TW202204334A - Menin inhibitors and methods of use for treating cancer - Google Patents
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Abstract
Description
本發明提供作為menin抑制劑之化合物及治療其中抑制menin提供益處之病狀及疾病的治療方法。The present invention provides compounds that are menin inhibitors and methods of treatment of conditions and diseases in which inhibition of menin provides benefits.
混合系白血病(MLL)為一種最初發現於人類白血病中之染色體易位位點處的原癌基因。歸因於染色體易位，MLL與多於40種不同搭配物蛋白質融合以產生嵌合融合蛋白之多種多樣的集合。MLL蛋白為一種對染色體進行共價修飾且在急性白血病之某些子集中突變之組蛋白甲基轉移酶。許多融合搭配物組成性活化MLL之新穎轉錄效應子特性，該等特性通常與其在急性白血病之動物模型中的致癌可能性相關。MLL通常與一組高度保守之輔因子結合以形成包括menin之大分子複合物，該大分子複合物為MEN1腫瘤抑制基因之產物。MEN1基因在遺傳性及偶發性內分泌腫瘤中突變。Mixed lineage leukemia (MLL) is a proto-oncogene at a chromosomal translocation site originally discovered in human leukemia. Due to chromosomal translocations, MLL is fused to more than 40 different partner proteins to generate a diverse collection of chimeric fusion proteins. The MLL protein is a histone methyltransferase that covalently modifies chromosomes and is mutated in certain subsets of acute leukemia. Many fusion partners constitutively activate novel transcriptional effector properties of MLL that are often associated with their oncogenic potential in animal models of acute leukemia. MLL typically binds to a set of highly conserved cofactors to form macromolecular complexes including menin, the product of the MEN1 tumor suppressor gene. The MEN1 gene is mutated in hereditary and sporadic endocrine tumors.
Menin涉及多種多樣的蛋白質-蛋白質相互作用網路。Cierpicki及Grembecka,Future Med. Chem. 6 :447-462 (2014)。menin之過度表現導致對經Ras轉化細胞之抑制。Menin與轉錄因子JunD及NF-κB相互作用且抑制其基因轉錄之活化。關於此等相互作用蛋白質之研究表明，menin主要經由對轉錄之抑制效果而發揮其作用。但一替代可能性為，menin經由目標基因之轉錄活化而介導其作用。另外，menin與RPA2相互作用，該RPA2為涉及DNA修復及複製之單股DNA結合蛋白質之組分。Menin亦與FANCD2相互作用，該FANCD2為在維持具有乳癌1基因(Brca1)產物之基因組穩定性方面扮演重要角色之細胞核蛋白質。Menin is involved in diverse protein-protein interaction networks. Cierpicki and Grembecka, Future Med. Chem. 6 :447-462 (2014). Overexpression of menin results in inhibition of Ras-transformed cells. Menin interacts with transcription factors JunD and NF-κB and inhibits the activation of their gene transcription. Studies of these interacting proteins suggest that menin exerts its effects primarily through repressive effects on transcription. An alternative possibility, however, is that menin mediates its effects through transcriptional activation of target genes. Additionally, menin interacts with RPA2, a component of single-stranded DNA-binding proteins involved in DNA repair and replication. Menin also interacts with FANCD2, a nuclear protein that plays an important role in maintaining the stability of the genome with the product of the breast cancer 1 gene (Brca1).
與其他蛋白質不具有顯著同源性之menin藉以充當腫瘤抑制因子的機制未得到完全理解。Menin在調節細胞增殖方面起作用，此係因為MEN1基因剔除小鼠顯示在神經內分泌組織中增殖增加，上皮細胞中menin之下調增加增殖，且如藉由氚化胸苷併入所分析，MEN1基因剔除纖維母細胞比野生型細胞更快速增殖。MEN1細胞亦對DNA損傷劑具有增加的敏感性。Menin與HOX基因之啟動子相互作用。The mechanisms by which menins, which do not share significant homology with other proteins, act as tumor suppressors are not fully understood. Menin plays a role in regulating cell proliferation as MEN1 knockout mice show increased proliferation in neuroendocrine tissues, menin downregulation in epithelial cells increases proliferation, and MEN1 knockout as analyzed by tritiated thymidine incorporation Fibroblasts proliferate more rapidly than wild-type cells. MEN1 cells also have increased sensitivity to DNA damaging agents. Menin interacts with the promoter of the HOX gene.
某些致癌MLL融合蛋白經由起始經MLL介導之白血病生成所需的高親和力相互作用而穩定地與menin結合。Menin為維持MLL相關聯但無其他癌基因誘導之骨髓轉化所必需的。menin之急性基因切除逆轉由ML-menin啟動子相關聯之複合物介導之HOX 基因表現，且特定言之消除MLL轉化白血病母細胞之分化遏止及致癌特性。Certain oncogenic MLL fusion proteins stably bind menin via high-affinity interactions required to initiate MLL-mediated leukemogenesis. Menin is required for the maintenance of MLL-associated but not other oncogene-induced myeloid transformation. Acute gene ablation of menin reverses HOX gene expression mediated by the ML-menin promoter-associated complex, and specifically abrogates the differentiation arresting and oncogenic properties of MLL-transformed leukemic blasts.
MLL融合蛋白(獲得性基因畸變之結果)經由兩種替代機制，藉由組成性轉錄效應子活性或誘導強制性MLL二聚化及寡聚化而轉化造血細胞。兩種機制導致HOX基因之子集(特定而言HOXA9)的不當表現，其一致表現為人類MLL白血病之典型特徵。MLL fusion proteins (the result of acquired genetic aberrations) transform hematopoietic cells through two alternative mechanisms, either by constitutive transcriptional effector activity or by induction of forced MLL dimerization and oligomerization. Both mechanisms lead to the inappropriate expression of a subset of HOX genes (specifically HOXA9), which are consistently characteristic of human MLL leukemia.
HOX 基因之異常表現亦見於具有NPM1 突變之AML患者中。NPM1 主要位於細胞核中且在不同細胞過程(包括核糖體組裝、核小體組裝及細胞增殖)中起作用。NPM1突變產生異常細胞質定位且構成AML中第二最頻繁突變之一，在所有AML患者中佔幾乎30%。近來已證實menin有助於調節HOX基因及活體外及活體內NPM1突變型AML細胞中之細胞增殖，但該機制大部分仍係未知的。Abnormal expression of HOX gene is also seen in AML patients with NPM1 mutation. NPM1 is primarily located in the nucleus and functions in different cellular processes, including ribosome assembly, nucleosome assembly, and cell proliferation. NPM1 mutations produce abnormal cytoplasmic localization and constitute one of the second most frequent mutations in AML, accounting for almost 30% of all AML patients. Menin has recently been shown to contribute to the regulation of HOX genes and cell proliferation in NPM1 mutant AML cells in vitro and in vivo, but the mechanism remains largely unknown.
Menin與以下相互作用：轉錄活化子，例如sc-Myb、MLL1、SMAD 1,3,5、Pem、Runx2、Hlbx9、ER、PPARγ、維生素D受體；轉錄抑制子，例如JunD、Sin3A、HDAC、EZH2、PRMT5、NFκB、Sirt1、CHES1；細胞信號傳導蛋白質，例如AKT、SOS1/GEF、β-連環蛋白、SMAD 1,3,5、NFκB、ER、PPARγ、維生素D受體；及其他蛋白質，例如細胞循環：RPA2、ASK；DNA修復：FANCD2；細胞結構：GFAP、vimenten、NMMHCIIA、IQGAP1；其他：涉及調節基因轉錄及細胞信號傳導之HSP70、CHIP (「menin相互作用蛋白質」)。Matkar,Trends in Biochemical Sciences 38 : 394-402 (2013)。靶向menin與小分子之相互作用(例如menin-MLL相互作用)呈現一種誘人的研發新抗癌劑之策略。參見 例如Cierpicki及Grembecka,Future Med. Chem. 6 :447-462 (2014)；He等人,J. Med. Chem. 57 :1543-1556 (2014)；及Borkin等人,Cancer Cell 27 :589-602 (2015); Krivtsov等人，Cancer Cell 36 : 660-673 (2019)；Klossowski等人，J. Clin. Invest. 130 :981-997 (2020)；Uckelmann等人，Science 367 :586-590 (2020)。Menin interacts with: transcriptional activators such as sc-Myb, MLL1, SMAD 1,3,5, Pem, Runx2, Hlbx9, ER, PPARγ, vitamin D receptors; transcriptional repressors such as JunD, Sin3A, HDAC, EZH2, PRMT5, NFκB, Sirt1, CHES1; cell signaling proteins such as AKT, SOS1/GEF, β-catenin, SMAD 1,3,5, NFκB, ER, PPARγ, vitamin D receptors; and other proteins such as Cell cycle: RPA2, ASK; DNA repair: FANCD2; Cell structure: GFAP, vimenten, NMMHCIIA, IQGAP1; others: HSP70, CHIP ("menin interacting proteins") involved in regulating gene transcription and cell signaling. Matkar, Trends in Biochemical Sciences 38 : 394-402 (2013). Targeting the interaction of menin with small molecules, such as the menin-MLL interaction, presents an attractive strategy to develop new anticancer agents. See , eg, Cierpicki and Grembecka, Future Med. Chem. 6 :447-462 (2014); He et al, J. Med. Chem. 57 :1543-1556 (2014); and Borkin et al, Cancer Cell 27 :589- 602 (2015); Krivtsov et al, Cancer Cell 36 : 660-673 (2019); Klossowski et al, J. Clin. Invest. 130 : 981-997 (2020); Uckelmann et al, Science 367 : 586-590 ( 2020).
破壞MLL與menin之相互作用之小分子揭示於以下中：美國專利第9,212,180號及第9,216,993號；美國專利申請公開案第2011/0065690號、第2014/0275070號、第2016/0045504號及第2016/0046647號；及國際公開案第WO 2017/192543號及第WO 2018/183857號；第WO 2019/191526號；第WO 2020/072391號及第PCT/US2020/053186號。破壞MLL與menin之相互作用的肽揭示於美國專利申請公開案第2009/0298772號中。Small molecules that disrupt the interaction of MLL with menin are disclosed in: US Patent Nos. 9,212,180 and 9,216,993; US Patent Application Publication Nos. 2011/0065690, 2014/0275070, 2016/0045504, and 2016 /0046647; and International Publication Nos. WO 2017/192543 and WO 2018/183857; WO 2019/191526; WO 2020/072391 and PCT/US2020/053186. Peptides that disrupt the interaction of MLL with menin are disclosed in US Patent Application Publication No. 2009/0298772.
持續需要新的小分子藥物以用於治療癌症及對menin抑制有反應之其他疾病。There is a continuing need for new small molecule drugs for the treatment of cancer and other diseases responsive to menin inhibition.
在一個態樣中，本發明提供式I -XXXIII 之化合物及其醫藥學上可接受之鹽，其在本文中統稱為「本發明之化合物」。本發明之化合物為menin抑制劑且因此適用於治療其中抑制menin向患者提供治療益處之疾病或病狀。In one aspect, the present invention provides compounds of Formulas I - XXXIII and pharmaceutically acceptable salts thereof, which are collectively referred to herein as "the compounds of the present invention." The compounds of the present invention are menin inhibitors and are therefore useful in the treatment of diseases or conditions in which inhibition of menin provides a therapeutic benefit to the patient.
在另一態樣中，本發明提供藉由向有需要之個體，例如人類投與治療有效量之本發明之化合物治療病狀或疾病的方法。疾病或病狀可藉由抑制menin來治療，例如癌症(例如白血病)、慢性自體免疫病症、發炎病狀、增殖性病症、敗血症或病毒性感染。亦提供預防非所需增殖性細胞(諸如癌症)在個體體內增殖之方法，其包含向處於發展特徵在於非所需增殖性細胞之病狀之風險下的個體投與治療有效量之本發明之化合物。在一些實施例中，本發明之化合物藉由在彼等細胞中誘導細胞凋亡及/或分化來減少非所需細胞之增殖。In another aspect, the present invention provides a method of treating a condition or disease by administering to an individual, eg, a human, in need thereof a therapeutically effective amount of a compound of the present invention. A disease or condition, such as cancer (eg, leukemia), chronic autoimmune disorders, inflammatory conditions, proliferative disorders, sepsis, or viral infections, can be treated by inhibiting menin. Also provided are methods of preventing the proliferation of undesired proliferative cells, such as cancer, in an individual comprising administering to an individual at risk of developing a condition characterized by undesired proliferative cells a therapeutically effective amount of one of the present invention compound. In some embodiments, the compounds of the present invention reduce the proliferation of unwanted cells by inducing apoptosis and/or differentiation in those cells.
在另一態樣中，本發明提供一種抑制個體體內之menin之方法，其包含向個體投與有效量之至少一種本發明之化合物。In another aspect, the present invention provides a method of inhibiting menin in a subject comprising administering to the subject an effective amount of at least one compound of the present invention.
在另一態樣中，本發明提供一種醫藥組合物，其包含本發明之化合物及賦形劑及/或藥學上可接受之載劑。In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention and an excipient and/or a pharmaceutically acceptable carrier.
在另一態樣中，本發明提供一種組合物，其包含本發明之化合物及賦形劑及/或醫藥學上可接受之載劑，以用於治療其中抑制menin提供益處之疾病或病狀(例如癌症)。In another aspect, the present invention provides a composition comprising a compound of the present invention and an excipient and/or a pharmaceutically acceptable carrier for use in the treatment of a disease or condition in which inhibition of menin provides benefit (eg cancer).
在另一態樣中，本發明提供一種組合物，其包含：(a)本發明之化合物；(b)第二治療活性劑；及(c)視情況選用之賦形劑及/或醫藥學上可接受之載劑。In another aspect, the present invention provides a composition comprising: (a) a compound of the present invention; (b) a second therapeutically active agent; and (c) optional excipients and/or pharmaceuticals acceptable carrier.
在另一態樣中，本發明提供一種用於治療所關注疾病或病狀(例如癌症)之本發明之化合物。In another aspect, the present invention provides a compound of the present invention for use in the treatment of a disease or condition of interest (eg, cancer).
在另一態樣中，本發明提供一種本發明之化合物之用途，其用於製造用於治療所關注疾病或病狀，例如癌症的藥劑。In another aspect, the present invention provides the use of a compound of the present invention in the manufacture of a medicament for the treatment of a disease or condition of interest, such as cancer.
在另一態樣中，本發明提供一種套組，其包含本發明之化合物，及視情況選用之包含適用於治療所關注疾病或病狀之第二治療劑的經封裝組合物，以及含有用於治療疾病或病狀(例如癌症)之說明的藥品說明書。In another aspect, the present invention provides a kit comprising a compound of the present invention, and optionally an encapsulated composition comprising a second therapeutic agent suitable for the treatment of a disease or condition of interest, and a A package insert with instructions for treating a disease or condition (eg, cancer).
本發明之另外實施例及優點將部分地在隨後的說明書中闡述且將經由說明書瞭解，或可藉由實踐本發明學習。本發明之實施例及優點將藉助於在隨附申請專利範圍中特別指出的要素及組合來認識到並達到。Additional embodiments and advantages of the invention will be set forth, in part, in the description that follows and will be learned from the description, or may be learned by practice of the invention. The embodiments and advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.
應理解，前述發明內容與以下實施方式僅為例示性及解釋性的，且不限制如所主張之本發明。It is to be understood that the foregoing summary and the following embodiments are exemplary and explanatory only and do not limit the invention as claimed.
相關申請案之交叉參考Cross-references to related applications
本申請案主張2020年4月8日提交之PCT申請案第PCT/CN2020/083753號及2020年9月29日提交之PCT申請案第PCT/CN2020/118816號的權益，其中之每一者之揭示內容以全文引用之方式併入。 美國政府許可權This application claims the benefit of PCT Application No. PCT/CN2020/083753, filed on April 8, 2020, and PCT Application No. PCT/CN2020/118816, filed on September 29, 2020, each of which The disclosure is incorporated by reference in its entirety. U.S. Government Licensing Rights
本發明係在美國政府支援下在由美國國家衛生研究院(National Institutes of Health)授予的授權號CA208267下進行。美國政府享有本發明的某些權利。 I. 本發明之化合物This invention was made with US Government support under Grant No. CA208267 awarded by the National Institutes of Health. The US Government has certain rights in this invention. I. Compounds of the present invention
本發明之化合物為menin抑制劑。The compounds of the present invention are menin inhibitors.
在一個實施例中，本發明之化合物為由式I
表示之化合物，
在另一實施例中，本發明之化合物為由式I 表示之化合物及其醫藥學上可接受之鹽，其中B為B-1、B-2、B-3、B-4、B-5或B-6。In another embodiment, the compound of the present invention is a compound represented by formula I and a pharmaceutically acceptable salt thereof, wherein B is B-1, B-2, B-3, B-4, B-5 or B-6.
在另一實施例中，本發明之化合物為由式I 表示之化合物及其醫藥學上可接受之鹽，其中各Ra 及Rb 為氫。In another embodiment, the compounds of the present invention are compounds represented by Formula I , and pharmaceutically acceptable salts thereof, wherein each of R a and R b is hydrogen.
在另一實施例中，本發明之化合物為由式II
或式III
中之任一者或多者表示之化合物：
在另一實施例中，本發明之化合物為由式II-III 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae II-III and pharmaceutically acceptable salts thereof.
在另一實施例中，本發明之化合物為由式II 表示之化合物及其醫藥學上可接受之鹽，其中E為E-1、E-2、E-3、E-4、E-5、E-6、E-7、E-8、E-9或E-10。In another embodiment, the compound of the present invention is a compound represented by formula II and a pharmaceutically acceptable salt thereof, wherein E is E-1, E-2, E-3, E-4, E-5 , E-6, E-7, E-8, E-9 or E-10.
在另一實施例中，本發明之化合物為由式II 表示之化合物及其醫藥學上可接受之鹽，其中E為E-1。In another embodiment, the compound of the present invention is a compound represented by formula II and pharmaceutically acceptable salts thereof, wherein E is E-1.
在另一實施例中，本發明之化合物為由式II 表示之化合物及其醫藥學上可接受之鹽，其中E為E-2。In another embodiment, the compounds of the present invention are compounds represented by Formula II and pharmaceutically acceptable salts thereof, wherein E is E-2.
在另一實施例中，本發明之化合物為由式II 表示之化合物及其醫藥學上可接受之鹽，其中E為E-3、E-4、E-5、E-6、E-7、E-8、E-9或E-10。In another embodiment, the compound of the present invention is a compound represented by formula II and a pharmaceutically acceptable salt thereof, wherein E is E-3, E-4, E-5, E-6, E-7 , E-8, E-9 or E-10.
在另一實施例中，本發明之化合物為由式III 表示之化合物及其醫藥學上可接受之鹽，其中E為E-11或E-12。In another embodiment, the compound of the present invention is a compound represented by formula III and pharmaceutically acceptable salts thereof, wherein E is E-11 or E-12.
在另一實施例中，本發明之化合物為由式II 表示之化合物及其醫藥學上可接受之鹽，其中E為E-13或E-14。In another embodiment, the compounds of the present invention are compounds represented by formula II and pharmaceutically acceptable salts thereof, wherein E is E-13 or E-14.
在另一實施例中，本發明之化合物為由式IV-XIII
中之任一者或多者表示之化合物：
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽。In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XIII and pharmaceutically acceptable salts thereof.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中至少一個Ra 為氫。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein at least one R a is hydrogen.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中各Ra 為氫。In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein each R a is hydrogen.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中至少一個Rb 為氫。In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein at least one Rb is hydrogen.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中各Rb 為氫。In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein each Rb is hydrogen.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中各Ra 及Rb 為氫。In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein each of R a and R b is hydrogen.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中Rc 為氫。In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein Rc is hydrogen.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中Rc 為鹵基。In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein Rc is halo.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中Rc 為氟。In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein Rc is fluoro.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中n為0。In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein n is 0.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中n為1。In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein n is 1.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中n為2。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein n is 2.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中n為0且Rc 為氫。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein n is 0 and Rc is hydrogen.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中n為1且Rc 為氫。In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein n is 1 and Rc is hydrogen.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中n為0且Rc 為鹵基。In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein n is 0 and Rc is halo.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中n為0且Rc 為氟。In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein n is 0 and Rc is fluoro.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中n為1且Rd 為鹵基。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein n is 1 and Rd is halo.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中n為1且Rd 為氟。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein n is 1 and Rd is fluoro.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中n為1且Rc 及Rd 各為氟。In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulas I-XIII , and pharmaceutically acceptable salts thereof, wherein n is 1 and Rc and Rd are each fluorine.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中R2 為氫。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein R2 is hydrogen .
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中R2 為鹵基。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I - XIII , and pharmaceutically acceptable salts thereof, wherein R2 is halo.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中R2 為氟。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I - XIII , and pharmaceutically acceptable salts thereof, wherein R2 is fluoro.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中R2 為甲氧基。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I - XIII , and pharmaceutically acceptable salts thereof, wherein R2 is methoxy.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中R2 為羥基。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I - XIII , and pharmaceutically acceptable salts thereof, wherein R2 is hydroxy.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中R為-C1 -C4 烷基。In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein R is -C 1 -C 4 alkyl.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中R為甲基。In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein R is methyl.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中R為-C1 -C4 鹵烷基。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein R is -C 1 -C 4 haloalkyl .
在另一實施例中，本發明之後化合物為由式I-XIII 表示之化合物及其醫藥學上可接受之鹽，其中B為B-1或B-2。In another embodiment, the compounds following the present invention are compounds represented by formulae I-XIII and pharmaceutically acceptable salts thereof, wherein B is B-1 or B-2.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中B為B-1。In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein B is B-1.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中B為B-2。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein B is B-2.
在另一實施例中，本發明之化合物為由式I-XIII 表示之化合物及其醫藥學上可接受之鹽，其中B為B-3。In another embodiment, the compounds of the present invention are compounds represented by formulae I-XIII and pharmaceutically acceptable salts thereof, wherein B is B-3.
在另一實施例中，本發明之化合物為由式I-XIII 表示之化合物及其醫藥學上可接受之鹽，其中B為B-4。In another embodiment, the compounds of the present invention are compounds represented by formulae I-XIII and pharmaceutically acceptable salts thereof, wherein B is B-4.
在另一實施例中，本發明之化合物為由式I-XIII 表示之化合物及其醫藥學上可接受之鹽，其中B為B-5。In another embodiment, the compounds of the present invention are compounds represented by formulas I-XIII and pharmaceutically acceptable salts thereof, wherein B is B-5.
在另一實施例中，本發明之化合物為由式I-XIII 表示之化合物及其醫藥學上可接受之鹽，其中B為B-6。In another embodiment, the compounds of the present invention are compounds represented by formulas I-XIII and pharmaceutically acceptable salts thereof, wherein B is B-6.
在另一實施例中，本發明之化合物為由式I-XIII 表示之化合物及其醫藥學上可接受之鹽，其中B為B-6，其中烷基為甲基。In another embodiment, the compounds of the present invention are compounds represented by formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein B is B-6, wherein alkyl is methyl.
在另一實施例中，本發明之化合物為由式I-XIII 表示之化合物及其醫藥學上可接受之鹽，其中B為B-7。In another embodiment, the compounds of the present invention are compounds represented by formulae I-XIII and pharmaceutically acceptable salts thereof, wherein B is B-7.
在另一實施例中，本發明之化合物為由式I-XIII 表示之化合物及其醫藥學上可接受之鹽，其中B為B-7，其中烷基為甲基。In another embodiment, the compounds of the present invention are compounds represented by formulae I-XIII and pharmaceutically acceptable salts thereof, wherein B is B-7, wherein alkyl is methyl.
在另一實施例中，本發明之化合物為由式I-XIII 表示之化合物及其醫藥學上可接受之鹽，其中B為B-8。In another embodiment, the compounds of the present invention are compounds represented by formulae I-XIII and pharmaceutically acceptable salts thereof, wherein B is B-8.
在另一實施例中，本發明之化合物為由式I-XIII 表示之化合物及其醫藥學上可接受之鹽，其中B為B-9。In another embodiment, the compounds of the present invention are compounds represented by formulas I-XIII and pharmaceutically acceptable salts thereof, wherein B is B-9.
在另一實施例中，本發明之化合物為由式I-XIII 表示之化合物及其醫藥學上可接受之鹽，其中B為B-10。In another embodiment, the compounds of the present invention are compounds represented by formulae I-XIII and pharmaceutically acceptable salts thereof, wherein B is B-10.
在另一實施例中，本發明之化合物為由式I-XIII 表示之化合物及其醫藥學上可接受之鹽，其中B為B-11。In another embodiment, the compounds of the present invention are compounds represented by formulae I-XIII and pharmaceutically acceptable salts thereof, wherein B is B-11.
在另一實施例中，本發明之化合物為由式I-XIII 表示之化合物及其醫藥學上可接受之鹽，其中B為B-12。In another embodiment, the compounds of the present invention are compounds represented by formulas I-XIII and pharmaceutically acceptable salts thereof, wherein B is B-12.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中R3a 及R3b 中之至少一者為氫。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein at least one of R 3a and R 3b is hydrogen.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中R3a 及R3b 兩者皆為氫。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein both R3a and R3b are hydrogen.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中R3a 及R3b 中之至少一者為鹵基。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein at least one of R 3a and R 3b is Halogen.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中R3a 及R3b 兩者皆為鹵基。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein both R 3a and R 3b are halo .
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中R3a 及R3b 中之至少一者為氟。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein at least one of R 3a and R 3b is fluorine.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中R3a 及R3b 兩者皆為氟。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein both R3a and R3b are fluoro.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中R3a 及R3b 中之至少一者為C1 -C4 烷基。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein at least one of R 3a and R 3b is C 1 -C 4 alkyl.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中R3a 及R3b 兩者皆為C1 -C4 烷基。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein both R 3a and R 3b are C 1 -C 4 alkyl.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中R3a 及R3b 中之至少一者為Me。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein at least one of R 3a and R 3b is Me.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中R3a 及R3b 兩者皆為Me。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein both R 3a and R 3b are Me.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中R3a 及R3b 中之至少一者為-CH2 NMe2 。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein at least one of R 3a and R 3b is -CH 2 NMe 2 .
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中R3a 及R3b 中之至少一者為-C(O)NMe2 。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein at least one of R 3a and R 3b is -C(O)NMe 2 .
在另一實施例中，本發明之化合物為由式I-XIII
中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中R3a
及R3b
中之至少一者為
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中X為X-1、X-2、X-3、X-4、X-5、X-6、X-7、X-8、X-9、X-10、X-11、X-12或X-13。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein X is X-1, X-2, X -3, X-4, X-5, X-6, X-7, X-8, X-9, X-10, X-11, X-12 or X-13.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中X為X-1、X-2、X-3、X-4、X-6、X-7、X-8、X-9、X-10、X-11、X-12或X-13。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein X is X-1, X-2, X -3, X-4, X-6, X-7, X-8, X-9, X-10, X-11, X-12 or X-13.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中X為X-14或X-15。In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein X is X-14 or X-15.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中X為X-1。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein X is X-1.
在另一實施例中，本發明之化合物為由式I-XIII
中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中X為X-1。在另一實施例中，o及p為0。在另一實施例中，X-1選自由以下組成之群：
在另一實施例中，X-1選自由以下組成之群：
在另一實施例中，X-1選自由以下組成之群：
在另一實施例中，X-1選自由以下組成之群：
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中X為X-2。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein X is X-2.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中X為X-3。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein X is X-3.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中X為X-4。In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein X is X-4.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中X為X-5。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein X is X-5.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中X為X-5且R10 為-CH2 CH=CH-Ra3 。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein X is X- 5 and R10 is -CH 2 CH=CH-R a3 .
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中X為X-6。In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein X is X-6.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中X為X-7。In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein X is X-7.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中X為X-8。In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein X is X-8.
在另一實施例中，本發明之化合物為由式I-XIII
中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中X為X-9。在另一實施例中，o及p為0。在另一實施例中，X-9選自由以下組成之群：
在另一實施例中，X-9選自由以下組成之群：
在另一實施例中，X-9選自由以下組成之群：
在另一實施例中，X-9選自由以下組成之群：
在另一實施例中，本發明之化合物為由式I-XIII
中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中X為X-10。在另一實施例中，o及p為0。在另一實施例中，X-10選自由以下組成之群：
在另一實施例中，X-10選自由以下組成之群：
在另一實施例中，X-10選自由以下組成之群：
在另一實施例中，X-10選自由以下組成之群：
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中X為X-11。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein X is X-11.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中X為X-12。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein X is X-12.
在另一實施例中，本發明之化合物為由式I-XIII
中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中X為X-13。在另一實施例中，o及p為0。在另一實施例中，X-13選自由以下組成之群：
在另一實施例中，X-13選自由以下組成之群：
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中X為X-14。In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein X is X-14.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中X為X-14且R6 為鹵基。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein X is X- 14 and R6 is halo .
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中X為X-15。In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein X is X-15.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中E為E-3。In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein E is E-3.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中m為1。In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein m is 1.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中m為2。In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein m is 2.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中J為-CN。In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein J is -CN.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中J為烷基磺醯基。In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein J is alkylsulfonyl.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中J為環烷基磺醯基。In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein J is cycloalkylsulfonyl.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中J為雜芳基磺醯基。In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein J is heteroarylsulfonyl.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中J為芳基磺醯基。In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein J is arylsulfonyl.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中J為雜環烷基磺醯基。In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein J is heterocycloalkylsulfonyl.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中J為甲醯胺基。In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein J is carboxamido.
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中J為-SO2 X。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein J is -SO2X .
在另一實施例中，本發明之化合物為由式I-XIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中J為-SO2 X且X為X-1、X-2、X-5或X-8。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XIII , and pharmaceutically acceptable salts thereof, wherein J is -SO2X and X is X- 1. X-2, X-5 or X-8.
在一些實施例中，本發明提供一種選自式XIV-XVIII
中之任一者之化合物：
在另一實施例中，本發明之化合物為由式XIV-XVIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XIV-XVIII and pharmaceutically acceptable salts thereof.
在另一實施例中，本發明之化合物為由式XIV-XVIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中Rc 為氫。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XIV-XVIII , and pharmaceutically acceptable salts thereof, wherein Rc is hydrogen.
在另一實施例中，本發明之化合物為由式XIV-XVIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中Rc 為鹵基。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XIV-XVIII , and pharmaceutically acceptable salts thereof, wherein Rc is halo.
在另一實施例中，本發明之化合物為由式XIV-XVIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中Rc 為氟。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XIV-XVIII , and pharmaceutically acceptable salts thereof, wherein Rc is fluoro.
在另一實施例中，本發明之化合物為由式XIV-XVIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中R2 為H。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XIV - XVIII , and pharmaceutically acceptable salts thereof, wherein R2 is H.
在另一實施例中，本發明之化合物為由式XIV-XVIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中R2 為氟。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XIV-XVIII , and pharmaceutically acceptable salts thereof, wherein R2 is fluoro.
在另一實施例中，本發明之化合物為由式XIV-XVIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中R2 為甲氧基。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XIV-XVIII , and pharmaceutically acceptable salts thereof, wherein R2 is methoxy.
在另一實施例中，本發明之化合物為由式XIV-XVIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中R2 為羥基。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XIV-XVIII , and pharmaceutically acceptable salts thereof, wherein R2 is hydroxy.
在另一實施例中，本發明之化合物為由式XIV-XVIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中R3a 及R3b 為H。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XIV-XVIII , and pharmaceutically acceptable salts thereof, wherein R3a and R3b are H.
在另一實施例中，本發明之化合物為由式XIV-XVIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中R3a 及R3b 中之至少一者為鹵基。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XIV-XVIII , and pharmaceutically acceptable salts thereof, wherein at least one of R 3a and R 3b is Halogen.
在另一實施例中，本發明之化合物為由式XIV-XVIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中R3a 及R3b 中之至少一者為氟。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XIV-XVIII , and pharmaceutically acceptable salts thereof, wherein at least one of R 3a and R 3b is fluorine.
在另一實施例中，本發明之化合物為由式XIV-XVIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中R3a 及R3b 為氟。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XIV-XVIII , and pharmaceutically acceptable salts thereof, wherein R3a and R3b are fluoro.
在另一實施例中，本發明之化合物為由式XIV-XVIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中R3a 及R3b 中之至少一者為C1 -C4 烷基。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XIV-XVIII , and pharmaceutically acceptable salts thereof, wherein at least one of R 3a and R 3b is C 1 -C 4 alkyl.
在另一實施例中，本發明之化合物為由式XIV-XVIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中R3a 及R3b 中之至少一者為Me。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XIV-XVIII , and pharmaceutically acceptable salts thereof, wherein at least one of R 3a and R 3b is Me.
在另一實施例中，本發明之化合物為由式XIV-XVIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中R3a 及R3b 中之至少一者為-CH2 NMe2 。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XIV-XVIII , and pharmaceutically acceptable salts thereof, wherein at least one of R 3a and R 3b is -CH 2 NMe 2 .
在另一實施例中，本發明之化合物為由式XIV-XVIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中R3a 及R3b 中之至少一者為-C(O)NMe2 。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XIV-XVIII , and pharmaceutically acceptable salts thereof, wherein at least one of R 3a and R 3b is -C(O)NMe 2 .
在另一實施例中，本發明之化合物為由式XIV-XVIII
中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中R3a
及R3b
中之至少一者為
在另一實施例中，本發明之化合物為由式XIV-XVIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中R3a 為-CH2 NMe2 且R3b 為氟。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XIV-XVIII , and pharmaceutically acceptable salts thereof, wherein R 3a is -CH 2 NMe 2 and R 3b is fluorine.
在另一實施例中，本發明之化合物為由式XIV-XVIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中R3a 為氟且R3b 為-CH2 NMe2 。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XIV-XVIII , and pharmaceutically acceptable salts thereof, wherein R3a is fluoro and R3b is -CH2 NMe 2 .
在另一實施例中，本發明之化合物為由式XIV-XVIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中X為X-1、X-2、X-3、X-4、X-5、X-6、X-7、X-8、X-9、X-10、X-11、X-12或X-13。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XIV-XVIII , and pharmaceutically acceptable salts thereof, wherein X is X-1, X-2, X -3, X-4, X-5, X-6, X-7, X-8, X-9, X-10, X-11, X-12 or X-13.
在另一實施例中，本發明之化合物為由式XIV-XVIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中X為X-1、X-2、X-3、X-4、X-6、X-7、X-8、X-9、X-10、X-11、X-12或X-13。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XIV-XVIII , and pharmaceutically acceptable salts thereof, wherein X is X-1, X-2, X -3, X-4, X-6, X-7, X-8, X-9, X-10, X-11, X-12 or X-13.
在另一實施例中，本發明之化合物為由式XIV-XVIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中X為X-14或X-15。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XIV-XVIII , and pharmaceutically acceptable salts thereof, wherein X is X-14 or X-15.
在另一實施例中，本發明之化合物為由式XIV-XVIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中X為X-1。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XIV-XVIII , and pharmaceutically acceptable salts thereof, wherein X is X-1.
在另一實施例中，本發明之化合物為由式XIV-XVIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中X為X-2。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XIV-XVIII , and pharmaceutically acceptable salts thereof, wherein X is X-2.
在另一實施例中，本發明之化合物為由式XIV-XVIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中X為X-5。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XIV-XVIII , and pharmaceutically acceptable salts thereof, wherein X is X-5.
在另一實施例中，本發明之化合物為由式XIV-XVIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中X為X-5且R10 為-CH2 CH=CH-Ra3 。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XIV-XVIII , and pharmaceutically acceptable salts thereof, wherein X is X- 5 and R10 is -CH 2 CH=CH-R a3 .
在另一實施例中，本發明之化合物為由式XIV-XVIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中X為X-6。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XIV-XVIII , and pharmaceutically acceptable salts thereof, wherein X is X-6.
在另一實施例中，本發明之化合物為由式XIV-XVIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中X為X-10。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XIV-XVIII , and pharmaceutically acceptable salts thereof, wherein X is X-10.
在另一實施例中，本發明之化合物為由式XIV-XVIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中X為X-11。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XIV-XVIII , and pharmaceutically acceptable salts thereof, wherein X is X-11.
在另一實施例中，本發明之化合物為由式XIV-XVIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中X為X-14。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XIV-XVIII , and pharmaceutically acceptable salts thereof, wherein X is X-14.
在另一實施例中，本發明之化合物為由式XIV-XVIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中X為X-14且R6 為鹵基。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XIV-XVIII , and pharmaceutically acceptable salts thereof, wherein X is X- 14 and R6 is halo .
在另一實施例中，本發明之化合物為由式XIV-XVIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中X為X-15。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XIV-XVIII , and pharmaceutically acceptable salts thereof, wherein X is X-15.
在一些實施例中，本發明提供一種選自式XIX-XXIV
中之任一者之化合物：
在另一實施例中，本發明之化合物為由式XIX-XXIV 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XIX-XXIV and pharmaceutically acceptable salts thereof.
在另一實施例中，本發明之化合物為由式XIX-XXIV 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中X為X-1、X-2、X-3、X-4、X-5、X-6、X-7、X-8、X-9、X-10、X-11、X12或X-13。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XIX-XXIV , and pharmaceutically acceptable salts thereof, wherein X is X-1, X-2, X -3, X-4, X-5, X-6, X-7, X-8, X-9, X-10, X-11, X12 or X-13.
在另一實施例中，本發明之化合物為由式XIX-XXIV 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中X為X-1、X-2、X-3、X-4、X-6、X-7、X-8、X9-、X-10、X-11、X12或X-13。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XIX-XXIV , and pharmaceutically acceptable salts thereof, wherein X is X-1, X-2, X -3, X-4, X-6, X-7, X-8, X9-, X-10, X-11, X12 or X-13.
在另一實施例中，本發明之化合物為由式XIX-XXIV 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中X為X-14或X-15。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XIX-XXIV , and pharmaceutically acceptable salts thereof, wherein X is X-14 or X-15.
在另一實施例中，本發明之化合物為由式XIX-XXIV 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中X為X-1、X-2、X-4、X-5、X-6、X-7、X-8、X-9、X-10、X-11、X12或X-13。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XIX-XXIV , and pharmaceutically acceptable salts thereof, wherein X is X-1, X-2, X -4, X-5, X-6, X-7, X-8, X-9, X-10, X-11, X12 or X-13.
在另一實施例中，本發明之化合物為由式XIX-XXIV 表示之化合物及其醫藥學上可接受之鹽，其中X為X-1。In another embodiment, the compounds of the present invention are compounds represented by formulas XIX-XXIV and pharmaceutically acceptable salts thereof, wherein X is X-1.
在另一實施例中，本發明之化合物為由式XIX-XXIV 表示之化合物及其醫藥學上可接受之鹽，其中X為X-2。In another embodiment, the compounds of the present invention are compounds represented by formulas XIX-XXIV and pharmaceutically acceptable salts thereof, wherein X is X-2.
在另一實施例中，本發明之化合物為由式XIX-XXIV 表示之化合物及其醫藥學上可接受之鹽，其中X為X-4。In another embodiment, the compounds of the present invention are compounds represented by formulas XIX-XXIV and pharmaceutically acceptable salts thereof, wherein X is X-4.
在另一實施例中，本發明之化合物為由式XIX-XXIV 表示之化合物及其醫藥學上可接受之鹽，其中X為X-5。In another embodiment, the compounds of the present invention are compounds represented by formulas XIX-XXIV and pharmaceutically acceptable salts thereof, wherein X is X-5.
在另一實施例中，本發明之化合物為由式XIX-XXIV 表示之化合物及其醫藥學上可接受之鹽，其中X為X-6。In another embodiment, the compounds of the present invention are compounds represented by formulas XIX-XXIV and pharmaceutically acceptable salts thereof, wherein X is X-6.
在另一實施例中，本發明之化合物為由式XIX-XXIV 表示之化合物及其醫藥學上可接受之鹽，其中X為X-7。In another embodiment, the compounds of the present invention are compounds represented by formulas XIX-XXIV and pharmaceutically acceptable salts thereof, wherein X is X-7.
在另一實施例中，本發明之化合物為由式XIX-XXIV 表示之化合物及其醫藥學上可接受之鹽，其中X為X-8。In another embodiment, the compounds of the present invention are compounds represented by formulas XIX-XXIV and pharmaceutically acceptable salts thereof, wherein X is X-8.
在另一實施例中，本發明之化合物為由式XIX-XXIV 表示之化合物及其醫藥學上可接受之鹽，其中X為X-9。In another embodiment, the compounds of the present invention are compounds represented by formulas XIX-XXIV and pharmaceutically acceptable salts thereof, wherein X is X-9.
在另一實施例中，本發明之化合物為由式XIX-XXIV 表示之化合物及其醫藥學上可接受之鹽，其中X為X-10。In another embodiment, the compounds of the present invention are compounds represented by formulas XIX-XXIV and pharmaceutically acceptable salts thereof, wherein X is X-10.
在另一實施例中，本發明之化合物為由式XIX-XXIV 表示之化合物及其醫藥學上可接受之鹽，其中X為X-11。In another embodiment, the compounds of the present invention are compounds represented by formulas XIX-XXIV and pharmaceutically acceptable salts thereof, wherein X is X-11.
在另一實施例中，本發明之化合物為由式XIX-XXIV 表示之化合物及其醫藥學上可接受之鹽，其中X為X-12。In another embodiment, the compounds of the present invention are compounds represented by formulas XIX-XXIV and pharmaceutically acceptable salts thereof, wherein X is X-12.
在另一實施例中，本發明之化合物為由式XIX-XXIV 表示之化合物及其醫藥學上可接受之鹽，其中X為X-13。In another embodiment, the compounds of the present invention are compounds represented by formulas XIX-XXIV and pharmaceutically acceptable salts thereof, wherein X is X-13.
在一些實施例中，本發明提供一種選自式XXV-XXVI
中之任一者之化合物：
在另一實施例中，本發明之化合物為由式XXV-XXVI 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXV-XXVI and pharmaceutically acceptable salts thereof.
在另一實施例中，本發明之化合物為由式XXV-XXVI 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中Ra 為氫。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXV-XXVI , and pharmaceutically acceptable salts thereof, wherein Ra is hydrogen.
在另一實施例中，本發明之化合物為由式XXV-XXVI 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中Ra 為甲基。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXV-XXVI , and pharmaceutically acceptable salts thereof, wherein Ra is methyl.
在一些實施例中，本發明提供一種選自式XXVII-XXVIII
中之任一者的化合物：
在一些實施例中，本發明提供一種選自式XXIX-XXX
中之任一者之化合物：
在另一實施例中，本發明之化合物為由式XXVII-XXVIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中J為-CN。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXVII-XXVIII , and pharmaceutically acceptable salts thereof, wherein J is -CN.
在另一實施例中，本發明之化合物為由式XXVII-XXVIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中J為烷基磺醯基。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXVII-XXVIII , and pharmaceutically acceptable salts thereof, wherein J is alkylsulfonyl.
在另一實施例中，本發明之化合物為由式XXVII-XXVIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中J為環烷基磺醯基。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXVII-XXVIII , and pharmaceutically acceptable salts thereof, wherein J is cycloalkylsulfonyl.
在另一實施例中，本發明之化合物為由式XXVII-XXVIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中J為雜芳基磺醯基。In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae XXVII-XXVIII , and pharmaceutically acceptable salts thereof, wherein J is heteroarylsulfonyl.
在另一實施例中，本發明之化合物為由式XXVII-XXVIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中J為芳基磺醯基。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXVII-XXVIII , and pharmaceutically acceptable salts thereof, wherein J is arylsulfonyl.
在另一實施例中，本發明之化合物為由式XXVII-XXVIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中J為雜環烷基磺醯基。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXVII-XXVIII , and pharmaceutically acceptable salts thereof, wherein J is heterocycloalkylsulfonyl.
在另一實施例中，本發明之化合物為由式XXVII-XXVIII 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中J為甲醯胺基。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXVII-XXVIII , and pharmaceutically acceptable salts thereof, wherein J is carboxamido.
在另一實施例中，本發明之化合物為由式XXVII-XXX 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中R4 為氫。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXVII - XXX , and pharmaceutically acceptable salts thereof, wherein R4 is hydrogen.
在另一實施例中，本發明之化合物為由式XXVII-XXX 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中R4 為甲基。In another embodiment, the compound of the present invention is a compound represented by any one or more of formulae XXVII-XXX , and pharmaceutically acceptable salts thereof, wherein R4 is methyl.
在另一實施例中，本發明之化合物為由式XXVII-XXX 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中Q為-NHCO2 CH3 。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXVII-XXX , and pharmaceutically acceptable salts thereof, wherein Q is -NHCO2CH3 .
在另一實施例中，本發明之化合物為由式XXVII-XXX 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中Rc 為鹵基。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXVII-XXX , and pharmaceutically acceptable salts thereof, wherein Rc is halo.
在另一實施例中，本發明之化合物為由式XXVII-XXX 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中Rc 為氟。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXVII-XXX , and pharmaceutically acceptable salts thereof, wherein Rc is fluoro.
在另一實施例中，本發明之化合物為由式XXVII-XXX 中之任一者或多者表示之化合物及其醫藥學上可接受之鹽，其中R2 為氫。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXVII-XXX , and pharmaceutically acceptable salts thereof, wherein R2 is hydrogen .
在一個實施例中，本發明之化合物為由式XXXI
表示之化合物：
在另一實施例中，本發明之化合物為由式XXXI
表示之化合物及其醫藥學上可接受之鹽，其中B為
在另一實施例中，本發明之化合物為由式XXXI 表示之化合物及其醫藥學上可接受之鹽，其中各Ra 及Rb 為氫。In another embodiment, the compounds of the present invention are compounds represented by formula XXXI and pharmaceutically acceptable salts thereof, wherein each of R a and R b is hydrogen.
在另一實施例中，本發明之化合物為由式XXXI 表示之化合物及其醫藥學上可接受之鹽，其中Rc 為氟且各n為0。In another embodiment, the compounds of the present invention are compounds represented by formula XXXI and pharmaceutically acceptable salts thereof, wherein Rc is fluorine and each n is 0.
在另一實施例中，本發明之化合物為由式XXXI 表示之化合物及其醫藥學上可接受之鹽，其中R為甲基。In another embodiment, the compound of the present invention is a compound represented by formula XXXI and pharmaceutically acceptable salts thereof, wherein R is methyl.
在一個實施例中，本發明之化合物為由式XXXII
表示之化合物：
在另一實施例中，本發明之化合物為由式XXXII 表示之化合物及其醫藥學上可接受之鹽，其中B為B-1或B-2。In another embodiment, the compound of the present invention is a compound represented by formula XXXII and a pharmaceutically acceptable salt thereof, wherein B is B-1 or B-2.
在另一實施例中，本發明之化合物為由式XXXII 表示之化合物及其醫藥學上可接受之鹽，其中R為甲基。In another embodiment, the compound of the present invention is a compound represented by formula XXXII and pharmaceutically acceptable salts thereof, wherein R is methyl.
在一個實施例中，本發明之化合物為由式XXXIII
表示之化合物，
在另一實施例中，本發明之化合物為由式XXXIII 表示之化合物及其醫藥學上可接受之鹽，其中R27 為甲基磺醯基。In another embodiment, the compound of the present invention is a compound represented by formula XXXIII and pharmaceutically acceptable salts thereof, wherein R 27 is methylsulfonyl.
在另一實施例中，本發明之化合物為由式XXXIII 表示之化合物及其醫藥學上可接受之鹽，其中R27 為環丙基磺醯基。In another embodiment, the compound of the present invention is a compound represented by formula XXXIII and pharmaceutically acceptable salts thereof, wherein R 27 is cyclopropylsulfonyl.
在另一實施例中，本發明之化合物為表1、1A、1B及1C之化合物中之任一者或多者及其醫藥學上可接受之鹽。表1、1A、1B及1C進一步提供表1、1A、1B及1C之化合物之化學名稱，其由Chemdraw®專業版16.0產生。若在其化學結構與化學名稱之間具有任何不明確性，本發明之化合物由其化學結構限定。
表1
在另一實施例中，本發明提供一種醫藥組合物，其包含本發明之化合物及醫藥學上可接受之載劑。In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier.
在另一實施例中，本發明之化合物為對映異構性增濃的，例如化合物之對映異構體過量或「ee」為約5%或更多，如藉由對掌性HPLC所量測。在另一實施例中，ee為約10%。在另一實施例中，ee為約20%。在另一實施例中，ee為約30%。在另一實施例中，ee為約40%。在另一實施例中，ee為約50%。在另一實施例中，ee為約60%。在另一實施例中，ee為約70%。在另一實施例中，ee為約80%。在另一實施例中，ee為約85%。在另一實施例中，ee為約90%。在另一實施例中，ee為約91%。在另一實施例中，ee為約92%。在另一實施例中，ee為約93%。在另一實施例中，ee為約94%。在另一實施例中，ee為約95%。在另一實施例中，ee為約96%。在另一實施例中，ee為約97%。在另一實施例中，ee為約98%。在另一實施例中，ee為約99%。In another embodiment, the compounds of the present invention are enantiomerically enriched, eg, the compounds have an enantiomeric excess or "ee" of about 5% or more, as determined by chiral HPLC Measure. In another embodiment, the ee is about 10%. In another embodiment, the ee is about 20%. In another embodiment, the ee is about 30%. In another embodiment, the ee is about 40%. In another embodiment, the ee is about 50%. In another embodiment, the ee is about 60%. In another embodiment, the ee is about 70%. In another embodiment, the ee is about 80%. In another embodiment, the ee is about 85%. In another embodiment, the ee is about 90%. In another embodiment, the ee is about 91%. In another embodiment, the ee is about 92%. In another embodiment, the ee is about 93%. In another embodiment, the ee is about 94%. In another embodiment, the ee is about 95%. In another embodiment, the ee is about 96%. In another embodiment, the ee is about 97%. In another embodiment, the ee is about 98%. In another embodiment, the ee is about 99%.
本發明涵蓋本發明之化合物之鹽的製備及用途。如本文所用，藥物「醫藥學上可接受之鹽」係指本發明之化合物之鹽或兩性離子形式。本發明之化合物之鹽可在化合物之最終分離及純化期間製備，或單獨藉由使化合物與適合的酸反應來製備。本發明之化合物之醫藥學上可接受之鹽可為用醫藥學上可接受之酸形成的酸加成鹽。可用以形成醫藥學上可接受之鹽之酸的實例包括無機酸，諸如硝酸、硼酸、鹽酸、氫溴酸、硫酸及磷酸；及有機酸，諸如草酸、馬來酸、丁二酸及檸檬酸。本發明之化合物之鹽的非限制性實例包括(但不限於)鹽酸鹽、氫溴酸鹽、氫碘酸鹽、硫酸鹽、硫酸氫鹽、2-羥基乙烷磺酸鹽、磷酸鹽、磷酸氫鹽、乙酸鹽、己二酸鹽、褐藻酸鹽、天冬胺酸鹽、苯甲酸鹽、硫酸氫鹽、丁酸鹽、樟腦酸鹽、樟腦磺酸鹽、二葡糖酸鹽、甘油磷酸鹽、半硫酸鹽、庚酸鹽、己酸鹽、甲酸鹽、丁二酸鹽、反丁烯二酸鹽、順丁烯二酸鹽、抗壞血酸鹽、羥乙磺酸鹽、水楊酸鹽、甲烷磺酸鹽、均三甲苯磺酸鹽、萘磺酸鹽、菸鹼酸鹽、2-萘磺酸鹽、草酸鹽、雙羥萘酸鹽、果膠酸鹽、過硫酸鹽、3-苯基丙酸鹽、苦味酸鹽、特戊酸鹽、丙酸鹽、三氯乙酸鹽、三氟乙酸鹽、磷酸鹽、麩胺酸鹽、碳酸氫鹽、對甲苯磺酸鹽、十一烷酸鹽、乳酸鹽、檸檬酸鹽、酒石酸鹽、葡糖酸鹽、甲烷磺酸鹽、乙烷二磺酸鹽、苯磺酸鹽及對甲苯磺酸鹽。此外，存在於本發明之化合物中之可用胺基可經以下各者四級銨化：甲基、乙基、丙基及丁基氯化物、溴化物及碘化物；二甲基、二乙基、二丁基及二戊基硫酸鹽；癸基、月桂基、肉豆蔻基及固醇氯化物、溴化物及碘化物；以及苯甲基及苯乙基溴化物。鑒於前述，本文中所出現之本發明的任何參考化合物意欲包括本發明化合物之化合物以及其醫藥學上可接受之鹽。 II. 本發明之治療方法.The present invention encompasses the preparation and use of salts of the compounds of the present invention. As used herein, a drug "pharmaceutically acceptable salt" refers to a salt or zwitterionic form of a compound of the present invention. Salts of compounds of the present invention can be prepared during the final isolation and purification of the compounds, or separately by reacting the compounds with a suitable acid. The pharmaceutically acceptable salts of the compounds of the present invention may be acid addition salts formed with pharmaceutically acceptable acids. Examples of acids that can be used to form pharmaceutically acceptable salts include inorganic acids such as nitric, boric, hydrochloric, hydrobromic, sulfuric, and phosphoric; and organic acids such as oxalic, maleic, succinic, and citric . Non-limiting examples of salts of the compounds of the present invention include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, 2-hydroxyethanesulfonate, phosphate, Hydrogen Phosphate, Acetate, Adipate, Alginate, Aspartate, Benzoate, Hydrogen Sulfate, Butyrate, Camphorate, Camphorsulfonate, Digluconate, Glycerophosphate, hemisulfate, heptanoate, caproate, formate, succinate, fumarate, maleate, ascorbate, isethionate, salicyl acid salt, methane sulfonate, mesitylene sulfonate, naphthalene sulfonate, nicotinate, 2-naphthalene sulfonate, oxalate, pamoate, pectate, persulfate , 3-phenylpropionate, picrate, pivalate, propionate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, p-toluenesulfonate, Undecanoate, lactate, citrate, tartrate, gluconate, methanesulfonate, ethanedisulfonate, benzenesulfonate and p-toluenesulfonate. In addition, the available amine groups present in the compounds of the present invention can be quaternary amonized with each of the following: methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dimethyl, diethyl , dibutyl and dipentyl sulfates; decyl, lauryl, myristyl and sterol chlorides, bromides and iodides; and benzyl and phenethyl bromides. In view of the foregoing, any reference to compounds of the invention appearing herein is intended to include compounds of the compounds of the invention as well as pharmaceutically acceptable salts thereof. II. The therapeutic method of the present invention.
本發明之化合物抑制menin且適用於治療多種疾病及病狀。特定言之，本發明之化合物適用於治療其中抑制menin提供益處之疾病或病狀之方法中，該疾病或病狀例如癌症及增殖性疾病。本發明之方法包含向有需要之個體投與治療有效量之本發明之化合物。本發明方法亦涵蓋除本發明之化合物以外，向個體投與第二治療劑。第二治療劑係選自已知為適用於治療折磨有需要之個體之疾病或病狀之藥物，例如已知為適用於治療特定癌症之化學治療劑及/或輻射。The compounds of the present invention inhibit menin and are useful in the treatment of a variety of diseases and conditions. In particular, the compounds of the present invention are useful in methods of treating diseases or conditions in which inhibition of menin provides benefit, such as cancer and proliferative diseases. The methods of the present invention comprise administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention. The methods of the present invention also encompass administering to an individual a second therapeutic agent in addition to a compound of the present invention. The second therapeutic agent is selected from drugs known to be suitable for the treatment of diseases or conditions afflicting individuals in need thereof, such as chemotherapeutic agents and/or radiation known to be suitable for the treatment of certain cancers.
本發明提供作為menin抑制劑之本發明之化合物，其用於治療其中抑制menin具有有益效果之疾病及病狀。本發明之化合物針對menin通常具有小於100 μM，例如小於50 μM、小於25 μM及小於5 μM、小於約1 µM、小於約0.5 µM、小於約0.1 µM、小於約0.05 µM或小於約0.01 µM的結合親和力(IC50 )。在一個實施例中，本發明係關於一種治療罹患其中抑制menin提供益處之疾病或病狀之個體的方法，該方法包含向有需要之個體投與治療有效量之本發明之化合物。The present invention provides compounds of the present invention as menin inhibitors for use in the treatment of diseases and conditions in which inhibition of menin has beneficial effects. The compounds of the invention typically have less than 100 μM, eg, less than 50 μM, less than 25 μM, and less than 5 μM, less than about 1 μM, less than about 0.5 μM, less than about 0.1 μM, less than about 0.05 μM, or less than about 0.01 μM, for menin Binding affinity ( IC50 ). In one embodiment, the present invention pertains to a method of treating an individual suffering from a disease or condition in which inhibition of menin provides benefit, the method comprising administering to the individual in need thereof a therapeutically effective amount of a compound of the present invention.
