mg, 0.19 mmol, 0.50 eq.) in THF (3 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The resulting mixture was purified by preparative TLC (CH 2 Cl 2 /7M NH 3 in MeOH = 20:1) and preparative HPLC (column: XBridge Shield RP18 OBD column, 19*250 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 +0.05% NH 3 . H 2 O), mobile phase B: ACN (1% 2 mM NH 3 -MEOH); flow rate: 25 mL/min mL/min; gradient: 51% B to 77% B in 10 min; wavelength: 254 nm/220 nm nm; RT1(min): 9.75; Runs: 4) to give 2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-N-(oxacyclohexan-4-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-amine (32.5 mg, 15.61%) as an off-white solid. LC-MS: (M+H) + found 537.15. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.77 – 7.65 (d, J = 6.8 Hz, 1H), 7.44 – 7.36 (dd, J = 2.0, 8.4 Hz, 1H), 7.30 – 7.21 (d, J = 2.0 Hz, 1H), 6.94 – 6.85 (d, J = 8.4 Hz, 1H), 6.83 – 6.73 (t, J = 7.1 Hz, 1H), 6.51 – 6.42 (t, J = 6.3 Hz, 1H), 6.32 – 6.22 (d, J = 7.5 Hz, 1H), 5.87 – 5.77 (d, J = 8.5 Hz, 1H), 4.37 – 4.26 (d, J = 6.3 Hz, 2H), 4.10 – 3.94 (m, 2H), 3.92 – 3.81 (m, 5H), 3.67 – 3.54 (s, 1H), 3.47 – 3.36 (td, J = 2.1, 11.6 Hz, 2H), 3.13 – 3.04 (s, 3H), 1.94 – 1.76 (m, 2H), 1.70 – 1.43 (m, 2H). Example 113. Synthesis of N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-(2-methoxyethyl)piperidin-4-amine
將N-{3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}-4-甲磺醯基-2-甲氧基苯胺(50 mg,0.10 mmol,1當量)、1-(2-甲氧基乙基)哌啶-4-胺(23 mg,0.15 mmol,1.5當量)、tBuXphos Pd G 3(41.0 mg,0.05 mmol,0.5當量)、t-BuONa (18.6 mg,0.19 mmol,2當量)及THF (3 mL)之混合物在65℃及氮氣氛圍下攪拌1 h,然後在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/ MeOH = 15:1)及製備型HPLC (管柱:XBridge Prep OBD C18管柱,19*250 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3),移動相B:ACN(1% 2mM NH 3-MEOH);流動速率:25 mL/min mL/min;梯度:在11 min內55% B至75% B;波長:254nm/220nm nm;RT1(min):9.33)純化,以得到呈白色固體之N-(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)-1-(2-甲氧基乙基)哌啶-4-胺(6.1 mg,10.14%)。LC-MS:(M+H) +實測值594.30。 1H NMR (400 MHz, DMSO- d 6) δ 7.71 (d, J= 6.8 Hz, 1H), 7.39 (dd, J= 8.3, 2.0 Hz, 1H), 7.25 (d, J= 2.0 Hz, 1H), 6.86 (d, J= 8.4 Hz, 1H), 6.80 (t, J= 7.2 Hz, 1H), 6.47 (t, J= 6.2 Hz, 1H), 6.22 (d, J= 7.6 Hz, 1H), 5.71 (d, J= 8.4 Hz, 1H), 4.31 (d, J= 6.2 Hz, 2H), 4.02 (m, 2H), 3.90 (s, 3H), 3.42 (t, J= 5.9 Hz, 2H), 3.23 (s, 3H), 3.09 (s, 3H), 2.84 (d, J= 11.3 Hz, 2H), 2.46 (t, J= 5.9 Hz, 2H), 2.18 – 2.00 (m, 3H), 1.87 (d, J= 12.5 Hz, 2H), 1.53 (m, 2H)。 實例4. 4-[(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)胺基]-1λ6-硫雜環己烷-1,1-二酮之合成 A mixture of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-4-methanesulfonyl-2-methoxyaniline (50 mg, 0.10 mmol, 1 eq), 1-(2-methoxyethyl)piperidin-4-amine (23 mg, 0.15 mmol, 1.5 eq), tBuXphos Pd G3 (41.0 mg, 0.05 mmol, 0.5 eq), t-BuONa (18.6 mg, 0.19 mmol, 2 eq) and THF (3 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h and then concentrated under reduced pressure. The residue was separated by preparative TLC (CH 2 Cl 2 / MeOH = 15:1) and preparative HPLC (column: XBridge Prep OBD C18 column, 19*250 mm, 5μm; mobile phase A: water (10mmol/L NH 4 HCO 3 ), mobile phase B: ACN (1% 2mM NH 3 -MEOH); flow rate: 25 mL/min mL/min; gradient: 55% B to 75% B in 11 min; wavelength: 254nm/220nm nm; RT1 (min): 9.33) to give N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-(2-methoxyethyl)piperidin-4-amine (6.1 mg, 10.14%) as a white solid. LC-MS: (M+H) + found 594.30. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.71 (d, J = 6.8 Hz, 1H), 7.39 (dd, J = 8.3, 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.80 (t, J = 7.2 Hz, 1H), 6.47 (t, J = 6.2 Hz, 1H), 6.22 (d, J = 7.6 Hz, 1H), 5.71 (d, J = 8.4 Hz, 1H), 4.31 (d, J = 6.2 Hz, 2H), 4.02 (m, 2H), 3.91 (s, 3H), 3.42 (t, J = 5.9 Hz, 2H), 3.23 (s, 3H), 3.09 (s, 3H), 2.84 (d, J = 11.3 Hz, 2H), 2.46 (t, J = 5.9 Hz, 2H), 2.18 – 2.00 (m, 3H), 1.87 (d, J = 12.5 Hz, 2H), 1.53 (m, 2H). Example 4. Synthesis of 4-[(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)amino]-1λ6-thiacyclohexane-1,1-dione
將N-{3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}-4-甲磺醯基-2-甲氧基苯胺(50 mg,0.10 mmol,1當量)、4-胺基-1λ6-硫雜環己烷-1,1-二酮(21.7 mg,0.15 mmol,1.5當量)、t-BuONa (18.6 mg,0.19 mmol,2當量)及tBuXPhos Pd G3 (38.5 mg,0.05 mmol,0.5當量)於THF (2 mL)中之混合物在65℃及氮氣氛圍下攪拌1 h。將所得混合物在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/於MeOH中之7M NH 3= 15:1)及製備型HPLC (管柱:XBridge Prep OBD C18管柱,19*250 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3),移動相B:ACN(1% 2mM NH 3-MEOH);流動速率:25 mL/min mL/min;梯度:在10 min內45% B至64% B;波長:254nm/220nm nm;RT1(min):9.55)純化,以得到呈灰白色固體之4-[(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)胺基]-1λ6-硫雜環己烷-1,1-二酮(4.1 mg,7.23%)。LC-MS:(M+H) +實測值585.20。 1H NMR (400 MHz, DMSO- d 6) δ 7.80 – 7.71 (d, J= 6.8 Hz, 1H), 7.44 – 7.35 (dd, J= 2.0, 8.4 Hz, 1H), 7.31 – 7.21 (d, J= 2.0 Hz, 1H), 6.92 – 6.78 (dd, J= 7.6, 13.9 Hz, 2H), 6.52 – 6.42 (t, J= 6.2 Hz, 1H), 6.35 – 6.25 (d, J= 7.6 Hz, 1H), 6.24 – 6.15 (d, J= 8.6 Hz, 1H), 4.38 – 4.25 (d, J= 6.3 Hz, 2H), 4.11 – 3.97 (m, 2H), 3.96 – 3.85 (s, 3H), 3.85 – 3.72 (d, J= 10.2 Hz, 1H), 3.31 – 3.27 (s, 2H), 3.16 – 3.06 (d, J= 15.4 Hz, 5H), 2.22 – 2.13 (d, J= 13.3 Hz, 2H), 2.13 – 2.00 (m, 2H)。 實例5. N-(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)-1-(2-甲磺醯基乙基)哌啶-4-胺之合成 A mixture of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-4-methanesulfonyl-2-methoxyaniline (50 mg, 0.10 mmol, 1 eq), 4-amino-1λ6-thiacyclohexane-1,1-dione (21.7 mg, 0.15 mmol, 1.5 eq), t-BuONa (18.6 mg, 0.19 mmol, 2 eq) and tBuXPhos Pd G3 (38.5 mg, 0.05 mmol, 0.5 eq) in THF (2 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 /7M NH 3 in MeOH = 15:1) and preparative HPLC (column: XBridge Prep OBD C18 column, 19*250 mm, 5μm; mobile phase A: water (10mmol/L NH 4 HCO 3 ), mobile phase B: ACN (1% 2mM NH 3 -MEOH); flow rate: 25 mL/min mL/min; gradient: 45% B to 64% B in 10 min; wavelength: 254nm/220nm nm; RT1 (min): 9.55) to give 4-[(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)amino]-1λ6-thiacyclohexane-1,1-dione (4.1 mg, 7.23%) as an off-white solid. LC-MS: (M+H) + found 585.20. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.80 – 7.71 (d, J = 6.8 Hz, 1H), 7.44 – 7.35 (dd, J = 2.0, 8.4 Hz, 1H), 7.31 – 7.21 (d, J = 2.0 Hz, 1H), 6.92 – 6.78 (dd, J = 7.6, 13.9 Hz, 2H), 6.52 – 6.42 (t, J = 6.2 Hz, 1H), 6.35 – 6.25 (d, J = 7.6 Hz, 1H), 6.24 – 6.15 (d, J = 8.6 Hz, 1H), 4.38 – 4.25 (d, J = 6.3 Hz, 2H), 4.11 – 3.97 (m, 2H), 3.96 – 3.85 (s, 3H), 3.85 – 3.72 (d, J = 10.2 Hz, 1H), 3.31 – 3.27 (s, 2H), 3.16 – 3.06 (d, J = 15.4 Hz, 5H), 2.22 – 2.13 (d, J = 13.3 Hz, 2H), 2.13 – 2.00 (m, 2H). Example 5. Synthesis of N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-(2-methylsulfonylethyl)piperidin-4-amine
將N-{3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}-4-甲磺醯基-2-甲氧基苯胺(150 mg,0.29 mmol,1當量)、1-(2-甲磺醯基乙基)哌啶-4-胺鹽酸鹽( 中間物35;105.8 mg,0.44 mmol,1.50當量)、t-BuONa (83.8 mg,0.87 mmol,3當量)及tBuXphos Pd G3 (69.2 mg,0.09 mmol,0.3當量)於THF (3 mL)中之混合物在65℃及氮氣氛圍下攪拌1 h。將所得混合物在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/於MeOH中之7 M NH 3= 15:1)及製備型HPLC (管柱:Xselect CSH C18 OBD 管柱,30*150mm 5μm;移動相A:水(0.1% FA),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在7 min內15% B至34% B梯度;波長:254nm/220nm nm;RT1(min):7.08;運行次數:2)純化,以得到呈白色固體之N-(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)-1-(2-甲磺醯基乙基)哌啶-4-胺(8.2 mg,4.35%)。LC-MS:(M+H) +實測值642.35。 1H NMR (400 MHz, DMSO- d 6) δ 7.71 (d, J= 6.8 Hz, 1H), 7.39 (dd, J= 8.3, 2.0 Hz, 1H), 7.25 (d, J= 2.0 Hz, 1H), 6.86 (d, J= 8.4 Hz, 1H), 6.79 (d, J= 7.1 Hz, 1H), 6.44 (t, J= 6.3 Hz, 1H), 6.23 (d, J= 7.6 Hz, 1H), 5.70 (d, J= 8.4 Hz, 1H), 4.31 (d, J= 6.2 Hz, 2H), 4.02 (m, 2H), 3.89 (s, 3H), 3.45 – 3.35 (m, 1H), 3.26 (s, 2H), 3.09 (s, 3H), 3.03 (s, 3H), 2.87 (d, J= 11.4 Hz, 2H), 2.70 (m, 2H), 2.16 – 2.09 (m, 2H), 1.90 (d, J= 12.4 Hz, 2H), 1.55 (m, 2H)。 實例114. N-(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)-2-甲基-2-氮雜螺[3.3]庚-6-胺之合成 A mixture of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-4-methanesulfonyl-2-methoxyaniline (150 mg, 0.29 mmol, 1 eq), 1-(2-methanesulfonylethyl)piperidin-4-amine hydrochloride ( Intermediate 35 ; 105.8 mg, 0.44 mmol, 1.50 eq), t-BuONa (83.8 mg, 0.87 mmol, 3 eq) and tBuXphos Pd G3 (69.2 mg, 0.09 mmol, 0.3 eq) in THF (3 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 /7 M NH 3 in MeOH = 15:1) and preparative HPLC (column: Xselect CSH C18 OBD column, 30*150 mm 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 15% B to 34% B in 7 min; wavelength: 254 nm/220 nm nm; RT1(min): 7.08; Runs: 2) to give N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-(2-methylsulfonylethyl)piperidin-4-amine (8.2 mg, 4.35%) as a white solid. LC-MS: (M+H) + found 642.35. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.71 (d, J = 6.8 Hz, 1H), 7.39 (dd, J = 8.3, 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.79 (d, J = 7.1 Hz, 1H), 6.44 (t, J = 6.3 Hz, 1H), 6.23 (d, J = 7.6 Hz, 1H), 5.70 (d, J = 8.4 Hz, 1H), 4.31 (d, J = 6.2 Hz, 2H), 4.02 (m, 2H), 3.89 (s, 3H), 3.45 – 3.35 (m, 1H), 3.26 (s, 2H), 3.09 (s, 3H), 3.03 (s, 3H), 2.87 (d, J = 11.4 Hz, 2H), 2.70 (m, 2H), 2.16 – 2.09 (m, 2H), 1.90 (d, J = 12.4 Hz, 2H), 1.55 (m, 2H). Example 114. Synthesis of N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-2-methyl-2-azaspiro[3.3]hept-6-amine
將N-{3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}-4-甲磺醯基-2-甲氧基苯胺(120 mg,0.23 mmol,1當量)、2-甲基-2-氮雜螺[3.3]庚-6-胺二鹽酸鹽(50.9 mg,0.25 mmol,1.1當量)、t-BuONa (89.3 mg,0.93 mmol,4當量)及tBuXPhos Pd G3 (92.3 mg,0.12 mmol,0.5當量)於THF (3 mL)中之混合物在65℃及氮氣氛圍下攪拌1 h。將所得混合物在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/於MeOH中之7 M NH 3= 15:1)及具有以下條件(管柱:XBridge Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3+0.05% NH 3 .H 2O),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在7 min內28% B至49% B;波長:254nm nm;RT1(min):7.03;運行次數:2)之製備型HPLC純化,以得到呈灰白色固體之N-(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)-2-甲基-2-氮雜螺[3.3]庚-6-胺(9.0 mg,6.90%)。LC-MS:(M+H) +實測值562.20。 1H NMR (400 MHz, DMSO- d 6) δ 7.76 – 7.68 (d, J= 6.8 Hz, 1H), 7.42 – 7.35 (dd, J= 2.0, 8.3 Hz, 1H), 7.29 – 7.18 (d, J= 2.0 Hz, 1H), 6.91 – 6.82 (d, J= 8.4 Hz, 1H), 6.82 – 6.72 (t, J= 7.1 Hz, 1H), 6.51 – 6.43 (t, J= 6.3 Hz, 1H), 6.26 – 6.19 (d, J= 6.6 Hz, 1H), 6.09 – 6.00 (d, J= 7.5 Hz, 1H), 4.36 – 4.25 (d, J= 6.3 Hz, 2H), 4.09 – 3.95 (m, 2H), 3.95 – 3.86 (s, 3H), 3.86 – 3.75 (m, 1H), 3.21 – 3.13 (s, 2H), 3.13 – 3.06 (s, 3H), 3.06 – 2.97 (s, 2H), 2.52 – 2.50 (d, J= 2.1 Hz, 2H), 2.16 – 2.12 (s, 3H), 2.12 – 2.05 (m, 2H)。 實例115. 2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-N-{2-氧雜螺[3.3]庚-6-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-胺之合成 A mixture of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-4-methanesulfonyl-2-methoxyaniline (120 mg, 0.23 mmol, 1 eq), 2-methyl-2-azaspiro[3.3]hept-6-amine dihydrochloride (50.9 mg, 0.25 mmol, 1.1 eq), t-BuONa (89.3 mg, 0.93 mmol, 4 eq) and tBuXPhos Pd G3 (92.3 mg, 0.12 mmol, 0.5 eq) in THF (3 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was separated by preparative TLC (CH 2 Cl 2 /7 M NH 3 in MeOH = 15:1) with the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 +0.05% NH 3 . H 2 O), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 28% B to 49% B in 7 min; wavelength: 254 nm nm; RT1(min): 7.03; runs: 2) to give N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-2-methyl-2-azaspiro[3.3]hept-6-amine (9.0 mg, 6.90%) as an off-white solid. LC-MS: (M+H) + found 562.20. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.76 – 7.68 (d, J = 6.8 Hz, 1H), 7.42 – 7.35 (dd, J = 2.0, 8.3 Hz, 1H), 7.29 – 7.18 (d, J = 2.0 Hz, 1H), 6.91 – 6.82 (d, J = 8.4 Hz, 1H), 6.82 – 6.72 (t, J = 7.1 Hz, 1H), 6.51 – 6.43 (t, J = 6.3 Hz, 1H), 6.26 – 6.19 (d, J = 6.6 Hz, 1H), 6.09 – 6.00 (d, J = 7.5 Hz, 1H), 9 – 3.86 ( s, 3H), 3.86 – 3.75 (m, 1H), 3.21 – 3.13 (s, 2H), 3.13 – 3.06 (s, 3H), 3.06 – 2.97 (s, 2H), 2.52 – 2.50 (d, J = 2.1 Hz, 2H), 2.16 – 2.12 (s, 3H), 2.12 – 2.05 (m, 2H). Example 115. Synthesis of 2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-N-{2-oxahistoro[3.3]hept-6-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-amine
將N-{3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}-4-甲磺醯基-2-甲氧基苯胺(50 mg,0.10 mmol,1當量)、2-氧雜螺[3.3]庚-6-胺鹽酸鹽(21.7 mg,0.15 mmol,1.5當量)、tBuXPhos Pd G 3(38.5 mg,0.05 mmol,0.5當量)及t-BuONa (37.2 mg,0.39 mmol,4當量)於THF (3 mL)中之混合物在65℃及氮氣氛圍下攪拌1 h。將所得混合物在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/ MeOH = 15:1)及製備型HPLC (管柱:XBridge Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3)+0.05%NH 3.H 2O,移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在7 min內30% B至57% B;波長:254nm/220nm nm;RT1(min):7.68)純化,以得到呈白色固體之2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-N-{2-氧雜螺[3.3]庚-6-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-胺(9 mg,16.45%)。LC-MS:(M+H) +實測值549.10。1H NMR (400 MHz, DMSO-d6) δ 7.73 (d, J= 6.8 Hz, 1H), 7.39 (dd, J= 8.4, 2.0 Hz, 1H), 7.25 (d, J= 2.0 Hz, 1H), 6.86 (d, J= 8.4 Hz, 1H), 6.79 (t, J= 7.1 Hz, 1H), 6.47 (t, J= 6.2 Hz, 1H), 6.29 (d, J= 6.7 Hz, 1H), 6.05 (d, J= 7.5 Hz, 1H), 4.62 (s, 2H), 4.48 (s, 2H), 4.31 (d, J= 6.2 Hz, 2H), 4.02 (d, J= 10.7 Hz, 2H), 3.89 (s, 3H), 3.79 (d, J= 7.2 Hz, 1H), 3.10 (s, 3H), 2.72 – 2.60 (m, 2H), 2.24 – 2.15 (m, 2H)。 實例6. (3R,4S)-3-氟-N-(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)-1-甲基哌啶-4-胺之合成 A mixture of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-4-methanesulfonyl-2-methoxyaniline (50 mg, 0.10 mmol, 1 eq), 2-oxaspiro[3.3]hept-6-amine hydrochloride (21.7 mg, 0.15 mmol, 1.5 eq), tBuXPhos Pd G 3 (38.5 mg, 0.05 mmol, 0.5 eq) and t-BuONa (37.2 mg, 0.39 mmol, 4 eq) in THF (3 mL) was stirred at 65° C. under nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was separated by preparative TLC (CH 2 Cl 2 / MeOH = 15:1) and preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5μm; mobile phase A: water (10mmol/L NH 4 HCO 3 )+0.05% NH 3 .H 2 O, mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 30% B to 57% B in 7 min; wavelength: 254nm/220nm nm; RT1 (min): 7.68) to give 2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-N-{2-oxaspiro[3.3]hept-6-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-amine (9 mg, 16.45%) as a white solid. LC-MS: (M+H) + found 549.10. 1H NMR (400 MHz, DMSO-d6) δ 7.73 (d, J = 6.8 Hz, 1H), 7.39 (dd, J = 8.4, 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.79 (t, J = 7.1 Hz, 1H), 6.47 (t, J = 6.2 Hz, 1H), 6.29 (d, J = 6.7 Hz, 1H), 6.05 (d, J = 7.5 Hz, 1H), 4.62 (s, 2H), 4.48 (s, 2H), 4.31 (d, 3 -[ ( 4 - methylsulfonyl-2 -methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine
將N-{3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}-4-甲磺醯基-2-甲氧基苯胺(120 mg,0.23 mmol,1當量)、(3R,4S)-3-氟-1-甲基哌啶-4-胺(52.4 mg,0.26 mmol,1.1當量)、t-BuONa (89.3 mg,0.93 mmol,4當量)及tBuXphos Pd G3 (92.3 mg,0.12 mmol,0.5當量)於THF (2 mL) 中之混合物在65℃及氮氣氛圍下攪拌1 h。過濾所得混合物,濾餅用DCM洗滌。將濾液在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/於MeOH中之7 M NH 3= 15:1)純化,以得到呈白色固體之(3R,4S)-3-氟-N-(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)-1-甲基哌啶-4-胺(40 mg,30.32%)。LC-MS:(M+H) +實測值568.20。 1H NMR (400 MHz, DMSO- d 6) δ 7.79 (d, J= 6.8 Hz, 1H), 7.39 (dd, J= 8.3, 2.0 Hz, 1H), 7.25 (d, J= 2.0 Hz, 1H), 6.93 – 6.74 (m, 2H), 6.48 (t, J= 6.2 Hz, 1H), 6.39 (d, J= 7.5 Hz, 1H), 5.37 (d, J= 9.2 Hz, 1H), 4.82 (d, J= 49.4 Hz, 1H), 4.31 (d, J= 6.2 Hz, 2H), 4.03 (m, 2H), 3.90 (s, 3H), 3.80 – 3.60 (m, 1H), 3.09 (s, 4H), 2.76 (d, J= 11.4 Hz, 1H), 2.19 (s, 4H), 2.13 – 2.03 (m, 1H), 1.85 – 1.73 (m, 2H)。 實例116. 4-[(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)胺基]哌啶-1-甲酸甲酯之合成 A mixture of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-4-methanesulfonyl-2-methoxyaniline (120 mg, 0.23 mmol, 1 eq), (3R,4S)-3-fluoro-1-methylpiperidin-4-amine (52.4 mg, 0.26 mmol, 1.1 eq), t-BuONa (89.3 mg, 0.93 mmol, 4 eq) and tBuXphos Pd G3 (92.3 mg, 0.12 mmol, 0.5 eq) in THF (2 mL) was stirred at 65° C. under nitrogen atmosphere for 1 h. The resulting mixture was filtered and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 /7 M NH 3 in MeOH = 15:1) to give (3R,4S)-3-fluoro-N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine (40 mg, 30.32%) as a white solid. LC-MS: (M+H) + found 568.20. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.79 (d, J = 6.8 Hz, 1H), 7.39 (dd, J = 8.3, 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.93 – 6.74 (m, 2H), 6.48 (t, J = 6.2 Hz, 1H), 6.39 (d, J = 7.5 Hz, 1H), 5.37 (d, J = 9.2 Hz, 1H), 4.82 (d, J = 49.4 Hz, 1H), 4.31 (d, J = 6.2 Hz, 2H), 4.03 (m, 2H), 3.90 (s, 3H), 3.80 – 3.60 (m, 1H), 3.09 (s, 4H), 2.76 (d, J = 11.4 Hz, 1H), 2.19 (s, 4H), 2.13 – 2.03 (m, 1H), 1.85 – 1.73 (m, 2H). Example 116. Synthesis of methyl 4-[(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)amino]piperidine-1-carboxylate
將N-{3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}-4-甲磺醯基-2-甲氧基苯胺(50 mg,0.10 mmol,1當量)、4-胺基哌啶-1-甲酸甲酯(31 mg,0.20 mmol,2當量)、tBuXPhos Pd G3 (8 mg,0.01 mmol,0.1當量)及t-BuONa (28 mg,0.29 mmol,3當量)於THF (2 mL)中之混合物在65℃及氬氣氛圍下攪拌0.5 h。所得混合物用水淬滅且用CH 2Cl 2(2*20 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用CH 2Cl 2/ MeOH (20:1)溶析以得到粗產物。殘餘物藉由具有以下條件(管柱,C18矽膠;移動相,於水中之MeCN (10mmol/L NH 4HCO 3),在20 min內10%至50%梯度;偵測器,UV 254 nm)之反相急速層析純化,以得到呈淺黃色固體之4-[(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)胺基]哌啶-1-甲酸甲酯(3.8 mg,6.33%)。LC-MS:(M+H) +實測值594.20。 1H NMR (400 MHz, DMSO- d 6) δ 7.73 (d, J= 6.7 Hz, 1H), 7.39 (dd, J= 8.3, 1.9 Hz, 1H), 7.25 (d, J= 2.0 Hz, 1H), 6.90 – 6.70 (m, 2H), 6.47 (t, J= 6.2 Hz, 1H), 6.29 (dd, J= 7.7, 4.2 Hz, 1H), 5.86 (d, J= 8.4 Hz, 1H), 4.31 (d, J= 6.2 Hz, 2H), 4.19 – 3.72 (m, 7H), 3.59 (s, 4H), 3.09 (s, 3H), 2.94 (s, 2H), 1.91 – 1.88 (m, 2H), 1.47 – 1.40 (m, 2H)。 實例7. 1-環丙基-N-(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)哌啶-4-胺之合成 A mixture of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-4-methanesulfonyl-2-methoxyaniline (50 mg, 0.10 mmol, 1 eq), methyl 4-aminopiperidine-1-carboxylate (31 mg, 0.20 mmol, 2 eq), tBuXPhos Pd G3 (8 mg, 0.01 mmol, 0.1 eq) and t-BuONa (28 mg, 0.29 mmol, 3 eq) in THF (2 mL) was stirred at 65 °C under an atmosphere of argon for 0.5 h. The resulting mixture was quenched with water and extracted with CH 2 Cl 2 (2*20 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH 2 Cl 2 / MeOH (20:1) to obtain a crude product. The residue was purified by reverse phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH 4 HCO 3 ) in water, gradient 10% to 50% in 20 min; detector, UV 254 nm) to give methyl 4-[(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)amino]piperidine-1-carboxylate (3.8 mg, 6.33%) as a light yellow solid. LC-MS: (M+H) + found 594.20. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.73 (d, J = 6.7 Hz, 1H), 7.39 (dd, J = 8.3, 1.9 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.90 – 6.70 (m, 2H), 6.47 (t, J = 6.2 Hz, 1H), 6.29 (dd, J = 7.7, 4.2 Hz, 1H), 5.86 (d, J = 8.4 Hz, 1H), 4.31 (d, J = 6.2 Hz, 2H), 4.19 – 3.72 (m, 7H), 3.59 (s, 4H), 3.09 (s, 3H), 2.94 (s, 2H), 1.91 – 1.88 (m, 2H), 1.47 – 1.40 (m, 2H). Example 7. Synthesis of 1-cyclopropyl-N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)piperidin-4-amine
將N-{3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}-4-甲磺醯基-2-甲氧基苯胺(100 mg,0.19 mmol,1當量)、1-環丙基哌啶-4-胺(55 mg,0.38 mmol,2當量)、t-BuXPhos Pd G3 (16 mg,0.02 mmol,0.1當量)及t-BuONa (56 mg,0.57 mmol,3當量)於THF (2.5 mL)中之混合物在65℃及氮氣氛圍下攪拌1 h。所得混合物用水淬滅且用CH 2Cl 2(3*30 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用CH 2Cl 2/ MeOH (10:1)溶析以得到粗產物,然後藉由具有以下條件(管柱:XBridge Prep OBD C18管柱,19*250 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3+0.05%NH 3H 2O),移動相B:ACN(1% 2mM NH 3-MEOH);流動速率:25 mL/min;梯度:在10min內60% B至80% B;波長:254nm/220nm nm;RT1(min):8.78;運行次數:3)之製備型HPLC進一步純化,以得到呈白色固體之1-環丙基-N-(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)哌啶-4-胺(5.7 mg,5.09%)。LC-MS:(M+H) +實測值576.20。 1H NMR (400 MHz, DMSO- d 6) δ 7.71 (d, J= 6.7 Hz, 1H), 7.39 (dd, J= 8.3, 2.0 Hz, 1H), 7.25 (d, J= 2.0 Hz, 1H), 6.86 (d, J= 8.4 Hz, 1H), 6.80 (t, J= 7.1 Hz, 1H), 6.48 (t, J= 6.2 Hz, 1H), 6.22 (d, J= 7.6 Hz, 1H), 5.71 (d, J= 8.4 Hz, 1H), 4.31 (d, J= 6.2 Hz, 2H), 4.02 (m, 2H), 3.89 (s, 3H), 3.37 – 3.35 (m, 1H), 3.09 (s, 3H), 2.98 – 2.81 (m, 2H), 2.37 – 2.20 (m, 2H), 1.87 – 1.85 (m, 2H), 1.60 – 1.57 (m, 1H), 1.49 – 1.43 (m, 2H), 0.47 – 0.35 (m, 2H), 0.28 (m, 2H)。 實例8. (3S,4R)-3-氟-N-(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)哌啶-4-胺之合成 步驟1. (3S,4R)-3-氟-4-[(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)胺基]哌啶-1-甲酸酯之合成 A mixture of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-4-methanesulfonyl-2-methoxyaniline (100 mg, 0.19 mmol, 1 eq), 1-cyclopropylpiperidin-4-amine (55 mg, 0.38 mmol, 2 eq), t-BuXPhos Pd G3 (16 mg, 0.02 mmol, 0.1 eq) and t-BuONa (56 mg, 0.57 mmol, 3 eq) in THF (2.5 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was quenched with water and extracted with CH 2 Cl 2 (3*30 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / MeOH (10:1) to obtain a crude product, and then purified by HPLC with the following conditions (column: XBridge Prep OBD C18 column, 19*250 mm, 5μm; mobile phase A: water (10mmol/L NH 4 HCO 3 +0.05% NH 3 H 2 O), mobile phase B: ACN (1% 2mM NH 3 -MEOH); flow rate: 25 mL/min; gradient: 60% B to 80% B in 10min; wavelength: 254nm/220nm The product was purified by preparative HPLC with 5% paraformaldehyde (5% dHO) ( 4% paraformaldehyde, 5% paraformaldehyde and 1% paraformaldehyde) ( ... 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.71 (d, J = 6.7 Hz, 1H), 7.39 (dd, J = 8.3, 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.80 (t, J = 7.1 Hz, 1H), 6.48 (t, J = 6.2 Hz, 1H), 6.22 (d, J = 7.6 Hz, 1H), 5.71 (d, J = 8.4 Hz, 1H), 4.31 (d, J = 6.2 Hz, 2H), 4.02 (m, 2H), 3.89 (s, 3H), 3.37 – 3.35 (m, 1H), 3.09 (s, 3H), 2.98 – 2.81 (m, 2H), 2.37 – 2.20 (m, 2H), 1.87 – 1.85 (m, 2H), 1.60 – 1.57 (m, 1H), 1.49 – 1.43 (m, 2H), 0.47 – 0.35 (m, 2H), 0.28 (m, 2H). Example 8. Synthesis of (3S,4R)-3-fluoro-N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)piperidin-4-amine Step 1. Synthesis of (3S,4R)-3-fluoro-4-[(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)amino]piperidine-1-carboxylate
將N-{3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}-4-甲磺醯基-2-甲氧基苯胺(200 mg,0.39 mmol,1當量)、(3S,4R)-4-胺基-3-氟哌啶-1-甲酸三級丁酯(126.8 mg,0.58 mmol,1.5當量)、t-BuONa (148.9 mg,1.55 mmol,4當量)及tBuXPhos Pd G3 (92.3 mg,0.12 mmol,0.3當量)於THF (2 mL)中之混合物在65℃下攪拌1h。使混合物冷卻至室溫,然後用乙酸乙酯(20mL)稀釋,用3*20 mL之鹽水洗滌。將有機層經無水硫酸鈉乾燥且在真空下濃縮,以得到呈黑色固體之(3S,4R)-3-氟-4-[(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)胺基]哌啶-1-甲酸酯(220 mg,粗物質)。LC-MS:(M+H)+實測值654.2。 步驟2. (3S,4R)-3-氟-N-(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)哌啶-4-胺之合成 A mixture of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-4-methanesulfonyl-2-methoxyaniline (200 mg, 0.39 mmol, 1 eq), (3S,4R)-4-amino-3-fluoropiperidine-1-carboxylic acid tributyl ester (126.8 mg, 0.58 mmol, 1.5 eq), t-BuONa (148.9 mg, 1.55 mmol, 4 eq) and tBuXPhos Pd G3 (92.3 mg, 0.12 mmol, 0.3 eq) in THF (2 mL) was stirred at 65 °C for 1 h. The mixture was cooled to room temperature and then diluted with ethyl acetate (20 mL), washed with 3*20 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give (3S,4R)-3-fluoro-4-[(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)amino]piperidine-1-carboxylate (220 mg, crude) as a black solid. LC-MS: (M+H)+ found 654.2. Step 2. Synthesis of (3S,4R)-3-fluoro-N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)piperidin-4-amine
向(3S,4R)-3-氟-4-[(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)胺基]哌啶-1-甲酸三級丁酯(150 mg,粗物質)於CH 2Cl 2(2 mL)中之攪拌溶液中添加CF 3COOH (1 mL)。將反應溶液在室溫下攪拌1h,然後用飽和NaHCO 3鹼化至pH 8且用EtOAc (3*10 mL)萃取。合併的有機層用無水硫酸鈉乾燥且在真空下濃縮。殘餘物藉由製備型HPLC (管柱:XBridge Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3)+0.05%NH 3 .H 2O,移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在7 min內22% B至48% B;波長:254nm/220nm nm;RT1(min):7.8)純化,以得到呈白色固體之(3S,4R)-3-氟-N-(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)哌啶-4-胺(17.1 mg,13.45%)。LC-MS:(M+H) +實測值554.20。 1H NMR (400 MHz, DMSO-d6) δ 7.77 (d, J= 6.8 Hz, 1H), 7.39 (dd, J= 8.4, 2.0 Hz, 1H), 7.25 (d, J= 2.0 Hz, 1H), 6.93 – 6.75 (m, 2H), 6.50 – 6.36 (m, 2H), 5.36 (d, J= 9.2 Hz, 1H), 4.71 (d, J= 50.5 Hz, 1H), 4.31 (d, J= 6.2 Hz, 2H), 4.03 (m, 2H), 3.90 (s, 3H), 3.86 – 3.68 (m, 1H), 3.09 (s, 4H), 3.00 – 2.89 (m, 1H), 2.81 (m, 1H), 2.64 – 2.54 (m, 1H), 2.41 – 2.04 (m, 1H), 1.73 (dd, J= 12.9, 4.2 Hz, 1H), 1.61 (m, 1H)。 實例117. 4-[(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)胺基]-N-甲基哌啶-1-甲醯胺之合成 步驟1. 4-[(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)胺基]哌啶-1-甲酸三級丁酯之合成 To a stirred solution of (3S,4R)-3-fluoro-4-[(2-{3-[(4-methanesulfonyl- 2 -methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)amino]piperidine-1-carboxylic acid tributyl ester (150 mg, crude) in CH2Cl2 (2 mL) was added CF3COOH (1 mL). The reaction solution was stirred at room temperature for 1 h, then basified to pH 8 with saturated NaHCO3 and extracted with EtOAc (3*10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 )+0.05% NH 3 . H 2 O, mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 22% B to 48% B in 7 min; wavelength: 254 nm/220 nm nm; RT1(min): 7.8) to obtain (3S,4R)-3-fluoro-N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)piperidin-4-amine (17.1) as a white solid. mg, 13.45%). LC-MS: (M+H) + found 554.20. 1 H NMR (400 MHz, DMSO-d6) δ 7.77 (d, J = 6.8 Hz, 1H), 7.39 (dd, J = 8.4, 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.93 – 6.75 (m, 2H), 6.50 – 6.36 (m, 2H), 5.36 (d, J = 9.2 Hz, 1H), 4.71 (d, J = 50.5 Hz, 1H), 4.31 (d, J = 6.2 Hz, 2H), 4.03 (m, 2H), 3.90 (s, 3H), 3.86 – 3.68 (m, 1H), 3.09 (s, 4H), 3.00 – 2.89 (m, 1H), 2.81 (m, 1H), 2.64 – 2.54 (m, 1H), 2.41 – 2.04 (m, 1H), 1.73 (dd, J = 12.9, 4.2 Hz, 1H), 1.61 (m, 1H). Example 117. Synthesis of 4-[(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)amino]-N-methylpiperidine-1-carboxamide Step 1. Synthesis of 4-[(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)amino]piperidine-1-carboxylic acid tributyl ester
將N-{3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}-4-甲磺醯基-2-甲氧基苯胺(550 mg,1.06 mmol,1當量)、4-胺基哌啶-1-甲酸三級丁酯(427 mg,2.13 mmol,2當量)、t-BuONa (205 mg,2.13 mmol,2當量)及tBuXphos Pd G3 (254 mg,0.32 mmol,0.3當量)於THF (10 mL)中之混合物在65℃及氮氣氛圍下攪拌1 h。過濾所得混合物,濾餅用EtOAc洗滌。濾液用水(30 mL)稀釋且用EtOAc (2*30mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用PE / EA (2:1)溶析,以得到呈黃色固體之4-[(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)胺基]哌啶-1-甲酸三級丁酯(330 mg,48.73%)。LC-MS:(M+H) +實測值636.2。 步驟3. N-(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)哌啶-4-胺之合成 A mixture of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-4-methanesulfonyl-2-methoxyaniline (550 mg, 1.06 mmol, 1 eq), tributyl 4-aminopiperidine-1-carboxylate (427 mg, 2.13 mmol, 2 eq), t-BuONa (205 mg, 2.13 mmol, 2 eq) and tBuXphos Pd G3 (254 mg, 0.32 mmol, 0.3 eq) in THF (10 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was filtered and the filter cake was washed with EtOAc. The filtrate was diluted with water (30 mL) and extracted with EtOAc (2*30 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (2:1) to give 4-[(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)amino]piperidine-1-carboxylic acid tributyl ester (330 mg, 48.73%) as a yellow solid. LC-MS: (M+H) + found 636.2. Step 3. Synthesis of N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)piperidin-4-amine
將4-[(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)胺基]哌啶-1-甲酸三級丁酯(50 mg,0.08 mmol,1當量)於TFA (0.3 mL)及DCM (0.6 mL)中之溶液在室溫及氮氣氛圍下攪拌1 h。將所得混合物在減壓下濃縮,以得到呈紅色油狀物之N-(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)哌啶-4-胺(42 mg,99.70%)。粗產物無需進一步純化直接用於下一步驟中。LC-MS:(M+H) +實測值536.2。 步驟4. 4-[(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)胺基]-N-甲基哌啶-1-甲醯胺之合成 A solution of tributyl 4-[(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)amino]piperidine-1-carboxylate (50 mg, 0.08 mmol, 1 eq) in TFA (0.3 mL) and DCM (0.6 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure to give N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)piperidin-4-amine (42 mg, 99.70%) as a red oil. The crude product was used directly in the next step without further purification. LC-MS: (M+H) + found 536.2. Step 4. Synthesis of 4-[(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)amino]-N-methylpiperidine-1-carboxamide
將N-(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)哌啶-4-胺(42 mg,0.08 mmol,1當量)於DCM (1 mL)中之溶液在0℃及氮氣氛圍下用TEA (119 mg,1.17 mmol,15當量)處理5 min,接著在0℃下添加N-甲基胺甲醯氯(8 mg,0.09 mmol,1.1當量)。將所得溶液在室溫及氮氣氛圍下攪拌30 min。將所得混合物在減壓下濃縮。粗產物(50 mg)藉由具有以下條件(管柱:Xcelect CSH F-pheny OBD管柱,30*150 mm,5μm;移動相A:水(0.1% FA),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在7 min內35% B至45% B;波長:254nm/220nm nm;RT1(min):6.5)之製備型HPLC純化,以得到呈白色固體之4-[(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)胺基]-N-甲基哌啶-1-甲醯胺(22.9 mg,48.98%)。LC-MS:(M+H) +實測值593.35。 1H NMR (400 MHz, DMSO- d 6) δ 7.72 (d, J= 6.8 Hz, 1H), 7.39 (dd, J= 8.4, 2.0 Hz, 1H), 7.25 (d, J= 2.0 Hz, 1H), 6.89 – 6.77 (m, 2H), 6.47 (d, J= 6.6 Hz, 1H), 6.40 (d, J= 4.6 Hz, 1H), 6.28 (d, J= 7.6 Hz, 1H), 5.82 (s, 1H), 4.31 (d, J= 5.3 Hz, 2H), 4.02 (m, 2H), 3.96 – 3.83 (m, 5H), 3.53 (s, 1H), 3.09 (s, 3H), 2.81 – 2.76 (m, 2H), 2.55 (d, J= 3.7 Hz, 3H), 1.91 – 1.82 (m, 2H), 1.45 – 1.31 (m, 2H)。 實例9. 1-異丙基-N-(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)哌啶-4-胺之合成 A solution of N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)piperidin-4-amine (42 mg, 0.08 mmol, 1 eq) in DCM (1 mL) was treated with TEA (119 mg, 1.17 mmol, 15 eq) at 0 °C under nitrogen atmosphere for 5 min, followed by the addition of N-methylaminomethyl chloride (8 mg, 0.09 mmol, 1.1 eq) at 0 °C. The resulting solution was stirred at room temperature under nitrogen atmosphere for 30 min. The resulting mixture was concentrated under reduced pressure. The crude product (50 mg) was purified by preparative HPLC with the following conditions (column: Xcelect CSH F-pheny OBD column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 35% B to 45% B in 7 min; wavelength: 254 nm/220 nm nm; RT1(min): 6.5) to give 4-[(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)amino]-N-methylpiperidine-1-carboxamide (22.9 mg, 48.98%) as a white solid. LC-MS: (M+H) + found 593.35. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.72 (d, J = 6.8 Hz, 1H), 7.39 (dd, J = 8.4, 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.89 – 6.77 (m, 2H), 6.47 (d, J = 6.6 Hz, 1H), 6.40 (d, J = 4.6 Hz, 1H), 6.28 (d, J = 7.6 Hz, 1H), 5.82 (s, 1H), 4.31 (d, J = 5.3 Hz, 2H), 4.02 (m, 2H), 3.96 – 3.83 (m, 5H), 3.53 (s, 1H), 3.09 (s, 3H), 2.81 – 2.76 (m, 2H), 2.55 (d, J = 3.7 Hz, 3H), 1.91 – 1.82 (m, 2H), 1.45 – 1.31 (m, 2H). Example 9. Synthesis of 1-isopropyl-N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)piperidin-4-amine
將N-(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)哌啶-4-胺(42 mg,0.078 mmol,1當量)於丙酮(1 mL)中之溶液在室溫下攪拌30 min。在室溫下向上述溶液中分三批添加NaBH(OAc) 3(83 mg,0.39 mmol,5當量)。將所得混合物在室溫下攪拌隔夜。用飽和NaHCO 3將混合物中和至pH 8且用CH 2Cl 2(3*10 mL)萃取。將合併的有機層在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/ MeOH 10:1)+0.1% NH 3·H 2O純化以得到粗產物,然後藉由具有以下條件之反相急速層析進一步純化:管柱,C18矽膠;移動相,於水中之MeCN (10 mmol/L NH 4HCO 3),在20 min內10%至50%梯度;偵測器,UV 254 nm,以得到呈白色固體之1-異丙基-N-(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)哌啶-4-胺(8.1 mg,17.45%)。LC-MS:(M+H) +實測值578.45。 1H NMR (400 MHz, DMSO- d 6) δ 7.72 (d, J= 6.7 Hz, 1H), 7.39 (dd, J= 8.3, 2.0 Hz, 1H), 7.25 (d, J= 2.0 Hz, 1H), 6.89 – 6.76 (m, 2H), 6.49 (t, J= 6.3 Hz, 1H), 6.23 (d, J= 7.6 Hz, 1H), 5.77 (s, 1H), 4.31 (d, J= 6.3 Hz, 2H), 4.06 – 3.98 (m, 2H), 3.90 (s, 3H), 3.38 (s, 1H), 3.10 (s, 3H), 2.83 (s, 3H), 2.28 (s, 1H), 1.93 (t, J= 8.0 Hz, 2H), 1.54 (s, 2H), 1.11 – 0.88 (m, 7H)。 實例10. 1-{4-[(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)胺基]哌啶-1-基}乙酮之合成 A solution of N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)piperidin-4-amine (42 mg, 0.078 mmol, 1 eq) in acetone (1 mL) was stirred at room temperature for 30 min. To the above solution was added NaBH(OAc) 3 (83 mg, 0.39 mmol, 5 eq) in three portions at room temperature. The resulting mixture was stirred at room temperature overnight. The mixture was neutralized to pH 8 with saturated NaHCO 3 and extracted with CH 2 Cl 2 (3*10 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 / MeOH 10:1) + 0.1% NH 3 ·H 2 O to give a crude product, which was then further purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH 4 HCO 3 ) in water, 10% to 50% gradient in 20 min; detector, UV 254 nm to give 1-isopropyl-N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)piperidin-4-amine (8.1 mmol/L) as a white solid. mg, 17.45%). LC-MS: (M+H) + found 578.45. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.72 (d, J = 6.7 Hz, 1H), 7.39 (dd, J = 8.3, 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.89 – 6.76 (m, 2H), 6.49 (t, J = 6.3 Hz, 1H), 6.23 (d, J = 7.6 Hz, 1H), 5.77 (s, 1H), 4.31 (d, J = 6.3 Hz, 2H), 4.06 – 3.98 (m, 2H), 3.90 (s, 3H), 3.38 (s, 1H), 3.10 (s, 3H), 2.83 (s, 3H), 2.28 (s, 1H), 1.93 (t, J = 8.0 Hz, 2H), 1.54 (s, 2H), 1.11 – 0.88 (m, 7H). Example 10. Synthesis of 1-{4-[(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)amino]piperidin-1-yl}ethanone
在0℃下,向N-(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)哌啶-4-胺(42 mg,0.08 mmol,1當量)及TEA (119 mg,1.17 mmol,15當量)於DCM (1 mL)中之攪拌溶液中添加乙醯氯(6 mg,0.07 mmol,0.9當量)。將所得混合物在室溫下攪拌30 min。所得混合物用水(10 mL)稀釋且用EtOAc (3*10 mL)萃取。將合併的有機層在減壓下濃縮。殘餘物藉由具有以下條件(管柱:XBridge Shield RP18 OBD管柱,30*150 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3+0.05%NH 3 .H 2O),移動相B:ACN;流動速率:60 mL/min;梯度:在7 min內30% B至50% B;波長:254nm/220nm nm;RT1(min):6.6)之製備型HPLC純化,以得到呈白色固體之1-{4-[(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)胺基]哌啶-1-基}乙酮(22.3 mg,48.94%)。LC-MS:(M+H) +實測值578.30。 1H NMR (400 MHz, DMSO- d 6) δ 7.73 (d, J= 6.7 Hz, 1H), 7.39 (dd, J= 8.3, 2.0 Hz, 1H), 7.25 (d, J= 2.0 Hz, 1H), 6.89 – 6.77 (m, 2H), 6.48 (t, J= 6.3 Hz, 1H), 6.30 (d, J= 7.6 Hz, 1H), 5.87 (d, J= 8.5 Hz, 1H), 4.31 (d, J= 6.2 Hz, 3H), 4.06 – 3.98 (m, 2H), 3.89 (s, 3H), 3.82 (d, J= 13.9 Hz, 1H), 3.69 – 3.55 (m, 1H), 3.21 – 3.09 (m, 1H), 3.09 (s, 3H), 2.70 (td, J= 12.7, 2.9 Hz, 1H), 2.00 (s, 3H), 1.98 – 1.85 (m, 2H), 1.54 – 1.28 (m, 2H)。 實例11. 1-{4-[(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)胺基]哌啶-1-基}-2-甲基丙-2-醇之合成 To a stirred solution of N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)piperidin-4-amine (42 mg, 0.08 mmol, 1 eq) and TEA (119 mg, 1.17 mmol, 15 eq) in DCM (1 mL) at 0°C was added acetyl chloride (6 mg, 0.07 mmol, 0.9 eq). The resulting mixture was stirred at room temperature for 30 min. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3*10 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative HPLC with the following conditions (column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 +0.05% NH 3 . H 2 O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 30% B to 50% B in 7 min; wavelength: 254 nm/220 nm; RT1 (min): 6.6) to obtain 1-{4-[(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)amino]piperidin-1-yl}ethanone (22.3 mmol/l) as a white solid. mg, 48.94%). LC-MS: (M+H) + found 578.30. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.73 (d, J = 6.7 Hz, 1H), 7.39 (dd, J = 8.3, 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.89 – 6.77 (m, 2H), 6.48 (t, J = 6.3 Hz, 1H), 6.30 (d, J = 7.6 Hz, 1H), 5.87 (d, J = 8.5 Hz, 1H), 4.31 (d, J = 6.2 Hz, 3H), 4.06 – 3.98 (m, 2H), 3.89 (s, 3H), 3.82 (d, J = 13.9 Hz, 1H), 3.69 – 3.55 (m, 1H), 3.21 – 3.09 (m, 1H), 3.09 (s, 3H), 2.70 (td, J = 12.7, 2.9 Hz, 1H), 2.00 (s, 3H), 1.98 – 1.85 (m, 2H), 1.54 – 1.28 (m, 2H). Example 11. Synthesis of 1-{4-[(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)amino]piperidin-1-yl}-2-methylpropan-2-ol
將N-(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)哌啶-4-胺(60 mg,0.12 mmol,1當量)、EtOH (0.6 mL)、K 2CO 3(62 mg,0.45 mmol,4當量)、H 2O (0.3 mL)及2,2-二甲基環氧乙烷(32 mg,0.45 mmol,4當量)之混合物在110℃下用微波輻射照射0.5 h。所得混合物用水(10 mL)稀釋且用EtOAc (3*10 mL)萃取。將合併的有機層在減壓下濃縮。殘餘物藉由具有以下條件(管柱:XBridge Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3+0.05% NH 3 .H 2O),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在7 min內33% B至60% B;波長:220nm nm;RT1(min):7.5)之製備型HPLC純化,以得到呈白色固體之1-{4-[(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)胺基]哌啶-1-基}-2-甲基丙-2-醇(22.2 mg,32.45%)。LC-MS:(M+H) +實測值608.15。 1H NMR (400 MHz, DMSO- d 6) δ 7.71 (d, J= 6.7 Hz, 1H), 7.39 (dd, J= 8.3, 2.0 Hz, 1H), 7.25 (d, J= 2.0 Hz, 1H), 6.86 (d, J= 8.4 Hz, 1H), 6.80 (t, J= 7.2 Hz, 1H), 6.48 (t, J= 6.2 Hz, 1H), 6.21 (d, J= 7.6 Hz, 1H), 5.67 (d, J= 8.2 Hz, 1H), 4.31 (d, J= 6.3 Hz, 2H), 4.04 (d, J= 3.4 Hz, 2H), 4.00 (d, J= 10.8 Hz, 1H), 3.90 (s, 3H), 3.30 (d, J= 10.8 Hz, 1H), 3.10 (s, 3H), 2.96 – 2.87 (m, 2H), 2.30 – 2.20 (m, 2H), 2.20 (s, 2H), 1.90 – 1.81 (m, 2H), 1.61 – 1.46 (m, 2H), 1.08 (s, 6H)。 實例12. (2S)-1-{4-[(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)胺基]哌啶-1-基}-3-甲氧基丙-2-醇之合成 A mixture of N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)piperidin-4-amine (60 mg, 0.12 mmol, 1 eq), EtOH (0.6 mL), K 2 CO 3 (62 mg, 0.45 mmol, 4 eq), H 2 O (0.3 mL) and 2,2-dimethyloxirane (32 mg, 0.45 mmol, 4 eq) was irradiated with microwave irradiation at 110 °C for 0.5 h. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3*10 mL). The combined organic layers were concentrated under reduced pressure. The residue was separated by HPLC with the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5μm; mobile phase A: water (10mmol/L NH 4 HCO 3 +0.05% NH 3 . H 2 O), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 33% B to 60% B in 7 min; wavelength: 220nm nm; RT1 (min): 7.5) to give 1-{4-[(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)amino]piperidin-1-yl}-2-methylpropan-2-ol (22.2 mg, 32.45%) as a white solid. LC-MS: (M+H) + found 608.15. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.71 (d, J = 6.7 Hz, 1H), 7.39 (dd, J = 8.3, 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.80 (t, J = 7.2 Hz, 1H), 6.48 (t, J = 6.2 Hz, 1H), 6.21 (d, J = 7.6 Hz, 1H), 5.67 (d, J = 8.2 Hz, 1H), 4.31 (d, J = 6.3 Hz, 2H), 4.04 (d, J = 3.4 Hz, 2H), 4.0 (d, J = 10.8 Hz, 1H), 3.90 (s, 3H), 3.30 (d, J = 10.8 Hz, 1H), 3.10 (s, 3H), 2.96 – 2.87 (m, 2H), 2.30 – 2.20 (m, 2H), 2.20 (s, 2H), 1.90 – 1.81 (m, 2H), 1.61 – 1.46 (m, 2H), 1.08 (s, 6H). Example 12. Synthesis of (2S)-1-{4-[(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)amino]piperidin-1-yl}-3-methoxypropan-2-ol
將N-(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)哌啶-4-胺(42 mg,0.08 mmol,1當量)、EtOH (0.5 mL)、K 2CO 3(43 mg,0.31 mmol,4當量)、H 2O (0.2 mL)及(2S)-2-(甲氧基甲基)環氧乙烷(21 mg,0.23 mmol,3當量)之混合物在110℃下用微波輻射照射0.5 h。所得混合物用水(10 mL)稀釋且用EtOAc (3*10 mL)萃取。將合併的有機層在減壓下濃縮。殘餘物藉由具有以下條件(管柱:XBridge Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3+0.05% NH 3 .H 2O),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在7 min內26% B至52% B;波長:220nm nm;RT1(min):7.5)之製備型HPLC純化,以得到呈白色固體之(2S)-1-{4-[(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)胺基]哌啶-1-基}-3-甲氧基丙-2-醇(17.7 mg,35.61%)。LC-MS:(M+H) +實測值624.45。 1H NMR (400 MHz, DMSO- d 6) δ 7.71 (d, J= 6.7 Hz, 1H), 7.39 (dd, J= 8.4, 2.0 Hz, 1H), 7.25 (d, J= 2.0 Hz, 1H), 6.86 (d, J= 8.4 Hz, 1H), 6.80 (t, J= 7.2 Hz, 1H), 6.47 (t, J= 6.2 Hz, 1H), 6.22 (d, J= 7.6 Hz, 1H), 5.70 (d, J= 8.3 Hz, 1H), 4.50 (d, J= 4.7 Hz, 1H), 4.31 (d, J= 6.3 Hz, 2H), 4.05 (d, J= 10.6 Hz, 1H), 3.99 (d, J= 10.8 Hz, 1H), 3.90 (s, 3H), 3.72 (q, J= 5.6 Hz, 1H), 3.35 (s, 1H), 3.31 – 3.27 (m, 1H), 3.25 (s, 3H), 3.24 – 3.18 (m, 1H), 3.09 (s, 3H), 2.90 – 2.79 (m, 2H), 2.31 (dd, J= 12.6, 5.1 Hz, 1H), 2.24 (dd, J= 12.7, 7.0 Hz, 1H), 2.11 (dd, J= 20.7, 10.8 Hz, 2H), 1.91 – 1.83 (m, 2H), 1.61 – 1.47 (m, 2H)。 實例14. (2R)-1-{4-[(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)胺基]哌啶-1-基}-3-甲氧基丙-2-醇之合成 A mixture of N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)piperidin-4-amine (42 mg, 0.08 mmol, 1 eq), EtOH (0.5 mL), K 2 CO 3 (43 mg, 0.31 mmol, 4 eq), H 2 O (0.2 mL) and (2S)-2-(methoxymethyl)oxirane (21 mg, 0.23 mmol, 3 eq) was irradiated with microwave radiation at 110 °C for 0.5 h. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3*10 mL). The combined organic layers were concentrated under reduced pressure. The residue was separated by HPLC with the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5μm; mobile phase A: water (10mmol/L NH 4 HCO 3 +0.05% NH 3 . H 2 O), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 26% B to 52% B in 7 min; wavelength: 220nm nm; RT1 (min): 7.5) was purified by preparative HPLC to give (2S)-1-{4-[(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)amino]piperidin-1-yl}-3-methoxypropan-2-ol (17.7 mg, 35.61%) as a white solid. LC-MS: (M+H) + found 624.45. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.71 (d, J = 6.7 Hz, 1H), 7.39 (dd, J = 8.4, 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.80 (t, J = 7.2 Hz, 1H), 6.47 (t, J = 6.2 Hz, 1H), 6.22 (d, J = 7.6 Hz, 1H), 5.70 (d, J = 8.3 Hz, 1H), 4.50 (d, J = 4.7 Hz, 1H), 4.31 (d, J = 6.3 Hz, 2H), 4.05 3.91 (d, J = 10.6 Hz, 1H), 3.99 (d, J = 10.8 Hz, 1H), 3.90 (s, 3H), 3.72 (q, J = 5.6 Hz, 1H), 3.35 (s, 1H), 3.31 – 3.27 (m, 1H), 3.25 (s, 3H), 3.24 – 3.18 (m, 1H), 3.09 (s, 3H), 2.91 – 2.89 (m, 2H), 2.30 (dd, J = 12.6, 5.1 Hz, 1H), 2.24 (dd, J = 12.7, 7.0 Hz, 1H), 2.13 (dd, J = 20.7, 10.8 Hz, 2H), 1.91 – 1.83 (m, 2H), 1.61 – 1.47 (m, 2H). Example 14. Synthesis of (2R)-1-{4-[(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)amino]piperidin-1-yl}-3-methoxypropan-2-ol
將N-(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)哌啶-4-胺(50 mg,0.09 mmol,1當量)、EtOH (0.6 mL)、K 2CO 3(52 mg,0.37 mmol,4當量)、(2R)-2-(甲氧基甲基)環氧乙烷(33 mg,0.37 mmol,4當量)及H 2O (0.3 mL)之混合物在110℃下用微波輻射照射0.5 h。所得混合物用水(10 mL)稀釋且用EA (3*10 mL)萃取。將合併的有機層在減壓下濃縮。殘餘物藉由具有以下條件(管柱:XBridge Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3)+0.05%NH 3 .H 2O,移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在7 min內26% B至52% B;波長:254nm/220nm nm;RT1(min):7.87)之製備型HPLC純化,以得到呈白色固體之(2R)-1-{4-[(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)胺基]哌啶-1-基}-3-甲氧基丙-2-醇(11.1 mg,18.93%)。LC-MS:(M+H) +實測值624.20。 1H NMR (400 MHz, DMSO- d 6) δ 7.71 (d, J= 6.7 Hz, 1H), 7.39 (dd, J= 8.3, 2.0 Hz, 1H), 7.25 (d, J= 2.0 Hz, 1H), 6.86 (d, J= 8.4 Hz, 1H), 6.80 (t, J= 7.1 Hz, 1H), 6.47 (t, J= 6.2 Hz, 1H), 6.22 (d, J= 7.6 Hz, 1H), 5.70 (d, J= 8.3 Hz, 1H), 4.50 (d, J= 4.6 Hz, 1H), 4.31 (d, J= 6.3 Hz, 2H), 4.06 – 3.98 (m, 2H), 3.90 (s, 3H), 3.72 (m, 1H), 3.32 – 3.16 (m, 6H), 3.09 (s, 3H), 2.92 – 2.76 (m, 2H), 2.39 – 2.19 (m, 2H), 2.15 – 2.07 (m, 2H), 1.88 – 1.86 (m, 2H), 1.57 – 1.52 (m, 2H)。 實例15. (3S,4R)-N-(3-乙基-2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}咪唑并[1,2-a]吡啶-8-基)-3-氟-1-甲基哌啶-4-胺之合成 步驟1. N-(3-{8-溴-3-乙基咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)-4-甲磺醯基-2-甲氧基苯胺之合成 A mixture of N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)piperidin-4-amine (50 mg, 0.09 mmol, 1 eq), EtOH (0.6 mL), K 2 CO 3 (52 mg, 0.37 mmol, 4 eq), (2R)-2-(methoxymethyl)oxirane (33 mg, 0.37 mmol, 4 eq) and H 2 O (0.3 mL) was irradiated with microwave irradiation at 110 °C for 0.5 h. The obtained mixture was diluted with water (10 mL) and extracted with EA (3*10 mL). The combined organic layers were concentrated under reduced pressure. The residue was separated by HPLC with the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5μm; mobile phase A: water (10mmol/L NH 4 HCO 3 )+0.05% NH 3 . H 2 O, mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 26% B to 52% B in 7 min; wavelength: 254nm/220nm nm; RT1 (min): 7.87) to give (2R)-1-{4-[(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)amino]piperidin-1-yl}-3-methoxypropan-2-ol (11.1 mg, 18.93%) as a white solid. LC-MS: (M+H) + found 624.20. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.71 (d, J = 6.7 Hz, 1H), 7.39 (dd, J = 8.3, 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.80 (t, J = 7.1 Hz, 1H), 6.47 (t, J = 6.2 Hz, 1H), 6.22 (d, J = 7.6 Hz, 1H), 5.70 (d, J = 8.3 Hz, 1H), 4.50 (d, J = 4.6 Hz, 1H), 4.31 (d, J = 6.3 Hz, 2H), 4.06 – 3.98 (m, 2H), 3.90 (s, 3H), 3.72 (m, 1H), 3.32 – 3.16 (m, 6H), 3.09 (s, 3H), 2.92 – 2.76 (m, 2H), 2.39 – 2.19 (m, 2H), 2.15 – 2.07 (m, 2H), 1.88 – 1.86 (m, 2H), 1.57 – 1.52 (m, 2H). Example 15. Synthesis of (3S,4R)-N-(3-ethyl-2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}imidazo[1,2-a]pyridin-8-yl)-3-fluoro-1-methylpiperidin-4-amine Step 1. Synthesis of N-(3-{8-bromo-3-ethylimidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-4-methanesulfonyl-2-methoxyaniline
向8-溴-3-乙基-2-碘咪唑并[1,2-a]吡啶( 中間物2;200.0 mg,0.56 mmol,1當量)於DMSO (10 mL)中之攪拌溶液中添加4-甲磺醯基-2-甲氧基-N-(丙-2-炔-1-基)苯胺( 中間物39;196.3 mg,0.82 mmol,1.20當量)、CuI (130.2 mg,0.64 mmol,1當量)、i-Pr 2NH (691.9 mg,6.82 mmol,10當量)及Pd(PPh 3) 4(316.1 mg,0.26 mmol,0.40當量)。將混合物在50℃及氮氣氛圍下攪拌16 h。混合物使用具有以下條件(移動相A:水,移動相B:ACN;流動速率:80 mL/min;梯度:在30 min內0% B至100% B;254/220 nm)之C18層析純化。此產生呈黃色固體之N-(3-{8-溴-3-乙基咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)-4-甲磺醯基-2-甲氧基苯胺(130.0 mg,49.4%)。LC-MS:(M+H) +實測值462.0。 步驟2. (3S,4R)-N-(3-乙基-2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}咪唑并[1,2-a]吡啶-8-基)-3-氟-1-甲基哌啶-4-胺之合成 To a stirred solution of 8-bromo-3-ethyl-2-iodoimidazo[1,2-a]pyridine ( Intermediate 2 ; 200.0 mg, 0.56 mmol, 1 eq) in DMSO (10 mL) was added 4-methanesulfonyl-2-methoxy-N-(prop-2-yn-1-yl)aniline ( Intermediate 39 ; 196.3 mg, 0.82 mmol, 1.20 eq), CuI (130.2 mg, 0.64 mmol, 1 eq), i-Pr 2 NH (691.9 mg, 6.82 mmol, 10 eq) and Pd(PPh 3 ) 4 (316.1 mg, 0.26 mmol, 0.40 eq). The mixture was stirred at 50 °C under nitrogen atmosphere for 16 h. The mixture was purified using C18 chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 80 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm). This produced N-(3-{8-bromo-3-ethylimidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-4-methanesulfonyl-2-methoxyaniline (130.0 mg, 49.4%) as a yellow solid. LC-MS: (M+H) + found 462.0. Step 2. Synthesis of (3S,4R)-N-(3-ethyl-2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}imidazo[1,2-a]pyridin-8-yl)-3-fluoro-1-methylpiperidin-4-amine
向N-(3-{8-溴-3-乙基咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)-4-甲磺醯基-2-甲氧基苯胺(130.0 mg,0.28 mmol,1當量)於1,4-二噁烷(5 mL)中之溶液中添加(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(48.3 mg,0.36 mmol,1.30當量)、BrettPhosPdG4 (51.0 mg,0.05 mmol,0.20當量)、RuPhos (52.5 mg,0.11 mmol,0.40當量)及Cs 2CO 3(458.1 mg,1.40 mmol,5當量)。將反應混合物在100℃及氮氣氛圍下加熱5 h。所得溶液使用具有以下條件(移動相A:水,移動相B:ACN;流動速率:60 mL/min;梯度:在30 min內0% B至100% B;254/220 nm)之C18層析純化。粗物質使用具有以下條件之製備型HPLC純化:(管柱:XBridge Prep Phenyl OBD管柱,19*250 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3+0.05%NH 3H 2O),移動相B:ACN;流動速率:25 mL/min mL/min;梯度:在10min內33% B至52% B;波長:254nm/220nm;RT = 9.75 min)。此產生呈白色固體之(3S,4R)-N-(3-乙基-2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}咪唑并[1,2-a]吡啶-8-基)-3-氟-1-甲基哌啶-4-胺(8.30 mg,5.7%)。LC-MS:(M+H) +實測值514.10。 1H NMR (400 MHz, DMSO- d 6) δ 7.60 (d, 1H), 7.45-7.40 (m, 1H), 7.25 (s, 1H), 6.91-6.82 (m, 1H), 6.80-6.69 (m, 1H), 6.45 (t, 1H), 6.34-6.25 (m, 1H), 5.30-5.20 (m, 1H), 4.80 (d, 1H), 4.30 (s, 2H), 3.90 (s, 3H), 3.80-3.50 (m, 1H), 3.10 (s, 3H), 3.08-2.95 (m, 1H), 2.90-2.80 (m, 2H), 2.79-2.70 (m, 1H), 2.30-2.00 (m, 5H), 1.80 (s, 2H), 1.10 (t, 3H)。 實例16. N-(3-乙基-2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}咪唑并[1,2-a]吡啶-8-基)-1-甲基哌啶-4-胺之合成 To a solution of N-(3-{8-bromo-3-ethylimidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-4-methanesulfonyl-2-methoxyaniline (130.0 mg, 0.28 mmol, 1 eq) in 1,4-dioxane (5 mL) were added (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (48.3 mg, 0.36 mmol, 1.30 eq), BrettPhosPdG4 (51.0 mg, 0.05 mmol, 0.20 eq), RuPhos (52.5 mg, 0.11 mmol, 0.40 eq) and Cs2CO3 ( 458.1 mg, 1.40 mmol, 5 eq). The reaction mixture was heated at 100 °C under nitrogen atmosphere for 5 h. The resulting solution was purified using C18 chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm). The crude material was purified using preparative HPLC with the following conditions: (column: XBridge Prep Phenyl OBD column, 19*250 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 +0.05% NH 3 H 2 O), mobile phase B: ACN; flow rate: 25 mL/min mL/min; gradient: 33% B to 52% B in 10 min; wavelength: 254 nm/220 nm; RT = 9.75 min). This resulted in (3S,4R)-N-(3-ethyl-2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}imidazo[1,2-a]pyridin-8-yl)-3-fluoro-1-methylpiperidin-4-amine (8.30 mg, 5.7%) as a white solid. LC-MS: (M+H) + found 514.10. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.60 (d, 1H), 7.45-7.40 (m, 1H), 7.25 (s, 1H), 6.91-6.82 (m, 1H), 6.80-6.69 (m, 1H), 6.45 (t, 1H), 6.34-6.25 (m, 1H), 5.30-5.20 (m, 1H), 4.80 (d, 1H), 4.30 (s, 2H), 3.90 (s, 3H), 3.80-3.50 (m, 1H), 3.10 (s, 3H), 3.08-2.95 (m, 1H), 2.90-2.80 (m, 2H), 2.79-2.70 (m, 1H), 2.30-2.00 (m, 5H), 1.80 (s, 2H), 1.10 (t, 3H). Example 16. Synthesis of N-(3-ethyl-2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine
在室溫下,向N-(3-{8-溴-3-乙基咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)-4-甲磺醯基-2-甲氧基苯胺(50 mg,0.11 mmol,1當量)於1,4-二噁烷(5 mL)中之攪拌溶液中添加1-甲基哌啶-4-胺(30.9 mg,0.27 mmol,2.50當量)、BrettPhosPdG3 (19.6 mg,0.02 mmol,0.20當量)、RuPhos (20.2 mg,0.04 mmol,0.40當量)及Cs 2CO 3(176.2 mg,0.55 mmol,5當量)。將反應混合物在100℃及氮氣氛圍下攪拌1 h。移除溶劑後,殘餘物使用具有以下條件(移動相A:水,移動相B:ACN;流動速率:60 mL/min;梯度:在30 min內0% B至80% B;254/220 nm)之C18層析純化。粗物質使用具有以下條件之製備型HPLC純化:(管柱:XBridge Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3+0.05% NH 3H 2O),移動相B:ACN;流動速率:60 mL/min;梯度:在7min內28% B至53% B;波長:254nm nm;RT = 7.15 min)。此產生呈黃色固體之N-(3-乙基-2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}咪唑并[1,2-a]吡啶-8-基)-1-甲基哌啶-4-胺(10.1 mg,18.2%)。LC-MS:(M+H) +實測值496.40。 1H NMR (400 MHz, DMSO- d 6) δ 7.50 (d, 1H), 7.35 (d, 1H), 7.20 (d, 1H), 6.90 (d, 1H), 6.80-6.60 (m, 1H), 6.59-6.33 (m, 1H), 6.29-6.00 (m, 1H), 5.58-5.49 (m, 1H), 4.30 (d, 2H), 3.90 (s, 3H), 3.10 (s, 3H), 3.00-2.80 (m, 2H), 2.76-2.60 (m, 2H), 2.10 (s, 3H), 2.08-1.95 (m, 2H), 1.92-1.82 (m, 2H), 1.58-1.40 (m, 3H), 1.11 (t, 3H)。 實例17. 4-{[3-(3-乙氧基-8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺之合成 步驟1. 4-[(3-{8-溴-3-乙氧基咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺之合成 To a stirred solution of N-(3-{8-bromo-3-ethylimidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-4-methanesulfonyl-2-methoxyaniline (50 mg, 0.11 mmol, 1 eq) in 1,4-dioxane (5 mL) at room temperature were added 1-methylpiperidin-4-amine (30.9 mg, 0.27 mmol, 2.50 eq), BrettPhosPdG3 (19.6 mg, 0.02 mmol, 0.20 eq), RuPhos (20.2 mg, 0.04 mmol, 0.40 eq) and Cs2CO3 (176.2 mg, 0.55 mmol, 5 eq). The reaction mixture was stirred at 100 °C under nitrogen atmosphere for 1 h. After removing the solvent, the residue was purified using C18 chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 80% B in 30 min; 254/220 nm). The crude material was purified using preparative HPLC with the following conditions: (column: XBridge Prep OBD C18 column, 30*150 mm, 5μm; mobile phase A: water (10mmol/L NH4HCO3 +0.05% NH3H2O ) , mobile phase B: ACN; flow rate: 60 mL/min; gradient: 28% B to 53% B in 7min; wavelength: 254nm nm; RT = 7.15 min). This resulted in N-(3-ethyl-2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine (10.1 mg, 18.2%) as a yellow solid. LC-MS: (M+H) + found 496.40. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.50 (d, 1H), 7.35 (d, 1H), 7.20 (d, 1H), 6.90 (d, 1H), 6.80-6.60 (m, 1H), 6.59-6.33 (m, 1H), 6.29-6.00 (m, 1H), 5.58-5.49 (m, 1H), 4.30 (d, 2H), 3.90 (s, 3H), 3.10 (s, 3H), 3.00-2.80 (m, 2H), 2.76-2.60 (m, 2H), 2.10 (s, 3H), 2.08-1.95 (m, 2H), 1.92-1.82 (m, 2H), 1.58-1.40 (m, 3H), 1.11 (t, 3H). Example 17. Synthesis of 4-{[3-(3-ethoxy-8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide Step 1. Synthesis of 4-[(3-{8-bromo-3-ethoxyimidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide
向8-溴-3-乙氧基-2-碘咪唑并[1,2-a]吡啶( 中間物3;300.0 mg,0.82 mmol,1當量)於DMSO (5 mL)中之攪拌溶液中添加3-甲氧基-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺( 中間物14;214.1 mg,0.98 mmol,1.20當量)、CuI (155.7 mg,0.82 mmol,1當量)、Pd(PPh 3) 4(188.9 mg,0.16 mmol,0.20當量) 及i-Pr 2NH (827.2 mg,8.17 mmol,10當量)。將所得混合物在30℃及氮氣氛圍下攪拌1h,然後藉由具有以下條件之反相急速層析純化:管柱,C18;移動相,於水中之MeCN (0.1% FA),在20 min內0%至65%梯度;偵測器,UV 254 nm。此產生呈棕色固體之4-[(3-{8-溴-3-乙氧基咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺(270.0 mg,72.22%)。LC-MS:(M+H) +實測值457.3 步驟2. 4-{[3-(3-乙氧基-8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺之合成 To a stirred solution of 8-bromo-3-ethoxy-2-iodoimidazo[1,2-a]pyridine ( intermediate 3 ; 300.0 mg, 0.82 mmol, 1 eq) in DMSO (5 mL) were added 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide ( intermediate 14 ; 214.1 mg, 0.98 mmol, 1.20 eq), CuI (155.7 mg, 0.82 mmol, 1 eq), Pd( PPh3 ) 4 (188.9 mg, 0.16 mmol, 0.20 eq) and i- Pr2NH (827.2 mg, 8.17 mmol, 10 eq). The resulting mixture was stirred at 30° C. under nitrogen atmosphere for 1 h and then purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN (0.1% FA) in water, gradient 0% to 65% in 20 min; detector, UV 254 nm. This resulted in 4-[(3-{8-bromo-3-ethoxyimidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (270.0 mg, 72.22%) as a brown solid. LC-MS: (M+H) + found 457.3 Step 2. Synthesis of 4-{[3-(3-ethoxy-8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide
向4-[(3-{8-溴-3-乙氧基咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺(150.0 mg,0.33 mmol,1當量)於THF (5 mL) 中之攪拌溶液中添加(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(134.5 mg,0.66 mmol,2當量)、t-BuXPhosPdG3 (52.2 mg,0.07 mmol,0.20當量)及t-BuONa (252.2 mg,2.62 mmol,8當量)。將所得混合物在65℃及氮氣氛圍下攪拌30min。移除溶劑之後,殘餘物藉由具有以下條件之反相急速層析純化:管柱,C18;移動相,於水中之MeCN (0.1% FA),在20 min內0%至20%梯度;偵測器,UV 254 nm。粗產物藉由具有以下條件(管柱:Xselect CSH C18 OBD管柱,30*150 mm,5 μm;移動相A:水(0.1% FA),移動相B:ACN;流動速率:60 mL/min;梯度:在7 min內10% B至20% B;波長:254nm/220nm;RT(min):6.25)之製備型HPLC純化,以得到呈黃色固體之4-{[3-(3-乙氧基-8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺(15.1 mg,9.05%)。LC-MS:(M+H) +實測值509.35。 1H NMR (400 MHz, DMSO- d 6) δ 8.07 (q, J= 4.5 Hz, 1H), 7.41 (dd, J= 8.2, 1.9 Hz, 1H), 7.38-7.32 (m, 2H), 6.76-6.65 (m, 2H), 6.22 (d, J= 7.4 Hz, 1H), 5.93 (t, J= 6.4 Hz, 1H), 5.26 (d, J= 9.2 Hz, 1H), 4.80 (d, J= 49.7 Hz, 1H), 4.35-4.21 (m, 4H), 3.84 (s, 3H), 3.68 (m, 1H), 3.03 (t, J= 11.3 Hz, 1H), 2.75 (d, J= 4.5 Hz, 4H), 2.34-2.15 (m, 4H), 2.14-2.06 (m, 1H), 1.86-1.72 (m, 2H), 1.24 (t, J= 7.0 Hz, 3H)。 實例18. (3S,4R)-3-氟-1-甲基-N-[2-(丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基]哌啶-4-胺之合成 To a stirred solution of 4-[(3-{8-bromo-3-ethoxyimidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (150.0 mg, 0.33 mmol, 1 eq) in THF (5 mL) was added (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (134.5 mg, 0.66 mmol, 2 eq), t-BuXPhosPdG3 (52.2 mg, 0.07 mmol, 0.20 eq) and t-BuONa (252.2 mg, 2.62 mmol, 8 eq). The resulting mixture was stirred at 65 °C under nitrogen atmosphere for 30 min. After removal of the solvent, the residue was purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN (0.1% FA) in water, gradient 0% to 20% in 20 min; detector, UV 254 nm. The crude product was purified by preparative HPLC with the following conditions (column: Xselect CSH C18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 10% B to 20% B in 7 min; wavelength: 254 nm/220 nm; RT (min): 6.25) to give 4-{[3-(3-ethoxy-8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (15.1 mg, 9.05%) as a yellow solid. LC-MS: (M+H) + found 509.35. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.07 (q, J = 4.5 Hz, 1H), 7.41 (dd, J = 8.2, 1.9 Hz, 1H), 7.38-7.32 (m, 2H), 6.76-6.65 (m, 2H), 6.22 (d, J = 7.4 Hz, 1H), 5.93 (t, J = 6.4 Hz, 1H), 5.26 (d, J = 9.2 Hz, 1H), 4.80 (d, J = 49.7 Hz, 1H), 4.35-4.21 (m, 4H), 3.84 (s, 3H), 3.68 (m, 1H), 3.03 (t, J = 11.3 Hz, 1H), 2.75 (d, J = 4.5 Hz, 4H), 2.34-2.15 (m, 4H), 2.14-2.06 (m, 1H), 1.86-1.72 (m, 2H), 1.24 (t, J = 7.0 Hz, 3H). Example 18. Synthesis of (3S,4R)-3-fluoro-1-methyl-N-[2-(prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]piperidin-4-amine
將8-溴-2-(丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶( 中間物4;60 mg,0.18 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(116.4 mg,0.56 mmol,3當量)、RuPhos (17.7 mg,0.03 mmol,0.2當量)、Cs 2CO 3(308.2 mg,0.94 mmol,5當量)及RuPhos Palladacycle Gen.4 (15.8 mg,0.01 mmol,0.1當量)於二噁烷(3 mL)中之混合物在80℃及氮氣氛圍下攪拌3 h。在真空下移除溶劑。殘餘物使用具有以下條件(移動相A:水,移動相B:ACN;流動速率:60 mL/min;梯度:在30 min內0% B至100% B;254/220 nm)之C18急速層析純化。粗物質使用具有以下條件之製備型HPLC進一步純化:管柱:XBridge Shield RP18 OBD管柱,30*150 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3+0.05%NH 3H 2O),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在7 min內27% B至52% B;波長:254nm/220nm nm;RT(min):6.58。此產生呈白色固體之(3S,4R)-3-氟-1-甲基-N-[2-(丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基]哌啶-4-胺(5.5 mg,7.88%)。LC-MS:(M+H) +實測值369.15。 1H NMR (400 MHz, DMSO- d 6) δ 7.81 (d, J= 6.7 Hz, 1H), 6.83 (t, J= 7.2 Hz, 1H), 6.40 (d, J= 7.5 Hz, 1H), 5.36 (d, J= 9.3 Hz, 1H), 4.96-4.65 (m, 1H), 4.12-4.07 (m, 2H), 3.74 (dt, J= 28.4, 8.5 Hz, 1H), 3.05 (t, J= 11.6 Hz, 1H), 2.78 (d, J= 11.5 Hz, 1H), 2.36-2.22 (m, 1H), 2.21 (s, 3H), 2.17-2.11 (m, 1H), 2.09 (s, 3H), 1.82 (m, 2H)。 實例19. 1-甲基-N-[2-(丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基]哌啶-4-胺之合成 A mixture of 8-bromo-2-(prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( Intermediate 4 ; 60 mg, 0.18 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (116.4 mg, 0.56 mmol, 3 eq), RuPhos (17.7 mg, 0.03 mmol, 0.2 eq), Cs2CO3 ( 308.2 mg, 0.94 mmol, 5 eq) and RuPhos Palladacycle Gen.4 (15.8 mg, 0.01 mmol, 0.1 eq) in dioxane (3 mL) was stirred at 80 °C under nitrogen atmosphere for 3 h. The solvent was removed under vacuum. The residue was purified by C18 flash chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm ). The crude material was further purified by preparative HPLC with the following conditions: column: XBridge Shield RP18 OBD column, 30*150 mm, 5μm; mobile phase A: water (10mmol/L NH4HCO3 + 0.05 % NH3H2O ), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 27% B to 52% B in 7 min; wavelength: 254nm/220nm nm; RT(min): 6.58. This resulted in (3S,4R)-3-fluoro-1-methyl-N-[2-(prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]piperidin-4-amine (5.5 mg, 7.88%) as a white solid. LC-MS: (M+H) + found 369.15. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.81 (d, J = 6.7 Hz, 1H), 6.83 (t, J = 7.2 Hz, 1H), 6.40 (d, J = 7.5 Hz, 1H), 5.36 (d, J = 9.3 Hz, 1H), 4.96-4.65 (m, 1H), 4.12-4.07 (m, 2H), 3.74 (dt, J = 28.4, 8.5 Hz, 1H), 3.05 (t, J = 11.6 Hz, 1H), 2.78 (d, J = 11.5 Hz, 1H), 2.36-2.22 (m, 1H), 2.21 (s, 3H), 2.17-2.11 (m, 1H), 2.09 (s, 3H), 1.82 (m, 2H). Example 19. Synthesis of 1-methyl-N-[2-(prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]piperidin-4-amine
向8-溴-2-(丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶( 中間物4;45 mg,0.14 mmol,1當量)於二噁烷(3 mL)中之攪拌溶液中添加1-甲基哌啶-4-胺(24.3 mg,0.21 mmol,1.5當量)、RuPhos (13.2 mg,0.02 mmol,0.2當量)、Cs 2CO 3(228.2 mg,0.70 mmol,5當量)及RuPhos Palladacycle Gen.4 (11.9 mg,0.01 mmol,0.1當量)。將所得混合物在80℃及氮氣氛圍下攪拌3 h。在真空下移除溶劑。殘餘物使用具有以下條件(移動相A:水,移動相B:ACN;流動速率:60 mL/min;梯度:在30 min內0% B至100% B;254/220 nm)之C18急速層析純化,然後藉由具有以下條件之製備型HPLC進一步純化:管柱:XBridge Shield RP18 OBD管柱,30*150 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3+0.05%NH 3H 2O),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在7 min內28% B至53% B;波長:254nm/220nm nm;RT (min):6.33。此產生呈白色固體之1-甲基-N-[2-(丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基]哌啶-4-胺(5.1 mg,10.16%)。LC-MS:(M+H) +實測值351.15。 1H NMR (400 MHz, DMSO- d 6) δ 7.71 (d, J= 6.7 Hz, 1H), 6.87-6.79 (m, 1H), 6.27 (d, J= 7.5 Hz, 1H), 4.09 -4.04 (m, 2H), 3.39 (td, J= 12.1, 11.6, 5.4 Hz, 1H), 2.73 (d, J= 11.4 Hz, 2H), 2.18 (s, 3H), 2.13-2.02 (m, 5H), 1.97-1.88 (m, 2H), 1.63-1.49 (m, 2H)。 實例20. (3S,4R)-3-氟-1-甲基-N-[2-(丙-1-炔-1-基)-3-(2,2,2-三氟乙基)吡唑并[1,5-a]吡啶-7-基]哌啶-4-胺之合成 To a stirred solution of 8-bromo-2-(prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( intermediate 4; 45 mg, 0.14 mmol, 1 eq) in dioxane (3 mL) was added 1-methylpiperidin-4-amine (24.3 mg, 0.21 mmol, 1.5 eq), RuPhos (13.2 mg, 0.02 mmol, 0.2 eq), Cs 2 CO 3 (228.2 mg, 0.70 mmol, 5 eq) and RuPhos Palladacycle Gen.4 (11.9 mg, 0.01 mmol, 0.1 eq). The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 3 h. The solvent was removed under vacuum. The residue was purified by C18 flash chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm ), and then further purified by preparative HPLC with the following conditions: column: XBridge Shield RP18 OBD column, 30*150 mm, 5μm; mobile phase A: water (10mmol/L NH4HCO3 + 0.05 % NH3H2O ), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 28% B to 53% B in 7 min; wavelength: 254nm/220nm nm; RT (min): 6.33. This resulted in 1-methyl-N-[2-(prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]piperidin-4-amine (5.1 mg, 10.16%) as a white solid. LC-MS: (M+H) + found 351.15. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.71 (d, J = 6.7 Hz, 1H), 6.87-6.79 (m, 1H), 6.27 (d, J = 7.5 Hz, 1H), 4.09 -4.04 (m, 2H), 3.39 (td, J = 12.1, 11.6, 5.4 Hz, 1H), 2.73 (d, J = 11.4 Hz, 2H), 2.18 (s, 3H), 2.13-2.02 (m, 5H), 1.97-1.88 (m, 2H), 1.63-1.49 (m, 2H). Example 20. Synthesis of (3S,4R)-3-fluoro-1-methyl-N-[2-(prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-7-yl]piperidin-4-amine
向7-溴-2-(丙-1-炔-1-基)-3-(2,2,2-三氟乙基)吡唑并[1,5-a]吡啶( 中間物5;160 mg,0.50 mmol,1當量)於THF (3 mL)中之溶液中添加(3S,4R)-3-氟-1-甲基哌啶-4-胺(133.4 mg,1.01 mmol,2當量)、t-BuONa (291 mg,3.03 mmol,6當量)、tBuXPhosPdG3 (25.1 mg,0.03 mmol,0.2當量)。將反應混合物在65℃及氮氣氛圍下攪拌30 min。移除溶劑之後,殘餘物使用具有以下條件(移動相A:水,移動相B:ACN;流動速率:60 mL/min;梯度:在30 min內0% B至100% B;254/220 nm)之C18急速層析純化。粗物質使用具有以下條件之製備型HPLC純化:管柱:XBridge Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3+ 0.05% NH 3H 2O),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在10 min內40% B至53% B;波長:220nm nm;RT(min):9.32。此產生呈白色固體之(3S,4R)-3-氟-1-甲基-N-[2-(丙-1-炔-1-基)-3-(2,2,2-三氟乙基)吡唑并[1,5-a]吡啶-7-基]哌啶-4-胺(18.6 mg,10.01%)。LC-MS:(M+H) +實測值369.10。 1H NMR (400 MHz, DMSO- d 6) δ 7.27 (t, J= 8.1 Hz, 1H), 7.01 (d, J= 8.7 Hz, 1H), 6.30 (d, J= 7.6 Hz, 1H), 6.19 (d, J= 9.1 Hz, 1H), 4.88 (d, J= 49.4 Hz, 1H), 4.00-3.60 (m, 3H), 3.07 (dt, J= 14.5, 6.8 Hz, 1H), 2.78 (d, J= 11.2 Hz, 1H), 2.41-2.04 (m, 8H), 1.89 (m, 2H)。 實例21. N-[3-乙烯基-2-(丙-1-炔-1-基)咪唑并[1,2-a]吡啶-8-基]-1-甲基哌啶-4-胺之合成 To a solution of 7-bromo-2-(prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine ( intermediate 5 ; 160 mg, 0.50 mmol, 1 eq) in THF (3 mL) were added (3S,4R)-3-fluoro-1-methylpiperidin-4-amine (133.4 mg, 1.01 mmol, 2 eq), t-BuONa (291 mg, 3.03 mmol, 6 eq), tBuXPhosPdG3 (25.1 mg, 0.03 mmol, 0.2 eq). The reaction mixture was stirred at 65 °C under nitrogen atmosphere for 30 min. After removing the solvent, the residue was purified by C18 flash chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm). The crude material was purified by preparative HPLC with the following conditions: column: XBridge Prep OBD C18 column, 30*150 mm, 5μm; mobile phase A: water (10mmol/L NH 4 HCO 3 + 0.05% NH 3 H 2 O), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 40% B to 53% B in 10 min; wavelength: 220nm nm; RT(min): 9.32. This resulted in (3S,4R)-3-fluoro-1-methyl-N-[2-(prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-7-yl]piperidin-4-amine (18.6 mg, 10.01%) as a white solid. LC-MS: (M+H) + found 369.10. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.27 (t, J = 8.1 Hz, 1H), 7.01 (d, J = 8.7 Hz, 1H), 6.30 (d, J = 7.6 Hz, 1H), 6.19 (d, J = 9.1 Hz, 1H), 4.88 (d, J = 49.4 Hz, 1H), 4.00-3.60 (m, 3H), 3.07 (dt, J = 14.5, 6.8 Hz, 1H), 2.78 (d, J = 11.2 Hz, 1H), 2.41-2.04 (m, 8H), 1.89 (m, 2H). Example 21. Synthesis of N-[3-vinyl-2-(prop-1-yn-1-yl)imidazo[1,2-a]pyridin-8-yl]-1-methylpiperidin-4-amine
將8-溴-3-乙烯基-2-(丙-1-炔-1-基)咪唑并[1,2-a]吡啶( 中間物6;100 mg,0.38 mmol,1當量)、1-甲基哌啶-4-胺(65.6 mg,0.58 mmol,1.5當量)、t-BuONa (73.6 mg,0.77 mmol,2當量)及tBuXPhos Pd G3 (152.1 mg,0.19 mmol,0.5當量)於THF (2 mL)中之溶液在65℃及氮氣氛圍下攪拌1 h。使混合物冷卻至室溫。所得混合物用水(50 mL)稀釋且用CH 2Cl 2(3*50 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/於MeOH中之7 M NH 3= 15:1)純化。粗產物藉由具有以下條件(管柱:XBridge Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3+0.05% NH 3H 2O),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在7 min內;波長:220nm nm;RT1(min):7.18;運行次數:3)之製備型HPLC純化,以得到呈灰白色固體之N-[3-乙烯基-2-(丙-1-炔-1-基)咪唑并[1,2-a]吡啶-8-基]-1-甲基哌啶-4-胺(15.0 mg,13.30%)。LC-MS:(M+H) +實測值295.10。 1H NMR (400 MHz, DMSO- d 6) δ 7.87 – 7.76 (d, J= 6.8 Hz, 1H), 7.10 – 6.96 (dd, J= 12.0, 17.7 Hz, 1H), 6.84 – 6.75 (t, J= 7.1 Hz, 1H), 6.30 – 6.21 (d, J= 7.5 Hz, 1H), 6.19 – 6.09 (dd, J= 1.4, 17.6 Hz, 1H), 5.71 – 5.59 (d, J= 8.4 Hz, 1H), 5.48 – 5.37 (dd, J= 1.3, 11.9 Hz, 1H), 3.40 – 3.34 (m, 1H), 2.78 – 2.65 (d, J= 11.1 Hz, 2H), 2.27 – 2.10 (d, J= 17.7 Hz, 6H), 2.09 – 1.97 (td, J= 2.5, 11.5 Hz, 2H), 1.96 – 1.83 (m, 2H), 1.65 – 1.48 (m, 2H)。 實例22. (3S,4R)-N-[3-乙烯基-2-(丙-1-炔-1-基)咪唑并[1,2-a]吡啶-8-基]-3-氟-1-甲基哌啶-4-胺之合成 A solution of 8-bromo-3-vinyl-2-(prop-1-yn-1-yl)imidazo[1,2-a]pyridine ( intermediate 6 ; 100 mg, 0.38 mmol, 1 eq), 1-methylpiperidin-4-amine (65.6 mg, 0.58 mmol, 1.5 eq), t-BuONa (73.6 mg, 0.77 mmol, 2 eq) and tBuXPhos Pd G3 (152.1 mg, 0.19 mmol, 0.5 eq) in THF (2 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The mixture was cooled to room temperature. The resulting mixture was diluted with water (50 mL) and extracted with CH 2 Cl 2 (3*50 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 /7 M NH 3 in MeOH = 15:1). The crude product was purified by preparative HPLC with the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 +0.05% NH 3 H 2 O), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: within 7 min; wavelength: 220 nm nm; RT1 (min): 7.18; number of runs: 3) to give N-[3-vinyl-2-(prop-1-yn-1-yl)imidazo[1,2-a]pyridin-8-yl]-1-methylpiperidin-4-amine (15.0 mg, 13.30%) as an off-white solid. LC-MS: (M+H) + found 295.10. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.87 – 7.76 (d, J = 6.8 Hz, 1H), 7.10 – 6.96 (dd, J = 12.0, 17.7 Hz, 1H), 6.84 – 6.75 (t, J = 7.1 Hz, 1H), 6.30 – 6.21 (d, J = 7.5 Hz, 1H), 6.19 – 6.09 (dd, J = 1.4, 17.6 Hz, 1H), 5.71 – 5.59 (d, J = 8.4 Hz, 1H), 5.48 – 5.37 (dd, J = 1.3, 11.9 Hz, 1H), 3.40 – 3.34 (m, 1H), 2.78 – 2.65 (d, J = 11.1 Hz, 2H), 2.27 – 2.10 (d, J = 17.7 Hz, 6H), 2.09 – 1.97 (td, J = 2.5, 11.5 Hz, 2H), 1.96 – 1.83 (m, 2H), 1.65 – 1.48 (m, 2H). Example 22. Synthesis of (3S,4R)-N-[3-vinyl-2-(prop-1-yn-1-yl)imidazo[1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine
將8-溴-3-乙烯基-2-(丙-1-炔-1-基)咪唑并[1,2-a]吡啶( 中間物6;100 mg,0.38 mmol,1當量)、t-BuONa (73.6 mg,0.77 mmol,2當量)及tBuXPhos Pd G3 (152.1 mg,0.19 mmol,0.5當量)於THF (2 mL)中之溶液在65℃及氮氣氛圍下攪拌1 h。所得混合物用水(50 mL)稀釋且用CH 2Cl 2(3*50 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/於MeOH中之7M NH 3= 15:1)純化。粗物質藉由具有以下條件(管柱:XBridge Shield RP18 OBD管柱,30*150 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在7 min內27% B至55% B;波長:254nm/220nm nm;RT1(min):6.1)之製備型HPLC純化,以得到呈灰白色固體之(3S,4R)-N-[3-乙烯基-2-(丙-1-炔-1-基)咪唑并[1,2-a]吡啶-8-基]-3-氟-1-甲基哌啶-4-胺(3.1 mg,2.59%)。LC-MS:(M+H) +實測值313.10。 1H NMR (400 MHz, DMSO- d 6) δ 7.94 – 7.85 (d, J= 6.8 Hz, 1H), 7.11 – 6.97 (dd, J= 12.0, 17.7 Hz, 1H), 6.87 – 6.78 (t, J= 7.1 Hz, 1H), 6.46 – 6.37 (d, J= 7.6 Hz, 1H), 6.21 – 6.10 (dd, J= 1.3, 17.7 Hz, 1H), 5.50 – 5.41 (dd, J= 1.4, 11.8 Hz, 1H), 5.40 – 5.31 (d, J= 9.3 Hz, 1H), 4.94 – 4.73 (d, J= 49.5 Hz, 1H), 3.82 – 3.63 (m, 1H), 3.11 – 2.98 (d, J= 11.3 Hz, 1H), 2.87 – 2.73 (d, J= 11.4 Hz, 1H), 2.37 – 2.28 (d, J= 13.4 Hz, 1H), 2.25 – 2.18 (s, 3H), 2.18 – 2.07 (s, 4H), 1.85 – 1.77 (m, 2H)。 實例23. 4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(丙-2-烯醯胺基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺之合成 步驟1. N-[8-溴-2-(3-{[2-甲氧基-4-(甲基胺甲醯基)苯基]胺基}丙-1-炔-1-基)咪唑并[1,2-a]吡啶-3-基]胺基甲酸三級丁酯之合成 A solution of 8-bromo-3-vinyl-2-(prop-1-yn-1-yl)imidazo[1,2-a]pyridine ( intermediate 6 ; 100 mg, 0.38 mmol, 1 eq.), t-BuONa (73.6 mg, 0.77 mmol, 2 eq.) and tBuXPhos Pd G3 (152.1 mg, 0.19 mmol, 0.5 eq.) in THF (2 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was diluted with water (50 mL) and extracted with CH 2 Cl 2 (3*50 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 /7M NH 3 in MeOH = 15:1). The crude material was purified by preparative HPLC with the following conditions (column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 27% B to 55% B in 7 min; wavelength: 254 nm/220 nm nm; RT1(min): 6.1) to give (3S,4R)-N-[3-vinyl-2-(prop-1-yn-1-yl)imidazo[1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine (3.1 mg, 2.59%) as an off-white solid. LC-MS: (M+H) + found 313.10. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.94 – 7.85 (d, J = 6.8 Hz, 1H), 7.11 – 6.97 (dd, J = 12.0, 17.7 Hz, 1H), 6.87 – 6.78 (t, J = 7.1 Hz, 1H), 6.46 – 6.37 (d, J = 7.6 Hz, 1H), 6.21 – 6.10 (dd, J = 1.3, 17.7 Hz, 1H), 5.50 – 5.41 (dd, J = 1.4, 11.8 Hz, 1H), 5.40 – 5.31 (d, J = 9.3 Hz, 1H), 4.94 – 4.73 (d, 3.82 – 3.63 (m, 1H), 3.11 – 2.98 (d, J = 11.3 Hz, 1H), 2.87 – 2.73 (d, J = 11.4 Hz, 1H), 2.37 – 2.28 (d, J = 13.4 Hz, 1H), 2.25 – 2.18 (s, 3H), 2.18 – 2.07 (s, 4H), 1.85 – 1.77 (m, 2H). Example 23. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(prop-2-enamido)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide Step 1. Synthesis of tributyl N-[8-bromo-2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)imidazo[1,2-a]pyridin-3-yl]carbamate
將N-{8-溴-2-碘咪唑并[1,2-a]吡啶-3-基}胺基甲酸三級丁酯( 中間物7;900 mg,2.05 mmol,1當量)、3-甲氧基-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺( 中間物14;538.1 mg,2.47 mmol,1.2當量)、i-Pr 2NH (2.08 g,20.54 mmol,10當量)、CuI (391.3 mg,2.05 mmol,1當量)及Pd(PPh 3) 4(474.8 mg,0.41 mmol,0.2當量)於DMSO (9 mL)中之溶液在室溫及氮氣氛圍下攪拌隔夜。所得混合物用EA (300 mL)稀釋且用5*500 mL之鹽水洗滌。有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用CH 2Cl 2/ MeOH (15:1)溶析,以得到呈棕色固體之N-[8-溴-2-(3-{[2-甲氧基-4-(甲基胺甲醯基)苯基]胺基}丙-1-炔-1-基)咪唑并[1,2-a]吡啶-3-基]胺基甲酸三級丁酯(900 mg,82.90%)。LC-MS:(M+H) +實測值528.1。 步驟2. N-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-2-(3-{[2-甲氧基-4-(甲基胺甲醯基)苯基]胺基}丙-1-炔-1-基)咪唑并[1,2-a]吡啶-3-基)胺基甲酸三級丁酯之合成 A solution of tributyl N-{8-bromo-2-iodoimidazo[1,2-a]pyridin-3-yl}carbamate ( intermediate 7 ; 900 mg, 2.05 mmol, 1 eq), 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide ( intermediate 14 ; 538.1 mg, 2.47 mmol, 1.2 eq), i- Pr2NH (2.08 g, 20.54 mmol, 10 eq), CuI (391.3 mg, 2.05 mmol, 1 eq) and Pd( PPh3 ) 4 (474.8 mg, 0.41 mmol, 0.2 eq) in DMSO (9 mL) was stirred at room temperature under nitrogen atmosphere overnight. The resulting mixture was diluted with EA (300 mL) and washed with 5*500 mL of brine. The organic layer was dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with CH 2 Cl 2 / MeOH (15:1) to give tributyl N-[8-bromo-2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)imidazo[1,2-a]pyridin-3-yl]carbamate (900 mg, 82.90%) as a brown solid. LC-MS: (M+H) + found 528.1. Step 2. Synthesis of tributyl N-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)imidazo[1,2-a]pyridin-3-yl)carbamate
將N-[8-溴-2-(3-{[2-甲氧基-4-(甲基胺甲醯基)苯基]胺基}丙-1-炔-1-基)咪唑并[1,2-a]吡啶-3-及]胺基甲酸三級丁酯(850 mg,1.61 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(659.9 mg,3.22 mmol,2當量)、t-BuONa (773.0 mg,8.05 mmol,5當量)及tBuXphos Pd G3 (383.4 mg,0.48 mmol,0.3當量)於THF (9 mL)中之溶液在65℃及氮氣氛圍下攪拌1 h。過濾所得混合物,濾餅用DCM洗滌。將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用CH 2Cl 2/於MeOH中之7 M NH 3= 15:1溶析,以得到呈棕色固體之N-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-2-(3-{[2-甲氧基-4-(甲基胺甲醯基)苯基]胺基}丙-1-炔-1-基)咪唑并[1,2-a]吡啶-3-基)胺基甲酸三級丁酯(670 mg,71.85%)。LC-MS:(M+H) +實測值580.4。 步驟3. 4-{[3-(3-胺基-8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺之合成 A solution of tributyl N-[8-bromo-2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)imidazo[1,2-a]pyridine-3-and]carbamate (850 mg, 1.61 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (659.9 mg, 3.22 mmol, 2 eq), t-BuONa (773.0 mg, 8.05 mmol, 5 eq) and tBuXphos Pd G3 (383.4 mg, 0.48 mmol, 0.3 eq) in THF (9 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was filtered and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH 2 Cl 2 /7 M NH 3 in MeOH = 15:1 to give tributyl N-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)imidazo[1,2-a]pyridin-3-yl)carbamate (670 mg, 71.85%) as a brown solid. LC-MS: (M+H) + found 580.4. Step 3. Synthesis of 4-{[3-(3-amino-8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide
在0℃下,向N-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-2-(3-{[2-甲氧基-4-(甲基胺甲醯基)苯基]胺基}丙-1-炔-1-基)咪唑并[1,2-a]吡啶-3-基)胺基甲酸三級丁酯(650 mg,1.12 mmol,1當量)及2,6-二甲基吡啶(600.78 mg,5.605 mmol,5當量)於DCM (7 mL)中之攪拌溶液中逐滴添加TMSOTf (1.25 g,5.61 mmol,5當量)。將所得溶液在室溫下攪拌30 min,然後在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/於MeOH中之7 M NH 3=15:1)純化,以得到呈棕色固體之4-{[3-(3-胺基-8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺(266 mg,49.47%)。LC-MS:(M+H) +實測值480.4。 步驟4. 4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(丙-2-烯醯胺基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺之合成 To a stirred solution of tributyl N-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)imidazo[1,2-a]pyridin-3-yl)carbamate (650 mg, 1.12 mmol, 1 eq) and 2,6-lutidine (600.78 mg, 5.605 mmol, 5 eq) in DCM (7 mL) was added TMSOTf (1.25 g, 5.61 mmol, 5 eq) dropwise at 0° C. The resulting solution was stirred at room temperature for 30 min and then concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 /7 M NH 3 in MeOH = 15:1) to give 4-{[3-(3-amino-8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (266 mg, 49.47%) as a brown solid. LC-MS: (M+H) + found 480.4. Step 4. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(prop-2-enamido)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide
在0℃下,向4-{[3-(3-胺基-8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺(90 mg,0.19 mmol,1當量)、丙烯酸(21 mg,0.29 mmol,1.5當量)及TEA (57 mg,0.56 mmol,3當量)於THF (2 mL)中之攪拌溶液中逐滴添加T 3P (179 mg,0.57 mmol,3當量,50 wt%於DMF中)。將所得混合物在室溫下攪拌1 h。所得溶液用水稀釋且用CH 2Cl 2(3*50 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由具有以下條件(管柱:XBridge Prep OBD C18管柱,19*250 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3+0.05%NH 3 .H 2O),移動相B:ACN(1% 2mM NH 3-MEOH);流動速率:25 mL/min mL/min;梯度:在10 min內33% B至52% B;波長:254nm/220nm nm;RT1(min):9.75;運行次數:4)之製備型HPLC純化,以得到呈灰白色固體之4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(丙-2-烯醯胺基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺(6 mg,5.77%)。LC-MS:(M+H) +實測值534.25。 1H NMR (400 MHz, DMSO- d 6) δ 10.35 (s, 1H), 8.10 (d, J= 4.6 Hz, 1H), 7.40 (d, J= 8.2 Hz, 1H), 7.33 (d, J= 1.8 Hz, 1H), 7.18 (d, J= 6.8 Hz, 1H), 6.75 (t, J= 7.1 Hz, 1H), 6.70 (d, J= 8.3 Hz, 1H), 6.49 (dd, J= 17.1, 10.3 Hz, 1H), 6.37 (d, J= 7.5 Hz, 1H), 6.34 – 6.24 (m, 1H), 5.94 (t, J= 6.1 Hz, 1H), 5.85 (d, J= 10.9 Hz, 1H), 5.38 (d, J= 9.2 Hz, 1H), 4.83 (d, J= 49.3 Hz, 1H), 4.24 (d, J= 6.2 Hz, 2H), 3.84 (s, 3H), 3.70 (d, J= 28.6 Hz, 1H), 3.03 (s, 1H), 2.75 (d, J= 4.5 Hz, 4H), 2.29 (d, J= 13.1 Hz, 1H), 2.19 (s, 3H), 2.10 (t, J= 11.3 Hz, 1H), 1.82 (d, J= 19.9 Hz, 2H)。 實例24. 4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2-甲基丙-2-烯醯胺基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺之合成 To a stirred solution of 4-{[3-(3-amino-8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (90 mg, 0.19 mmol, 1 eq), acrylic acid (21 mg, 0.29 mmol, 1.5 eq) and TEA (57 mg, 0.56 mmol, 3 eq) in THF (2 mL) was added T 3 P (179 mg, 0.57 mmol, 3 eq, 50 wt % in DMF) dropwise at 0° C. The resulting mixture was stirred at room temperature for 1 h. The resulting solution was diluted with water and extracted with CH 2 Cl 2 (3*50 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by HPLC with the following conditions (column: XBridge Prep OBD C18 column, 19*250 mm, 5μm; mobile phase A: water (10mmol/L NH 4 HCO 3 +0.05%NH 3 . H 2 O), mobile phase B: ACN (1% 2mM NH 3 -MEOH); flow rate: 25 mL/min mL/min; gradient: 33% B to 52% B in 10 min; wavelength: 254nm/220nm nm; RT1(min): 9.75; runs: 4) to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(prop-2-enamido)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (6 mg, 5.77%) as an off-white solid. LC-MS: (M+H) + found 534.25. 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.35 (s, 1H), 8.10 (d, J = 4.6 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H), 7.33 (d, J = 1.8 Hz, 1H), 7.18 (d, J = 6.8 Hz, 1H), 6.75 (t, J = 7.1 Hz, 1H), 6.70 (d, J = 8.3 Hz, 1H), 6.49 (dd, J = 17.1, 10.3 Hz, 1H), 6.37 (d, J = 7.5 Hz, 1H), 6.34 – 6.24 (m, 1H), 5.94 (t, J = 6.1 Hz, 1H), 5.85 (d, J = 10.9 Hz, 1H), 5.38 (d, J = 9.2 Hz, 1H), 4.83 (d, J = 49.3 Hz, 1H), 4.24 (d, J = 6.2 Hz, 2H), 3.84 (s, 3H), 3.70 (d, J = 28.6 Hz, 1H), 3.03 (s, 1H), 2.75 (d, J = 4.5 Hz, 4H), 2.29 (d, J = 13.1 Hz, 1H), 2.19 (s, 3H), 2.10 (t, J = 11.3 Hz, 1H), 1.82 (d, J = 19.9 Hz, 2H). Example 24. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2-methylprop-2-enamido)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide
在0℃下,向4-{[3-(3-胺基-8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺(90 mg,0.19 mmol,1當量)、甲基丙烯酸(24.2 mg,0.28 mmol,1.5當量)及TEA (57.0 mg,0.57 mmol,3當量)於THF (1 mL)中之攪拌溶液中添加T 3P (179.1 mg,0.57 mmol,3當量,50 wt%於DMF中)。將所得溶液在室溫下攪拌1 h,然後用水(50 mL)稀釋且用CH 2Cl 2(3*50 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由具有以下條件(管柱:YMC-Actus Triant C18 ExRs管柱,30*150 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3+0.05% NH 3 .H 2O),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在10 min內15% B至41% B;波長:220nm nm;RT1(min):9.28)之製備型HPLC純化,以得到呈白色固體之4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2-甲基丙-2-烯醯胺基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺(2.5 mg,2.39%)。LC-MS:(M+H) +實測值548.30。 1H NMR (400 MHz, DMSO- d 6) δ 10.02 (s, 1H), 8.09 (d, J= 4.7 Hz, 1H), 7.39 (dd, J= 8.3, 1.8 Hz, 1H), 7.33 (d, J= 1.9 Hz, 1H), 7.20 (d, J= 6.7 Hz, 1H), 6.75 (t, J= 7.1 Hz, 1H), 6.69 (d, J= 8.3 Hz, 1H), 6.36 (d, J= 7.6 Hz, 1H), 6.03 – 5.85 (m, 2H), 5.61 (s, 1H), 5.37 (d, J= 9.2 Hz, 1H), 4.83 (d, J= 49.4 Hz, 1H), 4.24 (d, J= 6.2 Hz, 2H), 3.83 (s, 3H), 3.70 (d, J= 31.1 Hz, 1H), 3.03 (t, J= 11.4 Hz, 1H), 2.75 (d, J= 4.5 Hz, 4H), 2.29 (d, J= 13.0 Hz, 1H), 2.19 (s, 3H), 2.10 (t, J= 10.4 Hz, 1H), 1.94 (s, 3H), 1.82 (dd, J= 11.9, 8.1 Hz, 2H)。 實例25. N-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-2-(3-{[2-甲氧基-4-(甲基胺甲醯基)苯基]胺基}丙-1-炔-1-基)咪唑并[1,2-a]吡啶-3-基)-N-甲基胺基甲酸三級丁酯之合成 步驟1. N-{8-溴-2-碘咪唑并[1,2-a]吡啶-3-基}-N-甲基胺基甲酸三級丁酯之合成 To a stirred solution of 4-{[3-(3-amino-8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (90 mg, 0.19 mmol, 1 eq), methacrylic acid (24.2 mg, 0.28 mmol, 1.5 eq) and TEA (57.0 mg, 0.57 mmol, 3 eq) in THF (1 mL) was added T3P (179.1 mg, 0.57 mmol, 3 eq, 50 wt% in DMF) at 0°C. The resulting solution was stirred at room temperature for 1 h, then diluted with water (50 mL) and extracted with CH2Cl2 (3* 50 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by HPLC with the following conditions (column: YMC-Actus Triant C18 ExRs column, 30*150 mm, 5μm; mobile phase A: water (10mmol/L NH 4 HCO 3 +0.05% NH 3 . H 2 O), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 15% B to 41% B in 10 min; wavelength: 220nm nm; RT1 (min): 9.28) was purified by preparative HPLC to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2-methylprop-2-enamido)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (2.5 mg, 2.39%) as a white solid. LC-MS: (M+H) + found 548.30. 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.02 (s, 1H), 8.09 (d, J = 4.7 Hz, 1H), 7.39 (dd, J = 8.3, 1.8 Hz, 1H), 7.33 (d, J = 1.9 Hz, 1H), 7.20 (d, J = 6.7 Hz, 1H), 6.75 (t, J = 7.1 Hz, 1H), 6.69 (d, J = 8.3 Hz, 1H), 6.36 (d, J = 7.6 Hz, 1H), 6.03 – 5.85 (m, 2H), 5.61 (s, 1H), 5.37 (d, J = 9.2 Hz, 1H), 4.83 (d, J = 49.4 Hz, 1H), 4.24 (d, J = 6.2 Hz, 2H), 3.83 (s, 3H), 3.70 (d, J = 31.1 Hz, 1H), 3.03 (t, J = 11.4 Hz, 1H), 2.75 (d, J = 4.5 Hz, 4H), 2.29 (d, J = 13.0 Hz, 1H), 2.19 (s, 3H), 2.10 (t, J = 10.4 Hz, 1H), 1.94 (s, 3H), 1.82 (dd, J = 11.9, 8.1 Hz, 2H). Example 25. Synthesis of tributyl N-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)imidazo[1,2-a]pyridin-3-yl)-N-methylcarbamate Step 1. Synthesis of N-{8-bromo-2-iodoimidazo[1,2-a]pyridin-3-yl}-N-methylcarbamic acid tert-butyl ester
將N-{8-溴-2-碘咪唑并[1,2-a]吡啶-3-基}胺基甲酸三級丁酯( 中間物7;1.6 g,3.65 mmol,1當量)於THF (15 mL) 中之溶液在0℃下用NaH (292.2 mg,7.30 mmol,2當量,60%)處理。將所得混合物攪拌5 min,然後逐滴添加MeI (1036.85 mg,7.304 mmol,2當量)。將反應在室溫下攪拌0.5 h,然後用水/冰淬滅且用CH 2Cl 2(3*200 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮,以得到呈灰色固體之N-{8-溴-2-碘咪唑并[1,2-a]吡啶-3-基}-N-甲基胺基甲酸三級丁酯(1.5 g,90.91%)。LC-MS:(M+H) +實測值453.9。 步驟2. N-[8-溴-2-(3-{[2-甲氧基-4-(甲基胺甲醯基)苯基]胺基}丙-1-炔-1-基)咪唑并[1,2-a]吡啶-3-基]-N-甲基胺基甲酸三級丁酯之合成 A solution of tributyl N-{8-bromo-2-iodoimidazo[1,2-a]pyridin-3-yl}carbamate ( intermediate 7 ; 1.6 g, 3.65 mmol, 1 eq) in THF (15 mL) was treated with NaH (292.2 mg, 7.30 mmol, 2 eq, 60%) at 0 °C. The resulting mixture was stirred for 5 min, then MeI (1036.85 mg, 7.304 mmol, 2 eq) was added dropwise. The reaction was stirred at room temperature for 0.5 h, then quenched with water/ice and extracted with CH2Cl2 (3*200 mL). The combined organic layers were dried over anhydrous Na2SO4 . After filtration, the filtrate was concentrated under reduced pressure to obtain tert-butyl N-{8-bromo-2-iodoimidazo[1,2-a]pyridin-3-yl}-N-methylcarbamate as a gray solid (1.5 g, 90.91%). LC-MS: (M+H) + found 453.9. Step 2. Synthesis of tert-butyl N-[8-bromo-2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)imidazo[1,2-a]pyridin-3-yl]-N-methylcarbamate
將N-{8-溴-2-碘咪唑并[1,2-a]吡啶-3-基}-N-甲基胺基甲酸三級丁酯(1.5 g,3.32mmol,1當量)、3-甲氧基-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺( 中間物14;0.80 g,3.65 mmol,1.1當量)、Pd(PPh 3) 4(0.77 g,0.66 mmol,0.2當量)、CuI (0.63 g,3.31 mmol,1當量)及i-Pr 2NH (3.36 g,33.20 mmol,10.0當量)於DMSO (15 mL)中之混合物在室溫及氮氣氛圍下攪拌1 h。所得混合物用EA (200mL)稀釋且用鹽水(3*200 mL)洗滌。有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用CH 2Cl 2/ MeOH (20:1)溶析,以得到呈黃色固體之N-[8-溴-2-(3-{[2-甲氧基-4-(甲基胺甲醯基)苯基]胺基}丙-1-炔-1-基)咪唑并[1,2-a]吡啶-3-基]-N-甲基胺基甲酸三級丁酯(1.3 g,72.22%)。LC-MS:(M+H) +實測值545.1。 步驟3. N-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-2-(3-{[2-甲氧基-4-(甲基胺甲醯基)苯基]胺基}丙-1-炔-1-基)咪唑并[1,2-a]吡啶-3-基)-N-甲基胺基甲酸三級丁酯之合成 A mixture of tert-butyl N-{8-bromo-2-iodoimidazo[1,2-a]pyridin-3-yl}-N-methylcarbamate (1.5 g, 3.32 mmol, 1 eq), 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide ( intermediate 14 ; 0.80 g, 3.65 mmol, 1.1 eq), Pd( PPh3 ) 4 (0.77 g, 0.66 mmol, 0.2 eq), CuI (0.63 g, 3.31 mmol, 1 eq) and i- Pr2NH (3.36 g, 33.20 mmol, 10.0 eq) in DMSO (15 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting mixture was diluted with EA (200 mL) and washed with brine (3*200 mL). The organic layer was dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with CH 2 Cl 2 / MeOH (20:1) to give N-[8-bromo-2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)imidazo[1,2-a]pyridin-3-yl]-N-methylcarbamic acid tributyl ester (1.3 g, 72.22%) as a yellow solid. LC-MS: (M+H) + found 545.1. Step 3. Synthesis of tributyl N-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)imidazo[1,2-a]pyridin-3-yl)-N-methylcarbamate
將N-[8-溴-2-(3-{[2-甲氧基-4-(甲基胺甲醯基)苯基]胺基}丙-1-炔-1-基)咪唑并[1,2-a]吡啶-3-基]-N-甲基胺基甲酸三級丁酯(1.4 g,2.58 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(1.06 g,5.16 mmol,2當量)、t-BuONa (1.49 g,15.48 mmol,6當量)及tBuXphos Pd G3 (0.62 g,0.77 mmol,0.3當量)於THF (14 mL)中之混合物在65℃及氮氣氛圍下攪拌1 h。過濾所得混合物,濾餅用DCM洗滌。將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用CH 2Cl 2/於MeOH中之7 M NH 3= 20:1溶析,以得到呈黃色固體之N-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-2-(3-{[2-甲氧基-4-(甲基胺甲醯基)苯基]胺基}丙-1-炔-1-基)咪唑并[1,2-a]吡啶-3-基)-N-甲基胺基甲酸三級丁酯(600 mg,39.09%)。LC-MS:(M+H) +實測值594.25。 步驟4. 4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(甲基胺基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺之合成 A mixture of tributyl N-[8-bromo-2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)imidazo[1,2-a]pyridin-3-yl]-N-methylcarbamate (1.4 g, 2.58 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (1.06 g, 5.16 mmol, 2 eq), t-BuONa (1.49 g, 15.48 mmol, 6 eq) and tBuXphos Pd G3 (0.62 g, 0.77 mmol, 0.3 eq) in THF (14 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was filtered and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 /7 M NH 3 in MeOH = 20:1 to give tributyl N-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)imidazo[1,2-a]pyridin-3-yl)-N-methylcarbamate (600 mg, 39.09%) as a yellow solid. LC-MS: (M+H) + found 594.25. Step 4. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(methylamino)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide
在0℃下,向N-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-2-(3-{[2-甲氧基-4-(甲基胺甲醯基)苯基]胺基}丙-1-炔-1-基)咪唑并[1,2-a]吡啶-3-基)-N-甲基胺基甲酸三級丁酯(600 mg,1.01 mmol,1當量)及二甲基吡啶(541.5 mg,5.05 mmol,5當量)於DCM (8 mL)中之攪拌溶液中逐滴添加TMSOTf (1.12 g,5.05 mmol,5當量)。將混合物在室溫下攪拌30 min,然後在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/於MeOH中之7 M NH 3= 15:1)及製備型HPLC (管柱:XBridge Shield RP18 OBD管柱,19*250 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3+0.05%NH 3H 2O),移動相B:MEOH;流動速率:25 mL/min mL/min;梯度:在10min內45% B至67% B;RT1(min):9)純化,以得到呈白色固體之4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(甲基胺基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺(11.7 mg,2.21%)。LC-MS:(M+H) +實測值494.25。 1H NMR (400 MHz, DMSO- d 6) δ 8.07 (d, J= 4.8 Hz, 1H), 7.44 – 7.27 (m, 3H), 6.72 (d, J= 8.3 Hz, 1H), 6.61 (t, J= 7.1 Hz, 1H), 6.11 (d, J= 7.4 Hz, 1H), 5.86 (t, J= 6.3 Hz, 1H), 5.45 (m, 1H), 5.13 (d, J= 9.4 Hz, 1H), 4.79 (d, J= 49.4 Hz, 1H), 4.22 (d, J= 6.3 Hz, 2H), 3.84 (s, 3H), 3.73 – 3.55 (m, 1H), 3.02 (t, J= 11.8 Hz, 1H), 2.93 (d, J= 5.2 Hz, 3H), 2.75 (d, J= 4.5 Hz, 4H), 2.28 (d, J= 13.0 Hz, 1H), 2.18 (s, 3H), 2.07 (d, J= 12.9 Hz, 1H), 1.78 (m, 3.8 Hz, 2H)。 實例26. 4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(N-甲基丙-2-烯醯胺基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺之合成 To a stirred solution of tributyl N-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-2-(3-{[2-methoxy-4-(methylaminocarbonyl)phenyl]amino}prop-1-yn-1-yl)imidazo[1,2-a]pyridin-3-yl)-N-methylcarbamate (600 mg, 1.01 mmol, 1 eq) and lutidine (541.5 mg, 5.05 mmol, 5 eq) in DCM (8 mL) was added TMSOTf (1.12 g, 5.05 mmol, 5 eq) dropwise at 0° C. The mixture was stirred at room temperature for 30 min and then concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 /7 M NH 3 in MeOH = 15:1) and preparative HPLC (column: XBridge Shield RP18 OBD column, 19*250 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 +0.05% NH 3 H 2 O), mobile phase B: MEOH; flow rate: 25 mL/min mL/min; gradient: 45% B to 67% in 10 min. B; RT1 (min): 9) to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(methylamino)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (11.7 mg, 2.21%) as a white solid. LC-MS: (M+H) + found 494.25. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.07 (d, J = 4.8 Hz, 1H), 7.44 – 7.27 (m, 3H), 6.72 (d, J = 8.3 Hz, 1H), 6.61 (t, J = 7.1 Hz, 1H), 6.11 (d, J = 7.4 Hz, 1H), 5.86 (t, J = 6.3 Hz, 1H), 5.45 (m, 1H), 5.13 (d, J = 9.4 Hz, 1H), 4.79 (d, J = 49.4 Hz, 1H), 4.22 (d, J = 6.3 Hz, 2H), 3.84 (s, 3H), 3.73 – 3.55 (m, 1H), 3.02 (t, J = 11.8 Hz, 1H), 2.93 (d, J = 5.2 Hz, 3H), 2.75 (d, J = 4.5 Hz, 4H), 2.28 (d, J = 13.0 Hz, 1H), 2.18 (s, 3H), 2.07 (d, J = 12.9 Hz, 1H), 1.78 (m, 3.8 Hz, 2H). Example 26. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(N-methylprop-2-enamido)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide
在室溫下,向4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(甲基胺基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺(150 mg,0.30 mmol,1當量)、丙烯酸(33 mg,0.45 mmol,1.5當量)及TEA (92 mg,0.90 mmol,3當量)於THF (2.0 mL)中之攪拌溶液中添加T 3P (290 mg,0.45 mmol,1.5當量,50wt%於DMF中)。將所得混合物在室溫下攪拌1 h。所得混合物用水(100 mL)稀釋且用CH 2Cl 2(3 * 100mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/於MeOH中之7 M NH 3= 20:1)及製備型HPLC (管柱:YMC-Actus Triant C18 ExRs管柱,30*150 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3+0.05% NH 3 .H 2O),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在9 min內17% B至42% B;波長:220nm nm;RT1(min):8.12)純化,以得到呈白色固體之4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(N-甲基丙-2-烯醯胺基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺(4.5 mg,2.70%)。LC-MS:(M+H) +實測值548.45。 1H NMR (400 MHz, DMSO- d 6) δ 8.09 (d, J= 4.8 Hz, 1H), 7.40 (m, 2H), 7.32 (s, 1H), 6.84 (t, J= 7.1 Hz, 1H), 6.64 (d, J= 8.2 Hz, 1H), 6.43 (d, J= 7.6 Hz, 1H), 6.20 (d, J= 16.7 Hz, 1H), 5.93 (t, J= 6.1 Hz, 1H), 5.86 – 5.70 (m, 1H), 5.51 (m, 2H), 4.82 (d, J= 49.5 Hz, 1H), 4.22 (d, J= 6.3 Hz, 2H), 3.83 (s, 3H), 3.72 (d, J= 29.4 Hz, 1H), 3.15 (s, 3H), 3.04 (d, J= 12.4 Hz, 1H), 2.75 (d, J= 4.4 Hz, 4H), 2.29 (d, J= 13.0 Hz, 1H), 2.19 (s, 3H), 2.10 (t, J= 11.1 Hz, 1H), 1.81 (d, J= 19.5 Hz, 2H)。 實例27. 2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-8-[(1-甲基哌啶-4-基)胺基]-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-6-醇TFA鹽之合成 步驟1. N-{3-[8-溴-6-(甲氧基甲氧基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}-4-甲磺醯基-2-甲氧基苯胺之合成 To a stirred solution of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(methylamino)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (150 mg, 0.30 mmol, 1 eq), acrylic acid (33 mg, 0.45 mmol, 1.5 eq) and TEA (92 mg, 0.90 mmol, 3 eq) in THF (2.0 mL) was added T 3 P (290 mg, 0.45 mmol, 1.5 eq, 50 wt% in DMF) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was diluted with water (100 mL) and extracted with CH 2 Cl 2 (3*100 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 /7 M NH 3 in MeOH = 20:1) and preparative HPLC (column: YMC-Actus Triant C18 ExRs column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 +0.05% NH 3 . H 2 O), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 17% B to 42% B in 9 min; wavelength: 220 nm nm; RT1 (min): 8.12) to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(N-methylprop-2-enamido)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (4.5 mg, 2.70%) as a white solid. LC-MS: (M+H) + found 548.45. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.09 (d, J = 4.8 Hz, 1H), 7.40 (m, 2H), 7.32 (s, 1H), 6.84 (t, J = 7.1 Hz, 1H), 6.64 (d, J = 8.2 Hz, 1H), 6.43 (d, J = 7.6 Hz, 1H), 6.20 (d, J = 16.7 Hz, 1H), 5.93 (t, J = 6.1 Hz, 1H), 5.86 – 5.70 (m, 1H), 5.51 (m, 2H), 4.82 (d, J = 49.5 Hz, 1H), 4.22 (d, J = 6.3 Hz, 3.83 (s, 3H), 3.72 (d, J = 29.4 Hz, 1H), 3.15 (s, 3H), 3.04 (d, J = 12.4 Hz, 1H), 2.75 (d, J = 4.4 Hz, 4H), 2.29 (d, J = 13.0 Hz, 1H), 2.19 (s, 3H), 2.10 (t, J = 11.1 Hz, 1H), 1.81 (d, J = 19.5 Hz, 2H). Example 27. Synthesis of 2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-ol TFA salt Step 1. Synthesis of N-{3-[8-bromo-6-(methoxymethoxy)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-4-methanesulfonyl-2-methoxyaniline
將8-溴-2-碘-6-(甲氧基甲氧基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶( 中間物8;760 mg,1.63 mmol,1當量)、4-甲磺醯基-2-甲氧基-N-(丙-2-炔-1-基)苯胺( 中間物39;430 mg,1.80 mmol,1.1當量)、Pd(PPh 3) 4(755 mg,0.65 mmol,0.4當量)、CuI (311 mg,1.63 mmol,1當量)及i-Pr 2NH (1.65 g,16.34 mmol,10當量)於DMSO (10 mL)中之溶液在室溫及氮氣氛圍下攪拌1h。反應藉由添加水(20 mL)來淬滅且用EtOAc (3*10 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由具有以下條件之反相急速層析純化:管柱,C18矽膠;移動相,於水中之MeCN (0.1% TFA),在10 min內50%至50%梯度;偵測器,UV 254 nm。此產生呈棕色固體之N-{3-[8-溴-6-(甲氧基甲氧基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}-4-甲磺醯基-2-甲氧基苯胺(680 mg,72.18%)。LC-MS:(M+H) +實測值:576.4。 步驟2. N-(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-6-(甲氧基甲氧基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)-1-甲基哌啶-4-胺之合成 A solution of 8-bromo-2-iodo-6-(methoxymethoxy)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( intermediate 8 ; 760 mg, 1.63 mmol, 1 eq), 4-methanesulfonyl-2-methoxy-N-(prop-2-yn-1-yl)aniline ( intermediate 39 ; 430 mg, 1.80 mmol, 1.1 eq), Pd( PPh3 ) 4 (755 mg, 0.65 mmol, 0.4 eq), CuI (311 mg, 1.63 mmol, 1 eq) and i- Pr2NH (1.65 g, 16.34 mmol, 10 eq) in DMSO (10 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The reaction was quenched by adding water (20 mL) and extracted with EtOAc (3*10 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% TFA) in water, 50% to 50% gradient in 10 min; detector, UV 254 nm. This produced N-{3-[8-bromo-6-(methoxymethoxy)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-4-methanesulfonyl-2-methoxyaniline (680 mg, 72.18%) as a brown solid. LC-MS: (M+H) + found: 576.4. Step 2. Synthesis of N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-6-(methoxymethoxy)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine
將N-{3-[8-溴-6-(甲氧基甲氧基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}-4-甲磺醯基-2-甲氧基苯胺(200 mg,0.35 mmol,1當量)、1-甲基哌啶-4-胺(396 mg,3.47 mmol,10當量)、BrettPhos Pd G4 (62.91 mg,0.07 mmol,0.2當量)、RuPhos (64 mg,0.14 mmol,0.4當量)及Cs 2CO 3(339 mg,1.04 mmol,3當量)於二噁烷(5 mL)中之混合物在100℃及氮氣氛圍下攪拌2h。反應用水淬滅且用EtOAc (3*50 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由具有以下條件之反相急速層析純化:管柱,C18矽膠;移動相,於水中之MeCN (0.1% TFA),在3 min內50%至50%梯度;偵測器,UV 254 nm。此產生呈黃色固體之N-(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-6-(甲氧基甲氧基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)-1-甲基哌啶-4-胺(100 mg,47.27%)。LC-MS:(M+H) +實測值:609.7。 步驟3. 2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-8-[(1-甲基哌啶-4-基)胺基]-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-6-醇TFA鹽之合成 A mixture of N-{3-[8-bromo-6-(methoxymethoxy)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-4-methanesulfonyl-2-methoxyaniline (200 mg, 0.35 mmol, 1 eq), 1-methylpiperidin-4-amine (396 mg, 3.47 mmol, 10 eq), BrettPhos Pd G4 (62.91 mg, 0.07 mmol, 0.2 eq), RuPhos (64 mg, 0.14 mmol, 0.4 eq ) and Cs2CO3 (339 mg, 1.04 mmol, 3 eq) in dioxane (5 mL) was stirred at 100 °C under nitrogen atmosphere for 2 h. The reaction was quenched with water and extracted with EtOAc (3*50 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% TFA) in water, 50% to 50% gradient in 3 min; detector, UV 254 nm. This gave N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-6-(methoxymethoxy)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine (100 mg, 47.27%) as a yellow solid. LC-MS: (M+H) + found: 609.7. Step 3. Synthesis of 2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-ol TFA salt
在0℃下,向N-(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-6-(甲氧基甲氧基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)-1-甲基哌啶-4-胺(100 mg,0.16 mmol,1當量)於MeOH (2 mL)中之溶液中逐滴添加HCl (0.5 mL)。將反應溶液在25℃下攪拌1 h,然後藉由具有以下條件(管柱:Xselect CSH Prep Fluoro-Phenyl管柱,19*250 mm,5μm;移動相A:水(0.05% TFA),移動相B:ACN;流動速率:25 mL/min mL/min;梯度:在12min內16% B至26% B;波長:254nm/220nm nm;RT1(min):7.35)之製備型HPLC純化,以得到呈黃色固體之2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-8-[(1-甲基哌啶-4-基)胺基]-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-6-醇(17.8 mg,19.19%)。LC-MS:(M+H) +實測值:566.20。 1H NMR (400 MHz, DMSO- d 6) δ 9.41 (s, 1H), 9.32 (s, 1H), 7.43 – 7.35 (m, 1H), 7.27 – 7.17 (m, 2H), 6.90 – 6.76 (m, 1H), 6.47 (s, 1H), 6.14 (d, J= 31.5 Hz, 1H), 6.08 – 5.99 (m, 1H), 4.62 (d, J= 5.3 Hz, 1H), 4.30 (s, 2H), 4.01 – 3.93 (m, 1H), 3.90 (d, J= 1.6 Hz, 3H), 3.86 – 3.55 (m, 2H), 3.49 (d, J= 11.6 Hz, 2H), 3.10 (s, 3H), 3.05 (d, J= 11.8 Hz, 1H), 2.85 – 2.72 (m, 3H), 2.16 – 1.68 (m, 4H)。 實例28. 4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺,甲酸鹽之合成 步驟1. 4-[(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺之合成 To a solution of N-(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-6-(methoxymethoxy)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine (100 mg, 0.16 mmol, 1 equiv) in MeOH (2 mL) was added HCl (0.5 mL) dropwise at 0 °C. The reaction solution was stirred at 25° C. for 1 h, and then purified by preparative HPLC with the following conditions (column: Xselect CSH Prep Fluoro-Phenyl column, 19*250 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min mL/min; gradient: 16% B to 26% B in 12 min; wavelength: 254 nm/220 nm nm; RT1 (min): 7.35) to obtain 2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-ol (17.8 mg, 19.19%). LC-MS: (M+H) + found: 566.20. 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.41 (s, 1H), 9.32 (s, 1H), 7.43 – 7.35 (m, 1H), 7.27 – 7.17 (m, 2H), 6.90 – 6.76 (m, 1H), 6.47 (s, 1H), 6.14 (d, J = 31.5 Hz, 1H), 6.08 – 5.99 (m, 1H), 4.62 (d, J = 5.3 Hz, 1H), 4.30 (s, 2H), 4.01 – 3.93 (m, 1H), 3.90 (d, J = 1.6 Hz, 3H), 3.86 – 3.55 (m, 2H), 3.49 (d, J = 11.6 Hz, 2H), 3.10 (s, 3H), 3.05 (d, J = 11.8 Hz, 1H), 2.85 – 2.72 (m, 3H), 2.16 – 1.68 (m, 4H). Example 28. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide, formate salt Step 1. Synthesis of 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide
在室溫下,向8-溴-2-碘-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶( 中間物9;150.0 mg,0.36 mmol,1當量)於DMSO (3 mL)中之攪拌溶液中添加3-甲氧基-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺( 中間物14;92.9 mg,0.43 mmol,1.20當量)、CuI (67.5 mg,0.36 mmol,1當量)、Pd(PPh 3) 4(82.0 mg,0.07 mmol,0.20當量)及i-Pr 2NH (358.9 mg,3.55 mmol,10當量)。將所得混合物在30℃及氮氣氛圍下攪拌1 h,然後藉由具有以下條件之C18反相急速層析純化:移動相,於水中之MeCN,在20 min內0%至70%梯度;偵測器,UV 254 nm。此產生呈棕色固體之4-[(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺(150.0 mg,82.40%)。 To a stirred solution of 8-bromo-2-iodo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridine ( Intermediate 9 ; 150.0 mg, 0.36 mmol, 1 eq) in DMSO (3 mL) were added 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide ( Intermediate 14 ; 92.9 mg, 0.43 mmol, 1.20 eq), CuI (67.5 mg, 0.36 mmol, 1 eq), Pd( PPh3 ) 4 (82.0 mg, 0.07 mmol, 0.20 eq) and i- Pr2NH (358.9 mg, 3.55 mmol, 10 eq) at room temperature. The resulting mixture was stirred at 30 °C under nitrogen atmosphere for 1 h and then purified by C18 reverse phase flash chromatography with the following conditions: mobile phase, MeCN in water, gradient 0% to 70% in 20 min; detector, UV 254 nm. This resulted in 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (150.0 mg, 82.40%) as a brown solid.
LC-MS:(M+H) +實測值513.3。 步驟2. 4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺之合成 LC-MS: (M+H) + found 513.3. Step 2. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide
向4-[(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺(150.0 mg,0.29 mmol,1當量)於THF (4.50 mL) 中之攪拌溶液中添加(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(149.8 mg,0.73 mmol,2.50當量)、t-BuXPhosPdG3 (116.1 mg,0.15 mmol,0.50當量)及t-BuONa (224.7 mg,2.34 mmol,8當量)。將所得混合物在65℃及氮氣氛圍下攪拌30 min,然後在減壓下濃縮。殘餘物藉由具有以下條件之C18反相急速層析純化:移動相,於水中之MeCN (0.1% FA),在20 min內0%至20%梯度;偵測器,UV 254 nm。粗產物藉由具有以下條件(管柱:Xselect CSH C18 OBD管柱,30*150 mm,5 μm;移動相A:水(0.1% FA),移動相B:ACN;流動速率:60 mL/min;梯度:在8 min內17% B至30% B;波長:254nm/220nm;RT(min):7.68)之製備型HPLC純化,以得到呈淺黃色固體之4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺(22.3 mg,13.52%)。LC-MS:(M+H) +實測值565.20。 1H NMR (400 MHz, DMSO- d 6) δ 8.18 (s, 0.8H), 8.11 (m, 1H), 7.86 (d, J= 6.7 Hz, 1H), 7.41 (dd, J= 8.2, 1.9 Hz, 1H), 7.34 (d, J= 1.9 Hz, 1H), 7.02 (t, J= 7.2 Hz, 1H), 6.75 (d, J= 8.3 Hz, 1H), 6.61 (d, J= 7.7 Hz, 1H), 6.01 (t, J= 6.3 Hz, 1H), 5.60 (d, J= 9.0 Hz, 1H), 4.82 (d, J= 49.4 Hz, 1H), 4.32 (d, J= 6.3 Hz, 2H), 3.84 (s, 4H), 3.03 (t, J= 11.5 Hz, 1H), 2.75 (d, J= 4.5 Hz, 4H), 2.19 (s, 4H), 2.14-2.03 (m, 1H), 1.92-1.71 (m, 2H)。 實例29. 4-{[3-(3-環丙基-8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺之合成 步驟1. 4-[(3-{8-溴-3-環丙基咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺之合成 To a stirred solution of 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (150.0 mg, 0.29 mmol, 1 eq) in THF (4.50 mL) were added (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (149.8 mg, 0.73 mmol, 2.50 eq), t-BuXPhosPdG3 (116.1 mg, 0.15 mmol, 0.50 eq) and t-BuONa (224.7 mg, 2.34 mmol, 8 eq). The resulting mixture was stirred at 65 °C under nitrogen atmosphere for 30 min and then concentrated under reduced pressure. The residue was purified by C18 reverse phase flash chromatography with the following conditions: mobile phase, MeCN (0.1% FA) in water, gradient 0% to 20% in 20 min; detector, UV 254 nm. The crude product was purified by preparative HPLC with the following conditions (column: Xselect CSH C18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 17% B to 30% B in 8 min; wavelength: 254 nm/220 nm; RT (min): 7.68) to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (22.3 mg, 13.52%) as a light yellow solid. LC-MS: (M+H) + found 565.20. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.18 (s, 0.8H), 8.11 (m, 1H), 7.86 (d, J = 6.7 Hz, 1H), 7.41 (dd, J = 8.2, 1.9 Hz, 1H), 7.34 (d, J = 1.9 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.75 (d, J = 8.3 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 6.01 (t, J = 6.3 Hz, 1H), 5.60 (d, J = 9.0 Hz, 1H), 4.82 (d, J = 49.4 Hz, 1H), 4.32 (d, J = 6.3 Hz, 2H), 3.84 (s, 4H), 3.03 (t, J = 11.5 Hz, 1H), 2.75 (d, J = 4.5 Hz, 4H), 2.19 (s, 4H), 2.14-2.03 (m, 1H), 1.92-1.71 (m, 2H). Example 29. Synthesis of 4-{[3-(3-cyclopropyl-8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide Step 1. Synthesis of 4-[(3-{8-bromo-3-cyclopropylimidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide
在室溫下,向8-溴-3-環丙基-2-碘咪唑并[1,2-a]吡啶( 中間物10;330.0 mg,0.91 mmol,1當量)於DMSO (10 mL)中之攪拌混合物中添加3-甲氧基-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺( 中間物14;238.1 mg,1.09 mmol,1.20當量)、CuI (173.1 mg,0.91 mmol,1當量)、i-Pr 2NH (920.0 mg,9.09 mmol,10當量)及Pd(PPh 3) 4(210.1 mg,0.18 mmol,0.20當量)。將所得混合物在40℃及氮氣氛圍下攪拌1 h,然後藉由具有以下條件之反相急速層析純化:管柱,C18;移動相,於水中之MeCN,在20 min內0%至70%梯度;偵測器,UV 254 nm。此產生呈棕色固體之4-[(3-{8-溴-3-環丙基咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺(331.0 mg,80.31%)。LC-MS:(M+H) +實測值453.3。 步驟2. 4-{[3-(3-環丙基-8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺之合成 To a stirred mixture of 8-bromo-3-cyclopropyl-2-iodoimidazo[1,2-a]pyridine ( intermediate 10 ; 330.0 mg, 0.91 mmol, 1 eq) in DMSO (10 mL) at room temperature were added 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide ( intermediate 14; 238.1 mg, 1.09 mmol, 1.20 eq), CuI (173.1 mg, 0.91 mmol, 1 eq), i- Pr2NH (920.0 mg, 9.09 mmol, 10 eq) and Pd( PPh3 ) 4 (210.1 mg, 0.18 mmol, 0.20 eq). The resulting mixture was stirred at 40 °C under nitrogen atmosphere for 1 h and then purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in water, gradient 0% to 70% in 20 min; detector, UV 254 nm. This produced 4-[(3-{8-bromo-3-cyclopropylimidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (331.0 mg, 80.31%) as a brown solid. LC-MS: (M+H) + found 453.3. Step 2. Synthesis of 4-{[3-(3-cyclopropyl-8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide
向4-[(3-{8-溴-3-環丙基咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺(150.0 mg,0.33 mmol,1當量)於THF (3 mL)中之混合物中添加(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(135.7 mg,0.66 mmol,2當量)、t-BuXPhosPdG3 (42.1 mg,0.05 mmol,0.16當量)及t-BuONa (252.9 mg,2.64 mmol,8當量),在65℃及氮氣氛圍下攪拌30 min。移除溶劑之後,殘餘物藉由具有以下條件之反相急速層析純化:管柱,C18;移動相,於水中之MeCN (0.1% TFA),在20 min內0%至30%梯度;偵測器,UV 254 nm。粗產物藉由具有以下條件之製備型HPLC純化:(管柱:XBridge Prep OBD C18管柱,30*150 mm,5 μm;移動相A:水(10mmol/L NH 4HCO 3+0.05%NH 3 .H 2O),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在8 min內20% B至46% B;波長:254nm/220nm nm;RT (min):7.35),以得到呈白色固體之4-{[3-(3-環丙基-8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺(22.9 mg,13.58%)。LC-MS:(M+H) +實測值505.20。 1H NMR (400 MHz, DMSO- d 6) δ 8.08 (m, 1H), 7.66 (d, J= 6.7 Hz, 1H), 7.43 (dd, J= 8.2, 1.8 Hz, 1H), 7.35 (d, J= 1.8 Hz, 1H), 6.83-6.72 (m, 2H), 6.33 (d, J= 7.5 Hz, 1H), 5.93 (t, J= 6.3 Hz, 1H), 5.26 (d, J= 9.3 Hz, 1H), 4.86 (d, J= 3.1 Hz, 1H), 4.26 (d, J= 6.3 Hz, 2H), 3.85 (s, 3H), 3.69 (m, 1H), 3.02 (t, J= 11.2 Hz, 1H), 2.75 (d, J= 4.5 Hz, 4H), 2.33-2.02 (m, 5H), 1.86 (tt, J= 8.0, 5.0 Hz, 1H), 1.78 (h, J= 3.7 Hz, 2H), 0.94 (dt, J= 8.2, 3.1 Hz, 2H), 0.81-0.72 (m, 2H)。 實例30. 4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(1,1,2,2,2-五氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺之合成 步驟1. 8-溴-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶之合成 To a mixture of 4-[(3-{8-bromo-3-cyclopropylimidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (150.0 mg, 0.33 mmol, 1 eq) in THF (3 mL) were added (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (135.7 mg, 0.66 mmol, 2 eq), t-BuXPhosPdG3 (42.1 mg, 0.05 mmol, 0.16 eq) and t-BuONa (252.9 mg, 2.64 mmol, 8 eq) and stirred at 65 °C under nitrogen atmosphere for 30 min. After removal of the solvent, the residue was purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN (0.1% TFA) in water, gradient from 0% to 30% in 20 min; detector, UV 254 nm. The crude product was purified by preparative HPLC with the following conditions: (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 +0.05% NH 3 . H 2 O), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 20% B to 46% B in 8 min; wavelength: 254 nm/220 nm nm; RT (min): 7.35) to give 4-{[3-(3-cyclopropyl-8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (22.9 mg, 13.58%) as a white solid. LC-MS: (M+H) + found 505.20. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.08 (m, 1H), 7.66 (d, J = 6.7 Hz, 1H), 7.43 (dd, J = 8.2, 1.8 Hz, 1H), 7.35 (d, J = 1.8 Hz, 1H), 6.83-6.72 (m, 2H), 6.33 (d, J = 7.5 Hz, 1H), 5.93 (t, J = 6.3 Hz, 1H), 5.26 (d, J = 9.3 Hz, 1H), 4.86 (d, J = 3.1 Hz, 1H), 4.26 (d, J = 6.3 Hz, 2H), 3.85 (s, 3H), 3.69 (m, δ 5.1 (m, 5H), 1.74 (tt, J = 8.0, 5.0 Hz, 1H), 1.83 (h, J = 3.7 Hz, 2H), 0.94 (dt, J = 8.2 , 3.1 Hz, 2H), 0.81-0.72 (m, 2H). Example 30. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide Step 1. Synthesis of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine
將8-溴-2-碘-3-(1,1,2,2,2-五氟乙基)咪唑并[1,2-a]吡啶( 中間物11;230.0 mg,0.52 mmol,1當量)於DMSO (5 mL)中之溶液用3-甲氧基-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺( 中間物14;227.7 mg,1.04 mmol,2當量)、i-Pr 2NH (527.8 mg,5.22 mmol,10當量)、Pd(PPh 3) 4(120.6 mg,0.10 mmol,0.20當量)及CuI (49. 7 mg,0.26 mmol,0.50當量)處理。將所得混合物在30℃及氮氣氛圍下攪拌1h,然後使用具有以下條件之C18急速層析純化:移動相A:水,移動相B:ACN;流動速率:60 mL/min;梯度:在15 min內0% B至100% B;波長:254 nm;220 nm。此產生呈白色固體之8-溴-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶(150.0 mg,54.5%)。LC-MS:(M+H) +實測值528.4。 步驟2. 4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(1,1,2,2,2-五氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺之合成 A solution of 8-bromo-2-iodo-3-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]pyridine ( intermediate 11 ; 230.0 mg, 0.52 mmol, 1 eq) in DMSO (5 mL) was treated with 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide ( intermediate 14 ; 227.7 mg, 1.04 mmol, 2 eq), i- Pr2NH (527.8 mg, 5.22 mmol, 10 eq), Pd( PPh3 ) 4 (120.6 mg, 0.10 mmol, 0.20 eq) and CuI (49.7 mg, 0.26 mmol, 0.50 eq). The resulting mixture was stirred at 30°C under nitrogen atmosphere for 1 h and then purified using C18 flash chromatography with the following conditions: mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 15 min; wavelength: 254 nm; 220 nm. This produced 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (150.0 mg, 54.5%) as a white solid. LC-MS: (M+H) + found 528.4. Step 2. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide
將4-({3-[8-溴-3-(1,1,2,2,2-五氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-3-甲氧基-N-甲基苯甲醯胺(89.0 mg,0.16 mmol,1當量)於THF (5 mL)中之溶液用t-BuONa (96.6 mg,1.00 mmol,6當量)、t-BuXPhosPdG3 (53.2 mg,0.06 mmol,0.40當量)及(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(68.7 mg,0.33 mmol,2當量)處理。將所得混合物在65℃及氮氣氛圍下攪拌30 min。移除溶劑後,殘餘物使用具有以下條件之C18急速層析純化:移動相A:水,移動相B:ACN;流動速率:60 mL/min;梯度:在30 min內0% B至100% B;254/220 nm。粗物質使用具有以下條件之製備型HPLC純化:管柱:Xselect CSH C18 OBD管柱,30*150mm,5μm;移動相A:水(0.1% FA),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在7 min內10% B至25% B;波長:254nm/220nm nm;RT1(min):6.02。此產生呈白色固體之4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(1,1,2,2,2-五氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺(1.50 mg,1.54%)。LC-MS:(M+H) +實測值583.30。 1H NMR (400 MHz, DMSO- d 6) δ 8.07 (m, 1H), 7.69 (d, J= 6.7 Hz, 1H), 7.39-7.34 (m, 2H), 6.97 (t, J= 7.3 Hz, 1H), 6.69 (d, J= 8.2 Hz, 1H), 6.59 (d, J= 7.7 Hz, 1H), 5.94 (t, J= 6.3 Hz, 1H), 5.62 (d, J= 8.9 Hz, 1H), 4.82 (d, J= 48 Hz, 1H), 4.27 (d, J= 6.3 Hz, 2H), 3.84 (s, 3H), 3.83-3.63 (m, 1H), 3.03 (t, J= 11.5 Hz, 1H), 2.75 (d, J= 4.4 Hz, 4H), 2.33-2.10 (m, 5H), 1.86 (tt, J= 11.9, 6.3 Hz, 1H), 1.80-1.73 (m, 1H)。 實例31. N-(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-8-[(1-甲基哌啶-4-基)胺基]-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-6-基)胺基甲酸三級丁酯之合成 步驟1. N-[6-溴-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基]-1-甲基哌啶-4-胺之合成 A solution of 4-({3-[8-bromo-3-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N-methylbenzamide (89.0 mg, 0.16 mmol, 1 eq) in THF (5 mL) was treated with t-BuONa (96.6 mg, 1.00 mmol, 6 eq), t-BuXPhosPdG3 (53.2 mg, 0.06 mmol, 0.40 eq) and (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (68.7 mg, 0.33 mmol, 2 eq). The resulting mixture was stirred at 65 °C under nitrogen atmosphere for 30 min. After removal of the solvent, the residue was purified by C18 flash chromatography with the following conditions: mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm. The crude material was purified by preparative HPLC with the following conditions: column: Xselect CSH C18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 10% B to 25% B in 7 min; wavelength: 254nm/220nm nm; RT1(min): 6.02. This resulted in 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (1.50 mg, 1.54%) as a white solid. LC-MS: (M+H) + found 583.30. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.07 (m, 1H), 7.69 (d, J = 6.7 Hz, 1H), 7.39-7.34 (m, 2H), 6.97 (t, J = 7.3 Hz, 1H), 6.69 (d, J = 8.2 Hz, 1H), 6.59 (d, J = 7.7 Hz, 1H), 5.94 (t, J = 6.3 Hz, 1H), 5.62 (d, J = 8.9 Hz, 1H), 4.82 (d, J = 48 Hz, 1H), 4.27 (d, J = 6.3 Hz, 2H), 3.84 (s, 3H), 3.83-3.63 (m, 1H), 3.03 (t, J = 11.5 Hz, 1H), 2.75 (d, J = 4.4 Hz, 4H), 2.33-2.10 (m, 5H), 1.86 (tt, J = 11.9, 6.3 Hz, 1H), 1.80-1.73 (m, 1H). Example 31. Synthesis of tributyl N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)carbamate Step 1. Synthesis of N-[6-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]-1-methylpiperidin-4-amine
將6-溴-8-氟-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶( 中間物12;4 g,9.46 mmol,1當量)、1-甲基哌啶-4-胺(8.64 g,75.66 mmol,8當量)及DIEA (8.56 g,66.20 mmol,7當量)於DMSO (40 mL)中之攪拌混合物在100℃下攪拌16 h。反應混合物用水(500 mL)稀釋且用EtOAc (3*500 mL)萃取。合併的有機層經硫酸鈉乾燥,過濾且真空濃縮。殘餘物藉由反相急速層析(管柱,C18矽膠;移動相,於0.1%TFA中之MeCN,在10 min內20%至40%梯度;偵測器,UV 220 nm)純化,以得到呈灰白色固體之N-[6-溴-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基]-1-甲基哌啶-4-胺(4.1 g,85%)。LC-MS:(M+H) +實測值:517.1。 步驟2. N-(6-溴-2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)-1-甲基哌啶-4-胺之合成 A stirred mixture of 6-bromo-8-fluoro-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( intermediate 12 ; 4 g, 9.46 mmol, 1 eq), 1-methylpiperidin-4-amine (8.64 g, 75.66 mmol, 8 eq) and DIEA (8.56 g, 66.20 mmol, 7 eq) in DMSO (40 mL) was stirred at 100 °C for 16 h. The reaction mixture was diluted with water (500 mL) and extracted with EtOAc (3*500 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in 0.1% TFA, gradient 20% to 40% in 10 min; detector, UV 220 nm) to give N-[6-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]-1-methylpiperidin-4-amine (4.1 g, 85%) as an off-white solid. LC-MS: (M+H) + found: 517.1. Step 2. Synthesis of N-(6-bromo-2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine
將N-[6-溴-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基]-1-甲基哌啶-4-胺(504 mg,0.97 mmol,1當量)、CuI (185 mg,0.97 mmol,1當量)、二異丙胺(986 mg,9.75 mmol,10當量)、Pd(PPh 3) 4(451 mg,0.39 mmol,0.4當量)及4-甲磺醯基-2-甲氧基-N-(丙-2-炔-1-基)苯胺(280 mg,1.17 mmol,1.2當量)於DMSO (3 mL)中之混合物在室溫及氮氣氛圍下攪拌1 h,之後用水淬滅(10 mL)。所得混合物用EtOAc (3*20 mL)萃取。合併的有機層經硫酸鈉乾燥,過濾且真空濃縮。殘餘物藉由反相急速層析(管柱,C18矽膠;移動相,於水中之0.1%TFA,在10 min內25%至40%梯度;偵測器,UV 220 nm)純化,以得到呈淺黃色固體之N-(6-溴-2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)-1-甲基哌啶-4-胺(470 mg,76.69%)。LC-MS:(M+H) +實測值:628.1。 步驟3. N-(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-8-[(1-甲基哌啶-4-基)胺基]-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-6-基)胺基甲酸三級丁酯之合成 A mixture of N-[6-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]-1-methylpiperidin-4-amine (504 mg, 0.97 mmol, 1 eq), CuI (185 mg, 0.97 mmol, 1 eq), diisopropylamine (986 mg, 9.75 mmol, 10 eq), Pd(PPh 3 ) 4 (451 mg, 0.39 mmol, 0.4 eq) and 4-methanesulfonyl-2-methoxy-N-(prop-2-yn-1-yl)aniline (280 mg, 1.17 mmol, 1.2 eq) in DMSO (3 mL) was stirred at room temperature under nitrogen atmosphere for 1 h and then quenched with water (10 mL). The resulting mixture was extracted with EtOAc (3*20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, 0.1% TFA in water, gradient from 25% to 40% in 10 min; detector, UV 220 nm) to give N-(6-bromo-2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine (470 mg, 76.69%) as a light yellow solid. LC-MS: (M+H) + found: 628.1. Step 3. Synthesis of tributyl N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)carbamate
將N-(6-溴-2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)-1-甲基哌啶-4-胺(100 mg,0.16 mmol,1當量)、胺基甲酸三級丁酯(93 mg,0.80 mmol,5當量)、2-甲基丙-2-醇鈉(46 mg,0.48 mmol,3當量)及tBuXPhos Pd G 3(13 mg,0.016 mmol,0.1當量)於THF (3 mL)中之混合物在65℃及氮氣氛圍下攪拌1 h。所得混合物用水(10 mL)稀釋且用EtOAc (3*10 mL)萃取。合併的有機層經硫酸鈉乾燥,過濾且真空濃縮。殘餘物藉由製備型HPLC (管柱:YMC-Actus Triart C18 150*30mm;移動相A:水(10mmol NH 4HCO 3),移動相B:CAN;流動速率:60 mL/min mL/min;梯度:在10 min內15% B至25% B;波長:254 nm;RT1(min):8)純化。凍乾產生呈灰白色固體之N-(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-8-[(1-甲基哌啶-4-基)胺基]-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-6-基)胺基甲酸三級丁酯(11.6 mg,10.97%)。LC-MS:(M+H) +實測值:655.60。 1H NMR (400 MHz, DMSO- d 6 ) δ 9.17 (s, 1H), 8.04 (s, 1H), 7.39 (dd, J= 8.4, 2.0 Hz, 1H), 7.25 (d, J= 2.0 Hz, 1H), 6.85 (d, J= 8.4 Hz, 1H), 6.47 (t, J= 6.3 Hz, 1H), 6.24 (d, J= 1.6 Hz, 1H), 5.81 (d, J= 7.8 Hz, 1H), 4.30 (d, J= 6.3 Hz, 2H), 3.90 (s, 5H), 3.16 (d, J= 9.9 Hz, 1H), 3.10 (s, 3H), 2.76 (d, J= 11.0 Hz, 2H), 2.17 (s, 3H), 1.97 (t, J= 11.3 Hz, 2H), 1.89 (d, J= 12.3 Hz, 2H), 1.56 (d, J= 11.5, 10.9 Hz, 2H), 1.47 (s, 9H)。 實例32. 2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-N8-(1-甲基哌啶-4-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-6,8-二胺之合成 A mixture of N-(6-bromo-2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine (100 mg, 0.16 mmol, 1 eq), tributyl carbamate (93 mg, 0.80 mmol, 5 eq), sodium 2-methylpropan-2-ol (46 mg, 0.48 mmol, 3 eq) and tBuXPhos Pd G 3 (13 mg, 0.016 mmol, 0.1 eq) in THF (3 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3*10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: YMC-Actus Triart C18 150*30 mm; mobile phase A: water (10 mmol NH 4 HCO 3 ), mobile phase B: CAN; flow rate: 60 mL/min mL/min; gradient: 15% B to 25% B in 10 min; wavelength: 254 nm; RT1(min): 8). Lyophilization gave tributyl N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)carbamate (11.6 mg, 10.97%) as an off-white solid. LC-MS: (M+H) + found: 655.60. 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.17 (s, 1H), 8.04 (s, 1H), 7.39 (dd, J = 8.4, 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.47 (t, J = 6.3 Hz, 1H), 6.24 (d, J = 1.6 Hz, 1H), 5.81 (d, J = 7.8 Hz, 1H), 4.30 (d, J = 6.3 Hz, 2H), 3.90 (s, 5H), 3.16 (d, J = 9.9 Hz, 1H), 3.10 (s, 3H), 2.76 (d, J = 11.0 Hz, 2H), 2.17 (s, 3H), 1.97 (t, J = 11.3 Hz, 2H), 1.89 (d, J = 12.3 Hz, 2H), 1.56 (d, J = 11.5, 10.9 Hz, 2H), 1.47 (s, 9H). Example 32. Synthesis of 2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-N8-(1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine-6,8-diamine
將N-(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-8-[(1-甲基哌啶-4-基)胺基]-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-6-基)胺基甲酸三級丁酯(100 mg,0.15 mmol,1當量)於DCM (2 mL)及TFA (1 mL)中之溶液在室溫下攪拌1 h。真空濃縮反應混合物。所得粗材料藉由製備型HPLC (管柱:XBridge Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3),移動相B:ACN;流動速率:62 mL/min mL/min;梯度:在9 min內71% B至76% B;波長:254nm/220nm nm;RT1(min):8.9)純化,以得到呈黃色固體之2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-N8-(1-甲基哌啶-4-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-6,8-二胺(5.9 mg,6.95%)。LC-MS:(M+H) +實測值:565.20。 1H NMR (400 MHz, DMSO-d6) δ 7.38 (dd, J= 8.3, 2.0 Hz, 1H), 7.25 (d, J= 2.0 Hz, 1H), 6.90 (s, 1H), 6.85 (d, J= 8.5 Hz, 1H), 6.45 (t, J= 6.2 Hz, 1H), 5.89 (d, J= 1.6 Hz, 1H), 5.49 (d, J= 8.2 Hz, 1H), 4.77 (s, 2H), 4.28 (d, J= 6.3 Hz, 2H), 3.89 (s, 5H), 3.22 (d, J= 9.9 Hz, 1H), 3.10 (s, 3H), 2.75 (d, J= 11.3 Hz, 2H), 2.18 (s, 3H), 2.01 (t, J= 11.3 Hz, 2H), 1.88 (d, J= 12.0 Hz, 2H), 1.55 (t, J= 10.0 Hz, 2H)。 實例33. 2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-N6-甲基-N8-(1-甲基哌啶-4-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-6,8-二胺之合成 步驟1. N-(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-8-[(1-甲基哌啶-4-基)胺基]-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-6-基)-N-甲基胺基甲酸三級丁酯之合成 A solution of tributyl N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)carbamate (100 mg, 0.15 mmol, 1 eq) in DCM (2 mL) and TFA (1 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo. The obtained crude material was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 62 mL/min mL/min; gradient: 71% B to 76% B in 9 min; wavelength: 254 nm/220 nm nm; RT1(min): 8.9) to give 2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-N8-(1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine-6,8-diamine (5.9 mg, 6.95%) as a yellow solid. LC-MS: (M+H) + found: 565.20. 1 H NMR (400 MHz, DMSO-d6) δ 7.38 (dd, J = 8.3, 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.90 (s, 1H), 6.85 (d, J = 8.5 Hz, 1H), 6.45 (t, J = 6.2 Hz, 1H), 5.89 (d, J = 1.6 Hz, 1H), 5.49 (d, J = 8.2 Hz, 1H), 4.77 (s, 2H), 4.28 (d, J = 6.3 Hz, 2H), 3.89 (s, 5H), 3.22 (d, J = 9.9 Hz, 1H), 3.10 (s, 3H), 2.75 (d, J = 11.3 Hz, 2H), 2.18 (s, 3H), 2.01 (t, J = 11.3 Hz, 2H), 1.88 (d, J = 12.0 Hz, 2H), 1.55 (t, J = 10.0 Hz, 2H). Example 33. Synthesis of 2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-N6-methyl-N8-(1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine-6,8-diamine Step 1. Synthesis of tributyl N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)-N-methylcarbamate
將N-(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-8-[(1-甲基哌啶-4-基)胺基]-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-6-基)胺基甲酸三級丁酯(190 mg,0.29 mmol,1當量)、K 2CO 3(118 mg,0.86 mmol,3當量)及MeI (48.7 mg,0.34 mmol,1.2當量)於THF (10 mL)中之混合物在室溫下攪拌1 h。反應混合物用水(20 mL)稀釋且水相EA (3*20 mL)萃取。合併的有機層經硫酸鈉乾燥,過濾且真空濃縮。殘餘物藉由具有以下條件(管柱,C18矽膠;移動相,於0.1%TFA中之MeCN,在10 min內20%至40%梯度;偵測器,UV 220 nm)之反相急速層析純化,以得到呈黑色油狀物之N-(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-8-[(1-甲基哌啶-4-基)胺基]-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-6-基)-N-甲基胺基甲酸三級丁酯(130 mg,67.01%)。LC-MS:(M+H) +實測值:679.3。 步驟2. 2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-N6-甲基-N8-(1-甲基哌啶-4-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-6,8-二胺之合成 A mixture of tributyl N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)carbamate (190 mg, 0.29 mmol, 1 eq), K 2 CO 3 (118 mg, 0.86 mmol, 3 eq) and MeI (48.7 mg, 0.34 mmol, 1.2 eq) in THF (10 mL) was stirred at room temperature for 1 h. The reaction mixture was diluted with water (20 mL) and the aqueous phase was extracted with EA (3*20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeCN in 0.1% TFA, gradient from 20% to 40% in 10 min; detector, UV 220 nm) to give tributyl N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)-N-methylcarbamate (130 mg, 67.01%) as a black oil. LC-MS: (M+H) + found: 679.3. Step 2. Synthesis of 2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-N6-methyl-N8-(1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine-6,8-diamine
將N-(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-8-[(1-甲基哌啶-4-基)胺基]-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-6-基)-N-甲基胺基甲酸三級丁酯(130 mg,0.19 mmol,1當量)於TFA (1.5 mL)及DCM (3 mL)中之混合物在室溫下攪拌1 h。真空濃縮反應混合物。殘餘物藉由製備型HPLC (管柱:X-Select Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(0.1% FA),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在7 min內30% B至50% B;波長:254nm/220nm nm;RT1(min):6.56)純化,以得到呈棕色固體之2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-N6-甲基-N8-(1-甲基哌啶-4-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-6,8-二胺(11.2 mg,10.11%)。LC-MS:(M+H) +實測值:579.30。 1H NMR (400 MHz, DMSO-d6) δ 7.39 (dd, J= 8.3, 2.1 Hz, 1H), 7.25 (d, J= 2.1 Hz, 1H), 6.97 (s, 1H), 6.84 (d, J= 8.4 Hz, 1H), 6.47 (t, J= 6.3 Hz, 1H), 5.94 – 5.81 (m, 1H), 4.82 (s, 1H), 4.29 (d, J= 6.2 Hz, 2H), 3.90 (s, 5H), 3.67 – 3.38 (m, 6H), 3.13 (s, 3H), 3.10 (m, 5H), 3.07 (m, 1H), 2.30 – 1.83 (m, 4H)。 實例34. N-(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-6-苯基-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)-1-甲基哌啶-4-胺,甲酸鹽之合成 A mixture of tributyl N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl)-N-methylcarbamate (130 mg, 0.19 mmol, 1 eq) in TFA (1.5 mL) and DCM (3 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: X-Select Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 30% B to 50% B in 7 min; wavelength: 254 nm/220 nm nm; RT1(min): 6.56) to give 2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-N6-methyl-N8-(1-methylpiperidin-4-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine-6,8-diamine (11.2 mg, 10.11%) as a brown solid. LC-MS: (M+H) + found: 579.30. 1 H NMR (400 MHz, DMSO-d6) δ 7.39 (dd, J = 8.3, 2.1 Hz, 1H), 7.25 (d, J = 2.1 Hz, 1H), 6.97 (s, 1H), 6.84 (d, J = 8.4 Hz, 1H), 6.47 (t, J = 6.3 Hz, 1H), 5.94 – 5.81 (m, 1H), 4.82 (s, 1H), 4.29 (d, J = 6.2 Hz, 2H), 3.90 (s, 5H), 3.67 – 3.38 (m, 6H), 3.13 (s, 3H), 3.10 (m, 5H), 3.07 (m, 1H), 2.30 – 1.83 (m, 4H). Example 34. Synthesis of N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-6-phenyl-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine, formate salt
將N-(6-溴-2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)-1-甲基哌啶-4-胺(100 mg,0.15 mmol,1當量)、苯基硼酸(29 mg,0.23 mmol,1.50當量)、Pd(dppf)Cl 2 .CH 2Cl 2(13 mg,0.02 mmol,0.10當量)及K 2CO 3(65 mg,0.48 mmol,3當量)於二噁烷(2 mL)及H 2O (0.5 mL)中之混合物在80℃及氮氣氛圍下攪拌1 h。混合物用水淬滅且用EtOAc (3*20 mL)萃取。合併的有機層經硫酸鈉乾燥,過濾且真空濃縮。殘餘物藉由製備型HPLC (管柱:XBridge Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在7 min內24% B至28% B;波長:254nm/220nm nm;RT1(min):6.8)純化。凍乾產生呈灰白色固體之N-(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-6-苯基-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)-1-甲基哌啶-4-胺;甲酸(8.4 mg,7.86%)。LC-MS:(M+H +)實測值:626.25。 1H NMR (400 MHz, DMSO-d 6) δ 8.28 (s, 1H), 8.04 (s, 1H), 7.73 – 7.68 (m, 2H), 7.48 (t, J= 7.6 Hz, 2H), 7.41 (dd, J= 8.1, 1.9 Hz, 2H), 7.26 (d, J= 2.0 Hz, 1H), 6.88 (d, J= 8.4 Hz, 1H), 6.51 – 6.45 (m, 2H), 5.83 (d, J= 8.5 Hz, 1H), 4.33 (d, J= 6.3 Hz, 2H), 4.17 – 4.09 (m, 2H), 3.91 (s, 3H), 3.57 – 3.51 (m, 1H), 3.11 (s, 3H), 2.75 (d, J= 11.5 Hz, 2H), 2.20 (s, 3H), 2.10 (t, J= 11.3 Hz, 2H), 1.92 (d, J= 12.2 Hz, 2H), 1.65 – 1.57 (m, 2H)。 實例35. 4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-N-甲基苯甲醯胺之合成 步驟1. 4-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-N-甲基苯甲醯胺之合成 A mixture of N-(6-bromo-2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine (100 mg, 0.15 mmol, 1 eq), phenylboronic acid (29 mg, 0.23 mmol, 1.50 eq), Pd(dppf)Cl 2 .CH 2 Cl 2 (13 mg, 0.02 mmol, 0.10 eq) and K 2 CO 3 (65 mg, 0.48 mmol, 3 eq) in dioxane (2 mL) and H 2 O (0.5 mL) was stirred at 80 °C under nitrogen atmosphere for 1 h. The mixture was quenched with water and extracted with EtOAc (3*20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 24% B to 28% B in 7 min; wavelength: 254 nm/220 nm nm; RT1(min): 6.8). Lyophilization yielded N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-6-phenyl-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine; formic acid (8.4 mg, 7.86%) as an off-white solid. LC-MS: (M+H + ) found: 626.25. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.28 (s, 1H), 8.04 (s, 1H), 7.73 – 7.68 (m, 2H), 7.48 (t, J = 7.6 Hz, 2H), 7.41 (dd, J = 8.1, 1.9 Hz, 2H), 7.26 (d, J = 2.0 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 6.51 – 6.45 (m, 2H), 5.83 (d, J = 8.5 Hz, 1H), 4.33 (d, J = 6.3 Hz, 2H), 4.17 – 4.09 (m, 2H), 3.91 (s, 3H), 3.57 – 3.51 (m, 1H), 3.11 (s, 3H), 2.75 (d, J = 11.5 Hz, 2H), 2.20 (s, 3H), 2.10 (t, J = 11.3 Hz, 2H), 1.92 (d, J = 12.2 Hz, 2H), 1.65 – 1.57 (m, 2H). Example 35. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide Step 1. Synthesis of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-N-methylbenzamide
將N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺( 中間物13;200 mg,1.06 mmol,1當量)、i-Pr 2NH (1.08 g,10.63 mmol,10當量)、8-溴-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶( 中間物1;430 mg,1.06 mmol,1當量)、Pd(PhP 3) 4(246 mg,0.21 mmol,0.2當量)及CuI (202 mg,1.06 mmol,1當量)於DMSO (2 mL)中之混合物在室溫及氮氣氛圍下攪拌隔夜。所得混合物用水(30 mL)稀釋且用EtOAc (3*30 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用CH 2Cl 2/ MeOH (30:1)溶析,以得到呈棕色固體之4-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-N-甲基苯甲醯胺(309 mg,62.50%)。LC-MS:(M+H) +實測值467.15。 步驟2. 4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-N-甲基苯甲醯胺之合成 A mixture of N-methyl-4-(prop-2-yn-1-ylamino)benzamide ( intermediate 13 ; 200 mg, 1.06 mmol, 1 eq), i-Pr 2 NH (1.08 g, 10.63 mmol, 10 eq), 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( intermediate 1 ; 430 mg, 1.06 mmol, 1 eq), Pd(PhP 3 ) 4 (246 mg, 0.21 mmol, 0.2 eq) and CuI (202 mg, 1.06 mmol, 1 eq) in DMSO (2 mL) was stirred at room temperature under nitrogen atmosphere overnight. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (3*30 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / MeOH (30:1) to give 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-N-methylbenzamide (309 mg, 62.50%) as a brown solid. LC-MS: (M+H) + found 467.15. Step 2. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide
將4-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-N-甲基苯甲醯胺(60 mg,0.13 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺.HCl (29 mg,0.14 mmol,1.1當量)、t-BuONa (50 mg,0.52 mmol,4當量)及二-三級丁基[2',4',6'-參(丙-2-基)-[1,1'-聯苯]-2-基]磷烷;{2'-胺基-[1,1'-聯苯]-2-基}甲磺酸鈀(10 mg,0.01 mmol,0.1當量)於THF (2 mL)中之混合物在65℃及氮氣氛圍下攪拌1 h。所得混合物用水(30 mL)稀釋且用EtOAc (3*30 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/MeOH 10:1)及製備型HPLC (管柱:XBridge Prep OBD C18管柱,19*250 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3+0.05%NH 3 .H 2O),移動相B:MEOH;流動速率:25 mL/min mL/min;梯度:在10min內45% B至63% B;波長:254nm/220nm nm;RT1(min):9.55;運行次數:3)純化,以得到呈白色固體之4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-N-甲基苯甲醯胺(6.2 mg,9.28%)。LC-MS:(M+H) +實測值517.30。 1H NMR (400 MHz, DMSO- d 6) δ 8.00 (d, J= 4.7 Hz, 1H), 7.78 (d, J= 6.8 Hz, 1H), 7.70 – 7.61 (m, 2H), 6.83 (t, J= 7.2 Hz, 1H), 6.74 – 6.66 (m, 2H), 6.59 (t, J= 6.1 Hz, 1H), 6.39 (d, J= 7.5 Hz, 1H), 5.36 (d, J= 9.2 Hz, 1H), 4.82 (d, J= 49.2 Hz, 1H), 4.23 (d, J= 6.1 Hz, 2H), 4.07 – 3.99 (m, 2H), 3.80 – 3.65 (m, 1H), 3.03 – 3.00 (m, 1H), 2.77 – 2.72 (m, 4H), 2.32 – 2.19 (m, 4H), 2.14 – 2.05 (m, 1H), 1.88 – 1.75 (m, 2H)。 實例36. 4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}3-甲氧基-N-甲基苯甲醯胺之合成 步驟1. 4-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-3-甲氧基-N-甲基苯甲醯胺之合成 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-N-methylbenzamide (60 mg, 0.13 mmol, 1 eq.), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine.HCl (29 mg, 0.14 mmol, 1.1 eq.), t-BuONa (50 mg, 0.52 mmol, 4 eq.) and di-tributyl[2',4',6'-tris(propan-2-yl)-[1,1'-biphenyl]-2-yl]phosphane;{2'-amino-[1,1'-biphenyl]-2-yl}methanesulfonate (10 mg, 0.01 mmol, 0.1 eq.) were dissolved in THF (2 The mixture in 10% ethyl acetate (50 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (3*30 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 /MeOH 10:1) and preparative HPLC (column: XBridge Prep OBD C18 column, 19*250 mm, 5μm; mobile phase A: water (10mmol/L NH 4 HCO 3 +0.05%NH 3 . H 2 O), mobile phase B: MEOH; flow rate: 25 mL/min mL/min; gradient: 45% B to 63% B in 10 min; wavelength: 254nm/220nm nm; RT1(min): 9.55; Runs: 3) to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide (6.2 mg, 9.28%) as a white solid. LC-MS: (M+H) + found 517.30. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.00 (d, J = 4.7 Hz, 1H), 7.78 (d, J = 6.8 Hz, 1H), 7.70 – 7.61 (m, 2H), 6.83 (t, J = 7.2 Hz, 1H), 6.74 – 6.66 (m, 2H), 6.59 (t, J = 6.1 Hz, 1H), 6.39 (d, J = 7.5 Hz, 1H), 5.36 (d, J = 9.2 Hz, 1H), 4.82 (d, J = 49.2 Hz, 1H), 4.23 (d, J = 6.1 Hz, 2H), 4.07 – 3.99 (m, 2H), 3.80 – 3.65 (m, 1H), 3.03 – 3.00 (m, 1H), 2.77 – 2.72 (m, 4H), 2.32 – 2.19 (m, 4H), 2.14 – 2.05 (m, 1H), 1.88 – 1.75 (m, 2H). Example 36. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}3-methoxy-N-methylbenzamide Step 1. Synthesis of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N-methylbenzamide
將8-溴-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶( 中間物1;400 mg,0.99 mmol,1當量)、3-甲氧基-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺( 中間物14;258.7 mg,1.19 mmol,1.2當量)、Pd(PPh 3) 4(228.3 mg,0.20 mmol,0.2當量)、i-Pr 2NH (1 g,9.88 mmol,10當量)及CuI (188 mg,0.99 mmol,1當量)於DMSO (2 mL)中之混合物在室溫及氮氣氛圍下攪拌1 h。所得溶液用EtOAc (100 mL)稀釋且用鹽水(3*100 mL)洗滌。有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/ MeOH 10:1)純化,以得到呈棕色固體之4-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-3-甲氧基-N-甲基苯甲醯胺(400 mg,81.76%)。LC-MS:(M+H) +實測值495.1。 步驟2. 4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}3-甲氧基-N-甲基苯甲醯胺之合成 A mixture of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( intermediate 1 ; 400 mg, 0.99 mmol, 1 eq), 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide ( intermediate 14 ; 258.7 mg, 1.19 mmol, 1.2 eq), Pd(PPh3) 4 (228.3 mg, 0.20 mmol, 0.2 eq), i- Pr2NH (1 g, 9.88 mmol, 10 eq) and CuI (188 mg, 0.99 mmol, 1 eq) in DMSO (2 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting solution was diluted with EtOAc (100 mL) and washed with brine (3*100 mL). The organic layer was dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 / MeOH 10:1) to give 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N-methylbenzamide (400 mg, 81.76%) as a brown solid. LC-MS: (M+H) + found 495.1. Step 2. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}3-methoxy-N-methylbenzamide
將4-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-3-甲氧基-N-甲基苯甲醯胺(300 mg,0.61 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(248.46 mg,1.212 mmol,2當量)、t-BuONa (291 mg,3.03 mmol,5當量)及tBuXphos Pd G3 (144.3 mg,0.18 mmol,0.3當量)於THF (3 mL)中之混合物在70℃及氮氣氛圍下攪拌1h。將所得混合物在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/於MeOH中之7 M NH 315:1)及製備型HPLC (管柱:Xcelect CSH F-pheny OBD管柱,30*150 mm,5μm;移動相A:水(0.1% FA),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在7 min內13% B至25% B;波長:254nm/220nm nm;RT1(min):6.3)純化,以得到呈白色固體之4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}3-甲氧基-N-甲基苯甲醯胺(42.5 mg,12.84%)。LC-MS:(M+H) +實測值547.25。 1H NMR (400 MHz, DMSO- d 6) δ 8.26 – 8.03 (m, 1H), 7.78 (d, J= 6.8 Hz, 1H), 7.41 (dd, J= 8.1, 1.8 Hz, 1H), 7.34 (d, J= 1.9 Hz, 1H), 6.83 (t, J= 7.1 Hz, 1H), 6.74 (d, J= 8.3 Hz, 1H), 6.39 (d, J= 7.6 Hz, 1H), 5.96 (t, J= 6.3 Hz, 1H), 5.38 (d, J= 9.2 Hz, 1H), 4.71 – 4.85 (d, J= 49.4 Hz, 1H), 4.27 (d, J= 6.3 Hz, 2H), 4.02 (m 2H), 3.84 (s, 3H), 3.70 (d, J= 30.1 Hz, 1H), 3.03 (t, J= 11.6 Hz, 1H), 2.75 (d, J= 4.4 Hz, 4H), 2.29 (d, J= 13.0 Hz, 1H), 2.19 (s, 3H), 2.08 (d, J= 8.6 Hz, 1H), 1.79 (d, J= 5.6 Hz, 2H)。 實例37及38. 4-{[3-(8-{[(4R)-3,3-二氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺(37)及4-{[3-(8-{[(4S)-3,3-二氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺(38)之合成 步驟1. 4-[(3-{8-[(3,3-二氟-1-甲基哌啶-4-基)胺基]-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺之合成 A mixture of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N-methylbenzamide (300 mg, 0.61 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (248.46 mg, 1.212 mmol, 2 eq), t-BuONa (291 mg, 3.03 mmol, 5 eq) and tBuXphos Pd G3 (144.3 mg, 0.18 mmol, 0.3 eq) in THF (3 mL) was stirred at 70 °C under nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 /7 M NH 3 in MeOH 15:1) and preparative HPLC (column: Xcelect CSH F-pheny OBD column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 13% B to 25% B in 7 min; wavelength: 254 nm/220 nm nm; RT1 (min): 6.3) to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}3-methoxy-N-methylbenzamide (42.5 mg, 12.84%) as a white solid. LC-MS: (M+H) + found 547.25. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.26 – 8.03 (m, 1H), 7.78 (d, J = 6.8 Hz, 1H), 7.41 (dd, J = 8.1, 1.8 Hz, 1H), 7.34 (d, J = 1.9 Hz, 1H), 6.83 (t, J = 7.1 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.39 (d, J = 7.6 Hz, 1H), 5.96 (t, J = 6.3 Hz, 1H), 5.38 (d, J = 9.2 Hz, 1H), 4.71 – 4.85 (d, J = 49.4 Hz, 1H), 4.27 (d, J = 6.3 Hz, 2H), 4.02 (m 2H), 3.84 (s, 3H), 3.70 (d, J = 30.1 Hz, 1H), 3.03 (t, J = 11.6 Hz, 1H), 2.75 (d, J = 4.4 Hz, 4H), 2.29 (d, J = 13.0 Hz, 1H), 2.19 (s, 3H), 2.08 (d, J = 8.6 Hz, 1H), 1.79 (d, J = 5.6 Hz, 2H). Examples 37 and 38. Synthesis of 4-{[3-(8-{[(4R)-3,3-difluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (37) and 4-{[3-(8-{[(4S)-3,3-difluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (38) Step 1. Synthesis of 4-[(3-{8-[(3,3-difluoro-1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide
將4-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-3-甲氧基-N-甲基苯甲醯胺(150 mg,0.30 mmol,1當量)、3,3-二氟-1-甲基哌啶-4-胺二鹽酸鹽(75 mg,0.33 mmol,1.1當量)、BrettPhos Pd G4 (28 mg,0.03 mmol,0.1當量)、RuPhos (29 mg,0.06 mmol,0.20當量)及Cs 2CO 3(395 mg,1.21 mmol,4當量)於二噁烷(4.5 mL)中之混合物在95℃及氬氣氛圍下攪拌隔夜。所得混合物用EA (50 mL)稀釋且用鹽水(2*50 mL)洗滌。有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用CH 2Cl 2/ MeOH (99:1)溶析,以得到呈淺黃色固體之4-[(3-{8-[(3,3-二氟-1-甲基哌啶-4-基)胺基]-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺(75 mg,43.87%)。LC-MS:(M+H) +實測值565.2。 步驟2. 掌性分離 A mixture of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N-methylbenzamide (150 mg, 0.30 mmol, 1 eq), 3,3-difluoro-1-methylpiperidin-4-amine dihydrochloride (75 mg, 0.33 mmol, 1.1 eq), BrettPhos Pd G4 (28 mg, 0.03 mmol, 0.1 eq), RuPhos (29 mg, 0.06 mmol, 0.20 eq) and Cs2CO3 (395 mg, 1.21 mmol, 4 eq) in dioxane (4.5 mL) was stirred at 95 °C under an atmosphere of argon overnight. The resulting mixture was diluted with EA (50 mL) and washed with brine (2*50 mL). The organic layer was dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / MeOH (99:1) to give 4-[(3-{8-[(3,3-difluoro-1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (75 mg, 43.87%) as a light yellow solid. LC-MS: (M+H) + found 565.2. Step 2. Chiral separation
粗產物4-[(3-{8-[(3,3-二氟-1-甲基哌啶-4-基)胺基]-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺(75 mg)藉由具有以下條件(管柱:CHIRALPAKIC-34.6*50mm,3.0um;移動相A:Hex(0.2%DEA):(EtOH:DCM=1:1)=65:35;梯度:等度;注入體積:3.0L mL)之製備型HPLC純化,以得到兩個級分: A ;(峰1):指定為呈白色固體之4-{[3-(8-{[(4R)-3,3-二氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺(17.9 mg,23.58%)。LC-MS:(M+H) +實測值565.20。 1H NMR (400 MHz, DMSO- d 6) δ 8.06 (dd, J= 8.2, 5.6 Hz, 2H), 7.41 (dd, J= 8.2, 1.9 Hz, 1H), 7.34 (d, J= 1.9 Hz, 1H), 6.88 (t, J= 7.2 Hz, 1H), 6.76 (d, J= 8.3 Hz, 1H), 6.62 (d, J= 7.6 Hz, 1H), 5.93 (t, J= 6.3 Hz, 1H), 4.37 – 4.27 (m, 3H), 4.03 (q, J= 10.6 Hz, 2H), 3.84 – 3.81 (m, 4H), 3.60 – 3.52 (m, 1H), 3.19 (t, J= 10.6 Hz, 1H), 2.98 – 2.83 (m, 1H), 2.75 (d, J= 4.5 Hz, 3H), 2.40 (s, 3H), 2.09 – 1.89 (m, 1H), 1.71 – 1.68 (m, 1H)。 B;(峰2):指定為呈白色固體之4-{[3-(8-{[(4S)-3,3-二氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺(16.5 mg,21.78%)。LC-MS:(M+H) +實測值565.20。 1H NMR (400 MHz, DMSO- d 6) δ 8.06 (dd, J= 8.3, 5.7 Hz, 2H), 7.41 (dd, J= 8.2, 1.9 Hz, 1H), 7.34 (d, J= 1.9 Hz, 1H), 6.88 (t, J= 7.2 Hz, 1H), 6.76 (d, J= 8.2 Hz, 1H), 6.62 (d, J= 7.6 Hz, 1H), 5.93 (t, J= 6.3 Hz, 1H), 4.37 – 4.27 (m, 3H), 4.03 (q, J= 10.7 Hz, 2H), 3.84 – 3.81 (m, 4H), 3.64 – 3.49 (m, 1H), 3.19 (t, J= 10.6 Hz, 1H), 2.98 – 2.83 (m, 1H), 2.75 (d, J= 4.4 Hz, 3H), 2.40 (s, 3H), 2.09 – 1.95 (m, 1H), 1.71 – 1.68 (m, 1H)。 實例39. N-[2-(3-{[2-甲氧基-4-(甲基胺甲醯基)苯基]胺基}丙-1-炔-1-基)-8-[(1-甲基哌啶-4-基)胺基]-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-6-基]胺基甲酸三級丁酯之合成 步驟1. 4-[(3-{6-溴-8-[(1-甲基哌啶-4-基)胺基]-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺之合成 The crude product 4-[(3-{8-[(3,3-difluoro-1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (75 mg) was purified by preparative HPLC with the following conditions (column: CHIRALPAKIC-3 4.6*50 mm, 3.0 um; mobile phase A: Hex (0.2% DEA): (EtOH: DCM = 1:1) = 65:35; gradient: isocratic; injection volume: 3.0 L mL) to obtain two fractions: A ; (Peak 1): designated as 4-{[3-(8-{[(4R)-3,3-difluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (17.9 mg, 23.58%) as a white solid. LC-MS: (M+H) + found 565.20. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.06 (dd, J = 8.2, 5.6 Hz, 2H), 7.41 (dd, J = 8.2, 1.9 Hz, 1H), 7.34 (d, J = 1.9 Hz, 1H), 6.88 (t, J = 7.2 Hz, 1H), 6.76 (d, J = 8.3 Hz, 1H), 6.62 (d, J = 7.6 Hz, 1H), 5.93 (t, J = 6.3 Hz, 1H), 4.37 – 4.27 (m, 3H), 4.03 (q, J = 10.6 Hz, 2H), 3.84 – 3.81 (m, 4H), 3.60 – 3.52 (m, 1H), 3.19 (t, J = 10.6 Hz, 1H), 2.98 – 2.83 (m, 1H), 2.75 (d, J = 4.5 Hz, 3H), 2.40 (s, 3H), 2.09 – 1.89 (m, 1H), 1.71 – 1.68 (m, 1H). B ; (Peak 2): designated as 4-{[3-(8-{[(4S)-3,3-difluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (16.5 mg, 21.78%) as a white solid. LC-MS: (M+H) + found 565.20. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.06 (dd, J = 8.3, 5.7 Hz, 2H), 7.41 (dd, J = 8.2, 1.9 Hz, 1H), 7.34 (d, J = 1.9 Hz, 1H), 6.88 (t, J = 7.2 Hz, 1H), 6.76 (d, J = 8.2 Hz, 1H), 6.62 (d, J = 7.6 Hz, 1H), 5.93 (t, J = 6.3 Hz, 1H), 4.37 – 4.27 (m, 3H), 4.03 (q, J = 10.7 Hz, 2H), 3.84 – 3.81 (m, 4H), 3.64 – 3.49 (m, 1H), 3.19 (t, J = 10.6 Hz, 1H), 2.98 – 2.83 (m, 1H), 2.75 (d, J = 4.4 Hz, 3H), 2.40 (s, 3H), 2.09 – 1.95 (m, 1H), 1.71 – 1.68 (m, 1H). Example 39. Synthesis of tributyl N-[2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl]carbamate Step 1. Synthesis of 4-[(3-{6-bromo-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide
將3-甲氧基-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺( 中間物14;2.9 g,13.29 mmol,1.1當量)、二異丙胺(12.22 g,120.79 mmol,10當量)、N-[6-溴-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基]-1-甲基哌啶-4-胺(6.25 g,12.08 mmol,1當量)、Pd(PPh 3) 4(5.58 g,4.83 mmol,0.4當量)及CuI (2.29 g,12.08 mmol,1當量)於DMSO (60 mL)中之混合物在室溫下攪拌1 h。所得混合物用水(400 mL)淬滅且用EtOAc (3*400 mL)萃取。合併的有機層經硫酸鈉乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由具有以下條件(管柱,C18矽膠;移動相,於水中之0.1% TFA,在10 min內30%至50%梯度;偵測器,UV 220 nm)之反相急速層析純化,以得到呈灰白色固體之所需化合物4-[(3-{6-溴-8-[(1-甲基哌啶-4-基)胺基]-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺(5.3 g,72.23%)。LC-MS:(M+H) +實測值:607.0。 步驟2. N-[2-(3-{[2-甲氧基-4-(甲基胺甲醯基)苯基]胺基}丙-1-炔-1-基)-8-[(1-甲基哌啶-4-基)胺基]-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-6-基]胺基甲酸三級丁酯之合成 A mixture of 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide ( intermediate 14 ; 2.9 g, 13.29 mmol, 1.1 equiv), diisopropylamine (12.22 g, 120.79 mmol, 10 equiv), N-[6-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]-1-methylpiperidin-4-amine (6.25 g, 12.08 mmol, 1 equiv), Pd( PPh3 ) 4 (5.58 g, 4.83 mmol, 0.4 equiv) and CuI (2.29 g, 12.08 mmol, 1 equiv) in DMSO (60 mL) was stirred at room temperature for 1 h. The resulting mixture was quenched with water (400 mL) and extracted with EtOAc (3*400 mL). The combined organic layers were dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, 0.1% TFA in water, gradient from 30% to 50% in 10 min; detector, UV 220 nm) to give the desired compound 4-[(3-{6-bromo-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (5.3 g, 72.23%) as an off-white solid. LC-MS: (M+H) + found: 607.0. Step 2. Synthesis of tributyl N-[2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl]carbamate
將4-[(3-{6-溴-8-[(1-甲基哌啶-4-基)胺基]-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺(100 mg,0.17 mmol,1當量)、BocNH 2(96.4 mg,0.83 mmol,5當量)、t-BuONa (47.5 mg,0.50 mmol,3當量)、tBuXPhos Pd G 3(13.1 mg,0.02 mmol,0.1當量)於THF (3 mL)中之混合物在60℃下攪拌1 h。所得混合物用水(100 mL)稀釋且用EtOAc (3*100 mL)萃取。合併的有機層經硫酸鈉乾燥,過濾且真空濃縮。殘餘物藉由製備型HPLC (管柱:YMC-Actus Triart C18 150*30mm;移動相A:水(10mmol NH 4HCO 3),移動相B:CAN;流動速率:60 mL/min mL/min;梯度:在10 min內15% B至25% B;波長:254 nm;RT1(min):8)純化,以得到呈灰白色固體之N-[2-(3-{[2-甲氧基-4-(甲基胺甲醯基)苯基]胺基}丙-1-炔-1-基)-8-[(1-甲基哌啶-4-基)胺基]-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-6-基]胺基甲酸三級丁酯(10.3 mg,9.72%)。LC-MS:(M+H) +實測值:644.35。 1H NMR (400 MHz, DMSO-d6) δ 9.16 (s, 1H), 8.14 – 7.99 (m, 2H), 7.41 (dd, J= 8.3, 1.8 Hz, 1H), 7.34 (d, J= 1.9 Hz, 1H), 6.73 (d, J= 8.3 Hz, 1H), 6.24 (d, J= 1.6 Hz, 1H), 5.95 (t, J= 6.3 Hz, 1H), 5.82 (d, J= 7.9 Hz, 1H), 4.26 (d, J= 6.3 Hz, 2H), 3.93 (m, 2H), 3.84 (s, 3H), 3.24 – 3.11 (m, 1H), 2.75 (d, J= 4.5 Hz, 5H), 2.17 (s, 3H), 2.03 – 1.93 (m, 2H), 1.89 (d, J= 12.5 Hz, 2H), 1.67 – 1.52 (m, 2H), 1.47 (s, 9H)。 實例40. 4-[(3-{6-胺基-8-[(1-甲基哌啶-4-基)胺基]-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺之合成 A mixture of 4-[(3-{6-bromo-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (100 mg, 0.17 mmol, 1 eq), BocNH2 (96.4 mg, 0.83 mmol, 5 eq), t-BuONa (47.5 mg, 0.50 mmol, 3 eq), tBuXPhosPdG3 (13.1 mg, 0.02 mmol, 0.1 eq) in THF (3 mL) was stirred at 60 °C for 1 h. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (3*100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: YMC-Actus Triart C18 150*30 mm; mobile phase A: water (10 mmol NH 4 HCO 3 ), mobile phase B: CAN; flow rate: 60 mL/min mL/min; gradient: 15% B to 25% B in 10 min; wavelength: 254 nm; RT1(min): 8) to obtain tributyl N-[2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl]carbamate (10.3 mg, 9.72%) as an off-white solid. LC-MS: (M+H) + found: 644.35. 1 H NMR (400 MHz, DMSO-d6) δ 9.16 (s, 1H), 8.14 – 7.99 (m, 2H), 7.41 (dd, J = 8.3, 1.8 Hz, 1H), 7.34 (d, J = 1.9 Hz, 1H), 6.73 (d, J = 8.3 Hz, 1H), 6.24 (d, J = 1.6 Hz, 1H), 5.95 (t, J = 6.3 Hz, 1H), 5.82 (d, J = 7.9 Hz, 1H), 4.26 (d, J = 6.3 Hz, 2H), 3.93 (m, 2H), 3.84 (s, 3H), 3.24 – 3.11 (m, 1H), 2.75 (d, J = 4.5 Hz, 5H), 2.17 (s, 3H), 2.03 – 1.93 (m, 2H), 1.89 (d, J = 12.5 Hz, 2H), 1.67 – 1.52 (m, 2H), 1.47 (s, 9H). Example 40. Synthesis of 4-[(3-{6-amino-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide
向N-[2-(3-{[2-甲氧基-4-(甲基胺甲醯基)苯基]胺基}丙-1-炔-1-基)-8-[(1-甲基哌啶-4-基)胺基]-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-6-基]胺基甲酸三級丁酯(100 mg,0.16 mmol,1當量)於DCM (2 mL)中之溶液中逐滴添加TFA (1 mL)。將溶液在室溫下攪拌1 h,然後真空濃縮。粗產物藉由製備型HPLC (管柱:XBridge Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在7 min內24% B至28% B;波長:254nm/220nm nm;RT1(min):6.8)純化,以得到呈黃色固體之4-[(3-{6-胺基-8-[(1-甲基哌啶-4-基)胺基]-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺(18.8 mg,22.26%)。LC-MS:(M+H) +實測值:544.25。 1H NMR (400 MHz, DMSO-d6) δ 8.10 (m, 1H), 7.47 – 7.31 (m, 2H), 6.90 (d, J= 1.6 Hz, 1H), 6.72 (d, J= 8.2 Hz, 1H), 6.04 – 5.86 (m, 2H), 5.53 (d, J= 8.1 Hz, 1H), 4.76 (s, 2H), 4.23 (dd, J= 10.5, 6.2 Hz, 2H), 3.94 – 3.75 (m, 5H), 3.24 (d, J= 9.6 Hz, 1H), 2.75 (d, J= 4.5 Hz, 5H), 2.14 (d, J= 56.4 Hz, 5H), 1.90 (d, J= 13.0 Hz, 2H), 1.72 – 1.50 (m, 2H)。 實例41. 4-[(3-{6-乙醯胺基-8-[(1-甲基哌啶-4-基)胺基]-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺之合成 To a solution of tributyl N-[2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl]carbamate (100 mg, 0.16 mmol, 1 eq) in DCM (2 mL) was added TFA (1 mL) dropwise. The solution was stirred at room temperature for 1 h and then concentrated in vacuo. The crude product was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 24% B to 28% B in 7 min; wavelength: 254 nm/220 nm nm; RT1(min): 6.8) to give 4-[(3-{6-amino-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (18.8 mg, 22.26%) as a yellow solid. LC-MS: (M+H) + found: 544.25. 1 H NMR (400 MHz, DMSO-d6) δ 8.10 (m, 1H), 7.47 – 7.31 (m, 2H), 6.90 (d, J = 1.6 Hz, 1H), 6.72 (d, J = 8.2 Hz, 1H), 6.04 – 5.86 (m, 2H), 5.53 (d, J = 8.1 Hz, 1H), 4.76 (s, 2H), 4.23 (dd, J = 10.5, 6.2 Hz, 2H), 3.94 – 3.75 (m, 5H), 3.24 (d, J = 9.6 Hz, 1H), 2.75 (d, J = 4.5 Hz, 5H), 2.14 (d, J = 56.4 Hz, 5H), 1.90 (d, J = 13.0 Hz, 2H), 1.72 – 1.50 (m, 2H). Example 41. Synthesis of 4-[(3-{6-acetamido-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide
在0℃下,向4-[(3-{6-胺基-8-[(1-甲基哌啶-4-基)胺基]-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺(100 mg,0.18 mmol,1當量)、DIEA (119 mg,0.92 mmol,5當量)及AcOH (16.6 mg,0.28 mmol,1.5當量)於DMF (2 mL)中之攪拌溶液中添加HATU (105 mg,0.28 mmol,1.5當量)。將反應混合物在室溫下攪拌1 h。用H 2O (10 mL)淬滅反應。混合物用EtOAc (3*10 mL)萃取。合併的有機層經硫酸鈉乾燥,過濾且真空濃縮。粗物質使用具有以下條件之製備型HPLC純化:管柱:X-Select Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(0.1%FA),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在7 min內30% B至50% B;波長:254nm/220nm nm;RT1(min):6.56。粗產物使用具有以下條件之製備型HPLC進一步純化:管柱:JW-CHIRALPAK IG,20*250mm,5um;移動相A:EtOH:DCM=1:2--HPLC,移動相B:Hex(0.5% 2M NH3-MeOH)--HPLC;流動速率:20 mL/min;梯度:在23.5min內70% B至70% B;波長:220/254 nm;RT1(min):16.33;RT2(min):20.6;樣品溶劑:EtOH:DCM=1:1--HPLC;樣品濃度:mg/mL;注入體積:0.5 mL;運行粗疏:4。此產生呈白色固體之4-[(3-{6-乙醯胺基-8-[(1-甲基哌啶-4-基)胺基]-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺(11.9 mg,11.05%)。LC-MS:(M+H) +實測值:586.25。 1H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 8.37 (s, 1H), 8.15 – 8.08 (m, 1H), 7.46 – 7.38 (m, 1H), 7.35 (d, J= 1.8 Hz, 1H), 6.73 (d, J= 8.3 Hz, 1H), 6.17 (d, J= 1.6 Hz, 1H), 5.96 (t, J= 6.3 Hz, 1H), 5.90 (d, J= 8.0 Hz, 1H), 4.26 (d, J= 6.3 Hz, 2H), 3.96 – 3.89 (m, 2H), 3.84 (s, 3H), 3.23 (d, J = 10.4 Hz, 1H), 2.80 (d, J= 11.3 Hz, 2H), 2.76 (d, J= 4.5 Hz, 3H), 2.21 (s, 3H), 2.11 – 2.01 (m, 5H), 1.94 – 1.86 (m, 2H), 1.68 – 1.55 (m, 2H)。 實例42. 3-甲氧基-N-甲基-4-[(3-{8-[(1-甲基哌啶-4-基)胺基]-6-(丙-2-烯醯胺基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]苯甲醯胺之合成 To a stirred solution of 4-[(3-{6-amino-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (100 mg, 0.18 mmol, 1 eq), DIEA (119 mg, 0.92 mmol, 5 eq) and AcOH (16.6 mg, 0.28 mmol, 1.5 eq) in DMF (2 mL) at 0°C was added HATU (105 mg, 0.28 mmol, 1.5 eq). The reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with H 2 O (10 mL). The mixture was extracted with EtOAc (3*10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified using preparative HPLC with the following conditions: column: X-Select Prep OBD C18 column, 30*150 mm, 5μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 30% B to 50% B in 7 min; wavelength: 254nm/220nm nm; RT1(min): 6.56. The crude product was further purified using preparative HPLC with the following conditions: column: JW-CHIRALPAK IG, 20*250mm, 5um; mobile phase A: EtOH:DCM=1:2--HPLC, mobile phase B: Hex(0.5% 2M NH3-MeOH)--HPLC; flow rate: 20 mL/min; gradient: 70% B to 70% B in 23.5 min; wavelength: 220/254 nm; RT1(min): 16.33; RT2(min): 20.6; sample solvent: EtOH:DCM=1:1--HPLC; sample concentration: mg/mL; injection volume: 0.5 mL; run length: 4. This resulted in 4-[(3-{6-acetamido-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (11.9 mg, 11.05%) as a white solid. LC-MS: (M+H) + found: 586.25. 1 H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 8.37 (s, 1H), 8.15 – 8.08 (m, 1H), 7.46 – 7.38 (m, 1H), 7.35 (d, J = 1.8 Hz, 1H), 6.73 (d, J = 8.3 Hz, 1H), 6.17 (d, J = 1.6 Hz, 1H), 5.96 (t, J = 6.3 Hz, 1H), 5.90 (d, J = 8.0 Hz, 1H), 4.26 (d, J = 6.3 Hz, 2H), 3.96 – 3.89 (m, 2H), 3.84 (s, 3H), 3.23 (d, J = 10.4 Hz, 1H), 2.80 (d, J = 11.3 Hz, 2H), 2.76 (d, J = 4.5 Hz, 3H), 2.21 (s, 3H), 2.11 – 2.01 (m, 5H), 1.94 – 1.86 (m, 2H), 1.68 – 1.55 (m, 2H). Example 42. Synthesis of 3-methoxy-N-methyl-4-[(3-{8-[(1-methylpiperidin-4-yl)amino]-6-(prop-2-enamido)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]benzamide
向4-[(3-{6-胺基-8-[(1-甲基哌啶-4-基)胺基]-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺(100 mg,0.18 mmol,1.0當量)、丙烯酸(20 mg,0.27 mmol,1.5當量)及DIEA (119 mg,0.92 mmol,5.0當量)於DMF (1 mL) 中之混合物中添加HATU (139 mg,0.34 mmol,2.0當量)。在室溫下攪拌1 h後,用水(10 mL)淬滅混合物且水相用EtOAc (3*10 mL)萃取。合併的有機層經硫酸鈉乾燥,過濾且真空濃縮。殘餘物藉由製備型HPLC (管柱:XBridge Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在7 min內45% B至49% B;波長:254nm/220nm nm;RT1(min):5.9)純化,以得到呈灰白色固體之3-甲氧基-N-甲基-4-[(3-{8-[(1-甲基哌啶-4-基)胺基]-6-(丙-2-烯醯胺基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]苯甲醯胺(8.2 mg,7.46%)。LC-MS:(M+H +)實測值:598.45。 1H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.12-8.08 (m, 1H), 7.41 (dd, J= 8.2, 1.8 Hz, 1H), 7.35 (d, J= 1.9 Hz, 1H), 6.72 (d, J= 8.3 Hz, 1H), 6.05 (s, 1H), 5.96 (t, J= 6.3 Hz, 1H), 5.76 (d, J= 8.0 Hz, 1H), 4.27 (d, J= 6.4 Hz, 2H), 4.17-4.09 (m, 2H), 3.84 (s, 3H), 3.24 (t, J= 7.8 Hz, 2H), 3.16 (d, J= 9.7 Hz, 1H), 2.75 (d, J= 4.5 Hz, 5H), 2.56 (d, J= 7.7 Hz, 2H), 2.18 (s, 3H), 2.00 (t, J= 11.3 Hz, 2H), 1.88 (d, J= 12.4 Hz, 2H), 1.63 – 1.52 (m, 2H)。 實例13. 3-甲氧基-N-甲基-4-[(3-{8-[(1-甲基哌啶-4-基)胺基]-6-(2-甲基丙-2-烯醯胺基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]苯甲醯胺,甲酸鹽之合成 To a mixture of 4-[(3-{6-amino-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (100 mg, 0.18 mmol, 1.0 equiv), acrylic acid (20 mg, 0.27 mmol, 1.5 equiv) and DIEA (119 mg, 0.92 mmol, 5.0 equiv) in DMF (1 mL) was added HATU (139 mg, 0.34 mmol, 2.0 equiv). After stirring at room temperature for 1 h, the mixture was quenched with water (10 mL) and the aqueous phase was extracted with EtOAc (3*10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 45% B to 49% B in 7 min; wavelength: 254 nm/220 nm nm; RT1 (min): 5.9) to obtain 3-methoxy-N-methyl-4-[(3-{8-[(1-methylpiperidin-4-yl)amino]-6-(prop-2-enamido)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]benzamide (8.2 mg, 7.46%). LC-MS: (M+H + ) found: 598.45. 1 H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.12-8.08 (m, 1H), 7.41 (dd, J = 8.2, 1.8 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 6.72 (d, J = 8.3 Hz, 1H), 6.05 (s, 1H), 5.96 (t, J = 6.3 Hz, 1H), 5.76 (d, J = 8.0 Hz, 1H), 4.27 (d, J = 6.4 Hz, 2H), 4.17-4.09 (m, 2H), 3.84 (s, 3H), 3.24 (t, J = 7.8 Hz, 2H), 3.16 (d, J = 9.7 Hz, 1H), 2.75 (d, J = 4.5 Hz, 5H), 2.56 (d, J = 7.7 Hz, 2H), 2.18 (s, 3H), 2.00 (t, J = 11.3 Hz, 2H), 1.88 (d, J = 12.4 Hz, 2H), 1.63 – 1.52 (m, 2H). Example 13. Synthesis of 3-methoxy-N-methyl-4-[(3-{8-[(1-methylpiperidin-4-yl)amino]-6-(2-methylprop-2-enamido)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]benzamide, formate salt
將4-[(3-{6-胺基-8-[(1-甲基哌啶-4-基)胺基]-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺(120 mg,0.22 mmol,1.0當量)、甲基丙烯酸(38 mg,0.44 mmol,2.0當量)、HATU (125 mg,0.33 mmol,1.5當量)及DIEA (142 mg,1.10 mmol,5.0當量)於DMF (2 mL)中之溶液在室溫下攪拌1 h。混合物用水(10 mL)稀釋且用EtOAc (3*10 mL)萃取。合併的有機層經硫酸鈉乾燥,過濾且真空濃縮。殘餘物藉由具有以下條件(管柱:X-Select Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(0.1%FA),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在7 min內30% B至50% B;波長:254nm/220nm nm;RT1(min):6.56)之製備型HPLC純化,以得到呈灰白色固體之3-甲氧基-N-甲基-4-[(3-{8-[(1-甲基哌啶-4-基)胺基]-6-(2-甲基丙-2-烯醯胺基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]苯甲醯胺;甲酸(17 mg,11.28%)。LC-MS:(M+H +)實測值:612.30。 1H NMR (400 MHz, DMSO-d6) δ 9.69 (s, 1H), 8.19 (s, 1H), 8.11 (d, J= 4.7 Hz, 1H), 7.44 – 7.34 (m, 2H), 6.73 (d, J= 8.3 Hz, 1H), 6.06 – 5.94 (m, 2H), 5.78 (d, J= 8.0 Hz, 1H), 4.30 – 4.04 (m, 4H), 3.85 (s, 3H), 3.44 (dd, J= 16.2, 6.9 Hz, 2H), 3.18 (s, 1H), 2.88 (dd, J= 16.1, 10.8 Hz, 1H), 2.76 (d, J = 4.4 Hz, 4H), 2.65 – 2.57 (m, 1H), 2.20 (s, 3H), 2.03 (t, J= 11.3 Hz, 2H), 1.89 (d, J= 12.4 Hz, 2H), 1.63 – 1.55 (m, 2H), 1.16 (d, J= 6.9 Hz, 3H)。 實例43. 4-((3-[6-(2-氯-2-氟乙醯胺基)-8-[(1-甲基哌啶-4-基)胺基]-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基胺基)-3-甲氧基-N-甲基苯甲醯胺,甲酸鹽之合成 A solution of 4-[(3-{6-amino-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (120 mg, 0.22 mmol, 1.0 equiv), methacrylic acid (38 mg, 0.44 mmol, 2.0 equiv), HATU (125 mg, 0.33 mmol, 1.5 equiv) and DIEA (142 mg, 1.10 mmol, 5.0 equiv) in DMF (2 mL) was stirred at room temperature for 1 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (3*10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC with the following conditions (column: X-Select Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 30% B to 50% B in 7 min; wavelength: 254 nm/220 nm nm; RT1 (min): 6.56) to obtain 3-methoxy-N-methyl-4-[(3-{8-[(1-methylpiperidin-4-yl)amino]-6-(2-methylprop-2-enamido)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]benzamide as an off-white solid; formic acid (17 mg, 11.28%). LC-MS: (M+H + ) found: 612.30. 1 H NMR (400 MHz, DMSO-d6) δ 9.69 (s, 1H), 8.19 (s, 1H), 8.11 (d, J = 4.7 Hz, 1H), 7.44 – 7.34 (m, 2H), 6.73 (d, J = 8.3 Hz, 1H), 6.06 – 5.94 (m, 2H), 5.78 (d, J = 8.0 Hz, 1H), 4.30 – 4.04 (m, 4H), 3.85 (s, 3H), 3.44 (dd, J = 16.2, 6.9 Hz, 2H), 3.18 (s, 1H), 2.88 (dd, J = 16.1, 10.8 Hz, 1H), 2.76 (d, J = 4.4 Hz, 4H), 2.65 – 2.57 (m, 1H), 2.20 (s, 3H), 2.03 (t, J = 11.3 Hz, 2H), 1.89 (d, J = 12.4 Hz, 2H), 1.63 – 1.55 (m, 2H), 1.16 (d, J = 6.9 Hz, 3H). Example 43. Synthesis of 4-((3-[6-(2-chloro-2-fluoroacetamido)-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-ylamino)-3-methoxy-N-methylbenzamide, formate salt
在室溫下,向4-[(3-(6-胺基-8-[(1-甲基哌啶-4-基)胺基]-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺(120 mg,0.22 mmol,1當量)、氯氟乙酸(29.8 mg,0.27 mmol,1.2當量)及DIEA (143 mg,1.11 mmol,5當量)於DMF (3 mL)中之溶液中添加HATU (100 mg,0.27 mmol,1.2當量)。將反應混合物在室溫下攪拌1 h,然後用水稀釋且用EtOAc (3*10 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。粗產物藉由具有以下條件(管柱:Xselect CSH Prep Fluoro-Phenyl管柱,19*250 mm,5μm;移動相A:水(0.1% FA),移動相B:ACN;流動速率:25 mL/min mL/min;梯度:在12min內19% B至29% B;波長:254nm/220nm nm;RT1(min):9.15)之製備型HPLC純化,以得到呈黃色固體之4-((3-[6-(2-氯-2-氟乙醯胺基)-8-[(1-甲基哌啶-4-基)胺基]-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基胺基)-3-甲氧基-N-甲基苯甲醯胺;甲酸(20.9 mg,13.65%)。LC-MS:(M+H) +實測值:638.25。 1H NMR (400 MHz, DMSO- d 6) δ 10.65 (d, J= 6.7 Hz, 1H), 9.36 (s, 1H), 8.38 – 8.23 (m, 1H), 8.18 – 8.04 (m, 1H), 7.48 – 7.30 (m, 2H), 6.93 (d, J= 48.9 Hz, 1H), 6.73 (d, J= 8.3 Hz, 1H), 6.48 – 6.28 (m, 2H), 5.98 (s, 1H), 4.28 (s, 2H), 4.10 – 3.93 (m, 2H), 3.85 (s, 3H), 3.78 – 3.50 (m, 3H), 3.30 – 2.99 (m, 2H), 2.77 (dd, J= 12.6, 4.0 Hz, 6H), 2.20 – 2.05 (m, 2H), 2.02 – 1.72 (m, 2H)。 實例44. 3-甲氧基-N-甲基-4-[(3-{6-[(甲基胺甲醯基)胺基]-8-[(1-甲基哌啶-4-基)胺基]-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]苯甲醯胺之合成 To a solution of 4-[(3-(6-amino-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-ylprop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (120 mg, 0.22 mmol, 1 eq), chlorofluoroacetic acid (29.8 mg, 0.27 mmol, 1.2 eq) and DIEA (143 mg, 1.11 mmol, 5 eq) in DMF (3 mL) at room temperature was added HATU (100 mg, 0.27 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for 1 h, then diluted with water and extracted with EtOAc (3*10 mL). The combined organic layers were purified by anhydrous Na 2 SO 4 Drying. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by HPLC with the following conditions (column: Xselect CSH Prep Fluoro-Phenyl column, 19*250 mm, 5μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 25 mL/min mL/min; gradient: 19% B to 29% B in 12 min; wavelength: 254nm/220nm nm; RT1(min): 9.15) was purified by preparative HPLC to give 4-((3-[6-(2-chloro-2-fluoroacetamido)-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-ylamino)-3-methoxy-N-methylbenzamide; formic acid (20.9 mg, 13.65%) as a yellow solid. LC-MS: (M+H) + found: 638.25. 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.65 (d, J = 6.7 Hz, 1H), 9.36 (s, 1H), 8.38 – 8.23 (m, 1H), 9 (m, 2H), 8.18 – 8.04 (m, 1H), 7.48 – 7.30 (m, 2H), 6.93 (d, J = 48.9 Hz, 1H), 6.73 (d, J = 8.3 Hz, 1H), 6.48 – 6.28 (m, 2H), 5.98 (s, 1H), 4.28 (s, 2H), 4.10 – 3.93 (m, 2H), 3.85 (s, 3H), 3.78 – 3.50 (m, 3H), 3.30 – 2.99 (m, 2H), 2.77 (dd, J = 12.6, 4.0 Hz, 6H), 2.20 – 2.05 (m, 2H), 2.18 – 2.31 (m, 2H), 2. 2H). Example 44. Synthesis of 3-methoxy-N-methyl-4-[(3-{6-[(methylaminoformyl)amino]-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]benzamide
將4-[(3-{6-溴-8-[(1-甲基哌啶-4-基)胺基]-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺(200 mg,0.33 mmol,1當量)、甲脲(48. 8 mg,0.66 mmol,2當量)、XantPhos (38.1 mg,0.07 mmol,0.2當量)、Cs 2CO 3(321.8 mg,0.99 mmol,3當量)及Pd 2(dba) 3(30.2 mg,0.03 mmol,0.1當量)於二噁烷(10 mL)中之混合物在100℃下攪拌16 h。反應混合物用水(200 mL)稀釋且用EA (3*200 mL)萃取。合併的有機層經硫酸鈉乾燥,過濾且真空濃縮。所得粗產物藉由製備型HPLC (管柱:XBridge Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3),移動相B:20mm NaOH+10%ACN;流動速率:60 mL/min mL/min;梯度:在9 min內71% B至76% B;波長:254nm/220nm nm;RT1(min):8.9)純化,以得到呈灰白色固體之3-甲氧基-N-甲基-4-[(3-{6-[(甲基胺甲醯基)胺基]-8-[(1-甲基哌啶-4-基)胺基]-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]苯甲醯胺(12.7 mg,6.42%)。LC-MS:(M+H) +實測值:601.45。 1H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H), 8.26 – 7.95 (m, 2H), 7.59 – 7.28 (m, 2H), 6.73 (d, J= 8.3 Hz, 1H), 6.26 – 5.88 (m, 3H), 5.75 (d, J= 8.2 Hz, 1H), 4.26 (d, J= 6.3 Hz, 2H), 3.84 (m, 5H), 3.28 – 3.14 (m, 1H), 2.76 (d, J= 4.4 Hz, 5H), 2.64 (d, J= 4.5 Hz, 3H), 2.17 (s, 3H), 2.03 – 1.83 (m, 4H), 1.71 – 1.49 (m, 2H)。 實例45. N-[2-(3-{[2-甲氧基-4-(甲基胺甲醯基)苯基]胺基}丙-1-炔-1-基)-8-[(1-甲基哌啶-4-基)胺基]-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-6-基]胺基甲酸甲酯之合成 A mixture of 4-[(3-{6-bromo-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (200 mg, 0.33 mmol, 1 eq), methylurea (48.8 mg, 0.66 mmol, 2 eq ) , XantPhos (38.1 mg, 0.07 mmol, 0.2 eq), Cs2CO3 (321.8 mg, 0.99 mmol, 3 eq) and Pd2 (dba) 3 (30.2 mg, 0.03 mmol, 0.1 eq) in dioxane (10 mL) was stirred at 100 °C for 16 h. The reaction mixture was diluted with water (200 mL) and extracted with EA (3*200 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 ), mobile phase B: 20 mm NaOH + 10% ACN; flow rate: 60 mL/min mL/min; gradient: 71% B to 76% B in 9 min; wavelength: 254 nm/220 nm nm; RT1 (min): 8.9) to give 3-methoxy-N-methyl-4-[(3-{6-[(methylaminoformyl)amino]-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]benzamide (12.7 mg, 6.42%) as an off-white solid. LC-MS: (M+H) + found: 601.45. 1 H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H), 8.26 – 7.95 (m, 2H), 7.59 – 7.28 (m, 2H), 6.73 (d, J = 8.3 Hz, 1H), 6.26 – 5.88 (m, 3H), 5.75 (d, J = 8.2 Hz, 1H), 4.26 (d, J = 6.3 Hz, 2H), 3.84 (m, 5H), 3.28 – 3.14 (m, 1H), 2.76 (d, J = 4.4 Hz, 5H), 2.64 (d, J = 4.5 Hz, 3H), 2.17 (s, 3H), 2.03 – 1.83 (m, 4H), 1.71 – 1.49 (m, 2H). Example 45. Synthesis of methyl N-[2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl]carbamate
將4-[(3-{6-溴-8-[(1-甲基哌啶-4-基)胺基]-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺(100 mg,0.17 mmol,1當量)、胺基甲酸甲酯(61.8 mg,0.83 mmol,5當量)、t-BuONa (47.5 mg,0.50 mmol,3當量)及tBuXPhos Pd G 3(13.1 mg,0.02 mmol,0.1當量)於THF (5 mL)中之混合物在65℃下攪拌1 h。反應混合物用水(200 mL)稀釋且用EA (3*200 mL)萃取。合併的有機層經硫酸鈉乾燥,過濾且真空濃縮。所得粗材料藉由製備型HPLC (管柱:XBridge Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3),移動相B:20mm NaOH+10%ACN;流動速率:60 mL/min mL/min;梯度:在9 min內71% B至76% B;波長:254nm/220nm nm;RT1(min):8.9)純化,以得到呈灰白色固體之N-[2-(3-{[2-甲氧基-4-(甲基胺甲醯基)苯基]胺基}丙-1-炔-1-基)-8-[(1-甲基哌啶-4-基)胺基]-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-6-基]胺基甲酸甲酯(15.5 mg,15.65%)。LC-MS:(M+H) +實測值:602.15。 1H NMR (400 MHz, DMSO-d6) δ 9.49 (s, 1H), 8.22 – 7.99 (m, 2H), 7.48 – 7.25 (m, 2H), 6.73 (d, J= 8.3 Hz, 1H), 6.23 (d, J= 1.6 Hz, 1H), 6.01 – 5.81 (m, 2H), 4.26 (d, J= 6.3 Hz, 2H), 3.84 (s, 5H), 3.67 (s, 3H), 3.18 (dd, J= 12.4, 7.7 Hz, 1H), 2.76 (t, J= 4.5 Hz, 5H), 2.17 (s, 3H), 2.06 – 1.81 (m, 4H), 1.66 – 1.50 (m, 2H)。 實例46. 4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N,N-二甲基苯甲醯胺之合成 步驟1. 4-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-3-甲氧基-N,N-二甲基苯甲醯胺之合成 A mixture of 4-[(3-{6-bromo-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (100 mg, 0.17 mmol, 1 eq), methyl carbamate (61.8 mg, 0.83 mmol, 5 eq), t-BuONa (47.5 mg, 0.50 mmol, 3 eq) and tBuXPhos Pd G 3 (13.1 mg, 0.02 mmol, 0.1 eq) in THF (5 mL) was stirred at 65 °C for 1 h. The reaction mixture was diluted with water (200 mL) and extracted with EA (3*200 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 ), mobile phase B: 20 mm NaOH+10% ACN; flow rate: 60 mL/min mL/min; gradient: 71% B to 76% B in 9 min; wavelength: 254 nm/220 nm nm; RT1 (min): 8.9) to obtain methyl N-[2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-6-yl]carbamate (15.5 mmol/L) as an off-white solid. mg, 15.65%). LC-MS: (M+H) + found: 602.15. 1 H NMR (400 MHz, DMSO-d6) δ 9.49 (s, 1H), 8.22 – 7.99 (m, 2H), 7.48 – 7.25 (m, 2H), 6.73 (d, J = 8.3 Hz, 1H), 6.23 (d, J = 1.6 Hz, 1H), 6.01 – 5.81 (m, 2H), 4.26 (d, J = 6.3 Hz, 2H), 3.84 (s, 5H), 3.67 (s, 3H), 3.18 (dd, J = 12.4, 7.7 Hz, 1H), 2.76 (t, J = 4.5 Hz, 5H), 2.17 (s, 3H), 2.06 – 1.81 (m, 4H), 1.66 – 1.50 (m, 2H). Example 46. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N,N-dimethylbenzamide Step 1. Synthesis of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N,N-dimethylbenzamide
向7-溴-2-碘-3-(2,2,2-三氟乙基)吡唑并[1,5-a]吡啶( 中間物1;200.0 mg,0.49 mmol,1當量)於DMSO (3 mL)中之攪拌溶液中添加3-甲氧基-N,N-二甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺( 中間物15;11.8 mg,0.05 mmol,2當量)、CuI (47.0 mg,0.25 mmol,0.50當量)、i-Pr 2NH (499.8 mg,4.94 mmol,10當量)及Pd(PPh 3) 4(34.7 mg,0.03 mmol,0.20當量)。將所得混合物在30℃及氮氣氛圍下攪拌1 h。所得溶液使用具有以下條件(移動相A:水,移動相B:ACN;流動速率:60 mL/min;梯度:在30 min內0% B至100% B;254/220 nm)之C18急速層析純化。此產生呈淺黃色油狀物之4-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-3-甲氧基-N,N-二甲基苯甲醯胺(96.0 mg,43.60%)。LC-MS:(M+H) +實測值510.1。 步驟2. 4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N,N-二甲基苯甲醯胺之合成 To a stirred solution of 7-bromo-2-iodo-3-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridine ( Intermediate 1 ; 200.0 mg, 0.49 mmol, 1 eq) in DMSO (3 mL) was added 3-methoxy-N,N-dimethyl-4-(prop-2-yn-1-ylamino)benzamide ( Intermediate 15 ; 11.8 mg, 0.05 mmol, 2 eq), CuI (47.0 mg, 0.25 mmol, 0.50 eq), i-Pr 2 NH (499.8 mg, 4.94 mmol, 10 eq) and Pd(PPh 3 ) 4 (34.7 mg, 0.03 mmol, 0.20 eq). The resulting mixture was stirred at 30 °C under nitrogen atmosphere for 1 h. The resulting solution was purified using C18 flash chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm). This produced 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N,N-dimethylbenzamide (96.0 mg, 43.60%) as a light yellow oil. LC-MS: (M+H) + found 510.1. Step 2. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N,N-dimethylbenzamide
在室溫下,向4-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-3-甲氧基-N,N-二甲基苯甲醯胺(100.0 mg,0.20 mmol,1當量)於THF (10 mL)中之攪拌溶液中逐份添加(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(51.9 mg,0.39 mmol,2當量)、t-BuONa (113.2 mg,1.18 mmol,6當量)及tBuXPhosPdG3 (62.4 mg,0.08 mmol,0.40當量)。將所得混合物在65℃及氮氣氛圍下攪拌30 min。移除溶劑之後,殘餘物藉由PTLC (CH 2Cl 2/ MeOH 20:1)純化以得到粗物質,接著藉由具有以下條件之製備型HPLC純化:管柱:XBridge Prep OBD C18管柱,19*250 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3+ 0.05% NH 3H 2O),移動相B:MeOH;流動速率:25 mL/min mL/min;梯度:在10min內49% B至72% B;波長:254nm/220nm nm;RT1(min):9.43;運行次數:3。此產生呈白色固體之4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N,N-二甲基苯甲醯胺(8.30 mg,7.54%)。LC-MS:(M+H) +實測值561.35。 1H NMR (400 MHz, DMSO- d 6) δ 7.81 (s, 1H), 6.95-6.89 (m, 2H), 6.87-6.81 (m, 1H), 6.79-6.72 (m, 1H), 6.45-6.35 (m, 1H), 5.85 (s, 1H), 4.81 (d, J= 8.4 Hz, 1H), 4.35 (s, 2H), 4.15-3.92 (m, 2H), 3.83 (s, 3H), 3.79 (d, 1H), 3.16 (s, 1H), 2.94 (s, 2H), 2.80-2.71 (m, 1H), 2.55-2.45 (m, 1H), 2.21-2.15 (m, 3H), 2.10 (s, 1H), 1.89-1.71 (m, 1H)。 實例47. N-乙基-4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基苯甲醯胺之合成 步驟1. 4-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-N-乙基-3-甲氧基苯甲醯胺之合成 To a stirred solution of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N,N-dimethylbenzamide (100.0 mg, 0.20 mmol, 1 eq) in THF (10 mL) were added (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (51.9 mg, 0.39 mmol, 2 eq), t-BuONa (113.2 mg, 1.18 mmol, 6 eq) and tBuXPhosPdG3 (62.4 mg, 0.08 mmol, 0.40 eq) portionwise at room temperature. The resulting mixture was stirred at 65 °C under nitrogen atmosphere for 30 min. After removing the solvent, the residue was purified by PTLC (CH 2 Cl 2 / MeOH 20:1) to obtain a crude material, and then purified by preparative HPLC with the following conditions: column: XBridge Prep OBD C18 column, 19*250 mm, 5μm; mobile phase A: water (10mmol/L NH 4 HCO 3 + 0.05% NH 3 H 2 O), mobile phase B: MeOH; flow rate: 25 mL/min mL/min; gradient: 49% B to 72% B in 10min; wavelength: 254nm/220nm nm; RT1(min): 9.43; number of runs: 3. This resulted in 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N,N-dimethylbenzamide (8.30 mg, 7.54%) as a white solid. LC-MS: (M+H) + found 561.35. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.81 (s, 1H), 6.95-6.89 (m, 2H), 6.87-6.81 (m, 1H), 6.79-6.72 (m, 1H), 6.45-6.35 (m, 1H), 5.85 (s, 1H), 4.81 (d, J = 8.4 Hz, 1H), 4.35 (s, 2H), 4.15-3.92 (m, 2H), 3.83 (s, 3H), 3.79 (d, 1H), 3.16 (s, 1H), 2.94 (s, 2H), 2.80-2.71 (m, 1H), 2.55-2.45 (m, 1H), 2.21-2.15 (m, 3H), 2.10 (s, 1H), 1.89-1.71 (m, 1H). Example 47. Synthesis of N-ethyl-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxybenzamide Step 1. Synthesis of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-N-ethyl-3-methoxybenzamide
向8-溴-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶( 中間物1;200.0 mg,0.49 mmol,1當量)於DMSO (5 mL)中之溶液中添加N-乙基-3-甲氧基-4-(丙-2-炔-1-基胺基)苯甲醯胺( 中間物16;229.4 mg,0.98 mmol,2當量)、i-Pr 2NH (499.8 mg,4.94 mmol,10當量)、Pd(PPh 3) 4(114.1 mg,0.10 mmol,0.20當量)及CuI (47.0 mg,0.25 mmol,0.50當量)。將反應混合物在30℃及氮氣氛圍下攪拌1h。所得溶液使用具有以下條件(移動相A:水,移動相B:ACN;流動速率:80 mL/min;梯度:在30 min內0% B至100% B;254/220 nm)之C18急速層析純化。此產生呈淺黃色固體之4-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-N-乙基-3-甲氧基苯甲醯胺(250.0 mg,99.4%)。LC-MS:(M+H) +實測值509.1。 步驟2. N-乙基-4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基苯甲醯胺之合成 To a solution of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( Intermediate 1 ; 200.0 mg, 0.49 mmol, 1 eq) in DMSO (5 mL) were added N-ethyl-3-methoxy-4-(prop-2-yn-1-ylamino)benzamide ( Intermediate 16 ; 229.4 mg, 0.98 mmol, 2 eq), i-Pr 2 NH (499.8 mg, 4.94 mmol, 10 eq), Pd(PPh 3 ) 4 (114.1 mg, 0.10 mmol, 0.20 eq) and CuI (47.0 mg, 0.25 mmol, 0.50 eq). The reaction mixture was stirred at 30° C. under nitrogen atmosphere for 1 h. The resulting solution was purified by C18 flash chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 80 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm). This produced 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-N-ethyl-3-methoxybenzamide (250.0 mg, 99.4%) as a light yellow solid. LC-MS: (M+H) + found 509.1. Step 2. Synthesis of N-ethyl-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxybenzamide
向4-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-N-乙基-3-甲氧基苯甲醯胺(200.0 mg,0.39 mmol,1當量)於THF (10 mL)中之溶液中添加(3S,4R)-3-氟-1-甲基哌啶-4-胺(103.8 mg,0.79 mmol,2當量)、t-BuONa (226.4 mg,2.36 mmole,6當量)及tBuXPhosPdG3 (124.8 mg,0.16 mmol,0.40當量)。將反應混合物在65℃及氮氣氛圍下攪拌30min。將所得混合物在減壓下濃縮。殘餘物使用具有以下條件(移動相A:水,移動相B:ACN;流動速率:80 mL/min;梯度:在30 min內0% B至100% B;254/220 nm)之C18急速層析純化。粗物質使用具有以下條件之製備型HPLC純化:XBridge Prep OBD C18管柱,19*250 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3+0.05%NH 3H 2O),移動相B:MeOH;流動速率:25 mL/min mL/min;梯度:在11min內45% B至67% B;波長:254nm/220nm nm;RT1(min):10.07。此產生呈棕色固體之N-乙基-4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基苯甲醯胺(6.50 mg,2.8%)。LC-MS:(M+H) +實測值561.20。 1H NMR (400 MHz, 氯仿- d) δ 7.38 (d, J= 1.9 Hz, 1H), 7.33 (d, J= 6.8 Hz, 1H), 7.22 (dd, J= 8.2, 1.9 Hz, 1H), 6.78-6.69 (m, 2H), 6.13 (d, J= 7.5 Hz, 1H), 5.99 (s, 1H), 5.45 (d, J= 9.2 Hz, 1H), 4.91 (s, 1H), 4.79 (s, 1H), 4.30 (s, 2H), 3.91 (s, 3H), 3.63 (m, 2H), 3.48 (m, 3H), 3.20 (d, J= 10.8 Hz, 1H), 2.94 (d, J= 11.5 Hz, 1H), 2.35 (s, 3H), 2.27-2.13 (m, 2H), 1.98 (m, 2H), 1.34-1.13 (t, J= 7.3 Hz, 3H)。 實例48. 4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-N-異丙基-3-甲氧基苯甲醯胺 之合成 步驟1. 4-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-N-異丙基-3-甲氧基苯甲醯胺之合成 To a solution of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-N-ethyl-3-methoxybenzamide (200.0 mg, 0.39 mmol, 1 eq) in THF (10 mL) were added (3S,4R)-3-fluoro-1-methylpiperidin-4-amine (103.8 mg, 0.79 mmol, 2 eq), t-BuONa (226.4 mg, 2.36 mmole, 6 eq) and tBuXPhosPdG3 (124.8 mg, 0.16 mmol, 0.40 eq). The reaction mixture was stirred at 65 °C under nitrogen atmosphere for 30 min. The resulting mixture was concentrated under reduced pressure. The residue was purified by C18 flash chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 80 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm). The crude material was purified by preparative HPLC with the following conditions: XBridge Prep OBD C18 column, 19*250 mm, 5μm ; mobile phase A: water (10mmol/L NH4HCO3 + 0.05 % NH3H2O ), mobile phase B: MeOH; flow rate: 25 mL/min mL/min; gradient: 45% B to 67% B in 11min; wavelength: 254nm/220nm nm; RT1(min): 10.07. This resulted in N-ethyl-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxybenzamide (6.50 mg, 2.8%) as a brown solid. LC-MS: (M+H) + found 561.20. 1 H NMR (400 MHz, CHLOROFORM- d ) δ 7.38 (d, J = 1.9 Hz, 1H), 7.33 (d, J = 6.8 Hz, 1H), 7.22 (dd, J = 8.2, 1.9 Hz, 1H), 6.78-6.69 (m, 2H), 6.13 (d, J = 7.5 Hz, 1H), 5.99 (s, 1H), 5.45 (d, J = 9.2 Hz, 1H), 4.91 (s, 1H), 4.79 (s, 1H), 4.30 (s, 2H), 3.91 (s, 3H), 3.63 (m, 2H), 3.48 (m, 3H), 3.20 (d, J = 10.8 Hz, 1H), 2.94 (d, J = 11.5 Hz, 1H), 2.35 (s, 3H), 2.27-2.13 (m, 2H), 1.98 (m, 2H), 1.34-1.13 (t, J = 7.3 Hz, 3H). Example 48. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-isopropyl-3-methoxybenzamide Step 1. Synthesis of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-N-isopropyl-3-methoxybenzamide
在室溫下,向8-溴-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶( 中間物1;438.4 mg,1.08 mmol,1當量)於DMSO (5 mL)中之攪拌混合物中添加N-異丙基-3-甲氧基-4-(丙-2-炔-1-基胺基)苯甲醯胺( 中間物16;293.3 mg,1.19 mmol,1.10當量)、CuI (103.1 mg,0.54 mmol,0.50當量)、i-Pr 2NH (75.0 mg,0.74 mmol,10當量)及Pd(PPh 3) 4(17.1 mg,0.02 mmol,0.20當量)。將所得混合物在30℃及氮氣氛圍下攪拌1h,然後藉由具有以下條件之反相急速層析純化:管柱,C18;移動相,於水中之MeCN,在20 min內0%至50%梯度;偵測器,UV 254 nm。此產生呈淺黃色固體之4-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-N-異丙基-3-甲氧基苯甲醯胺(240.0 mg,42.36%)。LC-MS:(M+H) +實測值523.4。 步驟2. 4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-N-異丙基-3-甲氧基苯甲醯胺之合成 To a stirred mixture of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( Intermediate 1 ; 438.4 mg, 1.08 mmol, 1 eq) in DMSO (5 mL) at room temperature were added N-isopropyl-3-methoxy-4-(prop-2-yn-1-ylamino)benzamide ( Intermediate 16 ; 293.3 mg, 1.19 mmol, 1.10 eq), CuI (103.1 mg, 0.54 mmol, 0.50 eq), i- Pr2NH (75.0 mg, 0.74 mmol, 10 eq) and Pd( PPh3 ) 4 (17.1 mg, 0.02 mmol, 0.20 eq). The resulting mixture was stirred at 30 °C under nitrogen atmosphere for 1 h and then purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in water, gradient 0% to 50% in 20 min; detector, UV 254 nm. This produced 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-N-isopropyl-3-methoxybenzamide (240.0 mg, 42.36%) as a light yellow solid. LC-MS: (M+H) + found 523.4. Step 2. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-isopropyl-3-methoxybenzamide
向4-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-N-異丙基-3-甲氧基苯甲醯胺(180.0 mg,0.34 mmol,1當量)於THF (5 mL)中之溶液中添加(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(141.1 mg,0.69 mmol,2當量)、t-BuXPhosPdG3 (43.7 mg,0.06 mmol,0.16當量)及t-BuONa (264.4 mg,2.75 mmol,8當量)。將反應混合物在65℃及氮氣氛圍下攪拌30 min。移除溶劑之後,殘餘物藉由具有以下條件之反相急速層析純化:管柱,C18;移動相,於水中之MeCN (0.1% FA),在20 min內0%至30%梯度;偵測器,UV 254 nm。粗產物藉由具有以下條件(管柱:XBridge Prep OBD C18管柱,19*250 mm,5 μm;移動相A:水(10mmol/L NH 4HCO 3+0.05%NH 3 .H 2O),移動相B:MEOH;流動速率:25 mL/min mL/min;梯度:在10min內52% B至72% B;波長:254nm/220nm nm;RT (min):9.65)之製備型HPLC純化,以得到呈白色固體之4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-N-異丙基-3-甲氧基苯甲醯胺(10.5 mg,5.08%)。LC-MS:(M+H) +實測值575.20。 1H NMR (400 MHz, DMSO- d 6) δ 7.80 (dd, J= 15.8, 7.3 Hz, 2H), 7.47-7.32 (m, 2H), 6.85-6.70 (m, 2H), 6.38 (d, J= 7.5 Hz, 1H), 5.91 (t, J= 6.4 Hz, 1H), 5.36 (d, J= 9.2 Hz, 1H), 4.81 (d, J= 49.5 Hz, 1H), 4.27 (d, J= 6.4 Hz, 2H), 4.14-3.96 (m, 3H), 3.85 (s, 3H), 3.77-3.63 (m, 1H), 3.02 (t, J= 11.4 Hz, 1H), 2.76 (d, J= 11.2 Hz, 1H), 2.42-1.99 (m, 5H), 1.89-1.75 (m, 2H), 1.15 (d, J= 6.7 Hz, 6H)。 實例49. N-環丙基-4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基苯甲醯胺之合成 步驟1. 4-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-N-環丙基-3-甲氧基苯甲醯胺之合成 To a solution of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-N-isopropyl-3-methoxybenzamide (180.0 mg, 0.34 mmol, 1 eq) in THF (5 mL) were added (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (141.1 mg, 0.69 mmol, 2 eq), t-BuXPhosPdG3 (43.7 mg, 0.06 mmol, 0.16 eq) and t-BuONa (264.4 mg, 2.75 mmol, 8 eq). The reaction mixture was stirred at 65 °C under nitrogen atmosphere for 30 min. After removal of the solvent, the residue was purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN (0.1% FA) in water, gradient from 0% to 30% in 20 min; detector, UV 254 nm. The crude product was purified by reverse phase flash chromatography with the following conditions (column: XBridge Prep OBD C18 column, 19*250 mm, 5 μm; mobile phase A: water (10mmol/L NH 4 HCO 3 +0.05%NH 3 . H 2 O), mobile phase B: MEOH; flow rate: 25 mL/min mL/min; gradient: 52% B to 72% B in 10 min; wavelength: 254nm/220nm nm; RT (min): 9.65) was purified by preparative HPLC to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-isopropyl-3-methoxybenzamide (10.5 mg, 5.08%) as a white solid. LC-MS: (M+H) + found 575.20. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.80 (dd, J = 15.8, 7.3 Hz, 2H), 7.47-7.32 (m, 2H), 6.85-6.70 (m, 2H), 6.38 (d, J = 7.5 Hz, 1H), 5.91 (t, J = 6.4 Hz, 1H), 5.36 (d, J = 9.2 Hz, 1H), 4.81 (d, J = 49.5 Hz, 1H), 4.27 (d, J = 6.4 Hz, 2H), 4.14-3.96 (m, 3H), 3.85 (s, 3H), 3.77-3.63 (m, 1H), 3.02 (t, J = 11.4 Hz, 1H), 2.76 (d, J = 11.2 Hz, 1H), 2.42-1.99 (m, 5H), 1.89-1.75 (m, 2H), 1.15 (d, J = 6.7 Hz, 6H). Example 49. Synthesis of N-cyclopropyl-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxybenzamide Step 1. Synthesis of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-N-cyclopropyl-3-methoxybenzamide
在室溫及氮氣氛圍下,向8-溴-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶( 中間物1;200.0 mg,0.49 mmol,1當量)於DMSO (10 mL)中之攪拌混合物中添加N-環丙基-3-甲氧基-4-(丙-2-炔-1-基胺基)苯甲醯胺( 中間物18;241.3 mg,0.99 mmol,2當量)、iPr 2NH (499.8 mg,4.94 mmol,10當量)、Pd(PPh 3) 4(114.1 mg,0.10 mmol,0.20當量)及CuI (47.0 mg,0.25 mmol,0.50當量)。將所得混合物在30℃及氮氣氛圍下攪拌1 h,然後使用具有以下條件(移動相A:水,移動相B:ACN;流動速率:80 mL/min;梯度:在20 min內0% B至50% B;254/220 nm)之C18急速層析純化。此產生呈黃色固體之4-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-N-環丙基-3-甲氧基苯甲醯胺(215.0 mg,83.5%)。LC-MS:(M+H) +實測值522.9。 步驟2. N-環丙基-4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基苯甲醯胺之合成 To a stirred mixture of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( Intermediate 1 ; 200.0 mg, 0.49 mmol, 1 eq) in DMSO (10 mL) were added N-cyclopropyl-3-methoxy-4-(prop-2-yn-1-ylamino)benzamide ( Intermediate 18 ; 241.3 mg, 0.99 mmol, 2 eq), iPr2NH (499.8 mg, 4.94 mmol, 10 eq), Pd( PPh3 ) 4 (114.1 mg, 0.10 mmol, 0.20 eq) and CuI (47.0 mg, 0.25 mmol, 0.50 eq) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 30° C. under nitrogen atmosphere for 1 h and then purified using C18 flash chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 80 mL/min; gradient: 0% B to 50% B in 20 min; 254/220 nm). This produced 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-N-cyclopropyl-3-methoxybenzamide (215.0 mg, 83.5%) as a yellow solid. LC-MS: (M+H) + found 522.9. Step 2. Synthesis of N-cyclopropyl-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxybenzamide
在室溫及氮氣氛圍下,向4-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-N-環丙基-3-甲氧基苯甲醯胺(185.0 mg,0.36 mmol,1當量)於THF (10 mL) 中之攪拌溶液中添加(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(93.8 mg,0.71 mmol,2當量)、t-BuONa (204.6 mg,2.13 mmol,6當量)及tBuXPhosPdG3 (112.8 mg,0.14 mmol,0.40當量)。將所得混合物在65℃及氮氣氛圍下攪拌30 min,然後冷卻至室溫且在減壓下濃縮。殘餘物使用具有以下條件(移動相A:水(0.1% TFA),移動相B:ACN;流動速率:80 mL/min;梯度:在20 min內0% B至50% B;254/220 nm)之C18急速層析純化。粗物質使用具有以下條件(管柱,Xbridge BEH Shield RP18 5μm,19*250mm;移動相A:水(10mmol/L NH 4HCO 3+0.05%NH 3H 2O),移動相B:MeOH;流動速率:25 mL/min mL/min;梯度:在11min內67% B至75% B;波長:254nm/220nm nm;RT1(min):10.58)之製備型HPLC純化。此產生呈白色固體之N-環丙基-4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基苯甲醯胺(16.2 mg,7.9%)。LC-MS:(M+H) +實測值573.20。 1H NMR (400 MHz, 氯仿- d) δ 7.38-7.29 (m, 2H), 7.17 (dd, J= 8.2, 1.9 Hz, 1H), 6.78-6.67 (m, 2H), 6.18-6.09 (m, 2H), 5.45 (d, J= 9.2 Hz, 1H), 5.00-4.65 (m, 2H), 4.29 (d, J= 5.4 Hz, 2H), 3.90 (s, 3H), 3.70-3.45 (m, 3H), 3.30-3.15 (m, 1H), 2.97-2.83 (m, 2H), 2.40-2.13 (m, 5H), 2.09-1.98 (m, 2H), 0.84 (td, J= 7.0, 5.2 Hz, 2H), 0.64-0.55 (m, 2H)。 實例50. (3S,4R)-3-氟-N-[2-(3-{[2-甲氧基-4-(吡咯啶-1-羰基)苯基]胺基}丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基]-1-甲基哌啶-4-胺之合成 步驟1. N-{3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}-2-甲氧基-4-(吡咯啶-1-羰基)苯胺之合成 To a stirred solution of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-N-cyclopropyl-3-methoxybenzamide (185.0 mg, 0.36 mmol, 1 eq) in THF (10 mL) were added (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (93.8 mg, 0.71 mmol, 2 eq), t-BuONa (204.6 mg, 2.13 mmol, 6 eq) and tBuXPhosPdG3 (112.8 mg, 0.14 mmol, 0.40 eq) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 65°C under nitrogen atmosphere for 30 min, then cooled to room temperature and concentrated under reduced pressure. The residue was purified by C18 flash chromatography with the following conditions (mobile phase A: water (0.1% TFA), mobile phase B: ACN; flow rate: 80 mL/min; gradient: 0% B to 50% B in 20 min; 254/220 nm). The crude material was purified using preparative HPLC with the following conditions (column, Xbridge BEH Shield RP18 5 μm, 19*250 mm; mobile phase A: water (10 mmol/L NH 4 HCO 3 +0.05% NH 3 H 2 O), mobile phase B: MeOH; flow rate: 25 mL/min mL/min; gradient: 67% B to 75% B in 11 min; wavelength: 254 nm/220 nm nm; RT1(min): 10.58). This resulted in N-cyclopropyl-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxybenzamide (16.2 mg, 7.9%) as a white solid. LC-MS: (M+H) + found 573.20. 1 H NMR (400 MHz, CHLOROFORM- d ) δ 7.38-7.29 (m, 2H), 7.17 (dd, J = 8.2, 1.9 Hz, 1H), 6.78-6.67 (m, 2H), 6.18-6.09 (m, 2H), 5.45 (d, J = 9.2 Hz, 1H), 5.00-4.65 (m, 2H), 4.29 (d, J = 5.4 Hz, 2H), 3.90 (s, 3H), 3.70-3.45 (m, 3H), 3.30-3.15 (m, 1H), 2.97-2.83 (m, 2H), 2.40-2.13 (m, 5H), 2.09-1.98 (m, 2H), 0.84 (td, J = 7.0, 5.2 Hz, 2H), 0.64-0.55 (m, 2H). Example 50. Synthesis of (3S,4R)-3-fluoro-N-[2-(3-{[2-methoxy-4-(pyrrolidine-1-carbonyl)phenyl]amino}prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]-1-methylpiperidin-4-amine Step 1. Synthesis of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-2-methoxy-4-(pyrrolidine-1-carbonyl)aniline
向2-甲氧基-N-(丙-2-炔-1-基)-4-(吡咯啶-1-羰基)苯胺( 中間物19;800.0 mg,3.10 mmol,1當量)於DMSO (15 mL)中之攪拌溶液中添加8-溴-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶( 中間物1;627.1 mg,1.55 mmol,0.5當量)、i-Pr 2NH (1.57 g,15.49 mmol,5當量)、CuI (147.5 mg,0.77 mmol,0.25當量)及Pd(PPh 3) 4(715.8 mg,0.62 mmol,0.2當量)。將反應混合物在30℃下攪拌1 h,然後使用具有以下條件(移動相A:水,移動相B:ACN;流動速率:60 mL/min;梯度:在30 min內0% B至100% B;254/220 nm)之C18層析純化,以得到呈黃色油狀物之N-{3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}-2-甲氧基-4-(吡咯啶-1-羰基)苯胺(700.0 mg,42.2%)。LC-MS:(M+H) +實測值535.1。 步驟2. (3S,4R)-3-氟-N-[2-(3-{[2-甲氧基-4-(吡咯啶-1-羰基)苯基]胺基}丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基]-1-甲基哌啶-4-胺之合成 To a stirred solution of 2-methoxy-N-(prop-2-yn-1-yl)-4-(pyrrolidine-1-carbonyl)aniline ( Intermediate 19 ; 800.0 mg, 3.10 mmol, 1 eq) in DMSO (15 mL) were added 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( Intermediate 1 ; 627.1 mg, 1.55 mmol, 0.5 eq), i- Pr2NH (1.57 g, 15.49 mmol, 5 eq), CuI (147.5 mg, 0.77 mmol, 0.25 eq) and Pd( PPh3 ) 4 (715.8 mg, 0.62 mmol, 0.2 eq). The reaction mixture was stirred at 30° C. for 1 h and then purified using C18 chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm) to give N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-2-methoxy-4-(pyrrolidine-1-carbonyl)aniline (700.0 mg, 42.2%) as a yellow oil. LC-MS: (M+H) + found 535.1. Step 2. Synthesis of (3S,4R)-3-fluoro-N-[2-(3-{[2-methoxy-4-(pyrrolidine-1-carbonyl)phenyl]amino}prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]-1-methylpiperidin-4-amine
向N-{3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}-2-甲氧基-4-(吡咯啶-1-羰基)苯胺(100 mg,0.18 mmol,1當量)於THF (3 mL)中之攪拌溶液中添加(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(77.8 mg,0.37 mmol,2當量)、t-BuONa (107.7 mg,1.122mmol,6當量)及tBuXPhosPdG3 (59.4 mg,0.08 mmol,0.4當量)。將反應混合物在65℃及氮氣氛圍下攪拌1 h。移除溶劑之後,殘餘物使用具有以下條件(移動相A:水,移動相B:ACN;流動速率:60 mL/min;梯度:在30 min內0% B至100% B;254/220 nm)之C18急速層析純化。粗物質使用具有以下條件(管柱:XBridge Prep OBD C18管柱,19*250 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3+ 0.05% NH 3H 2O),移動相B:MeOH;流動速率:25 mL/min mL/min;梯度:在10min內55% B至72% B;波長:254nm/220nm nm;RT1(min):9.38;運行次數:5)之製備型HPLC純化,以得到呈白色固體之(3S,4R)-3-氟-N-[2-(3-{[2-甲氧基-4-(吡咯啶-1-羰基)苯基]胺基}丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基]-1-甲基哌啶-4-胺(10.5 mg,9.46%)。LC-MS:(M+H) +實測值587.30。 1H NMR (400 MHz, DMSO- d 6) δ 7.79 (d, J= 6.8 Hz, 1H), 7.10 (dd, J= 8.1, 1.8 Hz, 1H), 7.04 (d, J= 1.8 Hz, 1H), 6.83 (t, J= 7.2 Hz, 1H), 6.73 (d, J= 8.2 Hz, 1H), 6.39 (d, J= 7.6 Hz, 1H), 5.91 (t, J= 6.3 Hz, 1H), 5.38 (d, J= 9.2 Hz, 1H), 4.82 (d, J= 49.6 Hz, 1H), 4.26 (d, J= 6.3 Hz, 2H), 4.03 (m, 2H), 3.82 (s, 3H), 3.66 (t, J= 8.2 Hz, 1H), 3.61-3.38 (m, 4H), 3.03 (t, J= 11.4 Hz, 1H), 2.76 (d, J= 11.3 Hz, 1H), 2.40-1.98 (m, 5H), 2.00-1.57 (m, 6H)。 實例51. 4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(1,1,2,2,2-五氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺之合成 步驟1. 4-(氮雜環丁烷-1-羰基)-N-{3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}-2-甲氧基苯胺之合成 To a stirred solution of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-2-methoxy-4-(pyrrolidine-1-carbonyl)aniline (100 mg, 0.18 mmol, 1 eq) in THF (3 mL) were added (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (77.8 mg, 0.37 mmol, 2 eq), t-BuONa (107.7 mg, 1.122 mmol, 6 eq) and tBuXPhosPdG3 (59.4 mg, 0.08 mmol, 0.4 eq). The reaction mixture was stirred at 65 °C under nitrogen atmosphere for 1 h. After removing the solvent, the residue was purified by C18 flash chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm ). The crude material was purified by C18 flash chromatography with the following conditions (column: XBridge Prep OBD C18 column, 19*250 mm, 5μm; mobile phase A: water (10mmol/L NH4HCO3 + 0.05% NH3H2O ), mobile phase B: MeOH; flow rate: 25 mL/min mL/min ; gradient: 55% B to 72% B in 10 min; wavelength: 254nm/220nm nm; RT1(min): 9.38; runs: 5) to give (3S,4R)-3-fluoro-N-[2-(3-{[2-methoxy-4-(pyrrolidine-1-carbonyl)phenyl]amino}prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]-1-methylpiperidin-4-amine (10.5 mg, 9.46%) as a white solid. LC-MS: (M+H) + found 587.30. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.79 (d, J = 6.8 Hz, 1H), 7.10 (dd, J = 8.1, 1.8 Hz, 1H), 7.04 (d, J = 1.8 Hz, 1H), 6.83 (t, J = 7.2 Hz, 1H), 6.73 (d, J = 8.2 Hz, 1H), 6.39 (d, J = 7.6 Hz, 1H), 5.91 (t, J = 6.3 Hz, 1H), 5.38 (d, J = 9.2 Hz, 1H), 4.82 (d, J = 49.6 Hz, 1H), 4.26 (d, J = 6.3 Hz, 2H), 4.03 (m, 2H), 3.82 (s, 3H), 3.66 (t, J = 8.2 Hz, 1H), 3.61-3.38 (m, 4H), 3.03 (t, J = 11.4 Hz, 1H), 2.76 (d, J = 11.3 Hz, 1H), 2.40-1.98 (m, 5H), 2.00-1.57 (m, 6H). Example 51. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide Step 1. Synthesis of 4-(Azocyclobutane-1-carbonyl)-N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-2-methoxyaniline
將8-溴-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶( 中間物1;200.0 mg,0.50 mmol,1當量)於DMSO (5 mL)中之溶液用4-(氮雜環丁烷-1-羰基)-2-甲氧基-N-(丙-2-炔-1-基)苯基( 中間物20;132.7 mg,0.54 mmol,1.10當量)、Pd(PPh 3) 4(114.1 mg,0.10 mmol,0.20當量)、CuI (38.1 mg,0.20 mmol,0.40當量)及i-Pr 2NH (499.8 mg,4.95 mmol,10當量)處理。將所得混合物在30℃及N 2氛圍下攪拌1h,然後使用具有以下條件之C18急速層析純化:移動相A:水,移動相B:ACN;流動速率:60 mL/min;梯度:在15 min內0% B至100% B;波長:254 nm;220 nm。此產生呈淺黃色固體之4-(氮雜環丁烷-1-羰基)-N-{3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}-2-甲氧基苯胺(340.0 mg,69.0%)。LC-MS:(M+H) +實測值521.1。 步驟2. 4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(1,1,2,2,2-五氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺之合成 A solution of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( Intermediate 1 ; 200.0 mg, 0.50 mmol, 1 equiv) in DMSO (5 mL) was treated with 4-(azacyclobutane-1-carbonyl)-2-methoxy-N-(prop-2-yn-1-yl)phenyl ( Intermediate 20 ; 132.7 mg, 0.54 mmol, 1.10 equiv), Pd( PPh3 ) 4 (114.1 mg, 0.10 mmol, 0.20 equiv), CuI (38.1 mg, 0.20 mmol, 0.40 equiv) and i- Pr2NH (499.8 mg, 4.95 mmol, 10 equiv). The resulting mixture was stirred at 30 °C under N2 atmosphere for 1 h and then purified using C18 flash chromatography with the following conditions: mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 15 min; wavelength: 254 nm; 220 nm. This produced 4-(azacyclobutane-1-carbonyl)-N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-2-methoxyaniline (340.0 mg, 69.0%) as a light yellow solid. LC-MS: (M+H) + found 521.1. Step 2. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide
將4-{4-[4-溴-1-(1,1,2,2,2-五氟乙基)-7aH-茚-2-基]丁-3-炔-1-基}-3-甲氧基-N-甲基苯甲醯胺(100.0 mg,0.20 mmol,1當量)於THF (3 mL)中之溶液用(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(77.6 mg,0.37 mmol,2當量)、t-BuONa (109.1 mg,1.13 mmol,6當量)及t-BuXPhosPdG3 (60.1 mg,0.07 mmol,0.40當量)處理。將所得混合物在65℃及氮氣氛圍下攪拌30 min。將所得混合物在減壓下濃縮。殘餘物使用具有以下條件之C18急速層析純化:移動相A:水(0.1% FA),移動相B:ACN;流動速率:60 mL/min;梯度:在30 min內0% B至100% B;254/220 nm。粗產物使用具有以下條件之製備型HPLC純化:管柱:XBridge Prep OBD C18管柱,19*250 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3+ 0.05% NH 3H 2O),移動相B:MeOH;流動速率:25 mL/min mL/min;梯度:在10min內54% B至68% B;波長:254nm/220nm nm;RT1(min):9.42;運行次數:6。此產生呈淺黃色固體之4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(1,1,2,2,2-五氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺(11.5 mg,10.43%)。LC-MS:(M+H) +實測值573.35。 1H NMR (400 MHz, DMSO- d 6) δ 7.79 (d, J= 6.8 Hz, 1H), 7.16 (dd, J= 8.2, 1.8 Hz, 1H), 7.11 (d, J= 1.8 Hz, 1H), 6.83 (t, J= 7.2 Hz, 1H), 6.74 (d, J= 8.3 Hz, 1H), 6.39 (d, J= 7.5 Hz, 1H), 6.05 (t, J= 6.3 Hz, 1H), 5.38 (d, J= 9.2 Hz, 1H), 4.83 (d, 1H), 4.52-4.19 (m, 4H), 4.02 (m, 4H), 3.83 (s, 3H), 3.77-3.63 (m, 1H), 3.03 (t, J= 11.3 Hz, 1H), 2.76 (d, J= 11.4 Hz, 1H), 2.32-2.18 (m, 3H), 2.19 (s, 3H), 2.09 (s, 1H), 1.88-1.75 (m, 2H)。 實例52. 5-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-N-甲基吡啶-2-甲醯胺之合成 步驟1. 5-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-N-甲基吡啶-2-甲醯胺之合成 A solution of 4-{4-[4-bromo-1-(1,1,2,2,2-pentafluoroethyl)-7aH-inden-2-yl]but-3-yn-1-yl}-3-methoxy-N-methylbenzamide (100.0 mg, 0.20 mmol, 1 eq) in THF (3 mL) was treated with (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (77.6 mg, 0.37 mmol, 2 eq), t-BuONa (109.1 mg, 1.13 mmol, 6 eq) and t-BuXPhosPdG3 (60.1 mg, 0.07 mmol, 0.40 eq). The resulting mixture was stirred at 65 °C under nitrogen atmosphere for 30 min. The resulting mixture was concentrated under reduced pressure. The residue was purified by C18 flash chromatography with the following conditions: mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm. The crude product was purified by preparative HPLC with the following conditions: column: XBridge Prep OBD C18 column, 19*250 mm, 5μm; mobile phase A: water (10mmol/L NH 4 HCO 3 + 0.05% NH 3 H 2 O), mobile phase B: MeOH; flow rate: 25 mL/min mL/min; gradient: 54% B to 68% B in 10 min; wavelength: 254nm/220nm nm; RT1(min): 9.42; number of runs: 6. This resulted in 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(1,1,2,2,2-pentafluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (11.5 mg, 10.43%) as a light yellow solid. LC-MS: (M+H) + found 573.35. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.79 (d, J = 6.8 Hz, 1H), 7.16 (dd, J = 8.2, 1.8 Hz, 1H), 7.11 (d, J = 1.8 Hz, 1H), 6.83 (t, J = 7.2 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.39 (d, J = 7.5 Hz, 1H), 6.05 (t, J = 6.3 Hz, 1H), 5.38 (d, J = 9.2 Hz, 1H), 4.83 (d, 1H), 4.52-4.19 (m, 4H), 4.02 (m, 4H), 3.83 (s, 3H), 3.77-3.63 (m, 1H), 3.03 (t, J = 11.3 Hz, 1H), 2.76 (d, J = 11.4 Hz, 1H), 2.32-2.18 (m, 3H), 2.19 (s, 3H), 2.09 (s, 1H), 1.88-1.75 (m, 2H). Example 52. Synthesis of 5-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylpyridine-2-carboxamide Step 1. Synthesis of 5-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-N-methylpyridine-2-carboxamide
將8-溴-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶( 中間物1;300 mg,0.74 mmol,1當量)、N-甲基-5-(丙-2-炔-1-基胺基)吡啶-2-甲醯胺( 中間物21;168.2 mg,0.89 mmol,1.2當量)、CuI (141.1 mg,0.74 mmol,1當量)、i-Pr 2NH (749.7 mg,7.40 mmol,10當量)及Pd(PPh 3) 4(171.2 mg,0.15 mmol,0.2當量)於DMSO (3 mL)中之溶液在室溫及氮氣氛圍下攪拌1 h。反應用EA (50 mL)稀釋且用鹽水(3*50 mL)洗滌。有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/於MeOH中之7M NH 3= 20:1)純化,以得到呈淺棕色固體之5-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-N-甲基吡啶-2-甲醯胺(212 mg,61.38%)。LC-MS:(M+H) +實測值466.0。 步驟2. 5-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-N-甲基吡啶-2-甲醯胺之合成 A solution of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( Intermediate 1 ; 300 mg, 0.74 mmol, 1 eq), N-methyl-5-(prop-2-yn-1-ylamino)pyridine-2-carboxamide ( Intermediate 21 ; 168.2 mg, 0.89 mmol, 1.2 eq), CuI (141.1 mg, 0.74 mmol, 1 eq), i-Pr 2 NH (749.7 mg, 7.40 mmol, 10 eq) and Pd(PPh 3 ) 4 (171.2 mg, 0.15 mmol, 0.2 eq) in DMSO (3 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The reaction was diluted with EA (50 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 /7M NH 3 in MeOH = 20:1) to give 5-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-N-methylpyridine-2-carboxamide (212 mg, 61.38%) as a light brown solid. LC-MS: (M+H) + found 466.0. Step 2. Synthesis of 5-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylpyridine-2-carboxamide
將5-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-N-甲基吡啶-2-甲醯胺(200 mg,0.43 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(176.0 mg,0.86 mmol,2當量)、t-BuONa (206.1 mg,2.15 mmol,5當量)及tBuXPhos Pd G3 (102.2 mg,0.13 mmol,0.3當量)於THF (2 mL)中之溶液在65℃及氮氣氛圍下攪拌1 h。過濾所得混合物且濾餅用DCM洗滌。將濾液在減壓下濃縮。殘餘物藉由具有以下條件(管柱:XBridge Prep OBD C18管柱,19*250 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3+0.05%NH 3H 2O),移動相B:ACN(1% 2mM NH 3-MeOH);流動速率:25 mL/min mL/min;梯度:在10min內45% B至64% B;波長:254nm/220nm nm;RT1(min):9.27;運行次數:3)之製備型HPLC純化,以得到呈白色固體之5-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-N-甲基吡啶-2-甲醯胺(10.1 mg,4.50%)。LC-MS:(M+H) +實測值518.15。 1H NMR (400 MHz, DMSO- d 6) δ 8.35 (q, J= 4.8 Hz, 1H), 8.06 (d, J= 2.7 Hz, 1H), 7.80 (t, J= 7.7 Hz, 2H), 7.17 (dd, J= 8.6, 2.8 Hz, 1H), 6.98 (t, J= 6.1 Hz, 1H), 6.83 (t, J= 7.2 Hz, 1H), 6.40 (d, J= 7.5 Hz, 1H), 5.37 (d, J= 9.2 Hz, 1H), 4.82 (d, J= 49.4 Hz, 1H), 4.31 (d, J= 6.1 Hz, 2H), 4.04 (q, J= 10.7 Hz, 2H), 3.78 – 3.62 (m, 1H), 3.03 (t, J= 11.5 Hz, 1H), 2.77 (d, J= 4.8 Hz, 4H), 2.29 (d, J= 13.0 Hz, 1H), 2.19 (s, 3H), 2.14 – 2.04 (m, 1H), 1.87 – 1.74 (m, 2H)。 實例53. 4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-N-甲基-3-(三氟甲氧基)苯甲醯胺之合成 步驟1. 4-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-N-甲基-3-(三氟甲氧基)苯甲醯胺之合成 A solution of 5-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-N-methylpyridine-2-carboxamide (200 mg, 0.43 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (176.0 mg, 0.86 mmol, 2 eq), t-BuONa (206.1 mg, 2.15 mmol, 5 eq) and tBuXPhos Pd G3 (102.2 mg, 0.13 mmol, 0.3 eq) in THF (2 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was filtered and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by HPLC with the following conditions (column: XBridge Prep OBD C18 column, 19*250 mm, 5μm; mobile phase A: water (10mmol/L NH 4 HCO 3 +0.05% NH 3 H 2 O), mobile phase B: ACN (1% 2mM NH 3 -MeOH); flow rate: 25 mL/min mL/min; gradient: 45% B to 64% B in 10min; wavelength: 254nm/220nm nm; RT1(min): 9.27; Runs: 3) to give 5-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylpyridine-2-carboxamide (10.1 mg, 4.50%) as a white solid. LC-MS: (M+H) + found 518.15. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.35 (q, J = 4.8 Hz, 1H), 8.06 (d, J = 2.7 Hz, 1H), 7.80 (t, J = 7.7 Hz, 2H), 7.17 (dd, J = 8.6, 2.8 Hz, 1H), 6.98 (t, J = 6.1 Hz, 1H), 6.83 (t, J = 7.2 Hz, 1H), 6.40 (d, J = 7.5 Hz, 1H), 5.37 (d, J = 9.2 Hz, 1H), 4.82 (d, J = 49.4 Hz, 1H), 4.31 (d, J = 6.1 Hz, 2H), 4.04 (q, J = 10.7 Hz, 2H), 3.78 – 3.62 (m, 1H), 3.03 (t, J = 11.5 Hz, 1H), 2.77 (d, J = 4.8 Hz, 4H), 2.29 (d, J = 13.0 Hz, 1H), 2.19 (s, 3H), 2.14 – 2.04 (m, 1H), 1.87 – 1.74 (m, 2H). Example 53. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methyl-3-(trifluoromethoxy)benzamide Step 1. Synthesis of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-N-methyl-3-(trifluoromethoxy)benzamide
將N-甲基-4-(丙-2-炔-1-基胺基)-3-(三氟甲氧基)苯甲醯胺( 中間物22;300 mg,1.10 mmol,1.30當量)、8-溴-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶( 中間物1;344 mg,0.85 mmol,1當量)、i-Pr 2NH (858 mg,8.47 mmol,10當量)、CuI (162 mg,0.84 mmol,1當量)及Pd(PPh 3) 4(392 mg,0.33 mmol,0.40當量)於DMSO (7 mL)中之混合物在室溫及氮氣氛圍下攪拌1 h。反應用EtOAc (40 mL)稀釋且用鹽水(3*40 mL)洗滌。有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型TLC (DCM/MeOH=20:1)純化,以得到呈淺黃色固體之4-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-N-甲基-3-(三氟甲氧基)苯甲醯胺(300 mg,59.60%)。LC-MS:(M+H) +實測值549.0。 步驟2. 4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-N-甲基-3-(三氟甲氧基)苯甲醯胺之合成 A mixture of N-methyl-4-(prop-2-yn-1-ylamino)-3-(trifluoromethoxy)benzamide ( intermediate 22; 300 mg, 1.10 mmol, 1.30 equiv), 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( intermediate 1 ; 344 mg, 0.85 mmol, 1 equiv), i- Pr2NH (858 mg, 8.47 mmol, 10 equiv), CuI (162 mg, 0.84 mmol, 1 equiv) and Pd( PPh3 ) 4 (392 mg, 0.33 mmol, 0.40 equiv) in DMSO (7 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The reaction was diluted with EtOAc (40 mL) and washed with brine (3*40 mL). The organic layer was dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM/MeOH=20:1) to give 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-N-methyl-3-(trifluoromethoxy)benzamide (300 mg, 59.60%) as a light yellow solid. LC-MS: (M+H) + found 549.0. Step 2. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methyl-3-(trifluoromethoxy)benzamide
將4-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-N-甲基-3-(三氟甲氧基)苯甲醯胺(100 mg,0.18 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(56 mg,0.27 mmol,1.50當量)、BrettPhos Pd G4 (50 mg,0.05 mmol,0.30當量)、RuPhos (51 mg,0.10 mmol,0.60當量)及Cs 2CO 3(238 mg,0.72 mmol,4當量)於二噁烷(4 mL)中之混合物在100℃及氮氣氛圍下攪拌6 h。在室溫下用水淬滅反應。所得混合物用EtOAc (3*30 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由具有以下條件之反相急速層析純化:管柱:XBridge C18 OBD Prep管柱,100、5 m,19 mm X 250 mm;移動相A:水(10 mmol/L NH 4HCO 3),移動相B:ACN;流動速率:25 mL/min mL/min;梯度:在7 min內45% B至55% B;波長:254 nm nm;RT1(min):7。此產生呈白色固體之4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-N-甲基-3-(三氟甲氧基)苯甲醯胺(3.2 mg,2.92%)。LC-MS:(M+H) +實測值601.50。 1H NMR (400 MHz, 氯仿- d) δ 7.69 (s, 1H), 7.62 (dd, J= 8.5, 2.0 Hz, 1H), 7.38 (d, J= 6.8 Hz, 1H), 6.94 (d, J= 8.5 Hz, 1H), 6.78 (t, J= 7.2 Hz, 1H), 6.20 (d, J= 7.5 Hz, 2H), 5.54 (d, J= 8.8 Hz, 1H),5.44 (d, J= 8.8 Hz, 1H), 5.05 (s, 1H), 4.58 – 4.52 (m, 2H), 3.77-3.75 (m, 3H), 3.33 (s, 1H), 3.10 - 2.95 (m, 4H), 2.53 (s, 4H), 2.11 (s, 3H)。 實例54. 4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-N-甲基-3-(三氟甲基)苯甲醯胺之合成 步驟1. 4-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-N-甲基-3-(三氟甲基)苯甲醯胺之合成 A mixture of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-N-methyl-3-(trifluoromethoxy)benzamide (100 mg, 0.18 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (56 mg, 0.27 mmol, 1.50 eq), BrettPhos Pd G4 (50 mg, 0.05 mmol, 0.30 eq), RuPhos (51 mg, 0.10 mmol, 0.60 eq) and Cs2CO3 ( 238 mg, 0.72 mmol, 4 eq) in dioxane (4 mL) was stirred at 100 °C under nitrogen atmosphere for 6 h. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3*30 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column: XBridge C18 OBD Prep column, 100, 5 m, 19 mm X 250 mm; mobile phase A: water (10 mmol/L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 25 mL/min mL/min; gradient: 45% B to 55% B in 7 min; wavelength: 254 nm nm; RT1 (min): 7. This resulted in 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methyl-3-(trifluoromethoxy)benzamide (3.2 mg, 2.92%) as a white solid. LC-MS: (M+H) + found 601.50. 1 H NMR (400 MHz, CHLOROFORM- d ) δ 7.69 (s, 1H), 7.62 (dd, J = 8.5, 2.0 Hz, 1H), 7.38 (d, J = 6.8 Hz, 1H), 6.94 (d, J = 8.5 Hz, 1H), 6.78 (t, J = 7.2 Hz, 1H), 6.20 (d, J = 7.5 Hz, 2H), 5.54 (d, J = 8.8 Hz, 1H),5.44 (d, J = 8.8 Hz, 1H), 5.05 (s, 1H), 4.58 – 4.52 (m, 2H), 3.77-3.75 (m, 3H), 3.33 (s, 1H), 3.10 - 2.95 (m, 4H), 2.53 (s, 4H), 2.11 (s, 3H). Example 54. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methyl-3-(trifluoromethyl)benzamide Step 1. Synthesis of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-N-methyl-3-(trifluoromethyl)benzamide
將8-溴-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶( 中間物1;300 mg,0.74 mmol,1當量)、N-甲基-4-(丙-2-炔-1-基胺基)-3-(三氟甲基)苯甲醯胺( 中間物23;227.8 mg,0.89 mmol,1.2當量)、i-Pr 2NH (749.7 mg,7.40 mmol,10當量)、CuI (141.1 mg,0.74 mmol,1當量)及Pd(PPh 3) 4(171.2 mg,0.15 mmol,0.2當量)於DMSO (5 mL)中之溶液在室溫及氮氣氛圍下攪拌1 h。所得混合物用EtOAc (100 mL)稀釋且用鹽水(3*100 mL)洗滌。有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/於MeOH中之7 M NH 3= 20:1)純化,以得到呈棕黃色固體之4-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-N-甲基-3-(三氟甲基)苯甲醯胺(320 mg,81.0%)。LC-MS:(M+H) +實測值533.6。 步驟2. 4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-N-甲基-3-(三氟甲基)苯甲醯胺之合成 A solution of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( Intermediate 1 ; 300 mg, 0.74 mmol, 1 eq), N-methyl-4-(prop-2-yn-1-ylamino)-3-(trifluoromethyl)benzamide ( Intermediate 23 ; 227.8 mg, 0.89 mmol, 1.2 eq), i-Pr 2 NH (749.7 mg, 7.40 mmol, 10 eq), CuI (141.1 mg, 0.74 mmol, 1 eq) and Pd(PPh 3 ) 4 (171.2 mg, 0.15 mmol, 0.2 eq) in DMSO (5 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting mixture was diluted with EtOAc (100 mL) and washed with brine (3*100 mL). The organic layer was dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 / 7 M NH 3 in MeOH = 20:1) to give 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-N-methyl-3-(trifluoromethyl)benzamide (320 mg, 81.0%) as a brownish yellow solid. LC-MS: (M+H) + found 533.6. Step 2. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methyl-3-(trifluoromethyl)benzamide
將4-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-N甲基-3-(三氟甲基)苯甲醯胺(100 mg,0.19 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(57.7 mg,0.28 mmol,1.50當量)、t-BuONa (90.1 mg,0.94 mmol,5當量)及tBuXPhos Pd G3 (29.8 mg,0.04 mmol,0.2當量)於THF (2 mL)中之溶液在65℃及氮氣氛圍下攪拌1 h。將所得混合物在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/於MeOH中之7 M NH 3= 20:1)及具有以下條件(管柱:XBridge Prep OBD C18管柱,19*250 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3+0.05%NH 3H 2O),移動相B:ACN(1% 2mM NH 3-MEOH);流動速率:25 mL/min mL/min;梯度:在10min內52% B至67% B;波長:254nm/220nm nm;RT1(min):9.32;運行次數:3)之製備型HPLC純化,以得到呈灰白色固體之4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-N-甲基-3-(三氟甲基)苯甲醯胺(16.7 mg,15.24%)。LC-MS:(M+H) +實測值585.15。 1H NMR (400 MHz, DMSO- d 6) δ 8.39 – 8.27 (d, J= 4.7 Hz, 1H), 8.04 – 7.94 (m, 2H), 7.84 – 7.76 (d, J= 6.8 Hz, 1H), 7.11 – 7.03 (d, J= 8.8 Hz, 1H), 6.89 – 6.79 (t, J= 7.2 Hz, 1H), 6.64 – 6.55 (t, J= 5.9 Hz, 1H), 6.44 – 6.34 (d, J= 7.6 Hz, 1H), 5.44 – 5.36 (d, J= 9.2 Hz, 1H), 4.93 – 4.72 (d, J= 49.4 Hz, 1H), 4.43 – 4.32 (d, J= 5.9 Hz, 2H), 4.11 – 3.94 (m, 2H), 3.81 – 3.60 (m, 1H), 3.11 – 2.95 (t, J= 11.5 Hz, 1H), 2.83 – 2.70 (d, J= 4.5 Hz, 4H), 2.37 – 2.15 (s, 4H), 2.15 – 2.03 (t, J= 10.8 Hz, 1H), 1.93 – 1.68 (dd, J= 8.1, 12.1 Hz, 2H)。 實例55. 3-氯-4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-N-甲基苯甲醯胺之合成 步驟1. 4-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-3-氯-N-甲基苯甲醯胺之合成 A solution of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-N-methyl-3-(trifluoromethyl)benzamide (100 mg, 0.19 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (57.7 mg, 0.28 mmol, 1.50 eq), t-BuONa (90.1 mg, 0.94 mmol, 5 eq) and tBuXPhos Pd G3 (29.8 mg, 0.04 mmol, 0.2 eq) in THF (2 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was separated by preparative TLC (CH 2 Cl 2 /7 M NH 3 in MeOH = 20:1) with the following conditions (column: XBridge Prep OBD C18 column, 19*250 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 +0.05% NH 3 H 2 O), mobile phase B: ACN (1% 2 mM NH 3 -MEOH); flow rate: 25 mL/min mL/min; gradient: 52% B to 67% B in 10 min; wavelength: 254 nm/220 nm nm; RT1(min): 9.32; runs: 3) to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methyl-3-(trifluoromethyl)benzamide (16.7 mg, 15.24%) as an off-white solid. LC-MS: (M+H) + found 585.15. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.39 – 8.27 (d, J = 4.7 Hz, 1H), 8.04 – 7.94 (m, 2H), 7.84 – 7.76 (d, J = 6.8 Hz, 1H), 7.11 – 7.03 (d, J = 8.8 Hz, 1H), 6.89 – 6.79 (t, J = 7.2 Hz, 1H), 6.64 – 6.55 (t, J = 5.9 Hz, 1H), 6.44 – 6.34 (d, J = 7.6 Hz, 1H), 5.44 – 5.36 (d, J = 9.2 Hz, 1H), 4.93 – 4.72 (d, J = 49.4 Hz, 1H), 4.43 – 4.32 (d, J = 5.9 Hz, 2H), 4.11 – 3.94 (m, 2H), 3.81 – 3.60 (m, 1H), 3.11 – 2.95 (t, J = 11.5 Hz, 1H), 2.83 – 2.70 (d, J = 4.5 Hz, 4H), 2.37 – 2.15 (s, 4H), 2.15 – 2.03 (t, J = 10.8 Hz, 1H), 1.93 – 1.68 (dd, J = 8.1, 12.1 Hz, 2H). Example 55. Synthesis of 3-chloro-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide Step 1. Synthesis of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-chloro-N-methylbenzamide
將3-氯-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺( 中間物24;400 mg,1.80 mmol,1.2當量)、8-溴-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶( 中間物1;606.2 mg,150 mmol,1當量)、Pd(PPh 3) 4(346.0 mg,0.30 mmol,0.2當量)、CuI (285.1 mg,1.50 mmol,1當量)及i-Pr 2NH (1.51 g,14.97 mmol,10當量)於DMSO (2 mL)中之混合物在室溫下攪拌1 h。所得混合物用EtOAc (50 mL)稀釋且用鹽水(3*50 mL)洗滌。有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用PE / EA (1:1)溶析,以得到呈黃色油狀物之4-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-3-氯-N-甲基苯甲醯胺(354 mg,47.32%)。LC-MS:(M+H) +實測值499.1。 步驟2. 3-氯-4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-N-甲基苯甲醯胺之合成 A mixture of 3-chloro-N-methyl-4-(prop-2-yn-1-ylamino)benzamide ( intermediate 24 ; 400 mg, 1.80 mmol, 1.2 equiv), 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( intermediate 1 ; 606.2 mg, 150 mmol, 1 equiv), Pd( PPh3 ) 4 (346.0 mg, 0.30 mmol, 0.2 equiv), CuI (285.1 mg, 1.50 mmol, 1 equiv) and i- Pr2NH (1.51 g, 14.97 mmol, 10 equiv) in DMSO (2 mL) was stirred at room temperature for 1 h. The resulting mixture was diluted with EtOAc (50 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (1:1) to give 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-chloro-N-methylbenzamide (354 mg, 47.32%) as a yellow oil. LC-MS: (M+H) + found 499.1. Step 2. Synthesis of 3-chloro-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide
將4-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-3-氯-N-甲基苯甲醯胺(300 mg,0.60 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺(198.4 mg,1.50 mmol,2.5當量)、t-BuONa (201.9 mg,2.10 mmol,3.5當量)及tBuXphos Pd G 3(190.8 mg,0.24 mmol,0.4當量)於THF (5 mL)中之混合物在65℃及氮氣氛圍下攪拌1 h。將所得混合物在減壓下濃縮。殘餘物藉由具有以下條件(管柱:XBridge Prep OBD C18管柱,19*250 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3+0.05%NH 3 .H 2O),移動相B:ACN(1% 2mM NH 3-MEOH);流動速率:25 mL/min mL/min;梯度:在11min內48% B至67% B;波長:254nm/220nm nm;RT1(min):10.8)之製備型HPLC純化,以得到呈白色固體之3-氯-4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-N-甲基苯甲醯胺(32.1 mg,9.65%)。LC-MS:(M+H) +實測值551.20。 1H NMR (400 MHz, DMSO- d 6) δ 8.19 (d, J= 4.6 Hz, 1H), 7.82 (d, J= 2.0 Hz, 1H), 7.78 (d, J= 6.8 Hz, 1H), 7.72 (dd, J= 8.6, 2.0 Hz, 1H), 6.94 (d, J= 8.5 Hz, 1H), 6.83 (t, J= 7.2 Hz, 1H), 6.45 (t, J= 6.0 Hz, 1H), 6.39 (d, J= 7.5 Hz, 1H), 5.36 (d, J= 9.2 Hz, 1H), 4.81 (d, J= 49.5 Hz, 1H), 4.34 (d, J= 6.1 Hz, 2H), 4.03 (m, 2H), 3.77 – 3.61 (m, 1H), 3.02 (t, J= 11.6 Hz, 1H), 2.74 (d, J= 4.4 Hz, 4H), 2.19 (s, 5H), 1.79 (d, J= 5.6 Hz,2H)。 實例56. 3-氰基-4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-N-甲基苯甲醯胺之合成 步驟1. N-{3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}-N-[2-氰基-4-(甲基胺甲醯基)苯基]胺基甲酸三級丁酯之合成 A mixture of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-chloro-N-methylbenzamide (300 mg, 0.60 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine (198.4 mg, 1.50 mmol, 2.5 eq), t-BuONa (201.9 mg, 2.10 mmol, 3.5 eq) and tBuXphos Pd G 3 (190.8 mg, 0.24 mmol, 0.4 eq) in THF (5 mL) was stirred at 65° C. under nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was separated by HPLC with the following conditions (column: XBridge Prep OBD C18 column, 19*250 mm, 5μm; mobile phase A: water (10mmol/L NH4HCO3 + 0.05 % NH3.H2O ), mobile phase B: ACN (1% 2mM NH3 - MEOH ); flow rate: 25 mL/min mL/min; gradient: 48% B to 67% B in 11min; wavelength: 254nm/220nm nm; RT1 (min): 10.8) to give 3-chloro-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide (32.1 mg, 9.65%) as a white solid. LC-MS: (M+H) + found 551.20. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.19 (d, J = 4.6 Hz, 1H), 7.82 (d, J = 2.0 Hz, 1H), 7.78 (d, J = 6.8 Hz, 1H), 7.72 (dd, J = 8.6, 2.0 Hz, 1H), 6.94 (d, J = 8.5 Hz, 1H), 6.83 (t, J = 7.2 Hz, 1H), 6.45 (t, J = 6.0 Hz, 1H), 6.39 (d, J = 7.5 Hz, 1H), 5.36 (d, J = 9.2 Hz, 1H), 4.81 (d, J = 49.5 Hz, 1H), 4.34 (d, J = 6.1 Hz, 2H), 4.03 (m, 2H), 3.77 – 3.61 (m, 1H), 3.02 (t, J = 11.6 Hz, 1H), 2.74 (d, J = 4.4 Hz, 4H), 2.19 (s, 5H), 1.79 (d, J = 5.6 Hz,2H). Example 56. Synthesis of 3-cyano-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide Step 1. Synthesis of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-N-[2-cyano-4-(methylaminoformyl)phenyl]carbamic acid tert-butyl ester
將N-[2-氰基-4-(甲基胺甲醯基)苯基]-N-(丙-2-炔-1-基)胺基甲酸三級丁酯( 中間物25;400 mg,1.28 mmol,1.2當量)、8-溴-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶( 中間物1;430.8 mg,1.06 mmol,1當量)、Pd(PPh 3) 4(245.9 mg,0.21 mmol,0.2當量)、CuI (202.6 mg,1.06 mmol,1當量)及i-Pr 2NH (1.07 g,10.63 mmol,10當量)於DMSO (2 mL)中之混合物保持在室溫下。將所得混合物在室溫及氮氣氛圍下攪拌1 h。所得混合物用EtOAc (50 mL)稀釋且用鹽水(2*50mL)洗滌。有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用PE / EA (1:1)溶析,以得到呈黃色油狀物之N-{3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}-N-[2-氰基-4-(甲基胺甲醯基)苯基]胺基甲酸三級丁酯(350 mg,55.73%)。LC-MS:(M+H) +實測值590.1。 步驟2. N-[2-氰基-4-(甲基胺甲醯基)苯基]-N-[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基甲酸三級丁酯之合成 A mixture of tributyl N-[2-cyano-4-(methylaminocarbonyl)phenyl]-N-(prop-2-yn-1-yl)carbamate ( Intermediate 25 ; 400 mg, 1.28 mmol, 1.2 equiv), 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( Intermediate 1 ; 430.8 mg, 1.06 mmol, 1 equiv), Pd(PPh 3 ) 4 (245.9 mg, 0.21 mmol, 0.2 equiv), CuI (202.6 mg, 1.06 mmol, 1 equiv) and i-Pr 2 NH (1.07 g, 10.63 mmol, 10 equiv) in DMSO (2 mL) was kept at room temperature. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting mixture was diluted with EtOAc (50 mL) and washed with brine (2*50 mL). The organic layer was dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (1:1) to give N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-N-[2-cyano-4-(methylcarbamoyl)phenyl]carbamic acid tributyl ester (350 mg, 55.73%) as a yellow oil. LC-MS: (M+H) + found 590.1. Step 2. Synthesis of tributyl N-[2-cyano-4-(methylaminocarbonyl)phenyl]-N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]carbamate
將N-{3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}-N-[2-氰基-4-(甲基胺甲醯基)苯基]胺基甲酸三級丁酯(450 mg,0.76 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(312.6 mg,1.52 mmol,2當量)、t-BuONa (366.3 mg,3.81 mmol,5當量)及tBuXphos Pd G 3(181.64mg,0.23 mmol,0.3當量)於THF (5 mL)中之溶液在65℃及氮氣氛圍下攪拌1 h。過濾所得混合物,濾餅用DCM洗滌。將濾液在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/於MeOH中之7 M NH 3= 20:1)純化,以得到呈棕色油狀物之N-[2-氰基-4-(甲基胺甲醯基)苯基]-N-[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基甲酸三級丁酯(261 mg,53.37%)。 步驟3. 3-氰基-4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-N-甲基苯甲醯胺之合成 A solution of tributyl N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-N-[2-cyano-4-(methylcarbamoyl)phenyl]carbamate (450 mg, 0.76 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (312.6 mg, 1.52 mmol, 2 eq), t-BuONa (366.3 mg, 3.81 mmol, 5 eq) and tBuXphos Pd G3 (181.64 mg, 0.23 mmol, 0.3 eq) in THF (5 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was filtered and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 /7 M NH 3 in MeOH = 20:1) to give tributyl N-[2-cyano-4-(methylaminocarbonyl)phenyl]-N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]carbamate (261 mg, 53.37%) as a brown oil. Step 3. Synthesis of 3-cyano-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide
在0℃下,向N-[2-氰基-4-(甲基胺甲醯基)苯基]-N-[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基甲酸三級丁酯(220 mg,0.34 mmol,1當量)及2,6-二甲基吡啶(183.7 mg,1.72 mmol,5當量)於DCM (2 mL)中之攪拌溶液中添加TMSOTf (381.0 mg,1.72 mmol,5當量)。將混合物在室溫下攪拌30 min。將所得混合物在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/於MeOH中之7 M NH 3= 15:1)及具有以下條件(管柱:XBridge Shield RP18 OBD管柱,19*250 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3+0.05%NH 3H 2O),移動相B:ACN(1% 2mM NH 3-MEOH);流動速率:25 mL/min mL/min;梯度:在11min內50% B至69% B;波長:254nm/220nm nm;RT1(min):9.52)之製備型HPLC純化,以得到呈白色固體之3-氰基-4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-N-甲基苯甲醯胺(17.0 mg,9.06%)。LC-MS:(M+H) +實測值542.25。 1H NMR (400 MHz, DMSO- d 6) δ 8.26 (d, J= 4.8 Hz, 1H), 8.07 – 7.91 (m, 2H), 7.79 (d, J= 6.8 Hz, 1H), 7.17 (t, J= 5.9 Hz, 1H), 7.02 (d, J= 8.9 Hz, 1H), 6.83 (t, J= 7.1 Hz, 1H), 6.40 (d, J= 7.6 Hz, 1H), 5.38 (d, J= 9.2 Hz, 1H), 4.83 (d, J= 49.5 Hz, 1H), 4.37 (d, J= 5.9 Hz, 2H), 4.04 (m, 2H), 3.70 (s, 1H), 3.05 (s, 1H), 2.75 (d, J= 4.5 Hz, 4H), 2.54 (s, 1H), 2.21 (s, 4H), 1.82 (d, J= 14.1 Hz, 2H)。 實例57. 3-環丙基-4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-N-甲基苯甲醯胺之合成 步驟1. 4-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-3-環丙基-N-甲基苯甲醯胺之合成 To a stirred solution of tributyl N-[2-cyano-4-(methylaminocarbonyl)phenyl]-N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]carbamate (220 mg, 0.34 mmol, 1 eq) and 2,6-lutidine (183.7 mg, 1.72 mmol, 5 eq) in DCM (2 mL) at 0°C was added TMSOTf (381.0 mg, 1.72 mmol, 5 eq). The mixture was stirred at room temperature for 30 min. The resulting mixture was concentrated under reduced pressure. The residue was separated by preparative TLC (CH 2 Cl 2 /7 M NH 3 in MeOH = 15:1) with the following conditions (column: XBridge Shield RP18 OBD column, 19*250 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 +0.05% NH 3 H 2 O), mobile phase B: ACN (1% 2 mM NH 3 -MEOH); flow rate: 25 mL/min mL/min; gradient: 50% B to 69% B in 11 min; wavelength: 254 nm/220 nm nm; RT1 (min): 9.52) was purified by preparative HPLC to give 3-cyano-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide (17.0 mg, 9.06%) as a white solid. LC-MS: (M+H) + found 542.25. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.26 (d, J = 4.8 Hz, 1H), 8.07 – 7.91 (m, 2H), 7.79 (d, J = 6.8 Hz, 1H), 7.17 (t, J = 5.9 Hz, 1H), 7.02 (d, J = 8.9 Hz, 1H), 6.83 (t, J = 7.1 Hz, 1H), 6.40 (d, J = 7.6 Hz, 1H), 5.38 (d, J = 9.2 Hz, 1H), 4.83 (d, J = 49.5 Hz, 1H), 4.37 (d, J = 5.9 Hz, 2H), 4.04 (m, 2H), 3.70 (s, 1H), 3.05 (s, 1H), 2.75 (d, J = 4.5 Hz, 4H), 2.54 (s, 1H), 2.21 (s, 4H), 1.82 (d, J = 14.1 Hz, 2H). Example 57. Synthesis of 3-cyclopropyl-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide Step 1. Synthesis of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-cyclopropyl-N-methylbenzamide
將8-溴-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶( 中間物1;300 mg,0.74 mmol,1當量)、3-環丙基-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺( 中間物26;203.0 mg,0.89 mmol,1.2當量)、CuI (141.1 mg,0.74 mmol,1當量)、i-Pr 2NH (749.7 mg,7.41 mmol,10當量)及Pd(PPh 3) 4(171.2 mg,0.15 mmol,0.2當量)於DMSO (3 mL)中之溶液在室溫及氮氣氛圍下攪拌1 h。所得混合物用3*20 mL之水洗滌。所得混合物用EA (100 mL)稀釋且用鹽水(3*100 mL)洗滌。有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/於MeOH中之7 M NH 3= 15:1)純化,以得到呈棕色油狀物之4-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-3-環丙基-N-甲基苯甲醯胺(230 mg,61.44%)。LC-MS:(M+H) +實測值505.0。 步驟2. 3-環丙基-4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-N-甲基苯甲醯胺之合成 A solution of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( Intermediate 1 ; 300 mg, 0.74 mmol, 1 eq), 3-cyclopropyl-N-methyl-4-(prop-2-yn-1-ylamino)benzamide ( Intermediate 26 ; 203.0 mg, 0.89 mmol, 1.2 eq), CuI (141.1 mg, 0.74 mmol, 1 eq), i-Pr 2 NH (749.7 mg, 7.41 mmol, 10 eq) and Pd(PPh 3 ) 4 (171.2 mg, 0.15 mmol, 0.2 eq) in DMSO (3 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting mixture was washed with 3*20 mL of water. The resulting mixture was diluted with EA (100 mL) and washed with brine (3*100 mL). The organic layer was dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 /7 M NH 3 in MeOH = 15:1) to give 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-cyclopropyl-N-methylbenzamide (230 mg, 61.44%) as a brown oil. LC-MS: (M+H) + found 505.0. Step 2. Synthesis of 3-cyclopropyl-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide
將4-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-3-環丙基-N-甲基苯甲醯胺(200 mg,0.40 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(162.4 mg,0.80 mmol,2當量)、t-BuONa (190.2 mg,2.00 mmol,5當量)及tBuXphos Pd G3 (94.3 mg,0.12 mmol,0.3當量)於THF (2 mL)中之溶液在65℃及氮氣氛圍下攪拌1 h。過濾所得混合物,濾餅用DCM洗滌。將濾液在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/於MeOH中之7 M NH 3= 15:1)及製備型HPLC (管柱:XBridge Prep Phenyl OBD管柱,19*250 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3+0.05%NH 3 .H 2O),移動相B:ACN(1% 2mM NH 3-MEOH);流動速率:25 mL/min mL/min;梯度:在11min內50% B至69% B;波長:254nm/220nm nm;RT1(min):9.95)純化,以得到呈白色固體之3-環丙基-4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-N-甲基苯甲醯胺(20.5 mg,9.11%)。LC-MS:(M+H) +實測值557.20。 1H NMR (400 MHz, DMSO- d 6) δ 8.06 (m, 1H), 7.79 (d, J= 6.8 Hz, 1H), 7.62 (dd, J= 8.4, 2.1 Hz, 1H), 7.44 (d, J= 2.1 Hz, 1H), 6.86 – 6.71 (m, 2H), 6.39 (d, J= 7.5 Hz, 1H), 6.15 (t, J= 6.1 Hz, 1H), 5.39 (d, J= 9.2 Hz, 1H), 4.82 (d, J= 49.5 Hz, 1H), 4.34 (d, J= 6.1 Hz, 2H), 4.02 (m, 2H), 3.79 – 3.61 (m, 1H), 3.03 (t, J= 11.6 Hz, 1H), 2.72 (d, J= 4.5 Hz, 4H), 2.18 (s, 4H), 2.12 – 2.02 (m, 1H), 1.89 – 1.73 (m, 2H), 1.67 (td, J= 8.3, 4.2 Hz, 1H), 0.97 – 0.84 (m, 2H), 0.60 – 0.48 (m, 2H)。 實例58. 3-乙基-4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-N-甲基苯甲醯胺之合成 步驟1. 4-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-3-乙基-N-甲基苯甲醯胺之合成 A solution of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-cyclopropyl-N-methylbenzamide (200 mg, 0.40 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (162.4 mg, 0.80 mmol, 2 eq), t-BuONa (190.2 mg, 2.00 mmol, 5 eq) and tBuXphos Pd G3 (94.3 mg, 0.12 mmol, 0.3 eq) in THF (2 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was filtered and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 /7 M NH 3 in MeOH = 15:1) and preparative HPLC (column: XBridge Prep Phenyl OBD column, 19*250 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 +0.05% NH 3 . H 2 O), mobile phase B: ACN (1% 2 mM NH 3 -MEOH); flow rate: 25 mL/min mL/min; gradient: 50% B to 69% B in 11 min; wavelength: 254 nm/220 nm nm; RT1 (min): 9.95) to give 3-cyclopropyl-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide (20.5 mg, 9.11%) as a white solid. LC-MS: (M+H) + found 557.20. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.06 (m, 1H), 7.79 (d, J = 6.8 Hz, 1H), 7.62 (dd, J = 8.4, 2.1 Hz, 1H), 7.44 (d, J = 2.1 Hz, 1H), 6.86 – 6.71 (m, 2H), 6.39 (d, J = 7.5 Hz, 1H), 6.15 (t, J = 6.1 Hz, 1H), 5.39 (d, J = 9.2 Hz, 1H), 4.82 (d, J = 49.5 Hz, 1H), 4.34 (d, J = 6.1 Hz, 2H), 4.02 (m, 2H), 3.79 – 3.61 (m, 1H), 3.03 (t, J = 11.6 Hz, 1H), 2.72 (d, J = 4.5 Hz, 4H), 2.18 (s, 4H), 2.12 – 2.02 (m, 1H), 1.89 – 1.73 (m, 2H), 1.67 (td, J = 8.3, 4.2 Hz, 1H), 0.97 – 0.84 (m, 2H), 0.60 – 0.48 (m, 2H). Example 58. Synthesis of 3-ethyl-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide Step 1. Synthesis of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-ethyl-N-methylbenzamide