由於本發明之化合物為menin蛋白之抑制劑，所以多種由menin介導之疾病及病狀可藉由使用此等化合物來治療。因此，本發明大體上係針對一種用於治療罹患病狀或病症或處於罹患該病狀或病症之風險下的動物(例如人類)之對menin抑制有反應之病狀或病症的方法，該方法包含向動物投與有效量之一或多種本發明的化合物。Since the compounds of the present invention are inhibitors of the menin protein, a variety of menin-mediated diseases and conditions can be treated by the use of these compounds. Accordingly, the present invention is generally directed to a method for treating a condition or disorder responsive to inhibition of menin in an animal (eg, a human) suffering from or at risk of suffering from a condition or disorder, the method This involves administering to an animal an effective amount of one or more compounds of the present invention.
本發明進一步係針對一種抑制有需要之個體中之menin之方法，該方法包含向動物投與有效量之至少一種本發明的化合物。The present invention is further directed to a method of inhibiting menin in an individual in need thereof, the method comprising administering to the animal an effective amount of at least one compound of the present invention.
本發明之方法可藉由以純化合物或以醫藥組合物形式投與本發明之化合物來實現。本發明之化合物之醫藥組合物或純化合物之投與可在所關注疾病或病狀發作期間或之後執行。通常，醫藥組合物為無菌的，且不含有將在投與時導致不良反應之有毒、致癌或致突變化合物。進一步提供套組，其包含經單獨或一起封裝之本發明之化合物及視情況選用之第二治療劑，以及具有使用此等活性劑之指示的說明書。The methods of the present invention can be carried out by administering the compounds of the present invention as pure compounds or in pharmaceutical compositions. Administration of pharmaceutical compositions or pure compounds of the compounds of the present invention can be performed during or after the onset of the disease or condition of interest. Typically, pharmaceutical compositions are sterile and do not contain toxic, carcinogenic or mutagenic compounds that would cause adverse reactions when administered. Kits are further provided comprising a compound of the invention and an optional second therapeutic agent, individually or together, and instructions with instructions for using these active agents.
在一個實施例中，本發明之化合物與適用於治療其中抑制menin提供益處之疾病或病狀的第二治療劑結合投與。第二治療劑不同於本發明之化合物。本發明之化合物與第二治療劑可同時或依序投與以達成所需效果。此外，本發明之化合物及第二治療劑可自單一組合物或兩種單獨組合物投與。In one embodiment, the compounds of the present invention are administered in combination with a second therapeutic agent suitable for treating a disease or condition in which inhibition of menin provides benefit. The second therapeutic agent is different from the compound of the present invention. The compounds of the present invention and the second therapeutic agent can be administered simultaneously or sequentially to achieve the desired effect. Furthermore, the compounds of the present invention and the second therapeutic agent can be administered from a single composition or from two separate compositions.
以提供其所需治療效果之量投與第二治療劑。各第二治療劑之有效劑量範圍為此項技術中已知的，且在此類已確立範圍內向有需要之個體投與第二治療劑。The second therapeutic agent is administered in an amount that provides its desired therapeutic effect. Effective dosage ranges for each second therapeutic agent are known in the art, and the second therapeutic agent is administered to an individual in need thereof within such established ranges.
本發明之化合物與第二治療劑可以單一單位劑量或單獨以多單位劑量一起投與，其中本發明之化合物在第二治療劑之前投與或反之亦然。可投與一或多個劑量之本發明之化合物及/或一或多個劑量之第二治療劑。因此，本發明之化合物可與例如但不限於抗癌劑之一或多種第二治療劑結合使用。The compound of the present invention and the second therapeutic agent may be administered together in a single unit dose or separately in multiple unit doses, wherein the compound of the present invention is administered before the second therapeutic agent or vice versa. One or more doses of a compound of the invention and/or one or more doses of a second therapeutic agent may be administered. Thus, the compounds of the present invention can be used in combination with one or more second therapeutic agents such as, but not limited to, anticancer agents.
可藉由本發明之方法治療的疾病及病狀包括(但不限於)癌症及其他增殖性病症、發炎性疾病、敗血症、自體免疫疾病及病毒性感染。在一個實施例中，用本發明之化合物或包含本發明之化合物之醫藥組合物來治療人類患者，其中以足以抑制患者體內之menin活性之量投與化合物。在另一實施例中，人類患者為需要治療疾病之18歲以上的人類成人。在另一實施例中，人類患者為需要治療疾病之不超過18歲的人類兒童。Diseases and conditions that can be treated by the methods of the present invention include, but are not limited to, cancer and other proliferative disorders, inflammatory diseases, sepsis, autoimmune diseases, and viral infections. In one embodiment, a human patient is treated with a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention, wherein the compound is administered in an amount sufficient to inhibit menin activity in the patient. In another embodiment, the human patient is a human adult over 18 years of age in need of treatment of the disease. In another embodiment, the human patient is a human child up to 18 years of age in need of treatment of the disease.
在另一態樣中，本發明提供一種治療個體之癌症之方法，其包含投與治療有效量之本發明之化合物。儘管不限於特定機制，但在一些實施例中，本發明之化合物藉由抑制menin來治療癌症。可治療癌症之實例包括(但不限於)表2之癌症中之任一者或多者。
表2
在另一實施例中，癌症為實體腫瘤。在另一實施例中，癌症為血液癌。例示性血液癌包括(但不限於)表3中列舉之癌症。在另一實施例中，血液癌為急性淋巴球性白血病、慢性淋巴球性白血病(包括B細胞慢性淋巴球性白血病)或急性骨髓性白血病。在另一實施例中，血液癌為骨髓發育不良症候群。
表3
在另一實施例中，癌症為白血病，例如選自以下之白血病：急性單核球性白血病、急性淋巴球性白血病、急性骨髓性白血病、慢性骨髓性白血病、慢性淋巴球性白血病及混合系白血病(MLL)。在另一實施例中，白血病為NPM1c突變型急性骨髓性白血病。在另一實施例中，白血病為MLL-r急性骨髓性白血病。在另一實施例中，白血病為MLL-r急性淋巴球性白血病。在另一實施例中，癌症為NUT-中線癌。在另一實施例中，癌症為多發性骨髓瘤。在另一實施例中，癌症為肺癌，諸如小細胞肺癌(SCLC)。在另一實施例中，癌症為神經母細胞瘤。在另一實施例中，癌症為伯基特氏淋巴瘤。在另一實施例中，癌症為宮頸癌。在另一實施例中，癌症為食道癌。在另一實施例中，癌症為卵巢癌。在另一實施例中，癌症為結腸直腸癌。在另一實施例中，癌症為***癌。在另一實施例中，癌症為乳癌。在另一實施例中，癌症為尤文氏肉瘤。In another embodiment, the cancer is a leukemia, eg, a leukemia selected from the group consisting of acute monocytic leukemia, acute lymphocytic leukemia, acute myeloid leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, and mixed lineage leukemia (MLL). In another embodiment, the leukemia is NPM1c mutant acute myeloid leukemia. In another embodiment, the leukemia is MLL-r acute myeloid leukemia. In another embodiment, the leukemia is MLL-r acute lymphoblastic leukemia. In another embodiment, the cancer is NUT-midline cancer. In another embodiment, the cancer is multiple myeloma. In another embodiment, the cancer is lung cancer, such as small cell lung cancer (SCLC). In another embodiment, the cancer is neuroblastoma. In another embodiment, the cancer is Burkitt's lymphoma. In another embodiment, the cancer is cervical cancer. In another embodiment, the cancer is esophageal cancer. In another embodiment, the cancer is ovarian cancer. In another embodiment, the cancer is colorectal cancer. In another embodiment, the cancer is prostate cancer. In another embodiment, the cancer is breast cancer. In another embodiment, the cancer is Ewing's sarcoma.
在另一實施例中，本發明提供一種治療良性增殖性病症之方法，該良性增殖性病症諸如(但不限於)良性軟組織腫瘤、骨腫瘤、腦及脊髓腫瘤、眼瞼及眼眶腫瘤、肉芽腫瘤、脂肪瘤、腦膜瘤、多發性內分泌瘤、鼻息肉、垂體腫瘤、促乳素瘤、大腦假腫瘤、皮脂溢性角化症、胃息肉、甲狀腺結節、胰臟囊性腫瘤、血管瘤、聲帶結節、息肉及囊腫、卡斯特萊曼(Castleman)疾病、慢性潛毛疾病、皮膚纖維瘤、毛髮囊腫、化膿性肉芽腫及青少年多發性息肉症候群。In another embodiment, the present invention provides a method of treating benign proliferative disorders such as, but not limited to, benign soft tissue tumors, bone tumors, brain and spinal cord tumors, eyelid and orbital tumors, granulation tumors, Lipomas, meningiomas, multiple endocrine tumors, nasal polyps, pituitary tumors, prolactinomas, cerebral pseudotumors, seborrheic keratosis, gastric polyps, thyroid nodules, pancreatic cystic tumors, hemangiomas, vocal cord nodules , Polyps and Cysts, Castleman's Disease, Chronic Latent Hair Disease, Dermatofibroma, Hair Cysts, Pyogenic Granuloma, and Juvenile Polyposis Syndrome.
本發明之化合物亦可藉由向需要此類治療之哺乳動物(特定而言人類)投與有效量之本化合物，來治療感染性及非感染性發炎事件及自體免疫及其他發炎性疾病。使用本文中所描述之化合物及方法治療之自體免疫及發炎性疾病、病症及症候群之實例包括：發炎性骨盆疾病、尿道炎、皮膚曬傷、鼻竇炎、肺炎、腦炎、腦膜炎、心肌炎、腎炎、骨髓炎、肌炎、肝炎、胃炎、腸炎、皮膚炎、齒齦炎、闌尾炎、胰臟炎、膽囊炎、無γ球蛋白血症、牛皮癬、過敏、克隆氏(Crohn's)病、腸激躁症候群、潰瘍性結腸炎、休格連氏(Sjogren's)疾病、組織移植排斥反應、經移植器官之超急性排斥、哮喘、過敏性鼻炎、慢性阻塞性肺病(COPD)、自體免疫多腺疾病(亦稱為自體免疫多腺症候群)、自體免疫禿髮、惡性貧血、絲球體腎炎、皮肌炎、多發性硬化、硬皮病、脈管炎、自體免疫溶血性及血小板減少性病況、古巴斯德氏(Goodpasture's)症候群、動脈粥樣硬化、艾迪森氏(Addison's)病、帕金森氏(Parkinson's)病、阿茲海默氏(Alzheimer's)症、I型糖尿病、敗血性休克、全身性紅斑性狼瘡症(SLE)、類風濕性關節炎、牛皮癬性關節炎、青少年關節炎、骨關節炎、慢性特發性血小板減少性紫癜、瓦爾登斯特倫巨球蛋白血症(Waldenstrom macroglobulinemia)、重症肌無力、橋本氏(Hashimoto's)甲狀腺炎、異位性皮膚炎、退化性關節病、白斑病、自體免疫垂體機能減退、格-巴二氏(Guillain-Barre)症候群、白塞氏(Behcet's)病、硬腫症(scleracierma)、蕈樣黴菌病、急性發炎反應(諸如急性呼吸窘迫症候群及局部缺血/再灌注損傷)及格雷夫氏(Graves's)病。The compounds of the present invention can also be used to treat infectious and non-infectious inflammatory events and autoimmune and other inflammatory diseases by administering an effective amount of the present compounds to mammals (particularly humans) in need of such treatment. Examples of autoimmune and inflammatory diseases, disorders and syndromes treated using the compounds and methods described herein include: inflammatory pelvic disease, urethritis, skin sunburn, sinusitis, pneumonia, encephalitis, meningitis, myocarditis , nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, cholecystitis, agammaglobulinemia, psoriasis, allergy, Crohn's disease, intestinal irritation Manic syndrome, ulcerative colitis, Sjogren's disease, tissue transplant rejection, hyperacute rejection of transplanted organs, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome), autoimmune alopecia, pernicious anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolysis, and thrombocytopenia Conditions, Goodpasture's Syndrome, Atherosclerosis, Addison's Disease, Parkinson's Disease, Alzheimer's Disease, Type I Diabetes, Septic Shock , systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, Waldenstrom macroglobulinemia ( Waldenstrom macroglobulinemia, myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis, degenerative joint disease, vitiligo, autoimmune hypopituitarism, Guillain-Barre syndrome, leukemia Behcet's disease, scleracierma, mycosis fungoides, acute inflammatory reactions such as acute respiratory distress syndrome and ischemia/reperfusion injury, and Graves' disease.
在另一實施例中，本發明提供一種藉由向需要此種治療之哺乳動物(特定而言人類)投與有效量之本發明之化合物，來治療諸如LPS誘導之內毒素休克及/或細菌誘導之敗血症的全身性發炎反應症候群的方法。In another embodiment, the present invention provides a treatment for endotoxic shock and/or bacteria such as LPS-induced by administering to a mammal (specifically a human) in need of such treatment an effective amount of a compound of the present invention Methods of Inducing Systemic Inflammatory Response Syndrome of Sepsis.
在另一實施例中，本發明提供一種用於治療病毒性感染及疾病之方法。使用本文中所描述之化合物及方法來治療之病毒性感染及疾病之實例包括基於游離基因體之DNA病毒，包括(但不限於)人類乳頭狀瘤病毒、疱疹病毒、埃-巴(Epstein-Barr)二氏病毒、人類免疫缺乏病毒、B型肝炎病毒及C型肝炎病毒。In another embodiment, the present invention provides a method for treating viral infections and diseases. Examples of viral infections and diseases that are treated using the compounds and methods described herein include episomal-based DNA viruses including, but not limited to, human papilloma virus, herpes virus, Epstein-Barr ) II virus, human immunodeficiency virus, hepatitis B virus and hepatitis C virus.
在另一實施例中，本發明提供活體內調節上文所提及之疾病(特定而言癌症、發炎性疾病及/或病毒性疾病)之蛋白質甲基化、基因表現、細胞增殖、細胞分化及/或細胞凋亡之治療方法，其係藉由向需要此種治療之個體投與治療有效量之本發明的化合物提供。In another embodiment, the present invention provides in vivo regulation of protein methylation, gene expression, cell proliferation, cell differentiation in the above-mentioned diseases, in particular cancer, inflammatory diseases and/or viral diseases and/or methods of treatment of apoptosis provided by administering to a subject in need of such treatment a therapeutically effective amount of a compound of the invention.
在另一實施例中，本發明提供一種藉由使細胞與本發明之化合物接觸來調節內源或異源啟動子活性之方法。In another embodiment, the present invention provides a method of modulating the activity of an endogenous or heterologous promoter by contacting a cell with a compound of the present invention.
在本發明之方法中，向有需要之人類投與通常根據醫藥學實踐所調配之治療有效量之本發明的化合物。是否指示此種治療視個體情況而定且經受醫療評定(診斷)，該醫療評定(診斷)考慮存在產生特定體徵、症狀及/或功能障礙之風險的體徵、症狀及/或功能障礙及其他因素。In the methods of the present invention, a therapeutically effective amount of a compound of the present invention is administered to a human in need thereof, usually formulated in accordance with the practice of medicine. Whether such treatment is indicated is on an individual basis and is subject to a medical assessment (diagnosis) that takes into account signs, symptoms and/or dysfunction and other factors that are at risk of producing specific signs, symptoms and/or dysfunction .
本發明之化合物可藉由任何適合途徑投與，例如藉由以下各者投與：經口、頰內、吸入、舌下、經直腸、經***、經由腰椎穿刺之腦池內或鞘內、經尿道、經鼻、經皮(亦即透皮)或非經腸(包括靜脈內、肌肉內、皮下、冠狀動脈內、皮內、***內、腹膜內、關節內、鞘內、眼球後、肺內注射及/或手術植入於特定部位處)。非經腸投與可使用穿刺及注射器或使用高壓技術來實現。The compounds of the present invention may be administered by any suitable route, for example, by oral, buccal, inhalation, sublingual, rectal, vaginal, intracisternal or intrathecal administration via lumbar puncture, Transurethral, transnasal, percutaneous (ie, transdermal) or parenteral (including intravenous, intramuscular, subcutaneous, intracoronary, intradermal, intramammary, intraperitoneal, intraarticular, intrathecal, retrobulbar, intrapulmonary injection and/or surgical implantation at specific sites). Parenteral administration can be accomplished using a puncture and syringe or using high pressure techniques.
醫藥組合物包括其中以有效量投與本發明之化合物以達成其預期目的之彼等。精確調配物、投與途徑及劑量藉由個別醫師鑒於所診斷病狀或疾病來判定。劑量及間隔可經單獨調整以提供足以維持治療效果之水準之本發明的化合物。Pharmaceutical compositions include those in which the compounds of the present invention are administered in effective amounts to achieve their intended purpose. The precise formulation, route of administration, and dosage are determined by the individual physician in view of the condition or disease being diagnosed. Doses and intervals can be adjusted individually to provide levels of the compounds of the invention sufficient to maintain therapeutic effect.
本發明之化合物之毒性及治療功效可藉由標準醫藥程序在細胞培養物中或實驗動物體內測定，例如以用於測定化合物之最大耐受劑量(MTD)，該最大耐受劑量定義為在動物體內不產生毒性之最高劑量。最大耐受劑量與治療效果(例如對腫瘤生長之抑制)之間的劑量比率為治療指數。劑量可視所採用劑型及所使用投與途徑而定在此範圍內變化。治療有效量之測定完全在熟習此項技術者之能力範圍內，尤其根據本文中所提供之詳細揭示內容來測定。Toxicity and therapeutic efficacy of the compounds of the present invention can be determined by standard pharmaceutical procedures in cell cultures or in experimental animals, eg, for determining the maximum tolerated dose (MTD) of the compounds, which is defined as the maximum tolerated dose (MTD) in animals The highest dose that does not produce toxicity in vivo. The dose ratio between the maximum tolerated dose and the therapeutic effect (eg, inhibition of tumor growth) is the therapeutic index. The dosage may vary within this range depending upon the dosage form employed and the route of administration employed. Determination of a therapeutically effective amount is well within the ability of those skilled in the art, especially in light of the detailed disclosure provided herein.
用於療法所需之治療有效量之本發明之化合物隨所治療病狀之性質、所需活性之時間長度及患者之年齡及病狀而變化，且最終藉由主治醫師來判定。劑量及間隔可經單獨調整以提供足以維持所需治療效果之血漿水準的menin抑制劑。所需劑量可宜以單一劑量投與，或以適當間隔作為多個劑量投與，例如以每天一次、兩次、三次、四次或更多次子劑量投與。在一個實施例中，每天一次(QD)投與本發明之化合物。在另一實施例中，每天兩次(BID)投與本發明之化合物。多個劑量通常為所需或必需的。舉例而言，本發明之化合物可按以下之頻率投與：以四天間隔按每天一次劑量遞送四次劑量(q4d × 4)；以三天間隔按每天一次劑量遞送四次劑量(q3d × 4)；以五天間隔每天遞送一次劑量(qd × 5)；每週一次劑量持續三週(qwk3)；五次每日劑量，其中兩天休息且另外五天每日劑量(5/2/5)；或經測定適合於該情況的任何劑量方案。The therapeutically effective amount of a compound of the invention required for therapy will vary with the nature of the condition being treated, the length of time of desired activity, and the age and condition of the patient, and is ultimately at the discretion of the attending physician. Doses and intervals can be adjusted individually to provide plasma levels of the menin inhibitor sufficient to maintain the desired therapeutic effect. The desired dose may conveniently be administered as a single dose, or as multiple doses at appropriate intervals, eg, as one, two, three, four or more sub-doses per day. In one embodiment, the compounds of the invention are administered once daily (QD). In another embodiment, a compound of the present invention is administered twice daily (BID). Multiple doses are often desired or necessary. For example, a compound of the present invention may be administered at the following frequency: four doses delivered as a daily dose at four-day intervals (q4d x 4); four doses as a daily dose delivered at three-day intervals (q3d x 4) ); daily doses delivered at five-day intervals (qd × 5); weekly doses for three weeks (qwk3); five daily doses with two days rest and five additional daily doses (5/2/5 ); or any dosage regimen determined to be suitable for the situation.
用於本發明之方法之本發明化合物可以每劑量約0.005至約1公克、每劑量約0.005至約500毫克、每劑量約0.05至約500毫克、每劑量約0.05至約250毫克或每劑量約0.5至約100毫克之量投與。舉例而言，本發明之化合物可每劑量按以下之量投與：約0.005毫克、約0.05毫克、約0.5毫克、約5毫克、約10毫克、約20毫克、約30毫克、約40毫克、約50毫克、約100毫克、約150毫克、約200毫克、約250毫克、約300毫克、約350毫克、約400毫克、約450毫克、約500毫克、約550毫克、約600毫克、約650毫克、約700毫克、約750毫克、約800毫克、約850毫克、約900毫克、約950毫克或約1公克，包括0.005毫克與1公克之間的所有劑量。The compounds of the invention for use in the methods of the invention may be about 0.005 to about 1 gram per dose, about 0.005 to about 500 mg per dose, about 0.05 to about 500 mg per dose, about 0.05 to about 250 mg per dose or about An amount of 0.5 to about 100 mg is administered. For example, the compounds of the present invention may be administered in the following amounts per dose: about 0.005 mg, about 0.05 mg, about 0.5 mg, about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1 gram, including all doses between 0.005 mg and 1 gram.
含有本發明之化合物之組合物或含有其之組合物的劑量可為約1 ng/kg至約200 mg/kg、約1 μg/kg至約100 mg/kg或約1 mg/kg至約50 mg/kg。組合物之劑量可處於任何劑量下，包括(但不限於)約1 μg/kg。組合物之劑量可處於任何劑量下，包括(但不限於)約1 μg/kg、約10 μg/kg、約25 μg/kg、約50 μg/kg、約75 μg/kg、約100 μg/kg、約125 μg/kg、約150 μg/kg、約175 μg/kg、約200 μg/kg、約225 μg/kg、約250 μg/kg、約275 μg/kg、約300 μg/kg、約325 μg/kg、約350 μg/kg、約375 μg/kg、約400 μg/kg、約425 μg/kg、約450 μg/kg、約475 μg/kg、約500 μg/kg、約525 μg/kg、約550 μg/kg、約575 μg/kg、約600 μg/kg、約625 μg/kg、約650 μg/kg、約675 μg/kg、約700 μg/kg、約725 μg/kg、約750 μg/kg、約775 μg/kg、約800 μg/kg、約825 μg/kg、約850 μg/kg、約875 μg/kg、約900 μg/kg、約925 μg/kg、約950 μg/kg、約975 μg/kg、約1 mg/kg、約5 mg/kg、約10 mg/kg、約15 mg/kg、約20 mg/kg、約25 mg/kg、約30 mg/kg、約35 mg/kg、約40 mg/kg、約45、約50 mg/kg、約60 mg/kg、約70 mg/kg、約80 mg/kg、約90 mg/kg、約100 mg/kg、約125 mg/kg、約150 mg/kg、約175 mg/kg、約200 mg/kg或更多。以上劑量為對平均案例之例示，但可存在其中需要更高或更低劑量之個別實例，且此類劑量在本發明之範疇內。實際上，醫師判定最適合於個別患者之實際給藥方案，該給藥方案可隨特定患者之年齡、體重及反應而變化。The dosage of a composition containing a compound of the present invention or a composition containing the same may be about 1 ng/kg to about 200 mg/kg, about 1 μg/kg to about 100 mg/kg, or about 1 mg/kg to about 50 mg/kg mg/kg. The dosage of the composition can be at any dosage, including but not limited to about 1 μg/kg. The dosage of the composition can be at any dosage, including but not limited to about 1 μg/kg, about 10 μg/kg, about 25 μg/kg, about 50 μg/kg, about 75 μg/kg, about 100 μg/kg kg, about 125 μg/kg, about 150 μg/kg, about 175 μg/kg, about 200 μg/kg, about 225 μg/kg, about 250 μg/kg, about 275 μg/kg, about 300 μg/kg, About 325 μg/kg, about 350 μg/kg, about 375 μg/kg, about 400 μg/kg, about 425 μg/kg, about 450 μg/kg, about 475 μg/kg, about 500 μg/kg, about 525 μg/kg, about 550 μg/kg, about 575 μg/kg, about 600 μg/kg, about 625 μg/kg, about 650 μg/kg, about 675 μg/kg, about 700 μg/kg, about 725 μg/kg kg, about 750 μg/kg, about 775 μg/kg, about 800 μg/kg, about 825 μg/kg, about 850 μg/kg, about 875 μg/kg, about 900 μg/kg, about 925 μg/kg, About 950 μg/kg, about 975 μg/kg, about 1 mg/kg, about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45, about 50 mg/kg, about 60 mg/kg, about 70 mg/kg, about 80 mg/kg, about 90 mg/kg, about 100 mg/kg, about 125 mg/kg, about 150 mg/kg, about 175 mg/kg, about 200 mg/kg or more. The above dosages are illustrative of the average case, but there may be individual instances where higher or lower dosages are required, and such dosages are within the scope of the present invention. In practice, the physician determines the actual dosing regimen most suitable for an individual patient, which may vary with the age, weight, and response of a particular patient.
如上所陳述，本發明之化合物可與第二治療活性劑組合投與。在一些實施例中，第二治療劑為表觀遺傳藥物。如本文所用，術語「表觀遺傳藥物」係指靶向表觀遺傳調節子之治療劑。表觀遺傳調節子之實例包括組蛋白離胺酸甲基轉移酶、組蛋白精胺酸甲基轉移酶、組蛋白去甲基酶、組蛋白去乙醯基酶、組蛋白乙醯基酶及DNA甲基轉移酶。組蛋白去乙醯酶抑制劑包括(但不限於)伏立諾他(vorinostat)。As stated above, the compounds of the present invention can be administered in combination with a second therapeutically active agent. In some embodiments, the second therapeutic agent is an epigenetic drug. As used herein, the term "epigenetic drug" refers to a therapeutic agent that targets epigenetic regulators. Examples of epigenetic regulators include histone lysine methyltransferase, histone arginine methyltransferase, histone demethylase, histone deacetylase, histone acetylase, and DNA methyltransferase. Histone deacetylase inhibitors include, but are not limited to, vorinostat.
在另一實施例中，化學治療劑或其他抗增殖劑可與本發明之化合物組合以治療增殖性疾病及癌症。可與本發明之化合物組合使用之療法及抗癌劑之實例包括手術、放射線療法(例如γ輻射、中子束放射線療法、電子放射線療法、質子療法、近接療法及全身性放射性同位素)、內分泌療法、生物反應調節劑(例如干擾素、介白素、腫瘤壞死因子(TNF)、高溫及超低溫療法、用以減弱任何不良影響之藥劑(例如抗嘔劑)及任何其他經批准的化學治療藥物。In another embodiment, chemotherapeutic or other antiproliferative agents can be combined with the compounds of the present invention to treat proliferative diseases and cancer. Examples of therapies and anticancer agents that may be used in combination with the compounds of the present invention include surgery, radiation therapy (eg, gamma radiation, neutron beam radiation therapy, electron radiation therapy, proton therapy, brachytherapy, and systemic radioisotopes), endocrine therapy , biological response modifiers (eg, interferons, interleukins, tumor necrosis factor (TNF), hyperthermia and hypothermia therapy, agents to attenuate any adverse effects (eg, antiemetics), and any other approved chemotherapeutic drugs.
在另一實施例中，本文所述之本發明化合物及醫藥組合物可與一或多種選自以下之物質組合使用：抗血管生成劑、信號轉導抑制劑、抗增生劑、糖酵解抑制劑、自體吞噬抑制劑、噬菌抑制劑、去甲基化劑、DOT1L抑制劑、IDH1抑制劑、IDH2抑制劑、IDH1/IDH2雙重抑制劑、LSD1抑制劑、XPO1抑制劑或達沙替尼(dastinib)。在另一實施例中，本發明化合物可與選自以下之第二治療劑組合使用：去甲基化劑、DOT1L抑制劑、IDH1抑制劑、IDH2抑制劑、IDH1/IDH2雙重抑制劑、LSD1抑制劑、XPO1抑制劑及達沙替尼。In another embodiment, the compounds and pharmaceutical compositions of the invention described herein may be used in combination with one or more substances selected from the group consisting of: anti-angiogenic agents, signal transduction inhibitors, anti-proliferative agents, glycolysis inhibitors drug, autophagy inhibitor, phagocytosis inhibitor, demethylating agent, DOT1L inhibitor, IDH1 inhibitor, IDH2 inhibitor, IDH1/IDH2 dual inhibitor, LSD1 inhibitor, XPO1 inhibitor, or dasatinib (dastinib). In another embodiment, the compounds of the present invention may be used in combination with a second therapeutic agent selected from the group consisting of demethylating agents, DOT1L inhibitors, IDH1 inhibitors, IDH2 inhibitors, dual IDH1/IDH2 inhibitors, LSD1 inhibitors agents, XPO1 inhibitors, and dasatinib.
去甲基化劑包括抑制或干擾DNA甲基化之物質。在一些實例中，去甲基化劑為DNA甲基轉移酶抑制劑。例示性非限制性去甲基化劑包括5-氮雜胞苷、地西他濱(decitabine)、甲胺喋呤、依達曲沙(edatrexate)、2'-去氧-5-氮雜胞苷、6-硫代鳥嘌呤、5-氟-2'-去氧胞苷、假異胞苷、5,6-二氫-5-氮雜胞苷、法紮拉濱(fazarabine)、澤布拉林(zebularine)、2'-去氧-5,6-二氫-5-氮雜胞苷、4'-硫代-2'-去氧胞苷、5-氮雜-4'-硫代-2'-去氧胞苷、RX-3117、SGI-110、NPEOC-DAC、CP-4200及2'3'5'三乙醯基-5-氮雜胞苷。Demethylating agents include substances that inhibit or interfere with DNA methylation. In some examples, the demethylating agent is a DNA methyltransferase inhibitor. Exemplary non-limiting demethylating agents include 5-azacytidine, decitabine, methotrexate, edatrexate, 2'-deoxy-5-azacytidine glycoside, 6-thioguanine, 5-fluoro-2'-deoxycytidine, pseudoisocytidine, 5,6-dihydro-5-azacytidine, fazarabine, zebu zebularine, 2'-deoxy-5,6-dihydro-5-azacytidine, 4'-thio-2'-deoxycytidine, 5-aza-4'-thio -2'-Deoxycytidine, RX-3117, SGI-110, NPEOC-DAC, CP-4200 and 2'3'5'triacetoxy-5-azacytidine.
組蛋白甲基轉移酶DOTlL之抑制劑之非限制性實例包括EPZ-5676、SGC-0946及EPZ004777。Non-limiting examples of inhibitors of the histone methyltransferase DOT1L include EPZ-5676, SGC-0946, and EPZ004777.
例示性非限制性IDH1抑制劑包括Tibsovo® (伊沃司迪尼(ivosidnib))、AG-881、AG-120、FT-2102 (奧盧司他尼(olutasidenib))、BAY1436032、IDH-305及ZX-06。IDH2抑制劑之例示性非限制性實例包括Idhifa® (艾那尼布(enasidenib)；AG-221)、AG-881、AGl-6780、SH1573及TQ05310。例示性非限制性IDH1/IDH2雙重抑制劑包括HMPL-306。Exemplary non-limiting IDH1 inhibitors include Tibsovo® (ivosidnib), AG-881, AG-120, FT-2102 (olutasidenib), BAY1436032, IDH-305 and ZX-06. Illustrative non-limiting examples of IDH2 inhibitors include Idhifa® (enasidenib; AG-221), AG-881, AG1-6780, SH1573, and TQ05310. Exemplary non-limiting dual IDH1/IDH2 inhibitors include HMPL-306.
LSD1抑制劑之例示性非限制性實例包括ORY-1001、OG-L002、SP2509、4SC-202、GSK2879552、T-3775440及RN-1。Illustrative, non-limiting examples of LSD1 inhibitors include ORY-1001, OG-L002, SP2509, 4SC-202, GSK2879552, T-3775440, and RN-1.
XPO1抑制劑之例示性非限制性實例包括塞利尼索(selinexor)(KPT-330)、KPT-8602、KPT25 l及SL-801。Illustrative, non-limiting examples of XPO1 inhibitors include selinexor (KPT-330), KPT-8602, KPT251, and SL-801.
抗血管生成劑，諸如MMP-2 (基質金屬蛋白酶2)抑制劑、MMP-9 (基質金屬蛋白酶9)抑制劑及COX-II (環加氧酶II)抑制劑可與本文所述之本發明化合物及醫藥組合物結合使用。例示性非限制性抗血管生成劑包括雷帕黴素(rapamycin)、坦羅莫司(temsirolimus) (CCI-779)、依維莫司(everolimus) (RAD001)、索拉非尼(sorafenib)、舒尼替尼(sunitinib)及貝伐單抗(bevacizumab)。例示性非限制性COX-II抑制劑包括CELEBREXTM (阿萊昔布(alecoxib))、伐地昔布(valdecoxib)及羅非昔布(rofecoxib)。例示性非限制性基質金屬蛋白酶抑制劑包括描述於以下中之抑制劑：WO 96/33172 (1996年10月24日公開)、WO 96/27583 (1996年3月7日公開)、歐洲專利申請案第97304971.1號(1997年7月8日申請)、歐洲專利申請案第99308617.2號(1999年10月29日申請)、WO 98/07697 (1998年2月26日公開)、WO 98/03516 (1998年1月29日公開)、WO 98/34918 (1998年8月13日公開)、WO 98/34915 (1998年8月13日公開)、WO 98/33768 (1998年8月6日公開)、WO 98/30566 (1998年7月16日公開)、歐洲專利公開案606,046 (1994年7月13日公開)、歐洲專利公開案931,788 (1999年7月28日公開)、WO 90/05719 (1990年5月31日公開)、WO 99/52910 (1999年10月21日公開)、WO 99/52889 (1999年10月21日公開)、WO 99/29667 (1999年6月17日公開)、PCT國際申請案第PCT/IB98/01113號(1998年7月21日申請)、歐洲專利申請案第99302232.1號(1999年3月25日申請)、英國專利申請案第9912961.1號(1999年6月3日申請)、美國臨時申請案第60/148,464號(1999年8月12日申請)、美國專利5,863,949 (1999年1月26日頒予)、美國專利5,861,510 (1999年1月19日頒予)及歐洲專利公開案780,386 (1997年6月25日公開)，全部均以全文引用之方式併入本文中。在某些實施例中，MMP-2及MMP-9抑制劑具有極少或沒有抑制MMP-1之活性。在某些實施例中，相對於其他基質金屬蛋白酶(例如MAP-1、MMP-3、MMP-4、MMP-5、MMP-6、MMP-7、MMP-8、MMP-10、MMP-11、MMP-12及MMP-13)，MMP-2及MMP-9抑制劑選擇性抑制MMP-2及/或AMP-9。例示性非限制性MMP抑制劑包括AG-3340、RO 32-3555及RS 13-0830。Anti-angiogenic agents, such as MMP-2 (matrix metalloproteinase 2) inhibitors, MMP-9 (matrix metalloproteinase 9) inhibitors, and COX-II (cyclooxygenase II) inhibitors can be used with the invention described herein The compound and the pharmaceutical composition are used in combination. Exemplary non-limiting anti-angiogenic agents include rapamycin, temsirolimus (CCI-779), everolimus (RAD001), sorafenib, Sunitinib and bevacizumab. Exemplary non-limiting COX-II inhibitors include CELEBREX™ (alecoxib), valdecoxib, and rofecoxib. Exemplary non-limiting matrix metalloproteinase inhibitors include those described in: WO 96/33172 (published October 24, 1996), WO 96/27583 (published March 7, 1996), European patent application Patent Application No. 97304971.1 (filed on July 8, 1997), European Patent Application No. 99308617.2 (filed on October 29, 1999), WO 98/07697 (published on February 26, 1998), WO 98/03516 ( Published on Jan. 29, 1998), WO 98/34918 (published on Aug. 13, 1998), WO 98/34915 (published on Aug. 13, 1998), WO 98/33768 (published on Aug. 6, 1998) , WO 98/30566 (published on July 16, 1998), European Patent Publication 606,046 (published on July 13, 1994), European Patent Publication 931,788 (published on July 28, 1999), WO 90/05719 ( Published on May 31, 1990), WO 99/52910 (published on October 21, 1999), WO 99/52889 (published on October 21, 1999), WO 99/29667 (published on June 17, 1999) , PCT International Application No. PCT/IB98/01113 (filed on July 21, 1998), European Patent Application No. 99302232.1 (filed on March 25, 1999), British Patent Application No. 9912961.1 (June 1999) filed on August 3), US Provisional Application No. 60/148,464 (filed on August 12, 1999), US Patent 5,863,949 (issued January 26, 1999), US Patent 5,861,510 (issued January 19, 1999) ) and European Patent Publication 780,386 (published June 25, 1997), all of which are incorporated herein by reference in their entirety. In certain embodiments, MMP-2 and MMP-9 inhibitors have little or no activity in inhibiting MMP-1. In certain embodiments, relative to other matrix metalloproteinases (eg, MAP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11 , MMP-12 and MMP-13), MMP-2 and MMP-9 inhibitors selectively inhibit MMP-2 and/or AMP-9. Exemplary non-limiting MMP inhibitors include AG-3340, RO 32-3555 and RS 13-0830.
例示性非限制性自體吞噬抑制劑包括氯喹(chloroquine)、3-甲基腺嘌呤、羥氯喹(hydroxychloroquine)(Plaquenil™)、巴弗洛黴素A1 (bafilomycin A1)、5-胺基-4-咪唑甲醯胺核糖苷(AICAR)、岡田井酸(okadaic acid)、抑制2A型或1型蛋白質磷酸酶之自體吞噬抑制性藻類毒素、cAMP類似物，及提高cAMP含量的藥物，諸如腺苷、LY204002、N6-巰基嘌呤核糖苷及長春鹼(vinblastine)。另外，亦可使用抑制蛋白質表現的反義或siRNA，包括(但不限於) ATG5 (其涉及自體吞噬)。Exemplary non-limiting autophagy inhibitors include chloroquine, 3-methyladenine, hydroxychloroquine (Plaquenil™), bafilomycin A1, 5-amino-4 -Imidazolecarboxamide riboside (AICAR), okadaic acid, autophagy-inhibiting algal toxins that inhibit type 2A or type 1 protein phosphatases, cAMP analogs, and drugs that increase cAMP levels, such as adenosine glycosides, LY204002, N6-mercaptopurine riboside and vinblastine. In addition, antisense or siRNA that inhibit the expression of proteins, including but not limited to ATG5 (which is involved in autophagy), can also be used.
例示性非限制性噬菌抑制劑包括Hu5F9-G4 (Forty-Seven)、CC-90002 (Celgene)、TTI-621 (Trillium)、ALX148 (Alexo Therapeutics)、SRF231 (Surface Oncology)、SHR-1603 (Hengrui)及IBI188 (Innovent Biologics)。Exemplary non-limiting phage inhibitors include Hu5F9-G4 (Forty-Seven), CC-90002 (Celgene), TTI-621 (Trillium), ALX148 (Alexo Therapeutics), SRF231 (Surface Oncology), SHR-1603 (Hengrui) ) and IBI188 (Innovent Biologics).
抗增殖化合物之實例包括(但不限於)芳香酶抑制劑；抗***；抗雄激素；性腺釋素促效劑；拓樸異構酶I抑制劑；拓樸異構酶II抑制劑；微管活性劑；烷基化劑；類視黃素、類胡蘿蔔素或生育酚；環加氧酶抑制劑；MMP抑制劑；mTOR抑制劑；抗代謝產物；鉑化合物；甲硫胺酸胺基肽酶抑制劑；雙膦酸鹽；抗增殖抗體；肝素酶抑制劑；Ras致癌同功異型物之抑制劑；端粒酶抑制劑；蛋白酶體抑制劑；用於治療血液科惡性疾病之化合物；Flt-3抑制劑；Hsp90抑制劑；運動素紡錘蛋白質抑制劑；MEK抑制劑；抗腫瘤抗生素；亞硝基脲；又似***抑制劑、靶向/降低蛋白質或脂質激酶活性之化合物、靶向/降低蛋白質或脂質磷酸酶活性之化合物或任何其他抗血管生成之化合物。Examples of antiproliferative compounds include, but are not limited to, aromatase inhibitors; antiestrogens; antiandrogens; gonadotropin agonists; topoisomerase I inhibitors; topoisomerase II inhibitors; Tube Actives; Alkylating Agents; Retinoids, Carotenoids, or Tocopherols; Cyclooxygenase Inhibitors; MMP Inhibitors; mTOR Inhibitors; Antimetabolites; Platinum Compounds; Methionine Amino Peptides Enzyme Inhibitors; Bisphosphonates; Antiproliferative Antibodies; Heparinase Inhibitors; Ras Carcinogenic Isoform Inhibitors; Telomerase Inhibitors; Proteasome Inhibitors; Compounds for the Treatment of Hematological Malignancies; Flt-3 Inhibitor; Hsp90 Inhibitor; Kinesin Spindle Protein Inhibitor; MEK Inhibitor; Antitumor Antibiotic; Nitrosourea; / Compounds that reduce protein or lipid phosphatase activity or any other anti-angiogenic compound.
非限制性例示性芳香酶抑制劑包括(但不限於)類固醇，諸如阿他美坦(atamestane)、依西美坦(exemestane)及福美司坦(formestane)；及非類固醇，諸如胺格魯米特(aminoglutethimide)、羅穀亞胺(roglethimide)、吡魯米特(pyridoglutethimide)、曲洛司坦(trilostane)、睪內酯(testolactone)、酮康唑(ketokonazole)、伏羅唑(vorozole)、法屈唑(fadrozole)、阿那曲唑(anastrozole)及來曲唑(letrozole)。Non-limiting exemplary aromatase inhibitors include, but are not limited to, steroids, such as atamestane, exemestane, and formestane; and non-steroids, such as amineglomib Aminoglutethimide, rogletimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, Fadrol fadrozole, anastrozole and letrozole.
非限制性抗***包括(但不限於)他莫昔芬(tamoxifen)、氟維司群(fulvestrant)、雷諾昔酚(raloxifene)及雷諾昔酚鹽酸鹽。抗雄激素包括(但不限於)比卡魯胺(bicalutamide)。高那瑞林(Gonadorelin)促效劑包括(但不限於)阿巴瑞克(abarelix)、戈舍瑞林(goserelin)及戈舍瑞林乙酸鹽。Non-limiting antiestrogens include, but are not limited to, tamoxifen, fulvestrant, raloxifene, and raloxifene hydrochloride. Anti-androgens include, but are not limited to, bicalutamide. Gonadorelin agonists include, but are not limited to, abarelix, goserelin, and goserelin acetate.
例示性拓樸異構酶I抑制劑包括(但不限於)拓朴替康(topotecan)、吉馬替康(gimatecan)、伊立替康(irinotecan)、喜樹鹼及其類似物、9-硝基喜樹鹼及大分子喜樹鹼結合物PNU-166148。拓樸異構酶II抑制劑包括(但不限於)蒽環黴素，諸如多柔比星(doxorubicin)、道諾黴素(daunorubicin)、表柔比星(epirubicin)、艾達黴素(idarubicin)及奈莫柔比星(nemorubicin)；蒽醌，諸如米托蒽醌(mitoxantrone)及洛索蒽醌(losoxantrone)；及鬼臼毒素，諸如依託泊苷(etoposide)及替尼泊苷(teniposide)。Exemplary topoisomerase I inhibitors include, but are not limited to, topotecan, gimatecan, irinotecan, camptothecin and analogs thereof, 9-nitro Camptothecin and macromolecular camptothecin conjugate PNU-166148. Topoisomerase II inhibitors include, but are not limited to, anthracyclines such as doxorubicin, daunorubicin, epirubicin, idarubicin ) and nemorubicin; anthraquinones such as mitoxantrone and losoxantrone; and podophyllotoxins such as etoposide and teniposide ).
微管活性劑包括微管穩定化、微管去穩定化合物，且微管蛋白聚合抑制劑包括(但不限於)紫杉烷(taxanes)，諸如太平洋紫杉醇(paclitaxel)及多烯紫杉醇(docetaxel)；長春花生物鹼(vinca alkaloids)，諸如長春鹼(vinblastine)、硫酸長春花鹼、長春新鹼(vincristine)及硫酸長春新鹼及長春瑞濱(vinorelbine)；迪斯德莫來(discodermolide)；秋水仙鹼(cochicine)及埃博黴素(epothilone)及其衍生物。Microtubule active agents include microtubule stabilizing, microtubule destabilizing compounds, and tubulin polymerization inhibitors include, but are not limited to, taxanes such as paclitaxel and docetaxel; Vinca alkaloids such as vinblastine, vinblastine sulfate, vincristine and vincristine sulfate and vinorelbine; discodermolide; autumn Narcissine (cochicine) and epothilone (epothilone) and their derivatives.
例示性非限制性烷基化劑包括環磷醯胺、異環磷醯胺、美法侖(melphalan)及亞硝基脲，諸如卡莫司汀(carmustine)及洛莫司汀(lomustine)。Exemplary non-limiting alkylating agents include cyclophosphamide, ifosfamide, melphalan, and nitrosoureas such as carmustine and lomustine.
例示性非限制性環加氧酶抑制劑包括Cox-2抑制劑、經5-烷基取代之2-芳胺基苯乙酸及衍生物，諸如塞內昔布(celecoxib)、羅非昔布(rofecoxib)、依他昔布(etoricoxib)、伐地昔布(valdecoxib)，或5-烷基-2-芳胺基苯乙酸，諸如魯米昔布(lumiracoxib)。Exemplary non-limiting cyclooxygenase inhibitors include Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acids and derivatives such as celecoxib, rofecoxib ( rofecoxib), etoricoxib, valdecoxib, or 5-alkyl-2-arylaminophenylacetic acids such as lumiracoxib.
例示性非限制性基質金屬蛋白酶抑制劑(「MMP抑制劑」)包括膠原蛋白肽模擬及非肽模擬抑制劑、四環素衍生物、巴馬司他(batimastat)、馬立馬司他(marimastat)、普啉司他(prinomastat)、美他司他(metastat)、BMS-279251、BAY 12-9566、TAA211、MMI270B及AAJ996。Exemplary non-limiting matrix metalloproteinase inhibitors ("MMP inhibitors") include collagen peptidomimetic and non-peptidimetic inhibitors, tetracycline derivatives, batimastat, marimastat, Prinomastat, metastat, BMS-279251, BAY 12-9566, TAA211, MMI270B and AAJ996.
例示性非限制性mTOR抑制劑包括抑制哺乳動物雷帕黴素目標(mTOR)且擁有抗增殖活性之化合物，諸如西羅莫司(sirolimus)、依維莫司(everolimus)、CCI-779及ABT578。Exemplary non-limiting mTOR inhibitors include compounds that inhibit the mammalian target of rapamycin (mTOR) and possess antiproliferative activity, such as sirolimus, everolimus, CCI-779 and ABT578 .
例示性非限制性抗代謝物包括5-氟尿嘧啶(5-FU)；卡培他濱(capecitabine)；吉西他濱(gemcitabine)；DNA去甲基化合物，諸如5-氮雜胞苷及地西他濱(decitabine)；甲胺喋呤及依達曲沙(edatrexate)；及葉酸拮抗劑，諸如培美曲塞(pemetrexed)。Exemplary non-limiting antimetabolites include 5-fluorouracil (5-FU); capecitabine; gemcitabine; DNA demethylation compounds such as 5-azacytidine and decitabine ( decitabine); methotrexate and edatrexate; and folic acid antagonists such as pemetrexed.
例示性非限制性鉑化合物包括卡鉑、順-鉑(cis-platin)、順鉑(cisplatinum)及奧沙利鉑(oxaliplatin)。Exemplary non-limiting platinum compounds include carboplatin, cis-platin, cisplatinum, and oxaliplatin.
例示性非限制性甲硫胺酸胺基肽酶抑制劑包括苯胍麥或其衍生物及PPI-2458。Exemplary non-limiting methionine aminopeptidase inhibitors include benzoguanidine or derivatives thereof and PPI-2458.
例示性非限制性雙膦酸鹽包括依替酮酸(etridonic acid)、氯膦酸、替魯羅酸(tiludronic acid)、帕米膦酸(pamidronic acid)、阿侖膦酸(alendronic acid)、伊班膦酸(ibandronic acid)、利塞膦酸(risedronic acid)及唑來膦酸(zoledronic acid)。Exemplary non-limiting bisphosphonates include etridonic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid and zoledronic acid.
例示性非限制性抗增殖抗體包括曲妥珠單抗(trastuzumab)、曲妥珠單抗-DMl、西妥昔單抗(cetuximab)、貝伐單抗(bevacizumab)、利妥昔單抗(rituximab)、PR064553及2C4。術語「抗體」意謂包括完整單株抗體、多株抗體、由至少兩種完整抗體形成之多特異性抗體以及抗體片段，只要其呈現所需生物活性即可。Exemplary non-limiting anti-proliferative antibodies include trastuzumab, trastuzumab-DMl, cetuximab, bevacizumab, rituximab ), PR064553 and 2C4. The term "antibody" is meant to include intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least two intact antibodies, and antibody fragments so long as they exhibit the desired biological activity.
例示性非限制性肝素酶抑制劑包括靶向硫酸肝素、降低或抑制其降解之化合物，諸如PI-88及OGT2115。Exemplary non-limiting heparanase inhibitors include compounds that target, reduce or inhibit degradation of heparin sulfate, such as PI-88 and OGT2115.
如本文所用，術語「Ras致癌同功異型物之抑制劑」(諸如H-Ras、K-Ras或N-Ras)係指靶向Ras、降低或抑制其致癌活性的化合物，例如法呢基(farnesyl)轉移酶抑制劑，諸如L-744832、DK8G557、替吡法尼(tipifarnib)及洛那法尼(lonafarnib)。As used herein, the term "inhibitor of an oncogenic isoform of Ras" (such as H-Ras, K-Ras, or N-Ras) refers to a compound that targets Ras, reducing or inhibiting its oncogenic activity, such as farnesyl ( farnesyl) transferase inhibitors such as L-744832, DK8G557, tipifarnib and lonafarnib.
例示性非限制性端粒酶抑制劑包括靶向端粒酶、降低或抑制其活性的化合物，諸如抑制端粒酶受體之化合物，諸如特羅他汀(telomestatin)。Exemplary non-limiting telomerase inhibitors include compounds that target telomerase, reduce or inhibit its activity, such as compounds that inhibit the telomerase receptor, such as telomestatin.
例示性非限制性蛋白酶體抑制劑包括靶向蛋白酶體、降低或抑制其活性的化合物，包括(但不限於)硼替佐米(bortezomid)。Exemplary non-limiting proteasome inhibitors include compounds that target, reduce or inhibit the activity of the proteasome, including, but not limited to, bortezomid.
如本文所用，片語「在治療血液科惡性疾病中使用化合物」包括FMS樣酪胺酸激酶抑制劑，其為靶向FMS樣酪胺酸激酶受體(Flt-3R)、降低或抑制其活性的化合物；干擾素、Ι-β-D阿糖呋喃胞嘧啶(ara-c)及白消安(bisulfan)；ALK抑制劑，其為靶向、降低或抑制退行性淋巴瘤激酶的化合物；及BH3模擬物，其為靶向、降低或抑制來自BCL-2家族之抗凋亡蛋白的化合物。As used herein, the phrase "use of a compound in the treatment of hematological malignancies" includes FMS-like tyrosine kinase inhibitors that target, reduce or inhibit the activity of the FMS-like tyrosine kinase receptor (Flt-3R) the compounds of ; interferon, 1-beta-D arabinofuranocytosine (ara-c) and busulfan (bisulfan); ALK inhibitors, which are compounds that target, reduce or inhibit degenerative lymphoma kinase; and BH3 mimetics, which are compounds that target, reduce or inhibit anti-apoptotic proteins from the BCL-2 family.
例示性非限制性Flt-3抑制劑包括吉列替尼(gilteritinib)、PKC412、米哚妥林(midostaurin)、星形孢菌素衍生物、SU11248及MLN518。Exemplary non-limiting Flt-3 inhibitors include gilteritinib, PKC412, midostaurin, staurosporine derivatives, SU11248, and MLN518.
例示性非限制性HSP90抑制劑包括靶向HSP90之固有ATP酶、降低或抑制其活性；或經由泛素蛋白酶體路徑降解、靶向、降低或抑制HSP90客戶蛋白的化合物。靶向HSP90之固有ATP酶、降低或抑制其活性之化合物尤其為抑制HSP90之ATP酶活性之化合物、蛋白質或抗體，諸如17-烯丙基胺基、17-去甲氧基格爾德黴素(17AAG) (一種格爾德黴素(geldanamycin)衍生物)；其他格爾德黴素相關化合物；根赤殼菌素(radicicol)；及HDAC抑制劑。Exemplary non-limiting HSP90 inhibitors include compounds that target the intrinsic ATPase of HSP90, reduce or inhibit its activity; or degrade, target, reduce or inhibit HSP90 client proteins via the ubiquitin-proteasome pathway. Compounds that target, reduce or inhibit the activity of the intrinsic ATPase of HSP90 are especially compounds, proteins or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino, 17-desmethoxygeldanamycin (17AAG) (a geldanamycin derivative); other geldanamycin-related compounds; radicicol; and HDAC inhibitors.
例示性非限制性BH3模擬物包括維納妥拉(venetoclax)。Exemplary non-limiting BH3 mimetics include venetoclax.