將3-乙基-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺( 中間物27;160.2 mg,0.74 mmol,1.2當量)、8-溴-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶( 中間物1;250 mg,0.62 mmol,1當量)、CuI (117.6 mg,0.62 mmol,1當量)、i-Pr 2NH (624.7 mg,6.17 mmol,10當量)及Pd(PPh 3) 4(214.0 mg,0.19 mmol,0.3當量)於DMSO (2 mL)中之溶液在室溫及氮氣氛圍下攪拌1 h。所得溶液藉由具有以下條件(管柱,C18矽膠;移動相,於水中之MeOH,在15min內10%至80%梯度;偵測器,UV 254 nm)之反相急速層析直接純化,以得到呈棕色固體之4-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-3-乙基-N-甲基苯甲醯胺(170 mg,55.82%)。LC-MS:(M+H) +實測值492.0。 步驟2. 3-乙基-4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-N-甲基苯甲醯胺之合成 A solution of 3-ethyl-N-methyl-4-(prop-2-yn-1-ylamino)benzamide ( intermediate 27 ; 160.2 mg, 0.74 mmol, 1.2 equiv), 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[ 1,2 -a]pyridine ( intermediate 1 ; 250 mg, 0.62 mmol, 1 equiv), CuI (117.6 mg, 0.62 mmol, 1 equiv), i- Pr2NH (624.7 mg, 6.17 mmol, 10 equiv) and Pd(PPh3) 4 (214.0 mg, 0.19 mmol, 0.3 equiv) in DMSO (2 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting solution was directly purified by reverse phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeOH in water, gradient 10% to 80% in 15 min; detector, UV 254 nm) to give 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-ethyl-N-methylbenzamide (170 mg, 55.82%) as a brown solid. LC-MS: (M+H) + found 492.0. Step 2. Synthesis of 3-ethyl-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide
將4-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-3-乙基-N-甲基苯甲醯胺(170 mg,0.35 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺(91.1 mg,0.70 mmol,2當量)、t-BuONa (165.6 mg,1.73 mmol,5當量)及tBuXphos Pd G3 (82.1 mg,0.10 mmol,0.3當量)於THF (2 mL)中之混合物在65℃及氮氣氛圍下攪拌1 h。將所得混合物在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/於MeOH中之7 M NH 3= 15:1)及製備型HPLC (管柱:XBridge Prep Phenyl OBD管柱,19*250 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3+0.05%NH 3 .H 2O),移動相B:MEOH;流動速率:25 mL/min mL/min;梯度:在11min內55% B至75% B;波長:254nm/220nm nm;RT1(min):9.95)純化,以得到呈白色固體之3-乙基-4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-N-甲基苯甲醯胺(36.2 mg,19.14%)。LC-MS:(M+H) +實測值544.50。 1H NMR (400 MHz, DMSO- d 6) δ 8.05 (d, J= 4.6 Hz, 1H), 7.79 (d, J= 6.8 Hz, 1H), 7.60 (dd, J= 8.4, 2.2 Hz, 1H), 7.55 (d, J= 2.1 Hz, 1H), 6.83 (t, J= 7.1 Hz, 1H), 6.76 (d, J= 8.5 Hz, 1H), 6.39 (d, J= 7.5 Hz, 1H), 6.05 (t, J= 6.1 Hz, 1H), 5.38 (d, J= 9.2 Hz, 1H), 4.82 (d, J= 49.3 Hz, 1H), 4.27 (d, J= 6.1 Hz, 2H), 4.02 (m, 2H), 3.70 (m, 1H), 3.01 (d, J= 11.4 Hz, 1H), 2.73 (d, J= 4.5 Hz, 4H), 2.48 (s, 1H), 2.18 (s, 4H), 2.12 – 2.01 (m, 2H), 1.81 (m, 2H), 1.17 (t, J= 7.4 Hz, 3H)。 實例59. 3-乙氧基-4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-N-甲基苯甲醯胺之合成 步驟1. 4-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-3-乙氧基-N-甲基苯甲醯胺之合成 A mixture of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-ethyl-N-methylbenzamide (170 mg, 0.35 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine (91.1 mg, 0.70 mmol, 2 eq), t-BuONa (165.6 mg, 1.73 mmol, 5 eq) and tBuXphos Pd G3 (82.1 mg, 0.10 mmol, 0.3 eq) in THF (2 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 /7 M NH 3 in MeOH = 15:1) and preparative HPLC (column: XBridge Prep Phenyl OBD column, 19*250 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 +0.05% NH 3 . H 2 O), mobile phase B: MEOH; flow rate: 25 mL/min mL/min; gradient: 55% B to 75% B in 11 min; wavelength: 254 nm/220 nm nm; RT1 (min): 9.95) to give 3-ethyl-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide (36.2 mg, 19.14%) as a white solid. LC-MS: (M+H) + found 544.50. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.05 (d, J = 4.6 Hz, 1H), 7.79 (d, J = 6.8 Hz, 1H), 7.60 (dd, J = 8.4, 2.2 Hz, 1H), 7.55 (d, J = 2.1 Hz, 1H), 6.83 (t, J = 7.1 Hz, 1H), 6.76 (d, J = 8.5 Hz, 1H), 6.39 (d, J = 7.5 Hz, 1H), 6.05 (t, J = 6.1 Hz, 1H), 5.38 (d, J = 9.2 Hz, 1H), 4.82 (d, J = 49.3 Hz, 1H), 4.27 (d, J = 6.1 Hz, 2H), 4.02 (m, 2H), 3.70 (m, 1H), 3.01 (d, J = 11.4 Hz, 1H), 2.73 (d, J = 4.5 Hz, 4H), 2.48 (s, 1H), 2.18 (s, 4H), 2.12 – 2.01 (m, 2H), 1.81 (m, 2H), 1.17 (t, J = 7.4 Hz, 3H). Example 59. Synthesis of 3-ethoxy-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide Step 1. Synthesis of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-ethoxy-N-methylbenzamide
將3-乙氧基-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺( 中間物28;400 mg,1.72 mmol,1當量)、8-溴-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶(697 mg,1.72 mmol,1當量)、CuI (327 mg,1.72 mmol,1當量)、Pd(PPh 3) 4(796 mg,0.69 mmol,0.4當量)及雙(丙-2-基)胺(1.74 g,17.22 mmol,10當量)於DMSO (10 mL)中之混合物在室溫下攪拌1 h。反應混合物用水(100 mL)稀釋且用EtOAc (2*100 mL)萃取。合併的有機層經硫酸鈉乾燥,過濾且真空濃縮。殘餘物藉由具有以下條件(管柱,C18矽膠;移動相,於0.1%TFA中之MeCN,在10 min內30%至50%梯度;偵測器,UV 220 nm)之反相急速層析純化,以得到呈棕色固體之4-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-3-乙氧基-N-甲基苯甲醯胺(400 mg,45.61%)。LC-MS:(M+H +)實測值:509.1。 步驟2. 3-乙氧基-4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-N-甲基苯甲醯胺之合成 A mixture of 3-ethoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide ( intermediate 28 ; 400 mg, 1.72 mmol, 1 eq), 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (697 mg, 1.72 mmol, 1 eq), CuI (327 mg, 1.72 mmol, 1 eq), Pd(PPh 3 ) 4 (796 mg, 0.69 mmol, 0.4 eq) and bis(propan-2-yl)amine (1.74 g, 17.22 mmol, 10 eq) in DMSO (10 mL) was stirred at room temperature for 1 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2*100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeCN in 0.1% TFA, gradient 30% to 50% in 10 min; detector, UV 220 nm) to give 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-ethoxy-N-methylbenzamide (400 mg, 45.61%) as a brown solid. LC-MS: (M+H + ) found: 509.1. Step 2. Synthesis of 3-ethoxy-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide
將4-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-3-乙氧基-N-甲基苯甲醯胺(200 mg,0.39 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺(77.9 mg,0.59 mmol,1.5當量)、t-BuONa (188 mg,1.96 mmol,5當量)及tBuXPhos Pd G 3(31.2 mg,0.04 mmol,0.1當量)於THF (5 mL)中之混合物在65℃下攪拌1 h。反應混合物用水(200 mL)稀釋且用EtOAc (3*200 mL)萃取。合併的有機層經硫酸鈉乾燥,過濾且真空濃縮。殘餘物藉由具有以下條件之反相急速層析純化:管柱,C18矽膠;移動相,於0.1%TFA中之MeCN,在10 min內30%至50%梯度;偵測器,UV 220 nm以得到粗產物(85%純度),然後藉由製備型HPLC (管柱:XBridge C18 OBD Prep管柱,100、5 m,19 mm X 250 mm;移動相A:水(10 mmol/L NH 4HCO 3),移動相B:20mm NaOH+10%ACN;流動速率:25 mL/min mL/min;梯度:在7 min內45% B至50% B;波長:254 nm nm;RT1(min):7)進一步純化,以得到呈灰白色固體之3-乙氧基-4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-N-甲基苯甲醯胺(8.1 mg,3.68%)。LC-MS:(M+H) +實測值:561.40。 1H NMR (400 MHz, DMSO-d6) δ 8.09 (d, J= 4.6 Hz, 1H), 7.79 (d, J= 6.8 Hz, 1H), 7.41 (dd, J= 8.3, 1.8 Hz, 1H), 7.34 (d, J= 2.0 Hz, 1H), 6.83 (t, J= 7.1 Hz, 1H), 6.75 (d, J= 8.3 Hz, 1H), 6.40 (d, J= 7.5 Hz, 1H), 5.86 (t, J= 6.4 Hz, 1H), 5.38 (d, J= 9.2 Hz, 1H), 4.82 (d, J= 49.4 Hz, 1H), 4.29 (d, J= 6.3 Hz, 2H), 4.14 – 3.96 (m, 4H), 3.81 – 3.57 (m, 1H), 3.03 (t, J= 11.3 Hz, 1H), 2.75 (d, J= 4.5 Hz, 4H), 2.39 – 2.27 (m, 1H), 2.19 (s, 3H), 2.10 (m, 1H), 1.81 (dd, J= 12.1, 8.1 Hz, 2H), 1.40 (t, J= 7.0 Hz, 3H)。 實例60. 3-(二氟甲氧基)-4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-N-甲基苯甲醯胺之合成 步驟1. 4-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-3-(二氟甲氧基)-N-甲基苯甲醯胺之合成 A mixture of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-ethoxy-N-methylbenzamide (200 mg, 0.39 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine (77.9 mg, 0.59 mmol, 1.5 eq), t-BuONa (188 mg, 1.96 mmol, 5 eq) and tBuXPhos Pd G 3 (31.2 mg, 0.04 mmol, 0.1 eq) in THF (5 mL) was stirred at 65 °C for 1 h. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (3*200 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in 0.1% TFA, gradient from 30% to 50% in 10 min; detector, UV 220 nm to obtain a crude product (85% purity), and then by preparative HPLC (column: XBridge C18 OBD Prep column, 100, 5 m, 19 mm × 250 mm; mobile phase A: water (10 mmol/L NH 4 HCO 3 ), mobile phase B: 20 mm NaOH + 10% ACN; flow rate: 25 mL/min mL/min; gradient: 45% B to 50% B in 7 min; wavelength: 254 nm nm; RT1 (min): 7) was further purified to give 3-ethoxy-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide (8.1 mg, 3.68%) as an off-white solid. LC-MS: (M+H) + found: 561.40. 1 H NMR (400 MHz, DMSO-d6) δ 8.09 (d, J = 4.6 Hz, 1H), 7.79 (d, J = 6.8 Hz, 1H), 7.41 (dd, J = 8.3, 1.8 Hz, 1H), 7.34 (d, J = 2.0 Hz, 1H), 6.83 (t, J = 7.1 Hz, 1H), 6.75 (d, J = 8.3 Hz, 1H), 6.40 (d, J = 7.5 Hz, 1H), 5.86 (t, J = 6.4 Hz, 1H), 5.38 (d, J = 9.2 Hz, 1H), 4.82 (d, J = 49.4 Hz, 1H), 4.29 (d, J = 6.3 Hz, 2H), 4.14 – 3.96 (m, 4H), 3.81 – 3.57 (m, 1H), 3.03 (t, J = 11.3 Hz, 1H), 2.75 (d, J = 4.5 Hz, 4H), 2.39 – 2.27 (m, 1H), 2.19 (s, 3H), 2.10 (m, 1H), 1.81 (dd, J = 12.1, 8.1 Hz, 2H), 1.40 (t, J = 7.0 Hz, 3H). Example 60. Synthesis of 3-(difluoromethoxy)-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide Step 1. Synthesis of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-(difluoromethoxy)-N-methylbenzamide
在室溫下,在5 mL密封管中添加3-(二氟甲氧基)-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺( 中間物29;100 mg,0.39 mmol,1當量)、8-溴-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶( 中間物1;160 mg,0.39 mmol,1當量)、Pd(PPh 3) 4(91 mg,0.08 mmol,0.2當量)、CuI (75 mg,0.39 mmol,1當量)、i-Pr 2NH (398 mg,3.93 mmol,10當量)及DMSO (2 mL)。將所得混合物在室溫及氮氣氛圍下攪拌1h。所得混合物用水(40 mL)稀釋且用EtOAc (3*40 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/ MeOH 20:1)純化,以得到呈黃色固體之4-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-3-(二氟甲氧基)-N-甲基苯甲醯胺(110 mg,52.64%)。LC-MS:(M+H) +實測值533.1。 步驟2. 3-(二氟甲氧基)-4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-N-甲基苯甲醯胺之合成 3-(Difluoromethoxy)-N-methyl-4-(prop-2-yn-1-ylamino)benzamide ( Intermediate 29 ; 100 mg, 0.39 mmol, 1 eq), 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( Intermediate 1 ; 160 mg, 0.39 mmol, 1 eq), Pd(PPh 3 ) 4 (91 mg, 0.08 mmol, 0.2 eq), CuI (75 mg, 0.39 mmol, 1 eq), i-Pr 2 NH (398 mg, 3.93 mmol, 10 eq) and DMSO (2 mL) were added to a 5 mL sealed tube at room temperature. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting mixture was diluted with water (40 mL) and extracted with EtOAc (3*40 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 / MeOH 20:1) to give 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-(difluoromethoxy)-N-methylbenzamide (110 mg, 52.64%) as a yellow solid. LC-MS: (M+H) + found 533.1. Step 2. Synthesis of 3-(difluoromethoxy)-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide
在室溫下,在10 mL密封管中添加4-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-3-(二氟甲氧基)-N-甲基苯甲醯胺(100 mg,0.19 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(42 mg,0.21 mmol,1.1當量)、BrettPhos Pd G4 (58 mg,0.04 mmol,0.2當量)、RuPhos (35 mg,0.08 mmol,0.4當量)、Cs 2CO 3(245 mg,0.75 mmol,4當量)及二噁烷(3 mL)。將所得混合物在100℃及氮氣氛圍下攪拌2 h。所得混合物用水稀釋且用EtOAc (3*20 mL)萃取。將合併的有機層在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/ MeOH 10:1)+0.2% NH 3·H 2O純化以得到40 mg粗產物,然後藉由具有以下條件之反相急速層析進一步純化:管柱,C18矽膠;移動相,於水中之MeCN (0.1% FA),在10 min內10%至50%梯度;偵測器,UV 254 nm,以得到呈白色固體之3-(二氟甲氧基)-4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-N-甲基苯甲醯胺(15.2 mg,13.68%)。LC-MS:(M+H) +實測值583.45。 1H NMR (400 MHz, DMSO- d 6) δ 8.20 (m, 1H), 7.79 (d, J= 6.8 Hz, 1H), 7.65 (dd, J= 8.5, 1.9 Hz, 1H), 7.58 (d, J= 1.9 Hz, 1H), 7.13 (t, J= 74.0 Hz, 1H), 6.91 (d, J= 8.5 Hz, 1H), 6.83 (t, J= 7.1 Hz, 1H), 6.39 (dd, J= 7.0, 3.9 Hz, 2H), 5.39 (d, J= 9.2 Hz, 1H), 4.82 (d, J= 49.8 Hz, 1H), 4.30 (d, J= 6.1 Hz, 2H), 4.03 (m, 2H), 3.85 – 3.57 (m, 1H), 3.10 – 2.96 (m, 1H), 2.83 – 2.65 (m, 4H), 2.35 – 2.20 (m, 1H), 2.19 (s, 3H), 2.11 – 2.06 (m, 1H), 1.89 – 1.70 (m, 2H)。 實例61. 4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-N-甲基-3-(2,2,2-三氟乙氧基)苯甲醯胺之合成 步驟1. 4-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-N-甲基-3-(2,2,2-三氟乙氧基)苯甲醯胺之合成 In a 10 mL sealed tube at room temperature, 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-(difluoromethoxy)-N-methylbenzamide (100 mg, 0.19 mmol, 1 eq), (3S,4R) -3 -fluoro-1-methylpiperidin-4-amine dihydrochloride (42 mg, 0.21 mmol, 1.1 eq), BrettPhos Pd G4 (58 mg, 0.04 mmol, 0.2 eq), RuPhos (35 mg, 0.08 mmol, 0.4 eq), Cs2CO3 (245 mg, 0.75 mmol, 4 eq) and dioxane (3 mL) were added. The resulting mixture was stirred at 100 °C under nitrogen atmosphere for 2 h. The resulting mixture was diluted with water and extracted with EtOAc (3*20 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 / MeOH 10:1) + 0.2% NH 3 ·H 2 O to give 40 mg of crude product, which was then further purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient from 10% to 50% in 10 min; detector, UV 254 nm to give 3-(difluoromethoxy)-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide (15.2 mg, 13.68%) as a white solid. LC-MS: (M+H) + found 583.45. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.20 (m, 1H), 7.79 (d, J = 6.8 Hz, 1H), 7.65 (dd, J = 8.5, 1.9 Hz, 1H), 7.58 (d, J = 1.9 Hz, 1H), 7.13 (t, J = 74.0 Hz, 1H), 6.91 (d, J = 8.5 Hz, 1H), 6.83 (t, J = 7.1 Hz, 1H), 6.39 (dd, J = 7.0, 3.9 Hz, 2H), 5.39 (d, J = 9.2 Hz, 1H), 4.82 (d, J = 49.8 Hz, 1H), 4.30 (d, J = 6.1 Hz, 2H), 4.03 (m, 2H), 3.85 – 3.57 (m, 1H), 3.10 – 2.96 (m, 1H), 2.83 – 2.65 (m, 4H), 2.35 – 2.20 (m, 1H), 2.19 (s, 3H), 2.11 – 2.06 (m, 1H), 1.89 – 1.70 (m, 2H). Example 61. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methyl-3-(2,2,2-trifluoroethoxy)benzamide Step 1. Synthesis of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-N-methyl-3-(2,2,2-trifluoroethoxy)benzamide
將N-甲基-4-(丙-2-炔-1-基胺基)-3-(2,2,2-三氟乙氧基)苯甲醯胺( 中間物30;200 mg,0.70 mmol,1當量)、8-溴-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶( 中間物1;424 mg,1.05 mmol,1.5當量)、DIEA (90 mg,0.70 mmol,1當量)、CuI (133 mg,0.70 mmol,1當量)及Pd(PPh 3) 4(161 mg,0.14 mmol,0.2當量)於DMSO (5 mL)中之溶液在室溫及氮氣氛圍下攪拌2 h。所得混合物用水淬滅且用EtOAc (3*30 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用PE / EA (5:1)溶析,以得到呈棕黃色固體之4-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-N-甲基-3-(2,2,2-三氟乙氧基)苯甲醯胺(213 mg,37.34%)。LC-MS:(M+H) +實測值563.1。 步驟2. 4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-N-甲基-3-(2,2,2-三氟乙氧基)苯甲醯胺之合成 A solution of N-methyl-4-(prop-2-yn-1-ylamino)-3-(2,2,2-trifluoroethoxy)benzamide ( Intermediate 30 ; 200 mg, 0.70 mmol, 1 eq), 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( Intermediate 1 ; 424 mg, 1.05 mmol, 1.5 eq), DIEA (90 mg, 0.70 mmol, 1 eq), CuI (133 mg, 0.70 mmol, 1 eq) and Pd(PPh 3 ) 4 (161 mg, 0.14 mmol, 0.2 eq) in DMSO (5 mL) was stirred at room temperature under nitrogen atmosphere for 2 h. The resulting mixture was quenched with water and extracted with EtOAc (3*30 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (5:1) to give 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-N-methyl-3-(2,2,2-trifluoroethoxy)benzamide (213 mg, 37.34%) as a brown solid. LC-MS: (M+H) + found 563.1. Step 2. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methyl-3-(2,2,2-trifluoroethoxy)benzamide
將4-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-N-甲基-3-(2,2,2-三氟乙氧基)苯甲醯胺(50 mg,0.09 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(20 mg,0.10 mmol,1.1當量)、tBuXPhos Pd G3 (7 mg,0.009 mmol,0.1當量)及t-BuONa (34 mg,0.36 mmol,4當量)於THF (1.5 mL)中之混合物在65℃及氮氣氛圍下攪拌1 h。所得混合物用水淬滅且用CH 2Cl 2(3*20 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用CH 2Cl 2/ MeOH (10:1)溶析以得到粗產物。粗產物(100 mg)藉由具有以下條件(管柱:XBridge Prep OBD C18管柱,19*250 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3+0.05%NH 3H 2O),移動相B:ACN(1% 2mM NH 3-MEOH);流動速率:25 mL/min mL/min;梯度:在11min內51% B至73% B;波長:254nm/220nm nm;RT1(min):10.75)之製備型HPLC純化,以得到呈白色固體之4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-N-甲基-3-(2,2,2-三氟乙氧基)苯甲醯胺(3.2 mg,5.85%)。LC-MS:(M+H) +實測值615.20。 1H NMR (400 MHz, DMSO- d 6) δ 8.07 (m, 1H), 7.78 (d, J= 6.8 Hz, 1H), 7.53 – 7.38 (m, 2H), 6.89 – 6.76 (m, 2H), 6.39 (d, J= 7.5 Hz, 1H), 5.87 (t, J= 6.2 Hz, 1H), 5.36 (d, J= 9.2 Hz, 1H), 4.92 – 4.68 (m, 3H), 4.31 (d, J= 6.3 Hz, 2H), 4.02 (m, 2H), 3.76 – 3.62 (m, 1H), 3.09 – 2.96 (m, 1H), 2.76 (d, J= 4.5 Hz, 4H), 2.30 – 2.18 (m, 4H), 2.12 – 2.07 (m, 1H), 1.83 – 1.77 (m, 2H)。 實例62. 4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-(2-甲氧基乙氧基)-N-甲基苯甲醯胺之合成 步驟1. 4-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-3-(2-甲氧基乙氧基)-N-甲基苯甲醯胺之合成 A mixture of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-N-methyl-3-(2,2,2-trifluoroethoxy)benzamide (50 mg, 0.09 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (20 mg, 0.10 mmol, 1.1 eq), tBuXPhos Pd G3 (7 mg, 0.009 mmol, 0.1 eq) and t-BuONa (34 mg, 0.36 mmol, 4 eq) in THF (1.5 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was quenched with water and extracted with CH 2 Cl 2 (3*20 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH 2 Cl 2 / MeOH (10:1) to obtain a crude product. The crude product (100 mg) was purified by XBridge Prep OBD C18 column with the following conditions (column: XBridge Prep OBD C18 column, 19*250 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 +0.05% NH 3 H 2 O), mobile phase B: ACN (1% 2 mM NH 3 -MEOH); flow rate: 25 mL/min mL/min; gradient: 51% B to 73% B in 11 min; wavelength: 254 nm/220 nm nm; RT1 (min): 10.75) to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methyl-3-(2,2,2-trifluoroethoxy)benzamide (3.2 mg, 5.85%) as a white solid. LC-MS: (M+H) + found 615.20. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.07 (m, 1H), 7.78 (d, J = 6.8 Hz, 1H), 7.53 – 7.38 (m, 2H), 6.89 – 6.76 (m, 2H), 6.39 (d, J = 7.5 Hz, 1H), 5.87 (t, J = 6.2 Hz, 1H), 5.36 (d, J = 9.2 Hz, 1H), 4.92 – 4.68 (m, 3H), 4.31 (d, J = 6.3 Hz, 2H), 4.02 (m, 2H), 3.76 – 3.62 (m, 1H), 3.09 – 2.96 (m, 1H), 2.76 (d, J = 4.5 Hz, 4H), 2.30 – 2.18 (m, 4H), 2.12 – 2.07 (m, 1H), 1.83 – 1.77 (m, 2H). Example 62. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-(2-methoxyethoxy)-N-methylbenzamide Step 1. Synthesis of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-(2-methoxyethoxy)-N-methylbenzamide
將8-溴-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶( 中間物1;200 mg,0.49 mmol,1當量)、3-(2-甲氧基乙氧基)-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺( 中間物31;156 mg,0.59 mmol,1.2當量)、CuI (94 mg,0.49 mmol,1當量)、i-Pr 2NH (500 mg,4.94 mmol,10當量)及Pd(PPh 3) 4(114 mg,0.10 mmol,0.2當量)於DMSO (2 mL)中之混合物在室溫及氮氣氛圍下攪拌2 h。所得混合物用水稀釋且用EtOAc (3*10 mL)萃取。將所得混合物在減壓下濃縮。殘餘物藉由製備型TLC (DCM:MeOH = 20:1)純化,以得到呈黃色固體之4-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-3-(2-甲氧基乙氧基)-N-甲基苯甲醯胺(188 mg,65.64%)。LC-MS:(M+H) +實測值539.0。 步驟2. 4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-(2-甲氧基乙氧基)-N-甲基苯甲醯胺之合成 A mixture of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( Intermediate 1 ; 200 mg, 0.49 mmol, 1 eq), 3-(2-methoxyethoxy)-N-methyl-4-(prop-2-yn-1-ylamino)benzamide ( Intermediate 31 ; 156 mg, 0.59 mmol, 1.2 eq), CuI (94 mg, 0.49 mmol, 1 eq), i-Pr 2 NH (500 mg, 4.94 mmol, 10 eq) and Pd(PPh 3 ) 4 (114 mg, 0.10 mmol, 0.2 eq) in DMSO (2 mL) was stirred at room temperature under nitrogen atmosphere for 2 h. The resulting mixture was diluted with water and extracted with EtOAc (3*10 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH = 20:1) to give 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-(2-methoxyethoxy)-N-methylbenzamide (188 mg, 65.64%) as a yellow solid. LC-MS: (M+H) + found 539.0. Step 2. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-(2-methoxyethoxy)-N-methylbenzamide
將4-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-3-(2-甲氧基乙氧基)-N-甲基苯甲醯胺(84 mg,0.16 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺(35 mg,0.17 mmol,1.1當量)、RuPhos (10.2 mg,0.02 mmol,0.14當量)、Cs 2CO 3(203.0 mg,0.62 mmol,4當量)及Brettphos Pd G4 (17 mg,0.01 mmol,0.07當量)於二噁烷(1.5 mL)中之混合物在95℃及氮氣氛圍下攪拌隔夜。使混合物冷卻至室溫。所得混合物用水稀釋且用CH 2Cl 2(3*50 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/ MeOH 10:1)純化,以得到粗產物。粗產物藉由具有以下條件(管柱:XBridge Prep OBD C18管柱,19*250 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3+0.05%NH 3H 2O),移動相B:MEOH;流動速率:25 mL/min mL/min;梯度:在10min內44% B至69% B;波長:254nm/220nm nm;RT1(min):9.9,運行次數:3)之製備型HPLC純化,以得到呈白色固體之4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-(2-甲氧基乙氧基)-N-甲基苯甲醯胺(6.3 mg,6.78%)。LC-MS:(M+H) +實測值591.35。 1H NMR (400 MHz, DMSO- d 6) δ 8.10 (m, 1H), 7.79 (d, J= 6.8 Hz, 1H), 7.42 (d, J= 8.3 Hz, 1H), 7.35 (s, 1H), 6.83 (t, J= 7.2 Hz, 1H), 6.76 (d, J= 8.3 Hz, 1H), 6.39 (d, J= 7.5 Hz, 1H), 5.80 (t, J= 6.4 Hz, 1H), 5.39 (d, J= 9.1 Hz, 1H), 4.82 (d, J= 49.5 Hz, 1H), 4.30 (d, J= 6.3 Hz, 2H), 4.14 (t, J= 4.6 Hz, 2H), 4.02 (m, 2H), 3.72 (s, 3H), 3.34 (s, 3H), 3.02 (t, J= 10.6 Hz, 1H), 2.74 (d, J= 4.4 Hz, 4H), 2.35 – 2.04 (m, 5H), 1.91 – 1.69 (m, 2H)。 實例63. 4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基苯磺醯胺之合成 步驟1. 4-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-3-甲氧基-N,N-雙({[2-(三甲基矽烷基)乙氧基]甲基})苯磺醯胺之合成 A mixture of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-(2-methoxyethoxy)-N-methylbenzamide (84 mg, 0.16 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine (35 mg, 0.17 mmol, 1.1 eq), RuPhos (10.2 mg, 0.02 mmol, 0.14 eq), Cs2CO3 ( 203.0 mg, 0.62 mmol, 4 eq) and Brettphos Pd G4 (17 mg, 0.01 mmol, 0.07 eq) in dioxane (1.5 mL) was stirred at 95 °C under nitrogen atmosphere overnight. The mixture was cooled to room temperature. The resulting mixture was diluted with water and extracted with CH 2 Cl 2 (3*50 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 / MeOH 10:1) to give a crude product. The crude product was purified by HPLC with the following conditions (column: XBridge Prep OBD C18 column, 19*250 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 +0.05% NH 3 H 2 O), mobile phase B: MEOH; flow rate: 25 mL/min mL/min; gradient: 44% B to 69% B in 10 min; wavelength: 254 nm/220 nm nm; RT1(min): 9.9, runs: 3) to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-(2-methoxyethoxy)-N-methylbenzamide (6.3 mg, 6.78%) as a white solid. LC-MS: (M+H) + found 591.35. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.10 (m, 1H), 7.79 (d, J = 6.8 Hz, 1H), 7.42 (d, J = 8.3 Hz, 1H), 7.35 (s, 1H), 6.83 (t, J = 7.2 Hz, 1H), 6.76 (d, J = 8.3 Hz, 1H), 6.39 (d, J = 7.5 Hz, 1H), 5.80 (t, J = 6.4 Hz, 1H), 5.39 (d, J = 9.1 Hz, 1H), 4.82 (d, J = 49.5 Hz, 1H), 4.30 (d, J = 6.3 Hz, 2H), 4.14 (t, J = 4.6 Hz, 2H), 4.02 (m, 2H), 3.72 (s, 3H), 3.34 (s, 3H), 3.02 (t, J = 10.6 Hz, 1H), 2.74 (d, J = 4.4 Hz, 4H), 2.35 – 2.04 (m, 5H), 1.91 – 1.69 (m, 2H). Example 63. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxybenzenesulfonamide Step 1. Synthesis of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N,N-bis({[2-(trimethylsilyl)ethoxy]methyl})benzenesulfonamide
將8-溴-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶( 中間物1;50 mg,0.12 mmol,1當量)、3-甲氧基-4-(丙-2-炔-1-基胺基)-N,N-雙({[2-(三甲基矽烷基)乙氧基]甲基})苯磺醯胺( 中間物32;74.2 mg,0.15 mmol,1.2當量)、CuI (23.5 mg,0.12 mmol,1當量)、i-Pr 2NH (124.9 mg,1.23 mmol,10當量)及Pd(PPh 3) 4(28.5 mg,0.025 mmol,0.2當量)於DMSO (2 mL)中之混合物在室溫及氮氣氛圍下攪拌1h。所得混合物用EA (50 mL)稀釋且用水(8*50 mL)洗滌。殘餘物藉由製備型TLC (PE / EA 1:1)純化,以得到呈棕色油狀物之4-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-3-甲氧基-N,N-雙({[2-(三甲基矽烷基)乙氧基]甲基})苯磺醯胺(63 mg,65.60%)。LC-MS:(M+H) +實測值777.1。 步驟2. 4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N,N-雙({[2-(三甲基矽烷基)乙氧基]甲基})苯磺醯胺之合成 A mixture of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( Intermediate 1 ; 50 mg, 0.12 mmol, 1 eq), 3-methoxy-4-(prop-2-yn-1-ylamino)-N,N-bis({[2-(trimethylsilyl)ethoxy]methyl})benzenesulfonamide ( Intermediate 32 ; 74.2 mg, 0.15 mmol, 1.2 eq), CuI (23.5 mg, 0.12 mmol, 1 eq), i-Pr 2 NH (124.9 mg, 1.23 mmol, 10 eq) and Pd(PPh 3 ) 4 (28.5 mg, 0.025 mmol, 0.2 eq) in DMSO (2 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting mixture was diluted with EA (50 mL) and washed with water (8*50 mL). The residue was purified by preparative TLC (PE/EA 1:1) to give 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N,N-bis({[2-(trimethylsilyl)ethoxy]methyl})benzenesulfonamide (63 mg, 65.60%) as a brown oil. LC-MS: (M+H) + found 777.1. Step 2. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N,N-bis({[2-(trimethylsilyl)ethoxy]methyl})benzenesulfonamide
將4-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-3-甲氧基-N,N-雙({[2-(三甲基矽烷基)乙氧基]甲基})苯磺醯胺(200 mg,0.26 mmol,1當量)、(3S,4R)-4-銨基-3-氟-1-甲基哌啶-1-鎓(69.0 mg,0.51 mmol,2當量)、t-BuONa (98.8 mg,1.03 mmol,4當量)及tBuXphos Pd G3 (102.1 mg,0.13 mmol,0.5當量)溶解於THF (3 mL)中。將所得混合物在65℃下攪拌1h,然後冷卻至室溫,用乙酸乙酯(30 mL)稀釋且用3*30 mL之鹽水洗滌。所得混合物經無水硫酸鈉乾燥且在真空下濃縮。殘餘物藉由具有以下條件(管柱,C18矽膠;移動相,於水中之ACN,在30min內0%至100%梯度;偵測器,UV 254 nm)之反向急速層析純化,以得到呈白色固體之4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N,N-雙({[2-(三甲基矽烷基)乙氧基]甲基})苯磺醯胺(90 mg,42.22%)。LC-MS:(M+H) +實測值829.3。 步驟3. 4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基苯磺醯胺之合成 4-({3-[8-Bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N,N-bis({[2-(trimethylsilyl)ethoxy]methyl})benzenesulfonamide (200 mg, 0.26 mmol, 1 eq), (3S,4R)-4-ammonium-3-fluoro-1-methylpiperidin-1-ium (69.0 mg, 0.51 mmol, 2 eq), t-BuONa (98.8 mg, 1.03 mmol, 4 eq) and tBuXphos Pd G3 (102.1 mg, 0.13 mmol, 0.5 eq) were dissolved in THF (3 mL). The resulting mixture was stirred at 65° C. for 1 h, then cooled to room temperature, diluted with ethyl acetate (30 mL) and washed with 3*30 mL of brine. The resulting mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by reverse phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, ACN in water, gradient from 0% to 100% in 30 min; detector, UV 254 nm) to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N,N-bis({[2-(trimethylsilyl)ethoxy]methyl})benzenesulfonamide (90 mg, 42.22%) as a white solid. LC-MS: (M+H) + found 829.3. Step 3. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxybenzenesulfonamide
向4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N,N-雙({[2-(三甲基矽烷基)乙氧基]甲基})苯磺醯胺(90 mg,0.11 mmol,1當量)於CH 2Cl 2(2 mL)中之攪拌溶液中添加CF 3COOH (1 mL)。將所得溶液在室溫下攪拌1h,然後用飽和NaHCO 3鹼化至pH 8。水層用EtOAc (3*5 mL)萃取。合併的有機層用無水硫酸鈉乾燥且在真空下濃縮。殘餘物藉由製備型HPLC (管柱:XBridge Prep OBD C18管柱,19*250 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3+0.05%NH 3H 2O),移動相B:MEOH;流動速率:25 mL/min mL/min;梯度:在10min內45% B至60% B;波長:254nm/220nm nm;RT1(min):9.75;運行次數:4)純化,以得到呈白色固體之4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基苯磺醯胺(8.9 mg,14.39%)。LC-MS:(M+H) +實測值569.15。 1H NMR (400 MHz, DMSO- d 6) δ 7.79 (d, J= 6.7 Hz, 1H), 7.31 (dd, J= 8.3, 2.0 Hz, 1H), 7.25 (d, J= 2.0 Hz, 1H), 6.99 (s, 2H), 6.87 – 6.76 (m, 2H), 6.39 (d, J= 7.5 Hz, 1H), 6.20 (t, J= 6.3 Hz, 1H), 5.37 (d, J= 9.2 Hz, 1H), 4.88 – 4.75 ((d, J= 12.9 Hz, 1H), 4.28 (d, J= 6.2 Hz, 2H), 4.14 – 3.99 (m, 2H), 3.85 (s, 3H), 3.75 – 3.63 (m, 1H), 3.03 (t, J= 11.4 Hz, 1H), 2.76 (d, J= 11.4 Hz, 1H), 2.29 (d, J= 12.9 Hz, 1H), 2.19 (s, 3H), 2.09 (dd, J= 20.9, 4.5 Hz, 1H), 1.80 (dd, J= 12.1, 8.3 Hz, 2H)。 實例64. 4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯磺醯胺之合成 步驟1. 4-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-3-甲氧基-N-甲基-N-{[2-(三甲基矽烷基)乙氧基]甲基}苯磺醯胺之合成 To a stirred solution of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N,N-bis({[2-(trimethylsilyl)ethoxy]methyl})benzenesulfonamide (90 mg, 0.11 mmol, 1 eq) in CH2Cl2 ( 2 mL) was added CF3COOH (1 mL). The resulting solution was stirred at room temperature for 1 h and then basified to pH 8 with saturated NaHCO3 . The aqueous layer was extracted with EtOAc (3*5 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 19*250 mm, 5μm; mobile phase A: water (10mmol/L NH4HCO3 +0.05% NH3H2O ), mobile phase B: MEOH; flow rate: 25 mL/min mL/min; gradient : 45% B to 60% B in 10min; wavelength: 254nm/ 220nm nm; RT1(min): 9.75; Run number: 4) to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxybenzenesulfonamide (8.9 mg, 14.39%) as a white solid. LC-MS: (M+H) + found 569.15. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.79 (d, J = 6.7 Hz, 1H), 7.31 (dd, J = 8.3, 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.99 (s, 2H), 6.87 – 6.76 (m, 2H), 6.39 (d, J = 7.5 Hz, 1H), 6.20 (t, J = 6.3 Hz, 1H), 5.37 (d, J = 9.2 Hz, 1H), 4.88 – 4.75 ((d, J = 12.9 Hz, 1H), 4.28 (d, J = 6.2 Hz, 2H), 4.14 – 3.99 (m, 2H), 3.85 (s, 3H), 3.75 – 3.63 (m, 1H), 3.03 (t, J = 11.4 Hz, 1H), 2.76 (d, J = 11.4 Hz, 1H), 2.29 (d, J = 12.9 Hz, 1H), 2.19 (s, 3H), 2.09 (dd, J = 20.9, 4.5 Hz, 1H), 1.80 (dd, J = 12.1, 8.3 Hz, 2H). Example 64. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzenesulfonamide Step 1. Synthesis of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N-methyl-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide
將3-甲氧基-N-甲基-4-(丙-2-炔-1-基胺基)-N-{[2-(三甲基矽烷基)乙氧基]甲基}苯磺醯胺( 中間物33;284.9 mg,0.74 mmol,1當量)、8-溴-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶( 中間物1;300 mg,0.74 mmol,1當量)、CuI (141.1 mg,0.74 mmol,1當量)、i-Pr 2NH (749.7 mg,7.41 mmol,10當量)及Pd(PPh 3) 4(171.2 mg,0.15 mmol,0.2當量)於DMSO (2 mL)中之混合物在室溫及氮氣氛圍下攪拌1h。所得混合物藉由具有以下條件(管柱,C18矽膠;移動相,於水中之ACN,在30min內0%至100%梯度;偵測器,UV 254 nm)之反相急速層析純化,以得到呈白色固體之4-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-3-甲氧基-N-甲基-N-{[2-(三甲基矽烷基)乙氧基]甲基}苯磺醯胺(230 mg,46.93%)。LC-MS:(M+H) +實測值661.1。 步驟2. 4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基-N-{[2-(三甲基矽烷基)乙氧基]甲基}苯磺醯胺之合成 A mixture of 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide ( intermediate 33 ; 284.9 mg, 0.74 mmol, 1 eq), 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( intermediate 1 ; 300 mg, 0.74 mmol, 1 eq), CuI (141.1 mg, 0.74 mmol, 1 eq), i- Pr2NH (749.7 mg, 7.41 mmol, 10 eq) and Pd( PPh3 ) 4 (171.2 mg, 0.15 mmol, 0.2 eq) in DMSO (2 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting mixture was purified by reverse phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, ACN in water, gradient from 0% to 100% in 30 min; detector, UV 254 nm) to give 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N-methyl-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide (230 mg, 46.93%) as a white solid. LC-MS: (M+H) + found 661.1. Step 2. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methyl-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide
將4-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-3-甲氧基-N-甲基-N-{[2-(三甲基矽烷基)乙氧基]甲基}苯磺醯胺(100 mg,0.15 mmol,1當量)、(3S,4R)-4-銨基-3-氟-1-甲基哌啶-1-鎓(40.6 mg,0.30 mmol,2當量)、t-BuONa (58.1 mg,0.60 mmol,4當量)及tBuXphos Pd G3 (36.0 mg,0.045 mmol,0.3當量)於THF (1 mL)中之混合物在65℃下攪拌1h。使混合物冷卻至室溫,然後在真空下濃縮。殘餘物藉由具有以下條件(管柱,C18矽膠;移動相,於水中之ACN,在30min內0%至100%梯度;偵測器,UV 254 nm)之反相急速層析純化,以得到呈棕色固體之4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基-N-{[2-(三甲基矽烷基)乙氧基]甲基}苯磺醯胺(80 mg,74.25%)。LC-MS:(M+H) +實測值713.3。 步驟3. 4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯磺醯胺之合成 A mixture of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N-methyl-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide (100 mg, 0.15 mmol, 1 eq), (3S,4R)-4-ammonium-3-fluoro-1-methylpiperidin-1-ium (40.6 mg, 0.30 mmol, 2 eq), t-BuONa (58.1 mg, 0.60 mmol, 4 eq) and tBuXphos Pd G3 (36.0 mg, 0.045 mmol, 0.3 eq) in THF (1 mL) was stirred at 65 °C for 1 h. The mixture was cooled to room temperature and then concentrated under vacuum. The residue was purified by reverse phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, ACN in water, gradient 0% to 100% in 30 min; detector, UV 254 nm) to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methyl-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide (80 mg, 74.25%) as a brown solid. LC-MS: (M+H) + found 713.3. Step 3. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzenesulfonamide
在室溫下,向4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基-N-{[2-(三甲基矽烷基)乙氧基]甲基}苯磺醯胺(130 mg,0.18 mmol,1當量)於CH 2Cl 2(2 mL)中之攪拌溶液中逐滴添加CF3COOH (1 mL)。將所得溶液攪拌0.5 h,然後用飽和NaHCO 3鹼化至pH 8。水層用EtOAc (3*50 mL)萃取。合併的有機層用無水硫酸鈉乾燥且在真空下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/ MeOH 10:1)純化,以得到呈白色固體之4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯磺醯胺(11.0 mg,10.34%)。LC-MS:(M+H) +實測值583.20。 1H NMR (400 MHz, DMSO- d 6) δ 7.79 (d, J= 6.8 Hz, 1H), 7.28 (dd, J= 8.3, 2.0 Hz, 1H), 7.15 (d, J= 2.0 Hz, 1H), 7.05 (m, 1H), 6.87 – 6.79 (m, 2H), 6.39 (d, J= 7.5 Hz, 1H), 6.32 (t, J= 6.2 Hz, 1H), 5.38 (d, J= 9.2 Hz, 1H), 4.88 (d, J= 11.2, 1H), 4.29 (d, J= 6.2 Hz, 2H), 4.06 – 4.01 (m, 2H), 3.86 (s, 3H), 3.79 – 3.58 (m, 1H), 3.04 (s, 1H), 2.77 (d, J= 11.2 Hz, 1H), 2.35 (d, J= 5.2 Hz, 4H), 2.19 (s, 3H), 2.11 (s, 1H), 1.79 (s, 2H)。 實例65. 4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N,N-二甲基苯磺醯胺之合成 步驟1. 4-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-3-甲氧基-N,N-二甲基苯磺醯胺之合成 To a stirred solution of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methyl-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide (130 mg, 0.18 mmol, 1 eq) in CH 2 Cl 2 (2 mL) was added CF 3 COOH (1 mL) dropwise at room temperature. The resulting solution was stirred for 0.5 h and then basified to pH 8 with saturated NaHCO 3. The aqueous layer was extracted with EtOAc (3*50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by preparative TLC (CH 2 Cl 2 / MeOH 10:1) to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzenesulfonamide (11.0 mg, 10.34%) as a white solid. LC-MS: (M+H) + found 583.20. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.79 (d, J = 6.8 Hz, 1H), 7.28 (dd, J = 8.3, 2.0 Hz, 1H), 7.15 (d, J = 2.0 Hz, 1H), 7.05 (m, 1H), 6.87 – 6.79 (m, 2H), 6.39 (d, J = 7.5 Hz, 1H), 6.32 (t, J = 6.2 Hz, 1H), 5.38 (d, J = 9.2 Hz, 1H), 4.88 (d, J = 11.2, 1H), 4.29 (d, J = 6.2 Hz, 2H), 4.06 – 4.01 (m, 2H), 3.86 (s, 3H), 3.79 – 3.58 (m, 1H), 3.04 (s, 1H), 2.77 (d, J = 11.2 Hz, 1H), 2.35 (d, J = 5.2 Hz, 4H), 2.19 (s, 3H), 2.11 (s, 1H), 1.79 (s, 2H). Example 65. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N,N-dimethylbenzenesulfonamide Step 1. Synthesis of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N,N-dimethylbenzenesulfonamide
將8-溴-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶( 中間物1;150 mg,0.37 mmol,1.0當量)、3-甲氧基-N,N-二甲基-4-(丙-2-炔-1-基胺基)苯磺醯胺( 中間物34;127.2 mg,0.47 mmol,1.3當量)、i-Pr 2NH (374.8 mg,3.70 mmol,10當量)、CuI (70.5 mg,0.37 mmol,1.0當量)及Pd(PPh 3)4 (214.0 mg,0.18 mmol,0.5當量)於DMSO (3 mL)中之混合物在室溫及氮氣氛圍下攪拌1 h。所得溶液藉由具有以下條件(管柱,C18矽膠;移動相,於水中之MeOH (10mmol/L NH 4HCO 3),在30min內0%至100%梯度;偵測器,UV 254 nm)之反相急速層析純化,以得到呈白色固體之4-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-3-甲氧基-N,N-二甲基苯磺醯胺(120 mg,59.41%)。LC-MS:(M+H) +實測值545.05。 步驟2. 4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N,N-二甲基苯磺醯胺之合成 A mixture of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( Intermediate 1 ; 150 mg, 0.37 mmol, 1.0 equiv), 3-methoxy-N,N-dimethyl-4-(prop-2-yn-1-ylamino)benzenesulfonamide ( Intermediate 34 ; 127.2 mg, 0.47 mmol, 1.3 equiv), i-Pr 2 NH (374.8 mg, 3.70 mmol, 10 equiv), CuI (70.5 mg, 0.37 mmol, 1.0 equiv) and Pd(PPh 3 ) 4 (214.0 mg, 0.18 mmol, 0.5 equiv) in DMSO (3 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting solution was purified by reverse phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeOH (10 mmol/L NH 4 HCO 3 ) in water, gradient from 0% to 100% in 30 min; detector, UV 254 nm) to give 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N,N-dimethylbenzenesulfonamide (120 mg, 59.41%) as a white solid. LC-MS: (M+H) + found 545.05. Step 2. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N,N-dimethylbenzenesulfonamide
將4-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-及]丙-2-炔-1-基}胺基)-3-甲氧基-N,N-二甲基苯磺醯胺(120 mg,0.22 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(90.2 mg,0.44 mmol,2當量)、t-BuONa (126.8 mg,1.32 mmol,6.0當量)及tBuXPhos Pd G3 (87.4 mg,0.11 mmol,0.5當量)於THF (2 mL) 中之混合物在65℃及氮氣氛圍下攪拌1 h。過濾所得混合物,濾餅用DCM洗滌。將濾液在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/於MeOH中之7M NH 3= 15:1)及製備型HPLC (管柱:XBridge Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(10mmol/L NH4HCO3)+0.05%NH3.H2O,移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在7 min內31% B至57% B;波長:254nm/220nm nm;RT1(min):7.88)純化,以得到呈白色固體之4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N,N-二甲基苯磺醯胺(13 mg,9.85%)。LC-MS:(M+H) +實測值597.30。 1H NMR (400 MHz, DMSO-d6) δ 7.79 (d, J= 6.8 Hz, 1H), 7.25 (dd, J= 8.5, 2.0 Hz, 1H), 7.05 (d, J= 2.0 Hz, 1H), 6.89 (d, J= 8.4 Hz, 1H), 6.83 (t, J= 7.1 Hz, 1H), 6.45 (t, J= 6.1 Hz, 1H), 6.40 (d, J= 7.6 Hz, 1H), 5.37 (d, J= 9.2 Hz, 1H), 4.82 (d, J= 49.5 Hz, 1H), 4.31 (d, J= 6.2 Hz, 2H), 4.04 (m, 2H), 3.85 (s, 3H), 3.81 – 3.57 (m, 1H), 3.03 (t, J= 11.6 Hz, 1H), 2.76 (d, J= 11.5 Hz, 1H), 2.56 (s, 6H), 2.29 (d, J= 13.0 Hz, 1H), 2.19 (s, 3H), 2.13 – 2.00 (m, 1H), 1.86 – 1.72 (m, 2H)。 實例66. (3S,4R)-N-[2-(3-{[4-(乙磺醯基)-2-甲氧基苯基]胺基}丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基]-3-氟-1-甲基哌啶-4-胺之合成 步驟1. N-{3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}-4-(乙磺醯基)-2-甲氧基苯胺之合成 A mixture of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N,N-dimethylbenzenesulfonamide (120 mg, 0.22 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (90.2 mg, 0.44 mmol, 2 eq), t-BuONa (126.8 mg, 1.32 mmol, 6.0 eq) and tBuXPhos Pd G3 (87.4 mg, 0.11 mmol, 0.5 eq) in THF (2 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was filtered and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 /7M NH 3 in MeOH = 15:1) and preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3) + 0.05% NH 3 .H 2 O, mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 31% B to 57% B in 7 min; wavelength: 254 nm/220 nm). nm; RT1 (min): 7.88) to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N,N-dimethylbenzenesulfonamide (13 mg, 9.85%) as a white solid. LC-MS: (M+H) + found 597.30. 1 H NMR (400 MHz, DMSO-d6) δ 7.79 (d, J = 6.8 Hz, 1H), 7.25 (dd, J = 8.5, 2.0 Hz, 1H), 7.05 (d, J = 2.0 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.83 (t, J = 7.1 Hz, 1H), 6.45 (t, J = 6.1 Hz, 1H), 6.40 (d, J = 7.6 Hz, 1H), 5.37 (d, J = 9.2 Hz, 1H), 4.82 (d, J = 49.5 Hz, 1H), 4.31 (d, J = 6.2 Hz, 2H), 4.04 (m, 3.85 (s, 3H), 3.81 – 3.57 (m, 1H), 3.03 (t, J = 11.6 Hz, 1H), 2.76 (d, J = 11.5 Hz, 1H), 2.56 (s, 6H), 2.29 (d, J = 13.0 Hz, 1H), 2.19 (s, 3H), 2.13 – 2.00 (m, 1H), 1.86 – 1.72 (m, 2H). Example 66. Synthesis of (3S,4R)-N-[2-(3-{[4-(ethylsulfonyl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine Step 1. Synthesis of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-4-(ethylsulfonyl)-2-methoxyaniline
將8-溴-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶( 中間物1;150 mg,0.37 mmol,1.0當量)、4-(乙磺醯基)-2-甲氧基-N-(丙-2-炔-1-基)苯胺( 中間物36;150.1 mg,0.59 mmol,1.2當量)、Pd(PPh 3) 4(119.9 mg,0.10 mmol,0.2當量)、CuI (93.1 mg,0.49 mmol,1.0當量)及i-Pr 2NH (500 mg,4.94 mmol,10.0當量)於DMSO (2 mL)中之混合物在室溫及氮氣氛圍下攪拌1 h。所得溶液藉由具有以下條件(管柱,C18矽膠;移動相,於水中之MeOH (10mmol/L NH 4HCO 3),在30 min內0%至100%梯度;偵測器,UV 254 nm)之反相急速層析直接純化,以得到呈黃色固體之N-{3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}-4-(乙磺醯基)-2-甲氧基苯胺(189 mg,72.1%)。LC-MS:(M+H) +實測值530.1。 步驟2. (3S,4R)-N-[2-(3-{[4-(乙磺醯基)-2-甲氧基苯基]胺基}丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基]-3-氟-1-甲基哌啶-4-胺之合成 A mixture of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( Intermediate 1 ; 150 mg, 0.37 mmol, 1.0 equiv), 4-(ethylsulfonyl)-2-methoxy-N-(prop-2-yn-1-yl)aniline ( Intermediate 36 ; 150.1 mg, 0.59 mmol, 1.2 equiv), Pd( PPh3 ) 4 (119.9 mg, 0.10 mmol, 0.2 equiv), CuI (93.1 mg, 0.49 mmol, 1.0 equiv) and i- Pr2NH (500 mg, 4.94 mmol, 10.0 equiv) in DMSO (2 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting solution was directly purified by reverse phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeOH (10 mmol/L NH 4 HCO 3 ) in water, gradient from 0% to 100% in 30 min; detector, UV 254 nm) to give N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-4-(ethylsulfonyl)-2-methoxyaniline (189 mg, 72.1%) as a yellow solid. LC-MS: (M+H) + found 530.1. Step 2. Synthesis of (3S,4R)-N-[2-(3-{[4-(ethylsulfonyl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine
將N-{3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}-4-(乙磺醯基)-2-甲氧基苯胺(189 mg,0.36 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺(150 mg,0.73 mmol,2.0當量)、t-BuONa (205.5 mg,2.14 mmol,6當量)及tBuXphos Pd G3 (141.5 mg,0.18 mmol,0.5當量)於THF (2 mL)中之混合物在65℃及氮氣氛圍下攪拌1 h。將所得混合物在減壓下濃縮。殘餘物藉由製備型TLC (DCM/於MeOH中之7 M NH 3= 20:1)及製備型HPLC (管柱:XBridge Shield RP18 OBD管柱,30*150 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3+0.05%NH 3 .H 2O),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在7 min內34% B至49% B;波長:254nm/220nm nm;RT1(min):6.95;運行次數:3)純化,以得到呈白色固體之(3S,4R)-N-[2-(3-{[4-(乙磺醯基)-2-甲氧基苯基]胺基}丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基]-3-氟-1-甲基哌啶-4-胺(38.9 mg,18.73%)。LC-MS:(M+H) +實測值582.20。 1H NMR (400 MHz, DMSO-d6) δ 7.80 (d, J= 6.8 Hz, 1H), 7.35 (dd, J= 8.4, 2.0 Hz, 1H), 7.18 (d, J= 2.0 Hz, 1H), 6.93 – 6.72 (m, 2H), 6.56 – 6.34 (m, 2H), 5.38 (d, J= 9.2 Hz, 1H), 4.82 (d, J= 49.4 Hz, 1H), 4.31 (d, J= 6.2 Hz, 2H), 4.04 (m, 2H), 3.89 (s, 3H), 3.81 – 3.57 (m, 1H), 3.16 (m, 2H), 3.03 (t, J= 11.3 Hz, 1H), 2.76 (d, J= 11.3 Hz, 1H), 2.28 (d, J= 12.9 Hz, 1H), 2.19 (s, 3H), 2.08 (d, J= 3.9 Hz, 1H), 1.87 – 1.71 (m, 2H), 1.08 (t, J= 7.3 Hz, 3H)。 實例67. (3S,4R)-N-[2-(3-{[4-(環丙烷磺醯基)-2-甲氧基苯基]胺基}丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基]-3-氟-1-甲基哌啶-4-胺之合成 步驟1. N-{3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}-4-(環丙烷磺醯基)-2-甲氧基苯胺之合成 A mixture of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-4-(ethylsulfonyl)-2-methoxyaniline (189 mg, 0.36 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine (150 mg, 0.73 mmol, 2.0 eq), t-BuONa (205.5 mg, 2.14 mmol, 6 eq) and tBuXphos Pd G3 (141.5 mg, 0.18 mmol, 0.5 eq) in THF (2 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM/7 M NH 3 in MeOH = 20:1) and preparative HPLC (column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 +0.05% NH 3 . H 2 O), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 34% B to 49% B in 7 min; wavelength: 254 nm/220 nm nm; RT1(min): 6.95; Runs: 3) to give (3S,4R)-N-[2-(3-{[4-(ethylsulfonyl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine (38.9 mg, 18.73%) as a white solid. LC-MS: (M+H) + found 582.20. 1 H NMR (400 MHz, DMSO-d6) δ 7.80 (d, J = 6.8 Hz, 1H), 7.35 (dd, J = 8.4, 2.0 Hz, 1H), 7.18 (d, J = 2.0 Hz, 1H), 6.93 – 6.72 (m, 2H), 6.56 – 6.34 (m, 2H), 5.38 (d, J = 9.2 Hz, 1H), 4.82 (d, J = 49.4 Hz, 1H), 4.31 (d, J = 6.2 Hz, 2H), 4.04 (m, 2H), 3.89 (s, 3H), 3.81 – 3.57 (m, 1H), 3.16 (m, 2H), 3.03 (t, J = 11.3 Hz, 1H), 2.76 (d, J = 11.3 Hz, 1H), 2.28 (d, J = 12.9 Hz, 1H), 2.19 (s, 3H), 2.08 (d, J = 3.9 Hz, 1H), 1.87 – 1.71 (m, 2H), 1.08 (t, J = 7.3 Hz, 3H). Example 67. Synthesis of (3S,4R)-N-[2-(3-{[4-(cyclopropanesulfonyl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine Step 1. Synthesis of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-4-(cyclopropanesulfonyl)-2-methoxyaniline
將4-(環丙烷磺醯基)-2-甲氧基-N-(丙-2-炔-1-基)苯胺( 中間物37;294.8 mg,1.11 mmol,1.5當量)、8-溴-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶( 中間物1;300 mg,0.74 mmol,1當量)、CuI (141.1 mg,0.74 mmol,1當量)、i-Pr 2NH (749.7 mg,7.40 mmol,10當量)及Pd(PPh 3) 4(171.22 mg,0.15 mmol,0.2當量)於DMSO (4 mL)中之混合物在室溫及氮氣氛圍下攪拌1 h。所得混合物用EtOAc (100 mL)稀釋且用鹽水(3*100 mL)洗滌。有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/ MeOH = 20:1)純化,以得到呈棕色固體之N-{3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}-4-(環丙烷磺醯基)-2-甲氧基苯胺(500 mg)。LC-MS:(M+H) +實測值542.1。 步驟2. (3S,4R)-N-[2-(3-{[4-(環丙烷磺醯基)-2-甲氧基苯基]胺基}丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基]-3-氟-1-甲基哌啶-4-胺之合成 A mixture of 4-(cyclopropanesulfonyl)-2-methoxy-N-(prop-2-yn-1-yl)aniline ( intermediate 37 ; 294.8 mg, 1.11 mmol, 1.5 equiv), 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( intermediate 1 ; 300 mg, 0.74 mmol, 1 equiv), CuI (141.1 mg, 0.74 mmol, 1 equiv), i- Pr2NH (749.7 mg, 7.40 mmol, 10 equiv) and Pd( PPh3 ) 4 (171.22 mg, 0.15 mmol, 0.2 equiv) in DMSO (4 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting mixture was diluted with EtOAc (100 mL) and washed with brine (3*100 mL). The organic layer was dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 / MeOH = 20:1) to give N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-4-(cyclopropanesulfonyl)-2-methoxyaniline (500 mg) as a brown solid. LC-MS: (M+H) + found 542.1. Step 2. Synthesis of (3S,4R)-N-[2-(3-{[4-(cyclopropanesulfonyl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine
將N-{3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}-4-(環丙烷磺醯基)-2-甲氧基苯胺(300 mg,0.55 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(226.9 mg,1.10 mmol,2當量)、t-BuONa (265.8 mg,2.76 mmol,5當量)及tBuXPhos Pd G3 (219.7 mg,0.28 mmol,0.5當量)於THF (4 mL)中之混合物在65℃及氮氣氛圍下攪拌1 h。使混合物冷卻至室溫。將所得混合物在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/於MeOH中之7M NH 3= 20:1)純化。殘餘物藉由具有以下條件(管柱:XBridge Prep OBD C18管柱,19*250 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3+0.05%NH 3 .H 2O),移動相B:ACN(1% 2mM NH 3-MEOH);流動速率:25 mL/min mL/min;梯度:在10min內55% B至66% B;波長:254nm/220nm nm;RT1(min):9.17;運行次數:5)之製備型HPLC純化,以得到呈灰白色固體之(3S,4R)-N-[2-(3-{[4-(環丙烷磺醯基)-2-甲氧基苯基]胺基}丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基]-3-氟-1-甲基哌啶-4-胺(31.1 mg,9.34%)。LC-MS:(M+H) +實測值594.25。1H NMR (400 MHz, DMSO-d6) δ 7.85 – 7.77 (d, J= 6.7 Hz, 1H), 7.41 – 7.28 (dd, J= 2.0, 8.3 Hz, 1H), 7.25 – 7.15 (d, J= 2.0 Hz, 1H), 6.93 – 6.79 (m, 2H), 6.56 – 6.46 (t, J= 6.2 Hz, 1H), 6.45 – 6.36 (d, J= 7.6 Hz, 1H), 5.55 – 5.46 (d, J= 9.0 Hz, 1H), 5.01 – 4.81 (d, J= 48.9 Hz, 1H), 4.39 – 4.29 (d, J= 6.2 Hz, 2H), 4.13 – 3.98 (m, 2H), 3.95 – 3.87 (s, 3H), 3.85 – 3.67 (d, J= 29.1 Hz, 1H), 3.29 – 3.15 (s, 1H), 3.00 – 2.87 (s, 1H), 2.79 – 2.68 (m, 1H), 2.64 – 2.54 (s,1H), 2.42 – 2.26 (s, 4H), 1.96 – 1.73 (m, 2H), 1.11 – 1.01 (dt, J= 3.3, 5.9 Hz, 2H), 1.01 – 0.92 (m, 2H)。 實例68. (3S,4R)-3-氟-N-(2-{3-[(2-氟-4-甲磺醯基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)-1-甲基哌啶-4-胺之合成 步驟1. N-{3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}-2-氟-4-甲磺醯基苯胺之合成 A mixture of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-4-(cyclopropanesulfonyl)-2-methoxyaniline (300 mg, 0.55 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (226.9 mg, 1.10 mmol, 2 eq), t-BuONa (265.8 mg, 2.76 mmol, 5 eq) and tBuXPhos Pd G3 (219.7 mg, 0.28 mmol, 0.5 eq) in THF (4 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 /7M NH 3 in MeOH = 20:1). The residue was purified by preparative TLC with the following conditions (column: XBridge Prep OBD C18 column, 19*250 mm, 5μm; mobile phase A: water (10mmol/L NH 4 HCO 3 +0.05% NH 3 .H 2 O), mobile phase B: ACN (1% 2mM NH 3 -MEOH); flow rate: 25 mL/min mL/min; gradient: 55% B to 66% B in 10min; wavelength: 254nm/220nm nm; RT1(min): 9.17; runs: 5) to give (3S,4R)-N-[2-(3-{[4-(cyclopropanesulfonyl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine (31.1 mg, 9.34%) as an off-white solid. LC-MS: (M+H) + found 594.25. 1H NMR (400 MHz, DMSO-d6) δ 7.85 – 7.77 (d, J = 6.7 Hz, 1H), 7.41 – 7.28 (dd, J = 2.0, 8.3 Hz, 1H), 7.25 – 7.15 (d, J = 2.0 Hz, 1H), 6.93 – 6.79 (m, 2H), 6.56 – 6.46 (t, J = 6.2 Hz, 1H), 6.45 – 6.36 (d, J = 7.6 Hz, 1H), 5.55 – 5.46 (d, J = 9.0 Hz, 1H), 5.01 – 4.81 (d, J = 9 – 3.87 (s, 3H), 3.85 – 3.67 (d, J = 29.1 Hz, 1H), 3.29 – 3.15 (s, 1H) , 3.00 – 2.87 (s, 1H), 2.79 – 2.68 (m, 1H), 2.64 – 2.54 (s,1H), 2.42 – 2.26 (s, 4H), 1.96 – 1.73 (m, 2H), 1.11 – 1.01 (dt, J = 3.3, 5.9 Hz, 2H), 1.01 – 0.92 (m, 2H). Example 68. Synthesis of (3S,4R)-3-fluoro-N-(2-{3-[(2-fluoro-4-methylsulfonylphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine Step 1. Synthesis of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-2-fluoro-4-methanesulfonylaniline
將8-溴-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶( 中間物1;360 mg,0.89 mmol,1當量),2-氟-4-甲磺醯基-N-(丙-2-炔-1-基)苯胺( 中間物38;222.2 mg,0.98 mmol,1.1當量)、CuI (169.3 mg,0.89 mmol,1.0當量)、Pd(PPh 3) 4(513.7 mg,0.45 mmol,0.5當量)及i-Pr 2NH (899.6 mg,8.89 mmol,10當量)於DMSO (4 mL) 中之混合物在室溫及氮氣氛圍下攪拌1 h。所得溶液藉由具有以下條件(管柱,C18矽膠;移動相,於水中之MeOH (10mmol/L NH 4HCO 3),在10 min內0%至100%梯度;偵測器,UV 254 nm)之反相急速層析直接純化,以得到呈白色固體之N-{3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}-2-氟-4-甲磺醯基苯胺(490 mg)。LC-MS:(M+H) +實測值503.9。 步驟2. (3S,4R)-3-氟-N-(2-{3-[(2-氟-4-甲磺醯基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)-1-甲基哌啶-4-胺之合成 A mixture of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( intermediate 1 ; 360 mg, 0.89 mmol, 1 eq), 2-fluoro-4-methanesulfonyl-N-(prop-2-yn-1-yl)aniline ( intermediate 38 ; 222.2 mg, 0.98 mmol, 1.1 eq), CuI (169.3 mg, 0.89 mmol, 1.0 eq), Pd( PPh3 ) 4 (513.7 mg, 0.45 mmol, 0.5 eq) and i- Pr2NH (899.6 mg, 8.89 mmol, 10 eq) in DMSO (4 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting solution was directly purified by reverse phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeOH (10 mmol/L NH 4 HCO 3 ) in water, gradient from 0% to 100% in 10 min; detector, UV 254 nm) to give N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-2-fluoro-4-methanesulfonylaniline (490 mg) as a white solid. LC-MS: (M+H) + found 503.9. Step 2. Synthesis of (3S,4R)-3-fluoro-N-(2-{3-[(2-fluoro-4-methylsulfonylphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine
將N-{3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}-2-氟-4-甲磺醯基苯胺(200 mg,0.40 mmol,1當量)、(3S,4R)-3-氟-1-甲基-哌啶-4-胺二鹽酸鹽(162.3 mg,0.80 mmol,2當量)、t-BuONa (228.69 mg,2.38 mmol,6當量)、tBuXPhos Pd G3 (157.5 mg,0.20 mmol,0.5當量)於THF (2.0 mL) 中之混合物在65℃及氮氣氛圍下攪拌1 h。過濾所得混合物,濾餅用DCM洗滌。將濾液在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/於MeOH中之7 M NH 3= 15:1)及具有以下條件(管柱:XBridge Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3)+0.05%NH 3 .H 2O,移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在7 min內26% B至52% B;波長:254nm/220nm nm;RT1(min):7.9)之製備型HPLC純化,以得到呈白色固體之(3S,4R)-3-氟-N-(2-{3-[(2-氟-4-甲磺醯基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)-1-甲基哌啶-4-胺(43.3 mg,19.53%)。LC-MS:(M+H) +實測值556.15。 1H NMR (400 MHz, DMSO- d 6) δ 7.80 (d, J= 6.8 Hz, 1H), 7.58 (d, J= 9.5 Hz, 2H), 7.08 (t, J= 8.5 Hz, 2H), 6.84 (t, J= 7.1 Hz, 1H), 6.40 (d, J= 7.6 Hz, 1H), 5.37 (d, J= 9.2 Hz, 1H), 4.82 (d, J= 49.6 Hz, 1H), 4.34 (d, J= 5.9 Hz, 2H), 4.05 (m, 2H), 3.71 (dd, J= 27.0, 7.9 Hz, 1H), 3.12 (s, 3H), 3.03 (t, J= 11.6 Hz, 1H), 2.76 (d, J= 11.2 Hz, 1H), 2.29 (d, J= 12.9 Hz, 1H), 2.19 (s, 3H), 2.08 (d, J= 7.2 Hz, 1H), 1.79 (d, J= 8.3 Hz, 2H)。 實例69. 4-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)-2-甲基丁-3-炔-2-醇之合成 步驟1. 4-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)-2-甲基丁-3-炔-2-醇之合成 A mixture of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-2-fluoro-4-methanesulfonylaniline (200 mg, 0.40 mmol, 1 eq), (3S,4R)-3-fluoro-1-methyl-piperidin-4-amine dihydrochloride (162.3 mg, 0.80 mmol, 2 eq), t-BuONa (228.69 mg, 2.38 mmol, 6 eq), tBuXPhos Pd G3 (157.5 mg, 0.20 mmol, 0.5 eq) in THF (2.0 mL) was stirred at 65° C. under nitrogen atmosphere for 1 h. The resulting mixture was filtered and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was separated by preparative TLC (CH 2 Cl 2 /7 M NH 3 in MeOH = 15:1) with the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 )+0.05% NH 3 . H 2 O, mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 26% B to 52% B in 7 min; wavelength: 254 nm/220 nm nm; RT1 (min): 7.9) to give (3S,4R)-3-fluoro-N-(2-{3-[(2-fluoro-4-methylsulfonylphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine (43.3 mg, 19.53%) as a white solid. LC-MS: (M+H) + found 556.15. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.80 (d, J = 6.8 Hz, 1H), 7.58 (d, J = 9.5 Hz, 2H), 7.08 (t, J = 8.5 Hz, 2H), 6.84 (t, J = 7.1 Hz, 1H), 6.40 (d, J = 7.6 Hz, 1H), 5.37 (d, J = 9.2 Hz, 1H), 4.82 (d, J = 49.6 Hz, 1H), 4.34 (d, J = 5.9 Hz, 2H), 4.05 (m, 2H), 3.71 (dd, J = 27.0, 7.9 Hz, 1H), 3.12 (s, 3H), 3.03 (t, J = 11.6 Hz, 1H), 2.76 (d, J = 11.2 Hz, 1H), 2.29 (d, J = 12.9 Hz, 1H), 2.19 (s, 3H), 2.08 (d, J = 7.2 Hz, 1H), 1.79 (d, J = 8.3 Hz, 2H). Example 69. Synthesis of 4-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)-2-methylbut-3-yn-2-ol Step 1. Synthesis of 4-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)-2-methylbut-3-yn-2-ol
將8-溴-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶( 中間物1;300.0 mg,0.74 mmol,1當量)於DMSO (5 mL)中之溶液用2-甲基-3-丁炔-2-醇(124.6 mg,1.48 mmol,2當量)、i-Pr 2NH (749.7 mg,7.40 mmol,10當量)、Pd(PPh 3) 4(171.2 mg,0.15 mmol,0.20當量)及CuI (70.5 mg,0.37 mmol,0.50當量)處理。將所得混合物在30℃及氮氣氛圍下攪拌1h,然後使用具有以下條件之C18急速層析純化:移動相A:水,移動相B:ACN;流動速率:60 mL/min;梯度:在15 min內0% B至100% B;波長:254 nm;220 nm。此產生呈白色固體之4-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)-2-甲基丁-3-炔-2-醇(230.0 mg,86.0%)。LC-MS:(M+H) +實測值361.0。 步驟2. 4-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)-2-甲基丁-3-炔-2-醇之合成 A solution of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( intermediate 1 ; 300.0 mg, 0.74 mmol, 1 eq) in DMSO (5 mL) was treated with 2-methyl-3-butyn-2-ol (124.6 mg, 1.48 mmol, 2 eq), i- Pr2NH (749.7 mg, 7.40 mmol, 10 eq), Pd( PPh3 ) 4 (171.2 mg, 0.15 mmol, 0.20 eq) and CuI (70.5 mg, 0.37 mmol, 0.50 eq). The resulting mixture was stirred at 30°C under nitrogen atmosphere for 1 h and then purified using C18 flash chromatography with the following conditions: mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 15 min; wavelength: 254 nm; 220 nm. This produced 4-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)-2-methylbut-3-yn-2-ol (230.0 mg, 86.0%) as a white solid. LC-MS: (M+H) + found 361.0. Step 2. Synthesis of 4-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)-2-methylbut-3-yn-2-ol
將4-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]-2-甲基丁-3-炔-2-醇(150.0 mg,0.42 mmol,1當量)於THF (3 mL)中之溶液用(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(170.4 mg,0.83 mmol,2當量)、t-BuONa (239.5 mg,2.49 mmol,6當量)及t-BuXPhosPdG3 (132.0 mg,0.17 mmol,0.40當量)處理。將所得混合物在65℃及氮氣氛圍下攪拌30 min。移除溶劑後,殘餘物使用具有以下條件之C18急速層析純化:移動相A:水,移動相B:ACN;流動速率:60 mL/min;梯度:在30 min內0% B至100% B;254/220 nm。粗產物使用具有以下條件之製備型HPLC純化:管柱:Xselect CSH C18 OBD管柱,30*150mm,5μm;移動相A:水(0.1% FA),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在7 min內10% B至25% B;波長:254nm/220nm nm;RT1(min):6.02。此產生呈白色固體之4-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)-2-甲基丁-3-炔-2-醇(20.7 mg,12.08%)。LC-MS:(M+H) +實測值413.10。 1H NMR (400 MHz, DMSO- d 6) 7.82 (d, J= 6.6 Hz, 1H), 6.85 (t, J= 7.2 Hz, 1H), 6.41 (d, J= 7.4 Hz, 1H), 5.40 (d, J= 8.7 Hz, 2H), 4.85 (d, J= 49.3 Hz, 1H), 4.11 (m, 2H), 3.80-3.67 (m, 1H), 3.08 (d, J= 11.8 Hz, 1H), 2.79 (d, J= 11.1 Hz, 1H), 2.38-2.06 (m, 5H), 1.84 (s, 2H), 1.50 (s, 6H)。 實例70. (2R)-4-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丁-3-炔-2-醇之合成 步驟1. (2R)-4-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丁-3-炔-2-醇之合成 A solution of 4-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]-2-methylbut-3-yn-2-ol (150.0 mg, 0.42 mmol, 1 eq) in THF (3 mL) was treated with (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (170.4 mg, 0.83 mmol, 2 eq), t-BuONa (239.5 mg, 2.49 mmol, 6 eq) and t-BuXPhosPdG3 (132.0 mg, 0.17 mmol, 0.40 eq). The resulting mixture was stirred at 65 °C under nitrogen atmosphere for 30 min. After removing the solvent, the residue was purified by C18 flash chromatography with the following conditions: mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm. The crude product was purified by preparative HPLC with the following conditions: column: Xselect CSH C18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 10% B to 25% B in 7 min; wavelength: 254nm/220nm nm; RT1(min): 6.02. This resulted in 4-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)-2-methylbut-3-yn-2-ol (20.7 mg, 12.08%) as a white solid. LC-MS: (M+H) + found 413.10. 1 H NMR (400 MHz, DMSO- d 6 ) 7.82 (d, J = 6.6 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.41 (d, J = 7.4 Hz, 1H), 5.40 (d, J = 8.7 Hz, 2H), 4.85 (d, J = 49.3 Hz, 1H), 4.11 (m, 2H), 3.80-3.67 (m, 1H), 3.08 (d, J = 11.8 Hz, 1H), 2.79 (d, J = 11.1 Hz, 1H), 2.38-2.06 (m, 5H), 1.84 (s, 2H), 1.50 (s, 6H). Example 70. Synthesis of (2R)-4-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)but-3-yn-2-ol Step 1. Synthesis of (2R)-4-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]but-3-yn-2-ol
在室溫下,向8-溴-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶( 中間物1;400.0 mg,0.98 mmol,1當量)於DMSO (10 mL)中之攪拌混合物中添加i-Pr 2NH (989.8 mg,9.80 mmol,10當量)、(2R)-丁-3-炔-2-醇(69.2 mg,0.98 mmol,1當量)、Pd(PPh 3) 4(228.3 mg,0.19 mmol,0.20當量)及CuI (94.1 mg,0.49 mmol,0.50當量)。將所得混合物在30℃及氮氣氛圍下攪拌1 h,然後使用具有以下條件(移動相A:水,移動相B:ACN;流動速率:60 mL/min;梯度:在15 min內0% B至100% B;波長:254 nm;220 nm)之C18急速層析純化,以得到呈黑色油狀物之(2R)-4-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丁-3-炔-2-醇(300.0 mg,82.5%)。LC-MS:(M+H) +實測值347.0。 步驟2. (2R)-4-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丁-3-炔-2-醇之合成 To a stirred mixture of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( Intermediate 1 ; 400.0 mg, 0.98 mmol, 1 eq) in DMSO (10 mL) at room temperature were added i- Pr2NH (989.8 mg, 9.80 mmol, 10 eq), (2R)-but-3-yn-2-ol (69.2 mg, 0.98 mmol, 1 eq), Pd( PPh3 ) 4 (228.3 mg, 0.19 mmol, 0.20 eq) and CuI (94.1 mg, 0.49 mmol, 0.50 eq). The resulting mixture was stirred at 30° C. under nitrogen atmosphere for 1 h, and then purified using C18 flash chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 15 min; wavelength: 254 nm; 220 nm) to give (2R)-4-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]but-3-yn-2-ol (300.0 mg, 82.5%) as a black oil. LC-MS: (M+H) + found 347.0. Step 2. Synthesis of (2R)-4-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)but-3-yn-2-ol
在室溫及氮氣氛圍下,向(2R)-4-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丁-3-炔-2-醇(200.0 mg,0.58 mmol,1當量)於THF (10 mL)中之攪拌混合物中添加(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(152.3 mg,1.15 mmol,2當量)、t-BuONa (332.2 mg,3.45 mmol,6當量)及tBuXPhosPdG3 (183.1 mg,0.23 mmol,0.40當量)。將所得混合物在65℃及氮氣氛圍下攪拌15 min,然後冷卻至室溫且在減壓下濃縮。粗產物藉由具有以下條件(管柱:XBridge Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3+0.05% NH 3H 2O),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在8 min內20% B至47% B;波長:220nm nm;RT1(min):7.22)之製備型HPLC純化。此產生呈黃色固體之(2R)-4-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丁-3-炔-2-醇(27.1 mg,11.7%)。LC-MS:(M+H) +實測值399.10。 1H NMR (400 MHz, DMSO- d 6) δ7.82 (d, J= 6.7 Hz, 1H), 6.84 (t, J= 7.1 Hz, 1H), 6.41 (d, J= 7.5 Hz, 1H), 5.48 (d, J= 5.0 Hz, 1H), 5.38 (d, J= 9.2 Hz, 1H), 4.84 (d, J= 49.6 Hz, 1H), 4.68-4.57 (m, 1H), 4.17-4.05 (m, 2H), 3.95-3.60 (m, 1H), 3.04 (t, J= 11.5 Hz, 1H), 2.77 (d, J= 11.3 Hz, 1H), 2.35-2.18 (m, 4H), 2.11 (s, 1H), 1.87-1.77 (m, 2H), 1.40 (d, J= 6.6 Hz, 3H)。 實例71. (2S)-4-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丁-3-炔-2-醇之合成 步驟1. 8-溴-2-{3-[(三級丁基二甲基矽烷基)氧基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶之合成 To a stirred mixture of (2R)-4-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]but-3-yn-2-ol (200.0 mg, 0.58 mmol, 1 eq) in THF (10 mL) were added (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (152.3 mg, 1.15 mmol, 2 eq), t-BuONa (332.2 mg, 3.45 mmol, 6 eq) and tBuXPhosPdG3 (183.1 mg, 0.23 mmol, 0.40 eq) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 65°C under nitrogen atmosphere for 15 min, then cooled to room temperature and concentrated under reduced pressure. The crude product was purified by preparative HPLC with the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 +0.05% NH 3 H 2 O), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 20% B to 47% B in 8 min; wavelength: 220 nm nm; RT1 (min): 7.22). This resulted in (2R)-4-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)but-3-yn-2-ol (27.1 mg, 11.7%) as a yellow solid. LC-MS: (M+H) + found 399.10. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.82 (d, J = 6.7 Hz, 1H), 6.84 (t, J = 7.1 Hz, 1H), 6.41 (d, J = 7.5 Hz, 1H), 5.48 (d, J = 5.0 Hz, 1H), 5.38 (d, J = 9.2 Hz, 1H), 4.84 (d, J = 49.6 Hz, 1H), 4.68-4.57 (m, 1H), 4.17-4.05 (m, 2H), 3.95-3.60 (m, 1H), 3.04 (t, J = 11.5 Hz, 1H), 2.77 (d, J = 11.3 Hz, 1H), 2.35-2.18 (m, 4H), 2.11 (s, 1H), 1.87-1.77 (m, 2H), 1.40 (d, J = 6.6 Hz, 3H). Example 71. Synthesis of (2S)-4-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)but-3-yn-2-ol Step 1. Synthesis of 8-bromo-2-{3-[(tributyldimethylsilyl)oxy]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine
向8-溴-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶( 中間物1;200.0 mg,0.49 mmol,1當量)於DMSO (10 mL)中之攪拌溶液中添加(2S)-丁-3-炔-2-醇(69.2 mg,0.99 mmol,2當量)、i-Pr 2NH (499.8 mg,4.94 mmol,10當量)、CuI (47.0 mg,0.25 mmol,0.50當量)及Pd(PPh 3) 4(228.3 mg,0.20 mmol,0.40當量)。將所得混合物在30℃及氮氣氛圍下攪拌1 h,然後使用具有以下條件之C18急速層析純化:移動相A:水,移動相B:ACN;流動速率:60 mL/min;梯度:在30 min內0% B至100% B;254/220 nm。此產生呈黃色固體之8-溴-2-{3-[(三級丁基二甲基矽烷基)氧基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶(94 mg,42.54%)。LC-MS:(M+H) +實測值348.1。 步驟2. (2S)-4-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丁-3-炔-2-醇之合成 To a stirred solution of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( Intermediate 1 ; 200.0 mg, 0.49 mmol, 1 eq) in DMSO (10 mL) were added (2S)-but-3-yn-2-ol (69.2 mg, 0.99 mmol, 2 eq), i- Pr2NH (499.8 mg, 4.94 mmol, 10 eq), CuI (47.0 mg, 0.25 mmol, 0.50 eq) and Pd( PPh3 ) 4 (228.3 mg, 0.20 mmol, 0.40 eq). The resulting mixture was stirred at 30°C under nitrogen atmosphere for 1 h and then purified using C18 flash chromatography with the following conditions: mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm. This produced 8-bromo-2-{3-[(tributyldimethylsilyl)oxy]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (94 mg, 42.54%) as a yellow solid. LC-MS: (M+H) + found 348.1. Step 2. Synthesis of (2S)-4-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)but-3-yn-2-ol
在室溫下,向(2S)-4-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丁-3-炔-2-醇(143 mg,0.41 mmol,1當量)於THF (3 mL)中之攪拌混合物中添加(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(108.9 mg,0.82 mmol,2當量)、t-BuONa (237.5 mg,2.47 mmol,6當量)及tBuXPhosPdG3 (126.2 mg,0.16 mmol,0.4當量)。將所得混合物在65℃及氮氣氛圍下攪拌30 min。移除溶劑後,殘餘物使用具有以下條件之C18急速層析純化:移動相A:水,移動相B:ACN;流動速率:60 mL/min;梯度:在30 min內0% B至100% B;254/220 nm。此產生呈黃色固體之(2S)-4-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丁-3-炔-2-醇(34.0 mg,20.72%)。LC-MS:(M+H) +實測值399.10。 1H NMR (400 MHz, DMSO- d 6) δ 7.82 (s, 1H), 6.85 (t, 1H), 6.41 (d, J= 5.6 Hz 1H), 5.55-5.51 (m, 1H), 5.38 (d, J= 8.2 Hz 1H), 4.82 (d, J= 49.2 Hz 1H), 4.61-4.58 (m, 1H), 4.17-4.13 (m, 2H), 3.74-3.70 (m, 1H), 3.06-3.03 (m, 1H), 2.74-2.71 (m, 1H), 2.25-2.10 (m, 5H), 1.75-1.71 (m, 2H), 1.40 (d, J= 6.8 Hz, 3H)。 實例72. (1S)-3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)-1-苯基丙-2-炔-1-醇之合成 步驟1. (1S)-3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]-1-苯基丙-2-炔-1-醇之合成 To a stirred mixture of (2S)-4-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]but-3-yn-2-ol (143 mg, 0.41 mmol, 1 eq) in THF (3 mL) was added (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (108.9 mg, 0.82 mmol, 2 eq), t-BuONa (237.5 mg, 2.47 mmol, 6 eq) and tBuXPhosPdG3 (126.2 mg, 0.16 mmol, 0.4 eq) at room temperature. The resulting mixture was stirred at 65 °C under nitrogen atmosphere for 30 min. After removal of the solvent, the residue was purified using C18 flash chromatography with the following conditions: mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm. This yielded (2S)-4-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)but-3-yn-2-ol (34.0 mg, 20.72%) as a yellow solid. LC-MS: (M+H) + found 399.10. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.82 (s, 1H), 6.85 (t, 1H), 6.41 (d, J = 5.6 Hz 1H), 5.55-5.51 (m, 1H), 5.38 (d, J = 8.2 Hz 1H), 4.82 (d, J = 49.2 Hz 1H), 4.61-4.58 (m, 1H), 4.17-4.13 (m, 2H), 3.74-3.70 (m, 1H), 3.06-3.03 (m, 1H), 2.74-2.71 (m, 1H), 2.25-2.10 (m, 5H), 1.75-1.71 (m, 2H), 1.40 (d, J = 6.8 Hz, 3H). Example 72. Synthesis of (1S)-3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)-1-phenylprop-2-yn-1-ol Step 1. Synthesis of (1S)-3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]-1-phenylprop-2-yn-1-ol
向8-溴-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶( 中間物1;1.20 g,2.96 mmol,1當量)於DMSO (10 mL)中之溶液中添加(1R)-1-苯基丙-2-炔-1-醇(587.5 mg,4.44 mmol,1.50當量)、二異丙胺(899.6 mg,8.88 mmol,3當量)、Pd(PPh 3) 4(684.9 mg,0.59 mmol,0.20當量)及CuI (225.7 mg,1.18 mmol,0.40當量)。將反應混合物在30℃下攪拌1 h,然後使用具有以下條件之C18急速層析純化:移動相A:水,移動相B:ACN;流動速率:60 mL/min;梯度:在30 min內0% B至100% B;254/220 nm。此產生呈白色固體之(1S)-3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]-1-苯基丙-2-炔-1-醇(340.0 mg,28.04%)。LC-MS:(M+H) +實測值409.0。 步驟2. 8-溴-2-[(3S)-3-[(三級丁基二甲基矽烷基)氧基]-3-苯基丙-1-炔-1-基]-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶之合成 To a solution of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( Intermediate 1 ; 1.20 g, 2.96 mmol, 1 eq) in DMSO (10 mL) were added (1R)-1-phenylprop-2-yn-1-ol (587.5 mg, 4.44 mmol, 1.50 eq), diisopropylamine (899.6 mg, 8.88 mmol, 3 eq), Pd( PPh3 ) 4 (684.9 mg, 0.59 mmol, 0.20 eq) and CuI (225.7 mg, 1.18 mmol, 0.40 eq). The reaction mixture was stirred at 30 °C for 1 h and then purified using C18 flash chromatography with the following conditions: mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm. This produced (1S)-3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]-1-phenylprop-2-yn-1-ol (340.0 mg, 28.04%) as a white solid. LC-MS: (M+H) + found 409.0. Step 2. Synthesis of 8-bromo-2-[(3S)-3-[(tributyldimethylsilyl)oxy]-3-phenylprop-1-yn-1-yl]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine
向(1S)-3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]-1-苯基丙-2-炔-1-醇(340.0 mg,0.83 mmol,1當量)於DCM (10 mL)中之溶液中添加咪唑(113.1 mg,1.66 mmol,2當量)及TBSCl (250.5 mg,1.66 mmol,2當量)。將反應混合物在室溫下攪拌1 h,然後用DCM稀釋且用鹽水洗滌。蒸發有機層,以得到呈白色固體之8-溴-2-[(3S)-3-[(三級丁基二甲基矽烷基)氧基]-3-苯基丙-1-炔-1-基]-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶(470.0 mg,108.06%)。LC-MS:(M+H) +實測值523.1。 步驟3. (3S,4R)-N-{2-[(3S)-3-[(三級丁基二甲基矽烷基)氧基]-3-苯基丙-1-炔-1-基]-3-(2,2,2三氟乙基)咪唑并[1,2-a]吡啶-8-基}-3-氟-1-甲基哌啶-4-胺之合成 To a solution of (1S)-3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]-1-phenylprop-2-yn-1-ol (340.0 mg, 0.83 mmol, 1 eq) in DCM (10 mL) was added imidazole (113.1 mg, 1.66 mmol, 2 eq) and TBSCl (250.5 mg, 1.66 mmol, 2 eq). The reaction mixture was stirred at room temperature for 1 h, then diluted with DCM and washed with brine. The organic layer was evaporated to give 8-bromo-2-[(3S)-3-[(tributyldimethylsilyl)oxy]-3-phenylprop-1-yn-1-yl]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (470.0 mg, 108.06%) as a white solid. LC-MS: (M+H) + found 523.1. Step 3. Synthesis of (3S,4R)-N-{2-[(3S)-3-[(tributyldimethylsilyl)oxy]-3-phenylprop-1-yn-1-yl]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl}-3-fluoro-1-methylpiperidin-4-amine
將8-溴-2-[(3S)-3-[(三級丁基二甲基矽烷基)氧基]-3-苯基丙-1-炔-1-基]-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶(120.0 mg,0.22 mmol,1當量)於THF (5 mL)中之溶液用(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(94.0 mg,0.45 mmol,2當量)、t-BuONa (132.2 mg,1.37 mmol,6當量)及t-BuXPhosPdG3 (72.8 mg,0.09 mmol,0.40當量)處理。將所得混合物在65℃及氮氣氛圍下攪拌30 min。移除溶劑後,殘餘物使用具有以下條件之C18急速層析純化:移動相A:水,移動相B:ACN;流動速率:60 mL/min;梯度:在30 min內0% B至100% B;254/220 nm。此產生(3S,4R)-N-{2-[(3S)-3-[(三級丁基二甲基矽烷基)氧基]-3-苯基丙-1-炔-1-基]-3-(2,2,2三氟乙基)咪唑并[1,2-a]吡啶-8-基}-3-氟-1-甲基哌啶-4-胺(70.0 mg,43.0%)。LC-MS:(M+H) +實測值575.3。 步驟4. (1S)-3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)-1-苯基丙-2-炔-1-醇之合成 A solution of 8-bromo-2-[(3S)-3-[(tributyldimethylsilyl)oxy]-3-phenylprop-1-yn-1-yl]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (120.0 mg, 0.22 mmol, 1 eq) in THF (5 mL) was treated with (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (94.0 mg, 0.45 mmol, 2 eq), t-BuONa (132.2 mg, 1.37 mmol, 6 eq) and t-BuXPhosPdG3 (72.8 mg, 0.09 mmol, 0.40 eq). The resulting mixture was stirred at 65 °C under nitrogen atmosphere for 30 min. After removal of the solvent, the residue was purified by C18 flash chromatography with the following conditions: mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm. This yielded (3S,4R)-N-{2-[(3S)-3-[(tributyldimethylsilyl)oxy]-3-phenylprop-1-yn-1-yl]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl}-3-fluoro-1-methylpiperidin-4-amine (70.0 mg, 43.0%). LC-MS: (M+H) + found 575.3. Step 4. Synthesis of (1S)-3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)-1-phenylprop-2-yn-1-ol
將(3S,4R)-N-{2-[(3S)-3-[(三級丁基二甲基矽烷基)氧基]-3-苯基丙-1-炔-1-基]-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基}-3-氟-1-甲基哌啶-4-胺(70.0 mg,0.17 mmol,1當量)於DCM (5 mL)中之溶液用Et 3N .3HF (1 mL,7.36 mmol,42.35當量)處理。將所得混合物在室溫下攪拌1h。移除溶劑後,殘餘物使用具有以下條件之C18急速層析純化:移動相A:水,移動相B:ACN;流動速率:60 mL/min;梯度:在30 min內0% B至100% B;254/220 nm。粗產物藉由具有以下條件(管柱:XBridge Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3)+0.05%NH 3.H 2O,移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在7 min內30% B至57% B;波長:254nm/220nm nm;RT1(min):7.97)之製備型HPLC純化。此產生呈白色固體之(1S)-3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)-1-苯基丙-2-炔-1-醇(18.1 mg,22.59%)。LC-MS:(M+H) +實測值461.20。 1H NMR (400 MHz, DMSO- d 6) δ 7.89-7.82 (m, 2H), 7.75 (d, J= 6.8 Hz, 1H), 7.55-7.46 (m, 1H), 7.40 (dd, J= 8.2, 6.9 Hz, 2H), 7.08 (d, J= 12.4 Hz, 1H), 6.69 (t, J= 7.1 Hz, 1H), 6.51 (d, J= 12.4 Hz, 1H), 6.22 (d, J= 7.5 Hz, 1H), 4.86-4.50 (m, 2H), 4.40-4.17 (m, 2H), 3.73-3.48 (m, 1H), 3.10-2.88 (m, 1H), 2.80-2.62 (m, 1H), 2.32-2.07 (m, 4H), 2.06 (t, J= 11.4 Hz, 1H), 1.69-1.60 (m, 1H), 1.59-1.46 (m, 1H)。 實例73. (1R)-3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)-1-苯基丙-2-炔-1-醇之合成 步驟1. (1R)-3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]-1-苯基丙-2-炔-1-醇之合成 A solution of (3S,4R)-N-{2-[(3S)-3-[(tributyldimethylsilyl)oxy]-3-phenylprop-1-yn-1-yl]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl}-3-fluoro-1-methylpiperidin-4-amine (70.0 mg, 0.17 mmol, 1 eq) in DCM (5 mL) was treated with Et3N.3HF (1 mL, 7.36 mmol, 42.35 eq). The resulting mixture was stirred at room temperature for 1 h. After removing the solvent, the residue was purified by C18 flash chromatography with the following conditions: mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm. The crude product was purified by preparative HPLC with the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5μm; mobile phase A: water (10mmol/L NH 4 HCO 3 )+0.05% NH 3 .H 2 O, mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 30% B to 57% B in 7 min; wavelength: 254nm/220nm nm; RT1(min): 7.97). This resulted in (1S)-3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)-1-phenylprop-2-yn-1-ol (18.1 mg, 22.59%) as a white solid. LC-MS: (M+H) + found 461.20. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.89-7.82 (m, 2H), 7.75 (d, J = 6.8 Hz, 1H), 7.55-7.46 (m, 1H), 7.40 (dd, J = 8.2, 6.9 Hz, 2H), 7.08 (d, J = 12.4 Hz, 1H), 6.69 (t, J = 7.1 Hz, 1H), 6.51 (d, J = 12.4 Hz, 1H), 6.22 (d, J = 7.5 Hz, 1H), 4.86-4.50 (m, 2H), 4.40-4.17 (m, 2H), 3.73-3.48 (m, 1H), 3.10-2.88 (m, 1H), 2.80-2.62 (m, 1H), 2.32-2.07 (m, 4H), 2.06 (t, J = 11.4 Hz, 1H), 1.69-1.60 (m, 1H), 1.59-1.46 (m, 1H). Example 73. Synthesis of (1R)-3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)-1-phenylprop-2-yn-1-ol Step 1. Synthesis of (1R)-3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]-1-phenylprop-2-yn-1-ol
向8-溴-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶( 中間物1;1.2 g,2.96 mmol,1當量)於DMSO (5 mL)中之溶液中添加(1S)-1-苯基丙-2-炔-1-醇(430.8 mg,3.26 mmol,1.1當量)、二異丙胺(899.6 mg,8.89 mmol,3當量)、Pd(PPh 3) 4(684.9 mg,0.59 mmol,0.2當量)及CuI (225.7 mg,1.19 mmol,0.4當量)。將反應混合物在30℃及氮氣氛圍下攪拌1 h,然後使用具有以下條件之C18急速層析純化:移動相A:水,移動相B:ACN;流動速率:60 mL/min;梯度:在30 min內0% B至100% B;254/220 nm。此產生呈黃色固體之(1R)-3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]-1-苯基丙-2-炔-1-醇(430 mg,35.46%)。LC-MS:(M+H) +實測值409.0。 步驟2. 8-溴-2-[(3R)-3-[(三級丁基二甲基矽烷基)氧基]-3-苯基丙-1-炔-1-基]-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶之合成 To a solution of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( intermediate 1 ; 1.2 g, 2.96 mmol, 1 eq) in DMSO (5 mL) were added (1S)-1-phenylprop-2-yn-1-ol (430.8 mg, 3.26 mmol, 1.1 eq), diisopropylamine (899.6 mg, 8.89 mmol, 3 eq), Pd( PPh3 ) 4 (684.9 mg, 0.59 mmol, 0.2 eq) and CuI (225.7 mg, 1.19 mmol, 0.4 eq). The reaction mixture was stirred at 30 °C under nitrogen atmosphere for 1 h and then purified using C18 flash chromatography with the following conditions: mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm. This produced (1R)-3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]-1-phenylprop-2-yn-1-ol (430 mg, 35.46%) as a yellow solid. LC-MS: (M+H) + found 409.0. Step 2. Synthesis of 8-bromo-2-[(3R)-3-[(tributyldimethylsilyl)oxy]-3-phenylprop-1-yn-1-yl]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine
向(1R)-3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]-1-苯基丙-2-炔-1-醇(300 mg,0.73 mmol,1當量)於DCM (10 mL)中之溶液中添加咪唑(99.8 mg,1.47 mmol,2當量)及TBSCl (221.0 mg,1.47 mmol,2當量)。將反應混合物在室溫下攪拌1 h,然後用DCM稀釋且用鹽水洗滌。有機層經Na 2SO 4乾燥且蒸發,以得到呈黃色油狀物之8-溴-2-[(3R)-3-[(三級丁基二甲基矽烷基)氧基]-3-苯基丙-1-炔-1-基]-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶(400 mg,粗物質)。LC-MS:(M+H) +實測值523.1。 步驟3. (3S,4R)-N-{2-[(3R)-3-[(三級丁基二甲基矽烷基)氧基]-3-苯基丙-1-炔-1-基]-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基}-3-氟-1-甲基哌啶-4-胺之合成 To a solution of (1R)-3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]-1-phenylprop-2-yn-1-ol (300 mg, 0.73 mmol, 1 eq) in DCM (10 mL) was added imidazole (99.8 mg, 1.47 mmol, 2 eq) and TBSCl (221.0 mg, 1.47 mmol, 2 eq). The reaction mixture was stirred at room temperature for 1 h, then diluted with DCM and washed with brine. The organic layer was dried over Na2SO4 and evaporated to give 8-bromo-2-[(3R)-3-[(tributyldimethylsilyl)oxy]-3-phenylprop-1-yn-1-yl]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (400 mg, crude) as a yellow oil. LC-MS: (M+H) + found 523.1. Step 3. Synthesis of (3S,4R)-N-{2-[(3R)-3-[(tributyldimethylsilyl)oxy]-3-phenylprop-1-yn-1-yl]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl}-3-fluoro-1-methylpiperidin-4-amine
向8-溴-2-[(3R)-3-[(三級丁基二甲基矽烷基)氧基]-3-苯基丙-1-炔-1-基]-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶(400 mg,0.76 mmol,1當量)於THF (5 mL)中之溶液中添加(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(470.2 mg,2.29 mmol,3當量)、tBuXPhosPdG3 (121.4 mg,0.15 mmol,0.2當量)及2-甲基丙-2-醇鈉(440.6 mg,4.58 mmol,6當量)。將反應混合物在65℃及氮氣氛圍下攪拌30 min。在真空下移除溶劑。殘餘物使用具有以下條件之C18急速層析純化:移動相A:水,移動相B:ACN;流動速率:60 mL/min;梯度:在30 min內0% B至100% B;254/220 nm。此產生呈黃色固體之(3S,4R)-N-{2-[(3R)-3-[(三級丁基二甲基矽烷基)氧基]-3-苯基丙-1-炔-1-基]-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基}-3-氟-1-甲基哌啶-4-胺(100 mg,22.77%)。LC-MS:(M+H) +實測值575.3。 步驟4. (1R)-3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)-1-苯基丙-2-炔-1-醇之合成 To a solution of 8-bromo-2-[(3R)-3-[(tributyldimethylsilyl)oxy]-3-phenylprop-1-yn-1-yl]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (400 mg, 0.76 mmol, 1 eq) in THF (5 mL) was added (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (470.2 mg, 2.29 mmol, 3 eq), tBuXPhosPdG3 (121.4 mg, 0.15 mmol, 0.2 eq) and sodium 2-methylpropan-2-ol (440.6 mg, 4.58 mmol, 6 eq). The reaction mixture was stirred at 65 °C under nitrogen atmosphere for 30 min. The solvent was removed under vacuum. The residue was purified by C18 flash chromatography with the following conditions: mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm. This produced (3S,4R)-N-{2-[(3R)-3-[(tributyldimethylsilyl)oxy]-3-phenylprop-1-yn-1-yl]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl}-3-fluoro-1-methylpiperidin-4-amine (100 mg, 22.77%) as a yellow solid. LC-MS: (M+H) + found 575.3. Step 4. Synthesis of (1R)-3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)-1-phenylprop-2-yn-1-ol
向(3S,4R)-N-{2-[(3R)-3-[(三級丁基二甲基矽烷基)氧基]-3-苯基丙-1-炔-1-基]-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基}-3-氟-1-甲基哌啶-4-胺(80 mg,0.14 mmol,1當量)於DCM (2 mL)中之溶液中添加TEA .3HF (89.8 mg,0.56 mmol,4當量)且將攪拌溶液在室溫下攪拌1 h。在真空下移除溶劑。殘餘物使用具有以下條件之C18急速層析純化:移動相A:水,移動相B:ACN;流動速率:60 mL/min;梯度:在30 min內0% B至100% B;254/220 nm。粗產物使用具有以下條件之製備型HPLC純化:管柱:XBridge Shield RP18 OBD管柱,30*150 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3+ 0.05% NH 3H 2O),移動相B:ACN (1% 2mM NH 3-MeOH);流動速率:25 mL/min mL/min;梯度:在10min內52% B至72% B;波長:254nm/220nm;RT1(min):9.28;運行次數:3。此產生呈黃色固體之(1R)-3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)-1-苯基丙-2-炔-1-醇(3.7 mg,5.74%)。LC-MS:(M+H) +實測值461.20。 1H NMR (400 MHz, DMSO- d 6) δ 7.90-7.82 (m, 2H), 7.74 (d, J= 6.8 Hz, 1H), 7.54-7.45 (m, 1H), 7.40 (dd, J= 8.4, 6.9 Hz, 2H), 7.08 (d, J= 12.4 Hz, 1H), 6.69 (t, J= 7.1 Hz, 1H), 6.51 (d, J= 12.4 Hz, 1H), 6.21 (d, J= 7.4 Hz, 1H), 4.79-4.56 (m, 2H), 4.28 (q, J= 10.8 Hz, 2H), 3.70-3.45 (m, 1H), 2.97 (t, J= 10.9 Hz, 1H), 2.69 (d, J= 11.0 Hz, 1H), 2.35-2.00 (m, 5H), 1.67-1.63 (m, 1H), 1.62-1.47 (m, 1H)。 實例74. (3S,4R)-N-[2-(4-胺基丁-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基]-3-氟-1-甲基哌啶-4-胺之合成 步驟1. N-{4-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丁-3-炔-1-基}胺基甲酸三級丁酯之合成 To a solution of (3S,4R)-N-{2-[(3R)-3-[(tributyldimethylsilyl)oxy]-3-phenylprop-1-yn-1-yl]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl}-3-fluoro-1-methylpiperidin-4-amine (80 mg, 0.14 mmol, 1 eq) in DCM (2 mL) was added TEA.3HF (89.8 mg, 0.56 mmol, 4 eq) and the stirred solution was stirred at room temperature for 1 h. The solvent was removed under vacuum. The residue was purified by C18 flash chromatography with the following conditions: mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm. The crude product was purified using preparative HPLC with the following conditions: column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 + 0.05% NH 3 H 2 O), mobile phase B: ACN (1% 2 mM NH 3 -MeOH); flow rate: 25 mL/min mL/min; gradient: 52% B to 72% B in 10 min; wavelength: 254 nm/220 nm; RT1 (min): 9.28; number of runs: 3. This resulted in (1R)-3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)-1-phenylprop-2-yn-1-ol (3.7 mg, 5.74%) as a yellow solid. LC-MS: (M+H) + found 461.20. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.90-7.82 (m, 2H), 7.74 (d, J = 6.8 Hz, 1H), 7.54-7.45 (m, 1H), 7.40 (dd, J = 8.4, 6.9 Hz, 2H), 7.08 (d, J = 12.4 Hz, 1H), 6.69 (t, J = 7.1 Hz, 1H), 6.51 (d, J = 12.4 Hz, 1H), 6.21 (d, J = 7.4 Hz, 1H), 4.79-4.56 (m, 2H), 4.28 (q, J = 10.8 Hz, 2H), 3.70-3.45 (m, 1H), 2.97 (t, J = 10.9 Hz, 1H), 2.69 (d, J = 11.0 Hz, 1H), 2.35-2.00 (m, 5H), 1.67-1.63 (m, 1H), 1.62-1.47 (m, 1H). Example 74. Synthesis of (3S,4R)-N-[2-(4-aminobut-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine Step 1. Synthesis of tert-butyl N-{4-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]but-3-yn-1-yl}carbamate
將8-溴-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶( 中間物1;1 g,2.47 mmol,1當量)、N-(丁-3-炔-1-基)胺基甲酸三級丁酯(0.44 g,2.59 mmol,1.05當量)、Pd(PPh 3) 4(0.14 g,0.12 mmol,0.05當量)、CuI (0.09 g,0.49 mmol,0.2當量)及DIEA (0.96 g,7.41 mmol,3當量)於 DMSO (10 mL)中之混合物 在25℃及氮氣下攪拌1 h。所得混合物藉由反相急速層析(管柱,C18矽膠;移動相,於水中之MeCN (0.1% FA),在30 min內0%至100%梯度;偵測器,UV 254 nm)純化,以得到呈黃色固體之N-{4-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丁-3-炔-1-基}胺基甲酸三級丁酯(560 mg,50.82%)。LC-MS:(M+H)+實測值446.3。 步驟2. N-[4-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丁-3-炔-1-基]胺基甲酸三級丁酯之合成 A mixture of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( intermediate 1 ; 1 g, 2.47 mmol, 1 eq), tert-butyl N-(but-3-yn-1-yl)carbamate (0.44 g, 2.59 mmol, 1.05 eq), Pd(PPh 3 ) 4 (0.14 g, 0.12 mmol, 0.05 eq), CuI (0.09 g, 0.49 mmol, 0.2 eq) and DIEA (0.96 g, 7.41 mmol, 3 eq) in DMSO (10 mL) was stirred at 25 °C under nitrogen for 1 h. The resulting mixture was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient 0% to 100% in 30 min; detector, UV 254 nm) to give tributyl N-{4-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]but-3-yn-1-yl}carbamate (560 mg, 50.82%) as a yellow solid. LC-MS: (M+H)+ found 446.3. Step 2. Synthesis of tributyl N-[4-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)but-3-yn-1-yl]carbamate
將N-{4-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丁-3-炔-1-基}胺基甲酸三級丁酯(270 mg,0.61 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(186.1 mg,0.91 mmol,1.5當量)、t-BuONa (232.6 mg,2.42 mmol,4當量)及tBuXPhos Pd G3 (144.2 mg,0.18 mmol,0.3當量)於THF (3 mL)中之混合物在65℃及氮氣氛圍下攪拌2 h。將混合物冷卻至室溫且在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/ MeOH 20:1)純化,以得到呈棕色固體之N-[4-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丁-3-炔-1-基]胺基甲酸三級丁酯(50 mg,16.61%)。LC-MS:(M+H) +實測值498.2。 步驟3. (3S,4R)-N-[2-(4-胺基丁-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基]-3-氟-1-甲基哌啶-4-胺之合成 A mixture of tributyl N-{4-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]but-3-yn-1-yl}carbamate (270 mg, 0.61 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (186.1 mg, 0.91 mmol, 1.5 eq), t-BuONa (232.6 mg, 2.42 mmol, 4 eq) and tBuXPhos Pd G3 (144.2 mg, 0.18 mmol, 0.3 eq) in THF (3 mL) was stirred at 65 °C under nitrogen atmosphere for 2 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative TLC ( CH2Cl2 /MeOH 20:1) to give tributyl N-[4-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)but-3-yn-1-yl]carbamate as a brown solid (50 mg, 16.61%). LC-MS: (M+H) + found 498.2. Step 3. Synthesis of (3S,4R)-N-[2-(4-aminobut-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine
向N-[4-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丁-3-炔-1-基]胺基甲酸三級丁酯(40 mg,0.08 mmol,1當量)於CH 2Cl 2(0.6 mL)中之攪拌溶液中添加CF 3COOH (0.3 mL)。將反應溶液在室溫下攪拌1h,然後在真空下濃縮。殘餘物藉由製備型HPLC (管柱:XBridge Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3+0.05%NH 3 .H 2O),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在7 min內17% B至42% B;波長:254nm/220nm nm;RT1(min):7.07;運行次數:3)純化,以得到呈白色固體之(3S,4R)-N-[2-(4-胺基丁-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基]-3-氟-1-甲基哌啶-4-胺(10.0 mg,30.64%)。LC-MS:(M+H) +實測值398.10。 1H NMR (400 MHz, DMSO- d 6) δ 7.82 (d, J= 6.8 Hz, 1H), 6.83 (t, J= 7.2 Hz, 1H), 6.40 (d, J= 7.6 Hz, 1H), 5.38 (d, J= 9.2 Hz, 1H), 4.84 (d, J= 8.8 Hz,, 1H), 4.12 (m, 2H), 3.75 (d, J= 8.8 Hz, 1H), 3.56 - 2.95 (m, 4H), 2.76 (t, J= 6.8 Hz, 3H), 2.52 - 2.11 (m, 6H), 1.81 (d, J= 9.4 Hz, 2H)。 實例75. (3S,4R)-N-[2-(3-胺基丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基]-3-氟-1-甲基哌啶-4-胺之合成 步驟1. N-{3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基甲酸三級丁酯之合成 To a stirred solution of tributyl N-[4-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)but-3-yn-1-yl]carbamate (40 mg, 0.08 mmol, 1 eq) in CH2Cl2 ( 0.6 mL) was added CF3COOH (0.3 mL). The reaction solution was stirred at room temperature for 1 h and then concentrated under vacuum. The residue was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 +0.05% NH 3 . H 2 O), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 17% B to 42% B in 7 min; wavelength: 254 nm/220 nm nm; RT1 (min): 7.07; number of runs: 3) to obtain (3S,4R)-N-[2-(4-aminobut-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine (10.0 mg, 30.64%). LC-MS: (M+H) + found 398.10. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.82 (d, J = 6.8 Hz, 1H), 6.83 (t, J = 7.2 Hz, 1H), 6.40 (d, J = 7.6 Hz, 1H), 5.38 (d, J = 9.2 Hz, 1H), 4.84 (d, J = 8.8 Hz,, 1H), 4.12 (m, 2H), 3.75 (d, J = 8.8 Hz, 1H), 3.56 - 2.95 (m, 4H), 2.76 (t, J = 6.8 Hz, 3H), 2.52 - 2.11 (m, 6H), 1.81 (d, J = 9.4 Hz, 2H). Example 75. Synthesis of (3S,4R)-N-[2-(3-aminoprop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine Step 1. Synthesis of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}carbamic acid tert-butyl ester
將8-溴-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶( 中間物1;500 mg,1.24 mmol,1當量)、4-甲磺醯基-2-甲氧基-N-(丙-2-炔-1-基)苯胺( 中間物39;70.9 mg,0.30 mmol,1.2當量)、Pd(PPh 3) 4(285.4 mg,0.25 mmol,0.2當量)、CuI (235.2 mg,1.24 mmol,1當量)及DIEA (159.6 mg,1.24 mmol,1當量) 於DMSO (5 mL)中之混合物在室溫下攪拌隔夜。所得混合物用EtOAc (30 mL)稀釋且用鹽水(3*30 mL)洗滌。有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由具有以下條件(管柱,C18矽膠;移動相,於水中之MeCN (0.1% FA),在30 min內0%至100%梯度;偵測器,UV 254 nm)之反相急速層析純化,以得到呈黃色固體之N-{3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基甲酸三級丁酯(274 mg,46.21%)。LC-MS:(M+H)+實測值432.0。 步驟2. N-[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基甲酸三級丁酯之合成 A mixture of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( Intermediate 1 ; 500 mg, 1.24 mmol, 1 eq), 4-methanesulfonyl-2-methoxy-N-(prop-2-yn-1-yl)aniline ( Intermediate 39 ; 70.9 mg, 0.30 mmol, 1.2 eq), Pd(PPh 3 ) 4 (285.4 mg, 0.25 mmol, 0.2 eq), CuI (235.2 mg, 1.24 mmol, 1 eq) and DIEA (159.6 mg, 1.24 mmol, 1 eq) in DMSO (5 mL) was stirred at room temperature overnight. The resulting mixture was diluted with EtOAc (30 mL) and washed with brine (3*30 mL). The organic layer was dried over anhydrous Na2SO4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient from 0% to 100% in 30 min; detector, UV 254 nm) to give tributyl N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}carbamate (274 mg, 46.21%) as a yellow solid. LC-MS: (M+H)+ found 432.0. Step 2. Synthesis of tributyl N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]carbamate
將N-{3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基甲酸三級丁酯(130 mg,0.30 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(92.5 mg,0.45 mmol,1.5當量)、t-BuONa (144.5 mg,1.51 mmol,5當量)及tBuXPhos Pd G3 (119.5 mg,0.15 mmol,0.5當量)於THF (2 mL)中之混合物在65℃下攪拌1 h。將混合物冷卻至室溫且在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/ MeOH 20:1)純化,以得到呈黃色固體之N-[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基甲酸三級丁酯(30 mg,20.63%)。LC-MS:(M+H) +實測值484.2。 步驟3. (3S,4R)-N-[2-(3-胺基丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基]-3-氟-1-甲基哌啶-4-胺之合成 A mixture of tributyl N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}carbamate (130 mg, 0.30 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (92.5 mg, 0.45 mmol, 1.5 eq), t-BuONa (144.5 mg, 1.51 mmol, 5 eq) and tBuXPhos Pd G3 (119.5 mg, 0.15 mmol, 0.5 eq) in THF (2 mL) was stirred at 65 °C for 1 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 / MeOH 20:1) to give tributyl N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]carbamate as a yellow solid (30 mg, 20.63%). LC-MS: (M+H) + found 484.2. Step 3. Synthesis of (3S,4R)-N-[2-(3-aminoprop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine
向N-[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基甲酸三級丁酯(20 mg,0.04 mmol,1當量)於CH 2Cl 2(2 mL)中之攪拌溶液中添加CF 3COOH (1 mL)。將反應溶液在室溫下攪拌1h,然後在真空下濃縮。殘餘物藉由製備型HPLC (管柱:XBridge Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3+0.05%NH 3 .H 2O),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在7 min內15% B至42% B;波長:254nm/220nm nm;RT1(min):7.52)純化,以得到呈白色固體之(3S,4R)-N-[2-(3-胺基丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基]-3-氟-1-甲基哌啶-4-胺(1.8 mg,11.30%)。LC-MS:(M+H) +實測值384.10。 1H NMR (400 MHz, DMSO- d 6) δ 7.82 (d, J= 6.8 Hz, 1H), 6.84 (t, J= 7.1 Hz, 1H), 6.41 (d, J= 7.5 Hz, 1H), 5.38 (d, J= 9.2 Hz, 1H), 4.90 - 4.77 (d, J= 18.0 Hz, 1H), 4.15 - 4.10 (m, 2H), 3.79 – 3.72 (m, 1H), 3.54 (s, 2H), 3.10 – 2.98 (m, 1H), 2.77 (d, J= 11.2 Hz, 1H), 2.30 - 1.97 (m, 7H), 1.81 (m, 2H)。 實例76. (3S,4R)-3-氟-N-(2-{3-[(4-甲磺醯基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)-1-甲基哌啶-4-胺之合成 步驟1. N-{3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}-4-甲磺醯基苯胺之合成 To a stirred solution of tributyl N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]carbamate (20 mg, 0.04 mmol , 1 eq) in CH2Cl2 (2 mL) was added CF3COOH (1 mL). The reaction solution was stirred at room temperature for 1 h and then concentrated under vacuum. The residue was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 +0.05% NH 3 . H 2 O), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 15% B to 42% B in 7 min; wavelength: 254 nm/220 nm nm; RT1(min): 7.52) to give (3S,4R)-N-[2-(3-aminoprop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine (1.8 mg, 11.30%) as a white solid. LC-MS: (M+H) + found 384.10. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.82 (d, J = 6.8 Hz, 1H), 6.84 (t, J = 7.1 Hz, 1H), 6.41 (d, J = 7.5 Hz, 1H), 5.38 (d, J = 9.2 Hz, 1H), 4.90 - 4.77 (d, J = 18.0 Hz, 1H), 4.15 - 4.10 (m, 2H), 3.79 – 3.72 (m, 1H), 3.54 (s, 2H), 3.10 – 2.98 (m, 1H), 2.77 (d, J = 11.2 Hz, 1H), 2.30 - 1.97 (m, 7H), 1.81 (m, 2H). Example 76. Synthesis of (3S,4R)-3-fluoro-N-(2-{3-[(4-methylsulfonylphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine Step 1. Synthesis of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-4-methanesulfonylaniline
將8-溴-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶( 中間物1;300 mg,0.74 mmol,1當量)、4-甲磺醯基-N-(丙-2-炔-1-基)苯胺( 中間物40;232.5 mg,1.11 mmol,1.5當量)、CuI (141.1 mg,0.74 mmol,1當量)、i-Pr 2NH (749.7 mg,7.41 mmol,10當量)及Pd(PPh 3) 4(171.2 mg,0.15 mmol,0.2當量)於DMSO (5 mL)中之溶液在室溫及氮氣氛圍下攪拌1 h。所得混合物用EtOAc (50mL)稀釋且用鹽水(3*50 mL)洗滌。有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/於MeOH中之7 M NH 3= 15:1)純化,以得到呈棕色固體之N-{3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}-4-甲磺醯基苯胺(180 mg,49.96%)。LC-MS:(M+H) +實測值488.0。 步驟2. (3S,4R)-3-氟-N-(2-{3-[(4-甲磺醯基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)-1-甲基哌啶-4-胺之合成 A solution of 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( intermediate 1 ; 300 mg, 0.74 mmol, 1 eq), 4-methanesulfonyl-N-(prop-2-yn-1-yl)aniline ( intermediate 40 ; 232.5 mg, 1.11 mmol, 1.5 eq), CuI (141.1 mg, 0.74 mmol, 1 eq), i-Pr 2 NH (749.7 mg, 7.41 mmol, 10 eq) and Pd(PPh 3 ) 4 (171.2 mg, 0.15 mmol, 0.2 eq) in DMSO (5 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting mixture was diluted with EtOAc (50 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 / 7 M NH 3 in MeOH = 15:1) to give N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-4-methanesulfonylaniline (180 mg, 49.96%) as a brown solid. LC-MS: (M+H) + found 488.0. Step 2. Synthesis of (3S,4R)-3-fluoro-N-(2-{3-[(4-methylsulfonylphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine
將N-{3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}-4-甲磺醯基苯胺(150 mg,0.31 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(126.5 mg,0.61 mmol,2當量)、t-BuONa (148.2 mg,1.54 mmol,5當量)及tBuXPhos Pd G3 (122.5 mg,0.15 mmol,0.5當量)於THF (3 mL)中之混合物在65℃及氮氣氛圍下攪拌1 h。將所得混合物在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/於MeOH中之7M NH 3= 20:1)及製備型HPLC (管柱:XBridge Prep OBD C18管柱,19*250 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3+0.05%NH 3 .H 2O),移動相B:MEOH;流動速率:25 mL/min mL/min;梯度:在10min內43% B至67% B;波長:254nm/220nm nm;RT1(min):9.6;運行次數:3)純化,以得到呈灰白色固體之(3S,4R)-3-氟-N-(2-{3-[(4-甲磺醯基苯基)胺基]丙-1-炔-1-基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基)-1-甲基哌啶-4-胺(14.4 mg,8.68%)。LC-MS:(M+H) +實測值538.15。 1H NMR (400 MHz, DMSO-d6) δ 7.85 – 7.76 (d, J= 6.8 Hz, 1H), 7.69 – 7.60 (m, 2H), 7.21 – 7.11 (t, J= 6.0 Hz, 1H), 6.90 – 6.79 (dd, J= 6.2, 8.1 Hz, 3H), 6.46 – 6.35 (d, J= 7.6 Hz, 1H), 5.45 – 5.30 (d, J= 9.2 Hz, 1H), 4.94 – 4.71 (d, J= 49.4 Hz, 1H), 4.36 – 4.22 (d, J= 6.0 Hz, 2H), 4.13 – 3.98 (m, 2H), 3.81 – 3.62 (m, 1H), 3.13 – 2.96 (s, 4H), 2.82 – 2.71 (d, J= 11.2 Hz, 1H), 2.36 – 2.05 (m, 5H), 1.89 – 1.73 (td, J= 3.8, 9.9 Hz, 2H)。 實例77. (3S,4R)-3-氟-N-[2-(3-{[2-甲氧基-4-(丙烷-2-磺醯基)苯基]胺基}丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基]-1-甲基哌啶-4-胺之合成 步驟1. N-{3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}-2-甲氧基-4-(丙烷-2-磺醯基)苯胺之合成 A mixture of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-4-methanesulfonylaniline (150 mg, 0.31 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (126.5 mg, 0.61 mmol, 2 eq), t-BuONa (148.2 mg, 1.54 mmol, 5 eq) and tBuXPhos Pd G3 (122.5 mg, 0.15 mmol, 0.5 eq) in THF (3 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 /7M NH 3 in MeOH = 20:1) and preparative HPLC (column: XBridge Prep OBD C18 column, 19*250 mm, 5μm; mobile phase A: water (10mmol/L NH 4 HCO 3 +0.05% NH 3 . H 2 O), mobile phase B: MEOH; flow rate: 25 mL/min mL/min; gradient: 43% B to 67% B in 10 min; wavelength: 254nm/220nm nm; RT1(min): 9.6; Runs: 3) to give (3S,4R)-3-fluoro-N-(2-{3-[(4-methylsulfonylphenyl)amino]prop-1-yn-1-yl}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine (14.4 mg, 8.68%) as an off-white solid. LC-MS: (M+H) + found 538.15. 1 H NMR (400 MHz, DMSO-d6) δ 7.85 – 7.76 (d, J = 6.8 Hz, 1H), 7.69 – 7.60 (m, 2H), 7.21 – 7.11 (t, J = 6.0 Hz, 1H), 6.90 – 6.79 (dd, J = 6.2, 8.1 Hz, 3H), 6.46 – 6.35 (d, J = 7.6 Hz, 1H), 5.45 – 5.30 (d, J = 9.2 Hz, 1H), 4.94 – 4.71 (d, J = 49.4 Hz, 1H), 4.36 – 4.22 (d, J = 6.0 Hz, 2H), 4.13 – 3.98 (m, 2H), 3.81 – 3.62 (m, 1H), 3.13 – 2.96 (s, 4H), 2.82 – 2.71 (d, J = 11.2 Hz, 1H), 2.36 – 2.05 (m, 5H), 1.89 – 1.73 (td, J = 3.8, 9.9 Hz, 2H). Example 77. Synthesis of (3S,4R)-3-fluoro-N-[2-(3-{[2-methoxy-4-(propane-2-sulfonyl)phenyl]amino}prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]-1-methylpiperidin-4-amine Step 1. Synthesis of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-2-methoxy-4-(propane-2-sulfonyl)aniline
將2-甲氧基-N-(丙-2-炔-1-基)-4-(丙烷-2-磺醯基)苯胺( 中間物41;277.3 mg,1.04 mmol,1.2當量)、8-溴-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶( 中間物1;350 mg,0.86 mmol,1當量)、CuI (136.6 mg,0.72 mmol,0.83當量)、Pd(PPh 3) 4(299.6 mg,0.26 mmol,0.3當量)、i-Pr 2NH (874.6 mg,8.64 mmol,10當量)於DMSO (4 mL)中之溶液在室溫及氮氣氛圍下攪拌1 h。溶液用EtOAc (50 mL)稀釋且用鹽水(3*50 mL)洗滌。有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型TLC (DCM / MeOH = 15:1)純化,以得到呈黃色固體之N-{3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}-2-甲氧基-4-(丙烷-2-磺醯基)苯胺(450 mg,95.74%)。LC-MS:(M+H) +實測值544.1。 步驟2. (3S,4R)-3-氟-N-[2-(3-{[2-甲氧基-4-(丙烷-2-磺醯基)苯基]胺基}丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基]-1-甲基哌啶-4-胺之合成 A solution of 2-methoxy-N-(prop-2-yn-1-yl)-4-(propane-2-sulfonyl)aniline ( intermediate 41 ; 277.3 mg, 1.04 mmol, 1.2 equiv), 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( intermediate 1 ; 350 mg, 0.86 mmol, 1 equiv), CuI (136.6 mg, 0.72 mmol, 0.83 equiv), Pd(PPh 3 ) 4 (299.6 mg, 0.26 mmol, 0.3 equiv), i-Pr 2 NH (874.6 mg, 8.64 mmol, 10 equiv) in DMSO (4 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The solution was diluted with EtOAc (50 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 15:1) to give N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-2-methoxy-4-(propane-2-sulfonyl)aniline (450 mg, 95.74%) as a yellow solid. LC-MS: (M+H) + found 544.1. Step 2. Synthesis of (3S,4R)-3-fluoro-N-[2-(3-{[2-methoxy-4-(propane-2-sulfonyl)phenyl]amino}prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]-1-methylpiperidin-4-amine
將N-{3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}-2-甲氧基-4-(丙烷-2-磺醯基)苯胺(300 mg,0.55 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺 二鹽酸鹽(224.5 mg,1.10 mmol,2當量)、t-BuONa (211.8 mg,2.20 mmol,4當量)及tBuXphos Pd G3 (131.3 mg,0.17 mmol,0.3當量)於THF (2 mL)中之混合物在65℃及氮氣氛圍下攪拌1 h。將所得混合物在減壓下濃縮。殘餘物藉由製備型TLC (DCM /於MeOH中之7M NH 3= 15:1)及製備型HPLC (管柱:XBridge Prep OBD C18管柱,19*250 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3+0.05%NH 3 .H 2O),移動相B:MEOH;流動速率:25 mL/min mL/min;梯度:在11 min內50% B至75% B;波長:254nm/220nm nm;RT1(min):10.63)純化,以得到呈白色固體之(3S,4R)-3-氟-N-[2-(3-{[2-甲氧基-4-(丙烷-2-磺醯基)苯基]胺基}丙-1-炔-1-基)-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基]-1-甲基哌啶-4-胺(49 mg,14.93%)。LC-MS:(M+H) +實測值596.45。 1H NMR (400 MHz, DMSO-d6) δ 7.80 (d, J= 6.8 Hz, 1H), 7.31 (dd, J= 8.3, 2.0 Hz, 1H), 7.13 (d, J= 2.0 Hz, 1H), 6.89 (d, J= 8.4 Hz, 1H), 6.83 (t, J= 7.1 Hz, 1H), 6.54 (t, J= 6.1 Hz, 1H), 6.40 (d, J= 7.6 Hz, 1H), 5.37 (d, J= 9.2 Hz, 1H), 4.82 (d, J= 49.5 Hz, 1H), 4.31 (d, J= 6.2 Hz, 2H), 4.04 (m, 2H), 3.88 (s, 3H), 3.71 (dd, J= 28.7, 8.4 Hz, 1H), 3.27 (m, 1H), 3.03 (t, J= 11.5 Hz, 1H), 2.76 (d, J= 11.5 Hz, 1H), 2.30 (t, J= 12.1 Hz, 1H), 2.19 (s, 3H), 2.10 (t, J= 6.9 Hz, 1H), 1.88 – 1.72 (m, 2H), 1.13 (d, J= 6.8 Hz, 6H)。 實例78. (3S,4R)-3-氟-N-[2-(3-{[2-甲氧基-4-(丙烷-2-磺醯基)苯基]胺基}丙-1-炔-1-基)-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-8-基]-1-甲基哌啶-4-胺之合成 步驟1. N-(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)-2-甲氧基-4-(丙烷-2-磺醯基)苯胺之合成 A mixture of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}-2-methoxy-4-(propane-2-sulfonyl)aniline (300 mg, 0.55 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (224.5 mg, 1.10 mmol, 2 eq), t-BuONa (211.8 mg, 2.20 mmol, 4 eq) and tBuXphos Pd G3 (131.3 mg, 0.17 mmol, 0.3 eq) in THF (2 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM/7M NH 3 in MeOH = 15:1) and preparative HPLC (column: XBridge Prep OBD C18 column, 19*250 mm, 5μm; mobile phase A: water (10mmol/L NH 4 HCO 3 +0.05% NH 3 . H 2 O), mobile phase B: MEOH; flow rate: 25 mL/min mL/min; gradient: 50% B to 75% B in 11 min; wavelength: 254nm/220nm nm; RT1 (min): 10.63) to give (3S,4R)-3-fluoro-N-[2-(3-{[2-methoxy-4-(propane-2-sulfonyl)phenyl]amino}prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl]-1-methylpiperidin-4-amine (49 mg, 14.93%) as a white solid. LC-MS: (M+H) + found 596.45. 1 H NMR (400 MHz, DMSO-d6) δ 7.80 (d, J = 6.8 Hz, 1H), 7.31 (dd, J = 8.3, 2.0 Hz, 1H), 7.13 (d, J = 2.0 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.83 (t, J = 7.1 Hz, 1H), 6.54 (t, J = 6.1 Hz, 1H), 6.40 (d, J = 7.6 Hz, 1H), 5.37 (d, J = 9.2 Hz, 1H), 4.82 (d, J = 49.5 Hz, 1H), 4.31 (d, J = 6.2 Hz, 2H), 4.04 (m, 3.88 (s, 3H), 3.71 (dd, J = 28.7, 8.4 Hz, 1H), 3.27 (m, 1H), 3.03 (t, J = 11.5 Hz, 1H), 2.76 (d, J = 11.5 Hz, 1H), 2.30 (t, J = 12.1 Hz, 1H), 2.19 (s, 3H), 2.10 (t, J = 6.9 Hz, 1H), 1.88 – 1.72 (m, 2H), 1.13 (d, J = 6.8 Hz, 6H). Example 78. Synthesis of (3S,4R)-3-fluoro-N-[2-(3-{[2-methoxy-4-(propane-2-sulfonyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]-1-methylpiperidin-4-amine Step 1. Synthesis of N-(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-2-methoxy-4-(propane-2-sulfonyl)aniline
將2-甲氧基-N-(丙-2-炔-1-基)-4-(丙烷-2-磺醯基)苯胺( 中間物41;214.9 mg,0.80 mmol,2當量)、8-溴-2-碘-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶( 中間物9;170 mg,0.40 mmol,1當量)、CuI (76.5 mg,0.40 mmol,1當量)、Pd(PPh 3) 4(139.3 mg,0.12 mmol,0.3當量)及i-Pr 2NH (406.7 mg,4.02 mmol,10當量)於DMSO (2 mL)中之溶液在室溫及氮氣氛圍下攪拌1 h。溶液用EtOAc (50 mL)稀釋且用鹽水(3*50 mL)洗滌。有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型TLC (DCM / MeOH = 20:1)純化,以得到呈黃色油狀物之N-(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)-2-甲氧基-4-(丙烷-2-磺醯基)苯胺(300 mg)。LC-MS:(M+H) +實測值562.4。 步驟2. (3S,4R)-3-氟-N-[2-(3-{[2-甲氧基-4-(丙烷-2-磺醯基)苯基]胺基}丙-1-炔-1-基)-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-8-基]-1-甲基哌啶-4-胺之合成 A solution of 2-methoxy-N-(prop-2-yn-1-yl)-4-(propane-2-sulfonyl)aniline ( intermediate 41 ; 214.9 mg, 0.80 mmol, 2 equiv), 8-bromo-2-iodo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine ( intermediate 9 ; 170 mg, 0.40 mmol, 1 equiv), CuI (76.5 mg, 0.40 mmol, 1 equiv), Pd( PPh3 ) 4 (139.3 mg, 0.12 mmol, 0.3 equiv) and i- Pr2NH (406.7 mg, 4.02 mmol, 10 equiv) in DMSO (2 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The solution was diluted with EtOAc (50 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 20:1) to give N-(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-2-methoxy-4-(propane-2-sulfonyl)aniline (300 mg) as a yellow oil. LC-MS: (M+H) + found 562.4. Step 2. Synthesis of (3S,4R)-3-fluoro-N-[2-(3-{[2-methoxy-4-(propane-2-sulfonyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]-1-methylpiperidin-4-amine
將N-(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)-2-甲氧基-4-(丙烷-2-磺醯基)苯胺(300 mg,0.53 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(218.3 mg,1.07 mmol,2當量)、t-BuONa (256.3 mg,2.67 mmol,5當量)及tBuXphos Pd G3 (84.8 mg,0.11 mmol,0.2當量)於THF (2 mL)中之混合物在65℃及氮氣氛圍下攪拌1 h。過濾所得混合物,濾餅用THF洗滌。將濾液在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/於MeOH中之7 M NH 3= 20:1)及製備型HPLC (管柱:XBridge Prep OBD C18管柱,19*250 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3+0.05%NH 3 .H 2O),移動相B:MEOH;流動速率:25 mL/min mL/min;梯度:在10min內55% B至85% B;波長:254nm/220nm nm;RT1(min):9.2;運行次數:4)純化,以得到呈白色固體之(3S,4R)-3-氟-N-[2-(3-{[2-甲氧基-4-(丙烷-2-磺醯基)苯基]胺基}丙-1-炔-1-基)-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-8-基]-1-甲基哌啶-4-胺(12.8 mg,3.83%)。LC-MS:(M+H) +實測值614.25。 1H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J= 6.7 Hz, 1H), 7.31 (d, J= 8.3 Hz, 1H), 7.14 (d, J= 1.9 Hz, 1H), 7.02 (t, J= 7.1 Hz, 1H), 6.89 (d, J= 8.4 Hz, 1H), 6.69 – 6.53 (m, 2H), 5.59 (d, J= 9.0 Hz, 1H), 4.83 (d, J= 49.8 Hz, 1H), 4.37 (d, J= 6.1 Hz, 2H), 3.88 (s, 3H), 3.74 (d, J= 29.9 Hz, 1H), 3.30 – 3.21 (m, 1H), 3.03 (s, 1H), 2.77 (d, J= 11.1 Hz, 1H), 2.29 (d, J= 12.9 Hz, 1H), 2.19 (s, 3H), 2.09 (t, J= 11.3 Hz, 1H), 1.86 (d, J= 12.0 Hz, 2H), 1.13 (d, J= 6.8 Hz, 6H)。 實例79. (3S,4R)-N-[2-(3-{[4-(乙磺醯基)-2-甲氧基苯基]胺基}丙-1-炔-1-基)-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-8-基]-3-氟-1-甲基哌啶-4-胺之合成 步驟1. N-(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)-4-(乙磺醯基)-2-甲氧基苯胺之合成 A mixture of N-(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-2-methoxy-4-(propane-2-sulfonyl)aniline (300 mg, 0.53 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (218.3 mg, 1.07 mmol, 2 eq), t-BuONa (256.3 mg, 2.67 mmol, 5 eq) and tBuXphos Pd G3 (84.8 mg, 0.11 mmol, 0.2 eq) in THF (2 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was filtered and the filter cake was washed with THF. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 /7 M NH 3 in MeOH = 20:1) and preparative HPLC (column: XBridge Prep OBD C18 column, 19*250 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 +0.05% NH 3 . H 2 O), mobile phase B: MEOH; flow rate: 25 mL/min mL/min; gradient: 55% B to 85% B in 10 min; wavelength: 254 nm/220 nm nm; RT1(min): 9.2; Runs: 4) to give (3S,4R)-3-fluoro-N-[2-(3-{[2-methoxy-4-(propane-2-sulfonyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]-1-methylpiperidin-4-amine (12.8 mg, 3.83%) as a white solid. LC-MS: (M+H) + found 614.25. 1 H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J = 6.7 Hz, 1H), 7.31 (d, J = 8.3 Hz, 1H), 7.14 (d, J = 1.9 Hz, 1H), 7.02 (t, J = 7.1 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.69 – 6.53 (m, 2H), 5.59 (d, J = 9.0 Hz, 1H), 4.83 (d, J = 49.8 Hz, 1H), 4.37 (d, J = 6.1 Hz, 2H), 3.88 (s, 3H), 3.74 (d, J = 29.9 Hz, 1H), 3.30 – 3.21 (m, 1H), 3.03 (s, 1H), 2.77 (d, J = 11.1 Hz, 1H), 2.29 (d, J = 12.9 Hz, 1H), 2.19 (s, 3H), 2.09 (t, J = 11.3 Hz, 1H), 1.86 (d, J = 12.0 Hz, 2H), 1.13 (d, J = 6.8 Hz, 6H). Example 79. Synthesis of (3S,4R)-N-[2-(3-{[4-(ethylsulfonyl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine Step 1. Synthesis of N-(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-4-(ethylsulfonyl)-2-methoxyaniline
將8-溴-2-碘-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶(500 mg,1.18 mmol,1當量)、4-(乙磺醯基)-2-甲氧基-N-(丙-2-炔-1-基)苯胺( 中間物36;432.9 mg,1.42 mmol,1.2當量)、Pd(PPh 3) 4(273.2 mg,0.24 mmol,0.2當量)、CuI (225.1 mg,1.18 mmol,1當量)及i-Pr 2NH (1.2 g,11.82 mmol,10當量)於DMSO (5 mL)中之溶液在室溫及氮氣氛圍下攪拌1 h。所得混合物用EtOAc (100 mL)稀釋且用鹽水(3*50 mL)洗滌。有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用CH 2Cl 2/ MeOH (30:1)溶析,以得到呈黃色固體之N-(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)-4-(乙磺醯基)-2-甲氧基苯胺(580 mg,89.47%)。LC-MS:(M+H) +實測值548.0。 步驟2. (3S,4R)-N-[2-(3-{[4-(乙磺醯基)-2-甲氧基苯基]胺基}丙-1-炔-1-基)-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-8-基]-3-氟-1-甲基哌啶-4-胺之合成 A solution of 8-bromo-2-iodo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridine (500 mg, 1.18 mmol, 1 eq), 4-(ethylsulfonyl)-2-methoxy-N-(prop-2-yn-1-yl)aniline ( intermediate 36 ; 432.9 mg, 1.42 mmol, 1.2 eq), Pd(PPh 3 ) 4 (273.2 mg, 0.24 mmol, 0.2 eq), CuI (225.1 mg, 1.18 mmol, 1 eq) and i-Pr 2 NH (1.2 g, 11.82 mmol, 10 eq) in DMSO (5 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting mixture was diluted with EtOAc (100 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with CH 2 Cl 2 / MeOH (30:1) to give N-(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-4-(ethylsulfonyl)-2-methoxyaniline (580 mg, 89.47%) as a yellow solid. LC-MS: (M+H) + found 548.0. Step 2. Synthesis of (3S,4R)-N-[2-(3-{[4-(ethylsulfonyl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine
將N-(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)-4-(乙磺醯基)-2-甲氧基苯胺(200 mg,0.37 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(149.0 mg,0.73 mmol,2當量)、t-BuONa (175.3 mg,1.83 mmol,5當量)及tBuXphos Pd G3 (144.9 mg,0.18 mmol,0.5當量)於THF (2 mL)中之混合物在65℃及氮氣氛圍下攪拌1 h。過濾所得混合物,濾餅用DCM洗滌。將濾液在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/於MeOH中之7 M NH 3= 30:1)及製備型HPLC (管柱:XBridge Prep OBD C18管柱,19*250 mm,5 μm;移動相A:水(10 mmol/L NH 4HCO 3+0.05%NH 3 .H 2O),移動相B:MEOH;流動速率:25 mL/min mL/min;梯度:在10min內58% B至78% B;波長:254nm/220nm nm;RT1(min):9.12;運行次數:4)純化,以得到呈白色固體之(3S,4R)-N-[2-(3-{[4-(乙磺醯基)-2-甲氧基苯基]胺基}丙-1-炔-1-基)-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-8-基]-3-氟-1-甲基哌啶-4-胺(54.0 mg,24.67%)。LC-MS:(M+H) +實測值600.10。 1H NMR (400 MHz, DMSO- d 6) δ 7.87 (d, J= 6.6 Hz, 1H), 7.34 (m, 2.0 Hz, 1H), 7.19 (d, J= 2.0 Hz, 1H), 7.10 – 6.99 (m, 1H), 6.88 (d, J= 8.4 Hz, 1H), 6.67 – 6.49 (m, 2H), 5.60 (d, J= 9.0 Hz, 1H), 4.83 (d, J= 49.6 Hz, 1H), 4.37 (d, J= 6.2 Hz, 2H), 3.89 (s, 3H), 3.82 – 3.60 (m, 1H), 3.17 (m, 2H), 3.03 (t, J= 11.6 Hz, 1H), 2.77 (d, J= 11.5 Hz, 1H), 2.19 (s, 4H), 2.09 (t, J= 11.2 Hz, 1H), 1.93 – 1.66 (m, 2H), 1.08 (t, J= 7.3 Hz, 3H)。 實例80. (3S,4R)-N-[2-(3-{[4-(乙磺醯基)-2-甲氧基苯基]胺基}丙-1-炔-1-基)-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-8-基]-3-氟哌啶-4-胺乙磺醯基 步驟1. (3S,4R)-4-((2-(3-((4-(乙基磺醯基)-2-甲氧基苯基)胺基)丙-1-炔-1-基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-8-基)胺基)-3-氟哌啶-1-甲酸三級丁酯之合成 A mixture of N-(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-4-(ethylsulfonyl)-2-methoxyaniline (200 mg, 0.37 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (149.0 mg, 0.73 mmol, 2 eq), t-BuONa (175.3 mg, 1.83 mmol, 5 eq) and tBuXphos Pd G3 (144.9 mg, 0.18 mmol, 0.5 eq) in THF (2 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was filtered and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 /7 M NH 3 in MeOH = 30:1) and preparative HPLC (column: XBridge Prep OBD C18 column, 19*250 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 +0.05% NH 3 . H 2 O), mobile phase B: MEOH; flow rate: 25 mL/min mL/min; gradient: 58% B to 78% B in 10 min; wavelength: 254 nm/220 nm). nm; RT1(min): 9.12; Runs: 4) to give (3S,4R)-N-[2-(3-{[4-(ethylsulfonyl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine (54.0 mg, 24.67%) as a white solid. LC-MS: (M+H) + found 600.10. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.87 (d, J = 6.6 Hz, 1H), 7.34 (m, 2.0 Hz, 1H), 7.19 (d, J = 2.0 Hz, 1H), 7.10 – 6.99 (m, 1H), 6.88 (d, J = 8.4 Hz, 1H), 6.67 – 6.49 (m, 2H), 5.60 (d, J = 9.0 Hz, 1H), 4.83 (d, J = 49.6 Hz, 1H), 4.37 (d, J = 6.2 Hz, 2H), 3.89 (s, 3H), 3.82 – 3.60 (m, 1H), 3.17 (m, 3.03 (t, J = 11.6 Hz, 1H), 2.77 (d, J = 11.5 Hz, 1H), 2.19 (s, 4H), 2.09 (t, J = 11.2 Hz, 1H), 1.93 – 1.66 (m, 2H), 1.08 (t, J = 7.3 Hz, 3H). Example 80. (3S,4R)-N-[2-(3-{[4-(ethylsulfonyl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]-3-fluoropiperidin-4-amineethylsulfonyl Step 1. Synthesis of tributyl (3S,4R)-4-((2-(3-((4-(ethylsulfonyl)-2-methoxyphenyl)amino)prop-1-yn-1-yl)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-8-yl)amino)-3-fluoropiperidine-1-carboxylate
將N-(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)-4-(乙磺醯基)-2-甲氧基苯胺(380 mg,0.69 mmol,1當量)、(3S,4R)-4-胺基-3-氟哌啶-1-甲酸三級丁酯(228 mg,1.05 mmol,1.51當量)、t-BuONa (136 mg,1.42 mmol,2.04當量)及tBuXphos Pd G3 (275 mg,0.35 mmol,0.50當量)於THF (4 mL)中之混合物在65℃及氮氣氛圍下攪拌1 h。過濾所得混合物,濾餅用DCM洗滌。將濾液在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/於MeOH中之7 M NH 3= 50:1)純化,以得到呈黃色固體之(3S,4R)-N-[2-(3-{[4-(乙磺醯基)-2-甲氧基苯基]胺基}丙-1-炔-1-基)-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-8-基]-3-氟哌啶-4-胺(250 mg,61.60%)。LC-MS:(M+H) +實測值686.3。 步驟2. (3S,4R)-N-[2-(3-{[4-(乙磺醯基)-2-甲氧基苯基]胺基}丙-1-炔-1-基)-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-8-基]-3-氟哌啶-4-胺之合成 A mixture of N-(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-4-(ethylsulfonyl)-2-methoxyaniline (380 mg, 0.69 mmol, 1 eq), (3S,4R)-4-amino-3-fluoropiperidine-1-carboxylic acid tributyl ester (228 mg, 1.05 mmol, 1.51 eq), t-BuONa (136 mg, 1.42 mmol, 2.04 eq) and tBuXphos Pd G3 (275 mg, 0.35 mmol, 0.50 eq) in THF (4 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was filtered and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 /7 M NH 3 in MeOH = 50:1) to give (3S,4R)-N-[2-(3-{[4-(ethylsulfonyl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]-3-fluoropiperidin-4-amine (250 mg, 61.60%) as a yellow solid. LC-MS: (M+H) + found 686.3. Step 2. Synthesis of (3S,4R)-N-[2-(3-{[4-(ethylsulfonyl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]-3-fluoropiperidin-4-amine
在0℃下,向(3S,4R)-4-{[2-(3-{[4-(乙磺醯基)-2-甲氧基苯基]胺基}丙-1-炔-1-基)-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-8-基]胺基}-3-氟哌啶-1-甲酸三級丁酯(250 mg,0.37 mmol,1當量)於DCM (5 mL)中之攪拌溶液中逐滴添加TFA (2.5 mL,33.66 mmol,92.32當量)。將所得混合物在室溫下攪拌30 min,然後用水稀釋且用飽和NaHCO 3鹼化至pH 8。所得混合物用CH 2Cl 2(3*50 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型HPLC (管柱:XBridge Prep OBD C18管柱,19*250 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3+0.05%NH 3 .H 2O),移動相B:MEOH;流動速率:25 mL/min mL/min;梯度:在10min內57% B至72% B;波長:254nm/220nm nm;RT1(min):9.65;運行次數:7)純化,以得到呈白色固體之(3S,4R)-N-[2-(3-{[4-(乙磺醯基)-2-甲氧基苯基]胺基}丙-1-炔-1-基)-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-8-基]-3-氟哌啶-4-胺(31 mg,14.39%)。LC-MS:(M+H) +實測值586.15。 1H NMR (400 MHz, DMSO- d 6) δ 7.86 (d, J= 6.6 Hz, 1H), 7.34 (m, 2.0 Hz, 1H), 7.19 (d, J= 2.0 Hz, 1H), 7.02 (t, J= 7.2 Hz, 1H), 6.88 (d, J= 8.4 Hz, 1H), 6.62 (d, J= 7.7 Hz, 1H), 6.54 (t, J= 6.2 Hz, 1H), 5.59 (d, J= 9.0 Hz, 1H), 4.72 (d, J= 50.5 Hz, 1H), 4.37 (d, J= 6.2 Hz, 2H), 3.89 (s, 4H), 3.23 – 3.05 (m, 3H), 2.94 (d, J= 13.1 Hz, 1H), 2.76 (m, 1H), 2.63 – 2.54 (m, 1H), 2.08 (s, 1H), 1.79 – 1.54 (m, 2H), 1.08 (t, J= 7.3 Hz, 3H)。 實例81. (3S,4R)-N-[2-(3-{[4-(環丙烷磺醯基)-2-甲氧基苯基]胺基}丙-1-炔-1-基)-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-8-基]-3-氟-1-甲基哌啶-4-胺之合成 步驟1. N-(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)-4-(環丙烷磺醯基)-2-甲氧基苯胺之合成 To a stirred solution of (3S,4R)-4-{[2-(3-{[4-(ethylsulfonyl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-8-yl]amino}-3-fluoropiperidine-1-carboxylic acid tributyl ester (250 mg, 0.37 mmol, 1 eq) in DCM (5 mL) at 0°C was added TFA (2.5 mL, 33.66 mmol, 92.32 eq) dropwise. The resulting mixture was stirred at room temperature for 30 min, then diluted with water and basified to pH 8 with saturated NaHCO 3. The resulting mixture was extracted with CH 2 Cl 2 (3*50 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 19*250 mm, 5μm; mobile phase A: water (10mmol/L NH 4 HCO 3 +0.05% NH 3 . H 2 O), mobile phase B: MEOH; flow rate: 25 mL/min mL/min; gradient: 57% B to 72% B in 10min; wavelength: 254nm/220nm nm; RT1(min): 9.65; Run number: 7) to give (3S,4R)-N-[2-(3-{[4-(ethylsulfonyl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]-3-fluoropiperidin-4-amine (31 mg, 14.39%) as a white solid. LC-MS: (M+H) + found 586.15. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.86 (d, J = 6.6 Hz, 1H), 7.34 (m, 2.0 Hz, 1H), 7.19 (d, J = 2.0 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 6.62 (d, J = 7.7 Hz, 1H), 6.54 (t, J = 6.2 Hz, 1H), 5.59 (d, J = 9.0 Hz, 1H), 4.72 (d, J = 50.5 Hz, 1H), 4.37 (d, J = 6.2 Hz, 2H), 3.89 (s, 4H), 3.23 – 3.05 (m, 3H), 2.94 (d, J = 13.1 Hz, 1H), 2.76 (m, 1H), 2.63 – 2.54 (m, 1H), 2.08 (s, 1H), 1.79 – 1.54 (m, 2H), 1.08 (t, J = 7.3 Hz, 3H). Example 81. Synthesis of (3S,4R)-N-[2-(3-{[4-(cyclopropanesulfonyl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine Step 1. Synthesis of N-(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-4-(cyclopropanesulfonyl)-2-methoxyaniline
將8-溴-2-碘-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶( 中間物9;200 mg,0.47 mmol,1當量)、4-(環丙烷磺醯基)-2-甲氧基-N-(丙-2-炔-1-基)苯胺( 中間物37;250.9 mg,0.95 mmol,2當量)、CuI (90.1 mg,0.47 mmol,1當量)、i-Pr 2NH (478.5 mg,4.73 mmol,10當量)及Pd(PPh 3) 4(109.3 mg,0.09 mmol,0.2當量)於DMSO (3 mL)中之溶液在室溫及氮氣氛圍下攪拌1 h。所得溶液用EtOAc (50 mL)稀釋且用鹽水(3*50 mL)洗滌。有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/ MeOH 20:1)純化,以得到呈棕色固體之N-(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)-4-(環丙烷磺醯基)-2-甲氧基苯胺(350 mg)。LC-MS:(M+H) +實測值560.0。 步驟2. (3S,4R)-N-[2-(3-{[4-(環丙烷磺醯基)-2-甲氧基苯基]胺基}丙-1-炔-1-基)-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-8-基]-3-氟-1-甲基哌啶-4-胺之合成 A solution of 8-bromo-2-iodo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridine ( intermediate 9 ; 200 mg, 0.47 mmol, 1 eq), 4-(cyclopropanesulfonyl)-2-methoxy-N-(prop-2-yn-1-yl)aniline ( intermediate 37 ; 250.9 mg, 0.95 mmol, 2 eq), CuI (90.1 mg, 0.47 mmol, 1 eq), i- Pr2NH (478.5 mg, 4.73 mmol, 10 eq) and Pd( PPh3 ) 4 (109.3 mg, 0.09 mmol, 0.2 eq) in DMSO (3 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting solution was diluted with EtOAc (50 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 / MeOH 20:1) to give N-(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-4-(cyclopropanesulfonyl)-2-methoxyaniline (350 mg) as a brown solid. LC-MS: (M+H) + found 560.0. Step 2. Synthesis of (3S,4R)-N-[2-(3-{[4-(cyclopropanesulfonyl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine
將N-(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)-4-(環丙烷磺醯基)-2-甲氧基苯胺(350 mg,0.63 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺(165.1 mg,1.25 mmol,2當量)、tBuXPhos Pd G3 (148.8 mg,0.19 mmol,0.3當量)及t-BuONa (300.1 mg,3.12 mmol,5當量)於THF (5 mL)中之混合物在65℃及氮氣氛圍下攪拌1 h。將所得混合物在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/於MeOH中之7 M NH 3= 30:1)純化及製備型HPLC (管柱:XBridge Prep OBD C18管柱,19*250 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3+0.05%NH 3 .H 2O),移動相B:MEOH;流動速率:25 mL/min mL/min;梯度:在10min內57% B至80% B;波長:254nm/220nm nm;RT1(min):9.2;運行次數:4)純化,以得到呈淺黃色固體之(3S,4R)-N-[2-(3-{[4-(環丙烷磺醯基)-2-甲氧基苯基]胺基}丙-1-炔-1-基)-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-8-基]-3-氟-1-甲基哌啶-4-胺(19.7 mg,5.12%)。LC-MS:(M+H) +實測值612.15。 1H NMR (400 MHz, DMSO-d6) δ 7.91 – 7.81 (d, J= 6.6 Hz, 1H), 7.39 – 7.30 (dd, J= 2.0, 8.3 Hz, 1H), 7.24 – 7.17 (d, J= 2.0 Hz, 1H), 7.08 – 6.98 (m, 1H), 6.91 – 6.84 (d, J= 8.4 Hz, 1H), 6.68 – 6.59 (d, J= 7.7 Hz, 1H), 6.58 – 6.49 (t, J= 6.2 Hz, 1H), 5.66 – 5.57 (d, J= 9.0 Hz, 1H), 4.94 – 4.73 (d, J= 49.5 Hz, 1H), 4.42 – 4.31 (d, J= 6.2 Hz, 2H), 3.94 – 3.86 (s, 3H), 3.85 – 3.66 (m, 1H), 3.11 – 2.96 (t, J= 11.5 Hz, 1H), 2.81 – 2.67 (m, 2H), 2.37 – 2.24 (m, 1H), 2.24 – 2.15 (s, 3H), 2.15 – 2.04 (t, J= 11.5 Hz, 1H), 1.95 – 1.82 (dd, J= 3.6, 12.1 Hz, 1H), 1.82 – 1.71 (d, J= 12.5 Hz, 1H), 1.11 – 1.01 (m, 2H), 1.01 – 0.92 (dd, J= 2.9, 7.8 Hz, 2H)。 實例82. (3S,4R)-3-氟-N-(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-8-基)-1-甲基哌啶-4-胺之合成 步驟1. N-(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)-4-甲磺醯基-2-甲氧基苯胺之合成 A mixture of N-(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-4-(cyclopropanesulfonyl)-2-methoxyaniline (350 mg, 0.63 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine (165.1 mg, 1.25 mmol, 2 eq), tBuXPhos Pd G3 (148.8 mg, 0.19 mmol, 0.3 eq) and t-BuONa (300.1 mg, 3.12 mmol, 5 eq) in THF (5 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 /7 M NH 3 in MeOH = 30:1) and preparative HPLC (column: XBridge Prep OBD C18 column, 19*250 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 +0.05% NH 3 . H 2 O), mobile phase B: MEOH; flow rate: 25 mL/min mL/min; gradient: 57% B to 80% B in 10 min; wavelength: 254 nm/220 nm nm; RT1(min): 9.2; Run number: 4) to give (3S,4R)-N-[2-(3-{[4-(cyclopropanesulfonyl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine (19.7 mg, 5.12%) as a light yellow solid. LC-MS: (M+H) + found 612.15. 1 H NMR (400 MHz, DMSO-d6) δ 7.91 – 7.81 (d, J = 6.6 Hz, 1H), 7.39 – 7.30 (dd, J = 2.0, 8.3 Hz, 1H), 7.24 – 7.17 (d, J = 2.0 Hz, 1H), 7.08 – 6.98 (m, 1H), 6.91 – 6.84 (d, J = 8.4 Hz, 1H), 6.68 – 6.59 (d, J = 7.7 Hz, 1H), 6.58 – 6.49 (t, J = 6.2 Hz, 1H), 5.66 – 5.57 (d, J = 9.0 Hz, 1H), 4.94 – 4.73 9 (d, J = 49.5 Hz, 1H), 4.42 – 4.31 (d, J = 6.2 Hz, 2H), 3.94 – 3.86 (s, 3H), 3.85 – 3.66 (m, 1H), 3.11 – 2.96 (t, J = 11.5 Hz, 1H), 2.81 – 2.67 (m, 2H), 2.37 – 2.24 (m, 1H), 2.24 – 2.15 (s, 3H), 2.15 – 2.04 (t, J = 11.5 Hz, 1H), 1.95 – 1.82 (dd, J = 3.6, 12.1 Hz, 1H), 1.82 – 1.71 (d, J = 12.5 Hz, 1H), 1.11 – 1.01 (m, 2H), 1.01 – 0.92 (dd, J = 2.9, 7.8 Hz, 2H). Example 82. Synthesis of (3S,4R)-3-fluoro-N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine Step 1. Synthesis of N-(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-4-methanesulfonyl-2-methoxyaniline
將8-溴-2-碘-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶( 中間物9;200.0 mg,0.47 mmol,1當量)、4-甲磺醯基-2-甲氧基-N-(丙-2-炔-1-基)苯胺( 中間物39;124.5 mg,0.52 mmol,1.10當量)、CuI (90.1 mg,0.47 mmol,1當量)、Pd(PPh 3) 4(109.3 mg,0.10 mmol,0.20當量)及i-Pr 2NH (478.5 mg,4.73 mmol,10當量)於DMSO (3 mL)中之溶液在30℃及氮氣氛圍下攪拌1 h。溶液藉由反相急速層析(管柱,C18;移動相,於水中之MeCN,在20 min內0%至50%梯度;偵測器,UV 254 nm)純化,以得到呈淺黃色固體之N-(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)-4-甲磺醯基-2-甲氧基苯胺(150.0 mg,59.37%)。LC-MS:(M+H) +實測值534.3。 步驟2. (3S,4R)-3-氟-N-(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-8-基)-1-甲基哌啶-4-胺之合成 A solution of 8-bromo-2-iodo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridine ( intermediate 9 ; 200.0 mg, 0.47 mmol, 1 eq), 4-methanesulfonyl-2-methoxy-N-(prop-2-yn-1-yl)aniline ( intermediate 39 ; 124.5 mg, 0.52 mmol, 1.10 eq), CuI (90.1 mg, 0.47 mmol, 1 eq), Pd( PPh3 ) 4 (109.3 mg, 0.10 mmol, 0.20 eq) and i- Pr2NH (478.5 mg, 4.73 mmol, 10 eq) in DMSO (3 mL) was stirred at 30 °C under nitrogen atmosphere for 1 h. The solution was purified by reverse phase flash chromatography (column, C18; mobile phase, MeCN in water, gradient 0% to 50% in 20 min; detector, UV 254 nm) to give N-(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-4-methanesulfonyl-2-methoxyaniline (150.0 mg, 59.37%) as a light yellow solid. LC-MS: (M+H) + found 534.3. Step 2. Synthesis of (3S,4R)-3-fluoro-N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine
將N-(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)-4-甲磺醯基-2-甲氧基苯胺(50.0 mg,0.09 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(38.4 mg,0.19 mmol,2當量)、t-BuXPhosPdG3 (29.8 mg,0.04 mmol,0.40當量)及t-BuONa (54.0 mg,0.56 mmol,6當量)於THF (1 mL)中之混合物在65℃及氮氣氛圍下攪拌30 min。將所得混合物在真空下濃縮。殘餘物藉由反相急速層析(管柱,C18;移動相,於水中之MeCN (0.1% FA),在20 min內0%至30%梯度;偵測器,UV 254 nm)及製備型HPLC (管柱:XBridge Prep OBD C18管柱,30*150 mm,5 μm;移動相A:水(10 mmol/L NH 4HCO 3)+0.05% NH 3 .H 2O,移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在7min內33% B至60% B;波長:254nm/220nm nm;RT(min):7.58)純化,以得到呈白色固體之(3S,4R)-3-氟-N-(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-8-基)-1-甲基哌啶-4-胺(19.9 mg,36.3%)。LC-MS:(M+H) +實測值586.25。 1H NMR (400 MHz, DMSO- d 6) δ 7.87 (d, J= 6.6 Hz, 1H), 7.39 (dd, J= 8.4, 2.0 Hz, 1H), 7 .25 (d, J= 2.0 Hz, 1H), 7.02 (t, J= 7.2 Hz, 1H), 6.87 (d, J= 8.4 Hz, 1H), 6.62 (d, J= 7.7 Hz, 1H), 6.53 (t, J= 6.2 Hz, 1H), 5.60 (d, J= 8.9 Hz, 1H), 4.83 (d, J= 49.5 Hz, 1H), 4.37 (d, J= 6.2 Hz, 2H), 3.90 (s, 3H), 3.79-3.58 (m, 1H), 3.10 (s, 3H), 3.03 (t, J= 10.7 Hz, 1H), 2.77 (d, J= 11.3 Hz, 1H), 2.34-2.15 (m, 4H), 2.09 (dd, J= 12.6, 9.8 Hz, 1H), 1.86 (m, 1H), 1.77 (dd, J= 13.7, 3.8 Hz, 1H)。 實例83. (3S,4R)-3-氟-N-(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-8-基)哌啶-4-胺)之合成 步驟1. (3S,4R)-3-氟-4-[(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-8-基)胺基]哌啶-1-甲酸三級丁酯之合成 A mixture of N-(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-4-methanesulfonyl-2-methoxyaniline (50.0 mg, 0.09 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (38.4 mg, 0.19 mmol, 2 eq), t-BuXPhosPdG3 (29.8 mg, 0.04 mmol, 0.40 eq) and t-BuONa (54.0 mg, 0.56 mmol, 6 eq) in THF (1 mL) was stirred at 65 °C under nitrogen atmosphere for 30 min. The resulting mixture was concentrated under vacuum. The residue was purified by reverse phase flash chromatography (column, C18; mobile phase, MeCN (0.1% FA) in water, gradient from 0% to 30% in 20 min; detector, UV 254 nm) and preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 )+0.05% NH 3 . H 2 O, mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 33% B to 60% B in 7 min; wavelength: 254 nm/220 nm). nm; RT (min): 7.58) to give (3S,4R)-3-fluoro-N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine (19.9 mg, 36.3%) as a white solid. LC-MS: (M+H) + found 586.25. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.87 (d, J = 6.6 Hz, 1H), 7.39 (dd, J = 8.4, 2.0 Hz, 1H), 7 .25 (d, J = 2.0 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 6.62 (d, J = 7.7 Hz, 1H), 6.53 (t, J = 6.2 Hz, 1H), 5.60 (d, J = 8.9 Hz, 1H), 4.83 (d, J = 49.5 Hz, 1H), 4.37 (d, J = 6.2 Hz, 2H), 3.90 (s, 3H), 3.79-3.58 (m, 1H), 3.10 (s, 3H), 3.03 (t, J = 10.7 Hz, 1H), 2.77 (d, J = 11.3 Hz, 1H), 2.34-2.15 (m, 4H), 2.09 (dd, J = 12.6, 9.8 Hz, 1H), 1.86 (m, 1H), 1.77 (dd, J = 13.7, 3.8 Hz, 1H). Example 83. Synthesis of (3S,4R)-3-fluoro-N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl)piperidin-4-amine) Step 1. Synthesis of tributyl (3S,4R)-3-fluoro-4-[(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl)amino]piperidine-1-carboxylate
將N-(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)-4-甲磺醯基-2-甲氧基苯胺(130 mg,0.24 mmol,1當量)、(3S,4R)-4-胺基-3-氟哌啶-1-甲酸三級丁酯(79 mg,0.36 mmol,1.50當量)、[2'-(二苯基磷烷基)-[1,1'-聯萘]-2-基]二苯基磷烷基;{2'-胺基-[1,1'-聯苯]-2-基}甲磺酸鈀(48 mg,0.05 mmol,0.20當量)、BINAP (60 mg,0.10 mmol,0.40當量)及Cs 2CO 3(158 mg,0.48 mmol,2當量)於二噁烷(10 mL)中之混合物在100℃及氮氣氛圍下攪拌4 h。反應用飽和NaHCO 3淬滅且用EtOAc (3*10 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由反相急速層析(管柱,C18矽膠;移動相,於水中之MeCN (0.1% FA),在10 min內10%至50%梯度;偵測器,UV 254 nm)純化,以得到呈黃色油狀物之(3S,4R)-3-氟-4-[(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-8-基)胺基]哌啶-1-甲酸三級丁酯(100 mg,61.19%)。LC-MS:(M+H) +實測值:672.4。 步驟2. (3S,4R)-3-氟-N-(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-8-基)哌啶-4-胺)之合成 N-(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-4-methanesulfonyl-2-methoxyaniline (130 mg, 0.24 mmol, 1 equiv), (3S,4R)-4-amino-3-fluoropiperidine-1-carboxylic acid tributyl ester (79 mg, 0.36 mmol, 1.50 equiv), [2'-(diphenylphosphatyl)-[1,1'-binaphthyl]-2-yl]diphenylphosphatyl;{2'-amino-[1,1'-biphenyl]-2-yl}methanesulfonate (48 mg, 0.05 mmol, 0.20 equiv), BINAP (60 mg, 0.10 mmol, 0.40 equiv) and Cs 2 CO 3 (158 mg, 0.48 mmol, 2 eq) in dioxane (10 mL) was stirred at 100 °C under nitrogen atmosphere for 4 h. The reaction was quenched with saturated NaHCO 3 and extracted with EtOAc (3*10 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient 10% to 50% in 10 min; detector, UV 254 nm) to give (3S,4R)-3-fluoro-4-[(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl)amino]piperidine-1-carboxylic acid tributyl ester (100 mg, 61.19%) as a yellow oil. LC-MS: (M+H) + found: 672.4. Step 2. Synthesis of (3S,4R)-3-fluoro-N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl)piperidin-4-amine)
在0℃下,向(3S,4R)-3-氟-4-[(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-8-基)胺基]哌啶-1-甲酸三級丁酯(100 mg,0.15 mmol,1當量) 於DCM (2 mL)中之攪拌溶液中逐滴添加TFA (0.5 mL)。將所得混合物在室溫下攪拌30 min。反應用飽和NaHCO 3淬滅且用DCM/MeOH (10:1) (3*10 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型HPLC (管柱:XSelect CSH Prep C18 OBD管柱,19*250 mm,5m;移動相A:水(10 mmol/L NH 4HCO 3),移動相B:ACN;流動速率:25 mL/min mL/min;梯度:在7 min內40% B至45% B;波長:254 nm nm;RT1(min):7)純化,以得到呈白色固體之(3S,4R)-3-氟-N-(2-{3-[(4-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-8-基)哌啶-4-胺) (32.4 mg,38.08%)。LC-MS:(M+H) +實測值:572.15。 1H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J= 6.6 Hz, 1H), 7.40 - 7.38 (m, 1H), 7.25 (d, J= 2.0 Hz, 1H), 7.02 (t, J= 7.2 Hz, 1H), 6.88 (d, J= 8.4 Hz, 1H), 6.63 (d, J= 7.7 Hz, 1H), 6.52 (t, J= 6.2 Hz, 1H), 5.58 (d, J= 9.0 Hz, 1H), 4.78 - 4.65 (m, 1H), 4.37 (d, J= 6.2 Hz, 2H), 3.90 (s, 3H), 3.87 - 3.78 (m, 1H), 3.19 - 3.13 (m, 1H), 3.10 (s, 3H), 2.96 - 2.91 (m, 1H), 2.83 - 2.69 (m, 1H), 2.61 – 2.55 (m, 1H), 2.07 (s, 1H), 1.73 - 1.63 (m, 2H)。 實例84. (3S,4R)-3-氟-N-(2-{3-[(5-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-8-基)-1-甲基哌啶-4-胺之合成 步驟1. N-(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)-5-甲磺醯基-2-甲氧基苯胺之合成 To a stirred solution of (3S,4R)-3-fluoro-4-[(2-{3-[(4-methanesulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-8-yl)amino]piperidine-1-carboxylic acid tributyl ester (100 mg, 0.15 mmol, 1 eq) in DCM (2 mL) at 0°C was added TFA (0.5 mL) dropwise. The resulting mixture was stirred at room temperature for 30 min. The reaction was quenched with saturated NaHCO 3 and extracted with DCM/MeOH (10:1) (3*10 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 . After filtration, the filtrate is concentrated under reduced pressure. The residue was purified by preparative HPLC (column: XSelect CSH Prep C18 OBD column, 19*250 mm, 5m; mobile phase A: water (10 mmol/L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 25 mL/min mL/min; gradient: 40% B to 45% B in 7 min; wavelength: 254 nm nm; RT1(min): 7) to give (3S,4R)-3-fluoro-N-(2-{3-[(4-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl)piperidin-4-amine) (32.4 mg, 38.08%) as a white solid. LC-MS: (M+H) + found: 572.15. 1 H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J = 6.6 Hz, 1H), 7.40 - 7.38 (m, 1H), 7.25 (d, J = 2.0 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 6.63 (d, J = 7.7 Hz, 1H), 6.52 (t, J = 6.2 Hz, 1H), 5.58 (d, J = 9.0 Hz, 1H), 4.78 - 4.65 (m, 1H), 4.37 (d, J = 6.2 Hz, 2H), 3.90 (s, 3H), 3.87 - 3.78 (m, 1H), 3.19 - 3.13 (m, 1H), 3.10 (s, 3H), 2.96 - 2.91 (m, 1H), 2.83 - 2.69 (m, 1H), 2.61 – 2.55 (m, 1H), 2.07 (s, 1H), 1.73 - 1.63 (m, 2H). Example 84. Synthesis of (3S,4R)-3-fluoro-N-(2-{3-[(5-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine Step 1. Synthesis of N-(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-5-methanesulfonyl-2-methoxyaniline
將5-甲磺醯基-2-甲氧基-N-(丙-2-炔-1-基)苯胺( 中間物42;120 mg,0.50 mmol,1當量)、8-溴-2-碘-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶(212.1 mg,0.50 mmol,1當量)、CuI (95.5 mg,0.50 mmol,1當量)、二異丙胺(507. 5 mg,5.01 mmol,10當量)及Pd(PPh 3) 4(231.8 mg,0.20 mmol,0.4當量)於DMSO (4 mL)中之溶液在室溫及氮氣氛圍下攪拌1 h。反應混合物用水(100 mL)稀釋且用EtOAc (2*100 mL)萃取。合併的有機層經硫酸鈉乾燥,過濾且真空濃縮。殘餘物藉由反相急速層析(管柱,C18矽膠;移動相,於水中之MeCN (0.1%NH 4HCO 3),在10 min內30%至50%梯度;偵測器,UV 220 nm)純化,以得到呈灰白色固體之N-(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)-5-甲磺醯基-2-甲氧基苯胺(120 mg,44.78%)。LC-MS:(M+H) +實測值:534.7。 步驟2. (3S,4R)-3-氟-N-(2-{3-[(5-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-8-基)-1-甲基哌啶-4-胺之合成 A solution of 5-methanesulfonyl-2-methoxy-N-(prop-2-yn-1-yl)aniline ( intermediate 42 ; 120 mg, 0.50 mmol, 1 eq), 8-bromo-2-iodo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine (212.1 mg, 0.50 mmol, 1 eq), CuI (95.5 mg, 0.50 mmol, 1 eq), diisopropylamine (507.5 mg, 5.01 mmol, 10 eq) and Pd(PPh 3 ) 4 (231.8 mg, 0.20 mmol, 0.4 eq) in DMSO (4 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2*100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (0.1% NH 4 HCO 3 ) in water, gradient 30% to 50% in 10 min; detector, UV 220 nm) to give N-(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-5-methylsulfonyl-2-methoxyaniline (120 mg, 44.78%) as an off-white solid. LC-MS: (M+H) + found: 534.7. Step 2. Synthesis of (3S,4R)-3-fluoro-N-(2-{3-[(5-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine
將N-(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)-5-甲磺醯基-2-甲氧基苯胺(120 mg,0.23 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(92.1 mg,0.45 mmol,2當量)、Cs 2CO 3(439.0 mg,1.35 mmol,6當量)、BINAP (55.9 mg,0.09 mmol,0.4當量)及RAC-BINAP-PD-G 3(44.6 mg,0.05 mmol,0.2當量)於二噁烷(4 mL)中之混合物在100℃及氮氣氛圍下攪拌16 h。反應混合物用水(10 mL)淬滅且用EtOAc (2*10 mL)萃取。合併的有機層經硫酸鈉乾燥,過濾且真空濃縮。殘餘物藉由反相急速層析(管柱,C18矽膠;移動相,於0.1%FA中之MeCN,在10 min內20%至50%梯度;偵測器,UV 220 nm)及製備型HPLC (管柱:Xselect CSH Prep Fluoro-Phenyl管柱,19*250 mm,5μm;移動相A:水(0.1% FA),移動相B:ACN;流動速率:25 mL/min mL/min;梯度:在12min內19% B至29% B;波長:254nm/220nm nm;RT1(min):9.35)純化,以得到呈灰白色固體之(3S,4R)-3-氟-N-(2-{3-[(5-甲磺醯基-2-甲氧基苯基)胺基]丙-1-炔-1-基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-8-基)-1-甲基哌啶-4-胺(22.1 mg,16.67%)。LC-MS:(M+H) +實測值:586.30。 1H NMR (400 MHz, DMSO-d 6) δ 7.86 (d, J= 6.6 Hz, 1H), 7.32 – 7.14 (m, 2H), 7.12 – 6.97 (m, 2H), 6.62 (d, J= 7.7 Hz, 1H), 6.08 (t, J= 6.4 Hz, 1H), 5.54 (d, J= 9.0 Hz, 1H), 4.83 (d, J= 49.2 Hz, 1H), 4.36 (d, J= 6.3 Hz, 2H), 3.90 (s, 3H), 3.71 (m, 1H), 3.10 (s, 3H), 3.05 (d, J= 11.6 Hz, 1H), 2.85 – 2.67 (m, 1H), 2.20 (s, 4H), 2.10 (d, J= 3.1 Hz, 1H), 1.94 – 1.72 (m, 2H)。 實例85. N-乙基-4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基苯甲醯胺之合成 步驟1. 4-[(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-N-乙基-3-甲氧基苯甲醯胺之合成 A mixture of N-(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-5-methanesulfonyl-2-methoxyaniline (120 mg, 0.23 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (92.1 mg, 0.45 mmol, 2 eq), Cs2CO3 (439.0 mg, 1.35 mmol, 6 eq), BINAP (55.9 mg, 0.09 mmol, 0.4 eq) and RAC-BINAP-PD- G3 (44.6 mg, 0.05 mmol, 0.2 eq) in dioxane (4 mL) was stirred at 100 °C under nitrogen atmosphere for 16 h. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (2*10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in 0.1% FA, gradient from 20% to 50% in 10 min; detector, UV 220 nm) and preparative HPLC (column: Xselect CSH Prep Fluoro-Phenyl column, 19*250 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 25 mL/min mL/min; gradient: 19% B to 29% B in 12 min; wavelength: 254 nm/220 nm nm; RT1 (min): 9.35) to give (3S,4R)-3-fluoro-N-(2-{3-[(5-methylsulfonyl-2-methoxyphenyl)amino]prop-1-yn-1-yl}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl)-1-methylpiperidin-4-amine (22.1 mg, 16.67%) as an off-white solid. LC-MS: (M+H) + found: 586.30. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.86 (d, J = 6.6 Hz, 1H), 7.32 – 7.14 (m, 2H), 7.12 – 6.97 (m, 2H), 6.62 (d, J = 7.7 Hz, 1H), 6.08 (t, J = 6.4 Hz, 1H), 5.54 (d, J = 9.0 Hz, 1H), 4.83 (d, J = 49.2 Hz, 1H), 4.36 (d, J = 6.3 Hz, 2H), 3.90 (s, 3H), 3.71 (m, 1H), 3.10 (s, 3H), 3.05 (d, J = 11.6 Hz, 1H), 2.85 – 2.67 (m, 1H), 2.20 (s, 4H), 2.10 (d, J = 3.1 Hz, 1H), 1.94 – 1.72 (m, 2H). Example 85. Synthesis of N-ethyl-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxybenzamide Step 1. Synthesis of 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-N-ethyl-3-methoxybenzamide
將8-溴-2-碘-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶( 中間物9;200.0 mg,0.47 mmol,1當量)、N-乙基-3-甲氧基-4-(丙-2-炔-1-基胺基)苯甲醯胺( 中間物16;131.8 mg,0.57 mmol,1.20當量)、i-Pr 2NH (478.5 mg,4.73 mmol,10當量)、CuI (45.0 mg,0.24 mmol,0.50當量)及Pd(PPh 3) 4(109.3 mg,0.10 mmol,0.20當量)於DMSO (15 mL)中之溶液在30℃及氮氣氛圍下攪拌1 h。所得溶液使用C18急速層析(移動相A:水,移動相B:ACN;流動速率:80 mL/min;梯度:在30 min內0% B至100% B;254/220 nm)純化,以得到呈淺黃色固體之4-[(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-N-乙基-3-甲氧基苯甲醯胺(168.2 mg,67.5%)。LC-MS:(M+H) +實測值529.2。 步驟2. N-乙基-4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基苯甲醯胺之合成 A solution of 8-bromo-2-iodo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridine ( intermediate 9 ; 200.0 mg, 0.47 mmol, 1 eq), N-ethyl-3-methoxy-4-(prop-2-yn-1-ylamino)benzamide ( intermediate 16 ; 131.8 mg, 0.57 mmol, 1.20 eq), i -Pr2NH (478.5 mg, 4.73 mmol, 10 eq), CuI (45.0 mg, 0.24 mmol, 0.50 eq) and Pd( PPh3 ) 4 (109.3 mg, 0.10 mmol, 0.20 eq) in DMSO (15 mL) was stirred at 30 °C under nitrogen atmosphere for 1 h. The resulting solution was purified by C18 flash chromatography (mobile phase A: water, mobile phase B: ACN; flow rate: 80 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm) to give 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-N-ethyl-3-methoxybenzamide (168.2 mg, 67.5%) as a light yellow solid. LC-MS: (M+H) + found 529.2. Step 2. Synthesis of N-ethyl-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxybenzamide
將4-[(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-N-乙基-3-甲氧基苯甲醯胺(50.0 mg,0.10 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(115.1 mg,0.56 mmol,2當量)、t-BuONa (161.8 mg,1.69 mmol,6當量)及tBuXPhosPdG3 (30.1 mg,0.04 mmol,0.40當量)於THF (2 mL)中之混合物在65℃及氮氣氛圍下攪拌20 min。將所得混合物在減壓下濃縮。殘餘物使用C18急速層析(移動相A:水(0.1% FA),移動相B:ACN;流動速率:80 mL/min;梯度:在30 min內0% B至100% B;254/220 nm)及製備型HPLC (管柱:XBridge Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3+0.05%NH 3 .H 2O),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在7 min內32% B至60% B;波長:254nm/220nm nm;RT1(min):7.25;運行次數:3)純化,以得到呈淺黃色固體之N-乙基-4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基苯甲醯胺(19.60 mg,12.1%)。LC-MS:(M+H) +實測值579.30。 1H NMR (400 MHz, DMSO- d 6) δ 8.15 (t, J= 5.6 Hz, 1H), 7.97-7.83 (m, 1H), 7.42 (dd, J= 8.3, 1.8 Hz, 1H), 7.35 (d, J= 1.9 Hz, 1H), 7.07-6.98 (m, 1H), 6.75 (d, J= 8.3 Hz, 1H), 6.61 (d, J= 7.7 Hz, 1H), 6.01 (t, J= 6.3 Hz, 1H), 5.60 (d, J= 9.0 Hz, 1H), 4.82 (d, J= 49.6 Hz, 1H), 4.32 (d, J= 6.3 Hz, 2H), 3.85 (s, 3H), 3.84-3.63 (m, 1H), 3.31-3.20 (m, 2H), 3.03 (t, J= 11.4 Hz, 1H), 2.77 (d, J= 11.2 Hz, 1H), 2.34-2.02 (m, 5H), 1.93-1.62 (m, 2H), 1.10 (t, J= 7.2 Hz, 3H)。 實例86. N-環丙基-4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基苯甲醯胺之合成 步驟1. 4-[(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-N-環丙基-3-甲氧基苯甲醯胺之合成 A mixture of 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-N-ethyl-3-methoxybenzamide (50.0 mg, 0.10 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (115.1 mg, 0.56 mmol, 2 eq), t-BuONa (161.8 mg, 1.69 mmol, 6 eq) and tBuXPhosPdG3 (30.1 mg, 0.04 mmol, 0.40 eq) in THF (2 mL) was stirred at 65 °C under nitrogen atmosphere for 20 min. The resulting mixture was concentrated under reduced pressure. The residue was purified by C18 flash chromatography (mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 80 mL/min; gradient: 0% B to 100% B in 30 min ; 254/220 nm) and preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5μm; mobile phase A: water (10mmol/L NH4HCO3 + 0.05 % NH3.H2O ), mobile phase B: ACN; flow rate: 60 mL /min mL/min; gradient: 32% B to 60% B in 7 min; wavelength: 254nm/220nm). nm; RT1(min): 7.25; Run number: 3) to give N-ethyl-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxybenzamide (19.60 mg, 12.1%) as a light yellow solid. LC-MS: (M+H) + found 579.30. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.15 (t, J = 5.6 Hz, 1H), 7.97-7.83 (m, 1H), 7.42 (dd, J = 8.3, 1.8 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.07-6.98 (m, 1H), 6.75 (d, J = 8.3 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 6.01 (t, J = 6.3 Hz, 1H), 5.60 (d, J = 9.0 Hz, 1H), 4.82 (d, J = 49.6 Hz, 1H), 4.32 (d, J = 6.3 Hz, 2H), 3.85 (s, 3H), 3.84-3.63 (m, 1H), 3.31-3.20 (m, 2H), 3.03 (t, J = 11.4 Hz, 1H), 2.77 (d, J = 11.2 Hz, 1H), 2.34-2.02 (m, 5H), 1.93-1.62 (m, 2H), 1.10 (t, J = 7.2 Hz, 3H). Example 86. Synthesis of N-cyclopropyl-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxybenzamide Step 1. Synthesis of 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-N-cyclopropyl-3-methoxybenzamide
將8-溴-2-碘-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶( 中間物9;200.0 mg,0.47 mmol,1當量)、N-環丙基-3-甲氧基-4-(丙-2-炔-1-基胺基)苯甲醯胺( 中間物18;121.3 mg,0.50 mmol,1.05當量)、CuI (90.1 mg,0.47 mmol,1當量)、i-Pr 2NH (478.5 mg,4.73 mmol,10當量)及Pd(PPh 3) 4(109.3 mg,0.10 mmol,0.20當量)於DMSO (3 mL)中之溶液在30℃及氮氣氛圍下攪拌1 h。所得溶液藉由反相急速層析(管柱,C18;移動相,於水中之MeCN,在20 min內0%至60%梯度;偵測器,UV 254 nm)純化,以得到呈淺黃色固體之4-[(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-N-環丙基-3-甲氧基苯甲醯胺(220 mg,86.27%)。LC-MS:(M+H) +實測值539.4。 步驟2. N-環丙基-4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基苯甲醯胺之合成 A solution of 8-bromo-2-iodo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine ( intermediate 9 ; 200.0 mg, 0.47 mmol, 1 eq), N-cyclopropyl-3-methoxy-4-(prop-2-yn-1-ylamino)benzamide ( intermediate 18 ; 121.3 mg, 0.50 mmol, 1.05 eq), CuI (90.1 mg, 0.47 mmol, 1 eq), i- Pr2NH (478.5 mg, 4.73 mmol, 10 eq) and Pd( PPh3 ) 4 (109.3 mg, 0.10 mmol, 0.20 eq) in DMSO (3 mL) was stirred at 30 °C under nitrogen atmosphere for 1 h. The resulting solution was purified by reverse phase flash chromatography (column, C18; mobile phase, MeCN in water, gradient 0% to 60% in 20 min; detector, UV 254 nm) to give 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-N-cyclopropyl-3-methoxybenzamide (220 mg, 86.27%) as a light yellow solid. LC-MS: (M+H) + found 539.4. Step 2. Synthesis of N-cyclopropyl-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxybenzamide
將4-[(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-N-環丙基-3-甲氧基苯甲醯胺(190.0 mg,0.35 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(144.5 mg,0.70 mmol,2當量)、tBuXPhosPdG3 (111.9 mg,0.14 mmol,0.40當量)及t-BuONa (203.1 mg,2.11 mmol,6當量)於THF (3 mL)中之混合物在65℃及氮氣氛圍下攪拌15 min。移除溶劑。殘餘物藉由反相急速層析(管柱,C18;移動相,於水中之MeCN (0.1% FA),在10 min內0%至30%梯度;偵測器,UV 254 nm)及製備型HPLC (管柱:XBridge Shield RP18 OBD管柱,30*150 mm,5 μm;移動相A:水(10 mmol/L NH 4HCO 3+0.05%NH 3 .H 2O),移動相B:ACN;流動速率:60 mL/min;梯度:在7min內37% B至55% B;波長:254nm/220nm;RT(min):6.42;運行次數:2)純化,以得到呈白色固體之N-環丙基-4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基苯甲醯胺(31.5 mg,15.03%)。LC-MS:(M+H) +實測值591.45。 1H NMR (400 MHz, DMSO- d 6) δ 8.11 (d, J= 4.0 Hz, 1H), 7.86 (d, J= 6.6 Hz, 1H), 7.41 (dd, J= 8.3, 1.8 Hz, 1H), 7.33 (d, J= 1.9 Hz, 1H), 7.02 (t, J= 7.2 Hz, 1H), 6.74 (d, J= 8.3 Hz, 1H), 6.61 (d, J= 7.7 Hz, 1H), 6.03 (t, J= 6.3 Hz, 1H), 5.60 (d, J= 9.0 Hz, 1H), 4.82 (d, J= 49.4 Hz, 1H), 4.32 (d, J= 6.3 Hz, 2H), 3.85 (s, 3H), 3.71 (dd, J= 28.2, 13.6 Hz, 1H), 3.09-2.97 (m, 1H), 2.79 (m, 2H), 2.32-1.97 (m, 5H), 1.83 (m, 2H), 0.66 (dt, J= 6.8, 3.3 Hz, 2H), 0.57-0.49 (m, 2H)。 實例87. (3S,4R)-N-[2-(3-{[4-(氮雜環丁烷-1-羰基)-2-甲氧基苯基]胺基}丙-1-炔-1-基)-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-8-基]-3-氟-1-甲基哌啶-4-胺之合成 步驟1. 4-(氮雜環丁烷-1-羰基)-N-(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)-2-甲氧基苯胺之合成 A mixture of 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-N-cyclopropyl-3-methoxybenzamide (190.0 mg, 0.35 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (144.5 mg, 0.70 mmol, 2 eq), tBuXPhosPdG3 (111.9 mg, 0.14 mmol, 0.40 eq) and t-BuONa (203.1 mg, 2.11 mmol, 6 eq) in THF (3 mL) was stirred at 65 °C under nitrogen atmosphere for 15 min. The solvent was removed. The residue was purified by reverse phase flash chromatography (column, C18; mobile phase, MeCN (0.1% FA) in water, gradient from 0% to 30% in 10 min; detector, UV 254 nm) and preparative HPLC (column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 +0.05% NH 3 . H 2 O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 37% B to 55% in 7 min. B; wavelength: 254nm/220nm; RT (min): 6.42; number of runs: 2) to give N-cyclopropyl-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxybenzamide (31.5 mg, 15.03%) as a white solid. LC-MS: (M+H) + found 591.45. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.11 (d, J = 4.0 Hz, 1H), 7.86 (d, J = 6.6 Hz, 1H), 7.41 (dd, J = 8.3, 1.8 Hz, 1H), 7.33 (d, J = 1.9 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 6.03 (t, J = 6.3 Hz, 1H), 5.60 (d, J = 9.0 Hz, 1H), 4.82 (d, J = 49.4 Hz, 1H), 4.32 (d, J = 6.3 Hz, 2H), 3.85 (s, 3H), 3.71 (dd, J = 28.2, 13.6 Hz, 1H), 3.09-2.97 (m, 1H), 2.79 (m, 2H), 2.32-1.97 (m, 5H), 1.83 (m, 2H), 0.66 (dt, J = 6.8, 3.3 Hz, 2H), 0.57-0.49 (m, 2H). Example 87. Synthesis of (3S,4R)-N-[2-(3-{[4-(Azocyclobutane-1-carbonyl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine Step 1. Synthesis of 4-(Azocyclobutane-1-carbonyl)-N-(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-2-methoxyaniline
將8-溴-2-碘-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶( 中間物9;340.0 mg,0.80 mmol,1當量)、4-(氮雜環丁烷-1-羰基)-2-甲氧基-N-(丙-2-炔-1-基)苯胺( 中間物20;216.0 mg,0.88 mmol,1.10當量)、Pd(PPh 3) 4(185.0 mg,0.16 mmol,0.20當量)、CuI (76.5 mg,0.40 mmol,0.50當量)及i-Pr 2NH (813.4 mg,8.04 mmol,10當量)於DMSO (5 mL)中之溶液在30℃下攪拌1 h。所得溶液使用C18急速層析(移動相A:水,移動相B:ACN;流動速率:60 mL/min;梯度:在30 min內0% B至100% B;254/220 nm)純化,以得到呈淺黃色固體之4-(氮雜環丁烷-1-羰基)-N-(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)-2-甲氧基苯胺(390.0 mg,89.96%)。LC-MS:(M+H) +實測值539.0。 步驟2. (3S,4R)-N-[2-(3-{[4-(氮雜環丁烷-1-羰基)-2-甲氧基苯基]胺基}丙-1-炔-1-基)-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-8-基]-3-氟-1-甲基哌啶-4-胺之合成 A solution of 8-bromo-2-iodo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridine ( intermediate 9 ; 340.0 mg, 0.80 mmol, 1 eq), 4-(azacyclobutane-1-carbonyl)-2-methoxy-N-(prop-2-yn-1-yl)aniline ( intermediate 20 ; 216.0 mg, 0.88 mmol, 1.10 eq), Pd( PPh3 ) 4 (185.0 mg, 0.16 mmol, 0.20 eq), CuI (76.5 mg, 0.40 mmol, 0.50 eq) and i- Pr2NH (813.4 mg, 8.04 mmol, 10 eq) in DMSO (5 mL) was stirred at 30 °C for 1 h. The resulting solution was purified using C18 flash chromatography (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm) to give 4-(azacyclobutane-1-carbonyl)-N-(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-2-methoxyaniline (390.0 mg, 89.96%) as a light yellow solid. LC-MS: (M+H) + found 539.0. Step 2. Synthesis of (3S,4R)-N-[2-(3-{[4-(Azocyclobutane-1-carbonyl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine
將4-(氮雜環丁烷-1-羰基)-N-(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)-2-甲氧基苯胺(100.0 mg,0.18 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(76.1 mg,0.37 mmol,2當量), t-BuONa (106.9 mg,1.11 mmol,6當量)及t-BuXPhosPdG3 (58.9 mg,0.07 mmol,0.40當量)於THF (1 mL)中之混合物在65℃及氮氣氛圍下攪拌30 min。移除溶劑之後,殘餘物使用C18急速層析(移動相A:水(0.1% FA),移動相B:ACN;流動速率:60 mL/min;梯度:在30 min內0% B至100% B;254/220 nm)及製備型HPLC (管柱:XBridge Prep Phenyl OBD管柱,19*250 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3+0.05%NH 3 .H 2O),移動相B:ACN;流動速率:25 mL/min;梯度:在10 min內42% B至52% B;波長:254nm/220 nm;RT(min):9.33;運行次數)純化,以得到呈白色固體之(3S,4R)-N-[2-(3-{[4-(氮雜環丁烷-1-羰基)-2-甲氧基苯基]胺基}丙-1-炔-1-基)-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-8-基]-3-氟-1-甲基哌啶-4-胺(14.6 mg,13.33%)。LC-MS:(M+H) +實測值591.15。 1H NMR (400 MHz, DMSO- d 6) δ 7.86 (d, J= 6.7 Hz, 1H), 7.16 (dd, J= 8.2, 1.8 Hz, 1H), 7.11 (d, J= 1.8 Hz, 1H), 7.02 (t, J= 7.2 Hz, 1H), 6.74 (d, J= 8.3 Hz, 1H), 6.61 (d, J= 7.7 Hz, 1H), 6.08 (t, J= 6.3 Hz, 1H), 5.59 (d, J= 9.0 Hz, 1H), 4.82 (d, J= 49.5 Hz, 1H), 4.32 (d, J= 6.3 Hz, 4H), 4.01 (s, 2H), 3.85 (s, 3H), 3.84-3.68 (m, 1H), 3.03 (t, J= 11.1 Hz, 1H), 2.75 (d, J= 9.0 Hz, 1H), 2.32-2.16 (m, 6H), 2.15-2.02 (m, 1H), 1.90-1.82 (m, 1H), 1.81-1.73 (m, 1H)。 實例88. 4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N,N-二甲基苯甲醯胺之合成 步驟1. 4-[(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N,N-二甲基苯甲醯胺之合成 A mixture of 4-(Azocyclobutane-1-carbonyl)-N-(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-2-methoxyaniline (100.0 mg, 0.18 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (76.1 mg, 0.37 mmol, 2 eq), t-BuONa (106.9 mg, 1.11 mmol, 6 eq) and t-BuXPhosPdG3 (58.9 mg, 0.07 mmol, 0.40 eq) in THF (1 mL) was stirred at 65 °C under nitrogen atmosphere for 30 min. After removing the solvent, the residue was purified by C18 flash chromatography (mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm) and preparative HPLC (column: XBridge Prep Phenyl OBD column, 19*250 mm, 5μm ; mobile phase A: water (10mmol/L NH4HCO3 + 0.05 % NH3.H2O ), mobile phase B: ACN; flow rate: 25 mL/min; gradient: 42% B to 52% B in 10 min ; wavelength: 254nm/220 nm; RT (min): 9.33; runs) to give (3S,4R)-N-[2-(3-{[4-(azacyclobutane-1-carbonyl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]-3-fluoro-1-methylpiperidin-4-amine (14.6 mg, 13.33%) as a white solid. LC-MS: (M+H) + found 591.15. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.86 (d, J = 6.7 Hz, 1H), 7.16 (dd, J = 8.2, 1.8 Hz, 1H), 7.11 (d, J = 1.8 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 6.08 (t, J = 6.3 Hz, 1H), 5.59 (d, J = 9.0 Hz, 1H), 4.82 (d, J = 49.5 Hz, 1H), 4.32 (d, J = 6.3 Hz, 4H), 4.01 (s, 2H), 3.85 (s, 3H), 3.84-3.68 (m, 1H), 3.03 (t, J = 11.1 Hz, 1H), 2.75 (d, J = 9.0 Hz, 1H), 2.32-2.16 (m, 6H), 2.15-2.02 (m, 1H), 1.90-1.82 (m, 1H), 1.81-1.73 (m, 1H). Example 88. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N,N-dimethylbenzamide Step 1. Synthesis of 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N,N-dimethylbenzamide
將3-甲氧基-N,N-二甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺( 中間物15;131.8 mg,0.57 mmol,1.20當量)、8-溴-2-碘-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶(200 mg,0.47 mmol,1當量)、i-Pr 2NH (478.5 mg,4.73 mmol,10當量)、Pd(PPh 3) 4(218.6 mg,0.19 mmol,0.40當量)及CuI (90.0 mg,0.47 mmol,1當量)於DMSO (2 mL)中之溶液在室溫及氮氣氛圍下攪拌1 h。反應用水(10 mL)淬滅且用EtOAc (3*10 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由反相急速層析(管柱,C18矽膠;移動相,於水中之MeCN (10mmol/L NH 4HCO 3),在10 min內30%至70%梯度;偵測器,UV 254 nm)純化,以得到呈黃色固體之4-[(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N,N-二甲基苯甲醯胺(200 mg,80.21%)。LC-MS:(M+H) +實測值:527.3。 步驟2. 4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N,N-二甲基苯甲醯胺之合成 A solution of 3-methoxy-N,N-dimethyl-4-(prop-2-yn-1-ylamino)benzamide ( intermediate 15 ; 131.8 mg, 0.57 mmol, 1.20 equiv), 8-bromo-2-iodo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine (200 mg, 0.47 mmol, 1 equiv), i-Pr 2 NH (478.5 mg, 4.73 mmol, 10 equiv), Pd(PPh 3 ) 4 (218.6 mg, 0.19 mmol, 0.40 equiv) and CuI (90.0 mg, 0.47 mmol, 1 equiv) in DMSO (2 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The reaction was quenched with water (10 mL) and extracted with EtOAc (3*10 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH 4 HCO 3 ) in water, gradient 30% to 70% in 10 min; detector, UV 254 nm) to give 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N,N-dimethylbenzamide (200 mg, 80.21%) as a yellow solid. LC-MS: (M+H) + found: 527.3. Step 2. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N,N-dimethylbenzamide
將4-[(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N,N-二甲基苯甲醯胺(90 mg,0.17 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(70.0 mg,0.34 mmol,2當量)、Cs 2CO 3(333.6 mg,1.03 mmol,6當量)、BINAP (42.51 mg,0.07 mmol,0.4當量)、RAC-BINAP-PD-G 3(33.87 mg,0.03 mmol,0.2當量)於二噁烷(3 mL)中之混合物在100℃及氮氣氛圍下攪拌16 h。反應混合物用水(100 mL)稀釋且用EtOAc (2*100 mL)萃取。合併的有機層經硫酸鈉乾燥,過濾且真空濃縮。殘餘物藉由反相急速層析(管柱,C18矽膠;移動相,於0.1%TFA中之MeCN,在10 min內20%至50%梯度;偵測器,UV 220 nm)及製備型HPLC (管柱:X-Select Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(0.1%FA),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在7 min內30% B至50% B;波長:254nm/220nm nm;RT1(min):6.56)純化,以得到呈灰白色固體之4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N,N-二甲基苯甲醯胺(11.6 mg,11.75%)。LC-MS:(M+H) +實測值:579.15。 1H NMR (400 MHz, DMSO-d 6) δ 7.87 (d, J= 6.6 Hz, 1H), 7.02 (t, J= 7.2 Hz, 1H), 6.95 (dd, J= 8.0, 1.8 Hz, 1H), 6.92 (d, J= 1.8 Hz, 1H), 6.75 (d, J= 8.1 Hz, 1H), 6.62 (d, J= 7.7 Hz, 1H), 5.90 (t, J= 6.3 Hz, 1H), 5.61 (d, J= 9.0 Hz, 1H), 4.84 (d, J= 49.3 Hz, 1H), 4.31 (d, J= 6.3 Hz, 2H), 3.82 (m, 4H), 3.05 (t, J= 11.7 Hz, 1H), 2.97 (s, 6H), 2.78 (d, J= 11.0 Hz, 1H), 2.37 – 2.18 (m, 4H), 2.17 – 2.05 (m, 1H), 1.96 – 1.71 (m, 2H)。 實例89. 4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-N-異丙基-3-甲氧基苯甲醯胺之合成 步驟1. 4-[(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-N-異丙基-3-甲氧基苯甲醯胺之合成 A mixture of 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N,N-dimethylbenzamide (90 mg, 0.17 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (70.0 mg, 0.34 mmol, 2 eq), Cs 2 CO 3 (333.6 mg, 1.03 mmol, 6 eq), BINAP (42.51 mg, 0.07 mmol, 0.4 eq), RAC-BINAP-PD-G 3 (33.87 mg, 0.03 mmol, 0.2 eq) in dioxane (3 mL) was stirred at 100° C. under nitrogen atmosphere for 16 hr. h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2*100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in 0.1% TFA, gradient from 20% to 50% in 10 min; detector, UV 220 nm) and preparative HPLC (column: X-Select Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 30% B to 50% B in 7 min; wavelength: 254 nm/220 nm nm; RT1 (min): 6.56) to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N,N-dimethylbenzamide (11.6 mg, 11.75%) as an off-white solid. LC-MS: (M+H) + found: 579.15. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.87 (d, J = 6.6 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.95 (dd, J = 8.0, 1.8 Hz, 1H), 6.92 (d, J = 1.8 Hz, 1H), 6.75 (d, J = 8.1 Hz, 1H), 6.62 (d, J = 7.7 Hz, 1H), 5.90 (t, J = 6.3 Hz, 1H), 5.61 (d, J = 9.0 Hz, 1H), 4.84 (d, J = 49.3 Hz, 1H), 4.31 (d, J = 6.3 Hz, 2H), 3.82 (m, 4H), 3.05 (t, J = 11.7 Hz, 1H), 2.97 (s, 6H), 2.78 (d, J = 11.0 Hz, 1H), 2.37 – 2.18 (m, 4H), 2.17 – 2.05 (m, 1H), 1.96 – 1.71 (m, 2H). Example 89. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-isopropyl-3-methoxybenzamide Step 1. Synthesis of 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-N-isopropyl-3-methoxybenzamide
將8-溴-2-碘-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶( 中間物9;200.0 mg,0.47 mmol,1當量)、N-異丙基-3-甲氧基-4-(丙-2-炔-1-基胺基)苯甲醯胺( 中間物17;122.3 mg,0.50 mmol,1.05當量)、CuI (90.1 mg,0.47 mmol,1當量)、i-Pr 2NH (478.5 mg,4.73 mmol,10當量)及Pd(PPh 3) 4(109.3 mg,0.10 mmol,0.20當量)於DMSO (3 mL)中之溶液在30℃及氮氣氛圍下攪拌1 h。所得溶液藉由反相急速層析(管柱,C18;移動相,於水中之MeCN,在20 min內0%至50%梯度;偵測器,UV 254 nm)純化,以得到呈白色固體之4-[(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-N-異丙基-3-甲氧基苯甲醯胺(177.0 mg,69.15%)。LC-MS:(M+H) +實測值541.4。 步驟2. 4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-N-異丙基-3-甲氧基苯甲醯胺之合成 A solution of 8-bromo-2-iodo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine ( intermediate 9 ; 200.0 mg, 0.47 mmol, 1 eq), N-isopropyl-3-methoxy-4-(prop-2-yn-1-ylamino)benzamide ( intermediate 17 ; 122.3 mg, 0.50 mmol, 1.05 eq), CuI (90.1 mg, 0.47 mmol, 1 eq), i- Pr2NH (478.5 mg, 4.73 mmol, 10 eq) and Pd( PPh3 ) 4 (109.3 mg, 0.10 mmol, 0.20 eq) in DMSO (3 mL) was stirred at 30 °C under nitrogen atmosphere for 1 h. The resulting solution was purified by reverse phase flash chromatography (column, C18; mobile phase, MeCN in water, gradient 0% to 50% in 20 min; detector, UV 254 nm) to give 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-N-isopropyl-3-methoxybenzamide (177.0 mg, 69.15%) as a white solid. LC-MS: (M+H) + found 541.4. Step 2. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-isopropyl-3-methoxybenzamide
將4-[(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-N-異丙基-3-甲氧基苯甲醯胺(170.0 mg,0.31 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(128.8 mg,0.63 mmol,2當量)、tBuXPhosPdG3 (99.8 mg,0.13 mmol,0.40當量)及t-BuONa (181.1 mg,1.88 mmol,6當量)於THF (5 mL)中之混合物在65℃及氮氣氛圍下攪拌30 min。所得混合物藉由反相急速層析(管柱,C18;移動相,於水中之MeCN (0.1% FA),在20 min內0%至40%梯度;偵測器,UV 254 nm)及製備型HPLC (管柱:XBridge Prep OBD C18管柱,30*150 mm,5 μm;移動相A:水(10mmol/L NH 4HCO 3)+0.05%NH 3 .H 2O,移動相B:ACN;流動速率:60 mL/min;梯度:在7min內35% B至62% B;波長:254nm/220nm;RT(min):7.42)純化,以得到呈白色固體之4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-N-異丙基-3-甲氧基苯甲醯胺(16.9 mg,8.90%)。LC-MS:(M+H) +實測值593.30。 1H NMR (400 MHz, DMSO- d 6) δ 7.86 (d, J= 7.1 Hz, 2H), 7.44 (dd, J= 8.3, 1.8 Hz, 1H), 7.35 (d, J= 1.9 Hz, 1H), 7.02 (t, J= 7.2 Hz, 1H), 6.74 (d, J= 8.3 Hz, 1H), 6.61 (d, J= 7.7 Hz, 1H), 6.00 (t, J= 6.3 Hz, 1H), 5.60 (d, J= 9.0 Hz, 1H), 4.82 (d, J= 49.5 Hz, 1H), 4.32 (d, J= 6.3 Hz, 2H), 4.15-4.02 (m, 1H), 3.86 (s, 3H), 3.72 (dd, J= 26.4, 12.0 Hz, 1H), 3.03 (t, J= 11.3 Hz, 1H), 2.80-2.73 (m, 1H), 2.28 (d, J= 13.0 Hz, 1H), 2.19 (s, 3H), 2.09 (dd, J= 12.7, 9.8 Hz, 1H), 1.87 (m, 1H), 1.80-1.73 (m, 1H), 1.15 (d, J= 6.6 Hz, 6H)。 實例90. 4-({3-[6-(2-氟丙-2-烯醯胺基)-8-[(1-甲基哌啶-4-基)胺基]-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-3-甲氧基-N-甲基苯甲醯胺之合成 A mixture of 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-N-isopropyl-3-methoxybenzamide (170.0 mg, 0.31 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (128.8 mg, 0.63 mmol, 2 eq), tBuXPhosPdG3 (99.8 mg, 0.13 mmol, 0.40 eq) and t-BuONa (181.1 mg, 1.88 mmol, 6 eq) in THF (5 mL) was stirred at 65 °C under nitrogen atmosphere for 30 min. The resulting mixture was purified by reverse phase flash chromatography (column, C18; mobile phase, MeCN (0.1% FA) in water, gradient from 0% to 40% in 20 min; detector, UV 254 nm) and preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 )+0.05% NH 3 . H 2 O, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 35% B to 62% in 7 min. B; wavelength: 254nm/220nm; RT (min): 7.42) to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-isopropyl-3-methoxybenzamide (16.9 mg, 8.90%) as a white solid. LC-MS: (M+H) + found 593.30. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.86 (d, J = 7.1 Hz, 2H), 7.44 (dd, J = 8.3, 1.8 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 6.00 (t, J = 6.3 Hz, 1H), 5.60 (d, J = 9.0 Hz, 1H), 4.82 (d, J = 49.5 Hz, 1H), 4.32 (d, J = 6.3 Hz, 2H), 3H), 4.15-4.02 (m, 1H), 3.86 (s, 3H), 3.72 (dd, J = 26.4, 12.0 Hz, 1H), 3.03 (t, J = 11.3 Hz, 1H), 2.80-2.73 (m, 1H), 2.28 (d, J = 13.0 Hz, 1H), 2.19 (s, 3H), 2.09 (dd, J = 12.7, 9.8 Hz, 1H), 1.87 (m, 1H), 1.80-1.73 (m, 1H), 1.15 (d, J = 6.6 Hz, 6H). Example 90. Synthesis of 4-({3-[6-(2-fluoroprop-2-enylamino)-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N-methylbenzamide
向4-[(3-{6-胺基-8-[(1-甲基哌啶-4-基)胺基]-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺(120 mg,0.22 mmol,1當量)、2-氟丙-2-烯酸(23.9 mg,0.26 mmol,1.2當量)及DIEA (142.7 mg,1.11 mmol,5當量)於DMF (3 mL)中之溶液中添加HATU (101 mg,0.26 mmol,1.2當量)。將反應混合物在25℃下攪拌1 h。反應用水淬滅且用EtOAc (3*10 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。粗產物藉由製備型HPLC (管柱:X-Select Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(0.1%FA),移動相B:ACN;流動速率:60 mL/min;梯度:在7 min內30% B至50% B;波長:254nm/220nm nm;RT1(min):6.56)純化,以得到呈黃色固體之4-({3-[6-(2-氟丙-2-烯醯胺基)-8-[(1-甲基哌啶-4-基)胺基]-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-3-甲氧基-N-甲基苯甲醯胺;甲酸(14 mg,9.58%)。LC-MS:(M+H) +實測值616.45。 1H NMR (400 MHz, DMSO- d 6) δ 10.15 (s, 1H), 8.11 (d, J= 5.3 Hz, 1H), 7.41 (d, J= 8.3 Hz, 1H), 7.35 (d, J= 2.0 Hz, 1H), 6.73 (d, J= 8.2 Hz, 1H), 6.03 (s, 1H), 5.99 – 5.88 (m, 2H), 5.40 – 5.18 (m, 1H), 4.35 – 4.06 (m, 4H), 3.85 (s, 4H), 3.55 – 3.44 (m, 1H), 3.19 (s, 1H), 2.76 (d, J= 4.4 Hz, 5H), 2.19 (s, 3H), 2.02 (t, J= 11.2 Hz, 2H), 1.88 (d, J= 12.2 Hz, 2H), 1.60 (d, J= 11.9 Hz, 2H)。 實例91. 4-((3-[6-(2-氯乙醯胺基)-8-[(1-甲基哌啶-4-基)胺基]-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基胺基)-3-甲氧基-N-甲基苯甲醯胺之合成 To a solution of 4-[(3-{6-amino-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (120 mg, 0.22 mmol, 1 eq), 2-fluoroprop-2-enoic acid (23.9 mg, 0.26 mmol, 1.2 eq) and DIEA (142.7 mg, 1.11 mmol, 5 eq) in DMF (3 mL) was added HATU (101 mg, 0.26 mmol, 1.2 eq). The reaction mixture was stirred at 25 °C for 1 h. The reaction was quenched with water and extracted with EtOAc (3*10 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: X-Select Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 30% B to 50% B in 7 min; wavelength: 254 nm/220 nm; RT1 (min): 6.56) to give 4-({3-[6-(2-fluoroprop-2-enamido)-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N-methylbenzamide as a yellow solid; formic acid (14 mg, 9.58%). LC-MS: (M+H) + found 616.45. 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.15 (s, 1H), 8.11 (d, J = 5.3 Hz, 1H), 7.41 (d, J = 8.3 Hz, 1H), 7.35 (d, J = 2.0 Hz, 1H), 6.73 (d, J = 8.2 Hz, 1H), 6.03 (s, 1H), 5.99 – 5.88 (m, 2H), 5.40 – 5.18 (m, 1H), 4.35 – 4.06 (m, 4H), 3.85 (s, 4H), 3.55 – 3.44 (m, 1H), 3.19 (s, 1H), 2.76 (d, J = 4.4 Hz, 5H), 2.19 (s, 3H), 2.02 (t, J = 11.2 Hz, 2H), 1.88 (d, J = 12.2 Hz, 2H), 1.60 (d, J = 11.9 Hz, 2H). Example 91. Synthesis of 4-((3-[6-(2-chloroacetamido)-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-ylamino)-3-methoxy-N-methylbenzamide
在0℃下,向氯乙酸(10.4 mg,0.11 mmol,1.20當量)、DIEA (35.7 mg,0.28 mmol,3當量)及4-[(3-(6-胺基-8-[(1-甲基哌啶-4-基)胺基]-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺(50 mg,0.09 mmol,1當量)於DMF (1 mL)中之攪拌溶液中添加HATU (42.0 mg,0.11 mmol,1.20當量)。將反應混合物在室溫下攪拌1 h。反應用水淬滅且用EtOAc (3*10 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型HPLC (管柱:XSelect Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(0.1% FA),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在17min內19% B至27% B;波長:254nm/220nm nm;RT1(min):6.2)純化,以得到呈灰白色固體之4-((3-[6-(2-氯乙醯胺基)-8-[(1-甲基哌啶-4-基)胺基]-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基胺基)-3-甲氧基-N-甲基苯甲醯胺(9.1 mg,15.76%)。LC-MS:(M+H) +實測值620.20。 1H NMR (400 MHz, DMSO-d 6) δ 10.28 (s, 1H), 8.30 (s, 1H), 8.14 – 8.02 (m, 1H), 7.34 – 7.32 (m, 1H), 7.27 (d, J= 1.9 Hz, 1H), 6.66 (d, J= 8.3 Hz, 1H), 6.64 (s, 1H), 6.12– 5.92 (m, 2H), 4.19 (d, J= 3.9 Hz, 4H), 3.92 (d, J= 10.9 Hz, 2H), 3.84 (s, 3H), 3.13(s, 1H), 2.84 (d, J= 11.1 Hz, 2H), 2.75 (d, J= 4.4 Hz, 3H), 2.14 (s, 3H), 2.08 (d, J= 11.5 Hz, 2H), 1.89 (d, J= 12.1 Hz, 2H), 1.64 (d, J= 11.8 Hz, 2H)。 實例92. 5-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-6-甲氧基-N-甲基吡啶-2-甲醯胺之合成 步驟1. 5-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-6-甲氧基-N-甲基吡啶-2-甲醯胺之合成 To a stirred solution of chloroacetic acid (10.4 mg, 0.11 mmol, 1.20 equiv), DIEA (35.7 mg, 0.28 mmol, 3 equiv) and 4-[(3-(6-amino-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-ylprop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (50 mg, 0.09 mmol, 1 equiv) in DMF (1 mL) at 0 °C was added HATU (42.0 mg, 0.11 mmol, 1.20 equiv). The reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with water and extracted with EtOAc (3*10 mL). The combined organic layers were purified by anhydrous Na 2 SO 4 Drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: XSelect Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 19% B to 27% B in 17 min; wavelength: 254 nm/220 nm). nm; RT1 (min): 6.2) to give 4-((3-[6-(2-chloroacetamido)-8-[(1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-ylamino)-3-methoxy-N-methylbenzamide (9.1 mg, 15.76%) as an off-white solid. LC-MS: (M+H) + found 620.20. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.28 (s, 1H), 8.30 (s, 1H), 8.14 – 8.02 (m, 1H), 7.34 – 7.32 (m, 1H), 7.27 (d, 9 Hz , 2H), 4.77 (d, J = 11.7 Hz, 3H), 3.65 (d, J = 12.1 Hz, 2H), 3.24 (d, J = 13.7 Hz, 3H), 3.10 (d, J = 14.9 Hz, 2H), 3.91 (d, J = 15.8 Hz, 2H), 3.89 (d, J = 16.1 Hz, 2H), 3.80 (s, 3H), 3.19 (d, J = 11.7 Hz, 2H), 3.90 (d, J = 12.8 Hz, 2H), 3.83 (s, 3H), 3.10 (d, J = 13.9 Hz , 2H), Hz, 2H). Example 92. Synthesis of 5-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-6-methoxy-N-methylpyridine-2-carboxamide Step 1. Synthesis of 5-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-6-methoxy-N-methylpyridine-2-carboxamide
將6-甲氧基-N-甲基-5-(丙-2-炔-1-基胺基)吡啶-2-甲醯胺( 中間物43;129.9 mg,0.59 mmol,1.2當量)、8-溴-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶( 中間物1;200 mg,0.49 mmol,1當量)、CuI (94.1 mg,0.49 mmol,1當量)、Pd(PPh3)4 (114.1 mg,0.10 mmol,0.2當量)及i-Pr2NH (499.8 mg,4.94 mmol,10當量)於DMSO (2 mL)中之溶液在室溫及氮氣氛圍下攪拌1.5 h。所得溶液用EtOAc (50 mL)稀釋且用水(3*50 mL)洗滌。合併的有機層經無水Na2SO4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型TLC (CH2Cl2 /於MeOH中之7 M NH3 = 15:1)純化,以得到呈棕色固體之5-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-6-甲氧基-N-甲基吡啶-2-甲醯胺(170 mg,69.36%)。LC-MS:(M+H) +實測值496.1。 步驟2. 5-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-6-甲氧基-N-甲基吡啶-2-甲醯胺之合成 A solution of 6-methoxy-N-methyl-5-(prop-2-yn-1-ylamino)pyridine-2-carboxamide ( intermediate 43 ; 129.9 mg, 0.59 mmol, 1.2 equiv), 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( intermediate 1 ; 200 mg, 0.49 mmol, 1 equiv), CuI (94.1 mg, 0.49 mmol, 1 equiv), Pd(PPh3)4 (114.1 mg, 0.10 mmol, 0.2 equiv) and i-Pr2NH (499.8 mg, 4.94 mmol, 10 equiv) in DMSO (2 mL) was stirred at room temperature under nitrogen atmosphere for 1.5 h. The resulting solution was diluted with EtOAc (50 mL) and washed with water (3*50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH2Cl2/7 M NH3 in MeOH = 15:1) to give 5-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-6-methoxy-N-methylpyridine-2-carboxamide (170 mg, 69.36%) as a brown solid. LC-MS: (M+H) + found 496.1. Step 2. Synthesis of 5-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-6-methoxy-N-methylpyridine-2-carboxamide
將5-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-6-甲氧基-N-甲基吡啶-2-甲醯胺(170 mg,0.34 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(140.5 mg,0.69 mmol,2當量)、t-BuONa (164.6 mg,1.72 mmol,5當量)、tBuXphos Pd G3 (54.4 mg,0.07 mmol,0.2當量)於THF (2 mL)中之混合物在65℃及氮氣氛圍下攪拌1.5 h。將所得混合物在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/於MeOH中之7 M NH 3= 15:1)及製備型HPLC (管柱:YMC-Actus Triant C18 ExRs管柱,19*250 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3+0.05% NH 3 .H 2O),移動相B:MEOH;流動速率:25 mL/min mL/min;梯度:在9 min內45% B至75% B;波長:220nm nm;RT1(min):8.68)純化,以得到呈白色固體之5-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-6-甲氧基-N-甲基吡啶-2-甲醯胺(9.6 mg,5.12%)。LC-MS:(M+H) +實測值548.20。 1H NMR (400 MHz, DMSO- d 6) δ 8.18 (d, J= 5.0 Hz, 1H), 7.79 (d, J= 6.8 Hz, 1H), 7.53 (d, J= 7.9 Hz, 1H), 7.04 (d, J= 8.0 Hz, 1H), 6.83 (t, J= 7.2 Hz, 1H), 6.39 (d, J= 7.4 Hz, 2H), 5.37 (d, J= 9.2 Hz, 1H), 4.82 (d, J= 49.5 Hz, 1H), 4.27 (d, J= 6.2 Hz, 2H), 4.02 (s, 5H), 3.80 – 3.60 (m, 1H), 3.03 (t, J= 11.2 Hz, 1H), 2.80 (d, J= 4.8 Hz, 4H), 2.18 (s, 4H), 2.11 (d, J= 14.7 Hz, 1H), 1.79 (d, J= 7.6 Hz, 2H)。 實例93. 5-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-6-甲氧基-N-甲基吡啶-2-甲醯胺之合成 步驟1. 5-[(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-6-甲氧基-N-甲基吡啶-2-甲醯胺之合成 A mixture of 5-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-6-methoxy-N-methylpyridine-2-carboxamide (170 mg, 0.34 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (140.5 mg, 0.69 mmol, 2 eq), t-BuONa (164.6 mg, 1.72 mmol, 5 eq), tBuXphos Pd G3 (54.4 mg, 0.07 mmol, 0.2 eq) in THF (2 mL) was stirred at 65° C. under nitrogen atmosphere for 1.5 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 /7 M NH 3 in MeOH = 15:1) and preparative HPLC (column: YMC-Actus Triant C18 ExRs column, 19*250 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 +0.05% NH 3 . H 2 O), mobile phase B: MEOH; flow rate: 25 mL/min mL/min; gradient: 45% B to 75% B in 9 min; wavelength: 220 nm nm; RT1 (min): 8.68) to give 5-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-6-methoxy-N-methylpyridine-2-carboxamide (9.6 mg, 5.12%) as a white solid. LC-MS: (M+H) + found 548.20. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.18 (d, J = 5.0 Hz, 1H), 7.79 (d, J = 6.8 Hz, 1H), 7.53 (d, J = 7.9 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.83 (t, J = 7.2 Hz, 1H), 6.39 (d, J = 7.4 Hz, 2H), 5.37 (d, J = 9.2 Hz, 1H), 4.82 (d, J = 49.5 Hz, 1H), 4.27 (d, J = 6.2 Hz, 2H), 4.02 (s, 5H), 3.80 – 3.60 (m, 1H), 3.03 (t, J = 11.2 Hz, 1H), 2.80 (d, J = 4.8 Hz, 4H), 2.18 (s, 4H), 2.11 (d, J = 14.7 Hz, 1H), 1.79 (d, J = 7.6 Hz, 2H). Example 93. Synthesis of 5-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-6-methoxy-N-methylpyridine-2-carboxamide Step 1. Synthesis of 5-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-6-methoxy-N-methylpyridine-2-carboxamide
將8-溴-2-碘-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶( 中間物9;170 mg,0.40 mmol,1當量)、6-甲氧基-N-甲基-5-(丙-2-炔-1-基胺基)吡啶-2-甲醯胺( 中間物43;105.7 mg,0.48 mmol,1.2當量)、Pd(PPh 3) 4(92.9 mg,0.08 mmol,0.2當量)、CuI (76.5 mg,0.40 mmol,1當量)及i-Pr 2NH (406.7 mg,4.02 mmol,10當量)於DMSO (2 mL)中之溶液在室溫及氮氣氛圍下攪拌1 h。所得溶液用EtOAc (100mL)稀釋且用鹽水(3*100 mL)洗滌。有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/ MeOH 10:1)純化,以得到呈棕色固體之5-[(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-6-甲氧基-N-甲基吡啶-2-甲醯胺(170 mg,82.24%)。LC-MS:(M+H) +實測值514.0。 步驟2. 5-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-6-甲氧基-N-甲基吡啶-2-甲醯胺之合成 A solution of 8-bromo-2-iodo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridine ( intermediate 9 ; 170 mg, 0.40 mmol, 1 eq), 6-methoxy-N-methyl-5-(prop-2-yn-1-ylamino)pyridine-2-carboxamide ( intermediate 43 ; 105.7 mg, 0.48 mmol, 1.2 eq), Pd( PPh3 ) 4 (92.9 mg, 0.08 mmol, 0.2 eq), CuI (76.5 mg, 0.40 mmol, 1 eq) and i- Pr2NH (406.7 mg, 4.02 mmol, 10 eq) in DMSO (2 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting solution was diluted with EtOAc (100 mL) and washed with brine (3*100 mL). The organic layer was dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 / MeOH 10:1) to give 5-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-6-methoxy-N-methylpyridine-2-carboxamide (170 mg, 82.24%) as a brown solid. LC-MS: (M+H) + found 514.0. Step 2. Synthesis of 5-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-6-methoxy-N-methylpyridine-2-carboxamide
將5-[(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-6-甲氧基-N-甲基吡啶-2-甲醯胺(170 mg,0.33 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(101.7 mg,0.50 mmol,1.5當量)、t-BuONa (158.8 mg,1.65 mmol,5當量)及tBuXphos Pd G3 (52.5 mg,0.07 mmol,0.2當量)於THF (2 mL)中之混合物在65℃及氮氣氛圍下攪拌1 h。將所得混合物在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/於MeOH中之7 M NH 3= 15:1)及製備型HPLC (管柱:XBridge Prep OBD C18管柱,19*250 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3+0.05%NH 3 .H 2O),移動相B:MEOH;流動速率:25 mL/min mL/min;梯度:在10min內55% B至75% B;波長:254nm/220nm nm;RT1(min):9.92;運行次數:4)純化,以得到呈白色固體之5-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-6-甲氧基-N-甲基吡啶-2-甲醯胺(25.3 mg,13.53%)。LC-MS:(M+H) +實測值566.15。 1H NMR (400 MHz, DMSO- d 6) δ 8.19 (d, J= 4.9 Hz, 1H), 7.86 (d, J= 6.7 Hz, 1H), 7.53 (d, J= 7.9 Hz, 1H), 7.10 – 6.94 (m, 2H), 6.62 (d, J= 7.7 Hz, 1H), 6.41 (t, J= 6.2 Hz, 1H), 5.59 (d, J= 9.0 Hz, 1H), 4.82 (d, J= 49.3 Hz, 1H), 4.33 (d, J= 6.2 Hz, 2H), 4.02 (s, 3H), 3.74 (d, J= 29.0 Hz, 1H), 3.03 (t, J= 11.4 Hz, 1H), 2.80 (d, J= 4.8 Hz, 4H), 2.28 (d, J= 13.0 Hz, 1H), 2.19 (s, 3H), 2.12 – 2.02 (m, 1H), 1.89 – 1.71 (m, 2H)。 實例94. 5-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-N-甲基吡啶-2-甲醯胺之合成 步驟1. 5-[(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-N-甲基吡啶-2-甲醯胺之合成 A mixture of 5-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-6-methoxy-N-methylpyridine-2-carboxamide (170 mg, 0.33 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (101.7 mg, 0.50 mmol, 1.5 eq), t-BuONa (158.8 mg, 1.65 mmol, 5 eq) and tBuXphos Pd G3 (52.5 mg, 0.07 mmol, 0.2 eq) in THF (2 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 /7 M NH 3 in MeOH = 15:1) and preparative HPLC (column: XBridge Prep OBD C18 column, 19*250 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 +0.05% NH 3 . H 2 O), mobile phase B: MEOH; flow rate: 25 mL/min mL/min; gradient: 55% B to 75% B in 10 min; wavelength: 254 nm/220 nm nm; RT1(min): 9.92; Run number: 4) to give 5-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-6-methoxy-N-methylpyridine-2-carboxamide (25.3 mg, 13.53%) as a white solid. LC-MS: (M+H) + found 566.15. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.19 (d, J = 4.9 Hz, 1H), 7.86 (d, J = 6.7 Hz, 1H), 7.53 (d, J = 7.9 Hz, 1H), 7.10 – 6.94 (m, 2H), 6.62 (d, J = 7.7 Hz, 1H), 6.41 (t, J = 6.2 Hz, 1H), 5.59 (d, J = 9.0 Hz, 1H), 4.82 (d, J = 49.3 Hz, 1H), 4.33 (d, J = 6.2 Hz, 2H), 4.02 (s, 3H), 3.74 (d, J = 29.0 Hz, 1H), 3.03 (t, J = 11.4 Hz, 1H), 2.80 (d, J = 4.8 Hz, 4H), 2.28 (d, J = 13.0 Hz, 1H), 2.19 (s, 3H), 2.12 – 2.02 (m, 1H), 1.89 – 1.71 (m, 2H). Example 94. Synthesis of 5-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylpyridine-2-carboxamide Step 1. Synthesis of 5-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-N-methylpyridine-2-carboxamide
將8-溴-2-碘-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶( 中間物9;150 mg,0.36 mmol,1當量)、N-甲基-5-(丙-2-炔-1-基胺基)吡啶-2-甲醯胺( 中間物21;80.5 mg,0.43 mmol,1.2當量)、CuI (67.5 mg,0.36 mmol,1當量)、i-Pr 2NH (358.9 mg,3.55 mmol,10當量)及 Pd(PPh 3) 4(163.9 mg,0.14 mmol,0.4當量)於DMSO (1 mL)中之溶液在室溫下攪拌1 h。所得溶液用EtOAc (50mL)稀釋且用鹽水(3*50 mL)洗滌。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/ MeOH =30:1)純化,以得到呈棕色固體之5-[(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-N-甲基吡啶-2-甲醯胺(145 mg,83.42%)。LC-MS:(M+H) +實測值485.3。 步驟2. 5-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-N-甲基吡啶-2-甲醯胺之合成 A solution of 8-bromo-2-iodo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridine ( intermediate 9 ; 150 mg, 0.36 mmol, 1 eq), N-methyl-5-(prop-2-yn-1-ylamino)pyridine-2-carboxamide ( intermediate 21 ; 80.5 mg, 0.43 mmol, 1.2 eq), CuI (67.5 mg, 0.36 mmol, 1 eq), i- Pr2NH (358.9 mg, 3.55 mmol, 10 eq) and Pd( PPh3 ) 4 (163.9 mg, 0.14 mmol, 0.4 eq) in DMSO (1 mL) was stirred at room temperature for 1 h. The resulting solution was diluted with EtOAc (50 mL) and washed with brine (3*50 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 / MeOH = 30:1) to give 5-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-N-methylpyridine-2-carboxamide (145 mg, 83.42%) as a brown solid. LC-MS: (M+H) + found 485.3. Step 2. Synthesis of 5-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylpyridine-2-carboxamide
將5-[(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-N-甲基吡啶-2-甲醯胺(145 mg,0.30 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(122.4 mg,0.60 mmol,2當量)、tBuXphos Pd G3 (71.4 mg,0.09 mmol,0.3當量)及tBuXphos Pd G3 (71.4 mg,0.09 mmol,0.3當量)於THF (1 mL)中之混合物在65℃下再攪拌1 h。將所得混合物在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/於MeOH中之7 M NH 3= 20:1)及製備型HPLC (管柱:XBridge Prep OBD C18管柱,19*250 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3+0.05%NH 3 .H 2O),移動相B:MEOH;流動速率:25 mL/min mL/min;梯度:在10min內50% B至75% B;波長:254nm/220nm nm;RT1(min):9.67;運行次數:2)純化,以得到呈黃色固體之5-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-N-甲基吡啶-2-甲醯胺(10.8 mg,6.72%)。LC-MS:(M+H) +實測值536.40。 1H NMR (400 MHz, DMSO- d 6) δ 8.35 (s, 1H), 8.08 (d, J= 2.7 Hz, 1H), 7.84 (dd, J= 21.8, 7.6 Hz, 2H), 7.17 (dd, J= 8.6, 2.8 Hz, 1H), 7.02 (t, J= 7.1 Hz, 2H), 6.62 (d, J= 7.7 Hz, 1H), 5.58 (d, J= 9.0 Hz, 1H), 4.83 (d, J= 49.5 Hz, 1H), 4.37 (d, J= 6.1 Hz, 2H), 3.85 – 3.58 (m, 1H), 3.20 – 2.92 (m, 1H), 2.77 (d, J= 4.9 Hz, 4H), 2.35 – 2.02 (m, 5H), 1.98 – 1.65 (m, 2H)。 實例95. 5-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-6-甲氧基-2,3-二氫異吲哚-1-酮之合成 步驟1. 5-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-6-甲氧基-2,3-二氫異吲哚-1-酮之合成 A mixture of 5-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-N-methylpyridine-2-carboxamide (145 mg, 0.30 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (122.4 mg, 0.60 mmol, 2 eq), tBuXphos Pd G3 (71.4 mg, 0.09 mmol, 0.3 eq) and tBuXphos Pd G3 (71.4 mg, 0.09 mmol, 0.3 eq) in THF (1 mL) was stirred at 65 °C for another 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 /7 M NH 3 in MeOH = 20:1) and preparative HPLC (column: XBridge Prep OBD C18 column, 19*250 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 +0.05% NH 3 . H 2 O), mobile phase B: MEOH; flow rate: 25 mL/min mL/min; gradient: 50% B to 75% B in 10 min; wavelength: 254 nm/220 nm nm; RT1(min): 9.67; Run number: 2) to give 5-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylpyridine-2-carboxamide (10.8 mg, 6.72%) as a yellow solid. LC-MS: (M+H) + found 536.40. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.35 (s, 1H), 8.08 (d, J = 2.7 Hz, 1H), 7.84 (dd, J = 21.8, 7.6 Hz, 2H), 7.17 (dd, J = 8.6, 2.8 Hz, 1H), 7.02 (t, J = 7.1 Hz, 2H), 6.62 (d, J = 7.7 Hz, 1H), 5.58 (d, J = 9.0 Hz, 1H), 4.83 (d, J = 49.5 Hz, 1H), 4.37 (d, J = 6.1 Hz, 2H), 3.85 – 3.58 (m, 1H), 3.20 – 2.92 (m, 1H), 2.77 (d, J = 4.9 Hz, 4H), 2.35 – 2.02 (m, 5H), 1.98 – 1.65 (m, 2H). Example 95. Synthesis of 5-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-6-methoxy-2,3-dihydroisoindol-1-one Step 1. Synthesis of 5-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-6-methoxy-2,3-dihydroisoindol-1-one
將6-甲氧基-5-(丙-2-炔-1-基胺基)-2,3-二氫異吲哚-1-酮( 中間物44;51 mg,0.24 mmol,1.19當量)、8-溴-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶( 中間物1;80 mg,0.20 mmol,1當量)、i-Pr 2NH (200 mg,1.98 mmol,10當量)、CuI (38 mg,0.20 mmol,1.01當量)及Pd(PPh 3) 4(40 mg,0.04 mmol,0.18當量)於DMSO (2 mL)中之溶液在65℃下攪拌1 h。所得溶液用EtOAc (50 mL)稀釋且用鹽水(3*50 mL)洗滌。有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/ MeOH =20:1)純化,以得到呈灰白色固體之5-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-6-甲氧基-2,3-二氫異吲哚-1-酮(50 mg,51.31%)。LC-MS:(M+H) +實測值493.0。 步驟2. 5-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-6-甲氧基-2,3-二氫異吲哚-1-酮之合成 A solution of 6-methoxy-5-(prop-2-yn-1-ylamino)-2,3-dihydroisoindol-1-one ( intermediate 44 ; 51 mg, 0.24 mmol, 1.19 equiv), 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( intermediate 1 ; 80 mg, 0.20 mmol, 1 equiv), i- Pr2NH (200 mg, 1.98 mmol, 10 equiv), CuI (38 mg, 0.20 mmol, 1.01 equiv) and Pd( PPh3 ) 4 (40 mg, 0.04 mmol, 0.18 equiv) in DMSO (2 mL) was stirred at 65 °C for 1 h. The resulting solution was diluted with EtOAc (50 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 / MeOH = 20:1) to give 5-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-6-methoxy-2,3-dihydroisoindol-1-one (50 mg, 51.31%) as an off-white solid. LC-MS: (M+H) + found 493.0. Step 2. Synthesis of 5-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-6-methoxy-2,3-dihydroisoindol-1-one
將5-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-6-甲氧基-2,3二氫異吲哚-1-酮(50 mg,0.10 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(42 mg,0.21 mmol,2.02當量)、t-BuONa (49 mg,0.51 mmol,5.03當量)及tBuXphos Pd G3 (50 mg,0.06 mmol,0.62當量)於THF (2 mL)中之混合物在65℃及氮氣氛圍下攪拌1 h。將所得混合物在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/於MeOH中之7 M NH 3= 15:1)純化,以得到呈灰白色固體之5-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-6-甲氧基-2,3-二氫異吲哚-1-酮(2.8 mg,4.92%)。LC-MS:(M+H) +實測值545.25。 1H NMR (400 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.79 (d, J= 6.8 Hz, 1H), 7.03 (s, 1H), 6.88 – 6.78 (m, 2H), 6.39 (d, J= 7.5 Hz, 1H), 6.13 (t, J= 6.3 Hz, 1H), 5.37 (d, J= 9.2 Hz, 1H), 4.81 (d, J= 49.8 Hz, 1H), 4.29 (d, J= 6.2 Hz, 2H), 4.20 (s, 2H), 4.03 (m, 2H), 3.86 (s, 3H), 3.71 (d, J= 26.9 Hz, 1H), 3.02 (t, J= 11.7 Hz, 1H), 2.82 – 2.64 (m, 1H), 2.38 – 2.23 (m, 1H), 2.18 (s, 3H), 2.14 – 2.03 (m, 1H), 1.85 – 1.73 (m, 2H)。 實例96. 5-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-6-甲氧基-2,3-二氫異吲哚-1-酮之合成 步驟1. 5-[(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-6-甲氧基-2,3-二氫異吲哚-1-酮之合成 A mixture of 5-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-6-methoxy-2,3-dihydroisoindol-1-one (50 mg, 0.10 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (42 mg, 0.21 mmol, 2.02 eq), t-BuONa (49 mg, 0.51 mmol, 5.03 eq) and tBuXphos Pd G3 (50 mg, 0.06 mmol, 0.62 eq) in THF (2 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 /7 M NH 3 in MeOH = 15:1) to give 5-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-6-methoxy-2,3-dihydroisoindol-1-one (2.8 mg, 4.92%) as an off-white solid. LC-MS: (M+H) + found 545.25. 1 H NMR (400 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.79 (d, J = 6.8 Hz, 1H), 7.03 (s, 1H), 6.88 – 6.78 (m, 2H), 6.39 (d, J = 7.5 Hz, 1H), 6.13 (t, J = 6.3 Hz, 1H), 5.37 (d, J = 9.2 Hz, 1H), 4.81 (d, J = 49.8 Hz, 1H), 4.29 (d, J = 6.2 Hz, 2H), 4.20 (s, 2H), 4.03 (m, 2H), 3.86 (s, 3H), 3.71 (d, J = 26.9 Hz, 1H), 3.02 (t, J = 11.7 Hz, 1H), 2.82 – 2.64 (m, 1H), 2.38 – 2.23 (m, 1H), 2.18 (s, 3H), 2.14 – 2.03 (m, 1H), 1.85 – 1.73 (m, 2H). Example 96. Synthesis of 5-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-6-methoxy-2,3-dihydroisoindol-1-one Step 1. Synthesis of 5-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-6-methoxy-2,3-dihydroisoindol-1-one
將6-甲氧基-5-(丙-2-炔-1-基胺基)-2,3-二氫異吲哚-1-酮( 中間物44;122.7 mg,0.57 mmol,1.2當量)、8-溴-2-碘-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶( 中間物9;200 mg,0.47 mmol,1當量)、CuI (90.1 mg,0.47 mmol,1當量)、i-Pr 2NH (478.5 mg,4.73 mmol,10當量)及Pd(PPh 3) 4(218.6 mg,0.19 mmol,0.4當量)於DMSO (1 mL)中之溶液在室溫及氮氣氛圍下攪拌1h。所得溶液用EtOAc (50 mL)稀釋且用鹽水(3*50 mL)洗滌。有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/於MeOH中之7 M NH 3= 20:1)純化,以得到呈白色固體之5-[(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-6-甲氧基-2,3-二氫異吲哚-1-酮(150 mg,62.0%)。LC-MS:(M+H) +實測值512.3。 步驟2. 5-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-6-甲氧基-2,3-二氫異吲哚-1-酮之合成 A solution of 6-methoxy-5-(prop-2-yn-1-ylamino)-2,3-dihydroisoindol-1-one ( intermediate 44 ; 122.7 mg, 0.57 mmol, 1.2 equiv), 8-bromo-2-iodo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine ( intermediate 9 ; 200 mg, 0.47 mmol, 1 equiv), CuI (90.1 mg, 0.47 mmol, 1 equiv), i- Pr2NH (478.5 mg, 4.73 mmol, 10 equiv) and Pd( PPh3 ) 4 (218.6 mg, 0.19 mmol, 0.4 equiv) in DMSO (1 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting solution was diluted with EtOAc (50 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 / 7 M NH 3 in MeOH = 20:1) to give 5-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-6-methoxy-2,3-dihydroisoindol-1-one (150 mg, 62.0%) as a white solid. LC-MS: (M+H) + found 512.3. Step 2. Synthesis of 5-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-6-methoxy-2,3-dihydroisoindol-1-one
將5-[(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-6-甲氧基-2,3-二氫異吲哚-1-酮(160 mg,0.31 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(128.6 mg,0.62 mmol,2當量)、t-BuONa (150.4 mg,1.57 mmol,5當量)及tBuXPhos Pd G3 (74.6 mg,0.09 mmol,0.30當量)於THF (4 mL)中之混合物在65℃及氮氣氛圍下攪拌1 h。將所得混合物在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/於MeOH中之7 M NH 3= 20:1)及製備型HPLC (管柱:XBridge Prep OBD C18管柱,19*250 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3+0.05%NH 3 .H 2O),移動相B:MEOH;流動速率:25 mL/min mL/min;梯度:在10min內50% B至78% B;波長:254nm/220nm nm;RT1(min):9.28;運行次數:3)純化,以得到呈黃色固體之5-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-6-甲氧基-2,3-二氫異吲哚-1-酮(17.3 mg,9.79%)。LC-MS:(M+H) +實測值563.15。 1H NMR (400 MHz, DMSO- d 6) δ 8.01 (s, 1H), 7.86 (d, J= 6.7 Hz, 1H), 7.08 – 6.95 (m, 2H), 6.84 (s, 1H), 6.62 (d, J= 7.7 Hz, 1H), 6.17 (t, J= 6.3 Hz, 1H), 5.59 (d, J= 9.0 Hz, 1H), 4.82 (d, J= 49.5 Hz, 1H), 4.34 (d, J= 6.2 Hz, 2H), 4.20 (s, 2H), 3.87 (s, 3H), 3.80 – 3.62 (m, 1H), 3.03 (t, J= 11.3 Hz, 1H), 2.76 (d, J= 11.2 Hz, 1H), 2.28 (d, J= 13.1 Hz, 1H), 2.19 (s, 3H), 2.09 (m, 1H), 1.93 – 1.69 (m, 2H)。 實例97. 4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(三氟甲基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺之合成 步驟1. 4-({3-[8-溴-3-(三氟甲基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-3-甲氧基-N-甲基苯甲醯胺之合成 A mixture of 5-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-6-methoxy-2,3-dihydroisoindol-1-one (160 mg, 0.31 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (128.6 mg, 0.62 mmol, 2 eq), t-BuONa (150.4 mg, 1.57 mmol, 5 eq) and tBuXPhos Pd G3 (74.6 mg, 0.09 mmol, 0.30 eq) in THF (4 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 /7 M NH 3 in MeOH = 20:1) and preparative HPLC (column: XBridge Prep OBD C18 column, 19*250 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 +0.05% NH 3 . H 2 O), mobile phase B: MEOH; flow rate: 25 mL/min mL/min; gradient: 50% B to 78% B in 10 min; wavelength: 254 nm/220 nm nm; RT1(min): 9.28; Run number: 3) to give 5-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-6-methoxy-2,3-dihydroisoindol-1-one (17.3 mg, 9.79%) as a yellow solid. LC-MS: (M+H) + found 563.15. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.01 (s, 1H), 7.86 (d, J = 6.7 Hz, 1H), 7.08 – 6.95 (m, 2H), 6.84 (s, 1H), 6.62 (d, J = 7.7 Hz, 1H), 6.17 (t, J = 6.3 Hz, 1H), 5.59 (d, J = 9.0 Hz, 1H), 4.82 (d, J = 49.5 Hz, 1H), 4.34 (d, J = 6.2 Hz, 2H), 4.20 (s, 2H), 3.87 (s, 3H), 3.80 – 3.62 (m, 1H), 3.03 (t, J = 11.3 Hz, 1H), 2.76 (d, J = 11.2 Hz, 1H), 2.28 (d, J = 13.1 Hz, 1H), 2.19 (s, 3H), 2.09 (m, 1H), 1.93 – 1.69 (m, 2H). Example 97. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide Step 1. Synthesis of 4-({3-[8-bromo-3-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N-methylbenzamide
將8-溴-2-碘-3-(三氟甲基)咪唑并[1,2-a]吡啶( 中間物45;415.0 mg,1.06 mmol,1當量)、3-甲氧基-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺( 中間物14;243.3 mg,1.12 mmol,1.05當量)、CuI (202.2 mg,1.06 mmol,1當量)、i-Pr 2NH (25.9 mg,0.26 mmol,10當量)及Pd(PPh 3) 4(5.9 mg,0.01 mmol,0.20當量)於DMSO (4 mL)中之溶液在30℃及氮氣氛圍下攪拌1 h。所得溶液藉由反相急速層析(管柱,C18;移動相,於水中之MeCN,在10 min內0%至50%梯度;偵測器,UV 254 nm)純化,以得到呈黃色固體之4-({3-[8-溴-3-(三氟甲基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-3-甲氧基-N-甲基苯甲醯胺(369.0 mg,72.22%)。LC-MS:(M+H) +實測值481.3。 步驟2. 4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(三氟甲基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺之合成 A solution of 8-bromo-2-iodo-3-(trifluoromethyl)imidazo[1,2-a]pyridine ( intermediate 45 ; 415.0 mg, 1.06 mmol, 1 eq), 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide ( intermediate 14 ; 243.3 mg, 1.12 mmol, 1.05 eq), CuI (202.2 mg, 1.06 mmol, 1 eq), i-Pr 2 NH (25.9 mg, 0.26 mmol, 10 eq) and Pd(PPh 3 ) 4 (5.9 mg, 0.01 mmol, 0.20 eq) in DMSO (4 mL) was stirred at 30° C. under nitrogen atmosphere for 1 h. The resulting solution was purified by reverse phase flash chromatography (column, C18; mobile phase, MeCN in water, gradient 0% to 50% in 10 min; detector, UV 254 nm) to give 4-({3-[8-bromo-3-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N-methylbenzamide (369.0 mg, 72.22%) as a yellow solid. LC-MS: (M+H) + found 481.3. Step 2. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide
將4-({3-[8-溴-3-(三氟甲基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-3-甲氧基-N-甲基苯甲醯胺(200.0 mg,0.42 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(170.5 mg,0.83 mmol,2當量)、t-BuXPhosPdG3 (132.0 mg,0.17 mmol,0.40當量)及t-BuONa (239.6 mg,2.50 mmol,6當量)於THF (4 mL)中之混合物在65℃及氮氣氛圍下攪拌30 min。在真空下移除溶劑。殘餘物藉由反相急速層析(管柱,C18;移動相,於水中之MeCN (0.1% FA),在10 min內0%至20%梯度;偵測器,UV 254 nm)及製備型HPLC (管柱:XBridge Prep OBD RP 18管柱,19*250 mm,5 μm;移動相A:水(10 mmol/L NH 4HCO 3+0.05%NH 3 .H 2O),移動相B:MEOH;流動速率:25 mL/min mL/min;梯度:在11 min內55% B至77% B;波長:254nm/220nm nm;RT (min):9.7)純化,以得到呈白色固體之4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(三氟甲基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺(10.7 mg,4.81%)。LC-MS:(M+H) +實測值533.20。 1H NMR (400 MHz, DMSO- d 6) δ 8.12 (m, 1H), 7.70 (d, J= 6.6 Hz, 1H), 7.41 (dd, J= 8.3, 1.9 Hz, 1H), 7.34 (d, J= 1.9 Hz, 1H), 7.00 (t, J= 7.2 Hz, 1H), 6.71 (d, J= 8.3 Hz, 1H), 6.60 (d, J= 7.8 Hz, 1H), 6.02 (t, J= 6.3 Hz, 1H), 5.67 (d, J= 8.9 Hz, 1H), 4.82 (d, J= 49.4 Hz, 1H), 4.29 (d, J= 6.3 Hz, 2H), 3.84 (s, 3H), 3.71 (dd, J= 28.5, 13.8 Hz, 1H), 3.03 (t, J= 11.6 Hz, 1H), 2.85-2.70 (m, 4H), 2.37-2.12 (m, 4H), 2.09 (dd, J= 12.8, 10.0 Hz, 1H), 1.87 (m, 1H), 1.76 (dd, J= 13.7, 4.0 Hz, 1H)。 實例98. 4-{[3-(7-氟-8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺之合成 步驟1. 4-({3-[8-溴-7-氟-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-3-甲氧基-N-甲基苯甲醯胺之合成 A mixture of 4-({3-[8-bromo-3-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N-methylbenzamide (200.0 mg, 0.42 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (170.5 mg, 0.83 mmol, 2 eq), t-BuXPhosPdG3 (132.0 mg, 0.17 mmol, 0.40 eq) and t-BuONa (239.6 mg, 2.50 mmol, 6 eq) in THF (4 mL) was stirred at 65 °C under nitrogen atmosphere for 30 min. The solvent was removed under vacuum. The residue was purified by reverse phase flash chromatography (column, C18; mobile phase, MeCN (0.1% FA) in water, gradient from 0% to 20% in 10 min; detector, UV 254 nm) and preparative HPLC (column: XBridge Prep OBD RP 18 column, 19*250 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 +0.05% NH 3 . H 2 O), mobile phase B: MEOH; flow rate: 25 mL/min mL/min; gradient: 55% B to 77% B in 11 min; wavelength: 254 nm/220 nm nm; RT (min): 9.7) to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (10.7 mg, 4.81%) as a white solid. LC-MS: (M+H) + found 533.20. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.12 (m, 1H), 7.70 (d, J = 6.6 Hz, 1H), 7.41 (dd, J = 8.3, 1.9 Hz, 1H), 7.34 (d, J = 1.9 Hz, 1H), 7.00 (t, J = 7.2 Hz, 1H), 6.71 (d, J = 8.3 Hz, 1H), 6.60 (d, J = 7.8 Hz, 1H), 6.02 (t, J = 6.3 Hz, 1H), 5.67 (d, J = 8.9 Hz, 1H), 4.82 (d, J = 49.4 Hz, 1H), 4.29 (d, J = 6.3 Hz, 2H), 3.84 (s, 3H), 3.71 (dd, J = 28.5, 13.8 Hz, 1H), 3.03 (t, J = 11.6 Hz, 1H), 2.85-2.70 (m, 4H), 2.37-2.12 (m, 4H), 2.09 (dd, J = 12.8, 10.0 Hz, 1H), 1.87 (m, 1H), 1.76 (dd, J = 13.7, 4.0 Hz, 1H). Example 98. Synthesis of 4-{[3-(7-fluoro-8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide Step 1. Synthesis of 4-({3-[8-bromo-7-fluoro-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N-methylbenzamide
將8-溴-7-氟-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶( 中間物46;1.34 g,3.17 mmol,1當量)、3-甲氧基-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺( 中間物14;0.83 g,3.80 mmol,1.20當量)、CuI (0.60 g,3.17 mmol,1當量)、Pd(PPh 3) 4(0.73 g,0.63 mmol,0.20當量)及i-Pr 2NH (3.21 g,31.68 mmol,10當量)於DMSO (10 mL)中之攪拌溶液在室溫及氮氣氛圍下攪拌1 h。所得溶液用水(50 mL)淬滅且用EtOAc (3*50 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由反相急速層析(管柱,C18矽膠;移動相,於水中之MeCN (0.1% TFA),在10 min內10%至50%梯度;偵測器,UV 254 nm)及矽膠管柱層析(PE / EA = 1:1)純化,以得到呈黃色固體之4-({3-[8-溴-7-氟-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-3-甲氧基-N-甲基苯甲醯胺(880 mg,48.16%)。LC-MS:(M+H) +實測值:513.0。 步驟2. 4-{[3-(7-氟-8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺之合成 A stirred solution of 8-bromo-7-fluoro-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( Intermediate 46 ; 1.34 g, 3.17 mmol, 1 eq), 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide ( Intermediate 14 ; 0.83 g, 3.80 mmol, 1.20 eq), CuI (0.60 g, 3.17 mmol, 1 eq), Pd( PPh3 ) 4 (0.73 g, 0.63 mmol, 0.20 eq) and i- Pr2NH (3.21 g, 31.68 mmol, 10 eq) in DMSO (10 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting solution was quenched with water (50 mL) and extracted with EtOAc (3*50 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (0.1% TFA) in water, gradient 10% to 50% in 10 min; detector, UV 254 nm) and silica gel column chromatography (PE / EA = 1:1) to give 4-({3-[8-bromo-7-fluoro-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N-methylbenzamide (880 mg, 48.16%) as a yellow solid. LC-MS: (M+H) + found: 513.0. Step 2. Synthesis of 4-{[3-(7-fluoro-8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide
將4-({3-[8-溴-7-氟-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-3-甲氧基-N-甲基苯甲醯胺(200 mg,0.39 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(161.2 mg,0.79 mmol,2當量)、tBuXphos Pd G3 (154 mg,0.20 mmol,0.50當量)及t-BuONa (224 mg,2.34 mmol,6當量)於THF (3 mL)中之混合物在65℃及氮氣氛圍下攪拌1 h。所得混合物用水(20 mL)淬滅且用EtOAc (3*20 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型HPLC (管柱:XBridge Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在9 min內40% B至60% B;波長:254nm/220nm nm;RT1(min):8.9)純化,以得到呈黃色固體之4-{[3-(7-氟-8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺(0.5 mg,0.22%)。LC-MS:(M+H) +實測值:565.40。 1H NMR (400 MHz, DMSO-d 6) δ 8.09 (d, J= 4.7 Hz, 1H), 7.76 (d, J= 7.7 Hz, 1H), 7.42 – 7.34 (m, 3H), 6.75 (d, J= 8.3 Hz, 1H), 5.94 (t, J= 6.3 Hz, 1H), 5.07 (d, J= 8.6 Hz, 1H), 4.86 (d, J= 49.5 Hz, 1H), 4.25(d, J= 6.3 Hz, 2H), 4.01 – 3.95 (m, 2H), 3.82 (s, 3H), 3.50 (s, 1H), 3.02 (t, J= 11.4 Hz, 1H), 2.80 (d, J= 11.5 Hz, 1H), 2.78 (d, J= 4.5 Hz, 3H), 2.28 (d, J= 12.9 Hz, 1H), 2.24 (s, 3H), 2.19 – 2.04 (m, 1H), 1.89 – 1.85 (m, 1H), 1.74 (d, J= 11.9 Hz, 1H)。 實例99. 4-{[3-(6-氟-8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺,甲酸鹽之合成 步驟1. 4-({3-[8-溴-6-氟-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-3-甲氧基-N-甲基苯甲醯胺之合成 A mixture of 4-({3-[8-bromo-7-fluoro-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N-methylbenzamide (200 mg, 0.39 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (161.2 mg, 0.79 mmol, 2 eq), tBuXphos Pd G3 (154 mg, 0.20 mmol, 0.50 eq) and t-BuONa (224 mg, 2.34 mmol, 6 eq) in THF (3 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was quenched with water (20 mL) and extracted with EtOAc (3*20 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 40% B to 60% B in 9 min; wavelength: 254 nm/220 nm nm; RT1 (min): 8.9) to obtain 4-{[3-(7-fluoro-8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (0.5 mg, 0.22%). LC-MS: (M+H) + found: 565.40. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.09 (d, J = 4.7 Hz, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.42 – 7.34 (m, 3H), 6.75 (d, J = 8.3 Hz, 1H), 5.94 (t, J = 6.3 Hz, 1H), 5.07 (d, J = 8.6 Hz, 1H), 4.86 (d, J = 49.5 Hz, 1H), 4.25(d, J = 6.3 Hz, 2H), 4.01 – 3.95 (m, 2H), 3.82 (s, 3H), 3.50 (s, 1H), 3.02 (t, J = 11.4 Hz, 1H), 2.80 (d, J = 11.5 Hz, 1H), 2.78 (d, J = 4.5 Hz, 3H), 2.28 (d, J = 12.9 Hz, 1H), 2.24 (s, 3H), 2.19 – 2.04 (m, 1H), 1.89 – 1.85 (m, 1H), 1.74 (d, J = 11.9 Hz, 1H). Example 99. Synthesis of 4-{[3-(6-fluoro-8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide, formate salt Step 1. Synthesis of 4-({3-[8-bromo-6-fluoro-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N-methylbenzamide
將8-溴-6-氟-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶( 中間物47;600 mg,1.42 mmol,1當量)、3-甲氧基-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺( 中間物14;402.5 mg,1.85 mmol,1.30當量)、CuI (270.2 mg,1.42 mmol,1當量)、Pd(PPh 3) 4(327.9 mg,0.28 mmol,0.20當量)及i-Pr 2NH (1.44 g,14.19 mmol,10當量)於DMSO (10 mL)中之溶液在室溫及氮氣氛圍下攪拌2 h,然後用水(100 mL)稀釋且用EtOAc (3*100 mL)萃取。合併的有機層經硫酸鈉乾燥,過濾且真空濃縮。殘餘物藉由反相急速層析(管柱,C18矽膠;移動相,於MeCN中之水(0.1%TFA),在10 min內25%至40%梯度;偵測器,UV 220 nm)純化,以得到呈黃色固體之4-({3-[8-溴-6-氟-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-3-甲氧基-N-甲基苯甲醯胺(270 mg,37.08%)。LC-MS:(M+H) +實測值:513.2。 步驟2. 4-{[3-(6-氟-8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺;甲酸鹽之合成 A solution of 8-bromo-6-fluoro-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( Intermediate 47 ; 600 mg, 1.42 mmol, 1 eq), 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide ( Intermediate 14 ; 402.5 mg, 1.85 mmol, 1.30 eq), CuI (270.2 mg, 1.42 mmol, 1 eq), Pd(PPh 3 ) 4 (327.9 mg, 0.28 mmol, 0.20 eq) and i-Pr 2 NH (1.44 g, 14.19 mmol, 10 eq) in DMSO (10 mL) was stirred at room temperature under nitrogen atmosphere for 2 h and then washed with water (100 mL). The mixture was diluted with 10% ethyl acetate (50 mL) and extracted with EtOAc (3*100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, water (0.1% TFA) in MeCN, gradient 25% to 40% in 10 min; detector, UV 220 nm) to give 4-({3-[8-bromo-6-fluoro-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N-methylbenzamide (270 mg, 37.08%) as a yellow solid. LC-MS: (M+H) + found: 513.2. Step 2. Synthesis of 4-{[3-(6-fluoro-8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide; formate salt
將4-({3-[8-溴-6-氟-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-3-甲氧基-N-甲基苯甲醯胺(270 mg,0.53 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(128.6 mg,0.63 mmol,1.20當量)、RuPhos (122.7 mg,0.26 mmol,0.50當量)、BrettPhos Pd G4 (208.9 mg,0.26 mmol,0.50當量)及Cs 2CO 3(514.2 mg,1.58 mmol,3當量)於二噁烷(10 mL)中之混合物在65℃及氮氣氛圍下攪拌3 h。反應混合物用水(50 mL)稀釋且用EtOAc (3*50 mL)萃取。合併的有機層經硫酸鈉乾燥,過濾且真空濃縮。殘餘物藉由製備型HPLC (管柱:Xselect CSH PrepC18管柱,30*150 mm,5μm;移動相A:水(0.1% FA),移動相B:ACN;流動速率:25 mL/min mL/min;梯度:在7min內42% B至50% B;波長:254nm/220nm nm;RT1(min):7)純化,以得到呈黃色油狀物之4-{[3-(6-氟-8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺;甲酸(9.7 mg,3.27%)。LC-MS:(M+H) +實測值:565.20。 1H NMR (400 MHz, DMSO-d 6) δ 8.15 – 7.99 (m, 2H), 7.46 – 7.37 (m, 1H), 7.35 (d, J= 1.9 Hz, 1H), 6.74 (d, J= 8.3 Hz, 1H), 6.59 – 6.46 (m, 1H), 5.96 (t, J= 6.2 Hz, 1H), 5.82 (d, J= 8.9 Hz, 1H), 4.82 (d, J= 49.5 Hz, 1H), 4.27 (d, J= 6.3 Hz, 2H), 4.09 – 3.96 (m, 2H), 3.85 (s, 4H), 3.03 (t, J= 11.5 Hz, 1H), 2.76 (d, J= 4.5 Hz, 4H), 2.37 – 2.21 (m, 1H), 2.19 (s, 3H), 2.10 (t, J= 11.1 Hz, 1H), 1.96 – 1.82 (m, 1H), 1.75 (d, J= 11.6 Hz, 1H)。 實例100. 4-{[3-(8-{[(3S,4R)-3-氟哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺之合成 步驟1. 4-[(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺之合成 4-({3-[8-bromo-6-fluoro-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-3-methoxy-N-methylbenzamide (270 mg, 0.53 mmol, 1 eq.), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (128.6 mg, 0.63 mmol, 1.20 eq.), RuPhos (122.7 mg, 0.26 mmol, 0.50 eq.), BrettPhos Pd G4 (208.9 mg, 0.26 mmol, 0.50 eq.) and Cs 2 CO 3 (514.2 mg, 1.58 mmol, 3 eq.) were dissolved in dioxane (10 The mixture was stirred at 65 °C under nitrogen atmosphere for 3 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3*50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Xselect CSH PrepC18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 25 mL/min mL/min; gradient: 42% B to 50% B in 7 min; wavelength: 254 nm/220 nm nm; RT1(min): 7) to give 4-{[3-(6-fluoro-8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide as a yellow oil; formic acid (9.7 mg, 3.27%). LC-MS: (M+H) + found: 565.20. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.15 – 7.99 (m, 2H), 7.46 – 7.37 (m, 1H), 7.35 (d, J = 1.9 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.59 – 6.46 (m, 1H), 5.96 (t, J = 6.2 Hz, 1H), 5.82 (d, J = 8.9 Hz, 1H), 4.82 (d, J = 49.5 Hz, 1H), 4.27 (d, J = 6.3 Hz, 2H), 4.09 – 3.96 (m, 2H), 3.85 (s, 4H), 3.03 (t, J = 11.5 Hz, 1H), 2.76 (d, J = 4.5 Hz, 4H), 2.37 – 2.21 (m, 1H), 2.19 (s, 3H), 2.10 (t, J = 11.1 Hz, 1H), 1.96 – 1.82 (m, 1H), 1.75 (d, J = 11.6 Hz, 1H). Example 100. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide Step 1. Synthesis of 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide
將8-溴-2-碘-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶( 中間物9;290 mg,0.69 mmol,1當量)、3-甲氧基-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺( 中間物14;150 mg,0.69 mmol,1當量)、Pd(PPh 3) 4(317 mg,0.27 mmol,0.4當量)、CuI (131 mg,0.69 mmol,1當量)及i-Pr 2NH (693.8 mg,6.86 mmol,10當量)於DMSO (3 mL)中之溶液在室溫及氮氣氛圍下攪拌1h。反應用水(10 mL)淬滅且用EtOAc (3*10 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由反相急速層析(管柱,C18矽膠;移動相,於水中之MeCN (10mmol/L NH 4HCO 3),在2 min內50%至50%梯度;偵測器,UV 254 nm)純化,以得到呈黃色固體之4-[(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺(150 mg,42.62%)。LC-MS:(M+H) +實測值513.0。 步驟2. (3S,4R)-3-氟-4-{[2-(3-{[2-甲氧基-4-(甲基胺甲醯基)苯基]胺基}丙-1-炔-1-基)-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-8-基]胺基}哌啶-1-甲酸三級丁酯之合成 A solution of 8-bromo-2-iodo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine ( intermediate 9 ; 290 mg, 0.69 mmol, 1 eq), 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide ( intermediate 14 ; 150 mg, 0.69 mmol, 1 eq), Pd (PPh3) 4 (317 mg, 0.27 mmol, 0.4 eq), CuI (131 mg, 0.69 mmol, 1 eq) and i- Pr2NH (693.8 mg, 6.86 mmol, 10 eq) in DMSO (3 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The reaction was quenched with water (10 mL) and extracted with EtOAc (3*10 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH 4 HCO 3 ) in water, 50% to 50% gradient in 2 min; detector, UV 254 nm) to give 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (150 mg, 42.62%) as a yellow solid. LC-MS: (M+H) + found 513.0. Step 2. Synthesis of (3S,4R)-3-fluoro-4-{[2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]amino}piperidine-1-carboxylic acid tributyl ester
將4-[(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺(150 mg,0.29 mmol,1當量)、(3S,4R)-4-胺基-3-氟哌啶-1-甲酸三級丁酯(95.7 mg,0.44 mmol,1.5當量)、RAC-BINAP-PD-G3 (58.0 mg,0.06 mmol,0.20當量)、BINAP (72.8 mg,0.12 mmol,0.4當量)及Cs 2CO 3(190.4 mg,0.58 mmol,2當量)於二噁烷(3 mL)中之混合物在100℃及氮氣氛圍下攪拌16 h。反應用水淬滅且用EtOAc (3*20 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由反相急速層析(管柱,C18矽膠;移動相,於水中之MeCN (0.1% FA),在3 min內50%至50%梯度;偵測器,UV 254 nm)純化,以得到呈黃色油狀物之(3S,4R)-3-氟-4-{[2-(3-{[2-甲氧基-4-(甲基胺甲醯基)苯基]胺基}丙-1-炔-1-基)-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-8-基]胺基}哌啶-1-甲酸三級丁酯(85 mg,44.70%)。LC-MS:(M+H) +實測值651.0。 步驟3. 4-{[3-(8-{[(3S,4R)-3-氟哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺之合成 A mixture of 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (150 mg, 0.29 mmol, 1 eq), (3S,4R)-4-amino-3-fluoropiperidine-1-carboxylic acid tributyl ester (95.7 mg, 0.44 mmol, 1.5 eq), RAC-BINAP-PD-G3 (58.0 mg, 0.06 mmol, 0.20 eq), BINAP (72.8 mg, 0.12 mmol, 0.4 eq) and Cs 2 CO 3 (190.4 mg, 0.58 mmol, 2 eq) in dioxane (3 mL) was stirred at 100 °C under nitrogen atmosphere for 16 h. The reaction was quenched with water and extracted with EtOAc (3*20 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient 50% to 50% in 3 min; detector, UV 254 nm) to give (3S,4R)-3-fluoro-4-{[2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]amino}piperidine-1-carboxylic acid tributyl ester (85 mg, 44.70%) as a yellow oil. LC-MS: (M+H) + found 651.0. Step 3. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide
將(3S,4R)-3-氟-4-{[2-(3-{[2-甲氧基-4-(甲基胺甲醯基)苯基]胺基}丙-1-炔-1-基)-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-8-基]胺基}哌啶-1-甲酸三級丁酯(85 mg,0.13 mmol,1當量)及TFA (0.8 mL)於DCM (3 mL)中之溶液在0℃下攪拌1 h。所得混合物用水(10 mL)稀釋且用飽和NaHCO 3鹼化至pH 8,然後用EtOAc (3*10 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。粗產物藉由製備型HPLC (管柱:Xbridge Prep Phenyl 19*250 mm,5μm;移動相A:水(10 mmol/L NH 4HCO 3),移動相B:ACN;流動速率:25 mL/min;梯度:在12min內40% B至60% B;波長:254nm/220nm nm;RT1(min):9.4)純化,以得到呈白色固體之4-{[3-(8-{[(3S,4R)-3-氟哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺(22.3 mg,31.01%)。LC-MS:(M+H) +實測值551.15。 1H NMR (400 MHz, DMSO- d 6) δ 8.11 (d, J= 4.7 Hz, 1H), 7.86 (d, J= 6.6 Hz, 1H), 7.41 (dd, J= 8.3, 1.9 Hz, 1H), 7.35 (d, J= 1.9 Hz, 1H), 7.06 – 6.98 (m, 1H), 6.76 (d, J= 8.3 Hz, 1H), 6.62 (d, J= 7.7 Hz, 1H), 6.01 (t, J= 6.3 Hz, 1H), 5.60 (d, J= 9.0 Hz, 1H), 4.72 (d, J= 50.5 Hz, 1H), 4.32 (d, J= 6.3 Hz, 2H), 3.92 – 3.75 (m, 4H), 3.13 (t, J= 12.6 Hz, 1H), 2.95 (d, J= 13.1 Hz, 1H), 2.85 – 2.66 (m, 4H), 2.60 (d, J= 11.6 Hz, 1H), 1.76 – 1.60 (m, 2H)。 實例101. 4-{[3-(8-{[(3R,4R)-3-氟氧雜環己-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺之合成 步驟1. 4-[(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺之合成 A solution of tributyl (3S,4R)-3-fluoro-4-{[2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]amino}piperidine-1-carboxylate (85 mg, 0.13 mmol, 1 eq.) and TFA (0.8 mL) in DCM (3 mL) was stirred at 0 °C for 1 h. The resulting mixture was diluted with water (10 mL) and basified to pH 8 with saturated NaHCO 3 , then extracted with EtOAc (3*10 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Xbridge Prep Phenyl 19*250 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 25 mL/min; gradient: 40% B to 60% B in 12 min; wavelength: 254 nm/220 nm; RT1(min): 9.4) to give 4-{[3-(8-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (22.3 mg, 31.01%) as a white solid. LC-MS: (M+H) + found 551.15. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.11 (d, J = 4.7 Hz, 1H), 7.86 (d, J = 6.6 Hz, 1H), 7.41 (dd, J = 8.3, 1.9 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.06 – 6.98 (m, 1H), 6.76 (d, J = 8.3 Hz, 1H), 6.62 (d, J = 7.7 Hz, 1H), 6.01 (t, J = 6.3 Hz, 1H), 5.60 (d, J = 9.0 Hz, 1H), 4.72 (d, J = 50.5 Hz, 1H), 4.32 (d, J = 6.3 Hz, 2H), 3.92 – 3.75 (m, 4H), 3.13 (t, J = 12.6 Hz, 1H), 2.95 (d, J = 13.1 Hz, 1H), 2.85 – 2.66 (m, 4H), 2.60 (d, J = 11.6 Hz, 1H), 1.76 – 1.60 (m, 2H). Example 101. Synthesis of 4-{[3-(8-{[(3R,4R)-3-fluorooxycyclohexyl-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide Step 1. Synthesis of 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide
將8-溴-2-碘-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶(1 g,2.36 mmol,1當量)、3-甲氧基-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺( 中間物14;0.62 g,2.84 mmol,1.2當量)、i-Pr 2NH (2.39 g,23.64 mmol,10當量)、CuI (0.45 g,2.36 mmol,1當量)及Pd(PPh 3) 4(0.55 g,0.47 mmol,0.2當量)於DMSO (10 mL)中之溶液在室溫及氮氣氛圍下攪拌1 h。所得混合物用EtOAc (100 mL)稀釋且用鹽水(3*50 mL)洗滌。有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用CH 2Cl 2/ MeOH (25:1)溶析,以得到呈淺黃色固體之4-[(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺(1 g,82.40%)。LC-MS:(M+H) +實測值513.1。 步驟2. 4-{[3-(8-{[(3R,4R)-3-氟氧雜環己-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺之合成 A solution of 8-bromo-2-iodo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine (1 g, 2.36 mmol, 1 eq), 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide ( Intermediate 14 ; 0.62 g, 2.84 mmol, 1.2 eq), i-Pr 2 NH (2.39 g, 23.64 mmol, 10 eq), CuI (0.45 g, 2.36 mmol, 1 eq) and Pd(PPh 3 ) 4 (0.55 g, 0.47 mmol, 0.2 eq) in DMSO (10 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting mixture was diluted with EtOAc (100 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with CH 2 Cl 2 / MeOH (25:1) to give 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (1 g, 82.40%) as a light yellow solid. LC-MS: (M+H) + found 513.1. Step 2. Synthesis of 4-{[3-(8-{[(3R,4R)-3-fluorooxycyclohexyl-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide
將4-[(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺(200 mg,0.39 mmol,1當量)(3R,4R)-3-氟氧雜環己-4-胺鹽酸鹽(92.8 mg,0.78 mmol,2當量)、t-BuONa (149.8 mg,1.56 mmol,4當量)及tBuXphos Pd G3 (154.8 mg,0.19 mmol,0.5當量)於THF (2 mL)中之混合物在65℃及氮氣氛圍下攪拌1 h。過濾所得混合物,濾餅用DCM洗滌。將濾液在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/於MeOH中之7 M NH3 = 30:1)及製備型HPLC (管柱:XBridge Prep OBD C18管柱,19*250 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3+0.05%NH 3 .H 2O),移動相B:MEOH;流動速率:25 mL/min mL/min;梯度:在10min內52% B至72% B;波長:254nm/220nm nm;RT1(min):9.5;運行次數:3)純化,以得到呈白色固體之4-{[3-(8-{[(3R,4R)-3-氟氧雜環己-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺(28.2 mg,13.03%)。LC-MS:(M+H) +實測值552.05。 1H NMR (400 MHz, DMSO- d 6) δ 8.11 (d, J= 4.7 Hz, 1H), 7.87 (d, J= 6.6 Hz, 1H), 7.41 (m, 1H), 7.34 (d, J= 1.9 Hz, 1H), 7.02 (t, J= 7.2 Hz, 1H), 6.75 (d, J= 8.3 Hz, 1H), 6.66 (d, J= 7.7 Hz, 1H), 6.01 (t, J= 6.3 Hz, 1H), 5.74 (d, J= 8.9 Hz, 1H), 4.78 (d, J= 49.3 Hz, 1H), 4.32 (d, J= 6.3 Hz, 2H), 3.97 (m, 10.6 Hz, 3H), 3.84 (s, 3H), 3.71 – 3.43 (m, 2H), 2.75 (d, J= 4.4 Hz, 3H), 1.93 (m, 4.7 Hz, 1H), 1.76 (d, J= 12.1 Hz, 1H)。 實例102. 4-{[3-(8-{[(3R,4S)-4-氟吡咯啶-3-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺之合成 步驟1. (3S,4R)-3-氟-4-{[2-(3-{[2-甲氧基-4-(甲基胺甲醯基)苯基]胺基}丙-1-炔-1-基)-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-8-基]胺基}吡咯啶-1-甲酸三級丁酯之合成 A mixture of 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (200 mg, 0.39 mmol, 1 eq)(3R,4R)-3-fluorooxacyclohexan-4-amine hydrochloride (92.8 mg, 0.78 mmol, 2 eq), t-BuONa (149.8 mg, 1.56 mmol, 4 eq) and tBuXphos Pd G3 (154.8 mg, 0.19 mmol, 0.5 eq) in THF (2 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was filtered and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 /7 M NH 3 in MeOH = 30:1) and preparative HPLC (column: XBridge Prep OBD C18 column, 19*250 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 +0.05% NH 3 . H 2 O), mobile phase B: MEOH; flow rate: 25 mL/min mL/min; gradient: 52% B to 72% B in 10 min; wavelength: 254 nm/220 nm nm; RT1(min): 9.5; Run number: 3) to give 4-{[3-(8-{[(3R,4R)-3-fluorooxocyclohexyl-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (28.2 mg, 13.03%) as a white solid. LC-MS: (M+H) + found 552.05. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.11 (d, J = 4.7 Hz, 1H), 7.87 (d, J = 6.6 Hz, 1H), 7.41 (m, 1H), 7.34 (d, J = 1.9 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.75 (d, J = 8.3 Hz, 1H), 6.66 (d, J = 7.7 Hz, 1H), 6.01 (t, J = 6.3 Hz, 1H), 5.74 (d, J = 8.9 Hz, 1H), 4.78 (d, J = 49.3 Hz, 1H), 4.32 (d, J = 6.3 Hz, 3H), 3.97 (m, 10.6 Hz, 3H), 3.84 (s, 3H), 3.71 – 3.43 (m, 2H), 2.75 (d, J = 4.4 Hz, 3H), 1.93 (m, 4.7 Hz, 1H), 1.76 (d, J = 12.1 Hz, 1H). Example 102. Synthesis of 4-{[3-(8-{[(3R,4S)-4-fluoropyrrolidin-3-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide Step 1. Synthesis of (3S,4R)-3-fluoro-4-{[2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]amino}pyrrolidine-1-carboxylic acid tributyl ester
將4-[(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺(400 mg,0.78 mmol,1當量)、(3R,4S)-3-胺基-4-氟吡咯啶-1-甲酸三級丁酯(238.7 mg,1.17 mmol,1.5當量)、t-BuONa (149.8 mg,1.56 mmol,2當量) 及tBuXphos Pd G3 (309.5 mg,0.39 mmol,0.5當量)於THF (5 mL)中之混合物在65℃及氮氣氛圍下攪拌1 h。過濾所得混合物,濾餅用DCM洗滌。將濾液在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/於MeOH中之7M NH 3= 50:1)純化,以得到呈黃色固體之(3S,4R)-3-氟-4-{[2-(3-{[2-甲氧基-4-(甲基胺甲醯基)苯基]胺基}丙-1-炔-1-基)-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-8-基]胺基}吡咯啶-1-甲酸三級丁酯(260 mg,52.41%)。LC-MS:(M+H) +實測值637.3。 步驟2. 4-{[3-(8-{[(3R,4S)-4-氟吡咯啶-3-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺之合成 A mixture of 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (400 mg, 0.78 mmol, 1 eq), (3R,4S)-3-amino-4-fluoropyrrolidine-1-carboxylic acid tributyl ester (238.7 mg, 1.17 mmol, 1.5 eq), t-BuONa (149.8 mg, 1.56 mmol, 2 eq) and tBuXphos Pd G3 (309.5 mg, 0.39 mmol, 0.5 eq) in THF (5 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was filtered and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 /7M NH 3 in MeOH = 50:1) to give (3S,4R)-3-fluoro-4-{[2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]amino}pyrrolidine-1-carboxylic acid tributyl ester (260 mg, 52.41%) as a yellow solid. LC-MS: (M+H) + found 637.3. Step 2. Synthesis of 4-{[3-(8-{[(3R,4S)-4-fluoropyrrolidin-3-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide
將(3S,4R)-3-氟-4-{[2-(3-{[2-甲氧基-4-(甲基胺甲醯基)苯基]胺基}丙-1-炔-1-基)-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-8-基]胺基}吡咯啶-1-甲酸三級丁酯(100 mg,0.16 mmol,1當量)及TFA (1 mL)於DCM (2 mL)中之溶液在室溫下攪拌0.5 h。用飽和NaHCO 3將所得溶液鹼化至pH 8且用CH 2Cl 2(3*50 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型HPLC (管柱:XBridge Prep Phenyl OBD管柱,19*250 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3+0.05%NH 3 .H 2O),移動相B:MEOH;流動速率:25 mL/min mL/min;梯度:在10min內55% B至75% B;波長:254nm/220nm nm;RT1(min):9.88;運行次數:3)純化,以得到呈白色固體之4-{[3-(8-{[(3R,4S)-4-氟吡咯啶-3-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺(13.5 mg,15.99%)。LC-MS:(M+H) +實測值537.15。 1H NMR (400 MHz, DMSO- d 6) δ 8.11 (d, J= 4.8 Hz, 1H), 7.87 (d, J= 6.7 Hz, 1H), 7.40 (m, 1H), 7.34 (d, J= 1.8 Hz, 1H), 7.03 (t, J= 7.2 Hz, 1H), 6.75 (d, J= 8.2 Hz, 1H), 6.61 (d, J= 7.7 Hz, 1H), 6.01 (t, J= 6.3 Hz, 1H), 5.92 (d, J= 8.4 Hz, 1H), 5.21 (m, 1H), 4.32 (d, J= 6.3 Hz, 2H), 4.16 – 3.96 (m, 1H), 3.84 (s, 3H), 3.32 – 3.10 (m, 3H), 2.99 (m, 1H), 2.80 (d, J= 10.0 Hz, 1H), 2.75 (d, J= 4.4 Hz, 3H)。 實例103. 4-{[3-(8-{[(3R,4S)-4-氟-1-甲基吡咯啶-3-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺之合成 A solution of (3S,4R)-3-fluoro-4-{[2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]amino}pyrrolidine-1-carboxylic acid tributyl ester (100 mg, 0.16 mmol, 1 eq.) and TFA (1 mL) in DCM (2 mL) was stirred at room temperature for 0.5 h. The resulting solution was alkalized to pH 8 with saturated NaHCO 3 and extracted with CH 2 Cl 2 (3*50 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: XBridge Prep Phenyl OBD column, 19*250 mm, 5μm; mobile phase A: water (10mmol/L NH4HCO3 + 0.05 % NH3.H2O ), mobile phase B: MEOH; flow rate: 25 mL/min mL/min; gradient: 55% B to 75% B in 10 min; wavelength: 254nm /220nm nm; RT1(min): 9.88; Run number: 3) to give 4-{[3-(8-{[(3R,4S)-4-fluoropyrrolidin-3-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (13.5 mg, 15.99%) as a white solid. LC-MS: (M+H) + found 537.15. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.11 (d, J = 4.8 Hz, 1H), 7.87 (d, J = 6.7 Hz, 1H), 7.40 (m, 1H), 7.34 (d, J = 1.8 Hz, 1H), 7.03 (t, J = 7.2 Hz, 1H), 6.75 (d, J = 8.2 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 6.01 (t, J = 6.3 Hz, 1H), 5.92 (d, J = 8.4 Hz, 1H), 5.21 (m, 1H), 4.32 (d, J = 6.3 Hz, 2H), 4.16 – 3.96 (m, 1H), 3.84 (s, 3H), 3.32 – 3.10 (m, 3H), 2.99 (m, 1H), 2.80 (d, J = 10.0 Hz, 1H), 2.75 (d, J = 4.4 Hz, 3H). Example 103. Synthesis of 4-{[3-(8-{[(3R,4S)-4-fluoro-1-methylpyrrolidin-3-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide
將4-{[3-(8-{[(3R,4S)-4-氟吡咯啶-3-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺(100 mg,0.19 mmol,1當量)及POM (83.9 mg,0.93 mmol,5當量)於MeOH (3 mL)中之溶液用AcOH (1滴)處理,接著在室溫下添加NaBH 3CN (35.1 mg,0.56 mmol,3當量)。將所得混合物在室溫下攪拌1 h。將所得混合物在40℃下再攪拌1 h。過濾所得混合物,濾餅用MeOH洗滌。將濾液在減壓下濃縮。粗產物(120 mg)藉由具有以下條件(管柱:XBridge Prep OBD C18管柱,19*250 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3+0.05%NH 3 .H 2O),移動相B:MEOH;流動速率:25 mL/min mL/min;梯度:在10min內55% B至74% B;波長:254nm/220nm nm;RT1(min):9.32,運行次數:3)之製備型HPLC純化,以得到呈白色固體之4-{[3-(8-{[(3R,4S)-4-氟-1-甲基吡咯啶-3-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺(18.1 mg,17.07%)。LC-MS:(M+H) +實測值551.15。 1H NMR (400 MHz, DMSO- d 6) δ 8.11 (d, J= 4.9 Hz, 1H), 7.87 (d, J= 6.7 Hz, 1H), 7.44 – 7.37 (m, 1H), 7.34 (d, J= 1.9 Hz, 1H), 7.02 (t, J= 7.2 Hz, 1H), 6.75 (d, J= 8.3 Hz, 1H), 6.63 (d, J= 7.6 Hz, 1H), 6.02 (t, J= 6.2 Hz, 1H), 5.91 (d, J= 8.5 Hz, 1H), 5.26 (d, J= 56.3 Hz, 1H), 4.28 (m, 3H), 3.84 (s, 3H), 3.06 m, 1H), 2.91 (t, J= 8.1 Hz, 1H), 2.75 (d, J= 4.4 Hz, 3H), 2.65 (m, 2H), 2.29 (s, 3H)。 實例104. 4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-(2-甲氧基乙氧基)-N-甲基苯甲醯胺之合成 步驟1. 4-[(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-(2-甲氧基乙氧基)-N-甲基苯甲醯胺之合成 A solution of 4-{[3-(8-{[(3R,4S)-4-fluoropyrrolidin-3-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (100 mg, 0.19 mmol, 1 eq) and POM (83.9 mg, 0.93 mmol, 5 eq) in MeOH (3 mL) was treated with AcOH (1 drop) followed by the addition of NaBH 3 CN (35.1 mg, 0.56 mmol, 3 eq) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was stirred at 40 °C for another 1 h. The resulting mixture was filtered and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure. The crude product (120 mg) was purified by HPLC with the following conditions (column: XBridge Prep OBD C18 column, 19*250 mm, 5μm; mobile phase A: water (10mmol/L NH 4 HCO 3 +0.05% NH 3 . H 2 O), mobile phase B: MEOH; flow rate: 25 mL/min mL/min; gradient: 55% B to 74% B in 10 min; wavelength: 254nm/220nm nm; RT1(min): 9.32, runs: 3) to give 4-{[3-(8-{[(3R,4S)-4-fluoro-1-methylpyrrolidin-3-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (18.1 mg, 17.07%) as a white solid. LC-MS: (M+H) + found 551.15. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.11 (d, J = 4.9 Hz, 1H), 7.87 (d, J = 6.7 Hz, 1H), 7.44 – 7.37 (m, 1H), 7.34 (d, J = 1.9 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.75 (d, J = 8.3 Hz, 1H), 6.63 (d, J = 7.6 Hz, 1H), 6.02 (t, J = 6.2 Hz, 1H), 5.91 (d, J = 8.5 Hz, 1H), 5.26 (d, J = 56.3 Hz, 1H), 4.28 (m, 3H), 3.84 (s, 3H), 3.06 m, 1H), 2.91 (t, J = 8.1 Hz, 1H), 2.75 (d, J = 4.4 Hz, 3H), 2.65 (m, 2H), 2.29 (s, 3H). Example 104. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-(2-methoxyethoxy)-N-methylbenzamide Step 1. Synthesis of 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-(2-methoxyethoxy)-N-methylbenzamide
將3-(2-甲氧基乙氧基)-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺( 中間物31;111.6 mg,0.43 mmol,1.2當量)、8-溴-2-碘-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶( 中間物9;150 mg,0.36 mmol,1當量)、CuI (67.5 mg,0.36 mmol,1當量)、i-Pr 2NH (0.50 mL,3.55 mmol,10當量)、Pd(PPh 3) 4(82.0 mg,0.07 mmol,0.2當量)於DMSO (1.5 mL)中之溶液在室溫及氮氣氛圍下攪拌2 h。將額外8-溴-2-碘-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶( 中間物9;50mg)添加至反應系統中且將混合物在室溫及氮氣氛圍下再攪拌1 h。所得混合物用DCM/MEOH=10:1 (10 mL)稀釋且用水(10 mL)洗滌。水層用DCM/MEOH=10:1 (3*10 mL)萃取。合併的有機層經無水Na 2SO 4乾燥,過濾之後,將濾液在減壓下濃縮。殘餘物藉由反相急速層析(管柱,C18矽膠;移動相,於水中之MeCN (10 mmol/L NH 4HCO 3),在20 min內0%至100%梯度;偵測器,UV 254 nm)純化,以得到呈棕色固體之4-[(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-(2-甲氧基乙氧基)-N-甲基苯甲醯胺(150 mg,73.76%)。LC-MS:(M+H) +實測值557.0。 步驟2. 4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-(2-甲氧基乙氧基)-N-甲基苯甲醯胺之合成 A solution of 3-(2-methoxyethoxy)-N-methyl-4-(prop-2-yn-1-ylamino)benzamide ( intermediate 31 ; 111.6 mg, 0.43 mmol, 1.2 equiv), 8-bromo-2-iodo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine ( intermediate 9 ; 150 mg, 0.36 mmol, 1 equiv), CuI (67.5 mg, 0.36 mmol, 1 equiv), i-Pr 2 NH (0.50 mL, 3.55 mmol, 10 equiv), Pd(PPh 3 ) 4 (82.0 mg, 0.07 mmol, 0.2 equiv) in DMSO (1.5 mL) was stirred at room temperature under nitrogen atmosphere for 2 h. Additional 8-bromo-2-iodo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine ( intermediate 9 ; 50 mg) was added to the reaction system and the mixture was stirred for another 1 h at room temperature under nitrogen atmosphere. The resulting mixture was diluted with DCM/MEOH=10:1 (10 mL) and washed with water (10 mL). The aqueous layer was extracted with DCM/MEOH=10:1 (3*10 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH 4 HCO 3 ) in water, gradient 0% to 100% in 20 min; detector, UV 254 nm) to give 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-(2-methoxyethoxy)-N-methylbenzamide (150 mg, 73.76%) as a brown solid. LC-MS: (M+H) + found 557.0. Step 2. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-(2-methoxyethoxy)-N-methylbenzamide
將4-[(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-(2-甲氧基乙氧基)-N-甲基苯甲醯胺(60 mg,0.11 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(24.3 mg,0.12 mmol,1.1當量)、tBuXphos Pd G3 (8.6 mg,0.01 mmol,0.1當量)及t-BuoNa (31.0 mg,0.32 mmol,3當量) 於THF (1 mL)中之混合物在65℃及氮氣氛圍下攪拌1 h。所得混合物用水(10 mL)稀釋且用EtOAc (3*10 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/ MeOH = 10:1)及反相急速層析(管柱,C18矽膠;移動相,於水中之MeCN (0.1% FA),在20 min內10%至50%梯度;偵測器,UV 254 nm)純化,以得到呈黃色固體之4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-(2-甲氧基乙氧基)-N-甲基苯甲醯胺(16.5 mg,25.18%)。LC-MS:(M+H) +實測值609.40。 1H NMR (400 MHz, DMSO-d6) δ 8.11 (m, 1H), 7.87 (d, J= 6.6 Hz, 1H), 7.42 (dd, J= 8.2, 1.8 Hz, 1H), 7.35 (d, J= 1.9 Hz, 1H), 7.02 (t, J= 7.2 Hz, 1H), 6.76 (d, J= 8.3 Hz, 1H), 6.61 (d, J= 7.7 Hz, 1H), 5.87 (t, J= 6.3 Hz, 1H), 5.62 (d, J= 9.0 Hz, 1H), 4.83 (d, J= 49.5 Hz, 1H), 4.35 (d, J= 6.3 Hz, 2H), 4.15 (dd, J= 5.7, 3.6 Hz, 2H), 3.80 – 3.67 (m, 3H), 3.52 (s, 3H), 3.03 (t, J= 11.5 Hz, 1H), 2.74 (d, J= 4.5 Hz, 4H), 2.28 (d, J= 12.9 Hz, 1H), 2.19 (s, 3H), 2.13 – 2.05 (m, 1H), 1.85 (dd, J= 12.0, 8.3 Hz, 1H), 1.79 – 1.70 (m, 1H)。 實例105. 3-(二氟甲氧基)-4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-N-甲基苯甲醯胺之合成 步驟1. 4-[(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-(二氟甲氧基)-N-甲基苯甲醯胺之合成 A mixture of 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-(2-methoxyethoxy)-N-methylbenzamide (60 mg, 0.11 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (24.3 mg, 0.12 mmol, 1.1 eq), tBuXphos Pd G3 (8.6 mg, 0.01 mmol, 0.1 eq) and t-BuoNa (31.0 mg, 0.32 mmol, 3 eq) in THF (1 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3*10 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 / MeOH = 10:1) and reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient 10% to 50% in 20 min; detector, UV 254 nm) to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-(2-methoxyethoxy)-N-methylbenzamide (16.5 mg, 25.18%) as a yellow solid. LC-MS: (M+H) + found 609.40. 1 H NMR (400 MHz, DMSO-d6) δ 8.11 (m, 1H), 7.87 (d, J = 6.6 Hz, 1H), 7.42 (dd, J = 8.2, 1.8 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.76 (d, J = 8.3 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 5.87 (t, J = 6.3 Hz, 1H), 5.62 (d, J = 9.0 Hz, 1H), 4.83 (d, J = 49.5 Hz, 1H), 4.35 (d, J = 6.3 Hz, 3H), 4.15 (dd, J = 5.7, 3.6 Hz, 2H), 3.80 – 3.67 (m, 3H), 3.52 (s, 3H), 3.03 (t, J = 11.5 Hz, 1H), 2.74 (d, J = 4.5 Hz, 4H), 2.28 (d, J = 12.9 Hz, 1H), 2.19 (s, 3H), 2.13 – 2.05 (m, 1H), 1.85 (dd, J = 12.0, 8.3 Hz, 1H), 1.79 – 1.70 (m, 1H). Example 105. Synthesis of 3-(difluoromethoxy)-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide Step 1. Synthesis of 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-(difluoromethoxy)-N-methylbenzamide
將3-(二氟甲氧基)-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺( 中間物29;100 mg,0.39 mmol,1當量)、8-溴-2-碘-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶( 中間物9;166.4 mg,0.39 mmol,1當量)、CuI (74.9 mg,0.39 mmol,1當量)、i-Pr 2NH (398.0 mg,3.93 mmol,10當量)及Pd(PPh 3) 4(90.9 mg,0.08 mmol,0.2當量)於DMSO (3 mL)中之溶液在室溫及氮氣氛圍下攪拌1 h。所得溶液藉由反相急速層析(管柱,C18矽膠;移動相,於水中之MeCN (0.1% FA),在10 min內40%至80%梯度;偵測器,UV 254 nm)純化,以得到呈黃色固體之4-[(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-(二氟甲氧基)-N-甲基苯甲醯胺(152 mg,66.55%)。LC-MS:(M+H) +實測值549.1。 步驟2. 3-(二氟甲氧基)-4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-N-甲基苯甲醯胺之合成 A solution of 3-(difluoromethoxy)-N-methyl-4-(prop-2-yn-1-ylamino)benzamide ( intermediate 29 ; 100 mg, 0.39 mmol, 1 eq), 8-bromo-2-iodo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine ( intermediate 9 ; 166.4 mg, 0.39 mmol, 1 eq), CuI (74.9 mg, 0.39 mmol, 1 eq), i- Pr2NH (398.0 mg, 3.93 mmol, 10 eq) and Pd( PPh3 ) 4 (90.9 mg, 0.08 mmol, 0.2 eq) in DMSO (3 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting solution was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient 40% to 80% in 10 min; detector, UV 254 nm) to give 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-(difluoromethoxy)-N-methylbenzamide (152 mg, 66.55%) as a yellow solid. LC-MS: (M+H) + found 549.1. Step 2. Synthesis of 3-(difluoromethoxy)-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide
將4-[(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-(二氟甲氧基)-N-甲基苯甲醯胺(20 mg,0.04 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(8.2 mg,0.04 mmol,1.1當量)、t-BuoNa (10.5 mg,0.11 mmol,3當量)及tBuXphos Pd G3 (2.9 mg,0.004 mmol,0.1當量)於THF (1 mL)中之混合物在65℃及氮氣氛圍下攪拌1 h。所得混合物用水(10ml)稀釋且用EtOAc (3*10 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/ MeOH = 10:1)純化兩次,以得到呈白色固體之3-(二氟甲氧基)-4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-N-甲基苯甲醯胺(11.3 mg,45.68%)。LC-MS:(M+H) +實測值601.15。 1H NMR (400 MHz, DMSO-d6) δ 8.20 (m, 1H), 7.87 (d, J= 6.7 Hz, 1H), 7.65 (dd, J= 8.5, 1.9 Hz, 1H), 7.58 (d, J= 1.9 Hz, 1H), 7.21 – 6.99 (m, 2H), 6.92 (dd, J= 8.5, 4.2 Hz, 1H), 6.62 (d, J= 7.7 Hz, 1H), 6.44 (t, J= 6.1 Hz, 1H), 5.61 (d, J= 9.0 Hz, 1H), 4.83 (d, J= 49.5 Hz, 1H), 4.35 (d, J= 6.1 Hz, 2H), 3.74 (d, J= 29.0 Hz, 1H), 3.03 (t, J= 11.4 Hz, 1H), 2.74 (d, J= 4.5 Hz, 4H), 2.19 (s, 4H), 2.14 – 2.04 (m, 1H), 1.96 – 1.71 (m, 2H)。 實例106. 4-[(3-{3-[(二氟甲基)硫基]-8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺之合成 步驟1. 4-[(3-{8-溴-3-[(二氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺之合成 A mixture of 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-(difluoromethoxy)-N-methylbenzamide (20 mg, 0.04 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (8.2 mg, 0.04 mmol, 1.1 eq), t-BuoNa (10.5 mg, 0.11 mmol, 3 eq) and tBuXphos Pd G3 (2.9 mg, 0.004 mmol, 0.1 eq) in THF (1 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was diluted with water (10 ml) and extracted with EtOAc (3*10 mL). The combined organic layer was dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified twice by preparative TLC (CH 2 Cl 2 / MeOH = 10:1) to give 3-(difluoromethoxy)-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide (11.3 mg, 45.68%) as a white solid. LC-MS: (M+H) + found 601.15. 1 H NMR (400 MHz, DMSO-d6) δ 8.20 (m, 1H), 7.87 (d, J = 6.7 Hz, 1H), 7.65 (dd, J = 8.5, 1.9 Hz, 1H), 7.58 (d, J = 1.9 Hz, 1H), 7.21 – 6.99 (m, 2H), 6.92 (dd, J = 8.5, 4.2 Hz, 1H), 6.62 (d, J = 7.7 Hz, 1H), 6.44 (t, J = 6.1 Hz, 1H), 5.61 (d, J = 9.0 Hz, 1H), 4.83 (d, J = 49.5 Hz, 1H), 4.35 (d, J = 6.1 Hz, 2H), 3.74 (d, J = 29.0 Hz, 1H), 3.03 (t, J = 11.4 Hz, 1H), 2.74 (d, J = 4.5 Hz, 4H), 2.19 (s, 4H), 2.14 – 2.04 (m, 1H), 1.96 – 1.71 (m, 2H). Example 106. Synthesis of 4-[(3-{3-[(difluoromethyl)thio]-8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide Step 1. Synthesis of 4-[(3-{8-bromo-3-[(difluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide
將8-溴-3-[(二氟甲基)硫基]-2-碘咪唑并[1,2-a]吡啶(110 mg,0.27 mmol,1當量)、3-甲氧基-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺(65 mg,0.30 mmol,1.1當量)、Pd(PPh 3) 4(69 mg,0.06 mmol,0.2當量)、CuI (56 mg,0.30 mmol,1.1當量)及i-Pr 2NH (276 mg,2.72 mmol,10當量)於DMSO (1 mL)中之溶液在室溫及氮氣氛圍下攪拌1 h。所得溶液用水(3 mL)稀釋且用CH 2Cl 2/ MeOH = 10:1 (3*5 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用CH 2Cl 2/ MeOH (10:1)溶析,以得到呈棕色固體之4-[(3-{8-溴-3-[(二氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺(127 mg,94.51%)。LC-MS:(M+H) +實測值495.0。 步驟2. 4-[(3-{3-[(二氟甲基)硫基]-8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺之合成 A solution of 8-bromo-3-[(difluoromethyl)thio]-2-iodoimidazo[1,2-a]pyridine (110 mg, 0.27 mmol, 1 eq), 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (65 mg, 0.30 mmol, 1.1 eq), Pd(PPh 3 ) 4 (69 mg, 0.06 mmol, 0.2 eq), CuI (56 mg, 0.30 mmol, 1.1 eq) and i-Pr 2 NH (276 mg, 2.72 mmol, 10 eq) in DMSO (1 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting solution was diluted with water (3 mL) and extracted with CH 2 Cl 2 / MeOH = 10:1 (3*5 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / MeOH (10:1) to give 4-[(3-{8-bromo-3-[(difluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (127 mg, 94.51%) as a brown solid. LC-MS: (M+H) + found 495.0. Step 2. Synthesis of 4-[(3-{3-[(difluoromethyl)thio]-8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide
將4-[(3-{8-溴-3-[(二氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺(102 mg,0.21 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(84 mg,0.42 mmol,2當量)、t-BuXPhos Pd G3 (81 mg,0.10 mmol,0.5當量)及t-BuONa (99 mg,1.03 mmol,5當量)於THF (1 mL)中之混合物在65℃及氮氣氛圍下攪拌1 h。使混合物冷卻至室溫。將所得混合物在真空下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/ MeOH 10:1)純化,以得到呈灰白色固體之4-[(3-{3-[(二氟甲基)硫基]-8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺(8.7 mg,7.59%)。LC-MS:(M+H) +實測值547.25。 1H NMR (400 MHz, DMSO- d 6) δ 8.09 (d, J= 4.8 Hz, 1H), 7.78 (d, J= 6.7 Hz, 1H), 7.44 – 7.13 (m, 3H), 6.96 (t, J= 7.2 Hz, 1H), 6.75 (d, J= 8.3 Hz, 1H), 6.55 (d, J= 7.6 Hz, 1H), 5.97 (t, J= 6.2 Hz, 1H), 5.52 (d, J= 9.0 Hz, 1H), 4.83 (d, J= 49.4 Hz, 1H), 4.29 (d, J= 6.2 Hz, 2H), 3.84 – 3.70 (m, 4H), 3.05 (s, 1H), 2.79 – 2.74 (m, 4H), 2.20 – 2.12 (m, 4H), 1.90 – 1.76 (m, 2H), 1.24 (s, 1H)。 實例107. 3-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-4-甲氧基-N-甲基苯甲醯胺之合成 步驟1. 3-[(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-4-甲氧基-N-甲基苯甲醯胺之合成 A mixture of 4-[(3-{8-bromo-3-[(difluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (102 mg, 0.21 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (84 mg, 0.42 mmol, 2 eq), t-BuXPhos Pd G3 (81 mg, 0.10 mmol, 0.5 eq) and t-BuONa (99 mg, 1.03 mmol, 5 eq) in THF (1 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by preparative TLC (CH 2 Cl 2 / MeOH 10:1) to give 4-[(3-{3-[(difluoromethyl)thio]-8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (8.7 mg, 7.59%) as an off-white solid. LC-MS: (M+H) + found 547.25. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.09 (d, J = 4.8 Hz, 1H), 7.78 (d, J = 6.7 Hz, 1H), 7.44 – 7.13 (m, 3H), 6.96 (t, J = 7.2 Hz, 1H), 6.75 (d, J = 8.3 Hz, 1H), 6.55 (d, J = 7.6 Hz, 1H), 5.97 (t, J = 6.2 Hz, 1H), 5.52 (d, J = 9.0 Hz, 1H), 4.83 (d, J = 49.4 Hz, 1H), 4.29 (d, J = 6.2 Hz, 2H), 3.84 – 3.70 (m, 4H), 3.05 (s, 1H), 2.79 – 2.74 (m, 4H), 2.20 – 2.12 (m, 4H), 1.90 – 1.76 (m, 2H), 1.24 (s, 1H). Example 107. Synthesis of 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide Step 1. Synthesis of 3-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-4-methoxy-N-methylbenzamide
將4-甲氧基-N-甲基-3-(丙-2-炔-1-基胺基)苯甲醯胺( 中間物49;139 mg,0.63 mmol,0.90當量)、8-溴-2-碘-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶(300 mg,0.71 mmol,1當量)、i-Pr 2NH (717 mg,7.09 mmol,10當量)、CuI (135 mg,0.71 mmol,1當量)及Pd(PPh 3) 4(327 mg,0.28 mmol,0.40當量)於DMSO (5 mL)中之溶液在室溫及氮氣氛圍下攪拌1 h。混合物用水(10 mL)淬滅且用EtOAc (3*20 mL)萃取。合併的有機層經硫酸鈉乾燥,過濾且真空濃縮。殘餘物藉由反相急速層析(管柱,C18矽膠;移動相,於水中之MeCN (10mmol/L NH 4HCO 3),在10 min內30%至40%梯度;偵測器,UV 254 nm)純化,以得到呈灰白色固體之3-[(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-4-甲氧基-N-甲基苯甲醯胺(170 mg,46.69%)。LC-MS:(M+H) +實測值:512.9。 步驟2. 3-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-4-甲氧基-N-甲基苯甲醯胺之合成 A solution of 4-methoxy-N-methyl-3-(prop-2-yn-1-ylamino)benzamide ( intermediate 49 ; 139 mg, 0.63 mmol, 0.90 equiv), 8-bromo-2-iodo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine (300 mg, 0.71 mmol, 1 equiv), i-Pr 2 NH (717 mg, 7.09 mmol, 10 equiv), CuI (135 mg, 0.71 mmol, 1 equiv) and Pd(PPh 3 ) 4 (327 mg, 0.28 mmol, 0.40 equiv) in DMSO (5 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The mixture was quenched with water (10 mL) and extracted with EtOAc (3*20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH 4 HCO 3 ) in water, gradient 30% to 40% in 10 min; detector, UV 254 nm) to give 3-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-4-methoxy-N-methylbenzamide (170 mg, 46.69%) as an off-white solid. LC-MS: (M+H) + found: 512.9. Step 2. Synthesis of 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide
將3-[(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-4-甲氧基-N-甲基苯甲醯胺(150 mg,0.29 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(119.9 mg,0.58 mmol,2當量)、Cs 2CO 3(571.2 mg,1.75 mmol,6當量)、BINAP (72.8 mg,0.12 mmol,0.4當量)及RAC-BINAP-PD-G 3(58.0 mg,0.06 mmol,0.2當量)於二噁烷(4 mL)中之混合物在100℃及氮氣氛圍下攪拌16 h。反應混合物用水(10 mL)淬滅且用EtOAc (2*10 mL)萃取。合併的有機層經硫酸鈉乾燥,過濾且真空濃縮。殘餘物藉由反相急速層析(管柱,C18矽膠;移動相,於0.1%TFA-水中之MeCN,在10 min內20%至50%梯度;偵測器,UV 220 nm)及製備型HPLC (管柱:X-Select Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(0.1%FA),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在7 min內30% B至50% B;波長:254nm/220nm nm;RT1(min):6.56)純化,以得到呈灰白色固體之3-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-4-甲氧基-N-甲基苯甲醯胺(16.7 mg,10.12%)。LC-MS:(M+H) +實測值:565.30。 1H NMR (400 MHz, DMSO-d 6) δ 8.14 (d, J= 4.6 Hz, 1H), 7.86 (d, J= 6.6 Hz, 1H), 7.25 (d, J= 2.0 Hz, 1H), 7.17 (dd, J= 8.2, 2.0 Hz, 1H), 7.01 (t, J= 7.2 Hz, 1H), 6.89 (d, J= 8.3 Hz, 1H), 6.61 (d, J= 7.7 Hz, 1H), 5.73 – 5.49 (m, 2H), 4.83 (d, J= 49.3 Hz, 1H), 4.32 (d, J= 6.4 Hz, 2H), 3.85 (s, 3H), 3.83 – 3.66 (m, 1H), 3.05 (t, J= 11.6 Hz, 1H), 2.90 – 2.71 (m, 4H), 2.21 (m, 4H), 2.13 (t, J= 11.3 Hz, 1H), 1.96 – 1.83 (m, 1H), 1.77 (dd, J= 13.3, 4.0 Hz, 1H)。 實例108. N-乙基-3-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-4-甲氧基苯甲醯胺之合成 步驟1. 3-[(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-N-乙基-4-甲氧基苯甲醯胺之合成 A mixture of 3-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-4-methoxy-N-methylbenzamide (150 mg, 0.29 mmol, 1 eq ) , (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (119.9 mg, 0.58 mmol, 2 eq), Cs2CO3 (571.2 mg, 1.75 mmol, 6 eq), BINAP (72.8 mg, 0.12 mmol, 0.4 eq) and RAC-BINAP-PD- G3 (58.0 mg, 0.06 mmol, 0.2 eq) in dioxane (4 mL) was stirred at 100 °C under nitrogen atmosphere for 16 h. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (2*10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in 0.1% TFA-water, gradient from 20% to 50% in 10 min; detector, UV 220 nm) and preparative HPLC (column: X-Select Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 30% B to 50% B in 7 min; wavelength: 254 nm/220 nm nm; RT1 (min): 6.56) to give 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide (16.7 mg, 10.12%) as an off-white solid. LC-MS: (M+H) + found: 565.30. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.14 (d, J = 4.6 Hz, 1H), 7.86 (d, J = 6.6 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 7.17 (dd, J = 8.2, 2.0 Hz, 1H), 7.01 (t, J = 7.2 Hz, 1H), 6.89 (d, J = 8.3 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 5.73 – 5.49 (m, 2H), 4.83 (d, J = 49.3 Hz, 1H), 4.32 (d, J = 6.4 Hz, 2H), 3.85 (s, 3H), 3.83 – 3.66 (m, 1H), 3.05 (t, J = 11.6 Hz, 1H), 2.90 – 2.71 (m, 4H), 2.21 (m, 4H), 2.13 (t, J = 11.3 Hz, 1H), 1.96 – 1.83 (m, 1H), 1.77 (dd, J = 13.3, 4.0 Hz, 1H). Example 108. Synthesis of N-ethyl-3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-4-methoxybenzamide Step 1. Synthesis of 3-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-N-ethyl-4-methoxybenzamide
將N-乙基-4-甲氧基-3-(丙-2-炔-1-基胺基)苯甲醯胺( 中間物50;66 mg,0.28 mmol,0.60當量)、8-溴-2-碘-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶(200 mg,0.47 mmol,1當量)、二異丙胺(478 mg,4.73 mmol,10當量)、Pd(PPh 3) 4(218 mg,0.19 mmol,0.40當量)及CuI (90 mg,0.47 mmol,1當量)於DMSO (3 mL)中之溶液在室溫及氮氣氛圍下攪拌1 h。反應用水(10 m L)淬滅且用乙酸乙酯(3*20 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由反相急速層析(管柱,C18矽膠;移動相,於水中之MeCN (10mmol/L NH 4HCO 3),在20 min內40%至60%梯度;偵測器,UV 254 nm)純化,以得到呈灰白色固體之3-[(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-N-乙基-4-甲氧基苯甲醯胺(60 mg,24.06%)。LC-MS:(M+H +)實測值:527.0。 步驟2. N-乙基-3-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-4-甲氧基苯甲醯胺之合成 A solution of N-ethyl-4-methoxy-3-(prop-2-yn-1-ylamino)benzamide ( intermediate 50 ; 66 mg, 0.28 mmol, 0.60 equiv), 8-bromo-2-iodo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine (200 mg, 0.47 mmol, 1 equiv), diisopropylamine (478 mg, 4.73 mmol, 10 equiv), Pd(PPh 3 ) 4 (218 mg, 0.19 mmol, 0.40 equiv) and CuI (90 mg, 0.47 mmol, 1 equiv) in DMSO (3 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (3*20 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH 4 HCO 3 ) in water, gradient 40% to 60% in 20 min; detector, UV 254 nm) to give 3-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-N-ethyl-4-methoxybenzamide (60 mg, 24.06%) as an off-white solid. LC-MS: (M+H + ) found: 527.0. Step 2. Synthesis of N-ethyl-3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-4-methoxybenzamide
將3-[(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-N-乙基-4-甲氧基苯甲醯胺(50 mg,0.10 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(20.4 mg,0.10 mmol,1當量)、Cs 2CO 3(185 mg,0.57 mmol,6當量)、BINAP (23 mg,0.04 mmol,0.40當量)及BINAP Pd G3 (19 mg,0.02 mmol,0.20當量)於1,4-二噁烷(2 mL)中之混合物在100℃及氮氣氛圍下攪拌 隔夜。反應用水淬滅且用乙酸乙酯(3*10 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型HPLC (管柱:X-Select Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(0.1%FA),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在7 min內30% B至50% B;波長:254nm/220nm nm;RT1(min):6.56)純化,以得到呈灰白色固體之N-乙基-3-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-4-甲氧基苯甲醯胺(14.0 mg,25.31%)。LC-MS:(M+H +)實測值:579.20。 1H NMR (400 MHz, DMSO- d 6 ) δ 8.18 (t, J= 5.6 Hz, 1H), 7.86 (d, J= 6.6 Hz, 1H), 7.26 (d, J= 2.0 Hz, 1H), 7.19 (dd, J= 8.3, 2.1 Hz, 1H), 7.06 – 6.98 (m, 1H), 6.89 (d, J= 8.4 Hz, 1H), 6.61 (d, J= 7.6 Hz, 1H), 5.65 – 5.58 (m, 2H), 4.83 (d, J= 49.4 Hz, 1H), 4.32 (d, J= 6.5 Hz, 2H), 3.85 (s, 3H), 3.72 (dd, J= 28.4, 13.8 Hz, 1H), 3.29 – 3.21 (m, 2H), 3.03 (t, J= 11.4 Hz, 1H), 2.77 (d, J= 11.3 Hz, 1H), 2.29 (d, J= 12.9 Hz, 1H), 2.19 (s, 3H), 2.10 (t, J= 11.2 Hz, 1H), 1.94 – 1.71 (m, 2H), 1.11 (t, J= 7.2 Hz, 3H)。 實例109. N-環丙基-3-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-4-甲氧基苯甲醯胺之合成 步驟1. 3-[(3-(8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基丙-2-炔-1-基)胺基]-N-環丙基-4-甲氧基苯甲醯胺之合成 A mixture of 3-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-N-ethyl-4-methoxybenzamide (50 mg, 0.10 mmol, 1 eq ) , (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (20.4 mg, 0.10 mmol, 1 eq), Cs2CO3 (185 mg, 0.57 mmol, 6 eq), BINAP (23 mg, 0.04 mmol, 0.40 eq) and BINAP Pd G3 (19 mg, 0.02 mmol, 0.20 eq) in 1,4-dioxane (2 mL) was stirred at 100 °C under nitrogen atmosphere overnight. The reaction was quenched with water and extracted with ethyl acetate (3*10 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: X-Select Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 30% B to 50% B in 7 min; wavelength: 254 nm/220 nm nm; RT1(min): 6.56) to give N-ethyl-3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-4-methoxybenzamide (14.0 mg, 25.31%) as an off-white solid. LC-MS: (M+H + ) found: 579.20. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.18 (t, J = 5.6 Hz, 1H), 7.86 (d, J = 6.6 Hz, 1H), 7.26 (d, J = 2.0 Hz, 1H), 7.19 (dd, J = 8.3, 2.1 Hz, 1H), 7.06 – 6.98 (m, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.61 (d, J = 7.6 Hz, 1H), 5.65 – 5.58 (m, 2H), 4.83 (d, J = 49.4 Hz, 1H), 4.32 (d, J = 6.5 Hz, 2H), 3.85 (s, 3H), 3.72 (dd, J = 28.4, 13.8 Hz, 1H), 3.29 – 3.21 (m, 2H), 3.03 (t, J = 11.4 Hz, 1H), 2.77 (d, J = 11.3 Hz, 1H), 2.29 (d, J = 12.9 Hz, 1H), 2.19 (s, 3H), 2.10 (t, J = 11.2 Hz, 1H), 1.94 – 1.71 (m, 2H), 1.11 (t, J = 7.2 Hz, 3H). Example 109. Synthesis of N-cyclopropyl-3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-4-methoxybenzamide Step 1. Synthesis of 3-[(3-(8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-ylprop-2-yn-1-yl)amino]-N-cyclopropyl-4-methoxybenzamide
將N-環丙基-4-甲氧基-3-(丙-2-炔-1-基胺基)苯甲醯胺( 中間物51;115.5 mg,0.47 mmol,1當量)、8-溴-2-碘-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶( 中間物9;200 mg,0.47 mmol,1當量)、Pd(PPh 3) 4(218.6 mg,0.19 mmol,0.40當量)、CuI (90.0 mg,0.47 mmol,1當量)及i-Pr 2NH (478.5 mg,4.73 mmol,10當量)於DMSO (2 mL)中之溶液在室溫及氮氣氛圍下攪拌1 h。反應用水(10 mL)淬滅且用EtOAc (3*25 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由反相急速層析(管柱,C18矽膠;移動相,於水中之MeCN (0.1% TFA),在10 min內40%至70%梯度;偵測器,UV 254 nm)純化,以得到呈黃色固體之3-[(3-(8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基丙-2-炔-1-基)胺基]-N-環丙基-4-甲氧基苯甲醯胺(200 mg,78.42%)。LC-MS:(M+H) +實測值539.1。 步驟2. N-環丙基-3-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-4-甲氧基苯甲醯胺之合成 A solution of N-cyclopropyl-4-methoxy-3-(prop-2-yn-1-ylamino)benzamide ( intermediate 51 ; 115.5 mg, 0.47 mmol, 1 eq), 8-bromo-2-iodo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine ( intermediate 9 ; 200 mg, 0.47 mmol, 1 eq), Pd( PPh3 ) 4 (218.6 mg, 0.19 mmol, 0.40 eq), CuI (90.0 mg, 0.47 mmol, 1 eq) and i- Pr2NH (478.5 mg, 4.73 mmol, 10 eq) in DMSO (2 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The reaction was quenched with water (10 mL) and extracted with EtOAc (3*25 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (0.1% TFA) in water, gradient 40% to 70% in 10 min; detector, UV 254 nm) to give 3-[(3-(8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-ylprop-2-yn-1-yl)amino]-N-cyclopropyl-4-methoxybenzamide (200 mg, 78.42%) as a yellow solid. LC-MS: (M+H) + found 539.1. Step 2. Synthesis of N-cyclopropyl-3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-4-methoxybenzamide