如本文所用，片語「靶向蛋白質或脂質激酶/降低其活性的化合物；或靶向蛋白質或脂質磷酸酶/降低其活性的化合物；或任何其他抗血管生成化合物」包括蛋白酪胺酸激酶及/或絲胺酸及/或蘇胺酸激酶抑制劑或脂質激酶抑制劑，諸如a)靶向血小板衍生生長因子受體(PDGFR)、降低或抑制其活性的化合物，諸如靶向PDGFR、降低或抑制其活性的化合物，諸如N-苯基-2-嘧啶-胺衍生物，諸如伊馬替尼(imatinib)、SUlOl、SU6668及GFB-111；b)靶向纖維母細胞生長因子受體(FGFR)、降低或抑制其活性的化合物；c)靶向似胰島素生長因子受體I (IGF-IR)、降低或抑制其活性的化合物，諸如靶向IGF-IR、降低或抑制其活性的化合物；d)靶向Trk受體酪胺酸激酶家族、降低或抑制其活性的化合物，或艾普瑞林(ephrin) B4抑制劑；e)靶向Axl受體酪胺酸激酶家族、降低或抑制其活性的化合物；f)靶向Ret受體酪胺酸激酶、降低或抑制其活性的化合物；g)靶向Kit/SCFR受體酪胺酸激酶、降低或抑制其活性的化合物，諸如伊馬替尼；h)靶向c-Kit受體酪胺酸激酶、降低或抑制其活性的化合物，諸如伊馬替尼；i)靶向c-Abl家族之成員、其基因融合產物(例如Bcr-Abl激酶)及突變體、降低或抑制其活性的化合物，諸如N-苯基-2-嘧啶-胺衍生物，諸如伊馬替尼或尼羅替尼(nilotinib)；PD180970；AG957；NSC 680410；PD173955；或達沙替尼(dasatinib)；j)靶向絲胺酸/蘇胺酸激酶之蛋白激酶C (PKC)及Raf家族之成員、MEK之成員、SRC、JAK、FAK、PDK1、PKB/Akt及Ras/MAPK家庭成員及/或週期素依賴性激酶家族(CDK)之成員、降低或抑制其活性的化合物，諸如美國專利第5,093,330號中所揭示的星形孢菌素衍生物，諸如米哚妥林；其他化合物的實例包括UCN-01、沙芬戈(safingol)、BAY 43-9006、苔蘚蟲素(bryostatin) 1、哌立福新(perifosine)；伊莫福新(ilmofosine)；RO 318220及RO 320432；GO 6976；Isis 3521；LY333531/LY379196；異喹啉化合物；法呢基轉移酶抑制劑；PD184352或QAN697或AT7519；k)靶向蛋白質-酪胺酸激酶、降低或抑制其活性的化合物，諸如甲磺酸伊馬替尼或泰福斯汀(tyrphostin)，諸如泰福斯汀A23/RG-50810；AG 99；泰福斯汀AG 213；泰福斯汀AG 1748；泰福斯汀AG 490；泰福斯汀B44；泰福斯汀B44 (+)對映異構體；泰福斯汀AG 555；AG 494；泰福斯汀AG 556、AG957及阿達斯汀(adaphostin) (4-{[(2,5-二羥基苯基)甲基]胺基}-苯甲酸金剛烷基酯；NSC 680410、阿達斯汀)；1)靶向受體酪胺酸激酶之表皮生長因子家族(呈均或雜二聚體形式之EGFR、ErbB2、ErbB3、ErbB4)及其突變體、降低或抑制其活性的化合物，諸如CP 358774、ZD 1839、ZM 105180；曲妥珠單抗、西妥昔單抗、吉非替尼(gefitinib)、埃羅替尼(erlotinib)、OSI-774、Cl-1033、EKB-569、GW-2016，抗體El.l、E2.4、E2.5、E6.2、E6.4、E2.11、E6.3及E7.6.3，及7H-吡咯并-[2,3-d]嘧啶衍生物；及m)靶向c-Met受體、降低或抑制其活性的化合物。As used herein, the phrase "a compound that targets a protein or lipid kinase/reduces its activity; or a compound that targets a protein or lipid phosphatase/reduces its activity; or any other anti-angiogenic compound" includes protein tyrosine kinases and A serine and/or threonine kinase inhibitor or a lipid kinase inhibitor, such as a) a compound that targets platelet-derived growth factor receptor (PDGFR), reduces or inhibits its activity, such as targets PDGFR, reduces or inhibits Compounds that inhibit its activity, such as N-phenyl-2-pyrimidin-amine derivatives, such as imatinib, SU101, SU6668 and GFB-111; b) targeting fibroblast growth factor receptor (FGFR) , compounds that reduce or inhibit its activity; c) compounds that target insulin-like growth factor receptor I (IGF-IR), reduce or inhibit its activity, such as compounds that target IGF-IR, reduce or inhibit its activity; d ) A compound targeting the Trk receptor tyrosine kinase family, reducing or inhibiting its activity, or an ephrin B4 inhibitor; e) targeting the Axl receptor tyrosine kinase family, reducing or inhibiting its activity f) compounds targeting Ret receptor tyrosine kinase, reducing or inhibiting its activity; g) compounds targeting Kit/SCFR receptor tyrosine kinase, reducing or inhibiting its activity, such as imatinib; h) compounds that target c-Kit receptor tyrosine kinase, reduce or inhibit its activity, such as imatinib; i) target members of the c-Abl family, gene fusion products thereof (eg Bcr-Abl kinase) and Mutants, compounds that reduce or inhibit their activity, such as N-phenyl-2-pyrimidin-amine derivatives, such as imatinib or nilotinib; PD180970; AG957; NSC 680410; PD173955; or Dasa dasatinib; j) protein kinase C (PKC) targeting serine/threonine kinases and members of the Raf family, members of MEK, SRC, JAK, FAK, PDK1, PKB/Akt and Ras/MAPK family members and/or members of the cyclin-dependent kinase family (CDK), compounds that reduce or inhibit their activity, such as staurosporine derivatives disclosed in US Pat. No. 5,093,330, such as midostaurin; others Examples of compounds include UCN-01, safingol, BAY 43-9006, bryostatin 1, perifosine; ilmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521; LY333531/LY379196; isoquinoline compounds; farnesyltransferase inhibitors; PD184352 or QAN697 or AT7519; k) Targeted proteins - tyrosine Kinases, compounds that reduce or inhibit their activity, such as imatinib mesylate or tyrphostin, such as typhostin A23/RG-50810; AG 99; typhostin AG 213; typhostin Taferstin AG 1748; Taferstin AG 490; Taferstin B44; Taferstin B44 (+) enantiomer; Taferstin AG 555; AG 494; Taferstin AG 556, AG957 and adaphostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-adamantyl benzoate; NSC 680410, adastin); 1) targeting receptor tyrosine Epidermal growth factor family of amino acid kinases (EGFR, ErbB2, ErbB3, ErbB4 in homo- or heterodimeric form) and mutants thereof, compounds that reduce or inhibit their activity, such as CP 358774, ZD 1839, ZM 105180; Tocilizumab, cetuximab, gefitinib, erlotinib, OSI-774, Cl-1033, EKB-569, GW-2016, antibodies El.l, E2. 4. E2.5, E6.2, E6.4, E2.11, E6.3 and E7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidine derivatives; and m) targeting c- Met receptors, compounds that reduce or inhibit their activity.
靶向蛋白質或脂質磷酸酶、降低或抑制其活性之例示性化合物包括磷酸酶1抑制劑、磷酸酶2A抑制劑或CDC25抑制劑，諸如岡田井酸(okadaic acid)或其衍生物。Exemplary compounds that target protein or lipid phosphatases, reduce or inhibit their activity include phosphatase 1 inhibitors, phosphatase 2A inhibitors, or CDC25 inhibitors, such as okadaic acid or derivatives thereof.
其他抗血管生成化合物包括具有另一活性機制(例如與蛋白質或脂質激酶抑制無關)之化合物，例如沙立度胺(thalidomide)及TNP-470。Other anti-angiogenic compounds include compounds that have another mechanism of activity (eg, unrelated to protein or lipid kinase inhibition), such as thalidomide and TNP-470.
另外非限制性例示性化學治療性化合物包括：道諾黴素(daunorubicin)、阿德力黴素(adriamycin)、Ara-C、VP-16、替尼泊苷、米托蒽醌、艾達黴素(idarubicin)、卡鉑(carboplatinum)、PKC412、6-巰基嘌呤(6-MP)、磷酸氟達拉濱(fludarabine phosphate)、奧曲肽(octreotide)、SOM230、FTY720、6-硫鳥嘌呤、克拉屈濱(cladribine)、6-巰基嘌呤、噴司他丁(pentostatin)、羥基脲、2-羥基-lH-異吲哚-l,3-二酮衍生物、1-(4-氯苯胺基)-4-(4-吡啶基甲基)酞𠯤或其醫藥學上可接受之鹽、1-(4-氯苯胺基)-4-(4-吡啶基甲基)酞𠯤丁二酸鹽、血管生長抑素、內皮生長抑素、鄰胺基苯甲酸醯胺、ZD4190、ZD6474、SU5416、SU6668、貝伐單抗(bevacizumab)、rhuMAb、rhuFab、macugon；FLT-4抑制劑、FLT-3抑制劑、VEGFR-2 IgG1抗體、RPI 4610、貝伐單抗、卟吩姆鈉(porfimer sodium)、阿奈可他(anecortave)、曲安西龍(triamcinolone)、氫皮質酮、11-a-表氫化皮質醇、皮質酮、17a-羥基孕酮、皮質固酮、去氧皮質固酮、睪固酮、雌酮、***(dexamethasone)、膚輕鬆(fluocinolone)、植物生物鹼、激素化合物及/或拮抗劑、生物反應調節劑(諸如淋巴介質或干擾素)、反義寡核苷酸或寡核苷酸衍生物、shRNA及siRNA，該等化學治療性化合物中之一或多者可與本發明之化合物組合使用。Additional non-limiting exemplary chemotherapeutic compounds include: daunorubicin, adriamycin, Ara-C, VP-16, teniposide, mitoxantrone, idamycin idarubicin, carboplatinum, PKC412, 6-mercaptopurine (6-MP), fludarabine phosphate, octreotide, SOM230, FTY720, 6-thioguanine, cladrix cladribine, 6-mercaptopurine, pentostatin, hydroxyurea, 2-hydroxy-lH-isoindole-l,3-dione derivatives, 1-(4-chloroanilino)- 4-(4-Pyridylmethyl)phthalein or its pharmaceutically acceptable salt, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalein succinate, vascular Somatostatin, endostatin, anthranilamide, ZD4190, ZD6474, SU5416, SU6668, bevacizumab, rhuMAb, rhuFab, macugon; FLT-4 inhibitor, FLT-3 inhibitor , VEGFR-2 IgG1 antibody, RPI 4610, bevacizumab, porfimer sodium, anecortave, triamcinolone, hydrocortisone, 11-a-epihydrocortical Alcohol, corticosterone, 17a-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone, dexamethasone, fluocinolone, plant alkaloids, hormonal compounds and/or antagonists , biological response modifiers (such as lymphatic mediators or interferons), antisense oligonucleotides or oligonucleotide derivatives, shRNA and siRNA, one or more of these chemotherapeutic compounds may be combined with the compounds of the invention used in combination.
第二治療劑之其他實例包括(但不限於)：用於阿茲海默氏症之治療，諸如多奈哌齊(donepezil)及雷斯替明(rivastigmine)；用於帕金森氏病之治療，諸如L-DOPA/卡比多巴(carbidopa)、恩他卡朋(entacapone)、羅匹尼羅(ropinrole)、普拉克索(pramipexole)、溴麥角環肽(bromocriptine)、培高利特(pergolide)、三己芬迪(trihexephendyl)及金剛胺(amantadine)；用於治療多發性硬化(MS)之藥劑，諸如β干擾素(例如AVONEX®及REBIF®)、醋酸格拉替雷(glatiramer acetate)及米托蒽醌；用於哮喘之治療，諸如沙丁胺醇(albuterol)及孟魯司特(montelukast)；用於治療精神***症之藥劑，諸如金普薩(zyprexa)、理斯必妥(risperdal)、思樂康(seroquel)及氟哌啶醇；抗炎劑，諸如皮質類固醇、TNF阻斷劑、IL-1 RA、硫唑嘌呤、環磷醯胺及柳氮磺胺吡啶；免疫調節劑，包括免疫抑制劑，諸如環孢素、他克莫司、雷帕黴素、黴酚酸嗎啉乙酯(mycophenolate mofetil)、干擾素、皮質類固醇、環磷醯胺、硫唑嘌呤及柳氮磺胺吡啶；神經營養因子，諸如乙醯膽鹼酯酶抑制劑、MAO抑制劑、干擾素、抗痙攣劑、離子通道阻斷劑、利魯唑(riluzole)或抗帕金森藥劑；用於治療心血管疾病之藥劑，諸如β阻斷劑、ACE抑制劑、利尿劑、硝酸鹽、鈣通道阻斷劑或士他汀(statin)；用於治療肝病之藥劑，諸如皮質類固醇、消膽胺(cholestyramine)、干擾素及抗病毒藥劑；用於治療血液病症之藥劑，諸如皮質類固醇、抗白血病藥劑或生長因子；或用於治療免疫缺乏病症之藥劑，諸如γ球蛋白，該等第二治療劑中之一或多者亦可與本發明之化合物亦可組合。Other examples of second therapeutic agents include, but are not limited to: for the treatment of Alzheimer's disease, such as donepezil and rivastigmine; for the treatment of Parkinson's disease, such as L -DOPA/carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl and amantadine; agents used in the treatment of multiple sclerosis (MS), such as beta interferons (eg AVONEX® and REBIF®), glatiramer acetate, and mitoxal Anthraquinones; used in the treatment of asthma, such as albuterol and montelukast; used in the treatment of schizophrenia, such as zyprexa, risperdal, Syrup seroquel and haloperidol; anti-inflammatory agents, such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulators, including immunosuppressants , such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine; neurotrophic factors, such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, ion channel blockers, riluzole or antiparkinsonian agents; agents for the treatment of cardiovascular disease, such as beta blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, or statins; agents used to treat liver disease, such as corticosteroids, cholestyramine, interferons, and Viral agents; agents for the treatment of blood disorders, such as corticosteroids, anti-leukemia agents, or growth factors; or agents for the treatment of immunodeficiency disorders, such as gamma globulin, one or more of these second therapeutic agents also It can also be combined with the compounds of the present invention.
上述第二治療活性劑如此項技術中所描述來製備及投與，該等第二治療活性劑中之一或多者可與本發明之化合物組合使用。The second therapeutically active agents described above are prepared and administered as described in the art, and one or more of these second therapeutically active agents may be used in combination with the compounds of the present invention.
本發明之化合物通常與針對預期投與途徑及標準醫藥實踐選擇之醫藥載劑摻合投與。根據本發明使用之醫藥組合物以習知方式使用一或多種生理學上可接受之載劑進行調配，該等生理學上可接受之載劑包含有助於處理本發明之化合物的賦形劑及/或助劑。The compounds of the present invention are generally administered in admixture with a pharmaceutical carrier selected for the intended route of administration and standard pharmaceutical practice. Pharmaceutical compositions for use in accordance with the present invention are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients which facilitate processing of the compounds of the present invention and/or auxiliaries.
此等醫藥組合物可例如藉由習知混合、溶解、粒化、糖衣藥丸形成、乳化、囊封、包覆或凍乾過程來製造。適當調配物視所選投與途徑而定。當經口投與治療有效量之本發明之化合物時，組合物通常呈錠劑、膠囊、粉劑、溶液或酏劑之形式。當以錠劑形式投與時，組合物另外可含有固體載劑，諸如明膠或佐劑。錠劑、膠囊及粉劑含有約0.01%至約95%，且較佳地約1%至約50%之本發明之化合物。當以液體形式投與時，可添加諸如水、石油或動物來源油或植物來源油之液體載劑。液體形式之組合物可進一步含有生理鹽水溶液、右旋糖或其他醣溶液或二醇。當以液體形式投與時，組合物含有約0.1重量%至約90重量%，且較佳地約1重量%至約50重量%之本發明之化合物。Such pharmaceutical compositions can be manufactured, for example, by conventional mixing, dissolving, granulating, dragee-forming, emulsifying, encapsulating, coating, or lyophilizing processes. Appropriate formulations depend on the route of administration chosen. When a therapeutically effective amount of a compound of the present invention is administered orally, the composition is usually in the form of a lozenge, capsule, powder, solution or elixir. When administered in tablet form, the compositions may additionally contain a solid carrier such as gelatin or an adjuvant. Tablets, capsules and powders contain from about 0.01% to about 95%, and preferably from about 1% to about 50%, of a compound of the invention. When administered in liquid form, liquid carriers such as water, petroleum or oils of animal or vegetable origin can be added. Compositions in liquid form may further contain physiological saline solution, dextrose or other sugar solutions or glycols. When administered in liquid form, the compositions contain from about 0.1% to about 90% by weight, and preferably from about 1% to about 50% by weight, of a compound of the present invention.
當藉由靜脈內、皮膚或皮下注射投與治療有效量之本發明之化合物時，組合物呈無熱原質非經腸可接受水溶液之形式。適當考慮pH、等張性、穩定性及其類似者製備此類非經腸可接受溶液在此項技術之技能範圍內。用於靜脈內、皮膚或皮下注射之較佳組合物通常含有等張媒劑。When a therapeutically effective amount of a compound of the present invention is administered by intravenous, dermal or subcutaneous injection, the composition is in the form of a pyrogen-free parenterally acceptable aqueous solution. It is within the skill of the art to prepare such parenterally acceptable solutions with due regard to pH, isotonicity, stability and the like. Preferred compositions for intravenous, dermal or subcutaneous injection typically contain an isotonic vehicle.
本發明之化合物可易於與此項技術中熟知的醫藥學上可接受之載劑組合。標準醫藥載劑描述於Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 第19版. 1995中。此類載劑使得能夠將活性劑調配為用於待治療患者口服攝取之錠劑、丸劑、糖衣藥丸、膠囊、液體、凝膠、糖漿、漿液、懸浮液及其類似者。經口使用之醫藥製劑可藉由以下操作而獲得：將本發明之化合物添加至固體賦形劑，視情況研磨所得混合物，及必要時在添加合適助劑之後加工顆粒之混合物以獲得錠劑或糖衣藥丸芯。適合的賦形劑包括例如填充劑及纖維素製劑。必要時，可添加崩解劑。The compounds of the present invention can be readily combined with pharmaceutically acceptable carriers well known in the art. Standard pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 19th Ed. 1995. Such carriers enable the active agent to be formulated as lozenges, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained by adding a compound of the present invention to a solid excipient, grinding the resulting mixture as appropriate, and processing the mixture of granules, after adding suitable auxiliaries, if necessary, to obtain lozenges or Dragee cores. Suitable excipients include, for example, fillers and cellulosic preparations. If necessary, a disintegrant can be added.
本發明之化合物可經調配以藉由注射(例如藉由快速注射或連續輸注)而進行非經腸投與。注射用調配物可呈單位劑型，例如以安瓿或多劑量容器形式，其中添加有防腐劑。組合物可採取諸如於油性或水性媒劑中之懸浮液、溶液或乳液之形式，且可含有諸如懸浮劑、穩定劑及/或分散劑之調配劑。The compounds of the present invention can be formulated for parenteral administration by injection (eg, by bolus injection or continuous infusion). Formulations for injection may be presented in unit dosage form, eg, in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
用於非經腸投與之醫藥組合物包括呈水可溶形式之活性劑水溶液。另外，可按適當油性注射懸浮液形式來製備本發明之化合物之懸浮液。適合的親脂性溶劑或媒劑包括脂肪油或合成脂肪酸酯。水性注射懸浮液可含有增加懸浮液之黏度的物質。視情況，懸浮液亦可含有適合的穩定劑或增加化合物溶解性且允許製備高度濃縮溶液之藥劑。可替代地，本組合物可呈粉末形式以用於在使用之前用適合的媒劑(例如，無菌無熱原質水)復原。Pharmaceutical compositions for parenteral administration include aqueous solutions of the active agent in water-soluble form. Additionally, suspensions of the compounds of the present invention may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils or synthetic fatty acid esters. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds and allow for the preparation of highly concentrated solutions. Alternatively, the present compositions may be in powder form for reconstitution with a suitable vehicle, eg, sterile pyrogen-free water, before use.
本發明之化合物亦可調配於經直腸組合物中，諸如例如含有習知栓劑基質之栓劑或保留灌腸劑。除先前所描述之調配物以外，本發明之化合物亦可經調配為貯存製劑。此類長效調配物可藉由植入(例如皮下或肌肉內)或藉由肌肉內注射來投與。因此，舉例而言，本發明之化合物可經調配有適合的聚合物或疏水性材料(例如呈於可接受油中之乳液)或離子交換樹脂。The compounds of the present invention may also be formulated in transrectal compositions such as, for example, suppositories or retention enemas containing conventional suppository bases. In addition to the formulations previously described, the compounds of the present invention can also be formulated as depot preparations. Such long-acting formulations can be administered by implantation (eg, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of the present invention can be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins.
特定言之，本發明之化合物可以含有賦形劑(諸如澱粉或乳糖)之錠劑的形式、或以膠囊或卵形栓劑形式(單獨或與賦形劑摻合)或呈含有調味劑或著色劑之酏劑或懸浮液形式經口、頰內或舌下投與。此類液體製劑可經製備有醫藥學上可接受之添加劑，諸如懸浮劑。亦可非經腸注射，例如靜脈內、肌肉內、皮下或冠狀動脈內注射本發明之化合物。對於非經腸投與，本發明之化合物通常以可含有其他物質之無菌水溶液的形式使用以製得與血液等張之溶液，該等其他物質例如鹽或單醣，諸如甘露醇或葡萄糖。In particular, the compounds of the present invention may be in the form of lozenges containing excipients such as starch or lactose, or in the form of capsules or oval suppositories (alone or in admixture with excipients) or in the form of flavoring or coloring agents The dose is administered orally, bucally or sublingually in the form of an elixir or suspension. Such liquid preparations may be prepared with pharmaceutically acceptable additives such as suspending agents. Parenteral injections, eg, intravenous, intramuscular, subcutaneous or intracoronary injection, of the compounds of the invention may also be used. For parenteral administration, the compounds of the present invention are typically used in the form of sterile aqueous solutions that may contain other substances, such as salts or monosaccharides, such as mannitol or dextrose, to make solutions isotonic with blood.
本發明提供與治療個體之疾病有關之以下特定實施例。The present invention provides the following specific examples related to the treatment of a disease in an individual.
實施例1.一種治療有需要之個體之方法，該方法包含向該個體投與治療有效量之本發明之化合物，其中該個體患有癌症。Example 1. A method of treating an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound of the present invention, wherein the individual has cancer.
實施例2.如實施例1之方法，其中該癌症為表2之癌症中之任一者或多者。Embodiment 2. The method of embodiment 1, wherein the cancer is any one or more of the cancers of Table 2.
實施例3.如實施例2之方法，其中該癌症為血液癌。Embodiment 3. The method of embodiment 2, wherein the cancer is a blood cancer.
實施例4.如實施例3之方法，其中該血液癌為表3之癌症中之任一者或多者。Embodiment 4. The method of embodiment 3, wherein the blood cancer is any one or more of the cancers of Table 3.
實施例5.如實施例1至4中任一項之方法，其進一步包含投與治療有效量之適用於治療癌症之第二治療劑。Embodiment 5. The method of any one of Embodiments 1-4, further comprising administering a therapeutically effective amount of a second therapeutic agent suitable for treating cancer.
實施例6.一種醫藥組合物，其包含本發明之化合物及醫藥學上可接受之載劑以用於治療癌症。Embodiment 6. A pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier for the treatment of cancer.
實施例7.如實施例6之醫藥組合物，其中該癌症為表2之癌症中之任一者或多者。Embodiment 7. The pharmaceutical composition of embodiment 6, wherein the cancer is any one or more of the cancers of Table 2.
實施例8.如實施例7之醫藥組合物，其中該癌症為血液癌。Embodiment 8. The pharmaceutical composition of Embodiment 7, wherein the cancer is hematological cancer.
實施例9.如實施例8之醫藥組合物，其中該血液癌為表3之癌症中之任一者或多者。Embodiment 9. The pharmaceutical composition of Embodiment 8, wherein the blood cancer is any one or more of the cancers of Table 3.
實施例10.一種本發明之化合物，其用於治療癌症。Example 10. A compound of the present invention for use in the treatment of cancer.
實施例11.如實施例10之化合物，其中該癌症為表2之癌症中之任一者或多者。Embodiment 11. The compound of Embodiment 10, wherein the cancer is any one or more of the cancers of Table 2.
實施例12.如實施例11之化合物，其中該癌症為血液癌。Embodiment 12. The compound of Embodiment 11, wherein the cancer is hematological cancer.
實施例13.如實施例12之化合物，其中該血液癌為表3之癌症中之任一者或多者。Embodiment 13. The compound of Embodiment 12, wherein the blood cancer is any one or more of the cancers of Table 3.
實施例14.一種本發明之化合物之用途，其用於製造用於治療癌症之藥劑。Example 14. Use of a compound of the present invention in the manufacture of a medicament for the treatment of cancer.
實施例15.如實施例14之用途，其中該癌症為表2之癌症中之任一者或多者。Embodiment 15. The use of embodiment 14, wherein the cancer is any one or more of the cancers of Table 2.
實施例16.如實施例15之用途，其中該癌症為血液癌。Embodiment 16. The use of embodiment 15, wherein the cancer is a blood cancer.
實施例17.如實施例16之用途，其中該血液癌為表3之癌症中之任一者或多者。 III. 本發明之套組Embodiment 17. The use of embodiment 16, wherein the blood cancer is any one or more of the cancers of Table 3. III. The kit of the present invention
在另一實施例中，本發明提供套組，其包含本發明之化合物(或包含本發明之化合物之組合物)，該等化合物以有助於其用以實踐本發明之方法的方式進行封裝。在一個實施例中，套組包括封裝於諸如密封瓶或器皿之容器中之本發明之化合物(或包含本發明之化合物之組合物)，其具有描述使用化合物或組合物實踐本發明之方法的貼附於容器或包括於套組中的標籤。在一個實施例中，將化合物或組合物封裝於單位劑型中。套組進一步可包括適用於根據預期投與途徑投與組合物之裝置。 IV. 定義In another embodiment, the present invention provides kits comprising compounds of the present invention (or compositions comprising compounds of the present invention) packaged in a manner that facilitates their use in practicing the methods of the present invention . In one embodiment, a kit includes a compound of the present invention (or a composition comprising a compound of the present invention) packaged in a container, such as a sealed bottle or vessel, with instructions describing methods of using the compound or composition to practice the present invention Labels affixed to containers or included in kits. In one embodiment, the compound or composition is packaged in a unit dosage form. The kit may further comprise a device suitable for administering the composition according to the intended route of administration. IV. Definitions
在本發明中，如其本身或作為另一基團之部分使用，術語「鹵基」係指-Cl、-F、-Br或-I。In the present invention, the term "halo" as used by itself or as part of another group refers to -Cl, -F, -Br or -I.
在本發明中，如由單獨或作為另一基團之部分使用，術語「硝基」係指-NO2 。In the present invention, the term "nitro" as used alone or as part of another group refers to -NO2 .
在本發明中，如由單獨或作為另一基團之部分使用，術語「氰基」係指-CN。In the present invention, the term "cyano" as used alone or as part of another group refers to -CN.
在本發明中，如其本身或作為另一基團之部分使用，術語「羥基」係指-OH。In the present invention, the term "hydroxyl" as used by itself or as part of another group refers to -OH.
在本發明中，如由單獨或作為另一基團之部分使用，術語「烷基」係指含有以下各者之未經取代的直鏈或支鏈脂族烴：一個至十二個碳原子，亦即C1-12 烷基；或指定碳原子數目，例如C1 烷基(諸如甲基)、C2 烷基(諸如乙基)、C3 烷基(諸如丙基或異丙基)、C1-3 烷基(諸如甲基、乙基、丙基或異丙基)等。在一個實施例中，烷基為C1-10 烷基。在另一實施例中，烷基為C1-6 烷基。在另一實施例中，烷基為C1-4 烷基。在另一實施例中，烷基為直鏈C1-10 烷基。在另一實施例中，烷基為支鏈C3-10 烷基。在另一實施例中，烷基為直鏈C1-6 烷基。在另一實施例中，烷基為分支鏈C3-6 烷基。在另一實施例中，烷基為直鏈C1-4 烷基。在另一實施例中，烷基為直鏈C3-4 烷基。在另一實施例中，烷基為直鏈或分支鏈C3-4 烷基。非限制性例示性C1-10 烷基包括：甲基、乙基、丙基、異丙基、丁基、第二丁基、三級丁基、異丁基、3-戊基、己基、庚基、辛基、壬基及癸基。非限制性例示性C1-4 烷基包括甲基、乙基、丙基、異丙基、丁基、第二丁基、三級丁基及異丁基。In the present invention, the term "alkyl" as used alone or as part of another group refers to an unsubstituted straight or branched chain aliphatic hydrocarbon containing from one to twelve carbon atoms , that is, C 1-12 alkyl; or specify the number of carbon atoms, such as C 1 alkyl (such as methyl), C 2 alkyl (such as ethyl), C 3 alkyl (such as propyl or isopropyl) , C 1-3 alkyl (such as methyl, ethyl, propyl or isopropyl) and the like. In one embodiment, the alkyl group is a C 1-10 alkyl group. In another embodiment, the alkyl group is a C 1-6 alkyl group. In another embodiment, the alkyl group is a C 1-4 alkyl group. In another embodiment, the alkyl group is a straight chain C 1-10 alkyl group. In another embodiment, the alkyl group is a branched C3-10 alkyl group. In another embodiment, the alkyl group is a straight chain C 1-6 alkyl group. In another embodiment, the alkyl group is a branched C3-6 alkyl group. In another embodiment, the alkyl group is a straight chain C 1-4 alkyl group. In another embodiment, the alkyl group is a straight chain C3-4 alkyl group. In another embodiment, the alkyl group is a straight or branched chain C3-4 alkyl group. Non-limiting exemplary C1-10 alkyl groups include: methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, isobutyl, 3-pentyl, hexyl, Heptyl, octyl, nonyl and decyl. Non-limiting exemplary C1-4 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary-butyl, and isobutyl.
在本發明中，如由單獨或作為另一基團之部分使用，術語「視情況經取代之烷基」係指未經取代或經獨立地選自由以下組成之群中之一個、兩個或三個取代基取代的烷基：硝基、鹵烷氧基、芳氧基、芳烷氧基、烷硫基、磺醯胺基、烷羰基、芳基羰基、烷基磺醯基、芳基磺醯基、羧基、羧基烷基及烷基羰氧基。在一個實施例中，視情況經取代之烷基經兩個取代基取代。在另一實施例中，視情況經取代之烷基經一個取代基取代。在另一實施例中，視情況經取代之烷基未經取代。非限制性例示性經取代之烷基包括-CH2 CH2 NO2 、-CH2 SO2 CH3 、-CH2 CH2 CO2 H、-CH2 SCH3 、-CH2 CH2 SO2 CH3 、-CH2 CH2 COPh及-CH2 OC(=O)CH3 。In the present invention, the term "optionally substituted alkyl" as used alone or as part of another group means unsubstituted or independently selected from one, two or Alkyl substituted with three substituents: nitro, haloalkoxy, aryloxy, aralkoxy, alkylthio, sulfonamido, alkcarbonyl, arylcarbonyl, alkylsulfonamido, aryl Sulfonyl, carboxyl, carboxyalkyl and alkylcarbonyloxy. In one embodiment, optionally substituted alkyl is substituted with two substituents. In another embodiment, an optionally substituted alkyl group is substituted with one substituent. In another embodiment, an optionally substituted alkyl group is unsubstituted. Non - limiting exemplary substituted alkyl groups include -CH2CH2NO2 , -CH2SO2CH3 , -CH2CH2CO2H , -CH2SCH3 , -CH2CH2SO2CH 3. -CH 2 CH 2 COPh and -CH 2 OC(=O)CH 3 .
在本發明中，如由單獨或作為另一基團之部分使用，術語「環烷基」係指含有一個至三個具有三個至十二個碳原子(亦即C3-12 環烷基)或指定碳數目之環的未經取代之飽和或部分不飽和(例如含有一個或兩個雙鍵)環脂族烴。在一個實施例中，環烷基具有兩個環。在另一實施例中，環烷基具有一個環。在另一實施例中，環烷基為飽和的。在另一實施例中，環烷基為不飽和的。在另一實施例中，環烷基為C3-8 環烷基。在另一實施例中，環烷基為C3-6 環烷基。術語「環烷基」意欲包括其中環-CH2 -經-C(=O)-置換之基團。非限制性例示性環烷基包括環丙基、環丁基、環戊基、環己基、環庚基、環辛基、降冰片烷基、十氫萘、金剛烷基、環己烯基、環戊烯基及環戊酮。In the present invention, the term "cycloalkyl" as used alone or as part of another group refers to a cycloalkyl group containing one to three carbon atoms (ie, C 3-12 cycloalkyl) having three to twelve carbon atoms. ) or unsubstituted saturated or partially unsaturated (eg containing one or two double bonds) cycloaliphatic hydrocarbons of a ring of the specified number of carbons. In one embodiment, a cycloalkyl group has two rings. In another embodiment, the cycloalkyl group has one ring. In another embodiment, the cycloalkyl group is saturated. In another embodiment, the cycloalkyl group is unsaturated. In another embodiment, the cycloalkyl group is a C 3-8 cycloalkyl group. In another embodiment, the cycloalkyl group is a C 3-6 cycloalkyl group. The term "cycloalkyl" is intended to include groups in which ring -CH2- is replaced by -C(=O)-. Non-limiting exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl, cyclohexenyl, cyclopentenyl and cyclopentanone.
在本發明中，如由單獨或作為另一基團之部分使用，術語「視情況經取代之環烷基」係指未經取代或經獨立地選自由以下組成之群中之一個、兩個或三個取代基取代的環烷基：鹵基、硝基、氰基、羥基、烷基羰氧基、環烷基羰基氧基、胺基、鹵烷基、羥烷基、烷氧基、鹵烷氧基、芳氧基、芳烷氧基、烷硫基、甲醯胺基、磺醯胺基、烷羰基、芳基羰基、烷基磺醯基、芳基磺醯基、羧基、羧基烷基、視情況經取代之烷基、視情況經取代之環烷基、烯基、炔基、視情況經取代之芳基、視情況經取代之雜芳基、視情況經取代之雜環基、烷氧基烷基、(胺基)烷基、(甲醯胺基)烷基、(雜環基)烷基、-OC(=O)-胺基、-N(R19a
)C(=O)-R19b
及-N(R20a
)SO2
-R20b
，其中R19a
係選自由氫及烷基組成之群，R19b
係選自由胺基、烷氧基、烷基(例如C1
-C6
烷基)及視情況經取代之芳基組成之群，R20a
係選自由氫及烷基組成之群，且R20b
係選自由胺基、烷基及視情況經取代之芳基組成之群。術語視情況經取代之環烷基包括具有稠合的視情況經取代之芳基(例如苯基)或稠合的視情況經取代之雜芳基(例如吡啶基)的環烷基。具有稠合的視情況經取代之芳基或稠合的視情況經取代之雜芳基的視情況經取代之環烷基可在環烷基環上之任何可用碳原子處與分子之其餘部分連接。在一個實施例中，視情況經取代之環烷基經兩個取代基取代。在另一實施例中，視情況經取代之環烷基經一個取代基取代。在另一實施例中，視情況經取代之環烷基未經取代。非限制性例示性經取代之環烷基包括：
在本發明中，如本文中由單獨或作為另一基團之部分使用，術語「伸環烷基」係指視情況經取代之環烷基的二價形式。在一個實施例中，伸環烷基為4員伸環烷基。在另一實施例中，伸環烷基為5員伸環烷基。在另一實施例中，伸環烷基為6員伸環烷基。非限制性例示性伸環烷基包括：
在本發明中，如由單獨或作為另一基團之部分使用，術語「芳基」係指具有六個至十四個碳原子之未經取代的單環或雙環芳環系統，亦即C6-14 芳基。非限制性例示性芳基包括苯基(縮寫為「Ph」)、萘基、菲基、蒽基、茚基、薁基、聯苯基、伸聯苯基及茀基。在一個實施例中，芳基為苯基或萘基。In the present invention, the term "aryl" as used alone or as part of another group refers to an unsubstituted monocyclic or bicyclic aromatic ring system having from six to fourteen carbon atoms, ie C 6-14 Aryl. Non-limiting exemplary aryl groups include phenyl (abbreviated "Ph"), naphthyl, phenanthryl, anthracenyl, indenyl, azulenyl, biphenyl, biextended, and indenyl. In one embodiment, the aryl group is phenyl or naphthyl.
在本發明中，如本文中其本身或作為另一基團之部分使用，術語「視情況經取代之芳基」係指未經取代或經一至五個獨立地選自由以下組成之群之取代基取代的芳基：鹵基、硝基、氰基、羥基、胺基、-CO-2 CH2 Ph、烷基胺基、二烷基胺基、視情況經取代之烷基、鹵烷基、羥烷基、烷氧基、鹵烷氧基、芳氧基、芳烷氧基、烷硫基、甲醯胺基、磺醯胺基、烷羰基、芳基羰基、烷基磺醯基、鹵烷基磺醯基、環烷基磺醯基、(環烷基)烷基磺醯基、芳基磺醯基、雜芳基磺醯基、雜環烷基磺醯基、羧基、羧基烷基、視情況經取代之環烷基、烯基、炔基、視情況經取代之芳基、視情況經取代之雜芳基、視情況經取代之雜環基、烷氧羰基、烷氧基烷基、(胺基)烷基、(甲醯胺基)烷基、(雜環基)烷基、-N(R19a )C(=O)-R19b 及-N(R20a )SO2- R20b ，其中R19a 、R19b 、R20a 及R20b 如關於視情況經取代之環烷基所定義。In the present invention, the term "optionally substituted aryl" as used herein by itself or as part of another group means unsubstituted or substituted with one to five independently selected from the group consisting of Aryl substituted with: halo, nitro, cyano, hydroxyl, amino, -CO- 2 CH 2 Ph, alkylamino, dialkylamino, optionally substituted alkyl, haloalkyl , hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkoxy, alkylthio, carboxamido, sulfonamido, alkanecarbonyl, arylcarbonyl, alkylsulfonamido, Haloalkylsulfonyl, cycloalkylsulfonyl, (cycloalkyl)alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocycloalkylsulfonyl, carboxyl, carboxyalkane base, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, alkoxycarbonyl, alkoxy Alkyl, (amino)alkyl, (carbamido)alkyl, (heterocyclyl)alkyl, -N(R 19a )C(=O)-R 19b and -N(R 20a )SO 2 - R 20b , wherein R 19a , R 19b , R 20a and R 20b are as defined for optionally substituted cycloalkyl.
在一個實施例中，視情況經取代之芳基為視情況經取代之苯基。在另一實施例中，視情況經取代之苯基具有四個取代基。在另一實施例中，視情況經取代之苯基具有三個取代基。在另一實施例中，視情況經取代之苯基具有兩個取代基。在另一實施例中，視情況經取代之苯基具有一個取代基。在另一實施例中，視情況經取代之苯基未經取代。非限制性例示性經取代之芳基包括2-甲基苯基、2-甲氧基苯基、2-氟苯基、2-氯苯基、2-溴苯基、3-甲基苯基、3-甲氧苯基、3-氟苯基、3-氯苯基、4-甲基苯基、4-乙基苯基、4-甲氧基苯基、4-氟苯基、4-氯苯基、2,6-二-氟苯基、2,6-二-氯苯基、2-甲基、3-甲氧苯基、2-乙基、3-甲氧苯基、3,4-二-甲氧苯基、3,5-二-氟苯基、3,5-二-甲基苯基、3,5-二甲氧基、4-甲基苯基、2-氟-3-氯苯基、3-氯-4-氟苯基、4-(吡啶-4-基磺醯基)苯基。術語視情況經取代之芳基包括具有稠合的視情況經取代之環烷基或稠合的視情況經取代之雜環基的苯基。具有稠合的視情況經取代之環烷基或稠合的視情況經取代之雜環基的視情況經取代之苯基可在苯環上之任何可用碳原子處與分子之其餘部分連接。非限制性實例包括：
視情況經取代之芳基之另外非限制性實例包括：
在本發明中，如由單獨或作為另一基團之部分使用，術語「烯基」係指含有一個、兩個或三個碳-碳雙鍵之烷基。在一個實施例中，烯基具有一個碳-碳雙鍵。在另一實施例中，烯基為C2-6 烯基。在另一實施例中，烯基為C2-4 烯基。非限制性例示性烯基包括：乙烯基、丙烯基、異丙烯基、丁烯基、第二丁烯基、戊烯基及己烯基。In the present invention, the term "alkenyl" as used alone or as part of another group refers to an alkyl group containing one, two or three carbon-carbon double bonds. In one embodiment, the alkenyl group has one carbon-carbon double bond. In another embodiment, the alkenyl group is a C 2-6 alkenyl group. In another embodiment, the alkenyl group is a C 2-4 alkenyl group. Non-limiting exemplary alkenyl groups include: vinyl, propenyl, isopropenyl, butenyl, second butenyl, pentenyl, and hexenyl.
在本發明中，如在本文中由單獨或作為另一基團之部分使用，術語「視情況經取代之烯基」係指未經取代或經獨立地選自由以下組成之群之一個、兩個或三個取代基取代的烯基：鹵基、硝基、氰基、羥基、胺基、烷基胺基、二烷基胺基、鹵烷基、羥烷基、烷氧基、鹵烷氧基、芳氧基、芳烷氧基、烷硫基、甲醯胺基、磺醯胺基、烷羰基、芳基羰基、烷基磺醯基、芳基磺醯基、羧基、羧基烷基、視情況經取代之烷基、視情況經取代之環烷基、烯基、炔基、視情況經取代之芳基、雜芳基及視情況經取代之雜環基。In the present invention, as used herein alone or as part of another group, the term "optionally substituted alkenyl" means unsubstituted or independently selected from one, two of the group consisting of Alkenyl substituted with one or three substituents: halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkane Oxy group, aryloxy group, aralkoxy group, alkylthio group, carboxamido group, sulfonamido group, alkanecarbonyl group, arylcarbonyl group, alkylsulfonyl group, arylsulfonyl group, carboxyl group, carboxyalkyl group , optionally substituted alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, heteroaryl, and optionally substituted heterocyclyl.
在本發明中，如由單獨或作為另一基團之部分使用，術語「炔基」係指含有一個至三個碳-碳參鍵之烷基。在一個實施例中，炔基具有一個碳-碳參鍵。在另一實施例中，炔基為C2-6 炔基。在另一實施例中，炔基為C2-4 炔基。非限制性例示性炔基包括乙炔基、丙炔基、丁炔基、2-丁炔基、戊炔基及己炔基。In the present invention, the term "alkynyl" as used alone or as part of another group refers to an alkyl group containing from one to three carbon-carbon linkages. In one embodiment, the alkynyl group has one carbon-carbon double bond. In another embodiment, the alkynyl group is a C 2-6 alkynyl group. In another embodiment, the alkynyl group is a C2-4alkynyl group. Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl.
在本發明中，如在本文中由單獨或作為部分使用，術語「視情況經取代之炔基」係指未經取代或經獨立地選自由以下組成之群之一個、兩個或三個取代基取代的炔基：鹵基、硝基、氰基、羥基、胺基、烷基胺基、二烷基胺基、鹵烷基、羥烷基、烷氧基、鹵烷氧基、芳氧基、芳烷氧基、烷硫基、甲醯胺基、磺醯胺基、烷羰基、芳基羰基、烷基磺醯基、芳基磺醯基、羧基、羧基烷基、視情況經取代之烷基、環烷基、烯基、炔基、視情況經取代之芳基、視情況經取代之雜芳基及雜環基。In the present invention, the term "optionally substituted alkynyl," as used herein alone or as part, means unsubstituted or substituted with one, two, or three independently selected from the group consisting of Alkynyl substituted with: halo, nitro, cyano, hydroxyl, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy group, aralkoxy, alkylthio, carboxamido, sulfonamido, alkcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxyl, carboxyalkyl, optionally substituted alkyl, cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, and heterocyclyl.
在本發明中，如由單獨或作為另一基團之部分使用，術語「鹵烷基」係指經一或多個氟、氯、溴及/或碘原子取代之烷基。在一個實施例中，烷基經一個、兩個或三個氟及/或氯原子取代。在另一實施例中，鹵烷基為C1-4 鹵烷基。非限制性例示性鹵烷基包括氟甲基、2-氟乙基、二氟甲基、三氟甲基、五氟乙基、1,1-二氟乙基、2,2-二氟乙基、2,2,2-三氟乙基、3,3,3-三氟丙基、4,4,4-三氟丁基及三氯甲基。In the present invention, the term "haloalkyl" as used alone or as part of another group refers to an alkyl group substituted with one or more fluorine, chlorine, bromine and/or iodine atoms. In one embodiment, the alkyl group is substituted with one, two or three fluorine and/or chlorine atoms. In another embodiment, the haloalkyl group is a C 1-4 haloalkyl group. Non-limiting exemplary haloalkyl groups include fluoromethyl, 2-fluoroethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl group, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl and trichloromethyl.
在本發明中，如由單獨或作為另一基團之部分使用，術語「羥烷基」係指經一個、兩個或三個羥基取代之烷基。在一個實施例中，羥烷基為單羥烷基，亦即經一個羥基取代之羥烷基。在另一實施例中，羥烷基為二羥烷基，亦即經兩個羥基取代之羥烷基。非限制性例示性羥烷基包括羥甲基、羥乙基、羥丙基及羥丁基，諸如1-羥乙基、2-羥乙基、1,2-二羥乙基、2-羥丙基、3-羥丙基、3-羥丁基、4-羥丁基、2-羥基-1-甲基丙基及1,3-二羥丙-2-基。In the present invention, the term "hydroxyalkyl" as used alone or as part of another group refers to an alkyl group substituted with one, two or three hydroxy groups. In one embodiment, the hydroxyalkyl group is a monohydroxyalkyl group, that is, a hydroxyalkyl group substituted with one hydroxy group. In another embodiment, the hydroxyalkyl group is a dihydroxyalkyl group, that is, a hydroxyalkyl group substituted with two hydroxy groups. Non-limiting exemplary hydroxyalkyl groups include hydroxymethyl, hydroxyethyl, hydroxypropyl, and hydroxybutyl, such as 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 2-hydroxyl propyl, 3-hydroxypropyl, 3-hydroxybutyl, 4-hydroxybutyl, 2-hydroxy-1-methylpropyl and 1,3-dihydroxypropan-2-yl.
在本發明中，如由單獨或作為另一基團之部分使用，術語「雜芳烷基」係指經一個、兩個或三個視情況經取代之雜芳基取代之烷基。在一個實施例中，雜芳烷基烷基為經一個視情況經取代之雜芳基取代之C1-4
烷基。非限制性例示性雜芳烷基包括：
在本發明中，如由單獨或作為另一基團之部分使用，術語「(環烷基)烷基」係指經視情況經取代之環烷基取代的烷基。在一個實施例中，(環烷基)烷基為「(C3-6
環烷基)C1-4
烷基」，亦即經視情況經取代之C3-6
環烷基取代之C1-4
烷基。非限制性例示性(環烷基)烷基包括：
在本發明中，如單獨或作為另一基團之部分使用，術語「烷磺醯基」係指經視情況經取代之烷基取代之磺醯基，亦即-SO2 -。非限制性例示性烷基磺醯基為-SO2 CH3 。In the present invention, the term "alkanesulfonyl" as used alone or as part of another group refers to a sulfonyl group substituted with an optionally substituted alkyl group, ie, -SO2- . A non - limiting exemplary alkylsulfonyl group is -SO2CH3 .
在本發明中，如單獨或作為另一基團之部分使用，術語「鹵烷基磺醯基」係指經鹵烷基取代之磺醯基，亦即-SO2 -。非限制性例示性烷基磺醯基為-SO2 CF3 。In the present invention, the term "haloalkylsulfonyl" as used alone or as part of another group refers to a sulfonyl group substituted with a haloalkyl group, ie -SO2- . A non - limiting exemplary alkylsulfonyl group is -SO2CF3 .
在本發明中，如單獨或作為另一基團之部分使用，術語「環烷基磺醯基」係指經視情況經取代之環烷基取代之磺醯基，亦即-SO2 -。非限制性例示性烷基磺醯基包括-SO2 -環丙基及-SO2 -環戊基。In the present invention, the term "cycloalkylsulfonyl" as used alone or as part of another group refers to a sulfonyl group substituted with an optionally substituted cycloalkyl group, ie, -SO2- . Non-limiting exemplary alkylsulfonyl groups include -SO2 -cyclopropyl and -SO2 -cyclopentyl.
在本發明中，如單獨作為另一基團之部分使用，術語「(環烷基)烷基磺醯基」係指經(環烷基)烷基取代之磺醯基，亦即-SO2
-。非限制性例示性(環烷基)烷基磺醯基包括：
在本發明中，如單獨或作為另一基團之部分使用，術語「芳基磺醯基」係指經視情況經取代之芳基取代之磺醯基，亦即-SO2 -。非限制性例示性芳基磺醯基為-SO2 Ph。In the present invention, the term "arylsulfonyl," as used alone or as part of another group, refers to a sulfonyl group substituted with an optionally substituted aryl group, ie, -SO2- . A non-limiting exemplary arylsulfonyl group is -SO2Ph .
在本發明中，如單獨或作為另一基團之部分使用，術語「雜芳基磺醯基」係指經視情況經取代之雜芳基取代之磺醯基，亦即-SO2
-。非限制性例示性雜芳基磺醯基包括：
在本發明中，如單獨或作為另一基團之部分使用，術語「雜環磺醯基」係指經視情況經取代之雜環基取代之磺醯基，亦即-SO2
-。非限制性例示性雜環磺醯基為：
在本發明中，如單獨或作為另一基團之部分使用，術語「磺醯胺基」係指式-SO2 NR21a R21b 之基團，其中R21a 及R21b 各自獨立地選自由氫、視情況經取代之烷基及視情況經取代之芳基組成之群，或R21a 及R21b 與其所連接之氮一起形成3至8員雜環基。非限制性例示性磺醯胺基包括-SO2 NH2 、-SO2 N(H)CH3 、-SO2 N(CH3 )2 及-SO2 N(H)Ph。In the present invention, the term "sulfonamido" as used alone or as part of another group refers to a group of formula -SO2NR21aR21b , wherein R21a and R21b are each independently selected from hydrogen , an optionally substituted alkyl group and an optionally substituted aryl group, or R 21a and R 21b together with the nitrogen to which they are attached form a 3- to 8-membered heterocyclic group. Non-limiting exemplary sulfonamido groups include -SO2NH2 , -SO2N (H) CH3 , -SO2N ( CH3 ) 2 , and -SO2N ( H)Ph.
在本發明中，如單獨或作為另一基團之部分使用，術語「烷氧基」係指與末端氧原子連接的視情況經取代之烷基、視情況經取代之環烷基、視情況經取代之烯基或視情況經取代之炔基。在一個實施例中，烷氧基為與末端氧原子連接之視情況經取代之烷基。在一個實施例中，烷氧基為與末端氧原子連接之C1-6 烷基。在另一實施例中，烷氧基為與末端氧原子連接之C1-4 烷基。非限制性例示性烷氧基包括甲氧基、乙氧基、三級丁氧基及-OCH2 SO2 CH3 。In the present invention, the term "alkoxy", as used alone or as part of another group, refers to an optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl, optionally attached to a terminal oxygen atom Substituted alkenyl or optionally substituted alkynyl. In one embodiment, an alkoxy group is an optionally substituted alkyl group attached to a terminal oxygen atom. In one embodiment, the alkoxy group is a C1-6 alkyl group attached to a terminal oxygen atom. In another embodiment, the alkoxy group is a C1-4 alkyl group attached to a terminal oxygen atom. Non-limiting exemplary alkoxy groups include methoxy, ethoxy, tertiary butoxy, and -OCH 2 SO 2 CH 3 .
在本發明中，如單獨或作為另一基團之部分使用，術語「烷硫基」係指與末端硫原子連接之視情況經取代之烷基。在一個實施例中，烷硫基為C1-4 烷硫基。非限制性例示性烷硫基包括-SCH3 及-SCH2 CH3 。In the present invention, the term "alkylthio" as used alone or as part of another group refers to an optionally substituted alkyl group attached to a terminal sulfur atom. In one embodiment, the alkylthio group is a C 1-4 alkylthio group. Non - limiting exemplary alkylthio groups include -SCH3 and -SCH2CH3 .
在本發明中，如單獨或作為另一基團之部分使用，術語「烷氧基烷基」係指經烷氧基取代之視情況選用的烷基。非限制性例示性烷氧烷基包括甲氧基甲基、甲氧基乙基、甲氧基丙基、甲氧基丁基、乙氧基甲基、乙氧基乙基、乙氧基丙基、乙氧基丁基、丙氧基甲基、異丙氧基甲基、丙氧基乙基、丙氧基丙基、丁氧基甲基、三級丁氧基甲基、異丁氧基甲基、第二丁氧基甲基及戊氧基甲基。In the present invention, the term "alkoxyalkyl" as used alone or as part of another group refers to an optional alkyl group substituted with an alkoxy group. Non-limiting exemplary alkoxyalkyl groups include methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl group, ethoxybutyl, propoxymethyl, isopropoxymethyl, propoxyethyl, propoxypropyl, butoxymethyl, tertiary butoxymethyl, isobutoxy methyl, second butoxymethyl and pentoxymethyl.
在本發明中，如單獨或作為另一基團之部分使用，術語「鹵烷氧基」係指與末端氧原子連接之鹵烷基。非限制性例示性鹵烷氧基包括氟甲氧基、二氟甲氧基、三氟甲氧基及2,2,2-三氟乙氧基。In the present invention, the term "haloalkoxy" as used alone or as part of another group refers to a haloalkyl group attached to a terminal oxygen atom. Non-limiting exemplary haloalkoxy groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy.
在本發明中，如單獨或作為另一基團之部分使用，術語「芳氧基」係指與末端氧原子連接之視情況經取代之芳基。非限制性例示性芳氧基為PhO-。In the present invention, the term "aryloxy" as used alone or as part of another group refers to an optionally substituted aryl group attached to a terminal oxygen atom. A non-limiting exemplary aryloxy group is PhO-.
在本發明中，如單獨或作為另一基團之部分使用，術語「芳烷氧基」係指與末端氧原子連接之芳烷基。非限制性例示性芳烷氧基包括PhCH2 O-及PhCH2 CH2 O-。In the present invention, the term "aralkoxy" as used alone or as part of another group refers to an aralkyl group attached to a terminal oxygen atom. Non - limiting exemplary aralkoxy groups include PhCH2O- and PhCH2CH2O- .
在本發明中，術語「雜芳基」係指具有5至14個環原子之未經取代之單環及雙環芳環系統，亦即5至14員雜芳基，其中環中之一者之至少一個碳原子經獨立地選自由氧、氮及硫組成之群的雜原子置換。在一個實施例中，雜芳基含有獨立地選自由以下氧、氮及硫組成之群之1、2、3或4個雜原子。在一個實施例中，雜芳基具有三個雜原子。在另一實施例中，雜芳基具有兩個雜原子。在另一實施例中，雜芳基具有一個雜原子。在另一實施例中，雜芳基為5至10員雜芳基。在另一實施例中，雜芳基為5或6員雜芳基。在另一實施例中，雜芳基具有5個環原子，例如噻吩基，一種具有四個碳原子及一個硫原子之5員雜芳基。在另一實施例中，雜芳基具有6個環原子，例如吡啶基，一種具有五個碳原子及一個氮原子之6員雜芳基。非限制性例示性雜芳基包括噻吩基、苯并[b]噻吩基、萘并[2,3-b]噻吩基、噻嗯基、呋喃基、苯并呋喃基、哌喃基、異苯并呋喃基、苯并㗁酮基、𠳭烯基、𠮿基、2H -吡咯基、吡咯基、咪唑基、吡唑基、吡啶基、吡𠯤基、嘧啶基、噠𠯤基、異吲哚基、3H -吲哚基、吲哚基、吲唑基、嘌呤基、異喹啉基、喹啉基、酞𠯤基、㖠啶基、㖕啉基、喹唑啉基、喋啶基、4aH -咔唑基、咔唑基、β-咔啉基、啡啶基、吖啶基、嘧啶基、啡啉基、啡𠯤基、噻唑基、異噻唑基、苯并噻唑基、異㗁唑基、呋呫基及啡㗁 𠯤基。在一個實施例中，雜芳基係選自由以下組成之群：噻吩基(例如噻吩-2-基及噻吩-3-基)、呋喃基(例如2-呋喃基及3-呋喃基)、吡咯基(例如1H-吡咯-2-基及1H-吡咯-3-基)、咪唑基(例如2H-咪唑-2-基及2H-咪唑-4-基)、吡唑基(例如1H-吡唑-3-基、1H-吡唑-4-基及1H-吡唑-5-基)、吡啶基(例如吡啶-2-基、吡啶-3-基及吡啶-4-基)、嘧啶基(例如嘧啶-2-基、嘧啶-4-基及嘧啶-5-基)、噻唑基(例如噻唑-2-基、噻唑-4-基及噻唑-5-基)、異噻唑基(例如異噻唑-3-基、異噻唑-4-基及異噻唑-5-基)、㗁唑基(例如㗁唑-2-基、㗁唑-4-基及㗁唑-5-基)、異㗁唑基(例如異㗁唑-3-基、異㗁唑-4-基及異㗁唑-5-基)及吲唑基(例如1H-吲唑-3-基)。術語「雜芳基」亦意欲包括可能的N-氧化物。非限制性例示性N-氧化物為吡啶基N-氧化物。In the present invention, the term "heteroaryl" refers to unsubstituted monocyclic and bicyclic aromatic ring systems having 5 to 14 ring atoms, ie 5 to 14 membered heteroaryl groups, wherein one of the rings is At least one carbon atom is replaced with a heteroatom independently selected from the group consisting of oxygen, nitrogen and sulfur. In one embodiment, a heteroaryl group contains 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur. In one embodiment, the heteroaryl group has three heteroatoms. In another embodiment, a heteroaryl group has two heteroatoms. In another embodiment, the heteroaryl group has one heteroatom. In another embodiment, the heteroaryl group is a 5 to 10 membered heteroaryl group. In another embodiment, the heteroaryl group is a 5- or 6-membered heteroaryl group. In another embodiment, a heteroaryl group has 5 ring atoms, eg, thienyl, a 5-membered heteroaryl group having four carbon atoms and one sulfur atom. In another embodiment, a heteroaryl group has 6 ring atoms, eg, pyridyl, a 6-membered heteroaryl group having five carbon atoms and one nitrogen atom. Non-limiting exemplary heteroaryl groups include thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thienyl, furyl, benzofuranyl, piperanyl, isophenyl furanyl, benzoketone, alkenyl, alkenyl, 2H -pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridyl, pyrimidinyl, pyridyl, isoindole base, 3 H -indolyl, indolyl, indazolyl, purinyl, isoquinolinyl, quinolinyl, phthaloyl, ethidyl, ethidyl, quinazolinyl, pteridyl, 4a H -carbazolyl, carbazolyl, β-carbolinyl, phenanthroid, acridine, pyrimidinyl, phenanthroline, phenanthyl, thiazolyl, isothiazolyl, benzothiazolyl, isothiazolyl oxazolyl, furanyl and phenanthyl. In one embodiment, the heteroaryl group is selected from the group consisting of: thienyl (eg, thien-2-yl and thien-3-yl), furyl (eg, 2-furyl and 3-furyl), pyrrole (eg 1H-pyrrol-2-yl and 1H-pyrrol-3-yl), imidazolyl (eg 2H-imidazol-2-yl and 2H-imidazol-4-yl), pyrazolyl (eg 1H-pyrazole -3-yl, 1H-pyrazol-4-yl and 1H-pyrazol-5-yl), pyridyl (eg pyridin-2-yl, pyridin-3-yl and pyridin-4-yl), pyrimidinyl ( such as pyrimidin-2-yl, pyrimidin-4-yl and pyrimidin-5-yl), thiazolyl (such as thiazol-2-yl, thiazol-4-yl and thiazol-5-yl), isothiazolyl (such as isothiazole -3-yl, isothiazol-4-yl and isothiazol-5-yl), oxazolyl (eg oxazol-2-yl, oxazol-4-yl and oxazol-5-yl), isoxazole radicals (eg isoxazol-3-yl, isoxazol-4-yl and isoxazol-5-yl) and indazolyl (eg 1H-indazol-3-yl). The term "heteroaryl" is also intended to include possible N-oxides. A non-limiting exemplary N-oxide is pyridyl N-oxide.