將3-[(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-N-環丙基-4-甲氧基苯甲醯胺(150 mg,0.28 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(114.1 mg,0.56 mmol,2當量)、BINAP (69.3 mg,0.11 mmol,0.40當量)、Cs 2CO 3(543.7 mg,1.67 mmol,6當量)及[2'-(二苯基磷烷基)-[1,1'-聯萘]-2-基]二苯基磷烷基;{2'-胺基-[1,1'-聯苯]-2-基}甲磺酸鈀(55.2 mg,0.06 mmol,0.20當量)於二噁烷(2 mL)中之混合物在100℃及氮氣氛圍下攪拌16 h。所得混合物用水(10 mL)稀釋且用EtOAc (3*15 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由反相急速層析(管柱,C18矽膠;移動相,於水中之MeCN (0.1% FA),在10 min內20%至50%梯度;偵測器,UV 254 nm)及製備型HPLC (管柱:X-Select Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(0.1%FA),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在7 min內30% B至50% B;波長:254nm/220nm nm;RT1(min):6.56)純化,以得到呈白色固體之N-環丙基-3-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-4-甲氧基苯甲醯胺(15.0 mg,7.62%)。LC-MS:(M+H) +實測值591.35。 1H NMR (400 MHz, DMSO-d 6) δ 8.13 (d, J= 4.0 Hz, 1H), 7.86 (d, J= 6.7 Hz, 1H), 7.22 (d, J= 2.1 Hz, 1H), 7.17 (dd, J= 8.3, 2.0 Hz, 1H), 7.02 (t, J= 7.2 Hz, 1H), 6.87 (d, J= 8.3 Hz, 1H), 6.61 (d, J= 7.7 Hz, 1H), 5.61 – 5.57(m, 2H), 4.88 (s, 1H), 4.32 (d, J= 6.5 Hz, 2H), 3.83 (s, 3H), 3.81 – 3.32 (m, 1H), 3.02 (t, J= 11.4 Hz, 1H), 2.79 – 2.74(m, 2H), 2.32 (d, J= 13.0 Hz, 1H), 2.20 (s, 3H), 2.18 – 2.09 (m, 1H), 1.85 – 1.78 (m, 1H), 1.77 (dd, J= 13.2, 3.9 Hz, 1H), 0.68 – 0.63(m, 2H), 0.54 – 0.52 (m, 2H)。 實例110. 6-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-7-甲氧基-3,4-二氫-2H-異喹啉-1-酮之合成 步驟1. 6-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-7-甲氧基-3,4-二氫-2H-異喹啉-1-酮之合成 3-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-N-cyclopropyl-4-methoxybenzamide (150 mg, 0.28 mmol, 1 eq.), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (114.1 mg, 0.56 mmol, 2 eq.), BINAP (69.3 mg, 0.11 mmol, 0.40 eq.), Cs 2 CO 3 (543.7 mg, 1.67 A mixture of 2-(4-(2-(diphenylphosphani)-[1,1'-binaphthyl]-2-yl]diphenylphosphani;{2'-amino-[1,1'-biphenyl]-2-yl}methanesulfonate (55.2 mg, 0.06 mmol, 0.20 equiv) in dioxane (2 mL) was stirred at 100 °C under nitrogen atmosphere for 16 h. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3*15 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient from 20% to 50% in 10 min; detector, UV 254 nm) and preparative HPLC (column: X-Select Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 30% B to 50% B in 7 min; wavelength: 254 nm/220 nm). nm; RT1 (min): 6.56) to give N-cyclopropyl-3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-4-methoxybenzamide (15.0 mg, 7.62%) as a white solid. LC-MS: (M+H) + found 591.35. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.13 (d, J = 4.0 Hz, 1H), 7.86 (d, J = 6.7 Hz, 1H), 7.22 (d, J = 2.1 Hz, 1H), 7.17 (dd, J = 8.3, 2.0 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.87 (d, J = 8.3 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 5.61 – 5.57(m, 2H), 4.88 (s, 1H), 4.32 (d, J = 6.5 Hz, 2H), 3.83 (s, 3H), 3.81 – 3.32 (m, 1H), 3.02 (t, J = 11.4 Hz, 1H), 2.79 – 2.74(m, 2H), 2.32 (d, J = 13.0 Hz, 1H), 2.20 (s, 3H), 2.18 – 2.09 (m, 1H), 1.85 – 1.78 (m, 1H), 1.77 (dd, J = 13.2, 3.9 Hz, 1H), 0.68 – 0.63(m, 2H), 0.54 – 0.52 (m, 2H). Example 110. Synthesis of 6-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-7-methoxy-3,4-dihydro-2H-isoquinolin-1-one Step 1. Synthesis of 6-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-7-methoxy-3,4-dihydro-2H-isoquinolin-1-one
將7-甲氧基-6-(丙-2-炔-1-基胺基)-3,4-二氫-2H-異喹啉-1-酮( 中間物52;300 mg,1.30 mmol,1.3當量)、8-溴-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶( 中間物1;406 mg,1.00 mmol,1當量)、Pd(PPh 3) 4(232 mg,0.20 mmol,0.2當量)、CuI (191 mg,1.00 mmol,1當量)及i-Pr 2NH (1.02 g,10.02 mmol,10當量)於DMSO (5 mL)中之溶液在室溫及氮氣氛圍下攪拌1 h 所得混合物用水(20 mL)稀釋且用CH 2Cl 2/MeOH=10:1 (3*20mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由反相急速層析(管柱,C18矽膠;移動相,於水中之MeCN (10mmol/L NH 4HCO 3),在10 min內10%至50%梯度;偵測器,UV 254 nm)純化,以得到呈淺黃色固體之6-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-7-甲氧基-3,4-二氫-2H-異喹啉-1-酮(300 mg,59.01%)。LC-MS:(M+H) +實測值507.2。 步驟2. 6-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-7-甲氧基-3,4-二氫-2H-異喹啉-1-酮之合成 A solution of 7-methoxy-6-(prop-2-yn-1-ylamino)-3,4-dihydro-2H-isoquinolin-1-one ( Intermediate 52 ; 300 mg, 1.30 mmol, 1.3 equiv), 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( Intermediate 1 ; 406 mg, 1.00 mmol, 1 equiv), Pd(PPh 3 ) 4 (232 mg, 0.20 mmol, 0.2 equiv), CuI (191 mg, 1.00 mmol, 1 equiv) and i-Pr 2 NH (1.02 g, 10.02 mmol, 10 equiv) in DMSO (5 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting mixture was diluted with water (20 mL) and washed with CH 2 Cl 4 . 2 /MeOH=10:1 (3*20mL) for extraction. The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH 4 HCO 3 ) in water, gradient 10% to 50% in 10 min; detector, UV 254 nm) to give 6-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-7-methoxy-3,4-dihydro-2H-isoquinolin-1-one (300 mg, 59.01%) as a light yellow solid. LC-MS: (M+H) + found 507.2. Step 2. Synthesis of 6-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-7-methoxy-3,4-dihydro-2H-isoquinolin-1-one
將6-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-7-甲氧基-3,4-二氫-2H-異喹啉-1-酮(250 mg,0.49 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(112 mg,0.54 mmol,1.1當量)、t-BuXPhos Pd G3 (196 mg,0.25 mmol,0.5當量)及t-BuONa (190 mg,1.97 mmol,4當量)於THF (5 mL)中之混合物在65℃及氮氣氛圍下攪拌1 h。所得混合物用水(20 mL)稀釋且用CH 2Cl 2/MeOH = 10:1 (2* 20 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析(CH 2Cl 2/ MeOH = 10:1)及製備型HPLC (管柱:XBridge Shield RP18 OBD管柱,30*150 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3+0.05%NH 3H 2O),移動相B:ACN;流動速率:60 mL/min;梯度:在7min內30% B至49% B;波長:254nm/220nm nm;RT1(min):6.72;運行次數:2)純化,以得到呈白色固體之6-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-7-甲氧基-3,4-二氫-2H-異喹啉-1-酮(33.5 mg,12.0%)。LC-MS:(M+H) +實測值559.50。 1H NMR (400 MHz, DMSO- d 6) δ 7.79 (d, J= 6.8 Hz, 1H), 7.50 (t, J= 2.7 Hz, 1H), 7.24 (s, 1H), 6.83 (t, J= 7.2 Hz, 1H), 6.58 (s, 1H), 6.40 (d, J= 7.6 Hz, 1H), 6.13 (t, J= 6.3 Hz, 1H), 5.39 (d, J= 9.2 Hz, 1H), 4.82 (d, J= 49.2 Hz, 1H), 4.27 (d, J= 6.3 Hz, 2H), 4.04 (m, 2H), 3.81 (s, 3H), 3.77 – 3.63 (m, 1H), 3.30 (dd, J= 8.1, 1.8 Hz, 2H), 3.03 (t, J= 11.4 Hz, 1H), 2.77 (t, J= 6.6 Hz, 3H), 2.18 (s, 4H), 2.09 (tt, J= 8.7, 4.1 Hz, 1H), 1.90 – 1.71 (m, 2H)。 實例111. 2-氯-4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-5-甲氧基-N-甲基苯甲醯胺之合成 步驟1. 3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-2-氯-5-甲氧基-N-甲基苯甲醯胺之合成 A mixture of 6-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-7-methoxy-3,4-dihydro-2H-isoquinolin-1-one (250 mg, 0.49 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (112 mg, 0.54 mmol, 1.1 eq), t-BuXPhos Pd G3 (196 mg, 0.25 mmol, 0.5 eq) and t-BuONa (190 mg, 1.97 mmol, 4 eq) in THF (5 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was diluted with water (20 mL) and extracted with CH 2 Cl 2 /MeOH = 10:1 (2* 20 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH 2 Cl 2 / MeOH = 10:1) and preparative HPLC (column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 +0.05% NH 3 H 2 O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 30% B to 49% B in 7 min; wavelength: 254 nm/220 nm nm; RT1(min): 6.72; Runs: 2) to give 6-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-7-methoxy-3,4-dihydro-2H-isoquinolin-1-one (33.5 mg, 12.0%) as a white solid. LC-MS: (M+H) + found 559.50. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.79 (d, J = 6.8 Hz, 1H), 7.50 (t, J = 2.7 Hz, 1H), 7.24 (s, 1H), 6.83 (t, J = 7.2 Hz, 1H), 6.58 (s, 1H), 6.40 (d, J = 7.6 Hz, 1H), 6.13 (t, J = 6.3 Hz, 1H), 5.39 (d, J = 9.2 Hz, 1H), 4.82 (d, J = 49.2 Hz, 1H), 4.27 (d, J = 6.3 Hz, 2H), 4.04 (m, 2H), 3.81 (s, 3H), 3.77 – 3.63 (m, 1H), 3.30 (dd, J = 8.1, 1.8 Hz, 2H), 3.03 (t, J = 11.4 Hz, 1H), 2.77 (t, J = 6.6 Hz, 3H), 2.18 (s, 4H), 2.09 (tt, J = 8.7, 4.1 Hz, 1H), 1.90 – 1.71 (m, 2H). Example 111. Synthesis of 2-chloro-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-5-methoxy-N-methylbenzamide Step 1. Synthesis of 3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl)amino)-2-chloro-5-methoxy-N-methylbenzamide
將2-氯-5-甲氧基-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺( 中間物53;20 mg,0.08 mmol,1當量)、8-溴-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶( 中間物1;32.1 mg,0.08 mmol,1當量)、CuI (180.9 mg,0.95 mmol,1當量)、二異丙胺(961.0 mg,9.50 mmol,10當量)及Pd(PPh 3) 4(219.5 mg,0.19 mmol,0.2當量)於DMSO (6 mL)中之溶液在室溫及氮氣氛圍下攪拌3 h。所得混合物用水稀釋且用EtOAc萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用CH 2Cl 2/ MeOH (10:1)溶析,以得到呈黃色固體之4-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-2-氯-5-甲氧基-N-甲基苯甲醯胺(320 mg,63.60%)。LC-MS:(M+H) +實測值529.1。 步驟2. 2-氯-4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-5-甲氧基-N-甲基苯甲醯胺之合成 A solution of 2-chloro-5-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide ( Intermediate 53 ; 20 mg, 0.08 mmol, 1 eq), 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( Intermediate 1 ; 32.1 mg, 0.08 mmol, 1 eq), CuI (180.9 mg, 0.95 mmol, 1 eq), diisopropylamine (961.0 mg, 9.50 mmol, 10 eq) and Pd(PPh 3 ) 4 (219.5 mg, 0.19 mmol, 0.2 eq) in DMSO (6 mL) was stirred at room temperature under nitrogen atmosphere for 3 h. The resulting mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / MeOH (10:1) to give 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-2-chloro-5-methoxy-N-methylbenzamide (320 mg, 63.60%) as a yellow solid. LC-MS: (M+H) + found 529.1. Step 2. Synthesis of 2-chloro-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-5-methoxy-N-methylbenzamide
將4-({3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}胺基)-2-氯-5-甲氧基-N-甲基苯甲醯胺(150 mg,0.28 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(64 mg,0.31 mmol,1.1當量)、tBuXphos Pd G3 (113 mg,0.14 mmol,0.5當量)及t-BuONa (109 mg,1.13 mmol,4當量)於THF (5 mL)中之混合物在65℃及氬氣氛圍下攪拌1 h。所得混合物用水(20 mL)稀釋且用CH 2Cl 2/MeOH=10/1 (3*20 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析(CH 2Cl 2/ MeOH = 10:1)及製備型HPLC (管柱:XBridge Shield RP18 OBD管柱,30*150 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3+0.05%NH 3 .H 2O),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在7min內30% B至49% B;波長:254nm/220nm nm;RT1(min):6.72;運行次數:2)純化,以得到呈白色固體之2-氯-4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-5-甲氧基-N-甲基苯甲醯胺(20.6 mg,12.52%)。LC-MS:(M+H) +實測值581.20。 1H NMR (400 MHz, DMSO- d 6) δ 8.01 (q, J= 4.5 Hz, 1H), 7.80 (d, J= 6.8 Hz, 1H), 6.92 (s, 1H), 6.83 (t, J= 7.2 Hz, 1H), 6.71 (s, 1H), 6.40 (d, J= 7.5 Hz, 1H), 6.09 (t, J= 6.3 Hz, 1H), 5.39 (d, J= 9.2 Hz, 1H), 4.82 (d, J= 49.2 Hz, 1H), 4.26 (d, J= 6.3 Hz, 2H), 4.07 (q, J= 10.6 Hz, 2H), 3.82 – 3.66 (m, 4H), 3.03 (t, J= 11.3 Hz, 1H), 2.77 – 2.72 (m, 4H), 2.3 – 2.18 (m, 4H), 2.12 – 2.06 (m, 1H), 1.83 – 1.75 (m, 2H)。 實例112. (3S,4R)-3-氟-1-甲基-N-{2-[3-(苯基胺基)丙-1-炔-1-基]-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基}哌啶-4-胺之合成 步驟1. N-{3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}苯胺之合成 A mixture of 4-({3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}amino)-2-chloro-5-methoxy-N-methylbenzamide (150 mg, 0.28 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (64 mg, 0.31 mmol, 1.1 eq), tBuXphos Pd G3 (113 mg, 0.14 mmol, 0.5 eq) and t-BuONa (109 mg, 1.13 mmol, 4 eq) in THF (5 mL) was stirred at 65 °C under an atmosphere of hydrogen for 1 h. The resulting mixture was diluted with water (20 mL) and extracted with CH 2 Cl 2 /MeOH=10/1 (3*20 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH 2 Cl 2 / MeOH = 10:1) and preparative HPLC (column: XBridge Shield RP18 OBD column, 30*150 mm, 5μm; mobile phase A: water (10mmol/L NH 4 HCO 3 +0.05% NH 3 . H 2 O), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 30% B to 49% B in 7min; wavelength: 254nm/220nm nm; RT1(min): 6.72; Runs: 2) to give 2-chloro-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-5-methoxy-N-methylbenzamide (20.6 mg, 12.52%) as a white solid. LC-MS: (M+H) + found 581.20. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.01 (q, J = 4.5 Hz, 1H), 7.80 (d, J = 6.8 Hz, 1H), 6.92 (s, 1H), 6.83 (t, J = 7.2 Hz, 1H), 6.71 (s, 1H), 6.40 (d, J = 7.5 Hz, 1H), 6.09 (t, J = 6.3 Hz, 1H), 5.39 (d, J = 9.2 Hz, 1H), 4.82 (d, J = 49.2 Hz, 1H), 4.26 (d, J = 6.3 Hz, 2H), 4.07 (q, J = 10.6 Hz, 2H), 3.82 – 3.66 (m, 4H), 3.03 (t, J = 11.3 Hz, 1H), 2.77 – 2.72 (m, 4H), 2.3 – 2.18 (m, 4H), 2.12 – 2.06 (m, 1H), 1.83 – 1.75 (m, 2H). Example 112. Synthesis of (3S,4R)-3-fluoro-1-methyl-N-{2-[3-(phenylamino)prop-1-yn-1-yl]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl}piperidin-4-amine Step 1. Synthesis of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}aniline
將N-(丙-2-炔-1-基)苯胺( 中間物54;50 mg,0.38 mmol,1當量)、8-溴-2-碘-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶( 中間物1;185 mg,0.46 mmol,1.2當量)、CuI (72.6 mg,0.38 mmol,1當量)、i-Pr 2NH (0.54 mL,3.81 mmol,10當量)及Pd(PPh 3) 4(88.1 mg,0.08 mmol,0.2當量)於DMSO (1.50 mL)中之溶液在30℃及氮氣氛圍下攪拌1 h。所得混合物用水(10 mL)稀釋且用EtOAc (3*10 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型TLC (PE / EA 1:1)純化,以得到呈棕色固體之N-{3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}苯胺(137 mg,80.92%)。LC-MS:(M+H) +實測值409.1 步驟2. (3S,4R)-3-氟-1-甲基-N-{2-[3-(苯基胺基)丙-1-炔-1-基]-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基}哌啶-4-胺之合成 A solution of N-(prop-2-yn-1-yl)aniline ( Intermediate 54 ; 50 mg, 0.38 mmol, 1 eq), 8-bromo-2-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine ( Intermediate 1 ; 185 mg, 0.46 mmol, 1.2 eq), CuI (72.6 mg, 0.38 mmol, 1 eq), i-Pr 2 NH (0.54 mL, 3.81 mmol, 10 eq) and Pd(PPh 3 ) 4 (88.1 mg, 0.08 mmol, 0.2 eq) in DMSO (1.50 mL) was stirred at 30° C. under nitrogen atmosphere for 1 h. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3*10 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA 1:1) to give N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}aniline (137 mg, 80.92%) as a brown solid. LC-MS: (M+H) + found 409.1 Step 2. Synthesis of (3S,4R)-3-fluoro-1-methyl-N-{2-[3-(phenylamino)prop-1-yn-1-yl]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl}piperidin-4-amine
將N-{3-[8-溴-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基]丙-2-炔-1-基}苯胺(150 mg,0.37 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(82.9 mg,0.40 mmol,1.1當量)、t-BuONa (105.9 mg,1.10 mmol,3當量)及tBuXphos Pd G3 (29.2 mg,0.04 mmol,0.1當量)於THF (4.50 mL)中之混合物唉65℃及氮氣氛圍下攪拌隔夜。所得混合物用水(20 mL)稀釋且用EtOAc (3*20 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型HPLC (管柱:Xselect CSH C18 OBD管柱,30*150mm,5μm;移動相A:水(0.1% FA),移動相B:ACN;流動速率:60 mL/min;梯度:在9 min內18% B至30% B;波長:254nm/220nm nm;RT1(min):8.68)純化,以得到呈白色固體之(3S,4R)-3-氟-1-甲基-N-{2-[3-(苯基胺基)丙-1-炔-1-基]-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-8-基}哌啶-4-胺(4.7 mg,2.68%)。LC-MS:(M+H) +實測值460.15。 1H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1H), 7.78 (d, J= 6.8 Hz, 1H), 7.13 (t, J= 7.9 Hz, 2H), 6.83 (t, J= 7.1 Hz, 1H), 6.71 (d, J= 7.9 Hz, 2H), 6.62 (t, J= 7.3 Hz, 1H), 6.39 (d, J= 7.5 Hz, 1H), 6.10 (t, J= 6.3 Hz, 1H), 5.38 (d, J= 9.2 Hz, 1H), 4.82 (d, J= 49.4 Hz, 1H), 4.16 (d, J= 6.2 Hz, 2H), 4.01 (m, 2H), 3.74 – 3.70 (m, 1H), 3.05 – 3.00 (m, 1H), 2.77 – 2.67 (m, 1H), 2.32 – 2.26 (m, 1H), 2.19 (s, 3H), 2.11 – 2.05 (m, 1H), 1.79 (m, 2H)。 實例124. 3-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-4-甲氧基-N-甲基苯甲醯胺之合成 步驟 1. 3-[(3-{8- 溴 -3-[( 三氟甲基 ) 硫基 ] 吲嗪 -2- 基 } 丙 -2- 炔 -1- 基 ) 胺基 ]-4- 甲氧基 -N- 甲基苯甲醯胺之合成 A mixture of N-{3-[8-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl]prop-2-yn-1-yl}aniline (150 mg, 0.37 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (82.9 mg, 0.40 mmol, 1.1 eq), t-BuONa (105.9 mg, 1.10 mmol, 3 eq) and tBuXphos Pd G3 (29.2 mg, 0.04 mmol, 0.1 eq) in THF (4.50 mL) was stirred at 65 °C under nitrogen atmosphere overnight. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (3*20 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Xselect CSH C18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 18% B to 30% B in 9 min; wavelength: 254 nm/220 nm; RT1(min): 8.68) to give (3S,4R)-3-fluoro-1-methyl-N-{2-[3-(phenylamino)prop-1-yn-1-yl]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-8-yl}piperidin-4-amine (4.7 mg, 2.68%) as a white solid. LC-MS: (M+H) + found 460.15. 1 H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1H), 7.78 (d, J = 6.8 Hz, 1H), 7.13 (t, J = 7.9 Hz, 2H), 6.83 (t, J = 7.1 Hz, 1H), 6.71 (d, J = 7.9 Hz, 2H), 6.62 (t, J = 7.3 Hz, 1H), 6.39 (d, J = 7.5 Hz, 1H), 6.10 (t, J = 6.3 Hz, 1H), 5.38 (d, J = 9.2 Hz, 1H), 4.82 (d, J = 49.4 Hz, 1H), 4.16 (d, J = 6.2 Hz, 2H), 4.01 (m, 2H), 3.74 – 3.70 (m, 1H), 3.05 – 3.00 (m, 1H), 2.77 – 2.67 (m, 1H), 2.32 – 2.26 (m, 1H), 2.19 (s, 3H), 2.11 – 2.05 (m, 1H), 1.79 (m, 2H). Example 124. Synthesis of 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide Step 1. Synthesis of 3-[(3-{8- bromo -3-[( trifluoromethyl ) thio ] indolizin -2- yl } prop -2- yn -1 - yl ) amino ]-4- methoxy -N- methylbenzamide
在室溫下,向8-溴-2-(3-溴丙-1-炔-1-基)-3-[(三氟甲基)硫基]吲嗪( 中間物57,250.00 mg,0.60 mmol,1.00當量)於DMF (4.00 mL)中之溶液中添加3-胺基-4-甲氧基-N-甲基苯甲醯胺(130.89 mg,0.73 mmol,1.20當量)及K 2CO 3(250.95 mg,1.81 mmol,3.00當量)。將反應混合物在70℃下攪拌1 h。所得混合物藉由具有以下條件之反相急速層析純化:管柱,C18;移動相,於水中之MeCN,在30 min內0%至100%梯度;偵測器,UV 254 nm。此產生呈白色固體之3-[(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)胺基]-4-甲氧基-N-甲基苯甲醯胺(150.00 mg,48.37%)。LC-MS:(M+H) +實測值512.15。 步驟2. 3-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-4-甲氧基-N-甲基苯甲醯胺之合成 To a solution of 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizine ( Intermediate 57 , 250.00 mg, 0.60 mmol, 1.00 equiv) in DMF (4.00 mL) was added 3-amino-4-methoxy-N-methylbenzamide (130.89 mg, 0.73 mmol , 1.20 equiv) and K2CO3 (250.95 mg, 1.81 mmol, 3.00 equiv) at room temperature. The reaction mixture was stirred at 70 °C for 1 h. The resulting mixture was purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in water, gradient from 0% to 100% in 30 min; detector, UV 254 nm. This resulted in 3-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-4-methoxy-N-methylbenzamide (150.00 mg, 48.37%) as a white solid. LC-MS: (M+H) + found 512.15. Step 2. Synthesis of 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide
向3-[(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)胺基]-4-甲氧基-N-甲基苯甲醯胺(150.00 mg,0.29 mmol,1.00當量)及(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(120.09 mg,0.59 mmol,2.00當量)於1,4-二噁烷(4.00 mL)中之溶液中添加Cs 2CO 3(572.34 mg,1.76 mmol,6.00當量)、BINAP (18.23 mg,0.03 mmol,0.10當量)及BINAP-Pd-G3 (29.05 mg,0.03 mmol,0.10當量)。將反應混合物在100℃及氮氣氛圍下攪拌4 h。移除溶劑後,殘餘物使用具有以下條件(移動相A:水,移動相B:ACN;流動速率:60 mL/min;梯度:在25 min內0% B至100% B;254/220 nm)之C18層析純化。粗物質藉由具有以下條件之製備型HPLC純化:(管柱:XBridge Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(10 mmol/L NH 4HCO 3+ 0.05% NH 3H 2O),移動相B:ACN;流動速率:60 /mL/min mL/min;梯度:在7 min內37% B至60% B;波長:220 nm;RT:6.53 min)。此產生呈灰白色固體之3-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-4-甲氧基-N-甲基苯甲醯胺(41.70 mg,25.22%)。LC-MS:(M+H) +實測值564.35。 1H NMR (400 MHz, DMSO- d 6) δ 8.11 (q, J= 4.5 Hz, 1H), 7.83 (d, J= 6.8 Hz, 1H), 7.26 (d, J= 2.1 Hz, 1H), 7.20-7.13 (m, 2H), 6.87 (d, J= 8.3 Hz, 1H), 6.74 (t, J= 7.2 Hz, 1H), 6.13 (d, J= 7.6 Hz, 1H), 5.79 (d, J= 8.2 Hz, 1H), 5.48 (t, J= 6.4 Hz, 1H), 4.82 (d, J= 49.4 Hz, 1H), 4.27 (d, J= 6.4 Hz, 2H), 3.84 (s, 3H), 3.58 (d, J= 28.9 Hz, 1H), 3.07-2.97 (m, 1H), 2.80 (d, J= 9.8 Hz, 1H), 2.75 (d, J= 4.5 Hz, 3H), 2.18 (s, 4H), 2.12-1.93 (m, 2H), 1.68 (d, J= 11.7 Hz, 1H)。 實例125. 3-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-4-甲氧基-N-甲基苯甲醯胺之合成 步驟 1. 3-[(3-{8- 溴 -3-[( 三氟甲基 ) 硫基 ] 吲嗪 -2- 基 } 丙 -2- 炔 -1- 基 ) 胺基 ]-4- 甲氧基 -N- 甲基苯甲醯胺之合成 To a solution of 3-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-4-methoxy-N-methylbenzamide (150.00 mg, 0.29 mmol, 1.00 equiv) and (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (120.09 mg, 0.59 mmol, 2.00 equiv) in 1,4-dioxane (4.00 mL) was added Cs2CO3 ( 572.34 mg, 1.76 mmol, 6.00 equiv), BINAP (18.23 mg, 0.03 mmol, 0.10 equiv) and BINAP-Pd-G3 (29.05 mg, 0.03 mmol, 0.10 equiv). The reaction mixture was stirred at 100°C under nitrogen atmosphere for 4 h. After removal of the solvent, the residue was purified using C18 chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 25 min; 254/220 nm). The crude material was purified by preparative HPLC with the following conditions: (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 + 0.05% NH 3 H 2 O), mobile phase B: ACN; flow rate: 60 /mL/min mL/min; gradient: 37% B to 60% B in 7 min; wavelength: 220 nm; RT: 6.53 min). This resulted in 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide (41.70 mg, 25.22%) as an off-white solid. LC-MS: (M+H) + found 564.35. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.11 (q, J = 4.5 Hz, 1H), 7.83 (d, J = 6.8 Hz, 1H), 7.26 (d, J = 2.1 Hz, 1H), 7.20-7.13 (m, 2H), 6.87 (d, J = 8.3 Hz, 1H), 6.74 (t, J = 7.2 Hz, 1H), 6.13 (d, J = 7.6 Hz, 1H), 5.79 (d, J = 8.2 Hz, 1H), 5.48 (t, J = 6.4 Hz, 1H), 4.82 (d, J = 49.4 Hz, 1H), 4.27 (d, J = 6.4 Hz, 2H), 3.84 (s, 3H), 3.58 (d, J = 28.9 Hz, 1H), 3.07-2.97 (m, 1H), 2.80 (d, J = 9.8 Hz, 1H), 2.75 (d, J = 4.5 Hz, 3H), 2.18 (s, 4H), 2.12-1.93 (m, 2H), 1.68 (d, J = 11.7 Hz, 1H). Example 125. Synthesis of 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide Step 1. Synthesis of 3-[(3-{8- bromo -3-[( trifluoromethyl ) thio ] indolizin -2- yl } prop -2- yn -1 - yl ) amino ]-4- methoxy -N- methylbenzamide
在室溫下,向8-溴-2-(3-溴丙-1-炔-1-基)-3-[(三氟甲基)硫基]吲嗪( 中間物57,200.00 mg,0.48 mmol,1.00當量)於DMF (4.00 mL)中之攪拌溶液中添加3-胺基-4-甲氧基-N-甲基苯甲醯胺(104.71 mg,0.58 mmol,1.20當量)及K 2CO 3(200.76 mg,1.45 mmol,3.00當量)。將反應混合物在70℃下攪拌1小時。所得混合物藉由具有以下條件之反相急速層析純化:管柱,C18;移動相,於水中之MeCN,在30 min內0%至100%梯度;偵測器,UV 254 nm。此產生呈白色固體之3-[(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)胺基]-4-甲氧基-N-甲基苯甲醯胺(150.00 mg,60.46%)。LC-MS:(M+H) +實測值512.10。 步驟2. (3S,4R)-3-氟-4-{[2-(3-{[2-甲氧基-5-(甲基胺甲醯基)苯基]胺基}丙-1-炔-1-基)-3-[(三氟甲基)硫基]吲嗪-8-基]胺基}哌啶-1-甲酸三級丁酯之合成 To a stirred solution of 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizine ( Intermediate 57 , 200.00 mg, 0.48 mmol, 1.00 equiv) in DMF (4.00 mL) was added 3-amino-4-methoxy-N-methylbenzamide (104.71 mg, 0.58 mmol, 1.20 equiv) and K2CO3 ( 200.76 mg, 1.45 mmol, 3.00 equiv) at room temperature. The reaction mixture was stirred at 70 °C for 1 hour. The resulting mixture was purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in water, gradient from 0% to 100% in 30 min; detector, UV 254 nm. This resulted in 3-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-4-methoxy-N-methylbenzamide (150.00 mg, 60.46%) as a white solid. LC-MS: (M+H) + found 512.10. Step 2. Synthesis of (3S,4R)-3-fluoro-4-{[2-(3-{[2-methoxy-5-(methylaminocarbonyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizin-8-yl]amino}piperidine-1-carboxylic acid tributyl ester
在室溫下,向3-[(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)胺基]-4-甲氧基-N-甲基苯甲醯胺(130.00 mg,0.25 mmol,1.00當量)及(3S,4R)-4-胺基-3-氟哌啶-1-甲酸三級丁酯(83.07 mg,0.38 mmol,1.50當量)於1,4-二噁烷(4.00 mL)中之溶液中添加Cs 2CO 3(248.01 mg,0.76 mmol,3.00當量)及Pd-PEPPSI-IHeptCl 3-氯吡啶(24.71 mg,0.03 mmol,0.10當量)。將反應混合物在100℃及氮氣氛圍下攪拌4 h。移除溶劑之後,殘餘物藉由具有以下條件之反相急速層析純化:管柱,C18;移動相,於水中之MeCN,在30 min內0%至100%梯度;偵測器,UV 254 nm。此產生呈棕色固體之(3S,4R)-3-氟-4-{[2-(3-{[2-甲氧基-5-(甲基胺甲醯基)苯基]胺基}丙-1-炔-1-基)-3-[(三氟甲基)硫基]吲嗪-8-基]胺基}哌啶-1-甲酸三級丁酯(120.00 mg,72.79%)。LC-MS:(M+H) +實測值650.15。 步驟3. 3-{[3-(8-{[(3S,4R)-3-氟哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-4-甲氧基-N-甲基苯甲醯胺之合成 To a solution of 3-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2-yn-1-yl)amino]-4-methoxy-N-methylbenzamide (130.00 mg, 0.25 mmol, 1.00 equiv) and tributyl (3S,4R)-4-amino-3-fluoropiperidine-1-carboxylate (83.07 mg, 0.38 mmol, 1.50 equiv) in 1,4-dioxane (4.00 mL) at room temperature were added Cs2CO3 (248.01 mg, 0.76 mmol, 3.00 equiv) and Pd-PEPPSI-IHeptCl 3 - chloropyridine (24.71 mg, 0.03 mmol, 0.10 equiv). The reaction mixture was stirred at 100 °C under nitrogen atmosphere for 4 h. After removal of the solvent, the residue was purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in water, gradient from 0% to 100% in 30 min; detector, UV 254 nm. This resulted in (3S,4R)-3-fluoro-4-{[2-(3-{[2-methoxy-5-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizin-8-yl]amino}piperidine-1-carboxylic acid tributyl ester (120.00 mg, 72.79%) as a brown solid. LC-MS: (M+H) + found 650.15. Step 3. Synthesis of 3-{[3-(8-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide
將(3S,4R)-3-氟-4-{[2-(3-{[2-甲氧基-5-(甲基胺甲醯基)苯基]胺基}丙-1-炔-1-基)-3-[(三氟甲基)硫基]吲嗪-8-基]胺基}哌啶-1-甲酸三級丁酯(100.00 mg,0.15 mmol,1.00當量)於DCM (1.50 mL) / TFA (0.50 mL)中之溶液在室溫下攪拌30 min。將所得混合物在減壓下濃縮。所得混合物用3x3 mL之DCM洗滌。將所得混合物在減壓下濃縮。粗產物藉由具有以下條件(管柱:XBridge Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(10 mmol/L NH 4HCO 3+ 0.05% NH 3.H 2O),移動相B:ACN;流動速率:60 mL/min;梯度:在7min內30% B至55% B;波長:254 nm/220 nm;RT:7.78 min)之製備型HPLC純化,以得到呈白色固體之3-{[3-(8-{[(3S,4R)-3-氟哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-4-甲氧基-N-甲基苯甲醯胺(39.90 mg,47.12%)。LC-MS:(M+H) +實測值550.20。 1H NMR (400 MHz, DMSO- d 6) δ 8.14 (q, J= 4.5 Hz, 1H), 7.84 (t, J= 6.7 Hz, 1H), 7.26 (d, J= 2.1 Hz, 1H), 7.22-7.13 (m, 2H), 6.87 (d, J= 8.3 Hz, 1H), 6.74 (t, J= 7.1 Hz, 1H), 6.14 (d, J= 7.6 Hz, 1H), 5.84 (d, J= 8.2 Hz, 1H), 5.54 (t, J= 6.5 Hz, 1H), 4.71 (d, J= 50.8 Hz, 1H), 4.27 (d, J= 6.4 Hz, 2H), 3.98-3.55 (m, 4H), 3.10 (t, J= 12.3 Hz, 1H), 2.97 (d, J= 13.4 Hz, 1H), 2.96-2.64 (m, 4H), 2.63-2.52 (m, 1H), 1.85-1.68 (m, 1H), 1.65-1.57 (m, 1H)。 實例126. 4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺之合成 步驟1. 4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺之合成 A solution of (3S,4R)-3-fluoro-4-{[2-(3-{[2-methoxy-5-(methylaminocarbonyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizin-8-yl]amino}piperidine-1-carboxylic acid tributyl ester (100.00 mg, 0.15 mmol, 1.00 equiv) in DCM (1.50 mL) / TFA (0.50 mL) was stirred at room temperature for 30 min. The resulting mixture was concentrated under reduced pressure. The resulting mixture was washed with 3x3 mL of DCM. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC with the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 + 0.05% NH 3 .H 2 O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 30% B to 55% B in 7 min; wavelength: 254 nm/220 nm; RT: 7.78 min) to give 3-{[3-(8-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide (39.90 mg, 47.12%) as a white solid. LC-MS: (M+H) + found 550.20. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.14 (q, J = 4.5 Hz, 1H), 7.84 (t, J = 6.7 Hz, 1H), 7.26 (d, J = 2.1 Hz, 1H), 7.22-7.13 (m, 2H), 6.87 (d, J = 8.3 Hz, 1H), 6.74 (t, J = 7.1 Hz, 1H), 6.14 (d, J = 7.6 Hz, 1H), 5.84 (d, J = 8.2 Hz, 1H), 5.54 (t, J = 6.5 Hz, 1H), 4.71 (d, J = 50.8 Hz, 1H), 4.27 (d, J = 6.4 Hz, 2H), 3.98-3.55 (m, 4H), 3.10 (t, J = 12.3 Hz, 1H), 2.97 (d, J = 13.4 Hz, 1H), 2.96-2.64 (m, 4H), 2.63-2.52 (m, 1H), 1.85-1.68 (m, 1H), 1.65-1.57 (m, 1H). Example 126. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide Step 1. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide
在室溫下,向4-[(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺( 中間物58,100.00 mg,0.19 mmol,1.00當量)及(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(60.02 mg,0.29 mmol,1.50當量)於1,4-二噁烷(2.00 mL)中之攪拌溶液中添加Cs 2CO 3(317.97 mg,0.98 mmol,5.00當量)、BINAP (12.15 mg,0.02 mmol,0.10當量)及BINAP-Pd-G3 (19.37 mg,0.02 mmol,0.10當量)。將反應混合物在100℃及氮氣氛圍下攪拌4 h。移除溶劑。殘餘物藉由具有以下條件之反相急速層析純化:管柱,C18;移動相,於水中之MeCN,在20 min內0%至70%梯度;偵測器,UV 254 nm。粗產物藉由具有以下條件(管柱:XBridge Prep OBD C18管柱,30*150 mm,5 μm;移動相A:水(10 mmol/L NH 4HCO 3+ 0.05% NH 3 .H 2O),移動相B:ACN;流動速率:60 mL/min;梯度:在7 min內38% B至63% B;波長:220 nm;RT:7.15 min)之製備型HPLC純化,以得到呈白色固體之4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺(19.60 mg,17.82%)。LC-MS:(M+H) +實測值564.20。 1H NMR (400 MHz, DMSO- d 6) δ 8.11 (d, J= 5.0 Hz, 1H), 7.85 (d, J= 6.9 Hz, 1H), 7.42 (d, J= 8.3 Hz, 1H), 7.34 (s, 1H), 7.20 (s, 1H), 6.76 (t, J= 8.5 Hz, 2H), 6.14 (d, J= 7.6 Hz, 1H), 5.97 (t, J= 6.1 Hz, 1H), 5.86 (d, J= 8.3 Hz, 1H), 4.82 (d, J= 48.8 Hz, 1H), 4.27 (d, J= 6.2 Hz, 2H), 3.84 (s, 3H), 3.58 (d, J= 29.0 Hz, 1H), 3.03 (t, J= 11.2 Hz, 1H), 2.90-2.62 (m, 4H), 2.32-2.18 (m, 4H), 2.17-1.92 (m, 2H), 1.71-1.63 (m, 1H)。 實例132. 3-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-4-甲氧基-N-甲基苯磺醯胺之合成 步驟 1. N-(3-{8- 溴 -3-[( 三氟甲基 ) 硫基 ] 吲嗪 -2- 基 } 丙 -2- 炔 -1- 基 )-4- 甲磺醯基 -2- 甲氧基苯胺之合成 To a stirred solution of 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide ( Intermediate 58 , 100.00 mg, 0.19 mmol, 1.00 equiv) and (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (60.02 mg, 0.29 mmol, 1.50 equiv) in 1,4-dioxane (2.00 mL) at room temperature were added Cs2CO3 ( 317.97 mg, 0.98 mmol, 5.00 equiv), BINAP (12.15 mg, 0.02 mmol, 0.10 equiv) and BINAP-Pd-G3 (19.37 mg, 0.02 mmol, 0.10 equiv). The reaction mixture was stirred at 100 °C under nitrogen atmosphere for 4 h. The solvent was removed. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in water, gradient 0% to 70% in 20 min; detector, UV 254 nm. The crude product was purified by preparative HPLC with the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 + 0.05% NH 3 . H 2 O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 38% B to 63% B in 7 min; wavelength: 220 nm; RT: 7.15 min) to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (19.60 mg, 17.82%) as a white solid. LC-MS: (M+H) + found 564.20. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.11 (d, J = 5.0 Hz, 1H), 7.85 (d, J = 6.9 Hz, 1H), 7.42 (d, J = 8.3 Hz, 1H), 7.34 (s, 1H), 7.20 (s, 1H), 6.76 (t, J = 8.5 Hz, 2H), 6.14 (d, J = 7.6 Hz, 1H), 5.97 (t, J = 6.1 Hz, 1H), 5.86 (d, J = 8.3 Hz, 1H), 4.82 (d, J = 48.8 Hz, 1H), 4.27 (d, J = 6.2 Hz, 2H), 3.84 (s, 3H), 3.58 (d, J = 29.0 Hz, 1H), 3.03 (t, J = 11.2 Hz, 1H), 2.90-2.62 (m, 4H), 2.32-2.18 (m, 4H), 2.17-1.92 (m, 2H), 1.71-1.63 (m, 1H). Example 132. Synthesis of 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzenesulfonamide Step 1. Synthesis of N-(3-{8- bromo -3-[( trifluoromethyl ) thio ] indolizin -2- yl } prop -2- yn -1 - yl )-4 -methanesulfonyl -2- methoxyaniline
在室溫及氮氣氛圍下,向8-溴-2-(3-溴丙-1-炔-1-基)-3-[(三氟甲基)硫基]吲嗪( 中間物57,300.00 mg,0.73 mmol,1.00當量)及N-{2-甲氧基-5-[甲基({[2-(三甲基矽烷基)乙氧基]甲基})胺磺醯基]苯基}胺基甲酸三級丁酯( 中間物60,324.39 mg,0.73 mmol,1.00當量)於DMF (10.00 mL)中之攪拌溶液中逐份添加Cs 2CO 3(165.88 mg,2.17 mmol,3.00當量)。將所得混合物在70℃及氮氣氛圍下攪拌1 h。所得混合物用EtOAc (50.00 mL)萃取。合併的有機層用鹽水(3 x 10.00 mL)洗滌且經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物使用具有以下條件(移動相A:水,移動相B:ACN;流動速率:60 mL/min;梯度:在15 min內0% B至100% B;波長:254 nm;220 nm)之C18急速層析純化。此產生呈黃色油狀物之N-(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)-N-{2-甲氧基-5-[甲基({[2-(三甲基矽烷基)乙氧基]甲基})胺磺醯基]苯基}胺基甲酸三級丁酯(350.00 mg,61.9%)。LC-MS:(M+H) +實測值778.12。 步驟2. N-[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]-N-{2-甲氧基-5-[甲基({[2-(三甲基矽烷基)乙氧基]甲基})胺磺醯基]苯基}胺基甲酸三級丁酯之合成 To a stirred solution of 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizine ( Intermediate 57 , 300.00 mg, 0.73 mmol, 1.00 equiv) and tert-butyl N-{2-methoxy-5-[methyl({[2-(trimethylsilyl)ethoxy]methyl})sulfamoyl]phenyl}carbamate ( Intermediate 60 , 324.39 mg, 0.73 mmol, 1.00 equiv) in DMF (10.00 mL) was added Cs2CO3 ( 165.88 mg, 2.17 mmol, 3.00 equiv) portionwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 70 °C under nitrogen atmosphere for 1 h. The resulting mixture was extracted with EtOAc (50.00 mL). The combined organic layers were washed with brine (3 x 10.00 mL) and dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified using C18 flash chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 15 min; wavelength: 254 nm; 220 nm). This resulted in tributyl N-(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)-N-{2-methoxy-5-[methyl({[2-(trimethylsilyl)ethoxy]methyl})sulfamoyl]phenyl}carbamate (350.00 mg, 61.9%) as a yellow oil. LC-MS: (M+H) + found 778.12. Step 2. Synthesis of tributyl N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]-N-{2-methoxy-5-[methyl({[2-(trimethylsilyl)ethoxy]methyl})sulfamoyl]phenyl}carbamate
在室溫及氮氣氛圍下,向N-(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)-N-{2-甲氧基-5-[甲基({[2-(三甲基矽烷基)乙氧基]甲基})胺磺醯基]苯基}胺基甲酸三級丁酯(300.00 mg,0.39 mmol,1.00當量)、Cs 2CO 3(627.56 mg,1.92 mmol,5.00當量)及(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(158.02 mg,0.77 mmol,2.00當量)於二噁烷(10.00 mL)中之攪拌混合物中逐份添加BINAP (95.95 mg,0.15 mmol,0.40當量)及BINAP-Pd-G3 (76.46 mg,0.07 mmol,0.20當量)。將所得混合物在100℃及氮氣氛圍下攪拌4 h。所得混合物用EtOAc (50.00 mL)萃取。過濾所得混合物且濾餅用EtOAc (2 x 50.00 mL)洗滌。合併的有機層用水(3 x 50.00 mL)洗滌且經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物使用具有以下條件(移動相A:水,移動相B:ACN;流動速率:60 mL/min;梯度:在15 min內0% B至100% B;波長:254 nm;220 nm)之C18急速層析純化。此產生呈黃色固體之N-[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]-N-{2-甲氧基-5-[甲基({[2-(三甲基矽烷基)乙氧基]甲基})胺磺醯基]苯基}胺基甲酸三級丁酯(200.00 mg,62.5%)。LC-MS:(M+H) +實測值830.30。 步驟3. 3-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-4-甲氧基-N-甲基苯磺醯胺之合成 To a stirred mixture of N-(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)-N-{2-methoxy-5-[methyl({[2-(trimethylsilyl)ethoxy]methyl})sulfamoyl]phenyl} carbamate (300.00 mg, 0.39 mmol, 1.00 equiv), Cs2CO3 (627.56 mg, 1.92 mmol, 5.00 equiv) and (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (158.02 mg, 0.77 mmol, 2.00 equiv) in dioxane (10.00 mL) was added BINAP (95.95 mg, 0.15 mmol, 0.40 equiv) and BINAP-Pd-G3 (76.46 mg, 0.07 mmol, 0.20 equiv). The resulting mixture was stirred at 100 °C under nitrogen atmosphere for 4 h. The resulting mixture was extracted with EtOAc (50.00 mL). The resulting mixture was filtered and the filter cake was washed with EtOAc (2 x 50.00 mL). The combined organic layer was washed with water (3 x 50.00 mL) and dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by C18 flash chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 15 min; wavelength: 254 nm; 220 nm). This yielded tributyl N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]-N-{2-methoxy-5-[methyl({[2-(trimethylsilyl)ethoxy]methyl})sulfamoyl]phenyl}carbamate (200.00 mg, 62.5%) as a yellow solid. LC-MS: (M+H) + found 830.30. Step 3. Synthesis of 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzenesulfonamide
將N-[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]-N-{2-甲氧基-5-[甲基({[2-(三甲基矽烷基)乙氧基]甲基})胺磺醯基]苯基}胺基甲酸三級丁酯(100.00 mg,0.12 mmol,1.00當量)於HCl (4M於MeOH中,10.00 mL)中之混合物在70℃下攪拌0.5 h。用飽和NaHCO 3(水溶液)將混合物中和至pH 7。過濾所得混合物且濾餅用MeOH (3 x 10.00 mL)洗滌。將濾液在減壓下濃縮。粗物質藉由具有以下條件(管柱:Sunfire prep C18管柱;移動相A:水(0.1% FA),移動相B:ACN;流動速率:60 mL/min;梯度:在15 min內0% B至100% B;波長:254 nm;220 nm)之製備型HPLC純化,以得到呈白色固體之3-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-4-甲氧基-N-甲基苯磺醯胺(12.8 mg,17.7%)。LC-MS:(M+H) +實測值600.20。 1H NMR (400 MHz, DMSO- d 6) δ 7.84 (d, J= 6.8 Hz, 1H), 7.17 (d, J= 0.9 Hz, 1H), 7.14-7.03 (m, 3H), 7.00 (d, J= 8.3 Hz, 1H), 6.75 (t, J= 7.2 Hz, 1H), 6.14 (d, J= 7.6 Hz, 1H), 5.92 (t, J= 6.3 Hz, 1H), 5.81 (d, J= 8.3 Hz, 1H), 4.88-4.76 (m, 1H), 4.26 (d, J= 6.3 Hz, 2H), 3.88 (s, 3H), 3.67-3.50 (m, 1H), 3.02 (t, J= 11.2 Hz, 1H), 2.80 (d, J= 10.8 Hz, 1H), 2.34 (d, J= 5.1 Hz, 3H), 2.30-2.14 (m, 4H), 2.13-1.92 (m, 2H), 1.68 (d, J= 12.0 Hz, 1H)。 實例135. 4-[(3-{3-[(二氟甲基)硫基]-8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}吲嗪-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺之合成 步驟 1. 4-[(3-{8- 溴 -3-[( 二氟甲基 ) 硫基 ] 吲嗪 -2- 基 } 丙 -2- 炔 -1- 基 ) 胺基 ]-3- 甲氧基 -N- 甲基苯甲醯胺之合成 A mixture of tributyl N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]-N-{2-methoxy-5-[methyl({[2-(trimethylsilyl)ethoxy]methyl})sulfamoyl]phenyl}carbamate (100.00 mg, 0.12 mmol, 1.00 equiv) in HCl (4M in MeOH, 10.00 mL) was stirred at 70 °C for 0.5 h. The mixture was neutralized to pH 7 with saturated NaHCO3 (aq). The resulting mixture was filtered and the filter cake was washed with MeOH (3 x 10.00 mL). The filtrate was concentrated under reduced pressure. The crude material was purified by preparative HPLC with the following conditions (column: Sunfire prep C18 column; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 15 min; wavelength: 254 nm; 220 nm) to give 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzenesulfonamide (12.8 mg, 17.7%) as a white solid. LC-MS: (M+H) + found 600.20. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.84 (d, J = 6.8 Hz, 1H), 7.17 (d, J = 0.9 Hz, 1H), 7.14-7.03 (m, 3H), 7.00 (d, J = 8.3 Hz, 1H), 6.75 (t, J = 7.2 Hz, 1H), 6.14 (d, J = 7.6 Hz, 1H), 5.92 (t, J = 6.3 Hz, 1H), 5.81 (d, J = 8.3 Hz, 1H), 4.88-4.76 (m, 1H), 4.26 (d, J = 6.3 Hz, 2H), 3.88 (s, 3H), 3.67-3.50 (m, 1H), 3.02 (t, J = 11.2 Hz, 1H), 2.80 (d, J = 10.8 Hz, 1H), 2.34 (d, J = 5.1 Hz, 3H), 2.30-2.14 (m, 4H), 2.13-1.92 (m, 2H), 1.68 (d, J = 12.0 Hz, 1H). Example 135. Synthesis of 4-[(3-{3-[(difluoromethyl)thio]-8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}indolizin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide Step 1. Synthesis of 4-[(3-{8- bromo -3-[( difluoromethyl ) thio ] indolizin -2- yl } prop -2- yn - 1 - yl ) amino ]-3 - methoxy -N- methylbenzamide
向8-溴-2-(3-溴丙-1-炔-1-基)-3-[(二氟甲基)硫基]吲嗪( 中間物64,350.00 mg,0.89 mmol,1.00當量)及4-胺基-3-甲氧基-N-甲基苯甲醯胺(159.65 mg,0.89 mmol,1.00當量)於DMF (5.00 mL)中之攪拌溶液中添加K 2CO 3(367.32 mg,2.66 mmol,3.00當量)。將反應混合物在70℃下攪拌1 h。所得溶液藉由具有以下條件之反相急速層析純化:管柱,C18;移動相,於水中之MeCN,在10 min內0%至60%梯度;偵測器,UV 254 nm。此產生呈淺黃色固體之4-[(3-{8-溴-3-[(二氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺(220.00 mg,50.23%)。LC-MS:(M+H) +實測值494.00。 步驟2. 4-[(3-{3-[(二氟甲基)硫基]-8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}吲嗪-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺之合成 To a stirred solution of 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(difluoromethyl)thio]indolizine ( intermediate 64 , 350.00 mg, 0.89 mmol, 1.00 equiv) and 4-amino- 3 -methoxy-N-methylbenzamide (159.65 mg, 0.89 mmol, 1.00 equiv) in DMF (5.00 mL) was added K2CO3 (367.32 mg, 2.66 mmol, 3.00 equiv). The reaction mixture was stirred at 70 °C for 1 h. The resulting solution was purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in water, gradient from 0% to 60% in 10 min; detector, UV 254 nm. This produced 4-[(3-{8-bromo-3-[(difluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (220.00 mg, 50.23%) as a light yellow solid. LC-MS: (M+H) + found 494.00. Step 2. Synthesis of 4-[(3-{3-[(difluoromethyl)thio]-8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}indolizin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide
向4-[(3-{8-溴-3-[(二氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺(200.00 mg,0.40 mmol,1.00當量)及(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(124.26 mg,0.61 mmol,1.50當量)於1,4-二噁烷(3.00 mL)中之攪拌溶液中添加BINAP (25.20 mg,0.04 mmol,0.10當量)、BINAP-Pd-G3 (40.16 mg,0.04 mmol,0.10當量)及Cs 2CO 3(658.08 mg,2.02 mmol,5.00當量)。將所得混合物在100℃及氮氣氛圍下攪拌5 h。在真空下移除溶劑。殘餘物藉由具有以下條件之反相急速層析純化:管柱,C18;移動相,於水中之ACN (0.1% FA),在15 min內0%至30%梯度;偵測器,UV 254 nm。粗產物藉由具有以下條件(管柱:XBridge Prep OBD C18管柱,30*150 mm,5 μm;移動相A:水(10 mmol/L NH 4HCO 3+ 0.05% NH 3.H 2O),移動相B:ACN;流動速率:60 mL/min;梯度:在7 min內31% B至58% B;波長:254nm/220nm;RT:7.5 min)之製備型HPLC純化,以得到呈白色固體之4-[(3-{3-[(二氟甲基)硫基]-8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}吲嗪-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺(76.1 mg,34.48%)。LC-MS:(M+H) +實測值546.40。 1H NMR (400 MHz, DMSO- d 6) δ 8.08 (d, J= 4.8 Hz, 1H), 7.79 (d, J= 6.9 Hz, 1H), 7.41 (dd, J= 8.3, 1.9 Hz, 1H), 7.33 (d, J= 1.8 Hz, 1H), 7.29-6.93 (m, 2H), 6.77 (d, J= 8.3 Hz, 1H), 6.67 (t, J= 7.2 Hz, 1H), 6.05 (d, J= 7.6 Hz, 1H), 5.91 (t, J= 6.1 Hz, 1H), 5.73 (d, J= 8.3 Hz, 1H), 4.82 (d, J= 49.6 Hz, 1H), 4.25 (d, J= 6.1 Hz, 2H), 3.84 (s, 3H), 3.57 (d, J= 29.6 Hz, 1H), 3.10-2.95 (m, 1H), 2.80 (d, J= 10.8 Hz, 1H), 2.75 (d, J= 4.4 Hz, 3H), 2.34-2.18 (m, 4H), 2.16-1.89 (m, 2H), 1.67 (d, J= 11.9 Hz, 1H)。 實例139. 4-{[3-(5-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-1-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺之合成 步驟 1. 4-[(3-{5- 氯 -1-[( 三氟甲基 ) 硫基 ] 吲嗪 -2- 基 } 丙 -2- 炔 -1- 基 ) 胺基 ]-3- 甲氧基 -N- 甲基苯甲醯胺之合成 To a stirred solution of 4-[(3-{8-bromo-3-[(difluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (200.00 mg, 0.40 mmol, 1.00 equiv) and (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (124.26 mg, 0.61 mmol, 1.50 equiv) in 1,4-dioxane (3.00 mL) was added BINAP (25.20 mg, 0.04 mmol, 0.10 equiv), BINAP-Pd-G3 (40.16 mg, 0.04 mmol, 0.10 equiv) and Cs2CO3 ( 658.08 mg, 2.02 mmol, 5.00 equiv). The resulting mixture was stirred at 100 °C under nitrogen atmosphere for 5 h. The solvent was removed under vacuum. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, ACN (0.1% FA) in water, gradient from 0% to 30% in 15 min; detector, UV 254 nm. The crude product was purified by preparative HPLC with the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 + 0.05% NH 3 .H 2 O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 31% B to 58% B in 7 min; wavelength: 254 nm/220 nm; RT: 7.5 min) to give 4-[(3-{3-[(difluoromethyl)thio]-8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}indolizin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (76.1 mg, 34.48%). LC-MS: (M+H) + found 546.40. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.08 (d, J = 4.8 Hz, 1H), 7.79 (d, J = 6.9 Hz, 1H), 7.41 (dd, J = 8.3, 1.9 Hz, 1H), 7.33 (d, J = 1.8 Hz, 1H), 7.29-6.93 (m, 2H), 6.77 (d, J = 8.3 Hz, 1H), 6.67 (t, J = 7.2 Hz, 1H), 6.05 (d, J = 7.6 Hz, 1H), 5.91 (t, J = 6.1 Hz, 1H), 5.73 (d, J = 8.3 Hz, 1H), 4.82 (d, J = 3H), 4.25 (d, J = 6.1 Hz, 2H), 3.84 (s, 3H), 3.57 (d, J = 29.6 Hz, 1H), 3.10-2.95 (m, 1H), 2.80 (d, J = 10.8 Hz, 1H), 2.75 (d, J = 4.4 Hz, 3H), 2.34-2.18 (m, 4H), 2.16-1.89 (m, 2H), 1.67 (d, J = 11.9 Hz, 1H). Example 139. Synthesis of 4-{[3-(5-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-1-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide Step 1. Synthesis of 4-[(3-{5- chloro -1-[( trifluoromethyl ) thio ] indolizin -2- yl } prop -2- yn - 1 - yl ) amino ]-3- methoxy -N- methylbenzamide
在室溫及氮氣氛圍下,向2-(3-溴丙-1-炔-1-基)-5-氯-1-[(三氟甲基)硫基]吲嗪( 中間物68,120 mg,0.326 mmol,1當量)於DMF (1.2 mL)中之攪拌溶液中逐份添加4-胺基-3-甲氧基-N-甲基苯甲醯胺(70.40 mg,0.391 mmol,1.2當量)及K 2CO 3(89.99 mg,0.652 mmol,2當量)。將所得混合物在70℃及氮氣氛圍下攪拌1h。藉由LCMS監測反應。可藉由LCMS偵測所需產物。使混合物冷卻至室溫。藉由在0℃下添加水(2 mL)來淬滅反應。所得混合物用CH 2Cl 2/ MeOH 10:1 (3 x 5mL)萃取。合併的有機層用鹽水(3x5 mL)洗滌、經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/ MeOH 10:1)純化,以得到呈黃色固體之4-[(3-{5-氯-1-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺(105 mg,68.93%)。LC-MS:(M+H) +實測值468。 步驟2. 4-{[3-(5-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-1-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺之合成 To a stirred solution of 2-(3-bromoprop-1-yn-1-yl)-5-chloro-1-[(trifluoromethyl)thio]indolizine ( intermediate 68 , 120 mg, 0.326 mmol, 1 eq) in DMF (1.2 mL) was added 4-amino-3-methoxy-N-methylbenzamide (70.40 mg, 0.391 mmol, 1.2 eq) and K2CO3 ( 89.99 mg, 0.652 mmol, 2 eq) portionwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 70°C under nitrogen atmosphere for 1 h. The reaction was monitored by LCMS. The desired product could be detected by LCMS. The mixture was cooled to room temperature. The reaction was quenched by the addition of water (2 mL) at 0°C. The resulting mixture was extracted with CH 2 Cl 2 / MeOH 10:1 (3 x 5 mL). The combined organic layers were washed with brine (3x5 mL), dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 / MeOH 10:1) to give 4-[(3-{5-chloro-1-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (105 mg, 68.93%) as a yellow solid. LC-MS: (M+H) + found 468. Step 2. Synthesis of 4-{[3-(5-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-1-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide
將4-[(3-{5-氯-1-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺(105 mg,0.224 mmol,1當量)及Cs 2CO 3(365 mg,1.120 mmol,5當量)於二噁烷(1 mL)中之混合物在80℃及氮氣氛圍下攪拌隔夜。藉由LCMS監測反應。可藉由LCMS偵測所需產物。使混合物冷卻至室溫。在0℃下用水淬滅反應。所得混合物用CH 2Cl 2/ MeOH 10:1 (3 x 5mL)萃取。合併的有機層用鹽水(3x5 mL)洗滌、經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/ MeOH 10:1)純化,以得到呈棕色固體之4-{[3-(5-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-1-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺(33.1 mg,25.25%)。LC-MS:(M+H) +實測值564.30。 1H NMR (400 MHz, DMSO- d 6) δ 8.18 (s, 1H), 8.09 (t, J= 4.6 Hz, 1H), 7.41 (dd, J= 8.3, 1.9 Hz, 1H), 7.34 (d, J= 1.9 Hz, 1H), 7.11 (dd, J= 8.8, 7.5 Hz, 1H), 6.96 (d, J= 8.8 Hz, 1H), 6.76 (d, J= 8.3 Hz, 1H), 6.37 (d, J= 7.8 Hz, 1H), 6.11 (d, J= 7.5 Hz, 1H), 5.94 (t, J= 6.2 Hz, 1H), 4.87 (d, J= 49.4 Hz, 1H), 4.28 (d, J= 6.1 Hz, 2H), 3.84 (s, 4H), 3.07 (s, 1H), 2.85 (s, 1H), 2.77 – 2.65 (m, 3H), 2.33 (m, 3H), 2.09 (d, J= 11.3 Hz, 2H), 1.73 (d, J= 9.9 Hz, 1H)。 實例154. 3-{[3-(6- 氟-8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-4-甲氧基-N-甲基苯甲醯胺之合成 步驟1. 8-溴-6-氟咪唑并[1,2-a]吡啶-2-甲酸乙酯之合成 A mixture of 4-[(3-{5-chloro-1-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (105 mg, 0.224 mmol, 1 eq) and Cs 2 CO 3 (365 mg, 1.120 mmol, 5 eq) in dioxane (1 mL) was stirred at 80 °C under nitrogen atmosphere overnight. The reaction was monitored by LCMS. The desired product could be detected by LCMS. The mixture was cooled to room temperature. The reaction was quenched with water at 0 °C. The resulting mixture was extracted with CH 2 Cl 2 / MeOH 10:1 (3 x 5 mL). The combined organic layers were washed with brine (3 x 5 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 / MeOH 10:1) to give 4-{[3-(5-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-1-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (33.1 mg, 25.25%) as a brown solid. LC-MS: (M+H) + found 564.30. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.18 (s, 1H), 8.09 (t, J = 4.6 Hz, 1H), 7.41 (dd, J = 8.3, 1.9 Hz, 1H), 7.34 (d, J = 1.9 Hz, 1H), 7.11 (dd, J = 8.8, 7.5 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H), 6.76 (d, J = 8.3 Hz, 1H), 6.37 (d, J = 7.8 Hz, 1H), 6.11 (d, J = 7.5 Hz, 1H), 5.94 (t, J = 6.2 Hz, 1H), 4.87 (d, J = 49.4 Hz, 1H), 4.28 (d, J = 6.1 Hz, 2H), 3.84 (s, 4H), 3.07 (s, 1H), 2.85 (s, 1H), 2.77 – 2.65 (m, 3H), 2.33 (m, 3H), 2.09 (d, J = 11.3 Hz, 2H), 1.73 (d, J = 9.9 Hz, 1H). Example 154. Synthesis of 3-{[3-(6- fluoro-8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide Step 1. Synthesis of 8-bromo-6-fluoroimidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester
在室溫及空氣氛圍下,向3-溴-5-氟吡啶-2-胺(5.00 g,26.17 mmol,1.00當量)於(20 mL)中之攪拌溶液中添加NaHCO 3(4.40 g,52.35 mmol,2.00當量)及3-溴-2-側氧基丙酸乙酯(10.21 g,52.35 mmol,2.00當量)。將所得混合物在100℃及空氣氛圍下攪拌2 h。所得混合物用EtOAc (3 x 15 mL)萃取。合併的有機層用鹽水洗滌,經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由具有以下條件之反相急速層析純化:管柱,C18矽膠;移動相,於水中之MeCN (10mmol/L NH 4HCO 3),在10 min內10%至50%梯度;偵測器,UV 254 nm。此產生呈淺黃色固體之8-溴-6-氟咪唑并[1,2-a]吡啶-2-甲酸乙酯(5.3 g,70.52%)。LC-MS:(M+H) +實測值:287。 步驟2. 8-溴-6-氟-3-碘咪唑并[1,2-a]吡啶-2-甲酸乙酯之合成 To a stirred solution of 3-bromo-5-fluoropyridin-2-amine (5.00 g, 26.17 mmol, 1.00 equiv) in (20 mL) were added NaHCO 3 (4.40 g, 52.35 mmol, 2.00 equiv) and ethyl 3-bromo-2-oxopropanoate (10.21 g, 52.35 mmol, 2.00 equiv) at room temperature under air atmosphere. The resulting mixture was stirred at 100 °C under air atmosphere for 2 h. The resulting mixture was extracted with EtOAc (3 x 15 mL). The combined organic layer was washed with brine and dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH 4 HCO 3 ) in water, gradient 10% to 50% in 10 min; detector, UV 254 nm. This yielded ethyl 8-bromo-6-fluoroimidazo[1,2-a]pyridine-2-carboxylate (5.3 g, 70.52%) as a light yellow solid. LC-MS: (M+H) + found: 287. Step 2. Synthesis of ethyl 8-bromo-6-fluoro-3-iodoimidazo[1,2-a]pyridine-2-carboxylate
在室溫及空氣氛圍下,向8-溴-6-氟咪唑并[1,2-a]吡啶-2-甲酸乙酯(6.40 g,22.29 mmol,1.00當量)於MeCN (60 mL)中之攪拌溶液中添加NIS (10.03 g,44.58 mmol,2.00當量)。將所得混合物在80℃及空氣氛圍下攪拌1 h。所得混合物用EtOAc (3 x 10 mL)萃取。合併的有機層用鹽水洗滌,經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由具有以下條件之反相急速層析純化:管柱,C18矽膠;移動相,於水中之MeCN (10mmol/L NH 4HCO 3),在10 min內10%至50%梯度;偵測器,UV 254 nm。此產生呈淺黃色固體之8-溴-6-氟-3-碘咪唑并[1,2-a]吡啶-2-甲酸乙酯(2.9 g,31.50%)。LC-MS:(M+H) +實測值:413。 步驟3. 8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-甲酸酯之合成 To a stirred solution of ethyl 8-bromo-6-fluoroimidazo[1,2-a]pyridine-2-carboxylate (6.40 g, 22.29 mmol, 1.00 equiv) in MeCN (60 mL) was added NIS (10.03 g, 44.58 mmol, 2.00 equiv) at room temperature under air atmosphere. The resulting mixture was stirred at 80 °C under air atmosphere for 1 h. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine and dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH 4 HCO 3 ) in water, gradient 10% to 50% in 10 min; detector, UV 254 nm. This yielded ethyl 8-bromo-6-fluoro-3-iodoimidazo[1,2-a]pyridine-2-carboxylate (2.9 g, 31.50%) as a light yellow solid. LC-MS: (M+H) + found: 413. Step 3. Synthesis of 8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine-2-carboxylate
在-30℃及氮氣氛圍下,向[(三氟甲基)硫基]銀(2.70 g,12.90 mmol,1.90當量)及碘化銅(I) (2.57 g,13.46 mmol,1.90當量)於ACN (20 mL)中之攪拌混合物中逐滴添加。將所得混合物在-30℃及氮氣氛圍下攪拌2 h。將所得混合物在室溫及氮氣氛圍下攪拌3 h。在室溫下,向上述混合物中添加於DMF (10 mL)中之8-溴-3-碘咪唑并[1,2-a]吡啶-2-甲酸乙酯(2.80g,7.08 mmol,1.00當量)及1,10-啡啉(140.52 mg,0.78 mmol,0.11當量)。將所得混合物在60℃下攪拌16 h。所得混合物用EtOAc (3 x 20 mL)萃取。合併的有機層用鹽水洗滌。殘餘物藉由矽膠管柱層析純化,用PE / EA (5:1)溶析,以得到呈黃色固體之8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-甲酸乙酯(600 mg,22.93%)。LC-MS:(M+H +)實測值:387。 步驟4. 8-溴-6-氟-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-甲酸之合成 To a stirred mixture of [(trifluoromethyl)thio]silver (2.70 g, 12.90 mmol, 1.90 equiv) and copper(I) iodide (2.57 g, 13.46 mmol, 1.90 equiv) in ACN (20 mL) was added dropwise at -30 °C under nitrogen atmosphere. The resulting mixture was stirred at -30 °C under nitrogen atmosphere for 2 h. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 3 h. To the above mixture was added ethyl 8-bromo-3-iodoimidazo[1,2-a]pyridine-2-carboxylate (2.80 g, 7.08 mmol, 1.00 equiv) and 1,10-phenanthroline (140.52 mg, 0.78 mmol, 0.11 equiv) in DMF (10 mL) at room temperature. The resulting mixture was stirred at 60 °C for 16 h. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine. The residue was purified by silica gel column chromatography and eluted with PE/EA (5:1) to give 8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (600 mg, 22.93%) as a yellow solid. LC-MS: (M+H + ) found: 387. Step 4. Synthesis of 8-bromo-6-fluoro-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine-2-carboxylic acid
在室溫及空氣氛圍下,向8-溴-6-氟-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-甲酸乙酯(550 mg,1.42 mmol,1.00當量)及鋰醇(lithiumol) (51 mg,2.13 mmol,1.50當量)於H 2O (3 mL)中之攪拌溶液中添加鋰醇(51mg,2.13 mmol,1.50當量)及水(39 mg,2.13 mmol,1.5當量)。將所得混合物在室溫及空氣氛圍下攪拌30 min。將所得混合物在減壓下濃縮。用濃HCl將混合物酸化至pH 6。所得混合物用EtOAc (3 x 10 mL)萃取。合併的有機層用鹽水洗滌,經無水Na2SO4乾燥。過濾之後,將濾液在減壓下濃縮。此產生呈灰白色固體之8-溴-6-氟-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-甲酸(470 mg,92.13%)。LC-MS:(M+H) +實測值:359。 步驟5. 8-溴-6-氟-2-碘-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶之合成 To a stirred solution of ethyl 8-bromo-6-fluoro-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine-2-carboxylate (550 mg, 1.42 mmol, 1.00 equiv) and lithiumol (51 mg, 2.13 mmol, 1.50 equiv) in H 2 O (3 mL) at room temperature under air atmosphere were added lithiumol (51 mg, 2.13 mmol, 1.50 equiv) and water (39 mg, 2.13 mmol, 1.5 equiv). The resulting mixture was stirred at room temperature under air atmosphere for 30 min. The resulting mixture was concentrated under reduced pressure. The mixture was acidified to pH 6 with concentrated HCl. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This gave 8-bromo-6-fluoro-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine-2-carboxylic acid (470 mg, 92.13%) as an off-white solid. LC-MS: (M+H) + found: 359. Step 5. Synthesis of 8-bromo-6-fluoro-2-iodo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine
在室溫及空氣氛圍下,向8-溴-6-氟-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-甲酸(460 mg,1.28 mmol,1.00當量)於DMSO (5 mL)中之攪拌溶液中添加I2 (650 mg,2.56 mmol,2.00當量)及K 3PO 4(544 mg,2.56 mmol,2.00當量)。將所得混合物在150℃及空氣氛圍下攪拌1 h。所得混合物用EtOAc (3 x 15 mL)萃取。合併的有機層用鹽水洗滌,經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由具有以下條件之反相急速層析純化:管柱,C18矽膠;移動相,於水中之MeCN (10mmol/L NH 4HCO 3),在10 min內10%至50%梯度;偵測器,UV 254 nm。此產生呈淺黃色固體之8-溴-6-氟-2-碘-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶(220 mg,38.94%)。LC-MS:(M+H +)實測值:441。 步驟6. 3-[(3-{8-溴-6-氟-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-4-甲氧基-N-甲基苯甲醯胺之合成 To a stirred solution of 8-bromo-6-fluoro-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine-2-carboxylic acid (460 mg, 1.28 mmol, 1.00 equiv) in DMSO (5 mL) at room temperature under air atmosphere, I2 (650 mg, 2.56 mmol, 2.00 equiv) and K 3 PO 4 (544 mg, 2.56 mmol, 2.00 equiv) were added. The resulting mixture was stirred at 150 °C under air atmosphere for 1 h. The resulting mixture was extracted with EtOAc (3 x 15 mL). The combined organic layer was washed with brine and dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH 4 HCO 3 ) in water, gradient 10% to 50% in 10 min; detector, UV 254 nm. This yielded 8-bromo-6-fluoro-2-iodo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine (220 mg, 38.94%) as a light yellow solid. LC-MS: (M+H + ) found: 441. Step 6. Synthesis of 3-[(3-{8-bromo-6-fluoro-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-4-methoxy-N-methylbenzamide
將8-溴-6-氟-2-碘-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶(200 mg,0.45 mmol,1.00當量)、4-甲氧基-N-甲基-3-(丙-2-炔-1-基胺基)苯甲醯胺(44.54 mg,0.20 mmol,0.45當量)、i-Pr 2NH (230 mg,2.27 mmol,5.00當量)、CuI (17 mg,0.09 mmol,0.20當量)及Pd(PPh 3) 4(52 mg,0.04 mmol,0.10當量)於DMSO (4 mL)中之混合物在室溫及氮氣氛圍下攪拌1 h。在室溫下用水淬滅反應。所得混合物用EtOAc (3 x 50 mL)萃取。合併的有機層用鹽水(2x50 mL)洗滌,經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/ MeOH 35:1)純化,以得到呈黃色固體之3-[(3-{8-溴-6-氟-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-4-甲氧基-N-甲基苯甲醯胺(100 mg,39.76%)。LC-MS:(M+H) +實測值:531。 步驟6. 3-{[3-(6-氟-8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-4-甲氧基-N-甲基苯甲醯胺之合成 A mixture of 8-bromo-6-fluoro-2-iodo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine (200 mg, 0.45 mmol, 1.00 equiv), 4-methoxy-N-methyl-3-(prop-2-yn-1-ylamino)benzamide (44.54 mg, 0.20 mmol, 0.45 equiv), i-Pr 2 NH (230 mg, 2.27 mmol, 5.00 equiv), CuI (17 mg, 0.09 mmol, 0.20 equiv) and Pd(PPh 3 ) 4 (52 mg, 0.04 mmol, 0.10 equiv) in DMSO (4 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine ( 2x50 mL) and dried over anhydrous Na2SO4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC ( CH2Cl2 /MeOH 35:1) to give 3-[(3-{8-bromo-6-fluoro-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-4-methoxy-N-methylbenzamide (100 mg, 39.76%) as a yellow solid. LC-MS: (M+H) + found: 531. Step 6. Synthesis of 3-{[3-(6-fluoro-8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide
將3-[(3-{8-溴-6-氟-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-4-甲氧基-N-甲基苯甲醯胺(95 mg,0.17 mmol,1.00當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(55 mg,0.27 mmol,1.50當量)、Cs 2CO 3(291 mg,0.90 mmol,5.00當量)、BINAP (45 mg,0.07 mmol,0.40當量)及[2'-(二苯基磷烷基)-[1,1'-聯苯]-2-基]二苯基磷烷基;{2'-胺基-[1,1'-聯苯]-2-基}甲磺酸鈀(36 mg,0.03 mmol,0.20當量)於二噁烷(3 mL)中之混合物在100℃及氮氣氛圍下攪拌隔夜。在室溫下用水淬滅反應。所得混合物用EtOAc (3 x 50mL)萃取。合併的有機層用鹽水(2x50 mL)洗滌,經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。粗產物藉由具有以下條件(管柱:X-Select Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(0.1%FA),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在7 min內30% B至50% B;波長:254nm/220nm nm;RT1(min):6.56)之製備型HPLC純化,以得到呈灰白色固體之3-{[3-(6-氟-8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-4-甲氧基-N-甲基苯甲醯胺(14.2 mg,13.59%)。LC-MS:(M+H) +實測值:583.05。 1H NMR (400 MHz, DMSO-d6) δ 8.15 (t, J = 4.5 Hz, 1H), 7.99 (s, J = 4.1 Hz, 1H), 7.24 (d, J = 2.1 Hz, 1H), 7.17 (s, J = 8.3, 2.1 Hz, 1H), 6.89 (d, J = 8.3 Hz, 1H), 6.74 (dd, J = 2.1 Hz, 1H), 6.11 (d, J = 8.9 Hz, 1H), 5.62 (t, J = 6.6 Hz, 1H), 4.89- 4.77 (m, 1H), 4.31 (d, J = 6.5 Hz, 2H), 3.85 (s, 3H), 3.80-3.73 (m, 1H), 3.03 (t, J = 11.4 Hz, 1H), 2.75 (s, 4H), 2.23 (s, 4H), 2.10 (t, J = 11.5 Hz, 1H), 1.95 (qd, J = 12.0, 3.7 Hz, 1H), 1.74 (d, J = 11.5 Hz, 1H)。 實例155. 4-{[3-(1-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-6-[(三氟甲基)硫基]吡咯并[1,2-a]吡嗪-7-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺;甲酸之合成 步驟1. 7-溴-1-氯-6-[(三氟甲基)硫基]吡咯并[1,2-a]吡嗪之合成 3-[(3-{8-bromo-6-fluoro-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-4-methoxy-N-methylbenzamide (95 mg, 0.17 mmol, 1.00 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (55 mg, 0.27 mmol, 1.50 equiv), Cs 2 CO 3 (291 mg, 0.90 mmol, 5.00 equiv), BINAP (45 mg, 0.07 A mixture of 2-(4-(2-(4-phenyl)-1-nitro-2-yl)-4-nitro-2-ol (30 mg, 0.20 equiv) and [2'-(diphenylphosphani)-[1,1'-biphenyl]-2-yl]diphenylphosphani;{2'-amino-[1,1'-biphenyl]-2-yl}methanesulfonate (36 mg, 0.03 mmol, 0.20 equiv) in dioxane (3 mL) was stirred at 100 °C under nitrogen atmosphere overnight. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL) and dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC with the following conditions (column: X-Select Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 30% B to 50% B in 7 min; wavelength: 254 nm/220 nm nm; RT1(min): 6.56) to give 3-{[3-(6-fluoro-8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide (14.2 mg, 13.59%) as an off-white solid. LC-MS: (M+H) + found: 583.05. 1 H NMR (400 MHz, DMSO-d6) δ 8.15 (t, J = 4.5 Hz, 1H), 7.99 (s, J = 4.1 Hz, 1H), 7.24 (d, J = 2.1 Hz, 1H), 7.17 (s, J = 8.3, 2.1 Hz, 1H), 6.89 (d, J = 8.3 Hz, 1H), 6.74 (dd, J = 2.1 Hz, 1H), 6.11 (d, J = 8.9 Hz, 1H), 5.62 (t, J = 6.6 Hz, 1H), 4.89- 4.77 (m, 1H), 4.31 (d, J = 6.5 Hz, 2H), 3.85 (s, 3H), 3.80-3.73 (m, 1H), 3.03 (t, J = 11.4 Hz, 1H), 2.75 (s, 4H), 2.23 (s, 4H), 2.10 (t, J = 11.5 Hz, 1H), 1.95 (qd, J = 12.0, 3.7 Hz, 1H), 1.74 (d, J = 11.5 Hz, 1H). Example 155. Synthesis of 4-{[3-(1-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-6-[(trifluoromethyl)thio]pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide; formic acid Step 1. Synthesis of 7-bromo-1-chloro-6-[(trifluoromethyl)thio]pyrrolo[1,2-a]pyrazine
向7-溴-1-氯吡咯并[1,2-a]吡嗪(500 mg,2.16 mmol,1.00當量)及2-[(三氟甲基)硫基]異吲哚-1,3-二酮(694.11 mg,2.81 mmol,1.30當量)於DMF (5.00 mL)中之攪拌混合物中添加NaCl (63.12 mg,1.08 mmol,0.50當量)。將所得混合物在90℃下攪拌16 h。用水(50 mL)淬滅反應。所得混合物用EtOAc (3 x 50 mL)萃取。合併的有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。殘餘物藉由具有以下條件之反相急速層析純化:管柱,C18矽膠;移動相,於水中之0.1%TFA,在10 min內25%至40%梯度;偵測器,UV 220 nm,以得到呈黃色固體之所需化合物7-溴-1-氯-6-[(三氟甲基)硫基]吡咯并[1,2-a]吡嗪(480 mg,67.03%)。LC-MS:(M+H) +實測值:331。 步驟2. (3S,4R)-N-{7-溴-6-[(三氟甲基)硫基]吡咯并[1,2-a]吡嗪-1-基}-3-氟-1-甲基哌啶-4-胺之合成 To a stirred mixture of 7-bromo-1-chloropyrrolo[1,2-a]pyrazine (500 mg, 2.16 mmol, 1.00 equiv) and 2-[(trifluoromethyl)thio]isoindole-1,3-dione (694.11 mg, 2.81 mmol, 1.30 equiv) in DMF (5.00 mL) was added NaCl (63.12 mg, 1.08 mmol, 0.50 equiv). The resulting mixture was stirred at 90 °C for 16 h. The reaction was quenched with water (50 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, 0.1% TFA in water, gradient from 25% to 40% in 10 min; detector, UV 220 nm to give the desired compound 7-bromo-1-chloro-6-[(trifluoromethyl)thio]pyrrolo[1,2-a]pyrazine (480 mg, 67.03%) as a yellow solid. LC-MS: (M+H) + found: 331. Step 2. Synthesis of (3S,4R)-N-{7-bromo-6-[(trifluoromethyl)thio]pyrrolo[1,2-a]pyrazin-1-yl}-3-fluoro-1-methylpiperidin-4-amine
在室溫及氮氣氛圍下,向7-溴-1-氯-6-[(三氟甲基)硫基]吡咯并[1,2-a]吡嗪(500.00 mg,1.51 mmol,1.00當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺(299.02 mg,2.26 mmol,1.50當量)、RAC-BINAP-PD-G 3(299.34 mg,0.30 mmol,0.20當量)、BINAP (375.63 mg,0.60 mmol,0.40當量)於二噁烷(5.00 mL)中之攪拌混合物中添加Cs 2CO 3(2.95 g,9.05 mmol,6.00當量)。將所得混合物在100℃下再攪拌1 h,之後用水(10 mL)淬滅。所得混合物用EtOAc (3 x 50 mL)萃取。合併的有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。殘餘物藉由具有以下條件之反相急速層析純化:管柱,C18矽膠;移動相,於水中之0.1%TFA,在10 min內25%至40%梯度;偵測器,UV 220 nm,以得到呈淺黃色固體之所需化合物(3S,4R)-N-{7-溴-6-[(三氟甲基)硫基]吡咯并[1,2-a]吡嗪-1-基}-3-氟-1-甲基哌啶-4-胺(350.00 mg,54.3%)。LC-MS:(M+H) +實測值:427。 步驟3. 4-{[3-(1-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-6-[(三氟甲基)硫基]吡咯并[1,2-a]吡嗪-7-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺;甲酸之合成 To a stirred mixture of 7-bromo-1-chloro-6-[(trifluoromethyl)thio]pyrrolo[1,2-a]pyrazine (500.00 mg, 1.51 mmol, 1.00 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine (299.02 mg, 2.26 mmol, 1.50 equiv), RAC-BINAP-PD- G3 (299.34 mg, 0.30 mmol, 0.20 equiv), BINAP (375.63 mg, 0.60 mmol, 0.40 equiv) in dioxane (5.00 mL) was added Cs2CO3 (2.95 g, 9.05 mmol, 6.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 °C for another 1 h before being quenched with water (10 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, 0.1% TFA in water, gradient from 25% to 40% in 10 min; detector, UV 220 nm to give the desired compound (3S,4R)-N-{7-bromo-6-[(trifluoromethyl)thio]pyrrolo[1,2-a]pyrazin-1-yl}-3-fluoro-1-methylpiperidin-4-amine (350.00 mg, 54.3%) as a light yellow solid. LC-MS: (M+H) + found: 427. Step 3. Synthesis of 4-{[3-(1-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-6-[(trifluoromethyl)thio]pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide; formic acid
在100℃及氮氣氛圍下,向(3S,4R)-N-{7-溴-6-[(三氟甲基)硫基]吡咯并[1,2-a]吡嗪-1-基}-3-氟-1-甲基哌啶-4-胺(100 mg,0.23 mmol,1當量)、二異丙胺(236.83 mg,2.34 mmol,10當量)、CuI (22.29 mg,0.12 mmol,0.5當量)、DavePhos (36.84 mg,0.1 mmol,0.4當量)、DavePhos Pd G 3(35.73 mg,0.05 mmol,0.2當量)於DMSO (3 mL)中之攪拌混合物中逐滴添加3-甲氧基-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺(61.30 mg,0.28 mmol,1.2當量)於DMSO (0.5 mL)中之溶液。將混合物在100℃及氮氣氛圍下攪拌2 h。反應混合物用水(100 mL)稀釋且水相用EtOAc (100 mL)萃取兩次。合併的有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。殘餘物藉由製備型TLC (DCM/MeOH=15:1)純化以得到產物(90%純度),所得粗材料藉由製備型HPLC (管柱:Xselect CSH Prep Fluoro-Phenyl管柱,19*250 mm,5μm;移動相A:水(0.1% FA),移動相B:ACN;流動速率:25 mL/min mL/min;梯度:在12min內8% B至18% B;波長:254nm/220nm nm;RT1(min):9.35)純化。凍乾產生呈灰白色固體之4-{[3-(1-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-6-[(三氟甲基)硫基]吡咯并[1,2-a]吡嗪-7-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺;甲酸(21.3 mg,14.77%)。LC-MS:(M+H) +實測值:565.25。 1H NMR (400 MHz, DMSO- d 6) δ 8.10 (m, 1H), 7.73 (d, J= 4.9 Hz, 1H), 7.46 – 7.33 (m, 4H), 7.30 (d, J= 4.9 Hz, 1H), 6.77 (d, J= 8.3 Hz, 1H), 5.96 (t, J= 6.2 Hz, 1H), 4.87 (d, J= 49.6 Hz, 1H), 4.28 (d, J= 6.2 Hz, 2H), 4.19 (d, J= 30.4 Hz, 1H), 3.84 (s, 3H), 3.09 (t, J= 11.7 Hz, 1H), 2.87 (d, J= 10.9 Hz, 1H), 2.76 (d, J= 4.5 Hz, 3H), 2.22 (m, 6H), 1.68 (d, J= 12.2 Hz, 1H)。 實例156. 3-{[3-(1-{[(3S,4R)-3- 氟-1-甲基哌啶-4-基]胺基}-6-[(三氟甲基)硫基]吡咯并[1,2-a]吡嗪-7-基)丙-2-炔-1-基]胺基}-4-甲氧基-N-甲基苯甲醯胺之合成 At 100 °C under nitrogen atmosphere, (3S,4R)-N-{7-bromo-6-[(trifluoromethyl)thio]pyrrolo[1,2-a]pyrazin-1-yl}-3-fluoro-1-methylpiperidin-4-amine (100 mg, 0.23 mmol, 1 eq), diisopropylamine (236.83 mg, 2.34 mmol, 10 eq), CuI (22.29 mg, 0.12 mmol, 0.5 eq), DavePhos (36.84 mg, 0.1 mmol, 0.4 eq), DavePhos Pd G 3 (35.73 mg, 0.05 mmol, 0.2 eq) in DMSO (3 To the stirred mixture in 4% paraformaldehyde (2-nitropropene) (5-nitropropene) (6 ... The residue was purified by preparative TLC (DCM/MeOH=15:1) to give the product (90% purity), and the crude material was purified by preparative HPLC (column: Xselect CSH Prep Fluoro-Phenyl column, 19*250 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 25 mL/min mL/min; gradient: 8% B to 18% B in 12 min; wavelength: 254 nm/220 nm nm; RT1 (min): 9.35). Lyophilization yielded 4-{[3-(1-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-6-[(trifluoromethyl)thio]pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide; formic acid (21.3 mg, 14.77%) as an off-white solid. LC-MS: (M+H) + found: 565.25. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.10 (m, 1H), 7.73 (d, J = 4.9 Hz, 1H), 7.46 – 7.33 (m, 4H), 7.30 (d, J = 4.9 Hz, 1H), 6.77 (d, J = 8.3 Hz, 1H), 5.96 (t, J = 6.2 Hz, 1H), 4.87 (d, J = 49.6 Hz, 1H), 4.28 (d, J = 6.2 Hz, 2H), 4.19 (d, J = 30.4 Hz, 1H), 3.84 (s, 3H), 3.08 (t, J = 11.7 Hz, 1H), 2.87 (d, J = 5. = 10.9 Hz, 1H), 2.76 (d, J = 4.5 Hz, 3H), 2.22 (m, 6H), 1.68 (d, J = 12.2 Hz, 1H). Example 156. Synthesis of 3-{[3-(1-{[(3S,4R)-3- fluoro-1-methylpiperidin-4-yl]amino}-6-[(trifluoromethyl)thio]pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide
在室溫及氮氣氛圍下,向(3S,4R)-N-{7-溴-6-[(三氟甲基)硫基]吡咯并[1,2-a]吡嗪-1-基}-3-氟-1-甲基哌啶-4-胺(根據實例154合成,100 mg,0.23 mmol,1.00當量)及4-甲氧基-N-甲基-3-(丙-2-炔-1-基胺基)苯甲醯胺(51.08 mg,0.23 mmol,1.00當量)於DMSO (3.00 mL)中之攪拌混合物中添加DIPA (236.84 mg,2.34 mmol,10.00當量)、CuI (22.29 mg,0.12 mmol,0.50當量)、DavePhos Pd G3 (35.73 mg,0.05 mmol,0.20當量)及DavePhos (36.84 mg,0.09 mmol,0.40當量)。將所得混合物在100℃下再攪拌2 h,之後用水(10 mL)淬滅。所得混合物用EtOAc (3 x 20 mL)萃取。合併的有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。殘餘物藉由具有以下條件之反相急速層析純化:管柱,C18矽膠;移動相,於水中之0.1%FA,在10 min內50%至60%梯度;偵測器,UV 220 nm。粗物質使用具有以下條件之製備型HPLC純化:管柱:X-Select Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(0.1%NH4HCO3),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在7 min內50% B至62% B;波長:254nm/220nm nm;RT1(min):6.56。此產生呈黃色固體之3-{[3-(1-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-6-[(三氟甲基)硫基]吡咯并[1,2-a]吡嗪-7-基)丙-2-炔-1-基]胺基}-4-甲氧基-N-甲基苯甲醯胺(11.7 mg,8.8%)。LC-MS:(M+H) +實測值:565.30。 1H NMR (400 MHz, DMSO-d6) δ 8.18 – 8.08 (m, 1H), 7.72 (d, J = 4.8 Hz, 1H), 7.37 (d, J = 7.9 Hz, 2H), 7.28 (dd, J = 11.5, 3.5 Hz, 2H), 7.18 (dd, J = 8.3, 2.0 Hz, 1H), 6.88 (d, J = 8.3 Hz, 1H), 5.55 (t, J = 6.5 Hz, 1H), 4.85 (d, J = 49.7 Hz, 1H), 4.28 (d, J = 6.4 Hz, 2H), 4.24 – 4.08 (m, 1H), 3.84 (s, 3H), 3.11 – 3.00 (m, 1H), 2.87 – 2.80 (m, 1H), 2.76 (d, J = 4.4 Hz, 3H), 2.28 – 1.88 (m, 6H), 1.67 (dd, J = 9.8, 4.9 Hz, 1H)。 實例185 (3S,4R)-N-[7-(3-{[4-(二甲基磷醯基)-2-甲氧基苯基]胺基}丙-1-炔-1-基)-6-[(三氟甲基)硫基]吡咯并[1,2-a]吡嗪-1-基]-3-氟-1-甲基哌啶-4-胺;甲酸之合成 步驟1. 4-(二甲基磷醯基)-2-甲氧基-N-(丙-2-炔-1-基)苯胺之合成 To a stirred mixture of (3S,4R)-N-{7-bromo-6-[(trifluoromethyl)thio]pyrrolo[1,2-a]pyrazin-1-yl}-3-fluoro-1-methylpiperidin-4-amine (synthesized according to Example 154, 100 mg, 0.23 mmol, 1.00 equiv) and 4-methoxy-N-methyl-3-(prop-2-yn-1-ylamino)benzamide (51.08 mg, 0.23 mmol, 1.00 equiv) in DMSO (3.00 mL) was added DIPA (236.84 mg, 2.34 mmol, 10.00 equiv), CuI (22.29 mg, 0.12 mmol, 0.50 equiv), DavePhos Pd G3 (35.73 mg, 0.05 mmol, 0.20 equiv) and DavePhos (36.84 mg, 0.09 mmol, 0.40 equiv). The resulting mixture was stirred at 100 °C for another 2 h before being quenched with water (10 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, 0.1% FA in water, gradient from 50% to 60% in 10 min; detector, UV 220 nm. The crude material was purified using preparative HPLC with the following conditions: column: X-Select Prep OBD C18 column, 30*150 mm, 5μm; mobile phase A: water (0.1% NH4HCO3), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 50% B to 62% B in 7 min; wavelength: 254nm/220nm nm; RT1(min): 6.56. This produced 3-{[3-(1-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-6-[(trifluoromethyl)thio]pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide (11.7 mg, 8.8%) as a yellow solid. LC-MS: (M+H) + found: 565.30. 1 H NMR (400 MHz, DMSO-d6) δ 8.18 – 8.08 (m, 1H), 7.72 (d, J = 4.8 Hz, 1H), 7.37 (d, J = 7.9 Hz, 2H), 7.28 (dd, J = 11.5, 3.5 Hz, 2H), 7.18 (dd, J = 8.3, 2.0 Hz, 1H), 6.88 (d, J = 8.3 Hz, 1H), 5.55 (t, J = 6.5 Hz, 1H), 4.85 (d, J = 49.7 Hz, 1H), 4.28 (d, J = 6.4 Hz, 2H), 4.24 – 4.08 (m, 1H), 3.84 (s, 3H), 3.11 – 3.00 (m, 1H), 2.87 – 2.80 (m, 1H), 2.76 (d, J = 4.4 Hz, 3H), 2.28 – 1.88 (m, 6H), 1.67 (dd, J = 9.8, 4.9 Hz, 1H). Example 185 Synthesis of (3S,4R)-N-[7-(3-{[4-(dimethylphosphinoyl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-6-[(trifluoromethyl)thio]pyrrolo[1,2-a]pyrazin-1-yl]-3-fluoro-1-methylpiperidin-4-amine; formic acid Step 1. Synthesis of 4-(dimethylphosphinoyl)-2-methoxy-N-(prop-2-yn-1-yl)aniline
將4-(二甲基磷醯基)-2-甲氧基苯胺(95 mg,0.48 mmol,1.00當量)於DMF (3 mL)中之溶液在室溫下用炔丙基溴(85 mg,0.72 mmol,1.50當量)處理,接著在室溫下逐份添加K2CO3 (132 mg,0.95 mmol,2.00當量)。將所得混合物在100℃下再攪拌3 h。藉由LCMS監測反應。反應用水淬滅且用CH 2Cl 2(3 x20 mL)萃取。合併的有機層用鹽水(2x10 mL)洗滌、經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由具有以下條件之反相急速層析純化:管柱,C18矽膠;移動相,於水中之MeOH (0.1% TFA),在10 min內10%至50%梯度;偵測器,UV 254 nm。將所得混合物在減壓下濃縮,以得到呈黃色油狀物之4-(二甲基磷醯基)-2-甲氧基-N-(丙-2-炔-1-基)苯胺(40 mg,35.35%)。LC-MS:(M+H) +實測值:238.05。 步驟2. (3S,4R)-N-[7-(3-{[4-(二甲基磷醯基)-2-甲氧基苯基]胺基}丙-1-炔-1-基)-6-[(三氟甲基)硫基]吡咯并[1,2-a]吡嗪-1-基]-3-氟-1-甲基哌啶-4-胺;甲酸之合成 A solution of 4-(dimethylphosphinoyl)-2-methoxyaniline (95 mg, 0.48 mmol, 1.00 equiv) in DMF (3 mL) was treated with propargyl bromide (85 mg, 0.72 mmol, 1.50 equiv) at room temperature, followed by the addition of K2CO3 (132 mg, 0.95 mmol, 2.00 equiv) portionwise at room temperature. The resulting mixture was stirred at 100 °C for another 3 h. The reaction was monitored by LCMS. The reaction was quenched with water and extracted with CH2Cl2 (3 x 20 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeOH (0.1% TFA) in water, gradient 10% to 50% in 10 min; detector, UV 254 nm. The resulting mixture was concentrated under reduced pressure to give 4-(dimethylphosphatyl)-2-methoxy-N-(prop-2-yn-1-yl)aniline (40 mg, 35.35%) as a yellow oil. LC-MS: (M+H) + found: 238.05. Step 2. Synthesis of (3S,4R)-N-[7-(3-{[4-(dimethylphosphinoyl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-6-[(trifluoromethyl)thio]pyrrolo[1,2-a]pyrazin-1-yl]-3-fluoro-1-methylpiperidin-4-amine; formic acid
將(3S,4R)-3-氟-N-{7-碘-6-[(三氟甲基)硫基]吡咯并[1,2-a]吡嗪-1-基}-1-甲基哌啶-4-胺(80 mg,0.17 mmol,1.00當量) 於DMSO (2 mL) 中之溶液在室溫及氮氣氛圍下用4-(二甲基磷醯基)-2-甲氧基-N-(丙-2-炔-1-基)苯胺(40 mg,0.17 mmol,1.00當量)及DIPA (85 mg,0.85 mmol,5.00當量) 處理,接著在室溫下逐份添加Pd(PPh3)4 (20 mg,0.02 mmol,0.10當量)及CuI (6 mg,0.03 mmol,0.20當量)。將所得混合物在70℃下再攪拌1h。藉由LCMS監測反應。反應用水淬滅且用EtOAc (3 x20 mL)萃取。合併的有機層用鹽水(2x10 mL)洗滌、經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。粗產物(30 mg)藉由具有以下條件(管柱:X-Select Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(0.1%FA),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在7 min內30% B至50% B;波長:254nm/220nm nm;RT1(min):6.56)之製備型HPLC純化,以得到呈白色固體之(3S,4R)-N-[7-(3-{[4-(二甲基磷醯基)-2-甲氧基苯基]胺基}丙-1-炔-1-基)-6-[(三氟甲基)硫基]吡咯并[1,2-a]吡嗪-1-基]-3-氟-1-甲基哌啶-4-胺;甲酸(15.8 mg,14.76%)。LC-MS:(M+H) +實測值:584.25。 1H NMR (400 MHz, DMSO-d6) δ 7.73 (d, J = 4.9 Hz, 1H), 7.39 (d, J = 0.9 Hz, 1H), 7.36 (d, J = 7.5 Hz, 1H), 7.30 (d, J = 4.9 Hz, 1H), 7.22-7.17 (m, 1H), 7.13 (dd, J = 11.9, 1.6 Hz, 1H), 6.83 (dd, J = 8.0, 3.0 Hz, 1H), 6.00 (t, J = 6.2 Hz, 1H), 4.86 (d, J = 49.5 Hz, 1H), 4.27 (d, J = 6.2 Hz, 2H), 4.18 (dd, J = 31.3, 7.2 Hz, 1H), 3.84 (s, 3H), 3.33 – 3.05 (m, 1H), 2.84 – 2.67 (m, 1H), 2.18 (s, 4H), 2.14 – 2.01 (m, 2H), 1.67 (dd, J = 9.6, 5.1 Hz, 1H), 1.58 (d, J = 13.1 Hz, 6H)。 實例186 8-{[3-(1-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-6-[(三氟甲基)硫基]吡咯并[1,2-a]吡嗪-7-基)丙-2-炔-1-基]胺基}-N-甲基咪唑并[1,2-a]吡啶-6-甲醯胺之合成 步驟1. 8-(丙-2-炔-1-基胺基)咪唑并[1,2-a]吡啶-6-甲酸甲酯之合成 A solution of (3S,4R)-3-fluoro-N-{7-iodo-6-[(trifluoromethyl)thio]pyrrolo[1,2-a]pyrazin-1-yl}-1-methylpiperidin-4-amine (80 mg, 0.17 mmol, 1.00 equiv) in DMSO (2 mL) was treated with 4-(dimethylphosphatyl)-2-methoxy-N-(prop-2-yn-1-yl)aniline (40 mg, 0.17 mmol, 1.00 equiv) and DIPA (85 mg, 0.85 mmol, 5.00 equiv) at room temperature under nitrogen atmosphere, followed by the portionwise addition of Pd(PPh3)4 (20 mg, 0.02 mmol, 0.10 equiv) and CuI (6 mg, 0.03 mmol, 0.20 equiv) at room temperature. The resulting mixture was stirred at 70 °C for another 1 h. The reaction was monitored by LCMS. The reaction was quenched with water and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (30 mg) was purified by preparative HPLC with the following conditions (column: X-Select Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 30% B to 50% B in 7 min; wavelength: 254 nm/220 nm nm; RT1(min): 6.56) to give (3S,4R)-N-[7-(3-{[4-(dimethylphosphinoyl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-6-[(trifluoromethyl)thio]pyrrolo[1,2-a]pyrazin-1-yl]-3-fluoro-1-methylpiperidin-4-amine as a white solid; formic acid (15.8 mg, 14.76%). LC-MS: (M+H) + found: 584.25. 1 H NMR (400 MHz, DMSO-d6) δ 7.73 (d, J = 4.9 Hz, 1H), 7.39 (d, J = 0.9 Hz, 1H), 7.36 (d, J = 7.5 Hz, 1H), 7.30 (d, J = 4.9 Hz, 1H), 7.22-7.17 (m, 1H), 7.13 (dd, J = 11.9, 1.6 Hz, 1H), 6.83 (dd, J = 8.0, 3.0 Hz, 1H), 6.00 (t, J = 6.2 Hz, 1H), 4.86 (d, J = 49.5 Hz, 1H), 4.27 (d, J = 6.2 Hz, 2H), 4.18 (dd, J = 31.3, 7.2 Hz, 1H), 3.84 (s, 3H), 3.33 – 3.05 (m, 1H), 2.84 – 2.67 (m, 1H), 2.18 (s, 4H), 2.14 – 2.01 (m, 2H), 1.67 (dd, J = 9.6, 5.1 Hz, 1H), 1.58 (d, J = 13.1 Hz, 6H). Example 186 Synthesis of 8-{[3-(1-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-6-[(trifluoromethyl)thio]pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl]amino}-N-methylimidazo[1,2-a]pyridine-6-carboxamide Step 1. Synthesis of 8-(prop-2-yn-1-ylamino)imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester
將8-胺基咪唑并[1,2-a]吡啶-6-甲酸甲酯(1.00 g,5.23 mmol,1當量)、炔丙基溴(933 mg,7.84 mmol,1.50當量)及DIEA (2.73 mL,15.69 mmol,3.00當量)於DMF (10 mL)中之溶液在70℃下攪拌16h。在0℃下用水淬滅反應。藉由過濾收集沉澱的固體且用MeOH (3x10 mL)洗滌。將濾液在減壓下濃縮。殘餘物藉由具有以下條件之反相急速層析純化:管柱,C18矽膠;移動相,於水中之MeCN (10mmol/L NH 4HCO 3),在20 min內40%至60%梯度;偵測器,UV 254 nm,以得到呈棕色固體之8-(丙-2-炔-1-基胺基)咪唑并[1,2-a]吡啶-6-甲酸甲酯(350 mg,29.19%)。LC-MS:(M+H +)實測值:230.10。 步驟2. 8-(丙-2-炔-1-基胺基)咪唑并[1,2-a]吡啶-6-甲酸之合成 A solution of methyl 8-aminoimidazo[1,2-a]pyridine-6-carboxylate (1.00 g, 5.23 mmol, 1 eq), propargyl bromide (933 mg, 7.84 mmol, 1.50 eq) and DIEA (2.73 mL, 15.69 mmol, 3.00 eq) in DMF (10 mL) was stirred at 70 °C for 16 h. The reaction was quenched with water at 0 °C. The precipitated solid was collected by filtration and washed with MeOH (3x10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH 4 HCO 3 ) in water, gradient from 40% to 60% in 20 min; detector, UV 254 nm to give methyl 8-(prop-2-yn-1-ylamino)imidazo[1,2-a]pyridine-6-carboxylate (350 mg, 29.19%) as a brown solid. LC-MS: (M+H + ) found: 230.10. Step 2. Synthesis of 8-(prop-2-yn-1-ylamino)imidazo[1,2-a]pyridine-6-carboxylic acid
將8-(丙-2-炔-1-基胺基)咪唑并[1,2-a]吡啶-6-甲酸甲酯(350 mg,1.53 mmol,1.00當量)及LiOH.H 2O (192 mg,4.58 mmol,3.00當量)於溶劑[H 2O (1 mL)、MeOH (1 mL)、THF (1 mL)]中之混合物在50℃下攪拌隔夜。將所得混合物在減壓下濃縮。所得混合物用水(20mL)稀釋且用4M HCl (水溶液)酸化至pH 5。藉由過濾收集沉澱的固體且在真空下乾燥,以得到呈淺棕色固體之8-(丙-2-炔-1-基胺基)咪唑并[1,2-a]吡啶-6-甲酸(300 mg,91.30%)。LC-MS:(M+H +)實測值:216.05 步驟3. N-甲基-8-(丙-2-炔-1-基胺基)咪唑并[1,2-a]吡啶-6-甲醯胺之合成 A mixture of methyl 8-(prop-2-yn-1-ylamino)imidazo[1,2-a]pyridine-6-carboxylate (350 mg, 1.53 mmol, 1.00 equiv) and LiOH.H 2 O (192 mg, 4.58 mmol, 3.00 equiv) in a solvent [H 2 O (1 mL), MeOH (1 mL), THF (1 mL)] was stirred at 50° C. overnight. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (20 mL) and acidified to pH 5 with 4M HCl (aq). The precipitated solid was collected by filtration and dried under vacuum to give 8-(prop-2-yn-1-ylamino)imidazo[1,2-a]pyridine-6-carboxylic acid (300 mg, 91.30%) as a light brown solid. LC-MS: (M+H + ) found: 216.05 Step 3. Synthesis of N-methyl-8-(prop-2-yn-1-ylamino)imidazo[1,2-a]pyridine-6-carboxamide
在室溫下,向8-(丙-2-炔-1-基胺基)咪唑并[1,2-a]吡啶-6-甲酸(250 mg,1.16 mmol,1.00當量)、8-(丙-2-炔-1-基胺基)咪唑并[1,2-a]吡啶-6-甲酸(250 mg,1.16 mmol,1當量)、甲胺鹽酸鹽(94mg,1.39 mmol,1.20當量)及DIEA (600 mg,4.65 mmol,4.00當量)於DMF (3 mL)中之攪拌溶液中添加HATU (883 mg,2.32 mmol,2.00當量)。將所得混合物在室溫下攪拌1 h。用水淬滅反應。所得混合物用EtOAc (3 x 30 mL)萃取。合併的有機層用鹽水(2x20 mL)洗滌、經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由與DCM (20 mL)一起濕磨來純化,以得到呈淺黃色固體之N-甲基-8-(丙-2-炔-1-基胺基)咪唑并[1,2-a]吡啶-6-甲醯胺(200 mg,75.43%)。LC-MS:(M+H +)實測值:228.95 步驟4. 8-{[3-(1-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-6-[(三氟甲基)硫基]吡咯并[1,2-a]吡嗪-7-基)丙-2-炔-1-基]胺基}-N-甲基咪唑并[1,2-a]吡啶-6-甲醯胺之合成 To a stirred solution of 8-(prop-2-yn-1-ylamino)imidazo[1,2-a]pyridine-6-carboxylic acid (250 mg, 1.16 mmol, 1.00 equiv), 8-(prop-2-yn-1-ylamino)imidazo[1,2-a]pyridine-6-carboxylic acid (250 mg, 1.16 mmol, 1 equiv), methylamine hydrochloride (94 mg, 1.39 mmol, 1.20 equiv) and DIEA (600 mg, 4.65 mmol, 4.00 equiv) in DMF (3 mL) at room temperature was added HATU (883 mg, 2.32 mmol, 2.00 equiv). The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with water. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (2x20 mL), dried over anhydrous Na2SO4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with DCM (20 mL) to give N-methyl-8-(prop-2-yn-1-ylamino)imidazo[1,2-a]pyridine-6-carboxamide (200 mg, 75.43%) as a light yellow solid. LC-MS: (M+H + ) found: 228.95 Step 4. Synthesis of 8-{[3-(1-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-6-[(trifluoromethyl)thio]pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl]amino}-N-methylimidazo[1,2-a]pyridine-6-carboxamide
將N-甲基-8-(丙-2-炔-1-基胺基)咪唑并[1,2-a]吡啶-6-甲醯胺(58 mg,0.25 mmol,1.20當量)、(3S,4R)-3-氟-N-{7-碘-6-[(三氟甲基)硫基]吡咯并[1,2-a]吡嗪-1-基}-1-甲基哌啶-4-胺(100 mg,0.21 mmol,1.00當量)、Pd(PPh 3) 4(49 mg,0.042 mmol,0.20當量)、CuI (4 mg,0.021 mmol,0.10當量)及DIPA (64 mg,0.63 mmol,3.00當量)於DMSO (1 mL)中之混合物在70℃及氮氣氛圍下攪拌2 h。用水淬滅反應。所得混合物用EtOAc (3 x 20mL)萃取。合併的有機層用鹽水(3x10 mL)洗滌、經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/ MeOH=10/1)純化,以得到粗產物(100 mg)。粗產物藉由具有以下條件(管柱:XBridge Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3),移動相B:ACN;流動速率:60 mL/min;梯度:在10 min內8% B至31% B;波長:254nm/220nm nm;RT1(min):9.25)之製備型HPLC純化,以得到呈灰白色固體之8-{[3-(1-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-6-[(三氟甲基)硫基]吡咯并[1,2-a]吡嗪-7-基)丙-2-炔-1-基]胺基}-N-甲基咪唑并[1,2-a]吡啶-6-甲醯胺(51.6 mg,42.04%)。LC-MS:(M+H +)實測值:575.20。 1H NMR (400 MHz, DMSO- d 6) 8.42 (d, J= 1.4 Hz, 1H), 8.40 – 8.37 (m, 1H), 7.95 (d, J= 1.2 Hz, 1H), 7.72 (d, J= 4.9 Hz, 1H), 7.51 (d, J= 1.2 Hz, 1H), 7.39 (s, 1H), 7.36 (d, J= 7.5 Hz, 1H), 7.30 (d, J= 4.9 Hz, 1H), 6.76 (d, J= 1.5 Hz, 1H), 6.65 (t, J= 6.4 Hz, 1H), 4.85 (d, J= 49.7 Hz, 1H), 4.42 (d, J= 6.4 Hz, 2H), 4.17 (d, J= 31.2 Hz, 1H), 3.05 (t, J= 11.4 Hz, 1H), 2.88 – 2.77 (m, 4H), 2.27 – 1.93 (m, 6H), 1.69 – 1.62 (m, 1H)。 實例196 4-[(3-{6-[(二氟甲基)硫基]-1-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}吡咯并[1,2-a]吡嗪-7-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺;甲酸之合成 步驟1. 7-溴-1-氯-6-[(二氟甲基)硫基]吡咯并[1,2-a]吡嗪之合成 A mixture of N-methyl-8-(prop-2-yn-1-ylamino)imidazo[1,2-a]pyridine-6-carboxamide (58 mg, 0.25 mmol, 1.20 equiv), (3S,4R)-3-fluoro-N-{7-iodo-6-[(trifluoromethyl)thio]pyrrolo[1,2-a]pyrazin-1-yl}-1-methylpiperidin-4-amine (100 mg, 0.21 mmol, 1.00 equiv), Pd(PPh 3 ) 4 (49 mg, 0.042 mmol, 0.20 equiv), CuI (4 mg, 0.021 mmol, 0.10 equiv) and DIPA (64 mg, 0.63 mmol, 3.00 equiv) in DMSO (1 mL) was stirred at 70° C. under nitrogen atmosphere for 2 h. The reaction was quenched with water. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (3 x 10 mL) and dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 / MeOH = 10/1) to give a crude product (100 mg). The crude product was purified by preparative HPLC with the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 8% B to 31% B in 10 min; wavelength: 254 nm/220 nm; RT1 (min): 9.25) to obtain 8-{[3-(1-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-6-[(trifluoromethyl)thio]pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl]amino}-N-methylimidazo[1,2-a]pyridine-6-carboxamide (51.6 mg, 42.04%). LC-MS: (M+H + ) found: 575.20. 1 H NMR (400 MHz, DMSO- d 6 ) 8.42 (d, J = 1.4 Hz, 1H), 8.40 – 8.37 (m, 1H), 7.95 (d, J = 1.2 Hz, 1H), 7.72 (d, J = 4.9 Hz, 1H), 7.51 (d, J = 1.2 Hz, 1H), 7.39 (s, 1H), 7.36 (d, J = 7.5 Hz, 1H), 7.30 (d, J = 4.9 Hz, 1H), 6.76 (d, J = 1.5 Hz, 1H), 6.65 (t, J = 6.4 Hz, 1H), 4.85 (d, J = 49.7 Hz, 1H), 4.42 (d, J = 6.4 Hz, 2H), 4.17 (d, J = 31.2 Hz, 1H), 3.05 (t, J = 11.4 Hz, 1H), 2.88 – 2.77 (m, 4H), 2.27 – 1.93 (m, 6H), 1.69 – 1.62 (m, 1H). Example 196 Synthesis of 4-[(3-{6-[(difluoromethyl)thio]-1-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}pyrrolo[1,2-a]pyrazin-7-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide; formic acid Step 1. Synthesis of 7-bromo-1-chloro-6-[(difluoromethyl)thio]pyrrolo[1,2-a]pyrazine
將7-溴-1-氯吡咯并[1,2-a]吡嗪(400 mg,1.73 mmol,1.00當量)、2-[(二氟甲基)硫基]異吲哚-1,3-二酮(475 mg,2.07 mmol,1.20當量)及TMSCl (206 mg,1.90 mmol,1.10當量)於DCE (10 mL)中之溶液/混合物在90℃及氮氣氛圍下攪拌隔夜。所得混合物用CH 2Cl 2(3 x 50 mL)萃取。合併的有機層用鹽水洗滌,經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由具有以下條件之反相急速層析純化:管柱,C18矽膠;移動相,於水中之MeCN (10mmol/L NH 4HCO 3),在10 min內40%至60%梯度;偵測器,UV 254 nm,以得到呈灰白色固體之7-溴-1-氯-6-[(二氟甲基)硫基]吡咯并[1,2-a]吡嗪(500 mg,92.28%)。LC-MS:(M+H +)實測值:312.85。 步驟2. (3S,4R)-N-{7-溴-6-[(二氟甲基)硫基]吡咯并[1,2-a]吡嗪-1-基}-3-氟-1-甲基哌啶-4-胺之合成 A solution/mixture of 7-bromo-1-chloropyrrolo[1,2-a]pyrazine (400 mg, 1.73 mmol, 1.00 equiv), 2-[(difluoromethyl)thio]isoindole-1,3-dione (475 mg, 2.07 mmol, 1.20 equiv) and TMSCl (206 mg, 1.90 mmol, 1.10 equiv) in DCE (10 mL) was stirred at 90 °C under nitrogen atmosphere overnight. The resulting mixture was extracted with CH 2 Cl 2 (3 x 50 mL). The combined organic layers were washed with brine and dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH 4 HCO 3 ) in water, gradient from 40% to 60% in 10 min; detector, UV 254 nm to give 7-bromo-1-chloro-6-[(difluoromethyl)thio]pyrrolo[1,2-a]pyrazine (500 mg, 92.28%) as an off-white solid. LC-MS: (M+H + ) found: 312.85. Step 2. Synthesis of (3S,4R)-N-{7-bromo-6-[(difluoromethyl)thio]pyrrolo[1,2-a]pyrazin-1-yl}-3-fluoro-1-methylpiperidin-4-amine
將7-溴-1-氯-6-[(二氟甲基)硫基]吡咯并[1,2-a]吡嗪(200 mg,0.64 mmol,1.00當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(196 mg,0.96 mmol,1.50當量)、BINAP (79 mg,0.13 mmol,0.20當量)、RAC-BINAP-PD-G3 (63 mg,0.06 mmol,0.10當量)及Cs 2CO 3(1039 mg,3.19 mmol,5.00當量)於二噁烷(5 mL)中之混合物在100℃及氮氣氛圍下攪拌隔夜。在室溫下用水淬滅反應。所得混合物用EtOAc (3 x 30 mL)萃取。合併的有機層用鹽水洗滌,經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/ MeOH 15:1)純化,以得到呈淺黃色固體之(3S,4R)-N-{7-溴-6-[(二氟甲基)硫基]吡咯并[1,2-a]吡嗪-1-基}-3-氟-1-甲基哌啶-4-胺(100 mg,38.30%)。LC-MS:(M+H +)實測值:408.95。 4-[(3-{6-[( 二氟甲基)硫基]-1-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}吡咯并[1,2-a]吡嗪-7-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺;甲酸之合成 A mixture of 7-bromo-1-chloro-6-[(difluoromethyl)thio]pyrrolo[1,2-a]pyrazine (200 mg, 0.64 mmol, 1.00 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (196 mg, 0.96 mmol, 1.50 equiv), BINAP (79 mg, 0.13 mmol, 0.20 equiv), RAC-BINAP-PD-G3 (63 mg, 0.06 mmol, 0.10 equiv) and Cs 2 CO 3 (1039 mg, 3.19 mmol, 5.00 equiv) in dioxane (5 mL) was stirred at 100 °C under nitrogen atmosphere overnight. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine and dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 / MeOH 15:1) to give (3S,4R)-N-{7-bromo-6-[(difluoromethyl)thio]pyrrolo[1,2-a]pyrazin-1-yl}-3-fluoro-1-methylpiperidin-4-amine (100 mg, 38.30%) as a light yellow solid. LC-MS: (M+H + ) found: 408.95. 4-[(3-{6-[( difluoromethyl)thio]-1-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}pyrrolo[1,2-a]pyrazin-7-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide; Synthesis of formic acid
在100℃及氮氣氛圍下,向(3S,4R)-N-{7-溴-6-[(二氟甲基)硫基]吡咯并[1,2-a]吡嗪-1-基}-3-氟-1-甲基哌啶-4-胺(100 mg,0.244 mmol,1當量)、DavePhos (38.46 mg,0.098 mmol,0.4當量)、DavePhos Pd G3 (37.30 mg,0.049 mmol,0.2當量)、CuI (23.27 mg,0.122 mmol,0.5當量)、CuI (23.27 mg,0.122 mmol,0.5當量)、DIPA (123.63 mg,1.220 mmol,5當量)於DMSO (3 mL)中之攪拌混合物中逐滴添加3-甲氧基-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺(63.99 mg,0.293 mmol,1.2當量)於DMSO(1 mL)中之溶液。將反應混合物在100℃下攪拌5 h。用水淬滅反應。所得混合物用EtOAc (3 x 30 mL)萃取。合併的有機層用鹽水洗滌,經無水Na2SO4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型TLC (CH2Cl2 / MeOH 12:1)純化,以得到粗產物。粗產物藉由具有以下條件(管柱:Xselect CSH Prep Fluoro-Phenyl管柱,19*250 mm,5μm;移動相A:水(0.1% FA),移動相B:ACN;流動速率:25 mL/min mL/min;梯度:在12min內30% B至60% B;波長:254nm/220nm nm;RT1(min):9.35)之製備型HPLC純化,以得到呈淺黃色固體之4-[(3-{6-[(二氟甲基)硫基]-1-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}吡咯并[1,2-a]吡嗪-7-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺;甲酸(14.6 mg,9.99%)。LC-MS:(M+H +)實測值:547.25。 1H NMR (400 MHz, DMSO- d 6) δ 8.14 – 8.06 (m, 1H), 7.65 (d, J= 4.9 Hz, 1H), 7.42 (dd, J= 8.3, 1.9 Hz, 1H), 7.39 – 7.06 (m, 5H), 6.77 (d, J= 8.3 Hz, 1H), 5.94 (t, J= 6.1 Hz, 1H), 4.85 (d, J= 49.7 Hz, 1H), 4.26 (d, J= 6.1 Hz, 2H), 4.17 (d, J= 30.4 Hz, 1H), 3.85 (s, 3H), 3.11 – 3.01 (m, 1H), 2.88 – 2.80 (m, 1H), 2.76 (d, J= 4.5 Hz, 3H), 2.30 – 2.08 (m, 4H), 2.08 – 1.93 (m, 2H), 1.66 (dd, J= 9.8, 4.9 Hz, 1H)。 實例206 4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡嗪-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺之合成 步驟1. 8-氯咪唑并[1,2-a]吡嗪-2-甲酸甲酯之合成 To (3S,4R)-N-{7-bromo-6-[(difluoromethyl)thio]pyrrolo[1,2-a]pyrazin-1-yl}-3-fluoro-1-methylpiperidin-4-amine (100 mg, 0.244 mmol, 1 eq), DavePhos (38.46 mg, 0.098 mmol, 0.4 eq), DavePhos Pd G3 (37.30 mg, 0.049 mmol, 0.2 eq), CuI (23.27 mg, 0.122 mmol, 0.5 eq), CuI (23.27 mg, 0.122 mmol, 0.5 eq), DIPA (123.63 mg, 1.220 mmol, 5 eq) in DMSO (3 To the stirred mixture in 4% paraformaldehyde (2-nitropropene) (4-nitropropene) (5-nitropropene) (6-nitropropene) (7-nitropropene) (6-nitropropene) (7-nitropropene) (6-nitropropene) (7-nitropropene) (6-nitropropene) (6-nitropropene) (7-nitropropene) (6-nitropropene) (6-nitropropene) (7-nitropropene) (6-nitropropene) (6-nitropropene) (7-nitropropene) (6-nitropropene) (6-nitropropene) (7-nitropropene) (6-nitropropene) (6-nitropropene) (7-nitropropene) (6-nitropropene) (6-nitropropene) (7-nitropropene) (6-nitropropene) (6-nitropropene) (7-nitropropene) (6-nitropropene) (6-nitropropene) (7-nitropropene) (6-nitropropene) (7-nitropropene) (6-nitropropene) (7-nitropropene) (6-nitropropene) (7-nitropropene) (6-nitropropene) (7-nitropropene) (6-nitropropene) (7-nitropropene) ( The crude product was purified by preparative HPLC with the following conditions (column: Xselect CSH Prep Fluoro-Phenyl column, 19*250 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 25 mL/min mL/min; gradient: 30% B to 60% B in 12 min; wavelength: 254 nm/220 nm nm; RT1 (min): 9.35) to obtain 4-[(3-{6-[(difluoromethyl)thio]-1-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}pyrrolo[1,2-a]pyrazin-7-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide as a light yellow solid; formic acid (14.6 mg, 9.99%). LC-MS: (M+H + ) found: 547.25. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.14 – 8.06 (m, 1H), 7.65 (d, J = 4.9 Hz, 1H), 7.42 (dd, J = 8.3, 1.9 Hz, 1H), 7.39 – 7.06 (m, 5H), 6.77 (d, J = 8.3 Hz, 1H), 5.94 (t, J = 6.1 Hz, 1H), 4.85 (d, J = 49.7 Hz, 1H), 4.26 (d, J = 6.1 Hz, 2H), 4.17 (d, J = 30.4 Hz, 1H), 3.85 (s, 3H), 3.11 – 3.01 (m, 1H), 2.88 – 2.80 (m, 1H), 2.76 (d, J = 4.5 Hz, 3H), 2.30 – 2.08 (m, 4H), 2.08 – 1.93 (m, 2H), 1.66 (dd, J = 9.8, 4.9 Hz, 1H). Example 206 Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyrazin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide Step 1. Synthesis of 8-chloroimidazo[1,2-a]pyrazine-2-carboxylic acid methyl ester
將3-氯吡嗪-2-胺(5 g,38.6 mmol,1當量)、3-溴-2-側氧基丙酸甲酯(4.93 mL,46.3 mmol,1.2當量)及NaHCO3 (3.89 g,46.3 mmol,1.2當量)混合於ACN (75 mL)中。將反應混合物在80℃下攪拌4h。使混合物冷卻至室溫。所得混合物用水(2200 mL)稀釋。將混合物在室溫下攪拌1h。藉由過濾收集沉澱的固體且用水(2x300 mL)洗滌。將所得固體在真空下風乾,以得到呈米色固體之8-氯咪唑并[1,2-a]吡嗪-2-甲酸甲酯(6 g,73.47%)。LC-MS:(M+H) +實測值212.00。 步驟2. 3-溴-8-氯咪唑并[1,2-a]吡嗪-2-甲酸甲酯之合成 3-Chloropyrazin-2-amine (5 g, 38.6 mmol, 1 eq.), methyl 3-bromo-2-oxopropanoate (4.93 mL, 46.3 mmol, 1.2 eq.) and NaHCO3 (3.89 g, 46.3 mmol, 1.2 eq.) were mixed in ACN (75 mL). The reaction mixture was stirred at 80 °C for 4 h. The mixture was cooled to room temperature. The resulting mixture was diluted with water (2200 mL). The mixture was stirred at room temperature for 1 h. The precipitated solid was collected by filtration and washed with water (2x300 mL). The resulting solid was air-dried under vacuum to give methyl 8-chloroimidazo[1,2-a]pyrazine-2-carboxylate (6 g, 73.47%) as a beige solid. LC-MS: (M+H) + found 212.00. Step 2. Synthesis of methyl 3-bromo-8-chloroimidazo[1,2-a]pyrazine-2-carboxylate
將8-氯咪唑并[1,2-a]吡嗪-2-甲酸甲酯(9.9 g,46.8 mmol,1當量)、NBS (9.58 g,53.8 mmol,1.15當量)及BPO (0.12 g,0.468 mmol,0.01當量)混合於ACN (100 mL)中。將反應混合物在80℃下攪拌1h。所得混合物用水(300 mL)稀釋。藉由過濾收集沉澱的固體且用水(1x100 mL)洗滌,風乾,以得到呈白色固體之3-溴-8-氯咪唑并[1,2-a]吡嗪-2-甲酸甲酯(10 g,73.58%)。LC-MS:(M+H) +實測值290.80。 步驟3. 8-氯-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡嗪-2-甲酸甲酯之合成 Methyl 8-chloroimidazo[1,2-a]pyrazine-2-carboxylate (9.9 g, 46.8 mmol, 1 eq.), NBS (9.58 g, 53.8 mmol, 1.15 eq.) and BPO (0.12 g, 0.468 mmol, 0.01 eq.) were mixed in ACN (100 mL). The reaction mixture was stirred at 80 °C for 1 h. The resulting mixture was diluted with water (300 mL). The precipitated solid was collected by filtration and washed with water (1 x 100 mL), air-dried to give methyl 3-bromo-8-chloroimidazo[1,2-a]pyrazine-2-carboxylate (10 g, 73.58%) as a white solid. LC-MS: (M+H) + found 290.80. Step 3. Synthesis of 8-chloro-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyrazine-2-carboxylic acid methyl ester
將CuI (2.62 g,13.8 mmol,2當量)及(三氟甲基)硫化銀(1+) (2.88 g,13.8 mmol,2當量)混合於ACN (20 mL)中。將反應混合物在-30℃至0℃下攪拌3h。依序添加DMF (20 mL)、3-溴-8-氯咪唑并[1,2-a]吡嗪-2-甲酸甲酯(2 g,6.89 mmol,1當量)及1,10-啡啉(0.25 g,1.38 mmol,0.2當量)。將反應混合物在100℃下攪拌4h。過濾所得混合物,濾餅用乙酸乙酯(2x100 mL)洗滌。濾液用鹽水(2x200 mL)洗滌。所得有機相用無水硫酸鈉乾燥且在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用PE / EA (5:1)溶析,以得到呈黃色固體之8-氯-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡嗪-2-甲酸甲酯(560 mg,26.10%)。LC-MS:(M+H) +實測值311.85。 步驟4. 8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡嗪-2-甲酸甲酯之合成 CuI (2.62 g, 13.8 mmol, 2 eq.) and (trifluoromethyl)silver(1+)sulfide (2.88 g, 13.8 mmol, 2 eq.) were mixed in ACN (20 mL). The reaction mixture was stirred at -30°C to 0°C for 3 h. DMF (20 mL), methyl 3-bromo-8-chloroimidazo[1,2-a]pyrazine-2-carboxylate (2 g, 6.89 mmol, 1 eq.) and 1,10-phenanthroline (0.25 g, 1.38 mmol, 0.2 eq.) were added sequentially. The reaction mixture was stirred at 100°C for 4 h. The resulting mixture was filtered and the filter cake was washed with ethyl acetate (2x100 mL). The filtrate was washed with brine (2x200 mL). The obtained organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (5:1) to give 8-chloro-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyrazine-2-carboxylic acid methyl ester (560 mg, 26.10%) as a yellow solid. LC-MS: (M+H) + found 311.85. Step 4. Synthesis of 8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyrazine-2-carboxylic acid methyl ester
將8-氯-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡嗪-2-甲酸甲酯(1.5 g,4.81 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(1.09 g,5.29 mmol,1.1當量)及Et 3N (2.44 g,24.1 mmol,5當量)混合於DMSO (20 mL)中。將反應混合物在150℃下攪拌4h。所得混合物用乙酸乙酯(200 mL)稀釋。所得混合物用3x200 mL之鹽水洗滌。有機相用無水硫酸鈉乾燥且在真空下濃縮。殘餘物藉由矽膠管柱層析純化,用CH2Cl2 / MeOH (30:1)溶析,以得到呈白色固體之8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡嗪-2-甲酸甲酯(1.2 g,61.20%)。LC-MS:(M+H) +實測值408.1。 步驟5. 8-{[(3R,4S)-4-氟吡咯啶-3-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡嗪-2-甲酸之合成 Methyl 8-chloro-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyrazine-2-carboxylate (1.5 g, 4.81 mmol, 1 eq.), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (1.09 g, 5.29 mmol, 1.1 eq.) and Et3N (2.44 g, 24.1 mmol, 5 eq.) were mixed in DMSO (20 mL). The reaction mixture was stirred at 150 °C for 4 h. The resulting mixture was diluted with ethyl acetate (200 mL). The resulting mixture was washed with 3x200 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with CH2Cl2/MeOH (30:1) to give methyl 8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyrazine-2-carboxylate (1.2 g, 61.20%) as a white solid. LC-MS: (M+H) + found 408.1. Step 5. Synthesis of 8-{[(3R,4S)-4-fluoropyrrolidin-3-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyrazine-2-carboxylic acid
將(3S,4R)-3-氟-4-{[2-(甲氧基羰基)-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡嗪-8-基]胺基}吡咯啶-1-甲酸三級丁酯(1.3 g,2.71 mmol,1當量)及LiOH (0.65 g,27.1 mmol,10當量)混合於H2O (10 mL)及THF (10 mL)中。將反應混合物在室溫下攪拌1h。用2M HCl (水溶液)將混合物酸化至pH 7。將所得混合物在減壓下濃縮。殘餘物藉由具有以下條件之反相急速層析純化:管柱,C18矽膠;移動相,於水中之MeCN (0.1% FA),在30 min內0%至100%梯度;偵測器,UV 254 nm,以得到呈白色固體之8-{[(3R,4S)-4-氟吡咯啶-3-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡嗪-2-甲酸(1.2 g,121.15%)。LC-MS:(M+H) +實測值394.1 步驟6. N-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡嗪-2-基)胺基甲酸三級丁酯之合成 (3S,4R)-3-Fluoro-4-{[2-(methoxycarbonyl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyrazin-8-yl]amino}pyrrolidine-1-carboxylic acid tributyl ester (1.3 g, 2.71 mmol, 1 eq) and LiOH (0.65 g, 27.1 mmol, 10 eq) were mixed in H2O (10 mL) and THF (10 mL). The reaction mixture was stirred at room temperature for 1 h. The mixture was acidified to pH 7 with 2M HCl (aq). The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient from 0% to 100% in 30 min; detector, UV 254 nm to give 8-{[(3R,4S)-4-fluoropyrrolidin-3-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyrazine-2-carboxylic acid (1.2 g, 121.15%) as a white solid. LC-MS: (M+H) + found 394.1 Step 6. Synthesis of tributyl N-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyrazin-2-yl)carbamate
將8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡嗪-2-甲酸(300 mg,0.763 mmol,1當量)溶解於t-BuOH (3 mL)中,依序添加DPPA (524 mg,1.91 mmol,2.5當量)及Et3N (231 mg,2.29 mmol,3當量)。將反應混合物在85℃下攪拌1h。使混合物冷卻至室溫。將所得混合物在真空下濃縮。所得混合物用乙酸乙酯(20 mL)稀釋。所得混合物用3x20 mL之飽和NaHCO3水溶液洗滌。將所得混合物在真空下濃縮。殘餘物藉由具有以下條件之反相急速層析純化:管柱,C18矽膠;移動相,於水中之MeOH (0.1% FA),在30 min內0%至100%梯度;偵測器,UV 254 nm,以得到呈白色固體之N-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡嗪-2-基)胺基甲酸三級丁酯(150 mg,42.34%)。LC-MS:(M+H) +實測值465.20 步驟7. N 8-[(3S,4R)-3-氟-1-甲基哌啶-4-基]-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡嗪-2,8-二胺之合成 8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyrazine-2-carboxylic acid (300 mg, 0.763 mmol, 1 eq) was dissolved in t-BuOH (3 mL), and DPPA (524 mg, 1.91 mmol, 2.5 eq) and Et3N (231 mg, 2.29 mmol, 3 eq) were added sequentially. The reaction mixture was stirred at 85 °C for 1 h. The mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The resulting mixture was diluted with ethyl acetate (20 mL). The resulting mixture was washed with 3x20 mL of saturated aqueous NaHCO3. The resulting mixture was concentrated under vacuum. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeOH (0.1% FA) in water, gradient from 0% to 100% in 30 min; detector, UV 254 nm to give tributyl N-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyrazin-2-yl)carbamate (150 mg, 42.34%) as a white solid. LC-MS: (M+H) + found 465.20 Step 7. Synthesis of N 8 -[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyrazine-2,8-diamine
將N-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡嗪-2-基)胺基甲酸三級丁酯(150 mg,0.323 mmol,1當量)溶解於CF3COOH (1 mL)及CH2Cl2 (1 mL)中。將反應混合物在室溫下攪拌1h。用飽和NaHCO3 (水溶液)將混合物鹼化至pH 8。水層用CH2Cl2 (3x10 mL)萃取。所得混合物用3x30 mL之鹽水洗滌。有機相用無水硫酸鈉乾燥且在真空下濃縮,以得到呈棕色油狀物之N8-[(3S,4R)-3-氟-1-甲基哌啶-4-基]-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡嗪-2,8-二胺(100 mg,84.98%)。LC-MS:(M+H) +實測值365.10 步驟8. (3S,4R)-3-氟-N-{2-碘-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡嗪-8-基}-1-甲基哌啶-4-胺之合成 N-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyrazin-2-yl)carbamic acid tributyl ester (150 mg, 0.323 mmol, 1 eq) was dissolved in CF3COOH (1 mL) and CH2Cl2 (1 mL). The reaction mixture was stirred at room temperature for 1 h. The mixture was basified to pH 8 with saturated NaHCO3 (aq). The aqueous layer was extracted with CH2Cl2 (3x10 mL). The resulting mixture was washed with 3x30 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum to give N8-[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyrazine-2,8-diamine (100 mg, 84.98%) as a brown oil. LC-MS: (M+H) + found 365.10 Step 8. Synthesis of (3S,4R)-3-fluoro-N-{2-iodo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyrazin-8-yl}-1-methylpiperidin-4-amine
將N8-[(3S,4R)-3-氟-1-甲基哌啶-4-基]-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡嗪-2,8-二胺(300 mg,0.823 mmol,1當量)、CH2I2 (3.3 g,12.3 mmol,15當量)及亞硝酸3-甲基丁酯(241 mg,2.06 mmol,2.5當量)混合於ACN (3 mL)中。將反應混合物在40℃下攪拌5h。使混合物冷卻至室溫。殘餘物藉由具有以下條件之反相急速層析純化:管柱,C18矽膠;移動相,於水中之MeCN (0.1% FA),在30 min內0%至100%梯度;偵測器,UV 254 nm,以得到呈棕色油狀物之(3S,4R)-3-氟-N-{2-碘-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡嗪-8-基}-1-甲基哌啶-4-胺(150 mg,38.33%)。LC-MS:(M+H) +實測值476.00 步驟9. 4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡嗪-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺之合成 N8-[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyrazine-2,8-diamine (300 mg, 0.823 mmol, 1 eq), CH2I2 (3.3 g, 12.3 mmol, 15 eq) and 3-methylbutyl nitrite (241 mg, 2.06 mmol, 2.5 eq) were mixed in ACN (3 mL). The reaction mixture was stirred at 40 °C for 5 h. The mixture was cooled to room temperature. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient from 0% to 100% in 30 min; detector, UV 254 nm to give (3S,4R)-3-fluoro-N-{2-iodo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyrazin-8-yl}-1-methylpiperidin-4-amine (150 mg, 38.33%) as a brown oil. LC-MS: (M+H) + found 476.00 Step 9. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyrazin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide
將(3S,4R)-3-氟-N-{2-碘-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡嗪-8-基}-1-甲基哌啶-4-胺(60 mg,0.126 mmol,1當量)、3-甲氧基-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺(86.5 mg,0.396 mmol,1.2當量)、CuI (62.9 mg,0.330 mmol,1當量)、Pd(PPh3)4 (76.3 mg,0.066 mmol,0.2當量)及i-Pr2NH (334 mg,3.30 mmol,10當量)混合於DMSO (1 mL)中。將反應混合物在室溫下攪拌1h。混合物藉由具有以下條件之反相急速層析純化:管柱,C18矽膠;移動相,於水中之MeCN (0.1% FA),在30 min內0%至100%梯度;偵測器,UV 254 nm,以得到呈白色固體之4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡嗪-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺(8.5 mg,11.87%)。LC-MS:(M+H) +實測值566.25。 1H NMR (400 MHz, DMSO- d 6) δ 8.22 (s, 0.2H), 8.12 (d, J= 4.8 Hz, 1H), 7.81 (d, J= 4.6 Hz, 1H), 7.52 (dd, J= 18.4, 6.1 Hz, 2H), 7.40 (d, J= 8.2 Hz, 1H), 7.34 (d, J= 1.9 Hz, 1H), 6.73 (d, J= 8.2 Hz, 1H), 6.02 (t, J= 6.4 Hz, 1H), 4.90 (d, J= 18.5 Hz, 1H), 4.33 (d, J= 6.3 Hz, 2H), 4.17 (d, J= 8.3 Hz,, 1H), 3.84 (s, 3H), 3.04 (t, J= 11.8 Hz, 1H), 2.78 (dd, J= 21.2, 6.5 Hz, 4H), 2.22 (d, J= 13.0 Hz, 1H), 2.18 (s, 3H), 2.07 (p, J= 13.9, 13.2 Hz, 2H), 1.66 (d, J= 9.9 Hz, 1H)。 實例214 4-{[3-(7-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吡唑并[1,5-c]嘧啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺之合成 步驟1. 3-[2-(甲基硫基)嘧啶-4-基]-2-側氧基丙酸乙酯之合成 (3S,4R)-3-Fluoro-N-{2-iodo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyrazin-8-yl}-1-methylpiperidin-4-amine (60 mg, 0.126 mmol, 1 eq), 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (86.5 mg, 0.396 mmol, 1.2 eq), CuI (62.9 mg, 0.330 mmol, 1 eq), Pd(PPh3)4 (76.3 mg, 0.066 mmol, 0.2 eq) and i-Pr2NH (334 mg, 3.30 mmol, 10 eq) were mixed in DMSO (1 mL). The reaction mixture was stirred at room temperature for 1 h. The mixture was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient from 0% to 100% in 30 min; detector, UV 254 nm to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyrazin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (8.5 mg, 11.87%) as a white solid. LC-MS: (M+H) + found 566.25. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.22 (s, 0.2H), 8.12 (d, J = 4.8 Hz, 1H), 7.81 (d, J = 4.6 Hz, 1H), 7.52 (dd, J = 18.4, 6.1 Hz, 2H), 7.40 (d, J = 8.2 Hz, 1H), 7.34 (d, J = 1.9 Hz, 1H), 6.73 (d, J = 8.2 Hz, 1H), 6.02 (t, J = 6.4 Hz, 1H), 4.90 (d, J = 18.5 Hz, 1H), 4.33 (d, J = 6.3 Hz, 2H), 4.17 (d, J = 8.3 Hz,, 1H), 3.84 (s, 3H), 3.04 (t, J = 11.8 Hz, 1H), 2.78 (dd, J = 21.2, 6.5 Hz, 4H), 2.22 (d, J = 13.0 Hz, 1H), 2.18 (s, 3H), 2.07 (p, J = 13.9, 13.2 Hz, 2H), 1.66 (d, J = 9.9 Hz, 1H). Example 214 Synthesis of 4-{[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]pyrazolo[1,5-c]pyrimidin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide Step 1. Synthesis of ethyl 3-[2-(methylthio)pyrimidin-4-yl]-2-oxopropionate
在室溫及空氣氛圍下,向4-甲基-2-(甲基硫基)嘧啶(10 g,71 mmol,1.00當量)及草酸乙酯(52.12 g,356.63 mmol,5.00當量)於THF (100 mL)中之攪拌溶液中逐份添加t-BuOK (16.01 g,142.65 mmol,2.00當量)。將所得混合物在室溫及空氣氛圍下攪拌15 min。所得混合物用水(50 mL)稀釋。所得混合物用EtOAc (3 x 50mL)萃取。合併的有機層用鹽水(1 x 50 mL)洗滌,經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由與PE (100 mL)一起濕磨來純化。此產生呈黃色固體之3-[2-(甲基硫基)嘧啶-4-基]-2-側氧基丙酸乙酯(15 g,87.52%)。LC-MS:(M+H) +實測值:241.05。 步驟2. (2E)-2-(N-羥基亞胺基)-3-[2-(甲基硫基)嘧啶-4-基]丙酸乙酯之合成 To a stirred solution of 4-methyl-2-(methylthio)pyrimidine (10 g, 71 mmol, 1.00 equiv) and ethyl oxalate (52.12 g, 356.63 mmol, 5.00 equiv) in THF (100 mL) was added t-BuOK (16.01 g, 142.65 mmol, 2.00 equiv) portionwise at room temperature and air atmosphere. The resulting mixture was stirred at room temperature and air atmosphere for 15 min. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1 x 50 mL) and dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by wet trituration with PE (100 mL). This gave ethyl 3-[2-(methylthio)pyrimidin-4-yl]-2-oxopropanoate (15 g, 87.52%) as a yellow solid. LC-MS: (M+H) + found: 241.05. Step 2. Synthesis of ethyl (2E)-2-(N-hydroxyimino)-3-[2-(methylthio)pyrimidin-4-yl]propanoate
在室溫及空氣氛圍下,向3-[2-(甲基硫基)嘧啶-4-基]-2-側氧基丙酸乙酯(15 g,62.42 mmol,1.00當量)及NH 2OH.HCl (4.77 g,68.67 mmol,1.10當量)於EtOH (100 mL)中之攪拌溶液中逐份添加NaOAc (7.68 g,93.64 mmol,1.50當量)。將所得混合物在80℃及空氣氛圍下攪拌2h。將所得混合物在減壓下濃縮。在室溫下用水(50 mL) 淬滅反應。所得混合物用EtOAc (3 x 100 mL)萃取。合併的有機層用鹽水(1 x 100 mL)洗滌,經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由與PE (100 mL)一起濕磨來純化。此產生呈黃色固體之(2E)-2-(N-羥基亞胺基)-3-[2-(甲基硫基)嘧啶-4-基]丙酸乙酯(15 g,94.12%)。LC-MS:(M+H) +實測值:256.00。 步驟3. 7-(甲基硫基)吡唑并[1,5-c]嘧啶-2-甲酸乙酯之合成 To a stirred solution of ethyl 3-[2-(methylthio)pyrimidin-4-yl]-2-oxopropanoate (15 g, 62.42 mmol, 1.00 equiv) and NH 2 OH.HCl (4.77 g, 68.67 mmol, 1.10 equiv) in EtOH (100 mL) was added NaOAc (7.68 g, 93.64 mmol, 1.50 equiv) portionwise at room temperature under air atmosphere. The resulting mixture was stirred at 80 °C under air atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure. The reaction was quenched with water (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1 x 100 mL) and dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by wet trituration with PE (100 mL). This gave ethyl (2E)-2-(N-hydroxyimino)-3-[2-(methylthio)pyrimidin-4-yl]propanoate (15 g, 94.12%) as a yellow solid. LC-MS: (M+H) + found: 256.00. Step 3. Synthesis of ethyl 7-(methylthio)pyrazolo[1,5-c]pyrimidine-2-carboxylate
在0℃及空氣氛圍下,向(2E)-2-(N-羥基亞胺基)-3-[2-(甲基硫基)嘧啶-4-基]丙酸乙酯(1.00 g,3.91 mmol,1.00當量)及TEA (11.89 g,117.51 mmol,2.00當量)於ACN (150 mL)中之攪拌溶液中逐份添加TsCl (11.20 g,58.75 mmol,1.00當量)。將所得混合物在室溫及空氣氛圍下攪拌1.5 h。在室溫下,歷時1 min向上述混合物中逐份添加氯化亞鐵(2.23 g,17.62 mmol,0.30當量)。將所得混合物在80℃下再攪拌隔夜。藉由LCMS監測反應。將所得混合物在減壓下濃縮。藉由在室溫下添加水(50 mL)來淬滅反應。所得混合物用EtOAc (3 x 50mL)萃取。合併的有機層用鹽水(1 x 50 mL)洗滌,經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用PE / EA (25:1)溶析,以得到呈黃色固體之7-(甲基硫基)吡唑并[1,5-c]嘧啶-2-甲酸乙酯(3 g,21.52%)。LC-MS:(M+H) +實測值:238.00。 步驟4. 7-(甲基硫基)吡唑并[1,5-c]嘧啶-2-甲酸之合成 To a stirred solution of ethyl (2E)-2-(N-hydroxyimino)-3-[2-(methylthio)pyrimidin-4-yl]propanoate (1.00 g, 3.91 mmol, 1.00 equiv) and TEA (11.89 g, 117.51 mmol, 2.00 equiv) in ACN (150 mL) at 0°C under air atmosphere was added TsCl (11.20 g, 58.75 mmol, 1.00 equiv) portionwise. The resulting mixture was stirred at room temperature under air atmosphere for 1.5 h. To the above mixture was added ferrous chloride (2.23 g, 17.62 mmol, 0.30 equiv) portionwise at room temperature over 1 min. The resulting mixture was stirred at 80°C overnight. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The reaction was quenched by adding water (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1 x 50 mL) and dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (25:1) to give ethyl 7-(methylthio)pyrazolo[1,5-c]pyrimidine-2-carboxylate (3 g, 21.52%) as a yellow solid. LC-MS: (M+H) + found: 238.00. Step 4. Synthesis of 7-(methylthio)pyrazolo[1,5-c]pyrimidine-2-carboxylic acid
將7-(甲基硫基)吡唑并[1,5-c]嘧啶-2-甲酸乙酯(2.00 g,8.42 mmol,1.00當量)於MeOH (5 mL)及H 2O (10 mL)中之溶液在室溫下用NaOH (1.06 g,25.28 mmol,3.00當量)處理。將所得混合物在室溫下攪拌1 h。用HCl (2 M,水溶液)將混合物中和至pH 6。所得混合物用EtOAc (3 x 50 mL)萃取。合併的有機層用鹽水(1 x 50 mL)洗滌,經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。此產生呈黃色固體之7-(甲基硫基)吡唑并[1,5-c]嘧啶-2-甲酸(1.38 g,78.25%)。粗產物無需進一步純化直接用於下一步驟中。LCMS:(M+H) +實測值210.20。 步驟5. N-[7-(甲基硫基)吡唑并[1,5-c]嘧啶-2-基]胺基甲酸三級丁酯之合成 A solution of ethyl 7-(methylthio)pyrazolo[1,5-c]pyrimidine-2-carboxylate (2.00 g, 8.42 mmol, 1.00 equiv) in MeOH (5 mL) and H 2 O (10 mL) was treated with NaOH (1.06 g, 25.28 mmol, 3.00 equiv) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The mixture was neutralized to pH 6 with HCl (2 M, aqueous solution). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1 x 50 mL) and dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. This gave 7-(methylthio)pyrazolo[1,5-c]pyrimidine-2-carboxylic acid (1.38 g, 78.25%) as a yellow solid. The crude product was used directly in the next step without further purification. LCMS: (M+H) + found 210.20. Step 5. Synthesis of tert-butyl N-[7-(methylthio)pyrazolo[1,5-c]pyrimidin-2-yl]carbamate
將7-(甲基硫基)吡唑并[1,5-c]嘧啶-2-甲酸(1.38 g,6.59 mmol,1.00當量)於t-BuOH (15 mL)中之溶液在室溫下用TEA (1.00 g,9.89 mmol,1.50當量)處理,接著在室溫及氮氣氛圍下逐滴添加DPPA (2.18 g,7.91 mmol,1.20當量)。將所得混合物在80℃及氮氣氛圍下攪拌隔夜。在室溫下用NaHCO 3淬滅反應。所得混合物用EtOAc (3 x 100 mL)萃取。合併的有機層用鹽水(1 x 100 mL)洗滌,經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用PE / EA (30:1)溶析,以得到呈黃色油狀物之N-[7-(甲基硫基)吡唑并[1,5-c]嘧啶-2-基]胺基甲酸三級丁酯(710 mg,38.40%)。LCMS:(M+H) +實測值281.10。 步驟6. 7-(甲基硫基)吡唑并[1,5-c]嘧啶-2-胺之合成 A solution of 7-(methylthio)pyrazolo[1,5-c]pyrimidine-2-carboxylic acid (1.38 g, 6.59 mmol, 1.00 equiv) in t-BuOH (15 mL) was treated with TEA (1.00 g, 9.89 mmol, 1.50 equiv) at room temperature, followed by the dropwise addition of DPPA (2.18 g, 7.91 mmol, 1.20 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C under nitrogen atmosphere overnight. The reaction was quenched with NaHCO 3 at room temperature. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1 x 100 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (30:1) to give tributyl N-[7-(methylthio)pyrazolo[1,5-c]pyrimidin-2-yl]carbamate (710 mg, 38.40%) as a yellow oil. LCMS: (M+H) + found 281.10. Step 6. Synthesis of 7-(methylthio)pyrazolo[1,5-c]pyrimidin-2-amine
將N-[7-(甲基硫基)吡唑并[1,5-c]嘧啶-2-基]胺基甲酸三級丁酯(620 mg,2.21 mmol,1.00當量)於DCM (7.50 mL)中之溶液在0℃下用TFA (2.50 mL)處理。將所得混合物在室溫下攪拌隔夜。用飽和NaHCO 3(水溶液)將混合物中和至pH 8。所得混合物用EtOAc (2 x 50 mL)萃取。合併的有機層用鹽水(1 x 50 mL)洗滌,經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。此產生呈棕色固體之7-(甲基硫基)吡唑并[1,5-c]嘧啶-2-胺(370 mg,92.83%)。粗產物無需進一步純化直接用於下一步驟中。LCMS:(M+H) +實測值181.05。 步驟7. 7-(甲基硫基)-3-[(三氟甲基)硫基]吡唑并[1,5-c]嘧啶-2-胺之合成 A solution of tributyl N-[7-(methylthio)pyrazolo[1,5-c]pyrimidin-2-yl]carbamate (620 mg, 2.21 mmol, 1.00 equiv) in DCM (7.50 mL) was treated with TFA (2.50 mL) at 0 °C. The resulting mixture was stirred at room temperature overnight. The mixture was neutralized to pH 8 with saturated NaHCO 3 (aq). The resulting mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (1 x 50 mL) and dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. This gave 7-(methylthio)pyrazolo[1,5-c]pyrimidin-2-amine (370 mg, 92.83%) as a brown solid. The crude product was used directly in the next step without further purification. LCMS: (M+H) + found 181.05. Step 7. Synthesis of 7-(methylthio)-3-[(trifluoromethyl)thio]pyrazolo[1,5-c]pyrimidin-2-amine
在室溫下,向7-(甲基硫基)吡唑并[1,5-c]嘧啶-2-胺(360 mg,1.99 mmol,1.00當量)及N-(三氟甲硫基)糖精(565 mg,1.99 mmol,1.00當量)於DCM (5.00 mL)中之攪拌溶液中逐滴添加TMSCl (282 mg,2.59 mmol,1.30當量)。將所得混合物在室溫下攪拌3 h。所得混合物用水(20.00 mL)稀釋。所得混合物用CH 2Cl 2(3 x 50 mL)萃取。合併的有機層用鹽水(1 x 50 mL)洗滌,經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型TLC (PE / EA 1:1)純化,以得到呈白色固體之7-(甲基硫基)-3-[(三氟甲基)硫基]吡唑并[1,5-c]嘧啶-2-胺(510 mg,91.09%)。LCMS:(M+H) +實測值280.90。 步驟8. 72-碘-7-(甲基硫基)-3-[(三氟甲基)硫基]吡唑并[1,5-c]嘧啶之合成 To a stirred solution of 7-(methylthio)pyrazolo[1,5-c]pyrimidin-2-amine (360 mg, 1.99 mmol, 1.00 equiv) and N-(trifluoromethylthio)saccharin (565 mg, 1.99 mmol, 1.00 equiv) in DCM (5.00 mL) was added TMSCl (282 mg, 2.59 mmol, 1.30 equiv) dropwise at room temperature. The resulting mixture was stirred at room temperature for 3 h. The resulting mixture was diluted with water (20.00 mL). The resulting mixture was extracted with CH 2 Cl 2 (3 x 50 mL). The combined organic layers were washed with brine (1 x 50 mL) and dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE/EA 1:1) to give 7-(methylthio)-3-[(trifluoromethyl)thio]pyrazolo[1,5-c]pyrimidin-2-amine (510 mg, 91.09%) as a white solid. LCMS: (M+H) + found 280.90. Step 8. Synthesis of 7-iodo-7-(methylthio)-3-[(trifluoromethyl)thio]pyrazolo[1,5-c]pyrimidine
在室溫下,向7-(甲基硫基)-3-[(三氟甲基)硫基]吡唑并[1,5-c]嘧啶-2-胺(510 mg,1.82 mmol,1.00當量)及亞硝酸異戊酯(639 mg,5.46 mmol,3.00當量)於ACN (8 mL)中之攪拌溶液中添加CH 2I 2(4.87 g,18.20 mmol,10.00當量)。將所得混合物在40℃下攪拌1h。所得混合物用水(50 mL)稀釋。所得混合物用EtOAc (2 x 50 mL)萃取。合併的有機層用鹽水(1 x 50 mL)洗滌,經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型TLC (PE / EA 15:1)純化,以得到呈黃色固體之2-碘-7-(甲基硫基)-3-[(三氟甲基)硫基]吡唑并[1,5-c]嘧啶(470 mg,58.11%)。LCMS:(M+H) +實測值391.85。 步驟9. To a stirred solution of 7-(methylthio)-3-[(trifluoromethyl)thio]pyrazolo[1,5-c]pyrimidin- 2 -amine (510 mg, 1.82 mmol, 1.00 equiv) and isoamyl nitrite (639 mg, 5.46 mmol, 3.00 equiv) in ACN (8 mL) was added CH2I2 (4.87 g, 18.20 mmol, 10.00 equiv) at room temperature. The resulting mixture was stirred at 40 °C for 1 h. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (1 x 50 mL) and dried over anhydrous Na2SO4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE/EA 15:1) to give 2-iodo-7-(methylthio)-3-[(trifluoromethyl)thio]pyrazolo[1,5-c]pyrimidine (470 mg, 58.11%) as a yellow solid. LCMS: (M+H) + found 391.85. Step 9.
在0℃下,向2-碘-7-(甲基硫基)-3-[(三氟甲基)硫基]吡唑并[1,5-c]嘧啶(200 mg,0.51 mmol,1.00當量)於DCM (4.00 mL)中之攪拌溶液中逐份添加m-CPBA (114 mg,0.66 mmol,1.30當量)。將所得混合物在室溫下攪拌1 h。所得混合物用水(20 mL)稀釋。所得混合物用CH 2Cl 2(2 x 30 mL)萃取。合併的有機層用鹽水(1 x 30 mL)洗滌,經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。粗產物無需進一步純化直接用於下一步驟中。LCMS:(M+H) +實測值407.85。 步驟10. (3S,4R)-3-氟-N-{2-碘-3-[(三氟甲基)硫基]吡唑并[1,5-c]嘧啶-7-基}-1-甲基哌啶-4-胺之合成 To a stirred solution of 2-iodo-7-(methylthio)-3-[(trifluoromethyl)thio]pyrazolo[1,5-c]pyrimidine (200 mg, 0.51 mmol, 1.00 equiv) in DCM (4.00 mL) at 0 °C was added m-CPBA (114 mg, 0.66 mmol, 1.30 equiv) portionwise. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with CH 2 Cl 2 (2 x 30 mL). The combined organic layers were washed with brine (1 x 30 mL) and dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LCMS: (M+H) + found 407.85. Step 10. Synthesis of (3S,4R)-3-fluoro-N-{2-iodo-3-[(trifluoromethyl)thio]pyrazolo[1,5-c]pyrimidin-7-yl}-1-methylpiperidin-4-amine
在室溫下,向2-碘-7-甲亞磺醯基-3-[(三氟甲基)硫基]吡唑并[1,5-c]嘧啶(180 mg,0.44 mmol,1.00當量)及(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(136 mg,0.66 mmol,1.50當量)於DMA (3.00 mL)中之攪拌溶液中添加DIEA (285 mg,2.21 mmol,5.00當量)。將所得混合物在50℃下攪拌1 h。所得混合物用水(20.00 mL)稀釋。所得混合物用EtOAc (2 x 30 mL)萃取。合併的有機層用鹽水(1 x 30 mL)洗滌,經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/ MeOH=20/1)純化,以得到呈黃色固體之(3S,4R)-3-氟-N-{2-碘-3-[(三氟甲基)硫基]吡唑并[1,5-c]嘧啶-7-基}-1-甲基哌啶-4-胺(140 mg,66.64%)。LCMS:(M+H) +實測值476.00 步驟11. 4-{[3-(7-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吡唑并[1,5-c]嘧啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺之合成 To a stirred solution of 2-iodo-7-methanesulfinyl-3-[(trifluoromethyl)thio]pyrazolo[1,5-c]pyrimidine (180 mg, 0.44 mmol, 1.00 equiv) and (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (136 mg, 0.66 mmol, 1.50 equiv) in DMA (3.00 mL) was added DIEA (285 mg, 2.21 mmol, 5.00 equiv) at room temperature. The resulting mixture was stirred at 50 °C for 1 h. The resulting mixture was diluted with water (20.00 mL). The resulting mixture was extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (1 x 30 mL) and dried over anhydrous Na2SO4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 / MeOH = 20/1) to give (3S,4R)-3-fluoro-N-{2-iodo-3-[(trifluoromethyl)thio]pyrazolo[1,5-c]pyrimidin-7-yl}-1-methylpiperidin-4-amine (140 mg, 66.64%) as a yellow solid. LCMS: (M+H) + found 476.00 Step 11. Synthesis of 4-{[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]pyrazolo[1,5-c]pyrimidin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide
在室溫及氮氣氛圍下,向(3S,4R)-3-氟-N-{2-碘-3-[(三氟甲基)硫基]吡唑并[1,5-c]嘧啶-7-基}-1-甲基哌啶-4-胺(130 mg,0.27 mmol,1.00當量)及3-甲氧基-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺(59 mg,0.27 mmol,1.00當量)於DMSO (2.00 mL)中之攪拌溶液中添加i-Pr 2NH (138 mg,1.37 mmol,5.00當量)、CuI (10 mg,0.05 mmol,0.20當量)及Pd(PPh 3) 4(31 mg,0.02 mmol,0.100當量)。將所得混合物在室溫及氮氣氛圍下攪拌1 h。所得混合物用水(20.00 mL)稀釋。所得混合物用EtOAc (3 x 30 mL)萃取。合併的有機層用鹽水(1x 30 mL)洗滌,經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/ MeOH 20:1)純化,以得到呈黃色油狀物之粗產物(150 mg)。粗產物藉由具有以下條件(管柱:XBridge Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在10 min內33% B至63% B;波長:254nm/220nm nm;RT 1(min):7.82)之製備型HPLC純化,以得到呈白色固體之4-{[3-(7-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吡唑并[1,5-c]嘧啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺(78.7 mg,50.87%)。LCMS:(M+H) +實測值566.15。 1H NMR (400 MHz, DMSO- d 6 ) 8.11-8.08 (m, 1H), 7.95 - 7.73 (m, 2H), 7.46 - 7.38 (m, 1H), 7.35 (d, J= 2.0 Hz, 1H), 6.99 (d, J= 6.1 Hz, 1H), 6.75 (d, J= 8.3 Hz, 1H), 6.05 (t, J= 6.3 Hz, 1H), 4.88 (d, J= 49.3 Hz, 1H), 4.37 (d, J= 6.3 Hz, 2H), 4.28 - 3.93 (m, 1H), 3.85 (s, 3H), 3.11 - 2.99 (m, 1H), 2.86 - 2.79 (m, 1H), 2.75 (d, J= 4.4 Hz, 3H), 2.29 - 1.98 (m, 6H), 1.78 - 1.64 (m, 1H)。 實例215 4-{[3-(7-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(1-氟乙基)硫基]吡唑并[1,5-c]嘧啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺之合成 步驟1. 3-[(二氟甲基)硫基]-7-(甲基硫基)吡唑并[1,5-c]嘧啶-2-胺之合成 To a stirred solution of (3S,4R)-3-fluoro-N-{2-iodo-3-[(trifluoromethyl)thio]pyrazolo[1,5-c]pyrimidin-7-yl}-1-methylpiperidin-4-amine (130 mg, 0.27 mmol, 1.00 equiv) and 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (59 mg, 0.27 mmol, 1.00 equiv) in DMSO (2.00 mL) were added i-Pr 2 NH (138 mg, 1.37 mmol, 5.00 equiv), CuI (10 mg, 0.05 mmol, 0.20 equiv) and Pd(PPh 3 ) 4 (31 mg, 0.02 mmol, 0.100 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting mixture was diluted with water (20.00 mL). The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (1 x 30 mL) and dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 / MeOH 20:1) to give the crude product (150 mg) as a yellow oil. The crude product was purified by preparative HPLC with the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 33% B to 63% B in 10 min; wavelength: 254 nm/220 nm nm; RT 1 (min): 7.82) to obtain 4-{[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]pyrazolo[1,5-c]pyrimidin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (78.7 mg, 50.87%). LCMS: (M+H) + found 566.15. 1 H NMR (400 MHz, DMSO- d 6 ) 8.11-8.08 (m, 1H), 7.95 - 7.73 (m, 2H), 7.46 - 7.38 (m, 1H), 7.35 (d, J = 2.0 Hz, 1H), 6.99 (d, J = 6.1 Hz, 1H), 6.75 (d, J = 8.3 Hz, 1H), 6.05 (t, J = 6.3 Hz, 1H), 4.88 (d, J = 49.3 Hz, 1H), 4.37 (d, J = 6.3 Hz, 2H), 4.28 - 3.93 (m, 1H), 3.85 (s, 3H), 3.11 - 2.99 (m, 1H), 2.86 - 2.79 (m, 1H), 2.75 (d, J = 4.4 Hz, 3H), 2.29 - 1.98 (m, 6H), 1.78 - 1.64 (m, 1H). Example 215 Synthesis of 4-{[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(1-fluoroethyl)thio]pyrazolo[1,5-c]pyrimidin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide Step 1. Synthesis of 3-[(difluoromethyl)thio]-7-(methylthio)pyrazolo[1,5-c]pyrimidin-2-amine
在室溫下,向7-(甲基硫基)吡唑并[1,5-c]嘧啶-2-胺(500 mg,2.77 mmol,1.00當量)及2-[(二氟甲基)硫基]異吲哚-1,3-二酮(763 mg,3.33 mmol,1.20當量)於DCE (5.00 mL)中之攪拌溶液中逐滴添加TMSCl (452 mg,4.16 mmol,1.50當量)。將所得混合物在室溫下攪拌1 h。所得混合物用水(30.00 mL)稀釋。所得混合物用EtOAc (3 x 50mL)萃取。合併的有機層用鹽水(1 x 50 mL)洗滌,經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用PE / EA (15:1)溶析,以得到呈黃色固體之3-[(二氟甲基)硫基]-7-(甲基硫基)吡唑并[1,5-c]嘧啶-2-胺(600 mg,82.45%)。LCMS:(M+H) +實測值262.95 步驟2. 3-[(二氟甲基)硫基]-2-碘-7-(甲基硫基)吡唑并[1,5-c]嘧啶之合成 To a stirred solution of 7-(methylthio)pyrazolo[1,5-c]pyrimidin-2-amine (500 mg, 2.77 mmol, 1.00 equiv) and 2-[(difluoromethyl)thio]isoindole-1,3-dione (763 mg, 3.33 mmol, 1.20 equiv) in DCE (5.00 mL) was added TMSCl (452 mg, 4.16 mmol, 1.50 equiv) dropwise at room temperature. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was diluted with water (30.00 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1 x 50 mL) and dried over anhydrous Na2SO4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (15:1) to give 3-[(difluoromethyl)thio]-7-(methylthio)pyrazolo[1,5-c]pyrimidin-2-amine (600 mg, 82.45%) as a yellow solid. LCMS: (M+H) + found 262.95 Step 2. Synthesis of 3-[(difluoromethyl)thio]-2-iodo-7-(methylthio)pyrazolo[1,5-c]pyrimidine
在室溫下,向3-[(二氟甲基)硫基]-7-(甲基硫基)吡唑并[1,5-c]嘧啶-2-胺(600 mg,2.28 mmol,1.00當量)及(3-甲基丁基)亞硝酸酯(804 mg,6.86 mmol,3.00當量)於ACN (8.00 mL)中之攪拌溶液中添加CH 2I 2(6.13 g,22.87 mmol,10.00當量)。將所得混合物在40℃下攪拌1 h。所得混合物用水(30.00 mL)稀釋。所得混合物用CH 2Cl 2(3 x 50 mL)萃取。合併的有機層用鹽水(1 x 50 mL)洗滌,經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用PE / EA (50:1)溶析,以得到呈白色固體之3-[(二氟甲基)硫基]-2-碘-7-(甲基硫基)吡唑并[1,5-c]嘧啶(330 mg,36.65%)。LCMS:(M+H) +實測值373.85 步驟3. To a stirred solution of 3-[(difluoromethyl)thio]-7-(methylthio)pyrazolo[1,5-c]pyrimidin-2-amine (600 mg, 2.28 mmol, 1.00 equiv) and (3-methylbutyl)nitrite (804 mg, 6.86 mmol, 3.00 equiv) in ACN (8.00 mL) was added CH2I2 (6.13 g, 22.87 mmol, 10.00 equiv) at room temperature. The resulting mixture was stirred at 40 °C for 1 h. The resulting mixture was diluted with water (30.00 mL). The resulting mixture was extracted with CH2Cl2 (3 x 50 mL). The combined organic layers were washed with brine (1 x 50 mL) and dried over anhydrous Na2SO4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (50:1) to give 3-[(difluoromethyl)thio]-2-iodo-7-(methylthio)pyrazolo[1,5-c]pyrimidine (330 mg, 36.65%) as a white solid. LCMS: (M+H) + found 373.85 Step 3.