在一個實施例中，雜芳基為5或6員雜芳基。在一個實施例中，雜芳基為5員雜芳基，亦即雜芳基為具有5個環原子之單環芳環系統，其中環之至少一個碳原子經獨立地選自氮、氧及硫之雜原子置換。非限制性例示性5員雜芳基包括噻吩基、呋喃基、吡咯基、㗁唑基、吡唑基、咪唑基、噻唑基、異噻唑基及異㗁唑基。在另一實施例中，雜芳基為6員雜芳基，例如雜芳基為具有6個環原子之單環芳環系統，其中環之至少一個碳原子經氮原子置換。非限制性例示性6員雜芳基包括吡啶基、吡𠯤基、嘧啶基及噠𠯤基。In one embodiment, the heteroaryl group is a 5- or 6-membered heteroaryl group. In one embodiment, a heteroaryl group is a 5-membered heteroaryl group, that is, a heteroaryl group is a monocyclic aromatic ring system having 5 ring atoms, wherein at least one carbon atom of the ring is independently selected from nitrogen, oxygen, and Heteroatom replacement of sulfur. Non-limiting exemplary 5-membered heteroaryl groups include thienyl, furyl, pyrrolyl, oxazolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, and isoxazolyl. In another embodiment, a heteroaryl group is a 6-membered heteroaryl group, eg, a heteroaryl group is a monocyclic aromatic ring system having 6 ring atoms wherein at least one carbon atom of the ring is replaced with a nitrogen atom. Non-limiting exemplary 6-membered heteroaryl groups include pyridyl, pyridyl, pyrimidinyl, and pyridyl.
在本發明中，如單獨或作為另一基團之部分使用，術語「視情況經取代之雜芳基」係指未經取代或經獨立地選自由以下組成之群之一個、兩個、三個或四個取代基取代的雜芳基：鹵基、硝基、氰基、羥基、胺基、烷基胺基、二烷基胺基、鹵烷基、羥烷基、烷氧基、鹵烷氧基、芳氧基、芳烷氧基、烷硫基、甲醯胺基、磺醯胺基、烷羰基、芳基羰基、烷基磺醯基、鹵烷基磺醯基、環烷基磺醯基、(環烷基)烷基磺醯基、芳基磺醯基、雜芳基磺醯基、羧基、羧基烷基、視情況經取代之烷基、視情況經取代之環烷基、烯基、炔基、視情況經取代之芳基、視情況經取代之雜芳基、視情況經取代之雜環基、烷氧基烷基、(胺基)烷基、(甲醯胺基)烷基、(雜環基)烷基、-N(R19a )C(=O)-R19b 及-N(R20a )SO2 -R20b ，其中R19a 、R19b 、R20a 及R20b 如關於視情況經取代之環烷基所定義。在一個實施例中，視情況經取代之雜芳基具有一個取代基。在另一實施例中，視情況經取代之雜芳基未經取代。任何可用碳或氮原子可經取代。術語視情況經取代之雜芳基包括具有稠合的視情況經取代之環烷基或稠合的視情況經取代之雜環基的雜芳基。具有稠合的視情況經取代之環烷基或稠合的視情況經取代之雜環基的視情況經取代之雜芳基可在雜芳環上之任何可用碳原子處與分子之其餘部分連接。In the present invention, the term "optionally substituted heteroaryl" as used alone or as part of another group means one, two, three, unsubstituted or independently selected from the group consisting of Heteroaryl substituted with one or four substituents: halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, halo Alkoxy, Aryloxy, Aralkoxy, Alkylthio, Carboxamido, Sulfonamido, Alkylcarbonyl, Arylcarbonyl, Alkylsulfonyl, Haloalkylsulfonyl, Cycloalkyl Sulfonyl, (cycloalkyl)alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, carboxy, carboxyalkyl, optionally substituted alkyl, optionally substituted cycloalkyl , alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, alkoxyalkyl, (amino)alkyl, (formamide (heterocyclyl)alkyl, -N(R 19a )C(=O)-R 19b and -N(R 20a )SO 2 -R 20b , wherein R 19a , R 19b , R 20a and R 20b is as defined for optionally substituted cycloalkyl. In one embodiment, the optionally substituted heteroaryl has one substituent. In another embodiment, the optionally substituted heteroaryl is unsubstituted. Any available carbon or nitrogen atom may be substituted. The term optionally substituted heteroaryl includes heteroaryl groups having a fused optionally substituted cycloalkyl group or a fused optionally substituted heterocyclyl group. An optionally substituted heteroaryl group having a fused optionally substituted cycloalkyl group or a fused optionally substituted heterocyclyl group can be attached to the rest of the molecule at any available carbon atom on the heteroaryl ring. connect.
在本發明中，如本文中本身或作為另一基團之部分使用，術語「伸雜芳基」係指視情況經取代之雜芳基之二價形式。在一個實施例中，伸雜芳基為5員伸雜芳基。5員伸雜芳基之非限制性實例包括：
5員伸雜芳基之另外非限制性實例包括：
在另一實施例中，伸雜芳基為6員伸雜芳基。6員伸雜芳基之非限制性實例包括：
在本發明中，如單獨或作為另一基團之部分使用，術語「雜環基」係指含有一個、兩個或三個具有三個至十四個環成員之環的未經取代之飽和及部分不飽和(例如含有一個或兩個雙鍵)環狀基團，亦即3至14員雜環基，其中環中之一者之至少一個碳原子經雜原子置換。各雜原子獨立地選自由以下組成之群：氧、硫(包括亞碸及碸)及/或氮原子(其可經氧化或四級銨化)。術語「雜環基」包括其中環-CH2 -經-C(=O)-置換之基團，例如環狀脲基，諸如2-咪唑啶酮，及環醯胺基，諸如β-內醯胺、γ-內醯胺、δ-內醯胺、ε-內醯胺及六哌𠯤-2-酮。術語「雜環基」亦包括具有稠合的視情況經取代之芳基的基團，例如吲哚啉基或𠳭烷-4-基。在一個實施例中，雜環基為C4-6 雜環基，亦即含有一個環及一個或兩個氧原子及/或氮原子之4、5或6員環狀基團。在一個實施例中，雜環基為含有一個環及一個氮原子之C4-6 雜環基。雜環基可視情況經由任何可用碳原子或氮原子與分子之其餘部分連接。非限制性例示性雜環基包括氮雜環基丁基、二氧雜環基己烷基、四氫哌喃基、2-側氧基吡咯啶-3-基、哌𠯤-2-酮、哌𠯤-2,6-二酮、2-咪唑啶酮、哌啶基、嗎啉基、哌𠯤基、吡咯啶基及吲哚啉基。雜環基之另外非限制性實例包括氧雜環基丁基及四氫呋喃基。In the present invention, the term "heterocyclyl" as used alone or as part of another group refers to an unsubstituted saturated ring containing one, two or three rings having three to fourteen ring members and partially unsaturated (eg containing one or two double bonds) cyclic groups, ie, 3 to 14 membered heterocyclyl groups wherein at least one carbon atom in one of the rings is replaced by a heteroatom. Each heteroatom is independently selected from the group consisting of oxygen, sulfur (including sulfite and sulfite), and/or a nitrogen atom (which may be oxidized or quaternary amonized). The term "heterocyclyl" includes groups in which ring -CH2- is replaced by -C(=O)-, eg, cyclic ureido groups, such as 2-imidazolidinone, and cyclic amido groups, such as beta-lactam. Amines, gamma-lactam, delta-lactam, ε-lactam and hexapiperidin-2-one. The term "heterocyclyl" also includes groups having a fused optionally substituted aryl group, such as indolinyl or oxalan-4-yl. In one embodiment, the heterocyclyl group is a C4-6 heterocyclyl group, ie, a 4-, 5- or 6-membered cyclic group containing one ring and one or two oxygen and/or nitrogen atoms. In one embodiment, the heterocyclyl group is a C4-6 heterocyclyl group containing one ring and one nitrogen atom. A heterocyclyl group is optionally attached to the rest of the molecule via any available carbon or nitrogen atom. Non-limiting exemplary heterocyclyl groups include azacyclylbutyl, dioxanylhexyl, tetrahydropyranyl, 2-oxypyrrolidin-3-yl, piperazine-2-one, Piperidine-2,6-dione, 2-imidazolidinone, piperidinyl, morpholinyl, piperidine, pyrrolidinyl and indolinyl. Additional non-limiting examples of heterocyclyl include oxetanyl and tetrahydrofuranyl.
在本發明中，如單獨或作為另一基團之部分使用，術語「視情況經取代之雜環基」係指未經取代或經獨立地選自由以下組成之群之一個、兩個、三個或四個取代基取代的雜環基：鹵基、硝基、氰基、羥基、胺基、烷基胺基、二烷基胺基、鹵烷基、羥烷基、烷氧基、鹵烷氧基、芳氧基、芳烷氧基、烷硫基、甲醯胺基、磺醯胺基、環烷基羰基、烷氧羰基、CF3
C(=O)-、芳基羰基、烷基磺醯基、芳基磺醯基、羧基、羧基烷基、烷基、視情況經取代之環烷基、烯基、炔基、視情況經取代之芳基、視情況經取代之雜芳基、視情況經取代之雜環基、烷氧基烷基、(胺基)烷基、(甲醯胺基)烷基、(雜環基)烷基、羥烷羰基及-N(R19a
)C(=O)-R19b
以及-N(R20a
)SO2
-R20b
，其中R19a
、R19b
、R20a
及R20b
如關於視情況經取代之環烷基所定義。取代可在任何可用碳原子或氮原子或兩者上發生。非限制性例示性經取代之雜環基包括：
在本發明中，如單獨或作為另一基團之部分使用，術語「胺基」係指式-NR22a R22b 之基團，其中R22a 及R22b 獨立地選自由以下組成之群：氫、烷基、芳烷基、羥烷基、視情況經取代之環烷基、視情況經取代之芳基、視情況經取代之雜環基及視情況經取代之雜芳基，或R22a 及R22b 一起形成3至8員視情況經取代之雜環基。非限制性例示性胺基包括-NH2 及-N(H)(CH3 )。In the present invention, the term "amino", as used alone or as part of another group, refers to a group of formula -NR 22a R 22b , wherein R 22a and R 22b are independently selected from the group consisting of: hydrogen , alkyl, aralkyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, and optionally substituted heteroaryl, or R 22a and R 22b together form a 3- to 8-membered optionally substituted heterocyclyl. Non-limiting exemplary amine groups include -NH2 and -N(H)( CH3 ).
在本發明中，如單獨或由另一基團之部分使用，術語「(胺基)烷基」係指經視情況經取代之胺基取代之烷基。非限制性例示性(胺基)烷基包括-CH2 CH2 NH2 及-CH2 CH2 N(H)CH3 、-CH2 CH2 N(CH3 )2 及-CH2 N(H)-環丙基。另外非限制性例示性(胺基)烷基包括-CH2 N(CH3 )2 。In the present invention, the term "(amino)alkyl" as used alone or as part of another group refers to an alkyl group substituted with an optionally substituted amino group. Non - limiting exemplary (amino)alkyl groups include -CH2CH2NH2 and -CH2CH2N (H) CH3 , -CH2CH2N ( CH3 ) 2 and -CH2N ( H )-cyclopropyl. Additional non-limiting exemplary (amino)alkyl groups include -CH2N ( CH3 ) 2 .
在本發明中，如單獨或作為另一基團之部分使用，術語「甲醯胺基」係指式-C(=O)NR23a
R23b
之基團，其中R23a
及R23b
各自獨立地選自由以下組成之群：氫、視情況經取代之烷基、羥烷基、視情況經取代之環烷基、視情況經取代之芳基、視情況經取代之雜環基及視情況經取代之雜芳基，或R23a
及R23b
與其所連接之氮一起形成3至8員視情況經取代之雜環基。在一個實施例中，R23a
及R23b
各自獨立地為氫或視情況經取代之烷基。在一個實施例中，R23a
及R23b
結合在一起從而與其所連接之氮一起形成3至8員視情況經取代之雜環基。非限制性例示性甲醯胺基包括-CONH2
、-CON(H)CH3
、-CON(CH3
)2
、-CON(H)Ph、
在本發明中，如單獨或作為另一基團之部分使用，術語「烷羰基」係指經烷基取代之羰基，亦即-C(=O)-。非限制性例示性烷羰基包括-C(=O)CH3 及-C(=O)CH2 CH2 CH2 CH3 。In the present invention, the term "alkylcarbonyl" as used alone or as part of another group refers to a carbonyl group substituted with an alkyl group, ie -C(=O)-. Non-limiting exemplary alkylcarbonyl groups include -C(=O) CH3 and -C ( = O ) CH2CH2CH2CH3 .
在本發明中，如單獨或作為另一基團之部分使用，術語「羥烷羰基」係指經羥烷基取代之羰基，亦即-C(=O)-。非限制性例示性烷羰基包括-C(=O)C(CH3 )2 OH及-C(=O)CH2 CH2 CH2 OH。In the present invention, the term "hydroxyalkylcarbonyl" as used alone or as part of another group refers to a carbonyl group substituted with a hydroxyalkyl group, ie -C(=O)-. Non-limiting exemplary alkylcarbonyl groups include -C (=O)C( CH3 )2OH and -C (=O ) CH2CH2CH2OH .
在本發明中，如單獨或作為另一基團之部分使用，術語「環烷基羰基」係指經環烷基取代之羰基，亦即-C(=O)-。非限制性例示性環烷基羰基為-C(=O)-環丙基。In the present invention, the term "cycloalkylcarbonyl" as used alone or as part of another group refers to a carbonyl group substituted with a cycloalkyl group, ie -C(=O)-. A non-limiting exemplary cycloalkylcarbonyl group is -C(=O)-cyclopropyl.
在本發明中，如單獨或作為另一基團之部分使用，術語「芳基羰基」係指經視情況經取代之芳基取代之羰基，亦即-C(=O)-。非限制性例示性芳基羰基為-COPh。In the present invention, the term "arylcarbonyl" as used alone or as part of another group refers to a carbonyl group substituted with an optionally substituted aryl group, ie -C(=O)-. A non-limiting exemplary arylcarbonyl group is -COPh.
在本發明中，如單獨或作為另一基團之部分使用，術語「烷氧羰基」係指經烷氧基取代之羰基，亦即-C(=O)-。在一個實施例中，烷氧基為C1-4 烷氧基。非限制性例示性烷氧羰基包括-C(=O)OMe、-C(=O)OEt及-C(=O)OtBu。In the present invention, the term "alkoxycarbonyl" as used alone or as part of another group refers to a carbonyl group substituted with an alkoxy group, ie -C(=O)-. In one embodiment, the alkoxy group is a C 1-4 alkoxy group. Non-limiting exemplary alkoxycarbonyl groups include -C(=O)OMe, -C(=O)OEt, and -C(=O)OtBu.
在本發明中，如單獨或作為另一基團之部分使用，術語「(烷氧羰基)烷基」係指經烷氧羰基取代之烷基。非限制性例示性(烷氧羰基)烷基包括-CH2 C(=O)OMe、-CH2 C(=O)OEt及-CH2 C(=O)OtBu。In the present invention, the term "(alkoxycarbonyl)alkyl" as used alone or as part of another group refers to an alkyl group substituted with an alkoxycarbonyl group. Non-limiting exemplary (alkoxycarbonyl)alkyl groups include -CH2C (=O)OMe, -CH2C (=O)OEt, and -CH2C (=O)OtBu.
在本發明中，如單獨或作為另一基團之部分使用，術語「羧基」係指式-CO2 H之基團。In the present invention, the term "carboxy", as used alone or as part of another group, refers to a group of formula -CO2H .
在本發明中，如單獨或作為另一基團之部分使用，術語「羧基烷基」係指經-CO2 H取代之烷基。非限制性例示性羧基烷基為-CH2 CO2 H。In the present invention, the term "carboxyalkyl" as used alone or as part of another group refers to an alkyl group substituted with -CO2H . A non - limiting exemplary carboxyalkyl group is -CH2CO2H .
在本發明中，如單獨或作為另一基團之部分使用，術語「芳烷基」係指經一個、兩個或三個視情況經取代之芳基取代之烷基。在一個實施例中，芳烷基為經一個視情況經取代之C5 或C6 芳基取代之C1-4 烷基。在另一實施例中，芳烷基為經一個視情況經取代之芳基取代之C1 烷基。在另一實施例中，芳烷基為經一個視情況經取代之芳基取代之C2 烷基。在另一實施例中，芳烷基為經一個視情況經取代之芳基取代之C3 烷基。在一個實施例中，芳烷基為經一個視情況經取代之苯基取代之C1 或C2 烷基。非限制性例示性芳烷基包括苯甲基、苯乙基、-CHPh2 、-CH(CH3 )Ph、-CH2 (4-F-Ph)、-CH2 (4-Me-Ph)、-CH2 (4-CF3 -Ph)及-CH(4-F-Ph)2 。In the present invention, the term "aralkyl" as used alone or as part of another group refers to an alkyl group substituted with one, two or three optionally substituted aryl groups. In one embodiment, aralkyl is C 1-4 alkyl substituted with one optionally substituted C 5 or C 6 aryl. In another embodiment, aralkyl is C1 alkyl substituted with one optionally substituted aryl. In another embodiment, aralkyl is C2 alkyl substituted with one optionally substituted aryl. In another embodiment, aralkyl is C3 alkyl substituted with one optionally substituted aryl. In one embodiment, aralkyl is a C1 or C2 alkyl substituted with one optionally substituted phenyl. Non-limiting exemplary aralkyl groups include benzyl, phenethyl, -CHPh2 , -CH( CH3 )Ph, -CH2 (4-F-Ph), -CH2 (4-Me-Ph) , -CH 2 (4-CF 3 -Ph) and -CH(4-F-Ph) 2 .
在本發明中，如單獨或由另一基團之部分使用，術語「(雜環基)烷基」係指經視情況經取代之雜環基取代之烷基。在一個實施例中，(雜環基)烷基為經一個視情況經取代之雜環基取代的C1-4
烷基。非限制性例示性(雜環基)烷基包括：
在本發明中，如單獨或作為另一基團之部分使用，術語「(雜芳基)烷基」係指經視情況經取代之雜芳基取代之烷基。在一個實施例中，(雜芳基)烷基為經一個視情況經取代之雜芳基取代之C1-4
烷基。在另一實施例中，(雜芳基)烷基為經一個視情況經取代之雜芳基取代之C1
烷基。非限制性例示性(雜芳基)烷基包括：
在本發明中，如單獨或作為另一基團之部分使用，術語「(甲醯胺基)烷基」係指經一個或兩個甲醯胺基取代之烷基。在一個實施例中，(甲醯胺基)烷基為經一個甲醯胺基取代之C1-4 烷基，亦即(甲醯胺基)C1-4 烷基。在另一實施例中，(甲醯胺基)烷基為經兩個甲醯胺基取代之C1-4 烷基。非限制性例示性(甲醯胺基)烷基包括-CH2 CONH2 、-C(H)CH3 -CONH2 及-CH2 CON(H)CH3 。In the present invention, the term "(carbamido)alkyl" as used alone or as part of another group refers to an alkyl group substituted with one or two carboxamido groups. In one embodiment, (carbamido)alkyl is C 1-4 alkyl substituted with one formamido group, ie (carbamido)C 1-4 alkyl. In another embodiment, (carbamido)alkyl is C 1-4 alkyl substituted with two carboxamido groups. Non-limiting exemplary (carbamido)alkyl groups include -CH2CONH2 , -C(H) CH3 - CONH2, and -CH2CON (H ) CH3 .
在本發明中，如單獨或作為另一基團之部分使用，術語「(芳氧基)烷基」係指經芳氧基取代之烷基。在一個實施例中，「(芳氧基)烷基」為經芳氧基取代之C1-4 烷基。在一個實施例中，「(芳氧基)烷基」為經芳氧基取代之C2-4 烷基。非限制性例示性(芳氧基)烷基包括-CH2 CH2 OPh及-CH2 CH2 CH2 OPh。In the present invention, the term "(aryloxy)alkyl" as used alone or as part of another group refers to an alkyl group substituted with an aryloxy group. In one embodiment, "(aryloxy)alkyl" is C 1-4 alkyl substituted with aryloxy. In one embodiment, "(aryloxy)alkyl" is C2-4 alkyl substituted with aryloxy. Non - limiting exemplary ( aryloxy ) alkyl groups include -CH2CH2OPh and -CH2CH2CH2OPh .
在本發明中，如單獨或作為另一基團之部分使用，術語「烷基羰氧基」係指經烷羰基取代之氧基，例如-O-。非限制性例示性「烷基羰氧基」包括-OC(=O)CH2 CH3 、-OC(=O)CH3 ，亦即乙醯氧基、-OC(=O)CH2 CH2 CH3 及-OC(=O)CH(CH3 )2 。In the present invention, the term "alkylcarbonyloxy" as used alone or as part of another group refers to an oxy group substituted with an alkcarbonyl group, eg -O-. Non-limiting exemplary "alkylcarbonyloxy" include -OC(=O) CH2CH3 , -OC( = O) CH3 , ie acetoxy, -OC(=O ) CH2CH2 CH 3 and -OC(=O)CH(CH 3 ) 2 .
在本發明中，如單獨或作為另一基團之部分使用，術語「環烷基羰基氧基」係指經環烷基羰基取代之氧基，例如-O-。非限制性例示性「環烷基羰基氧基」包括-OC(=O)-環丙基、-OC(=O)-環丁基及-OC(=O)-環戊基。In the present invention, the term "cycloalkylcarbonyloxy" as used alone or as part of another group refers to an oxy group substituted with a cycloalkylcarbonyl group, eg -O-. Non-limiting exemplary "cycloalkylcarbonyloxy" include -OC(=O)-cyclopropyl, -OC(=O)-cyclobutyl, and -OC(=O)-cyclopentyl.
如本文所用，術語「menin抑制劑」或「menin之抑制劑」係指干擾(例如抑制)menin-MLL融合蛋白相互作用之化合物。As used herein, the term "menin inhibitor" or "inhibitor of menin" refers to a compound that interferes with (eg, inhibits) the interaction of a menin-MLL fusion protein.
術語「其中抑制menin提供益處之疾病或病狀」係關於其中menin及/或menin與menin相互作用蛋白質之相互作用對於例如彼疾病或病狀之發作、進展或表現為重要或必要之疾病或病狀，或已知藉由menin抑制劑治療之疾病或病狀。此類病狀之實例包括(但不限於)癌症、慢性自體免疫疾病、發炎性疾病、增殖性疾病、敗血症及病毒性感染。一般熟習此項技術者易於能夠例如藉由可宜用以評定特定化合物之活性的分析，來判定化合物是否治療由任何特定細胞類型之menin介導之疾病或病狀。The term "disease or condition in which inhibition of menin provides a benefit" refers to a disease or condition in which menin and/or the interaction of menin and menin-interacting proteins is important or necessary for, for example, the onset, progression or manifestation of that disease or condition. symptoms, or diseases or conditions known to be treated by menin inhibitors. Examples of such conditions include, but are not limited to, cancer, chronic autoimmune diseases, inflammatory diseases, proliferative diseases, sepsis, and viral infections. One of ordinary skill in the art is readily able to determine whether a compound treats a disease or condition mediated by menin of any particular cell type, eg, by assays that can be suitably used to assess the activity of a particular compound.
術語「第二治療劑」係指不同於本發明之化合物且已知治療所關注疾病或病狀之治療劑。舉例而言，當癌症為所關注疾病或病狀時，第二治療劑可為如紫杉醇之已知化學治療藥物或例如輻射。The term "second therapeutic agent" refers to a therapeutic agent other than a compound of the present invention and known to treat the disease or condition of interest. For example, when cancer is the disease or condition of interest, the second therapeutic agent may be known chemotherapeutic drugs such as paclitaxel or radiation, for example.
術語「疾病」或「病狀」表示障礙及/或異常，其一般而言被視為病理學病狀或功能，且自身可以特定體徵、症狀及/或功能障礙之形式顯現。如下文所證實，本發明之化合物為menin抑制劑且可用於治療其中menin抑制提供益處之疾病及病狀。The terms "disease" or "condition" refer to disorders and/or abnormalities, which are generally considered to be pathological conditions or functions and which manifest themselves in the form of specific signs, symptoms and/or dysfunctions. As demonstrated below, the compounds of the present invention are menin inhibitors and are useful in the treatment of diseases and conditions in which menin inhibition provides benefits.
如本文所用，術語「治療(treat/treating/treatment)」及其類似者係指消除、減輕或改善疾病或病狀及/或與其相關之症狀。儘管不排除，但治療疾病或病狀不需要完全消除疾病、病狀或與其相關之症狀。如本文所用，術語「治療(treat/treating/treatment)」及其類似者可包括「預防性治療」，其係指降低個體之疾病或病狀復發之機率或先前所控制疾病或病狀之復發機率，該個體未患但處於疾病或病狀復發或疾病或病狀之再發之風險下或易復發疾病或病狀或易受疾病或病狀之復發影響。術語「治療」及同義詞涵蓋向需要此類治療之個體投與治療有效量之本發明之化合物。As used herein, the terms "treat/treating/treatment" and the like refer to eliminating, alleviating or ameliorating a disease or condition and/or symptoms associated therewith. Although not excluded, treatment of a disease or condition does not require complete elimination of the disease, condition, or symptoms associated therewith. As used herein, the terms "treat/treating/treatment" and the like may include "prophylactic treatment," which refers to reducing the chance of recurrence of a disease or condition in an individual or recurrence of a previously controlled disease or condition The probability that the individual does not have the disease or condition but is at risk of, or susceptible to, or susceptible to a recurrence of a disease or condition or a recurrence of a disease or condition. The terms "treatment" and synonyms encompass the administration of a therapeutically effective amount of a compound of the present invention to an individual in need of such treatment.
在本發明之含義內，「治療」亦包括復發防治或階段防治以及治療急性或慢性體徵、症狀及/或功能障礙。治療可為症狀定向的，例如以抑制症狀。其可在較短時段內實現、在中等時期內定向或可為長期治療，例如在維持療法之上下文內。"Treatment" within the meaning of the present invention also includes relapse prevention or stage prevention and treatment of acute or chronic signs, symptoms and/or dysfunctions. Treatment may be symptom-directed, eg, to suppress symptoms. It may be achieved over a shorter period of time, directed over an intermediate period of time, or may be a long-term treatment, such as in the context of maintenance therapy.
如本文所用，術語「治療有效量」或「有效劑量」係指在藉由本發明之方法投與時足以向有需要之個體有效遞送用於治療所關注病狀或疾病之活性成分之活性成分的量。在癌症或其他增殖病症之情況下，治療有效量之藥劑可減少(亦即在一定程度上延緩且較佳地終止)非所需細胞增殖；減少癌細胞之數目；減小腫瘤大小；抑制(亦即在一定程度上延緩且較佳地終止)癌細胞浸潤至周邊器官中；抑制(亦即在一定程度上延緩且較佳地終止)腫瘤轉移；在一定程度上抑制腫瘤生長；降低目標細胞中之menin相互作用；及/或在一定程度上緩解與癌症相關之症狀中之一或多者。在所投與化合物或組合物防止生長及/或殺死現有癌細胞之情況下，其可為細胞抑制及/或細胞毒性的。As used herein, the term "therapeutically effective amount" or "effective dose" refers to an amount of an active ingredient that, when administered by the methods of the present invention, is sufficient to effectively deliver to an individual in need thereof the active ingredient for the treatment of the condition or disease of interest quantity. In the case of cancer or other proliferative disorders, a therapeutically effective amount of an agent can reduce (ie, delay to some extent and preferably stop) unwanted cell proliferation; reduce the number of cancer cells; reduce tumor size; inhibit ( that is, to some extent delay and preferably stop) cancer cell infiltration into surrounding organs; inhibit (that is, to some extent delay and preferably stop) tumor metastasis; inhibit tumor growth to some extent; reduce target cells and/or alleviate to some extent one or more of the symptoms associated with cancer. Where the administered compound or composition prevents growth and/or kills existing cancer cells, it may be cytostatic and/or cytotoxic.
術語「容器」意謂因而適用於儲存、運送、分配及/或操縱醫藥產品之任何盛器及密封件。The term "container" means any container and closure thus suitable for storing, transporting, dispensing and/or manipulating a medicinal product.
術語「說明書」意謂隨附醫藥產品之資訊，該資訊提供對如何投與產品以及允許醫師、藥劑師及患者考慮產品之用途而做出知情決策所需的安全性及功效資料之描述。藥品說明書一般視為醫藥產品之「標籤」。The term "insert label" means the information accompanying a medicinal product that provides a description of how the product is to be administered and the safety and efficacy information needed to allow physicians, pharmacists and patients to make informed decisions considering the use of the product. Drug inserts are generally regarded as the "label" of a medicinal product.
「並行投與」、「組合投與」、「同時投與」及類似片語意謂向正在治療之個體並行投與兩種或多於兩種試劑。「並行」意謂以任何次序在不同時間點同時或依序投與各藥劑。然而，若不同時投與，則意謂以使得提供所需治療效果且可協同作用之次序及在時間上充分接近地向個體投與該等藥劑。舉例而言，本發明之化合物可作為第二治療劑同時或以任何次序在不同時間點依序投與。本發明之化合物及第二治療劑可以任何適當形式且藉由任何適合途徑單獨投與。當不並行投與本發明之化合物及第二治療劑時，應理解，其可以任何次序向有需要之個體投與。舉例而言，本發明之化合物可在向有需要之個體投與第二治療劑治療模式(例如放射線療法)之前(例如5分鐘、15分鐘、30分鐘、45分鐘、1小時、2小時、4小時、6小時、12小時、24小時、48小時、72小時、96小時、1週、2週、3週、4週、5週、6週、8週或12週之前)、與其同時或在其之後(例如5分鐘、15分鐘、30分鐘、45分鐘、1小時、2小時、4小時、6小時、12小時、24小時、48小時、72小時、96小時、1週、2週、3週、4週、5週、6週、8週或12週之後)進行投與。在各種實施例中，本發明之化合物與第二治療劑相隔1分鐘、相隔10分鐘、相隔30分鐘、相隔少於1小時、相隔1小時、相隔1小時至2小時、相隔2小時至3小時、相隔3小時至4小時、相隔4小時至5小時、相隔5小時至6小時、相隔6小時至7小時、相隔7小時至8小時、相隔8小時至9小時、相隔9小時至10小時、相隔10小時至11小時、相隔11小時至12小時、相隔不大於24小時或相隔不大於48小時進行投與。在一個實施例中，組合療法之組分相隔約1分鐘至約24小時投與。"Concurrent administration," "combination administration," "simultaneous administration," and similar phrases mean that two or more agents are administered concurrently to an individual being treated. "Concurrent" means that the agents are administered simultaneously or sequentially at different time points in any order. However, if not administered simultaneously, it is meant that the agents are administered to the subject in an order and sufficiently close in time to provide the desired therapeutic effect and to act synergistically. For example, a compound of the present invention can be administered as a second therapeutic agent simultaneously or sequentially at different time points in any order. The compounds of the present invention and the second therapeutic agent can be administered separately in any suitable form and by any suitable route. When the compound of the present invention and the second therapeutic agent are not administered concurrently, it is understood that they can be administered to an individual in need thereof in any order. For example, the compounds of the invention can be administered to an individual in need thereof prior to administration of a second therapeutic agent treatment modality (eg, radiation therapy) (eg, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours) hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks ago), at the same time or at the same time as After that (e.g. 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks). In various embodiments, the compound of the invention and the second therapeutic agent are 1 minute apart, 10 minutes apart, 30 minutes apart, less than 1 hour apart, 1 hour apart, 1 hour to 2 hours apart, 2 hours to 3 hours apart , 3 hours to 4 hours apart, 4 hours to 5 hours apart, 5 hours to 6 hours apart, 6 hours to 7 hours apart, 7 hours to 8 hours apart, 8 hours to 9 hours apart, 9 hours to 10 hours apart, Administrations are performed 10 to 11 hours apart, 11 to 12 hours apart, no more than 24 hours apart, or no more than 48 hours apart. In one embodiment, the components of the combination therapy are administered about 1 minute to about 24 hours apart.
除非另有指示，否則術語「一(a/an)」、「該(the)」及類似提及物在本發明之情形下(尤其在技術方案之情形下)之使用應解釋為涵蓋單數及複數兩者。除非本文中另有指示，否則本文中對值之範圍之敍述意欲充當各自參考屬於範圍內之各單獨值的簡寫方法，且各單獨值併入至本說明書中，如同其在本文中單獨敍述一般。除非以其他方式主張，否則本文中所提供之對任何及所有實例或例示性語言(例如「諸如」)之使用意欲較佳地說明本發明且不對本發明之範疇進行限制。本說明書中之任何語言均不應解釋為指示實踐本發明所必需之任何未主張要素。Unless otherwise indicated, use of the terms "a/an", "the" and similar references in the context of the present invention (especially in the context of technical solutions) should be construed to encompass the singular and plural of both. Unless otherwise indicated herein, recitations of ranges of values herein are intended to serve as a shorthand method of each referencing each separate value falling within the range, and each separate value is incorporated into the specification as if it were individually recited herein. . Unless otherwise claimed, the use of any and all examples or illustrative language (eg, "such as") provided herein is intended to better illustrate the invention and not to limit the scope of the invention. No language in this specification should be construed as indicating any non-claimed element essential to the practice of the invention.
如本文所用之術語「約」在與數值或值範圍組合使用時意謂值或值之範圍可偏離至對於一般熟習此項技術者而言認為合理的程度。As used herein, the term "about" when used in combination with a value or range of values means that the value or range of values can deviate to the extent deemed reasonable to one of ordinary skill in the art.
本發明之化合物具有不對稱中心且因此可產生對映異構體、非對映異構體及其他立體異構形式。本發明涵蓋使用所有此類可能的形式，以及其外消旋及解析形式及其混合物。鑒於本發明，個別對映異構體可根據此項技術中已知的方法分離。當本文所述之化合物含有烯烴雙鍵或其他幾何不對稱性中心時，除非另外規定，否則預期其包括E及Z幾何異構體。本發明亦涵蓋所有互變異構體。出於本申請案之目的，在一些實施例中，某些化合物已指定為具有特定立體化學組態，其尚未藉由x射線結晶學或任何其他方式確認實。一般熟習此項技術者可使用一或多種熟知方法(包括x射線結晶學)或藉由其他光譜技術(諸如NMR (使用對掌性衍生劑、Mosher酯分析等))確認本文所揭示之化合物中之任一者之絕對組態。The compounds of the present invention possess asymmetric centers and thus can give rise to enantiomers, diastereomers, and other stereoisomeric forms. The present invention contemplates the use of all such possible forms, as well as their racemic and analytical forms, and mixtures thereof. In view of the present invention, individual enantiomers can be separated according to methods known in the art. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they are intended to include both E and Z geometric isomers unless otherwise specified. The present invention also encompasses all tautomers. For the purposes of this application, in some embodiments, certain compounds have been assigned to have a particular stereochemical configuration, which has not been confirmed by x-ray crystallography or any other means. One of ordinary skill in the art can confirm the presence of compounds disclosed herein using one or more well-known methods, including x-ray crystallography, or by other spectroscopic techniques, such as NMR (using parachiral derivatizing agents, Mosher ester analysis, etc.) The absolute configuration of either.
如本文所用，術語「立體異構體」為針對個別分子之所有異構體的通用術語，所述異構體僅在其原子於空間中之取向方面不同。其包括對映異構體及化合物之具有超過一個不為彼此之鏡像的對掌性中心之異構體(非對映異構體)。As used herein, the term "stereoisomer" is a generic term for all isomers of an individual molecule that differ only in the orientation of their atoms in space. It includes enantiomers and isomers of compounds with more than one chiral center that are not mirror images of each other (diastereomers).
術語「對掌性中心」或「不對稱碳原子」係指與四個不同基團連接之碳原子。The term "opposite chiral center" or "asymmetric carbon atom" refers to a carbon atom to which four different groups are attached.
術語「對映異構體」及「對映異構」係指不能疊加於其鏡像上且因此具有光學活性的分子，其中對映異構體沿一個方向旋轉偏光平面，其鏡像化合物則沿相反方向旋轉偏光平面。The terms "enantiomer" and "enantiomer" refer to molecules that cannot be superimposed on their mirror images and are therefore optically active, wherein the enantiomer rotates the plane of polarization in one direction and the mirror image compound in the opposite direction Direction rotates the polarizing plane.
術語「外消旋」係指對映異構體之等量部分之混合物且該混合物為無光學活性的。在一個實施例中，本發明之化合物為外消旋的。The term "racemic" refers to a mixture of equal parts of enantiomers and the mixture is optically inactive. In one embodiment, the compounds of the present invention are racemic.
術語「絕對組態」係指對掌性分子實體(或基團)之原子的空間排列及其立體化學描述，例如R或S。The term "absolute configuration" refers to the spatial arrangement of atoms of a chiral molecular entity (or group) and its stereochemical description, eg, R or S.
除非另有指示，否則本說明書中所使用之立體化學術語及定則預期與Pure & Appl. Chem 68 :2193 (1996)中所描述之彼等一致。Unless otherwise indicated, stereochemical terms and conventions used in this specification are intended to be consistent with those described in Pure & Appl. Chem 68 :2193 (1996).
術語「對映異構體過量」或「ee」係指一種對映異構體與另一種對映異構體相比存在多少之量度。對於R 及S 對映異構體之混合物，對映異構過量百分比經定義為│R-S │*100，其中R 及S 為對映異構體於混合物中之各別莫耳或重量分數以使得R +S =1。藉由對掌性物質之旋光度的瞭解，對映異構體過量百分比定義為([α]obs /[α]max )×100，其中[α]obs 為對映異構體之混合物的旋光度且[α]max 為純對映異構體之旋光度。對映異構體過量之測定可使用多種分析技術，包括NMR光譜法、對掌性管柱層析或旋光測定法。在一個實施例中，藉由對掌性HPLC來測定ee。 V. 本發明之化合物之合成The term "enantiomeric excess" or "ee" refers to a measure of how much one enantiomer is present compared to the other. For mixtures of R and S enantiomers, the percent enantiomeric excess is defined as | RS |*100, where R and S are the respective molar or weight fractions of the enantiomers in the mixture such that R + S = 1. With knowledge of the optical rotation of chiral substances, the percent enantiomeric excess is defined as ([α] obs /[α] max )×100, where [α] obs is the optical rotation of the mixture of enantiomers and [α] max is the optical rotation of the pure enantiomer. Enantiomeric excess can be determined using a variety of analytical techniques, including NMR spectroscopy, chiral column chromatography, or polarimetry. In one embodiment, ee is determined by chiral HPLC. V. Synthesis of Compounds of the Invention
本發明之化合物可藉由實例中所描述之方法及藉由此項技術中已知之相關方法來製備。The compounds of the present invention can be prepared by the methods described in the Examples and by related methods known in the art.
舉例而言，式I
化合物(其中E為E-1、E-2、E-3、E-4及E-5)可藉由流程1中所示之通用方法製備。在鹼(例如K2
CO3
)存在下，氮雜環丁烷2-A與芳基氟化物2-B之間發生親核芳族取代反應，得到式I
化合物(2-C)。
流程1
或者，式I
化合物(其中E為E-6、E-7及E-8)可藉由流程2中所示之通用方法製備。在鹼(例如K2
CO3
)存在下，氮雜環丁烷3-A與親電試劑3-B (LG=離去基)之間發生親核取代反應，得到式I
化合物(3-C)。
流程2
式XXXI
化合物可例如藉由流程3中所示之通用方法製備。芳基溴4-A經由鈴木偶合及後續酸水解轉化為醛4-C。哌啶4-D與醛4-C之還原胺化反應得到式XXXI
化合物(4-E)。
流程3
態樣IAspect I
態樣1. 一種化合物，其具有式I
，
態樣2. 如態樣1之化合物，其具有式II
：
或其醫藥學上可接受之鹽，其中E為E-1、E-2、E-3、E-4、E-5、E-6、E-7、E-8、E-9或E-10。or a pharmaceutically acceptable salt thereof, wherein E is E-1, E-2, E-3, E-4, E-5, E-6, E-7, E-8, E-9 or E -10.
態樣3. 如態樣1之化合物，其具有式III
：
或其醫藥學上可接受之鹽，其中E為E-11或E-12。or a pharmaceutically acceptable salt thereof, wherein E is E-11 or E-12.
態樣4. 如態樣1之化合物，其具有式XII
：
或其醫藥學上可接受之鹽。or its pharmaceutically acceptable salt.
態樣5. 如態樣1之化合物，其具有式XIII
：
或其醫藥學上可接受之鹽。or its pharmaceutically acceptable salt.
態樣6. 如態樣1至4中任一者之化合物或其醫藥學上可接受之鹽，其中： 各Ra 獨立地選自由H及C1 -C4 烷基組成之群； 各Rb 獨立地選自由H及C1-C4 烷基組成之群； Rc 為氟； R為C1 -C4 烷基； B為B-1或B-2。Aspect 6. The compound of any one of Aspects 1 to 4, or a pharmaceutically acceptable salt thereof, wherein: each R a is independently selected from the group consisting of H and C 1 -C 4 alkyl; each R b is independently selected from the group consisting of H and C1- C4 alkyl; R c is fluoro; R is C1 - C4 alkyl; B is B-1 or B-2.
態樣7. 如態樣6之化合物或其醫藥學上可接受之鹽，其中B為B-1。Aspect 7. The compound of Aspect 6 or a pharmaceutically acceptable salt thereof, wherein B is B-1.
態樣8. 如態樣6之化合物或其醫藥學上可接受之鹽，其中B為B-2。Aspect 8. The compound of Aspect 6 or a pharmaceutically acceptable salt thereof, wherein B is B-2.
態樣9. 如態樣6之化合物或其醫藥學上可接受之鹽，其中R為甲基。Aspect 9. The compound of Aspect 6, or a pharmaceutically acceptable salt thereof, wherein R is methyl.
態樣10. 如態樣1至9中任一者之化合物或其醫藥學上可接受之鹽，其中R3a 及R3b 中之至少一者為鹵素。Aspect 10. The compound of any one of Aspects 1 to 9, or a pharmaceutically acceptable salt thereof, wherein at least one of R 3a and R 3b is halogen.
態樣11. 如態樣1至9中任一者之化合物或其醫藥學上可接受之鹽，其中R3a 及R3b 中之至少一者為氟。Aspect 11. The compound of any one of Aspects 1 to 9, or a pharmaceutically acceptable salt thereof, wherein at least one of R 3a and R 3b is fluoro.
態樣12. 如態樣1至4中任一者之化合物或其醫藥學上可接受之鹽，其中R2 為氫。Aspect 12. The compound of any one of Aspects 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen.
態樣13. 如態樣1至4中任一者之化合物或其醫藥學上可接受之鹽，其中R2 為氟。Aspect 13. The compound of any one of Aspects 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R 2 is fluoro.
態樣14. 如態樣1至4中任一者之化合物或其醫藥學上可接受之鹽，其中R2 為甲氧基。Aspect 14. The compound of any one of Aspects 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R 2 is methoxy.
態樣15. 如態樣1至4中任一者之化合物或其醫藥學上可接受之鹽，其中R2 為羥基。Aspect 15. The compound of any one of Aspects 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R 2 is hydroxy.
態樣16. 如態樣1至2及6至10中任一者之化合物或其醫藥學上可接受之鹽，其中E為E-1或E-2。Aspect 16. The compound of any one of Aspects 1 to 2 and 6 to 10, or a pharmaceutically acceptable salt thereof, wherein E is E-1 or E-2.
態樣17. 如態樣1至2及6至10中任一者之化合物或其醫藥學上可接受之鹽，其中E為E-1。Aspect 17. The compound of any one of Aspects 1 to 2 and 6 to 10, or a pharmaceutically acceptable salt thereof, wherein E is E-1.
態樣18. 如態樣17之化合物或其醫藥學上可接受之鹽，其中X為X-1。Aspect 18. The compound of Aspect 17, or a pharmaceutically acceptable salt thereof, wherein X is X-1.
態樣19. 如態樣17之化合物或其醫藥學上可接受之鹽，其中X為X-2。Aspect 19. The compound of Aspect 17 or a pharmaceutically acceptable salt thereof, wherein X is X-2.
態樣20. 如態樣17之化合物或其醫藥學上可接受之鹽，其中X為X-11。Aspect 20. The compound of Aspect 17 or a pharmaceutically acceptable salt thereof, wherein X is X-11.
態樣21. 如態樣1至2及6至10中任一者之化合物或其醫藥學上可接受之鹽，其中E為E-3。Aspect 21. The compound of any one of Aspects 1 to 2 and 6 to 10, or a pharmaceutically acceptable salt thereof, wherein E is E-3.
態樣22. 一種化合物或醫藥學上可接受之鹽，該化合物選自表1之化合物中之一或多者。Aspect 22. A compound or a pharmaceutically acceptable salt selected from one or more of the compounds in Table 1.
態樣23. 一種醫藥組合物，其包含如態樣1至22中任一者之化合物或其醫藥學上可接受之鹽及醫藥學上可接受之載劑。Aspect 23. A pharmaceutical composition comprising the compound of any one of Aspects 1 to 22, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
態樣24. 一種治療患者之方法，該方法包含向該患者投與治療有效量之如態樣1至22中任一者之化合物或其醫藥學上可接受之鹽，其中該患者患有癌症、慢性自體免疫病症、炎性病狀、增生性病症、敗血症或病毒感染。Aspect 24. A method of treating a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of any one of aspects 1 to 22, or a pharmaceutically acceptable salt thereof, wherein the patient has cancer , chronic autoimmune disorders, inflammatory conditions, proliferative disorders, sepsis or viral infections.
態樣25. 如態樣24之方法，其中該患者患有癌症。Aspect 25. The method of Aspect 24, wherein the patient has cancer.
態樣26. 如態樣25之方法，其中該癌症為表2之癌症中之任一者或多者。Aspect 26. The method of Aspect 25, wherein the cancer is any one or more of the cancers of Table 2.
態樣27. 如態樣25之方法，其中該癌症係選自由以下組成之群：急性淋巴球性白血病、急性單核細胞性白血病、急性骨髓性白血病、慢性骨髓性白血病、慢性淋巴球性白血病及混合系白血病。Aspect 27. The method of Aspect 25, wherein the cancer is selected from the group consisting of: acute lymphocytic leukemia, acute monocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia and mixed lineage leukemia.
態樣28. 如態樣24至27中任一者之方法，其進一步包含投與適用於治療疾病或病狀之治療有效量之第二治療劑。Aspect 28. The method of any one of Aspects 24-27, further comprising administering a therapeutically effective amount of a second therapeutic agent suitable for treating a disease or condition.
態樣29. 如態樣23之醫藥組合物，其用於治療癌症、慢性自體免疫病症、炎性病狀、增生性病症、敗血症或病毒感染。Aspect 29. The pharmaceutical composition of Aspect 23, for use in the treatment of cancer, chronic autoimmune disorders, inflammatory conditions, proliferative disorders, sepsis, or viral infections.
態樣30. 如態樣29之醫藥組合物，其用於治療癌症。Aspect 30. The pharmaceutical composition of Aspect 29, for use in the treatment of cancer.
態樣31. 如態樣30之醫藥組合物，其中該癌症為表2之癌症中之任一者或多者。Aspect 31. The pharmaceutical composition of Aspect 30, wherein the cancer is any one or more of the cancers of Table 2.
態樣32. 如態樣30之醫藥組合物，其中該癌症係選自由以下組成之群：急性淋巴球性白血病、急性單核細胞性白血病、急性骨髓性白血病、慢性骨髓性白血病、慢性淋巴球性白血病及混合系白血病。Aspect 32. The pharmaceutical composition of Aspect 30, wherein the cancer is selected from the group consisting of: acute lymphocytic leukemia, acute monocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia leukemia and mixed lineage leukemia.
態樣33. 如態樣1至22中任一者之化合物或其醫藥學上可接受之鹽，其用於治療癌症、慢性自體免疫病症、炎性病狀、增生性病症、敗血症或病毒感染。Aspect 33. The compound of any one of Aspects 1 to 22, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, chronic autoimmune disorders, inflammatory conditions, proliferative disorders, sepsis or viral infections .
態樣34. 如態樣33之化合物，其用於治療癌症。Aspect 34. The compound of Aspect 33, for use in the treatment of cancer.
態樣35. 如態樣34之化合物，其中該癌症為表2之癌症中之任一者或多者。Aspect 35. The compound of Aspect 34, wherein the cancer is any one or more of the cancers of Table 2.
態樣36. 如態樣34之化合物，其中該癌症係選自由以下組成之群：急性淋巴球性白血病、急性單核細胞性白血病、急性骨髓性白血病、慢性骨髓性白血病、慢性淋巴球性白血病及混合系白血病。Aspect 36. The compound of aspect 34, wherein the cancer is selected from the group consisting of: acute lymphocytic leukemia, acute monocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia and mixed lineage leukemia.
態樣37. 一種如態樣1至22中任一者之化合物或其醫藥學上可接受之鹽的用途，其係用於製造用以治療癌症、慢性自體免疫病症、炎性病狀、增生性病症、敗血症或病毒感染之藥劑。Aspect 37. Use of a compound according to any one of Aspects 1 to 22, or a pharmaceutically acceptable salt thereof, in the manufacture of a compound for the treatment of cancer, chronic autoimmune disorders, inflammatory conditions, hyperplasia Medications for sexually transmitted diseases, sepsis or viral infections.
態樣38. 如態樣37之用途，其用於治療癌症。Aspect 38. The use of Aspect 37, for the treatment of cancer.
態樣39. 如態樣38之用途，其中該癌症為表2之癌症中之任一者或多者。Aspect 39. The use of Aspect 38, wherein the cancer is any one or more of the cancers of Table 2.
態樣40. 如態樣38之用途，其中該癌症係選自由以下組成之群：急性淋巴球性白血病、急性單核細胞性白血病、急性骨髓性白血病、慢性骨髓性白血病、慢性淋巴球性白血病及混合譜系白血病。Aspect 40. The use of aspect 38, wherein the cancer is selected from the group consisting of: acute lymphocytic leukemia, acute monocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia and mixed lineage leukemia.
態樣IIAspect II
態樣1. 一種化合物，其具有式I
：
態樣2. 如態樣1之化合物，其具有式II
：
態樣3. 如態樣1之化合物，其具有式III
：
態樣4. 如態樣1之化合物，其具有式XII
：
態樣5. 如態樣1之化合物，其具有式XIII
：
態樣6. 如態樣1至4中任一者之化合物或其醫藥學上可接受之鹽，其中： 各Ra 獨立地選自由H及C1 -C4 烷基組成之群； 各Rb 獨立地選自由H及C1 -C4 烷基組成之群； Rc 為氟； R為C1 -C4 烷基； B為B-1或B-2。Aspect 6. The compound of any one of Aspects 1 to 4, or a pharmaceutically acceptable salt thereof, wherein: each R a is independently selected from the group consisting of H and C 1 -C 4 alkyl; each R b is independently selected from the group consisting of H and C 1 -C 4 alkyl; R c is fluoro; R is C 1 -C 4 alkyl; B is B-1 or B-2.
態樣7. 如態樣6之化合物或其醫藥學上可接受之鹽，其中B為B-1。Aspect 7. The compound of Aspect 6 or a pharmaceutically acceptable salt thereof, wherein B is B-1.
態樣8. 如態樣6之化合物或其醫藥學上可接受之鹽，其中B為B-2。Aspect 8. The compound of Aspect 6 or a pharmaceutically acceptable salt thereof, wherein B is B-2.
態樣9. 如態樣6之化合物或其醫藥學上可接受之鹽，其中R為甲基。Aspect 9. The compound of Aspect 6, or a pharmaceutically acceptable salt thereof, wherein R is methyl.
態樣10. 如態樣1至9中任一者之化合物或其醫藥學上可接受之鹽，其中R3a 及R3b 中之至少一者為鹵素。Aspect 10. The compound of any one of Aspects 1 to 9, or a pharmaceutically acceptable salt thereof, wherein at least one of R 3a and R 3b is halogen.
態樣11. 如態樣1至9中任一者之化合物或其醫藥學上可接受之鹽，其中R3a 及R3b 中之至少一者為氟。Aspect 11. The compound of any one of Aspects 1 to 9, or a pharmaceutically acceptable salt thereof, wherein at least one of R 3a and R 3b is fluoro.
態樣12. 如態樣1至9中任一者之化合物或其醫藥學上可接受之鹽，其中R3a 及R3b 中之至少一者為(胺基)烷基或甲醯胺基。Aspect 12. The compound of any one of Aspects 1 to 9, or a pharmaceutically acceptable salt thereof, wherein at least one of R 3a and R 3b is (amino)alkyl or formamido.
態樣13. 如態樣1至4中任一者之化合物或其醫藥學上可接受之鹽，其中R2 為氫。Aspect 13. The compound of any one of Aspects 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen.
態樣14. 如態樣1至4中任一者之化合物或其醫藥學上可接受之鹽，其中R2 為氟。Aspect 14. The compound of any one of Aspects 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R 2 is fluoro.
態樣15. 如態樣1至4中任一者之化合物或其醫藥學上可接受之鹽，其中R2 為甲氧基。Aspect 15. The compound of any one of Aspects 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R 2 is methoxy.
態樣16. 如態樣1至4中任一者之化合物或其醫藥學上可接受之鹽，其中R2 為羥基。Aspect 16. The compound of any one of Aspects 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R 2 is hydroxy.
態樣17. 如態樣1至2及6至16中任一者之化合物或其醫藥學上可接受之鹽，其中E為E-1或E-2。Aspect 17. The compound of any one of Aspects 1 to 2 and 6 to 16, or a pharmaceutically acceptable salt thereof, wherein E is E-1 or E-2.
態樣18. 如態樣1至2及6至16中任一者之化合物或其醫藥學上可接受之鹽，其中E為E-1。Aspect 18. The compound of any one of Aspects 1 to 2 and 6 to 16, or a pharmaceutically acceptable salt thereof, wherein E is E-1.
態樣19. 如態樣18之化合物或其醫藥學上可接受之鹽，其中X為X-1。Aspect 19. The compound of Aspect 18 or a pharmaceutically acceptable salt thereof, wherein X is X-1.
態樣20. 如態樣18之化合物或其醫藥學上可接受之鹽，其中X為X-2。Aspect 20. The compound of Aspect 18 or a pharmaceutically acceptable salt thereof, wherein X is X-2.
態樣21. 如態樣18之化合物或其醫藥學上可接受之鹽，其中X為X-11。Aspect 21. The compound of Aspect 18 or a pharmaceutically acceptable salt thereof, wherein X is X-11.
態樣22. 如態樣1至2及6至16中任一者之化合物或其醫藥學上可接受之鹽，其中E為E-3。Aspect 22. The compound of any one of Aspects 1 to 2 and 6 to 16, or a pharmaceutically acceptable salt thereof, wherein E is E-3.
態樣23. 一種化合物，其具有式XXXI ：Aspect 23. A compound having formula XXXI :
態樣24. 如態樣23之化合物或其醫藥學上可接受之鹽，其中：
B為
態樣25. 一種化合物，其具有式XXXII
：
態樣26. 如態樣25之化合物或其醫藥學上可接受之鹽，其中：
B為
態樣27. 一種化合物，其具有式XXXIII
：
態樣28. 一種化合物或醫藥學上可接受之鹽，該化合物選自表1、1A、1B或1C之化合物中之一或多者。Aspect 28. A compound or a pharmaceutically acceptable salt selected from one or more of the compounds of Tables 1, 1A, 1B, or 1C.
態樣29. 一種醫藥組合物，其包含如態樣1至28中任一者之化合物或其醫藥學上可接受之鹽及醫藥學上可接受之載劑。Aspect 29. A pharmaceutical composition comprising the compound of any one of Aspects 1 to 28, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
態樣30. 一種治療患者之方法，該方法包含向該患者投與治療有效量之如態樣1至28中任一者之化合物或其醫藥學上可接受之鹽，其中該患者患有癌症、慢性自體免疫病症、炎性病狀、增生性病症、敗血症或病毒感染。Aspect 30. A method of treating a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of any one of aspects 1 to 28, or a pharmaceutically acceptable salt thereof, wherein the patient has cancer , chronic autoimmune disorders, inflammatory conditions, proliferative disorders, sepsis or viral infections.
態樣31. 如態樣30之方法，其中該患者患有癌症。Aspect 31. The method of Aspect 30, wherein the patient has cancer.
態樣32. 如態樣31之方法，其中該癌症為表2之癌症中之任一者或多者。Aspect 32. The method of Aspect 31, wherein the cancer is any one or more of the cancers of Table 2.
態樣33. 如態樣32之方法，其中該癌症係選自由以下組成之群：急性淋巴球性白血病、急性單核細胞性白血病、急性骨髓性白血病、慢性骨髓性白血病、慢性淋巴球性白血病及混合系白血病。Aspect 33. The method of Aspect 32, wherein the cancer is selected from the group consisting of: acute lymphocytic leukemia, acute monocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia and mixed lineage leukemia.
態樣34. 如態樣30至33中任一者之方法，其進一步包含投與治療有效量之適用於治療該疾病或病狀之第二治療劑。Aspect 34. The method of any one of Aspects 30-33, further comprising administering a therapeutically effective amount of a second therapeutic agent suitable for treating the disease or condition.
態樣35. 如態樣29之醫藥組合物，其用於治療癌症、慢性自體免疫病症、炎性病狀、增生性病症、敗血症或病毒感染。Aspect 35. The pharmaceutical composition of Aspect 29, for use in the treatment of cancer, chronic autoimmune disorders, inflammatory conditions, proliferative disorders, sepsis, or viral infections.
態樣36. 如態樣35之醫藥組合物，其用於治療癌症。Aspect 36. The pharmaceutical composition of Aspect 35, for use in the treatment of cancer.
態樣37. 如態樣36之醫藥組合物，其中該癌症為表2之癌症中之任一者或多者。Aspect 37. The pharmaceutical composition of Aspect 36, wherein the cancer is any one or more of the cancers of Table 2.
態樣38. 如態樣37之醫藥組合物，其中該癌症係選自由以下組成之群：急性淋巴球性白血病、急性單核細胞性白血病、急性骨髓性白血病、慢性骨髓性白血病、慢性淋巴球性白血病及混合系白血病。Aspect 38. The pharmaceutical composition of Aspect 37, wherein the cancer is selected from the group consisting of: acute lymphocytic leukemia, acute monocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia leukemia and mixed lineage leukemia.
態樣39. 如態樣1至28中任一者之化合物或其醫藥學上可接受之鹽，其用於治療癌症、慢性自體免疫病症、炎性病狀、增生性病症、敗血症或病毒感染。Aspect 39. The compound of any one of Aspects 1 to 28, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, chronic autoimmune disorders, inflammatory conditions, proliferative disorders, sepsis or viral infections .
態樣40. 如態樣39之化合物，其用於治療癌症。Aspect 40. The compound of Aspect 39, for use in the treatment of cancer.
態樣41. 如態樣40之化合物，其中該癌症為表2之癌症中之任一者或多者。Aspect 41. The compound of Aspect 40, wherein the cancer is any one or more of the cancers of Table 2.
態樣42. 如態樣41之化合物，其中該癌症係選自由以下組成之群：急性淋巴球性白血病、急性單核細胞性白血病、急性骨髓性白血病、慢性骨髓性白血病、慢性淋巴球性白血病及混合系白血病。Aspect 42. The compound of aspect 41, wherein the cancer is selected from the group consisting of: acute lymphocytic leukemia, acute monocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia and mixed lineage leukemia.
態樣43. 一種如態樣1至28中任一者之化合物或其醫藥學上可接受之鹽的用途，其係用於製造用以治療癌症、慢性自體免疫病症、炎性病狀、增生性病症、敗血症或病毒感染之藥劑。Aspect 43. Use of a compound according to any one of Aspects 1 to 28, or a pharmaceutically acceptable salt thereof, in the manufacture of a compound for the treatment of cancer, chronic autoimmune disorders, inflammatory conditions, hyperplasia Medications for sexually transmitted diseases, sepsis or viral infections.
態樣44. 如態樣43之用途，其係用於治療癌症。Aspect 44. The use of Aspect 43, for the treatment of cancer.
態樣45. 如態樣44之用途，其中該癌症為表2之癌症中之任一者或多者。Aspect 45. The use of Aspect 44, wherein the cancer is any one or more of the cancers of Table 2.
態樣46. 如態樣45之用途，其中該癌症係選自由以下組成之群：急性淋巴球性白血病、急性單核細胞性白血病、急性骨髓性白血病、慢性骨髓性白血病、慢性淋巴球性白血病及混合譜系白血病。 實例 實例1Aspect 46. The use of Aspect 45, wherein the cancer is selected from the group consisting of: acute lymphocytic leukemia, acute monocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia and mixed lineage leukemia. Example Example 1
合成中間物(S9
)
((1S ,2R )-2-羥基環戊基)胺基甲酸三級丁酯(S1)：在0℃下，向(1R,2S)-2-胺基環丁烷鹽酸鹽S0 (11 g，79.9 mmol)及Boc2 O (20.9 g，95.9 mmol)於二氯甲烷(200 mL)中之溶液中逐滴添加Et3 N (20.9 mL，119.9 mmol)。使反應混合物升溫至室溫。在攪拌隔夜之後，用飽和鹽水洗滌反應混合物，且用二氯甲烷萃取水相兩次。經合併之有機溶劑經Na2 SO4 乾燥，過濾且真空濃縮。藉由急驟管柱層析純化殘餘物，得到呈油狀物之中間物S1 (15.5 g，96%)。1 H NMR (400 MHz, CDCl3 ) δ 4.85 (s, 1H), 4.16 (s, 1H), 3.80 (s, 1H), 2.02-1.95 (m, 1H), 1.93-1.87 (m, 1H), 1.86-1.77 (m, 2H), 1.70-1.65 (m, 1H), 1.59-1.51 (m, 2H), 1.45 (s, 9H)。(( 1S , 2R )-2-hydroxycyclopentyl)carbamate tertiary butyl ester (S1): at 0 °C, to (1R,2S)-2-aminocyclobutane hydrochloride S0 (11 g, 79.9 mmol) and Boc2O (20.9 g , 95.9 mmol) in dichloromethane (200 mL) was added Et3N (20.9 mL, 119.9 mmol) dropwise. The reaction mixture was allowed to warm to room temperature. After stirring overnight, the reaction mixture was washed with saturated brine, and the aqueous phase was extracted twice with dichloromethane. The combined organic solvents were dried over Na2SO4 , filtered and concentrated in vacuo. The residue was purified by flash column chromatography to give Intermediate S1 (15.5 g, 96%) as an oil. 1 H NMR (400 MHz, CDCl 3 ) δ 4.85 (s, 1H), 4.16 (s, 1H), 3.80 (s, 1H), 2.02-1.95 (m, 1H), 1.93-1.87 (m, 1H), 1.86-1.77 (m, 2H), 1.70-1.65 (m, 1H), 1.59-1.51 (m, 2H), 1.45 (s, 9H).
(3aS ,6aR )-四氫環戊并[d ][1,2,3]㗁噻唑-3(3aH )-甲酸三級丁酯2-氧化物(S2)：在-35℃下，向亞硫醯二氯(7 mL，96.3 mmol)於無水乙腈(150 mL)中之溶液中添加中間物S1 (15.5 g，77.0 mmol)於乙腈(150 mL)中之溶液。接著，逐滴添加吡啶(18.7 mL，231 mmol)，且使反應混合物緩慢升溫至室溫。在攪拌隔夜之後，濃縮反應混合物，且添加水及乙酸乙酯。分離有機層且用乙酸乙酯萃取水層三次。經合併之有機溶劑經Na2 SO4 乾燥，過濾且濃縮。藉由管柱層析純化殘餘物，得到呈油狀物之中間物S2 (18.8 g，98%)。1H NMR (400 MHz, CDCl3) δ 5.74 (t, J = 4.6 Hz, 1H), 4.46 (s, 1H), 2.14-2.09 (m, 1H), 1.90-1.68 (m, 5H), 1.52 (s, 9H)。(3aS, 6aR )-tetrahydrocyclopenta[ d ][1,2,3]thiazole-3( 3aH ) -carboxylate tertiary butyl ester 2-oxide (S2): at -35°C , to a solution of thionite dichloride (7 mL, 96.3 mmol) in dry acetonitrile (150 mL) was added a solution of intermediate S1 (15.5 g, 77.0 mmol) in acetonitrile (150 mL). Next, pyridine (18.7 mL, 231 mmol) was added dropwise, and the reaction mixture was slowly warmed to room temperature. After stirring overnight, the reaction mixture was concentrated, and water and ethyl acetate were added. The organic layer was separated and the aqueous layer was extracted three times with ethyl acetate. The combined organic solvents were dried over Na2SO4 , filtered and concentrated. The residue was purified by column chromatography to give Intermediate S2 (18.8 g, 98%) as an oil. 1H NMR (400 MHz, CDCl3) δ 5.74 (t, J = 4.6 Hz, 1H), 4.46 (s, 1H), 2.14-2.09 (m, 1H), 1.90-1.68 (m, 5H), 1.52 (s, 9H).
(3aS ,6aR )-四氫環戊并[d ][1,2,3]㗁噻唑-3(3aH )-甲酸三級丁酯2,2-二氧化物(S3)：在0℃下，向中間物S2 (18.8 g，76 mmol)於乙腈(100 mL)及H2 O (100 mL)中之溶液中分批添加NaIO4 (24.4 g，114 mmol)，隨後添加RuCl3 .3H2 O (315 mg，1.5 mmol)。在室溫下攪拌反應物2小時。接著，用二***萃取水層三次。經合併之有機溶劑經Na2 SO4 乾燥，過濾且濃縮。藉由管柱層析純化殘餘物，得到呈白色固體之標題化合物S3 (19 g，95%)。1 H NMR (400 MHz, CDCl3 ) δ 5.18-5.15 (m, 1H), 4.56-4.53 (m, 1H), 2.23-2.18 (m, 1H), 2.06-1.95 (m, 3H), 1.87-1.77 (m, 2H), 1.55 (s, 9H)。C10 H17 NO5 S [M + Na]+ 之ESI-MS計算值= 286.07，實驗值：286.10。(3aS, 6aR )-tetrahydrocyclopenta[ d ][1,2,3]thiazole-3( 3aH ) -carboxylate tertiary butyl ester 2,2-dioxide (S3): at 0 To a solution of intermediate S2 (18.8 g, 76 mmol) in acetonitrile (100 mL) and H 2 O (100 mL) was added NaIO 4 (24.4 g, 114 mmol) in portions at C, followed by RuCl 3 . 3H2O (315 mg, 1.5 mmol). The reaction was stirred at room temperature for 2 hours. Next, the aqueous layer was extracted three times with diethyl ether. The combined organic solvents were dried over Na2SO4 , filtered and concentrated. The residue was purified by column chromatography to give the title compound S3 (19 g, 95%) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 5.18-5.15 (m, 1H), 4.56-4.53 (m, 1H), 2.23-2.18 (m, 1H), 2.06-1.95 (m, 3H), 1.87-1.77 (m, 2H), 1.55 (s, 9H). ESI-MS calculated for C10H17NO5S [M+Na] + = 286.07 , found: 286.10 .
2- (1-苯甲基哌啶-4-基)-2-(3-氟苯基)乙腈(S5)：向2-(3-氟苯基)乙腈(5 g，37.01 mmol)於MeOH (50 mL)中之溶液中添加甲醇鈉(12 mL，55.52 mmol，25 wt%於甲醇中)，且短暫攪拌。向此溶液中添加1-苯甲基哌啶-4-酮(7.01 g，37.01 mmol)，且使反應物回流。在隔夜之後，移除溶劑，添加水及EtOAc且進行分離。將水層用EtOAc再萃取兩次，經Na2 SO4 乾燥，過濾且濃縮，得到S4，其不經進一步純化即使用。 2- (1-Benzylpiperidin-4-yl)-2-(3-fluorophenyl)acetonitrile (S5): To 2-(3-fluorophenyl)acetonitrile (5 g, 37.01 mmol) in MeOH To the solution in (50 mL) was added sodium methoxide (12 mL, 55.52 mmol, 25 wt% in methanol) and stirred briefly. To this solution was added 1-benzylpiperidin-4-one (7.01 g, 37.01 mmol) and the reaction was brought to reflux. After overnight, the solvent was removed, water and EtOAc were added and the separation was performed. The aqueous layer was extracted two more times with EtOAc, dried over Na2SO4 , filtered and concentrated to give S4, which was used without further purification.
將粗S4 (37.01 mmol)再溶解於MeOH (50 mL)中，且緩慢添加NaBH4 (4.2 g，111.03 mmol)。在隔夜之後，藉由TLC檢查反應(若反應不完全，則添加更多NaBH4 )。在完成S4轉化為S5之後，添加8 mL水且濃縮反應物。再添加水及EtOAc且分離各層。將水層用EtOAc萃取三次，經Na2 SO4 乾燥，過濾，濃縮且藉由管柱層析(DCM/EtOAc梯度)純化，得到呈油狀物之S5。1 H NMR (400 MHz, MeOD-d4 ) δ 7.44-7.38 (m, 1H), 7.32-7.28 (m, 4H), 7.27-7.22 (m, 1H), 7.18-7.16 (m, 1H), 7.13-7.05 (m, 2H), 3.98 (d,J = 7.1 Hz, 1H), 3.48 (s, 2H), 2.96-2.87 (m, 2H), 2.00-1.92 (m, 2H), 1.87-1.80 (m, 1H), 1.79-1.72 (m, 1H), 1.59-1.52 (m, 1H), 1.50-1.39 (m, 2H); C20 H21 FN2 [M + H]+ 之ESI-MS計算值= 309.17，實驗值：309.16。Crude S4 (37.01 mmol) was redissolved in MeOH (50 mL) and NaBH4 (4.2 g, 111.03 mmol) was added slowly. After overnight, the reaction was checked by TLC (if the reaction was incomplete, more NaBH4 was added ) . After the conversion of S4 to S5 was complete, 8 mL of water was added and the reaction was concentrated. Additional water and EtOAc were added and the layers were separated. The aqueous layer was extracted three times with EtOAc, dried over Na2SO4 , filtered, concentrated and purified by column chromatography (DCM/EtOAc gradient) to give S5 as an oil. 1 H NMR (400 MHz, MeOD- d 4 ) δ 7.44-7.38 (m, 1H), 7.32-7.28 (m, 4H), 7.27-7.22 (m, 1H), 7.18-7.16 (m, 1H), 7.13 -7.05 (m, 2H), 3.98 (d, J = 7.1 Hz, 1H), 3.48 (s, 2H), 2.96-2.87 (m, 2H), 2.00-1.92 (m, 2H), 1.87-1.80 (m , 1H), 1.79-1.72 (m, 1H), 1.59-1.52 (m, 1H), 1.50-1.39 (m, 2H); ESI-MS calculated for C 20 H 21 FN 2 [M + H] + = 309.17, experimental value: 309.16.
((1S,2R)-2-((S)-(1-苯甲基哌啶-4-基)(氰基)(3-氟苯基)甲基)環戊基)胺基甲酸三級丁酯(S7)及((1S,2R)-2-((R)-(1-苯甲基哌啶-4-基)(氰基)(3-氟苯基)甲基)環戊基)胺基甲酸三級丁酯(S8)：向乾燥圓底燒瓶中添加化合物S5 (2.18 g，7.07 mmol)、18-冠-6 (5.61 g，21.21 mmol)及化合物S3 (5.58 g，21.21 mmol)。接著，用擦拭紙覆蓋燒瓶且在乾燥器中於真空下乾燥1至2天。在乾燥步驟之後，自乾燥器移出燒瓶且迅速用隔膜封蓋。對系統抽真空且在氮氣氛圍下加以保護。接著，將燒瓶中之內含物用60 mL新鮮蒸餾THF完全溶解。接著，對溶液短暫抽真空，且置於氮氣氛圍下。(另外重複此吹掃兩次)。將反應物冷卻至0℃，逐滴添加KHMDS (0.5M於甲苯中，42.4 mL，21.21 mmol)，且接著使反應物升溫至室溫且攪拌隔夜。在隔夜之後，添加濃H2 SO4 (0.6 mL，11.31 mmol)於H2 O (10 mL)中之溶液(注意：溶液之pH應＜ 7)，且劇烈攪拌溶液隔夜。接著，將反應混合物用飽和NaHCO3 緩慢淬滅且鹼化，並用乙酸乙酯萃取三次。經合併之有機溶劑經Na2 SO4 乾燥，過濾且濃縮。藉由管柱層析純化殘餘物，得到呈黃色固體之比率為3:2的非對映異構體混合物(2.5 g，73%)。接著，藉由逆相製備型HPLC來分離非對映異構體，分別得到呈三氟乙酸鹽之對映體純標題化合物S7 (1.2 g，36%)及S8 (0.8 g，24%)。亦可藉由在比率為4:1之己烷與二氯甲烷溶液中再結晶，來分離對映純化合物S7。關於 S7 之資料 ：1 H NMR (400 MHz, MeOD-d4 ) δ 7.44-7.39 (m, 1H), 7.35 (d,J = 7.9 Hz, 1H), 7.31-7.22 (m, 6H), 7.11-7.06 (m, 1H), 3.82-3.77 (m, 1H), 3.46 (s, 2H), 2.91 (t,J = 12.5 Hz, 2H), 2.81-2.76 (m, 1H), 2.07-1.93 (m, 5H), 1.80-1.72 (m, 1H), 1.62-1.46 (m, 5H), 1.33 (s, 9H), 1.27-1.17 (m, 2H); C30 H38 FN3 O2 [M + H]+ 之ESI-MS計算值 = 492.29，實驗值：492.36. [α]D 20 = + 23.1, (c 1.17×10-3 g/mL, MeOH);t R (UPLC) = 4.46 min。關於 S8 之資料 ： 1 H NMR (400 MHz, MeOD-d4 ) δ 7.50-7.43 (m, 6H), 7.27 (d,J = 7.3 Hz, 1H), 7.20 (d,J = 9.9 Hz, 1H), 7.14 (t,J = 8.3 Hz, 1H), 4.24 (s, 2H), 4.02-3.98 (m, 1H), 3.54-3.45 (m, 2H), 3.08 (t,J = 11.4 Hz, 2H), 2.88-2.83 (m, 2H), 2.59 (t,J = 11.8 Hz, 1H), 2.25 (d,J = 14.0 Hz, 1H), 1.99-1.87 (m, 2H), 1.79-1.74 (m, 1H), 1.67-1.57 (m, 3H), 1.46 (s, 9H), 1.43-1.37 (m, 2H), 1.33-1.18 (m, 1H); C30 H38 FN3 O2 [M + H]+ 之ESI-MS計算值= 492.29，實驗值：492.36. [α]D 20 = + 9.4, (c 1.07 ×10-3 g/mL, MeOH);t R (UPLC) = 4.63 min。藉由S7之單晶x射線分析來測定S7及S8之絕對立體化學。參見S. Xu等人,「Design of the First-in-Class, Highly Potent Irreversible Inhibitor Targeting theMenin-MLL Protein-Protein Interaction」, 57 Angew. Chem. Int. Ed. 1601-05 (2018)。((1S,2R)-2-((S)-(1-benzylpiperidin-4-yl)(cyano)(3-fluorophenyl)methyl)cyclopentyl)carbamic acid tertiary Butyl ester (S7) and ((1S,2R)-2-((R)-(1-benzylpiperidin-4-yl)(cyano)(3-fluorophenyl)methyl)cyclopentyl ) tertiary butyl carbamate (S8): To a dry round bottom flask was added compound S5 (2.18 g, 7.07 mmol), 18-crown-6 (5.61 g, 21.21 mmol) and compound S3 (5.58 g, 21.21 mmol) ). Next, cover the flask with wipes and dry under vacuum in a desiccator for 1 to 2 days. After the drying step, the flask was removed from the desiccator and quickly capped with a septum. The system was evacuated and protected under nitrogen atmosphere. Next, the contents of the flask were completely dissolved with 60 mL of freshly distilled THF. Next, the solution was evacuated briefly and placed under a nitrogen atmosphere. (This purge was repeated two additional times). The reaction was cooled to 0°C, KHMDS (0.5M in toluene, 42.4 mL, 21.21 mmol) was added dropwise, and the reaction was then allowed to warm to room temperature and stirred overnight. After overnight, a solution of concentrated H2SO4 (0.6 mL, 11.31 mmol) in H2O ( 10 mL) was added (note: pH of the solution should be < 7), and the solution was stirred vigorously overnight. Next, the reaction mixture was slowly quenched with saturated NaHCO3 and basified, and extracted three times with ethyl acetate. The combined organic solvents were dried over Na2SO4 , filtered and concentrated. The residue was purified by column chromatography to give a 3:2 mixture of diastereomers as a yellow solid (2.5 g, 73%). The diastereomers were then separated by reverse phase preparative HPLC to give the enantiomerically pure title compounds S7 (1.2 g, 36%) and S8 (0.8 g, 24%), respectively, as trifluoroacetate salts. Enantiopure compound S7 can also be isolated by recrystallization from a 4:1 ratio of hexane to dichloromethane solution. Information on S7 : 1 H NMR (400 MHz, MeOD- d 4 ) δ 7.44-7.39 (m, 1H), 7.35 (d, J = 7.9 Hz, 1H), 7.31-7.22 (m, 6H), 7.11- 7.06 (m, 1H), 3.82-3.77 (m, 1H), 3.46 (s, 2H), 2.91 (t, J = 12.5 Hz, 2H), 2.81-2.76 (m, 1H), 2.07-1.93 (m, 5H), 1.80-1.72 (m, 1H), 1.62-1.46 (m, 5H), 1.33 (s, 9H), 1.27-1.17 (m, 2H); C 30 H 38 FN 3 O 2 [M + H] + ESI-MS calculated value = 492.29, found: 492.36. [α] D 20 = + 23.1, (c 1.17×10 -3 g/mL, MeOH); t R (UPLC) = 4.46 min. Information on S8 : 1 H NMR (400 MHz, MeOD- d 4 ) δ 7.50-7.43 (m, 6H), 7.27 (d, J = 7.3 Hz, 1H), 7.20 (d, J = 9.9 Hz, 1H) , 7.14 (t, J = 8.3 Hz, 1H), 4.24 (s, 2H), 4.02-3.98 (m, 1H), 3.54-3.45 (m, 2H), 3.08 (t, J = 11.4 Hz, 2H), 2.88-2.83 (m, 2H), 2.59 (t, J = 11.8 Hz, 1H), 2.25 (d, J = 14.0 Hz, 1H), 1.99-1.87 (m, 2H), 1.79-1.74 (m, 1H) , 1.67-1.57 (m, 3H), 1.46 (s, 9H), 1.43-1.37 (m, 2H), 1.33-1.18 (m, 1H); C 30 H 38 FN 3 O 2 [M + H] + ESI-MS calculated = 492.29, found: 492.36. [α] D 20 = + 9.4, (c 1.07 × 10 -3 g/mL, MeOH); t R (UPLC) = 4.63 min. The absolute stereochemistry of S7 and S8 was determined by single crystal x-ray analysis of S7. See S. Xu et al., "Design of the First-in-Class, Highly Potent Irreversible Inhibitor Targeting the Menin-MLL Protein-Protein Interaction", 57 Angew. Chem. Int. Ed. 1601-05 (2018).
合成S9：向乾燥RB燒瓶中添加S7 (3 g，6.1 mmol)，接著用擦拭紙覆蓋且置於已置於真空下之乾燥器中持續1至2天。在真空抽吸步驟之後，自乾燥器移出燒瓶，且迅速用隔膜封蓋，且在N2 氛圍下對系統抽真空。向燒瓶中添加無水甲苯(30 ml，Sigma，目錄號244511)且在冰浴中冷卻至0℃。在0℃下，在攪拌下，用注射器緩慢將二異丁基氫化鋁(25%於甲苯中，16.4 mL，24.4 mmol，4當量)注入至反應混合物中。接著，移出冰浴，且使用UPLC-質譜監測反應(約4h)。在S7之質量(492)消失之後，在0℃下將20 ml NaOH (1M)溶液緩慢添加至反應混合物中，以淬滅反應物。在攪拌5 min之後，移出冰浴且再添加20 ml飽和鹽水。接著，添加約50 mL EtOAc且形成凝膠。用矽藻土過濾凝膠，用EtOAc洗滌，且合併溶劑。分別用EtOAc及DCM萃取溶液兩次。有機溶劑經Na2 SO4 乾燥，過濾且旋轉真空濃縮。接著添加DCM (50 ml)，且再次濃縮(重複兩次以完全移除EtOAc)。Synthesis of S9: S7 (3 g, 6.1 mmol) was added to a dry RB flask, then covered with wipes and placed in a desiccator that had been placed under vacuum for 1-2 days. After the vacuum step, the flask was removed from the desiccator and quickly capped with a septum, and the system was evacuated under a N2 atmosphere. Anhydrous toluene (30 ml, Sigma, cat. no. 244511) was added to the flask and cooled to 0°C in an ice bath. Diisobutylaluminum hydride (25% in toluene, 16.4 mL, 24.4 mmol, 4 equiv) was slowly injected into the reaction mixture with a syringe at 0 °C with stirring. Next, the ice bath was removed and the reaction was monitored using UPLC-mass spectrometry (about 4 h). After the mass of S7 (492) disappeared, 20 ml of NaOH (1 M) solution was slowly added to the reaction mixture at 0 °C to quench the reaction. After stirring for 5 min, the ice bath was removed and another 20 ml saturated brine was added. Next, about 50 mL of EtOAc was added and a gel formed. The gel was filtered through celite, washed with EtOAc, and the solvents were combined. The solution was extracted twice with EtOAc and DCM, respectively. The organic solvent was dried over Na2SO4 , filtered and concentrated in vacuo. Then DCM (50 ml) was added and concentrated again (repeated twice to completely remove EtOAc).
接著，將殘餘物再溶解於MeOH (100 mL)中，且在0℃下緩慢添加NaBH4 (461 mg，12.2 mmol，4當量)，在室溫下攪拌反應混合物，且使用UPLC-質譜監測反應(約2天)。若仍存在亞胺中間物(質量：495)，則每12小時添加NaBH4 (1當量)。在亞胺中間物消失之後，濃縮反應混合物且用水稀釋。分別用EtOAc及DCM萃取溶液兩次。有機溶劑經Na2 SO4 乾燥，過濾且旋轉真空濃縮，得到無需進一步純化之粗產物S9 (質量：496)。1 H NMR (400 MHz, MeOD-d4 ) δ 7.41-7.35 (m, 1H), 7.33-7.23 (m, 6H), 7.18 (d,J = 11.6 Hz, 1H), 6.99-6.95 (m, 1H), 4.07-4.02 (m, 1H), 3.52-3.44 (m, 2H), 3.24 (d,J = 14.4 Hz, 1H), 3.09 (d,J = 14.4 Hz, 1H), 2.98 (d,J = 11.2 Hz, 1H), 2.91 (d,J = 10.8 Hz, 1H), 2.35-2.29 (m, 1H), 2.12-2.04 (m, 2H), 2.01-1.94 (m, 2H), 1.77-1.69 (m, 1H), 1.61-1.58 (m, 1H), 1.54-1.47 (m, 2H), 1.44 (s, 9H), 1.41-1.29 (m, 3H), 1.22-1.14 (m, 2H); C30 H42 FN3 O2 [M + H]+ 之ESI-MS計算值 = 496.33，實驗值：496.48。 實例2The residue was then redissolved in MeOH (100 mL) and NaBH4 (461 mg, 12.2 mmol, 4 equiv) was added slowly at 0 °C, the reaction mixture was stirred at room temperature, and the reaction was monitored using UPLC-Mass Spectrometry (about 2 days). If the imine intermediate (mass: 495) was still present, NaBH4 ( 1 equiv) was added every 12 hours. After disappearance of the imine intermediate, the reaction mixture was concentrated and diluted with water. The solution was extracted twice with EtOAc and DCM, respectively. The organic solvent was dried over Na2SO4 , filtered and concentrated in vacuo to give the crude product S9 (mass: 496) without further purification. 1 H NMR (400 MHz, MeOD- d 4 ) δ 7.41-7.35 (m, 1H), 7.33-7.23 (m, 6H), 7.18 (d, J = 11.6 Hz, 1H), 6.99-6.95 (m, 1H) ), 4.07-4.02 (m, 1H), 3.52-3.44 (m, 2H), 3.24 (d, J = 14.4 Hz, 1H), 3.09 (d, J = 14.4 Hz, 1H), 2.98 (d, J = 11.2 Hz, 1H), 2.91 (d, J = 10.8 Hz, 1H), 2.35-2.29 (m, 1H), 2.12-2.04 (m, 2H), 2.01-1.94 (m, 2H), 1.77-1.69 (m , 1H), 1.61-1.58 (m, 1H), 1.54-1.47 (m, 2H), 1.44 (s, 9H), 1.41-1.29 (m, 3H), 1.22-1.14 (m, 2H); C 30 H ESI-MS calculated for 42FN3O2 [ M + H] + = 496.33, found: 496.48. Example 2
合成中間物((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(哌啶-4-基)乙基)環戊基)胺基甲酸甲酯(E5)
((1S,2R)-2-((S)-(1-苯甲基哌啶-4-基)(氰基)(3-氟苯基)甲基)環戊基)胺基甲酸甲酯(E3)：將化合物S7 (1.0 g，2.04 mmol)溶解於DCM (2 mL)中，接著添加CF3 CO2 H (6 mL)。15分鐘後，反應完成，且真空移除溶劑以產生E1，其不經純化即使用。在0℃下，將二碳酸二甲酯(410 mg，3.05 mmol)添加至E1及Et3 N (1.13 mL，8.16 mmol)於DCM (30 mL)中之溶液中。2小時後，濃縮反應物且藉由管柱層析純化以產生E2 (770 mg)。((1S,2R)-Methyl 2-((S)-(1-benzylpiperidin-4-yl)(cyano)(3-fluorophenyl)methyl)cyclopentyl)carbamate (E3): Compound S7 (1.0 g, 2.04 mmol) was dissolved in DCM ( 2 mL), followed by the addition of CF3CO2H (6 mL). After 15 minutes, the reaction was complete and the solvent was removed in vacuo to yield El, which was used without purification. Dimethyl dicarbonate (410 mg, 3.05 mmol) was added to a solution of El and Et3N (1.13 mL, 8.16 mmol) in DCM (30 mL) at 0 °C. After 2 hours, the reaction was concentrated and purified by column chromatography to give E2 (770 mg).
((1S,2R)-2-((S)-2-胺基-1-(1-苯甲基哌啶-4-基)-1-(3-氟苯基)乙基)環戊基)胺基甲酸甲酯(E3)：在0℃下，緩慢添加氫化二異丁基鋁(3.90 mL，6.86 mmol)至E2 (770 mg，1.715 mmol)於甲苯(17 mL)中之溶液中。在0℃下1小時之後，使反應物升溫至室溫持續15分鐘，接著用2M NaOH緩慢淬滅反應物。將搜淬滅之反應物用乙酸乙酯及鹽水稀釋且萃取3次。經合併之有機層經硫酸鈉乾燥，經由矽藻土過濾，濃縮且抽真空以移除殘餘溶劑。將此粗產物再溶解於甲醇中，接著用NaBH4 (130 mg，3.43 mmol)處理。在隔夜之後，用2M NaOH淬滅反應物，用乙酸乙酯及鹽水稀釋，且接著萃取3次。經合併之有機層經硫酸鈉乾燥，過濾，濃縮且抽真空，以移除殘餘溶劑，得到粗E3 (775 mg)。((1S,2R)-2-((S)-2-amino-1-(1-benzylpiperidin-4-yl)-1-(3-fluorophenyl)ethyl)cyclopentyl ) Methyl carbamate (E3): Diisobutylaluminum hydride (3.90 mL, 6.86 mmol) was slowly added to a solution of E2 (770 mg, 1.715 mmol) in toluene (17 mL) at 0 °C. After 1 hour at 0°C, the reaction was allowed to warm to room temperature for 15 minutes, then the reaction was slowly quenched with 2M NaOH. The quenched reaction was diluted with ethyl acetate and brine and extracted 3 times. The combined organic layers were dried over sodium sulfate, filtered through celite, concentrated and evacuated to remove residual solvent. This crude product was redissolved in methanol and then treated with NaBH4 ( 130 mg, 3.43 mmol). After overnight, the reaction was quenched with 2M NaOH, diluted with ethyl acetate and brine, and then extracted 3 times. The combined organic layers were dried over sodium sulfate, filtered, concentrated and evacuated to remove residual solvent to give crude E3 (775 mg).
((1S,2R)-2-((S)-1-(1-苯甲基哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯(E4)：在0℃下，將乙酸銨(340 mg，4.42 mmol)、乙二醛(641 µL，40%於水中，4.42 mmol)及乙醛(495 µL，8.83 mmol))添加至E3 (400 mg，0.883 mmol)於甲醇(25 mL)中之溶液中。在0℃下攪拌30分鐘之後，自冰浴移出反應物且使其在室溫下攪拌1小時，且接著加熱至60℃。在60℃下加熱隔夜之後，濃縮反應物且藉由製備型HPLC純化以產生E4 (406 mg)。((1S,2R)-2-((S)-1-(1-benzylpiperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H- Imidazol-1-yl)ethyl)cyclopentyl)carbamate (E4): At 0 °C, combine ammonium acetate (340 mg, 4.42 mmol), glyoxal (641 µL, 40% in water, 4.42 mmol) and acetaldehyde (495 µL, 8.83 mmol)) were added to a solution of E3 (400 mg, 0.883 mmol) in methanol (25 mL). After stirring at 0°C for 30 minutes, the reaction was removed from the ice bath and allowed to stir at room temperature for 1 hour, and then heated to 60°C. After heating at 60°C overnight, the reaction was concentrated and purified by preparative HPLC to yield E4 (406 mg).
((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(哌啶-4-基)乙基)環戊基)胺基甲酸甲酯(E5)：用10 mL甲醇溶解化合物5 (406 mg，0.784 mmol)，且藉由短暫抽真空，隨後添加氮氣氛圍吹掃溶液兩次。快速添加Pd/C (200 mg，10%/碳)，且將反應物抽真空且置於H2 氛圍下2小時。在經由矽藻土濾出Pd/C催化劑之後，真空移除溶劑，得到E5 (318 mg)，其不經進一步純化即使用。 實例3((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(piperidin-4-yl )ethyl)cyclopentyl)carbamate (E5): Compound 5 (406 mg, 0.784 mmol) was dissolved in 10 mL of methanol and the solution was purged twice by a brief vacuum followed by the addition of a nitrogen atmosphere. Pd/C (200 mg, 10%/carbon) was added quickly, and the reaction was evacuated and placed under an atmosphere of H2 for 2 hours. After filtering off the Pd/C catalyst through celite, the solvent was removed in vacuo to give E5 (318 mg) which was used without further purification. Example 3
製備中間物((1S,2R)-2-((S)-1-(3-氟苯基)-1-(哌啶-4-基)-2-(4H-1,2,4-***-4-基)乙基)環戊基)胺基甲酸甲酯(T2)
步驟A：((1S,2R)-2-((S)-1-(1-苯甲基哌啶-4-基)-1-(3-氟苯基)-2-(4H-1,2,4-***-4-基)乙基)環戊基)胺基甲酸甲酯(T1)Step A: ((1S,2R)-2-((S)-1-(1-benzylpiperidin-4-yl)-1-(3-fluorophenyl)-2-(4H-1, 2,4-Triazol-4-yl)ethyl)cyclopentyl)carbamate (T1)
在70℃下使原甲酸三乙酯(1.29 mL，7.716 mmol，1.8當量)、甲醯肼(397 mg，6.614 mmol，1.5當量)於MeOH (10 mL)中之溶液回流。接著將((1S,2R)-2-((S)-2-胺基-1-(1-苯甲基哌啶-4-基)-1-(3-氟苯基)乙基)環戊基)胺基甲酸酯(E3) (2 g，4.409 mmol，1.0當量)添加至以上溶液中。進一步使混合物回流隔夜。使反應物冷卻至室溫且在減壓下濃縮。藉由矽膠急驟管柱層析純化殘餘物，得到呈白色固體之T1 (1.8 g，產率81%)。LC-MS: 506 (M+H)+ 。A solution of triethyl orthoformate (1.29 mL, 7.716 mmol, 1.8 equiv), carboxylhydrazine (397 mg, 6.614 mmol, 1.5 equiv) in MeOH (10 mL) was refluxed at 70 °C. Then the ((1S,2R)-2-((S)-2-amino-1-(1-benzylpiperidin-4-yl)-1-(3-fluorophenyl)ethyl) ring Amyl)carbamate (E3) (2 g, 4.409 mmol, 1.0 equiv) was added to the above solution. The mixture was further refluxed overnight. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give T1 (1.8 g, 81% yield) as a white solid. LC-MS: 506 (M+H) + .
步驟B：((1S,2R)-2-((S)-1-(3-氟苯基)-1-(哌啶-4-基)-2-(4H-1,2,4-***-4-基)乙基)環戊基)胺基甲酸甲酯(T2)Step B: ((1S,2R)-2-((S)-1-(3-fluorophenyl)-1-(piperidin-4-yl)-2-(4H-1,2,4-tris Methyl oxazol-4-yl)ethyl)cyclopentyl)carbamate (T2)
向((1S,2R)-2-((S)-1-(1-苯甲基哌啶-4-基)-1-(3-氟苯基)-2-(4H-1,2,4-***-4-基)乙基)環戊基)胺基甲酸甲酯(T1) (1.8 g，3.56 mmol，1.0當量)於CF3 CH2 OH (18 mL)中之混合物中添加20% Pd(OH)2 /C (0.36 g，10% w/wt)。在H2 氛圍(1 atm)下於25℃攪拌反應物16h。過濾混合物，且在減壓下濃縮濾液，得到T2 (1.4 g，產率95%)，其直接用於下一步驟。LC-MS: 416 (M+1)+ 。 實例4To ((1S,2R)-2-((S)-1-(1-benzylpiperidin-4-yl)-1-(3-fluorophenyl)-2-(4H-1,2, To a mixture of methyl 4-triazol-4-yl)ethyl)cyclopentyl)carbamate (T1) (1.8 g, 3.56 mmol, 1.0 equiv) in CF3CH2OH ( 18 mL) was added 20 % Pd(OH) 2 /C (0.36 g, 10% w/wt). The reaction was stirred at 25 °C for 16 h under a H2 atmosphere (1 atm). The mixture was filtered, and the filtrate was concentrated under reduced pressure to give T2 (1.4 g, 95% yield), which was used directly in the next step. LC-MS: 416 (M+1) + . Example 4
製備((1S,2R)-2-((S)-1-(1-(氮雜環丁烷-3-基甲基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-吡唑-1-基)乙基)環戊基)胺基甲酸甲酯(D6)
步驟A：((1S,2R)-2-((S)-1-(1-苯甲基哌啶-4-基)-1-(3-氟苯基)-2-((3-(三甲基矽烷基)丙-2-炔-1-基)胺基)乙基)環戊基)胺基甲酸甲酯(D1)Step A: ((1S,2R)-2-((S)-1-(1-benzylpiperidin-4-yl)-1-(3-fluorophenyl)-2-((3-( Methyl trimethylsilyl)prop-2-yn-1-yl)amino)ethyl)cyclopentyl)carbamate (D1)
在室溫下攪拌((1S,2R)-2-((S)-2-胺基-1-(1-苯甲基哌啶-4-基)-1-(3-氟苯基)乙基)環戊基)胺基甲酸甲酯(E3) (2 g，4.42 mmol，1.0當量)及3-(三甲基矽烷基)丙醛(668 mg，5.3 mmol，1.2當量)於DCE (15 mL)中之溶液3h。隨後向上述溶液中添加NaBH3 CN (1.388 g，22.1 mmol，5當量)，且在室溫下攪拌混合物隔夜。接著用水(15 mL)淬滅反應物且用EtOAc (15 mL×2)萃取。將有機層用鹽水(15 mL)洗滌，經Na2 SO4 乾燥，過濾且在減壓下濃縮。藉由矽膠急驟管柱層析純化殘餘物，得到呈白色固體之D1 (2.3 g，產率93%)。LC-MS: 564 (M+1)+ 。((1S,2R)-2-((S)-2-amino-1-(1-benzylpiperidin-4-yl)-1-(3-fluorophenyl)ethyl Methyl)cyclopentyl)carbamate (E3) (2 g, 4.42 mmol, 1.0 equiv) and 3-(trimethylsilyl)propanal (668 mg, 5.3 mmol, 1.2 equiv) in DCE (15 mL) in the solution for 3h. To the above solution was then added NaBH3CN (1.388 g, 22.1 mmol, 5 equiv) and the mixture was stirred at room temperature overnight. The reaction was then quenched with water (15 mL) and extracted with EtOAc (15 mL x 2). The organic layer was washed with brine (15 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give D1 (2.3 g, 93% yield) as a white solid. LC-MS: 564 (M+1) + .
步驟B：((1S,2R)-2-((S)-1-(1-苯甲基哌啶-4-基)-1-(3-氟苯基)-2-(丙-2-炔-1-基胺基)乙基)環戊基)胺基甲酸甲酯(D2)Step B: ((1S,2R)-2-((S)-1-(1-benzylpiperidin-4-yl)-1-(3-fluorophenyl)-2-(propan-2- Alkyn-1-ylamino)ethyl)cyclopentyl)carbamate (D2)
在室溫下攪拌((1S,2R)-2-((S)-1-(1-苯甲基哌啶-4-基)-1-(3-氟苯基)-2-((3-(三甲基矽烷基)丙-2-炔-1-基)胺基)乙基)環戊基)胺基甲酸甲酯(D1) (2.3 g，4.08 mmol，1.0當量)及K2 CO3 (1.69 g，12.24 mmol，3.0當量)於MeOH (15 mL)中之混合物4h。過濾反應混合物。減壓濃縮濾液。藉由矽膠急驟管柱層析純化殘餘物，得到呈白色固體之D2 (1 g，產率95%)。LC-MS: 492 (M+1)+ 。((1S,2R)-2-((S)-1-(1-benzylpiperidin-4-yl)-1-(3-fluorophenyl)-2-((3 Methyl -(trimethylsilyl)prop-2-yn-1-yl)amino)ethyl)cyclopentyl)carbamate (D1) (2.3 g, 4.08 mmol, 1.0 equiv) and K 2 CO A mixture of 3 (1.69 g, 12.24 mmol, 3.0 equiv) in MeOH (15 mL) for 4 h. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give D2 (1 g, 95% yield) as a white solid. LC-MS: 492 (M+1) + .
步驟C：1-((S)-2-(1-苯甲基哌啶-4-基)-2-(3-氟苯基)-2-((1R,2S)-2-((甲氧基羰基)胺基)環戊基)乙基)-1H-吡唑2-氧化物(D3)Step C: 1-((S)-2-(1-benzylpiperidin-4-yl)-2-(3-fluorophenyl)-2-((1R,2S)-2-((methyl Oxycarbonyl)amino)cyclopentyl)ethyl)-1H-pyrazole 2-oxide (D3)
在0℃下攪拌((1S,2R)-2-((S)-1-(1-苯甲基哌啶-4-基)-1-(3-氟苯基)-2-(丙-2-炔-1-基胺基)乙基)環戊基)胺基甲酸甲酯(D2) (700 mg，1.43 mmol，1.0當量)、NaNO2 (295 mg，4.28 mmol，3當量)及AgOTf (36 mg，0.14 mmol，0.1當量) 於CHCl3 (10 mL)中之混合物，接著添加乙酸(2.5 mL)。在室溫下攪拌反應混合物16h。接著將反應混合物倒入水(10 mL)中且用NaHCO3 飽和水溶液(15 mL)稀釋，並用DCM (20 mL×3)萃取。將有機層用鹽水(20 mL)洗滌，經Na2 SO4 乾燥，過濾且在減壓下濃縮。藉由矽膠急驟管柱層析純化殘餘物，得到呈白色固體之D3 (500 mg，產率92%)。LC-MS: 521 (M+1)+ 。((1S,2R)-2-((S)-1-(1-benzylpiperidin-4-yl)-1-(3-fluorophenyl)-2-(propane- Methyl 2-yn-1-ylamino)ethyl)cyclopentyl)carbamate (D2) (700 mg, 1.43 mmol, 1.0 equiv), NaNO 2 (295 mg, 4.28 mmol, 3 equiv) and AgOTf (36 mg, 0.14 mmol, 0.1 equiv) in CHCl3 (10 mL) followed by acetic acid (2.5 mL). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was then poured into water (10 mL) and diluted with saturated aqueous NaHCO 3 (15 mL) and extracted with DCM (20 mL×3). The organic layer was washed with brine (20 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give D3 (500 mg, 92% yield) as a white solid. LC-MS: 521 (M+1) + .
步驟D：((1S,2R)-2-((S)-1-(3-氟苯基)-1-(哌啶-4-基)-2-(1H-吡唑-1-基)乙基)環戊基)胺基甲酸甲酯(D4)Step D: ((1S,2R)-2-((S)-1-(3-fluorophenyl)-1-(piperidin-4-yl)-2-(1H-pyrazol-1-yl) Ethyl)cyclopentyl)carbamate (D4)
在H2 氛圍(1 atm)下，於室溫攪拌1-((S)-2-(1-苯甲基哌啶-4-基)-2-(3-氟苯基)-2-((1R,2S)-2-((甲氧基羰基)胺基)環戊基)乙基)-1H-吡唑2-氧化物(D3)(500 mg，0.96 mmol)及20% Pd(OH)2 /C (100 mg，20% w/wt)於CF3 CH2 OH (15 ml)中之混合物16h。過濾混合物，且在減壓下濃縮濾液，得到呈白色固體之D4 (270 mg，產率68%)。LC-MS: 415 (M+1)+ 。1-((S)-2-( 1 -benzylpiperidin-4-yl)-2-(3-fluorophenyl)-2-( (1R,2S)-2-((methoxycarbonyl)amino)cyclopentyl)ethyl)-1H-pyrazole 2-oxide (D3) (500 mg, 0.96 mmol) and 20% Pd(OH) ) 2 /C (100 mg, 20% w/wt) in CF 3 CH 2 OH (15 ml) for 16 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give D4 (270 mg, 68% yield) as a white solid. LC-MS: 415(M+1) + .
步驟E：3-((4-((S)-1-(3-氟苯基)-1-((1R,2S)-2-((甲氧基羰基)胺基)環戊基)-2-(1H-吡唑-1-基)乙基)哌啶-1-基)甲基)氮雜環丁烷-1-甲酸三級丁酯(D5)Step E: 3-((4-((S)-1-(3-fluorophenyl)-1-((1R,2S)-2-((methoxycarbonyl)amino)cyclopentyl)- 2-(1H-Pyrazol-1-yl)ethyl)piperidin-1-yl)methyl)azetidine-1-carboxylic acid tertiary butyl ester (D5)
在N2 氛圍下，於80℃攪拌((1S,2R)-2-((S)-1-(3-氟苯基)-1-(哌啶-4-基)-2-(1H-吡唑-1-基)乙基)環戊基)胺基甲酸甲酯(D4) (270 mg，0.651 mmol，1.0當量)、3-(((甲基磺醯基)氧基)甲基)氮雜環丁烷-1-甲酸三級丁酯(173 mg，0.651 mmol，1.0當量)、K2 CO3 (180 mg，1.303 mmol，2.0當量)及KI (216.25 mg，1.303 mmol，2.0當量)於MeCN (10 mL)中之混合物16h。接著用水(15 mL)淬滅反應物且用EtOAc (15 mL×2)萃取。將有機層用鹽水(15 mL)洗滌，經Na2 SO4 乾燥，過濾且在減壓下濃縮。藉由矽膠急驟管柱層析純化殘餘物，得到呈黃色油狀物之D5 (63 mg，產率17%)。LC-MS: 584 (M+1)+ 。((1S,2R) -2 -((S)-1-(3-fluorophenyl)-1-(piperidin-4-yl)-2-(1H- Pyrazol-1-yl)ethyl)cyclopentyl)carbamate (D4) (270 mg, 0.651 mmol, 1.0 equiv), 3-(((methylsulfonyl)oxy)methyl) tert-butyl azetidine-1-carboxylate (173 mg, 0.651 mmol, 1.0 equiv), K2CO3 ( 180 mg , 1.303 mmol, 2.0 equiv) and KI (216.25 mg, 1.303 mmol, 2.0 equiv) Mixture in MeCN (10 mL) for 16 h. The reaction was then quenched with water (15 mL) and extracted with EtOAc (15 mL x 2). The organic layer was washed with brine (15 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give D5 (63 mg, 17% yield) as a yellow oil. LC-MS: 584 (M+1) + .
步驟F：((1S,2R)-2-((S)-1-(1-(氮雜環丁烷-3-基甲基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-吡唑-1-基)乙基)環戊基)胺基甲酸甲酯(D6)Step F: ((1S,2R)-2-((S)-1-(1-(azetidin-3-ylmethyl)piperidin-4-yl)-1-(3-fluorobenzene yl)-2-(1H-pyrazol-1-yl)ethyl)cyclopentyl)carbamate (D6)
在25℃下攪拌3-((4-((S)-1-(3-氟苯基)-1-((1R,2S)-2-((甲氧基羰基)胺基)環戊基)-2-(1H-吡唑-1-基)乙基)哌啶-1-基)甲基)氮雜環丁烷-1-甲酸三級丁酯(D5) (62 mg，0.106 mmol)於DCM (2 mL)及TFA (1 mL)中之溶液2h。接著在減壓下濃縮反應混合物，得到呈棕色油狀物之D6 (50 mg，TFA鹽，粗產物)，其直接用於下一步驟。LC-MS: 484 (M+1)+ 。 實例5Stir 3-((4-((S)-1-(3-fluorophenyl)-1-((1R,2S)-2-((methoxycarbonyl)amino)cyclopentyl at 25°C )-2-(1H-pyrazol-1-yl)ethyl)piperidin-1-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (D5) (62 mg, 0.106 mmol) Solution in DCM (2 mL) and TFA (1 mL) for 2 h. The reaction mixture was then concentrated under reduced pressure to give D6 (50 mg, TFA salt, crude) as a brown oil, which was used directly in the next step. LC-MS: 484 (M+1) + . Example 5
製備((1S,2R)-2-((S)-1-(3-氟苯基)-2-(1H-咪唑-1-基)-1-(1-((1-(4-((2-乙烯基吡啶-4-基)磺醯基)苯基)氮雜環丁烷-3-基)甲基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯(化合物15)
步驟A：2-溴-4-((4-氟苯基)硫基)吡啶Step A: 2-Bromo-4-((4-fluorophenyl)sulfanyl)pyridine
在N2 氛圍下，於80℃攪拌2-溴-4-氟吡啶(0.47 mL，4.5 mmol，1.0當量)、4-氟苯硫醇(0.6 g，4.5 mmol，1.0當量)及K2 CO3 (1.3 g，9 mmol，2.0當量)於1,4-二㗁烷(10 mL)中之混合物隔夜。接著用水(15 mL)淬滅反應物且用EtOAc (15 mL×2)萃取。將有機層用鹽水(15 mL)洗滌，經Na2 SO4 乾燥，過濾且在減壓下濃縮。藉由矽膠急驟管柱層析純化殘餘物，得到呈白色固體之2-溴-4-((4-氟苯基)磺醯基)吡啶(653 mg，產率50%)。LC-MS: 284 (M+1)+ 。2-Bromo-4-fluoropyridine (0.47 mL, 4.5 mmol, 1.0 equiv), 4 -fluorobenzenethiol (0.6 g, 4.5 mmol, 1.0 equiv) and K2CO3 were stirred at 80 °C under N2 atmosphere (1.3 g, 9 mmol, 2.0 equiv) in 1,4-dioxane (10 mL) overnight. The reaction was then quenched with water (15 mL) and extracted with EtOAc (15 mL x 2). The organic layer was washed with brine (15 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give 2-bromo-4-((4-fluorophenyl)sulfonyl)pyridine (653 mg, 50% yield) as a white solid. LC-MS: 284 (M+1) + .
步驟B：2-溴-4-((4-氟苯基)磺醯基)吡啶Step B: 2-Bromo-4-((4-fluorophenyl)sulfonyl)pyridine
在室溫下攪拌2-溴-4-((4-氟苯基)硫基)吡啶(653 mg，2.3 mmol，1.0當量)、過硫酸氫鉀(4.2 g，6.9 mmol，3.0當量)於丙酮(5 mL)及水(8 mL)中之混合物隔夜。接著用水(15 mL)淬滅反應物且用EtOAc (15 mL×2)萃取。將有機層用鹽水(15 mL)洗滌，經Na2 SO4 乾燥，過濾且在減壓下濃縮。藉由矽膠急驟管柱層析純化殘餘物，得到呈白色固體之2-溴-4-((4-氟苯基)磺醯基)吡啶(398 mg，產率55%)。LC-MS: 316 (M+1)+ 。Stir 2-bromo-4-((4-fluorophenyl)sulfanyl)pyridine (653 mg, 2.3 mmol, 1.0 equiv), potassium hydrogen persulfate (4.2 g, 6.9 mmol, 3.0 equiv) in acetone at room temperature (5 mL) and water (8 mL) overnight. The reaction was then quenched with water (15 mL) and extracted with EtOAc (15 mL x 2). The organic layer was washed with brine (15 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give 2-bromo-4-((4-fluorophenyl)sulfonyl)pyridine (398 mg, 55% yield) as a white solid. LC-MS: 316(M+1) + .