在0℃下,向3-[(二氟甲基)硫基]-2-碘-7-(甲基硫基)吡唑并[1,5-c]嘧啶(160 mg,0.43 mmol,1.00當量)於DCM (3.00 mL)中之攪拌溶液中逐份添加m-CPBA (96 mg,0.56 mmol,1.30當量)。將所得混合物在室溫下攪拌1 h。可藉由LCMS偵測所需產物。所得混合物用水(20.00mL)稀釋。所得混合物用CH 2Cl 2(2 x 30 mL)萃取。合併的有機層用鹽水(1 x 30 mL)洗滌,經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。粗產物無需進一步純化直接用於下一步驟中。LCMS:(M+H) +實測值389.85。 步驟4. (3S,4R)-N-{3-[(二氟甲基)硫基]-2-碘吡唑并[1,5-c]嘧啶-7-基}-3-氟-1-甲基哌啶-4-胺之合成 To a stirred solution of 3-[(difluoromethyl)thio]-2-iodo-7-(methylthio)pyrazolo[1,5-c]pyrimidine (160 mg, 0.43 mmol, 1.00 equiv) in DCM (3.00 mL) at 0 °C was added m-CPBA (96 mg, 0.56 mmol, 1.30 equiv) portionwise. The resulting mixture was stirred at room temperature for 1 h. The desired product could be detected by LCMS. The resulting mixture was diluted with water (20.00 mL). The resulting mixture was extracted with CH 2 Cl 2 (2 x 30 mL). The combined organic layers were washed with brine (1 x 30 mL) and dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LCMS: (M+H) + found 389.85. Step 4. Synthesis of (3S,4R)-N-{3-[(difluoromethyl)thio]-2-iodopyrazolo[1,5-c]pyrimidin-7-yl}-3-fluoro-1-methylpiperidin-4-amine
在室溫下,向3-[(二氟甲基)硫基]-2-碘-7-甲亞磺醯基吡唑并[1,5-c]嘧啶(250 mg,0.64 mmol,1.00當量)及(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(145 mg,0.71 mmol,1.10當量)於DMA (3.00 mL)中之攪拌溶液中逐滴添加DIEA (415 mg,3.21 mmol,5.00當量)。將所得混合物在50℃下攪拌2h。所得混合物用水(20.00mL)稀釋。所得混合物用EtOAc (2 x 30 mL)萃取。合併的有機層用鹽水(1 x 30 mL)洗滌,經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/ MeOH 20:1)純化,以得到呈黃色固體之(3S,4R)-N-{3-[(二氟甲基)硫基]-2-碘吡唑并[1,5-c]嘧啶-7-基}-3-氟-1-甲基哌啶-4-胺(120 mg,40.85%)。LCMS:(M+H) +實測值457.95。 步驟5. 4-{[3-(7-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(1-氟乙基)硫基]吡唑并[1,5-c]嘧啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺之合成 To a stirred solution of 3-[(difluoromethyl)thio]-2-iodo-7-methanesulfinylpyrazolo[1,5-c]pyrimidine (250 mg, 0.64 mmol, 1.00 equiv) and (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (145 mg, 0.71 mmol, 1.10 equiv) in DMA (3.00 mL) was added DIEA (415 mg, 3.21 mmol, 5.00 equiv) dropwise at room temperature. The resulting mixture was stirred at 50 °C for 2 h. The resulting mixture was diluted with water (20.00 mL). The resulting mixture was extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (1 x 30 mL) and dried over anhydrous Na2SO4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 / MeOH 20:1) to give (3S,4R)-N-{3-[(difluoromethyl)thio]-2-iodopyrazolo[1,5-c]pyrimidin-7-yl}-3-fluoro-1-methylpiperidin-4-amine (120 mg, 40.85%) as a yellow solid. LCMS: (M+H) + found 457.95. Step 5. Synthesis of 4-{[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(1-fluoroethyl)thio]pyrazolo[1,5-c]pyrimidin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide
在室溫及氮氣氛圍下,向(3S,4R)-N-{3-[(二氟甲基)硫基]-2-碘吡唑并[1,5-c]嘧啶-7-基}-3-氟-1-甲基哌啶-4-胺(120 mg,0.26 mmol,1.00當量)及3-甲氧基-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺(57 mg,0.26 mmol,1.00當量)於DMSO (3.00 mL)中之攪拌溶液中添加i-Pr 2NH (132 mg,1.31 mmol,5.00當量)、CuI (10 mg,0.05 mmol,0.20當量)及Pd(PPh 3) 4(30 mg,0.02 mmol,0.10當量)。將所得混合物在室溫及氮氣氛圍下攪拌1 h。所得混合物用水(20.00 mL)稀釋。所得混合物用EtOAc (3 x 30 mL)萃取。合併的有機層用鹽水(1 x 30 mL)洗滌,經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/ MeOH =20/1)純化,以得到呈黃色油狀物之粗產物(120 mg)。粗產物藉由具有以下條件(管柱:XBridge Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在10 min內31% B至51% B;波長:254nm/220nm nm;RT1(min):7.98)之製備型HPLC純化,以得到呈灰白色固體之4-{[3-(7-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(1-氟乙基)硫基]吡唑并[1,5-c]嘧啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺(26.8 mg,18.77%)。LCMS:(M+H) +實測值548.15。 1H NMR (400 MHz, DMSO- d 6 ) 8.16 - 8.01 (m, 1H), 7.82 - 7.64 (m, 2H), 7.43 - 7.38 (m, 1H), 7.34 (d, J= 1.7 Hz, 1H), 7.13 (d, J= 55.7 Hz, 1H), 6.91 (d, J= 6.2 Hz, 1H), 6.74 (d, J= 8.3 Hz, 1H), 6.02 (t, J= 6.3 Hz, 1H), 4.87 (d, J= 49.6 Hz, 1H), 4.33 (d, J= 6.3 Hz, 2H), 4.24 - 4.02 (m, 1H), 3.85 (s, 3H), 3.15 - 2.98 (m, 1H), 2.81 (d, J= 10.7 Hz, 1H), 2.75 (d, J= 4.5 Hz, 3H), 2.30 - 1.99 (m, 6H), 1.76 - 1.63 (m, 1H)。 實例216 3-{[3-(7-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吡唑并[1,5-a]嘧啶-2-基)丙-2-炔-1-基]胺基}-4-甲氧基-N-甲基苯甲醯胺之合成 步驟1. 2-溴-7-氯-3-碘吡唑并[1,5-a]嘧啶之合成 To a stirred solution of (3S,4R)-N-{3-[(difluoromethyl)thio]-2-iodopyrazolo[1,5-c]pyrimidin-7-yl}-3-fluoro-1-methylpiperidin-4-amine (120 mg, 0.26 mmol, 1.00 equiv) and 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (57 mg, 0.26 mmol, 1.00 equiv) in DMSO (3.00 mL) at room temperature under nitrogen atmosphere were added i- Pr2NH (132 mg, 1.31 mmol, 5.00 equiv), CuI (10 mg, 0.05 mmol, 0.20 equiv) and Pd( PPh3 ) 4 (30 mg, 0.02 mmol, 0.10 equiv). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting mixture was diluted with water (20.00 mL). The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (1 x 30 mL) and dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 / MeOH = 20/1) to give a crude product (120 mg) as a yellow oil. The crude product was purified by preparative HPLC with the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 31% B to 51% B in 10 min; wavelength: 254 nm/220 nm nm; RT1 (min): 7.98) to obtain 4-{[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(1-fluoroethyl)thio]pyrazolo[1,5-c]pyrimidin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (26.8 mg, 18.77%). LCMS: (M+H) + found 548.15. 1 H NMR (400 MHz, DMSO- d 6 ) 8.16 - 8.01 (m, 1H), 7.82 - 7.64 (m, 2H), 7.43 - 7.38 (m, 1H), 7.34 (d, J = 1.7 Hz, 1H), 7.13 (d, J = 55.7 Hz, 1H), 6.91 (d, J = 6.2 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.02 (t, J = 6.3 Hz, 1H), 4.87 (d, J = 49.6 Hz, 1H), 4.33 (d, J = 6.3 Hz, 2H), 4.24 - 4.02 (m, 1H), 3.85 (s, 3H), 3.15 - 2.98 (m, 1H), 2.81 (d, J = 10.7 Hz, 1H), 2.75 (d, J = 4.5 Hz, 3H), 2.30 - 1.99 (m, 6H), 1.76 - 1.63 (m, 1H). Example 216 Synthesis of 3-{[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]pyrazolo[1,5-a]pyrimidin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide Step 1. Synthesis of 2-bromo-7-chloro-3-iodopyrazolo[1,5-a]pyrimidine
在圓底燒瓶中裝入2-溴-7-氯吡唑并[1,5-a]嘧啶(4 g,17.207 mmol,1當量)、NIS (15.48 g,68.828 mmol,4當量) 及攪拌棒。添加ACN (50 mL),且將溶液在25℃下攪拌2 h。混合物用飽和Na 2CO 3(水溶液)淬滅。反應混合物用水(50 mL)稀釋且水相用DCM (40 mL)萃取三次。合併的有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。殘餘物藉由具有以下條件之反相急速層析純化:管柱,C18矽膠;移動相,於水中之MeCN,在10min內0%至100%梯度;偵測器,UV 220 nm。真空濃縮產生2-溴-7-氯-3-碘吡唑并[1,5-a]嘧啶(5 g,81.09%)固體。LC-MS:(M+H) +實測值:358.0。 步驟2. (3S,4R)-N-{2-溴-3-碘吡唑并[1,5-a]嘧啶-7-基}-3-氟-1-甲基哌啶-4-胺之合成 A round-bottom flask was charged with 2-bromo-7-chloropyrazolo[1,5-a]pyrimidine (4 g, 17.207 mmol, 1 eq), NIS (15.48 g, 68.828 mmol, 4 eq) and a stirring bar. ACN (50 mL) was added and the solution was stirred at 25 °C for 2 h. The mixture was quenched with saturated Na2CO3 ( aq ). The reaction mixture was diluted with water (50 mL) and the aqueous phase was extracted three times with DCM (40 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, gradient 0% to 100% in 10 min; detector, UV 220 nm. Concentration in vacuo gave 2-bromo-7-chloro-3-iodopyrazolo[1,5-a]pyrimidine (5 g, 81.09%) as a solid. LC-MS: (M+H) + found: 358.0. Step 2. Synthesis of (3S,4R)-N-{2-bromo-3-iodopyrazolo[1,5-a]pyrimidin-7-yl}-3-fluoro-1-methylpiperidin-4-amine
在圓底燒瓶中裝入2-溴-7-氯-3-碘吡唑并[1,5-a]嘧啶(1 g,2.790 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺(0.55 g,4.185 mmol,1.5當量)、TEA (1.69 g,16.740 mmol,6當量) 及攪拌棒。添加DMSO (15 mL),且將溶液在100℃下攪拌1 h。反應混合物用水(50 mL)稀釋且水相用DCM (50mL)萃取三次。合併的有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。殘餘物藉由具有以下條件之反相急速層析純化:管柱,C18矽膠;移動相,於水中之MeCN,在10min內0%至100%梯度;偵測器,UV 220 nm。真空濃縮產生呈黃色固體之(3S,4R)-N-{2-溴-3-碘吡唑并[1,5-a]嘧啶-7-基}-3-氟-1-甲基哌啶-4-胺(1.26 g,99.44%)。LC-MS:(M+H)+實測值:453.95。 步驟3. (3S,4R)-N-{2-溴-3-[(三氟甲基)硫基]吡唑并[1,5-a]嘧啶-7-基}-3-氟-1-甲基哌啶-4-胺之合成 A round-bottom flask was charged with 2-bromo-7-chloro-3-iodopyrazolo[1,5-a]pyrimidine (1 g, 2.790 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine (0.55 g, 4.185 mmol, 1.5 eq), TEA (1.69 g, 16.740 mmol, 6 eq) and a stirring bar. DMSO (15 mL) was added and the solution was stirred at 100 °C for 1 h. The reaction mixture was diluted with water (50 mL) and the aqueous phase was extracted three times with DCM (50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, gradient 0% to 100% in 10 min; detector, UV 220 nm. Concentration in vacuo gave (3S,4R)-N-{2-bromo-3-iodopyrazolo[1,5-a]pyrimidin-7-yl}-3-fluoro-1-methylpiperidin-4-amine (1.26 g, 99.44%) as a yellow solid. LC-MS: (M+H)+ found: 453.95. Step 3. Synthesis of (3S,4R)-N-{2-bromo-3-[(trifluoromethyl)thio]pyrazolo[1,5-a]pyrimidin-7-yl}-3-fluoro-1-methylpiperidin-4-amine
在25℃及氮氣氛圍下,向(3S,4R)-N-{2-溴-3-碘吡唑并[1,5-a]嘧啶-7-基}-3-氟-1-甲基哌啶-4-胺(1.3 g,2.863 mmol,1當量) 及(三氟甲硫基)銀(I) (1803.11 mg,8.589 mmol,3當量) 於ACN (90 mL) 中之混合物中添加2,2'-聯吡啶(894.28 mg,5.726 mmol,2當量)及CuI (1090.48 mg,5.726 mmol,2.00當量)。將混合物在90℃下攪拌16 h。混合物用水及NH 3.H 2O淬滅。反應混合物用水(100 mL)稀釋且水相用EA (100 mL)萃取三次。合併的有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。殘餘物藉由製備型TLC (DCM/MeOH;比率:20/1)純化,以得到呈黃色固體之(3S,4R)-N-{2-溴-3-[(三氟甲基)硫基]吡唑并[1,5-a]嘧啶-7-基}-3-氟-1-甲基哌啶-4-胺(600 mg,48.94%)。LC-MS:(M+H) +實測值:428.00。 步驟3. (3S,4R)-3-氟-N-{2-碘-3-[(三氟甲基)硫基]吡唑并[1,5-a]嘧啶-7-基}-1-甲基哌啶-4-胺之合成 To a mixture of (3S,4R)-N-{2-bromo-3-iodopyrazolo[1,5-a]pyrimidin-7-yl}-3-fluoro-1-methylpiperidin-4-amine (1.3 g, 2.863 mmol, 1 eq.) and (trifluoromethylthio)silver(I) (1803.11 mg, 8.589 mmol, 3 eq.) in ACN (90 mL) at 25°C under nitrogen atmosphere, 2,2'-bipyridine (894.28 mg, 5.726 mmol, 2 eq.) and CuI (1090.48 mg, 5.726 mmol, 2.00 eq.) were added. The mixture was stirred at 90°C for 16 h. The mixture was quenched with water and NH 3 .H 2 O. The reaction mixture was diluted with water (100 mL) and the aqueous phase was extracted three times with EA (100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative TLC (DCM/MeOH; ratio: 20/1) to give (3S,4R)-N-{2-bromo-3-[(trifluoromethyl)thio]pyrazolo[1,5-a]pyrimidin-7-yl}-3-fluoro-1-methylpiperidin-4-amine (600 mg, 48.94%) as a yellow solid. LC-MS: (M+H) + found: 428.00. Step 3. Synthesis of (3S,4R)-3-fluoro-N-{2-iodo-3-[(trifluoromethyl)thio]pyrazolo[1,5-a]pyrimidin-7-yl}-1-methylpiperidin-4-amine
在可再密封的反應小瓶中裝入(3S,4R)-N-{2-溴-3-[(三氟甲基)硫基]吡唑并[1,5-a]嘧啶-7-基}-3-氟-1-甲基哌啶-4-胺(300 mg,0.701 mmol,1當量)、NaI (1.05 g,7.010 mmol,10當量)、NaI (1.05 g,7.010 mmol,10當量)、CuI (40.02 mg,0.210 mmol,0.3當量)、(1S,2S)-1-N,2-N-二甲基環己烷-1,2-二胺(49.82 mg,0.350 mmol,0.5當量) 及攪拌棒,之後抽真空且用氮氣吹掃三次。添加DMF (1 mL),且將混合物在110℃下攪拌16 h。將反應混合物過濾(通過矽藻土墊),用EA洗滌墊,且將濾液真空濃縮。反應混合物用水(10 mL)稀釋且水相用EA (10 mL)萃取三次。合併的有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。殘餘物藉由製備型TLC (DCM/MeOH;比率:20/1)純化,以得到呈黃色固體之(3S,4R)-3-氟-N-{2-碘-3-[(三氟甲基)硫基]吡唑并[1,5-a]嘧啶-7-基}-1-甲基哌啶-4-胺(200 mg,60.07%)。LC-MS:(M+H) +實測值:476.00。 步驟4. 3-{[3-(7-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吡唑并[1,5-a]嘧啶-2-基)丙-2-炔-1-基]胺基}-4-甲氧基-N-甲基苯甲醯胺之合成 A resealable reaction vial was charged with (3S,4R)-N-{2-bromo-3-[(trifluoromethyl)thio]pyrazolo[1,5-a]pyrimidin-7-yl}-3-fluoro-1-methylpiperidin-4-amine (300 mg, 0.701 mmol, 1 eq), NaI (1.05 g, 7.010 mmol, 10 eq), NaI (1.05 g, 7.010 mmol, 10 eq), CuI (40.02 mg, 0.210 mmol, 0.3 eq), (1S,2S)-1-N,2-N-dimethylcyclohexane-1,2-diamine (49.82 mg, 0.350 mmol, 0.5 eq) and a stir bar, then evacuated and purged with nitrogen three times. DMF (1 mL) was added, and the mixture was stirred at 110 °C for 16 h. The reaction mixture was filtered (through a pad of celite), the pad was washed with EA, and the filtrate was concentrated in vacuo. The reaction mixture was diluted with water (10 mL) and the aqueous phase was extracted three times with EA (10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative TLC (DCM/MeOH; ratio: 20/1) to give (3S,4R)-3-fluoro-N-{2-iodo-3-[(trifluoromethyl)thio]pyrazolo[1,5-a]pyrimidin-7-yl}-1-methylpiperidin-4-amine (200 mg, 60.07%) as a yellow solid. LC-MS: (M+H) + found: 476.00. Step 4. Synthesis of 3-{[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]pyrazolo[1,5-a]pyrimidin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide
在可再密封的反應小瓶中裝入(3S,4R)-3-氟-N-{2-碘-3-[(三氟甲基)硫基]吡唑并[1,5-a]嘧啶-7-基}-1-甲基哌啶-4-胺(100 mg,0.210 mmol,1當量)、4-甲氧基-N-甲基-3-(丙-2-炔-1-基胺基)苯甲醯胺(68.89 mg,0.315 mmol,1.5當量)、DIPA (85.17 mg,0.840 mmol,4當量)、CuI (4.01 mg,0.021 mmol,0.1當量)、Pd(PPh 3) 4(48.63 mg,0.042 mmol,0.2當量) 及攪拌棒,之後抽真空且用氮氣吹掃三次。添加DMSO (2 mL),且將混合物在70℃下攪拌1 h。反應混合物用水(10 mL)稀釋且水相用EA (20 mL)萃取三次。合併的有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗材料藉由製備型HPLC (管柱:X-Select Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(0.1%FA),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在7 min內30% B至50% B;波長:254nm/220nm nm;RT1(min):6.56)純化。凍乾產生呈灰白色固體之3-{[3-(7-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吡唑并[1,5-a]嘧啶-2-基)丙-2-炔-1-基]胺基}-4-甲氧基-N-甲基苯甲醯胺(24 mg,20.17%)。LC-MS:(M+H)+實測值:566.30。 1H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J = 5.5 Hz, 1H), 8.14 (m, 1H), 7.82 (d, J = 8.3 Hz, 1H), 7.24 (d, J = 2.0 Hz, 1H), 7.17 (dd, J = 8.4, 2.1 Hz, 1H), 6.89 (d, J = 8.3 Hz, 1H), 6.67 (d, J = 5.6 Hz, 1H), 5.65 (t, J = 6.5 Hz, 1H), 4.82 (d, J = 49.4 Hz, 1H), 4.35 (d, J = 6.5 Hz, 2H), 4.00 (d, J = 25.1 Hz, 1H), 3.85 (s, 3H), 3.04 (t, J = 11.5 Hz, 1H), 2.80 (d, J = 10.8 Hz, 1H), 2.74 (d, J = 4.4 Hz, 3H), 2.37 – 2.23 (m, 1H), 2.19 (s, 3H), 2.10 (m, 1H), 1.71 (d, J = 12.2 Hz, 1H)。 實例219 4-[(3-{3-[(二氟甲基)硫基]-7-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}吡唑并[1,5-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺之合成 步驟1. 2-碘吡唑并[1,5-a]吡啶之合成 A resealable reaction vial was charged with (3S,4R)-3-fluoro-N-{2-iodo-3-[(trifluoromethyl)thio]pyrazolo[1,5-a]pyrimidin-7-yl}-1-methylpiperidin-4-amine (100 mg, 0.210 mmol, 1 eq), 4-methoxy-N-methyl-3-(prop-2-yn-1-ylamino)benzamide (68.89 mg, 0.315 mmol, 1.5 eq), DIPA (85.17 mg, 0.840 mmol, 4 eq), CuI (4.01 mg, 0.021 mmol, 0.1 eq), Pd( PPh3 ) 4 (48.63 mg, 0.042 mmol, 0.2 eq) and a stirring bar, then evacuated and purged with nitrogen three times. DMSO (2 mL) was added, and the mixture was stirred at 70 °C for 1 h. The reaction mixture was diluted with water (10 mL) and the aqueous phase was extracted three times with EA (20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by preparative HPLC (column: X-Select Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 30% B to 50% B in 7 min; wavelength: 254 nm/220 nm nm; RT1 (min): 6.56). Lyophilization gave 3-{[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]pyrazolo[1,5-a]pyrimidin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide (24 mg, 20.17%) as an off-white solid. LC-MS: (M+H)+ found: 566.30. 1 H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J = 5.5 Hz, 1H), 8.14 (m, 1H), 7.82 (d, J = 8.3 Hz, 1H), 7.24 (d, J = 2.0 Hz, 1H), 7.17 (dd, J = 8.4, 2.1 Hz, 1H), 6.89 (d, J = 8.3 Hz, 1H), 6.67 (d, J = 5.6 Hz, 1H), 5.65 (t, J = 6.5 Hz, 1H), 4.82 (d, J = 49.4 Hz, 1H), 4.35 (d, J = 6.5 Hz, 2H), 4.00 (d, J = 25.1 Hz, 3H), 3.85 (s, 3H), 3.04 (t, J = 11.5 Hz, 1H), 2.80 (d, J = 10.8 Hz, 1H), 2.74 (d, J = 4.4 Hz, 3H), 2.37 – 2.23 (m, 1H), 2.19 (s, 3H), 2.10 (m, 1H), 1.71 (d, J = 12.2 Hz, 1H). Example 219 Synthesis of 4-[(3-{3-[(difluoromethyl)thio]-7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}pyrazolo[1,5-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide Step 1. Synthesis of 2-iodopyrazolo[1,5-a]pyridine
在0℃下,將BF 3.Et 2O (11.80 mL,93.116 mmol,1.10當量)添加至吡唑并[1,5-a]吡啶(10 g,84.646 mmol,1當量)於THF (100 mL)中之溶液中且攪拌10 min。將混合物冷卻至-78℃,並且逐滴添加1-(氯鎂)-2,2,6,6-四甲基哌啶;氯鋰(102 mL,101.580 mmol,1.20當量)且將混合物攪拌15 min,之後逐滴添加I 2(32.23 g,126.969 mmol,1.5當量)於THF (100 mL)中之溶液且使混合物緩慢溫熱至環境溫度持續隔夜。混合物藉由添加飽和Na 2S 2O 3水溶液(50 mL)及飽和NH 4Cl水溶液(50 mL)淬滅,用EtOAc (3x80 mL)淬滅,合併的有機物用鹽水(50 mL)洗滌,經Na 2SO 4乾燥且真空濃縮。殘餘物藉由矽膠管柱層析純化,用PE / EA (3:1)溶析,以得到呈淺黃色油狀物之2-碘吡唑并[1,5-a]吡啶(7.9 g,38.24%)。LC-MS:(M+H) +實測值245。 步驟2. 7-溴-2-碘吡唑并[1,5-a]吡啶之合成 BF3.Et2O (11.80 mL, 93.116 mmol, 1.10 equiv) was added to a solution of pyrazolo [1,5-a]pyridine (10 g, 84.646 mmol, 1 equiv) in THF (100 mL) at 0°C and stirred for 10 min. The mixture was cooled to -78°C and 1-(chloromagnesium)-2,2,6,6-tetramethylpiperidine; lithium chloride (102 mL, 101.580 mmol, 1.20 equiv) was added dropwise and the mixture was stirred for 15 min before a solution of I2 (32.23 g, 126.969 mmol, 1.5 equiv) in THF (100 mL) was added dropwise and the mixture was allowed to slowly warm to ambient temperature overnight. The mixture was quenched by adding saturated aqueous Na2S2O3 ( 50 mL) and saturated aqueous NH4Cl (50 mL), quenched with EtOAc (3x80 mL), the combined organics were washed with brine (50 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluted with PE/EA (3:1) to give 2-iodopyrazolo[1,5-a]pyridine (7.9 g, 38.24%) as a light yellow oil. LC-MS: (M+H) + found 245. Step 2. Synthesis of 7-bromo-2-iodopyrazolo[1,5-a]pyridine
將2-碘吡唑并[1,5-a]吡啶(7.9 g,32.372 mmol,1當量)於THF (100 mL)中之溶液冷卻至-78℃,之後逐滴添加1-(氯鎂)-2,2,6,6-四甲基哌啶;氯鋰(32 mL,32.372 mmol,1當量)且將混合物攪拌20 min。逐滴添加1,2-二溴-1,1,2,2-四氯乙烷(15.81 g,48.558 mmol,1.5當量)於THF (10 mL)中之溶液且使混合物溫熱至環境溫度持續隔夜。混合物藉由添加飽和NH 4Cl水溶液(50 mL)淬滅,用EtOAc (2x80 mL)萃取,合併的有機物用鹽水(90 mL)洗滌,經Na 2SO 4乾燥且真空濃縮。殘餘物藉由具有以下條件之反相急速層析純化:管柱,C18矽膠;移動相,於水中之MeCN (0.1% FA),在30 min內10%至50%梯度;偵測器,UV 254 nm,以得到呈淺黃色固體之7-溴-2-碘吡唑并[1,5-a]吡啶(4 g,38.26%)。LC-MS:(M+H) +實測值323、325。 步驟3. 7-溴-3-[(二氟甲基)硫基]-2-碘吡唑并[1,5-a]吡啶之合成 A solution of 2-iodopyrazolo[1,5-a]pyridine (7.9 g, 32.372 mmol, 1 eq) in THF (100 mL) was cooled to -78 °C before 1-(chloromagnesium)-2,2,6,6-tetramethylpiperidine; lithium chloride (32 mL, 32.372 mmol, 1 eq) was added dropwise and the mixture was stirred for 20 min. A solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (15.81 g, 48.558 mmol, 1.5 eq) in THF (10 mL) was added dropwise and the mixture was allowed to warm to ambient temperature overnight. The mixture was quenched by addition of saturated aqueous NH 4 Cl solution (50 mL), extracted with EtOAc (2×80 mL), the combined organics were washed with brine (90 mL), dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, 10% to 50% gradient in 30 min; detector, UV 254 nm to give 7-bromo-2-iodopyrazolo[1,5-a]pyridine (4 g, 38.26%) as a light yellow solid. LC-MS: (M+H) + found 323, 325. Step 3. Synthesis of 7-bromo-3-[(difluoromethyl)thio]-2-iodopyrazolo[1,5-a]pyridine
在室溫及氮氣氛圍下,向7-溴-2-碘吡唑并[1,5-a]吡啶(2 g,6.19 mmol,1當量)及2-[(二氟甲基)硫基]異吲哚-1,3-二酮(1.56 g,6.81 mmol,1.1當量)於DCE (30 mL)中之攪拌溶液中逐滴添加TMSCl (1.35 g,12.386 mmol,2當量)。將所得混合物在90℃及氮氣氛圍下攪拌隔夜。將所得混合物在減壓下濃縮。殘餘物藉由具有以下條件之反相急速層析純化:管柱,C18矽膠;移動相,於水中之MeCN (0.1% FA),在10 min內10%至50%梯度;偵測器,UV 254 nm,以得到呈淺黃色固體之7-溴-3-[(二氟甲基)硫基]-2-碘吡唑并[1,5-a]吡啶(1.6 g,63.79%)。LC-MS:(M+H) +實測值405、407。 步驟4. 4-[(3-{7-溴-3-[(二氟甲基)硫基]吡唑并[1,5-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺之合成 To a stirred solution of 7-bromo-2-iodopyrazolo[1,5-a]pyridine (2 g, 6.19 mmol, 1 eq) and 2-[(difluoromethyl)thio]isoindole-1,3-dione (1.56 g, 6.81 mmol, 1.1 eq) in DCE (30 mL) was added TMSCl (1.35 g, 12.386 mmol, 2 eq) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 90 °C under nitrogen atmosphere overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient 10% to 50% in 10 min; detector, UV 254 nm to give 7-bromo-3-[(difluoromethyl)thio]-2-iodopyrazolo[1,5-a]pyridine (1.6 g, 63.79%) as a light yellow solid. LC-MS: (M+H) + found 405, 407. Step 4. Synthesis of 4-[(3-{7-bromo-3-[(difluoromethyl)thio]pyrazolo[1,5-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide
在室溫及氮氣氛圍下,向7-溴-3-[(二氟甲基)硫基]-2-碘吡唑并[1,5-a]吡啶(1 g,2.469 mmol,1當量)及3-甲氧基-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺(0.67 g,3.086 mmol,1.25當量)於1,4-二噁烷(10 mL)中之攪拌混合物中逐份添加Pd(PPh 3) 2Cl 2(0.17 g,0.247 mmol,0.1當量)及CuI (0.47 g,2.469 mmol,1當量)、K 3PO 4(3.14 g,14.814 mmol,6當量)。將所得混合物在室溫及氮氣氛圍下攪拌隔夜。在室溫下用水淬滅反應。所得混合物用EtOAc (3 x 120 mL)萃取。合併的有機層用水(2x120 mL)洗滌,經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由具有以下條件之反相急速層析純化:管柱,C18矽膠;移動相,於水中之MeCN (0.1% FA),在30 min內10%至40%梯度;偵測器,UV 254 nm。此產生呈棕色固體之4-[(3-{7-溴-3-[(二氟甲基)硫基]吡唑并[1,5-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺(207.4 mg,11.94%)。LC-MS:(M+H) +實測值495、497。 步驟5. 4-[(3-{3-[(二氟甲基)硫基]-7-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}吡唑并[1,5-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺之合成 To a stirred mixture of 7-bromo-3-[(difluoromethyl)thio]-2-iodopyrazolo[1,5-a]pyridine (1 g, 2.469 mmol, 1 eq) and 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (0.67 g, 3.086 mmol, 1.25 eq) in 1,4-dioxane (10 mL) at room temperature under nitrogen atmosphere was added Pd(PPh 3 ) 2 Cl 2 (0.17 g, 0.247 mmol, 0.1 eq) and CuI (0.47 g, 2.469 mmol, 1 eq), K 3 PO 4 (3.14 g, 14.814 mmol, 6 eq) portionwise. The resulting mixture was stirred at room temperature under nitrogen atmosphere overnight. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 120 mL). The combined organic layers were washed with water (2 x 120 mL) and dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient 10% to 40% in 30 min; detector, UV 254 nm. This gave 4-[(3-{7-bromo-3-[(difluoromethyl)thio]pyrazolo[1,5-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (207.4 mg, 11.94%) as a brown solid. LC-MS: (M+H) + found 495, 497. Step 5. Synthesis of 4-[(3-{3-[(difluoromethyl)thio]-7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}pyrazolo[1,5-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide
在室溫及氮氣氛圍下,向4-[(3-{7-溴-3-[(二氟甲基)硫基]吡唑并[1,5-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺(180 mg,0.254 mmol,1當量,70%)及(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(105 mg,0.508 mmol,2當量)於THF (3 mL)中之攪拌混合物中逐份添加第3代t-BuXPhos預催化劑(41 mg,0.051 mmol,0.2當量)及t-BuONa (123 mg,1.270 mmol,5當量)。將所得混合物在65℃及氮氣氛圍下攪拌1 h。所得混合物用CH 2Cl 2/MeOH (3 x 50 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用CH 2Cl 2/ MeOH (10:1)溶析,以得到呈黃色固體之4-[(3-{3-[(二氟甲基)硫基]-7-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}吡唑并[1,5-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺(45.2 mg,31.44%)。LC-MS:(M+H) +實測值547.15。 1H NMR (400 MHz, DMSO- d 6) δ 8.11 (q, J= 4.5 Hz, 1H), 7.48 – 7.36 (m, 2H), 7.34 (d, J= 1.9 Hz, 1H), 7.16 (t, J= 55.8 Hz, 1H), 6.96 (d, J= 8.5 Hz, 1H), 6.76 (d, J= 8.2 Hz, 1H), 6.44 – 6.38 (m, 2H), 6.02 (t, J= 6.2 Hz, 1H), 4.86 (d, J= 49.5 Hz, 1H), 4.32 (d, J= 6.2 Hz, 2H), 3.91 – 3.82 (m, 4H), 3.06 (t, J= 11.6 Hz, 1H), 2.75 (d, J= 4.4 Hz, 4H), 2.33 – 2.12 (m, 5H), 2.01 – 1.74 (m, 2H)。 實例223 4-{[3-(7-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吡唑并[1,5-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺之合成 步驟1. 2-碘吡唑并[1,5-a]吡啶之合成 To a stirred mixture of 4-[(3-{7-bromo-3-[(difluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (180 mg, 0.254 mmol, 1 eq, 70%) and (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (105 mg, 0.508 mmol, 2 eq) in THF (3 mL) at room temperature under nitrogen atmosphere were added 3rd generation t-BuXPhos precatalyst (41 mg, 0.051 mmol, 0.2 eq) and t-BuONa (123 mg, 1.270 mmol, 5 eq) portionwise. The resulting mixture was stirred at 65 °C under nitrogen atmosphere for 1 h. The resulting mixture was extracted with CH 2 Cl 2 /MeOH (3 x 50 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with CH 2 Cl 2 /MeOH (10:1) to give 4-[(3-{3-[(difluoromethyl)thio]-7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}pyrazolo[1,5-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (45.2 mg, 31.44%) as a yellow solid. LC-MS: (M+H) + found 547.15. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.11 (q, J = 4.5 Hz, 1H), 7.48 – 7.36 (m, 2H), 7.34 (d, J = 1.9 Hz, 1H), 7.16 (t, J = 55.8 Hz, 1H), 6.96 (d, J = 8.5 Hz, 1H), 6.76 (d, J = 8.2 Hz, 1H), 6.44 – 6.38 (m, 2H), 6.02 (t, J = 6.2 Hz, 1H), 4.86 (d, J = 49.5 Hz, 1H), 4.32 (d, J = 6.2 Hz, 2H), 3.91 – 3.82 (m, 4H), 3.06 (t, J = 11.6 Hz, 1H), 2.75 (d, J = 4.4 Hz, 4H), 2.33 – 2.12 (m, 5H), 2.01 – 1.74 (m, 2H). Example 223 Synthesis of 4-{[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide Step 1. Synthesis of 2-iodopyrazolo[1,5-a]pyridine
在0℃下,將BF 3.Et 2O (3.96 g,27.93 mmol,1.10當量)添加至吡唑并[1,5-a]吡啶(3.00 g,25.39 mmol,1.00當量)於THF (20.00 mL)中之溶液中且將其攪拌10 min。將混合物冷卻至-78℃,然後在氮氣氛圍下逐滴添加TMPMgCl.LiCl (1M,30.47 mL,30.47 mmol,1.20當量)。攪拌15 min之後,在氮氣氛圍下逐滴添加I 2(9.67 g,38.09 mmol,1.50當量)於THF (10.00 mL)中之溶液,且使反應混合物緩慢溫熱至環境溫度持續隔夜。藉由添加飽和Na 2S 2O 3水溶液(20.00 mL)及飽和NH 4Cl水溶液(20.00 mL)淬滅所得混合物。將其用EtOAc (3x40.00 mL)萃取且合併的有機物用鹽水(2x40.00 mL)洗滌,經Na 2SO 4乾燥且真空濃縮。殘餘物藉由具有以下條件之反相急速層析純化:管柱,C18;移動相,於水中之MeCN,在30 min內0%至60%梯度;偵測器,UV 254 nm。此產生呈淺棕色油狀物之2-碘吡唑并[1,5-a]吡啶(1.6 g,25.82%)。LC-MS:(M+H) +實測值244.95。 步驟2. 7-溴-2-碘吡唑并[1,5-a]吡啶之合成 BF3.Et2O (3.96 g, 27.93 mmol, 1.10 equiv) was added to a solution of pyrazolo [1,5-a]pyridine (3.00 g, 25.39 mmol, 1.00 equiv) in THF (20.00 mL) at 0°C and stirred for 10 min. The mixture was cooled to -78°C and then TMPMgCl.LiCl (1 M, 30.47 mL, 30.47 mmol, 1.20 equiv) was added dropwise under nitrogen atmosphere. After stirring for 15 min, a solution of I2 (9.67 g, 38.09 mmol, 1.50 equiv) in THF (10.00 mL) was added dropwise under nitrogen atmosphere and the reaction mixture was allowed to slowly warm to ambient temperature overnight. The resulting mixture was quenched by the addition of saturated aqueous Na2S2O3 (20.00 mL) and saturated aqueous NH4Cl (20.00 mL). It was extracted with EtOAc (3x40.00 mL) and the combined organics were washed with brine ( 2x40.00 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in water, gradient 0% to 60% in 30 min; detector, UV 254 nm. This produced 2-iodopyrazolo[1,5-a]pyridine (1.6 g, 25.82%) as a light brown oil. LC-MS: (M+H) + found 244.95. Step 2. Synthesis of 7-bromo-2-iodopyrazolo[1,5-a]pyridine
將2-碘吡唑并[1,5-a]吡啶(1.60 g,6.56 mmol,1.00當量)於THF (15.00 mL)中之溶液冷卻至-78℃,然後在氮氣氛圍下逐滴添加TMPMgCl.LiCl (1M,7.87 mL,7.87 mmol,1.20當量)。攪拌20 min之後,逐滴添加1,2-二溴-1,1,2,2-四氯乙烷(3.20 g,9.83 mmol,1.50當量)於THF (10.00 mL)中之溶液且將反應混合物在室溫下攪拌2 h。藉由添加飽和NH 4Cl水溶液(30 mL)淬滅所得混合物且將其用EtOAc (3x40 mL)萃取。合併的有機物用鹽水(2x40 mL)洗滌,經Na 2SO 4乾燥且真空濃縮。殘餘物藉由具有以下條件之反相急速層析純化:管柱,C18;移動相,於水中之MeCN,在10 min內0%至60%梯度;偵測器,UV 254 nm。此產生呈淺黃色固體之7-溴-2-碘吡唑并[1,5-a]吡啶(1.3 g,61.40%)。LC-MS:(M+H) +實測值322.86。 步驟3. 7-溴-2-碘-3-[(三氟甲基)硫基]吡唑并[1,5-a]吡啶之合成 A solution of 2-iodopyrazolo[1,5-a]pyridine (1.60 g, 6.56 mmol, 1.00 equiv) in THF (15.00 mL) was cooled to -78 °C and then TMPMgCl.LiCl (1 M, 7.87 mL, 7.87 mmol, 1.20 equiv) was added dropwise under nitrogen atmosphere. After stirring for 20 min, a solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (3.20 g, 9.83 mmol, 1.50 equiv) in THF (10.00 mL) was added dropwise and the reaction mixture was stirred at room temperature for 2 h. The resulting mixture was quenched by the addition of saturated aqueous NH 4 Cl solution (30 mL) and extracted with EtOAc (3×40 mL). The combined organics were washed with brine ( 2x40 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in water, gradient 0% to 60% in 10 min; detector, UV 254 nm. This produced 7-bromo-2-iodopyrazolo[1,5-a]pyridine (1.3 g, 61.40%) as a light yellow solid. LC-MS: (M+H) + found 322.86. Step 3. Synthesis of 7-bromo-2-iodo-3-[(trifluoromethyl)thio]pyrazolo[1,5-a]pyridine
向7-溴-2-碘吡唑并[1,5-a]吡啶(1.35 g,4.18 mmol,1.00當量)於DMF (15.00 mL)中之攪拌溶液中添加2-[(三氟甲基)硫基]異吲哚-1,3-二酮(1.24 g,5.02 mmol,1.20當量)及NaCl (24.43 mg,0.42 mmol,0.10當量)。將所得混合物在90℃及氮氣氛圍下攪拌16 h。所得溶液藉由具有以下條件之反相急速層析純化:管柱,C18;移動相,於水中之MeCN,在20 min內0%至80%梯度;偵測器,UV 254 nm。此產生呈淺黃色固體之7-溴-2-碘-3-[(三氟甲基)硫基]吡唑并[1,5-a]吡啶(820.00 mg,46.37%)。LC-MS:(M+H) +實測值422.82。 步驟4. 4-[(3-{7-溴-3-[(三氟甲基)硫基]吡唑并[1,5-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺之合成 To a stirred solution of 7-bromo-2-iodopyrazolo[1,5-a]pyridine (1.35 g, 4.18 mmol, 1.00 equiv) in DMF (15.00 mL) was added 2-[(trifluoromethyl)thio]isoindole-1,3-dione (1.24 g, 5.02 mmol, 1.20 equiv) and NaCl (24.43 mg, 0.42 mmol, 0.10 equiv). The resulting mixture was stirred at 90 °C under nitrogen atmosphere for 16 h. The resulting solution was purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in water, gradient from 0% to 80% in 20 min; detector, UV 254 nm. This produced 7-bromo-2-iodo-3-[(trifluoromethyl)thio]pyrazolo[1,5-a]pyridine (820.00 mg, 46.37%) as a light yellow solid. LC-MS: (M+H) + found 422.82. Step 4. Synthesis of 4-[(3-{7-bromo-3-[(trifluoromethyl)thio]pyrazolo[1,5-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide
向7-溴-2-碘-3-[(三氟甲基)硫基]吡唑并[1,5-a]吡啶(300.00 mg,0.71 mmol,1.00當量)及3-甲氧基-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺(193.49 mg,0.89 mmol,1.25當量)於1,4-二噁烷(2.00 mL)中之攪拌溶液中添加CuI (135.07 mg,0.71 mmol,1.00當量)及K 3PO 4(903.28 mg,4.25 mmol,6.00當量)。將所得混合物在室溫及氮氣氛圍下攪拌16 h。在真空下移除溶劑且殘餘物藉由具有以下條件之反相急速層析純化:管柱,C18;移動相,於水中之MeCN,在40 min內0%至55%梯度;偵測器,UV 254 nm。此產生呈淺黃色固體之4-[(3-{7-溴-3-[(三氟甲基)硫基]吡唑并[1,5-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺(45.00 mg,12.36%)。LC-MS:(M+H) +實測值513.01。 步驟5. 4-{[3-(7-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吡唑并[1,5-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺之合成 To a stirred solution of 7-bromo-2-iodo-3-[(trifluoromethyl)thio]pyrazolo[1,5-a]pyridine (300.00 mg, 0.71 mmol, 1.00 equiv) and 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (193.49 mg, 0.89 mmol, 1.25 equiv) in 1,4-dioxane (2.00 mL) was added CuI (135.07 mg, 0.71 mmol, 1.00 equiv) and K 3 PO 4 (903.28 mg, 4.25 mmol, 6.00 equiv). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 16 h. The solvent was removed under vacuum and the residue was purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in water, gradient 0% to 55% in 40 min; detector, UV 254 nm. This resulted in 4-[(3-{7-bromo-3-[(trifluoromethyl)thio]pyrazolo[1,5-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (45.00 mg, 12.36%) as a light yellow solid. LC-MS: (M+H) + found 513.01. Step 5. Synthesis of 4-{[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide
向4-[(3-{7-溴-3-[(三氟甲基)硫基]吡唑并[1,5-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺(70.00 mg,0.14 mmol,1.00當量)及(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(55.94 mg,0.27 mmol,2.00當量)於THF (1.00 mL)中之攪拌溶液中添加tBuXPhosPd G3 (43.33 mg,0.05 mmol,0.40當量)及t-BuONa (78.63 mg,0.82 mmol,6.00當量)。將所得混合物在60℃及氮氣氛圍下攪拌20min。移除溶劑之後,殘餘物藉由具有以下條件之反相急速層析純化:管柱,C18;移動相,於水中之MeCN (0.1% FA),在20 min內0%至30%梯度;偵測器,UV 254 nm。粗產物藉由具有以下條件(管柱:XBridge Prep OBD C18管柱,30*150 mm,5 μm;移動相A:水(10 mmol/L NH 4HCO 3+ 0.05% NH 3H 2O),移動相B:ACN;流動速率:60 mL/min;梯度:在7min內33% B至63% B;波長:254nm/220 nm;RT(min):6.67)之製備型HPLC純化,以得到呈白色固體之4-{[3-(7-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吡唑并[1,5-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺(16.1 mg,20.91%)。LC-MS:(M+H) +實測值565.30。 1H NMR (400 MHz, DMSO- d 6) δ 8.11 (q, J= 4.4 Hz, 1H), 7.50 (t, J= 8.2 Hz, 1H), 7.41 (dd, J= 8.2, 1.8 Hz, 1H), 7.35 (d, J= 1.8 Hz, 1H), 7.01 (d, J= 8.5 Hz, 1H), 6.77 (d, J= 8.3 Hz, 1H), 6.49 (dd, J= 8.3, 5.4 Hz, 2H), 6.03 (t, J= 6.3 Hz, 1H), 4.86 (d, J= 49.5 Hz, 1H), 4.35 (d, J= 6.3 Hz, 2H), 3.85 (s, 4H), 3.05 (t, J= 11.5 Hz, 1H), 2.75 (d, J= 4.5 Hz, 4H), 2.35-2.05 (m, 5H), 2.04-1.90 (m, 1H), 1.81 (d, J= 11.7 Hz, 1H)。 實例251 rel-4-{[3-(8-{[(1R,5R,6S,7S)-6-氟-3-氧雜-9-氮雜雙環[3.3.1]壬-7-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺之合成 步驟1. 7-[(三乙基矽烷基)氧基]-3-氧雜-9-氮雜雙環[3.3.1]壬-6-烯-9-甲酸三級丁酯之合成 To a stirred solution of 4-[(3-{7-bromo-3-[(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (70.00 mg, 0.14 mmol, 1.00 equiv) and (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (55.94 mg, 0.27 mmol, 2.00 equiv) in THF (1.00 mL) was added tBuXPhosPd G3 (43.33 mg, 0.05 mmol, 0.40 equiv) and t-BuONa (78.63 mg, 0.82 mmol, 6.00 equiv). The resulting mixture was stirred at 60 °C under nitrogen atmosphere for 20 min. After removal of the solvent, the residue was purified by reverse phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN (0.1% FA) in water, gradient from 0% to 30% in 20 min; detector, UV 254 nm. The crude product was purified by reverse phase flash chromatography with the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 + 0.05% NH 3 H 2 O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 33% B to 63% B in 7 min; wavelength: 254 nm/220 nm; RT (min): 6.67) to give 4-{[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (16.1 mg, 20.91%) as a white solid. LC-MS: (M+H) + found 565.30. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.11 (q, J = 4.4 Hz, 1H), 7.50 (t, J = 8.2 Hz, 1H), 7.41 (dd, J = 8.2, 1.8 Hz, 1H), 7.35 (d, J = 1.8 Hz, 1H), 7.01 (d, J = 8.5 Hz, 1H), 6.77 (d, J = 8.3 Hz, 1H), 6.49 (dd, J = 8.3, 5.4 Hz, 2H), 6.03 (t, J = 6.3 Hz, 1H), 4.86 (d, J = 49.5 Hz, 1H), 4.35 (d, J = 6.3 Hz, 2H), 3.85 (s, 4H), 3.05 (t, J = 11.5 Hz, 1H), 2.75 (d, J = 4.5 Hz, 4H), 2.35-2.05 (m, 5H), 2.04-1.90 (m, 1H), 1.81 (d, J = 11.7 Hz, 1H). Example 251 Synthesis of rel-4-{[3-(8-{[(1R,5R,6S,7S)-6-fluoro-3-oxadiazol-9-azabicyclo[3.3.1]non-7-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide Step 1. Synthesis of tert-butyl 7-[(triethylsilyl)oxy]-3-oxa-9-azabicyclo[3.3.1]non-6-ene-9-carboxylate
在-78℃及氮氣氛圍下,向7-側氧基-3-氧雜-9-氮雜雙環[3.3.1]壬烷-9-甲酸三級丁酯(2.8 g,11.61 mmol,1當量)於THF (40 mL)中之混合物中逐滴添加LDA (1.74 g,16.25 mmol,1.4當量)。將混合物在-78℃下攪拌1 h。然後在-78℃下添加氯三乙基矽烷(2.10 g,13.93 mmol,1.2當量)。將混合物在-10℃下攪拌2 h。混合物用NaHCO 3(10%水溶液)淬滅且水相用EA (300 mL)萃取三次。合併的有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。產生呈黃色油狀物之7-[(三乙基矽烷基)氧基]-3-氧雜-9-氮雜雙環[3.3.1]壬-6-烯-9-甲酸三級丁酯(3 g,72.71%) (粗物質)。 步驟2. (1S,5S,6S)-6-氟-7-側氧基-3-氧雜-9-氮雜雙環[3.3.1]壬烷-9-甲酸三級丁酯之合成 To a mixture of tributyl 7-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (2.8 g, 11.61 mmol, 1 eq) in THF (40 mL) was added LDA (1.74 g, 16.25 mmol, 1.4 eq) dropwise at -78 °C under nitrogen atmosphere. The mixture was stirred at -78 °C for 1 h. Chlorotriethylsilane (2.10 g, 13.93 mmol, 1.2 eq) was then added at -78 °C. The mixture was stirred at -10 °C for 2 h. The mixture was quenched with NaHCO 3 (10% aqueous solution) and the aqueous phase was extracted three times with EA (300 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. This gave tert-butyl 7-[(triethylsilyl)oxy]-3-oxa-9-azabicyclo[3.3.1]non-6-ene-9-carboxylate (3 g, 72.71%) as a yellow oil (crude). Step 2. Synthesis of tert-butyl (1S,5S,6S)-6-fluoro-7-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate
在-30℃及氮氣氛圍下,向Selectfluor (4.48 g,12.66 mmol,1.5當量)於ACN (50 mL)中之混合物中逐滴添加7-[(三乙基矽烷基)氧基]-3-氧雜-9-氮雜雙環[3.3.1]壬-6-烯-9-甲酸三級丁酯(3 g,8.44 mmol,1當量)。將混合物在-30℃下攪拌30 min。然後將混合物在10℃下攪拌30 min。混合物用水淬滅。且水相用EA (300 mL)萃取三次。合併的有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。殘餘物藉由具有以下條件之反相急速層析純化:管柱,C18矽膠;移動相,於0.1%TFA中之MeOH,在10 min內35%至60%梯度;偵測器,UV 220 nm,以得到呈淺黃色固體之(1S,5S,6S)-6-氟-7-側氧基-3-氧雜-9-氮雜雙環[3.3.1]壬烷-9-甲酸三級丁酯(2 g,91.42%)。LC-MS:(M-t-Bu +)實測值:204.10。 步驟3. (1S,5S,6R,7R)-7-胺基-6-氟-3-氧雜-9-氮雜雙環[3.3.1]壬烷-9-甲酸三級丁酯之合成 To a mixture of Selectfluor (4.48 g, 12.66 mmol, 1.5 eq.) in ACN (50 mL) was added tributyl 7-[(triethylsilyl)oxy]-3-oxa-9-azabicyclo[3.3.1]non-6-ene-9-carboxylate (3 g, 8.44 mmol, 1 eq.) dropwise at -30 °C under nitrogen atmosphere. The mixture was stirred at -30 °C for 30 min. Then the mixture was stirred at 10 °C for 30 min. The mixture was quenched with water. And the aqueous phase was extracted three times with EA (300 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeOH in 0.1% TFA, gradient 35% to 60% in 10 min; detector, UV 220 nm to give (1S,5S,6S)-6-fluoro-7-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylic acid tributyl ester (2 g, 91.42%) as a light yellow solid. LC-MS: (Mt-Bu + ) found: 204.10. Step 3. Synthesis of (1S,5S,6R,7R)-7-amino-6-fluoro-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester
將(1S,5S,6S)-6-氟-7-側氧基-3-氧雜-9-氮雜雙環[3.3.1]壬烷-9-甲酸三級丁酯(500 mg,1.93 mmol,1當量)及NH 4OAc (1.04 g,13.50 mmol,7當量)於MeOH (10 mL)中之混合物在室溫下攪拌2 h,然後添加NaBH 3CN (181.77 mg,2.89 mmol,1.5當量),將混合物在60℃下攪拌16 h。反應混合物用水(10 mL)淬滅,且將混合物真空濃縮。殘餘物藉由具有以下條件之反相急速層析純化:管柱,C18矽膠;移動相,於0.1%FA中之MeCN,在10 min內20%至40%梯度;偵測器,UV 200 nm,以得到呈灰白色油狀物之(1S,5S,6R,7R)-7-胺基-6-氟-3-氧雜-9-氮雜雙環[3.3.1]壬烷-9-甲酸三級丁酯(400 mg,79.68%)。LC-MS:(M+H +)實測值:261.10。 步驟4. (1S,5S,6R,7R)-6-氟-7-{[2-(3-{[2-甲氧基-4-(甲基胺甲醯基)苯基]胺基}丙-1-炔-1-基)-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-8-基]胺基}-3-氧雜-9-氮雜雙環[3.3.1]壬烷-9-甲酸三級丁酯之合成 A mixture of tributyl (1S,5S,6S)-6-fluoro-7-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (500 mg, 1.93 mmol, 1 eq) and NH4OAc (1.04 g, 13.50 mmol, 7 eq) in MeOH (10 mL) was stirred at room temperature for 2 h, then NaBH3CN (181.77 mg, 2.89 mmol, 1.5 eq) was added and the mixture was stirred at 60°C for 16 h. The reaction mixture was quenched with water (10 mL), and the mixture was concentrated in vacuo. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in 0.1% FA, gradient from 20% to 40% in 10 min; detector, UV 200 nm to give (1S,5S,6R,7R)-7-amino-6-fluoro-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylic acid tributyl ester (400 mg, 79.68%) as an off-white oil. LC-MS: (M+H + ) found: 261.10. Step 4. Synthesis of (1S,5S,6R,7R)-6-fluoro-7-{[2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]amino}-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylic acid tributyl ester
將4-[(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺(360 mg,0.70 mmol,1當量)、(1S,5S,6R,7R)-7-胺基-6-氟-3-氧雜-9-氮雜雙環[3.3.1]壬烷-9-甲酸三級丁酯(219.07 mg,0.84 mmol,1.2當量)、Cs 2CO 3(685.49 mg,2.103 mmol,3當量)、Pd-PEPPSI-IHeptCl 3-氯吡啶(34.15 mg,0.04 mmol,0.05當量)於二噁烷(8 mL)中之混合物在100℃及氮氣氛圍下攪拌16 h。反應混合物用水(100 mL)稀釋且水相用EA (100 mL)萃取兩次。合併的有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。殘餘物藉由製備型TLC (DCM/MeOH=20:1)純化,以得到呈淺黃色固體之(1S,5S,6R,7R)-6-氟-7-{[2-(3-{[2-甲氧基-4-(甲基胺甲醯基)苯基]胺基}丙-1-炔-1-基)-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-8-基]胺基}-3-氧雜-9-氮雜雙環[3.3.1]壬烷-9-甲酸三級丁酯(380 mg,78.22%)。LC-MS:(M+H +)實測值:693.35。 步驟5. 4-{[3-(8-{[(1S,5S,6R,7R)-6-氟-3-氧雜-9-氮雜雙環[3.3.1]壬-7-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺之合成 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (360 mg, 0.70 mmol, 1 eq.), (1S,5S,6R,7R)-7-amino-6-fluoro-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylic acid tributyl ester (219.07 mg, 0.84 mmol, 1.2 eq.), Cs 2 CO 3 (685.49 mg, 2.103 mmol, 3 eq.), Pd-PEPPSI-IHeptCl 3-chloropyridine (34.15 mg, 0.04 mmol, 0.05 eq.) in dioxane (8 The mixture in 100 mL) was stirred at 100 °C under nitrogen atmosphere for 16 h. The reaction mixture was diluted with water (100 mL) and the aqueous phase was extracted twice with EA (100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative TLC (DCM/MeOH=20:1) to give (1S,5S,6R,7R)-6-fluoro-7-{[2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]amino}-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylic acid tributyl ester (380 mg, 78.22%) as a light yellow solid. LC-MS: (M+H + ) found: 693.35. Step 5. Synthesis of 4-{[3-(8-{[(1S,5S,6R,7R)-6-fluoro-3-oxa-9-azabicyclo[3.3.1]non-7-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide
將(1S,5S,6R,7R)-6-氟-7-{[2-(3-{[2-甲氧基-4-(甲基胺甲醯基)苯基]胺基}丙-1-炔-1-基)-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-8-基]胺基}-3-氧雜-9-氮雜雙環[3.3.1]壬烷-9-甲酸三級丁酯(160 mg,0.23 mmol,1當量)於DCM (3 mL)及TFA (1.5 mL)中之混合物在室溫及空氣氛圍下攪拌1 h。將所得混合物在減壓下濃縮。所得混合物用EA (50 ml)稀釋,然後用飽和NaHCO3 (水溶液)將混合物鹼化至pH 8。水層用EtOAc (2x50 mL)萃取。將所得混合物在真空下濃縮。所得粗材料藉由製備型HPLC (管柱:X-Select Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(0.1%FA),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在7 min內30% B至50% B;波長:254nm/220nm nm;RT1(min):6.56)純化。凍乾產生呈黃色固體之4-{[3-(8-{[(1S,5S,6R,7R)-6-氟-3-氧雜-9-氮雜雙環[3.3.1]壬-7-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺(100 mg,73.06%)。LC-MS:(M+H +)實測值:593.20。 步驟5. rel-4-{[3-(8-{[(1R,5R,6S,7S)-6-氟-3-氧雜-9-氮雜雙環[3.3.1]壬-7-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺之合成 A mixture of (1S,5S,6R,7R)-6-fluoro-7-{[2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]amino}-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylic acid tributyl ester (160 mg, 0.23 mmol, 1 eq.) in DCM (3 mL) and TFA (1.5 mL) was stirred at room temperature under air atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with EA (50 ml), and then the mixture was basified to pH 8 with saturated NaHCO3 (aq.). The aqueous layer was extracted with EtOAc (2x50 mL). The resulting mixture was concentrated under vacuum. The crude material was purified by preparative HPLC (column: X-Select Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 30% B to 50% B in 7 min; wavelength: 254 nm/220 nm nm; RT1 (min): 6.56). Lyophilization gave 4-{[3-(8-{[(1S,5S,6R,7R)-6-fluoro-3-oxa-9-azabicyclo[3.3.1]non-7-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (100 mg, 73.06%) as a yellow solid. LC-MS: (M+H + ) found: 593.20. Step 5. Synthesis of rel-4-{[3-(8-{[(1R,5R,6S,7S)-6-fluoro-3-oxa-9-azabicyclo[3.3.1]non-7-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide
所得4-{[3-(8-{[(1S,5S)-6-氟-3-氧雜-9-氮雜雙環[3.3.1]壬-7-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺(100 mg,0.169 mmol,1當量)用掌性製備型HPLC (管柱:CHIRALPAKIF3;移動相A:Hex(0.1%DEA):EtOH=50:50;流動速率:1mL/min mL/min;梯度:等度;注入體積:2uL mL)純化。凍乾產生呈灰白色固體之rel-4-{[3-(8-{[(1R,5R,6S,7S)-6-氟-3-氧雜-9-氮雜雙環[3.3.1]壬-7-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺(9.0 mg,8.84%)。LC-MS:(M+H) +實測值:593.20。 1H NMR (400 MHz, DMSO- d 6) δ 8.11 (m, 1H), 7.83 (d, J= 6.6 Hz, 1H), 7.41 (dd, J= 8.3, 1.9 Hz, 1H), 7.35 (d, J= 1.9 Hz, 1H), 7.03 (dd, J= 7.7, 6.7 Hz, 1H), 6.95 (d, J= 10.7 Hz, 1H), 6.76 (d, J= 8.3 Hz, 1H), 6.56 (d, J= 7.7 Hz, 1H), 6.01 (t, J= 6.3 Hz, 1H), 4.63 (m, 1H), 4.32 (d, J= 6.3 Hz, 2H), 4.06 (s, 1H), 3.85 (s, 3H), 3.80 (d, J= 11.2 Hz, 1H), 3.74 – 3.61 (m, 3H), 2.92 (m, 2H), 2.75 (d, J= 4.4 Hz, 3H), 2.35 (dd, J= 14.7, 8.3 Hz, 1H), 1.57 (d, J= 14.1 Hz, 1H)。 實例275 4-{[3-(7-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吡唑并[1,5-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺之合成 步驟1. 3-[5-(甲基胺甲醯基)-2-(丙-2-炔-1-基胺基)苯氧基]氮雜環丁烷-1-甲酸三級丁酯之合成 The obtained 4-{[3-(8-{[(1S,5S)-6-fluoro-3-oxa-9-azabicyclo[3.3.1]non-7-yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (100 mg, 0.169 mmol, 1 equivalent) was purified by chiral preparative HPLC (column: CHIRALPAK IF3; mobile phase A: Hex (0.1% DEA): EtOH = 50:50; flow rate: 1 mL/min mL/min; gradient: isocratic; injection volume: 2 uL mL). Lyophilization gave rel-4-{[3-(8-{[(1R,5R,6S,7S)-6-fluoro-3-oxa-9-azabicyclo[3.3.1]non-7-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (9.0 mg, 8.84%) as an off-white solid. LC-MS: (M+H) + found: 593.20. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.11 (m, 1H), 7.83 (d, J = 6.6 Hz, 1H), 7.41 (dd, J = 8.3, 1.9 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.03 (dd, J = 7.7, 6.7 Hz, 1H), 6.95 (d, J = 10.7 Hz, 1H), 6.76 (d, J = 8.3 Hz, 1H), 6.56 (d, J = 7.7 Hz, 1H), 6.01 (t, J = 6.3 Hz, 1H), 4.63 (m, 1H), 4.32 (d, J = 6.3 Hz, 3H), 4.06 (s, 1H), 3.85 (s, 3H), 3.80 (d, J = 11.2 Hz, 1H), 3.74 – 3.61 (m, 3H), 2.92 (m, 2H), 2.75 (d, J = 4.4 Hz, 3H), 2.35 (dd, J = 14.7, 8.3 Hz, 1H), 1.57 (d, J = 14.1 Hz, 1H). Example 275 Synthesis of 4-{[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide Step 1. Synthesis of tert-butyl 3-[5-(methylaminoformyl)-2-(prop-2-yn-1-ylamino)phenoxy]azinecyclobutane-1-carboxylate
在室溫下,向3-羥基-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺(204 mg,0.99 mmol,1.00當量)及3-碘氮雜環丁烷-1-甲酸三級丁酯(311 mg,1.09 mmol,1.10當量)於DMF (4.00 mL)中之攪拌溶液中添加Cs 2CO 3(976 mg,2.99 mmol,3.00當量)。將所得混合物在50℃下攪拌2 h。過濾所得混合物,濾餅用乙酸乙酯(3 x 10 mL)洗滌。將濾液在減壓下濃縮。殘餘物藉由具有以下條件之反相急速層析純化:管柱,C18矽膠;移動相,於水中之MeCN (10 mmol/L NH 4HCO 3),在10 min內10%至50%梯度;偵測器,UV 254 nm。此產生呈黃色油狀物之3-[5-(甲基胺甲醯基)-2-(丙-2-炔-1-基胺基)苯氧基]氮雜環丁烷-1-甲酸三級丁酯(200 mg,55.71%)。LC-MS:(M+H) +實測值:360.15。 步驟2. 3-{2-[(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-5-(甲基胺甲醯基)苯氧基}氮雜環丁烷-1-甲酸三級丁酯之合成 To a stirred solution of 3-hydroxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (204 mg, 0.99 mmol, 1.00 equiv) and tert-butyl 3-iodoazolobutane-1-carboxylate (311 mg, 1.09 mmol, 1.10 equiv) in DMF (4.00 mL) at room temperature was added Cs 2 CO 3 (976 mg, 2.99 mmol, 3.00 equiv). The resulting mixture was stirred at 50 °C for 2 h. The resulting mixture was filtered and the filter cake was washed with ethyl acetate (3 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH 4 HCO 3 ) in water, gradient 10% to 50% in 10 min; detector, UV 254 nm. This yielded tert-butyl 3-[5-(methylaminoformyl)-2-(prop-2-yn-1-ylamino)phenoxy]azepanocyclobutane-1-carboxylate (200 mg, 55.71%) as a yellow oil. LC-MS: (M+H) + found: 360.15. Step 2. Synthesis of tert-butyl 3-{2-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-5-(methylaminoformyl)phenoxy}azinecyclobutane-1-carboxylate
在室溫及氮氣氛圍下,向3-[5-(甲基胺甲醯基)-2-(丙-2-炔-1-基胺基)苯氧基]氮雜環丁烷-1-甲酸三級丁酯(230 mg,0.64 mmol,1.00當量)及8-溴-2-碘-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶(270 mg,0.64 mmol,1.00當量)於DMSO (4.00 mL)中之攪拌溶液中添加Pd(PPh 3) 4(36 mg,0.032 mmol,0.05當量)及CuI (12 mg,0.064 mmol,0.10當量)以及i-Pr 2NH (161 mg,1.60 mmol,2.50當量)。將所得混合物在室溫及氮氣氛圍下攪拌1 h。殘餘物藉由具有以下條件之反相急速層析純化:管柱,C18矽膠;移動相,於水中之MeCN (10 mmol/L NH 4HCO 3),在10 min內10%至50%梯度;偵測器,UV 254 nm。此產生3-{2-[(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-5-(甲基胺甲醯基)苯氧基}氮雜環丁烷-1-甲酸三級丁酯(380 mg,粗物質)。粗物質藉由矽膠管柱層析純化,用CH 2Cl 2/ MeOH (20:1)溶析,以得到呈黃色固體之3-{2-[(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-5-(甲基胺甲醯基)苯氧基}氮雜環丁烷-1-甲酸三級丁酯(250 mg,59.69%)。LC-MS:(M+H) +實測值:654.15。 步驟3. 3-(2-{[3-(8-{[(3R,4R)-3-氟氧雜環己-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-5-(甲基胺甲醯基)苯氧基)氮雜環丁烷-1-甲酸三級丁酯之合成 To a stirred solution of tributyl 3-[5-(methylaminocarbonyl)-2-(prop-2-yn-1-ylamino)phenoxy]azepanocyclobutane-1-carboxylate (230 mg, 0.64 mmol, 1.00 equiv) and 8-bromo-2-iodo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine (270 mg, 0.64 mmol, 1.00 equiv) in DMSO (4.00 mL) at room temperature under nitrogen atmosphere were added Pd(PPh 3 ) 4 (36 mg, 0.032 mmol, 0.05 equiv) and CuI (12 mg, 0.064 mmol, 0.10 equiv) and i-Pr 2 NH (161 mg, 1.60 mmol, 2.50 equiv). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 h. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH 4 HCO 3 ) in water, gradient from 10% to 50% in 10 min; detector, UV 254 nm. This yielded tributyl 3-{2-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-5-(methylaminocarbonyl)phenoxy}azepanocyclobutane-1-carboxylate (380 mg, crude material). The crude material was purified by silica gel column chromatography, eluting with CH 2 Cl 2 / MeOH (20:1) to give tert-butyl 3-{2-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-5-(methylaminoformyl)phenoxy}azepanocyclobutane-1-carboxylate (250 mg, 59.69%) as a yellow solid. LC-MS: (M+H) + found: 654.15. Step 3. Synthesis of tert-butyl 3-(2-{[3-(8-{[(3R,4R)-3-fluorooxycyclohexyl-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-5-(methylaminoformyl)phenoxy)azinecyclobutane-1-carboxylate
在室溫及氮氣氛圍下,向3-{2-[(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-5-(甲基胺甲醯基)苯氧基}氮雜環丁烷-1-甲酸三級丁酯(270 mg,0.41 mmol,1.00當量)及(3R,4R)-3-氟氧雜環己-4-胺(73 mg,0.61 mmol,1.50當量)於二噁烷(8.00 mL) 中之攪拌溶液中添加Pd-PEPPSI-IHeptCl 3-氯吡啶(40 mg,0.041 mmol,0.10當量)及Cs 2CO 3(672 mg,2.06 mmol,5.00當量)。將所得混合物在100℃及氮氣氛圍下攪拌隔夜。反應用NaHCO 3水溶液淬滅。所得混合物用EtOAc (4 x 10 mL)萃取。合併的有機層用鹽水洗滌,經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用CH 2Cl 2/ MeOH (20:1)溶析,以得到呈黃色固體之3-(2-{[3-(8-{[(3R,4R)-3-氟氧雜環己-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-5-(甲基胺甲醯基)苯氧基)氮雜環丁烷-1-甲酸三級丁酯(270 mg,94.48%)。LC-MS:(M+H) +實測值:693.25。 步驟4. 3-(氮雜環丁-3-基氧基)-4-{[3-(8-{[(3R,4R)-3-氟氧雜環己-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-N-甲基苯甲醯胺之合成 To a stirred solution of tributyl 3-{2-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-5-(methylaminocarbonyl)phenoxy}azepanobutane-1-carboxylate (270 mg, 0.41 mmol, 1.00 equiv) and (3R,4R)-3-fluorooxacyclohexan-4-amine (73 mg, 0.61 mmol, 1.50 equiv) in dioxane (8.00 mL) was added Pd-PEPPSI-IHeptCl 3-chloropyridine (40 mg, 0.041 mmol, 0.10 equiv) and Cs 2 CO 3 (672 mg, 2.06 mmol, 5.00 equiv). The resulting mixture was stirred at 100 °C under nitrogen atmosphere overnight. The reaction was quenched with aqueous NaHCO 3 solution. The resulting mixture was extracted with EtOAc (4 x 10 mL). The combined organic layers were washed with brine and dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with CH 2 Cl 2 / MeOH (20:1) to give tert-butyl 3-(2-{[3-(8-{[(3R,4R)-3-fluorooxacyclohex-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-5-(methylaminoformyl)phenoxy)azinecyclobutane-1-carboxylate (270 mg, 94.48%) as a yellow solid. LC-MS: (M+H) + found: 693.25. Step 4. Synthesis of 3-(azacyclobut-3-yloxy)-4-{[3-(8-{[(3R,4R)-3-fluorooxacyclohexyl-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide
在0℃下,向3-(2-{[3-(8-{[(3R,4R)-3-氟氧雜環己-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-5-(甲基胺甲醯基)苯氧基)氮雜環丁烷-1-甲酸三級丁酯(150 mg,0.21 mmol,1.00當量)於DCM (3.00 mL)中之攪拌溶液中逐滴添加TFA (1.00 mL)。將所得混合物在室溫下攪拌0.5 h。用飽和NaHCO 3(水溶液)將混合物/殘餘物鹼化至pH 8。所得混合物用CH 2Cl 2/MeOH (10:1, 5 x 5 mL)萃取。合併的有機層用鹽水洗滌,經無水Na2SO4乾燥。過濾之後,將濾液在減壓下濃縮。此產生呈黃色固體之3-(氮雜環丁-3-基氧基)-4-{[3-(8-{[(3R,4R)-3-氟氧雜環己-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-N-甲基苯甲醯胺(120 mg,93.52%)。LC-MS:(M+H) +實測值:593.20。 步驟5. 4-{[3-(8-{[(3R,4R)-3-氟氧雜環己-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-N-甲基-3-[(1-甲基氮雜環丁-3-基)氧基]苯甲醯胺之合成 To a stirred solution of tributyl 3-(2-{[3-(8-{[(3R,4R)-3-fluorooxacyclohex-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-5-(methylaminocarbonyl)phenoxy)azepanocyclobutane-1-carboxylate (150 mg, 0.21 mmol, 1.00 equiv) in DCM (3.00 mL) at 0°C was added TFA (1.00 mL) dropwise. The resulting mixture was stirred at room temperature for 0.5 h. The mixture/residue was basified to pH 8 with saturated NaHCO3 (aq). The resulting mixture was extracted with CH 2 Cl 2 /MeOH (10:1, 5 x 5 mL). The combined organic layers were washed with brine and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. This resulted in 3-(azacyclobutan-3-yloxy)-4-{[3-(8-{[(3R,4R)-3-fluorooxacyclohexan-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide (120 mg, 93.52%) as a yellow solid. LC-MS: (M+H) + found: 593.20. Step 5. Synthesis of 4-{[3-(8-{[(3R,4R)-3-fluorooxycyclohexyl-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methyl-3-[(1-methylazolobutyl-3-yl)oxy]benzamide
在室溫下,向3-(氮雜環丁-3-基氧基)-4-{[3-(8-{[(3R,4R)-3-氟氧雜環己-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-N-甲基苯甲醯胺(115 mg,0.19 mmol,1.00當量)及POM (11 mg,0.38 mmol,2.00當量)於MeOH (5.00 mL)中之攪拌溶液中添加HOAc (11 mg,0.19 mmol,1.00當量)及NaBH 3CN (36 mg,0.58 mmol,3.00當量)。將所得混合物在50℃下攪拌3 h。反應用NaHCO 3水溶液淬滅。所得混合物用CH 2Cl 2/ MeOH (10:1,4 x 10 mL)萃取。合併的有機層用鹽水洗滌,經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。粗產物(110 mg)藉由具有以下條件(管柱:xBridge Prep Phenyl,5μm OBD 19*250mm;移動相A:水(10 mmol/L NH 4HCO 3),移動相B:ACN;流動速率:20 mL/min mL/min;梯度:在20 MIN內等度35%B - 65%B;波長:220/254 nm;RT1(min):14)之製備型HPLC純化,以得到呈白色固體之4-{[3-(8-{[(3R,4R)-3-氟氧雜環己-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-N-甲基-3-[(1-甲基氮雜環丁-3-基)氧基]苯甲醯胺(50.7 mg,42.34%)。LC-MS:(M+H) +實測值:607.10。 1H NMR (400 MHz, DMSO-d6) δ 8.08 (d, J = 4.6 Hz, 1H), 7.88 (d, J = 6.6 Hz, 1H), 7.42 (dd, J = 8.3, 1.9 Hz, 1H), 7.08 (d, J = 1.8 Hz, 1H), 7.03 (t, J = 7.2 Hz, 1H), 6.77 (dd, J = 8.4, 1.6 Hz, 1H), 6.67 (d, J = 7.7 Hz, 1H), 6.04 (t, J = 6.3 Hz, 1H), 5.75 (d, J = 9.0 Hz, 1H), 4.86 - 4.73 (m, 2H), 4.34 (d, J = 6.2 Hz, 2H), 4.05 - 3.90 (m, 3H), 3.79 – 3.75 (m, 2H), 3.67 -3.33 (m, 2H), 3.06 – 3.03 (m, 2H), 2.75 - 2.65 (m, 3H), 2.31 (s, 3H), 1.93 -1.92 (m, 1H), 1.83 -1.78 (m, 1H)。 實例308 N-[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]-5-甲氧基-2H-吲唑-6-胺之合成 步驟1. 5-甲氧基-6-硝基-2-(氧雜環己-2-基)吲唑之合成 To a stirred solution of 3-(azacyclobutan-3-yloxy)-4-{[3-(8-{[(3R,4R)-3-fluorooxacyclohexan-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide (115 mg, 0.19 mmol, 1.00 equiv) and POM (11 mg, 0.38 mmol, 2.00 equiv) in MeOH (5.00 mL) was added HOAc (11 mg, 0.19 mmol, 1.00 equiv) and NaBH 3 CN (36 mg, 0.58 mmol, 3.00 equiv) at room temperature. The resulting mixture was stirred at 50 °C for 3 h. The reaction was quenched with aqueous NaHCO 3 solution. The resulting mixture was extracted with CH 2 Cl 2 / MeOH (10:1, 4 x 10 mL). The combined organic layers were washed with brine and dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (110 mg) was purified by HPLC with the following conditions (column: xBridge Prep Phenyl, 5μm OBD 19*250mm; mobile phase A: water (10 mmol/L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 20 mL/min mL/min; gradient: isocratic 35%B - 65%B in 20 MIN; wavelength: 220/254 nm; RT1 (min): 14) was purified by preparative HPLC to give 4-{[3-(8-{[(3R,4R)-3-fluorooxazolohexan-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-N-methyl-3-[(1-methylazolobutan-3-yl)oxy]benzamide (50.7 mg, 42.34%) as a white solid. LC-MS: (M+H) + found: 607.10. 1 H NMR (400 MHz, DMSO-d6) δ 8.08 (d, J = 4.6 Hz, 1H), 7.88 (d, J = 6.6 Hz, 1H), 7.42 (dd, J = 8.3, 1.9 Hz, 1H), 7.08 (d, J = 1.8 Hz, 1H), 7.03 (t, J = 7.2 Hz, 1H), 6.77 (dd, J = 8.4, 1.6 Hz, 1H), 6.67 (d, J = 7.7 Hz, 1H), 6.04 (t, J = 6.3 Hz, 1H), 5.75 (d, J = 9.0 Hz, 1H), 4.86 - 4.73 (m, 2H), 4.34 (d, J = 6.2 Hz, 2H), 4.05 - 3.90 (m, 3H), 3.79 – 3.75 (m, 2H), 3.67 -3.33 (m, 2H), 3.06 – 3.03 (m, 2H), 2.75 - 2.65 (m, 3H), 2.31 (s, 3H), 1.93 -1.92 (m, 1H), 1.83 -1.78 (m, 1H). Example 308 Synthesis of N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]-5-methoxy-2H-indazol-6-amine Step 1. Synthesis of 5-methoxy-6-nitro-2-(oxacyclohexyl-2-yl)indazole
在室溫及空氣氛圍下,向5-甲氧基-6-硝基-2H-吲唑(1 g,5.17 mmol,1.00當量)及DHP (650 mg,7.76 mmol,1.50當量)於DCM (10 mL)中之攪拌溶液中逐份添加TsOH (90 mg,0.51 mmol,0.10當量)。將所得混合物在50℃及空氣氣氛下攪拌隔夜。將所得混合物在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用PE / EA (5:1)溶析,以得到呈黃色固體之5-甲氧基-6-硝基-2-(氧雜環己-2-基)吲唑(1.20 g,83.60%)。LC-MS:(M+H) +實測值:278。 步驟2. 5-甲氧基-2-(氟氧雜環己-2-基)吲唑-6-胺之合成 To a stirred solution of 5-methoxy-6-nitro-2H-indazole (1 g, 5.17 mmol, 1.00 equiv) and DHP (650 mg, 7.76 mmol, 1.50 equiv) in DCM (10 mL) was added TsOH (90 mg, 0.51 mmol, 0.10 equiv) portionwise at room temperature and air atmosphere. The resulting mixture was stirred at 50 °C and air atmosphere overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (5:1) to give 5-methoxy-6-nitro-2-(oxacyclohexan-2-yl)indazole (1.20 g, 83.60%) as a yellow solid. LC-MS: (M+H) + found: 278. Step 2. Synthesis of 5-methoxy-2-(fluorooxycyclohexyl-2-yl)indazole-6-amine
在室溫及空氣氛圍下,向5-甲氧基-6-硝基-2-(氧雜環己-2-基)吲唑(1.10 g,3.96 mmol,1.00當量)及Fe (2.22 g,39.67 mmol,10.00當量)於MeOH (10 mL)中之攪拌溶液中逐份添加NH 4Cl (4.24 g,79.34 mmol,20.00當量)。過濾所得混合物,濾餅用EtOAc (3x10 mL)洗滌。將濾液在減壓下濃縮。合併的有機層用鹽水(1x10 mL)洗滌,經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。將所得混合物在減壓下濃縮。此產生呈黃色固體之5-甲氧基-2-(氧雜環己-2-基)吲唑-6-胺(0.8 g,81.54%)。LC-MS:(M+H) +實測值:248。 步驟3. 5-甲氧基-2-(氧雜環己-2-基)-N-(丙-2-炔-1-基)吲唑-6-胺之合成 To a stirred solution of 5-methoxy-6-nitro-2-(oxacyclohexan-2-yl)indazole (1.10 g, 3.96 mmol, 1.00 equiv) and Fe (2.22 g, 39.67 mmol, 10.00 equiv) in MeOH (10 mL) was added NH 4 Cl (4.24 g, 79.34 mmol, 20.00 equiv) portionwise at room temperature under air atmosphere. The resulting mixture was filtered and the filter cake was washed with EtOAc (3×10 mL). The filtrate was concentrated under reduced pressure. The combined organic layers were washed with brine (1×10 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure. This gave 5-methoxy-2-(oxacyclohex-2-yl)indazol-6-amine (0.8 g, 81.54%) as a yellow solid. LC-MS: (M+H) + found: 248. Step 3. Synthesis of 5-methoxy-2-(oxacyclohex-2-yl)-N-(prop-2-yn-1-yl)indazol-6-amine
在室溫及空氣氛圍下,向5-甲氧基-2-(氧雜環己-2-基)吲唑-6-胺(1.00 g,4.04 mmol,1.00當量)及炔丙基溴(0.53 g,4.44 mmol,1.10當量)於DMF (10 mL)中之攪拌溶液中逐份添加K 2CO 3(1.68 g,12.13 mmol,3.00當量)。將所得混合物在70℃及空氣氛圍下攪拌2 h。在室溫下用水淬滅反應。所得混合物用EtOAc (3 x 100 mL)萃取。合併的有機層用鹽水(2x100 mL)洗滌,經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由具有以下條件之反相急速層析純化:管柱,C18矽膠;移動相,於水中之MeCN (0.1% TFA),在10 min內10%至50%梯度;偵測器,UV 254 nm。此產生呈棕色固體之5-甲氧基-2-(氧雜環己-2-基)-N-(丙-2-炔-1-基)吲唑-6-胺(0.8 g,69.33%)。LC-MS:(M+H +)實測值:286。 步驟4. N-(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)-5-甲氧基-2-(氧雜環己-2-基)吲唑-6-胺)之合成 To a stirred solution of 5-methoxy-2-(oxacyclohexan-2-yl)indazol-6-amine (1.00 g, 4.04 mmol, 1.00 equiv) and propargyl bromide (0.53 g, 4.44 mmol, 1.10 equiv) in DMF (10 mL) was added K 2 CO 3 (1.68 g, 12.13 mmol, 3.00 equiv) portionwise at room temperature under air atmosphere. The resulting mixture was stirred at 70 °C under air atmosphere for 2 h. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% TFA) in water, gradient 10% to 50% in 10 min; detector, UV 254 nm. This yielded 5-methoxy-2-(oxacyclohex-2-yl)-N-(prop-2-yn-1-yl)indazol-6-amine (0.8 g, 69.33%) as a brown solid. LC-MS: (M+H + ) found: 286. Step 4. Synthesis of N-(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-5-methoxy-2-(oxacyclohexyl-2-yl)indazol-6-amine)
在室溫及氮氣氛圍下,向5-甲氧基-2-(氧雜環己-2-基)-N-(丙-2-炔-1-基)吲唑-6-胺(135 mg,0.47 mmol,1.00當量)及8-溴-2-碘-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶(200 mg,0.47 mmol,1.00當量)於DMSO (4 mL)中之攪拌溶液中逐份添加CuI (90 mg,0.47 mmol,1.00當量)及i-Pr 2NH (479 mg,4.73 mmol,10.00當量)。在室溫下,歷時1min向上述混合物中逐份添加Pd(PPh 3) 4(219 mg,0.18 mmol,0.40當量)。將所得混合物在室溫下再攪拌1h。殘餘物藉由具有以下條件之反相急速層析純化:管柱,C18矽膠;移動相,於水中之MeCN (0.1% TFA),在10 min內10%至50%梯度;偵測器,UV 254 nm。此產生呈黃色固體之N-(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)-5-甲氧基-2-(氧雜環己-2-基)吲唑-6-胺) (190 mg,65.74%)。LC-MS:(M+H) +實測值:580。 步驟5. N-[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]-5-甲氧基-2-(氧雜環己-2-基)吲唑-6-胺之合成 To a stirred solution of 5-methoxy-2-(oxacyclohexan-2-yl)-N-(prop-2-yn-1-yl)indazol-6-amine (135 mg, 0.47 mmol, 1.00 equiv) and 8-bromo-2-iodo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridine (200 mg, 0.47 mmol, 1.00 equiv) in DMSO (4 mL) was added CuI (90 mg, 0.47 mmol, 1.00 equiv) and i-Pr 2 NH (479 mg, 4.73 mmol, 10.00 equiv) portionwise at room temperature under nitrogen atmosphere. To the above mixture was added Pd(PPh 3 ) 4 (219 mg, 0.18 mmol, 0.40 equiv) portionwise at room temperature over 1 min. The resulting mixture was stirred at room temperature for another 1 h. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% TFA) in water, gradient 10% to 50% in 10 min; detector, UV 254 nm. This yielded N-(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-5-methoxy-2-(oxacyclohexan-2-yl)indazol-6-amine) (190 mg, 65.74%) as a yellow solid. LC-MS: (M+H) + found: 580. Step 5. Synthesis of N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]-5-methoxy-2-(oxacyclohexyl-2-yl)indazol-6-amine
將N-(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)-5-甲氧基-2-(氧雜環己-2-基)吲唑-6-胺(186 mg,0.32 mmol,1.00當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(131 mg,0.64 mmol,2.00當量)、Cs 2CO 3(626mg,1.92 mmol,6.00當量)、BINAP (80 mg,0.12 mmol,0.40當量)及[2'-(二苯基磷烷基)-[1,1'-聯萘]-2-基]二苯基磷烷基;{2'-胺基-[1,1'-聯苯]-2-基}甲磺酸鈀(64 mg,0.06 mmol,0.20當量)於1,4-二噁烷(4 mL)中之混合物在100℃及氮氣氛圍下攪拌2 h。在室溫下用水淬滅反應。所得混合物用EtOAc (3 x 30 mL)萃取。合併的有機層用鹽水(2x30 mL)洗滌,經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由具有以下條件之反相急速層析純化:管柱,C18矽膠;移動相,於水中之MeCN (0.1% FA),在5 min內28%至30%梯度;偵測器,UV 254 nm。此產生呈黃色固體之N-[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]-5-甲氧基-2-(氧雜環己-2-基)吲唑-6-胺(110 mg,54.12%)。LC-MS:(M+H +)實測值:632。 步驟6. N-[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]-5-甲氧基-2H-吲唑-6-胺之合成 N-(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)-5-methoxy-2-(oxacyclohexan-2-yl)indazol-6-amine (186 mg, 0.32 mmol, 1.00 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (131 mg, 0.64 mmol, 2.00 equiv), Cs 2 CO 3 (626 mg, 1.92 mmol, 6.00 equiv), BINAP (80 mg, 0.12 A mixture of 2-(4-(2-(diphenylphosphani)-[1,1'-binaphthyl]-2-yl]diphenylphosphani;{2'-amino-[1,1'-biphenyl]-2-yl}methanesulfonate (64 mg, 0.06 mmol, 0.20 equiv) in 1,4-dioxane (4 mL) was stirred at 100 °C under nitrogen atmosphere for 2 h. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (2 x 30 mL) and dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient 28% to 30% in 5 min; detector, UV 254 nm. This yielded N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]-5-methoxy-2-(oxacyclohexan-2-yl)indazol-6-amine (110 mg, 54.12%) as a yellow solid. LC-MS: (M+H + ) found: 632. Step 6. Synthesis of N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]-5-methoxy-2H-indazol-6-amine
在0℃下,向N-[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]-5-甲氧基-2-(氧雜環己-2-基)吲唑-6-胺(100 mg,0.15 mmol,1.00當量)於MeOH (2.5 mL)中之攪拌混合物中逐滴添加HCl (0.65 mL)。將混合物在室溫下攪拌4 h。用飽和NaHCO3 (水溶液)將混合物鹼化至pH 8。所得混合物用EtOAc (3 x 20mL)萃取。合併的有機層用鹽水(2x20mL)洗滌,經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。粗產物藉由具有以下條件(管柱:XBridge Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在9 min內50% B至60% B;波長:254nm/220nm nm;RT1(min):8.9)之製備型HPLC純化,以得到呈白色固體之N-[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]-5-甲氧基-2H-吲唑-6-胺(33.2 mg,38.22%)。LC-MS:(M+H) +實測值:548。1H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 7.86 (d, J = 6.6 Hz, 1H), 7.74 (d, J = 1.4 Hz, 1H), 7.08 – 6.98 (m, 2H), 6.67 (d, J = 1.0 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 5.84 (t, J = 6.2 Hz, 1H), 5.60 (d, J = 9.0 Hz, 1H), 4.89-4.76 (s, 1H), 4.34 (d, J = 6.3 Hz, 2H), 3.85 (m, 3H), 3.77-3.68 (s, 1H), 3.08-2.77 (m, 2H), 2.29 - 2.19 (m, 1H), 2.19 (m, 3H), 2.14 – 2.05 (m, 1H), 1.94 – 1.73 (m, 2H)。 實例322 4-{[3-(8-{[(4S)-3,3-二氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺之合成 步驟1. 4-[(3-{8-[(1,1-二側氧基-1λ6-硫雜環戊-3-基)胺基]-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺之合成 To a stirred mixture of N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]-5-methoxy-2-(oxacyclohexan-2-yl)indazol-6-amine (100 mg, 0.15 mmol, 1.00 equiv) in MeOH (2.5 mL) at 0°C was added HCl (0.65 mL) dropwise. The mixture was stirred at room temperature for 4 h. The mixture was basified to pH 8 with saturated NaHCO3 (aq). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL) and dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC with the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 50% B to 60% B in 9 min; wavelength: 254 nm/220 nm nm; RT1(min): 8.9) to give N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]-5-methoxy-2H-indazol-6-amine (33.2 mg, 38.22%) as a white solid. LC-MS: (M+H) + found: 548. 1H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 7.86 (d, J = 6.6 Hz, 1H), 7.74 (d, J = 1.4 Hz, 1H), 7.08 – 6.98 (m, 2H), 6.67 (d, J = 1.0 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 5.84 (t, J = 6.2 Hz, 1H), 5.60 (d, J = 9.0 Hz, 1H), 4.89-4.76 (s, 1H), 4.34 (d, J = 6.3 Hz, 2H), 3.85 (m, 3H), 3.77-3.68 (s, 1H), 3.08-2.77 (m, 2H), 2.29 - 2.19 (m, 1H), 2.19 (m, 3H), 2.14 – 2.05 (m, 1H), 1.94 – 1.73 (m, 2H). Example 322 Synthesis of 4-{[3-(8-{[(4S)-3,3-difluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide Step 1. Synthesis of 4-[(3-{8-[(1,1-dioxo-1λ6-thiocyclopent-3-yl)amino]-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide
向4-[(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺(500.00 mg,0.97 mmol,1.00當量)及3-胺基-1λ6-硫雜環戊烷-1,1-二酮鹽酸鹽(167.18 mg,0.97 mmol,1.00當量)於二噁烷(8.00 mL)中之溶液中添加BINAP (130.30 mg,0.20 mmol,0.20當量)、Cs 2CO 3(952.07 mg,2.92 mmol,3.00當量)及BINAP-Pd-G3 (96.66 mg,0.10 mmol,0.10當量)。在100℃及氮氣氛圍下攪拌12 h之後,將所得混合物在減壓下濃縮。殘餘物使用具有以下條件(移動相A:水,移動相B:ACN;流動速率:65 mL/min;梯度:在25 min內0% B至100% B;254/220 nm)之C18層析純化,以得到呈黃色油狀物之4-[(3-{8-[(1,1-二側氧基-1λ6-硫雜環戊-3-基)胺基]-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺(360.00 mg,65.1%)。LC-MS:(M+H) +實測值568.10。 步驟2. 4-{[3-(8-{[(4S)-3,3-二氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺之合成 To a solution of 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (500.00 mg, 0.97 mmol, 1.00 equiv) and 3-amino-1λ6-thiacyclopentane-1,1-dione hydrochloride (167.18 mg, 0.97 mmol, 1.00 equiv) in dioxane (8.00 mL) was added BINAP (130.30 mg, 0.20 mmol, 0.20 equiv), Cs 2 CO 3 (952.07 mg, 2.92 mmol, 3.00 equiv) and BINAP-Pd-G3 (96.66 mg, 0.10 mmol, 0.10 eq). After stirring at 100 °C under nitrogen atmosphere for 12 h, the resulting mixture was concentrated under reduced pressure. The residue was purified using C18 chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 65 mL/min; gradient: 0% B to 100% B in 25 min; 254/220 nm) to give 4-[(3-{8-[(1,1-dioxo-1λ6-thiocyclopentan-3-yl)amino]-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (360.00 mg, 65.1%) as a yellow oil. LC-MS: (M+H) + found 568.10. Step 2. Synthesis of 4-{[3-(8-{[(4S)-3,3-difluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide
4-[(3-{8-[(3,3-二氟-1-甲基哌啶-4-基)胺基]-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺(360.00 mg,0.64 mmol,1.00當量)藉由具有以下條件(Column:CHIRALPAK IH-3 4.6*50mm,3.0um;移動相A:Hex (0.2% DEA):(MeOH:DCM=1:1)=70:30;梯度:等度;注入體積:3.0 mL)之掌性HPLC純化,以得到呈白色固體之4-{[3-(8-{[(4S)-3,3-二氟-1-甲基哌啶-4-基]胺基}-3-(2,2,2-三氟乙基)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺(24.3 mg,6.7%)。LC-MS:(M+H) +實測值568.10。 1H NMR (400 MHz, DMSO- d 6) δ 8.10 (s, 1H), 7.89 (d, J= 6.8 Hz, 1H), 7.41 (d, J= 9.6 Hz, 1H), 7.34 (s, 1H), 7.04-7.00 (m, 1H), 6.79-6.73 (m, 2H), 6.57 (d, J= 7.6 Hz, 1H), 6.03-6.00 (m, 1H), 4.45-4.41 (m, 1H), 4.32 (s, 2H), 3.84 (s, 3H), 3.61-3.56 (m, 1H), 3.38-3.33 (m, 1H), 3.20-3.10 (m, 2H), 2.75 (s, 3H), 2.51-2.47 (m, 1H), 2.28-2.23 (m, 1H)。 實例324 4-{[3-(8-{[(1S,2S,3R,5R)-2-氟-8-氮雜雙環[3.2.1]辛-3-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺之合成 步驟1. (1S,2R,3R,5R)-2-氟-3-{[2-(3-{[2-甲氧基-4-(甲基胺甲醯基)苯基]胺基}丙-1-炔-1-基)-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-8-基]胺基}-8-氮雜雙環[3.2.1]辛烷-8-甲酸三級丁酯之合成 4-[(3-{8-[(3,3-difluoro-1-methylpiperidin-4-yl)amino]-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (360.00 mg, 0.64 mmol, 1.00 equiv) was prepared by HPLC with the following conditions (Column: CHIRALPAK IH-3 4.6*50mm, 3.0um; Mobile phase A: Hex (0.2% DEA):(MeOH:DCM=1:1)=70:30; Gradient: Isocratic; Injection volume: 3.0 The mixture was purified by chiral HPLC with 1% paraformaldehyde (5% ethanol, 1% ethanol) and 4-{[3-(8-{[(4S)-3,3-difluoro-1-methylpiperidin-4-yl]amino}-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (24.3 mg, 6.7%) as a white solid. LC-MS: (M+H) + found 568.10. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.10 (s, 1H), 7.89 (d, J = 6.8 Hz, 1H), 7.41 (d, J = 9.6 Hz, 1H), 7.34 (s, 1H), 7.04-7.00 (m, 1H), 6.79-6.73 (m, 2H), 6.57 (d, J = 7.6 Hz, 1H), 6.03-6.00 (m, 1H), 4.45-4.41 (m, 1H), 4.32 (s, 2H), 3.84 (s, 3H), 3.61-3.56 (m, 1H), 3.38-3.33 (m, 1H), 3.20-3.10 (m, 2H), 2.75 (s, 3H), 2.51-2.47 (m, 1H), 2.28-2.23 (m, 1H). Example 324 Synthesis of 4-{[3-(8-{[(1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]oct-3-yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide Step 1. Synthesis of (1S,2R,3R,5R)-2-fluoro-3-{[2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]amino}-8-azabicyclo[3.2.1]octane-8-carboxylic acid tributyl ester
在室溫及氮氣氛圍下,向4-[(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺(150 mg,0.292 mmol,1.00當量)及(1S,2R,3R,5R)-3-胺基-2-氟-8-氮雜雙環[3.2.1]辛烷-8-甲酸三級丁酯(4.76 mg,0.02 mmol,2.00當量)於1,4-二噁烷(3 mL) 中之攪拌溶液中逐份添加Cs2CO3 (286 mg,0.876 mmol,3當量)、BINAP (73 mg,0.12 mmol,0.40當量)及RAC-BINAP-PD-G3 (58 mg,0.06 mmol,0.20當量)。將所得混合物在100℃下再攪拌4h。藉由LCMS監測反應。反應藉由添加水來淬滅且用EtOAc (3 x 10 mL)萃取。合併的有機層用鹽水(2x10 mL)洗滌,經無水Na2SO4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用CH2Cl2 / MeOH (25:1)溶析,以得到呈棕色固體之(1S,2R,3R,5R)-2-氟-3-{[2-(3-{[2-甲氧基-4-(甲基胺甲醯基)苯基]胺基}丙-1-炔-1-基)-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-8-基]胺基}-8-氮雜雙環[3.2.1]辛烷-8-甲酸三級丁酯。LC-MS:(M+H) +實測值:677.50。 步驟2. 4-{[3-(8-{[(1S,2S,3R,5R)-2-氟-8-氮雜雙環[3.2.1]辛-3-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺之合成 To a stirred solution of 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (150 mg, 0.292 mmol, 1.00 equiv) and (1S,2R,3R,5R)-3-amino-2-fluoro-8-azabicyclo[3.2.1]octane-8-carboxylic acid tributyl ester (4.76 mg, 0.02 mmol, 2.00 equiv) in 1,4-dioxane (3 mL) was added Cs2CO3 (286 mg, 0.876 mmol, 3 equiv), BINAP (73 mg, 0.12 mmol, 0.40 equiv) and RAC-BINAP-PD-G3 (58 mg, 0.06 mmol, 0.20 equiv). The resulting mixture was stirred at 100 °C for another 4 h. The reaction was monitored by LCMS. The reaction was quenched by adding water and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with CH2Cl2/MeOH (25:1) to give (1S,2R,3R,5R)-2-fluoro-3-{[2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]amino}-8-azabicyclo[3.2.1]octane-8-carboxylic acid tributyl ester as a brown solid. LC-MS: (M+H) + found: 677.50. Step 2. Synthesis of 4-{[3-(8-{[(1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]oct-3-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide
將(1S,2R,3R,5R)-2-氟-3-{[2-(3-{[2-甲氧基-4-(甲基胺甲醯基)苯基]胺基}丙-1-炔-1-基)-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-8-基]胺基}-8-氮雜雙環[3.2.1]辛烷-8-甲酸三級丁酯(50 mg,0.077 mmol,1.00當量)於TFA (0.3 mL) /DCM (0.9 mL) (3:1) 中之溶液保持在室溫下。將所得混合物在室溫下再攪拌1h。藉由LCMS監測反應。將所得混合物在減壓下濃縮。反應用水淬滅且用CH2Cl2 (3 x10 mL)萃取。合併的有機層用鹽水(2x10 mL)洗滌,經無水Na2SO4乾燥。過濾之後,將濾液在減壓下濃縮。粗產物(30 mg)藉由具有以下條件(管柱:X-Select Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(0.1%FA),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在7 min內30% B至50% B;波長:254nm/220nm nm;RT1(min):6.56)之製備型HPLC純化,以得到呈灰白色固體之4-{[3-(8-{[(1S,2S,3R,5R)-2-氟-8-氮雜雙環[3.2.1]辛-3-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺(9.5 mg,22.30%)。LC-MS:(M+H) +實測值:577.10。 1H NMR (400 MHz, DMSO- d 6) δ 8.17 (s, 0H), 8.10 (d, J= 4.6 Hz, 1H), 7.86 (d, J= 6.7 Hz, 1H), 7.41 (dd, J= 8.3, 1.9 Hz, 1H), 7.34 (d, J= 1.8 Hz, 1H), 7.02 (t, J= 7.2 Hz, 1H), 6.74 (d, J= 8.3 Hz, 1H), 6.69 (d, J= 7.7 Hz, 1H), 6.99 (t, J= 6.3 Hz, 1H), 5.47 (d, J= 9.4 Hz, 1H), 4..52 (s, 1H), 4.31 (d, J= 6.3 Hz, 2H), 3.98 (s, 1H), 3.84 (s, 3H), 3.58 -3.44 (m, 3H), 2.75 (d, J= 4.5 Hz, 3H), 1.83-1.69 m, 6H)。 實例329 rel-4-{[3-(8-{[(1R,5R,6S,7S)-6-氟-3-氧雜-9-氮雜雙環[3.3.1]壬-7-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺之合成 步驟1. 7-[(三乙基矽烷基)氧基]-3-氧雜-9-氮雜雙環[3.3.1]壬-6-烯-9-甲酸三級丁酯之合成 A solution of (1S,2R,3R,5R)-2-fluoro-3-{[2-(3-{[2-methoxy-4-(methylaminocarbonyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]amino}-8-azabicyclo[3.2.1]octane-8-carboxylic acid tributyl ester (50 mg, 0.077 mmol, 1.00 equiv) in TFA (0.3 mL)/DCM (0.9 mL) (3:1) was kept at room temperature. The resulting mixture was stirred at room temperature for another 1 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The reaction was quenched with water and extracted with CH2Cl2 (3 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (30 mg) was purified by HPLC with the following conditions (column: X-Select Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 30% B to 50% B in 7 min; wavelength: 254nm/220nm nm; RT1 (min): 6.56) was purified by preparative HPLC to give 4-{[3-(8-{[(1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]oct-3-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (9.5 mg, 22.30%) as an off-white solid. LC-MS: (M+H) + found: 577.10. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.17 (s, 0H), 8.10 (d, J = 4.6 Hz, 1H), 7.86 (d, J = 6.7 Hz, 1H), 7.41 (dd, J = 8.3, 1.9 Hz, 1H), 7.34 (d, J = 1.8 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.69 (d, J = 7.7 Hz, 1H), 6.99 (t, J = 6.3 Hz, 1H), 5.47 (d, J = 9.4 Hz, 1H), 4.52 (s, 1H), 4.31 (d, J = 6.3 Hz, 2H), 3.98 (s, 1H), 3.84 (s, 3H), 3.58 -3.44 (m, 3H), 2.75 (d, J = 4.5 Hz, 3H), 1.83-1.69 m, 6H). Example 329 Synthesis of rel-4-{[3-(8-{[(1R,5R,6S,7S)-6-fluoro-3-oxadiazol-9-azabicyclo[3.3.1]non-7-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide Step 1. Synthesis of tert-butyl 7-[(triethylsilyl)oxy]-3-oxa-9-azabicyclo[3.3.1]non-6-ene-9-carboxylate
在-78℃及氮氣氛圍下,向7-側氧基-3-氧雜-9-氮雜雙環[3.3.1]壬烷-9-甲酸三級丁酯(2.8 g,11.61 mmol,1當量)於THF (40 mL)中之混合物中逐滴添加LDA (1.74 g,16.25 mmol,1.4當量)。將混合物在-78℃下攪拌1 h。然後在-78℃下添加氯三乙基矽烷(2.10 g,13.93 mmol,1.2當量)。將混合物在-10℃下攪拌2 h。混合物用NaHCO 3(10%水溶液)淬滅且水相用EA (300 mL)萃取三次。合併的有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。產生呈黃色油狀物之7-[(三乙基矽烷基)氧基]-3-氧雜-9-氮雜雙環[3.3.1]壬-6-烯-9-甲酸三級丁酯(3 g,72.71%) (粗物質)。 步驟2. (1S,5S,6S)-6-氟-7-側氧基-3-氧雜-9-氮雜雙環[3.3.1]壬烷-9-甲酸三級丁酯之合成 To a mixture of tributyl 7-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (2.8 g, 11.61 mmol, 1 eq) in THF (40 mL) was added LDA (1.74 g, 16.25 mmol, 1.4 eq) dropwise at -78 °C under nitrogen atmosphere. The mixture was stirred at -78 °C for 1 h. Chlorotriethylsilane (2.10 g, 13.93 mmol, 1.2 eq) was then added at -78 °C. The mixture was stirred at -10 °C for 2 h. The mixture was quenched with NaHCO 3 (10% aqueous solution) and the aqueous phase was extracted three times with EA (300 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. This gave tert-butyl 7-[(triethylsilyl)oxy]-3-oxa-9-azabicyclo[3.3.1]non-6-ene-9-carboxylate (3 g, 72.71%) as a yellow oil (crude). Step 2. Synthesis of tert-butyl (1S,5S,6S)-6-fluoro-7-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate
在-30℃及氮氣氛圍下,向Selectfluor (4.48 g,12.66 mmol,1.5當量)於ACN (50 mL)中之混合物中逐滴添加7-[(三乙基矽烷基)氧基]-3-氧雜-9-氮雜雙環[3.3.1]壬-6-烯-9-甲酸三級丁酯(3 g,8.44 mmol,1當量)。將混合物在-30℃下攪拌30 min。然後將混合物在10℃下攪拌30 min。混合物用水淬滅。且水相用EA (300 mL)萃取三次。合併的有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。殘餘物藉由具有以下條件之反相急速層析純化:管柱,C18矽膠;移動相,於0.1%TFA中之MeOH,在10 min內35%至60%梯度;偵測器,UV 220 nm,以得到呈淺黃色固體之(1S,5S,6S)-6-氟-7-側氧基-3-氧雜-9-氮雜雙環[3.3.1]壬烷-9-甲酸三級丁酯(2 g,91.42%)。LC-MS:(M-t-Bu +)實測值:204.10。 步驟3. (1S,5S,6R,7R)-7-胺基-6-氟-3-氧雜-9-氮雜雙環[3.3.1]壬烷-9-甲酸三級丁酯之合成 To a mixture of Selectfluor (4.48 g, 12.66 mmol, 1.5 eq.) in ACN (50 mL) was added tributyl 7-[(triethylsilyl)oxy]-3-oxa-9-azabicyclo[3.3.1]non-6-ene-9-carboxylate (3 g, 8.44 mmol, 1 eq.) dropwise at -30 °C under nitrogen atmosphere. The mixture was stirred at -30 °C for 30 min. Then the mixture was stirred at 10 °C for 30 min. The mixture was quenched with water. And the aqueous phase was extracted three times with EA (300 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeOH in 0.1% TFA, gradient 35% to 60% in 10 min; detector, UV 220 nm to give (1S,5S,6S)-6-fluoro-7-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylic acid tributyl ester (2 g, 91.42%) as a light yellow solid. LC-MS: (Mt-Bu + ) found: 204.10. Step 3. Synthesis of (1S,5S,6R,7R)-7-amino-6-fluoro-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester
將(1S,5S,6S)-6-氟-7-側氧基-3-氧雜-9-氮雜雙環[3.3.1]壬烷-9-甲酸三級丁酯(500 mg,1.93 mmol,1當量)及NH 4OAc (1.04 g,13.50 mmol,7當量)於MeOH (10 mL)中之混合物在室溫下攪拌2 h,然後添加NaBH 3CN (181.77 mg,2.89 mmol,1.5當量),將混合物在60℃下攪拌16 h。反應混合物用水(10 mL)淬滅,且將混合物真空濃縮。殘餘物藉由具有以下條件之反相急速層析純化:管柱,C18矽膠;移動相,於0.1%FA中之MeCN,在10 min內20%至40%梯度;偵測器,UV 200 nm,以得到呈灰白色油狀物之(1S,5S,6R,7R)-7-胺基-6-氟-3-氧雜-9-氮雜雙環[3.3.1]壬烷-9-甲酸三級丁酯(400 mg,79.68%)。LC-MS:(M+H +)實測值:261.10。 步驟4. (1S,5S,6R,7R)-6-氟-7-{[2-(3-{[2-甲氧基-4-(甲基胺甲醯基)苯基]胺基}丙-1-炔-1-基)-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-8-基]胺基}-3-氧雜-9-氮雜雙環[3.3.1]壬烷-9-甲酸三級丁酯之合成 A mixture of tributyl (1S,5S,6S)-6-fluoro-7-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (500 mg, 1.93 mmol, 1 eq) and NH4OAc (1.04 g, 13.50 mmol, 7 eq) in MeOH (10 mL) was stirred at room temperature for 2 h, then NaBH3CN (181.77 mg, 2.89 mmol, 1.5 eq) was added and the mixture was stirred at 60°C for 16 h. The reaction mixture was quenched with water (10 mL) and the mixture was concentrated in vacuo. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in 0.1% FA, gradient from 20% to 40% in 10 min; detector, UV 200 nm to give (1S,5S,6R,7R)-7-amino-6-fluoro-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylic acid tributyl ester (400 mg, 79.68%) as an off-white oil. LC-MS: (M+H + ) found: 261.10. Step 4. Synthesis of (1S,5S,6R,7R)-6-fluoro-7-{[2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]amino}-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylic acid tributyl ester
將4-[(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺(360 mg,0.70 mmol,1當量)、(1S,5S,6R,7R)-7-胺基-6-氟-3-氧雜-9-氮雜雙環[3.3.1]壬烷-9-甲酸三級丁酯(219.07 mg,0.84 mmol,1.2當量)、Cs 2CO 3(685.49 mg,2.103 mmol,3當量)、Pd-PEPPSI-IHeptCl 3-氯吡啶(34.15 mg,0.04 mmol,0.05當量)於二噁烷(8 mL)中之混合物在100℃及氮氣氛圍下攪拌16 h。反應混合物用水(100 mL)稀釋且水相用EA (100 mL)萃取兩次。合併的有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。殘餘物藉由製備型TLC (DCM/MeOH=20:1)純化,以得到呈淺黃色固體之(1S,5S,6R,7R)-6-氟-7-{[2-(3-{[2-甲氧基-4-(甲基胺甲醯基)苯基]胺基}丙-1-炔-1-基)-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-8-基]胺基}-3-氧雜-9-氮雜雙環[3.3.1]壬烷-9-甲酸三級丁酯(380 mg,78.22%)。LC-MS:(M+H +)實測值:693.35。 步驟5. 4-{[3-(8-{[(1S,5S,6R,7R)-6-氟-3-氧雜-9-氮雜雙環[3.3.1]壬-7-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺之合成 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (360 mg, 0.70 mmol, 1 eq.), (1S,5S,6R,7R)-7-amino-6-fluoro-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylic acid tributyl ester (219.07 mg, 0.84 mmol, 1.2 eq.), Cs 2 CO 3 (685.49 mg, 2.103 mmol, 3 eq.), Pd-PEPPSI-IHeptCl 3-chloropyridine (34.15 mg, 0.04 mmol, 0.05 eq.) in dioxane (8 The mixture in 100 mL) was stirred at 100 °C under nitrogen atmosphere for 16 h. The reaction mixture was diluted with water (100 mL) and the aqueous phase was extracted twice with EA (100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative TLC (DCM/MeOH=20:1) to give (1S,5S,6R,7R)-6-fluoro-7-{[2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]amino}-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylic acid tributyl ester (380 mg, 78.22%) as a light yellow solid. LC-MS: (M+H + ) found: 693.35. Step 5. Synthesis of 4-{[3-(8-{[(1S,5S,6R,7R)-6-fluoro-3-oxa-9-azabicyclo[3.3.1]non-7-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide
將(1S,5S,6R,7R)-6-氟-7-{[2-(3-{[2-甲氧基-4-(甲基胺甲醯基)苯基]胺基}丙-1-炔-1-基)-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-8-基]胺基}-3-氧雜-9-氮雜雙環[3.3.1]壬烷-9-甲酸三級丁酯(160 mg,0.23 mmol,1當量)於DCM (3 mL)及TFA (1.5 mL)中之混合物在室溫及空氣氛圍下攪拌1 h。將所得混合物在減壓下濃縮。所得混合物用EA (50 ml)稀釋,然後用飽和NaHCO3 (水溶液)將混合物鹼化至pH 8。水層用EtOAc (2x50 mL)萃取。將所得混合物在真空下濃縮。所得粗材料藉由製備型HPLC (管柱:X-Select Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(0.1%FA),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在7 min內30% B至50% B;波長:254nm/220nm nm;RT1(min):6.56)純化。凍乾產生呈黃色固體之4-{[3-(8-{[(1S,5S,6R,7R)-6-氟-3-氧雜-9-氮雜雙環[3.3.1]壬-7-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺(100 mg,73.06%)。LC-MS:(M+H +)實測值:593.20。 步驟6. rel-4-{[3-(8-{[(1R,5R,6S,7S)-6-氟-3-氧雜-9-氮雜雙環[3.3.1]壬-7-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺之合成 A mixture of (1S,5S,6R,7R)-6-fluoro-7-{[2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-8-yl]amino}-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylic acid tributyl ester (160 mg, 0.23 mmol, 1 eq.) in DCM (3 mL) and TFA (1.5 mL) was stirred at room temperature under air atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with EA (50 ml), and then the mixture was basified to pH 8 with saturated NaHCO3 (aq.). The aqueous layer was extracted with EtOAc (2x50 mL). The resulting mixture was concentrated under vacuum. The crude material was purified by preparative HPLC (column: X-Select Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 30% B to 50% B in 7 min; wavelength: 254 nm/220 nm nm; RT1 (min): 6.56). Lyophilization gave 4-{[3-(8-{[(1S,5S,6R,7R)-6-fluoro-3-oxa-9-azabicyclo[3.3.1]non-7-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (100 mg, 73.06%) as a yellow solid. LC-MS: (M+H + ) found: 593.20. Step 6. Synthesis of rel-4-{[3-(8-{[(1R,5R,6S,7S)-6-fluoro-3-oxadiazol-9-azabicyclo[3.3.1]non-7-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide
所得4-{[3-(8-{[(1S,5S)-6-氟-3-氧雜-9-氮雜雙環[3.3.1]壬-7-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺(100 mg,0.169 mmol,1當量)用掌性製備型HPLC (管柱:CHIRALPAKIF3;移動相A:Hex(0.1%DEA):EtOH=50:50;流動速率:1mL/min mL/min;梯度:等度;注入體積:2uL mL)純化。凍乾產生呈灰白色固體之rel-4-{[3-(8-{[(1R,5R,6S,7S)-6-氟-3-氧雜-9-氮雜雙環[3.3.1]壬-7-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺(9.0 mg,8.84%)。LC-MS:(M+H) +實測值:593.20。 1H NMR (400 MHz, DMSO- d 6) δ 8.11 (m, 1H), 7.83 (d, J= 6.6 Hz, 1H), 7.41 (dd, J= 8.3, 1.9 Hz, 1H), 7.35 (d, J= 1.9 Hz, 1H), 7.03 (dd, J= 7.7, 6.7 Hz, 1H), 6.95 (d, J= 10.7 Hz, 1H), 6.76 (d, J= 8.3 Hz, 1H), 6.56 (d, J= 7.7 Hz, 1H), 6.01 (t, J= 6.3 Hz, 1H), 4.63 (m, 1H), 4.32 (d, J= 6.3 Hz, 2H), 4.06 (s, 1H), 3.85 (s, 3H), 3.80 (d, J= 11.2 Hz, 1H), 3.74 – 3.61 (m, 3H), 2.92 (m, 2H), 2.75 (d, J= 4.4 Hz, 3H), 2.35 (dd, J= 14.7, 8.3 Hz, 1H), 1.57 (d, J= 14.1 Hz, 1H)。 The obtained 4-{[3-(8-{[(1S,5S)-6-fluoro-3-oxa-9-azabicyclo[3.3.1]non-7-yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (100 mg, 0.169 mmol, 1 equivalent) was purified by chiral preparative HPLC (column: CHIRALPAK IF3; mobile phase A: Hex (0.1% DEA): EtOH = 50:50; flow rate: 1 mL/min mL/min; gradient: isocratic; injection volume: 2 uL mL). Lyophilization gave rel-4-{[3-(8-{[(1R,5R,6S,7S)-6-fluoro-3-oxa-9-azabicyclo[3.3.1]non-7-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (9.0 mg, 8.84%) as an off-white solid. LC-MS: (M+H) + found: 593.20. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.11 (m, 1H), 7.83 (d, J = 6.6 Hz, 1H), 7.41 (dd, J = 8.3, 1.9 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.03 (dd, J = 7.7, 6.7 Hz, 1H), 6.95 (d, J = 10.7 Hz, 1H), 6.76 (d, J = 8.3 Hz, 1H), 6.56 (d, J = 7.7 Hz, 1H), 6.01 (t, J = 6.3 Hz, 1H), 4.63 (m, 1H), 4.32 (d, J = 6.3 Hz, 3H), 4.06 (s, 1H), 3.85 (s, 3H), 3.80 (d, J = 11.2 Hz, 1H), 3.74 – 3.61 (m, 3H), 2.92 (m, 2H), 2.75 (d, J = 4.4 Hz, 3H), 2.35 (dd, J = 14.7, 8.3 Hz, 1H), 1.57 (d, J = 14.1 Hz, 1H).
下表2中之式(I)化合物可類似於實例124-126、128、132、135、154-156、185-186、196、206、214-216、219、223、251、275、286-287、308、315、322、324及329來製備。
表2. 式(I)化合物
步驟1:將8-溴-2-(3-溴丙-1-炔-1-基)-3-[(三氟甲基)硫基]吲嗪(700.0 mg,1.70 mmol,1.00當量)、5-胺基-6-甲氧基吡啶-3-甲酸甲酯(370.5 mg,2.03 mmol,1.20當量)及K 2CO 3(702.7 mg,5.09 mmol,3.00當量)於DMF (3.00 mL)中之混合物在70℃下攪拌2 h。過濾所得混合物且濾液藉由反相急速層析(管柱,C18;移動相,於水中之MeCN,在30 min內0%至100%梯度;偵測器,UV 254 nm)純化,以得到呈棕色固體之4-[(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)胺基]-3-甲氧基苯甲酸甲酯(450.0 mg,51.73%)。LC-MS:(M+H) +實測值513.1。 Step 1 : A mixture of 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizine (700.0 mg, 1.70 mmol, 1.00 equiv), 5-amino-6- methoxypicolinic acid methyl ester (370.5 mg, 2.03 mmol, 1.20 equiv) and K2CO3 (702.7 mg, 5.09 mmol, 3.00 equiv) in DMF (3.00 mL) was stirred at 70 °C for 2 h. The resulting mixture was filtered and the filtrate was purified by reverse phase flash chromatography (column, C18; mobile phase, MeCN in water, gradient 0% to 100% in 30 min; detector, UV 254 nm) to give methyl 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-3-methoxybenzoate (450.0 mg, 51.73%) as a brown solid. LC-MS: (M+H) + found 513.1.
步驟2. 將4-[(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)胺基]-3-甲氧基苯甲酸甲酯(450.0 mg,0.88 mmol,1.00當量)及NaOH (350.6 mg,8.77 mmol,10.00當量,5.00 mL H 2O)於MeOH (10.00 mL)中之溶液在70℃下攪拌1天。用1 M HCl將混合物酸化至pH 5。藉由過濾收集沉澱的固體且用H 2O洗滌,以得到呈棕黃色固體之4-[(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)胺基]-3-甲氧基苯甲酸(400.0 mg,91.39%)。LC-MS:(M+H) +實測值499.1。 Step 2. A solution of methyl 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-3-methoxybenzoate (450.0 mg, 0.88 mmol, 1.00 equiv) and NaOH (350.6 mg, 8.77 mmol, 10.00 equiv, 5.00 mL H2O ) in MeOH (10.00 mL) was stirred at 70°C for 1 day. The mixture was acidified to pH 5 with 1 M HCl. The precipitated solid was collected by filtration and washed with H2O to give 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-3-methoxybenzoic acid (400.0 mg, 91.39%) as a brown solid. LC-MS: (M+H) + found 499.1.
步驟3. 向4-[(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)胺基]-3-甲氧基苯甲酸(260.0 mg,0.52 mmol,1.00當量)於DMF (4.00 mL)中之攪拌溶液中添加HATU (297.0 mg,0.78 mmol,1.50當量)及Et 3N (158.1 mg,1.56 mmol,3.00當量)。將反應混合物在室溫下攪拌10 min。向上述溶液中添加(R)-1-胺基-2-丙醇(46.9 mg,0.63 mmol,1.20當量)。將所得溶液在室溫下再攪拌1 h。所得溶液使用C18層析(移動相A:水,移動相B:ACN;流動速率:60 mL/min;梯度:在25 min內0% B至100% B;254/220 nm)純化,以得到呈棕色固體之4-[(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)胺基]-N-[(2R)-2-羥丙基]-3-甲氧基苯甲醯胺(200.0 mg,69.03%)。LC-MS:(M+H) +實測值556.1。 Step 3. To a stirred solution of 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-3-methoxybenzoic acid (260.0 mg, 0.52 mmol, 1.00 equiv) in DMF (4.00 mL) was added HATU (297.0 mg, 0.78 mmol, 1.50 equiv) and Et3N (158.1 mg, 1.56 mmol, 3.00 equiv). The reaction mixture was stirred at room temperature for 10 min. To the above solution was added (R)-1-amino-2-propanol (46.9 mg, 0.63 mmol, 1.20 equiv). The resulting solution was stirred at room temperature for another 1 h. The resulting solution was purified using C18 chromatography (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 25 min; 254/220 nm) to give 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-N-[(2R)-2-hydroxypropyl]-3-methoxybenzamide (200.0 mg, 69.03%) as a brown solid. LC-MS: (M+H) + found 556.1.
步驟4. 將4-[(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)胺基]-N-[(2R)-2-羥丙基]-3-甲氧基苯甲醯胺(160.0 mg,0.29 mmol,1.00當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(117.9 mg,0.58 mmol,2.00當量)、Cs 2CO 3(562.2 mg,1.73 mmol,6.00當量)、BINAP (17.9 mg,0.03 mmol,0.10當量)及BINAP-Pd-G3 (28.5 mg,0.03 mmol,0.10當量)於1,4-二噁烷(3.00 mL)中之混合物在100℃及氮氣氛圍下攪拌4 h。移除溶劑之後,殘餘物使用C18層析(移動相A:水,移動相B:ACN;流動速率:60 mL/min;梯度:在25 min內0% B至100% B;254/220 nm)及製備型HPLC (管柱:RP Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(10 mmol/L NH 4HCO 3+ 0.05% NH 3 .H 2O),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在8 min內31% B至61% B;波長:220nm nm;RT:8.25 min)純化,以得到呈灰白色固體之4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-N-[(2R)-2-羥丙基]-3-甲氧基苯甲醯胺(23.6 mg,13.14%)。LC-MS:(M+H) +實測值608.40。 1H NMR (400 MHz, DMSO- d 6) δ 8.11 (t, J= 5.8 Hz, 1H), 7.85 (d, J= 6.8 Hz, 1H), 7.45 (dd, J= 8.3, 1.8 Hz, 1H), 7.36 (d, J= 1.8 Hz, 1H), 7.20 (s, 1H), 6.80-6.71 (m, 2H), 6.14 (d, J= 7.6 Hz, 1H), 5.97 (t, J= 6.2 Hz, 1H), 5.85 (d, J= 8.2 Hz, 1H), 4.92-4.67 (m, 2H), 4.28 (d, J= 6.2 Hz, 2H), 3.85 (s, 3H), 3.76 (dt, J= 11.8, 6.0 Hz, 1H), 3.65-3.50 (m, 1H), 3.17 (td, J= 6.0, 2.7 Hz, 2H), 3.02 (t, J= 11.1 Hz, 1H), 2.81 (d, J= 10.7 Hz, 1H), 2.32-2.14 (s, 4H), 2.12-1.92 (m, 2H), 1.72-1.64 (m, 1H), 1.05 (d, J= 6.2 Hz, 3H)。 實例475 4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-N-[(2S)-2-羥丙基]-3-甲氧基苯甲醯胺之合成 Step 4. 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-N-[(2R)-2-hydroxypropyl]-3-methoxybenzamide (160.0 mg, 0.29 mmol, 1.00 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (117.9 mg, 0.58 mmol, 2.00 equiv), Cs 2 CO 3 (562.2 mg, 1.73 mmol, 6.00 equiv), BINAP (17.9 mg, 0.03 mmol, 0.10 equiv) and BINAP-Pd-G3 (28.5 mg, 0.03 mmol, 0.10 equivalent) in 1,4-dioxane (3.00 mL) was stirred at 100 °C under nitrogen atmosphere for 4 h. After removing the solvent, the residue was purified by C18 chromatography (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 25 min; 254/220 nm) and preparative HPLC (column: RP Prep OBD C18 column, 30*150 mm, 5μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 + 0.05% NH 3 . H 2 O), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 31% B to 61% B in 8 min; wavelength: 220nm nm; RT: 8.25 min) to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-[(2R)-2-hydroxypropyl]-3-methoxybenzamide (23.6 mg, 13.14%) as an off-white solid. LC-MS: (M+H) + found 608.40. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.11 (t, J = 5.8 Hz, 1H), 7.85 (d, J = 6.8 Hz, 1H), 7.45 (dd, J = 8.3, 1.8 Hz, 1H), 7.36 (d, J = 1.8 Hz, 1H), 7.20 (s, 1H), 6.80-6.71 (m, 2H), 6.14 (d, J = 7.6 Hz, 1H), 5.97 (t, J = 6.2 Hz, 1H), 5.85 (d, J = 8.2 Hz, 1H), 4.92-4.67 (m, 2H), 4.28 (d, J = 6.2 Hz, 2H), 3.85 (s, 3H), 3.76 (dt, J = 11.8, 6.0 Hz, 1H), 3.65-3.50 (m, 1H), 3.17 (td, J = 6.0, 2.7 Hz, 2H), 3.02 (t, J = 11.1 Hz, 1H), 2.81 (d, J = 10.7 Hz, 1H), 2.32-2.14 (s, 4H), 2.12-1.92 (m, 2H), 1.72-1.64 (m, 1H), 1.05 (d, J = 6.2 Hz, 3H). Example 475 Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-[(2S)-2-hydroxypropyl]-3-methoxybenzamide
步驟1:向4-[(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)胺基]-3-甲氧基苯甲酸(300.0 mg,0.60 mmol,1.00當量)於DMF (6.00 mL)中之攪拌溶液中添加HATU (342.7 mg,0.90 mmol,1.50當量)及Et 3N (182.4 mg,1.80 mmol,3.00當量)。將反應混合物在室溫下攪拌10 min。向上述溶液中添加(2S)-1-胺基丙-2-醇(54.2 mg,0.72 mmol,1.20當量)且將溶液在室溫下攪拌1 h。所得溶液使用C18層析(移動相A:水;移動相B:ACN;流動速率:60 mL/min;梯度:在25min內0% B至100% B;254/220 nm)純化,以得到呈棕色固體之4-[(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)胺基]-N-[(2S)-2-羥丙基]-3-甲氧基苯甲醯胺(200.0 mg,59.83%)。LC-MS:(M+H) +實測值556.1。 Step 1 : To a stirred solution of 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-3-methoxybenzoic acid (300.0 mg, 0.60 mmol, 1.00 equiv) in DMF (6.00 mL) was added HATU (342.7 mg, 0.90 mmol, 1.50 equiv) and Et3N (182.4 mg, 1.80 mmol, 3.00 equiv). The reaction mixture was stirred at room temperature for 10 min. To the above solution was added (2S)-1-aminopropan-2-ol (54.2 mg, 0.72 mmol, 1.20 equiv) and the solution was stirred at room temperature for 1 h. The resulting solution was purified using C18 chromatography (mobile phase A: water; mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 25 min; 254/220 nm) to give 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-N-[(2S)-2-hydroxypropyl]-3-methoxybenzamide (200.0 mg, 59.83%) as a brown solid. LC-MS: (M+H) + found 556.1.
步驟2. 將4-[(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)胺基]-N-[(2S)-2-羥丙基]-3-甲氧基苯甲醯胺(150.0 mg,0.27 mmol,1.00當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(110.6 mg,0.54 mmol,2.00當量)、Cs 2CO 3(527.0 mg,1.62 mmol,6.00當量)、BINAP (16.8 mg,0.03 mmol,0.10當量)及BINAP-Pd-G3 (26.8 mg,0.03 mmol,0.10當量)於1,4-二噁烷(3.00 mL)中之混合物在100℃及氮氣氛圍下攪拌4 h。移除溶劑之後,殘餘物使用C18層析(移動相A:水,移動相B:ACN;流動速率:60 mL/min;梯度:在25 min內0% B至100% B;254/220 nm)及製備型HPLC (管柱:RP Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(10 mmol/L NH 4HCO 3+ 0.05% NH 3 .H 2O),移動相B:ACN;流動速率:60 mL/min;梯度:在8 min內35% B至60% B;波長:220 nm;RT:7.95 min)純化,以得到呈灰白色固體之4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-N-[(2S)-2-羥丙基]-3-甲氧基苯甲醯胺(65.3 mg,39.14%)。LC-MS:(M+H) +實測值608.45。 1H NMR (400 MHz, DMSO- d 6) δ 8.11 (t, J= 5.8 Hz, 1H), 7.85 (d, J= 6.8 Hz, 1H), 7.45 (dd, J= 8.2, 1.9 Hz, 1H), 7.36 (d, J= 1.9 Hz, 1H), 7.20 (s, 1H), 6.80-6.71 (m, 2H), 6.14 (d, J= 7.6 Hz, 1H), 5.97 (t, J= 6.2 Hz, 1H), 5.85 (d, J= 8.3 Hz, 1H), 4.91-4.65 (m, 2H), 4.28 (d, J= 6.2 Hz, 2H), 3.85 (s, 3H), 3.80-3.70 (m, 1H), 3.58 (d, J= 28.5 Hz, 1H), 3.17 (td, J= 6.0, 3.2 Hz, 2H), 3.08-2.97 (m, 1H), 2.80 (d, J= 10.8 Hz, 1H), 2.35-2.10 (m, 4H), 2.09- 1.87 (m, 2H), 1.72-1.63 (m, 1H), 1.05 (d, J= 6.2 Hz, 3H)。 實例419 4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-N-[(1-羥基環丙基)甲基]-3-甲氧基苯甲醯胺之合成 Step 2. 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-N-[(2S)-2-hydroxypropyl]-3-methoxybenzamide (150.0 mg, 0.27 mmol, 1.00 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (110.6 mg, 0.54 mmol, 2.00 equiv), Cs 2 CO 3 (527.0 mg, 1.62 mmol, 6.00 equiv), BINAP (16.8 mg, 0.03 mmol, 0.10 equiv) and BINAP-Pd-G3 (26.8 mg, 0.03 mmol, 0.10 equivalent) in 1,4-dioxane (3.00 mL) was stirred at 100 °C under nitrogen atmosphere for 4 h. After removing the solvent, the residue was purified by C18 chromatography (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 25 min; 254/220 nm) and preparative HPLC (column: RP Prep OBD C18 column, 30*150 mm, 5μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 + 0.05% NH 3 . H 2 O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 35% B to 60% B in 8 min; wavelength: 220 nm; RT: 7.95 min) to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-[(2S)-2-hydroxypropyl]-3-methoxybenzamide (65.3 mg, 39.14%) as an off-white solid. LC-MS: (M+H) + found 608.45. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.11 (t, J = 5.8 Hz, 1H), 7.85 (d, J = 6.8 Hz, 1H), 7.45 (dd, J = 8.2, 1.9 Hz, 1H), 7.36 (d, J = 1.9 Hz, 1H), 7.20 (s, 1H), 6.80-6.71 (m, 2H), 6.14 (d, J = 7.6 Hz, 1H), 5.97 (t, J = 6.2 Hz, 1H), 5.85 (d, J = 8.3 Hz, 1H), 4.91-4.65 (m, 2H), 4.28 (d, J = 6.2 Hz, 2H), 3.85 (s, 3H), 3.80-3.70 (m, 1H), 3.58 (d, J = 28.5 Hz, 1H), 3.17 (td, J = 6.0, 3.2 Hz, 2H), 3.08-2.97 (m, 1H), 2.80 (d, J = 10.8 Hz, 1H), 2.35-2.10 (m, 4H), 2.09- 1.87 (m, 2H), 1.72-1.63 (m, 1H), 1.05 (d, J = 6.2 Hz, 3H). Example 419 Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-[(1-hydroxycyclopropyl)methyl]-3-methoxybenzamide
步驟1:在0℃下,向4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-3-甲氧基苯甲酸(80 mg,0.15 mmol,1當量)、DIEA (112.68 mg,0.870 mmol,6當量)、1-(胺基甲基)環丙-1-醇(25.3 mg,0.29 mmol,2當量)於DMF (2 mL)中之攪拌溶液中添加HATU (82.9 mg,0.22 mmol,1.5當量)。將溶液在25℃下攪拌1 h,然後用水(10 mL)稀釋且用EA (3*10 mL)萃取。合併的有機層經硫酸鈉乾燥,過濾且真空濃縮。殘餘物藉由製備型HPLC (管柱:X-Select Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(0.1%FA),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在7 min內30% B至50% B;波長:254nm/220nm nm;RT1(min):6.56)純化,以得到呈灰白色固體之4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-N-[(1-羥基環丙基)甲基]-3-甲氧基苯甲醯胺(23.2 mg,25.77%)。LC-MS:(M-H +)實測值:620.35。 1H NMR (400 MHz, DMSO-d6) δ 8.10 (t, J= 5.7 Hz, 1H), 7.86 (d, J = 6.8 Hz, 1H), 7.47 (dd, J= 8.3, 1.9 Hz, 1H), 7.38 (d, J= 1.9 Hz, 1H), 7.20 (s, 1H), 6.82 – 6.71 (m, 2H), 6.15 (d, J= 7.6 Hz, 1H), 5.97 (t, J= 6.2 Hz, 1H), 5.86 (d, J= 8.2 Hz, 1H), 5.42 (s, 1H), 4.84 (d, J= 49.2 Hz, 1H), 4.29 (d, J= 6.2 Hz, 2H), 3.86 (s, 3H), 3.64 (s, 1H), 3.42 (d, J= 5.7 Hz, 2H), 3.05 (d, J= 12.0 Hz, 1H), 2.84 (d, J= 10.8 Hz, 1H), 2.22 (s, 4H), 2.14 (t, J= 11.7 Hz, 1H), 2.00 (m, 1H), 1.70 (d, J= 12.5 Hz, 1H), 0.54 (m, 4H)。 實例430 4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-N-[(1-羥基環丙基)甲基]-3-甲氧基苯甲醯胺之合成 Step 1 : To a stirred solution of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-3-methoxybenzoic acid (80 mg, 0.15 mmol, 1 eq), DIEA (112.68 mg, 0.870 mmol, 6 eq), 1-(aminomethyl)cyclopropan-1-ol (25.3 mg, 0.29 mmol, 2 eq) in DMF (2 mL) was added HATU (82.9 mg, 0.22 mmol, 1.5 eq) at 0°C. The solution was stirred at 25°C for 1 h, then diluted with water (10 mL) and extracted with EA (3*10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: X-Select Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 30% B to 50% B in 7 min; wavelength: 254 nm/220 nm nm; RT1(min): 6.56) to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-[(1-hydroxycyclopropyl)methyl]-3-methoxybenzamide (23.2 mg, 25.77%) as an off-white solid. LC-MS: (MH + ) found: 620.35. 1 H NMR (400 MHz, DMSO-d6) δ 8.10 (t, J = 5.7 Hz, 1H), 7.86 (d, J = 6.8 Hz, 1H), 7.47 (dd, J = 8.3, 1.9 Hz, 1H), 7.38 (d, J = 1.9 Hz, 1H), 7.20 (s, 1H), 6.82 – 6.71 (m, 2H), 6.15 (d, J = 7.6 Hz, 1H), 5.97 (t, J = 6.2 Hz, 1H), 5.86 (d, J = 8.2 Hz, 1H), 5.42 (s, 1H), 4.84 (d, J = 49.2 Hz, 1H), 4.29 (d, J = 6.2 Hz, 2H), 3.86 (s, 3H), 3.64 (s, 1H), 3.42 (d, J = 5.7 Hz, 2H), 3.05 (d, J = 12.0 Hz, 1H), 2.84 (d, J = 10.8 Hz, 1H), 2.22 (s, 4H), 2.14 (t, J = 11.7 Hz, 1H), 2.00 (m, 1H), 1.70 (d, J = 12.5 Hz, 1H), 0.54 (m, 4H). Example 430 Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-[(1-hydroxycyclopropyl)methyl]-3-methoxybenzamide
步驟1:向4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}苯甲酸(60 mg,0.12 mmol,1當量)、2-甲磺醯基乙胺(18.5 mg,0.15 mmol,1.3當量)及DIEA (89.4 mg,0.69 mmol,6當量)於DMF(1mL)中之攪拌溶液中添加HATU (65.7 mg,0.17 mmol,1.5當量),且將所得溶液在室溫下攪拌1 h。混合物用水(20 mL)稀釋且用EtOAc (2*20mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型HPLC (管柱:XBridge Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(10 mmol/L NH 4HCO 3),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在8 min內33% B至57% B;波長:254nm/220nm nm;RT1(min):8.1)純化,以得到呈白色固體之4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-N-(2-甲磺醯基乙基)苯甲醯胺(17.2 mg,23.28%)。LC-MS:(M+H) +實測值:626.25。 1H NMR (400 MHz, DMSO-d6) δ8.15 (d, J= 4.7 Hz, 1H), 7.92 (d, J= 4.9 Hz, 1H), 7.66 (d, J= 4.9 Hz, 2H), 7.42 (d, J= 7.5 Hz, 1H), 7.34 – 6.93 (m, 4H), 6.85 – 6.63 (m, 1H), 5.86 (d, J= 55.8 Hz, 1H), 4.85 (d, J= 6.1 Hz, 1H), 4.25 (d, J= 6.1 Hz, 2H), 3.85 (s, 3H), 2.90 – 2.83 (m, 1H), 2.81 – 2.79 (m, 4H), 2.76 (d, J= 4.5 Hz, 1H), 2.28 (d, J= 13.0 Hz, 1H), 2.23 – 2.13 (m, 3H), 2.10 – 1.93 (m, 3H), 1.82 – 1.79 (m, 1H)。 實例406 1-(4-{[3-(8-{[(3S,4R)-3-氟哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-3-甲氧基苯甲醯基)-3-甲基氮雜環丁-3-醇之合成 Step 1 : To a stirred solution of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}benzoic acid (60 mg, 0.12 mmol, 1 eq), 2-methylsulfonylethylamine (18.5 mg, 0.15 mmol, 1.3 eq) and DIEA (89.4 mg, 0.69 mmol, 6 eq) in DMF (1 mL) was added HATU (65.7 mg, 0.17 mmol, 1.5 eq) and the resulting solution was stirred at room temperature for 1 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (2*20 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 33% B to 57% B in 8 min; wavelength: 254 nm/220 nm nm; RT1(min): 8.1) to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-(2-methylsulfonylethyl)benzamide (17.2 mg, 23.28%) as a white solid. LC-MS: (M+H) + found: 626.25. 1 H NMR (400 MHz, DMSO-d6) δ8.15 (d, J = 4.7 Hz, 1H), 7.92 (d, J = 4.9 Hz, 1H), 7.66 (d, J = 4.9 Hz, 2H), 7.42 (d, J = 7.5 Hz, 1H), 7.34 – 6.93 (m, 4H), 6.85 – 6.63 (m, 1H), 5.86 (d, J = 55.8 Hz, 1H), 4.85 (d, J = 6.1 Hz, 1H), 4.25 (d, J = 6.1 Hz, 2H), 3.85 (s, 3H), 2.90 – 2.83 (m, 1H), 2.81 – 2.79 (m, 4H), 2.76 (d, J = 4.5 Hz, 1H), 2.28 (d, J = 13.0 Hz, 1H), 2.23 – 2.13 (m, 3H), 2.10 – 1.93 (m, 3H), 1.82 – 1.79 (m, 1H). Example 406 Synthesis of 1-(4-{[3-(8-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-3-methoxybenzyl)-3-methylazidocyclobutan-3-ol
步驟1:在室溫下,向4-{[3-(8-{[(3S,4R)-1-(三級丁氧基羰基)-3-氟哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-3-甲氧基苯甲酸(300.0 mg,0.47 mmol,1.00當量)、DIEA (304.5 mg,2.35 mmol,5.00當量)及3-甲基氮雜環丁-3-醇鹽酸鹽(87.4 mg,0.70 mmol,1.50當量)於DMF (3.00 mL)中之攪拌溶液中添加HATU (268.8 mg,0.70 mmol,1.50當量)。將溶液在室溫下攪拌1 h。所得溶液使用C18急速層析(移動相A:水,移動相B:ACN;流動速率:60 mL/min;梯度:在30 min內0% B至100% B;254/220 nm)純化,以得到呈黃色固體之(3S,4R)-3-氟-4-{[2-(3-{[4-(3-羥基-3-甲基氮雜環丁烷-1-羰基)-2-甲氧基苯基]胺基}丙-1-炔-1-基)-3-[(三氟甲基)硫基]吲嗪-8-基]胺基}哌啶-1-甲酸三級丁酯(270 mg,81.19%)。LC-MS:(M+H) +實測值706.3。 Step 1 : To a stirred solution of 4-{[3-(8-{[(3S,4R)-1-(tributyloxycarbonyl)-3-fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-3-methoxybenzoic acid (300.0 mg, 0.47 mmol, 1.00 equiv), DIEA (304.5 mg, 2.35 mmol, 5.00 equiv) and 3-methylazinecyclobutan-3-ol hydrochloride (87.4 mg, 0.70 mmol, 1.50 equiv) in DMF (3.00 mL) at room temperature was added HATU (268.8 mg, 0.70 mmol, 1.50 equiv). The solution was stirred at room temperature for 1 h. The resulting solution was purified by C18 flash chromatography (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm) to give (3S,4R)-3-fluoro-4-{[2-(3-{[4-(3-hydroxy-3-methylazinocyclobutane-1-carbonyl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizin-8-yl]amino}piperidine-1-carboxylic acid tributyl ester (270 mg, 81.19%) as a yellow solid. LC-MS: (M+H) + found 706.3.
步驟2. 在0℃下,向(3S,4R)-3-氟-4-{[2-(3-{[4-(3-羥基-3-甲基氮雜環丁烷-1-羰基)-2-甲氧基苯基]胺基}丙-1-炔-1-基)-3-[(三氟甲基)硫基]吲嗪-8-基]胺基}哌啶-1-甲酸三級丁酯(70.0 mg,0.09 mmol,1.00當量)於DCM (3.00 mL)中之攪拌溶液中添加TFA (0.50 mL)。將所得溶液在室溫下攪拌30 min,然後用飽和NaHCO 3中和至pH 8且用EA (3*50 mL)萃取。有機層經Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物使用製備型HPLC (管柱:XBridge Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(10 mmol/L NH 4HCO 3+ 0.05% NH 3 .H 2O),移動相B:ACN;流動速率:60 mL/min;梯度:在8 min內33% B至58% B;波長:220 nm;RT:6.6 min)純化,以得到呈白色固體之1-(4-{[3-(8-{[(3S,4R)-3-氟哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-3-甲氧基苯甲醯基)-3-甲基氮雜環丁-3-醇(18.4 mg,28.76%)。LC-MS:(M+H) +實測值606.20。 1H NMR (400 MHz, DMSO- d 6) δ 7.84 (d, J= 6.8 Hz, 1H), 7.22 (s, 1H), 7.17 (dd, J= 8.4, 1.8 Hz, 1H), 7.11 (d, J= 1.8 Hz, 1H), 6.80-6.71 (m, 2H), 6.15 (d, J= 7.6 Hz, 1H), 6.03 (t, J= 6.2 Hz, 1H), 5.82 (d, J= 8.2 Hz, 1H), 5.62 (s, 1H), 4.72 (d, J= 50.4 Hz, 1H), 4.28 (d, J= 6.1 Hz, 2H), 4.22-3.53 (m, 8H), 3.11 (td, J= 12.1, 11.2, 5.9 Hz, 1H), 2.97 (d, J= 13.1 Hz, 1H), 2.76 (dd, J= 39.0, 14.4 Hz, 1H), 2.58 (t, J= 12.2 Hz, 1H), 1.79 (m, 1H), 1.62 (dd, J= 12.5, 4.1 Hz, 1H), 1.37 (s, 3H)。 實例492 4-{[3-(8-{[(3S,4R)-3-氟哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-N-甲基苯甲醯胺之合成 Step 2. To a stirred solution of (3S,4R)-3-fluoro-4-{[2-(3-{[4-(3-hydroxy-3-methylazinocyclobutane-1-carbonyl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizin-8-yl]amino}piperidine-1-carboxylic acid tributyl ester (70.0 mg, 0.09 mmol, 1.00 equiv) in DCM (3.00 mL) at 0°C was added TFA (0.50 mL). The resulting solution was stirred at room temperature for 30 min, then neutralized with saturated NaHCO 3 to pH 8 and extracted with EA (3*50 mL). The organic layer was dried over Na 2 SO 4 . After filtration, the filtrate is concentrated under reduced pressure. The residue was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 + 0.05% NH 3 . H 2 O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 33% B to 58% B in 8 min; wavelength: 220 nm; RT: 6.6 min) to obtain 1-(4-{[3-(8-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-3-methoxybenzyl)-3-methylazidocyclobutan-3-ol (18.4 mg, 28.76%). LC-MS: (M+H) + found 606.20. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.84 (d, J = 6.8 Hz, 1H), 7.22 (s, 1H), 7.17 (dd, J = 8.4, 1.8 Hz, 1H), 7.11 (d, J = 1.8 Hz, 1H), 6.80-6.71 (m, 2H), 6.15 (d, J = 7.6 Hz, 1H), 6.03 (t, J = 6.2 Hz, 1H), 5.82 (d, J = 8.2 Hz, 1H), 5.62 (s, 1H), 4.72 (d, J = 50.4 Hz, 1H), 4.28 (d, J = 6.1 Hz, 2H), δ 4.22-3.53 (m, 8H), 3.11 (td, J = 12.1, 11.2, 5.9 Hz, 1H), 2.97 (d, J = 13.1 Hz, 1H), 2.76 (dd, J = 39.0, 14.4 Hz, 1H), 2.58 (t, J = 12.2 Hz, 1H), 1.79 (m, 1H), 1.62 (dd, J = 12.5, 4.1 Hz, 1H), 1.37 (s, 3H). Example 492 Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide
步驟1:將4-[(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)胺基]-N-甲基苯甲醯胺(185 mg,0.38 mmol,1當量)、(3S,4R)-4-胺基-3-氟哌啶-1-甲酸三級丁酯(125.6 mg,0.58 mmol,1.5當量)、RAC-BINAP-Pd-G3 (76.1 mg,0.08 mmol,0.2當量)、BINAP (119.4 mg,0.19 mmol,0.5當量)及Cs 2CO 3(249.9 mg,0.77 mmol,2當量)於二噁烷(2 mL)中之混合物在100℃及氮氣氛圍下攪拌1h。所得混合物用水(50 mL)稀釋且用DCM (3*50mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由反相急速層析(管柱,C18矽膠;移動相,於水中之MeCN,在30 min內0%至100%梯度;偵測器,UV 254 nm)純化,以得到呈黃色固體之(3S,4R)-3-氟-4-{[2-(3-{[4-(甲基胺甲醯基)苯基]胺基}丙-1-炔-1-基)-3-[(三氟甲基)硫基]吲嗪-8-基]胺基}哌啶-1-甲酸三級丁酯(65 mg,27.35%)。LC-MS:(M+H) +實測值620.3。 Step 1 : A mixture of 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-N-methylbenzamide (185 mg, 0.38 mmol, 1 eq), (3S,4R)-4-amino-3-fluoropiperidine-1-carboxylic acid tributyl ester (125.6 mg, 0.58 mmol, 1.5 eq), RAC-BINAP-Pd-G3 (76.1 mg, 0.08 mmol, 0.2 eq), BINAP (119.4 mg, 0.19 mmol, 0.5 eq) and Cs2CO3 ( 249.9 mg, 0.77 mmol, 2 eq) in dioxane (2 mL) was stirred at 100 °C under nitrogen atmosphere for 1 h. The resulting mixture was diluted with water (50 mL) and extracted with DCM (3*50 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in water, gradient 0% to 100% in 30 min; detector, UV 254 nm) to give (3S,4R)-3-fluoro-4-{[2-(3-{[4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizin-8-yl]amino}piperidine-1-carboxylic acid tributyl ester (65 mg, 27.35%) as a yellow solid. LC-MS: (M+H) + found 620.3.
步驟2. 將(3S,4R)-3-氟-4-{[2-(3-{[4-(甲基胺甲醯基)苯基]胺基}丙-1-炔-1-基)-3-[(三氟甲基)硫基]吲嗪-8-基]胺基}哌啶-1-甲酸三級丁酯(50 mg,0.08 mmol,1當量)及TFA (0.2 mL)於DCM (1 mL)中之溶液在室溫下攪拌1 h。用飽和NaHCO 3將溶液鹼化至pH 8且用DCM (3*50 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型HPLC (管柱:XBridge Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3+0.05% NH 3 .H 2O),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在8 min內29% B至54% B;波長:220nm nm;RT1(min):7.58)純化,以得到呈淺黃色固體之4-{[3-(8-{[(3S,4R)-3-氟哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-N-甲基苯甲醯胺(14.8 mg,34.99%)。LC-MS:(M+H) +實測值520.10。 1H NMR (400 MHz, DMSO- d 6) δ 8.03 (d, J= 4.7 Hz, 1H), 7.86 (t, J= 7.2 Hz, 1H), 7.73 – 7.55 (m, 2H), 7.21 (d, J= 13.5 Hz, 1H), 6.90 – 6.41 (m, 4H), 6.17 (dd, J= 13.6, 7.6 Hz, 1H), 5.89 (dd, J= 28.6, 8.3 Hz, 1H), 4.72 (d, J= 50.8 Hz, 1H), 4.24 (d, J= 6.1 Hz, 2H), 3.69 (d, J= 29.3 Hz, 1H), 3.15 – 2.78 (m, 3H), 2.78 – 2.64 (m, 4H), 2.64 – 2.54 (m, 1H), 1.85 – 1.72 (m, 1H), 1.61 (d, J= 12.2 Hz, 1H)。 實例504 4-{[3-(8-{[(3S,4R)-3-氟-1-(氧雜環丁-3-基)哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺之合成 Step 2. A solution of (3S,4R)-3-fluoro-4-{[2-(3-{[4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizin-8-yl]amino}piperidine-1-carboxylic acid tributyl ester (50 mg, 0.08 mmol, 1 eq.) and TFA (0.2 mL) in DCM (1 mL) was stirred at room temperature for 1 h. The solution was basified to pH 8 with saturated NaHCO 3 and extracted with DCM (3*50 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 +0.05% NH 3 . H 2 O), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 29% B to 54% B in 8 min; wavelength: 220 nm nm; RT1(min): 7.58) to give 4-{[3-(8-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide (14.8 mg, 34.99%) as a light yellow solid. LC-MS: (M+H) + found 520.10. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.03 (d, J = 4.7 Hz, 1H), 7.86 (t, J = 7.2 Hz, 1H), 7.73 – 7.55 (m, 2H), 7.21 (d, J = 13.5 Hz, 1H), 6.90 – 6.41 (m, 4H), 6.17 (dd, J = 13.6, 7.6 Hz, 1H), 5.89 (dd, J = 28.6, 8.3 Hz, 1H), 4.72 (d, J = 50.8 Hz, 1H), 4.24 (d, J = 6.1 Hz, 2H), 3.69 (d, J = 29.3 Hz, 1H), 3.15 – 2.78 (m, 3H), 2.78 – 2.64 (m, 4H), 2.64 – 2.54 (m, 1H), 1.85 – 1.72 (m, 1H), 1.61 (d, J = 12.2 Hz, 1H). Example 504 Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-(oxocyclobutan-3-yl)piperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide
步驟1:在室溫下,向4-[(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)胺基]-3-甲氧基苯甲酸(200.0 mg,0.40 mmol,1.00當量)及HATU (228.5 mg,0.60 mmol,1.50當量)於DMF (3.00 mL)中之攪拌溶液中添加TEA (121.6 mg,1.20 mmol,3.00當量)及CH 3NH 2 .HCl (40.6 mg,0.60 mmol,1.50當量)。將反應在室溫下攪拌1 h。所得溶液藉由反相急速層析(管柱,C18;移動相,於水中之MeCN,在20 min內0%至100%梯度;偵測器,UV 254 nm)純化,以得到呈淺黃色固體之4-[(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺(110 mg,53.60%)。LC-MS:(M+H) +實測值:511.9。 Step 1 : To a stirred solution of 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-3-methoxybenzoic acid (200.0 mg, 0.40 mmol, 1.00 equiv) and HATU (228.5 mg, 0.60 mmol , 1.50 equiv) in DMF (3.00 mL) was added TEA (121.6 mg, 1.20 mmol , 3.00 equiv) and CH3NH2.HCl (40.6 mg, 0.60 mmol, 1.50 equiv) at room temperature. The reaction was stirred at room temperature for 1 h. The resulting solution was purified by reverse phase flash chromatography (column, C18; mobile phase, MeCN in water, gradient from 0% to 100% in 20 min; detector, UV 254 nm) to give 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (110 mg, 53.60%) as a light yellow solid. LC-MS: (M+H) + found: 511.9.
步驟2:將4-[(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)胺基]-3-甲氧基-N-甲基苯甲醯胺(110.0 mg,0.22 mmol,1.00當量)、(3S,4R)-4-胺基-3-氟哌啶-1-甲酸三級丁酯(70.3 mg,0.32 mmol,1.50當量)、Cs 2CO 3(279.8 mg,0.86 mmol,4.00當量)、BINAP (26.7 mg,0.04 mmol,0.20當量)及BINAP-Pd-G3 (42.6 mg,0.04 mmol,0.20當量)於1,4-二噁烷(1.50 mL)中之混合物在100℃及氮氣氛圍下攪拌1 h。將所得混合物在真空下濃縮。殘餘物藉由反相急速層析(管柱,C18;移動相,於水中之MeCN,在20 min內0%至100%梯度;偵測器,UV 254 nm)純化,以得到呈黃色固體之(3S,4R)-3-氟-4-{[2-(3-{[2-甲氧基-4-(甲基胺甲醯基)苯基]胺基}丙-1-炔-1-基)-3-[(三氟甲基)硫基]吲嗪-8-基]胺基}哌啶-1-甲酸三級丁酯(110 mg,78.86%)。LC-MS:(M+H) +實測值:650.2。 Step 2: 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N-methylbenzamide (110.0 mg, 0.22 mmol, 1.00 equiv), (3S,4R)-4-amino-3-fluoropiperidine-1-carboxylic acid tributyl ester (70.3 mg, 0.32 mmol, 1.50 equiv), Cs 2 CO 3 (279.8 mg, 0.86 mmol, 4.00 equiv), BINAP (26.7 mg, 0.04 mmol, 0.20 equiv) and BINAP-Pd-G3 (42.6 mg, 0.04 mmol, 0.20 equiv) were dissolved in 1,4-dioxane (1.50 The mixture in 20 mL) was stirred at 100 °C under nitrogen atmosphere for 1 h. The resulting mixture was concentrated under vacuum. The residue was purified by reverse phase flash chromatography (column, C18; mobile phase, MeCN in water, gradient from 0% to 100% in 20 min; detector, UV 254 nm) to give (3S,4R)-3-fluoro-4-{[2-(3-{[2-methoxy-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizin-8-yl]amino}piperidine-1-carboxylic acid tributyl ester (110 mg, 78.86%) as a yellow solid. LC-MS: (M+H) + found: 650.2.
步驟3. 在室溫下,向(3S,4R)-3-氟-4-{[2-(3-{[2-甲氧基-4-(甲基胺甲醯基)苯基]胺基}丙-1-炔-1-基)-3-[(三氟甲基)硫基]吲嗪-8-基]胺基}哌啶-1-甲酸三級丁酯(100.0 mg,0.15 mmol,1.00當量)於DCM (1.20 mL)中之攪拌溶液中逐滴添加TFA (0.40 mL)。將所得溶液在室溫下攪拌0.5 h。將所得混合物在真空下濃縮,以得到呈棕色固體之4-{[3-(8-{[(3S,4R)-3-氟哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺三氟乙酸鹽(80 mg,94.57%)。LC-MS:(M+H) +實測值:550.3。 Step 3. To a stirred solution of (3S,4R)-3-fluoro-4-{[2-(3-{[2-methoxy-4-(methylaminocarbonyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizin-8-yl]amino}piperidine-1-carboxylic acid tributyl ester (100.0 mg, 0.15 mmol, 1.00 equiv) in DCM (1.20 mL) was added TFA (0.40 mL) dropwise at room temperature. The resulting solution was stirred at room temperature for 0.5 h. The resulting mixture was concentrated under vacuum to give 4-{[3-(8-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide trifluoroacetate (80 mg, 94.57%) as a brown solid. LC-MS: (M+H) + found: 550.3.
步驟4. 將4-{[3-(8-{[(3S,4R)-3-氟哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺三氟乙酸鹽(70.0 mg,0.13 mmol,1.00當量)、3-氧雜環丁酮(45.9 mg,0.64 mmol,5.00當量)及NaOAc (31.4 mg,0.38 mmol,3.00當量)於MeOH (1.50 mL)中之混合物在室溫下攪拌1 h。然後添加NaBH 3CN (24.0 mg,0.38 mmol,3.00當量)且將溶液在室溫下再攪拌2 h。所得溶液藉由反相急速層析(管柱,C18;移動相,於水中之MeCN (0.1% FA),在20 min內0%至100%梯度;偵測器,UV 254 nm)及製備型HPLC (管柱:XBridge Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(10 mmol/L NH 4HCO 3+ 0.05% NH 3 .H 2O),移動相B:ACN;流動速率:60 mL/min;梯度:在30min內33% B至60% B;波長:254 nm/220 nm;RT:7.73 min)純化,以得到呈灰白色固體之4-{[3-(8-{[(3S,4R)-3-氟-1-(氧雜環丁-3-基)哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺(33.1 mg,42.57%)。LC-MS:(M+H) +實測值:606.20。 1H NMR (400 MHz, DMSO- d 6) δ 8.10 (d, J= 4.7 Hz, 1H), 7.85 (d, J= 6.9 Hz, 1H), 7.45-7.30 (m, 2H), 7.21 (s, 1H), 6.80-6.71 (m, 2H), 6.15 (d, J= 7.6 Hz, 1H), 5.95 (t, J= 6.2 Hz, 1H), 5.86 (d, J= 8.2 Hz, 1H), 4.85 (d, J= 49.4 Hz, 1H), 4.54 (td, J= 6.4, 2.9 Hz, 2H), 4.42 (dt, J= 24.8, 6.1 Hz, 2H), 4.27 (d, J= 6.2 Hz, 2H), 3.84 (s, 3H), 3.65 (d, J= 28.8 Hz, 1H), 3.49 (m, 1H), 2.96 (t, J= 11.1 Hz, 1H), 2.75 (d, J= 4.5 Hz, 4H), 2.19 (dd, J= 37.5, 12.8 Hz, 1H), 2.00 (m, 2H), 1.72 (d, J= 11.9 Hz, 1H)。 實例436 4-{[3-(8-{[(3S,4R)-3-氟-1-(氧雜環丁-3-基)哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-3-甲氧基-N-甲基苯甲醯胺之合成 Step 4. A mixture of 4-{[3-(8-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide trifluoroacetate (70.0 mg, 0.13 mmol, 1.00 equiv), 3-oxacyclobutanone (45.9 mg, 0.64 mmol, 5.00 equiv) and NaOAc (31.4 mg, 0.38 mmol, 3.00 equiv) in MeOH (1.50 mL) was stirred at room temperature for 1 h. NaBH3CN (24.0 mg, 0.38 mmol, 3.00 equiv) was then added and the solution was stirred at room temperature for another 2 h. The resulting solution was purified by reverse phase flash chromatography (column, C18; mobile phase, MeCN (0.1% FA) in water, gradient from 0% to 100% in 20 min; detector, UV 254 nm) and preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 + 0.05% NH 3 . H 2 O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 33% B to 60% B in 30 min; wavelength: 254 nm/220 nm; RT: 7.73 min) to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-(oxacyclobutan-3-yl)piperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide (33.1 mg, 42.57%) as an off-white solid. LC-MS: (M+H) + found: 606.20. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.10 (d, J = 4.7 Hz, 1H), 7.85 (d, J = 6.9 Hz, 1H), 7.45-7.30 (m, 2H), 7.21 (s, 1H), 6.80-6.71 (m, 2H), 6.15 (d, J = 7.6 Hz, 1H), 5.95 (t, J = 6.2 Hz, 1H), 5.86 (d, J = 8.2 Hz, 1H), 4.85 (d, J = 49.4 Hz, 1H), 4.54 (td, J = 6.4, 2.9 Hz, 2H), 4.42 (dt, J = 24.8, 6.1 Hz, 2H), 4.27 (d, J = 6.2 Hz, 2H), 3.84 (s, 3H), 3.65 (d, J = 28.8 Hz, 1H), 3.49 (m, 1H), 2.96 (t, J = 11.1 Hz, 1H), 2.75 (d, J = 4.5 Hz, 4H), 2.19 (dd, J = 37.5, 12.8 Hz, 1H), 2.00 (m, 2H), 1.72 (d, J = 11.9 Hz, 1H). Example 436 Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-(oxacyclobutan-3-yl)piperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N-methylbenzamide
步驟1:在0℃下,向3-羥基-4-硝基苯甲酸(2 g,10.92 mmol,1當量)、CH 3NH 2 .HCl (1.11 g,16.38 mmol,1.50當量)、DIEA (2.38 mL)於DMF (20 mL)中之攪拌溶液中逐份添加HATU (6.23 g,16.38 mmol,1.50當量)。將反應在室溫下攪拌1 h。所得溶液藉由反相急速層析(管柱,C18矽膠;移動相,於水中之MeCN (0.1% FA),在30 min內0%至100%梯度;偵測器,UV 254 nm)純化,以得到呈黃色固體之3-羥基-N-甲基-4-硝基苯甲醯胺(1.8 g,84.02%)。LC-MS:(M+H) +實測值197.1。 Step 1 : To a stirred solution of 3-hydroxy-4-nitrobenzoic acid (2 g, 10.92 mmol , 1 eq), CH3NH2.HCl (1.11 g, 16.38 mmol, 1.50 eq), DIEA (2.38 mL) in DMF (20 mL) was added HATU (6.23 g, 16.38 mmol, 1.50 eq) portionwise at 0° C. The reaction was stirred at room temperature for 1 h. The resulting solution was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient 0% to 100% in 30 min; detector, UV 254 nm) to give 3-hydroxy-N-methyl-4-nitrobenzamide (1.8 g, 84.02%) as a yellow solid. LC-MS: (M+H) + found 197.1.
步驟2. 將3-羥基-N-甲基-4-硝基苯甲醯胺(600 mg,3.06 mmol,1當量)、溴氟甲烷(0.39 mL,6.118 mmol,2當量)及K 2CO 3(845 mg,6.12 mmol,2.00當量)於DMF (6 mL)中之混合物在室溫下攪拌1 h。過濾所得混合物且濾液藉由反相急速層析(管柱,C18矽膠;移動相,於水中之MeCN (10mmol/L NH 4HCO 3),在20 min內0%至100%梯度;偵測器,UV 254 nm)純化,以得到呈淺黃色固體之3-(氟甲氧基)-N-甲基-4-硝基苯甲醯胺(650 mg,93.13%)。LC-MS:(M+H) +實測值229.3。 Step 2. A mixture of 3-hydroxy-N-methyl-4-nitrobenzamide (600 mg, 3.06 mmol, 1 eq), bromofluoromethane (0.39 mL, 6.118 mmol, 2 eq) and K 2 CO 3 (845 mg, 6.12 mmol, 2.00 eq) in DMF (6 mL) was stirred at room temperature for 1 h. The resulting mixture was filtered and the filtrate was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH 4 HCO 3 ) in water, gradient 0% to 100% in 20 min; detector, UV 254 nm) to give 3-(fluoromethoxy)-N-methyl-4-nitrobenzamide (650 mg, 93.13%) as a light yellow solid. LC-MS: (M+H) + found 229.3.
步驟3. 將3-(氟甲氧基)-N-甲基-4-硝基苯甲醯胺(650 mg,2.85 mmol,1當量)、Fe (735 mg,13.15 mmol,5當量)及NH 4Cl (762 mg,14.25 mmol,5當量)於EtOH (5 mL) / H 2O (1 mL)中之混合物在70℃下攪拌1 h。過濾所得混合物,濾餅用MeOH洗滌。將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用CH 2Cl 2/ MeOH (10:1)溶析,以得到呈無色油狀物之4-胺基-3-(氟甲氧基)-N-甲基苯甲醯胺(550 mg,97.42%)。LC-MS:(M+H) +實測值199.4。 Step 3. A mixture of 3-(fluoromethoxy)-N-methyl-4-nitrobenzamide (650 mg, 2.85 mmol, 1 eq.), Fe (735 mg, 13.15 mmol, 5 eq.) and NH 4 Cl (762 mg, 14.25 mmol, 5 eq.) in EtOH (5 mL) / H 2 O (1 mL) was stirred at 70° C. for 1 h. The resulting mixture was filtered and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH 2 Cl 2 / MeOH (10:1) to give 4-amino-3-(fluoromethoxy)-N-methylbenzamide (550 mg, 97.42%) as a colorless oil. LC-MS: (M+H) + found 199.4.
步驟4. 將4-胺基-3-(氟甲氧基)-N-甲基苯甲醯胺(96 mg,0.48 mmol,1.00當量)、8-溴-2-(3-溴丙-1-炔-1-基)-3-[(三氟甲基)硫基]吲嗪(200 mg,0.48 mmol,1.00當量)及K 2CO 3(201 mg,1.45 mmol,3當量)於ACN (2 mL)中之混合物在70℃下攪拌隔夜。將所得混合物在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用PE / EA (1:1)溶析,以得到呈淺黃色固體之4-[(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)胺基]-3-(氟甲氧基)-N-甲基苯甲醯胺(130 mg,50.62%)。LC-MS:(M+H) +實測值530.2。 Step 4. A mixture of 4-amino-3-(fluoromethoxy)-N-methylbenzamide (96 mg, 0.48 mmol, 1.00 equiv), 8-bromo-2-(3-bromoprop-1-yn-1 - yl)-3-[(trifluoromethyl)thio]indolizine (200 mg, 0.48 mmol, 1.00 equiv) and K2CO3 (201 mg, 1.45 mmol, 3 equiv) in ACN (2 mL) was stirred at 70°C overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (1:1) to give 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-3-(fluoromethoxy)-N-methylbenzamide (130 mg, 50.62%) as a light yellow solid. LC-MS: (M+H) + found 530.2.
步驟5. 將4-[(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)胺基]-3-(氟甲氧基)-N-甲基苯甲醯胺(100 mg,0.19 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(58 mg,0.28 mmol,1.5當量)、Pd-PEPPSI-IHeptCl 3-氯吡啶(37 mg,0.04 mmol,0.2當量)及Cs 2CO 3(308 mg,0.95 mmol,5當量)於二噁烷(1.5 mL)中之混合物在100℃及氮氣氛圍下攪拌4 h。將所得混合物在減壓下濃縮。殘餘物藉由矽膠管柱層析(用CH 2Cl 2/ MeOH (10:1)溶析) 及 製備型HPLC (管柱:XBridge Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(10 mmol/L NH 4HCO 3+0.05% NH 3 .H 2O),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在8 min內38% B至63% B;波長:220nm nm;RT1(min):6.53)純化,以得到呈白色固體之4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-3-(氟甲氧基)-N-甲基苯甲醯胺(40.7 mg,37.11%)。LC-MS:(M+H) +實測值582.40。 1H NMR (400 MHz, DMSO- d 6) δ 8.15 (m, 1H), 7.85 (d, J= 6.8 Hz, 1H), 7.55 (m, 2H), 7.28 – 7.15 (m, 1H), 6.86 (d, J= 8.9 Hz, 1H), 6.75 (t, J= 7.2 Hz, 1H), 6.25 (t, J= 6.2 Hz, 1H), 6.14 (d, J= 7.6 Hz, 1H), 5.90 (s, 1H), 5.85 (d, J= 8.3 Hz, 1H), 5.76 (s, 1H), 4.82 (d, J= 49.5 Hz, 1H), 4.29 (d, J= 6.2 Hz, 2H), 3.58 (d, J= 28.8 Hz, 1H), 3.03 (t, J= 11.2 Hz, 1H), 2.81 (d, J= 10.5 Hz, 1H), 2.75 (d, J= 4.4 Hz, 3H), 2.18 (s, 4H), 2.00 (m, 2H), 1.67 (d, J= 12.1 Hz, 1H)。 實例469 4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-3-羥基-N-甲基苯甲醯胺之合成 Step 5. A mixture of 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-3-(fluoromethoxy)-N-methylbenzamide (100 mg, 0.19 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (58 mg, 0.28 mmol, 1.5 eq), Pd-PEPPSI-IHeptCl 3-chloropyridine (37 mg, 0.04 mmol , 0.2 eq) and Cs2CO3 (308 mg, 0.95 mmol, 5 eq) in dioxane (1.5 mL) was stirred at 100°C under nitrogen atmosphere for 4 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with CH 2 Cl 2 / MeOH (10:1)) and preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 +0.05% NH 3 . H 2 O), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 38% B to 63% B in 8 min; wavelength: 220 nm). nm; RT1 (min): 6.53) to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-3-(fluoromethoxy)-N-methylbenzamide (40.7 mg, 37.11%) as a white solid. LC-MS: (M+H) + found 582.40. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.15 (m, 1H), 7.85 (d, J = 6.8 Hz, 1H), 7.55 (m, 2H), 7.28 – 7.15 (m, 1H), 6.86 (d, J = 8.9 Hz, 1H), 6.75 (t, J = 7.2 Hz, 1H), 6.25 (t, J = 6.2 Hz, 1H), 6.14 (d, J = 7.6 Hz, 1H), 5.90 (s, 1H), 5.85 (d, J = 8.3 Hz, 1H), 5.76 (s, 1H), 4.82 (d, J = 49.5 Hz, 1H), 4.29 (d, 3.58 (d, J = 28.8 Hz, 1H), 3.03 (t, J = 11.2 Hz, 1H), 2.81 ( d, J = 10.5 Hz, 1H), 2.75 (d, J = 4.4 Hz, 3H), 2.18 (s, 4H), 2.00 (m, 2H), 1.67 (d, J = 12.1 Hz, 1H). Example 469 Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-3-hydroxy-N-methylbenzamide
步驟1:將3-羥基-N-甲基-4-硝基苯甲醯胺(1 g,5.10 mmol,1.00當量)、Cs 2CO 3(4.98 g,15.29 mmol,3.00當量)及溴(甲氧基)甲烷(960.3 mg,7.65 mmol,1.50當量)於DMF (10.00 mL)中之混合物在0℃下攪拌2 h。所得混合物用水(100 mL)稀釋且用DCM (3*100 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由反相急速層析(管柱,C18矽膠;移動相,於ACN中之水(0.1% FA),在20 min內0%至100%梯度;偵測器,UV 254 nm)純化,以得到呈黃色固體之3-(甲氧基甲氧基)-N-甲基-4-硝基苯甲醯胺(1.00 g,81.7%)。LC-MS:(M+H) +實測值:241.0。 Step 1 : A mixture of 3-hydroxy-N-methyl-4-nitrobenzamide (1 g, 5.10 mmol, 1.00 equiv), Cs 2 CO 3 (4.98 g, 15.29 mmol, 3.00 equiv) and bromo(methoxy)methane (960.3 mg, 7.65 mmol, 1.50 equiv) in DMF (10.00 mL) was stirred at 0 °C for 2 h. The resulting mixture was diluted with water (100 mL) and extracted with DCM (3*100 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, water (0.1% FA) in ACN, gradient 0% to 100% in 20 min; detector, UV 254 nm) to give 3-(methoxymethoxy)-N-methyl-4-nitrobenzamide (1.00 g, 81.7%) as a yellow solid. LC-MS: (M+H) + found: 241.0.
步驟2. 將3-(甲氧基甲氧基)-N-甲基-4-硝基苯甲醯胺(950 mg,3.96 mmol,1.00當量)、Fe (2.21 g,39.55 mmol,10.00當量)及NH 4Cl (1.06 g,19.78 mmol,5.00當量)於EtOH (10.00 mL)/H 2O (0.50 mL)中之溶液之混合物在80℃下攪拌2 h。所得混合物用水(50 mL)稀釋且用DCM (3*100 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮,以得到呈棕色油狀物之4-胺基-3-(甲氧基甲氧基)-N-甲基苯甲醯胺(700 mg,84.19%)。LC-MS:(M+H) +實測值:211.0。 Step 2. A mixture of 3-(methoxymethoxy)-N-methyl-4-nitrobenzamide (950 mg, 3.96 mmol, 1.00 equiv), Fe (2.21 g, 39.55 mmol, 10.00 equiv) and NH 4 Cl (1.06 g, 19.78 mmol, 5.00 equiv) in EtOH (10.00 mL)/H 2 O (0.50 mL) was stirred at 80° C. for 2 h. The resulting mixture was diluted with water (50 mL) and extracted with DCM (3*100 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to give 4-amino-3-(methoxymethoxy)-N-methylbenzamide (700 mg, 84.19%) as a brown oil. LC-MS: (M+H) + found: 211.0.
步驟3. 將4-胺-3-(甲氧基甲氧基)-N-甲基苯甲醯胺(200 mg,0.95 mmol,1.00當量)、8-溴-2-(3-溴丙-1-炔-1-基)-3-[(三氟甲基)硫基]吲嗪(196.5 mg,0.48 mmol,0.50當量)及K 2CO 3(394.4 mg,2.85 mmol,3.00當量)於ACN (6.00 mL)中之混合物在70℃下攪拌隔夜。所得混合物用EA (100 mL)稀釋且用鹽水(3*100 mL)洗滌。有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型TLC (PE: EA= 1:1)純化,以得到呈黃色油狀物之4-[(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)胺基]-3-(甲氧基甲氧基)-N-甲基苯甲醯胺(200 mg,38.76%)。LC-MS:(M+H +)實測值:542.0。 Step 3. A mixture of 4-amine-3-(methoxymethoxy)-N-methylbenzamide (200 mg, 0.95 mmol, 1.00 equiv), 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizine (196.5 mg, 0.48 mmol, 0.50 equiv) and K 2 CO 3 (394.4 mg, 2.85 mmol, 3.00 equiv) in ACN (6.00 mL) was stirred at 70° C. overnight. The resulting mixture was diluted with EA (100 mL) and washed with brine (3*100 mL). The organic layer was dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE: EA = 1:1) to give 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-3-(methoxymethoxy)-N-methylbenzamide (200 mg, 38.76%) as a yellow oil. LC-MS: (M+H + ) found: 542.0.
步驟4. 將4-[(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)胺基]-3-(甲氧基甲氧基)-N-甲基苯甲醯胺(200 mg,0.37 mmol,1.00當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(113.5 mg,0.55 mmol,1.50當量)、RAC-BINAP-PD-G3 (36.6 mg,0.04 mmol,0.10當量)、BINAP (45.9 mg,0.07 mmol,0.20當量)及Cs 2CO 3(720.9 mg,2.21 mmol,6.00當量)於1,4-二噁烷(3.00 mL)中之混合物在100℃及氮氣氛圍下攪拌1 h。將所得混合物在減壓下濃縮。殘餘物藉由製備型TLC (DCM:MeOH = 15:1)純化,以得到呈黃色固體之4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-3-(甲氧基甲氧基)-N-甲基苯甲醯胺(180 mg,82.2%)。LC-MS:(M+H) +實測值:551.2。 Step 4. 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-3-(methoxymethoxy)-N-methylbenzamide (200 mg, 0.37 mmol, 1.00 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (113.5 mg, 0.55 mmol, 1.50 equiv), RAC-BINAP-PD-G3 (36.6 mg, 0.04 mmol, 0.10 equiv), BINAP (45.9 mg, 0.07 mmol, 0.20 equiv) and Cs 2 CO 3 (720.9 mg, 2.21 mmol, 6.00 equiv) were dissolved in 1,4-dioxane (3.00 The mixture in 20 mL) was stirred at 100 °C under nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH = 15:1) to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-3-(methoxymethoxy)-N-methylbenzamide (180 mg, 82.2%) as a yellow solid. LC-MS: (M+H) + found: 551.2.
步驟5. 在0℃下,向4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-3-(甲氧基甲氧基)-N-甲基苯甲醯胺(70 mg,0.12 mmol,1當量)於MeOH (6 mL,148.193 mmol,1256.76當量)中之攪拌溶液中添加1M HCl (0.5 mL)。將所得混合物在室溫下攪拌6 h,然後用飽和NaHCO 3(10 mL)鹼化至pH 8且用CH 2Cl 2(3*10 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型HPLC (管柱:XBridge Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(10 mmol/L NH 4HCO 3),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在8 min內2% B至24% B;波長:254 nm/220 nm;RT1(min):8.1)純化,以得到呈灰白色固體之4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-3-羥基-N-甲基苯甲醯胺(12.8 mg,19.67%)。LC-MS:(M+H) +實測值:550.20。 1H NMR (400 MHz, DMSO- d 6) δ 9.51 (d, J= 1.5 Hz, 1H), 7.98 (d, J= 4.8 Hz, 1H), 7.86 (d, J= 6.8 Hz, 1H), 7.29–7.16 (m, 3H), 6.80–6.66 (m, 2H), 6.15 (d, J= 7.6 Hz, 1H), 5.85 (d, J= 8.2 Hz, 1H), 5.73–5.62 (m, 1H), 4.83 (d, J= 49.4 Hz, 1H), 4.27 (d, J= 6.1 Hz, 2H), 3.60 (d, J= 29.1 Hz, 1H), 3.04 (s, 1H), 2.82 (d, J = 10.3 Hz, 1H), 2.72 (d, J = 4.5 Hz, 3H), 2.19 (s, 4H), 2.09 (dd, J = 12.8, 10.1 Hz, 1H), 2.00 (d, J = 11.8 Hz, 1H), 1.69 (d, J = 12.2 Hz, 1H)。 實例455 4-{[3-(8-{[(3S,4R)-3-氟哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-3-羥基-N-甲基苯甲醯胺之合成 Step 5. To a stirred solution of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-3-(methoxymethoxy)-N-methylbenzamide (70 mg, 0.12 mmol, 1 eq) in MeOH (6 mL, 148.193 mmol, 1256.76 eq) at 0°C was added 1 M HCl (0.5 mL). The resulting mixture was stirred at room temperature for 6 h, then basified to pH 8 with saturated NaHCO 3 (10 mL) and extracted with CH 2 Cl 2 (3*10 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 . After filtration, the filtrate is concentrated under reduced pressure. The residue was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 2% B to 24% B in 8 min; wavelength: 254 nm/220 nm; RT1(min): 8.1) to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-3-hydroxy-N-methylbenzamide (12.8 mg, 19.67%) as an off-white solid. LC-MS: (M+H) + found: 550.20. 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.51 (d, J = 1.5 Hz, 1H), 7.98 (d, J = 4.8 Hz, 1H), 7.86 (d, J = 6.8 Hz, 1H), 7.29–7.16 (m, 3H), 6.80–6.66 (m, 2H), 6.15 (d, J = 7.6 Hz, 1H), 5.85 (d, J = 8.2 Hz, 1H), 5.73–5.62 (m, 1H), 4.83 (d, J = 49.4 Hz, 1H), 4.27 (d, J = 6.1 Hz, 2H), 3.60 (d, J = 29.1 Hz, 1H), 3.04 (s, 1H), 2.82 (d, J = 10.3 Hz, 1H), 2.72 (d, J = 4.5 Hz, 3H), 2.19 (s, 4H), 2.09 (dd, J = 12.8, 10.1 Hz, 1H), 2.00 (d, J = 11.8 Hz, 1H), 1.69 (d, J = 12.2 Hz, 1H). Example 455 Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-3-hydroxy-N-methylbenzamide
步驟1:將4-[(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)胺基]-3-(甲氧基甲氧基)-N-甲基苯甲醯胺(150 mg,0.28 mmol,1當量)、(3S,4R)-4-胺基-3-氟哌啶-1-甲酸三級丁酯(72.4 mg,0.33 mmol,1.2當量)、Cs 2CO 3(270.3 mg,0.83 mmol,3當量)、BINAP (17.2 mg,0.03 mmol,0.1當量)及RAC-BINAP-PD-G3 (17.2 mg,0.03 mmol,0.1當量) 於1,4-二噁烷(1 mL)中之混合物在100℃下攪拌2 h。所得混合物用水(50 mL)稀釋且用CH 2Cl 2(3*50 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型TLC (PE / EA=1:1)純化,以得到呈淺黃色固體之(3S,4R)-3-氟-4-{[2-(3-{[2-(甲氧基甲氧基)-4-(甲基胺甲醯基)苯基]胺基}丙-1-炔-1-基)-3-[(三氟甲基)硫基]吲嗪-8-基]胺基}哌啶-1-甲酸三級丁酯(160 mg,76.60%)。LC-MS:(M+H) +實測值:680.0。 Step 1 : A mixture of 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-3-(methoxymethoxy)-N-methylbenzamide (150 mg, 0.28 mmol, 1 eq), (3S,4R)-4-amino-3-fluoropiperidine-1-carboxylic acid tributyl ester (72.4 mg, 0.33 mmol, 1.2 eq), Cs2CO3 (270.3 mg, 0.83 mmol, 3 eq), BINAP (17.2 mg, 0.03 mmol , 0.1 eq) and RAC-BINAP-PD-G3 (17.2 mg, 0.03 mmol, 0.1 eq) in 1,4-dioxane (1 mL) was stirred at 100 °C for 2 h. The resulting mixture was diluted with water (50 mL) and extracted with CH 2 Cl 2 (3*50 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA=1:1) to give (3S,4R)-3-fluoro-4-{[2-(3-{[2-(methoxymethoxy)-4-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizin-8-yl]amino}piperidine-1-carboxylic acid tributyl ester (160 mg, 76.60%) as a light yellow solid. LC-MS: (M+H) + found: 680.0.
步驟2. 在0℃下,向(3S,4R)-3-氟-4-{[2-(3-{[2-(甲氧基甲氧基)-4-(甲基胺甲醯基)苯基]胺基}丙-1-炔-1-基)-3-[(三氟甲基)硫基]吲嗪-8-基]胺基}哌啶-1-甲酸三級丁酯(150 mg,0.22 mmol,1當量)於MeOH (5 mL)中之攪拌溶液中添加2 M HCl (1 mL)。將所得溶液在室溫下攪拌5 h,然後用飽和NaHCO 3(8 mL)鹼化至pH 8且用CH 2Cl 2(3*20 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型HPLC (管柱:XBridge Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(10mmol/L NH 4HCO 3),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在10 min內33% B至53% B;波長:254 nm/220 nm;RT1(min):7.92)純化,以得到呈灰白色固體之4-{[3-(8-{[(3S,4R)-3-氟哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-3-羥基-N-甲基苯甲醯胺(9 mg,7.61%)。LC-MS:(M+H) +實測值:536.15。 1H NMR (400 MHz, DMSO- d 6) δ 9.51 (s, 1H), 7.98 (d, J= 4.9 Hz, 1H), 7.85 (d, J= 6.9 Hz, 1H), 7.24 (m, J= 14.6, 5.9 Hz, 3H), 6.80–6.65 (m, 2H), 6.15 (d, J= 7.6 Hz, 1H), 5.84 (d, J= 8.1 Hz, 1H), 5.67 (t, J= 6.2 Hz, 1H), 4.72 (d, J= 50.5 Hz, 1H), 4.27 (d, J= 6.1 Hz, 2H), 3.70 (d, J= 29.7 Hz, 1H), 3.11 (t, J= 12.5 Hz, 1H), 2.98 (d, J= 13.0 Hz, 1H), 2.86–2.68 (m, 4H), 2.60 (d, J= 12.0 Hz, 1H), 2.04 (d, J= 33.5 Hz, 1H), 1.88–1.71 (m, 1H), 1.62 (d, J= 12.4 Hz, 1H)。 實例466. 3-氯-4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-N-甲基苯甲醯胺之合成 Step 2. To a stirred solution of (3S,4R)-3-fluoro-4-{[2-(3-{[2-(methoxymethoxy)-4-(methylaminocarbonyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizin-8-yl]amino}piperidine-1-carboxylic acid tributyl ester (150 mg, 0.22 mmol, 1 eq) in MeOH (5 mL) was added 2 M HCl (1 mL) at 0°C. The resulting solution was stirred at room temperature for 5 h, then basified to pH 8 with saturated NaHCO 3 (8 mL) and extracted with CH 2 Cl 2 (3*20 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 . After filtration, the filtrate is concentrated under reduced pressure. The residue was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 33% B to 53% B in 10 min; wavelength: 254 nm/220 nm; RT1(min): 7.92) to give 4-{[3-(8-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-3-hydroxy-N-methylbenzamide (9 mg, 7.61%) as an off-white solid. LC-MS: (M+H) + found: 536.15. 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.51 (s, 1H), 7.98 (d, J = 4.9 Hz, 1H), 7.85 (d, J = 6.9 Hz, 1H), 7.24 (m, J = 14.6, 5.9 Hz, 3H), 6.80–6.65 (m, 2H), 6.15 (d, J = 7.6 Hz, 1H), 5.84 (d, J = 8.1 Hz, 1H), 5.67 (t, J = 6.2 Hz, 1H), 4.72 (d, J = 50.5 Hz, 1H), 4.27 (d, J = 6.1 Hz, 2H), 3.70 (d, J = 29.7 Hz, 1H), 3.11 (t, J = 12.5 Hz, 1H), 2.98 (d, J = 13.0 Hz, 1H), 2.86–2.68 (m, 4H), 2.60 (d, J = 12.0 Hz, 1H), 2.04 (d, J = 33.5 Hz, 1H), 1.88–1.71 (m, 1H), 1.62 (d, J = 12.4 Hz, 1H). Example 466. Synthesis of 3-chloro-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide
步驟1. 在0℃下,向4-胺基-3-氯苯甲酸(1 g,5.84 mmol,1當量)、CH 3NH 2 .HCl (511 mg,7.58 mmol,1.3當量)、DIEA (3.01 g,23.31 mmol,4當量)於DMF (10 mL)中之攪拌溶液中添加HATU (2.66 g,6.99 mmol,1.2當量)。將所得混合物在室溫下攪拌1 h,然後在減壓下濃縮。殘餘物藉由矽膠管柱層析,用PE / EA (5:1)溶析,以得到呈黃色油狀物之4-胺基-3-氯-N-甲基苯甲醯胺(1 g,92.94%)。LC-MS:(M+H) +實測值185.0。 Step 1. To a stirred solution of 4-amino-3-chlorobenzoic acid (1 g, 5.84 mmol, 1 eq.), CH 3 NH 2 . HCl (511 mg, 7.58 mmol, 1.3 eq.), DIEA (3.01 g, 23.31 mmol, 4 eq.) in DMF (10 mL) at 0°C was added HATU (2.66 g, 6.99 mmol, 1.2 eq.). The resulting mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EA (5:1) to give 4-amino-3-chloro-N-methylbenzamide (1 g, 92.94%) as a yellow oil. LC-MS: (M+H) + found 185.0.
步驟2. 將4-胺基-3-氯-N-甲基苯甲醯胺(200 mg,1.08 mmol,1當量)、8-溴-2-(3-溴丙-1-炔-1-基)-3-[(三氟甲基)硫基]吲嗪(447 mg,1.08 mmol,1當量)及K 2CO 3(449 mg,3.25 mmol,3當量)於ACN (1.5 mL)中之混合物在70℃下攪拌隔夜。過濾所得混合物且將濾液在減壓下濃縮。殘餘物藉由反相急速層析(管柱,C18矽膠;移動相,於水中之MeCN (0.1% FA),在30 min內0%至100%梯度;偵測器,UV 254 nm)純化,以得到呈白色固體之4-[(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)胺基]-3-氯-N-甲基苯甲醯胺(70 mg,12.50%)。LC-MS:(M+H) +實測值516.1。 Step 2. A mixture of 4-amino-3-chloro-N-methylbenzamide (200 mg, 1.08 mmol, 1 eq), 8-bromo-2-(3-bromoprop-1-yn-1- yl )-3-[(trifluoromethyl)thio]indolizine (447 mg, 1.08 mmol, 1 eq) and K2CO3 (449 mg, 3.25 mmol, 3 eq) in ACN (1.5 mL) was stirred at 70°C overnight. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient 0% to 100% in 30 min; detector, UV 254 nm) to give 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-3-chloro-N-methylbenzamide (70 mg, 12.50%) as a white solid. LC-MS: (M+H) + found 516.1.