步驟C：4-((4-氟苯基)磺醯基)-2-乙烯基吡啶Step C: 4-((4-Fluorophenyl)sulfonyl)-2-vinylpyridine
在N2 氛圍下，於90℃攪拌2-溴-4-((4-氟苯基)磺醯基)吡啶(1.0當量，348 mg，1.1 mmol)、4,4,5,5-四甲基-2-乙烯基-1,3,2-二氧雜硼戊烷(339 mg，2.2 mmol，2.0當量)、Pd(dppf)Cl2 (80 mg，0.1 mmol，0.1當量)、Na2 CO3 (233 mg，2.2 mmol，2.0當量)於1,4-二㗁烷(10 mL)及H2 O (1 mL)中之混合物隔夜。接著用水(15 mL)淬滅反應物且用EtOAc (15 mL×2)萃取。將有機層用鹽水(15 mL)洗滌，經Na2 SO4 乾燥，過濾且在減壓下濃縮。藉由矽膠急驟管柱層析純化殘餘物，得到呈白色固體之4-((4-氟苯基)磺醯基)-2-乙烯基吡啶(229 mg，產率75%)。LC-MS: 264 (M+1)+ 。 2 -Bromo-4-((4-fluorophenyl)sulfonyl)pyridine (1.0 equiv, 348 mg, 1.1 mmol), 4,4,5,5-tetramethyl were stirred at 90 °C under N atmosphere yl-2-vinyl-1,3,2-dioxaborolane (339 mg, 2.2 mmol, 2.0 equiv), Pd(dppf)Cl 2 (80 mg, 0.1 mmol, 0.1 equiv), Na 2 CO A mixture of 3 (233 mg, 2.2 mmol, 2.0 equiv) in 1,4-dioxane (10 mL) and H2O (1 mL) overnight. The reaction was then quenched with water (15 mL) and extracted with EtOAc (15 mL x 2). The organic layer was washed with brine (15 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give 4-((4-fluorophenyl)sulfonyl)-2-vinylpyridine (229 mg, 75% yield) as a white solid. LC-MS: 264 (M+1) + .
步驟D：((1S,2R)-2-((S)-1-(3-氟苯基)-2-(1H-咪唑-1-基)-1-(1-((1-(4-((2-乙烯基吡啶-4-基)磺醯基)苯基)氮雜環丁烷-3-基)甲基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯(化合物15)Step D: ((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)-1-(1-((1-(4 -((2-Vinylpyridin-4-yl)sulfonyl)phenyl)azetidin-3-yl)methyl)piperidin-4-yl)ethyl)cyclopentyl)carbamic acid Methyl ester (compound 15)
在80℃下攪拌((1S,2R)-2-((S)-1-(1-(氮雜環丁烷-3-基甲基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯(100 mg，0.207 mmol，1.0當量)、4-((4-氟苯基)磺醯基)-2-乙烯基吡啶(82 mg，0.31 mmol，1.5當量)及K2 CO3 (57 mg，0.414 mmol，2.0當量)於MeCN (15 mL)中之混合物16h。接著用水(10 mL)淬滅反應物且用EtOAc (10 mL×2)萃取。將有機層用鹽水(10 mL)洗滌，經Na2 SO4 乾燥，過濾且在減壓下濃縮。藉由矽膠急驟管柱層析及RP-製備型HPLC純化殘餘物，得到呈白色固體之化合物15 (58 mg，產率37%)。LC-MS: 727 (M+1)+ .1 H NMR (400 MHz, MeOD-d4 ) δ 8.66 (d, 1H), 7.83 (d, 1H), 7.74 - 7.70 (m, 2H), 7.67 (s, 1H), 7.62 (dd, 1H), 7.43 (s, 2H), 7.37 (d, 1H), 7.06 (d, 2H), 6.93 - 6.82 (m, 2H), 6.45 (d, 2H), 6.30 (dd, 1H), 5.60 (dd, 1H), 4.81 (d, 1H), 4.61 (d, 1H), 4.10 - 4.00 (m, 3H), 3.63 - 3.55 (m, 2H), 3.51 (s, 3H), 2.96 - 2.86 (m, 2H), 2.80 (d, 1H), 2.67 - 2.60 (m, 1H), 2.60 - 2.50 (m, 2H), 2.12 (t, 1H), 2.01 - 1.88 (m, 3H), 1.86 - 1.77 (m, 1H), 1.59 - 1.46 (m, 2H), 1.42 - 1.33 (m, 2H), 1.22 - 1.09 (m, 3H), 0.83 - 0.71 (m, 1H)。 實例6Stir ((1S,2R)-2-((S)-1-(1-(azetidin-3-ylmethyl)piperidin-4-yl)-1-(3- Fluorophenyl)-2-(1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate (100 mg, 0.207 mmol, 1.0 equiv), 4-((4-fluorophenyl)sulfonic acid A mixture of acyl)-2-vinylpyridine (82 mg, 0.31 mmol, 1.5 equiv) and K2CO3 ( 57 mg , 0.414 mmol, 2.0 equiv) in MeCN (15 mL) for 16 h. The reaction was then quenched with water (10 mL) and extracted with EtOAc (10 mL x 2). The organic layer was washed with brine (10 mL), dried over Na2SO4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography and RP-preparative HPLC to give compound 15 (58 mg, 37% yield) as a white solid. LC-MS: 727 (M+1) + .1H NMR (400 MHz, MeOD- d4 ) δ 8.66 (d, 1H), 7.83 (d, 1H), 7.74 - 7.70 (m, 2H), 7.67 ( s, 1H), 7.62 (dd, 1H), 7.43 (s, 2H), 7.37 (d, 1H), 7.06 (d, 2H), 6.93 - 6.82 (m, 2H), 6.45 (d, 2H), 6.30 (dd, 1H), 5.60 (dd, 1H), 4.81 (d, 1H), 4.61 (d, 1H), 4.10 - 4.00 (m, 3H), 3.63 - 3.55 (m, 2H), 3.51 (s, 3H ), 2.96 - 2.86 (m, 2H), 2.80 (d, 1H), 2.67 - 2.60 (m, 1H), 2.60 - 2.50 (m, 2H), 2.12 (t, 1H), 2.01 - 1.88 (m, 3H) ), 1.86 - 1.77 (m, 1H), 1.59 - 1.46 (m, 2H), 1.42 - 1.33 (m, 2H), 1.22 - 1.09 (m, 3H), 0.83 - 0.71 (m, 1H). Example 6
製備((1S,2R)-2-((S)-1-(3-氟苯基)-1-(1-((1-(2-(6-((4-氟苯基)磺醯基)嘧啶-4-基)乙基)氮雜環丁烷-3-基)甲基)哌啶-4-基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯(化合物88)及((1S,2R)-2-((S)-1-(3-氟苯基)-2-(1H-咪唑-1-基)-1-(1-((1-(6-乙烯基嘧啶-4-基)氮雜環丁烷-3-基)甲基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯(化合物26)
步驟A：4-氯-6-((4-氟苯基)硫基)嘧啶Step A: 4-Chloro-6-((4-fluorophenyl)thio)pyrimidine
向4,6-二氯嘧啶(1.8 mL，20.1 mmol，1.2當量)及4-氟苯硫醇(2.2 g，16.7 mmol，1.0當量)於丙酮(75 mL)中之溶液中添加1 N NaOH水溶液(50.3 mL，50.3 mmol，3.0當量)。在室溫下攪拌混合物2h。接著用水(20 mL)淬滅反應物且用EtOAc (20 mL×3)萃取。將有機層用鹽水(20 mL)洗滌，經Na2 SO4 乾燥，過濾且在減壓下濃縮。藉由矽膠急驟管柱層析純化殘餘物，得到呈白色固體之4-氯-6-((4-氟苯基)硫基)嘧啶。LC-MS: 241 (M+1)+ 。To a solution of 4,6-dichloropyrimidine (1.8 mL, 20.1 mmol, 1.2 equiv) and 4-fluorobenzenethiol (2.2 g, 16.7 mmol, 1.0 equiv) in acetone (75 mL) was added 1 N aqueous NaOH (50.3 mL, 50.3 mmol, 3.0 equiv). The mixture was stirred at room temperature for 2 h. The reaction was then quenched with water (20 mL) and extracted with EtOAc (20 mL x 3). The organic layer was washed with brine (20 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give 4-chloro-6-((4-fluorophenyl)thio)pyrimidine as a white solid. LC-MS: 241 (M+1) + .
步驟B：4-氯-6-((4-氟苯基)磺醯基)嘧啶Step B: 4-Chloro-6-((4-fluorophenyl)sulfonyl)pyrimidine
向4-氯-6-((4-氟苯基)硫基)嘧啶(1.4 g，5.8 mmol，1.0當量)於水(20 mL)及丙酮(20 mL)中之溶液中分批添加過硫酸氫鉀(7.7 g，17.5 mmol，3.0當量)。在室溫下攪拌混合物隔夜。接著用水(20 mL)淬滅反應物且用EtOAc (20 mL×3)萃取。將有機層用鹽水(20 mL)洗滌，經Na2 SO4 乾燥，過濾且在減壓下濃縮。藉由矽膠急驟管柱層析來純化殘餘物，得到呈白色固體之4-氯-6-((4-氟苯基)磺醯基)嘧啶(1.2 g，產率76%)。LC-MS: 273 (M+H)+ 。To a solution of 4-chloro-6-((4-fluorophenyl)thio)pyrimidine (1.4 g, 5.8 mmol, 1.0 equiv) in water (20 mL) and acetone (20 mL) was added persulfuric acid portionwise Potassium hydrogen (7.7 g, 17.5 mmol, 3.0 equiv). The mixture was stirred at room temperature overnight. The reaction was then quenched with water (20 mL) and extracted with EtOAc (20 mL x 3). The organic layer was washed with brine (20 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give 4-chloro-6-((4-fluorophenyl)sulfonyl)pyrimidine (1.2 g, 76% yield) as a white solid. LC-MS: 273 (M+H) + .
步驟C：4-((4-氟苯基)磺醯基)-6-乙烯基嘧啶Step C: 4-((4-Fluorophenyl)sulfonyl)-6-vinylpyrimidine
在N2 氛圍下，於100℃攪拌4-氯-6-((4-氟苯基)磺醯基)嘧啶(400 mg，1.5 mmol，1.0當量)、三丁基(乙烯基)錫烷(0.6 mL，2.2 mmol，1.5當量)及Pd(PPh3 )4 (169 mg，0.15 mmol，0.1當量)於甲苯(10 mL)中之混合物隔夜。用1 M KF水溶液(20 mL)淬滅反應混合物且用EtOAc (20 mL×3)萃取。將有機層用鹽水(20 mL)洗滌，經Na2 SO4 乾燥，過濾且在減壓下濃縮。藉由矽膠急驟管柱層析純化殘餘物，得到呈黃色油狀物之4-((4-氟苯基)磺醯基)-6-乙烯基嘧啶(200 mg，產率52%)。LC-MS: 265 (M+H)+ 。4 - Chloro-6-((4-fluorophenyl)sulfonyl)pyrimidine (400 mg, 1.5 mmol, 1.0 equiv), tributyl(vinyl)stannane ( 0.6 mL, 2.2 mmol, 1.5 equiv) and Pd( PPh3 ) 4 (169 mg, 0.15 mmol, 0.1 equiv) in toluene (10 mL) overnight. The reaction mixture was quenched with 1 M aqueous KF (20 mL) and extracted with EtOAc (20 mL x 3). The organic layer was washed with brine (20 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give 4-((4-fluorophenyl)sulfonyl)-6-vinylpyrimidine (200 mg, 52% yield) as a yellow oil. LC-MS: 265 (M+H) + .
步驟D：((1S,2R)-2-((S)-1-(3-氟苯基)-1-(1-((1-(2-(6-((4-氟苯基)磺醯基)嘧啶-4-基)乙基)氮雜環丁烷-3-基)甲基)哌啶-4-基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯(化合物88)及((1S,2R)-2-((S)-1-(3-氟苯基)-2-(1H-咪唑-1-基)-1-(1-((1-(6-乙烯基嘧啶-4-基)氮雜環丁烷-3-基)甲基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯(化合物26)Step D: ((1S,2R)-2-((S)-1-(3-fluorophenyl)-1-(1-((1-(2-(6-((4-fluorophenyl)) Sulfonyl)pyrimidin-4-yl)ethyl)azetidine-3-yl)methyl)piperidin-4-yl)-2-(1H-imidazol-1-yl)ethyl)cyclopentane Methyl)carbamate (Compound 88) and ((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)-1- Methyl (1-((1-(6-vinylpyrimidin-4-yl)azetidin-3-yl)methyl)piperidin-4-yl)ethyl)cyclopentyl)carbamate (Compound 26)
在80℃下攪拌((1S,2R)-2-((S)-1-(1-(氮雜環丁烷-3-基甲基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯(242 mg，0.5 mmol，1.0當量)、4-乙烯基-6-(4-氟苯磺醯基)嘧啶(164 mg，0.6 mmol，1.2當量)、K2 CO3 (428 mg，3.1 mmol，6.2當量)於MeCN (10 mL)中之混合物隔夜。接著用水(10 mL)淬滅反應物，用DCM (10 mL×3)萃取。將有機層用鹽水(10 mL)洗滌，經Na2 SO4 乾燥，過濾且在減壓下濃縮。藉由矽膠急驟管柱層析及RP-製備型HPLC純化殘餘物，得到呈白色固體之化合物88 (13.5 mg，產率4%)，LC-MS: 748 (M+H)+ 及呈白色固體之化合物26 (10.1 mg，產率3%)，LC-MS: 588 (M+H)+ 。化合物881 H NMR (400 MHz, MeOD-d4 ) δ 9.16 (s, 1H), 8.18 (s, 1H), 8.13 - 8.09 (m, 2H), 7.75 - 7.73 (m, 1H), 7.49 - 7.333 (m, 5H), 7.12 - 7.07 (m, 2H), 6.97 (s, 1H), 4.83 (d, 1H), 4.63 (d, 1H), 4.07 - 4.01 (m, 1H), 4.00 - 3.91 (m, 2H), 3.63 - 3.50 (m, 5H), 3.45 - 3.35 (m, 2H), 3.19 - 3.12 (m, 3H), 3.04 - 2.85 (m, 4H), 2.63 - 2.58 (m, 1H), 2.43 - 2.27 (m, 3H), 2.03 (d, 1H), 1.88 - 1.82 (m, 1H), 1.69 - 1.62 (m, 1H), 1.54 - 1.46 (m, 1H), 1.40 - 1.32 (m, 2H), 1.28 - 1.12 (m, 3H), 0.90 - 0.75 (m, 1H)。化合物261 H NMR (400 MHz, MeOD-d4 ) δ 8.35 (s, 1H), 7.76 (s, 1H), 7.49 - 7.39 (m, 3H), 7.13 - 7.11 (m, 2H), 6.99 (s, 1H), 6.62 (dd, 1H), 6.39 - 6.26 (m, 2H), 5.59 (d, 1H), 4.84 (d, 1H), 4.66 (d, 1H), 4.27 - 4.23 (m, 2H), 4.11 - 4.04 (m, 1H), 3.85 - 3.76 (m, 3H), 3.54 (s, 3H), 3.29 - 3.06 (m, 5H), 2.69 - 2.54 (m, 3H), 2.41 - 2.35 (m, 1H), 2.08 (d, 1H), 1.87 - 1.83 (m, 1H), 1.75 (d, 1H), 1.51 (d, 1H), 1.40 - 1.38 (m, 2H), 1.23 - 1.15 (m, 2H), 1.01 - 0.87 (m, 1H)。 實例7Stir ((1S,2R)-2-((S)-1-(1-(azetidin-3-ylmethyl)piperidin-4-yl)-1-(3- Fluorophenyl)-2-(1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate (242 mg, 0.5 mmol, 1.0 equiv), 4-vinyl-6-(4-fluoro) A mixture of phenylsulfonyl)pyrimidine (164 mg, 0.6 mmol, 1.2 equiv), K2CO3 (428 mg, 3.1 mmol, 6.2 equiv) in MeCN (10 mL) overnight. The reaction was then quenched with water (10 mL) and extracted with DCM (10 mL x 3). The organic layer was washed with brine (10 mL), dried over Na2SO4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography and RP-preparative HPLC to give compound 88 (13.5 mg, 4% yield) as a white solid, LC-MS: 748 (M+H) + and a white solid Compound 26 (10.1 mg, 3% yield), LC-MS: 588 (M+H) + . Compound 88 1 H NMR (400 MHz, MeOD- d 4 ) δ 9.16 (s, 1H), 8.18 (s, 1H), 8.13 - 8.09 (m, 2H), 7.75 - 7.73 (m, 1H), 7.49 - 7.333 (m, 5H), 7.12 - 7.07 (m, 2H), 6.97 (s, 1H), 4.83 (d, 1H), 4.63 (d, 1H), 4.07 - 4.01 (m, 1H), 4.00 - 3.91 (m , 2H), 3.63 - 3.50 (m, 5H), 3.45 - 3.35 (m, 2H), 3.19 - 3.12 (m, 3H), 3.04 - 2.85 (m, 4H), 2.63 - 2.58 (m, 1H), 2.43 - 2.27 (m, 3H), 2.03 (d, 1H), 1.88 - 1.82 (m, 1H), 1.69 - 1.62 (m, 1H), 1.54 - 1.46 (m, 1H), 1.40 - 1.32 (m, 2H) , 1.28 - 1.12 (m, 3H), 0.90 - 0.75 (m, 1H). Compound 26 1 H NMR (400 MHz, MeOD- d 4 ) δ 8.35 (s, 1H), 7.76 (s, 1H), 7.49 - 7.39 (m, 3H), 7.13 - 7.11 (m, 2H), 6.99 (s , 1H), 6.62 (dd, 1H), 6.39 - 6.26 (m, 2H), 5.59 (d, 1H), 4.84 (d, 1H), 4.66 (d, 1H), 4.27 - 4.23 (m, 2H), 4.11 - 4.04 (m, 1H), 3.85 - 3.76 (m, 3H), 3.54 (s, 3H), 3.29 - 3.06 (m, 5H), 2.69 - 2.54 (m, 3H), 2.41 - 2.35 (m, 1H) ), 2.08 (d, 1H), 1.87 - 1.83 (m, 1H), 1.75 (d, 1H), 1.51 (d, 1H), 1.40 - 1.38 (m, 2H), 1.23 - 1.15 (m, 2H), 1.01 - 0.87 (m, 1H). Example 7
製備((1S,2R)-2-((S)-1-(1-((1-(4-((3-(((E)-4-(二甲基胺基)-4-側氧基丁-2-烯-1-基)胺甲醯基)苯基)磺醯基)-2-氟苯基)氮雜環丁烷-3-基)甲基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯(化合物61)
步驟A：3-((3,4-二氟苯基)硫基)苯甲酸苯甲酯Step A: Benzyl 3-((3,4-difluorophenyl)thio)benzoate
在N2 氛圍下，於100℃攪拌3-碘苯甲酸苯甲酯(4 g，11.8 mmol，1.0當量；Ref: Bioorganic and Medicinal Chemistry; 第20卷；nb. 16; (2012); 第5027-5032頁)、Xant-Phos (1.4 g，2.4 mmol，0.2當量)、3,4-二氟苯硫醇(2.6 g，17.7 mmol，1.5當量)、Pd2 (dba)3 (1.1 g，1.2 mmol，0.1當量)及DIPEA (5.8 mL，35mmol，3.0當量)於二㗁烷(50 mL)中之混合物隔夜。接著用水(150 mL)淬滅反應物且用EtOAc (150 mL×2)萃取。將有機層用鹽水(150 mL)洗滌，經Na2 SO4 乾燥，過濾且在減壓下濃縮。藉由矽膠急驟管柱層析來純化殘餘物，得到呈無色油狀物之產物3-((3,4-二氟苯基)硫基)苯甲酸苯甲酯(4 g，產率95%)。Benzyl 3-iodobenzoate (4 g, 11.8 mmol, 1.0 equiv; Ref: Bioorganic and Medicinal Chemistry; Vol. 20; nb. 16; (2012); 5027- 5032 pages), Xant-Phos (1.4 g, 2.4 mmol, 0.2 equiv), 3,4-difluorobenzenethiol (2.6 g, 17.7 mmol, 1.5 equiv), Pd 2 (dba) 3 (1.1 g, 1.2 mmol) , 0.1 equiv) and DIPEA (5.8 mL, 35 mmol, 3.0 equiv) in dioxane (50 mL) overnight. The reaction was then quenched with water (150 mL) and extracted with EtOAc (150 mL x 2). The organic layer was washed with brine (150 mL), dried over Na2SO4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give the product benzyl 3-((3,4-difluorophenyl)thio)benzoate (4 g, 95% yield) as a colorless oil ).
步驟B：3-((3,4-二氟苯基)磺醯基)苯甲酸苯甲酯Step B: Benzyl 3-((3,4-difluorophenyl)sulfonyl)benzoate
在0℃下向3-((3,4-二氟苯基)硫基)苯甲酸苯甲酯(2 g，5.6 mmol，1.0當量)於DCM (30 mL)中之溶液中添加m-CPBA (4.5 g，22.4 mmol，4.0當量)。在室溫下攪拌混合物隔夜。用3 mL Na2 S2 O3 飽和水溶液淬滅混合物，用NaHCO3 飽和水溶液(50 mL)稀釋，且用DCM (50 mL×2)萃取。經合併之有機層用鹽水(30 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮，藉由矽膠急驟管柱層析純化殘餘物，得到呈白色油狀物之3-((3,4-二氟苯基)磺醯基)苯甲酸苯甲酯(2.1 g，產率96%)。To a solution of benzyl 3-((3,4-difluorophenyl)thio)benzoate (2 g, 5.6 mmol, 1.0 equiv) in DCM (30 mL) at 0 °C was added m-CPBA (4.5 g, 22.4 mmol, 4.0 equiv). The mixture was stirred at room temperature overnight. The mixture was quenched with 3 mL of saturated aqueous Na2S2O3, diluted with saturated aqueous NaHCO3 ( 50 mL), and extracted with DCM (50 mL x 2 ). The combined organic layers were washed with brine (30 mL), dried over Na 2 SO 4 and concentrated under reduced pressure, the residue was purified by silica gel flash column chromatography to give 3-((3 as a white oil ,4-Difluorophenyl)sulfonyl)benzyl benzoate (2.1 g, 96% yield).
步驟C：3-((3,4-二氟苯基)磺醯基)苯甲酸Step C: 3-((3,4-Difluorophenyl)sulfonyl)benzoic acid
在H2 氛圍(1 atm)下將3-((3,4-二氟苯基)磺醯基)苯甲酸苯甲酯(1.53 g，3.9 mmol)及15% Pd-C (0.15 g，10% w/wt)之混合物於THF (10 mL)中氫化2h。接著將混合物過濾且在減壓下濃縮。藉由矽膠急驟管柱層析來純化殘餘物，得到呈白色固體之3-((3,4-二氟苯基)磺醯基)苯甲酸(900 mg，產率77%)。LC-MS: 297 (M-H)- 。Benzyl 3-((3,4-difluorophenyl)sulfonyl)benzoate (1.53 g, 3.9 mmol) and 15% Pd-C (0.15 g, 10 mmol) were combined under H atmosphere ( 1 atm) % w/wt) was hydrogenated in THF (10 mL) for 2 h. The mixture was then filtered and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give 3-((3,4-difluorophenyl)sulfonyl)benzoic acid (900 mg, 77% yield) as a white solid. LC-MS: 297(MH) - .
步驟D：(E)-3-((3,4-二氟苯基)磺醯基)-N-(4-(二甲基胺基)-4-側氧基丁-2-烯-1-基)苯甲醯胺Step D: (E)-3-((3,4-Difluorophenyl)sulfonyl)-N-(4-(dimethylamino)-4-oxybut-2-ene-1 -yl)benzamide
在室溫下攪拌3-((3,4-二氟苯基)磺醯基)苯甲酸(226 mg，0.758 mmol，1.0當量)、DIPEA (0.5 mL，3 mmol，4.0當量)、HATU (575 mg，1.5 mmol，2.0當量)及(E)-4-胺基-N,N-二甲基丁-2-烯醯胺(145 mg，1.1 mmol，1.5當量)於THF (15 mL)中之混合物2h。用H2 O (10 mL)稀釋反應混合物且用EtOAc (10 mL×3)萃取。經合併之有機層用鹽水(10 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮。藉由矽膠急驟管柱層析來純化殘餘物，得到呈白色固體之(E)-3-((3,4-二氟苯基)磺醯基)-N-(4-(二甲基胺基)-4-側氧基丁-2-烯-1-基)苯甲醯胺(252 mg，產率81%)。LC-MS: 409 (M+H)+ 。Stir at room temperature 3-((3,4-difluorophenyl)sulfonyl)benzoic acid (226 mg, 0.758 mmol, 1.0 equiv), DIPEA (0.5 mL, 3 mmol, 4.0 equiv), HATU (575 mg, 1.5 mmol, 2.0 equiv) and (E)-4-amino-N,N-dimethylbut-2-enamide (145 mg, 1.1 mmol, 1.5 equiv) in THF (15 mL) mixture for 2h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give (E)-3-((3,4-difluorophenyl)sulfonyl)-N-(4-(dimethylamine) as a white solid (252 mg, 81% yield). LC-MS: 409 (M+H) + .
步驟E：((1S,2R)-2-((S)-1-(1-((1-(4-((3-(((E)-4-(二甲基胺基)-4-側氧基丁-2-烯-1-基)胺甲醯基)苯基)磺醯基)-2-氟苯基)氮雜環丁烷-3-基)甲基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯(化合物61)Step E: ((1S,2R)-2-((S)-1-(1-((1-(4-((3-(((E)-4-(dimethylamino)-4 -Pendant oxybut-2-en-1-yl)aminocarbinyl)phenyl)sulfonyl)-2-fluorophenyl)azetidin-3-yl)methyl)piperidine-4 -yl)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate (Compound 61)
在80℃下攪拌(E)-3-((3,4-二氟苯基)磺醯基)-N-(4-(二甲基胺基)-4-側氧基丁-2-烯-1-基)苯甲醯胺(74 mg，0.18 mmol，1.1當量)、((1S,2R)-2-((S)-1-(1-(氮雜環丁烷-3-基甲基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯(200 mg，0.16 mmol，1.0當量)、K2 CO3 (136 mg，1.0 mmol，6.0當量)於MeCN (10 mL)中之混合物隔夜。用H2 O (10 mL)稀釋反應混合物且用DCM (10 mL×3)萃取。經合併之有機層用鹽水(10 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮。藉由製備型TLC及RP-製備型HPLC純化殘餘物，得到呈白色固體之化合物61 (21.8 mg，產率15%)。LC MS: 872 (M+H)+ .1 H NMR (400 MHz, MeOD-d4 ) δ 8.35 (s, 1H), 8.06 (dd, 2H), 7.76 (s, 1H), 7.68 - 7.64 (m, 1H), 7.60 (dd, 1H), 7.54 (dd, 1H), 7.48 - 7.44 (m, 2H), 7.40 (d, 1H), 7.13 - 7.08 (m, 2H), 6.98 (s, 1H), 6.75 (dt, 1H), 6.58 - 6.53 (m, 2H), 4.84 (d, 1H), 4.65 (d, 1H), 4.29 - 4.21 (m, 2H), 4.18 (dd, 2H), 4.10 - 4.04 (m, 1H), 3.85 - 3.78 (m, 2H), 3.53 (s, 3H), 3.35 (d, 1H), 3.23 (d, 1H), 3.17 - 3.13 (m, 2H), 3.14 - 3.07 (m, 4H), 2.98 (s, 3H), 2.77 - 2.55 (m, 3H), 2.44 - 2.37 (m, 1H), 2.10 (d, 1H), 1.92 - 1.86 (m, 1H), 1.75 (d, 1H), 1.55 - 1.46 (m, 1H), 1.42 - 1.36 (m, 2H), 1.32 - 1.10 (m, 3H), 1.02 - 0.85 (m, 1H)。 實例8Stir (E)-3-((3,4-difluorophenyl)sulfonyl)-N-(4-(dimethylamino)-4-oxybut-2-ene at 80°C -1-yl)benzamide (74 mg, 0.18 mmol, 1.1 equiv), ((1S,2R)-2-((S)-1-(1-(azetidin-3-ylmethyl) yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate (200 mg, 0.16 mmol, 1.0 equiv), K2CO3 ( 136 mg , 1.0 mmol, 6.0 equiv) in MeCN (10 mL) overnight. The reaction mixture was diluted with H2O (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by preparative TLC and RP-preparative HPLC to give compound 61 (21.8 mg, 15% yield) as a white solid. LC MS: 872 (M+H) + .1H NMR (400 MHz, MeOD- d4 ) δ 8.35 (s, 1H), 8.06 (dd, 2H), 7.76 (s, 1H), 7.68 - 7.64 (m , 1H), 7.60 (dd, 1H), 7.54 (dd, 1H), 7.48 - 7.44 (m, 2H), 7.40 (d, 1H), 7.13 - 7.08 (m, 2H), 6.98 (s, 1H), 6.75 (dt, 1H), 6.58 - 6.53 (m, 2H), 4.84 (d, 1H), 4.65 (d, 1H), 4.29 - 4.21 (m, 2H), 4.18 (dd, 2H), 4.10 - 4.04 ( m, 1H), 3.85 - 3.78 (m, 2H), 3.53 (s, 3H), 3.35 (d, 1H), 3.23 (d, 1H), 3.17 - 3.13 (m, 2H), 3.14 - 3.07 (m, 4H), 2.98 (s, 3H), 2.77 - 2.55 (m, 3H), 2.44 - 2.37 (m, 1H), 2.10 (d, 1H), 1.92 - 1.86 (m, 1H), 1.75 (d, 1H) , 1.55 - 1.46 (m, 1H), 1.42 - 1.36 (m, 2H), 1.32 - 1.10 (m, 3H), 1.02 - 0.85 (m, 1H). Example 8
製備((1S,2R)-2-((S)-1-(1-((1-(2-氟-4-((3-(((E)-3-(甲基磺醯基)烯丙基)胺甲醯基)雙環[1.1.1]戊烷-1-基)磺醯基)苯基)氮雜環丁烷-3-基)甲基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯(化合物68)
步驟A：3-((3,4-二氟苯基)硫基)雙環[1.1.1]戊烷-1-甲酸甲酯Step A: Methyl 3-((3,4-difluorophenyl)thio)bicyclo[1.1.1]pentane-1-carboxylate
在室溫下攪拌1,2-雙(3,4-二氟苯基)二硫烷(2.2 g，7.6 mmol，1.0當量；Ref: Phosphorus, Sulfur and Silicon and the Related Elements, 2009, 第184卷, 8, 第2058-2065頁)、3-(甲氧基羰基)雙環[1.1.1]戊烷-1-羧酸(1.29 g，7.6 mmol，1.0當量)、AgNO3 (643 mg，3.8 mmol，0.5當量)及K2 (S2 O8 ) (6.15 g，22.7 mmol，3.0當量)於H2 O/MeCN (3 mL，1/1)中之混合物24h。用H2 O (30 mL)稀釋反應混合物且用DCM (30 mL×3)萃取。經合併之有機層用鹽水(30 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮。藉由矽膠急驟管柱層析純化殘餘物，得到呈白色固體之3-((3,4-二氟苯基)硫基)雙環[1.1.1]戊烷-1-甲酸甲酯(1.3 g，產率63%)。1,2-Bis(3,4-difluorophenyl)disulfane (2.2 g, 7.6 mmol, 1.0 equiv.; Ref: Phosphorus, Sulfur and Silicon and the Related Elements, 2009, vol. 184) was stirred at room temperature , 8, pp. 2058-2065), 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid (1.29 g, 7.6 mmol, 1.0 equiv), AgNO 3 (643 mg, 3.8 mmol) , 0.5 equiv) and K2(S2O8) (6.15 g , 22.7 mmol, 3.0 equiv ) in H2O /MeCN ( 3 mL, 1/1) for 24h. The reaction mixture was diluted with H2O (30 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give methyl 3-((3,4-difluorophenyl)thio)bicyclo[1.1.1]pentane-1-carboxylate (1.3 g) as a white solid , the yield is 63%).
步驟B：3-((3,4-二氟苯基)磺醯基)雙環[1.1.1]戊烷-1-甲酸甲酯Step B: Methyl 3-((3,4-difluorophenyl)sulfonyl)bicyclo[1.1.1]pentane-1-carboxylate
在室溫下攪拌3-((3,4-二氟苯基)硫基)雙環[1.1.1]戊烷-1-甲酸甲酯(200 mg，0.437 mmol，1.0當量)及m-CPBA (225 mg，1.3 mmol，3.0當量)於10 mL DCM中之混合物16h。用NaHCO3 飽和水溶液(10 mL)稀釋反應混合物且用EtOAc (10 mL×3)萃取。經合併之有機層用鹽水(10 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮。藉由矽膠急驟管柱層析來純化殘餘物，得到呈白色固體之3-((3,4-二氟苯基)磺醯基)雙環[1.1.1]戊烷-1-甲酸甲酯(209 mg，產率98%)。Methyl 3-((3,4-difluorophenyl)thio)bicyclo[1.1.1]pentane-1-carboxylate (200 mg, 0.437 mmol, 1.0 equiv) and m-CPBA ( 225 mg, 1.3 mmol, 3.0 equiv) in 10 mL DCM for 16 h. The reaction mixture was diluted with saturated aqueous NaHCO3 (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give methyl 3-((3,4-difluorophenyl)sulfonyl)bicyclo[1.1.1]pentane-1-carboxylate ( 209 mg, 98% yield).
步驟C：3-((3-氟-4-(3-((4-((S)-1-(3-氟苯基)-2-(1H-咪唑-1-基)-1-((1R,2S)-2-((甲氧基羰基)胺基)環戊基)乙基)哌啶-1-基)甲基)氮雜環丁烷-1-基)苯基)磺醯基)雙環[1.1.1]戊烷-1-甲酸甲酯Step C: 3-((3-Fluoro-4-(3-((4-((S)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)-1-( (1R,2S)-2-((methoxycarbonyl)amino)cyclopentyl)ethyl)piperidin-1-yl)methyl)azetidin-1-yl)phenyl)sulfonyl base) bicyclo[1.1.1]pentane-1-carboxylic acid methyl ester
在80℃下攪拌((1S,2R)-2-((S)-1-(1-(氮雜環丁烷-3-基甲基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯(239 mg，0.496 mmol，1.0當量)、K2 CO3 (205 mg，1.488 mmol，3.0當量)及3-((3,4-二氟苯基)磺醯基)雙環[1.1.1]戊烷-1-甲酸甲酯(120 mg，0.397 mmol，0.9當量)於CH3 CN (20 mL)中之混合物16h。用水(10 mL)稀釋反應混合物且用DCM (10 mL×3)萃取。經合併之有機層用鹽水(10 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮。藉由矽膠急驟管柱層析來純化殘餘物，得到呈白色固體之3-((3-氟-4-(3-((4-((S)-1-(3-氟苯基)-2-(1H-咪唑-1-基)-1-((1R,2S)-2-((甲氧基羰基)胺基)環戊基)乙基)哌啶-1-基)甲基)氮雜環丁烷-1-基)苯基)磺醯基)雙環[1.1.1]戊烷-1-甲酸甲酯(101 mg，產率27%)。LC-MS: 766 (M+H)+ 。Stir ((1S,2R)-2-((S)-1-(1-(azetidin-3-ylmethyl)piperidin-4-yl)-1-(3- Fluorophenyl)-2-(1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate (239 mg, 0.496 mmol, 1.0 equiv), K2CO3 ( 205 mg , 1.488 mmol, 3.0 equiv) and methyl 3-((3,4-difluorophenyl)sulfonyl)bicyclo[1.1.1]pentane-1-carboxylate (120 mg, 0.397 mmol, 0.9 equiv) in CH 3 CN ( 20 mL) for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give 3-((3-fluoro-4-(3-((4-((S)-1-(3-fluorophenyl)-) as a white solid 2-(1H-imidazol-1-yl)-1-((1R,2S)-2-((methoxycarbonyl)amino)cyclopentyl)ethyl)piperidin-1-yl)methyl) Azetidine-1-yl)phenyl)sulfonyl)bicyclo[1.1.1]pentane-1-carboxylic acid methyl ester (101 mg, 27% yield). LC-MS: 766 (M+H) + .
步驟D：3-((3-氟-4-(3-((4-((S)-1-(3-氟苯基)-2-(1H-咪唑-1-基)-1-((1R,2S)-2-((甲氧基羰基)胺基)環戊基)乙基)哌啶-1-基)甲基)氮雜環丁烷-1-基)苯基)磺醯基)雙環[1.1.1]戊烷-1-羧酸Step D: 3-((3-Fluoro-4-(3-((4-((S)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)-1-( (1R,2S)-2-((methoxycarbonyl)amino)cyclopentyl)ethyl)piperidin-1-yl)methyl)azetidin-1-yl)phenyl)sulfonyl base) bicyclo[1.1.1]pentane-1-carboxylic acid
在室溫下攪拌3-((3-氟-4-(3-((4-((S)-1-(3-氟苯基)-2-(1H-咪唑-1-基)-1-((1R,2S)-2-((甲氧基羰基)胺基)環戊基)乙基)哌啶-1-基)甲基)氮雜環丁烷-1-基)苯基)磺醯基)雙環[1.1.1]戊烷-1-甲酸甲酯(101 mg，0.132 mmol，1.0當量)及LiOH (4 mg，0.198 mmol，1.5當量)於THF/H2 O (6 mL，5/1)中之混合物3h。在減壓下濃縮反應混合物，得到呈白色固體之3-((3-氟-4-(3-((4-((S)-1-(3-氟苯基)-2-(1H-咪唑-1-基)-1-((1R,2S)-2-((甲氧基羰基)胺基)環戊基)乙基)哌啶-1-基)甲基)氮雜環丁烷-1-基)苯基)磺醯基)雙環[1.1.1]戊烷-1-羧酸(99 mg，產率100%)且直接用於下一步驟。LC-MS: 752 (M+H)+ 。3-((3-Fluoro-4-(3-((4-((S)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)-1 was stirred at room temperature -((1R,2S)-2-((methoxycarbonyl)amino)cyclopentyl)ethyl)piperidin-1-yl)methyl)azetidin-1-yl)phenyl) Sulfonyl)bicyclo[1.1.1]pentane-1-carboxylic acid methyl ester (101 mg, 0.132 mmol, 1.0 equiv) and LiOH (4 mg, 0.198 mmol, 1.5 equiv) in THF/H 2 O (6 mL, The mixture in 5/1) was 3h. The reaction mixture was concentrated under reduced pressure to give 3-((3-fluoro-4-(3-((4-((S)-1-(3-fluorophenyl)-2-(1H-) as a white solid. Imidazol-1-yl)-1-((1R,2S)-2-((methoxycarbonyl)amino)cyclopentyl)ethyl)piperidin-1-yl)methyl)azetidine -1-yl)phenyl)sulfonyl)bicyclo[1.1.1]pentane-1-carboxylic acid (99 mg, 100% yield) and used directly in the next step. LC-MS: 752 (M+H) + .
步驟E：((1S,2R)-2-((S)-1-(1-((1-(2-氟-4-((3-(((E)-3-(甲基磺醯基)烯丙基)胺甲醯基)雙環[1.1.1]戊烷-1-基)磺醯基)苯基)氮雜環丁烷-3-基)甲基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯(化合物68)Step E: ((1S,2R)-2-((S)-1-(1-((1-(2-Fluoro-4-((3-((((E)-3-(methylsulfonyl) yl)allyl)carbamoyl)bicyclo[1.1.1]pentan-1-yl)sulfonyl)phenyl)azetidin-3-yl)methyl)piperidin-4-yl )-methyl 1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate (Compound 68)
在室溫下攪拌3-((3-氟-4-(3-((4-((S)-1-(3-氟苯基)-2-(1H-咪唑-1-基)-1-((1R,2S)-2-((甲氧基羰基)胺基)環戊基)乙基)哌啶-1-基)甲基)氮雜環丁烷-1-基)苯基)磺醯基)雙環[1.1.1]戊烷-1-羧酸(60 mg，0.08 mmol，1.0當量)、(E)-3-(甲基磺醯基)丙-2-烯-1-胺(24 mg，0.16 mmol，2.0當量)、DIPEA (31 mg，0.239 mmol，3.0當量)及HATU (24 mg，0.16 mmol，2.0當量)於THF (10 mL)中之混合物3小時。用水(10 mL)稀釋反應混合物且用DCM (10 mL×3)萃取。經合併之有機層用鹽水(10 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮。藉由製備型TLC及RP-製備型HPLC純化殘餘物，得到呈白色固體之化合物68。LC-MS: 869 (M+H)+ .1 H NMR (400 MHz, MeOD-d4 ) δ 7.68 (s, 1H), 7.46 - 7.44 (m, 3H), 7.40 - 7.31 (m, 2H), 7.10 - 7.05 (m, 2H), 6.94 (s, 1H), 6.89 - 6.70 (m, 1H), 6.65 - 6.53 (m, 2H), 4.83 (s, 1H), 4.64 (d, 1H), 4.30 - 4.20 (m, 3H), 4.16 (d, 1H), 4.05 (dd, 1H), 3.77 (t, 2H), 3.53 (s, 3H), 3.08 (s, 2H), 3.00 - 2.91 (m, 6H), 2.85 (d, 1H), 2.65 (d, 3H), 2.37 (s, 3H), 2.29 (s, 3H), 2.21 - 2.15 (m, 1H), 2.08 - 2.11 (m, 2H), 1.95 (d, 1H),1.88 - 1.80 (m, 1H), 1.63 - 1.56 (m, 1H), 1.53 - 1.47 (m, 1H), 1.37 - 1.34 (m, 4H), 1.20 - 1.10 (m, 1H), 0.85 - 0.72 (m, 1H)。 實例93-((3-Fluoro-4-(3-((4-((S)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)-1 was stirred at room temperature -((1R,2S)-2-((methoxycarbonyl)amino)cyclopentyl)ethyl)piperidin-1-yl)methyl)azetidin-1-yl)phenyl) Sulfonyl)bicyclo[1.1.1]pentane-1-carboxylic acid (60 mg, 0.08 mmol, 1.0 equiv), (E)-3-(methylsulfonyl)prop-2-en-1-amine (24 mg, 0.16 mmol, 2.0 equiv), DIPEA (31 mg, 0.239 mmol, 3.0 equiv) and HATU (24 mg, 0.16 mmol, 2.0 equiv) in THF (10 mL) for 3 hours. The reaction mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by preparative TLC and RP-preparative HPLC to give compound 68 as a white solid. LC-MS: 869 (M+H) + . 1 H NMR (400 MHz, MeOD- d 4 ) δ 7.68 (s, 1H), 7.46 - 7.44 (m, 3H), 7.40 - 7.31 (m, 2H), 7.10 - 7.05 (m, 2H), 6.94 (s, 1H), 6.89 - 6.70 (m, 1H), 6.65 - 6.53 (m, 2H), 4.83 (s, 1H), 4.64 (d, 1H), 4.30 - 4.20 (m, 3H), 4.16 (d, 1H), 4.05 (dd, 1H), 3.77 (t, 2H), 3.53 (s, 3H), 3.08 (s, 2H), 3.00 - 2.91 (m, 6H) , 2.85 (d, 1H), 2.65 (d, 3H), 2.37 (s, 3H), 2.29 (s, 3H), 2.21 - 2.15 (m, 1H), 2.08 - 2.11 (m, 2H), 1.95 (d , 1H),1.88 - 1.80 (m, 1H), 1.63 - 1.56 (m, 1H), 1.53 - 1.47 (m, 1H), 1.37 - 1.34 (m, 4H), 1.20 - 1.10 (m, 1H), 0.85 - 0.72 (m, 1H). Example 9
製備((1S,2R)-2-((S)-1-(1-((1-(2-氟-4-((2-((E)-3-(甲基磺醯基)烯丙基)-3-側氧基異吲哚啉-5-基)磺醯基)苯基)氮雜環丁烷-3-基)甲基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯(化合物69)
步驟A：6-溴-2-(2,2-二甲氧基乙基)異吲哚啉-1-酮Step A: 6-Bromo-2-(2,2-dimethoxyethyl)isoindolin-1-one
在100℃下攪拌6-溴異吲哚啉-1-酮(1.5 g，7.1 mmol，1.0當量)、2-氯-1,1-二甲氧基乙烷(1.3 mL，10.6 mmol，1.5當量)及Cs2 CO3 (4.6 g，14.1 mmol，2.0當量)於DMF (30 mL)中之混合物隔夜。用H2 O (100 mL)稀釋反應混合物且用DCM (100 mL×3)萃取。經合併之有機層用鹽水(100 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮。藉由矽膠急驟管柱層析來純化殘餘物，得到呈黃色固體之6-溴-2-(2,2-二甲氧基乙基)異吲哚啉-1-酮(1.75 g，產率82%)。LC-MS: 300, 302 (M+H)+ 。Stir 6-bromoisoindolin-1-one (1.5 g, 7.1 mmol, 1.0 equiv), 2-chloro-1,1-dimethoxyethane (1.3 mL, 10.6 mmol, 1.5 equiv) at 100 °C ) and Cs2CO3 ( 4.6 g, 14.1 mmol, 2.0 equiv) in DMF (30 mL) overnight. The reaction mixture was diluted with H2O (100 mL) and extracted with DCM (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give 6-bromo-2-(2,2-dimethoxyethyl)isoindolin-1-one (1.75 g, yield) as a yellow solid 82%). LC-MS: 300, 302 (M+H) + .
步驟B：6-((3,4-二氟苯基)硫基)-2-(2,2-二甲氧基乙基)異吲哚啉-1-酮Step B: 6-((3,4-Difluorophenyl)thio)-2-(2,2-dimethoxyethyl)isoindolin-1-one
在N2 氛圍下，於100℃攪拌6-溴-2-(2,2-二甲氧基乙基)異吲哚啉-1-酮(1.6 g，5.3 mmol，1.0當量)、3,4-二氟苯-1-硫醇(0.9 mL，8 mmol，1.5當量)、Pd2 (dba)3 (0.49 g，0.5 mmol，0.1當量)、XantPhos (0.62 g，1.1mmol，0.2當量)及DIPEA (2.6 mL，16 mmol，3.0當量)於二㗁烷(30 mL)中之混合物隔夜。將反應混合物冷卻至室溫，用H2 O (20 mL)稀釋且用DCM (20 mL×3)萃取。經合併之有機層用鹽水(20 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮。藉由矽膠急驟管柱層析來純化殘餘物，得到呈黃色固體之6-((3,4-二氟苯基)硫基)-2-(2,2-二甲氧基乙基)異吲哚啉-1-酮(1.8 g，產率92%)。LC-MS: 366 (M+H)+ 。Under N atmosphere, 6-bromo- 2- (2,2-dimethoxyethyl)isoindolin-1-one (1.6 g, 5.3 mmol, 1.0 equiv), 3,4 was stirred at 100 °C - Difluorobenzene-1-thiol (0.9 mL, 8 mmol, 1.5 equiv), Pd2(dba )3 ( 0.49 g, 0.5 mmol, 0.1 equiv), XantPhos (0.62 g, 1.1 mmol, 0.2 equiv) and DIPEA (2.6 mL, 16 mmol, 3.0 equiv) in dioxane (30 mL) overnight. The reaction mixture was cooled to room temperature, diluted with H2O (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give 6-((3,4-difluorophenyl)sulfanyl)-2-(2,2-dimethoxyethyl)iso as a yellow solid Indolin-1-one (1.8 g, 92% yield). LC-MS: 366 (M+H) + .
步驟C：6-((3,4-二氟苯基)磺醯基)-2-(2,2-二甲氧基乙基)異吲哚啉-1-酮Step C: 6-((3,4-Difluorophenyl)sulfonyl)-2-(2,2-dimethoxyethyl)isoindolin-1-one
在0℃下向6-((3,4-二氟苯基)硫基)-2-(2,2-二甲氧基乙基)異吲哚啉-1-酮(1.75 g，4.8 mmol，1.0當量)於DCM (40 mL)中之溶液中添加m-CPBA (2.5 g，14.4 mmol，43%，3.0當量)。在室溫下攪拌混合物隔夜。用3 mL Na2 SO3 飽和水溶液淬滅反應混合物，用NaHCO3 飽和水溶液(40 mL)稀釋，且用DCM (40 mL×2)萃取。經合併之有機層用鹽水(20 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮。藉由矽膠急驟管柱層析來純化殘餘物，得到呈白色固體之6-((3,4-二氟苯基)磺醯基)-2-(2,2-二甲氧基乙基)異吲哚啉-1-酮(825 mg，產率43%)。LC-MS: 398 (M+H)+ 。To 6-((3,4-difluorophenyl)sulfanyl)-2-(2,2-dimethoxyethyl)isoindolin-1-one (1.75 g, 4.8 mmol) at 0 °C , 1.0 equiv) in DCM (40 mL) was added m-CPBA (2.5 g, 14.4 mmol, 43%, 3.0 equiv). The mixture was stirred at room temperature overnight. The reaction mixture was quenched with 3 mL of saturated aqueous Na2SO3, diluted with saturated aqueous NaHCO3 ( 40 mL), and extracted with DCM (40 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give 6-((3,4-difluorophenyl)sulfonyl)-2-(2,2-dimethoxyethyl) as a white solid Isoindolin-1-one (825 mg, 43% yield). LC-MS: 398 (M+H) + .
步驟D：2-(6-((3,4-二氟苯基)磺醯基)-1-側氧基異吲哚啉-2-基)乙醛Step D: 2-(6-((3,4-Difluorophenyl)sulfonyl)-1-oxyisoindolin-2-yl)acetaldehyde
在室溫下攪拌6-((3,4-二氟苯基)磺醯基)-2-(2,2-二甲氧基乙基)異吲哚啉-1-酮(800 mg，2 mmol)於DCM (10 mL)及TFA (3 mL)中之混合物1h。接著用H2 O (20 mL)稀釋反應混合物且用DCM (20 mL×3)萃取。經合併之有機層用鹽水(20 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮。藉由矽膠急驟管柱層析來純化殘餘物，得到呈白色固體之2-(6-((3,4-二氟苯基)磺醯基)-1-側氧基異吲哚啉-2-基)乙醛(350 mg，產率49%)。LC-MS: 352 (M+H)+ 。6-((3,4-Difluorophenyl)sulfonyl)-2-(2,2-dimethoxyethyl)isoindolin-1-one (800 mg, 2 mmol) in DCM (10 mL) and TFA (3 mL) for 1 h. The reaction mixture was then diluted with H2O (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give 2-(6-((3,4-difluorophenyl)sulfonyl)-1-oxyisoindoline-2 as a white solid -yl)acetaldehyde (350 mg, 49% yield). LC-MS: 352 (M+H) + .
步驟E：(E)-6-((3,4-二氟苯基)磺醯基)-2-(3-(甲基磺醯基)烯丙基)異吲哚啉-1-酮Step E: (E)-6-((3,4-Difluorophenyl)sulfonyl)-2-(3-(methylsulfonyl)allyl)isoindolin-1-one
在N2 氛圍下，於0℃添加(甲烷磺醯基甲基)膦酸二乙酯(98 mg，0.4 mmol，1.0當量)於THF (4 mL)中之混合物中添加NaH (60%於油中，24 mg，0.6 mmol，1.5當量)。接著在室溫下攪拌混合物1h。在0℃下將2-(6-((3,4-二氟苯基)磺醯基)-1-側氧基異吲哚啉-2-基)乙醛(100 mg，0.29 mmol，0.7當量)於THF (1 mL)中之溶液添加至上述溶液中。在室溫下攪拌混合物1h。將混合物倒入10 mL NH4 Cl飽和水溶液中且用EtOAc (10 mL×2)萃取。經合併之有機層用鹽水(20 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮。藉由矽膠急驟管柱層析純化殘餘物，得到呈黃色油狀物之(E)-6-((3,4-二氟苯基)磺醯基)-2-(3-(甲基磺醯基)烯丙基)異吲哚啉-1-酮(40 mg，產率33%)。LC-MS: 428 (M+H)+ 。Under N2 atmosphere, diethyl (methanesulfonylmethyl)phosphonate (98 mg, 0.4 mmol, 1.0 equiv) in THF (4 mL) was added at 0 °C to a mixture of NaH (60% in oil) , 24 mg, 0.6 mmol, 1.5 equiv). The mixture was then stirred at room temperature for 1 h. 2-(6-((3,4-Difluorophenyl)sulfonyl)-1-oxyisoindolin-2-yl)acetaldehyde (100 mg, 0.29 mmol, 0.7 equiv.) in THF (1 mL) was added to the above solution. The mixture was stirred at room temperature for 1 h. The mixture was poured into 10 mL of saturated aqueous NH4Cl and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give (E)-6-((3,4-difluorophenyl)sulfonyl)-2-(3-(methylsulfonyl) as a yellow oil Acyl)allyl)isoindolin-1-one (40 mg, 33% yield). LC-MS: 428 (M+H) + .
步驟F：((1S,2R)-2-((S)-1-(1-((1-(2-氟-4-((2-((E)-3-(甲基磺醯基)烯丙基)-3-側氧基異吲哚啉-5-基)磺醯基)苯基)氮雜環丁烷-3-基)甲基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯(化合物69)Step F: ((1S,2R)-2-((S)-1-(1-((1-(2-Fluoro-4-((2-((E)-3-(methylsulfonyl )allyl)-3-oxyisoindolin-5-yl)sulfonyl)phenyl)azetidin-3-yl)methyl)piperidin-4-yl)-1- Methyl (3-fluorophenyl)-2-(1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate (Compound 69)
在N2 氛圍下，於80℃攪拌((1S,2R)-2-((S)-1-(1-(氮雜環丁烷-3-基甲基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯(57 mg，0.1 mmol，1.0當量)、(E)-6-((3,4-二氟苯基)磺醯基)-2-(3-(甲基磺醯基)烯丙基)異吲哚啉-1-酮(50 mg，0.1 mmol，1.0當量)及K2 CO3 (97 mg，0.7 mmol，7.0當量)於DMSO (4 mL)中之混合物2h。接著，用H2 O (10 mL)稀釋混合物且用EtOAc (10 mL×3)萃取。經合併之有機層用鹽水(10 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮。藉由RP-製備型HPLC純化殘餘物，得到呈白色固體之化合物69 (9.7 mg，產率9%)。LC-MS: 897 (M+H)+ .1 H NMR (400 MHz, MeOD-d4 ) δ 8.26 (d, 1H), 8.17 (d, 1H), 7.79 (d, 1H), 7.70 (s, 1H), 7.60 (dd, 1H), 7.51 (dd, 1H), 7.47 - 7.36 (m, 5H), 7.12 - 7.04 (m, 2H), 6.94 (s, 1H), 6.55 - 6.50 (m, 1H), 5.49 - 5.04 (m, 1H), 4.82 - 4.77 (m, 3H), 4.62 (d, 1H), 4.25 - 4.18 (m, 2H), 4.05 (dd, 1H), 3.97 (d, 1H), 3.78 - 3.73 (m, 2H), 3.52 (s, 3H), 3.13 - 3.07 (m, 1H), 3.02 - 2.95 (m, 5H), 2.85 2.79 (m, 2H), 2.66 - 2.60 (m, 1H), 2.28 - 2.20 (m, 2H), 2.00 (d, 1H), 1.87 - 1.80 (m, 1H), 1.63 (d, 1H), 1.53 - 1.48 (m, 1H), 1.39 - 1.34 (m, 2H), 1.24 - 1.11 (m, 4H), 0.92 - 0.78 (m, 1H)。 實例10((1S,2R) -2 -((S)-1-(1-(azetidin-3-ylmethyl)piperidin-4-yl)- Methyl 1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate (57 mg, 0.1 mmol, 1.0 equiv), (E)-6- ((3,4-Difluorophenyl)sulfonyl)-2-(3-(methylsulfonyl)allyl)isoindolin-1-one (50 mg, 0.1 mmol, 1.0 equiv) and a mixture of K2CO3 (97 mg , 0.7 mmol, 7.0 equiv) in DMSO (4 mL) for 2 h. Then, the mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by RP-preparative HPLC to give compound 69 (9.7 mg, 9% yield) as a white solid. LC-MS: 897 (M+H) + . 1 H NMR (400 MHz, MeOD- d 4 ) δ 8.26 (d, 1H), 8.17 (d, 1H), 7.79 (d, 1H), 7.70 (s, 1H), 7.60 (dd, 1H), 7.51 (dd, 1H), 7.47 - 7.36 (m, 5H), 7.12 - 7.04 (m, 2H), 6.94 (s, 1H), 6.55 - 6.50 (m, 1H) , 5.49 - 5.04 (m, 1H), 4.82 - 4.77 (m, 3H), 4.62 (d, 1H), 4.25 - 4.18 (m, 2H), 4.05 (dd, 1H), 3.97 (d, 1H), 3.78 - 3.73 (m, 2H), 3.52 (s, 3H), 3.13 - 3.07 (m, 1H), 3.02 - 2.95 (m, 5H), 2.85 2.79 (m, 2H), 2.66 - 2.60 (m, 1H), 2.28 - 2.20 (m, 2H), 2.00 (d, 1H), 1.87 - 1.80 (m, 1H), 1.63 (d, 1H), 1.53 - 1.48 (m, 1H), 1.39 - 1.34 (m, 2H), 1.24 - 1.11 (m, 4H), 0.92 - 0.78 (m, 1H). Example 10
製備((1S,2R)-2-((S)-1-(1-((1-(3-((二甲基胺基)甲基)-2-氟-4-((1-((E)-3-(甲基磺醯基)烯丙基)-1H-吡唑-4-基)磺醯基)苯基)氮雜環丁烷-3-基)甲基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯(化合物76)
步驟A：2-((二甲基胺基)甲基)-3,4-二氟苯硫醇鉀Step A: Potassium 2-((dimethylamino)methyl)-3,4-difluorobenzenethiolate
在N2 氛圍下，於-60℃向3-((2-((二甲基胺基)甲基)-3,4-二氟苯基)硫基)丙酸甲酯(800 mg，2.765 mmol，1.0當量)於THF (5 mL)中之攪拌溶液中添加t-BuOK (465 mg，4.15 mmol，1.5當量)於1 mL THF中之溶液。在此溫度下攪拌反應混合物1h。接著使反應混合物升溫至室溫，直接用於下一步驟。LC-MS: 202 (M-1)- 。Under N atmosphere, methyl 3-(( 2 -((dimethylamino)methyl)-3,4-difluorophenyl)thio)propanoate (800 mg, 2.765 mmol, 1.0 equiv) in THF (5 mL) was added a solution of t-BuOK (465 mg, 4.15 mmol, 1.5 equiv) in 1 mL THF. The reaction mixture was stirred at this temperature for 1 h. The reaction mixture was then warmed to room temperature and used directly in the next step. LC-MS: 202 (M-1) - .
步驟B：1-(2,3-二氟-6-((1-(四氫-2H-哌喃-2-基)-1H-吡唑-4-基)硫基)苯基)-N,N-二甲基甲胺Step B: 1-(2,3-Difluoro-6-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)sulfanyl)phenyl)-N ,N-Dimethylmethylamine
向2-((二甲基胺基)甲基)-3,4-二氟苯硫醇鉀(600 mg，2.952 mmol，1.0當量)及4-碘-1-(四氫-2H-哌喃-2-基)-1H-吡唑(985.07 mg，3.542 mmol，1.1當量)於甲苯(12 mL)中之溶液中添加CS2 CO3 (2.8 g，8.6 mmol，3.0當量)、1,10-啡啉水合物(517.4 mg，2.87 mmol，1.0當量)，隨後添加CuI (545.2 mg，2.76 mmol，1.0當量)。接著在N2氛圍下於100℃攪拌反應混合物隔夜。用H2 O (10 mL)稀釋反應混合物且用EtOAc (10 mL×3)萃取。經合併之有機層用鹽水(10 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮。藉由矽膠急驟管柱層析純化殘餘物，得到呈黃色油狀物之1-(2,3-二氟-6-((1-(四氫-2H-哌喃-2-基)-1H-吡唑-4-基)硫基)苯基)-N,N-二甲基甲胺(950 mg，產率91%)。LC-MS: 354 (M+1)+ 。To 2-((dimethylamino)methyl)-3,4-difluorobenzenethiolate potassium (600 mg, 2.952 mmol, 1.0 equiv) and 4-iodo-1-(tetrahydro-2H-pyran -2-yl)-1H-pyrazole (985.07 mg, 3.542 mmol, 1.1 equiv) in toluene ( 12 mL) was added CS2CO3 (2.8 g, 8.6 mmol, 3.0 equiv), 1,10- phenanthroline hydrate (517.4 mg, 2.87 mmol, 1.0 equiv) followed by CuI (545.2 mg, 2.76 mmol, 1.0 equiv). The reaction mixture was then stirred at 100°C overnight under N2 atmosphere. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give 1-(2,3-difluoro-6-((1-(tetrahydro-2H-pyran-2-yl)-1H as a yellow oil -pyrazol-4-yl)thio)phenyl)-N,N-dimethylmethanamine (950 mg, 91% yield). LC-MS: 354 (M+1) + .
步驟C：1-(2,3-二氟-6-((1-(四氫-2H-哌喃-2-基)-1H-吡唑-4-基)磺醯基)苯基)-N,N-二甲基甲胺Step C: 1-(2,3-Difluoro-6-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)sulfonyl)phenyl)- N,N-Dimethylmethylamine
在室溫下向1-(2,3-二氟-6-((1-(四氫-2H-哌喃-2-基)-1H-吡唑-4-基)硫基)苯基)-N,N-二甲基甲胺(700 mg，1.981 mmol，1.0當量)於丙酮/H2 O (120 mL，2:1)中之攪拌溶液中添加過硫酸氫鉀(2.44 mg，3.961 mmol，2.0當量)。接著在室溫下攪拌反應溶液16h。在減壓下濃縮反應溶液且用DCM (30 mL×3)萃取。經合併之有機層用鹽水(30 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮。藉由矽膠急驟管柱層析來純化殘餘物，得到呈黃色油狀物之1-(2,3-二氟-6-((1-(四氫-2H-哌喃-2-基)-1H-吡唑-4-基)磺醯基)苯基)-N,N-二甲基甲胺(400 mg，產率52%)。LC-MS: 386 (M+1)+ 。To 1-(2,3-difluoro-6-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)sulfanyl)phenyl) at room temperature To a stirred solution of -N,N-dimethylmethylamine (700 mg, 1.981 mmol, 1.0 equiv) in acetone/ H2O (120 mL, 2:1) was added potassium hydrogen persulfate (2.44 mg, 3.961 mmol) , 2.0 equiv). The reaction solution was then stirred at room temperature for 16 h. The reaction solution was concentrated under reduced pressure and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give 1-(2,3-difluoro-6-((1-(tetrahydro-2H-pyran-2-yl)- as a yellow oil 1H-Pyrazol-4-yl)sulfonyl)phenyl)-N,N-dimethylmethanamine (400 mg, 52% yield). LC-MS: 386 (M+1) + .
步驟D：1-(6-((1H-吡唑-4-基)磺醯基)-2,3-二氟苯基)-N,N-二甲基甲胺Step D: 1-(6-((1H-pyrazol-4-yl)sulfonyl)-2,3-difluorophenyl)-N,N-dimethylmethanamine
向1-(2,3-二氟-6-((1-(四氫-2H-哌喃-2-基)-1H-吡唑-4-基)磺醯基)苯基)-N,N-二甲基甲胺(400 mg，1.038 mmol)於DCM (15 mL)中之溶液中添加TFA (3 ml)。在50℃下攪拌反應混合物隔夜。在減壓下濃縮反應溶液，不經任何進一步純化即得到呈白色油狀物之1-(6-((1H-吡唑-4-基)磺醯基)-2,3-二氟苯基)-N,N-二甲基甲胺(280 mg，產率90%)。LC-MS: 302 (M+1)+ 。To 1-(2,3-difluoro-6-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)sulfonyl)phenyl)-N, To a solution of N-dimethylmethylamine (400 mg, 1.038 mmol) in DCM (15 mL) was added TFA (3 ml). The reaction mixture was stirred at 50°C overnight. The reaction solution was concentrated under reduced pressure to give 1-(6-((1H-pyrazol-4-yl)sulfonyl)-2,3-difluorophenyl as a white oil without any further purification )-N,N-dimethylmethylamine (280 mg, 90% yield). LC-MS: 302(M+1) + .
步驟E：(E)-1-(2,3-二氟-6-((1-(3-(甲基磺醯基)烯丙基)-1H-吡唑-4-基)磺醯基)苯基)-N,N-二甲基甲胺Step E: (E)-1-(2,3-Difluoro-6-((1-(3-(methylsulfonyl)allyl)-1H-pyrazol-4-yl)sulfonyl )phenyl)-N,N-dimethylmethylamine
向1-(6-((1H-吡唑-4-基)磺醯基)-2,3-二氟苯基)-N,N-二甲基甲胺(200 mg，0.66 mmol，1.0當量)及K2 CO3 (183 mg，1.3 mmol，2.0當量)於MeCN (5 mL)中之溶液中添加(E)-3-溴-1-(甲基磺醯基)丙-1-烯(159 mg，0.8 mmol，1.2當量)。在室溫下攪拌混合物2h。用H2 O (10 mL)稀釋反應混合物且用EtOAc (10 mL×3)萃取。經合併之有機層用鹽水(10 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮。藉由矽膠急驟管柱層析來純化殘餘物，得到呈黃色固體之(E)-1-(2,3-二氟-6-((1-(3-(甲基磺醯基)烯丙基)-1H-吡唑-4-基)磺醯基)苯基)-N,N-二甲基甲胺(30 mg，產率11%)。LC-MS: 420 (M+1)+ 。To 1-(6-((1H-pyrazol-4-yl)sulfonyl)-2,3-difluorophenyl)-N,N-dimethylmethanamine (200 mg, 0.66 mmol, 1.0 equiv. ) and K 2 CO 3 (183 mg, 1.3 mmol, 2.0 equiv) in MeCN (5 mL) was added (E)-3-bromo-1-(methylsulfonyl)prop-1-ene ( 159 mg, 0.8 mmol, 1.2 equiv). The mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give (E)-1-(2,3-difluoro-6-((1-(3-(methylsulfonyl)allyl) as a yellow solid (30 mg, 11% yield). LC-MS: 420 (M+1) + .
步驟F：((1S,2R)-2-((S)-1-(1-((1-(3-((二甲基胺基)甲基)-2-氟-4-((1-((E)-3-(甲基磺醯基)烯丙基)-1H-吡唑-4-基)磺醯基)苯基)氮雜環丁烷-3-基)甲基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯(化合物76)Step F: ((1S,2R)-2-((S)-1-(1-((1-(3-((dimethylamino)methyl)-2-fluoro-4-((1 -((E)-3-(Methylsulfonyl)allyl)-1H-pyrazol-4-yl)sulfonyl)phenyl)azetidin-3-yl)methyl)piperidine Methyl pyridin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate (Compound 76)
向((1S,2R)-2-((S)-1-(1-(氮雜環丁烷-3-基甲基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯(35 mg，0.07 mmol，1.0當量)及(E)-1-(2,3-二氟-6-((1-(3-(甲基磺醯基)烯丙基)-1H-吡唑-4-基)磺醯基)苯基)-N,N-二甲基甲胺(30 mg，0.072 mmol，1.0當量)於MeCN (15 mL)中之溶液中添加K2 CO3 (58 mg，0.422 mmol，6.0當量)。接著在N2氛圍下於80℃攪拌反應混合物16h。藉由LCMS偵測兩種異構體(具有副產物之混合物)。用H2 O (10 mL)稀釋反應混合物且用DCM (10 mL×3)萃取。經合併之有機層用鹽水(10 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮。藉由矽膠急驟管柱層析及RP-製備型HPLC純化殘餘物，得到呈白色固體之化合物76 (3.04 mg，產率5%)。LC-MS: 897 (M+1)+ 。1 H NMR (400 MHz, MeOD-d4 ) δ 8.59 (s, 1H), 7.98 (s, 1H), 7.88 (d, 1H), 7.53 - 7.40 (m, 3H), 7.31 (d, 1H), 7.16 (t, 1H), 7.00 (s, 1H), 6.80 (s, 1H), 6.70 (t, 1H), 6.46 - 6.33 (m, 1H), 4.70 (d, 1H), 4.49 (s, 2H), 4.41 (d, 1H), 4.32 (s, 2H), 4.01 (d, 3H), 3.90 (s, 2H), 3.64 (s, 3H), 3.46 (d, 1H), 3.23 - 3.17 (m, 3H), 2.98 (s, 3H), 2.92 (s, 6H), 2.65 - 2.58 (m, 6H), 2.23 - 2.15 (m, 1H), 1.93 - 1.79 (m, 2H), 1.57 - 1.46 (m, 2H), 1.43 - 1.30 (m, 4H), 1.25 - 1.15 (m, 2H), 0.93 - 0.80 (m, 1H)。 實例11To ((1S,2R)-2-((S)-1-(1-(azetidin-3-ylmethyl)piperidin-4-yl)-1-(3-fluorophenyl) - Methyl 2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate (35 mg, 0.07 mmol, 1.0 equiv) and (E)-1-(2,3 -Difluoro-6-((1-(3-(methylsulfonyl)allyl)-1H-pyrazol-4-yl)sulfonyl)phenyl)-N,N-dimethylmethane To a solution of the amine (30 mg, 0.072 mmol, 1.0 equiv) in MeCN ( 15 mL) was added K2CO3 (58 mg , 0.422 mmol, 6.0 equiv). The reaction mixture was then stirred at 80 °C for 16 h under N2 atmosphere. Both isomers (mixture with by-products) were detected by LCMS. The reaction mixture was diluted with H2O (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography and RP-preparative HPLC to give compound 76 (3.04 mg, 5% yield) as a white solid. LC-MS: 897(M+1) + . 1 H NMR (400 MHz, MeOD- d 4 ) δ 8.59 (s, 1H), 7.98 (s, 1H), 7.88 (d, 1H), 7.53 - 7.40 (m, 3H), 7.31 (d, 1H), 7.16 (t, 1H), 7.00 (s, 1H), 6.80 (s, 1H), 6.70 (t, 1H), 6.46 - 6.33 (m, 1H), 4.70 (d, 1H), 4.49 (s, 2H) , 4.41 (d, 1H), 4.32 (s, 2H), 4.01 (d, 3H), 3.90 (s, 2H), 3.64 (s, 3H), 3.46 (d, 1H), 3.23 - 3.17 (m, 3H) ), 2.98 (s, 3H), 2.92 (s, 6H), 2.65 - 2.58 (m, 6H), 2.23 - 2.15 (m, 1H), 1.93 - 1.79 (m, 2H), 1.57 - 1.46 (m, 2H) ), 1.43 - 1.30 (m, 4H), 1.25 - 1.15 (m, 2H), 0.93 - 0.80 (m, 1H). Example 11
製備((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-((1-((1-(甲基磺醯基)哌啶-4-基)甲基)氮雜環丁烷-3-基)甲基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯(化合物86)
向((1S,2R)-2-((S)-1-(1-(氮雜環丁烷-3-基甲基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯(60 mg，0.121 mmol，1.0當量)於DMF (5 mL)中之溶液中添加甲烷磺酸(1-(甲基磺醯基)哌啶-4-基)甲酯(39 mg，0.15 mmol，1.2當量；Ref: Journal of Medicinal Chemistry; 第55卷; 5; (2012); 第2416-2426頁)、KI (40 mg，0.241 mmol 2.0當量)及K2 CO3 (100 mg，0.723 mmol，6.0當量)。接著在N2 氛圍下於80℃攪拌反應混合物24h。將反應溶液冷卻至室溫，用H2 O (10 mL)稀釋且用DCM (10 mL×3)萃取。經合併之有機層用鹽水(10 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮。藉由製備型TLC及RP-製備型HPLC純化殘餘物，得到呈白色固體之化合物86 (5 mg，產率6%)。LC-MS: 673 (M+H)+ 。1 H NMR (400 MHz, MeOD-d4 ) δ 7.48 - 7.42 (m, 2H), 7.35 (d, 1H), 7.09 (t, 1H), 6.69 (d, 1H), 6.65 (s, 1H), 4.57 (d, 1H), 4.33 (d, 1H), 4.00 (dd, 1H), 3.68 (d, 2H), 3.61 (s, 3H), 3.60 - 3.58 (m, 2H), 2.98 - 2.87 (m, 3H), 2.79 (s, 3H), 2.76 (s, 1H), 2.72 - 2.64 (m, 3H), 2.60 (dd, 1H), 2.52 - 2.43 (m, 4H), 2.43 (s, 3H), 2.20 (t, 1H), 2.01 - 1.92 (m, 3H), 1.87 (s, 1H), 1.78 (d, 2H), 1.63 (d, 1H), 1.51 (s, 2H), 1.36 - 1.17 (m, 7H), 0.72 (dd, 1H)。 實例12To ((1S,2R)-2-((S)-1-(1-(azetidin-3-ylmethyl)piperidin-4-yl)-1-(3-fluorophenyl) To a solution of methyl 2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate (60 mg, 0.121 mmol, 1.0 equiv) in DMF (5 mL) was added (1-(Methylsulfonyl)piperidin-4-yl)methyl methanesulfonate (39 mg, 0.15 mmol, 1.2 equiv; Ref: Journal of Medicinal Chemistry; Vol. 55; 5; (2012); Vol. 2416-2426), KI (40 mg, 0.241 mmol 2.0 equiv) and K2CO3 ( 100 mg, 0.723 mmol, 6.0 equiv). The reaction mixture was then stirred at 80 °C for 24 h under N2 atmosphere. The reaction solution was cooled to room temperature, diluted with H 2 O (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by preparative TLC and RP-preparative HPLC to give compound 86 (5 mg, 6% yield) as a white solid. LC-MS: 673 (M+H) + . 1 H NMR (400 MHz, MeOD- d 4 ) δ 7.48 - 7.42 (m, 2H), 7.35 (d, 1H), 7.09 (t, 1H), 6.69 (d, 1H), 6.65 (s, 1H), 4.57 (d, 1H), 4.33 (d, 1H), 4.00 (dd, 1H), 3.68 (d, 2H), 3.61 (s, 3H), 3.60 - 3.58 (m, 2H), 2.98 - 2.87 (m, 3H), 2.79 (s, 3H), 2.76 (s, 1H), 2.72 - 2.64 (m, 3H), 2.60 (dd, 1H), 2.52 - 2.43 (m, 4H), 2.43 (s, 3H), 2.20 (t, 1H), 2.01 - 1.92 (m, 3H), 1.87 (s, 1H), 1.78 (d, 2H), 1.63 (d, 1H), 1.51 (s, 2H), 1.36 - 1.17 (m, 7H) ), 0.72 (dd, 1H). Example 12
製備((1S,2R)-2-((S)-1-(3-氟苯基)-2-(1H-咪唑-1-基)-1-(1-((1-(7-((1-甲基-1H-吡唑-4-基)磺醯基)異吲哚啉-4-基)氮雜環丁烷-3-基)甲基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯(化合物92)
步驟A：2-(三級丁氧基羰基)-7-氟異吲哚啉-4-硫醇鉀Step A: Potassium 2-(tertiary butoxycarbonyl)-7-fluoroisoindoline-4-thiolate
在-40℃下向4-氟-7-((3-甲氧基-3-側氧基丙基)硫基)異吲哚啉-2-甲酸三級丁酯(400 mg，1.12 mmol，1.0當量)於無水THF (10 ml)中之混合物中添加t-BuOK (189 mg，1.68 mmol，1.5當量)。在此溫度下攪拌混合物1h。接著，將反應混合物直接用於下一步驟。To 4-fluoro-7-((3-methoxy-3-pendoxopropyl)thio)isoindoline-2-carboxylic acid tert-butyl ester (400 mg, 1.12 mmol, 1.0 equiv) in dry THF (10 ml) was added t-BuOK (189 mg, 1.68 mmol, 1.5 equiv). The mixture was stirred at this temperature for 1 h. Next, the reaction mixture was used directly in the next step.
步驟B：4-氟-7-((1-甲基-1H-吡唑-4-基)硫基)異吲哚啉-2-甲酸三級丁酯Step B: tert-butyl 4-fluoro-7-((1-methyl-1H-pyrazol-4-yl)sulfanyl)isoindoline-2-carboxylate
在N2 氛圍下，於80℃攪拌2-(三級丁氧基羰基)-7-氟異吲哚啉-4-硫醇鉀(500 mg，1.85 mmol，1.0當量)、Pd2 (dba)3 (169 mg，0.185 mmol，0.1當量)、Xant-Phos (214 mg，0.37 mmol，0.2當量)、DIPEA (0.93 mL，5.6 mmol，3.0當量)及4-碘-1-甲基-1H-吡唑(386 mg，1.85 mmol，1.0當量)於THF (10 ml)中之混合物隔夜。接著，用H2 O (30 mL)稀釋反應混合物且用EtOAc (30 mL×3)萃取。經合併之有機層用鹽水(30 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮。藉由矽膠急驟管柱層析純化殘餘物，得到呈無色油狀物之4-氟-7-((1-甲基-1H-吡唑-4-基)硫基)異吲哚啉-2-甲酸三級丁酯(50 mg，產率7%)。LC-MS: 372 (M+Na)+ 。Potassium 2-(tertiary butoxycarbonyl)-7-fluoroisoindoline-4-thiolate (500 mg, 1.85 mmol, 1.0 equiv), Pd 2 (dba) were stirred at 80 °C under N 2 atmosphere 3 (169 mg, 0.185 mmol, 0.1 equiv), Xant-Phos (214 mg, 0.37 mmol, 0.2 equiv), DIPEA (0.93 mL, 5.6 mmol, 3.0 equiv) and 4-iodo-1-methyl-1H-pyridine A mixture of azole (386 mg, 1.85 mmol, 1.0 equiv) in THF (10 ml) overnight. Then, the reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give 4-fluoro-7-((1-methyl-1H-pyrazol-4-yl)thio)isoindoline-2 as a colorless oil - tertiary butyl formate (50 mg, 7% yield). LC-MS: 372 (M+Na) + .
步驟C：4-氟-7-((1-甲基-1H-吡唑-4-基)磺醯基)異吲哚啉-2-甲酸三級丁酯Step C: 4-Fluoro-7-((1-methyl-1H-pyrazol-4-yl)sulfonyl)isoindoline-2-carboxylic acid tert-butyl ester
在0℃下向4-氟-7-((1-甲基-1H-吡唑-4-基)硫基)異吲哚啉-2-甲酸三級丁酯(50 mg，0.14 mmol，1.0當量)於丙酮(3 ml)及H2 O (3 ml)中之混合物中添加過硫酸氫鉀(175 mg，0.28 mmol，2.0當量)。接著在室溫下攪拌混合物隔夜。用H2 O (10 mL)稀釋反應混合物且用EtOAc (10 mL×3)萃取。經合併之有機層用鹽水(10 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮。藉由矽膠急驟管柱層析純化殘餘物，得到呈白色固體之4-氟-7-((1-甲基-1H-吡唑-4-基)磺醯基)異吲哚啉-2-甲酸三級丁酯(35 mg，產率64%)。LC MS: 404 (M+Na)+ 。To tert-butyl 4-fluoro-7-((1-methyl-1H-pyrazol-4-yl)sulfanyl)isoindoline-2-carboxylate (50 mg, 0.14 mmol, 1.0 equiv) to a mixture of acetone (3 ml) and H2O (3 ml) was added potassium hydrogen persulfate (175 mg, 0.28 mmol, 2.0 equiv). The mixture was then stirred at room temperature overnight. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give 4-fluoro-7-((1-methyl-1H-pyrazol-4-yl)sulfonyl)isoindoline-2- as a white solid Tertiary butyl formate (35 mg, 64% yield). LC MS: 404 (M+Na) + .
步驟D：4-(3-((4-((S)-1-(3-氟苯基)-2-(1H-咪唑-1-基)-1-((1R,2S)-2-((甲氧基羰基)胺基)環戊基)乙基)哌啶-1-基)甲基)氮雜環丁烷-1-基)-7-((1-甲基-1H-吡唑-4-基)磺醯基)異吲哚啉-2-甲酸三級丁酯Step D: 4-(3-((4-((S)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)-1-((1R,2S)-2- ((Methoxycarbonyl)amino)cyclopentyl)ethyl)piperidin-1-yl)methyl)azetidin-1-yl)-7-((1-methyl-1H-pyridine oxazol-4-yl)sulfonyl)isoindoline-2-carboxylic acid tertiary butyl ester
在80℃下攪拌4-氟-7-((1-甲基-1H-吡唑-4-基)磺醯基)異吲哚啉-2-甲酸三級丁酯(35 mg，0.092 mmol，1.0當量)、((1S,2R)-2-((S)-1-(1-(氮雜環丁烷-3-基甲基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯(45 mg，0.092 mmol，1.0當量)及K2 CO3 (76 mg，0.551 mmol，6.0當量)於MeCN (10 ml)中之混合物隔夜。接著在室溫下攪拌混合物隔夜。用H2 O (10 mL)稀釋反應混合物且用DCM (10 mL×3)萃取。經合併之有機層用鹽水(10 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮。藉由矽膠急驟管柱層析來純化殘餘物，得到呈白色固體之4-(3-((4-((S)-1-(3-氟苯基)-2-(1H-咪唑-1-基)-1-((1R,2S)-2-((甲氧基羰基)胺基)環戊基)乙基)哌啶-1-基)甲基)氮雜環丁烷-1-基)-7-((1-甲基-1H-吡唑-4-基)磺醯基)異吲哚啉-2-甲酸三級丁酯(30 mg，產率38%)。LC-MS: 845 (M+H)+ 。Stir at 80°C tert-butyl 4-fluoro-7-((1-methyl-1H-pyrazol-4-yl)sulfonyl)isoindoline-2-carboxylate (35 mg, 0.092 mmol, 1.0 equiv), ((1S,2R)-2-((S)-1-(1-(azetidin-3-ylmethyl)piperidin-4-yl)-1-(3-fluoro Methyl phenyl)-2-(1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate (45 mg, 0.092 mmol, 1.0 equiv) and K2CO3 ( 76 mg , 0.551 mmol, 6.0 equiv) in MeCN (10 ml) overnight. The mixture was then stirred at room temperature overnight. The reaction mixture was diluted with H2O (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give 4-(3-((4-((S)-1-(3-fluorophenyl)-2-(1H-imidazole-1 as a white solid) -yl)-1-((1R,2S)-2-((methoxycarbonyl)amino)cyclopentyl)ethyl)piperidin-1-yl)methyl)azetidine-1- yl)-7-((1-methyl-1H-pyrazol-4-yl)sulfonyl)isoindoline-2-carboxylic acid tert-butyl ester (30 mg, 38% yield). LC-MS: 845 (M+H) + .
步驟E：((1S,2R)-2-((S)-1-(3-氟苯基)-2-(1H-咪唑-1-基)-1-(1-((1-(7-((1-甲基-1H-吡唑-4-基)磺醯基)異吲哚啉-4-基)氮雜環丁烷-3-基)甲基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯(化合物92)Step E: ((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)-1-(1-((1-(7 -((1-Methyl-1H-pyrazol-4-yl)sulfonyl)isoindolin-4-yl)azetidin-3-yl)methyl)piperidin-4-yl) Ethyl)cyclopentyl)methylcarbamate (Compound 92)
在0℃下向4-(3-((4-((S)-1-(3-氟苯基)-2-(1H-咪唑-1-基)-1-((1R,2S)-2-((甲氧基羰基)胺基)環戊基)乙基)哌啶-1-基)甲基)氮雜環丁烷-1-基)-7-((1-甲基-1H-吡唑-4-基)磺醯基)異吲哚啉-2-甲酸三級丁酯(30 mg，0.036 mmol)於DCM (3 ml)中之混合物中添加TFA (1 ml)。在室溫下攪拌混合物3h。在減壓下濃縮反應混合物且藉由RP-製備型HPLC純化殘餘物，得到呈白色固體之化合物92 (6 mg，產率22%)。LC-MS: 745 (M+H)+ 。1 H NMR (400 MHz, MeOD-d4 ) δ 8.12 (s, 1H), 7.71 (s, 1H), 7.67 - 7.65 (m, 2H), 7.46 - 7.43 (m, 2H), 7.37 (d, 1H), 7.10 - 7.04 (m, 2H), 6.93 (s, 1H), 6.33 (d, 1H), 4.81 (d, 1H), 4.61 (d, 1H), 4.38 (s, 2H), 4.23 (s, 2H), 4.16 (t, 2H), 4.05 (dd, 1H), 3.88 (s, 3H), 3.73 - 3.67 (m, 2H), 3.52 (s, 3H), 2.96 - 2.80 (m, 3H), 2.67 - 2.56 (m, 3H), 2.20 - 2.12 (m, 1H), 2.05 - 1.93 (m, 3H), 1.86 - 1.79 (m, 1H), 1.59 - 1.53 (m, 1H), 1.52 - 1.47 (m, 1H), 1.43 - 1.33 (m, 3H), 1.22 - 1.10 (m, 2H), 0.85 - 0.73 (m, 1H)。 實例13To 4-(3-((4-((S)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)-1-((1R,2S)- 2-((Methoxycarbonyl)amino)cyclopentyl)ethyl)piperidin-1-yl)methyl)azetidin-1-yl)-7-((1-methyl-1H -Pyrazol-4-yl)sulfonyl)isoindoline-2-carboxylic acid tert-butyl ester (30 mg, 0.036 mmol) in DCM (3 ml) was added TFA (1 ml). The mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by RP-preparative HPLC to give compound 92 (6 mg, 22% yield) as a white solid. LC-MS: 745 (M+H) + . 1 H NMR (400 MHz, MeOD- d 4 ) δ 8.12 (s, 1H), 7.71 (s, 1H), 7.67 - 7.65 (m, 2H), 7.46 - 7.43 (m, 2H), 7.37 (d, 1H) ), 7.10 - 7.04 (m, 2H), 6.93 (s, 1H), 6.33 (d, 1H), 4.81 (d, 1H), 4.61 (d, 1H), 4.38 (s, 2H), 4.23 (s, 2H), 4.16 (t, 2H), 4.05 (dd, 1H), 3.88 (s, 3H), 3.73 - 3.67 (m, 2H), 3.52 (s, 3H), 2.96 - 2.80 (m, 3H), 2.67 - 2.56 (m, 3H), 2.20 - 2.12 (m, 1H), 2.05 - 1.93 (m, 3H), 1.86 - 1.79 (m, 1H), 1.59 - 1.53 (m, 1H), 1.52 - 1.47 (m, 1H), 1.43 - 1.33 (m, 3H), 1.22 - 1.10 (m, 2H), 0.85 - 0.73 (m, 1H). Example 13
製備((1S,2R)-2-((S)-氰基(1-((1-(5-氰基-1,2,3,4-四氫異喹啉-8-基)氮雜環丁烷-3-基)甲基)哌啶-4-基)(3-氟苯基)甲基)環戊基)胺基甲酸甲酯(化合物97)
步驟A：8-溴異喹啉-5-胺Step A: 8-Bromoisoquinolin-5-amine
在N2 氛圍下，於50℃攪拌8-溴-5-硝基異喹啉(1 g，3.9 mmol，1.0當量)、Fe (2.2 g，39.5 mmol，10.0當量)及NH4 Cl (1.06 g，19.7 mmol，5.0當量)於MeOH (10 mL)及H2 O (3 mL)中之混合物2h。使反應混合物冷卻至室溫，經由矽藻土墊過濾且用DCM (40 mL)洗滌。經合併之有機層用鹽水(40 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮，藉由矽膠急驟管柱層析純化殘餘物，得到呈黃色固體之8-溴異喹啉-5-胺(700 mg，產率79%)。LC-MS: 223, 225 (M+H)+ 。8-Bromo-5-nitroisoquinoline (1 g, 3.9 mmol, 1.0 equiv), Fe (2.2 g, 39.5 mmol, 10.0 equiv) and NH4Cl (1.06 g) were stirred at 50 °C under N2 atmosphere , 19.7 mmol, 5.0 equiv) in MeOH (10 mL) and H2O (3 mL) for 2 h. The reaction mixture was cooled to room temperature, filtered through a pad of celite and washed with DCM (40 mL). The combined organic layers were washed with brine (40 mL), dried over Na 2 SO 4 and concentrated under reduced pressure, the residue was purified by silica gel flash column chromatography to give 8-bromoisoquinoline- as a yellow solid 5-amine (700 mg, 79% yield). LC-MS: 223, 225 (M+H) + .
步驟B：8-溴異喹啉-5-甲腈Step B: 8-Bromoisoquinoline-5-carbonitrile
在N2 氛圍下，於50℃攪拌CuCN (843 mg，9.4 mmol，1.0當量)於DMSO (10 mL)中之混合物5 min。接著逐滴添加亞硝酸異戊酯(1.2 mL，9.4 mmol，1.0當量)。在50℃下攪拌混合物10 min之後，逐滴添加含8-溴異喹啉-5-胺(700 mg，3.1 mmol，0.3當量)之DMSO (3 mL)。在50℃下攪拌混合物30 min。在0℃下用50 mL 30%NH3 . H2 O水溶液淬滅反應混合物且用EtOAc (50 mL×3)萃取。經合併之有機層用鹽水(10 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮。藉由矽膠急驟管柱層析純化殘餘物，得到呈白色固體之8-溴異喹啉-5-甲腈(200 mg，產率27%)。LC-MS: 233, 235 (M+H)+ 。A mixture of CuCN (843 mg, 9.4 mmol, 1.0 equiv) in DMSO (10 mL) was stirred at 50 °C for 5 min under N2 atmosphere. Then isoamyl nitrite (1.2 mL, 9.4 mmol, 1.0 equiv) was added dropwise. After stirring the mixture for 10 min at 50 °C, 8-bromoisoquinolin-5-amine (700 mg, 3.1 mmol, 0.3 equiv) in DMSO (3 mL) was added dropwise. The mixture was stirred at 50 °C for 30 min. The reaction mixture was quenched with 50 mL of 30% aqueous NH3.H2O at 0 °C and extracted with EtOAc (50 mL x 3 ) . The combined organic layers were washed with brine (10 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give 8-bromoisoquinoline-5-carbonitrile (200 mg, 27% yield) as a white solid. LC-MS: 233, 235 (M+H) + .
步驟C：((1S,2R)-2-((S)-氰基(1-((1-(5-氰基異喹啉-8-基)氮雜環丁烷-3-基)甲基)哌啶-4-基)(3-氟苯基)甲基)環戊基)胺基甲酸甲酯Step C: ((1S,2R)-2-((S)-cyano(1-((1-(5-cyanoisoquinolin-8-yl)azetidin-3-yl)methan yl)piperidin-4-yl)(3-fluorophenyl)methyl)cyclopentyl)carbamate
在N2 氛圍下，於100℃攪拌((1S,2R)-2-((S)-(1-(氮雜環丁烷-3-基甲基)哌啶-4-基)(氰基)(3-氟苯基)甲基)環戊基)胺基甲酸甲酯(150 mg，0.35 mmol，1.0當量)、8-溴異喹啉-5-甲腈(81.6 mg，0.35 mmol，1.0當量)、X-Phos (33 mg，0.07 mmol，0.2當量)、Pd2 (dba)3 (32 mg，0.04 mmol，0.1當量)及Cs2 CO3 (358 mg，1.1 mmol，3.0當量)於甲苯(5 mL)中之混合物隔夜。接著，用H2 O (10 mL)稀釋混合物且用DCM (10 mL×3)萃取。經合併之有機層用鹽水(10 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮。藉由矽膠急驟管柱層析來純化殘餘物，得到呈黃色固體之((1S,2R)-2-((S)-氰基(1-((1-(5-氰基異喹啉-8-基)氮雜環丁烷-3-基)甲基)哌啶-4-基)(3-氟苯基)甲基)環戊基)胺基甲酸甲酯(70 mg，產率34%)。LC-MS: 581 (M+H)+ 。((1S,2R) -2 -((S)-(1-(azetidin-3-ylmethyl)piperidin-4-yl)(cyano) )(3-fluorophenyl)methyl)cyclopentyl)carbamate (150 mg, 0.35 mmol, 1.0 equiv), 8-bromoisoquinoline-5-carbonitrile (81.6 mg, 0.35 mmol, 1.0 equiv), X-Phos (33 mg, 0.07 mmol, 0.2 equiv), Pd2(dba )3 ( 32 mg, 0.04 mmol, 0.1 equiv) and Cs2CO3 ( 358 mg, 1.1 mmol, 3.0 equiv) in toluene (5 mL) of the mixture overnight. Then, the mixture was diluted with H2O (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give ((1S,2R)-2-((S)-cyano(1-((1-(5-cyanoisoquinoline-) as a yellow solid 8-yl)azetidin-3-yl)methyl)piperidin-4-yl)(3-fluorophenyl)methyl)cyclopentyl)carbamate (70 mg, yield 34 %). LC-MS: 581 (M+H) + .
步驟D：((1S,2R)-2-((S)-氰基(1-((1-(5-氰基-1,2,3,4-四氫異喹啉-8-基)氮雜環丁烷-3-基)甲基)哌啶-4-基)(3-氟苯基)甲基)環戊基)胺基甲酸甲酯(化合物97)Step D: ((1S,2R)-2-((S)-cyano(1-((1-(5-cyano-1,2,3,4-tetrahydroisoquinolin-8-yl) Azetidine-3-yl)methyl)piperidin-4-yl)(3-fluorophenyl)methyl)cyclopentyl)carbamate (Compound 97)
向((1S,2R)-2-((S)-氰基(1-((1-(5-氰基異喹啉-8-基)氮雜環丁烷-3-基)甲基)哌啶-4-基)(3-氟苯基)甲基)環戊基)胺基甲酸甲酯(70 mg，0.12 mmol，1.0當量)於AcOH (3 mL)中之混合物中添加NaBH4 (9 mg，0.24 mmol，2.0當量)。在室溫下攪拌混合物20 min。接著用NaHCO3 飽和水溶液(15 mL)稀釋混合物且用DCM (15 mL×3)萃取。合併之有機層用鹽水(15 mL)洗滌，經Na2S O4 乾燥且在減壓下濃縮，藉由RP-製備型HPLC純化殘餘物，得到呈白色固體之化合物97 (5 mg，產率7%)。LC-MS: 585 (M+H)+ 。1 H NMR (400 MHz, MeOD-d4 ) δ 7.42 - 7.32 (m, 3H), 7.24 (d, 1H), 7.12 - 7.07 (m, 1H), 6.34 (d, 1H), 4.13 - 4.06 (m, 2H), 3.88 - 3.83 (m, 1H), 3.77 (s, 2H), 3.63 (t, 2H), 3.44 (s, 3H), 3.07 (t, 2H), 2.94 - 2.80 (m, 6H), 2.59 (d, 2H), 2.05 - 1.93 (m, 4H), 1.83 - 1.77 (m, 1H), 1.70 - 1.44 (m, 6H), 1.37 - 1.28 (m, 2H)。 實例14To ((1S,2R)-2-((S)-cyano(1-((1-(5-cyanoisoquinolin-8-yl)azetidin-3-yl)methyl) Piperidin-4-yl)(3-fluorophenyl)methyl)cyclopentyl)carbamate (70 mg, 0.12 mmol, 1.0 equiv) in AcOH ( 3 mL) was added NaBH4 ( 9 mg, 0.24 mmol, 2.0 equiv). The mixture was stirred at room temperature for 20 min. The mixture was then diluted with saturated aqueous NaHCO 3 (15 mL) and extracted with DCM (15 mL x 3). The combined organic layers were washed with brine (15 mL), dried over Na 2 SO 4 and concentrated under reduced pressure, the residue was purified by RP-preparative HPLC to give compound 97 (5 mg, yield 7) as a white solid %). LC-MS: 585 (M+H) + . 1 H NMR (400 MHz, MeOD- d 4 ) δ 7.42 - 7.32 (m, 3H), 7.24 (d, 1H), 7.12 - 7.07 (m, 1H), 6.34 (d, 1H), 4.13 - 4.06 (m , 2H), 3.88 - 3.83 (m, 1H), 3.77 (s, 2H), 3.63 (t, 2H), 3.44 (s, 3H), 3.07 (t, 2H), 2.94 - 2.80 (m, 6H), 2.59 (d, 2H), 2.05 - 1.93 (m, 4H), 1.83 - 1.77 (m, 1H), 1.70 - 1.44 (m, 6H), 1.37 - 1.28 (m, 2H). Example 14
製備((1S,2R)-2-((S)-2-(氮雜環丁烷-1-基)-1-(3-氟苯基)-1-(1-((1-(7-(((R)-1-(((E)-3-(甲基磺醯基)烯丙基)胺甲醯基) 哌啶-3-基)磺醯基)異吲哚啉-4-基)氮雜環丁烷-3-基)甲基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯(化合物104)
步驟A：1-溴-2,3-雙(溴甲基)-4-氟苯Step A: 1-Bromo-2,3-bis(bromomethyl)-4-fluorobenzene
在90℃下攪拌1-溴-4-氟-2,3-二甲基苯(10 g，49.25 mmol，1.0當量)、BPO (1.19 g，4.93 mmol，0.1當量)及NBS (17.53 g，98.49 mmol，2.0當量)於CCl4 (300 ml)中之混合物16h。在減壓下濃縮反應混合物且藉由矽膠急驟管柱層析純化殘餘物，得到呈白色固體之1-溴-2,3-雙(溴甲基)-4-氟苯(14 g，產率78%)。1-Bromo-4-fluoro-2,3-dimethylbenzene (10 g, 49.25 mmol, 1.0 equiv), BPO (1.19 g, 4.93 mmol, 0.1 equiv) and NBS (17.53 g, 98.49 equiv) were stirred at 90 °C mmol, 2.0 equiv) in CCl4 (300 ml) for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel flash column chromatography to give 1-bromo-2,3-bis(bromomethyl)-4-fluorobenzene (14 g, yield) as a white solid 78%).
步驟B：4-溴-7-氟-2-(4-甲氧基苯甲基)異吲哚啉Step B: 4-Bromo-7-fluoro-2-(4-methoxybenzyl)isoindoline
在80℃下攪拌1-溴-2,3-雙(溴甲基)-4-氟苯(12 g，33.25 mmol，1.0當量)、(4-甲氧基苯基)甲胺(5.47 g，39.91 mmol，1.2當量)及K2 CO3 (18.38 g，133.02 mmol，4.0當量)於EtOH (800 ml)中之溶液2h。將反應混合物倒入NaHCO3 飽和水溶液(200 mL)中且用EtOAc (150 mL × 3)萃取。經合併之有機層用鹽水(10 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮。藉由矽膠急驟管柱層析來純化殘餘物，得到4-溴-7-氟-2-(4-甲氧基苯甲基)異吲哚啉(6 g，產率54%)。LC-MS: 336, 338 (M+H)+ 。1-Bromo-2,3-bis(bromomethyl)-4-fluorobenzene (12 g, 33.25 mmol, 1.0 equiv), (4-methoxyphenyl)methanamine (5.47 g, 1.0 equiv) were stirred at 80 °C. 39.91 mmol, 1.2 equiv) and K2CO3 (18.38 g, 133.02 mmol, 4.0 equiv) in EtOH (800 ml) for 2h. The reaction mixture was poured into saturated aqueous NaHCO 3 (200 mL) and extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give 4-bromo-7-fluoro-2-(4-methoxybenzyl)isoindoline (6 g, 54% yield). LC-MS: 336, 338 (M+H) + .
步驟C：4-溴-7-氟異吲哚啉Step C: 4-Bromo-7-fluoroisoindoline
在室溫下向4-溴-7-氟-2-(4-甲氧基苯甲基)異吲哚啉(6 g，17.85 mmol，1.0當量)於氯苯(60 ml)中之溶液中添加氯甲酸1-氯乙酯(7.65 g，53.54 mmol，3.0當量)。接著在110℃下加熱反應物3h。在減壓下濃縮反應混合物且用PE/EtOAc (20/1，30 ml)濕磨。過濾產物，得到4-溴-7-氟異吲哚啉HCl鹽(3.3 g，產率74%)。LC-MS: 216, 218 (M+H)+ 。To a solution of 4-bromo-7-fluoro-2-(4-methoxybenzyl)isoindoline (6 g, 17.85 mmol, 1.0 equiv) in chlorobenzene (60 ml) at room temperature 1-Chloroethyl chloroformate (7.65 g, 53.54 mmol, 3.0 equiv) was added. The reaction was then heated at 110 °C for 3 h. The reaction mixture was concentrated under reduced pressure and triturated with PE/EtOAc (20/1, 30 ml). The product was filtered to give 4-bromo-7-fluoroisoindoline HCl salt (3.3 g, 74% yield). LC-MS: 216, 218 (M+H) + .
步驟D：4-溴-7-氟異吲哚啉-2-甲酸三級丁酯Step D: 4-Bromo-7-fluoroisoindoline-2-carboxylic acid tertiary butyl ester
在0℃下向4-溴-7-氟異吲哚啉HCl鹽(3.3 g，15.27 mmol，1.0當量)於THF (20 ml)中之溶液中添加TEA (4.2 ml、30.55 mmol，2.0當量)及Boc2 O (5.0 g，22.91 mmol，1.5當量)。在室溫下攪拌反應混合物1h。用H2 O (30 mL)稀釋反應混合物且用EtOAc (30 mL×3)萃取。經合併之有機層用鹽水(30 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮。藉由矽膠急驟管柱層析純化殘餘物，得到4-溴-7-氟異吲哚啉-2-甲酸三級丁酯(4.2 g，產率87%)。LC-MS: 316, 318 (M+H)+ 。To a solution of 4-bromo-7-fluoroisoindoline HCl salt (3.3 g, 15.27 mmol, 1.0 equiv) in THF (20 ml) at 0 °C was added TEA (4.2 ml, 30.55 mmol, 2.0 equiv) and Boc2O (5.0 g , 22.91 mmol, 1.5 equiv). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give tert-butyl 4-bromo-7-fluoroisoindoline-2-carboxylate (4.2 g, 87% yield). LC-MS: 316, 318 (M+H) + .
步驟E：4-氟-7-((3-甲氧基-3-側氧基丙基)硫基)異吲哚啉-2-甲酸三級丁酯Step E: 4-Fluoro-7-((3-methoxy-3-pendoxopropyl)sulfanyl)isoindoline-2-carboxylic acid tert-butyl ester
在N2 氛圍下，於100℃攪拌4-溴-7-氟異吲哚啉-2-甲酸三級丁酯(4.2 g，13.28 mmol，1.0當量)、3-巰基丙酸甲酯(2.39 g，19.93 mmol，1.5當量)、Pd2 (dba)3 (0.61 g，0.66 mmol，0.05當量)、Xant-Phos (0.38 g，0.66 mmol，0.05當量)及DIPEA (5.2 g，39.85 mmol，2當量)於甲苯(15 ml)中之混合物16h。在減壓下濃縮反應混合物。藉由矽膠急驟管柱層析純化粗物質，得到呈黃色油狀物之4-氟-7-((3-甲氧基-3-側氧基丙基)硫基)異吲哚啉-2-甲酸三級丁酯(3.7 g，產率78%)。LC-MS: 378 (M+Na)+ 。Under N atmosphere, tert-butyl 4-bromo-7-fluoroisoindoline- 2 -carboxylate (4.2 g, 13.28 mmol, 1.0 equiv), methyl 3-mercaptopropionate (2.39 g) were stirred at 100 °C , 19.93 mmol, 1.5 equiv), Pd 2 (dba) 3 (0.61 g, 0.66 mmol, 0.05 equiv), Xant-Phos (0.38 g, 0.66 mmol, 0.05 equiv) and DIPEA (5.2 g, 39.85 mmol, 2 equiv) Mixture in toluene (15 ml) for 16 h. The reaction mixture was concentrated under reduced pressure. The crude material was purified by silica gel flash column chromatography to give 4-fluoro-7-((3-methoxy-3-pendoxypropyl)thio)isoindoline-2 as a yellow oil - tertiary butyl formate (3.7 g, 78% yield). LC-MS: 378 (M+Na) + .
步驟F及G：(R)-4-((1-((苯甲基氧基)羰基)哌啶-3-基)硫基)-7-氟異吲哚啉-2-甲酸三級丁酯Steps F and G: (R)-4-((1-((benzyloxy)carbonyl)piperidin-3-yl)sulfanyl)-7-fluoroisoindoline-2-carboxylic acid tertiary butyl ester
在-40℃下向4-氟-7-((3-甲氧基-3-側氧基丙基)硫基)異吲哚啉-2-甲酸三級丁酯(1.5 g，4.22 mmol，1.0當量)於THF (20 ml)中之混合物中添加t-BuOK (0.71 g，6.33 mmol，1.5當量)。接著在室溫下攪拌混合物1h。接著將(S)-3-((甲基磺醯基)氧基)哌啶-1-甲酸苯甲酯(1.16 g，3.71 mmol，0.88當量)及K2 CO3 (1.03 g，7.43 mmol，1.76當量)添加至上述混合物中。在80℃下攪拌反應混合物16h。在減壓下濃縮反應混合物，且藉由矽膠急驟管柱層析純化粗物質，得到呈黃色油狀物之(R)-4-((1-((苯甲基氧基)羰基)哌啶-3-基)硫基)-7-氟異吲哚啉-2-甲酸三級丁酯(1.1 g，產率61%)。LC-MS: 509 (M+Na)+ 。To tert-butyl 4-fluoro-7-((3-methoxy-3-oxypropyl)thio)isoindoline-2-carboxylate (1.5 g, 4.22 mmol, 1.0 equiv) in THF (20 ml) was added t-BuOK (0.71 g, 6.33 mmol, 1.5 equiv). The mixture was then stirred at room temperature for 1 h. Then (S)-3-((methylsulfonyl)oxy)piperidine-1-carboxylic acid benzyl (1.16 g, 3.71 mmol, 0.88 equiv) and K 2 CO 3 (1.03 g, 7.43 mmol, 1.76 equiv) was added to the above mixture. The reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was concentrated under reduced pressure, and the crude material was purified by silica gel flash column chromatography to give (R)-4-((1-((benzyloxy)carbonyl)piperidine as a yellow oil -3-yl)thio)-7-fluoroisoindoline-2-carboxylic acid tert-butyl ester (1.1 g, 61% yield). LC-MS: 509 (M+Na) + .
步驟H：(R)-4-((1-((苯甲基氧基)羰基)哌啶-3-基)磺醯基)-7-氟異吲哚啉-2-甲酸三級丁酯Step H: (R)-tertiary butyl 4-((1-((benzyloxy)carbonyl)piperidin-3-yl)sulfonyl)-7-fluoroisoindoline-2-carboxylate
在0℃下向(R)-4-((1-((苯甲基氧基)羰基)哌啶-3-基)硫基)-7-氟異吲哚啉-2-甲酸三級丁酯(1.1 g，2.26 mmol，1.0當量)於丙酮(10 ml)及H2 O (5 ml)中之混合物中添加過硫酸氫鉀(4.16 g，6.78 mmol，3.0當量)。在室溫下攪拌混合物16h。在室溫下攪拌反應混合物1h。用H2 O (30 mL)稀釋反應混合物且用EtOAc (30 mL×3)萃取。經合併之有機層用鹽水(30 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮。藉由矽膠急驟管柱層析來純化殘餘物，得到呈無色油狀物之(R)-4-((1-((苯甲基氧基)羰基)哌啶-3-基)磺醯基)-7-氟異吲哚啉-2-甲酸三級丁酯(900 mg，產率76%)。LC-MS: 541 (M+Na)+ 。To (R)-4-((1-((benzyloxy)carbonyl)piperidin-3-yl)sulfanyl)-7-fluoroisoindoline-2-carboxylic acid tertiary butyl at 0°C To a mixture of ester (1.1 g, 2.26 mmol, 1.0 equiv) in acetone (10 ml) and H2O (5 ml) was added potassium hydrogen persulfate (4.16 g, 6.78 mmol, 3.0 equiv). The mixture was stirred at room temperature for 16 h. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give (R)-4-((1-((benzyloxy)carbonyl)piperidin-3-yl)sulfonyl as a colorless oil )-tertiary butyl 7-fluoroisoindoline-2-carboxylate (900 mg, 76% yield). LC-MS: 541 (M+Na) + .
步驟I：4-(3-((4-((S)-2-(氮雜環丁烷-1-基)-1-(3-氟苯基)-1-((1R,2S)-2-((甲氧基羰基)胺基)環戊基)乙基)哌啶-1-基)甲基)氮雜環丁烷-1-基)-7-(((R)-1-((苯甲基氧基)羰基)哌啶-3-基)磺醯基)異吲哚啉-2-甲酸三級丁酯Step 1: 4-(3-((4-((S)-2-(azetidin-1-yl)-1-(3-fluorophenyl)-1-((1R,2S)- 2-((Methoxycarbonyl)amino)cyclopentyl)ethyl)piperidin-1-yl)methyl)azetidin-1-yl)-7-(((R)-1- ((Benzyloxy)carbonyl)piperidin-3-yl)sulfonyl)isoindoline-2-carboxylic acid tert-butyl ester
在80℃下攪拌(R)-4-((1-((苯甲基氧基)羰基)哌啶-3-基)磺醯基)-7-氟異吲哚啉-2-甲酸三級丁酯(500 mg，0.96 mmol，1.0當量)、((1S,2R)-2-((S)-2-(氮雜環丁烷-1-基)-1-(1-(氮雜環丁烷-3-基甲基)哌啶-4-基)-1-(3-氟苯基)乙基)環戊基)胺基甲酸甲酯(F3) (455 mg，0.96 mmol，1.0當量)及K2 CO3 (266 mg，1.92 mmol，2.0當量)於DMSO (20 ml)中之混合物16h。用H2 O (30 mL)稀釋反應混合物且用EtOAc (30 mL×3)萃取。經合併之有機層用鹽水(30 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮。藉由矽膠急驟管柱層析來純化殘餘物，得到呈白色固體之4-(3-((4-((S)-2-(氮雜環丁烷-1-基)-1-(3-氟苯基)-1-((1R,2S)-2-((甲氧基羰基)胺基)環戊基)乙基)哌啶-1-基)甲基)氮雜環丁烷-1-基)-7-(((R)-1-((苯甲基氧基)羰基)哌啶-3-基)磺醯基)異吲哚啉-2-甲酸三級丁酯(200 mg，產率21%)。LC-MS: 971 (M+H)+ 。Stir (R)-4-((1-((benzyloxy)carbonyl)piperidin-3-yl)sulfonyl)-7-fluoroisoindoline-2-carboxylic acid tertiary at 80°C Butyl ester (500 mg, 0.96 mmol, 1.0 equiv), ((1S,2R)-2-((S)-2-(azetidin-1-yl)-1-(1-(azetidine) Butan-3-ylmethyl)piperidin-4-yl)-1-(3-fluorophenyl)ethyl)cyclopentyl)carbamate (F3) (455 mg, 0.96 mmol, 1.0 equiv. ) and K2CO3 ( 266 mg , 1.92 mmol, 2.0 equiv) in DMSO (20 ml) for 16 h. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give 4-(3-((4-((S)-2-(azetidin-1-yl)-1-(3 as a white solid -Fluorophenyl)-1-((1R,2S)-2-((methoxycarbonyl)amino)cyclopentyl)ethyl)piperidin-1-yl)methyl)azetidine- 1-yl)-7-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)sulfonyl)isoindoline-2-carboxylic acid tertiary butyl ester (200 mg, yield 21%). LC-MS: 971 (M+H) + .