步驟3. 將4-[(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)胺基]-3-氯-N-甲基苯甲醯胺(60 mg,0.12 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺(23 mg,0.17 mmol,1.5當量)、Pd-PEPPSI-IHeptCl 3-氯吡啶(33 mg,0.04 mmol,0.3當量)及Cs 2CO 3(189 mg,0.58 mmol,5當量)於二噁烷(1.5 mL)中之混合物在100℃及氮氣氛圍下攪拌5 h。將所得混合物在減壓下濃縮且殘餘物藉由反相急速層析(管柱,C18矽膠;移動相,於水中之MeCN (0.1% FA),在20 min內0%至100%梯度;偵測器,UV 254 nm)及製備型HPLC (管柱:XBridge Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(10 mmol/L NH 4HCO 3)+0.05%NH 3 .H 2O,移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在7min內40% B至67%B;波長:254nm/220nm nm;RT1(min):6.92)純化,以得到呈淺黃色固體之3-氯-4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-N-甲基苯甲醯胺(5.3 mg,7.90%)。LC-MS:(M+H) +實測值568.35。 1H NMR (400 MHz, DMSO-d6) δ 8.20 (d, J= 4.7 Hz, 1H), 7.84 (d, J= 6.8 Hz, 2H), 7.72 (dd, J= 8.6, 2.0 Hz, 1H), 7.21 (d, J= 0.9 Hz, 1H), 6.96 (d, J= 8.6 Hz, 1H), 6.75 (t, J= 7.2 Hz, 1H), 6.47 (t, J= 6.0 Hz, 1H), 6.14 (d, J= 7.6 Hz, 1H), 5.84 (d, J= 8.2 Hz, 1H), 4.82 (d, J= 49.5 Hz, 1H), 4.35 (d, J= 6.0 Hz, 2H), 3.58 (d, J= 29.5 Hz, 1H), 3.02 (t, J= 11.3 Hz, 1H), 2.81 (d, J= 10.9 Hz, 1H), 2.74 (d, J= 4.4 Hz, 3H), 2.18 (s, 4H), 2.07 (s, 3H), 1.68 (d, J= 12.3 Hz, 1H)。 實例446. 4-{[3-(1-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-6-[(三氟甲基)硫基]吡咯并[1,2-a]吡嗪-7-基)丙-2-炔-1-基]胺基}-3-羥基-N-甲基苯甲醯胺之合成 Step 3. A mixture of 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-3-chloro-N-methylbenzamide (60 mg, 0.12 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine (23 mg, 0.17 mmol, 1.5 eq), Pd-PEPPSI-IHeptCl 3-chloropyridine (33 mg, 0.04 mmol, 0.3 eq) and Cs2CO3 (189 mg, 0.58 mmol, 5 eq) in dioxane (1.5 mL) was stirred at 100°C under nitrogen atmosphere for 5 h. The resulting mixture was concentrated under reduced pressure and the residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient from 0% to 100% in 20 min; detector, UV 254 nm) and preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 )+0.05% NH 3 . H 2 O, mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 40% B to 67% B in 7 min; wavelength: 254 nm/220 nm). nm; RT1 (min): 6.92) to give 3-chloro-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide (5.3 mg, 7.90%) as a light yellow solid. LC-MS: (M+H) + found 568.35. 1 H NMR (400 MHz, DMSO-d6) δ 8.20 (d, J = 4.7 Hz, 1H), 7.84 (d, J = 6.8 Hz, 2H), 7.72 (dd, J = 8.6, 2.0 Hz, 1H), 7.21 (d, J = 0.9 Hz, 1H), 6.96 (d, J = 8.6 Hz, 1H), 6.75 (t, J = 7.2 Hz, 1H), 6.47 (t, J = 6.0 Hz, 1H), 6.14 (d, J = 7.6 Hz, 1H), 5.84 (d, J = 8.2 Hz, 1H), 4.82 (d, J = 49.5 Hz, 1H), 4.35 (d, J = 6.0 Hz, 2H), 3.58 (d, J = 29.5 Hz, 1H), 3.02 (t, J = 11.3 Hz, 1H), 2.81 (d, J = 10.9 Hz, 1H), 2.74 (d, J = 4.4 Hz, 3H), 2.18 (s, 4H), 2.07 (s, 3H), 1.68 (d, J = 12.3 Hz, 1H). Example 446. Synthesis of 4-{[3-(1-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-6-[(trifluoromethyl)thio]pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl]amino}-3-hydroxy-N-methylbenzamide
步驟1. 在0℃下,向3-甲氧基-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺(500 mg,2.29 mmol,1當量)於DCM(5mL)中之攪拌溶液中添加BBr 3(4.58 mL,4.58 mmol,2當量)。將所得混合物在0℃下攪拌1 h。藉由在0℃下添加飽和NaHCO 3(30 mL)來淬滅反應。水層用CH 2Cl 2(3*30 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由反相急速層析(管柱,C18矽膠;移動相,於水中之MeCN (0.1% FA),在20 min內0%至100%梯度;偵測器,UV 254 nm)純化,以得到呈黃色固體之3-羥基-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺(250 mg,53.43%)。LC-MS:(M+H) +實測值:204.9。 Step 1. To a stirred solution of 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (500 mg, 2.29 mmol, 1 eq.) in DCM (5 mL) at 0°C was added BBr 3 (4.58 mL, 4.58 mmol, 2 eq.). The resulting mixture was stirred at 0°C for 1 h. The reaction was quenched by the addition of saturated NaHCO 3 (30 mL) at 0°C. The aqueous layer was extracted with CH 2 Cl 2 (3*30 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient 0% to 100% in 20 min; detector, UV 254 nm) to give 3-hydroxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (250 mg, 53.43%) as a yellow solid. LC-MS: (M+H) + found: 204.9.
步驟2. 將3-羥基-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺(50 mg,0.25 mmol,1.2當量)、(3S,4R)-3-氟-N-{7-碘-6-[(三氟甲基)硫基]吡咯并[1,2-a]吡嗪-1-基}-1-甲基哌啶-4-胺(96.8 mg,0.20 mmol,1當量)、DIEPA (103.2 mg,1.02 mmol,5當量)、CuI (3.89 mg,0.02 mmol,0.1當量)及Pd(PPh 3) 4(23.6 mg,0.02 mmol,0.1當量)於DMSO (2 mL)中之混合物在70℃及氮氣氛圍下攪拌1 h。所得混合物用水(20 mL)稀釋且用EtOAc (3*20 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型HPLC (管柱:X-Select Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(0.1%FA),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在7 min內30% B至50% B;波長:254nm/220nm nm;RT1(min):6.56)純化,以得到呈白色固體之4-{[3-(1-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-6-[(三氟甲基)硫基]吡咯并[1,2-a]吡嗪-7-基)丙-2-炔-1-基]胺基}-3-羥基-N-甲基苯甲醯胺(10.2 mg,8.68%)。LC-MS:(M+H) +實測值:551.30。 1H NMR (400 MHz, DMSO-d6) δ 9.50 (s, 1H), 7.98 (d, J= 4.7 Hz, 1H), 7.73 (d, J= 4.8 Hz, 1H), 7.40 (d, J= 0.9 Hz, 1H), 7.36 (d, J= 7.5 Hz, 1H), 7.30 (d, J= 4.9 Hz, 1H), 7.26 (dd, J= 8.2, 2.0 Hz, 1H), 7.23 (d, J= 1.9 Hz, 1H), 6.71 (d, J= 8.2 Hz, 1H), 5.68 (t, J= 6.3 Hz, 1H), 4.85 (d, J= 50.0 Hz, 1H), 4.27 (d, J= 6.2 Hz, 2H), 4.18 (d, J= 34.7 Hz, 1H), 3.31 (m, 1H), 3.07 (d, J= 11.9 Hz, 1H), 2.83 (s, 1H), 2.72 (d, J= 4.5 Hz, 3H), 2.19 (s, 3H), 2.16 – 1.87 (m, 3H), 1.67 (d, J= 11.4 Hz, 1H)。 實例450. 3-(二氟甲基)-4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-N-甲基苯甲醯胺之合成 Step 2. A mixture of 3-hydroxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (50 mg, 0.25 mmol, 1.2 equiv), (3S,4R)-3-fluoro-N-{7-iodo-6-[(trifluoromethyl)thio]pyrrolo[1,2-a]pyrazin-1-yl}-1-methylpiperidin-4-amine (96.8 mg, 0.20 mmol, 1 equiv), DIEPA (103.2 mg, 1.02 mmol, 5 equiv), CuI (3.89 mg, 0.02 mmol, 0.1 equiv) and Pd(PPh 3 ) 4 (23.6 mg, 0.02 mmol, 0.1 equiv) in DMSO (2 mL) was stirred at 70° C. under nitrogen atmosphere for 1 h. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (3*20 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: X-Select Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 30% B to 50% B in 7 min; wavelength: 254 nm/220 nm nm; RT1(min): 6.56) to give 4-{[3-(1-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-6-[(trifluoromethyl)thio]pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl]amino}-3-hydroxy-N-methylbenzamide (10.2 mg, 8.68%) as a white solid. LC-MS: (M+H) + found: 551.30. 1 H NMR (400 MHz, DMSO-d6) δ 9.50 (s, 1H), 7.98 (d, J = 4.7 Hz, 1H), 7.73 (d, J = 4.8 Hz, 1H), 7.40 (d, J = 0.9 Hz, 1H), 7.36 (d, J = 7.5 Hz, 1H), 7.30 (d, J = 4.9 Hz, 1H), 7.26 (dd, J = 8.2, 2.0 Hz, 1H), 7.23 (d, J = 1.9 Hz, 1H), 6.71 (d, J = 8.2 Hz, 1H), 5.68 (t, J = 6.3 Hz, 1H), 4.85 (d, J = 50.0 Hz, 3H), 4.27 (d, J = 6.2 Hz, 2H), 4.18 (d, J = 34.7 Hz, 1H), 3.31 (m, 1H), 3.07 (d, J = 11.9 Hz, 1H), 2.83 (s, 1H), 2.72 (d, J = 4.5 Hz, 3H), 2.19 (s, 3H), 2.16 – 1.87 (m, 3H), 1.67 (d, J = 11.4 Hz, 1H). Example 450. Synthesis of 3-(difluoromethyl)-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide
步驟1. 在0℃下,向3-甲醯基-4-硝基苯甲酸甲酯(2 g,9.56 mmol,1當量)於DCM (20 mL)中之攪拌溶液中逐滴添加DAST (1.85 g,11.474 mmol,1.2當量)。將溶液在室溫下攪拌1 h,然後在室溫下用水淬滅。所得混合物用DCM (3*50 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮,以得到呈黃色油狀物之3-(二氟甲基)-4-硝基苯甲酸甲酯(2.42 g)。 Step 1. To a stirred solution of methyl 3-methyl-4-nitrobenzoate (2 g, 9.56 mmol, 1 eq.) in DCM (20 mL) at 0°C was added DAST (1.85 g, 11.474 mmol, 1.2 eq.) dropwise. The solution was stirred at room temperature for 1 h and then quenched with water at room temperature. The resulting mixture was extracted with DCM (3*50 mL). The combined organic layers were dried over anhydrous Na2SO4 . After filtration, the filtrate was concentrated under reduced pressure to give methyl 3-(difluoromethyl)-4-nitrobenzoate (2.42 g) as a yellow oil.
步驟2:將3-(二氟甲基)-4-硝基苯甲酸甲酯(2.4 g,10.38 mmol,1當量)及NaOH (2.08 g,51.92 mmol,5當量)於MeOH (12 mL)/H 2O (12 mL)中之混合物在室溫下攪拌1 h。用1 M HCl將混合物酸化至pH 6且用DCM (3*100 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮,以得到呈淺黃色固體之3-(二氟甲基)-4-硝基苯甲酸(1.976 g,87.65%)。LC-MS:(M-H) -實測值216.0。 Step 2: A mixture of methyl 3-(difluoromethyl)-4-nitrobenzoate (2.4 g, 10.38 mmol, 1 eq.) and NaOH (2.08 g, 51.92 mmol, 5 eq.) in MeOH (12 mL)/H 2 O (12 mL) was stirred at room temperature for 1 h. The mixture was acidified to pH 6 with 1 M HCl and extracted with DCM (3*100 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure to give 3-(difluoromethyl)-4-nitrobenzoic acid (1.976 g, 87.65%) as a light yellow solid. LC-MS: (MH) - found 216.0.
步驟3. 在0℃下,向3-(二氟甲基)-4-硝基苯甲酸(1.8 g,8.29 mmol,1當量)、甲胺鹽酸鹽(0.67 g,9.95 mmol,1.2當量)及DIEA (4.29 g,33.16 mmol,4當量)於DMF (20 mL)中之攪拌溶液中添加HATU (4.73 g,12.44 mmol,1.5當量)。將混合物在室溫下攪拌1 h,然後用EA (50 mL)稀釋且用3*50 mL之鹽水洗滌。有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在真空下濃縮。殘餘物藉由反相急速層析(管柱,C18矽膠;移動相,於水中之MeCN,在30 min內0%至100%梯度;偵測器,UV 254 nm)純化,以得到呈淺黃色固體之3-(二氟甲基)-N-甲基-4-硝基苯甲醯胺(1.19 g,62.26%)。LC-MS:(M-H) -實測值229.1。 Step 3. To a stirred solution of 3-(difluoromethyl)-4-nitrobenzoic acid (1.8 g, 8.29 mmol, 1 eq), methylamine hydrochloride (0.67 g, 9.95 mmol, 1.2 eq) and DIEA (4.29 g, 33.16 mmol, 4 eq) in DMF (20 mL) at 0°C was added HATU (4.73 g, 12.44 mmol, 1.5 eq). The mixture was stirred at room temperature for 1 h, then diluted with EA (50 mL) and washed with 3*50 mL of brine. The organic layer was dried over anhydrous Na2SO4 . After filtration, the filtrate was concentrated under vacuum. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in water, gradient 0% to 100% in 30 min; detector, UV 254 nm) to give 3-(difluoromethyl)-N-methyl-4-nitrobenzamide (1.19 g, 62.26%) as a light yellow solid. LC-MS: (MH) - found 229.1.
步驟4. 將3-(二氟甲基)-N-甲基-4-硝基苯甲醯胺(1 g,4.35 mmol,1當量)及Pd/C (2.31 g,21.73 mmol,5當量)於MeOH (10 mL)中之混合物在室溫及氫氣氛圍下攪拌1h。過濾所得混合物,濾餅用MeOH洗滌。將濾液在減壓下濃縮。殘餘物藉由反相急速層析(管柱,C18矽膠;移動相,於水中之MeOH,在50 min內0%至100%梯度;偵測器,UV 254 nm)純化,以得到呈黃色油狀物之4-胺基-3-(二氟甲基)-N-甲基苯甲醯胺(750 mg,86.23%)。LC-MS:(M+H) +實測值201.1。 Step 4. A mixture of 3-(difluoromethyl)-N-methyl-4-nitrobenzamide (1 g, 4.35 mmol, 1 eq.) and Pd/C (2.31 g, 21.73 mmol, 5 eq.) in MeOH (10 mL) was stirred at room temperature under hydrogen atmosphere for 1 h. The resulting mixture was filtered and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeOH in water, gradient 0% to 100% in 50 min; detector, UV 254 nm) to give 4-amino-3-(difluoromethyl)-N-methylbenzamide (750 mg, 86.23%) as a yellow oil. LC-MS: (M+H) + found 201.1.
步驟5. 將8-溴-2-(3-溴丙-1-炔-1-基)-3-[(三氟甲基)硫基]吲嗪(200 mg,0.48 mmol,1當量)、K 2CO 3(200.7 mg,1.45 mmol,3當量)及4-胺基-3-(二氟甲基)-N-甲基苯甲醯胺(116.3 mg,0.58 mmol,1.2當量)於ACN (2 mL)中之混合物在70℃下攪拌4 h。過濾所得混合物且將濾液在減壓下濃縮。殘餘物藉由製備型TLC (PE:EA= 1:1)純化,以得到呈棕色固體之4-[(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)胺基]-3-(二氟甲基)-N-甲基苯甲醯胺(42 mg,16.29%)。LC-MS:(M+H) +實測值532.1。 Step 5. A mixture of 8-bromo-2-(3-bromoprop-1-yn-1- yl )-3-[(trifluoromethyl)thio]indolizine (200 mg, 0.48 mmol, 1 eq), K2CO3 (200.7 mg, 1.45 mmol, 3 eq) and 4-amino-3-(difluoromethyl)-N-methylbenzamide (116.3 mg, 0.58 mmol, 1.2 eq) in ACN (2 mL) was stirred at 70°C for 4 h. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE:EA=1:1) to give 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-3-(difluoromethyl)-N-methylbenzamide (42 mg, 16.29%) as a brown solid. LC-MS: (M+H) + found 532.1.
步驟6. 將4-[(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)胺基]-3-(二氟甲基)-N-甲基苯甲醯胺(40 mg,0.08 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(23.1 mg,0.11 mmol,1.5當量)、Pd-PEPPSI-IHeptCl 3-氯吡啶(14.6 mg,0.02 mmol,0.2當量)及Cs 2CO 3(97.9 mg,0.30 mmol,4當量)於1,4-二噁烷(1 mL)中之混合物在100℃及氮氣氛圍下攪拌0.5 h。將所得混合物在減壓下濃縮。殘餘物藉由製備型HPLC (管柱:XBridge Shield RP18 OBD管柱,30*150 mm,5μm;移動相A:水(10 mmol/L NH 4HCO 3+0.05%NH 3 .H 2O),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在7min內38% B至63% B;波長:254 nm/220 nm;RT1(min):6.62;運行次數:2)純化,以得到呈深黃色固體之3-(二氟甲基)-4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-N-甲基苯甲醯胺(4.5 mg,9.77%)。LC-MS:(M+H) +實測值584.15。 1H NMR (400 MHz, DMSO- d 6) δ 8.24 (d, J= 4.6 Hz, 1H), 8.01 – 7.70 (m, 3H), 7.22 (d, J= 2.8 Hz, 1H), 7.09 (s, 1H), 7.01 – 6.93 (m, 1H), 6.76 (t, J= 7.2 Hz, 1H), 6.57 (t, J= 5.9 Hz, 1H), 6.14 (d, J= 7.6 Hz, 1H), 5.85 (d, J= 8.2 Hz, 1H), 4.82 (d, J= 49.4 Hz, 1H), 4.34 (d, J= 5.8 Hz, 2H), 3.59 (d, J= 29.7 Hz, 1H), 3.08 – 2.98 (m, 1H), 2.81 (d, J= 10.9 Hz, 1H), 2.75 (d, J= 4.4 Hz, 3H), 2.18 (s, 4H), 2.09 – 1.92 (m, 2H), 1.68 (d, J= 11.8 Hz, 1H)。 實例502. 3-氟-4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-N-甲基苯甲醯胺之合成 Step 6. A mixture of 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-3-(difluoromethyl)-N-methylbenzamide (40 mg, 0.08 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (23.1 mg, 0.11 mmol , 1.5 eq), Pd-PEPPSI-IHeptCl 3-chloropyridine (14.6 mg, 0.02 mmol, 0.2 eq) and Cs2CO3 (97.9 mg, 0.30 mmol, 4 eq) in 1,4-dioxane (1 mL) was stirred at 100°C under nitrogen atmosphere for 0.5 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 +0.05% NH 3 . H 2 O), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 38% B to 63% B in 7 min; wavelength: 254 nm/220 nm; RT1(min): 6.62; Run number: 2) to give 3-(difluoromethyl)-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide (4.5 mg, 9.77%) as a dark yellow solid. LC-MS: (M+H) + found 584.15. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.24 (d, J = 4.6 Hz, 1H), 8.01 – 7.70 (m, 3H), 7.22 (d, J = 2.8 Hz, 1H), 7.09 (s, 1H), 7.01 – 6.93 (m, 1H), 6.76 (t, J = 7.2 Hz, 1H), 6.57 (t, J = 5.9 Hz, 1H), 6.14 (d, J = 7.6 Hz, 1H), 5.85 (d, J = 8.2 Hz, 1H), 4.82 (d, J = 49.4 Hz, 1H), 4.34 (d, J = 5.8 Hz, 2H), 3.59 (d, J = 29.7 Hz, 1H), 3.08 – 2.98 (m, 1H), 2.81 (d, J = 10.9 Hz, 1H), 2.75 (d, J = 4.4 Hz, 3H), 2.18 (s, 4H), 2.09 – 1.92 (m, 2H), 1.68 (d, J = 11.8 Hz, 1H). Example 502. Synthesis of 3-fluoro-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide
步驟1. 在0℃下,向4-胺基-3-氟苯甲酸(2.00 g,12.89 mmol,1.00當量)、CH 3NH 2 .HCl (1.75 g,25.91 mmol,2.00當量)及NaHCO 3(5.42 g,64.46 mmol,5.00當量)於DMF (20.00 mL)中之攪拌混合物中逐份添加HATU (7.35 g,19.34 mmol,1.50當量)。將溶液在室溫下攪拌2 h。所得溶液使用C18急速層析(管柱:C18管柱;移動相A:水,移動相B:ACN;流動速率:60 mL/min;梯度:在15 min內0% B至100% B;波長:254 nm;220 nm)純化,以得到呈黃色固體之4-胺基-3-氟-N-甲基苯甲醯胺(1.50 g,68.80%)。LC-MS:(M+H) +實測值169.1。 Step 1. To a stirred mixture of 4-amino-3-fluorobenzoic acid (2.00 g, 12.89 mmol , 1.00 equiv), CH3NH2.HCl (1.75 g, 25.91 mmol, 2.00 equiv) and NaHCO3 ( 5.42 g, 64.46 mmol, 5.00 equiv) in DMF (20.00 mL) was added HATU (7.35 g, 19.34 mmol, 1.50 equiv) portionwise at 0°C. The solution was stirred at room temperature for 2 h. The resulting solution was purified by C18 flash chromatography (column: C18 column; mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 15 min; wavelength: 254 nm; 220 nm) to obtain 4-amino-3-fluoro-N-methylbenzamide (1.50 g, 68.80%) as a yellow solid. LC-MS: (M+H) + found 169.1.
步驟2. 在0℃下,向4-胺基-3-氟-N-甲基苯甲醯胺(1.00 g,5.94 mmol,1.00當量)及(Boc) 2O (1.29 g,5.94 mmol,1.00當量)於二噁烷(20.00 mL)中之攪拌混合物中添加DMAP (720.0 mg,5.94 mmol,1.00當量)。將所得混合物在60℃下攪拌2 h。移除溶劑之後,殘餘物使用C18急速層析(管柱:C18管柱;移動相A:水(0.1% FA),移動相B:ACN;流動速率:60 mL/min;梯度:在15 min內0% B至100% B;波長:254 nm;220 nm)純化,以得到呈白色固體之N-[2-氟-4-(甲基胺甲醯基)苯基]胺基甲酸三級丁酯(0.50 g,31.41%)。LC-MS:(M+H) +實測值269.1。 Step 2. To a stirred mixture of 4-amino-3-fluoro-N-methylbenzamide (1.00 g, 5.94 mmol, 1.00 equiv) and (Boc) 2O (1.29 g, 5.94 mmol, 1.00 equiv) in dioxane (20.00 mL) was added DMAP (720.0 mg, 5.94 mmol, 1.00 equiv) at 0°C. The resulting mixture was stirred at 60°C for 2 h. After removing the solvent, the residue was purified by C18 flash chromatography (column: C18 column; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 15 min; wavelength: 254 nm; 220 nm) to give tributyl N-[2-fluoro-4-(methylaminocarbonyl)phenyl]carbamate (0.50 g, 31.41%) as a white solid. LC-MS: (M+H) + found 269.1.
步驟3. 將N-[2-氟-4-(甲基胺甲醯基)苯基]胺基甲酸三級丁酯(200.0 mg,0.74 mmol,1.00當量)、8-溴-2-(3-溴丙-1-炔-1-基)-3-[(三氟甲基)硫基]吲嗪(307.9 mg,0.74 mmol,1.00當量)及Cs 2CO 3(728.7 mg,2.23 mmol,3.00當量)於DMF (5.00 mL)中之混合物在室溫下攪拌2 h。過濾所得混合物且濾液使用C18急速層析(管柱:C18管柱;移動相A:水,移動相B:ACN;流動速率:60 mL/min;梯度:在15 min內0% B至100% B;波長:254 nm;220 nm)純化,以得到呈黃色固體之N-(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)-N-[2-氟-4-(甲基胺甲醯基)苯基]胺基甲酸三級丁酯(300.0 mg,67.25%)。LC-MS:(M+H) +實測值600.0。 Step 3. A mixture of tributyl N-[2-fluoro-4-(methylaminocarbonyl)phenyl]carbamate (200.0 mg, 0.74 mmol, 1.00 equiv), 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizine (307.9 mg, 0.74 mmol, 1.00 equiv) and Cs2CO3 ( 728.7 mg, 2.23 mmol, 3.00 equiv) in DMF (5.00 mL) was stirred at room temperature for 2 h. The resulting mixture was filtered and the filtrate was purified using C18 flash chromatography (column: C18 column; mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 15 min; wavelength: 254 nm; 220 nm) to give tributyl N-(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)-N-[2-fluoro-4-(methylcarbamoyl)phenyl]carbamate (300.0 mg, 67.25%) as a yellow solid. LC-MS: (M+H) + found 600.0.
步驟4. 將N-(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)-N-[2-氟-4-(甲基胺甲醯基)苯基]胺基甲酸三級丁酯(200.0 mg,0.33 mmol,1.00當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺鹽酸鹽(66.0 mg,0.50 mmol,1.50當量)、Pd-PEPPSI-IHeptCl 3-氯吡啶(32.4 mg,0.03 mmol,0.10當量)及Cs 2CO 3(542.6 mg,1.66 mmol,5.00當量)於1,4-二噁烷(5.00 mL)中之混合物在100℃及氮氣氛圍下攪拌3 h。將所得混合物在減壓下濃縮。殘餘物使用C18急速層析(管柱:C18管柱;移動相A:水(0.1% FA),移動相B:ACN;流動速率:60 mL/min;梯度:在15 min內0% B至100% B;波長:254 nm;220 nm)純化,以得到呈黃色油狀物之N-[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]-N-[2-氟-4-(甲基胺甲醯基)苯基]胺基甲酸三級丁酯(150.0 mg,69.10%)。LC-MS:(M+H) +實測值652.2。 Step 4. N-(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)-N-[2-fluoro-4-(methylcarbamoyl)phenyl]carbamic acid tributyl ester (200.0 mg, 0.33 mmol, 1.00 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine hydrochloride (66.0 mg, 0.50 mmol, 1.50 equiv), Pd-PEPPSI-IHeptCl 3-chloropyridine (32.4 mg, 0.03 mmol, 0.10 equiv) and Cs 2 CO 3 (542.6 mg, 1.66 mmol, 5.00 equiv) were dissolved in 1,4-dioxane (5.00 The mixture was stirred at 100°C under nitrogen atmosphere for 3 h. The obtained mixture was concentrated under reduced pressure. The residue was purified by C18 flash chromatography (column: C18 column; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 15 min; wavelength: 254 nm; 220 nm) to give tributyl N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]-N-[2-fluoro-4-(methylaminocarbonyl)phenyl]carbamate (150.0 mg, 69.10%) as a yellow oil. LC-MS: (M+H) + found 652.2.
將N-[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]-N-[2-氟-4-(甲基胺甲醯基)苯基]胺基甲酸三級丁酯(150.0 mg,0.23 mmol,1.00當量)於含4M HCl (g)之1,4-二噁烷(5.00 mL)中之溶液在室溫下攪拌1 h。將所得混合物在減壓下濃縮。殘餘物藉由製備型HPLC (管柱:XBridge Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(10 mmol/L NH 4HCO 3+ 0.05% NH 3 .H 2O),移動相B:ACN;流動速率:60 mL/min;梯度:在8 min內39% B至64% B;波長:220 nm;RT:7.17 min)純化,以得到呈灰色固體之3-氟-4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-N-甲基苯甲醯胺(53.2 mg,33.88%)。LC-MS:(M+H) +實測值552.15。 1H NMR (400 MHz, DMSO- d 6) δ 8.17 (m, 1H), 7.84 (d, J= 6.9 Hz, 1H), 7.63-7.51 (m, 2H), 7.21 (s, 1H), 6.96 (t, J= 8.6 Hz, 1H), 6.75 (t, J= 7.2 Hz, 1H), 6.57 (td, J= 6.2, 2.0 Hz, 1H), 6.14 (d, J= 7.6 Hz, 1H), 5.85 (d, J= 8.3 Hz, 1H), 4.91-4.74 (m, 1H), 4.30 (d, J= 6.2 Hz, 2H), 3.67-3.51 (m, 1H), 3.03 (t, J= 11.2 Hz, 1H), 2.85-2.72 (m, 4H), 2.32-1.92 (m, 6H), 1.68 (d, J= 11.6 Hz, 1H)。 實例432. 3-氰基-4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-N-甲基苯甲醯胺之合成 A solution of tributyl N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]-N-[2-fluoro-4-(methylaminocarbonyl)phenyl]carbamate (150.0 mg, 0.23 mmol, 1.00 equiv) in 4M HCl (g) in 1,4-dioxane (5.00 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 + 0.05% NH 3 . H 2 O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 39% B to 64% B in 8 min; wavelength: 220 nm; RT: 7.17 min) to give 3-fluoro-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide (53.2 mg, 33.88%) as a gray solid. LC-MS: (M+H) + found 552.15. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.17 (m, 1H), 7.84 (d, J = 6.9 Hz, 1H), 7.63-7.51 (m, 2H), 7.21 (s, 1H), 6.96 (t, J = 8.6 Hz, 1H), 6.75 (t, J = 7.2 Hz, 1H), 6.57 (td, J = 6.2, 2.0 Hz, 1H), 6.14 (d, J = 7.6 Hz, 1H), 5.85 (d, J = 8.3 Hz, 1H), 4.91-4.74 (m, 1H), 4.30 (d, J = 6.2 Hz, 2H), 3.67-3.51 (m, 1H), 3.03 (t, J = 11.2 Hz, 1H), 2.85-2.72 (m, 4H), 2.32-1.92 (m, 6H), 1.68 (d, J = 11.6 Hz, 1H). Example 432. Synthesis of 3-cyano-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide
步驟1. 將4-胺基-3-氰基苯甲酸甲酯(1 g,5.67 mmol,1當量)、(Boc) 2O (1.49 g,6.81 mmol,1.2當量)及DMAP (2.08 g,17.03 mmol,3當量)於1,4-二噁烷(15 mL)中之溶液在100℃下攪拌隔夜。所得混合物用水(200 mL)稀釋且用EtOAc (3*200 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用PE / EA (4:1)溶析,以得到呈灰白色固體之4-[(三級丁氧基羰基)胺基]-3-氰基苯甲酸甲酯(780 mg,49.74%)。LC-MS:(M-H) -實測值275.2。 Step 1. A solution of methyl 4-amino-3-cyanobenzoate (1 g, 5.67 mmol, 1 eq.), (Boc) 2O (1.49 g, 6.81 mmol, 1.2 eq.) and DMAP (2.08 g, 17.03 mmol, 3 eq.) in 1,4-dioxane (15 mL) was stirred at 100°C overnight. The resulting mixture was diluted with water (200 mL) and extracted with EtOAc (3*200 mL). The combined organic layers were dried over anhydrous Na2SO4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (4:1) to give methyl 4-[(tert-butyloxycarbonyl)amino]-3-cyanobenzoate (780 mg, 49.74%) as an off-white solid. LC-MS: (MH) - found 275.2.
步驟2. 將4-[(三級丁氧基羰基)胺基]-3-氰基苯甲酸甲酯(240.8 mg,0.87 mmol,1.2當量)、8-溴-2-(3-溴丙-1-炔-1-基)-3-[(三氟甲基)硫基]吲嗪(300 mg,0.72 mmol,1當量)及Cs 2CO 3(709.9 mg,2.18 mmol,3當量)於DMF (5 mL)中之混合物在室溫及氮氣氛圍下攪拌1 h。所得混合物用EtOAc (200 mL)稀釋且用水(3*200 mL)洗滌。有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮,以得到呈棕黃色油狀物之4-[(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)(三級丁氧基羰基)胺基]-3-氰基苯甲酸甲酯(580 mg)。LC-MS:(M+H) +實測值607.9。 Step 2. A mixture of methyl 4-[(tri-butyloxycarbonyl)amino]-3-cyanobenzoate (240.8 mg, 0.87 mmol, 1.2 eq), 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)thio] indolizine (300 mg, 0.72 mmol, 1 eq) and Cs2CO3 (709.9 mg, 2.18 mmol, 3 eq) in DMF (5 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting mixture was diluted with EtOAc (200 mL) and washed with water (3*200 mL). The organic layer was dried over anhydrous Na2SO4 . After filtration, the filtrate was concentrated under reduced pressure to give methyl 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)(t-butyloxycarbonyl)amino]-3-cyanobenzoate (580 mg) as a brown oil. LC-MS: (M+H) + found 607.9.
步驟3. 將4-[(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)(三級丁氧基羰基)胺基]-3-氰基苯甲酸甲酯(580 mg,0.95 mmol,1當量)及NaOH (190.6 mg,4.76 mmol,5當量)於MeOH (4.5 mL)/H 2O (1.5 mL)中之溶液在室溫下攪拌1 h。用檸檬酸將混合物酸化至pH 5且用CH 2Cl 2(3*200 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮,以得到呈棕黃色油狀物之4-[(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)(三級丁氧基羰基)胺基]-3-氰基苯甲酸(550 mg,97.07%)。LC-MS:(M+H) +實測值596.0。 Step 3. A solution of methyl 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)(t-butyloxycarbonyl)amino]-3-cyanobenzoate (580 mg, 0.95 mmol, 1 eq) and NaOH (190.6 mg, 4.76 mmol, 5 eq) in MeOH (4.5 mL)/ H2O (1.5 mL) was stirred at room temperature for 1 h. The mixture was acidified to pH 5 with citric acid and extracted with CH2Cl2 (3*200 mL). The combined organic layers were dried over anhydrous Na2SO4 . After filtration, the filtrate was concentrated under reduced pressure to give 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)(t-butyloxycarbonyl)amino]-3-cyanobenzoic acid (550 mg, 97.07%) as a brown oil. LC-MS: (M+H) + found 596.0.
步驟4. 將4-[(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)(三級丁氧基羰基)胺基]-3-氰基苯甲酸(550 mg,0.92 mmol,1當量)、甲胺鹽酸鹽(93.7 mg,1.39 mmol,1.5當量)、HATU (351.8 mg,0.92 mmol,1當量)及DIEA (597.9 mg,4.62 mmol,5當量)於DMF (6 mL)中之溶液在室溫下攪拌1 h。所得溶液藉由反相急速層析(管柱,C18矽膠;移動相,於水中之MeCN,在20 min內0%至100%梯度;偵測器,UV 254 nm)純化,以得到呈淺棕色固體之N-(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)-N-[2-氰基-4-(甲基胺甲醯基)苯基]胺基甲酸三級丁酯(380 mg,67.96%)。LC-MS:(M+H) +實測值608.9。 Step 4. A solution of 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)(t-butyloxycarbonyl)amino]-3-cyanobenzoic acid (550 mg, 0.92 mmol, 1 eq), methylamine hydrochloride (93.7 mg, 1.39 mmol, 1.5 eq), HATU (351.8 mg, 0.92 mmol, 1 eq) and DIEA (597.9 mg, 4.62 mmol, 5 eq) in DMF (6 mL) was stirred at room temperature for 1 h. The resulting solution was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in water, gradient 0% to 100% in 20 min; detector, UV 254 nm) to give tributyl N-(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)-N-[2-cyano-4-(methylcarbamoyl)phenyl]carbamate (380 mg, 67.96%) as a light brown solid. LC-MS: (M+H) + found 608.9.
步驟5. 將N-(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)-N-[2-氰基-4-(甲基胺甲醯基)苯基]胺基甲酸三級丁酯(380 mg,0.62 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(256.6 mg,1.25 mmol,2當量)、Pd-PEPPSI-IHeptCl 3-氯吡啶(243.7 mg,0.25 mmol,0.4當量)及Cs 2CO 3(1.02 g,3.13 mmol,5當量)於二噁烷(5 mL)中之混合物在100℃及氮氣氛圍下攪拌3 h。所得混合物用水(150 mL)稀釋且用CH 2Cl 2(3 *100 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/MeOH=10:1)純化,以得到呈棕色固體之N-[2-氰基-4-(甲基胺甲醯基)苯基]-N-[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基甲酸三級丁酯(320 mg,77.66%)。LC-MS:(M+H) +實測值659.4。 Step 5. A mixture of tributyl N-(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)-N-[2-cyano-4-(methylcarbamoyl)phenyl]carbamate (380 mg, 0.62 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (256.6 mg, 1.25 mmol, 2 eq), Pd-PEPPSI-IHeptCl 3- chloropyridine (243.7 mg, 0.25 mmol, 0.4 eq) and Cs2CO3 ( 1.02 g, 3.13 mmol, 5 eq) in dioxane (5 mL) was stirred at 100°C under nitrogen atmosphere for 3 h. The resulting mixture was diluted with water (150 mL) and extracted with CH 2 Cl 2 (3 * 100 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 /MeOH=10:1) to give tributyl N-[2-cyano-4-(methylaminocarbonyl)phenyl]-N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]carbamate (320 mg, 77.66%) as a brown solid. LC-MS: (M+H) + found 659.4.
步驟6. 將N-[2-氰基-4-(甲基胺甲醯基)苯基]-N-[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基甲酸三級丁酯(200 mg,0.30 mmol,1當量)及4 M HCl (氣體)於含1,4-二噁烷(0.8 mL)之DCM (4 mL)中之溶液在室溫下攪拌1h。用飽和NaHCO 3將混合物鹼化至pH 8且用CH 2Cl 2(3*100 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型HPLC (管柱:XBridge Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(10 mmol/L NH 4HCO 3+0.05% NH 3 .H 2O),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在8 min內35% B至60% B;波長:220nm nm;RT1(min):8.27)純化,以得到呈灰白色固體之3-氰基-4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-N-甲基苯甲醯胺(71.5 mg,40.43%)。LC-MS:(M+H) +實測值559.15。 1H NMR (400 MHz, DMSO-d6) δ 8.28 (d, J= 4.7 Hz, 1H), 8.02 (d, J= 2.1 Hz, 1H), 7.96 (dd, J= 8.9, 2.2 Hz, 1H), 7.84 (d, J= 6.8 Hz, 1H), 7.20 (d, J= 13.7 Hz, 2H), 7.03 (d, J= 8.9 Hz, 1H), 6.76 (t, J= 7.2 Hz, 1H), 6.14 (d, J= 7.6 Hz, 1H), 5.84 (d, J= 8.3 Hz, 1H), 4.82 (d, J= 49.4 Hz, 1H), 4.37 (d, J= 5.9 Hz, 2H), 3.59 (d, J= 30.0 Hz, 1H), 3.03 (t, J= 11.3 Hz, 1H), 2.81 (d, J= 11.0 Hz, 1H), 2.75 (d, J= 4.4 Hz, 3H), 2.29 (t, J= 14.0 Hz, 1H), 2.18 (s, 3H), 2.17 – 1.92 (m, 2H), 1.68 (d, J= 12.4 Hz, 1H)。 實例495. 3-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-N2,N6-二甲基吡啶-2,6-二甲醯胺之合成 Step 6. A solution of tributyl N-[2-cyano-4-(methylaminocarbonyl)phenyl]-N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]carbamate (200 mg, 0.30 mmol, 1 eq) and 4 M HCl (gas) in DCM (4 mL) containing 1,4-dioxane (0.8 mL) was stirred at room temperature for 1 h. The mixture was basified to pH 8 with saturated NaHCO 3 and extracted with CH 2 Cl 2 (3*100 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 . After filtration, the filtrate is concentrated under reduced pressure. The residue was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 +0.05% NH 3 . H 2 O), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 35% B to 60% B in 8 min; wavelength: 220 nm nm; RT1 (min): 8.27) to obtain 3-cyano-4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-methylbenzamide (71.5 mg, 40.43%). LC-MS: (M+H) + found 559.15. 1 H NMR (400 MHz, DMSO-d6) δ 8.28 (d, J = 4.7 Hz, 1H), 8.02 (d, J = 2.1 Hz, 1H), 7.96 (dd, J = 8.9, 2.2 Hz, 1H), 7.84 (d, J = 6.8 Hz, 1H), 7.20 (d, J = 13.7 Hz, 2H), 7.03 (d, J = 8.9 Hz, 1H), 6.76 (t, J = 7.2 Hz, 1H), 6.14 (d, J = 7.6 Hz, 1H), 5.84 (d, J = 8.3 Hz, 1H), 4.82 (d, J = 49.4 Hz, 1H), 4.37 (d, 3H ), 2.51 (d, J = 14.0 Hz, 1H), 2.89 (d, J = 5.9 Hz, 2H), 3.59 (d, J = 30.0 Hz, 1H), 3.03 (t, J = 11.3 Hz, 1H), 2.81 (d, J = 11.0 Hz, 1H), 2.75 (d, J = 4.4 Hz, 3H), 2.29 (t, J = 14.0 Hz, 1H), 2.18 (s, 3H), 2.17 – 1.92 (m, 2H), 1.68 (d, J = 12.4 Hz, 1H). Example 495. Synthesis of 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N2,N6-dimethylpyridine-2,6-dimethylamide
步驟1. 將2,6-二溴-3-硝基吡啶(200.0 mg,0.71 mmol,1.00當量)、Fe (158.5 mg,2.84 mmol,4.00當量)及NH 4Cl (151.8 mg,2.84 mmol,4.00當量)於EtOH (4.00 mL)/H 2O (1.00 mL)中之混合物在70℃下攪拌1 h。過濾所得混合物且濾餅用EtOH洗滌。將濾液在減壓下濃縮。殘餘物用水(50.00 mL)稀釋且用EtOAc (3*50.00 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮,以得到呈淺綠色固體之2,6-二溴吡啶-3-胺(180.00 mg,粗物質)。粗產物無需進一步純化直接用於下一步驟中。LC-MS:(M+H) +實測值252.9。 Step 1. A mixture of 2,6-dibromo-3-nitropyridine (200.0 mg, 0.71 mmol, 1.00 equiv), Fe (158.5 mg, 2.84 mmol, 4.00 equiv) and NH 4 Cl (151.8 mg, 2.84 mmol, 4.00 equiv) in EtOH (4.00 mL)/H 2 O (1.00 mL) was stirred at 70° C. for 1 h. The resulting mixture was filtered and the filter cake was washed with EtOH. The filtrate was concentrated under reduced pressure. The residue was diluted with water (50.00 mL) and extracted with EtOAc (3*50.00 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to give 2,6-dibromopyridin-3-amine (180.00 mg, crude) as a light green solid. The crude product was used directly in the next step without further purification. LC-MS: (M+H) + found 252.9.
步驟2. 向2,6-二溴吡啶-3-胺(180.0 mg,0.72 mmol,1.00當量)於THF (4.00 mL)中之溶液中添加Boc 2O (467.9 mg,2.15 mmol,3.00當量)、DMAP (8.7 mg,0.07 mmol,0.10當量)及Et 3N (216.9 mg,2.15 mmol,3.00當量)。將混合物在80℃下攪拌1 h。移除溶劑之後,殘餘物使用C18層析(移動相A:水,移動相B:ACN;流動速率:65 mL/min;梯度:在25 min內0% B至100% B;254/220 nm)純化,以得到呈白色固體之N-(三級丁氧基羰基)-N-(2,6-二溴吡啶-3-基)胺基甲酸三級丁酯(270.00 mg,83.57%)。LC-MS:(M+H) +實測值453.0。 Step 2. To a solution of 2,6-dibromopyridin-3-amine (180.0 mg, 0.72 mmol, 1.00 equiv) in THF (4.00 mL) was added Boc2O (467.9 mg, 2.15 mmol, 3.00 equiv), DMAP (8.7 mg, 0.07 mmol, 0.10 equiv) and Et3N (216.9 mg, 2.15 mmol, 3.00 equiv). The mixture was stirred at 80 °C for 1 h. After removal of the solvent, the residue was purified by C18 chromatography (mobile phase A: water, mobile phase B: ACN; flow rate: 65 mL/min; gradient: 0% B to 100% B in 25 min; 254/220 nm) to give tert-butyl N-(tert-butyloxycarbonyl)-N-(2,6-dibromopyridin-3-yl)carbamate (270.00 mg, 83.57%) as a white solid. LC-MS: (M+H) + found 453.0.
步驟3. 將N-(三級丁氧基羰基)-N-(2,6-二溴吡啶-3-基)胺基甲酸三級丁酯(290.0 mg,0.64 mmol,1.00當量)、Pd(dppf)Cl 2(140.8 mg,0.19 mmol,0.30當量)、TEA (1.95 g,19.23 mmol,30.00當量)及MeNH 2 .HCl (173.2 mg,2.56 mmol,4.00當量)於DMA (10.00 mL)中之混合物在100℃及CO氛圍(10 atm)下攪拌16 h。所得混合物使用C18急速層析(移動相A:水,移動相B:ACN;流動速率:60 mL/min;梯度:在30 min內0% B至100% B;254/220 nm)純化,以得到呈淺黃色固體之N-[2,6-雙(甲基胺甲醯基)吡啶-3-基]胺基甲酸三級丁酯(190.0 mg,96.07%)。LC-MS:(M+H) +實測值309.2。 Step 3. A mixture of tert-butyl N-(tert-butyloxycarbonyl)-N-(2,6-dibromopyridin-3-yl)carbamate (290.0 mg, 0.64 mmol, 1.00 equiv), Pd(dppf) Cl2 (140.8 mg, 0.19 mmol, 0.30 equiv), TEA (1.95 g, 19.23 mmol, 30.00 equiv) and MeNH2.HCl ( 173.2 mg, 2.56 mmol, 4.00 equiv) in DMA (10.00 mL) was stirred at 100 °C under CO atmosphere (10 atm) for 16 h. The resulting mixture was purified by C18 flash chromatography (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm) to give tributyl N-[2,6-bis(methylaminoformyl)pyridin-3-yl]carbamate (190.0 mg, 96.07%) as a light yellow solid. LC-MS: (M+H) + found 309.2.
步驟4. 向N-[2,6-雙(甲基胺甲醯基)吡啶-3-基]胺基甲酸三級丁酯(190.0 mg,0.62 mmol,1.00當量)於MeOH (1.00 mL)中之溶液中添加於1,4-二噁烷(1.00 mL)中之4 M HCl (g)。將所得混合物在室溫下攪拌1 h。在真空下移除溶劑,以得到呈淺黃色固體之3-胺基-N2,N6-二甲基吡啶-2,6-二甲醯胺鹽酸鹽(130.0 mg,101.32%)。LC-MS:(M+H) +實測值209.1。 Step 4. To a solution of tributyl N-[2,6-bis(methylaminoformyl)pyridin-3-yl]carbamate (190.0 mg, 0.62 mmol, 1.00 equiv) in MeOH (1.00 mL) was added 4 M HCl (g) in 1,4-dioxane (1.00 mL). The resulting mixture was stirred at room temperature for 1 h. The solvent was removed under vacuum to give 3-amino-N2,N6-dimethylpyridine-2,6-dicarboxamide hydrochloride (130.0 mg, 101.32%) as a light yellow solid. LC-MS: (M+H) + found 209.1.
步驟5. 將3-胺基-N2,N6-二甲基吡啶-2,6-二甲醯胺(130.0 mg,0.62 mmol,1.00當量)、8-溴-2-(3-溴丙-1-炔-1-基)-3-[(三氟甲基)硫基]吲嗪(257.9 mg,0.62 mmol,1.00當量)及4-甲基苯-1-磺酸(43.0 mg,0.25 mmol,0.40當量)於ACN (3.00 mL)中之溶液在80℃及N 2氛圍下攪拌16 h。所得溶液藉由C18急速層析(移動相A:水;移動相B:ACN;流動速率:60 mL/min;梯度:在30 min內0% B至100% B;254/220 nm)純化,以得到呈灰白色固體之3-[(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)胺基]-N2,N6-二甲基吡啶-2,6-二甲醯胺(40.0 mg,11.86%)。LC-MS:(M+H) +實測值540.0。 Step 5. A solution of 3-amino-N2,N6-dimethylpyridine-2,6-dimethylamide (130.0 mg, 0.62 mmol, 1.00 equiv), 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizine (257.9 mg, 0.62 mmol, 1.00 equiv) and 4-methylbenzene-1-sulfonic acid (43.0 mg, 0.25 mmol, 0.40 equiv) in ACN (3.00 mL) was stirred at 80 °C under N2 atmosphere for 16 h. The resulting solution was purified by C18 flash chromatography (mobile phase A: water; mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm) to give 3-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-N2,N6-dimethylpyridine-2,6-dicarboxamide (40.0 mg, 11.86%) as an off-white solid. LC-MS: (M+H) + found 540.0.
步驟6. 將3-[(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)胺基]-N2,N6-二甲基吡啶-2,6-二甲醯胺(40.0 mg,0.05 mmol,1.00當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(22.8 mg,0.11 mmol,2.00當量)、Cs 2CO 3(108.5 mg,0.34 mmol,6.00當量)、BINAP (3.5 mg,0.01 mmol,0.10當量)及BINAP-Pd-G3 (5.5 mg,0.01 mmol,0.10當量)於二噁烷(2.00 mL)中之混合物在100℃及N 2氛圍下攪拌16 h。移除溶劑之後,殘餘物使用C18急速層析(移動相A:水(0.1% FA),移動相B:ACN;流動速率:60 mL/min;梯度:在30 min內0% B至100% B;254/220 nm)及製備型HPLC (管柱:XBridge Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(10 mmol/L NH 4HCO 3+ 0.05% NH 3 .H 2O),移動相B:ACN;流動速率:60 mL/min;梯度:在8 min內36% B至61% B;波長:220 nm;RT:7.58 min)純化,以得到呈黃色固體之3-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-N2,N6-二甲基吡啶-2,6-二甲醯胺(5.80 mg,20.96%)。LC-MS:(M+H) +實測值592.20。 1H NMR (400 MHz, DMSO- d 6) δ 8.01 (d, J= 8.8 Hz, 1H), 7.86 (d, J= 6.8 Hz, 1H), 7.50 (d, J= 8.9 Hz, 1H), 7.18 (s, 1H), 6.79 (t, J= 7.2 Hz, 1H), 6.15 (d, J= 7.6 Hz, 1H), 4.85 (d, J= 49.6 Hz, 1H), 4.46 (s, 2H), 3.64-3.57 (m, 1H), 3.05 (t, J= 11.0 Hz, 1H), 3.03-2.71 (m, 7H), 2.35-2.06 (m, 5H), 2.00 (d, J= 13.0 Hz, 1H), 1.81-1.66 (m, 1H)。 實例433. 5-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-6-甲氧基-N-甲基吡啶-2-甲醯胺之合成 Step 6. 3-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-N2,N6-dimethylpyridine-2,6-dicarboxamide (40.0 mg, 0.05 mmol, 1.00 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (22.8 mg, 0.11 mmol, 2.00 equiv), Cs2CO3 (108.5 mg, 0.34 mmol, 6.00 equiv), BINAP (3.5 mg, 0.01 mmol , 0.10 equiv) and BINAP-Pd-G3 (5.5 mg, 0.01 mmol, 0.10 equiv) were dissolved in dioxane (2.00 The mixture was stirred at 100 °C under N 2 atmosphere for 16 h. After removing the solvent, the residue was purified by C18 flash chromatography (mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm) and preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 + 0.05% NH 3 . H 2 O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 36% B to 61% B in 8 min; wavelength: 220 nm; RT: 7.58 min) to give 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N2,N6-dimethylpyridine-2,6-dicarboxamide (5.80 mg, 20.96%) as a yellow solid. LC-MS: (M+H) + found 592.20. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.01 (d, J = 8.8 Hz, 1H), 7.86 (d, J = 6.8 Hz, 1H), 7.50 (d, J = 8.9 Hz, 1H), 7.18 (s, 1H), 6.79 (t, J = 7.2 Hz, 1H), 6.15 (d, J = 7.6 Hz, 1H), 4.85 (d, J = 49.6 Hz, 1H), 4.46 (s, 2H), 3.64-3.57 (m, 1H), 3.05 (t, J = 11.0 Hz, 1H), 3.03-2.71 (m, 7H), 2.35-2.06 (m, 5H), 2.00 (d, J = 13.0 Hz, 1H), 1.81-1.66 (m, 1H). Example 433. Synthesis of 5-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-6-methoxy-N-methylpyridine-2-carboxamide
步驟1. 將8-溴-2-(3-溴丙-1-炔-1-基)-3-[(三氟甲基)硫基]吲嗪(250 mg,0.61 mmol,1當量)、5-胺基-6-甲氧基-N-甲基吡啶-2-甲醯胺(219.3 mg,1.21 mmol,2當量)及K 2CO 3(250.9 mg,1.82 mmol,3當量)於ACN (6 mL)中之混合物在70℃下攪拌2天。過濾所得混合物,濾餅用DCM洗滌。將濾液在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/MeOH=20:1)純化,以得到呈黃色固體之5-[(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)胺基]-6-甲氧基-N-甲基吡啶-2-甲醯胺(150 mg,47.80%)。LC-MS:(M+H) +實測值514.3。 Step 1. A mixture of 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizine (250 mg, 0.61 mmol, 1 eq.), 5-amino-6-methoxy-N-methylpyridine-2-carboxamide (219.3 mg, 1.21 mmol, 2 eq.) and K 2 CO 3 (250.9 mg, 1.82 mmol, 3 eq.) in ACN (6 mL) was stirred at 70° C. for 2 days. The resulting mixture was filtered and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 /MeOH=20:1) to give 5-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-6-methoxy-N-methylpyridine-2-carboxamide (150 mg, 47.80%) as a yellow solid. LC-MS: (M+H) + found 514.3.
步驟2. 將5-[(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)胺基]-6-甲氧基-N-甲基吡啶-2-甲醯胺(76 mg,0.15 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(60.7 mg,0.30 mmol,2當量)、Cs 2CO 3(241.2 mg,0.74 mmol,5當量)及1-甲基-4-(丙-2-基)苯;N-[(1R,2R)-2-胺基-1,2-二苯基乙基]-N-(氯釕)-4-甲基苯-1-磺醯胺(18.8 mg,0.03 mmol,0.2當量)於1,4-二噁烷(1.5 mL)中之混合物在100℃下再攪拌2 h。過濾所得混合物且將濾液在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/MeOH=20:1)純化,以得到呈白色固體之5-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-6-甲氧基-N-甲基吡啶-2-甲醯胺(24.3 mg,28.98%)。LC-MS:(M+H) +實測值565.35。 1H NMR (400 MHz, DMSO- d 6) δ 8.18 (d, J= 4.9 Hz, 1H), 7.84 (d, J= 6.8 Hz, 1H), 7.53 (d, J= 7.9 Hz, 1H), 7.05 (d, J= 7.9 Hz, 1H), 6.75 (t, J= 7.2 Hz, 1H), 6.37 (t, J= 6.2 Hz, 1H), 6.14 (d, J= 7.6 Hz, 1H), 5.85 (d, J= 8.2 Hz, 1H), 4.82 (d, J= 49.5 Hz, 1H), 4.28 (d, J= 6.2 Hz, 2H), 4.01 (s, 3H), 3.58 (d, J= 28.9 Hz, 1H), 3.09 – 2.95 (m, 1H), 2.80 (d, J= 4.9 Hz, 4H), 2.18 (s, 4H), 2.16 – 1.91 (m, 2H), 1.73 – 1.57 (m, 1H)。 實例493. 4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-N1,N3-二甲基苯-1,3-二甲醯胺之合成 Step 2. 5-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-6-methoxy-N-methylpyridine-2-carboxamide (76 mg, 0.15 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (60.7 mg, 0.30 mmol, 2 eq), Cs 2 CO 3 (241.2 mg, 0.74 mmol, 5 eq) and 1-methyl-4-(propan-2-yl)benzene; N-[(1R,2R)-2-amino-1,2-diphenylethyl]-N-(chlororuthenium)-4-methylbenzene-1-sulfonamide (18.8 mg, 0.03 mmol, 0.2 eq.) in 1,4-dioxane (1.5 mL) was stirred at 100° C. for another 2 h. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 /MeOH=20:1) to give 5-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-6-methoxy-N-methylpyridine-2-carboxamide (24.3 mg, 28.98%) as a white solid. LC-MS: (M+H) + found 565.35. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.18 (d, J = 4.9 Hz, 1H), 7.84 (d, J = 6.8 Hz, 1H), 7.53 (d, J = 7.9 Hz, 1H), 7.05 (d, J = 7.9 Hz, 1H), 6.75 (t, J = 7.2 Hz, 1H), 6.37 (t, J = 6.2 Hz, 1H), 6.14 (d, J = 7.6 Hz, 1H), 5.85 (d, J = 8.2 Hz, 1H), 4.82 (d, J = 49.5 Hz, 1H), 4.28 (d, J = 6.2 Hz, 2H), 4.01 (s, 3H), 3.58 (d, J = 28.9 Hz, 1H), 3.09 – 2.95 (m, 1H), 2.80 (d, J = 4.9 Hz, 4H), 2.18 (s, 4H), 2.16 – 1.91 (m, 2H), 1.73 – 1.57 (m, 1H). Example 493. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N1,N3-dimethylbenzene-1,3-dicarboxamide
步驟1. 將4-胺基苯-1,3-二甲酸(600 mg,3.31 mmol,1當量)、甲胺鹽酸鹽(447.3 mg,6.62 mmol,2當量)、HATU (2.52 g,6.62 mmol,2當量)及DIEA (1.71 g,13.25 mmol,4當量)於DMF (7 mL)中之溶液在室溫下攪拌1 h。所得溶液藉由反相急速層析(管柱,C18矽膠;移動相,於水中之MeOH (10 mmol/L NH 4HCO 3),在15 min內0%至50%梯度;偵測器,UV 254 nm)純化,以得到呈淺黃色固體之4-胺基-N1,N3-二甲基苯-1,3-二甲醯胺(480 mg,69.93%)。LC-MS:(M-H) -實測值206.1。 Step 1. A solution of 4-aminobenzene-1,3-dicarboxylic acid (600 mg, 3.31 mmol, 1 eq), methylamine hydrochloride (447.3 mg, 6.62 mmol, 2 eq), HATU (2.52 g, 6.62 mmol, 2 eq) and DIEA (1.71 g, 13.25 mmol, 4 eq) in DMF (7 mL) was stirred at room temperature for 1 h. The resulting solution was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeOH (10 mmol/L NH 4 HCO 3 ) in water, gradient 0% to 50% in 15 min; detector, UV 254 nm) to give 4-amino-N1,N3-dimethylbenzene-1,3-dicarboxamide (480 mg, 69.93%) as a light yellow solid. LC-MS: (MH) - found 206.1.
步驟2. 將8-溴-2-(3-溴丙-1-炔-1-基)-3-[(三氟甲基)硫基]吲嗪(200 mg,0.48 mmol,1當量)、4-胺基-N1,N3-二甲基苯-1,3-二甲醯胺(110.4 mg,0.53 mmol,1.1當量)及K 2CO 3(200.8 mg,1.45 mmol,3當量)於DMF (3 mL)中之混合物在70℃下攪拌2 h。所得混合物用CH 2Cl 2(20 mL)稀釋且用水(3*20 mL)洗滌。有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型TLC (EA)純化,以得到呈棕黃色固體之4-[(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)胺基]-N1,N3-二甲基苯-1,3-二甲醯胺(145 mg,55.52%)。LC-MS:(M+H) +實測值539.1。 Step 2. A mixture of 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizine (200 mg, 0.48 mmol, 1 eq.), 4-amino-N1,N3-dimethylbenzene- 1,3 -dicarboxamide (110.4 mg, 0.53 mmol, 1.1 eq.) and K2CO3 ( 200.8 mg, 1.45 mmol, 3 eq.) in DMF (3 mL) was stirred at 70°C for 2 h. The resulting mixture was diluted with CH2Cl2 (20 mL) and washed with water (3*20 mL). The organic layer was dried over anhydrous Na2SO4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (EA) to give 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-N1,N3-dimethylbenzene-1,3-dicarboxamide (145 mg, 55.52%) as a brown solid. LC-MS: (M+H) + found 539.1.
步驟3. 將4-[(3-{8-b溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)胺基]-N1,N3-二甲基苯-1,3-二甲醯胺(140 mg,0.26 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(79.9 mg,0.39 mmol,1.5當量)、RAC-BINAP-PD-G3 (51.5 mg,0.05 mmol,0.2當量)、BINAP (32.3 mg,0.05 mmol,0.2當量)及Cs 2CO 3(422.9 mg,1.30 mmol,5當量)於1,4-二噁烷(2 mL)中之混合物在100℃及氮氣氛圍下攪拌1h。所得混合物用水(15 mL)稀釋且用CH 2Cl 2(3 *15 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/MeOH=10:1)及製備型HPLC (管柱:XBridge Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(10 mmol/L NH 4HCO 3+0.05% NH 3 .H 2O),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在8 min內34% B至59% B;波長:220 nm;RT1(min):7.25)純化,以得到呈灰白色固體之4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-N1,N3-二甲基苯-1,3-二甲醯胺(5.5 mg,3.51%)。LC-MS:(M+H) +實測值591.20。 1H NMR (400 MHz, DMSO- d 6) δ 8.47 – 8.36 (d, J= 4.7 Hz, 1H), 8.34 – 8.23 (t, J= 5.8 Hz, 1H), 8.13 – 8.02 (dd, J= 3.5, 9.3 Hz, 2H), 7.90 – 7.83 (d, J= 6.9 Hz, 1H), 7.83 – 7.76 (dd, J= 2.1, 8.8 Hz, 1H), 7.29 – 7.18 (s, 1H), 6.96 – 6.87 (d, J= 8.8 Hz, 1H), 6.81 – 6.72 (t, J= 7.2 Hz, 1H), 6.19 – 6.11 (d, J= 7.6 Hz, 1H), 5.89 – 5.80 (d, J= 8.3 Hz, 1H), 4.94 – 4.74 (d, J= 49.4 Hz, 1H), 4.47 – 4.31 (d, J= 5.8 Hz, 2H), 3.69 – 3.49 (d, J= 28.2 Hz, 1H), 3.10 – 2.97 (s, 1H), 2.89 – 2.79 (s, 2H), 2.79 – 2.73 (d, J= 4.5 Hz, 6H), 2.23 – 2.16 (s, 3H), 2.14 – 1.95 (m, 2H), 1.73 – 1.65 (d, J= 12.2 Hz, 1H)。 實例481. 3-{[3-(8-{[(3S,4R)-3-氟-1-(氧雜環丁-3-基)哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-4-甲氧基-N-甲基苯甲醯胺之合成 Step 3. 4-[(3-{8-b-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-N1,N3-dimethylbenzene-1,3-dicarboxamide (140 mg, 0.26 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (79.9 mg, 0.39 mmol, 1.5 eq), RAC-BINAP-PD-G3 (51.5 mg, 0.05 mmol, 0.2 eq), BINAP (32.3 mg, 0.05 mmol, 0.2 eq) and Cs2CO3 ( 422.9 mg, 1.30 mmol, 5 eq) were dissolved in 1,4-dioxane (2 The mixture in 100 mL) was stirred at 100 °C under nitrogen atmosphere for 1 h. The resulting mixture was diluted with water (15 mL) and extracted with CH 2 Cl 2 (3 * 15 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was separated by preparative TLC (CH 2 Cl 2 /MeOH=10:1) and preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 +0.05% NH 3 . H 2 O), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 34% B to 59% B in 8 min; wavelength: 220 nm; RT1 (min): 7.25) to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N1,N3-dimethylbenzene-1,3-dicarboxamide (5.5 mg, 3.51%) as an off-white solid. LC-MS: (M+H) + found 591.20. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.47 – 8.36 (d, J = 4.7 Hz, 1H), 8.34 – 8.23 (t, J = 5.8 Hz, 1H), 8.13 – 8.02 (dd, J = 3.5, 9.3 Hz, 2H), 7.90 – 7.83 (d, J = 6.9 Hz, 1H), 7.83 – 7.76 (dd, J = 2.1, 8.8 Hz, 1H), 7.29 – 7.18 (s, 1H), 6.96 – 6.87 (d, J = 8.8 Hz, 1H), 6.81 – 6.72 (t, J = 7.2 Hz, 1H), 6.19 – 6.11 (d, J = 7.6 Hz, 1H), 5.89 – 5.80 (d, J = 8.3 Hz, 1H), 4.94 – 4.74 (d, J = 49.4 Hz, 1H), 4.47 – 4.31 (d, J = 5.8 Hz, 2H), 3.69 – 3.49 (d, J = 28.2 Hz, 1H), 3.10 – 2.97 (s, 1H), 2.89 – 2.79 (s, 2H), 2.79 – 2.73 (d, J = 4.5 Hz, 6H), 2.23 – 2.16 (s, 3H), 2.14 – 1.95 (m, 2H), 1.73 – 1.65 (d, J = 12.2 Hz, 1H). Example 481. Synthesis of 3-{[3-(8-{[(3S,4R)-3-fluoro-1-(oxacyclobutan-3-yl)piperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide
步驟1 將8-溴-2-(3-溴丙-1-炔-1-基)-3-[(三氟甲基)硫基]吲嗪(1.00 g,2.42 mmol,1.00當量)、3-胺基-4-甲氧基-N-甲基苯甲醯胺(523.5 mg,2.91 mmol,1.20當量)及K 2CO 3(1.00 g,7.26 mmol,3.00當量)於DMF (10.00 mL)中之混合物在70℃下攪拌1 h。過濾所得混合物且濾液使用C18急速層析(移動相A:水;移動相B:ACN;流動速率:80 mL/min;梯度:在30 min內0% B至100% B;254/220 nm)純化,以得到呈白色固體之3-[(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)胺基]-4-甲氧基-N-甲基苯甲醯胺(650.0 mg,52.4%)。LC-MS:(M+H) +實測值512.0。 Step 1 A mixture of 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizine (1.00 g, 2.42 mmol, 1.00 equiv ), 3-amino-4-methoxy-N-methylbenzamide (523.5 mg, 2.91 mmol, 1.20 equiv) and K2CO3 (1.00 g, 7.26 mmol, 3.00 equiv) in DMF (10.00 mL) was stirred at 70 °C for 1 h. The resulting mixture was filtered and the filtrate was purified using C18 flash chromatography (mobile phase A: water; mobile phase B: ACN; flow rate: 80 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm) to give 3-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-4-methoxy-N-methylbenzamide (650.0 mg, 52.4%) as a white solid. LC-MS: (M+H) + found 512.0.
步驟2. 將3-[(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)胺基]-4-甲氧基-N-甲基苯甲醯胺(640.0 mg,1.25 mmol,1.00當量)、(3S,4R)-4-胺基-3-氟哌啶-1-甲酸三級丁酯(408.9 mg,1.87 mmol,1.50當量)、Cs 2CO 3(1.22 g,3.75 mmol,3.00當量)、BINAP (77.8 mg,0.12 mmol,0.10當量)及BINAP-Pd-G3 (123.9 mg,0.12 mmol,0.10當量)於1,4-二噁烷(10.00 mL)中之混合物在100℃及氮氣氛圍下攪拌3 h。移除溶劑之後,殘餘物藉由反相急速層析(管柱,C18;移動相,於水中之MeCN (0.1% FA),在20 min內0%至100%梯度;偵測器,UV 254 nm)純化,以得到呈淺棕色固體之(3S,4R)-3-氟-4-{[2-(3-{[2-甲氧基-5-(甲基胺甲醯基)苯基]胺基}丙-1-炔-1-基)-3-[(三氟甲基)硫基]吲嗪-8-基]胺基}哌啶-1-甲酸三級丁酯(630.0 mg,77.6%)。LC-MS:(M+H) +實測值650.2。 Step 2. 3-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-4-methoxy-N-methylbenzamide (640.0 mg, 1.25 mmol, 1.00 equiv), (3S,4R)-4-amino-3-fluoropiperidine-1-carboxylic acid tributyl ester (408.9 mg, 1.87 mmol, 1.50 equiv), Cs 2 CO 3 (1.22 g, 3.75 mmol, 3.00 equiv), BINAP (77.8 mg, 0.12 mmol, 0.10 equiv) and BINAP-Pd-G3 (123.9 mg, 0.12 mmol, 0.10 equiv) were dissolved in 1,4-dioxane (10.00 The mixture in 20 mL) was stirred at 100 °C under nitrogen atmosphere for 3 h. After removing the solvent, the residue was purified by reverse phase flash chromatography (column, C18; mobile phase, MeCN (0.1% FA) in water, gradient from 0% to 100% in 20 min; detector, UV 254 nm) to give (3S,4R)-3-fluoro-4-{[2-(3-{[2-methoxy-5-(methylaminoformyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizin-8-yl]amino}piperidine-1-carboxylic acid tributyl ester (630.0 mg, 77.6%) as a light brown solid. LC-MS: (M+H) + found 650.2.
步驟3. 在室溫下,向(3S,4R)-3-氟-4-{[2-(3-{[2-甲氧基-5-(甲基胺甲醯基)苯基]胺基}丙-1-炔-1-基)-3-[(三氟甲基)硫基]吲嗪-8-基]胺基}哌啶-1-甲酸三級丁酯(620.0 mg,0.95 mmol,1.00當量)於DCM (9.00 mL)中之攪拌溶液中添加TFA (3.00 mL)。將反應在室溫下攪拌1 h。將所得溶液在真空下濃縮,以得到呈深綠色半固體之3-{[3-(8-{[(3S,4R)-3-氟哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-4-甲氧基-N-甲基苯甲醯胺三氟乙酸鹽(1.08 g,粗物質)。LC-MS:(M+H) +實測值550.2。 Step 3. To a stirred solution of (3S,4R)-3-fluoro-4-{[2-(3-{[2-methoxy-5-(methylaminocarbonyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizin-8-yl]amino}piperidine-1-carboxylic acid tributyl ester (620.0 mg, 0.95 mmol, 1.00 equiv) in DCM (9.00 mL) was added TFA (3.00 mL) at room temperature. The reaction was stirred at room temperature for 1 h. The resulting solution was concentrated under vacuum to give 3-{[3-(8-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide trifluoroacetate (1.08 g, crude) as a dark green semisolid. LC-MS: (M+H) + found 550.2.
步驟4. 將3-{[3-(8-{[(3S,4R)-3-氟哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-4-甲氧基-N-甲基苯甲醯胺三氟乙酸鹽(100.0 mg,0.18 mmol,1.00當量)、3-氧雜環丁酮(65.6 mg,0.91 mmol,5.00當量)及NaOAc (44.8 mg,0.55 mmol,3.00當量)於MeOH (3.00 mL)中之溶液在室溫下攪拌1 h。然後在室溫下添加NaBH 3CN (34.3 mg,0.55 mmol,3.00當量)。將反應在室溫下再攪拌3 h。所得溶液使用C18急速層析(移動相A:水,移動相B:ACN;流動速率:80 mL/min;梯度:在30 min內0% B至100% B;254/220 nm)及製備型HPLC (管柱:XBridge Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(10 mmol/L NH 4HCO 3+ 0.05% NH 3 .H 2O),移動相B:ACN;流動速率:60 mL/min;梯度:在7 min內32% B至59% B;波長:254 nm/220 nm;RT:7.67 min)純化,以得到呈白色固體之3-{[3-(8-{[(3S,4R)-3-氟-1-(氧雜環丁-3-基)哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-4-甲氧基-N-甲基苯甲醯胺(21.0 mg,18.8%)。LC-MS:(M+H) +實測值606.20。 1H NMR (400 MHz, DMSO- d 6) δ 8.14 (d, J= 4.7 Hz, 1H), 7.84 (d, J= 6.8 Hz, 1H), 7.26 (d, J= 2.1 Hz, 1H), 7.21-7.13 (m, 2H), 6.88 (d, J= 8.3 Hz, 1H), 6.75 (t, J= 7.2 Hz, 1H), 6.14 (d, J= 7.6 Hz, 1H), 5.84 (d, J= 8.2 Hz, 1H), 5.52 (t, J= 6.5 Hz, 1H), 4.85 (d, J= 49.2 Hz, 1H), 4.54 (td, J= 6.5, 2.7 Hz, 2H), 4.45 (t, J= 6.1 Hz, 1H), 4.39 (t, J= 6.1 Hz, 1H), 4.27 (d, J= 6.4 Hz, 2H), 3.84 (s, 3H), 3.83-3.58 (m, 1H), 3.48 (m, 1H), 2.96 (t, J= 10.9 Hz, 1H), 2.75 (d, J= 4.5 Hz, 4H), 2.24 (d, J= 12.8 Hz, 1H), 2.02 (td, J= 21.0, 19.7, 9.4 Hz, 2H), 1.71 (d, J= 11.9 Hz, 1H)。 實例477. 3-{[3-(8-{[(3S,4R)-3-氟哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-4-羥基-N-甲基苯甲醯胺之合成 Step 4. A solution of 3-{[3-(8-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide trifluoroacetate (100.0 mg, 0.18 mmol, 1.00 equiv), 3-oxacyclobutanone (65.6 mg, 0.91 mmol, 5.00 equiv) and NaOAc (44.8 mg, 0.55 mmol, 3.00 equiv) in MeOH (3.00 mL) was stirred at room temperature for 1 h. Then NaBH3CN (34.3 mg, 0.55 mmol, 3.00 equiv) was added at room temperature. The reaction was stirred for another 3 h at room temperature. The resulting solution was purified by C18 flash chromatography (mobile phase A: water, mobile phase B: ACN; flow rate: 80 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm) and preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 + 0.05% NH 3 . H 2 O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 32% B to 59% B in 7 min; wavelength: 254 nm/220 nm; RT: 7.67 min) to give 3-{[3-(8-{[(3S,4R)-3-fluoro-1-(oxacyclobutan-3-yl)piperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide (21.0 mg, 18.8%) as a white solid. LC-MS: (M+H) + found 606.20. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.14 (d, J = 4.7 Hz, 1H), 7.84 (d, J = 6.8 Hz, 1H), 7.26 (d, J = 2.1 Hz, 1H), 7.21-7.13 (m, 2H), 6.88 (d, J = 8.3 Hz, 1H), 6.75 (t, J = 7.2 Hz, 1H), 6.14 (d, J = 7.6 Hz, 1H), 5.84 (d, J = 8.2 Hz, 1H), 5.52 (t, J = 6.5 Hz, 1H), 4.85 (d, J = 49.2 Hz, 1H), 4.54 (td, J = 3H), 4.45 (t, J = 6.1 Hz, 1H), 4.39 (t, J = 6.1 Hz, 1H), 4.27 (d, J = 6.4 Hz, 2H), 3.84 (s, 3H), 3.83-3.58 (m, 1H), 3.48 (m, 1H), 2.96 (t, J = 10.9 Hz, 1H), 2.75 (d, J = 4.5 Hz, 4H), 2.24 (d, J = 12.8 Hz, 1H), 2.02 (td, J = 21.0, 19.7, 9.4 Hz, 2H), 1.71 (d, J = 11.9 Hz, 1H). Example 477. Synthesis of 3-{[3-(8-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-hydroxy-N-methylbenzamide
步驟1 在0℃及空氣氛圍下,向(3S,4R)-3-氟-4-{[2-(3-{[2-甲氧基-5-(甲基胺甲醯基)苯基]胺基}丙-1-炔-1-基)-3-[(三氟甲基)硫基]吲嗪-8-基]胺基}哌啶-1-甲酸三級丁酯(200.0 mg,0.31 mmol,1.00當量)於DCM (10.00 mL)中之攪拌溶液中逐滴添加BBr 3(1M於DCM中,5.00 mL)。將所得混合物在室溫下攪拌2 h,然後在0℃下用MeOH淬滅。將所得溶液在減壓下濃縮。殘餘物藉由製備型HPLC (管柱:Xselect CSH C18 OBD管柱,30*150 mm,5μm;移動相A:水(0.1% FA),移動相B:ACN;流動速率:60 mL/min;梯度:在7 min內17% B至30% B;波長:254nm/220nm;RT:6.4 min)純化,以得到呈灰色固體之3-{[3-(8-{[(3S,4R)-3-氟哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-4-羥基-N-甲基苯甲醯胺(18.40 mg,11.16%)。LC-MS:(M+H) +實測值536.15。 1H NMR (400 MHz, DMSO- d 6 ) δ 8.27 (s, 1H), 8.06 (m, 1H), 7.86 (d, J= 6.8 Hz, 1H), 7.25-7.18 (m, 2H), 7.04 (dd, J= 8.1, 2.0 Hz, 1H), 6.80-6.67 (m, 2H), 6.17 (d, J= 7.6 Hz, 1H), 5.93 (d, J= 8.1 Hz, 1H), 5.26 (s, 1H), 4.86 (d, J= 48.8 Hz, 1H), 4.26 (d, J= 4.4 Hz, 2H), 3.88-3.82 (m, 1H), 3.29 (t, J= 12.2 Hz, 1H), 3.08 (dd, J= 26.6, 13.5 Hz, 2H), 2.99-2.76 (m, 1H), 2.74 (d, J= 4.4 Hz, 3H), 1.99-1.85 (m, 1H), 1.77-1.69 (m, 1H)。 實例489. 3-{[3-(8-{[(3S,4R)-3-氟-1-[(2S*)-2-羥丙基]哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-4-甲氧基-N-甲基苯甲醯胺之合成 Step 1 To a stirred solution of (3S,4R)-3-fluoro-4-{[2-(3-{[2-methoxy-5-(methylaminocarbonyl)phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizin-8-yl]amino}piperidine-1-carboxylic acid tributyl ester (200.0 mg, 0.31 mmol, 1.00 equiv) in DCM (10.00 mL) was added BBr3 (1 M in DCM, 5.00 mL) dropwise at 0°C under air atmosphere. The resulting mixture was stirred at room temperature for 2 h and then quenched with MeOH at 0°C. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Xselect CSH C18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 17% B to 30% B in 7 min; wavelength: 254 nm/220 nm; RT: 6.4 min) to give 3-{[3-(8-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-hydroxy-N-methylbenzamide (18.40 mg, 11.16%) as a gray solid. LC-MS: (M+H) + found 536.15. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.27 (s, 1H), 8.06 (m, 1H), 7.86 (d, J = 6.8 Hz, 1H), 7.25-7.18 (m, 2H), 7.04 (dd, J = 8.1, 2.0 Hz, 1H), 6.80-6.67 (m, 2H), 6.17 (d, J = 7.6 Hz, 1H), 5.93 (d, J = 8.1 Hz, 1H), 5.26 (s, 1H), 4.86 (d, J = 48.8 Hz, 1H), 4.26 (d, J = 4.4 Hz, 2H), 3.88-3.82 (m, 1H), 3.29 (t, J = 12.2 Hz, 1H), 3.08 (dd, J = 26.6, 13.5 Hz, 2H), 2.99-2.76 (m, 1H), 2.74 (d, J = 4.4 Hz, 3H), 1.99-1.85 (m, 1H), 1.77-1.69 (m, 1H). Example 489. Synthesis of 3-{[3-(8-{[(3S,4R)-3-fluoro-1-[(2S*)-2-hydroxypropyl]piperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide
步驟1 將3-{[3-(8-{[(3S,4R)-3-氟哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-4-甲氧基-N-甲基苯甲醯胺(300.0 mg,0.55 mmol,1.00當量)、環氧丙烷(158.5 mg,2.73 mmol,5.00當量)及K 2CO 3(301.8 mg,2.18 mmol,4.00當量)於DMF (5.00 mL)中之混合物在100℃下攪拌16 h。過濾混合物且濾液藉由反相急速層析(管柱,C18;移動相,於水中之MeCN (0.1% NH 3 .H 2O),在20 min內0%至60%梯度;偵測器,UV 254 nm)純化,以得到呈棕色固體之3-{[3-(8-{[(3S,4R)-3-氟-1-(2-羥丙基)哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-4-甲氧基-N-甲基苯甲醯胺(200 mg,60.29%)。然後將其藉由製備型SFC (管柱:Lux 3u Cellulose-3,4.6*150 mm,3 um;移動相A:CO 2,移動相B:MeOH;流動速率:100 mL/mi;梯度:等度20% B;管柱溫度(℃):25;背壓(巴):100;波長:220 nm;RT(min):1.7;樣品溶劑:MeOH;注入體積:1.5 mL;運行次數:30)分離,以得到呈灰白色固體之3-{[3-(8-{[(3S,4R)-3-氟-1-[(2S*)-2-羥丙基]哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-4-甲氧基-N-甲基苯甲醯胺(43.4 mg,21.70%)。LC-MS:(M+H) +實測值606.40。 1H NMR (400 MHz, DMSO- d 6) δ 8.13 (d, J= 4.7 Hz, 1H), 7.83 (d, J= 6.8 Hz, 1H), 7.26 (d, J= 2.0 Hz, 1H), 7.17 (d, J= 8.8 Hz, 2H), 6.87 (d, J= 8.3 Hz, 1H), 6.74 (t, J= 7.2 Hz, 1H), 6.13 (d, J= 7.6 Hz, 1H), 5.81 (d, J= 8.2 Hz, 1H), 5.52 (t, J= 6.5 Hz, 1H), 4.81 (d, J= 49.7 Hz, 1H), 4.28 (t, J= 5.1 Hz, 3H), 3.84 (s, 3H), 3.74 (dt, J= 11.2, 6.0 Hz, 1H), 3.61 (d, J= 29.6 Hz, 1H), 3.14 (t, J= 11.2 Hz, 1H), 2.90 (d, J= 13.9 Hz, 1H), 2.75 (d, J= 4.5 Hz, 3H), 2.42-2.15 (m, 4H), 1.98 (m, 1H), 1.67 (d, J= 12.2 Hz, 1H), 1.04 (d, J= 6.1 Hz, 3H)。 實例480. 3-{[3-(8-{[(3S,4R)-3-氟-1-[(2R*)-2-羥丙基]哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-4-甲氧基-N-甲基苯甲醯胺之合成 Step 1 A mixture of 3-{[3-(8-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide (300.0 mg, 0.55 mmol, 1.00 equiv), propylene oxide (158.5 mg, 2.73 mmol, 5.00 equiv) and K2CO3 ( 301.8 mg, 2.18 mmol, 4.00 equiv) in DMF (5.00 mL) was stirred at 100 °C for 16 h. The mixture was filtered and the filtrate was purified by reverse phase flash chromatography (column, C18; mobile phase, MeCN (0.1% NH 3 . H 2 O) in water, gradient 0% to 60% in 20 min; detector, UV 254 nm) to give 3-{[3-(8-{[(3S,4R)-3-fluoro-1-(2-hydroxypropyl)piperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide (200 mg, 60.29%) as a brown solid. Then, it was subjected to preparative SFC (column: Lux 3u Cellulose-3, 4.6*150 mm, 3 um; mobile phase A: CO 2 , mobile phase B: MeOH; flow rate: 100 mL/min; gradient: isocratic 20% B; column temperature (℃): 25; back pressure (bar): 100; wavelength: 220 nm; RT (min): 1.7; sample solvent: MeOH; injection volume: 1.5 mL; run number: 30) to give 3-{[3-(8-{[(3S,4R)-3-fluoro-1-[(2S*)-2-hydroxypropyl]piperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide (43.4 mg, 21.70%) as an off-white solid. LC-MS: (M+H) + found 606.40. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.13 (d, J = 4.7 Hz, 1H), 7.83 (d, J = 6.8 Hz, 1H), 7.26 (d, J = 2.0 Hz, 1H), 7.17 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.3 Hz, 1H), 6.74 (t, J = 7.2 Hz, 1H), 6.13 (d, J = 7.6 Hz, 1H), 5.81 (d, J = 8.2 Hz, 1H), 5.52 (t, J = 6.5 Hz, 1H), 4.81 (d, J = 49.7 Hz, 1H), 4.28 (t, J = 5.1 Hz, 3H), 3.84 (s, 3H), 3.74 (dt, J = 11.2, 6.0 Hz, 1H), 3.61 (d, J = 29.6 Hz, 1H), 3.14 (t, J = 11.2 Hz, 1H), 2.90 (d, J = 13.9 Hz, 1H), 2.75 (d, J = 4.5 Hz, 3H), 2.42-2.15 (m, 4H), 1.98 (m, 1H), 1.67 (d, J = 12.2 Hz, 1H), 1.04 (d, J = 6.1 Hz, 3H). Example 480. Synthesis of 3-{[3-(8-{[(3S,4R)-3-fluoro-1-[(2R*)-2-hydroxypropyl]piperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide
步驟1 將3-{[3-(8-{[(3S,4R)-3-氟哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-4-甲氧基-N-甲基苯甲醯胺(300.0 mg,0.55 mmol,1.00當量)、環氧丙烷(158.5 mg,2.73 mmol,5.00當量)及K 2CO 3(301.8 mg,2.18 mmol,4.00當量)於DMF (5.00 mL)中之混合物在100℃下攪拌16 h。過濾混合物且濾液藉由反相急速層析(管柱,C18;移動相,於水中之MeCN (0.1% NH 3 .H 2O),在20 min內0%至60%梯度;偵測器,UV 254 nm)純化,以得到呈棕色固體之3-{[3-(8-{[(3S,4R)-3-氟-1-(2-羥丙基)哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-4-甲氧基-N-甲基苯甲醯胺(200 mg,60.29%)。然後將其藉由製備型SFC (管柱:Lux 3u Cellulose-3,4.6*150 mm,3 um;移動相A:CO 2,移動相B:MeOH;流動速率:100 mL/mi;梯度:等度20% B;管柱溫度(℃):25;背壓(巴):100;波長:220 nm;RT(min):1.7;樣品溶劑:MeOH;注入體積:1.5 mL;運行次數:30)分離,以得到呈灰白色固體之3-{[3-(8-{[(3S,4R)-3-氟-1-[(2S*)-2-羥丙基]哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-4-甲氧基-N-甲基苯甲醯胺(43.4 mg,21.70%)。LC-MS:(M+H) +實測值606.40。 1H NMR (400 MHz, DMSO- d 6) δ 8.13 (d, J= 4.7 Hz, 1H), 7.83 (d, J= 6.8 Hz, 1H), 7.26 (d, J= 2.0 Hz, 1H), 7.17 (d, J= 8.8 Hz, 2H), 6.87 (d, J= 8.3 Hz, 1H), 6.74 (t, J= 7.2 Hz, 1H), 6.13 (d, J= 7.6 Hz, 1H), 5.81 (d, J= 8.2 Hz, 1H), 5.52 (t, J= 6.5 Hz, 1H), 4.81 (d, J= 49.7 Hz, 1H), 4.28 (t, J= 5.1 Hz, 3H), 3.84 (s, 3H), 3.74 (dt, J= 11.2, 6.0 Hz, 1H), 3.61 (d, J= 29.6 Hz, 1H), 3.14 (t, J= 11.2 Hz, 1H), 2.90 (d, J= 13.9 Hz, 1H), 2.75 (d, J= 4.5 Hz, 3H), 2.42-2.15 (m, 4H), 1.98 (m, 1H), 1.67 (d, J= 12.2 Hz, 1H), 1.04 (d, J= 6.1 Hz, 3H)。 實例459. 3-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-N-(2-羥基-2-甲基丙基)-4-(氧雜環丁-3-基氧基)苯甲醯胺之合成 Step 1 A mixture of 3-{[3-(8-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide (300.0 mg, 0.55 mmol, 1.00 equiv), propylene oxide (158.5 mg, 2.73 mmol, 5.00 equiv) and K2CO3 ( 301.8 mg, 2.18 mmol, 4.00 equiv) in DMF (5.00 mL) was stirred at 100 °C for 16 h. The mixture was filtered and the filtrate was purified by reverse phase flash chromatography (column, C18; mobile phase, MeCN (0.1% NH 3 . H 2 O) in water, gradient 0% to 60% in 20 min; detector, UV 254 nm) to give 3-{[3-(8-{[(3S,4R)-3-fluoro-1-(2-hydroxypropyl)piperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide (200 mg, 60.29%) as a brown solid. Then, it was subjected to preparative SFC (column: Lux 3u Cellulose-3, 4.6*150 mm, 3 um; mobile phase A: CO 2 , mobile phase B: MeOH; flow rate: 100 mL/min; gradient: isocratic 20% B; column temperature (℃): 25; back pressure (bar): 100; wavelength: 220 nm; RT (min): 1.7; sample solvent: MeOH; injection volume: 1.5 mL; run number: 30) to give 3-{[3-(8-{[(3S,4R)-3-fluoro-1-[(2S*)-2-hydroxypropyl]piperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N-methylbenzamide (43.4 mg, 21.70%) as an off-white solid. LC-MS: (M+H) + found 606.40. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.13 (d, J = 4.7 Hz, 1H), 7.83 (d, J = 6.8 Hz, 1H), 7.26 (d, J = 2.0 Hz, 1H), 7.17 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.3 Hz, 1H), 6.74 (t, J = 7.2 Hz, 1H), 6.13 (d, J = 7.6 Hz, 1H), 5.81 (d, J = 8.2 Hz, 1H), 5.52 (t, J = 6.5 Hz, 1H), 4.81 (d, J = 49.7 Hz, 1H), 4.28 (t, J = 5.1 Hz, 3H), 3.84 (s, 3H), 3.74 (dt, J = 11.2, 6.0 Hz, 1H), 3.61 (d, J = 29.6 Hz, 1H), 3.14 (t, J = 11.2 Hz, 1H), 2.90 (d, J = 13.9 Hz, 1H), 2.75 (d, J = 4.5 Hz, 3H), 2.42-2.15 (m, 4H), 1.98 (m, 1H), 1.67 (d, J = 12.2 Hz, 1H), 1.04 (d, J = 6.1 Hz, 3H). Example 459. Synthesis of 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-(2-hydroxy-2-methylpropyl)-4-(oxocyclobutan-3-yloxy)benzamide
步驟1 將4-羥基-3-硝基苯甲酸甲酯(3.00 g,15.21 mmol,1.00當量)、3-碘氧雜環丁烷(8.40 g,45.65 mmol,3.00當量)及Cs 2CO 3(14.87 g,45.65 mmol,3.00當量)於DMF (30 mL)中之混合物在100℃下攪拌24 h。所得混合物用水(100 mL)稀釋且用EtOAc (3*100 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用PE / EA (5:1)溶析,以得到呈棕色固體之3-硝基-4-(氧雜環丁-3-基氧基)苯甲酸甲酯(930 mg,24.14%)。LC-MS:(M+H) +實測值254.2。 Step 1 A mixture of methyl 4-hydroxy-3-nitrobenzoate (3.00 g, 15.21 mmol, 1.00 equiv), 3-iodooxycyclobutane (8.40 g, 45.65 mmol, 3.00 equiv) and Cs 2 CO 3 (14.87 g, 45.65 mmol, 3.00 equiv) in DMF (30 mL) was stirred at 100 °C for 24 h. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (3*100 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (5:1) to give methyl 3-nitro-4-(oxacyclobutan-3-yloxy)benzoate (930 mg, 24.14%) as a brown solid. LC-MS: (M+H) + found 254.2.
步驟2. 將3-硝基-4-(氧雜環丁-3-基氧基)苯甲酸甲酯(930 mg,3.67 mmol,1.00當量)、NH 4Cl (1.18 g,22.04 mmol,6.00當量)及Fe (1.23 g,22.03 mmol,6.00當量)於EtOH (15 mL)/H 2O (5 mL)中之混合物在70℃下攪拌1 h。過濾所得混合物,濾餅用乙酸乙酯洗滌。濾液用水(100 mL)稀釋且用EtOAc (3*100 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用PE / EA (12:1)溶析,以得到呈黃色固體之3-胺基-4-(氧雜環丁-3-基氧基)苯甲酸甲酯(800 mg,97.58%)。LC-MS:(M+H) +實測值224.1。 Step 2. A mixture of methyl 3-nitro-4-(oxacyclobutan-3-yloxy)benzoate (930 mg, 3.67 mmol, 1.00 equiv), NH 4 Cl (1.18 g, 22.04 mmol, 6.00 equiv) and Fe (1.23 g, 22.03 mmol, 6.00 equiv) in EtOH (15 mL)/H 2 O (5 mL) was stirred at 70° C. for 1 h. The resulting mixture was filtered and the filter cake was washed with ethyl acetate. The filtrate was diluted with water (100 mL) and extracted with EtOAc (3*100 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (12:1) to give methyl 3-amino-4-(oxacyclobutan-3-yloxy)benzoate (800 mg, 97.58%) as a yellow solid. LC-MS: (M+H) + found 224.1.
步驟3. 將3-胺基-4-(氧雜環丁-3-基氧基)苯甲酸甲酯(486 mg,2.18 mmol,1.50當量)、K 2CO 3(602 mg,4.36 mmol,3.00當量)及8-溴-2-(3-溴丙-1-炔-1-基)-3-[(三氟甲基)硫基]吲嗪(600 mg,1.45 mmol,1.00當量)於ACN (8 mL)中之混合物在70℃下攪拌隔夜。所得混合物用水(50 mL)稀釋且用DCM (3*50 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型TLC (PE / EA=2 / 1)純化,以得到呈棕色固體之3-[(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)胺基]-4-(氧雜環丁-3-基氧基)苯甲酸甲酯(520 mg,64.46%)。LC-MS:(M+H) +實測值555.1。 Step 3. A mixture of methyl 3-amino-4-(oxacyclobutan-3-yloxy)benzoate (486 mg, 2.18 mmol, 1.50 equiv), K 2 CO 3 (602 mg, 4.36 mmol, 3.00 equiv) and 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizine (600 mg, 1.45 mmol, 1.00 equiv) in ACN (8 mL) was stirred at 70° C. overnight. The resulting mixture was diluted with water (50 mL) and extracted with DCM (3*50 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE/EA=2/1) to give methyl 3-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-4-(oxacyclobutan-3-yloxy)benzoate (520 mg, 64.46%) as a brown solid. LC-MS: (M+H) + found 555.1.
步驟4. 將3-[(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)胺基]-4-(氧雜環丁-3-基氧基)苯甲酸甲酯(530 mg,0.95 mmol,1.00當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(391 mg,1.91 mmol,2.00當量)、Cs 2CO 3(1.87 g,5.72 mmol,6.00當量)、BINAP (237 mg,0.38 mmol,0.40當量)及RAC-BINAP-PD-G3 (189 mg,0.19 mmol,0.20當量)於二噁烷(10 mL)中之混合物在100℃及氮氣氛圍下攪拌隔夜。反應用水(50 mL)稀釋且用EtOAc (3*50 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/MeOH=20/1)純化,以得到呈棕色固體之3-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-4-(氧雜環丁-3-基氧基)苯甲酸甲酯(340 mg,58.73%)。LC-MS:(M+H) +實測值607.3。 Step 4. Methyl 3-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-4-(oxacyclobutan-3-yloxy)benzoate (530 mg, 0.95 mmol, 1.00 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (391 mg, 1.91 mmol, 2.00 equiv), Cs2CO3 (1.87 g, 5.72 mmol, 6.00 equiv), BINAP (237 mg, 0.38 mmol, 0.40 equiv) and RAC-BINAP-PD-G3 (189 mg, 0.19 mmol , 0.20 equiv) were stirred in dioxane (10% MgSO4). The mixture in 50 mL) was stirred at 100 °C under nitrogen atmosphere overnight. The reaction was diluted with water (50 mL) and extracted with EtOAc (3*50 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 /MeOH=20/1) to give methyl 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-(oxacyclobutan-3-yloxy)benzoate (340 mg, 58.73%) as a brown solid. LC-MS: (M+H) + found 607.3.
步驟5. 在室溫下,向3-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-4-(氧雜環丁-3-基氧基)苯甲酸甲酯(330 mg,0.54 mmol,1.00當量)於MeOH (3 mL)/THF (3 mL) /H 2O (3 mL)中之攪拌溶液中添加NaOH (217 mg,5.44 mmol,10.00當量)。將所得混合物在60℃下攪拌2 h。用1 M HCl將混合物酸化至pH 5,然後用EtOAc (3*50 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。粗產物無需進一步純化直接用於下一步驟中。LC-MS:(M+H) +實測值593.0。 Step 5. To a stirred solution of methyl 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-(oxacyclobutan-3-yloxy)benzoate (330 mg, 0.54 mmol, 1.00 equiv) in MeOH (3 mL)/THF (3 mL)/ H2O (3 mL) was added NaOH (217 mg, 5.44 mmol, 10.00 equiv) at room temperature. The resulting mixture was stirred at 60 °C for 2 h. The mixture was acidified to pH 5 with 1 M HCl and then extracted with EtOAc (3*50 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LC-MS: (M+H) + found 593.0.
步驟6. 在0℃下,向3-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-4-(氧雜環丁-3-基氧基)苯甲酸(70 mg,0.11 mmol,1.00當量)、1-胺基-2-甲基丙-2-醇(12.6 mg,0.14 mmol,1.2當量)及DIEA (46 mg,0.35 mmol,3.00當量)於DMF (1 mL)中之攪拌混合物中添加HATU (54 mg,0.14 mmol,1.20當量)。將混合物在室溫下攪拌1 h。反應用水(30 mL)稀釋且用EtOAc (3*30 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型HPLC (管柱:X-Select Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(0.1%FA),移動相B:ACN;流動速率:60 mL/min;梯度:在7 min內30% B至50% B;波長:254 nm/220 nm;RT1(min):6.56)純化,以得到呈灰白色固體之3-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-N-(2-羥基-2-甲基丙基)-4-(氧雜環丁-3-基氧基)苯甲醯胺(26.5 mg,33.50%)。LC-MS:(M+H) +實測值:664.35。 1H NMR (400 MHz, DMSO- d 6 ) δ7.95 (d, J= 6.8 Hz, 1H), 7.81 (dd, J= 12.2, 8.1 Hz, 1H), 7.35 (s, 1H), 7.2 (dd, J= 8.1, 2.1 Hz, 1H),7.1 (s,1H), 6.86 (t, J= 7.2 Hz, 1H), 6.54 (s,1H), 6.14 (d, J= 7.6 Hz, 1H), 5.83 (s, 2H), 5.45 (s,1H), 4.97 (d, J= 6.2 Hz, 2H), 4.91-4.80 (m,1H), 4.63 (s, 3H), 4.3 (s, 2H), 3.81 (d, J= 10.8 Hz, 1H), 3.3 (s, 2H), 3.12 (t, J= 11.5 Hz, 1H), 2.88 (s, 1H), 2.31-2.15 (m,4H),2.12 (s,1H),1.99 (d, J= 13.3 Hz, 1H),1.75-1.64 (m,1H),1.15(s,6H)。 實例413. 3-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-N-甲基-4-[(1s,3s)-3-羥基環丁氧基]苯甲醯胺之合成 Step 6. To a stirred mixture of 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-(oxacyclobutan-3-yloxy)benzoic acid (70 mg, 0.11 mmol, 1.00 equiv), 1-amino-2-methylpropan-2-ol (12.6 mg, 0.14 mmol, 1.2 equiv) and DIEA (46 mg, 0.35 mmol, 3.00 equiv) in DMF (1 mL) was added HATU (54 mg, 0.14 mmol, 1.20 equiv) at 0° C. The mixture was stirred at room temperature for 1 h. The reaction was diluted with water (30 mL) and extracted with EtOAc (3*30 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: X-Select Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 30% B to 50% B in 7 min; wavelength: 254 nm/220 nm; RT1(min): 6.56) to obtain 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-(2-hydroxy-2-methylpropyl)-4-(oxacyclobutan-3-yloxy)benzamide (26.5 mg, 33.50%). LC-MS: (M+H) + found: 664.35. 1 H NMR (400 MHz, DMSO- d 6 ) δ7.95 (d, J = 6.8 Hz, 1H), 7.81 (dd, J = 12.2, 8.1 Hz, 1H), 7.35 (s, 1H), 7.2 (dd, J = 8.1, 2.1 Hz, 1H),7.1 (s,1H), 6.86 (t, J = 7.2 Hz, 1H), 6.54 (s,1H), 6.14 (d, J = 7.6 Hz, 1H), 5.83 (s, 2H), 5.45 (s,1H), 4.97 (d, J = 6.2 Hz, 2H), 4.91-4.80 (m,1H), 4.63 (s, 3H), 4.3 (s, 2H), 3.81 (d, J = 10.8 Hz, 1H), 3.3 (s, 2H), 3.12 (t, J = 11.5 Hz, 1H), 2.88 (s, 1H), 2.31-2.15 (m,4H),2.12 (s,1H),1.99 (d, J = 13.3 Hz, 1H),1.75-1.64 (m,1H),1.15(s,6H). Example 413. Synthesis of 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-methyl-4-[(1s,3s)-3-hydroxycyclobutoxy]benzamide
步驟1. 在0℃下,向環丁烷-1,3-二醇(444.6 mg,5.05 mmol,1當量)於DMF (2 mL)中之攪拌溶液中添加NaH (403.7 mg,10.09 mmol,2當量,60%)。將所得混合物在室溫下攪拌5 min。然後添加4-氟-N-甲基-3-硝基苯甲醯胺(1 g,5.047 mmol,1當量)且將反應在室溫下攪拌1 h。將反應在0℃下用水淬滅且用EtOAc (2*50mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由反相急速層析(管柱,C18矽膠;移動相,於水中之MeCN (0.1% FA),在30 min內10%至50%梯度;偵測器,UV 254 nm)純化,以得到呈黃色油狀物之4-(3-羥基環丁氧基)-N-甲基-3-硝基苯甲醯胺(300 mg,13.40%)。LC-MS:(M+H)+實測值267.1。 Step 1. To a stirred solution of cyclobutane-1,3-diol (444.6 mg, 5.05 mmol, 1 eq.) in DMF (2 mL) at 0°C was added NaH (403.7 mg, 10.09 mmol, 2 eq., 60%). The resulting mixture was stirred at room temperature for 5 min. Then 4-fluoro-N-methyl-3-nitrobenzamide (1 g, 5.047 mmol, 1 eq.) was added and the reaction was stirred at room temperature for 1 h. The reaction was quenched with water at 0°C and extracted with EtOAc (2*50 mL). The combined organic layers were dried over anhydrous Na2SO4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient 10% to 50% in 30 min; detector, UV 254 nm) to give 4-(3-hydroxycyclobutoxy)-N-methyl-3-nitrobenzamide (300 mg, 13.40%) as a yellow oil. LC-MS: (M+H)+ found 267.1.
步驟2. 將4-(3-羥基環丁氧基)-N-甲基-3-硝基苯甲醯胺(100 mg,0.30 mmol,1當量)、Fe (83.9 mg,1.50 mmol,5當量)、NH 4Cl (32.1 mg,0.60 mmol,2當量)、H 2O (1 mL)及EtOH (1 mL)之混合物在70℃下攪拌1 h。過濾所得混合物,濾餅用CH 2Cl 2洗滌。將濾液在減壓下濃縮。殘餘物藉由反相急速層析(管柱,C18矽膠;移動相,於水中之MeCN (0.1% FA),在30 min內0%至100%梯度;偵測器,UV 254 nm)純化,以得到呈黃色固體之3-胺基-4-(3-羥基環丁氧基)-N-甲基苯甲醯胺(100 mg,70.43%)。LC-MS:(M+H)+實測值237.1。 Step 2. A mixture of 4-(3-hydroxycyclobutoxy)-N-methyl-3-nitrobenzamide (100 mg, 0.30 mmol, 1 eq), Fe (83.9 mg, 1.50 mmol, 5 eq), NH 4 Cl (32.1 mg, 0.60 mmol, 2 eq), H 2 O (1 mL) and EtOH (1 mL) was stirred at 70° C. for 1 h. The resulting mixture was filtered and the filter cake was washed with CH 2 Cl 2. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient 0% to 100% in 30 min; detector, UV 254 nm) to give 3-amino-4-(3-hydroxycyclobutoxy)-N-methylbenzamide (100 mg, 70.43%) as a yellow solid. LC-MS: (M+H)+ found 237.1.
步驟3. 將3-胺基-4-(3-羥基環丁氧基)-N-甲基苯甲醯胺(100 mg,0.42 mmol,1.00當量)、8-溴-2-(3-溴丙-1-炔-1-基)-3-[(三氟甲基)硫基]吲嗪(174.8 mg,0.42 mmol,1當量)及K 2CO 3(175.5 mg,1.27 mmol,3當量)於乙腈(2 mL)中之混合物在70℃下攪拌3 h。過濾混合物且濾液藉由反相急速層析(管柱,C18矽膠;移動相,於水中之MeCN (0.1% FA),在30 min內0%至100%梯度;偵測器,UV 254 nm)純化,以得到呈黃色固體之3-[(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)胺基]-4-(3-羥基環丁氧基)-N-甲基苯甲醯胺(80 mg,33.25%)。LC-MS:(M+H) +實測值568.0。 Step 3. A mixture of 3-amino-4-(3-hydroxycyclobutoxy)-N-methylbenzamide (100 mg, 0.42 mmol, 1.00 equiv), 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizine (174.8 mg, 0.42 mmol, 1 equiv) and K2CO3 (175.5 mg, 1.27 mmol, 3 equiv) in acetonitrile (2 mL) was stirred at 70°C for 3 h. The mixture was filtered and the filtrate was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient 0% to 100% in 30 min; detector, UV 254 nm) to give 3-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-4-(3-hydroxycyclobutoxy)-N-methylbenzamide (80 mg, 33.25%) as a yellow solid. LC-MS: (M+H) + found 568.0.
步驟4. 將3-[(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)胺基]-4-(3-羥基環丁氧基)-N-甲基苯甲醯胺(120 mg,0.21 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺(41.9 mg,0.32 mmol,1.5當量)、t-BuONa (101.5 mg,1.06 mmol,5當量)及tBuXPhos Pd G3 (50.3 mg,0.06 mmol,0.3當量)於THF (2 mL)中之混合物在65℃及氮氣氛圍下攪拌1 h。將混合物在減壓下濃縮且殘餘物藉由反相急速層析(管柱,C18矽膠;移動相,於水中之MeCN (0.1% FA),在20 min內0%至100%梯度;偵測器,UV 254 nm)純化,以得到呈黃色固體之3-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-4-(3-羥基環丁氧基)-N-甲基苯甲醯胺(40 mg,30.58%)。LC-MS:(M+H) +實測值620.3。 Step 4. A mixture of 3-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2-yn-1-yl)amino]-4-(3-hydroxycyclobutoxy)-N-methylbenzamide (120 mg, 0.21 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine (41.9 mg, 0.32 mmol, 1.5 eq), t-BuONa (101.5 mg, 1.06 mmol, 5 eq) and tBuXPhos Pd G3 (50.3 mg, 0.06 mmol, 0.3 eq) in THF (2 mL) was stirred at 65 °C under nitrogen atmosphere for 1 h. The mixture was concentrated under reduced pressure and the residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient 0% to 100% in 20 min; detector, UV 254 nm) to give 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-(3-hydroxycyclobutoxy)-N-methylbenzamide (40 mg, 30.58%) as a yellow solid. LC-MS: (M+H) + found 620.3.
步驟5. 3-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-4-(3-羥基環丁氧基)-N-甲基苯甲醯胺(40 mg,0.07 mmol,1當量)藉由掌性HPLC (管柱:CHIRALPAKIF-34.6*50 mm,3.0 um;移動相A:MtBE (0.2% DEA):(EtOH:DCM=1:1)=70:30;流動速率:1.0 ml/min mL/min;梯度:等度;注入體積:5.0L mL)分離,以得到呈白色固體之3-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-N-甲基-4-[(1s,3s)-3-羥基環丁氧基]苯甲醯胺(1.1 mg,2.74%)。LC-MS:(M+H)+實測值620.35。 1H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J= 4.7 Hz, 1H), 7.85 (d, J= 6.9 Hz, 1H), 7.25 (d, J= 2.0 Hz, 1H), 7.19 (s, 1H), 7.10 (dd, J= 8.2, 2.1 Hz, 1H), 6.75 (t, J= 7.2 Hz, 1H), 6.61 (d, J= 8.3 Hz, 1H), 6.14 (d, J= 7.7 Hz, 1H), 5.87 (s, 1H), 5.53 (t, J= 6.4 Hz, 1H), 5.18 (d, J= 5.5 Hz, 1H), 4.86 (dt, J= 6.6, 3.1 Hz, 2H), 4.40 (m, 1H), 4.28 (d, J= 6.4 Hz, 2H), 3.65 (d, J= 5.5 Hz, 1H), 3.1 (d, J= 5.5 Hz, 1H),2.84 (s, 1H), 2.74 (d, J= 4.5 Hz, 3H), 2.43 – 2.18 (m, 8H), 2.09 – 1.95 (m, 2H), 1.71 (s, 1H)。 實例497. 3-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-N-甲基-4-[(1r,3r)-3-羥基環丁氧基]苯甲醯胺之合成 Step 5. 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-(3-hydroxycyclobutoxy)-N-methylbenzamide (40 mg, 0.07 mmol, 1 equivalent) was purified by chiral HPLC (column: CHIRALPAK IF-3 4.6*50 mm, 3.0 um; mobile phase A: MtBE (0.2% DEA):(EtOH:DCM=1:1)=70:30; flow rate: 1.0 ml/min mL/min; gradient: isocratic; injection volume: 5.0 L mL) to give 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-methyl-4-[(1s,3s)-3-hydroxycyclobutoxy]benzamide (1.1 mg, 2.74%) as a white solid. LC-MS: (M+H)+ found 620.35. 1 H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J = 4.7 Hz, 1H), 7.85 (d, J = 6.9 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 7.19 (s, 1H), 7.10 (dd, J = 8.2, 2.1 Hz, 1H), 6.75 (t, J = 7.2 Hz, 1H), 6.61 (d, J = 8.3 Hz, 1H), 6.14 (d, J = 7.7 Hz, 1H), 5.87 (s, 1H), 5.53 (t, J = 6.4 Hz, 1H), 5.18 (d, J = 5.5 Hz, 1H), 4.86 (dt, J = 6.6, 3.1 Hz, 2H), 4.40 (m, 1H), 4.28 (d, J = 6.4 Hz, 2H), 3.65 (d, J = 5.5 Hz, 1H), 3.1 (d, J = 5.5 Hz, 1H),2.84 (s, 1H), 2.74 (d, J = 4.5 Hz, 3H), 2.43 – 2.18 (m, 8H), 2.09 – 1.95 (m, 2H), 1.71 (s, 1H). Example 497. Synthesis of 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-methyl-4-[(1r,3r)-3-hydroxycyclobutoxy]benzamide
步驟1. 3-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-4-(3-羥基環丁氧基)-N-甲基苯甲醯胺(40 mg,0.07 mmol,1當量)藉由掌性HPLC (管柱:CHIRALPAKIF-34.6*50 mm,3.0 um;移動相A:MtBE (0.2% DEA):(EtOH:DCM=1:1)=70:30;流動速率:1.0 ml/min mL/min;梯度:等度;注入體積:5.0 L mL)分離,以得到呈白色固體之3-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-N-甲基-4-[(1r,3r)-3-羥基環丁氧基]苯甲醯胺(9.8 mg,24.38%)。LC-MS:(M+H) +實測值620.30。 1H NMR (400 MHz, DMSO-d6) δ 8.12 (m, 1H), 7.84 (d, J= 6.8 Hz, 1H), 7.24 (d, J= 2.1 Hz, 1H), 7.19 (d, J= 0.9 Hz, 1H), 7.10 (dd, J= 8.3, 2.0 Hz, 1H), 6.75 (t, J= 7.2 Hz, 1H), 6.68 (d, J= 8.4 Hz, 1H), 6.14 (d, J= 7.6 Hz, 1H), 5.84 (d, J= 8.2 Hz, 1H), 5.50 (t, J= 6.4 Hz, 1H), 5.21 (d, J= 6.3 Hz, 1H), 4.83 (d, J= 49.4 Hz, 1H), 4.29 (dd, J= 11.0, 6.6 Hz, 3H), 3.85 (m, 1H), 3.59 (d, J= 29.2 Hz, 1H), 3.04 (s, 1H), 2.83 (m, 3H), 2.74 (d, J= 4.5 Hz, 3H), 2.19 (s, 4H), 2.08 (d, J= 6.3 Hz, 1H), 2.05 – 1.87 (m, 3H), 1.68 (d, J= 12.2 Hz, 1H)。 實例503. 8-{[3-(8-{[(3R,4S)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-N-甲基咪唑并[1,2-a]吡啶-6-甲醯胺之合成 Step 1. 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-4-(3-hydroxycyclobutoxy)-N-methylbenzamide (40 mg, 0.07 mmol, 1 equivalent) was purified by chiral HPLC (column: CHIRALPAK IF-3 4.6*50 mm, 3.0 um; mobile phase A: MtBE (0.2% DEA):(EtOH:DCM=1:1)=70:30; flow rate: 1.0 ml/min mL/min; gradient: isocratic; injection volume: 5.0 L mL) to give 3-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-methyl-4-[(1r,3r)-3-hydroxycyclobutoxy]benzamide (9.8 mg, 24.38%) as a white solid. LC-MS: (M+H) + found 620.30. 1 H NMR (400 MHz, DMSO-d6) δ 8.12 (m, 1H), 7.84 (d, J = 6.8 Hz, 1H), 7.24 (d, J = 2.1 Hz, 1H), 7.19 (d, J = 0.9 Hz, 1H), 7.10 (dd, J = 8.3, 2.0 Hz, 1H), 6.75 (t, J = 7.2 Hz, 1H), 6.68 (d, J = 8.4 Hz, 1H), 6.14 (d, J = 7.6 Hz, 1H), 5.84 (d, J = 8.2 Hz, 1H), 5.50 (t, J = 6.4 Hz, 1H), 5.21 (d, J = 6.3 Hz, 3H), 4.83 (d, J = 49.4 Hz, 1H), 4.29 (dd, J = 11.0, 6.6 Hz, 3H), 3.85 (m, 1H), 3.59 (d, J = 29.2 Hz, 1H), 3.04 (s, 1H), 2.83 (m, 3H), 2.74 (d, J = 4.5 Hz, 3H), 2.19 (s, 4H), 2.08 (d, J = 6.3 Hz, 1H), 2.05 – 1.87 (m, 3H), 1.68 (d, J = 12.2 Hz, 1H). Example 503. Synthesis of 8-{[3-(8-{[(3R,4S)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-methylimidazo[1,2-a]pyridine-6-carboxamide
步驟1. 將8-溴-2-(3-溴丙-1-炔-1-基)-3-[(三氟甲基)硫基]吲嗪(500.0 mg,1.21 mmol,1.00當量)、8-胺基咪唑并[1,2-a]吡啶-6-甲酸甲酯(277.7 mg,1.45 mmol,1.20當量)及K 2CO 3(836.5 mg,6.06 mmol,5.00當量)於ACN (8.00 mL)中之混合物在90℃下攪拌2 h。過濾所得混合物且濾液藉由反相急速層析(管柱,C18;移動相,於水中之MeCN,在30 min內0%至100%梯度;偵測器,UV 254 nm)純化,以得到呈棕色固體之8-[(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)胺基]咪唑并[1,2-a]吡啶-6-甲酸甲酯(180.0 mg,28.41%)。LC-MS:(M+H) +實測值523.1。 Step 1. A mixture of 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizine (500.0 mg, 1.21 mmol, 1.00 equiv), methyl 8-aminoimidazo[1,2-a]pyridine-6-carboxylate (277.7 mg, 1.45 mmol, 1.20 equiv) and K2CO3 ( 836.5 mg, 6.06 mmol, 5.00 equiv) in ACN (8.00 mL) was stirred at 90°C for 2 h. The resulting mixture was filtered and the filtrate was purified by reverse phase flash chromatography (column, C18; mobile phase, MeCN in water, gradient 0% to 100% in 30 min; detector, UV 254 nm) to give methyl 8-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]imidazo[1,2-a]pyridine-6-carboxylate (180.0 mg, 28.41%) as a brown solid. LC-MS: (M+H) + found 523.1.
步驟2. 將8-[(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)胺基]咪唑并[1,2-a]吡啶-6-甲酸甲酯(180.0 mg,0.34 mmol,1.00當量)及NaOH水溶液(137.6 mg,3.44 mmol,10.00當量,5.00 mL H 2O)於MeOH (5.00 mL)中之溶液在70℃下攪拌隔夜。用1 M HCl將所得混合物酸化至pH 5。藉由過濾收集沉澱的固體且用H 2O洗滌,然後在真空下乾燥,以得到呈棕色固體之8-[(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)胺基]咪唑并[1,2-a]吡啶-6-甲酸(130.0 mg,74.21%)。LC-MS:(M+H) +實測值509.1。 Step 2. A solution of methyl 8-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]imidazo[1,2-a]pyridine-6-carboxylate (180.0 mg, 0.34 mmol, 1.00 equiv) and aqueous NaOH (137.6 mg, 3.44 mmol, 10.00 equiv, 5.00 mL H 2 O) in MeOH (5.00 mL) was stirred at 70° C. overnight. The resulting mixture was acidified to pH 5 with 1 M HCl. The precipitated solid was collected by filtration and washed with H2O , then dried under vacuum to give 8-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]imidazo[1,2-a]pyridine-6-carboxylic acid (130.0 mg, 74.21%) as a brown solid. LC-MS: (M+H) + found 509.1.
步驟3. 在室溫下,向8-[(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)胺基]咪唑并[1,2-a]吡啶-6-甲酸(120.0 mg,0.24 mmol,1.00當量)於DMF (3.00 mL)中之攪拌溶液中添加HATU (134.4 mg,0.35 mmol,1.50當量)及Et 3N (71.5 mg,0.71 mmol,3.00當量)。將所得混合物在室溫下攪拌10 min。然後添加CH 3NH 2 .HCl (19.1 mg,0.28 mmol,1.20當量)且將所得混合物在室溫下再攪拌1小時。所得溶液使用C18急速層析(移動相A:水,移動相B:ACN;流動速率:80 mL/min;梯度:在30 min內0% B至100% B;254/220 nm)純化,以得到呈淺棕色固體之8-[(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)胺基]-N-甲基咪唑并[1,2-a]吡啶-6-甲醯胺(80.0 mg,65.00%)。LC-MS:(M+H) +實測值522.1。 Step 3. To a stirred solution of 8-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]imidazo[1,2-a]pyridine-6-carboxylic acid (120.0 mg, 0.24 mmol, 1.00 equiv) in DMF (3.00 mL) was added HATU (134.4 mg, 0.35 mmol , 1.50 equiv) and Et3N (71.5 mg, 0.71 mmol, 3.00 equiv) at room temperature. The resulting mixture was stirred at room temperature for 10 min. Then CH3NH2.HCl (19.1 mg, 0.28 mmol , 1.20 equiv) was added and the resulting mixture was stirred at room temperature for another hour. The resulting solution was purified by C18 flash chromatography (mobile phase A: water, mobile phase B: ACN; flow rate: 80 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm) to give 8-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-N-methylimidazo[1,2-a]pyridine-6-carboxamide (80.0 mg, 65.00%) as a light brown solid. LC-MS: (M+H) + found 522.1.
步驟4. 將8-[(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)胺基]-N-甲基咪唑并[1,2-a]吡啶-6-甲醯胺(80.0 mg,0.15 mmol,1.00當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(47.1 mg,0.23 mmol,1.50當量)、Cs 2CO 3(249.5 mg,0.77 mmol,5.00當量)及Pd-PEPPSI-IHeptCl 3-氯吡啶(29.8 mg,0.03 mmol,0.20當量)於1,4-二噁烷(2.00 mL)中之混合物在100℃及氮氣氛圍下攪拌4 h。移除溶劑之後,殘餘物使用C18層析(移動相A:水,移動相B:ACN;流動速率:60 mL/min;梯度:在25 min內0% B至100% B;254/220 nm)及製備型HPLC (管柱:XBridge Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(10 mmol/L NH 4HCO 3+ 0.05% NH 3 .H 2O),移動相B:ACN;流動速率:60 mL/min;梯度:在7 min內28% B至55% B;波長:254 nm/220 nm;RT:7.63 min)純化,以得到呈灰白色固體之8-{[3-(8-{[(3R,4S)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-N-甲基咪唑并[1,2-a]吡啶-6-甲醯胺(17.0 mg,19.25%)。LC-MS:(M+H) +實測值574.20。 1H NMR (400 MHz, DMSO- d 6) δ 8.43-8.35 (m, 2H), 7.95 (d, J= 1.2 Hz, 1H), 7.83 (d, J= 6.8 Hz, 1H), 7.50 (d, J= 1.3 Hz, 1H), 7.19 (s, 1H), 6.78-6.70 (m, 2H), 6.63 (t, J= 6.4 Hz, 1H), 6.13 (d, J= 7.6 Hz, 1H), 5.82 (d, J= 8.2 Hz, 1H), 4.81 (d, J= 49.5 Hz, 1H), 4.41 (d, J= 6.3 Hz, 2H), 3.58 (d, J= 28.6 Hz, 1H), 3.02 (t, J= 11.1 Hz, 1H), 2.79 (d, J= 4.4 Hz, 4H), 2.31-2.14 (m, 4H), 2.13-1.86 (m, 2H), 1.67 (d, J= 11.9 Hz, 1H)。 實例439. 2-(3-{[6-(二甲基磷醯基)-4-甲氧基吡啶-3-基]胺基}丙-1-炔-1-基)-N-[(3S,4R)-3-氟-1-甲基哌啶-4-基]-3-[(三氟甲基)硫基]吲嗪-8-胺之合成 Step 4. 8-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-N-methylimidazo[1,2-a]pyridine-6-carboxamide (80.0 mg, 0.15 mmol, 1.00 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (47.1 mg, 0.23 mmol, 1.50 equiv), Cs 2 CO 3 (249.5 mg, 0.77 mmol, 5.00 equiv) and Pd-PEPPSI-IHeptCl 3-chloropyridine (29.8 mg, 0.03 mmol, 0.20 equiv) were dissolved in 1,4-dioxane (2.00 The mixture was stirred at 100 °C under nitrogen atmosphere for 4 h. After removing the solvent, the residue was purified by C18 chromatography (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 25 min; 254/220 nm) and preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 + 0.05% NH 3 . H 2 O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 28% B to 55% B in 7 min; wavelength: 254 nm/220 nm; RT: 7.63 min) to give 8-{[3-(8-{[(3R,4S)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-methylimidazo[1,2-a]pyridine-6-carboxamide (17.0 mg, 19.25%) as an off-white solid. LC-MS: (M+H) + found 574.20. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.43-8.35 (m, 2H), 7.95 (d, J = 1.2 Hz, 1H), 7.83 (d, J = 6.8 Hz, 1H), 7.50 (d, J = 1.3 Hz, 1H), 7.19 (s, 1H), 6.78-6.70 (m, 2H), 6.63 (t, J = 6.4 Hz, 1H), 6.13 (d, J = 7.6 Hz, 1H), 5.82 (d, J = 8.2 Hz, 1H), 4.81 (d, J = 49.5 Hz, 1H), 4.41 (d, J = 6.3 Hz, 2H), 3.58 (d, J = 28.6 Hz, 1H), 3.02 (t, J = 11.1 Hz, 1H), 2.79 (d, J = 4.4 Hz, 4H), 2.31-2.14 (m, 4H), 2.13-1.86 (m, 2H), 1.67 (d, J = 11.9 Hz, 1H). Example 439. Synthesis of 2-(3-{[6-(dimethylphosphinoyl)-4-methoxypyridin-3-yl]amino}prop-1-yn-1-yl)-N-[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]-3-[(trifluoromethyl)thio]indolizin-8-amine
步驟1. 將6-氯-4-甲氧基吡啶-3-胺(2 g,12.61 mmol,1當量)、Dppf (2.79 g,5.04 mmol,0.4當量)、Pd(OAc) 2(283.1 mg,1.26 mmol,0.1當量)、DIEA (0.88 mL,5.04 mmol,0.4當量)及(甲基膦醯基)甲烷(1.48 g,18.92 mmol,1.5當量)於DMF (20 mL)中之溶液在120℃及氮氣氛圍下攪拌2 h。所得溶液藉由反相急速層析(管柱,C18矽膠;移動相,於水中之MeCN (10 mmol/L NH 4HCO 3),在25 min內0%至100%梯度;偵測器,UV 254 nm)純化,以得到呈白色固體之6-(二甲基磷醯基)-4-甲氧基吡啶-3-胺(1.36 g,53.87%)。LC-MS:(M+H) +實測值201.1。 Step 1. A solution of 6-chloro-4-methoxypyridin-3-amine (2 g, 12.61 mmol, 1 eq), Dppf (2.79 g, 5.04 mmol, 0.4 eq), Pd(OAc) 2 (283.1 mg, 1.26 mmol, 0.1 eq), DIEA (0.88 mL, 5.04 mmol, 0.4 eq) and (methylphosphonyl)methane (1.48 g, 18.92 mmol, 1.5 eq) in DMF (20 mL) was stirred at 120 °C under nitrogen atmosphere for 2 h. The resulting solution was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH 4 HCO 3 ) in water, gradient 0% to 100% in 25 min; detector, UV 254 nm) to give 6-(dimethylphosphatyl)-4-methoxypyridin-3-amine (1.36 g, 53.87%) as a white solid. LC-MS: (M+H) + found 201.1.
步驟2. 在室溫下,向6-(二甲基磷醯基)-4-甲氧基吡啶-3-胺(1.16 g,5.80 mmol,1當量)及DMAP (141.6 mg,1.16 mmol,0.2當量)於1,4-二噁烷(12 mL)中之攪拌溶液中逐滴添加(Boc) 2O (2.48 mL,11.59 mmol,2當量)。將所得溶液在70℃下攪拌0.5 h,然後在減壓下濃縮。殘餘物藉由反相急速層析(管柱,C18矽膠;移動相,於水中之MeCN (10 mmol/L NH 4HCO 3),在15 min內0%至90%梯度;偵測器,UV 254 nm)純化,以得到呈白色固體之N-(三級丁氧基羰基)-N-[6-(二甲基磷醯基)-4-甲氧基吡啶-3-基]胺基甲酸三級丁酯(1.45 g,62.49%)。LC-MS:(M+H) +實測值401.2。 Step 2. To a stirred solution of 6-(dimethylphosphatyl)-4-methoxypyridin-3-amine (1.16 g, 5.80 mmol, 1 eq) and DMAP (141.6 mg, 1.16 mmol, 0.2 eq) in 1,4-dioxane (12 mL) was added (Boc) 2O (2.48 mL, 11.59 mmol, 2 eq) dropwise at room temperature. The resulting solution was stirred at 70 °C for 0.5 h and then concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH 4 HCO 3 ) in water, gradient 0% to 90% in 15 min; detector, UV 254 nm) to give tert-butyl N-(tert-butyloxycarbonyl)-N-[6-(dimethylphosphatyl)-4-methoxypyridin-3-yl]carbamate (1.45 g, 62.49%) as a white solid. LC-MS: (M+H) + found 401.2.
步驟3. 將N-(三級丁氧基羰基)-N-[6-(二甲基磷醯基)-4-甲氧基吡啶-3-基]胺基甲酸三級丁酯(1.5 g,3.75 mmol,1當量)及K 2CO 3(1.55 g,11.24 mmol,3.00當量)於MeOH (15 mL)中之混合物在室溫下攪拌1.5 h。將所得混合物在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用CH 2Cl 2/ MeOH (10:1)溶析,以得到呈白色固體之N-[6-(二甲基磷醯基)-4-甲氧基吡啶-3-基]胺基甲酸三級丁酯(1.1 g,97.78%)。LC-MS:(M+H) +實測值301.1。 Step 3. A mixture of tert-butyl N-(tert-butyloxycarbonyl)-N-[6-(dimethylphosphinoyl)-4-methoxypyridin-3-yl]carbamate (1.5 g, 3.75 mmol, 1 eq.) and K 2 CO 3 (1.55 g, 11.24 mmol, 3.00 eq.) in MeOH (15 mL) was stirred at room temperature for 1.5 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using CH 2 Cl 2 / MeOH (10:1) for elution to give tert-butyl N-[6-(dimethylphosphinoyl)-4-methoxypyridin-3-yl]carbamate (1.1 g, 97.78%) as a white solid. LC-MS: (M+H) + found 301.1.
步驟4. 將N-[6-(二甲基磷醯基)-4-甲氧基吡啶-3-基]胺基甲酸三級丁酯(200 mg,0.67 mmol,1當量)、8-溴-2-(3-溴丙-1-炔-1-基)-3-[(三氟甲基)硫基]吲嗪(275.1 mg,0.67 mmol,1當量)及Cs 2CO 3(651.0 mg,2.00 mmol,3當量)於DMF (2 mL)中之混合物在70℃下攪拌1.5 h。混合物用水(30 mL)稀釋且用CH 2Cl 2(3*30 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用CH 2Cl 2/ MeOH (10:1)溶析,以得到呈棕黃色固體之N-(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)-N-[6-(二甲基磷醯基)-4-甲氧基吡啶-3-基]胺基甲酸三級丁酯(320 mg,59.26%)。LC-MS:(M+H) +實測值632.1。 Step 4. A mixture of tributyl N-[6-(dimethylphosphinoyl)-4-methoxypyridin-3-yl]carbamate (200 mg, 0.67 mmol, 1 eq.), 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizine (275.1 mg, 0.67 mmol, 1 eq.) and Cs 2 CO 3 (651.0 mg, 2.00 mmol, 3 eq.) in DMF (2 mL) was stirred at 70° C. for 1.5 h. The mixture was diluted with water (30 mL) and extracted with CH 2 Cl 2 (3*30 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with CH 2 Cl 2 / MeOH (10:1) to give tributyl N-(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)-N-[6-(dimethylphosphatyl)-4-methoxypyridin-3-yl]carbamate (320 mg, 59.26%) as a brown solid. LC-MS: (M+H) + found 632.1.
步驟5. 將N-(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)-N-[6-(二甲基磷醯基)-4-甲氧基吡啶-3-基]胺基甲酸三級丁酯(150 mg,0.24 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺2HCl (72.6 mg,0.34 mmol,1.5當量)、Cs 2CO 3(386.4 mg,1.19 mmol,5當量)及Pd-PEPPSI-IHeptCl 3-氯吡啶(46.2 mg,0.05 mmol,0.2當量)於二噁烷(1.5 mL)中之混合物在100℃及氮氣氛圍下攪拌4 h。將所得混合物在減壓下濃縮。殘餘物藉由反相急速層析(管柱,C18矽膠;移動相,於水中之MeCN (0.1% NH 3 .H 2O),在25 min內0%至100%梯度;偵測器,UV 254 nm)純化,以得到呈棕黃色固體之N-[6-(二甲基磷醯基)-4-甲氧基吡啶-3-基]-N-[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基甲酸三級丁酯(130 mg,80.17%)。LC-MS:(M+H) +實測值684.3。 Step 5. A mixture of tributyl N-(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)-N-[6-(dimethylphosphatyl)-4-methoxypyridin-3-yl]carbamate (150 mg, 0.24 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine 2HCl (72.6 mg, 0.34 mmol, 1.5 eq), Cs2CO3 (386.4 mg, 1.19 mmol, 5 eq) and Pd-PEPPSI-IHeptCl 3-chloropyridine (46.2 mg, 0.05 mmol , 0.2 eq) in dioxane (1.5 mL) was stirred at 100°C under nitrogen atmosphere for 4 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (0.1% NH 3 .H 2 O) in water, gradient 0% to 100% in 25 min; detector, UV 254 nm) to give tributyl N-[6-(dimethylphosphatyl)-4-methoxypyridin-3-yl]-N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]carbamate (130 mg, 80.17%) as a brownish yellow solid. LC-MS: (M+H) + found 684.3.
步驟6. 在0℃下,向N-[6-(二甲基磷醯基)-4-甲氧基吡啶-3-基]-N-[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基甲酸三級丁酯(130 mg,0.19 mmol,1當量)於DCM (1.5 mL)中之攪拌溶液中逐滴添加於1,4-二噁烷(0.3 mL,9.87 mmol,51.93當量)中之4M HCl (氣體)。將所得混合物在室溫下攪拌1 h,然後在真空下濃縮。殘餘物藉由製備型HPLC (管柱:XBridge Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(10 mmol/L NH 4HCO 3+0.05% NH 3 .H 2O),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在8 min內28% B至53% B;波長:220 nm nm;RT1(min):7.75)純化,以得到呈粉紅色固體之2-(3-{[6-(二甲基磷醯基)-4-甲氧基吡啶-3-基]胺基}丙-1-炔-1-基)-N-[(3S,4R)-3-氟-1-甲基哌啶-4-基]-3-[(三氟甲基)硫基]吲嗪-8-胺(47.6 mg,42.81%)。LC-MS:(M+H) +實測值584.15。 1H NMR (400 MHz, DMSO- d 6) δ 8.18 (s, 1H), 7.84 (d, J= 6.8 Hz, 1H), 7.36 (d, J= 5.8 Hz, 1H), 7.23 (s, 1H), 6.75 (t, J= 7.2 Hz, 1H), 6.19 – 6.09 (m, 2H), 5.84 (d, J= 8.3 Hz, 1H), 4.82 (d, J= 49.4 Hz, 1H), 4.33 (d, J= 6.4 Hz, 2H), 3.93 (s, 3H), 3.59 (d, J= 29.1 Hz, 1H), 3.09 – 2.98 (m, 1H), 2.86 – 2.76 (m, 1H), 2.35 – 2.13 (m, 4H), 2.12 – 1.92 (m, 2H), 1.73 – 1.64 (m, 1H), 1.58 (d, J= 13.4 Hz, 6H)。 實例420. 2-(3-{[6-(二甲基磷醯基)吡啶-3-基]胺基}丙-1-炔-1-基)-N-[(3S,4R)-3-氟-1-甲基哌啶-4-基]-3-[(三氟甲基)硫基]吲嗪-8-胺之合成 Step 6. To a stirred solution of tributyl N-[6-(dimethylphosphatyl)-4-methoxypyridin-3-yl]-N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]carbamate (130 mg, 0.19 mmol, 1 eq) in DCM (1.5 mL) at 0° C. was added 4 M HCl (g) in 1,4-dioxane (0.3 mL, 9.87 mmol, 51.93 eq) dropwise. The resulting mixture was stirred at room temperature for 1 h and then concentrated under vacuum. The residue was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 +0.05% NH 3 . H 2 O), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 28% B to 53% B in 8 min; wavelength: 220 nm nm; RT1(min): 7.75) to obtain 2-(3-{[6-(dimethylphosphatyl)-4-methoxypyridin-3-yl]amino}prop-1-yn-1-yl)-N-[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]-3-[(trifluoromethyl)thio]indolizin-8-amine (47.6 mg, 42.81%). LC-MS: (M+H) + found 584.15. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.18 (s, 1H), 7.84 (d, J = 6.8 Hz, 1H), 7.36 (d, J = 5.8 Hz, 1H), 7.23 (s, 1H), 6.75 (t, J = 7.2 Hz, 1H), 6.19 – 6.09 (m, 2H), 5.84 (d, J = 8.3 Hz, 1H), 4.82 (d, J = 49.4 Hz, 1H), 4.33 (d, J = 6.4 Hz, 2H), 3.93 (s, 3H), 3.59 (d, J = 29.1 Hz, 1H), 3.09 – 2.98 (m, 1H), 2.86 – 2.76 (m, 1H), 2.35 – 2.13 (m, 4H), 2.12 – 1.92 (m, 2H), 1.73 – 1.64 (m, 1H), 1.58 (d, J = 13.4 Hz, 6H). Example 420. Synthesis of 2-(3-{[6-(dimethylphosphinoyl)pyridin-3-yl]amino}prop-1-yn-1-yl)-N-[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]-3-[(trifluoromethyl)thio]indolizin-8-amine
步驟1. 將6-溴吡啶-3-胺(1.50 g,8.67 mmol,1.00當量)、(甲基膦醯基)甲烷(1.69 g,21.67 mmol,2.5當量)、Pd(OAc) 2(291.9 mg,1.30 mmol,0.15當量)、Xantphos (1.00 g,1.73 mmol,0.20當量)及DIEA (3.36 g,26.01 mmol,3.00當量)於DMF (10.00 mL)中之溶液在130℃下攪拌2 h。所得溶液藉由反相急速層析(管柱,C18;移動相,於水中之MeCN,在30 min內0%至100%梯度;偵測器,UV 254 nm)純化,以得到呈粉紅色固體之6-(二甲基磷醯基)吡啶-3-胺(850 mg,57.35%)。LC-MS:(M+H) +實測值171.1。 Step 1. A solution of 6-bromopyridin-3-amine (1.50 g, 8.67 mmol, 1.00 equiv), (methylphosphonyl)methane (1.69 g, 21.67 mmol, 2.5 equiv), Pd(OAc) 2 (291.9 mg, 1.30 mmol, 0.15 equiv), Xantphos (1.00 g, 1.73 mmol, 0.20 equiv) and DIEA (3.36 g, 26.01 mmol, 3.00 equiv) in DMF (10.00 mL) was stirred at 130 °C for 2 h. The resulting solution was purified by reverse phase flash chromatography (column, C18; mobile phase, MeCN in water, gradient 0% to 100% in 30 min; detector, UV 254 nm) to give 6-(dimethylphosphatyl)pyridin-3-amine (850 mg, 57.35%) as a pink solid. LC-MS: (M+H) + found 171.1.
步驟2. 在室溫下,向6-(二甲基磷醯基)吡啶-3-胺(850.0 mg,4.99 mmol,1.00當量)於DMF (5.00 mL)中之攪拌溶液中添加Boc 2O (1.09 g,4.99 mmol,1.00當量)、DMAP (305.2 mg,2.50 mmol,0.50當量)及Et 3N (1.52 g,14.99 mmol,3.00當量)。將反應在100℃下攪拌1 h。所得溶液藉由反相急速層析(管柱,C18;移動相,於水中之MeCN,在25 min內0%至100%梯度;偵測器,UV 254 nm)純化,以得到呈棕黃色固體之N-[6-(二甲基磷醯基)吡啶-3-基]胺基甲酸三級丁酯(295 mg,21.85%)。LC-MS:(M+H) +實測值271.1。 Step 2. To a stirred solution of 6-(dimethylphosphinoyl)pyridin-3-amine (850.0 mg, 4.99 mmol, 1.00 equiv) in DMF (5.00 mL) at room temperature was added Boc2O (1.09 g, 4.99 mmol, 1.00 equiv), DMAP (305.2 mg, 2.50 mmol, 0.50 equiv) and Et3N (1.52 g, 14.99 mmol, 3.00 equiv). The reaction was stirred at 100 °C for 1 h. The resulting solution was purified by reverse phase flash chromatography (column, C18; mobile phase, MeCN in water, gradient 0% to 100% in 25 min; detector, UV 254 nm) to give tributyl N-[6-(dimethylphosphinoyl)pyridin-3-yl]carbamate (295 mg, 21.85%) as a brownish yellow solid. LC-MS: (M+H) + found 271.1.
步驟3. 將N-[6-(二甲基磷醯基)吡啶-3-基]胺基甲酸三級丁酯(275.0 mg,1.02 mmol,1.00當量)、8-溴-2-(3-溴丙-1-炔-1-基)-3-[(三氟甲基)硫基]吲嗪(420.3 mg,1.02 mmol,1.00當量)及Cs 2CO 3(994.6 mg,3.05 mmol,3.00當量)於DMF (3.00 mL)中之混合物在室溫下攪拌16 h。過濾混合物且濾液藉由反相急速層析(管柱,C18;移動相,於水中之MeCN,在10 min內0%至100%梯度;偵測器,UV 254 nm)純化,以得到呈白色固體之N-(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)-N-[6-(二甲基磷醯基)吡啶-3-基]胺基甲酸三級丁酯(291 mg,47.47%)。LC-MS:(M+H) +實測值602.0。 Step 3. A mixture of tributyl N-[6-(dimethylphosphinoyl)pyridin-3-yl]carbamate (275.0 mg, 1.02 mmol, 1.00 equiv), 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizine (420.3 mg, 1.02 mmol, 1.00 equiv) and Cs2CO3 ( 994.6 mg, 3.05 mmol, 3.00 equiv) in DMF (3.00 mL) was stirred at room temperature for 16 h. The mixture was filtered and the filtrate was purified by reverse phase flash chromatography (column, C18; mobile phase, MeCN in water, gradient 0% to 100% in 10 min; detector, UV 254 nm) to give tributyl N-(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)-N-[6-(dimethylphosphinoyl)pyridin-3-yl]carbamate (291 mg, 47.47%) as a white solid. LC-MS: (M+H) + found 602.0.
步驟4. 將N-(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)-N-[6-(二甲基磷醯基)吡啶-3-基]胺基甲酸三級丁酯(80.0 mg,0.13 mmol,1.00當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺鹽酸鹽(54.5 mg,0.27 mmol,2.00當量)、Cs 2CO 3(216.3 mg,0.66 mmol,5.00當量)及Pd-PEPPSI-IHeptCl 3-氯吡啶(12.9 mg,0.01 mmol,0.10當量)於二噁烷(2.00 mL)中之混合物在100℃及氮氣氛圍下攪拌16 h。移除溶劑之後,殘餘物使用C18急速層析(移動相A:水,移動相B:ACN;流動速率:60 mL/min;梯度:在30 min內0% B至100% B;254/220 nm)純化,以得到呈黃色固體之N-[6-(二甲基磷醯基)吡啶-3-基]-N-[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基甲酸三級丁酯(80 mg,92.16%)。LC-MS:(M+H) +實測值654.2。 Step 4. A mixture of tributyl N-(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)-N-[6-(dimethylphosphinoyl)pyridin-3-yl]carbamate (80.0 mg, 0.13 mmol, 1.00 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine hydrochloride (54.5 mg, 0.27 mmol, 2.00 equiv), Cs2CO3 (216.3 mg, 0.66 mmol, 5.00 equiv) and Pd-PEPPSI-IHeptCl 3-chloropyridine (12.9 mg, 0.01 mmol , 0.10 equiv) in dioxane (2.00 mL) was stirred at 100°C under nitrogen atmosphere for 16 hr. h. After removal of the solvent, the residue was purified by C18 flash chromatography (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm) to give tributyl N-[6-(dimethylphosphatyl)pyridin-3-yl]-N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]carbamate (80 mg, 92.16%) as a yellow solid. LC-MS: (M+H) + found 654.2.
步驟5: 向N-[6-(二甲基磷醯基)吡啶-3-基]-N-[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基甲酸三級丁酯(70.0 mg,0.10 mmol,1.00當量)於DCM (3.00 mL)中之攪拌溶液中添加TFA (0.50 mL)。將所得混合物在室溫下攪拌1 h。用飽和NaHCO 3中和混合物且用EA萃取。合併的有機層經Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物使用製備型HPLC (管柱:XBridge Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(10 mmol/L NH 4HCO 3+ 0.05% NH 3 .H 2O),移動相B:ACN;流動速率:60 mL/min;梯度:在7 min內28% B至49% B;波長:254 nm/220 nm;RT(min):7.73)純化,以得到呈白色固體之2-(3-{[6-(二甲基磷醯基)吡啶-3-基]胺基}丙-1-炔-1-基)-N-[(3S,4R)-3-氟-1-甲基哌啶-4-基]-3-[(三氟甲基)硫基]吲嗪-8-胺(38.1 mg,64.21%)。LC-MS:(M+H) +實測值554.25。 1H NMR (400 MHz, DMSO- d 6) δ 8.24 (d, J= 2.7 Hz, 1H), 7.85 (d, J= 6.8 Hz, 1H), 7.68 (dd, J= 8.4, 4.9 Hz, 1H), 7.23 (s, 1H), 7.16 (dt, J= 8.5, 2.8 Hz, 1H), 6.96 (t, J= 6.2 Hz, 1H), 6.76 (t, J= 7.2 Hz, 1H), 6.15 (d, J= 7.6 Hz, 1H), 5.85 (d, J= 8.2 Hz, 1H), 4.82 (d, J= 49.5 Hz, 1H), 4.31 (d, J= 6.1 Hz, 2H), 3.59 (d, J= 29.3 Hz, 1H), 3.03 (t, J= 11.3 Hz, 1H), 2.85-2.77 (m, 1H), 2.41-1.89 (m, 6H), 1.68 (d, J= 12.0 Hz, 1H), 1.56 (d, J= 13.4 Hz, 6H)。 實例428. 2-(3-{[5-(二甲基磷醯基)吡啶-2-基]胺基}丙-1-炔-1-基)-N-[(3S,4R)-3-氟-1-甲基哌啶-4-基]-3-[(三氟甲基)硫基]吲嗪-8-胺之合成 Step 5: To a stirred solution of tributyl N-[6-(dimethylphosphinoyl)pyridin-3-yl]-N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]carbamate (70.0 mg, 0.10 mmol, 1.00 equiv) in DCM (3.00 mL) was added TFA (0.50 mL). The resulting mixture was stirred at room temperature for 1 h. The mixture was neutralized with saturated NaHCO 3 and extracted with EA. The combined organic layers were dried over Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 + 0.05% NH 3 . H 2 O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 28% B to 49% B in 7 min; wavelength: 254 nm/220 nm; RT (min): 7.73) to obtain 2-(3-{[6-(dimethylphosphatyl)pyridin-3-yl]amino}prop-1-yn-1-yl)-N-[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]-3-[(trifluoromethyl)thio]indolizin-8-amine (38.1 mg, 64.21%). LC-MS: (M+H) + found 554.25. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.24 (d, J = 2.7 Hz, 1H), 7.85 (d, J = 6.8 Hz, 1H), 7.68 (dd, J = 8.4, 4.9 Hz, 1H), 7.23 (s, 1H), 7.16 (dt, J = 8.5, 2.8 Hz, 1H), 6.96 (t, J = 6.2 Hz, 1H), 6.76 (t, J = 7.2 Hz, 1H), 6.15 (d, J = 7.6 Hz, 1H), 5.85 (d, J = 8.2 Hz, 1H), 4.82 (d, J = 49.5 Hz, 1H), 4.31 (d, J = 6.1 Hz, 2H), 3.59 (d, J = 29.3 Hz, 1H), 3.03 (t, J = 11.3 Hz, 1H), 2.85-2.77 (m, 1H), 2.41-1.89 (m, 6H), 1.68 (d, J = 12.0 Hz, 1H), 1.56 (d, J = 13.4 Hz, 6H). Example 428. Synthesis of 2-(3-{[5-(dimethylphosphinoyl)pyridin-2-yl]amino}prop-1-yn-1-yl)-N-[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]-3-[(trifluoromethyl)thio]indolizine-8-amine
步驟1. 將5-溴吡啶-2-胺(2 g,11.56 mmol,1當量)、(甲基膦醯基)甲烷(1.80 g,23.12 mmol,2.00當量)、Pd(OAc) 2(779 mg,3.47 mmol,0.3當量)、XantPhos (1.34 g,2.31 mmol,0.2當量)及DIEA (6.04 mL,34.68 mmol,3當量)於DMF (20 mL)中之混合物在120℃及氮氣氛圍下攪拌2 h。過濾所得混合物,濾餅用MeOH洗滌。將濾液在減壓下濃縮,以得到呈黃色油狀物之粗5-(二甲基磷醯基)吡啶-2-胺(2 g),其無需進一步純化直接用於下一步驟中。LC-MS:(M+H) +實測值171.2。 Step 1. A mixture of 5-bromopyridin-2-amine (2 g, 11.56 mmol, 1 eq), (methylphosphonyl)methane (1.80 g, 23.12 mmol, 2.00 eq), Pd(OAc) 2 (779 mg, 3.47 mmol, 0.3 eq), XantPhos (1.34 g, 2.31 mmol, 0.2 eq) and DIEA (6.04 mL, 34.68 mmol, 3 eq) in DMF (20 mL) was stirred at 120 °C under nitrogen atmosphere for 2 h. The resulting mixture was filtered and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure to give crude 5-(dimethylphosphatyl)pyridin-2-amine (2 g) as a yellow oil, which was used directly in the next step without further purification. LC-MS: (M+H) + found 171.2.
步驟2: 在室溫及氮氣氛圍下,向5-(二甲基磷醯基)吡啶-2-胺(2.7 g,15.87 mmol,1當量)及二碳酸二-三級丁酯(6.93 g,31.74 mmol,2當量)於二噁烷(30 mL)中之攪拌溶液中添加DMAP (194 mg,1.59 mmol,0.10當量)。將反應在100℃下攪拌1 h。所得溶液用水 (50 mL)稀釋且用EtOAc (3*50 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用CH 2Cl 2/ MeOH (10:1)溶析,以得到呈黃色固體之N-(三級丁氧基羰基)-N-[5-(二甲基磷醯基)吡啶-2-基]胺基甲酸三級丁酯(1.7 g,28.92%)。LC-MS:(M+H) +實測值371.1。 Step 2: To a stirred solution of 5-(dimethylphosphinoyl)pyridin-2-amine (2.7 g, 15.87 mmol, 1 eq.) and di-tert-butyl dicarbonate (6.93 g, 31.74 mmol, 2 eq.) in dioxane (30 mL) was added DMAP (194 mg, 1.59 mmol, 0.10 eq.) at room temperature under nitrogen atmosphere. The reaction was stirred at 100 °C for 1 h. The resulting solution was diluted with water (50 mL) and extracted with EtOAc (3*50 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH 2 Cl 2 / MeOH (10:1) to give tert-butyl N-(tert-butyloxycarbonyl)-N-[5-(dimethylphosphatyl)pyridin-2-yl]carbamate (1.7 g, 28.92%) as a yellow solid. LC-MS: (M+H) + found 371.1.
步驟3:將N-(三級丁氧基羰基)-N-[5-(二甲基磷醯基)吡啶-2-基]胺基甲酸三級丁酯(1.2 g,3.240 mmol,1當量)及K 2CO 3(1.34 g,9.72 mmol,3當量)於MeOH (10 mL)中之混合物在室溫下攪拌1 h。過濾所得混合物且將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用CH 2Cl 2/MeOH (10:1)溶析,以得到呈白色固體之N-[5-(二甲基磷醯基)吡啶-2-基]胺基甲酸三級丁酯(700 mg,79.94%)。LC-MS:(M+H) +實測值271.3。 Step 3: A mixture of tert-butyl N-(tert-butyloxycarbonyl)-N-[5-(dimethylphosphinoyl)pyridin-2-yl]carbamate (1.2 g, 3.240 mmol, 1 eq.) and K 2 CO 3 (1.34 g, 9.72 mmol, 3 eq.) in MeOH (10 mL) was stirred at room temperature for 1 h. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH 2 Cl 2 /MeOH (10:1) to give tert-butyl N-[5-(dimethylphosphinoyl)pyridin-2-yl]carbamate (700 mg, 79.94%) as a white solid. LC-MS: (M+H) + found 271.3.
步驟4:將N-[5-(二甲基磷醯基)吡啶-2-基]胺基甲酸三級丁酯(131 mg,0.48 mmol,1當量)、8-溴-2-(3-溴丙-1-炔-1-基)-3-[(三氟甲基)硫基]吲嗪(200 mg,0.48 mmol,1.00當量) 及K 2CO 3(201 mg,1.45 mmol,3.00當量)於ACN (2 mL)中之混合物在70℃下攪拌2 h。過濾所得混合物且將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用CH 2Cl 2/MeOH (10:1)溶析,以得到呈淺棕色固體之N-(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)-N-[5-(甲基磷醯基)吡啶-2-基]胺基甲酸三級丁酯(170 mg,58.28%)。LC-MS:(M+H) +實測值602.2。 Step 4: A mixture of tributyl N-[5-(dimethylphosphinoyl)pyridin-2-yl]carbamate (131 mg, 0.48 mmol, 1 eq), 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizine (200 mg, 0.48 mmol, 1.00 eq) and K2CO3 (201 mg, 1.45 mmol, 3.00 eq) in ACN (2 mL) was stirred at 70°C for 2 h. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with CH 2 Cl 2 /MeOH (10:1) to give tributyl N-(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)-N-[5-(methylphosphonyl)pyridin-2-yl]carbamate (170 mg, 58.28%) as a light brown solid. LC-MS: (M+H) + found 602.2.
步驟5:將N-(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)-N-[5-(二甲基磷醯基)吡啶-2-基]胺基甲酸三級丁酯(160 mg,0.27 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(82 mg,0.40 mmol,1.5當量)、Pd-PEPPSI-IHeptCl 3-氯吡啶(52 mg,0.05 mmol,0.2當量)及Cs 2CO 3(433 mg,1.33 mmol,5當量)於二噁烷(2 mL)中之混合物在100℃及氮氣氛圍下攪拌4 h。過濾所得混合物,濾餅用DCM洗滌。將濾液在減壓下濃縮。殘餘物藉由反相急速層析(管柱,C18矽膠;移動相,於水中之MeCN (10 mmol/L NH 4HCO 3),在20 min內0%至80%梯度;偵測器,UV 254 nm)純化,以得到呈黃色固體之N-[5-(二甲基磷醯基)吡啶-2-基]-N-[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基甲酸三級丁酯(100 mg,57.60%)。LC-MS:(M+H) +實測值654.0。 Step 5: A mixture of tributyl N-(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2-yn-1-yl)-N-[5-(dimethylphosphatyl)pyridin-2-yl]carbamate (160 mg, 0.27 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (82 mg, 0.40 mmol, 1.5 eq), Pd-PEPPSI-IHeptCl 3 -chloropyridine (52 mg, 0.05 mmol, 0.2 eq) and Cs2CO3 (433 mg, 1.33 mmol, 5 eq) in dioxane (2 mL) was stirred at 100 °C under nitrogen atmosphere for 4 h. The resulting mixture was filtered and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (10 mmol/L NH 4 HCO 3 ) in water, gradient 0% to 80% in 20 min; detector, UV 254 nm) to give tributyl N-[5-(dimethylphosphatyl)pyridin-2-yl]-N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]carbamate (100 mg, 57.60%) as a yellow solid. LC-MS: (M+H) + found 654.0.
步驟6:在室溫下,向N-[5-(二甲基磷醯基)吡啶-2-基]-N-[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基甲酸三級丁酯(80 mg,0.12 mmol,1當量)於DCM (2 mL)中之攪拌溶液中逐滴添加於1,4-二噁烷(0.4 mL)中之HCl (氣體)。將所得混合物在室溫下攪拌1 h,然後在減壓下濃縮。殘餘物藉由製備型HPLC (管柱:XBridge Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(10 mmol/L NH 4HCO 3+0.05% NH 3 .H 2O),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在8 min內26% B至51% B;波長:220 nm nm;RT1(min):7.78)純化,以得到呈淺黃色固體之2-(3-{[5-(二甲基磷醯基)吡啶-2-基]胺基}丙-1-炔-1-基)-N-[(3S,4R)-3-氟-1-甲基哌啶-4-基]-3-[(三氟甲基)硫基]吲嗪-8-胺(23.7 mg,34.98%)。LC-MS:(M+H) +實測值554.20。 1H NMR (400 MHz, DMSO- d 6) δ 8.35 (dd, J= 6.6, 2.2 Hz, 1H), 7.85 (d, J= 6.8 Hz, 1H), 7.72 (m, 1H), 7.55 (t, J= 5.9 Hz, 1H), 7.23 (s, 1H), 6.76 (t, J= 7.2 Hz, 1H), 6.66 (dt, J= 8.6, 1.4 Hz, 1H), 6.15 (d, J= 7.6 Hz, 1H), 5.83 (d, J= 8.3 Hz, 1H), 4.83 (d, J= 49.5 Hz, 1H), 4.41 (d, J= 5.9 Hz, 2H), 3.70 – 3.50 (m, 1H), 3.03 (t, J= 10.9 Hz, 1H), 2.81 (d, J= 10.6 Hz, 1H), 2.19 (s, 4H), 2.14 – 1.91 (m, 2H), 1.74 – 1.62 (m, 1H), 1.59 (d, J= 13.3 Hz, 6H)。 實例402. 2-(3-{[5-(二甲基磷醯基)-3-甲氧基吡啶-2-基]胺基}丙-1-炔-1-基)-N-[(3S,4R)-3-氟-1-甲基哌啶-4-基]-3-[(三氟甲基)硫基]吲嗪-8-胺之合成 Step 6: To a stirred solution of tributyl N-[5-(dimethylphosphatyl)pyridin-2-yl]-N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]carbamate (80 mg, 0.12 mmol, 1 eq) in DCM (2 mL) was added HCl (g) in 1,4-dioxane (0.4 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure. The residue was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 +0.05% NH 3 . H 2 O), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 26% B to 51% B in 8 min; wavelength: 220 nm nm; RT1(min): 7.78) to obtain 2-(3-{[5-(dimethylphosphinoyl)pyridin-2-yl]amino}prop-1-yn-1-yl)-N-[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]-3-[(trifluoromethyl)thio]indolizin-8-amine (23.7 mg, 34.98%). LC-MS: (M+H) + found 554.20. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.35 (dd, J = 6.6, 2.2 Hz, 1H), 7.85 (d, J = 6.8 Hz, 1H), 7.72 (m, 1H), 7.55 (t, J = 5.9 Hz, 1H), 7.23 (s, 1H), 6.76 (t, J = 7.2 Hz, 1H), 6.66 (dt, J = 8.6, 1.4 Hz, 1H), 6.15 (d, J = 7.6 Hz, 1H), 5.83 (d, J = 8.3 Hz, 1H), 4.83 (d, J = 49.5 Hz, 1H), 4.41 (d, J = 5.9 Hz, 3.70 – 3.50 (m, 1H), 3.03 (t, J = 10.9 Hz, 1H), 2.81 (d, J = 10.6 Hz, 1H), 2.19 (s, 4H), 2.14 – 1.91 (m, 2H), 1.74 – 1.62 (m, 1H), 1.59 (d, J = 13.3 Hz, 6H). Example 402. Synthesis of 2-(3-{[5-(dimethylphosphinoyl)-3-methoxypyridin-2-yl]amino}prop-1-yn-1-yl)-N-[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]-3-[(trifluoromethyl)thio]indolizin-8-amine
步驟1. 將5-溴-3-甲氧基吡啶-2-胺(2 g,9.85 mmol,1當量)、(甲基膦醯基)甲烷(2.31 g,29.55 mmol,3當量)、DIEA (3.82 g,29.55 mmol,3當量)、Pd(OAc) 2(442.3 mg,1.97 mmol,0.2當量)及XantPhos (1.71 g,2.96 mmol,0.3當量)於DMF (10 mL)中之混合物在120℃下攪拌24 h。過濾所得混合物且濾餅用DCM洗滌。將濾液在減壓下濃縮。殘餘物藉由反相急速層析(管柱,C 18矽膠;移動相,於MeCN中之水,在30 min內0%至100%梯度;偵測器,UV 254 nm)純化,以得到呈黃色油狀物之5-(二甲基磷醯基)-3-甲氧基吡啶-2-胺(1.5 g,76.07%)。LC-MS:(M+H) +實測值201.0。 Step 1. A mixture of 5-bromo-3-methoxypyridin-2-amine (2 g, 9.85 mmol, 1 eq), (methylphosphonyl)methane (2.31 g, 29.55 mmol, 3 eq), DIEA (3.82 g, 29.55 mmol, 3 eq), Pd(OAc) 2 (442.3 mg, 1.97 mmol, 0.2 eq) and XantPhos (1.71 g, 2.96 mmol, 0.3 eq) in DMF (10 mL) was stirred at 120 °C for 24 h. The resulting mixture was filtered and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, water in MeCN, gradient 0% to 100% in 30 min; detector, UV 254 nm) to give 5-(dimethylphosphatyl)-3-methoxypyridin-2-amine (1.5 g, 76.07%) as a yellow oil. LC-MS: (M+H) + found 201.0.
步驟2:在0℃下,向5-(二甲基磷醯基)-3-甲氧基吡啶-2-胺(1.40 g,6.99 mmol,1當量)於1,4-二噁烷(10 mL)中之攪拌溶液中添加二碳酸二-三級丁酯(6.11 g,27.98 mmol,4當量)及DMAP (256.3 mg,2.10 mmol,0.3當量)。將反應在100℃下攪拌1.5h。所得溶液用水(100 mL)稀釋且用DCM (3*100 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由反相急速層析(管柱,C 18矽膠;移動相,於MeCN中之水,在30 min內0%至100%梯度;偵測器,UV 254 nm)純化,以得到呈黃色油狀物之N-(三級丁氧基羰基)-N-[5-(二甲基磷醯基)-3-甲氧基吡啶-2-基]胺基甲酸三級丁酯(1.80 g,64.28%)。LC-MS:(M+H) +實測值401.1。 Step 2: To a stirred solution of 5-(dimethylphosphinoyl)-3-methoxypyridin-2-amine (1.40 g, 6.99 mmol, 1 eq.) in 1,4-dioxane (10 mL) at 0 °C was added di-tert-butyl dicarbonate (6.11 g, 27.98 mmol, 4 eq.) and DMAP (256.3 mg, 2.10 mmol, 0.3 eq.). The reaction was stirred at 100 °C for 1.5 h. The resulting solution was diluted with water (100 mL) and extracted with DCM (3*100 mL). The combined organic layers were dried over anhydrous Na2SO4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, water in MeCN, gradient 0% to 100% in 30 min; detector, UV 254 nm) to give tert-butyl N-(tert-butyloxycarbonyl)-N-[5-(dimethylphosphinoyl)-3-methoxypyridin-2-yl]carbamate (1.80 g, 64.28%) as a yellow oil. LC-MS: (M+H) + found 401.1.
步驟3:將N-(三級丁氧基羰基)-N-[5-(二甲基磷醯基)-3-甲氧基吡啶-2-基]胺基甲酸三級丁酯(1.80 g,4.49 mmol,1當量)及K 2CO 3(1.86 g,13.48 mmol,3當量)於MeOH (15 mL) 中之混合物在25℃下攪拌12 h。所得混合物用水(100 mL)稀釋且用DCM (3*100 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由反相急速層析(管柱,C 18矽膠;移動相,於MeCN中之水,在30 min內0%至100%梯度;偵測器,UV 254 nm)純化,以得到呈黃色油狀物之N-[5-(二甲基磷醯基)-3-甲氧基吡啶-2-基]胺基甲酸三級丁酯(1.30 g,96.30%)。LC-MS:(M+H) +實測值301.3。 Step 3: A mixture of tert-butyl N-(tert-butyloxycarbonyl)-N-[5-(dimethylphosphinoyl)-3-methoxypyridin-2-yl]carbamate (1.80 g, 4.49 mmol, 1 eq.) and K 2 CO 3 (1.86 g, 13.48 mmol, 3 eq.) in MeOH (15 mL) was stirred at 25 °C for 12 h. The resulting mixture was diluted with water (100 mL) and extracted with DCM (3*100 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, water in MeCN, gradient 0% to 100% in 30 min; detector, UV 254 nm) to give tributyl N-[5-(dimethylphosphatyl)-3-methoxypyridin-2-yl]carbamate (1.30 g, 96.30%) as a yellow oil. LC-MS: (M+H) + found 301.3.
步驟4:將N-[5-(二甲基磷醯基)-3-甲氧基吡啶-2-基]胺基甲酸三級丁酯(300 mg,1.00 mmol,1當量)、8-溴-2-(3-溴丙-1-炔-1-基)-3-[(三氟甲基)硫基]吲嗪(412.6 mg,1.00 mmol,1當量)及Cs 2CO 3(976.5 mg,3.00 mmol,3當量)於MeCN (4 mL)中之混合物在70℃下攪拌3 h。所得混合物用水(50 mL)稀釋且用DCM (3*50 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由反相急速層析(管柱,C 18矽膠;移動相,於MeCN中之水,在30 min內0%至100%梯度;偵測器,UV 254 nm)純化,以得到呈黃色固體之N-(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)-N-[5-(二甲基磷醯基)-3-甲氧基吡啶-2-基]胺基甲酸三級丁酯(400 mg,63.31%)。LC-MS:(M+H) +實測值631.9。 Step 4: A mixture of tributyl N-[5-(dimethylphosphinoyl)-3-methoxypyridin-2-yl]carbamate (300 mg, 1.00 mmol, 1 eq.), 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizine (412.6 mg, 1.00 mmol, 1 eq.) and Cs 2 CO 3 (976.5 mg, 3.00 mmol, 3 eq.) in MeCN (4 mL) was stirred at 70 °C for 3 h. The resulting mixture was diluted with water (50 mL) and extracted with DCM (3*50 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, water in MeCN, gradient 0% to 100% in 30 min; detector, UV 254 nm) to give tributyl N-(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)-N-[5-(dimethylphosphinoyl)-3-methoxypyridin-2-yl]carbamate as a yellow solid (400 mg, 63.31%). LC-MS: (M+H) + found 631.9.
步驟5:將N-(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)-N-[5-(二甲基磷醯基)-3-甲氧基吡啶-2-基]胺基甲酸三級丁酯(150 mg,0.24 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(72.9 mg,0.36 mmol,1.5當量)、Cs 2CO 3(386.4 mg,1.19 mmol,5當量)及Pd-PEPPSI-IHeptCl 3-氯吡啶(46.2 mg,0.05 mmol,0.2當量) 於1,4-二噁烷(3 mL)中之混合物在100℃下攪拌4 h。所得混合物用水(50 mL)稀釋且用DCM (5*50 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由反相急速層析(管柱,C 18矽膠;移動相,於MeCN中之水,在30 min內0%至100%梯度;偵測器,UV 254 nm)純化,以得到呈黃色固體之N-[5-(二甲基磷醯基)-3-甲氧基吡啶-2-基]-N-[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基甲酸三級丁酯(140 mg,86.33%)。LC-MS:(M+H) +實測值684.4。 Step 5: A mixture of tributyl N-(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)-N-[5-(dimethylphosphatyl)-3-methoxypyridin- 2- yl]carbamate (150 mg, 0.24 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (72.9 mg, 0.36 mmol, 1.5 eq), Cs2CO3 (386.4 mg, 1.19 mmol, 5 eq) and Pd-PEPPSI-IHeptCl 3-chloropyridine (46.2 mg, 0.05 mmol, 0.2 eq) in 1,4-dioxane (3 mL) was stirred at 100 °C for 4 h. The resulting mixture was diluted with water (50 mL) and extracted with DCM (5*50 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, water in MeCN, gradient 0% to 100% in 30 min; detector, UV 254 nm) to give tributyl N-[5-(dimethylphosphatyl)-3-methoxypyridin-2-yl]-N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]carbamate (140 mg, 86.33%) as a yellow solid. LC-MS: (M+H) + found 684.4.
步驟6:在0℃下,向N-[5-(二甲基磷醯基)-3-甲氧基吡啶-2-基]-N-[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基甲酸三級丁酯(140 mg,0.21 mmol,1當量)於DCM (1.5 mL) 中之攪拌溶液中添加於1,4-二噁烷(1.02 mL,4.10 mmol,20當量)中之4 M HCl (氣體)。將反應在25℃下攪拌1 h。將所得溶液在減壓下濃縮。殘餘物藉由製備型HPLC (管柱:XBridge Prep OBD C 18管柱,30*150 mm,5μm;移動相A:水(10 mmol/L NH 4HCO 3)+0.05%NH 3 .H 2O,移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在7min內29% B至54% B;波長:254 nm/220 nm;RT1(min):7.52)純化,以得到呈灰白色固體之2-(3-{[5-(二甲基磷醯基)-3-甲氧基吡啶-2-基]胺基}丙-1-炔-1-基)-N-[(3S,4R)-3-氟-1-甲基哌啶-4-基]-3-[(三氟甲基)硫基]吲嗪-8-胺(73.6 mg,61.53%)。LC-MS:(M+H) +實測值584.45。 1H NMR (400 MHz, DMSO-d6) 7.98 (dd, J= 6.7, 1.6 Hz, 1H), 7.84 (d, J= 6.8 Hz, 1H), 7.29-7.17 (m, 2H), 7.07 (t, J= 6.0 Hz, 1H), 6.75 (t, J= 7.2 Hz, 1H), 6.14 (d, J= 7.6 Hz, 1H), 5.80 (d, J= 8.3 Hz, 1H), 4.82 (d, J= 49.4 Hz, 1H), 4.43 (d, J= 6.0 Hz, 2H), 3.86 (s, 3H), 3.59 (d, J= 28.9 Hz, 1H), 3.02 (t, J= 11.1 Hz, 1H), 2.81 (d, J= 10.9 Hz, 1H), 2.19 (m, 4H), 2.13-1.92 (m, 2H), 1.64 (s, 4H), 1.60 (s, 3H)。 實例445. 2-(3-{[2-(二甲基磷醯基)-4-甲氧基嘧啶-5-基]胺基}丙-1-炔-1-基)-N-[(3S,4R)-3-氟-1-甲基哌啶-4-基]-3-[(三氟甲基)硫基]吲嗪-8-胺之合成 Step 6: To a stirred solution of tributyl N-[5-(dimethylphosphatyl)-3-methoxypyridin-2-yl]-N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]carbamate (140 mg, 0.21 mmol, 1 eq) in DCM (1.5 mL) at 0 °C was added 4 M HCl (g) in 1,4-dioxane (1.02 mL, 4.10 mmol, 20 eq). The reaction was stirred at 25 °C for 1 h. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: XBridge Prep OBD C 18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 )+0.05% NH 3 . H 2 O, mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 29% B to 54% B in 7 min; wavelength: 254 nm/220 nm; RT1 (min): 7.52) to give 2-(3-{[5-(dimethylphosphinoyl)-3-methoxypyridin-2-yl]amino}prop-1-yn-1-yl)-N-[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]-3-[(trifluoromethyl)thio]indolizin-8-amine (73.6 mg, 61.53%) as an off-white solid. LC-MS: (M+H) + found 584.45. 1 H NMR (400 MHz, DMSO-d6) 7.98 (dd, J = 6.7, 1.6 Hz, 1H), 7.84 (d, J = 6.8 Hz, 1H), 7.29-7.17 (m, 2H), 7.07 (t, J = 6.0 Hz, 1H), 6.75 (t, J = 7.2 Hz, 1H), 6.14 (d, J = 7.6 Hz, 1H), 5.80 (d, J = 8.3 Hz, 1H), 4.82 (d, J = 49.4 Hz, 1H), 4.43 (d, J = 6.0 Hz, 2H), 3.86 (s, 3H), 3.59 (d, J = 28.9 Hz, 1H), 3.02 (t, J = 11.1 Hz, 1H), 2.81 (d, J = 10.9 Hz, 1H), 2.19 (m, 4H), 2.13-1.92 (m, 2H), 1.64 (s, 4H), 1.60 (s, 3H). Example 445. Synthesis of 2-(3-{[2-(dimethylphosphinoyl)-4-methoxypyrimidin-5-yl]amino}prop-1-yn-1-yl)-N-[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]-3-[(trifluoromethyl)thio]indolizin-8-amine
步驟1. 將2-氯-4-甲氧基嘧啶-5-胺(500.0 mg,3.13 mmol,1.00當量)、(甲基膦醯基)甲烷(317.9 mg,4.07 mmol,1.30當量)、DIEA (162.0 mg,1.25 mmol,0.40當量)、DPPF (692.3 mg,1.25 mmol,0.40當量)及Pd(OAc) 2(70.4 mg,0.31 mmol,0.10當量)於DMF (5.00 mL)中之混合物在 120℃及氮氣氛圍下攪拌1 h。所得混合物使用C18急速層析(移動相A:水,移動相B:ACN;流動速率:60 mL/min;梯度:在30 min內0% B至100% B;254/220 nm)純化,以得到呈淺棕色固體之2-(二甲基磷醯基)-4-甲氧基嘧啶-5-胺(380.0 mg,60.29%)。LC-MS:(M+H) +實測值202.1。 Step 1. A mixture of 2-chloro-4-methoxypyrimidin-5-amine (500.0 mg, 3.13 mmol, 1.00 equiv), (methylphosphonyl)methane (317.9 mg, 4.07 mmol, 1.30 equiv), DIEA (162.0 mg, 1.25 mmol, 0.40 equiv), DPPF (692.3 mg, 1.25 mmol, 0.40 equiv) and Pd(OAc) 2 (70.4 mg, 0.31 mmol, 0.10 equiv) in DMF (5.00 mL) was stirred at 120 °C under nitrogen atmosphere for 1 h. The resulting mixture was purified using C18 flash chromatography (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm) to give 2-(dimethylphosphatyl)-4-methoxypyrimidin-5-amine (380.0 mg, 60.29%) as a light brown solid. LC-MS: (M+H) + found 202.1.
步驟2:將2-(二甲基磷醯基)-4-甲氧基嘧啶-5-胺(370.0 mg,1.84 mmol,1.10當量)、8-溴-2-(3-溴丙-1-炔-1-基)-3-[(三氟甲基)硫基]吲嗪(690.7 mg,1.67 mmol,1.00當量)及K 2CO 3(693.3 mg,5.01 mmol,3.00當量)於DMF (2.00 mL)中之混合物在70℃下攪拌2 h。過濾混合物且濾液使用C18急速層析(移動相A:水,移動相B:ACN;流動速率:60 mL/min;梯度:在30 min內0% B至100% B;254/220 nm)純化,以得到呈白色固體之N-(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)-N-[2-(二甲基磷醯基)-4-甲氧基嘧啶-5-基]胺基甲酸三級丁酯(240.0 mg,22.66%)。LC-MS:(M+H) +實測值533.0。 Step 2: A mixture of 2-(dimethylphosphinoyl)-4-methoxypyrimidin-5-amine (370.0 mg, 1.84 mmol, 1.10 equiv), 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizine (690.7 mg, 1.67 mmol, 1.00 equiv) and K2CO3 ( 693.3 mg, 5.01 mmol, 3.00 equiv) in DMF (2.00 mL) was stirred at 70 °C for 2 h. The mixture was filtered and the filtrate was purified using C18 flash chromatography (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm) to give tributyl N-(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)-N-[2-(dimethylphosphinoyl)-4-methoxypyrimidin-5-yl]carbamate (240.0 mg, 22.66%) as a white solid. LC-MS: (M+H) + found 533.0.
步驟3:將N-(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)-7-(二甲基磷醯基)-1,3-二氫-2-苯并呋喃-4-胺(100.0 mg,0.18 mmol,1.00當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(76.9 mg,0.37mmol,2.00當量)、Cs 2CO 3(366.6 mg,1.13 mmol,6.00當量)及Pd-PEPPSI-IHeptCl 3-氯吡啶(18.3 mg,0.02 mmol,0.10當量)於1,4-二噁烷(2.00 mL)中之混合物在100℃及N 2氛圍下攪拌16 h。移除溶劑之後,殘餘物使用C18急速層析(移動相A:水(0.1% FA),移動相B:ACN;流動速率:60 mL/min;梯度:在30 min內0% B至100% B;254/220 nm)及製備型HPLC (Xselect CSH C18 OBD管柱,30*150 mm,5μm;移動相A:水(0.1% FA),移動相B:ACN;流動速率:60 mL/min;梯度:在7 min內16% B至30% B;波長:254nm/220 nm;RT:7.82 min)純化,以得到呈白色固體之2-(3-{[2-(二甲基磷醯基)-4-甲氧基嘧啶-5-基]胺基}丙-1-炔-1-基)-N-[(3S,4R)-3-氟-1-甲基哌啶-4-基]-3-[(三氟甲基)硫基]吲嗪-8-胺;FA鹽(20.40 mg,17.70%)。LC-MS:(M+H)+實測值585.35。 1H NMR (400 MHz, DMSO-d6) δ 8.18 (d, J= 71.6 Hz, 2H), 7.90 (d, J= 6.9 Hz, 1H), 7.15 (s, 1H), 6.81 (t, J= 7.2 Hz, 1H), 6.19 (d, J= 7.6 Hz, 1H), 5.01 (d, J= 48.2 Hz, 1H), 4.34 (s, 2H), 4.03 (s, 3H), 3.78 (dd, J= 29.1, 11.7 Hz, 1H), 3.44 (t, J= 11.8 Hz, 1H), 3.18 (d, J= 11.6 Hz, 1H), 2.89 (dd, J= 38.9, 13.8 Hz, 1H), 2.70 (t, J= 11.7 Hz, 1H), 2.53 (s, 3H), 2.10 (dt, J= 17.5, 9.3 Hz, 1H), 1.88 (d, J= 13.4 Hz, 1H), 1.72 (d, J= 13.5 Hz, 6H)。 實例429. 2-(3-{[6-(二甲基磷醯基)嗒嗪-3-基]胺基}丙-1-炔-1-基)-N-[(3S,4R)-3-氟-1-甲基哌啶-4-基]-3-[(三氟甲基)硫基]吲嗪-8-胺之合成 Step 3: A mixture of N-(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)-7-(dimethylphosphatyl)-1,3-dihydro-2-benzofuran-4-amine (100.0 mg, 0.18 mmol, 1.00 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (76.9 mg, 0.37 mmol, 2.00 equiv), Cs2CO3 (366.6 mg, 1.13 mmol, 6.00 equiv) and Pd-PEPPSI-IHeptCl 3-chloropyridine (18.3 mg, 0.02 mmol , 0.10 equiv) in 1,4-dioxane (2.00 mL) was heated at 100 °C and N 2 atmosphere for 16 h. After removing the solvent, the residue was purified by C18 flash chromatography (mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 30 min; 254/220 nm) and preparative HPLC (Xselect CSH C18 OBD column, 30*150 mm, 5μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 16% B to 30% B in 7 min; wavelength: 254nm/220 nm; RT: 7.82 min) to give 2-(3-{[2-(dimethylphosphinoyl)-4-methoxypyrimidin-5-yl]amino}prop-1-yn-1-yl)-N-[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]-3-[(trifluoromethyl)thio]indolizin-8-amine; FA salt (20.40 mg, 17.70%) as a white solid. LC-MS: (M+H)+ found 585.35. 1 H NMR (400 MHz, DMSO-d6) δ 8.18 (d, J = 71.6 Hz, 2H), 7.90 (d, J = 6.9 Hz, 1H), 7.15 (s, 1H), 6.81 (t, J = 7.2 Hz, 1H), 6.19 (d, J = 7.6 Hz, 1H), 5.01 (d, J = 48.2 Hz, 1H), 4.34 (s, 2H), 4.03 (s, 3H), 3.78 (dd, J = 29.1, 11.7 Hz, 1H), 3.44 (t, J = 11.8 Hz, 1H), 3.18 (d, J = 11.6 Hz, 1H), 2.89 (dd, J = 38.9, 13.8 Hz, 1H), 2.70 (t, J = 11.7 Hz, 1H), 2.53 (s, 3H), 2.10 (dt, J = 17.5, 9.3 Hz, 1H), 1.88 (d, J = 13.4 Hz, 1H), 1.72 (d, J = 13.5 Hz, 6H). Example 429. Synthesis of 2-(3-{[6-(dimethylphosphinoyl)pyridazin-3-yl]amino}prop-1-yn-1-yl)-N-[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]-3-[(trifluoromethyl)thio]indolizin-8-amine
步驟1. 將6-溴嗒嗪-3-胺(500 mg,2.87 mmol,1當量)、(甲基膦醯基)甲烷(672.9 mg,8.62 mmol,3當量)、XantPhos (665.1 mg,1.15 mmol,0.4當量)、Pd(AcO) 2(129.0 mg,0.58 mmol,0.2當量)及DIEA (1.00 g,7.76 mmol,2.7當量)於DMF (3 mL)中之混合物在130℃及氮氣氛圍下攪拌3 h。所得混合物用水(50 mL)稀釋且用CH 2Cl 2/MeOH=10:1 (5*50 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮,以得到呈棕色固體之6-(二甲基磷醯基)嗒嗪-3-胺(450 mg,91.50%)。LC-MS:(M+H) +實測值172.3。 Step 1. A mixture of 6-bromopyridazin-3-amine (500 mg, 2.87 mmol, 1 eq.), (methylphosphonyl)methane (672.9 mg, 8.62 mmol, 3 eq.), XantPhos (665.1 mg, 1.15 mmol, 0.4 eq.), Pd(AcO) 2 (129.0 mg, 0.58 mmol, 0.2 eq.) and DIEA (1.00 g, 7.76 mmol, 2.7 eq.) in DMF (3 mL) was stirred at 130° C. under nitrogen atmosphere for 3 h. The resulting mixture was diluted with water (50 mL) and extracted with CH 2 Cl 2 /MeOH=10:1 (5*50 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to give 6-(dimethylphosphatyl)pyridazin-3-amine (450 mg, 91.50%) as a brown solid. LC-MS: (M+H) + found 172.3.
步驟2:將6-(二甲基磷醯基)嗒嗪-3-胺(1 g,5.84 mmol,1當量)、二碳酸二-三級丁酯(2.55 g,11.69 mmol,2當量)及DMAP (71.4 mg,0.58 mmol,0.1當量)於二噁烷(8 mL)中之溶液在100℃下攪拌2 h。所得混合物用水(50 mL)稀釋且用CH 2Cl 2(3*50 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型TLC (PE/EA=2:1)純化,以得到呈棕色固體之N-(三級丁氧基羰基)-N-[6-(二甲基磷醯基)嗒嗪-3-基]胺基甲酸三級丁酯(1 g,46.08%)。LC-MS:(M+H) +實測值372.2。 Step 2: A solution of 6-(dimethylphosphino)pyridazin-3-amine (1 g, 5.84 mmol, 1 eq.), di-tert-butyl dicarbonate (2.55 g, 11.69 mmol, 2 eq.) and DMAP (71.4 mg, 0.58 mmol, 0.1 eq.) in dioxane (8 mL) was stirred at 100 °C for 2 h. The resulting mixture was diluted with water (50 mL) and extracted with CH 2 Cl 2 (3*50 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE/EA=2:1) to give tert-butyl N-(tert-butyloxycarbonyl)-N-[6-(dimethylphosphatyl)pyridazin-3-yl]carbamate (1 g, 46.08%) as a brown solid. LC-MS: (M+H) + found 372.2.
步驟3:將N-(三級丁氧基羰基)-N-[6-(二甲基磷醯基)嗒嗪-3-基]胺基甲酸三級丁酯(900 mg,2.42 mmol,1當量)及K 2CO 3(1.00 g,7.27 mmol,3當量)於MeOH (10 mL) 中之混合物在室溫下攪拌2 h。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型TLC (PE/EA=1:1)純化,以得到呈棕色固體之N-[6-(二甲基磷醯基)嗒嗪-3-基]胺基甲酸三級丁酯(550 mg,83.67%)。LC-MS:(M+H) +實測值272.1。 Step 3: A mixture of tert-butyl N-(tert-butyloxycarbonyl)-N-[6-(dimethylphosphino)pyridazin-3-yl]carbamate (900 mg, 2.42 mmol, 1 eq.) and K 2 CO 3 (1.00 g, 7.27 mmol, 3 eq.) in MeOH (10 mL) was stirred at room temperature for 2 h. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE/EA=1:1) to give tert-butyl N-[6-(dimethylphosphino)pyridazin-3-yl]carbamate (550 mg, 83.67%) as a brown solid. LC-MS: (M+H) + found 272.1.
步驟4:將N-[6-(二甲基磷醯基)嗒嗪-3-基]胺基甲酸三級丁酯(150 mg,0.55 mmol,1.00當量)、8-溴-2-(3-溴丙-1-炔-1-基)-3-[(三氟甲基)硫基]吲嗪(228.4 mg,0.55 mmol,1.00當量)及Cs 2CO 3(540.5 mg,1.66 mmol,3當量)於MeCN (5 mL)中之混合物在70℃下攪拌2 h。所得混合物用水(50 mL)稀釋且用DCM (3*50 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型TLC (PE/EA=2:1)純化,以得到呈棕色固體之N-(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)-N-[6-(二甲基磷醯基)嗒嗪-3-基]胺基甲酸三級丁酯(240 mg,71.93%)。LC-MS:(M+H) +實測值603.1。 Step 4: A mixture of tributyl N-[6-(dimethylphosphino)pyridazin-3-yl]carbamate (150 mg, 0.55 mmol, 1.00 equiv), 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizine (228.4 mg, 0.55 mmol, 1.00 equiv) and Cs 2 CO 3 (540.5 mg, 1.66 mmol, 3 equiv) in MeCN (5 mL) was stirred at 70 °C for 2 h. The resulting mixture was diluted with water (50 mL) and extracted with DCM (3*50 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE/EA=2:1) to give tributyl N-(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)-N-[6-(dimethylphosphatyl)pyridazin-3-yl]carbamate (240 mg, 71.93%) as a brown solid. LC-MS: (M+H) + found 603.1.
步驟5:將N-(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)-N-[6-(二甲基磷醯基)嗒嗪-3-基]胺基甲酸三級丁酯(140 mg,0.23 mmol,1當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(71.4 mg,0.35 mmol,1.5當量)、Pd-PEPPSI-IHeptCl 3-氯吡啶(45.2 mg,0.05 mmol,0.2當量)及Cs 2CO 3(378.0 mg,1.16 mmol,5.00當量)於1,4-二噁烷(2 mL)中之混合物在100℃及氮氣氛圍下攪拌5 h。所得混合物用水(50 mL)稀釋且用EtOAc (3*50 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型TLC (PE/EA=2:1)純化,以得到呈棕色固體之N-[6-(二甲基磷醯基)嗒嗪-3-基]-N-[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基甲酸三級丁酯(120 mg,79.00%)。LC-MS:(M+H) +實測值655.4。 Step 5: A mixture of tributyl N-(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)-N-[6-(dimethylphosphatidyl)pyridazin-3-yl]carbamate (140 mg, 0.23 mmol, 1 eq), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (71.4 mg, 0.35 mmol, 1.5 eq), Pd-PEPPSI-IHeptCl 3 -chloropyridine (45.2 mg, 0.05 mmol, 0.2 eq) and Cs2CO3 (378.0 mg, 1.16 mmol, 5.00 eq) in 1,4-dioxane (2 mL) was stirred at 100 °C under nitrogen atmosphere for 5 h. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (3*50 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE/EA=2:1) to give tributyl N-[6-(dimethylphosphinoyl)pyridazin-3-yl]-N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]carbamate (120 mg, 79.00%) as a brown solid. LC-MS: (M+H) + found 655.4.
步驟6:在室溫下,向N-[6-(二甲基磷醯基)嗒嗪-3-基]-N-[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基甲酸三級丁酯(120 mg,0.18 mmol,1當量)於DCM (2 mL)中之溶液中添加於1,4-二噁烷(0.4 mL)中之4M HCl (氣體)。將反應在室溫下攪拌30 min。將所得溶液在減壓下濃縮。殘餘物使用C18急速層析(管柱:XBridge Shield RP18 OBD管柱,30*150 mm,5μm;移動相A:水(10 mmol/L NH 4HCO 3+0.05%NH 3 .H 2O),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在7min內27% B至47% B;波長:254nm/220nm nm;RT1(min):6.85;運行次數:3)純化,以得到呈灰白色固體之2-(3-{[6-(二甲基磷醯基)嗒嗪-3-基]胺基}丙-1-炔-1-基)-N-[(3S,4R)-3-氟-1-甲基哌啶-4-基]-3-[(三氟甲基)硫基]吲嗪-8-胺(57.1 mg,56.17%)。LC-MS:(M+H) +實測值555.25。 1H NMR (400 MHz, DMSO- d 6) δ 7.87 (t, J= 7.0 Hz, 2H), 7.73 (dd, J= 9.1, 4.1 Hz, 1H), 7.25 (s, 1H), 7.02 (dd, J= 9.2, 2.6 Hz, 1H), 6.76 (t, J= 7.2 Hz, 1H), 6.15 (d, J= 7.6 Hz, 1H), 5.84 (d, J= 8.3 Hz, 1H), 4.83 (d, J= 49.5 Hz, 1H), 4.53 (d, J= 5.8 Hz, 2H), 3.60 (d, J= 28.6 Hz, 1H), 3.02 (m, 1H), 2.81 (d, J= 10.7 Hz, 1H), 2.19 (s, 4H), 2.12 – 1.93 (m, 2H), 1.69 (d, J= 13.6 Hz, 7H)。 實例437. 7-(二甲基磷醯基)-N-[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]-1,3-苯并噁唑-4-胺之合成 Step 6: To a solution of tributyl N-[6-(dimethylphosphinoyl)pyridazin-3-yl]-N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]carbamate (120 mg, 0.18 mmol, 1 eq) in DCM (2 mL) was added 4M HCl (g) in 1,4-dioxane (0.4 mL) at room temperature. The reaction was stirred at room temperature for 30 min. The resulting solution was concentrated under reduced pressure. The residue was purified by C18 flash chromatography (column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 +0.05% NH 3 . H 2 O), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 27% B to 47% B in 7 min; wavelength: 254 nm/220 nm). nm; RT1(min): 6.85; Runs: 3) to give 2-(3-{[6-(dimethylphosphinoyl)pyridazin-3-yl]amino}prop-1-yn-1-yl)-N-[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]-3-[(trifluoromethyl)thio]indolizin-8-amine (57.1 mg, 56.17%) as an off-white solid. LC-MS: (M+H) + found 555.25. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.87 (t, J = 7.0 Hz, 2H), 7.73 (dd, J = 9.1, 4.1 Hz, 1H), 7.25 (s, 1H), 7.02 (dd, J = 9.2, 2.6 Hz, 1H), 6.76 (t, J = 7.2 Hz, 1H), 6.15 (d, J = 7.6 Hz, 1H), 5.84 (d, J = 8.3 Hz, 1H), 4.83 (d, J = 49.5 Hz, 1H), 4.53 (d, J = 5.8 Hz, 2H), 3.60 (d, J = 28.6 Hz, 1H), 3.03 (m, 1H), 2.81 (d, J = 10.7 Hz, 1H), 2.19 (s, 4H), 2.12 – 1.93 (m, 2H), 1.69 (d, J = 13.6 Hz, 7H). Example 437. Synthesis of 7-(dimethylphosphinoyl)-N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]-1,3-benzoxazol-4-amine
步驟1. 在-40℃及氮氣氛圍下,向1,3-苯并噁唑-4-胺(1.00 g,7.45 mmol,1.00當量)於DMF (10.00 mL)中之溶液中逐滴添加NIS (1.30 g,5.78 mmol,0.78當量)於DMF (10.00 mL)中之溶液。將混合物在室溫下攪拌16 h。所得溶液使用C18急速層析(移動相A:水(0.1% FA),移動相B:ACN;流動速率:80 mL/min;梯度:在20 min內0% B至50% B;254/220 nm)純化,以得到呈黃色固體之7-碘-1,3-苯并噁唑-4-胺(1.83 g,94.40%)。LC-MS:(M+H) +實測值261.0。 Step 1. To a solution of 1,3-benzoxazol-4-amine (1.00 g, 7.45 mmol, 1.00 equiv) in DMF (10.00 mL) was added dropwise a solution of NIS (1.30 g, 5.78 mmol, 0.78 equiv) in DMF (10.00 mL) at -40°C under nitrogen atmosphere. The mixture was stirred at room temperature for 16 h. The resulting solution was purified using C18 flash chromatography (mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 80 mL/min; gradient: 0% B to 50% B in 20 min; 254/220 nm) to give 7-iodo-1,3-benzoxazol-4-amine (1.83 g, 94.40%) as a yellow solid. LC-MS: (M+H) + found 261.0.
步驟2:將7-碘-1,3-苯并噁唑-4-胺(1.00 g,3.85 mmol,1.00當量)、乙酸鈀(207.2 mg,0.92 mmol,0.24當量)、XantPhos (400.5 mg,0.69 mmol,0.18當量)、DIEA (1.09 g,8.46 mmol,2.20當量)及(甲基膦醯基)甲烷(900.5 mg,11.54 mmol,3.00當量)於DMF (10.00 mL)中之溶液在80℃及氮氣氛圍下攪拌1 h。所得溶液使用C18急速層析(移動相A:水,移動相B:ACN;流動速率:80 mL/min;梯度:在20 min內0% B至10% B;254/220 nm)純化,以得到呈綠色固體之7-(二甲基磷醯基)-1,3-苯并噁唑-4-胺(300.0 mg,37.12%)。LC-MS:(M+H) +實測值211.2。 Step 2: A solution of 7-iodo-1,3-benzoxazol-4-amine (1.00 g, 3.85 mmol, 1.00 equiv), sodium acetate (207.2 mg, 0.92 mmol, 0.24 equiv), XantPhos (400.5 mg, 0.69 mmol, 0.18 equiv), DIEA (1.09 g, 8.46 mmol, 2.20 equiv) and (methylphosphonyl)methane (900.5 mg, 11.54 mmol, 3.00 equiv) in DMF (10.00 mL) was stirred at 80 °C under nitrogen atmosphere for 1 h. The resulting solution was purified using C18 flash chromatography (mobile phase A: water, mobile phase B: ACN; flow rate: 80 mL/min; gradient: 0% B to 10% B in 20 min; 254/220 nm) to give 7-(dimethylphosphatyl)-1,3-benzoxazol-4-amine (300.0 mg, 37.12%) as a green solid. LC-MS: (M+H) + found 211.2.
步驟3:將7-(二甲基磷醯基)-1,3-苯并噁唑-4-胺(106.8 mg,0.51 mmol,1.05當量)、8-溴-2-(3-溴丙-1-炔-1-基)-3-[(三氟甲基)硫基]吲嗪(200.0 mg,0.48 mmol,1.00當量)及K 2CO 3(200.8 mg,1.45 mmol,3.00當量)於ACN (3.00 mL)中之混合物在70℃下攪拌8 h。過濾混合物且濾液使用C18急速層析(移動相A:水(10 mmol/L NH 4HCO 3),移動相B:ACN;流動速率:80 mL/min;梯度:在20 min內0% B至70% B;254/220 nm)純化,以得到呈黃色固體之N-(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)-7-(二甲基磷醯基)-1,3-苯并噁唑-4-胺(100.0 mg,38.08%)。LC-MS:(M+H) +實測值542.1。 Step 3: A mixture of 7-(dimethylphosphatyl)-1,3-benzoxazol-4-amine (106.8 mg, 0.51 mmol, 1.05 equiv), 8-bromo-2-(3-bromoprop-1-yn-1 - yl)-3-[(trifluoromethyl)thio]indolizine (200.0 mg, 0.48 mmol, 1.00 equiv) and K2CO3 (200.8 mg, 1.45 mmol, 3.00 equiv) in ACN (3.00 mL) was stirred at 70 °C for 8 h. The mixture was filtered and the filtrate was purified using C18 flash chromatography (mobile phase A: water (10 mmol/L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 80 mL/min; gradient: 0% B to 70% B in 20 min; 254/220 nm) to give N-(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)-7-(dimethylphosphatyl)-1,3-benzoxazol-4-amine (100.0 mg, 38.08%) as a yellow solid. LC-MS: (M+H) + found 542.1.
步驟4:將N-(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)-7-(二甲基磷醯基)-1,3-苯并噁唑-4-胺(85.0 mg,0.16 mmol,1.00當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(48.2 mg,0.24 mmol,1.50當量)、Pd-PEPPSI-IHeptCl 3-氯吡啶(15.3 mg,0.02 mmol,0.10當量)及Cs 2CO 3(306.4 mg,0.94 mmol,6.00當量)於1,4-二噁烷(2.00 mL)中之混合物在100℃及氮氣氛圍下攪拌16 h。移除溶劑之後,殘餘物使用C18急速層析(移動相A:水(0.1% FA),移動相B:ACN;流動速率:80 mL/min;梯度:在20 min內0% B至30% B;254/220 nm)及製備型HPLC (管柱:XBridge Prep OBD C18管柱,30*150 mm,5 μm;移動相A:水(10 mmol/L NH 4HCO 3+ 0.05% NH 3 .H 2O),移動相B:ACN;流動速率:60 mL/min;梯度:在8 min內30% B至55% B;波長:220 nm;RT:7.27 min),以得到呈白色固體之7-(二甲基磷醯基)-N-[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]-1,3-苯并噁唑-4-胺(11.20 mg,12.01%)。LC-MS:(M+H) +實測值594.25。 1H NMR (400 MHz, DMSO- d 6) δ 8.68 (s, 1H), 7.84 (d, J= 6.9 Hz, 1H), 7.54 (dd, J= 11.8, 8.2 Hz, 1H), 7.19 (d, J= 8.4 Hz, 2H), 6.82 (dd, J= 8.4, 1.3 Hz, 1H), 6.75 (t, J= 7.2 Hz, 1H), 6.14 (d, J= 7.6 Hz, 1H), 5.85 (d, J= 8.2 Hz, 1H), 4.89 (s, 1H), 4.47 (d, J= 6.2 Hz, 2H), 3.59 (d, J= 29.4 Hz, 1H), 3.05 (s, 1H), 2.83 (d, J= 10.8 Hz, 1H), 2.27-1.99 (m, 6H), 1.70 (d, J= 13.4 Hz, 7H)。 實例389. 7-(二甲基磷醯基)-N-[3-(8-{[(3R,4S)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]-1,3-苯并噻唑-4-胺;甲酸之合成 Step 4: A mixture of N-(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)-7-(dimethylphosphatyl)-1,3-benzoxazol-4-amine (85.0 mg, 0.16 mmol, 1.00 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (48.2 mg, 0.24 mmol, 1.50 equiv), Pd-PEPPSI-IHeptCl 3-chloropyridine (15.3 mg, 0.02 mmol, 0.10 equiv) and Cs2CO3 ( 306.4 mg, 0.94 mmol, 6.00 equiv) in 1,4-dioxane (2.00 mL) was stirred at 100 °C under nitrogen atmosphere for 16 hr. h. After removing the solvent, the residue was purified by C18 flash chromatography (mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 80 mL/min; gradient: 0% B to 30% B in 20 min; 254/220 nm) and preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 + 0.05% NH 3 . H 2 O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 30% B to 55% B in 8 min; wavelength: 220 nm; RT: 7.27 min) to give 7-(dimethylphosphatyl)-N-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]-1,3-benzoxazol-4-amine (11.20 mg, 12.01%) as a white solid. LC-MS: (M+H) + found 594.25. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.68 (s, 1H), 7.84 (d, J = 6.9 Hz, 1H), 7.54 (dd, J = 11.8, 8.2 Hz, 1H), 7.19 (d, J = 8.4 Hz, 2H), 6.82 (dd, J = 8.4, 1.3 Hz, 1H), 6.75 (t, J = 7.2 Hz, 1H), 6.14 (d, J = 7.6 Hz, 1H), 5.85 (d, J = 8.2 Hz, 1H), 4.89 (s, 1H), 4.47 (d, J = 6.2 Hz, 2H), 3.59 (d, J = 29.4 Hz, 1H), 3.05 (s, 1H), 2.83 (d, J = 10.8 Hz, 1H), 2.27-1.99 (m, 6H), 1.70 (d, J = 13.4 Hz, 7H). Example 389. Synthesis of 7-(dimethylphosphonyl)-N-[3-(8-{[(3R,4S)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]-1,3-benzothiazol-4-amine; formic acid
步驟1. 在0℃下,向1,3-苯并噻唑-4-胺(1 g,6.65 mmol,1.00當量)於ACN (15 mL,285.36 mmol,42.86當量)中之攪拌混合物中逐份添加NIS (1.50 g,6.65 mmol,1.00當量)。將混合物在室溫下攪拌1 h。將反應在室溫下用水淬滅且用CH 2Cl 2/MEOH (10/1)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用PE / EA (50:1)溶析,以得到呈黃色固體之7-碘-1,3-苯并噻唑-4-胺(1.7 g,87.30%)。LC-MS:(M+H) +實測值:277.1。 Step 1. To a stirred mixture of 1,3-benzothiazol-4-amine (1 g, 6.65 mmol, 1.00 equiv) in ACN (15 mL, 285.36 mmol, 42.86 equiv) at 0°C was added NIS (1.50 g, 6.65 mmol, 1.00 equiv) portionwise. The mixture was stirred at room temperature for 1 h. The reaction was quenched with water at room temperature and extracted with CH2Cl2 /MEOH (10/1). The combined organic layers were dried over anhydrous Na2SO4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EA (50:1) to give 7-iodo-1,3-benzothiazol-4-amine (1.7 g, 87.30%) as a yellow solid. LC-MS: (M+H) + found: 277.1.
步驟2:將7-碘-1,3-苯并噻唑-4-胺(850 mg,3.07 mmol,1.00當量)、(甲基膦醯基)甲烷(601 mg,7.69 mmol,2.50當量)、Pd(OAc) 2(104 mg,0.46 mmol,0.15當量)、XantPhos (267 mg,0.46 mmol,0.15當量)及DIEA (796mg,6.15 mmol,2.00當量)於DMF (10 mL)中之混合物在100℃及氮氣氛圍下攪拌1 h。將反應在室溫下用水淬滅且用CH 2Cl 2/MeOH (10/1)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由矽膠管柱層析純化,用CH 2Cl 2/ MeOH (60:1)溶析,以得到呈黃色固體之7-(二甲基磷醯基)-1,3-苯并噻唑-4-胺(640 mg,87.76%)。LC-MS:(M+H) +實測值:227.2。 Step 2: A mixture of 7-iodo-1,3-benzothiazol-4-amine (850 mg, 3.07 mmol, 1.00 equiv), (methylphosphonyl)methane (601 mg, 7.69 mmol, 2.50 equiv), Pd(OAc) 2 (104 mg, 0.46 mmol, 0.15 equiv), XantPhos (267 mg, 0.46 mmol, 0.15 equiv) and DIEA (796 mg, 6.15 mmol, 2.00 equiv) in DMF (10 mL) was stirred at 100 °C under nitrogen atmosphere for 1 h . The reaction was quenched with water at room temperature and extracted with CH2Cl2 /MeOH (10/1). The combined organic layers were dried over anhydrous Na2SO4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH 2 Cl 2 / MeOH (60:1) to give 7-(dimethylphosphatyl)-1,3-benzothiazol-4-amine (640 mg, 87.76%) as a yellow solid. LC-MS: (M+H) + found: 227.2.
步驟3:將8-溴-2-(3-溴丙-1-炔-1-基)-3-[(三氟甲基)硫基]吲嗪(200 mg,0.48 mmol,1.00當量)、7-(二甲基磷醯基)-1,3-苯并噻唑-4-胺(131 mg,0.58 mmol,1.20當量)及K 2CO 3(201 mg,1.45 mmol,3.00當量)於MeCN (5 mL)中之混合物在70℃下攪拌隔夜。反應用水(50 mL)稀釋且用EtOAc (3*50mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型TLC (CH 2Cl 2/MeOH=20:1)純化,以得到呈黃色油狀物之N-(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)-7-(二甲基磷醯基)-1,3-苯并噻唑-4-胺(100 mg,34.14%)。LC-MS:(M+H) +實測值:558.1。 Step 3: A mixture of 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizine (200 mg, 0.48 mmol, 1.00 equiv), 7-(dimethylphosphinoyl)-1,3-benzothiazol-4-amine (131 mg, 0.58 mmol, 1.20 equiv) and K 2 CO 3 (201 mg, 1.45 mmol, 3.00 equiv) in MeCN (5 mL) was stirred at 70 °C overnight. The reaction was diluted with water (50 mL) and extracted with EtOAc (3*50 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 /MeOH=20:1) to give N-(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)-7-(dimethylphosphatyl)-1,3-benzothiazol-4-amine (100 mg, 34.14%) as a yellow oil. LC-MS: (M+H) + found: 558.1.
步驟4:將N-(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)-7-(二甲基磷醯基)-1,3-苯并噻唑-4-胺(90 mg,0.16 mmol,1.00當量)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(50 mg,0.24 mmol,1.50當量)、Cs 2CO 3(263 mg,0.80 mmol,5.00當量)及Pd-PEPPSI-IHeptCl 3-氯吡啶(31 mg,0.03 mmol,0.20當量)於1,4-二噁烷(3 mL)中之混合物在100℃及氮氣氛圍下攪拌2 h。反應用水(50 mL)稀釋且用EtOAc (3*50mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型HPLC (管柱:X-Select Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(0.1%FA),移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在7 min內30% B至50% B;波長:254nm/220nm nm;RT1(min):6.56)純化,以得到呈淺棕色固體之7-(二甲基磷醯基)-N-[3-(8-{[(3R,4S)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]-1,3-苯并噻唑-4-胺;甲酸(36 mg,36.31%)。LC-MS:(M+H) +實測值:610.15。 1H NMR (400 MHz, DMSO-d 6) δ 9.26 (s, 1H), 7.85 (d, J= 6.8 Hz, 1H), 7.61 (dd, J= 12.2, 8.1 Hz, 1H), 7.25 – 7.18 (m, 2H), 6.93 (dd, J= 8.1, 2.1 Hz, 1H), 6.76 (t, J= 7.2 Hz, 1H), 6.14 (d, J= 7.6 Hz, 1H), 5.83 (d, J= 8.3 Hz, 1H), 4.88 (s, 1H), 4.47 (d, J= 6.2 Hz, 2H), 3.63 (s, 1H), 3.03 (t, J= 11.2 Hz, 1H), 2.81 (d, J= 10.8 Hz, 1H), 2.19 (s, 4H), 2.09 (t, J= 11.5 Hz, 1H), 1.98 (s, 1H), 1.69 (d, J= 13.3 Hz, 7H)。 實例483. 8-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-N-甲基-[1,2,4]三唑并[4,3-a]吡啶-6-甲醯胺之合成 Step 4: A mixture of N-(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)-7-(dimethylphosphatyl)-1,3-benzothiazol-4-amine (90 mg, 0.16 mmol, 1.00 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4- amine dihydrochloride (50 mg, 0.24 mmol, 1.50 equiv), Cs2CO3 (263 mg, 0.80 mmol, 5.00 equiv) and Pd-PEPPSI-IHeptCl 3-chloropyridine (31 mg, 0.03 mmol, 0.20 equiv) in 1,4-dioxane (3 mL) was stirred at 100 °C under nitrogen atmosphere for 2 h. The reaction was diluted with water (50 mL) and extracted with EtOAc (3*50 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: X-Select Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 30% B to 50% B in 7 min; wavelength: 254 nm/220 nm nm; RT1(min): 6.56) to give 7-(dimethylphosphatyl)-N-[3-(8-{[(3R,4S)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]-1,3-benzothiazol-4-amine; formic acid (36 mg, 36.31%) as a light brown solid. LC-MS: (M+H) + found: 610.15. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.26 (s, 1H), 7.85 (d, J = 6.8 Hz, 1H), 7.61 (dd, J = 12.2, 8.1 Hz, 1H), 7.25 – 7.18 (m, 2H), 6.93 (dd, J = 8.1, 2.1 Hz, 1H), 6.76 (t, J = 7.2 Hz, 1H), 6.14 (d, J = 7.6 Hz, 1H), 5.83 (d, J = 8.3 Hz, 1H), 4.88 (s, 1H), 4.47 (d, J = 6.2 Hz, 2H), 3.63 (s, 1H), 3.03 (t, J = 11.2 Hz, 1H), 2.81 (d, J = 10.8 Hz, 1H), 2.19 (s, 4H), 2.09 (t, J = 11.5 Hz, 1H), 1.98 (s, 1H), 1.69 (d, J = 13.3 Hz, 7H). Example 483. Synthesis of 8-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-methyl-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide
步驟1. 在室溫下,向6-氯-5-硝基吡啶-3-甲酸(2 g,9.87 mmol,1當量)、CH 3NH 2 .HCl (1.33 g,19.75 mmol,2當量)及DIEA (6.38 g,49.37 mmol,5當量)於DMF (20 mL)中之攪拌溶液中添加T 3P (9.43 g,14.81 mmol,1.5當量,50%於DMF中)。將反應在25℃下攪拌1 h。所得溶液藉由反相急速層析(管柱,C18矽膠;移動相,於MeCN中之水,在30 min內0%至100%梯度;偵測器,UV 254 nm)純化,以得到呈黃色固體之6-氯-N-甲基-5-硝基吡啶-3-甲醯胺(1.6 g,75.16%)。LC-MS:(M+H) +實測值216.0。 Step 1. To a stirred solution of 6-chloro-5-nitropyridine- 3 -carboxylic acid (2 g , 9.87 mmol, 1 eq), CH3NH2.HCl (1.33 g, 19.75 mmol, 2 eq) and DIEA (6.38 g, 49.37 mmol, 5 eq) in DMF (20 mL) was added T3P (9.43 g, 14.81 mmol, 1.5 eq, 50% in DMF) at room temperature. The reaction was stirred at 25 °C for 1 h. The resulting solution was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, water in MeCN, gradient from 0% to 100% in 30 min; detector, UV 254 nm) to give 6-chloro-N-methyl-5-nitropyridine-3-carboxamide (1.6 g, 75.16%) as a yellow solid. LC-MS: (M+H) + found 216.0.
步驟2:在室溫下,向6-氯-N-甲基-5-硝基吡啶-3-甲醯胺(1.4 g,6.49 mmol,1當量)於1,4-二噁烷(10 mL)中之攪拌溶液中添加NH 2NH 2 .H 2O (1.63 g,32.47 mmol,5當量)。將反應混合物在60℃下攪拌1.5 h。藉由過濾收集沉澱的固體且用DCM洗滌,以得到呈紫色固體之6-肼基-N-甲基-5-硝基吡啶-3-甲醯胺(1 g,72.92%)。LC-MS:(M+H) +實測值212.2。 Step 2: To a stirred solution of 6-chloro-N-methyl-5-nitropyridine-3-carboxamide (1.4 g, 6.49 mmol , 1 eq.) in 1,4-dioxane (10 mL) was added NH2NH2.H2O (1.63 g, 32.47 mmol, 5 eq.) at room temperature . The reaction mixture was stirred at 60 °C for 1.5 h. The precipitated solid was collected by filtration and washed with DCM to give 6-hydrazino-N-methyl-5-nitropyridine-3-carboxamide (1 g, 72.92%) as a purple solid. LC-MS: (M+H) + found 212.2.
步驟3:在室溫下,向6-肼基-N-甲基-5-硝基吡啶-3-甲醯胺(900 mg,4.26 mmol,1當量)於DMF (10 mL)中之攪拌溶液中添加原甲酸三甲酯(4.52 g,42.62 mmol,10當量),接著添加催化量之PTSA (293.6 mg,1.71 mmol,0.4當量)。將反應混合物在65℃下攪拌3 h。藉由過濾收集沉澱的固體且用DCM洗滌,以得到呈黃色固體之N-甲基-8-硝基-[1,2,4]三唑并[4,3-a]吡啶-6-甲醯胺(600 mg,63.65%)。LC-MS:(M+H) +實測值220.0。 Step 3: To a stirred solution of 6-hydrazino-N-methyl-5-nitropyridine-3-carboxamide (900 mg, 4.26 mmol, 1 eq.) in DMF (10 mL) was added trimethyl orthoformate (4.52 g, 42.62 mmol, 10 eq.) followed by a catalytic amount of PTSA (293.6 mg, 1.71 mmol, 0.4 eq.) at room temperature. The reaction mixture was stirred at 65 °C for 3 h. The precipitated solid was collected by filtration and washed with DCM to give N-methyl-8-nitro-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide (600 mg, 63.65%) as a yellow solid. LC-MS: (M+H) + found 220.0.
步驟4:將N-甲基-8-硝基-[1,2,4]三唑并[4,3-a]吡啶-6-甲醯胺(600 mg,2.71 mmol,1當量)、Fe (1.21 g,21.70 mmol,8當量)及NH 4Cl (1.45 g,27.13 mmol,10當量)於EtOH (3 mL)/水(1 mL) 中之混合物在70℃下攪拌1.5 h。過濾所得混合物且濾餅用DCM洗滌。將濾液在減壓下濃縮。殘餘物藉由反相急速層析(管柱,C18矽膠;移動相,於MeCN中之水,在30 min內0%至100%梯度;偵測器,UV 254 nm)純化,以得到呈黃色固體之8-胺基-N-甲基-[1,2,4]三唑并[4,3-a]吡啶-6-甲醯胺(250 mg,48.20%)。LC-MS:(M+H) +實測值192.1。 Step 4: A mixture of N-methyl-8-nitro-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide (600 mg, 2.71 mmol, 1 eq), Fe (1.21 g, 21.70 mmol, 8 eq) and NH 4 Cl (1.45 g, 27.13 mmol, 10 eq) in EtOH (3 mL)/water (1 mL) was stirred at 70° C. for 1.5 h. The resulting mixture was filtered and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, water in MeCN, gradient 0% to 100% in 30 min; detector, UV 254 nm) to give 8-amino-N-methyl-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide (250 mg, 48.20%) as a yellow solid. LC-MS: (M+H) + found 192.1.
步驟5:將8-胺基-N-甲基-[1,2,4]三唑并[4,3-a]吡啶-6-甲醯胺(100 mg,0.52 mmol,1當量)、8-溴-2-(3-溴丙-1-炔-1-基)-3-[(三氟甲基)硫基]吲嗪(216.0 mg,0.52 mmol,1當量)及K 2CO 3(216.9 mg,1.57 mmol,3當量)於DMF (2 mL)中之混合物在70℃下攪拌3h。過濾所得混合物且濾液藉由反相急速層析(管柱,C18矽膠;移動相,於MeCN之水,在30 min內0%至50%梯度;偵測器,UV 254 nm)純化,以得到呈黃色固體之8-[(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)胺基]-N-甲基-[1,2,4]三唑并[4,3-a]吡啶-6-甲醯胺(60 mg,9.86%)。LC-MS:(M+H) +實測值522.8。 Step 5: A mixture of 8-amino-N-methyl-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide (100 mg, 0.52 mmol, 1 eq), 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizine (216.0 mg, 0.52 mmol, 1 eq) and K2CO3 (216.9 mg, 1.57 mmol, 3 eq) in DMF (2 mL) was stirred at 70 °C for 3 h. The resulting mixture was filtered and the filtrate was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in water, gradient 0% to 50% in 30 min; detector, UV 254 nm) to give 8-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-N-methyl-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide (60 mg, 9.86%) as a yellow solid. LC-MS: (M+H) + found 522.8.
步驟6:將8-[(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)胺基]-N-甲基-[1,2,4]三唑并[4,3-a]吡啶-6-甲醯胺(60 mg,0.05 mmol,1當量,45%)、(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(15.9 mg,0.08 mmol,1.5當量)、Cs 2CO 3(67.24 mg,0.208 mmol,4當量)及Pd-PEPPSI-IHeptCl 3-氯吡啶(10.0 mg,0.01 mmol,0.2當量)於1,4-二噁烷(2 mL) 中之混合物在100℃下攪拌6 h。所得混合物用水(20 mL)稀釋且用DCM (3*20 mL)萃取。合併的有機層經無水Na 2SO 4乾燥。過濾之後,將濾液在減壓下濃縮。殘餘物藉由製備型HPLC (管柱:XBridge Prep OBD C18管柱,30*150 mm,5μm;移動相A:水(10 mmol/L NH 4HCO 3)+0.05%NH 3 .H 2O,移動相B:ACN;流動速率:60 mL/min mL/min;梯度:在7 min內28% B至55% B;波長:254 nm/220 nm;RT1(min):7.53)純化,以得到呈灰白色固體之8-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-N-甲基-[1,2,4]三唑并[4,3-a]吡啶-6-甲醯胺(7 mg,23.61%)。LC-MS:(M+H) +實測值575.35。 1H NMR (400 MHz, DMSO-d6)8.68 (d, J= 1.4 Hz, 1H), 8.58-8.51 (m, 1H), 8.47 (s, 1H), 7.82 (d, J= 6.9 Hz, 1H), 7.19 (s, 1H), 7.14 (d, J= 1.4 Hz, 1H), 7.06 (t, J= 6.3 Hz, 1H), 6.74 (t, J= 7.2 Hz, 1H), 6.13 (d, J= 7.7 Hz, 1H), 5.81 (d, J= 8.3 Hz, 1H), 4.81 (d, J= 49.4 Hz, 1H), 4.44 (d, J= 6.3 Hz, 2H), 3.58 (d, J= 30.5 Hz, 1H), 3.02 (t, J= 11.1 Hz, 1H), 2.81 (d, J= 4.5 Hz, 4H), 2.18 (s, 4H), 2.13-1.91 (m, 2H), 1.67 (d, J= 11.8 Hz, 1H)。 實例491. 4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-N-[(2R*)-2-羥基(2- 2H)丙基]-3-甲氧基苯甲醯胺之合成 Step 6: A mixture of 8-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}prop-2-yn-1-yl)amino]-N-methyl-[1,2,4]triazolo[ 4,3 -a]pyridine-6-carboxamide (60 mg, 0.05 mmol, 1 eq, 45%), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (15.9 mg, 0.08 mmol, 1.5 eq), Cs2CO3 (67.24 mg, 0.208 mmol, 4 eq) and Pd-PEPPSI-IHeptCl 3-chloropyridine (10.0 mg, 0.01 mmol, 0.2 eq) in 1,4-dioxane (2 mL) was stirred at 100 °C for 6 h. The resulting mixture was diluted with water (20 mL) and extracted with DCM (3*20 mL). The combined organic layers were dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH 4 HCO 3 )+0.05% NH 3 . H 2 O, mobile phase B: ACN; flow rate: 60 mL/min mL/min; gradient: 28% B to 55% B in 7 min; wavelength: 254 nm/220 nm; RT1 (min): 7.53) to give 8-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-methyl-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide (7 mg, 23.61%) as an off-white solid. LC-MS: (M+H) + found 575.35. 1 H NMR (400 MHz, DMSO-d6)8.68 (d, J = 1.4 Hz, 1H), 8.58-8.51 (m, 1H), 8.47 (s, 1H), 7.82 (d, J = 6.9 Hz, 1H), 7.19 (s, 1H), 7.14 (d, J = 1.4 Hz, 1H), 7.06 (t, J = 6.3 Hz, 1H), 6.74 (t, J = 7.2 Hz, 1H), 6.13 (d, J = 7.7 Hz, 1H), 5.81 (d, J = 8.3 Hz, 1H), 4.81 (d, J = 49.4 Hz, 1H), 4.44 (d, J = 6.3 Hz, 3.58 (d, J = 30.5 Hz, 1H), 3.02 (t, J = 11.1 Hz, 1H), 2.81 (d, J = 4.5 Hz, 4H), 2.18 (s, 4H), 2.13-1.91 (m, 2H), 1.67 (d, J = 11.8 Hz, 1H). Example 491. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-[(2R*)-2-hydroxy(2- 2 H)propyl]-3-methoxybenzamide
步驟1. 在0℃及空氣氛圍下,向3-甲氧基-4-硝基苯甲酸(1.00 g,5.07 mmol,1.00當量)於DMF (10.00 mL)中之攪拌溶液中逐份添加α-胺基丙酮鹽酸鹽(666.82 mg,6.09 mmol,1.20當量)、DIEA (3.27 g,25.36 mmol,5.00當量)及HATU (2.89 g,7.61 mmol,1.50當量)。將混合物在室溫下攪拌1 h。所得溶液使用具有以下條件(移動相A:水,移動相B:ACN;流動速率:80 mL/min;梯度:在20 min內0% B至40% B;254/220 nm)之C18急速層析純化。此產生呈黃色油狀物之3-甲氧基-4-硝基-N-(2-側氧基丙基)苯甲醯胺(750.00 mg,58.62%)。LC-MS:(M-H) -實測值251.0。 Step 1. To a stirred solution of 3-methoxy-4-nitrobenzoic acid (1.00 g, 5.07 mmol, 1.00 equiv) in DMF (10.00 mL) were added α-aminoacetone hydrochloride (666.82 mg, 6.09 mmol, 1.20 equiv), DIEA (3.27 g, 25.36 mmol, 5.00 equiv) and HATU (2.89 g, 7.61 mmol, 1.50 equiv) portionwise at 0°C under air atmosphere. The mixture was stirred at room temperature for 1 h. The resulting solution was purified using C18 flash chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 80 mL/min; gradient: 0% B to 40% B in 20 min; 254/220 nm). This resulted in 3-methoxy-4-nitro-N-(2-oxopropyl)benzamide (750.00 mg, 58.62%) as a yellow oil. LC-MS: (MH) - found 251.0.
步驟2:在0℃及空氣氛圍下,向3-甲氧基-4-硝基-N-(2-側氧基丙基)苯甲醯胺(740.00 mg,2.93 mmol,1.00當量)於MeOH (8.00 mL)中之攪拌溶液中逐份添加硼氘化鈉(sodium borodeuteride) (245.61 mg,5.87 mmol,2.00當量)。將混合物在室溫下攪拌1 h。在0℃下用水(2.00 mL)淬滅反應。所得混合物使用具有以下條件(移動相A:水,移動相B:ACN;流動速率:80 mL/min;梯度:在20 min內0% B至30% B;254/220 nm)之C18急速層析純化。此產生呈黃色油狀物之N-[2-羥基(2- 2H)丙基]-3-甲氧基-4-硝基苯甲醯胺(560.00 mg,74.78%)。LC-MS:(M+H) +實測值256.1。 Step 2: To a stirred solution of 3-methoxy-4-nitro-N-(2-oxopropyl)benzamide (740.00 mg, 2.93 mmol, 1.00 equiv) in MeOH (8.00 mL) was added portionwise sodium borodeuteride (245.61 mg, 5.87 mmol, 2.00 equiv) at 0 °C under air atmosphere. The mixture was stirred at room temperature for 1 h. The reaction was quenched with water (2.00 mL) at 0 °C. The resulting mixture was purified using C18 flash chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 80 mL/min; gradient: 0% B to 30% B in 20 min; 254/220 nm). This resulted in N-[2-hydroxy(2- 2 H)propyl]-3-methoxy-4-nitrobenzamide (560.00 mg, 74.78%) as a yellow oil. LC-MS: (M+H) + found 256.1.
步驟3:在氮氣氛圍下,向N-[2-羥基(2- 2H)丙基]-3-甲氧基-4-硝基苯甲醯胺(560.00 mg,2.19 mmol,1.00當量)於i-PrOH (6.00 mL)中之攪拌溶液中添加Pd/C (100.00 mg)。將混合物在室溫及氫氣氛圍下攪拌隔夜。過濾所得混合物且濾餅用i-PrOH (3x2.00 mL)洗滌。將濾液在減壓下濃縮。此產生呈灰色油狀物之4-胺基-N-[2-羥基(2- 2H)丙基]-3-甲氧基苯甲醯胺(440.00 mg,89.03%)。LC-MS:(M+H) +實測值226.1。 Step 3: To a stirred solution of N-[2-hydroxy( 2-2H )propyl]-3-methoxy-4-nitrobenzamide (560.00 mg, 2.19 mmol, 1.00 equiv) in i-PrOH (6.00 mL) under nitrogen atmosphere was added Pd/C (100.00 mg). The mixture was stirred overnight at room temperature under hydrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with i-PrOH (3x2.00 mL). The filtrate was concentrated under reduced pressure. This gave 4-amino-N-[2-hydroxy( 2-2H )propyl]-3-methoxybenzamide (440.00 mg, 89.03%) as a grey oil. LC-MS: (M+H) + found 226.1.
步驟4:在室溫下,向4-胺基-N-[2-羥基(2- 2H)丙基]-3-甲氧基苯甲醯胺(200.00 mg,0.89 mmol,1.00當量)及8-溴-2-(3-溴丙-1-炔-1-基)-3-[(三氟甲基)硫基]吲嗪(293.38 mg,0.71 mmol,0.80當量)於DMF (2.00 mL)中之攪拌混合物中添加K 2CO 3(368.11 mg,2.66 mmol,3.00當量)。將混合物在70℃下攪拌1 h。所得溶液使用具有以下條件(移動相A:水,移動相B:ACN;流動速率:80 mL/min;梯度:在20 min內0% B至75% B;254/220 nm)之C18急速層析純化。此產生呈白色固體之4-[(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)胺基]-N-[2-羥基(2- 2H)丙基]-3-甲氧基苯甲醯胺(245.00 mg,49.51%)。LC-MS:(M+H) +實測值557.0。 Step 4: To a stirred mixture of 4-amino-N-[2-hydroxy(2- 2 H)propyl]-3-methoxybenzamide (200.00 mg, 0.89 mmol, 1.00 equiv) and 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-[(trifluoromethyl)thio]indolizine (293.38 mg, 0.71 mmol, 0.80 equiv) in DMF (2.00 mL) was added K 2 CO 3 (368.11 mg, 2.66 mmol, 3.00 equiv) at room temperature. The mixture was stirred at 70 °C for 1 h. The resulting solution was purified using C18 flash chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 80 mL/min; gradient: 0% B to 75% B in 20 min; 254/220 nm). This produced 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-N-[2-hydroxy(2- 2 H)propyl]-3-methoxybenzamide (245.00 mg, 49.51%) as a white solid. LC-MS: (M+H) + found 557.0.
步驟5:在室溫下,向4-[(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)胺基]-N-[2-羥基(2- 2H)丙基]-3-甲氧基苯甲醯胺(240.00 mg,0.43 mmol,1.00當量)及(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(114.80 mg,0.56 mmol,1.30當量)於1,4-二噁烷(3.00 mL)中之攪拌混合物中添加BINAP (26.81 mg,0.04 mmol,0.10當量)、BINAP-Pd-G3 (42.73 mg,0.04 mmol,0.10當量)及Cs 2CO 3(841.73 mg,2.59 mmol,6.00當量)。將混合物在100℃及氮氣氛圍下攪拌3 h。移除溶劑之後,殘餘物使用具有以下條件(移動相A:水(0.1% FA),移動相B:ACN;流動速率:80 mL/min;梯度:在20 min內0% B至25% B;254/220 nm)之C18急速層析純化。粗產物藉由具有以下條件(管柱:Lux3umCellulose2;移動相A:Hex (0.2% DEA):EtOH=80:20;流動速率:1 mL/min;梯度:等度;注入體積:1 mL)之製備型-掌性HPLC純化,以得到呈白色固體之4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-N-[(2R*)-2-羥基(2- 2H)丙基]-3-甲氧基苯甲醯胺(35.6 mg,13.50%)。LC-MS:(M+H) +實測值609.2。 1H NMR (400 MHz, DMSO- d 6) δ 8.11 (t, J= 5.9 Hz, 1H), 7.85 (d, J= 6.9 Hz, 1H), 7.45 (d, J= 8.3 Hz, 1H), 7.37 (d, J= 1.7 Hz, 1H), 7.19 (s, 1H), 6.80-6.71 (m, 2H), 6.14 (d, J= 7.6 Hz, 1H), 5.97 (t, J= 6.2 Hz, 1H), 5.86 (d, J= 8.2 Hz, 1H), 4.83 (d, J= 49.4 Hz, 1H), 4.72 (s, 1H), 4.28 (d, J= 6.2 Hz, 2H), 3.85 (s, 3H), 3.60 (d, J= 29.6 Hz, 1H), 3.23-3.12 (m, 2H), 3.05 (s, 1H), 2.83 (d, J= 10.9 Hz, 1H), 2.36-2.19 (m, 4H), 2.18-2.05 (m, 1H), 1.99 (d, J= 12.5 Hz, 1H), 1.68 (d, J= 12.4 Hz, 1H), 1.04 (s, 3H)。 實例487. 4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-N-[(2R*)-2-羥基(2-2H)丙基]-3-甲氧基苯甲醯胺之合成 Step 5: To a stirred mixture of 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-N-[2-hydroxy(2- 2 H)propyl]-3-methoxybenzamide (240.00 mg, 0.43 mmol, 1.00 equiv) and (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (114.80 mg, 0.56 mmol, 1.30 equiv) in 1,4-dioxane (3.00 mL) at room temperature were added BINAP (26.81 mg, 0.04 mmol, 0.10 equiv), BINAP-Pd-G3 (42.73 mg, 0.04 mmol, 0.10 equiv) and Cs2 CO 3 (841.73 mg, 2.59 mmol, 6.00 equiv). The mixture was stirred at 100 °C under nitrogen atmosphere for 3 h. After removing the solvent, the residue was purified by C18 flash chromatography with the following conditions (mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 80 mL/min; gradient: 0% B to 25% B in 20 min; 254/220 nm). The crude product was purified by preparative-chiral HPLC with the following conditions (column: Lux3um Cellulose2; mobile phase A: Hex (0.2% DEA): EtOH = 80:20; flow rate: 1 mL/min; gradient: isocratic; injection volume: 1 mL) to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-[(2R*)-2-hydroxy(2- 2 H)propyl]-3-methoxybenzamide (35.6 mg, 13.50%) as a white solid. LC-MS: (M+H) + found 609.2. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.11 (t, J = 5.9 Hz, 1H), 7.85 (d, J = 6.9 Hz, 1H), 7.45 (d, J = 8.3 Hz, 1H), 7.37 (d, J = 1.7 Hz, 1H), 7.19 (s, 1H), 6.80-6.71 (m, 2H), 6.14 (d, J = 7.6 Hz, 1H), 5.97 (t, J = 6.2 Hz, 1H), 5.86 (d, J = 8.2 Hz, 1H), 4.83 (d, J = 49.4 Hz, 1H), 4.72 (s, 1H), 4.28 (d, J = 3.85 (s, 3H), 3.60 (d, J = 29.6 Hz, 1H), 3.23-3.12 (m, 2H), 3.05 (s, 1H), 2.83 (d, J = 10.9 Hz, 1H), 2.36-2.19 (m, 4H), 2.18-2.05 (m, 1H), 1.99 (d, J = 12.5 Hz, 1H), 1.68 (d, J = 12.4 Hz, 1H), 1.04 (s, 3H). Example 487. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-[(2R*)-2-hydroxy(2-2H)propyl]-3-methoxybenzamide
步驟1. 在室溫下,向4-[(3-{8-溴-3-[(三氟甲基)硫基]吲嗪-2-基}丙-2-炔-1-基)胺基]-N-[2-羥基(2-2H)丙基]-3-甲氧基苯甲醯胺(240.00 mg,0.43 mmol,1.00當量)及(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(114.80 mg,0.56 mmol,1.30當量)於1,4-二噁烷(3.00 mL)中之攪拌混合物中添加BINAP (26.81 mg,0.04 mmol,0.10當量)、BINAP-Pd-G3 (42.73 mg,0.04 mmol,0.10當量)及Cs 2CO 3(841.73 mg,2.59 mmol,6.00當量)。將反應混合物在100℃及氮氣氛圍下攪拌3 h。移除溶劑之後,殘餘物使用具有以下條件(移動相A:水,移動相B:ACN;流動速率:80 mL/min;梯度:在20 min內0% B至25% B;254/220 nm)之C18急速層析純化。粗產物藉由具有以下條件(管柱:Lux3umCellulose2;移動相A:Hex (0.2% DEA):EtOH=80:20;流動速率:1 mL/min;梯度:等度;注入體積:3 mL)之製備型-掌性HPLC純化,以得到呈白色固體之4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吲嗪-2-基)丙-2-炔-1-基]胺基}-N-[(2R*)-2-羥基(2-2H)丙基]-3-甲氧基苯甲醯胺(39.8 mg,15.05%)。LC-MS:(M+H) +實測值609.2。 1H NMR (400 MHz, DMSO- d 6) δ 8.11 (t, J= 5.8 Hz, 1H), 7.85 (d, J= 6.8 Hz, 1H), 7.45 (dd, J= 8.3, 1.8 Hz, 1H), 7.36 (d, J= 1.8 Hz, 1H), 7.19 (d, J= 0.8 Hz, 1H), 6.80-6.71 (m, 2H), 6.14 (d, J= 7.6 Hz, 1H), 5.97 (t, J= 6.2 Hz, 1H), 5.87 (d, J= 8.2 Hz, 1H), 4.84 (d, J= 49.0 Hz, 1H), 4.72 (s, 1H), 4.28 (d, J= 6.2 Hz, 2H), 3.85 (s, 3H), 3.61 (d, J= 29.1 Hz, 1H), 3.23-3.12 (m, 2H), 3.08 (s, 1H), 2.85 (s, 1H), 2.40-2.10 (m, 5H), 2.00 (d, J= 11.6 Hz, 1H), 1.70 (d, J= 12.3 Hz, 1H), 1.04 (s, 3H)。 實例476. 4-((3-(8-(((3S,4R)-3-氟-1-(甲基-d3)哌啶-4-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺之合成 Step 1. To a stirred mixture of 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]indolizin-2-yl}prop-2-yn-1-yl)amino]-N-[2-hydroxy(2-2H)propyl]-3-methoxybenzamide (240.00 mg, 0.43 mmol, 1.00 equiv) and (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (114.80 mg, 0.56 mmol, 1.30 equiv) in 1,4-dioxane (3.00 mL) was added BINAP (26.81 mg, 0.04 mmol, 0.10 equiv), BINAP-Pd-G3 (42.73 mg, 0.04 mmol, 0.10 equiv) and Cs2CO at room temperature. 3 (841.73 mg, 2.59 mmol, 6.00 equiv). The reaction mixture was stirred at 100 °C under nitrogen atmosphere for 3 h. After removing the solvent, the residue was purified by C18 flash chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 80 mL/min; gradient: 0% B to 25% B in 20 min; 254/220 nm). The crude product was purified by preparative-chiral HPLC with the following conditions (column: Lux3um Cellulose2; mobile phase A: Hex (0.2% DEA): EtOH = 80:20; flow rate: 1 mL/min; gradient: isocratic; injection volume: 3 mL) to give 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]indolizin-2-yl)prop-2-yn-1-yl]amino}-N-[(2R*)-2-hydroxy(2-2H)propyl]-3-methoxybenzamide (39.8 mg, 15.05%) as a white solid. LC-MS: (M+H) + found 609.2. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.11 (t, J = 5.8 Hz, 1H), 7.85 (d, J = 6.8 Hz, 1H), 7.45 (dd, J = 8.3, 1.8 Hz, 1H), 7.36 (d, J = 1.8 Hz, 1H), 7.19 (d, J = 0.8 Hz, 1H), 6.80-6.71 (m, 2H), 6.14 (d, J = 7.6 Hz, 1H), 5.97 (t, J = 6.2 Hz, 1H), 5.87 (d, J = 8.2 Hz, 1H), 4.84 (d, J = 49.0 Hz, 1H), 4.72 (s, 3H), 4.28 (d, J = 6.2 Hz, 2H), 3.85 (s, 3H), 3.61 (d, J = 29.1 Hz, 1H), 3.23-3.12 (m, 2H), 3.08 (s, 1H), 2.85 (s, 1H), 2.40-2.10 (m, 5H), 2.00 (d, J = 11.6 Hz, 1H), 1.70 (d, J = 12.3 Hz, 1H), 1.04 (s, 3H). Example 476. Synthesis of 4-((3-(8-(((3S,4R)-3-fluoro-1-(methyl-d3)piperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide
步驟1. 向8-溴咪唑并[1,2-a]吡啶-2-甲酸乙酯(200 g,743.23 mmol,1 當量)及氨;硫氰酸(113.15 g,1.49 mol,113.15 mL,2 當量)於MeOH (2000 mL)中之溶液中添加NCS (200.00 g,1.50 mol,2.02 當量)。將混合物在20℃下攪拌2小時。(5批) LCMS顯示反應物1被消耗且給出所需質量(M+1 = 327 Rt = 0.483 min)。將反應混合物在真空下濃縮,添加DCM (3 L)。將所得混合物攪拌30 min且過濾,濾餅用DCM (1 L)洗滌,收集濾液,濾液用10% NH 4Cl (4L)洗滌,有機相用矽膠過濾,並且濾液用10% NH 4Cl (4L)洗滌,經Na 2SO 4乾燥且過濾。殘餘物與MTBE (1 L)一起在25℃下濕磨1小時且過濾以得到黃色固體。獲得呈黃色固體之8-溴-3-氰硫基咪唑并[1,2-a]吡啶-2-甲酸乙酯(900 g,2.76 mol,74.25%產率)。 1H NMR (400 MHz, DMSO-d 6) δ = 8.82 - 8.66 (m, 1H), 8.08 -7.92 (m, 1H), 7.25 (t, J = 7.2 Hz, 1H), 4.52 - 4.33 (m, 2H), 1.40 (t, J = 7.2 Hz, 3H)。 Step 1. To a solution of ethyl 8-bromoimidazo[1,2-a]pyridine-2-carboxylate (200 g, 743.23 mmol, 1 eq ) and ammonia; thiocyanic acid (113.15 g, 1.49 mol, 113.15 mL, 2 eq ) in MeOH (2000 mL) was added NCS (200.00 g, 1.50 mol, 2.02 eq ). The mixture was stirred at 20 °C for 2 h. (5 batches) LCMS showed reactant 1 was consumed and the desired mass was given (M+1 = 327 Rt = 0.483 min). The reaction mixture was concentrated under vacuum and DCM (3 L) was added. The resulting mixture was stirred for 30 min and filtered, the filter cake was washed with DCM (1 L), the filtrate was collected, the filtrate was washed with 10% NH 4 Cl (4 L), the organic phase was filtered with silica gel, and the filtrate was washed with 10% NH 4 Cl (4 L), dried over Na 2 SO 4 and filtered. The residue was wet triturated with MTBE (1 L) at 25° C. for 1 hour and filtered to give a yellow solid. Ethyl 8-bromo-3-thiocyanatoimidazo[1,2-a]pyridine-2-carboxylate (900 g, 2.76 mol, 74.25% yield) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ = 8.82 - 8.66 (m, 1H), 8.08 -7.92 (m, 1H), 7.25 (t, J = 7.2 Hz, 1H), 4.52 - 4.33 (m, 2H), 1.40 (t, J = 7.2 Hz, 3H).
步驟2:向8-溴-3-氰硫基咪唑并[1,2-a]吡啶-2-甲酸乙酯(225 g,689.83 mmol,1 當量)基Cs 2CO 3(337.50 g,1.04 mol,1.5 當量)於ACN (1500 mL)及DMF (500 mL)中之溶液中添加TMSCF 3(117.71 g,827.79 mmol,1.2 當量)。將混合物在20℃下攪拌2小時。(4批) LCMS顯示8-溴-3-氰硫基咪唑并[1,2-a]吡啶-2-甲酸乙酯被消耗且給出所需質量(M+1 = 371 Rt = 0.556 min)。將反應混合物在真空下濃縮,用H 2O (2000 mL)稀釋,用EA (1000 mL ×3)萃取。有機層用鹽水(3000 mL)洗滌,經Na 2SO 4乾燥且過濾。粗產物用DCM (500 mL)溶解且通過矽膠過濾。真空濃縮濾液。獲得呈黃色固體之 8-溴-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-甲酸乙酯(660 g,1.79 mol,64.79%產率)。其由HNMR確認。 1H NMR (400 MHz, DMSO-d 6) δ = 8.79 (d, J= 6.8 Hz, 1H), 8.03 - 7.98 (m, 1H), 7.23 (t, J= 7.2 Hz, 1H), 4.50 - 4.29 (m, 2H), 1.35 (t, J= 7.2 Hz, 3H)。 Step 2: To a solution of ethyl 8-bromo-3-thiocyanatoimidazo[1,2-a]pyridine-2-carboxylate (225 g, 689.83 mmol, 1 eq .) ylCs 2 CO 3 (337.50 g, 1.04 mol, 1.5 eq. ) in ACN (1500 mL) and DMF (500 mL) was added TMSCF 3 (117.71 g, 827.79 mmol, 1.2 eq. ). The mixture was stirred at 20 °C for 2 h. (4 batches) LCMS showed ethyl 8-bromo-3-thiocyanatoimidazo[1,2-a]pyridine-2-carboxylate was consumed and the desired mass was given (M+1 = 371 Rt = 0.556 min). The reaction mixture was concentrated under vacuum, diluted with H 2 O (2000 mL), extracted with EA (1000 mL × 3). The organic layer was washed with brine (3000 mL), dried over Na 2 SO 4 and filtered. The crude product was dissolved in DCM (500 mL) and filtered through silica gel. The filtrate was concentrated under vacuum. Ethyl 8-bromo-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridine-2-carboxylate (660 g, 1.79 mol, 64.79% yield) was obtained as a yellow solid. It was confirmed by HNMR. 1 H NMR (400 MHz, DMSO-d 6 ) δ = 8.79 (d, J = 6.8 Hz, 1H), 8.03 - 7.98 (m, 1H), 7.23 (t, J = 7.2 Hz, 1H), 4.50 - 4.29 (m, 2H), 1.35 (t, J = 7.2 Hz, 3H).
步驟3:向8-溴-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-甲酸乙酯(350.00 g,948.11 mmol,1 當量)於MeOH (2500 mL)中之溶液中添加於H 2O (350 mL)中之LiOH.H 2O (79.57 g,1.90 mol,2 當量)。將混合物在20℃下攪拌1小時。(2批) LCMS顯示8-溴-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-甲酸乙酯被消耗且給出所需質量(M+1 = 341 Rt = 0.452 min)。用6N HCl (350 mL)將反應混合物調整至pH = 1~2。過濾混合物且濾餅用MeOH (200 mL)洗滌。粗產物直接用於下一步驟中。獲得呈黃色固體之 8-溴-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-甲酸(520 g,1.52 mol,80.40%產率),其由HNMR確認。 1H NMR (400 MHz, DMSO-d 6) δ = 8.77 (d, J = 6.8 Hz, 1H), 7.98 (d, J = 7.2 Hz, 1H), 7.21 (t, J = 7.2 Hz, 1H)。 Step 3: To a solution of ethyl 8-bromo-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridine-2-carboxylate (350.00 g, 948.11 mmol, 1 eq ) in MeOH (2500 mL) was added LiOH.H 2 O (79.57 g, 1.90 mol, 2 eq ) in H 2 O (350 mL). The mixture was stirred at 20 °C for 1 hour. (2 batches) LCMS showed ethyl 8-bromo-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridine-2-carboxylate was consumed and the desired mass was given (M+1 = 341 Rt = 0.452 min). The reaction mixture was adjusted to pH = 1~2 with 6N HCl (350 mL). The mixture was filtered and the filter cake was washed with MeOH (200 mL). The crude product was used directly in the next step. 8-Bromo-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridine-2-carboxylic acid (520 g, 1.52 mol, 80.40% yield) was obtained as a yellow solid, which was confirmed by HNMR. 1 H NMR (400 MHz, DMSO-d 6 ) δ = 8.77 (d, J = 6.8 Hz, 1H), 7.98 (d, J = 7.2 Hz, 1H), 7.21 (t, J = 7.2 Hz, 1H).
步驟4:向8-溴-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-甲酸(100 g,293.17 mmol,1 當量)及磷酸三鉀(130.00 g,612.44 mmol,2.09 當量)於DMF (1500 mL)中之溶液中添加I 2(450 g,1.77 mol,357.14 mL,6.05 當量)。將混合物在140℃下攪拌8小時。(4批) LCMS顯示8-溴-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-甲酸被消耗且給出所需質量(M+1 = 423 Rt = 0.591 min)。將反應混合物冷卻至20℃,然後倒入10%亞硫酸鈉溶液(6 L)中,攪拌0.5小時且過濾。收集濾餅且用EA (2000 mL)稀釋。有機層用飽和NaHCO 3(2000 mL)洗滌,然後用鹽水(2000 mL)洗滌。有機層用Na 2SO 4乾燥並且過濾且濃縮。將殘餘物與MTBE:PE = 1:1 (100 mL)一起在20℃下濕磨1小時且過濾以得到灰白色固體。獲得呈灰白色固體之 8-溴-2-碘-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶(370 g,813.49 mmol,69.37%產率,93%純度),其由HNMR、FNMR HPLC及LCMS確認。MS (ESI):422.8 (M+H) +。 1H NMR (400 MHz, DMSO-d6) δ = 8.71 (d, J = 6.8 Hz, 1H), 7.93 - 7.82 (m, 1H), 7.12 (t, J = 7.2 Hz, 1H)。 Step 4: To a solution of 8-bromo-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridine-2-carboxylic acid (100 g, 293.17 mmol, 1 eq ) and tripotassium phosphate (130.00 g, 612.44 mmol, 2.09 eq ) in DMF (1500 mL) was added I2 (450 g, 1.77 mol, 357.14 mL, 6.05 eq ). The mixture was stirred at 140 °C for 8 h. (4 batches) LCMS showed 8-bromo-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridine-2-carboxylic acid was consumed and the desired mass was given (M+1 = 423 Rt = 0.591 min). The reaction mixture was cooled to 20°C, then poured into 10% sodium sulfite solution (6 L), stirred for 0.5 hours and filtered. The filter cake was collected and diluted with EA (2000 mL). The organic layer was washed with saturated NaHCO 3 (2000 mL) and then with brine (2000 mL). The organic layer was dried over Na 2 SO 4 and filtered and concentrated. The residue was wet triturated with MTBE:PE = 1:1 (100 mL) at 20°C for 1 hour and filtered to obtain an off-white solid. 8-Bromo-2-iodo-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridine (370 g, 813.49 mmol, 69.37% yield, 93% purity) was obtained as an off-white solid, which was confirmed by HNMR, FNMR HPLC and LCMS. MS (ESI): 422.8 (M+H) +. 1 H NMR (400 MHz, DMSO-d6) δ = 8.71 (d, J = 6.8 Hz, 1H), 7.93 - 7.82 (m, 1H), 7.12 (t, J = 7.2 Hz, 1H).
步驟5:向3-甲氧基-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺(28.0 g,128 mmol,1.00當量)及8-溴-2-碘-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶(54.3 g,128 mmol,1.00當量)於DMSO (250 mL)中之溶液中添加CuI (2.44 g,12.8 mmol,0.10當量)、DIPA (38.9 g,385 mmol,54.4 mL,3.00當量)及Pd(PPh3)4 (1.48 g,1.28 mmol,0.01當量),將混合物除氣且用N2吹掃3次,攪拌幾分鐘後溫度升至40℃,在環境溫度(25℃)及N2下攪拌16h,觀測到深棕色澄清溶液。LCMS顯示偵測到87%的所需質量。向攪拌的水(1.0 L)中倒入反應溶液,形成大量灰色沉澱,藉由過濾收集固體且用水(300 mL × 3)洗滌。將粗產物與MTBE (1.0 L)一起濕磨,濾餅用MTBE (300 mL)洗滌,然後在真空下乾燥以得到65 g灰色粉末,所得固體用MeCN/水(v/v=1:6,600 mL)稀釋且凍乾。TLC (EA)顯示觀測到三個斑點。殘餘物藉由HNMR矽膠層析(ISCO®;80 g SepaFlash®二氧化矽急速管柱,20~100%乙酸乙酯/石油醚之溶析液,在80 mL/min下7~15% MeOH/DCM梯度)純化。獲得呈灰色固體之4-((3-(8-溴-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺(47.2 g,91.95 mmol,71.67%產率),其由HNMR確定。MS (ESI):513.0 (M+H) +。 1H NMR (400 MHz, DMSO-d6) δ = 8.64 (d, J = 6.8 Hz, 1H),8.10 (br d, J = 4.4 Hz, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.44 -7.38 (m, 1H), 7.34 (d, J = 1.6 Hz, 1H), 7.13 (t, J = 7.2 Hz,1H), 6.76 (d, J = 8.4 Hz, 1H), 6.02 (t, J = 6.4 Hz, 1H), 4.34 (d,J = 6.4 Hz, 2H), 3.84 (s, 3H), 3.33 (s, 4H), 2.75 (d, J = 4.4 Hz,3H), 2.54 (s, 2H)。 Step 5: To a solution of 3-methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (28.0 g, 128 mmol, 1.00 equiv) and 8-bromo-2-iodo-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridine (54.3 g, 128 mmol, 1.00 equiv) in DMSO (250 mL) were added CuI (2.44 g, 12.8 mmol, 0.10 equiv), DIPA (38.9 g, 385 mmol, 54.4 mL, 3.00 equiv) and Pd(PPh3)4 (1.48 g, 1.28 mmol, 0.01 eq.), the mixture was degassed and purged with N2 three times, stirred for a few minutes and then the temperature was raised to 40°C. After stirring at ambient temperature (25°C) and under N2 for 16 h, a dark brown clear solution was observed. LCMS showed that 87% of the desired mass was detected. The reaction solution was poured into stirred water (1.0 L), and a large amount of gray precipitate was formed. The solid was collected by filtration and washed with water (300 mL × 3). The crude product was wet-triturated with MTBE (1.0 L), the filter cake was washed with MTBE (300 mL), and then dried under vacuum to obtain 65 g of gray powder. The resulting solid was diluted with MeCN/water (v/v=1:6, 600 mL) and freeze-dried. TLC (EA) showed three spots observed. The residue was purified by HNMR silica gel chromatography (ISCO®; 80 g SepaFlash® silica flash column, 20-100% ethyl acetate/petroleum ether eluent, 7-15% MeOH/DCM gradient at 80 mL/min). 4-((3-(8-bromo-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide (47.2 g, 91.95 mmol, 71.67% yield) was obtained as a gray solid, which was confirmed by HNMR. MS (ESI): 513.0 (M+H) +. 1 H NMR (400 MHz, DMSO-d6) δ = 8.64 (d, J = 6.8 Hz, 1H),8.10 (br d, J = 4.4 Hz, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.44 -7.38 (m, 1H), 7.34 (d, J = 1.6 Hz, 1H), 7.13 (t, J = 7.2 Hz,1H), 6.76 (d, J = 8.4 Hz, 1H), 6.02 (t, J = 6.4 Hz, 1H), 4.34 (d,J = 6.4 Hz, 2H), 3.84 (s, 3H), 3.33 (s, 4H), 2.75 (d, J = 4.4 Hz,3H), 2.54 (s, 2H).
步驟6:向4-((3-(8-溴-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺(9.20 g,17.9 mmol,1.00當量)及(3S,4R)-4-胺基-3-氟哌啶-1-甲酸三級丁酯(4.69 g,21.5 mmol,1.20當量)於二噁烷(180 mL)中之懸浮液中添加Cs 2CO 3(11.7 g,35.8 mmol,2.0當量)、BINAP (1.12 g,1.79 mmol,0.1當量)及rac-BINAP-Pd-G 3(889 mg,896 μmol,0.05當量),將所得混合物除氣且用N2吹掃3次,然後在100℃及N2下攪拌16h,觀測到深棕色懸浮液。LCMS顯示大部分反應物被消耗且偵測到具有所需質量之主峰。合併四批,用水(1 L)稀釋且用EA (500 mL × 3)萃取,有機層用鹽水(400 mL × 3)洗滌且經Na2SO4乾燥,在真空下濃縮。TLC顯示觀測到四個斑點(Rf=0.7、0.5、0.55、0.15)。殘餘物藉由急速矽膠層析(ISCO®;120 g × 2 SepaFlash®二氧化矽急速管柱,在90 mL/min下0~ 85%乙酸乙酯/石油醚梯度之溶析液)純化,在真空下濃縮溶析液(Rf=0.5)。獲得呈黃色固體之(3S,4R)-3-氟-4-((2-(3-((2-甲氧基-4-(甲基胺甲醯基)苯基)胺基)丙-1-炔-1-基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-8-基)胺基)哌啶-1-甲酸三級丁酯(25 g,29.78 mmol,41.54%產率,77.50%純度) (Rf=0.5),其藉由LCMS確定。MS (ESI):651.4 (M+H) +。 Step 6: To a suspension of 4-((3-(8-bromo-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide (9.20 g, 17.9 mmol, 1.00 equiv) and (3S,4R)-4-amino- 3 -fluoropiperidine-1-carboxylic acid tributyl ester (4.69 g, 21.5 mmol, 1.20 equiv) in dioxane (180 mL) was added Cs2CO3 (11.7 g, 35.8 mmol, 2.0 equiv), BINAP (1.12 g, 1.79 mmol, 0.1 equiv) and rac-BINAP-Pd- G3 (889 mg, 896 μmol, 0.05 eq.), the resulting mixture was degassed and purged with N2 three times, then stirred at 100°C and N2 for 16 h, a dark brown suspension was observed. LCMS showed that most of the reactants were consumed and a main peak with the desired mass was detected. Four batches were combined, diluted with water (1 L) and extracted with EA (500 mL × 3), the organic layer was washed with brine (400 mL × 3) and dried over Na2SO4, and concentrated under vacuum. TLC showed that four spots were observed (Rf = 0.7, 0.5, 0.55, 0.15). The residue was purified by flash silica gel chromatography (ISCO®; 120 g × 2 SepaFlash® silica flash column, 0-85% ethyl acetate/petroleum ether gradient at 90 mL/min), and the eluate was concentrated under vacuum (Rf = 0.5). (3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4-(methylaminoformyl)phenyl)amino)prop-1-yn-1-yl)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-8-yl)amino)piperidine-1-carboxylic acid tributyl ester (25 g, 29.78 mmol, 41.54% yield, 77.50% purity) was obtained as a yellow solid (Rf=0.5), which was determined by LCMS. MS (ESI): 651.4 (M+H) +.
步驟7:向(3S,4R)-3-氟-4-((2-(3-((2-甲氧基-4-(甲基胺甲醯基)苯基)胺基)丙-1-炔-1-基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-8-基)胺基)哌啶-1-甲酸三級丁酯(25 g,29.58 mmol,1當量)於MeOH (200 mL)中之溶液中添加HCl/MeOH (4 M, 100 mL),將混合物在25℃下攪拌1h,觀測到黃色懸浮液。TLC (EA)顯示反應物(Rf=0.5)被消耗且觀測到新的主要斑點(Rf=0.01)。將混合物在真空下濃縮。獲得呈黃色固體之4-((3-(8-(((3S,4R)-3-氟哌啶-4-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺(25.9 g,粗物質,HCl) (Rf=0.01),其藉由LCMS確定。MS (ESI):551.3 (M+H) +。Step 7: To a solution of tributyl (3S,4R)-3-fluoro-4-((2-(3-((2-methoxy-4-(methylaminocarbonyl)phenyl)amino)prop-1-yn-1-yl)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-8-yl)amino)piperidine-1-carboxylate (25 g, 29.58 mmol, 1 eq) in MeOH (200 mL) was added HCl/MeOH (4 M, 100 mL) and the mixture was stirred at 25 °C for 1 h. A yellow suspension was observed. TLC (EA) showed that the reactant (Rf=0.5) was consumed and a new major spot (Rf=0.01) was observed. The mixture was concentrated under vacuum. 4-((3-(8-(((3S,4R)-3-fluoropiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide (25.9 g, crude, HCl) was obtained as a yellow solid (Rf=0.01), which was determined by LCMS. MS (ESI): 551.3 (M+H) +.
步驟8:向4-((3-(8-(((3S,4R)-3-氟哌啶-4-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺(400 mg,726.52 μmol,1當量)於CD 3OD (5 mL)中之溶液中添加AcOK (713.02 mg,7.27 mmol,10當量)及(CD 2O) n(235.39 mg,13.08 mmol,18當量)。將混合物在25℃下攪拌1小時。然後添加NaBD 4(137.42 mg,3.63 mmol,5當量)。將混合物在25℃下攪拌0.5小時。LCMS (EW44940-43-P1A)顯示4-((3-(8-(((3S,4R)-3-氟哌啶-4-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺被消耗且給出所需質量(M+1 = 568.3 Rt = 0.457 min)。將反應混合物在減壓下濃縮以得到殘餘物。殘餘物藉由製備型HPLC (管柱:Waters Xbridge Prep OBD C18 150*40mm*10um;移動相:[水(NH4HCO3)-ACN];梯度:歷時15 min,28%-58% B)純化。獲得呈白色固體之4-((3-(8-(((3S,4R)-3-氟-1-(甲基-d3)哌啶-4-基)胺基)-3-((三氟甲基)硫代)咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基)胺基)-3-甲氧基-N-甲基苯甲醯胺(160 mg,277.60 μmol,38.21%產率,98.48%純度)。LCMS (ESI):滯留時間:0.460 min,[M+H +] =568.4。 1H NMR (400 MHz, DMSO-d 6) δ = 8.10 (d, J = 4.8 Hz, 1H), 7.86 (d, J = 6.4 Hz, 1H), 7.40 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 7.34 (d, J = 2.4 Hz, 1H), 7.01 (t, J = 7.2 Hz, 1H), 6.74 (d, J = 8.4 Hz, 1H), 6.61 (d, J = 7.8 Hz, 1H), 6.00 (t, J = 6.0 Hz, 1H), 5.59 (d, J = 9.2 Hz, 1H), 4.82 (d, J = 49.6, 1H), 4.31 (d, J = 6.4 Hz, 2H), 3.84 (s, 3H), 3.81 - 3.64 (m, 1H), 3.05 - 2.99 (m, 1H), 2.76 – 2.73 (m, 4H), 2.30 - 2.16 (m, 1H), 2.11 - 2.06 (m, 1H), 1.92 - 1.80 (m, 1H), 1.80 - 1.72 (m, 1H)。 實例442. 4-((3-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-((三氟甲基)硫代)吲嗪-2-基)丙-2-炔-1-基)胺基)-3-(甲氧基-d 3)-N-甲基苯甲醯胺之合成 Step 8: To a solution of 4-((3-(8-(((3S,4R)-3-fluoropiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide (400 mg, 726.52 μmol, 1 eq) in CD3OD (5 mL) was added AcOK (713.02 mg, 7.27 mmol, 10 eq) and ( CD2O ) n (235.39 mg, 13.08 mmol, 18 eq). The mixture was stirred at 25 °C for 1 h. Then NaBD4 (137.42 mg, 3.63 mmol, 5 eq) was added. The mixture was stirred at 25 °C for 0.5 h. LCMS (EW44940-43-P1A) showed 4-((3-(8-(((3S,4R)-3-fluoropiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide was consumed and gave the desired mass (M+1 = 568.3 Rt = 0.457 min). The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 28%-58% B over 15 min). 4-((3-(8-(((3S,4R)-3-fluoro-1-(methyl-d3)piperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide (160 mg, 277.60 μmol, 38.21% yield, 98.48% purity) was obtained as a white solid. LCMS (ESI): retention time: 0.460 min, [M+H + ] = 568.4. 1 H NMR (400 MHz, DMSO-d 6 ) δ = 8.10 (d, J = 4.8 Hz, 1H), 7.86 (d, J = 6.4 Hz, 1H), 7.40 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 7.34 (d, J = 2.4 Hz, 1H), 7.01 (t, J = 7.2 Hz, 1H), 6.74 (d, J = 8.4 Hz, 1H), 6.61 (d, J = 7.8 Hz, 1H), 6.00 (t, J = 6.0 Hz, 1H), 5.59 (d, J = 9.2 Hz, 1H), 4.82 (d, J = 49.6, 1H), 4.31 (d, J = 6.4 Hz, 2H), 3.84 (s, 3H), 3.81 - 3.64 (m, 1H), 3.05 - 2.99 (m, 1H), 2.76 – 2.73 (m, 4H), 2.30 - 2.16 (m, 1H), 2.11 - 2.06 (m, 1H), 1.92 - 1.80 (m, 1H), 1.80 - 1.72 (m, 1H). Example 442. Synthesis of 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-(methoxy-d 3 )-N-methylbenzamide
步驟1. 向3-氟-4-硝基苯甲酸(5 g,27.01 mmol,1 當量)於DMF (50 mL)中之溶液中添加HATU (15.41 g,40.52 mmol,1.5 當量)、DIPEA (10.47 g,81.03 mmol,14.11 mL,3 當量)及甲胺鹽酸鹽(2.19 g,32.41 mmol,1.2 當量),將反應混合物在25℃下攪拌2小時。TLC (PE/EA = 1/1)顯示反應物1 (Rf = 0)被完全消耗且形成一個新斑點(Rf = 0.5)。根據TLC,反應為乾淨的。LCMS (EW47880-16-P1A)顯示反應物被完全消耗且形成一個具有所需質量之主峰。反應混合物用100 mL H 2O稀釋且用EA (50 mL * 3)萃取。合併的有機層用飽和NaCl水溶液(50 mL * 3)洗滌,經Na 2SO 4乾燥,過濾且在減壓下濃縮以得到殘餘物。殘餘物藉由急速矽膠層析(ISCO®;80 g SepaFlash®二氧化矽急速管柱,在36 mL/min下0~50%乙酸乙酯/石油醚梯度之溶析液)純化。獲得呈黃色固體之3-氟-N-甲基-4-硝基苯甲醯胺(5 g,22.67 mmol,83.94%產率,89.85%純度)。MS (ESI):198.9 (M+H) +。 Step 1. To a solution of 3-fluoro-4-nitrobenzoic acid (5 g, 27.01 mmol, 1 eq ) in DMF (50 mL) was added HATU (15.41 g, 40.52 mmol, 1.5 eq ), DIPEA (10.47 g, 81.03 mmol, 14.11 mL, 3 eq ) and methylamine hydrochloride (2.19 g, 32.41 mmol, 1.2 eq ) and the reaction mixture was stirred at 25 °C for 2 hours. TLC (PE/EA = 1/1) showed that reactant 1 (Rf = 0) was completely consumed and a new spot (Rf = 0.5) was formed. The reaction was clean according to TLC. LCMS (EW47880-16-P1A) showed that the reactant was completely consumed and a major peak with the desired mass was formed. The reaction mixture was diluted with 100 mL H 2 O and extracted with EA (50 mL * 3). The combined organic layers were washed with saturated aqueous NaCl solution (50 mL * 3), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® silica flash column, 0-50% ethyl acetate/petroleum ether gradient eluent at 36 mL/min). 3-Fluoro-N-methyl-4-nitrobenzamide (5 g, 22.67 mmol, 83.94% yield, 89.85% purity) was obtained as a yellow solid. MS (ESI): 198.9 (M+H) +.
步驟2:向3-氟-N-甲基-4-硝基苯甲醯胺(5 g,25.23 mmol,1 當量)於DMF (50 mL)中之溶液中添加Cs 2CO 3(24.66 g,75.70 mmol,3 當量)及CD 3OD (2.73 g,75.70 mmol,3.07 mL,3 當量),將反應混合物在25℃下攪拌2小時。LCMS顯示反應物被完全消耗且形成一個具有所需質量之主峰。反應混合物用80 mL H 2O稀釋且用EA (50 mL * 3)萃取。合併的有機層用飽和NaCl水溶液(50 mL * 3)洗滌,經Na 2SO 4乾燥,過濾且在減壓下濃縮以得到殘餘物。粗產物無需純化即用於下一步驟。獲得呈黃色固體之3-(甲氧基-d3)-N-甲基-4-硝基苯甲醯胺(5 g,23.45 mmol,92.94%產率,100%純度)。MS (ESI):214.0 (M+H) +。 Step 2: To a solution of 3-fluoro-N-methyl-4-nitrobenzamide (5 g, 25.23 mmol, 1 eq. ) in DMF (50 mL) were added Cs 2 CO 3 (24.66 g, 75.70 mmol, 3 eq .) and CD 3 OD (2.73 g, 75.70 mmol, 3.07 mL, 3 eq. ), and the reaction mixture was stirred at 25° C. for 2 hours. LCMS showed that the reactant was completely consumed and one major peak with the desired mass was formed. The reaction mixture was diluted with 80 mL of H 2 O and extracted with EA (50 mL * 3). The combined organic layers were washed with saturated aqueous NaCl solution (50 mL * 3), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to obtain a residue. The crude product was used in the next step without purification. 3-(Methoxy-d3)-N-methyl-4-nitrobenzamide (5 g, 23.45 mmol, 92.94% yield, 100% purity) was obtained as a yellow solid. MS (ESI): 214.0 (M+H) +.
步驟3:在N 2下,向3-(甲氧基-d3)-N-甲基-4-硝基苯甲醯胺(4 g,18.76 mmol,1 當量)於MeOH (40 mL)中之溶液中添加Pd/C (400 mg,10%純度)。將懸浮液在真空下除氣且用H 2吹掃三次。將混合物在H 2(15psi)及25℃下攪拌2小時。LCMS顯示反應物被完全消耗且形成一個具有所需質量之主峰。過濾反應混合物且濃縮濾液。粗產物無需純化即用於下一步驟。獲得呈白色固體之4-胺基-3-(甲氧基-d3)-N-甲基苯甲醯胺(3.2 g,16.62 mmol,88.58%產率,95.15%純度)。MS (ESI):184.0 (M+H) +。 Step 3: To a solution of 3-(methoxy-d3)-N-methyl-4-nitrobenzamide (4 g, 18.76 mmol, 1 eq ) in MeOH (40 mL) under N2 was added Pd/C (400 mg, 10% purity). The suspension was degassed under vacuum and purged with H2 three times. The mixture was stirred under H2 (15 psi) at 25 °C for 2 h. LCMS showed that the reactant was completely consumed and one major peak with the desired mass was formed. The reaction mixture was filtered and the filtrate was concentrated. The crude product was used in the next step without purification. 4-Amino-3-(methoxy-d3)-N-methylbenzamide (3.2 g, 16.62 mmol, 88.58% yield, 95.15% purity) was obtained as a white solid. MS (ESI): 184.0 (M+H) +.
步驟4:在10℃下,向3-(8-溴-3-((三氟甲基)硫代)吲嗪-2-基)丙-2-炔-1-醇(130 g,371.27 mmol,1 當量)於DCM (1500 mL)中之溶液中添加PPh 3(146.07 g,556.90 mmol,1.5 當量)及CBr 4(147.75 g,445.52 mmol,1.2 當量)。將混合物在25℃及N 2下攪拌2小時。TLC (PE: EA = 10: 1)顯示化合物1 (Rf = 0.2)被消耗且形成新斑點(Rf = 0.4)。LCMS顯示反應物被完全消耗且偵測到一個具有所需質量之主峰。將反應混合物在減壓下濃縮以移除溶劑。殘餘物藉由急速矽膠層析(ISCO®;3000 g SepaFlash®二氧化矽急速管柱,在500 mL/min下0~16%乙酸乙酯/石油醚梯度之溶析液)純化。獲得呈黃色油狀物之8-溴-2-(3-溴丙-1-炔-1-基)-3-((三氟甲基)硫代)吲嗪(160 g,356.61 mmol,96.05%產率,92.06%純度)。MS (ESI):413.9 (M+H) +。 1H NMR: 400 MHz, 氯仿-d δ = 8.37 (d, J= 7.2Hz, 1H), 7.22 - 7.18 (m, 1H), 6.87 (s, 1H), 6.66 (t, J= 7.2 Hz, 1H), 4.23 (s, 2H)。 Step 4: To a solution of 3-(8-bromo-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-ol (130 g, 371.27 mmol, 1 eq ) in DCM (1500 mL) was added PPh3 (146.07 g, 556.90 mmol, 1.5 eq ) and CBr4 (147.75 g, 445.52 mmol, 1.2 eq ) at 10 °C. The mixture was stirred at 25 °C under N2 for 2 h. TLC (PE:EA = 10:1) showed that compound 1 (Rf = 0.2) was consumed and a new spot (Rf = 0.4) was formed. LCMS showed that the reactant was completely consumed and one major peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by flash silica chromatography (ISCO®; 3000 g SepaFlash® silica flash column, 0-16% ethyl acetate/petroleum ether gradient at 500 mL/min). 8-Bromo-2-(3-bromoprop-1-yn-1-yl)-3-((trifluoromethyl)thio)indolizine (160 g, 356.61 mmol, 96.05% yield, 92.06% purity) was obtained as a yellow oil. MS (ESI): 413.9 (M+H) +. 1 H NMR: 400 MHz, CHLOROFORM-d δ = 8.37 (d, J = 7.2 Hz, 1H), 7.22 - 7.18 (m, 1H), 6.87 (s, 1H), 6.66 (t, J = 7.2 Hz, 1H), 4.23 (s, 2H).
步驟5:向8-溴-2-(3-溴丙-1-炔-1-基)-3-((三氟甲基)硫代)吲嗪(2.5 g,6.05 mmol,1 當量)及4-胺基-3-(甲氧基-d3)-N-甲基苯甲醯胺(1.33 g,7.26 mmol,1.2 當量)於DMF (30 mL)中之溶液中添加K 2CO 3(1.67 g,12.11 mmol,2 當量)及KI (1.51 g,9.08 mmol,1.5 當量)。將混合物在80℃下攪拌1小時。LCMS (EW47880-23-P1A)顯示8-溴-2-(3-溴丙-1-炔-1-基)-3-((三氟甲基)硫代)吲嗪被完全消耗,並且在LC-MS上顯示數個新峰且偵測到47.86 %之所需化合物。TLC (PE: EA = 1: 1)顯示8-bromo-2-(3-溴丙-1-炔-1-基)-3-((三氟甲基)硫代)吲嗪(Rf = 0.8)被消耗且形成新斑點(Rf = 0.2)。反應混合物用50 mL H 2O稀釋且用EA (50 mL * 3)萃取。合併的有機層用飽和NaCl水溶液(50 mL * 2)洗滌,經Na 2SO 4乾燥,過濾且在減壓下濃縮以得到殘餘物。殘餘物藉由急速矽膠層析(ISCO®;20 g SepaFlash®二氧化矽急速管柱,在36 mL/min下0~67%乙酸乙酯/石油醚梯度之溶析液)純化。獲得呈黃色固體之4-((3-(8-溴-3-((三氟甲基)硫代)吲嗪-2-基)丙-2-炔-1-基)胺基)-3-(甲氧基-d3)-N-甲基苯甲醯胺(1.7 g,3.18 mmol,52.55%產率,96.42%純度)。MS (ESI):517.0 (M+H) +。 Step 5: To a solution of 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-((trifluoromethyl)thio)indolizine (2.5 g, 6.05 mmol, 1 eq ) and 4-amino-3-(methoxy-d3)-N - methylbenzamide (1.33 g, 7.26 mmol, 1.2 eq ) in DMF (30 mL) was added K2CO3 (1.67 g, 12.11 mmol, 2 eq ) and KI (1.51 g, 9.08 mmol, 1.5 eq ). The mixture was stirred at 80 °C for 1 h. LCMS (EW47880-23-P1A) showed that 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-((trifluoromethyl)thio)indolizine was completely consumed, and several new peaks appeared on LC-MS and 47.86 % of the desired compound was detected. TLC (PE: EA = 1: 1) showed that 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-((trifluoromethyl)thio)indolizine (Rf = 0.8) was consumed and a new spot was formed (Rf = 0.2). The reaction mixture was diluted with 50 mL H 2 O and extracted with EA (50 mL * 3). The combined organic layers were washed with saturated aqueous NaCl solution (50 mL * 2), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, 0-67% ethyl acetate/petroleum ether gradient eluent at 36 mL/min). 4-((3-(8-bromo-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-(methoxy-d3)-N-methylbenzamide (1.7 g, 3.18 mmol, 52.55% yield, 96.42% purity) was obtained as a yellow solid. MS (ESI): 517.0 (M+H) +.
步驟6:向4-((3-(8-溴-3-((三氟甲基)硫代)吲嗪-2-基)丙-2-炔-1-基)胺基)-3-(甲氧基-d3)-N-甲基苯甲醯胺(600 mg,1.16 mmol,1 當量)及(3S,4R)-3-氟-1-甲基哌啶-4-胺(235.60 mg,1.40 mmol,1.2 當量,HCl)於2-甲基丁-2-醇(8 mL)中之溶液中添加Cs 2CO 3(1.90 g,5.82 mmol,5 當量)、二環己基-[3, 6-二甲氧基y-2-(2,4,6-三異丙基苯基)苯基]磷烷;甲磺酸鹽;[2-[2-甲基胺基)苯基]苯基]鈀(1+) (107.17 mg,116.42 μmol,0.1 當量)。將混合物在100℃及N 2下攪拌16 h。LC-MS (EW47880-15-P1A)顯示4-((3-(8-溴-3-((三氟甲基)硫代)吲嗪-2-基)丙-2-炔-1-基)胺基)-3-(甲氧基-d3)-N-甲基苯甲醯胺被完全消耗,在LC-MS上顯示數個新峰且偵測到57.90%之所需質量。將反應混合物在20 mL水與EA (20 mL*3)之間分配。分離有機相,用飽和NaCl水溶液(20 mL*3)洗滌,經Na 2SO 4乾燥,過濾且在減壓下濃縮以得到殘餘物。殘餘物藉由製備型HPLC (管柱:Phenomenex Luna C18 150*25 mm*10um;移動相:[水(TFA) -ACN];梯度:歷時9 min,26%-56% B)純化。獲得呈黃色固體之 4-((3-(8-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-3-((三氟甲基)硫代)吲嗪-2-基)丙-2-炔-1-基)胺基)-3-(甲氧基-d3)-N-甲基苯甲醯胺(103.86 mg,152.59 μmol,13.11%產率,98.19%純度,TFA鹽)。MS (ESI):568.1 (M+H) +。 1H NMR: 400 MHz, DMSO-d 6δ = 9.87 - 9.73 (m, 1H), 8.17 -8.08 (m, 1H), 7.91 (d, J= 6.8 Hz, 1H), 7.45 - 7.39 (m, 1H), 7.36 - 7.33 (m, 1H), 7.19 (s, 1H), 6.83 - 6.75 (m, 2H), 6.22 -6.16 (m, 1H), 6.08 (br d, J= 7.2 Hz, 1H), 5.25 - 5.07 (m, 1H), 4.28 (s, 2H), 3.97 - 3.77 (m, 2H), 3.53 - 3.50 (m, 2H), 3.22 -3.12 (m, 1H), 2.83 (br s, 3H), 2.76 (d, J= 4.4 Hz, 3H), 2.26 -2.10 (m, 1H), 2.04 - 1.91 (m, 1H)。 實例505. 4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-( 2H 3)甲氧基-N-甲基苯甲醯胺之合成 Step 6: To a solution of 4-((3-(8-bromo-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-(methoxy-d3)-N-methylbenzamide (600 mg, 1.16 mmol, 1 eq ) and (3S,4R)-3-fluoro-1-methylpiperidin-4-amine (235.60 mg, 1.40 mmol, 1.2 eq , HCl) in 2-methylbutan- 2 -ol (8 mL) was added Cs2CO3 (1.90 g, 5.82 mmol, 5 eq ), dicyclohexyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane; mesylate; [2-[2-methylamino)phenyl]phenyl]palladium(1+) (107.17 mg, 116.42 μmol, 0.1 eq .). The mixture was stirred at 100 °C and N2 for 16 h. LC-MS (EW47880-15-P1A) showed that 4-((3-(8-bromo-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-(methoxy-d3)-N-methylbenzamide was completely consumed, several new peaks were shown on LC-MS and 57.90% of the desired mass was detected. The reaction mixture was partitioned between 20 mL of water and EA (20 mL*3). The organic phase was separated, washed with saturated NaCl aqueous solution (20 mL*3), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25 mm*10um; mobile phase: [water (TFA) -ACN]; gradient: 26%-56% B over 9 min). 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-(methoxy-d3)-N-methylbenzamide (103.86 mg, 152.59 μmol, 13.11% yield, 98.19% purity, TFA salt) was obtained as a yellow solid. MS (ESI): 568.1 (M+H) +. 1 H NMR: 400 MHz, DMSO-d 6 δ = 9.87 - 9.73 (m, 1H), 8.17 -8.08 (m, 1H), 7.91 (d, J = 6.8 Hz, 1H), 7.45 - 7.39 (m, 1H), 7.36 - 7.33 (m, 1H), 7.19 (s, 1H), 6.83 - 6.75 (m, 2H), 6.22 -6.16 (m, 1H), 6.08 (br d, J = 7.2 Hz, 1H), 5.25 - 5.07 (m, 1H), 4.28 (s, 2H), 3.97 - 3.77 (m, 2H), 3.53 - 3.5 (m, 2H), 3.22 -3.12 (m, 1H), 2.83 (br s, 3H), 2.76 (d, J = 4.4 Hz, 3H), 2.26 -2.10 (m, 1H), 2.04 - 1.91 (m, 1H). Example 505. Synthesis of 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-( 2 H 3 )methoxy-N-methylbenzamide
步驟1. 將3-氟-4-硝基苯甲酸(6.00 g,32.41 mmol,1.00當量)及HATU (18.49 g,48.61 mmol,1.50當量)於DMF (50.00 mL)中之混合物在室溫及空氣氛圍下攪拌0.5 h。在室溫下向上述混合物中逐份添加CH 3NH 2HCl (2.63 g,38.89 mmol,1.20當量)及NaHCO 3(8.17 g,97.23 mmol,3.00當量)。將所得混合物在室溫下再攪拌1.5 h。所得溶液藉由具有以下條件(移動相A:水(0.05% FA),移動相B:ACN;流動速率:60 mL/min;梯度:在25 min內0% B至100% B;波長:254 nm;220 nm)之C18層析純化,以得到呈白色固體之3-氟-N-甲基-4-硝基苯甲醯胺(5.40 g,84.08%)。LC-MS:(M+H) +實測值199.10。 Step 1. A mixture of 3-fluoro-4-nitrobenzoic acid (6.00 g, 32.41 mmol, 1.00 equiv) and HATU (18.49 g, 48.61 mmol, 1.50 equiv) in DMF (50.00 mL) was stirred at room temperature under air atmosphere for 0.5 h. To the above mixture were added CH 3 NH 2 HCl (2.63 g, 38.89 mmol, 1.20 equiv) and NaHCO 3 (8.17 g, 97.23 mmol, 3.00 equiv) portionwise at room temperature. The resulting mixture was stirred at room temperature for another 1.5 h. The resulting solution was purified by C18 chromatography with the following conditions (mobile phase A: water (0.05% FA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 25 min; wavelength: 254 nm; 220 nm) to give 3-fluoro-N-methyl-4-nitrobenzamide (5.40 g, 84.08%) as a white solid. LC-MS: (M+H) + found 199.10.
步驟2:向3-氟-N-甲基-4-硝基苯甲醯胺(1.10 g,5.55 mmol,1.00當量)於DMF (10.00 mL)中之溶液中添加Cs 2CO 3(5.43 g,16.65 mmol,3.00當量)及CD 3OD (600.64 mg,16.65 mmol,3.00當量)。將反應混合物在室溫下攪拌1 h。混合物用H 2O (30.00 mL)稀釋且用EA (20 mLx3)萃取。合併的有機層用飽和鹽水(20 mLx3)洗滌,經Na 2SO 4乾燥,過濾且在減壓下濃縮,以得到呈黃色固體之3-( 2H 3)甲氧基-N-甲基-4-硝基苯甲醯胺(1.10 g,92.94%)。粗產物無需純化即用於下一步驟。LC-MS:(M+H) +實測值214.15。 Step 2: To a solution of 3-fluoro-N-methyl-4-nitrobenzamide (1.10 g, 5.55 mmol, 1.00 equiv) in DMF (10.00 mL) was added Cs 2 CO 3 (5.43 g, 16.65 mmol, 3.00 equiv) and CD 3 OD (600.64 mg, 16.65 mmol, 3.00 equiv). The reaction mixture was stirred at room temperature for 1 h. The mixture was diluted with H 2 O (30.00 mL) and extracted with EA (20 mL×3). The combined organic layers were washed with saturated brine (20 mL x 3), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give 3-( 2 H 3 )methoxy-N-methyl-4-nitrobenzamide (1.10 g, 92.94%) as a yellow solid. The crude product was used in the next step without purification. LC-MS: (M+H) + found 214.15.
步驟3:在氮氣氛圍下,向3-( 2H 3)甲氧基-N-甲基-4-硝基苯甲醯胺(1.10 g,5.15 mmol,1.00當量)於IPA (20.00 mL)中之溶液中添加Pd/C (110.00 mg)。將混合物在室溫及氫氣氛圍使用氫氣球氫化2 h。然後,將所得溶液通過矽藻土墊過濾。將濾液在減壓下濃縮,以得到呈粉紅色固體之3-( 2H 3)甲氧基-N-甲基-4-硝基苯甲醯胺(1.10 g,92.94%)。粗產物無需純化即用於下一步驟。LC-MS:(M+H) +實測值184.20。 Step 3: To a solution of 3-( 2H3 )methoxy-N-methyl-4-nitrobenzamide (1.10 g, 5.15 mmol, 1.00 equiv) in IPA (20.00 mL) was added Pd/C ( 110.00 mg) under nitrogen atmosphere. The mixture was hydrogenated using a hydrogen balloon for 2 h at room temperature under hydrogen atmosphere. The resulting solution was then filtered through a diatomaceous earth pad. The filtrate was concentrated under reduced pressure to give 3-( 2H3 )methoxy-N-methyl-4-nitrobenzamide (1.10 g, 92.94%) as a pink solid. The crude product was used in the next step without purification. LC-MS: (M+H) + found 184.20.
步驟4:在室溫下,向4-胺基-3-( 2H 3)甲氧基-N-甲基苯甲醯胺(700.00 mg,3.82 mmol,1.00當量)於DMF (10.00 mL)中之攪拌溶液中逐份添加炔丙基溴(545.38 mg,4.58 mmol,1.20當量)及DIEA (1.97 g,15.28 mmol,4.00當量)。將所得混合物在70℃下攪拌2 h。所得溶液藉由具有以下條件(移動相A:水,移動相B:ACN;流動速率:60 mL/min;梯度:在25 min內0% B至100% B;254/220 nm)之C18層析純化。此產生呈黃色固體之3-( 2H 3)甲氧基-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺(490.00 mg,57.96%)。LC-MS:(M+H) +實測值222.15。 Step 4: To a stirred solution of 4 - amino-3-( 2H3 )methoxy-N-methylbenzamide (700.00 mg, 3.82 mmol, 1.00 equiv) in DMF (10.00 mL) were added propargyl bromide (545.38 mg, 4.58 mmol, 1.20 equiv) and DIEA (1.97 g, 15.28 mmol, 4.00 equiv) portionwise at room temperature. The resulting mixture was stirred at 70 °C for 2 h. The resulting solution was purified by C18 chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 25 min; 254/220 nm). This resulted in 3-( 2 H 3 )methoxy-N-methyl-4-(prop-2-yn-1-ylamino)benzamide (490.00 mg, 57.96%) as a yellow solid. LC-MS: (M+H) + found 222.15.
步驟5:在室溫下,向8-溴-2-碘-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶(170.00 mg,0.40 mmol,1.00當量)及3-( 2H 3)甲氧基-N-甲基-4-(丙-2-炔-1-基胺基)苯甲醯胺(106.72 mg,0.48 mmol,1.20當量)於DMSO (2.00 mL)中之攪拌溶液中逐份添加CuI (76.54 mg,0.40 mmol,1.00當量)、i-Pr 2NH (406.70 mg,4.02 mmol,10.00當量)及Pd(PPh 3) 4(46.44 mg,0.04 mmol,0.10當量)。將所得混合物在室溫及氮氣氛圍下攪拌2 h。所得混合物藉由具有以下條件(移動相A:水,移動相B:ACN;流動速率:60 mL/min;梯度:在25 min內0% B至100% B;254/220 nm)之C18層析純化。此產生呈淺棕色固體之4-[(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-( 2H 3)甲氧基-N-甲基苯甲醯胺(140.00 mg,67.46%)。LC-MS:(M+H) +實測值516.10。 Step 5: To a stirred solution of 8-bromo-2-iodo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridine (170.00 mg, 0.40 mmol, 1.00 equiv) and 3-( 2H3 )methoxy-N-methyl-4-(prop-2- yn -1-ylamino)benzamide (106.72 mg, 0.48 mmol, 1.20 equiv) in DMSO (2.00 mL) were added CuI (76.54 mg, 0.40 mmol, 1.00 equiv), i- Pr2NH (406.70 mg, 4.02 mmol, 10.00 equiv) and Pd( PPh3 ) 4 (46.44 mg, 0.04 mmol, 0.10 equiv) portionwise at room temperature. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 h. The resulting mixture was purified by C18 chromatography with the following conditions (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 100% B in 25 min; 254/220 nm). This produced 4-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1-yl)amino]-3-( 2 H 3 )methoxy-N-methylbenzamide (140.00 mg, 67.46%) as a light brown solid. LC-MS: (M+H) + found 516.10.
步驟6:在室溫下,向4-[(3-{8-溴-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基}丙-2-炔-1-基)胺基]-3-( 2H 3)甲氧基-N-甲基苯甲醯胺(140.00 mg,0.27 mmol,1.00當量)及(3S,4R)-3-氟-1-甲基哌啶-4-胺二鹽酸鹽(111.22 mg,0.54 mmol,2.00當量)於1,4-二噁烷(2.00 mL)中之攪拌溶液中逐份添加Cs 2CO 3(530.04 mg,1.626 mmol,6.00當量)及Pd-PEPPSI-IHeptCl 3-氯吡啶(26.40 mg,0.02 mmol,0.10當量)。將所得混合物在100℃及氮氣氛圍下攪拌4 h。移除溶劑之後,殘餘物藉由具有以下條件(移動相A:水(0.1% NH 3.H 2O + 10 mmol/L NH 4HCO 3),移動相B:ACN;流動速率:60 mL/min;梯度:在30 min內0% B至70% B;254/220 nm)之C18層析純化。此產生呈灰白色固體之4-{[3-(8-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]咪唑并[1,2-a]吡啶-2-基)丙-2-炔-1-基]胺基}-3-( 2H 3)甲氧基-N-甲基苯甲醯胺(65.90 mg,42.56%)。LC-MS:(M+H) +實測值568.15。 1H NMR (400 MHz, DMSO- d 6) δ 8.09 (q, J= 4.5 Hz, 1H), 7.86 (d, J= 6.7 Hz, 1H), 7.40 (dd, J= 8.2, 1.9 Hz, 1H), 7.34 (d, J= 1.9 Hz, 1H), 7.02 (dd, J= 7.7, 6.7 Hz, 1H), 6.75 (d, J= 8.3 Hz, 1H), 6.61 (d, J= 7.7 Hz, 1H), 5.99 (t, J= 6.3 Hz, 1H), 5.62 (d, J= 9.0 Hz, 1H), 4.84 (d, J= 49.3 Hz, 1H), 4.32 (d, J= 6.3 Hz, 2H), 3.88 - 3.61 (m, 1H), 3.07 (t, J= 11.4 Hz, 1H), 2.88-2.70 (m, 4H), 2.42-2.10 (m, 5H), 1.88 (qd, J= 12.0, 3.7 Hz, 1H), 1.83-1.72 (m, 1H)。 實例470. 3-((3-(1-(((3S,4R)-3-氟-1-甲基哌啶-4-基)胺基)-6-((三氟甲基)硫代)吡咯并[1,2-a]吡嗪-7-基)丙-2-炔-1-基)胺基)-4-(甲氧基-d 3)-N-甲基苯甲醯胺之合成 Step 6: To a stirred solution of 4-[(3-{8-bromo-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl}prop-2-yn-1- yl)amino]-3-(2H3 ) methoxy-N-methylbenzamide (140.00 mg, 0.27 mmol, 1.00 equiv) and (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (111.22 mg, 0.54 mmol, 2.00 equiv) in 1,4 -dioxane (2.00 mL) were added Cs2CO3 (530.04 mg, 1.626 mmol, 6.00 equiv) and Pd-PEPPSI-IHeptCl 3-chloropyridine (26.40 mg, 0.02 mmol, 0.10 equiv). The resulting mixture was stirred at 100 °C under nitrogen atmosphere for 4 h. After removing the solvent, the residue was purified by C18 chromatography with the following conditions (mobile phase A: water (0.1% NH 3 .H 2 O + 10 mmol/L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 0% B to 70% B in 30 min; 254/220 nm). This resulted in 4-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-3-( 2 H 3 )methoxy-N-methylbenzamide (65.90 mg, 42.56%) as an off-white solid. LC-MS: (M+H) + found 568.15. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.09 (q, J = 4.5 Hz, 1H), 7.86 (d, J = 6.7 Hz, 1H), 7.40 (dd, J = 8.2, 1.9 Hz, 1H), 7.34 (d, J = 1.9 Hz, 1H), 7.02 (dd, J = 7.7, 6.7 Hz, 1H), 6.75 (d, J = 8.3 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 5.99 (t, J = 6.3 Hz, 1H), 5.62 (d, J = 9.0 Hz, 1H), 4.84 (d, J = 49.3 Hz, 1H), 4.32 (d, J = 6.3 Hz, 2H), 3.88 - 3.61 (m, 1H), 3.07 (t, J = 11.4 Hz, 1H), 2.88-2.70 (m, 4H), 2.42-2.10 (m, 5H), 1.88 (qd, J = 12.0, 3.7 Hz, 1H), 1.83-1.72 (m, 1H). Example 470. Synthesis of 3-((3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)-4-(methoxy-d 3 )-N-methylbenzamide
步驟1. 向7-溴-1-氯-6-((三氟甲基)硫代)吡咯并[1,2-a]吡嗪(200 mg,603.25 μmol,1當量)及(3S,4R)-4-胺基-3-氟-哌啶-1-甲酸三級丁酯(158 mg,723.89 μmol,1.2當量)於DMSO (4 mL)中之溶液中添加KF (175.23 mg,3.02 mmol,5當量)。將混合物在140℃攪拌3小時。LCMS (EW46021-6-P1A)顯示7-溴-1-氯-6-((三氟甲基)硫代)吡咯并[1,2-a]吡嗪被完全消耗且偵測到一個具有所需m/z之主峰。將混合物添加至H 2O (20 mL)中,觀測到一些固體。過濾混合物。濾餅用H 2O (5 mL)洗滌,然後乾燥以得到殘餘物,其藉由LCMS (EW46021-6-P1B)及HNMR (EW46021-6-P1A)檢查。水相用EA (30 mL * 3)萃取。合併的有機層用鹽水(30 mL)洗滌,經Na 2SO 4乾燥,過濾且在減壓下濃縮,以得到殘餘物。將殘餘物與濾餅合併且一起純化。合併的粗物質藉由急速矽膠層析(ISCO®;20 g SepaFlash®二氧化矽急速管柱,在60 mL/min下0~30%乙酸乙酯/石油醚梯度之溶析液,TLC (PE/EA = 3:1,Rf = 0.4))純化。獲得呈黃色固體之(3S,4R)-4-((7-溴-6-((三氟甲基)硫代)吡咯并[1,2-a]吡嗪-1-基)胺基)-3-氟哌啶-1-甲酸三級丁酯(270 mg,520.07 μmol,86.21%產率,98.88%純度),其藉由LCMS及SFC檢查。MS (ESI):513.1 (M+H) +。 1H NMR: 400 MHz, DMSO-d 6δ = 7.82 (d, J= 4.8 Hz, 1H), 7.52 (s, 1H), 7.43 (d, J= 7.6 Hz, 1H), 7.33 (d, J= 5.2 Hz, 1H), 5.03 - 4.78 (m, 1H), 4.52 - 4.34 (m, 1H), 4.31 - 4.16 (m, 1H), 4.14 - 3.95 (m, 1H), 3.19 - 2.81 (m, 2H), 1.94 - 1.82 (m, 1H), 1.76 - 1.64 (m, 1H), 1.42 (s, 9H)。 Step 1. To a solution of 7-bromo-1-chloro-6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazine (200 mg, 603.25 μmol, 1 eq) and (3S,4R)-4-amino-3-fluoro-piperidine-1-carboxylic acid tributyl ester (158 mg, 723.89 μmol, 1.2 eq) in DMSO (4 mL) was added KF (175.23 mg, 3.02 mmol, 5 eq). The mixture was stirred at 140 °C for 3 h. LCMS (EW46021-6-P1A) showed that 7-bromo-1-chloro-6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazine was completely consumed and one major peak with the desired m/z was detected. The mixture was added to H 2 O (20 mL), and some solid was observed. The mixture was filtered. The filter cake was washed with H 2 O (5 mL), and then dried to obtain a residue, which was checked by LCMS (EW46021-6-P1B) and HNMR (EW46021-6-P1A). The aqueous phase was extracted with EA (30 mL * 3). The combined organic layers were washed with brine (30 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to obtain a residue. The residue was combined with the filter cake and purified together. The combined crude material was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, 0-30% ethyl acetate/petroleum ether gradient at 60 mL/min, TLC (PE/EA = 3:1, Rf = 0.4)). (3S,4R)-4-((7-bromo-6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazin-1-yl)amino)-3-fluoropiperidine-1-carboxylic acid tributyl ester (270 mg, 520.07 μmol, 86.21% yield, 98.88% purity) was obtained as a yellow solid, which was checked by LCMS and SFC. MS (ESI): 513.1 (M+H) +. 1 H NMR: 400 MHz, DMSO-d 6 δ = 7.82 (d, J = 4.8 Hz, 1H), 7.52 (s, 1H), 7.43 (d, J = 7.6 Hz, 1H), 7.33 (d, J = 5.2 Hz, 1H), 5.03 - 4.78 (m, 1H), 4.52 - 4.34 (m, 1H), 4.31 - 4.16 (m, 1H), 4.14 - 3.95 (m, 1H), 3.19 - 2.81 (m, 2H), 1.94 - 1.82 (m, 1H), 1.76 - 1.64 (m, 1H), 1.42 (s, 9H).
步驟2:向4-氟-N-甲基-3-硝基苯甲醯胺(4 g,20.19 mmol,1當量)於DMF (60 mL)中之溶液中添加Cs 2CO 3(19.73 g,60.56 mmol,3當量)及CD 3OD (2.18 g,60.56 mmol,2.46 mL,3當量)。將混合物在25℃攪拌2小時。LCMS (EW46021-9-P1A)顯示4-氟-N-甲基-3-硝基苯甲醯胺被完全消耗且偵測到一個具有所需m/z之主峰。將混合物添加至H 2O (300 mL)中,然後用EA (100 mL * 5)萃取。合併的有機層經Na 2SO 4乾燥,過濾且濃縮以得到殘餘物。無需進一步純化。獲得黃色固體之4-(甲氧基-d 3)-N-甲基-3-硝基苯甲醯胺(5.6 g,粗物質),其藉由HNMR檢查。MS (ESI):214.2 (M+H) +。 1H NMR: 400 MHz, DMSO-d 6δ = 8.60 (br d, J= 4.4 Hz, 1H), 8.36 (d, J= 2.4 Hz, 1H), 8.20 - 8.09 (m, 1H), 7.46 (d, J= 8.8 Hz, 1H), 2.79 (d, J= 4.4 Hz, 3H)。 Step 2: To a solution of 4-fluoro-N-methyl-3-nitrobenzamide (4 g, 20.19 mmol, 1 eq) in DMF (60 mL) were added Cs 2 CO 3 (19.73 g, 60.56 mmol, 3 eq) and CD 3 OD (2.18 g, 60.56 mmol, 2.46 mL, 3 eq). The mixture was stirred at 25 °C for 2 hours. LCMS (EW46021-9-P1A) showed that 4-fluoro-N-methyl-3-nitrobenzamide was completely consumed and one major peak with the desired m/z was detected. The mixture was added to H 2 O (300 mL) and then extracted with EA (100 mL * 5). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated to give a residue. No further purification was required. 4-(Methoxy-d 3 )-N-methyl-3-nitrobenzamide (5.6 g, crude) was obtained as a yellow solid, which was checked by HNMR. MS (ESI): 214.2 (M+H) +. 1 H NMR: 400 MHz, DMSO-d 6 δ = 8.60 (br d, J = 4.4 Hz, 1H), 8.36 (d, J = 2.4 Hz, 1H), 8.20 - 8.09 (m, 1H), 7.46 (d, J = 8.8 Hz, 1H), 2.79 (d, J = 4.4 Hz, 3H).
步驟3:向4-(甲氧基-d 3)-N-甲基-3-硝基苯甲醯胺(5 g,23.45 mmol,1當量)於EtOH (100 mL)及H 2O (30 mL)中之溶液中添加Fe (5.24 g,93.81 mmol,4當量)及NH 4Cl (6.27 g,117.26 mmol,5當量)。將混合物在80℃下攪拌1 h。TLC (PE/EA = 0:1)顯示4-(甲氧基-d 3)-N-甲基-3-硝基苯甲醯胺(Rf = 0.55)被完全消耗且形成一個主要新斑點(Rf = 0.45)。對混合物進行後處理。過濾混合物且濾餅用EA (150 mL)及DCM (150 mL)洗滌。濃縮濾液以移除EtOH。然後水相用DCM (100 mL * 3)及EA (100 mL * 3)萃取。合併的有機層經Na 2SO 4乾燥,過濾且濃縮以得到殘餘物。獲得呈棕色油狀物之 3-胺基-4-(甲氧基-d3)-N-甲基苯甲醯胺(5 g,粗物質),其藉由HNMR檢查。 1HNMR: 400 MHz, 氯仿-d, δ = 7.17 (d, J= 2.0 Hz, 1H), 7.14 - 7.07 (m, 1H), 6.75 (d, J= 8.4 Hz, 1H), 6.15 (brs, 1H), 2.96 (d, J=5.2 Hz, 3H)。 Step 3: To a solution of 4-(methoxy-d 3 )-N-methyl-3-nitrobenzamide (5 g, 23.45 mmol, 1 eq) in EtOH (100 mL) and H 2 O (30 mL) were added Fe (5.24 g, 93.81 mmol, 4 eq) and NH 4 Cl (6.27 g, 117.26 mmol, 5 eq). The mixture was stirred at 80 °C for 1 h. TLC (PE/EA = 0:1) showed that 4-(methoxy-d 3 )-N-methyl-3-nitrobenzamide (Rf = 0.55) was completely consumed and one major new spot (Rf = 0.45) was formed. The mixture was worked up. The mixture was filtered and the filter cake was washed with EA (150 mL) and DCM (150 mL). The filtrate was concentrated to remove EtOH. The aqueous phase was then extracted with DCM (100 mL * 3) and EA (100 mL * 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated to give a residue. 3-amino-4-(methoxy-d3)-N-methylbenzamide (5 g, crude) was obtained as a brown oil, which was checked by HNMR. 1 HNMR: 400 MHz, CHLOROFORM-d, δ = 7.17 (d, J = 2.0 Hz, 1H), 7.14 - 7.07 (m, 1H), 6.75 (d, J = 8.4 Hz, 1H), 6.15 (brs, 1H), 2.96 (d, J =5.2 Hz, 3H).
步驟4:向3-胺基-4-(甲氧基-d3)-N-甲基苯甲醯胺(4.5 g,24.56 mmol,1當量)於ACN (90 mL)中之溶液中添加Cs 2CO 3(16.00 g,49.12 mmol,2當量)及3-溴丙-1-炔(5.84 g,49.12 mmol,4.23 mL,2當量)。將混合物在60℃下攪拌5小時。LCMS (EW46021-14-P1A)顯示剩餘15%之4 3-胺基-4-(甲氧基-d3)-N-甲基苯甲醯胺且偵測到53%之所需m/z。TLC (PE/EA = 0:1)顯示3-胺基-4-(甲氧基-d3)-N-甲基苯甲醯胺剩餘(Rf = 0.5)且形成一個新斑點(Rf = 0.6)。過濾混合物且濾餅用EA (200 mL)洗滌。將濾液在減壓下濃縮以得到殘餘物。殘餘物藉由急速矽膠層析(ISCO®;60 g SepaFlash®二氧化矽急速管柱,在80 mL/min下0~100%乙酸乙酯/石油醚梯度之溶析液)純化。獲得呈黃色油狀物之4-(甲氧基-d3)-N-甲基-3-(丙-2-炔-1-基胺基)苯甲醯胺(3.3 g,12.45 mmol,50.70%產率,83.50%純度),其藉由LCMS及HNMR檢查。4-(甲氧基-d3)-N-甲基-3-(丙-2-炔-1-基胺基)苯甲醯胺(1.86 g,10.15 mmol,41.33%產率)作為黃色油狀物循環。MS (ESI):222.0 (M+H) +。 1HNMR: 400 MHz, 氯仿-d, δ = 7.16 - 7.10 (m, 2H), 6.76 (d, J= 8.4 Hz, 1H), 6.12 (br s, 1H), 4.53 (br s, 1H), 4.01 (d, J= 1.6 Hz, 2H), 2.99 (d, J= 4.8 Hz, 3H), 2.27 - 2.21 (m, 1H)。 Step 4: To a solution of 3-amino- 4- (methoxy-d3)-N-methylbenzamide (4.5 g, 24.56 mmol, 1 eq) in ACN (90 mL) was added Cs2CO3 (16.00 g, 49.12 mmol, 2 eq) and 3-bromoprop-1-yne (5.84 g, 49.12 mmol, 4.23 mL, 2 eq). The mixture was stirred at 60 °C for 5 h. LCMS (EW46021-14-P1A) showed 15% of 4-(methoxy-d3)-N-methylbenzamide remaining and 53% of the desired m/z was detected. TLC (PE/EA = 0:1) showed 3-amino-4-(methoxy-d3)-N-methylbenzamide remaining (Rf = 0.5) and a new spot formed (Rf = 0.6). The mixture was filtered and the filter cake was washed with EA (200 mL). The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica chromatography (ISCO®; 60 g SepaFlash® silica flash column, 0-100% ethyl acetate/petroleum ether gradient at 80 mL/min). 4-(Methoxy-d3)-N-methyl-3-(prop-2-yn-1-ylamino)benzamide (3.3 g, 12.45 mmol, 50.70% yield, 83.50% purity) was obtained as a yellow oil, which was checked by LCMS and HNMR. 4-(Methoxy-d3)-N-methyl-3-(prop-2-yn-1-ylamino)benzamide (1.86 g, 10.15 mmol, 41.33% yield) was recycled as a yellow oil. MS (ESI): 222.0 (M+H) +. 1 H NMR: 400 MHz, CHLOROFORM-d, δ = 7.16 - 7.10 (m, 2H), 6.76 (d, J = 8.4 Hz, 1H), 6.12 (br s, 1H), 4.53 (br s, 1H), 4.01 (d, J = 1.6 Hz, 2H), 2.99 (d, J = 4.8 Hz, 3H), 2.27 - 2.21 (m, 1H).
步驟5:將(3S,4R)-4-((7-溴-6-((三氟甲基)硫代)吡咯并[1,2-a]吡嗪-1-基)胺基)-3-氟哌啶-1-甲酸三級丁酯(100 mg,194.80 μmol,1當量)、4-(甲氧基-d3)-N-甲基-3-(丙-2-炔-1-基胺基)苯甲醯胺(92.92 mg,350.64 μmol,1.8當量)、[2-(2-胺基苯基)苯基]鈀(1+);雙(1-金剛烷基)-丁基-磷烷;甲磺酸鹽(14.19 mg,19.48 μmol,0.1當量)、Cs 2CO 3(126.94 mg,389.60 μmol,2 當量)於DMSO (2.5 mL)中之混合物除氣且用N 2吹掃3次,然後將混合物分5批在90℃及N 2氛圍下攪拌3小時。LCMS顯示(3S,4R)-4-((7-溴-6-((三氟甲基)硫代)吡咯并[1,2-a]吡嗪-1-基)胺基)-3-氟哌啶-1-甲酸三級丁酯被完全消耗且偵測到46%之所需m/z。TLC (PE/EA = 0:1)顯示(3S,4R)-4-((7-溴-6-((三氟甲基)硫代)吡咯并[1,2-a]吡嗪-1-基)胺基)-3-氟哌啶-1-甲酸三級丁酯(Rf = 0.75)被消耗且形成一個主要新斑點(Rf = 0.5)。對反應進行後處理。過濾混合物且濾餅用EA (50 mL)洗滌。將濾液添加至50 mL H 2O中且用EA (30 mL *3)萃取。合併的有機層經Na 2SO 4乾燥,過濾且在減壓下濃縮以得到殘餘物。殘餘物藉由急速矽膠層析(ISCO®;60 g SepaFlash®二氧化矽急速管柱,在60 mL/min下0~100%乙酸乙酯/石油醚梯度之溶析液)純化。獲得呈黃色固體之(3S,4R)-3-氟-4-((7-(3-((2-(甲氧基-d 3)-5-(甲基胺甲醯基)苯基)胺基)丙-1-炔-1-基)-6-((三氟甲基)硫代)吡咯并[1,2-a]吡嗪-1-基)胺基)哌啶-1-甲酸三級丁酯(270 mg,349.05 μmol,35.84%產率,84.51%純度),其藉由LCMS檢查。MS (ESI):654.3 (M+H) +。 Step 5: (3S,4R)-4-((7-bromo-6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazin-1-yl)amino)-3-fluoropiperidine-1-carboxylic acid tributyl ester (100 mg, 194.80 μmol, 1 eq.), 4-(methoxy-d3)-N-methyl-3-(prop-2-yn-1-ylamino)benzamide (92.92 mg, 350.64 μmol, 1.8 eq.), [2-(2-aminophenyl)phenyl]palladium(1+); bis(1-adamantyl)-butyl-phosphane; mesylate (14.19 mg, 19.48 μmol, 0.1 eq.), Cs 2 CO 3 (126.94 mg, 389.60 μmol, 2 A mixture of (3S,4R)-4-((7-bromo-6-((trifluoromethyl)thio)pyrrolo[ 1,2 -a]pyrazin-1-yl)amino)-3-fluoropiperidine-1 - carboxylic acid tert-butyl ester (Rf = 0.75) was consumed and a major new spot (Rf = 0.5) was formed. The reaction was worked up. The mixture was filtered and the filter cake was washed with EA (50 mL). The filtrate was added to 50 mL of H 2 O and extracted with EA (30 mL *3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (ISCO®; 60 g SepaFlash® silica flash column, 0-100% ethyl acetate/petroleum ether gradient eluent at 60 mL/min). (3S,4R)-3-fluoro-4-((7-(3-((2-(methoxy- d3 )-5-(methylaminocarbonyl)phenyl)amino)prop-1-yn-1-yl)-6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazin-1-yl)amino)piperidine-1-carboxylic acid tributyl ester (270 mg, 349.05 μmol, 35.84% yield, 84.51% purity) was obtained as a yellow solid, which was checked by LCMS. MS (ESI): 654.3 (M+H)+.
步驟6:向(3S,4R)-3-氟-4-((7-(3-((2-(甲氧基-d 3)-5-(甲基胺甲醯基)苯基)胺基)丙-1-炔-1-基)-6-((三氟甲基)硫代)吡咯并[1,2-a]吡嗪-1-基)胺基)哌啶-1-甲酸三級丁酯(270 mg,413.03 μmol,1當量)於DCM (5 mL)中之溶液中添加HCl/二噁烷(4 M,3 mL,29.05當量)。將混合物在25℃下攪拌0.5小時。LCMS (EW46021-21-P1A)顯示(3S,4R)-3-氟-4-((7-(3-((2-(甲氧基-d 3)-5-(甲基胺甲醯基)苯基)胺基)丙-1-炔-1-基)-6-((三氟甲基)硫代)吡咯并[1,2-a]吡嗪-1-基)胺基)哌啶-1-甲酸三級丁酯被消耗且偵測到68%之所需m/z。濃縮混合物以得到殘餘物。獲得呈黃色固體之化合物3-[3-[1-[[(3S,4R)-3-氟-4-哌啶基]胺基]-6-(三氟甲基硫基)吡咯并[1,2-a]吡嗪-7-基]丙-2-炔基胺基]-N-甲基-4-(三氘甲氧基)苯甲醯胺(284 mg,粗物質,HCl)。MS (ESI):554.2 (M+H) +。向3-[3-[1-[[(3S,4R)-3-氟-4-哌啶基]胺基]-6-(三氟甲基硫基)吡咯并[1,2-a]吡嗪-7-基]丙-2-炔基胺基]-N-甲基-4-(三氘甲氧基)苯甲醯胺(340 mg,576.22 μmol,1當量,HCl)於MeOH (15 mL)中之溶液中添加KOAc (565.52 mg,5.76 mmol,10當量)及(HCHO)n (172.87 mg,5.76 mmol,10當量)。將混合物在25℃下攪拌0.5 h。然後添加NaBH(OAc) 3(366.38 mg,1.73 mmol,3當量),將混合物在25℃下攪拌1小時。LCMS顯示起始材料被消耗且偵測到63%之所需m/z。TLC (DCM:MeOH = 10:1)顯示形成一個主要新斑點(Rf = 0.3)。將 NH 3. H 2O (37%,0.5 mL)添加至混合物中。然後添加50 mL H 2O且用EA (30 mL *3)萃取。合併的有機層經Na 2SO 4乾燥,過濾且在減壓下濃縮以得到殘餘物。殘餘物藉由急速矽膠層析(ISCO®;20 g SepaFlash®二氧化矽急速管柱,在50 mL/min下0~100% EA/PE、0~10% MeOH/DCM梯度)純化,以得到180 mg粗物質,其藉由LCMS及HPLC檢查。粗物質藉由製備型HPLC (管柱:Welch Ultimate XB-CN 250*50*10um;移動相:[己烷-EtOH];梯度:歷時15 min,10%-50% B)進一步純化。獲得呈白色固體之標題化合物(102 mg,175.13 μmol,30.39%產率,97.46%純度),其由LCMS、HPLC、HNMR、FNMR及SFC檢查。MS (ESI):568.1 (M+H) +。 1HNMR: 400 MHz, DMSO-d 6, δ = 8.18 - 8.08 (m, 1H), 7.71 (d, J= 4.8 Hz, 1H), 7.39 - 7.33 (m, 2H), 7.29 (d, J= 4.8 Hz, 1H), 7.26 (d, J= 2.0 Hz, 1H), 7.20 - 7.13 (m, 1H), 6.87 (d, J= 8.4 Hz, 1H), 5.54 (t, J= 6.4 Hz, 1H), 4.92 - 4.77 (m, 1H), 4.27 (d, J= 6.4 Hz, 2H), 4.23 - 4.06 (m, 1H), 3.09 - 2.98 (m, 1H), 2.82 (br d, J= 7.6 Hz, 1H), 2.74 (d, J= 4.4 Hz, 3H), 2.23 -1.97 (m, 6H), 1.65 (br d, J= 12.4 Hz, 1H)。 實例506. 3-{[3-(7-{[(3S,4R)-3-氟-1-甲基哌啶-4-基]胺基}-3-[(三氟甲基)硫基]吡唑并[1,5-a]吡啶-2-基)丙-2-炔-1-基]胺基}-4-(2H3)甲氧基-N-甲基苯甲醯胺之合成 Step 6: To a solution of tributyl (3S,4R)-3-fluoro-4-((7-(3-((2-(methoxy- d3 )-5-(methylaminocarbonyl)phenyl)amino)prop-1-yn-1-yl)-6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazin-1-yl)amino)piperidine-1-carboxylate (270 mg, 413.03 μmol, 1 eq) in DCM (5 mL) was added HCl/dioxane (4 M, 3 mL, 29.05 eq). The mixture was stirred at 25 °C for 0.5 h. LCMS (EW46021-21-P1A) showed tributyl (3S,4R)-3-fluoro-4-((7-(3-((2-(methoxy- d3 )-5-(methylaminocarbonyl)phenyl)amino)prop-1-yn-1-yl)-6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazin-1-yl)amino)piperidine-1-carboxylate was consumed and 68% of the desired m/z was detected. The mixture was concentrated to give a residue. The compound 3-[3-[1-[[(3S,4R)-3-fluoro-4-piperidinyl]amino]-6-(trifluoromethylsulfanyl)pyrrolo[1,2-a]pyrazin-7-yl]prop-2-ynylamino]-N-methyl-4-(trideuteriomethoxy)benzamide (284 mg, crude material, HCl) was obtained as a yellow solid. MS (ESI): 554.2 (M+H) +. To a solution of 3-[3-[1-[[(3S,4R)-3-fluoro-4-piperidinyl]amino]-6-(trifluoromethylsulfanyl)pyrrolo[1,2-a]pyrazin-7-yl]prop-2-ynylamino]-N-methyl-4-(trideuteromethoxy)benzamide (340 mg, 576.22 μmol, 1 eq, HCl) in MeOH (15 mL) was added KOAc (565.52 mg, 5.76 mmol, 10 eq) and (HCHO)n (172.87 mg, 5.76 mmol, 10 eq). The mixture was stirred at 25 °C for 0.5 h. NaBH(OAc) 3 (366.38 mg, 1.73 mmol, 3 eq) was then added and the mixture was stirred at 25 °C for 1 hour. LCMS showed that the starting material was consumed and 63% of the desired m/z was detected. TLC (DCM:MeOH = 10:1) showed the formation of a major new spot (Rf = 0.3). NH 3 .H 2 O (37%, 0.5 mL) was added to the mixture. Then 50 mL of H 2 O was added and extracted with EA (30 mL * 3). The combined organic layer was dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, 0-100% EA/PE, 0-10% MeOH/DCM gradient at 50 mL/min) to give 180 mg of crude material, which was checked by LCMS and HPLC. The crude material was further purified by preparative HPLC (column: Welch Ultimate XB-CN 250*50*10um; mobile phase: [hexane-EtOH]; gradient: 10%-50% B over 15 min). The title compound (102 mg, 175.13 μmol, 30.39% yield, 97.46% purity) was obtained as a white solid, which was checked by LCMS, HPLC, HNMR, FNMR and SFC. MS (ESI): 568.1 (M+H) +. 1 HNMR: 400 MHz, DMSO-d 6 , δ = 8.18 - 8.08 (m, 1H), 7.71 (d, J = 4.8 Hz, 1H), 7.39 - 7.33 (m, 2H), 7.29 (d, J = 4.8 Hz, 1H), 7.26 (d, J = 2.0 Hz, 1H), 7.20 - 7.13 (m, 1H), 6.87 (d, J = 8.4 Hz, 1H), 5.54 (t, J = 6.4 Hz, 1H), 4.92 - 4.77 (m, 1H), 4.27 (d, J = 6.4 Hz, 2H), 4.23 - 4.06 (m, 1H), 3.09 δ 5.14 (m, 4H) , 2.73 ( m , 5H), 1.22 (m , 4H), 1.67 (m, 5H), 1.11 (m, 4H), 1.5 (m, 5H). 3-{[3-(7-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)thio]pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl]amino}-4-(2H3)methoxy-N-methylbenzamide
步驟1. 向7-溴-1-氯-6-((三氟甲基)硫代)吡咯并[1,2-a]吡嗪(200 mg,603.25 μmol,1當量)及(3S,4R)-4-胺基-3-氟-哌啶-1-甲酸三級丁酯(158 mg,723.89 μmol,1.2當量)於DMSO (4 mL)中之溶液中添加KF (175.23 mg,3.02 mmol,5當量)。將混合物在140℃攪拌3小時。LCMS (EW46021-6-P1A)顯示7-溴-1-氯-6-((三氟甲基)硫代)吡咯并[1,2-a]吡嗪被完全消耗且偵測到一個具有所需m/z之主峰。將混合物添加至H 2O (20 mL)中,觀測到一些固體。過濾混合物。濾餅用H 2O (5 mL)洗滌,然後乾燥以得到殘餘物,其藉由LCMS (EW46021-6-P1B)及HNMR (EW46021-6-P1A)檢查。水相用EA (30 mL * 3)萃取。合併的有機層用鹽水(30 mL)洗滌,經Na 2SO 4乾燥,過濾且在減壓下濃縮,以得到殘餘物。將殘餘物與濾餅合併且一起純化。合併的粗物質藉由急速矽膠層析(ISCO®;20 g SepaFlash®二氧化矽急速管柱,在60 mL/min下0~30%乙酸乙酯/石油醚梯度之溶析液,TLC (PE/EA = 3:1,Rf = 0.4))純化。獲得呈黃色固體之(3S,4R)-4-((7-溴-6-((三氟甲基)硫代)吡咯并[1,2-a]吡嗪-1-基)胺基)-3-氟哌啶-1-甲酸三級丁酯(270 mg,520.07 μmol,86.21%產率,98.88%純度),其藉由LCMS及SFC檢查。MS (ESI):513.1 (M+H) +。 1H NMR: 400 MHz, DMSO-d 6δ = 7.82 (d, J= 4.8 Hz, 1H), 7.52 (s, 1H), 7.43 (d, J= 7.6 Hz, 1H), 7.33 (d, J= 5.2 Hz, 1H), 5.03 - 4.78 (m, 1H), 4.52 - 4.34 (m, 1H), 4.31 - 4.16 (m, 1H), 4.14 - 3.95 (m, 1H), 3.19 - 2.81 (m, 2H), 1.94 - 1.82 (m, 1H), 1.76 - 1.64 (m, 1H), 1.42 (s, 9H)。 檢定表面電漿子共振(SPR)檢定方案 Step 1. To a solution of 7-bromo-1-chloro-6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazine (200 mg, 603.25 μmol, 1 eq) and (3S,4R)-4-amino-3-fluoro-piperidine-1-carboxylic acid tributyl ester (158 mg, 723.89 μmol, 1.2 eq) in DMSO (4 mL) was added KF (175.23 mg, 3.02 mmol, 5 eq). The mixture was stirred at 140 °C for 3 h. LCMS (EW46021-6-P1A) showed that 7-bromo-1-chloro-6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazine was completely consumed and one major peak with the desired m/z was detected. The mixture was added to H 2 O (20 mL), and some solid was observed. The mixture was filtered. The filter cake was washed with H 2 O (5 mL), and then dried to obtain a residue, which was checked by LCMS (EW46021-6-P1B) and HNMR (EW46021-6-P1A). The aqueous phase was extracted with EA (30 mL * 3). The combined organic layers were washed with brine (30 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to obtain a residue. The residue was combined with the filter cake and purified together. The combined crude material was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, 0-30% ethyl acetate/petroleum ether gradient at 60 mL/min, TLC (PE/EA = 3:1, Rf = 0.4)). (3S,4R)-4-((7-bromo-6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazin-1-yl)amino)-3-fluoropiperidine-1-carboxylic acid tributyl ester (270 mg, 520.07 μmol, 86.21% yield, 98.88% purity) was obtained as a yellow solid, which was checked by LCMS and SFC. MS (ESI): 513.1 (M+H) +. 1 H NMR: 400 MHz, DMSO-d 6 δ = 7.82 (d, J = 4.8 Hz, 1H), 7.52 (s, 1H), 7.43 (d, J = 7.6 Hz, 1H), 7.33 (d, J = 5.2 Hz, 1H), 5.03 - 4.78 (m, 1H), 4.52 - 4.34 (m, 1H), 4.31 - 4.16 (m, 1H), 4.14 - 3.95 (m, 1H), 3.19 - 2.81 (m, 2H), 1.94 - 1.82 (m, 1H), 1.76 - 1.64 (m, 1H), 1.42 (s, 9H). Surface Plasmon Resonance (SPR) Assay Solution
SPR實驗係在Biacore8K儀器上執行。藉由使蛋白質溶液以典型10 μg/mL濃度,5 μL/min流動速率流過感測器晶片70秒,將生物素化的重組p53 Y220C突變蛋白(胺基酸殘基94-293)固定於鏈黴抗生物素蛋白感測器晶片(感測器晶片SA)上。將化合物以2倍、7點連續稀釋;最高濃度視效能而變化。化合物結合親和力係在多循環動力學模式中,以30 μL/min流動速率與60秒締合時間及120秒解離時間來量測。運行緩衝液含有50 mM Tris,pH 7.5、100 mM NaCl、1 mM DTT、0.01% Brij35、0.05% Tween-20及1% DMSO。將檢定溫度保持在16℃或20℃下且使用Biacore Insight評估軟體將資料擬合至1:1結合模型中。 熱漂移檢定(TSA)方案 SPR experiments were performed on a Biacore8K instrument. Biotinylated recombinant p53 Y220C mutant protein (amino acid residues 94-293) was immobilized on a streptavidin sensor chip (sensor chip SA) by flowing the protein solution through the sensor chip at a typical concentration of 10 μg/mL at a flow rate of 5 μL/min for 70 seconds. Compounds were diluted in a 2-fold, 7-point serial dilution; the highest concentration varied depending on potency. Compound binding affinities were measured in multicycle kinetic mode at a flow rate of 30 μL/min with an association time of 60 seconds and a dissociation time of 120 seconds. Running buffer contained 50 mM Tris, pH 7.5, 100 mM NaCl, 1 mM DTT, 0.01% Brij35, 0.05% Tween-20, and 1% DMSO. The assay temperature was maintained at 16°C or 20°C and the data were fit to a 1:1 binding model using Biacore Insight evaluation software. Thermal Shift Assay (TSA) Protocol
在400倍稀釋的Sypro Orange (ThermoFisher Scientific目錄編號4461146)存在下,將5 μM重組p53 Y220C突變蛋白(胺基酸殘基94-293)與10 μM或100 μM化合物在384孔PCR板(Applied Biosystems目錄編號4483285)上在20℃下於含有20 mM HEPES,pH7.4、100 mM NaCl、0.01%普朗尼克F-127及1% DMSO之緩衝液中一起孵育3小時。體積為5 μL/孔。然後將密封板負載至QuantStudio 7 Flex儀器上以便進行熔融溫度(T M)量測。以0.03℃/秒之速率,將溫度自30℃增加至50℃。將資料擬合至Boltzmann二狀態模型中以確定T M。 螢光素酶報導基因檢定方案 5 μM recombinant p53 Y220C mutant protein (amino acid residues 94-293) was incubated with 10 μM or 100 μM compounds in a 384-well PCR plate (Applied Biosystems Catalog No. 4483285) in the presence of 400-fold diluted Sypro Orange (ThermoFisher Scientific Catalog No. 4461146) for 3 hours at 20°C in a buffer containing 20 mM HEPES, pH 7.4, 100 mM NaCl, 0.01% Pluronic F-127, and 1% DMSO. The volume was 5 μL/well. The sealed plate was then loaded onto the QuantStudio 7 Flex instrument for melting temperature (T M ) measurements. The temperature was increased from 30°C to 50°C at a rate of 0.03°C/sec. The data were fitted to a Boltzmann two-state model to determine T M . Luciferase reporter gene assay protocol
藉由慢病毒轉導,使由p53反應元件驅動之螢光素酶報導基因(Luc) (LTV-p53-Luc (SKU#:LTLR007);G&P Biosciences)及可誘導p53 Y220C構築體(Tet-One可誘導表現系統;Takara)在NCIH1299細胞中穩定表現。然後將細胞用於p53報導基因檢定。將5,000個細胞接種於384板之各孔中且在化合物處理之前,在含有0.5 ug/mL去氧羥四環素(D3072;Sigma)之培養基中培養24小時。6小時化合物處理之後,將相等體積之One-Glo試劑(E6110;Promega)添加至各孔中且在室溫下,伴以振盪,將板孵育5分鐘。螢光素酶活性用PheraStar微孔板讀取器來直接量測。藉由作為陽性對照之10 uM工具化合物刺激螢光素酶活性且計算AC 50。 細胞增殖檢定 A p53 response element-driven luciferase reporter gene (Luc) (LTV-p53-Luc (SKU#: LTLR007); G&P Biosciences) and an inducible p53 Y220C construct (Tet-One Inducible Expression System; Takara) were stably expressed in NCIH1299 cells by lentiviral transduction. The cells were then used for p53 reporter gene assays. 5,000 cells were seeded in each well of a 384-well plate and cultured in medium containing 0.5 ug/mL deoxytetracycline (D3072; Sigma) for 24 hours prior to compound treatment. After 6 hours of compound treatment, an equal volume of One-Glo reagent (E6110; Promega) was added to each well and the plates were incubated for 5 minutes at room temperature with shaking. Luciferase activity was directly measured using a PheraStar microplate reader. Luciferase activity was stimulated by 10 uM tool compound as a positive control and the AC50 was calculated. Cell Proliferation Assay
藉由慢病毒轉導,使可誘導p53 Y220C及R273H構築體(Tet-One可誘導表現系統;Takara)在NCIH1299細胞中穩定表現。NUGC3、A549、BxPC3、T3M4、HuH7、HCC2935、MFE296、NCIH1299、NCIH1299可誘導p53 Y220C,及NCIH1299可誘導p53 R273H細胞株用於細胞增殖檢定。將250-500個細胞接種於384板之各孔中,然後使用Echo或Tecan將化合物分配於各孔中。孵育5天之後,將相等體積之CellTiter-Glo試劑(G7570;Promega)添加至各孔中且伴以振盪,將板在室溫下孵育10分鐘。發光信號藉由PheraStar微孔板讀取器來量測且計算IC 50。 Inducible p53 Y220C and R273H constructs (Tet-One Inducible Expression System; Takara) were stably expressed in NCIH1299 cells by lentiviral transduction. NUGC3, A549, BxPC3, T3M4, HuH7, HCC2935, MFE296, NCIH1299, NCIH1299 Inducible p53 Y220C, and NCIH1299 Inducible p53 R273H cell lines were used for cell proliferation assays. 250-500 cells were seeded into each well of a 384-well plate, and compounds were dispensed into each well using an Echo or Tecan. After 5 days of incubation, an equal volume of CellTiter-Glo reagent (G7570; Promega) was added to each well and the plate was incubated at room temperature for 10 minutes with shaking. The luminescence signal was measured by a PheraStar microplate reader and the IC50 was calculated.
表A示出了SPR p53 Y220C Kd_動力學(nM)、TSA p53 Y220C dTM (deg C)、Luc p53 Y220C AC
50(nM)、CTG H1299 p53 Y220C IC
50(nM)、CTG H1299 p53 R273H IC
50(nM)及CTG NUGC3 p53 Y220C IC
50(nM)檢定之結果。活性類別如下:
• SPR p53 Y220C Kd_動力學(nM):D ≥ 1000 > C ≥ 100 > B ≥ 10 > A
• TSA p53 Y220C dTM (deg C,100 µM):A ≥ 10 > B ≥ 5 > C ≥ 1 > D
• TSA p53 Y220C dTM (deg C,10 µM):A ≥ 10 > B ≥ 5 > C ≥ 1 > D
• CTG NUGC3 p53 Y220C IC
50(nM):D ≥ 3000 > C ≥ 1500 > B ≥ 750 > A
• CTG H1299 p53 Y220C IC
50(nM):D ≥ 3000 > C ≥ 1500 > B ≥ 750 > A
• CTG H1299 p53 R273H IC
50(nM):A ≥ 10000 > B ≥ 8000 > C ≥ 5000 > D
• CTG H1299 p53親代IC
50(nM):A ≥ 10000 > B ≥ 8000 > C ≥ 5000 > D
• Luc p53 Y220C AC
50(nM):D ≥ 3000 > C ≥ 1500 > B ≥ 750 > A
• Luc p53 Y220C Emax (nM):A ≥ 90 > B ≥ 80 > C ≥ 70 > D
表A.
TW202421628A_112140291_SEQL.xmlTW202421628A_112140291_SEQL.xml
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