步驟J：4-(3-((4-((S)-2-(氮雜環丁烷-1-基)-1-(3-氟苯基)-1-((1R,2S)-2-((甲氧基羰基)胺基)環戊基)乙基)哌啶-1-基)甲基)氮雜環丁烷-1-基)-7-(((R)-哌啶-3-基)磺醯基)異吲哚啉-2-甲酸三級丁酯Step J: 4-(3-((4-((S)-2-(azetidin-1-yl)-1-(3-fluorophenyl)-1-((1R,2S)- 2-((Methoxycarbonyl)amino)cyclopentyl)ethyl)piperidin-1-yl)methyl)azetidin-1-yl)-7-(((R)-piperidine -3-yl)sulfonyl)isoindoline-2-carboxylic acid tertiary butyl ester
在H2 氛圍(1 atm)下，於室溫攪拌4-(3-((4-((S)-2-(氮雜環丁烷-1-基)-1-(3-氟苯基)-1-((1R,2S)-2-((甲氧基羰基)胺基)環戊基)乙基)哌啶-1-基)甲基)氮雜環丁烷-1-基)-7-(((R)-1-((苯甲基氧基)羰基)哌啶-3-基)磺醯基)異吲哚啉-2-甲酸三級丁酯(200 mg，0.206 mmol)及10% Pd/C (20 mg)於MeOH (10 ml)中之混合物16h。過濾反應混合物且在減壓下濃縮，得到呈白色固體之4-(3-((4-((S)-2-(氮雜環丁烷-1-基)-1-(3-氟苯基)-1-((1R,2S)-2-((甲氧基羰基)胺基)環戊基)乙基)哌啶-1-基)甲基)氮雜環丁烷-1-基)-7-(((R)-哌啶-3-基)磺醯基)異吲哚啉-2-甲酸三級丁酯(160 mg，產率92%)。LC-MS: 837 (M+H)+ 。4-(3-((4-((S)-2-(azetidin-1-yl)-1-(3-fluorophenyl) was stirred at room temperature under a H atmosphere ( 1 atm) )-1-((1R,2S)-2-((methoxycarbonyl)amino)cyclopentyl)ethyl)piperidin-1-yl)methyl)azetidin-1-yl) - tert-butyl 7-(((R)-1-((benzyloxy)carbonyl)piperidin-3-yl)sulfonyl)isoindoline-2-carboxylate (200 mg, 0.206 mmol ) and a mixture of 10% Pd/C (20 mg) in MeOH (10 ml) for 16 h. The reaction mixture was filtered and concentrated under reduced pressure to give 4-(3-((4-((S)-2-(azetidin-1-yl)-1-(3-fluorobenzene as a white solid) yl)-1-((1R,2S)-2-((methoxycarbonyl)amino)cyclopentyl)ethyl)piperidin-1-yl)methyl)azetidin-1-yl )-7-(((R)-piperidin-3-yl)sulfonyl)isoindoline-2-carboxylic acid tert-butyl ester (160 mg, 92% yield). LC-MS: 837 (M+H) + .
步驟K：4-(3-((4-((S)-2-(氮雜環丁烷-1-基)-1-(3-氟苯基)-1-((1R,2S)-2-((甲氧基羰基)胺基)環戊基)乙基)哌啶-1-基)甲基)氮雜環丁烷-1-基)-7-(((R)-1-(((E)-3-(甲基磺醯基)烯丙基)胺甲醯基)哌啶-3-基)磺醯基)異吲哚啉-2-甲酸三級丁酯Step K: 4-(3-((4-((S)-2-(azetidin-1-yl)-1-(3-fluorophenyl)-1-((1R,2S)- 2-((Methoxycarbonyl)amino)cyclopentyl)ethyl)piperidin-1-yl)methyl)azetidin-1-yl)-7-(((R)-1- (((E)-3-(Methylsulfonyl)allyl)carbamoyl)piperidin-3-yl)sulfonyl)isoindoline-2-carboxylic acid tertiary butyl ester
在室溫下攪拌(2E)-3-甲烷磺醯基丙-2-烯-1-胺(38 mg，0.28 mmol，1.47當量；Ref: Journal of Medicinal Chemistry; 35; 6; (1992); 第1067-1075頁)、CDI (46 mg，0.28 mmol，1.47當量)及TEA (58 mg，0.57 mmol，3.94當量)於THF (3 ml)中之混合物1h。接著添加含4-(3-((4-((S)-2-(氮雜環丁烷-1-基)-1-(3-氟苯基)-1-((1R,2S)-2-((甲氧基羰基)胺基)環戊基)乙基) 哌啶-1-基)甲基)氮雜環丁烷-1-基)-7-(((R)-哌啶-3-基)磺醯基)異吲哚啉-2-甲酸三級丁酯(160 mg，0.19 mmol，1.0當量)之THF (2 ml)且攪拌混合物16h。用H2 O (10 mL)稀釋反應混合物且用EtOAc (10 mL×3)萃取。經合併之有機層用鹽水(10 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮。藉由矽膠急驟管柱層析純化殘餘物，得到呈無色油狀物之4-(3-((4-((S)-2-(氮雜環丁烷-1-基)-1-(3-氟苯基)-1-((1R,2S)-2-((甲氧基羰基)胺基)環戊基)乙基)哌啶-1-基)甲基)氮雜環丁烷-1-基)-7-(((R)-1-(((E)-3-(甲基磺醯基)烯丙基)胺甲醯基)哌啶-3-基)磺醯基)異吲哚啉-2-甲酸三級丁酯(70 mg，產率36%)。LC-MS: 998 (M+H)+ 。(2E)-3-methanesulfonylprop-2-en-1-amine (38 mg, 0.28 mmol, 1.47 equiv; Ref: Journal of Medicinal Chemistry; 35; 6; (1992); 1067-1075), a mixture of CDI (46 mg, 0.28 mmol, 1.47 equiv) and TEA (58 mg, 0.57 mmol, 3.94 equiv) in THF (3 ml) for 1 h. Then add 4-(3-((4-((S)-2-(azetidin-1-yl)-1-(3-fluorophenyl)-1-((1R,2S)- 2-((Methoxycarbonyl)amino)cyclopentyl)ethyl)piperidin-1-yl)methyl)azetidin-1-yl)-7-(((R)-piperidine -3-yl)sulfonyl)isoindoline-2-carboxylic acid tert-butyl ester (160 mg, 0.19 mmol, 1.0 equiv) in THF (2 ml) and the mixture was stirred for 16 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give 4-(3-((4-((S)-2-(azetidin-1-yl)-1-( as a colorless oil 3-Fluorophenyl)-1-((1R,2S)-2-((methoxycarbonyl)amino)cyclopentyl)ethyl)piperidin-1-yl)methyl)azetidine -1-yl)-7-(((R)-1-(((E)-3-(methylsulfonyl)allyl)carbamoyl)piperidin-3-yl)sulfonyl ) tertiary butyl isoindoline-2-carboxylate (70 mg, 36% yield). LC-MS: 998 (M+H) + .
步驟L：((1S,2R)-2-((S)-2-(氮雜環丁烷-1-基)-1-(3-氟苯基)-1-(1-((1-(7-(((R)-1-(((E)-3-(甲基磺醯基)烯丙基)胺甲醯基)哌啶-3-基)磺醯基)異吲哚啉-4-基)氮雜環丁烷-3-基)甲基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯Step L: ((1S,2R)-2-((S)-2-(azetidin-1-yl)-1-(3-fluorophenyl)-1-(1-((1- (7-(((R)-1-(((E)-3-(methylsulfonyl)allyl)carbamoyl)piperidin-3-yl)sulfonyl)isoindoline -4-yl)azetidin-3-yl)methyl)piperidin-4-yl)ethyl)cyclopentyl)carbamate
在室溫下攪拌4-(3-((4-((S)-2-(氮雜環丁烷-1-基)-1-(3-氟苯基)-1-((1R,2S)-2-((甲氧基羰基)胺基)環戊基)乙基)哌啶-1-基)甲基)氮雜環丁烷-1-基)-7-(((R)-1-(((E)-3-(甲基磺醯基)烯丙基)胺甲醯基)哌啶-3-基)磺醯基)異吲哚啉-2-甲酸三級丁酯(70 mg，0.07 mmol)於DCM (3 ml)及TFA (1 ml)中之混合物3h。在減壓下濃縮反應混合物且藉由RP-製備型HPLC純化粗物質，得到呈白色固體之((1S,2R)-2-((S)-2-(氮雜環丁烷-1-基)-1-(3-氟苯基)-1-(1-((1-(7-(((R)-1-(((E)-3-(甲基磺醯基)烯丙基)胺甲醯基)哌啶-3-基)磺醯基)異吲哚啉-4-基)氮雜環丁烷-3-基)甲基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯(化合物104) (20 mg，產率31%)。LC-MS: 898 (M+H)+ 。1 H NMR (400 MHz, MeOD-d4 ) δ 7.63 (d, 1H), 7.40 (dd, 1H), 7.15 (t, 2H), 7.06 (t, 1H), 6.84 (dt, 1H), 6.59 (dt, 1H), 6.49 (d, 1H), 4.77 (d, 2H), 4.60 (s, 2H), 4.35 - 4.28 (m, 2H), 4.15 - 4.02 (m, 2H), 4.00 - 3.84 (m, 6H), 3.74 - 3.67 (m, 3H), 3.59 - 3.46 (m, 2H), 3.41 (s, 3H), 3.17 - 3.13 (m, 5H), 3.05 - 2.98 (m, 1H), 2.96 (s, 3H), 2.71 - 2.53 (m, 3H), 2.37 - 2.24 (m, 2H), 2.17 - 1.97 (m, 3H), 1.95 - 1.77 (m, 5H), 1.75 - 1.23 (m, 9H)。 實例15Stir 4-(3-((4-((S)-2-(azetidin-1-yl)-1-(3-fluorophenyl)-1-(((1R,2S) at room temperature )-2-((methoxycarbonyl)amino)cyclopentyl)ethyl)piperidin-1-yl)methyl)azetidin-1-yl)-7-(((R)- 1-(((E)-3-(methylsulfonyl)allyl)carbamoyl)piperidin-3-yl)sulfonyl)isoindoline-2-carboxylic acid tertiary butyl ester ( 70 mg, 0.07 mmol) in DCM (3 ml) and TFA (1 ml) for 3 h. The reaction mixture was concentrated under reduced pressure and the crude material was purified by RP-preparative HPLC to give ((1S,2R)-2-((S)-2-(azetidin-1-yl) as a white solid )-1-(3-Fluorophenyl)-1-(1-((1-(7-(((R)-1-(((E)-3-(methylsulfonyl)allyl ) carbamoyl)piperidin-3-yl)sulfonyl)isoindolin-4-yl)azetidin-3-yl)methyl)piperidin-4-yl)ethyl) ring Methyl amyl)carbamate (compound 104) (20 mg, 31% yield). LC-MS: 898 (M+H) + . 1 H NMR (400 MHz, MeOD- d 4 ) δ 7.63 (d, 1H), 7.40 (dd, 1H), 7.15 (t, 2H), 7.06 (t, 1H), 6.84 (dt, 1H), 6.59 ( dt, 1H), 6.49 (d, 1H), 4.77 (d, 2H), 4.60 (s, 2H), 4.35 - 4.28 (m, 2H), 4.15 - 4.02 (m, 2H), 4.00 - 3.84 (m, 6H), 3.74 - 3.67 (m, 3H), 3.59 - 3.46 (m, 2H), 3.41 (s, 3H), 3.17 - 3.13 (m, 5H), 3.05 - 2.98 (m, 1H), 2.96 (s, 3H), 2.71 - 2.53 (m, 3H), 2.37 - 2.24 (m, 2H), 2.17 - 1.97 (m, 3H), 1.95 - 1.77 (m, 5H), 1.75 - 1.23 (m, 9H). Example 15
製備((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-((1-((2-側氧基-2,3-二氫-1H-苯并[d]咪唑-5-基)磺醯基)氮雜環丁烷-3-基)甲基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯(化合物101)
在0℃下向((1S,2R)-2-((S)-1-(1-(氮雜環丁烷-3-基甲基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯(50 mg，0.1 mmol)及2-側氧基-2,3-二氫-1H-苯并[d]咪唑-5-磺醯氯(28 mg，0.12 mmol)於DCM (5 mL)中之溶液中添加TEA (0.04 mL，0.3 mmol)。在室溫下攪拌混合物2小時。接著用H2 O (10 mL)稀釋反應混合物且用DCM (10 mL×3)萃取。經合併之有機層用鹽水(10 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮。藉由製備型TLC及RP-製備型HPLC純化殘餘物，得到呈白色固體之化合物101 (17 mg，產率25%)。LC-MS: 694 (M+H)+ 。1 H NMR (400 MHz, MeOD-d4 ) δ 7.58 - 7.50 (m, 1H), 7.49 - 7.36 (m, 3H), 7.35 - 7.22 (m, 2H), 7.13 - 7.05 (m, 1H), 6.70 (d, 1H), 6.64 (d, 1H), 4.52 (d, 1H), 4.31 (d, 1H), 4.02 - 3.93 (m, 1H), 4.84 (t, 2H), 3.58 (s, 3H), 3.40 - 3.30 (m, 2H), 2.78 - 2.65 (m, 1H), 2.63 - 2.50 (m, 3H), 2.43 (s, 3H), 2.20 - 2.03 (m, 3H), 1.95 - 1.72 (m, 4H), 1.63 - 1.42 (m, 2H), 1.40 - 1.12 (m, 5H), 0.78 - 0.62 (m, 1H)。 實例16To ((1S,2R)-2-((S)-1-(1-(azetidin-3-ylmethyl)piperidin-4-yl)-1-(3- Fluorophenyl)-methyl 2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate (50 mg, 0.1 mmol) and 2-oxy-2,3 -Dihydro-1H-benzo[d]imidazole-5-sulfonyl chloride (28 mg, 0.12 mmol) in DCM (5 mL) was added TEA (0.04 mL, 0.3 mmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was then diluted with H2O (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by preparative TLC and RP-preparative HPLC to give compound 101 (17 mg, 25% yield) as a white solid. LC-MS: 694 (M+H) + . 1 H NMR (400 MHz, MeOD- d 4 ) δ 7.58 - 7.50 (m, 1H), 7.49 - 7.36 (m, 3H), 7.35 - 7.22 (m, 2H), 7.13 - 7.05 (m, 1H), 6.70 (d, 1H), 6.64 (d, 1H), 4.52 (d, 1H), 4.31 (d, 1H), 4.02 - 3.93 (m, 1H), 4.84 (t, 2H), 3.58 (s, 3H), 3.40 - 3.30 (m, 2H), 2.78 - 2.65 (m, 1H), 2.63 - 2.50 (m, 3H), 2.43 (s, 3H), 2.20 - 2.03 (m, 3H), 1.95 - 1.72 (m, 4H) ), 1.63 - 1.42 (m, 2H), 1.40 - 1.12 (m, 5H), 0.78 - 0.62 (m, 1H). Example 16
製備((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-((1-((2-側氧基-2,3-二氫-1H-苯并[d]咪唑-5-基)甲基)氮雜環丁烷-3-基)甲基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯(化合物102)
在室溫下攪拌((1S,2R)-2-((S)-1-(1-(氮雜環丁烷-3-基甲基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯(60 mg，0.12 mmol，1.0當量)、2-側氧基-2,3-二氫-1H-苯并[d]咪唑-5-甲醛(24 mg，0.15 mmol，1.25當量)及AcOH (7 mg，0.12 mmol，1.0當量)於DCM (6 mL)中之混合物1小時。接著添加NaBH3 CN (15 mg，0.24 mmol，2.0當量)，且在室溫下攪拌混合物隔夜。接著用H2 O (10 mL)稀釋反應混合物且用DCM (10 mL×3)萃取。經合併之有機層用鹽水(10 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮。藉由製備型TLC及RP-製備型HPLC純化殘餘物，得到呈白色固體之化合物102 (3.5 mg，產率5%)。LC-MS: 644 (M+H)+ 。1 H NMR (400 MHz, MeOD-d4 ) δ 7.53 - 7.43 (m, 2H), 7.40 - 7.36 (m, 1H), 7.16 - 7.05 (m, 4H), 6.95 (s, 1H), 6.77 (s, 1H), 4.65 (d, 1H), 4.38 (d, 1H), 4.23 (s, 2H), 4.10 - 3.95 (m, 3H), 3.81 - 3.72 (m, 2H), 3.61 (s, 3H), 3.20 - 3.05 (m, 2H), 3.00 - 2.92 (m, 1H), 2.90 - 2.75 (m, 2H), 2.65 - 2.53 (m, 1H), 2.54 (s, 3H), 2.43 - 2.16 (m, 3H), 2.13 - 2.02 (m, 1H), 1.95 - 1.83 (m, 1H), 1.77 - 1.67 (m, 1H), 1.55 - 1.43 (m, 1H), 1.40 - 1.12 (m, 5H), 0.79 - 0.65 (m, 1H)。 實例17((1S,2R)-2-((S)-1-(1-(azetidin-3-ylmethyl)piperidin-4-yl)-1-(3- Fluorophenyl)-methyl 2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate (60 mg, 0.12 mmol, 1.0 equiv), 2-pendoxo- A mixture of 2,3-dihydro-1H-benzo[d]imidazole-5-carbaldehyde (24 mg, 0.15 mmol, 1.25 equiv) and AcOH (7 mg, 0.12 mmol, 1.0 equiv) in DCM (6 mL) 1 hour. Then NaBH3CN (15 mg, 0.24 mmol, 2.0 equiv) was added and the mixture was stirred at room temperature overnight. The reaction mixture was then diluted with H2O (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by preparative TLC and RP-preparative HPLC to give compound 102 (3.5 mg, 5% yield) as a white solid. LC-MS: 644 (M+H) + . 1 H NMR (400 MHz, MeOD- d 4 ) δ 7.53 - 7.43 (m, 2H), 7.40 - 7.36 (m, 1H), 7.16 - 7.05 (m, 4H), 6.95 (s, 1H), 6.77 (s , 1H), 4.65 (d, 1H), 4.38 (d, 1H), 4.23 (s, 2H), 4.10 - 3.95 (m, 3H), 3.81 - 3.72 (m, 2H), 3.61 (s, 3H), 3.20 - 3.05 (m, 2H), 3.00 - 2.92 (m, 1H), 2.90 - 2.75 (m, 2H), 2.65 - 2.53 (m, 1H), 2.54 (s, 3H), 2.43 - 2.16 (m, 3H) ), 2.13 - 2.02 (m, 1H), 1.95 - 1.83 (m, 1H), 1.77 - 1.67 (m, 1H), 1.55 - 1.43 (m, 1H), 1.40 - 1.12 (m, 5H), 0.79 - 0.65 (m, 1H). Example 17
製備((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-((1-(2-側氧基-2,3-二氫-1H-苯并[d]咪唑-5-基)氮雜環丁烷-3-基)甲基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯(化合物103)
步驟A：((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-((1-(2-側氧基-1,3-雙((2-(三甲基矽烷基)乙氧基)甲基)-2,3-二氫-1H-苯并[d]咪唑-5-基)氮雜環丁烷-3-基)甲基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯Step A: ((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1-( (1-(2-Oxy-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazole- 5-yl)azetidin-3-yl)methyl)piperidin-4-yl)ethyl)cyclopentyl)carbamate
在N2 氛圍下，於100℃攪拌((1S,2R)-2-((S)-1-(1-(氮雜環丁烷-3-基甲基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯(80 mg，0.16 mmol)、5-溴-1,3-雙((2-(三甲基矽烷基)乙氧基)甲基)-1,3-二氫-2H-苯并[d]咪唑-2-酮(83 mg，0.18 mmol)、Pd2 (dba)3 (15 mg，0.016 mmol)、X-Phos (8 mg，0.016 mmol)及Cs2 CO3 (157 mg，0.48 mmol)於甲苯(5 mL)中之混合物16小時。接著用H2 O (10 mL)稀釋反應混合物且用EtOAc (10 mL×3)萃取。將有機層用鹽水(10 mL)洗滌，經Na2 SO4 乾燥，過濾且在減壓下濃縮。藉由矽膠急驟管柱層析純化殘餘物，得到呈黃色固體之((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-((1-(2-側氧基-1,3-雙((2-(三甲基矽烷基)乙氧基)甲基)-2,3-二氫-1H-苯并[d]咪唑-5-基)氮雜環丁烷-3-基)甲基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯(40 mg，產率28%)。LC-MS: 890 (M+H)+ 。((1S,2R) -2 -((S)-1-(1-(azetidin-3-ylmethyl)piperidin-4-yl)- Methyl 1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate (80 mg, 0.16 mmol), 5-bromo- 1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (83 mg, 0.18 mmol) , Pd2(dba )3 ( 15 mg, 0.016 mmol), X-Phos (8 mg, 0.016 mmol) and a mixture of Cs2CO3 ( 157 mg, 0.48 mmol) in toluene (5 mL) for 16 h. The reaction mixture was then diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The organic layer was washed with brine (10 mL), dried over Na2SO4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give ((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H) as a yellow solid -Imidazol-1-yl)-1-(1-((1-(2-oxy-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2, Methyl 3-dihydro-1H-benzo[d]imidazol-5-yl)azetidine-3-yl)methyl)piperidin-4-yl)ethyl)cyclopentyl)carbamate (40 mg, 28% yield). LC-MS: 890 (M+H) + .
步驟B：((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-((1-(2-側氧基-2,3-二氫-1H-苯并[d]咪唑-5-基)氮雜環丁烷-3-基)甲基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯Step B: ((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1-( (1-(2-Oxy-2,3-dihydro-1H-benzo[d]imidazol-5-yl)azetidin-3-yl)methyl)piperidin-4-yl) Ethyl)cyclopentyl)carbamate
在0℃下攪拌((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-((1-(2-側氧基-1,3-雙((2-(三甲基矽烷基)乙氧基)甲基)-2,3-二氫-1H-苯并[d]咪唑-5-基)氮雜環丁烷-3-基)甲基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯(40 mg，0.045 mmol)於TFA (2 mL)中之溶液0.5小時，接著在減壓下濃縮。向殘餘物添加MeOH (2 mL)及NH3 .H2 O (1 mL)。在室溫下攪拌混合物2小時。接著用H2 O (10 mL)稀釋反應混合物且用EtOAc (10 mL×3)萃取。經合併之有機層用鹽水(10 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮。藉由RP-製備型HPLC純化殘餘物，得到呈白色固體之化合物103 (10 mg，產率36%)。LC-MS: 630 (M+H)+ 。1 H NMR (400 MHz, MeOD-d4 ) δ 7.50 - 7.33 (m, 3H), 7.14 - 7.05 (m, 1H), 6.86 (d, 1H), 6.70 (d, 1H), 6.66 (d, 1H), 6.25 - 6.16 (m, 2H), 4.54 (d, 1H), 4.34 (d, 1H), 4.10 - 3.90 (m, 3H), 3.61 (s, 3H), 3.39 (t, 2H), 2.99 - 2.80 (m, 3H), 2.65 - 2.51 (m, 3H), 2.44 (s, 3H), 2.25 - 2.17 (m, 1H), 2.04 - 1.90 (m, 3H), 1.89 - 1.80 (m, 1H), 1.72 - 1.59 (m, 1H), 1.55 - 1.43 (m, 1H), 1.42 - 1.15 (m, 5H), 0.83 - 0.70 (m, 1H)。 實例18Stir ((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1 at 0°C -((1-(2-Oxy-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d] Imidazol-5-yl)azetidin-3-yl)methyl)piperidin-4-yl)ethyl)cyclopentyl)carbamate (40 mg, 0.045 mmol) in TFA (2 mL) ) for 0.5 h, then concentrated under reduced pressure. To the residue was added MeOH ( 2 mL) and NH3.H2O ( 1 mL). The mixture was stirred at room temperature for 2 hours. The reaction mixture was then diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by RP-preparative HPLC to give compound 103 (10 mg, 36% yield) as a white solid. LC-MS: 630 (M+H) + . 1 H NMR (400 MHz, MeOD- d 4 ) δ 7.50 - 7.33 (m, 3H), 7.14 - 7.05 (m, 1H), 6.86 (d, 1H), 6.70 (d, 1H), 6.66 (d, 1H) ), 6.25 - 6.16 (m, 2H), 4.54 (d, 1H), 4.34 (d, 1H), 4.10 - 3.90 (m, 3H), 3.61 (s, 3H), 3.39 (t, 2H), 2.99 - 2.80 (m, 3H), 2.65 - 2.51 (m, 3H), 2.44 (s, 3H), 2.25 - 2.17 (m, 1H), 2.04 - 1.90 (m, 3H), 1.89 - 1.80 (m, 1H), 1.72 - 1.59 (m, 1H), 1.55 - 1.43 (m, 1H), 1.42 - 1.15 (m, 5H), 0.83 - 0.70 (m, 1H). Example 18
製備((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-((1-(2-側氧基-2,3-二氫-1H-苯并[d]咪唑-4-基)氮雜環丁烷-3-基)甲基)哌啶-4-基)乙基)環戊基)胺基甲酸酯(化合物127)
步驟A：4-溴-1,3-雙((2-(三甲基矽烷基)乙氧基)甲基)-1,3-二氫-2H-苯并[d]咪唑-2-酮Step A: 4-Bromo-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one
在0℃下攪拌4-溴-1,3-二氫-2H-苯并[d]咪唑-2-酮(300 mg，1.4 mmol)及NaH (60%於油中，112 mg，2.8 mmol)於DMF (5 mL)中之混合物1小時。接著添加SEMCl (705 mg，4.2 mmol)且在室溫下攪拌混合物2小時。將混合物倒入NH4 Cl飽和水溶液(20 mL)中且用EtOAc (20 mL×3)萃取。經合併之有機層用鹽水(20 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮。藉由矽膠急驟管柱層析來純化殘餘物，得到呈白色固體之4-溴-1,3-雙((2-(三甲基矽烷基)乙氧基)甲基)-1,3-二氫-2H-苯并[d]咪唑-2-酮(500 mg，產率75%)。LC-MS: 473 (M+H)+ 。Stir 4-bromo-1,3-dihydro-2H-benzo[d]imidazol-2-one (300 mg, 1.4 mmol) and NaH (60% in oil, 112 mg, 2.8 mmol) at 0 °C Mixture in DMF (5 mL) for 1 hour. Then SEMCl (705 mg, 4.2 mmol) was added and the mixture was stirred at room temperature for 2 hours. The mixture was poured into saturated aqueous NH4Cl (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give 4-bromo-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3- as a white solid Dihydro-2H-benzo[d]imidazol-2-one (500 mg, 75% yield). LC-MS: 473 (M+H) + .
步驟B：((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-((1-(2-側氧基-1,3-雙((2-(三甲基矽烷基)乙氧基)甲基)-2,3-二氫-1H-苯并[d]咪唑-4-基)氮雜環丁烷-3-基)甲基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯Step B: ((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1-( (1-(2-Oxy-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazole- 4-yl)azetidin-3-yl)methyl)piperidin-4-yl)ethyl)cyclopentyl)carbamate
在N2 氛圍下，於110℃攪拌((1S,2R)-2-((S)-1-(1-(氮雜環丁烷-3-基甲基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯(67 mg，0.13 mmol)、4-溴-1,3-雙((2-(三甲基矽烷基)乙氧基)甲基)-1,3-二氫-2H-苯并[d]咪唑-2-酮(76 mg，0.16 mmol)、Pd2 (dba)3 (12 mg，0.013 mmol)、BINAP (8 mg，0.013 mmol)及t-BuONa (39 mg，0.40 mmol)於甲苯(3 mL)中之混合物16小時。接著在減壓下濃縮反應溶液且藉由矽膠急驟管柱層析純化殘餘物，得到呈白色固體之((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-((1-(2-側氧基-1,3-雙((2-(三甲基矽烷基)乙氧基)甲基)-2,3-二氫-1H-苯并[d]咪唑-4-基)氮雜環丁烷-3-基)甲基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯(30 mg，產率26%)。LC-MS: 890 (M+H)+ 。((1S,2R) -2 -((S)-1-(1-(azetidin-3-ylmethyl)piperidin-4-yl)- Methyl 1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate (67 mg, 0.13 mmol), 4-bromo- 1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (76 mg, 0.16 mmol) , Pd2(dba )3 ( 12 mg, 0.013 mmol), BINAP (8 mg, 0.013 mmol) and t-BuONa (39 mg, 0.40 mmol) in toluene (3 mL) for 16 h. The reaction solution was then concentrated under reduced pressure and the residue was purified by silica gel flash column chromatography to give ((1S,2R)-2-((S)-1-(3-fluorophenyl)- as a white solid 2-(2-Methyl-1H-imidazol-1-yl)-1-(1-((1-(2-oxy-1,3-bis((2-(trimethylsilyl)ethyl) oxy)methyl)-2,3-dihydro-1H-benzo[d]imidazol-4-yl)azetidin-3-yl)methyl)piperidin-4-yl)ethyl) Methyl cyclopentyl)carbamate (30 mg, 26% yield). LC-MS: 890 (M+H) + .
步驟C：((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-((1-(2-側氧基-2,3-二氫-1H-苯并[d]咪唑-4-基)氮雜環丁烷-3-基)甲基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯(化合物127)Step C: ((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1-( (1-(2-Oxy-2,3-dihydro-1H-benzo[d]imidazol-4-yl)azetidin-3-yl)methyl)piperidin-4-yl) Ethyl)cyclopentyl)methylcarbamate (Compound 127)
在0℃下攪拌((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-((1-(2-側氧基-1,3-雙((2-(三甲基矽烷基)乙氧基)甲基)-2,3-二氫-1H-苯并[d]咪唑-4-基)氮雜環丁烷-3-基)甲基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯(10 mg，0.011 mmol)於TFA (2 mL)中之溶液0.5小時，接著在減壓下濃縮。向殘餘物添加MeOH (2 mL)及NH3 .H2 O (1 mL)。在室溫下攪拌混合物2小時。接著用H2 O (10 mL)稀釋反應混合物且用EtOAc (10 mL×3)萃取。經合併之有機層用鹽水(10 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮。藉由RP-製備型HPLC純化殘餘物，得到呈白色固體之化合物127 (2 mg，產率28%)。LC-MS: 630 (M+H)+ 。1 H NMR (400 MHz, MeOD-d4 ) δ 7.50 - 7.33 (m, 3H), 7.14 - 7.05 (m, 1H), 6.90 (t, 1H), 6.74 (s, 1H), 6.69 (s, 1H), 6.55 (d, 1H), 6.21 (d, 1H), 4.54 (d, 1H), 4.37 (d, 1H), 4.05 - 3.90 (m, 1H), 3.61 (s, 3H), 3.60 - 3.56 (m, 2H), 3.12 - 3.04 (m, 1H), 2.98 - 2.88 (m, 2H), 2.79 - 2.67 (m, 2H), 2.65 - 2.57 (m, 1H), 2.46 (s, 3H), 2.32 - 2.25 (m, 1H), 2.08 - 1.97 (m, 3H), 1.92 - 1.81 (m, 1H), 1.75 - 1.65 (m, 1H), 1.64 - 1.45 (m, 3H), 1.43 - 1.10 (m, 5H), 0.83 - 0.70 (m, 1H)。 實例19Stir ((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1 at 0°C -((1-(2-Oxy-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d] Imidazol-4-yl)azetidin-3-yl)methyl)piperidin-4-yl)ethyl)cyclopentyl)carbamate (10 mg, 0.011 mmol) in TFA (2 mL) ) for 0.5 h, then concentrated under reduced pressure. To the residue was added MeOH ( 2 mL) and NH3.H2O ( 1 mL). The mixture was stirred at room temperature for 2 hours. The reaction mixture was then diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by RP-preparative HPLC to give compound 127 (2 mg, 28% yield) as a white solid. LC-MS: 630 (M+H) + . 1 H NMR (400 MHz, MeOD- d 4 ) δ 7.50 - 7.33 (m, 3H), 7.14 - 7.05 (m, 1H), 6.90 (t, 1H), 6.74 (s, 1H), 6.69 (s, 1H) ), 6.55 (d, 1H), 6.21 (d, 1H), 4.54 (d, 1H), 4.37 (d, 1H), 4.05 - 3.90 (m, 1H), 3.61 (s, 3H), 3.60 - 3.56 ( m, 2H), 3.12 - 3.04 (m, 1H), 2.98 - 2.88 (m, 2H), 2.79 - 2.67 (m, 2H), 2.65 - 2.57 (m, 1H), 2.46 (s, 3H), 2.32 - 2.25 (m, 1H), 2.08 - 1.97 (m, 3H), 1.92 - 1.81 (m, 1H), 1.75 - 1.65 (m, 1H), 1.64 - 1.45 (m, 3H), 1.43 - 1.10 (m, 5H) ), 0.83 - 0.70 (m, 1H). Example 19
製備((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(4-(甲基磺醯胺基甲基)苯乙基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯(化合物129)
步驟A：2-(4-(胺基甲基)苯基)乙-1-醇Step A: 2-(4-(Aminomethyl)phenyl)ethan-1-ol
在室溫下向4-(2-羥乙基)苯甲腈(850 mg，5.7 mmol)於MeOH (10 mL)中之溶液中添加10% Pd/C (200 mg，濕)及濃HCl (1 mL)。在H2 氛圍下，於室溫攪拌反應混合物10 h。過濾混合物且在減壓下濃縮，得到呈白色固體之2-(4-(胺基甲基)苯基)乙-1-醇(550 mg，產率63%)。LC-MS: 152 (M+H)+ 。To a solution of 4-(2-hydroxyethyl)benzonitrile (850 mg, 5.7 mmol) in MeOH (10 mL) was added 10% Pd/C (200 mg, wet) and concentrated HCl ( 1 mL). The reaction mixture was stirred at room temperature for 10 h under H2 atmosphere. The mixture was filtered and concentrated under reduced pressure to give 2-(4-(aminomethyl)phenyl)ethan-1-ol (550 mg, 63% yield) as a white solid. LC-MS: 152 (M+H) + .
步驟B：(4-(2-羥乙基)苯甲基)胺基甲酸三級丁酯Step B: Tertiary butyl (4-(2-hydroxyethyl)benzyl)carbamate
在室溫下向2-(4-(胺基甲基)苯基)乙-1-醇(300 mg，1.98 mmol，1.0當量)於DCM (10 mL)中之溶液中添加Boc2 O (648 mg，2.97 mmol)及TEA (0.55 mL，3.96 mmol)。在此溫度下攪拌反應混合物2h。用水(20 mL)稀釋混合物且用DCM (20 mL×3)萃取。經合併之有機層用鹽水(20 mL)洗滌，經無水Na2 SO4 乾燥且在減壓下濃縮。藉由急驟層析純化殘餘物，得到呈黃色固體之(4-(2-羥乙基)苯甲基)胺基甲酸三級丁酯(400 mg，產率80%)。LC-MS: 252 (M+H)+ 。To a solution of 2-(4-(aminomethyl)phenyl)ethan-l-ol (300 mg, 1.98 mmol, 1.0 equiv) in DCM (10 mL) at room temperature was added Boc 2 O (648 mg, 2.97 mmol) and TEA (0.55 mL, 3.96 mmol). The reaction mixture was stirred at this temperature for 2 h. The mixture was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash chromatography to give tert-butyl (4-(2-hydroxyethyl)benzyl)carbamate (400 mg, 80% yield) as a yellow solid. LC-MS: 252 (M+H) + .
步驟C：甲烷磺酸4-(((三級丁氧基羰基)胺基)甲基)苯乙酯Step C: 4-(((tertiary butoxycarbonyl)amino)methyl)phenethyl methanesulfonate
在0℃下向4-(2-羥乙基)苯甲基胺基甲酸三級丁酯(350 mg，1.39 mmol)於DCM (10 mL)中之溶液中添加TEA (0.38 mL，2.78 mmol)，隨後添加MsCl (0.11 mL，1.39 mmol)。在室溫下攪拌混合物1小時。將混合物倒入水(20 mL)中且用DCM (20 mL×3)萃取。合併之有機層用鹽水洗滌，經無水Na2 SO4 乾燥且在減壓下濃縮。藉由急驟層析純化殘餘物，得到呈白色固體之甲烷磺酸4-(((三級丁氧基羰基)胺基)甲基)苯乙酯(220 mg，產率66%)。LC-MS: 330 (M+H)+ 。To a solution of tert-butyl 4-(2-hydroxyethyl)benzylcarbamate (350 mg, 1.39 mmol) in DCM (10 mL) was added TEA (0.38 mL, 2.78 mmol) at 0 °C , followed by the addition of MsCl (0.11 mL, 1.39 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was poured into water (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash chromatography to give 4-(((tertiary butoxycarbonyl)amino)methyl)phenethyl methanesulfonate (220 mg, 66% yield) as a white solid. LC-MS: 330 (M+H) + .
步驟D：((1S,2R)-2-((S)-1-(1-(4-(((三級丁氧基羰基)胺基)甲基)苯乙基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯Step D: ((1S,2R)-2-((S)-1-(1-(4-(((tertiary butoxycarbonyl)amino)methyl)phenethyl)piperidine-4- yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate
在室溫下向((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(哌啶-4-基)乙基)環戊基)胺基甲酸甲酯(E5) (150 mg，0.35 mmol)於MeCN (10 mL)中之溶液中添加甲烷磺酸4-(((三級丁氧基羰基)胺基)甲基)苯乙酯(115 mg，0.35 mmol)、K2 CO3 (96 mg，0.70 mmol)及KI (58 mg，0.35 mmol)。在80℃下攪拌反應混合物10小時。用水(20 mL)稀釋經冷卻之混合物且用DCM (20 mL×3)萃取。經合併之有機層用鹽水(20 mL)洗滌，經無水Na2 SO4 乾燥且在減壓下濃縮。藉由急驟層析純化殘餘物，得到呈棕色固體之((1S,2R)-2-((S)-1-(1-(4-(((三級丁氧基羰基)胺基)甲基)苯乙基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯(140 mg，產率60%)。LC-MS: 662 (M+H)+ 。To ((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(piperidine) at room temperature To a solution of pyridin-4-yl)ethyl)cyclopentyl)carbamate (E5) (150 mg, 0.35 mmol) in MeCN (10 mL) was added methanesulfonic acid 4-(((tertiary butane) Oxycarbonyl)amino)methyl)phenethyl ester ( 115 mg, 0.35 mmol), K2CO3 (96 mg , 0.70 mmol) and KI (58 mg, 0.35 mmol). The reaction mixture was stirred at 80°C for 10 hours. The cooled mixture was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash chromatography to give ((1S,2R)-2-((S)-1-(1-(4-(((tertiary butoxycarbonyl)amino)methan as a brown solid yl)phenethyl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamic acid Methyl ester (140 mg, 60% yield). LC-MS: 662 (M+H) + .
步驟E：((1S,2R)-2-((S)-1-(1-(4-(胺基甲基)苯乙基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯Step E: ((1S,2R)-2-((S)-1-(1-(4-(aminomethyl)phenethyl)piperidin-4-yl)-1-(3-fluorobenzene yl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate methyl ester
在室溫下向((1S,2R)-2-((S)-1-(1-(4-(((三級丁氧基羰基)胺基)甲基)苯乙基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯(140 mg，0.21 mmol)於DCM (6 mL)中之溶液中添加TFA (2 mL)。在室溫下攪拌反應混合物1小時。在減壓下濃縮混合物。接著用NaHCO3 飽和水溶液(30 mL)稀釋殘餘物且用DCM (20 mL×3)萃取。用鹽水(30 mL)洗滌合併之有機層，經Na2 SO乾燥且在減壓下濃縮，得到呈棕色油狀物之((1S,2R)-2-((S)-1-(1-(4-(胺基甲基)苯乙基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯(110 mg，產率93%)。LC-MS: 562 (M+H)+ 。To ((1S,2R)-2-((S)-1-(1-(4-(((tertiary butoxycarbonyl)amino)methyl)phenethyl)piperidine- Methyl 4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate (140 mg, 0.21 mmol) To a solution in DCM (6 mL) was added TFA (2 mL). The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The residue was then diluted with saturated aqueous NaHCO 3 (30 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO and concentrated under reduced pressure to give ((1S,2R)-2-((S)-1-(1- as a brown oil) (4-(Aminomethyl)phenethyl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl) Methyl cyclopentyl)carbamate (110 mg, 93% yield). LC-MS: 562 (M+H) + .
步驟F：((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(4-(甲基磺醯胺基甲基)苯乙基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯(化合物129)Step F: ((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1-( Methyl 4-(methylsulfonamidomethyl)phenethyl)piperidin-4-yl)ethyl)cyclopentyl)carbamate (Compound 129)
在0℃下向((1S,2R)-2-((S)-1-(1-(4-(胺基甲基)苯乙基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯(56 mg，0.1 mmol)於DCM (5 mL)中之溶液中添加TEA (27 μL，0.2 mmol)，隨後添加MsCl (8 μL，0.1 mmol)，且在此溫度下攪拌混合物1小時。將混合物倒入水(10 mL)中且用DCM (10 mL×3)萃取。經合併之有機層用鹽水(10 mL)洗滌，經無水Na2 SO4 乾燥且在減壓下濃縮。藉由製備型TLC及RP-製備型HPLC純化殘餘物，得到呈白色固體之化合物129 (8 mg，產率12%)。LC-MS: 640 (M+H)+ 。1 H NMR (400 MHz, DMSO-d6 ) δ 7.49 - 7.36 (m, 4H), 7.25 - 7.19 (m, 2H), 7.18 - 7.10 (m, 3H), 6.64 (s, 1H), 6.54 (s, 1H), 4.46 (d, 1H), 4.25 (d, 1H), 4.09 (s, 2H), 3.85 - 3.75 (m, 1H), 3.49 (s, 3H), 3.46 - 3.43 (m, 1H), 2.94 - 2.83 (m, 1H), 2.82 (s, 3H), 2.81 - 2.73 (m, 1H), 2.68 - 2.56 (m, 3H), 2.42 - 2.28 (m, 2H), 2.34 (s, 3H), 2.20 - 1.95 (m, 1H), 1.90 - 1.83 (m, 1H), 1.75 (t, 3H), 1.50 - 1.35 (m, 2H), 1.30 - 0.95 (m, 4H), 1.18 - 1.07 (m, 1H), 0.60 - 0.42 (m, 1H)。 實例20To ((1S,2R)-2-((S)-1-(1-(4-(aminomethyl)phenethyl)piperidin-4-yl)-1-(3- Fluorophenyl)-methyl 2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate (56 mg, 0.1 mmol) in DCM (5 mL) TEA (27 μL, 0.2 mmol) was added followed by MsCl (8 μL, 0.1 mmol) and the mixture was stirred at this temperature for 1 hour. The mixture was poured into water (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by preparative TLC and RP-preparative HPLC to give compound 129 (8 mg, 12% yield) as a white solid. LC-MS: 640 (M+H) + . 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.49 - 7.36 (m, 4H), 7.25 - 7.19 (m, 2H), 7.18 - 7.10 (m, 3H), 6.64 (s, 1H), 6.54 (s , 1H), 4.46 (d, 1H), 4.25 (d, 1H), 4.09 (s, 2H), 3.85 - 3.75 (m, 1H), 3.49 (s, 3H), 3.46 - 3.43 (m, 1H), 2.94 - 2.83 (m, 1H), 2.82 (s, 3H), 2.81 - 2.73 (m, 1H), 2.68 - 2.56 (m, 3H), 2.42 - 2.28 (m, 2H), 2.34 (s, 3H), 2.20 - 1.95 (m, 1H), 1.90 - 1.83 (m, 1H), 1.75 (t, 3H), 1.50 - 1.35 (m, 2H), 1.30 - 0.95 (m, 4H), 1.18 - 1.07 (m, 1H) ), 0.60 - 0.42 (m, 1H). Example 20
製備((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(2-(2-側氧基-2,3-二氫-1H-苯并[d]咪唑-5-基)乙基)哌啶-4-基)乙基)環戊基)胺基甲酸酯(化合物132)
步驟A：5-烯丙基-1,3-雙((2-(三甲基矽烷基)乙氧基)甲基)-1,3-二氫-2H-苯并[d]咪唑-2-酮Step A: 5-Allyl-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-benzo[d]imidazole-2 -ketone
在N2 氛圍下，於80℃攪拌5-溴-1,3-雙((2-(三甲基矽烷基)乙氧基)甲基)-1,3-二氫-2H-苯并[d]咪唑-2-酮(300 mg，0.63 mmol，1.0當量)、2-烯丙基-4,4,5,5-四甲基-1,3,2-二氧雜硼戊烷(160 mg，0.95 mmol)、Pd(dppf)Cl2 (46 mg，0.063 mmol)、K3 PO4 (400 mg，1.89 mmol)及H2 O (1 mL)於1,4-二㗁烷(5 mL)中之混合物16 h。接著用H2 O (10 mL)稀釋反應混合物且用EtOAc (20 mL×3)萃取。經合併之有機層用鹽水(10 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮。藉由矽膠急驟層析純化殘餘物，得到呈白色固體之5-烯丙基-1,3-雙((2-(三甲基矽烷基)乙氧基)甲基)-1,3-二氫-2H-苯并[d]咪唑-2-酮(255 mg，產率93%)。LC-MS: 435 (M+H)+ 。5 - Bromo-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-benzo[ d] Imidazol-2-one (300 mg, 0.63 mmol, 1.0 equiv), 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (160 mg, 0.95 mmol), Pd(dppf)Cl 2 (46 mg, 0.063 mmol), K 3 PO 4 (400 mg, 1.89 mmol) and H 2 O (1 mL) in 1,4-dioxane (5 mL) ) for 16 h. The reaction mixture was then diluted with H2O (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography to give 5-allyl-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-di as a white solid Hydro-2H-benzo[d]imidazol-2-one (255 mg, 93% yield). LC-MS: 435 (M+H) + .
步驟B：2-(2-側氧基-1,3-雙((2-(三甲基矽烷基)乙氧基)甲基)-2,3-二氫-1H-苯并[d]咪唑-5-基)乙醛Step B: 2-(2-Oxy-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d] imidazol-5-yl)acetaldehyde
在0℃下，向5-烯丙基-1,3-雙((2-(三甲基矽烷基)乙氧基)甲基)-1,3-二氫-2H-苯并[d]咪唑-2-酮(250 mg，0.58 mmol)、K2 OsO4 (10 mg，cat.)及H2 O (1 mL)於THF (5 mL)中之溶液中添加NaIO4 (370 mg，1.73 mmol)且在此溫度下攪拌混合物30 min。接著用H2 O (10 mL)稀釋反應混合物且用EtOAc (10 mL×3)萃取。經合併之有機層用鹽水(10 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮。藉由矽膠急驟層析純化殘餘物，得到呈白色固體之2-(2-側氧基-1,3-雙((2-(三甲基矽烷基)乙氧基)甲基)-2,3-二氫-1H-苯并[d]咪唑-5-基)乙醛(140 mg，產率55%)。LC-MS: 437 (M+H)+ 。To 5-allyl-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-benzo[d] at 0 °C Imidazol- 2 -one (250 mg, 0.58 mmol), K2OsO4 (10 mg, cat.) and H2O (1 mL) in THF (5 mL) was added NaIO4 (370 mg, 1.73 mmol) and the mixture was stirred at this temperature for 30 min. The reaction mixture was then diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography to give 2-(2-oxy-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2 as a white solid, 3-Dihydro-1H-benzo[d]imidazol-5-yl)acetaldehyde (140 mg, 55% yield). LC-MS: 437 (M+H) + .
步驟C：((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(2-(2-側氧基-1,3-雙((2-(三甲基矽烷基)乙氧基)甲基)-2,3-二氫-1H-苯并[d]咪唑-5-基)乙基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯Step C: ((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1-( 2-(2-Oxy-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazole-5 -yl)ethyl)piperidin-4-yl)ethyl)cyclopentyl)carbamate
在室溫下攪拌2-(2-側氧基-1,3-雙((2-(三甲基矽烷基)乙氧基)甲基)-2,3-二氫-1H-苯并[d]咪唑-5-基)乙醛(60 mg，0.141 mmol)、((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(哌啶-4-基)乙基)環戊基)胺基甲酸甲酯(E5) (73 mg，0.168 mmol)及AcOH (8 mg，0.141 mmol)於DCM (10 mL)中之混合物1小時。接著添加NaBH(OAc)3 (59 mg，0.282 mmol)，且在室溫下攪拌反應混合物16 h。用H2 O (10 mL)稀釋混合物，用NaHCO3 飽和水溶液調整至pH約7且用DCM (10 mL×3)萃取。經合併之有機層用鹽水(10 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮。藉由矽膠急驟層析純化殘餘物，得到呈黃色固體之((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(2-(2-側氧基-1,3-雙((2-(三甲基矽烷基)乙氧基)甲基)-2,3-二氫-1H-苯并[d]咪唑-5-基)乙基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯(40 mg，產率33%)。LC-MS: 849 (M+H)+ 。2-(2-Oxy-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[ d] Imidazol-5-yl)acetaldehyde (60 mg, 0.141 mmol), ((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl- Methyl 1H-imidazol-1-yl)-1-(piperidin-4-yl)ethyl)cyclopentyl)carbamate (E5) (73 mg, 0.168 mmol) and AcOH (8 mg, 0.141 mmol) Mixture in DCM (10 mL) for 1 hour. Then NaBH(OAc) 3 (59 mg, 0.282 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with H 2 O (10 mL), adjusted to pH about 7 with saturated aqueous NaHCO 3 and extracted with DCM (10 mL×3). The combined organic layers were washed with brine (10 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography to give ((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazole) as a yellow solid -1-yl)-1-(1-(2-(2-oxy-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-di Hydro-lH-benzo[d]imidazol-5-yl)ethyl)piperidin-4-yl)ethyl)cyclopentyl)carbamate (40 mg, 33% yield). LC-MS: 849 (M+H) + .
步驟D：((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(2-(2-側氧基-2,3-二氫-1H-苯并[d]咪唑-5-基)乙基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯(化合物132)Step D: ((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1-( Methyl 2-(2-oxy-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)piperidin-4-yl)ethyl)cyclopentyl)carbamate Esters (Compound 132)
在0℃下向((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(2-(2-側氧基-1,3-雙((2-(三甲基矽烷基)乙氧基)甲基)-2,3-二氫-1H-苯并[d]咪唑-5-基)乙基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯(40 mg，0.047 mmol)於DCM (6 mL)中之溶液中添加TFA (2 mL)。在25℃下攪拌反應混合物3小時。在減壓下濃縮混合物。藉由RP-製備型HPLC純化殘餘物，得到呈白色固體之化合物132 (8 mg，產率30%)。LC-MS: 589 (M+H)+ 。1 H NMR (400 MHz, MeOD-d4 ) δ 7.50 - 7.42 (m, 2H), 7.40 - 7.35 (m, 1H), 7.13 - 7.06 (m, 1H), 6.94 (d, 1H), 6.90 - 6.85 (m, 2H), 6.72 (d, 1H), 6.68 (d, 1H), 4.56 (d, 1H), 4.36 (d, 1H), 4.05 - 3.95 (m, 1H), 3.60 (s, 3H), 3.20 - 3.11 (m, 1H), 3.10 - 3.02 (m, 1H), 2.85 - 2.72 (m, 2H), 2.70 - 2.55 (m, 3H), 2.45 (s, 3H), 2.35 - 1.99 (m, 4H), 1.93 - 1.82 (m, 1H), 1.78 - 1.67 (m, 1H), 1.57 - 1.45 (m, 1H), 1.42 - 1.10 (m, 5H), 0.87 - 0.72 (m, 1H)。 實例21To ((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1 at 0°C -(2-(2-Oxy-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazole To a solution of methyl-5-yl)ethyl)piperidin-4-yl)ethyl)cyclopentyl)carbamate (40 mg, 0.047 mmol) in DCM (6 mL) was added TFA (2 mL) . The reaction mixture was stirred at 25°C for 3 hours. The mixture was concentrated under reduced pressure. The residue was purified by RP-preparative HPLC to give compound 132 (8 mg, 30% yield) as a white solid. LC-MS: 589 (M+H) + . 1 H NMR (400 MHz, MeOD- d 4 ) δ 7.50 - 7.42 (m, 2H), 7.40 - 7.35 (m, 1H), 7.13 - 7.06 (m, 1H), 6.94 (d, 1H), 6.90 - 6.85 (m, 2H), 6.72 (d, 1H), 6.68 (d, 1H), 4.56 (d, 1H), 4.36 (d, 1H), 4.05 - 3.95 (m, 1H), 3.60 (s, 3H), 3.20 - 3.11 (m, 1H), 3.10 - 3.02 (m, 1H), 2.85 - 2.72 (m, 2H), 2.70 - 2.55 (m, 3H), 2.45 (s, 3H), 2.35 - 1.99 (m, 4H) ), 1.93 - 1.82 (m, 1H), 1.78 - 1.67 (m, 1H), 1.57 - 1.45 (m, 1H), 1.42 - 1.10 (m, 5H), 0.87 - 0.72 (m, 1H). Example 21
製備((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(((1r,3S)-3-((2-側氧基-2,3-二氫-1H-苯并[d]咪唑-5-基)氧基)環丁基)甲基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯(化合物136)
步驟A：5-溴-1,3-雙((2-(三甲基矽烷基)乙氧基)甲基)-1,3-二氫-2H-苯并[d]咪唑-2-酮Step A: 5-Bromo-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one
在0℃下向5-溴-1,3-二氫-2H-苯并[d]咪唑-2-酮(4 g，18.8 mmol)於DMF (40 mL)中之溶液中添加NaH (1.9 g，46.9 mmol，60% wt/wt 於油中)且在此溫度下攪拌混合物10 min。在0℃下將(2-(氯甲氧基)乙基)三甲基矽烷(7.2 g，43.2 mmol)於THF (10 mL)中之溶液添加至反應物中。在室溫下攪拌反應混合物2 h。將混合物倒入NH4 Cl飽和水溶液(50 mL)中且用EtOAc (80 mL×2)萃取。合併之有機層用水、鹽水(50 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮至乾燥。藉由急驟層析純化殘餘物，得到呈白色固體之5-溴-1,3-雙((2-(三甲基矽烷基)乙氧基)甲基)-1,3-二氫-2H-苯并[d]咪唑-2-酮(5.3 g，產率59%)。LC-MS: 473, 475 (M+H)+ 。To a solution of 5-bromo-1,3-dihydro-2H-benzo[d]imidazol-2-one (4 g, 18.8 mmol) in DMF (40 mL) at 0 °C was added NaH (1.9 g) , 46.9 mmol, 60% wt/wt in oil) and the mixture was stirred at this temperature for 10 min. A solution of (2-(chloromethoxy)ethyl)trimethylsilane (7.2 g, 43.2 mmol) in THF (10 mL) was added to the reaction at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The mixture was poured into saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (80 mL x 2). The combined organic layers were washed with water, brine (50 mL), dried over Na 2 SO 4 and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography to give 5-bromo-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H as a white solid - Benzo[d]imidazol-2-one (5.3 g, 59% yield). LC-MS: 473, 475 (M+H) + .
步驟B：5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)-1,3-雙((2-(三甲基矽烷基)乙氧基)甲基)-1,3-二氫-2H-苯并[d]咪唑-2-酮Step B: 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3-bis((2-(trimethylsilane) yl)ethoxy)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one
在室溫下向5-溴-1,3-雙((2-(三甲基矽烷基)乙氧基)甲基)-1,3-二氫-2H-苯并[d]咪唑-2-酮(2 g，4.2 mmol)及4,4,4',4',5,5,5',5'-八甲基-2,2'-雙(1,3,2-二氧雜硼戊烷) (1.6 g，6.3 mmol)於1,4-二㗁烷(25 mL)中之溶液中添加Pd(dppf)Cl2 (310 mg，0.42 mmol)及AcOK (1.2 g，12.7 mmol)。在N2 氛圍下於100℃攪拌混合物18小時。過濾混合物且在減壓下濃縮至乾燥。藉由急驟層析純化殘餘物，得到呈黃色油狀物之5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)-1,3-雙((2-(三甲基矽烷基)乙氧基)甲基)-1,3-二氫-2H-苯并[d]咪唑-2-酮(2 g，產率91%)。LC-MS: 521 (M+H)+ 。To 5-bromo-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-benzo[d]imidazole-2 at room temperature -ketone (2 g, 4.2 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxa boropentane) (1.6 g, 6.3 mmol) in 1,4-dioxane (25 mL) was added Pd(dppf)Cl2 (310 mg , 0.42 mmol) and AcOK (1.2 g, 12.7 mmol) . The mixture was stirred at 100 °C for 18 h under N2 atmosphere. The mixture was filtered and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography to give 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 as a yellow oil ,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (2 g, 91% yield ). LC-MS: 521 (M+H) + .
步驟C：5-羥基-1,3-雙((2-(三甲基矽烷基)乙氧基)甲基)-1H-苯并[d]咪唑-2(3H)-酮Step C: 5-Hydroxy-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2(3H)-one
在0℃下向5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)-1,3-雙((2-(三甲基矽烷基)乙氧基)甲基)-1H-苯并[d]咪唑-2(3H)-酮(1 g，1.9 mmol，1.0當量)及NaOH (1 M於H2 O中，1.9 mL，1.9 mmol，1.0當量)於THF (15 mL)中之溶液中添加H2 O2 (330 mg，2.9 mmol，30% wt/wt於H2 O中)。在室溫攪拌反應混合物30 min。用1 N HCl水溶液將混合物調節至pH約7且用EtOAc (60 mL×2)萃取。合併之有機層用鹽水(20 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮至乾燥。藉由急驟層析純化殘餘物，得到呈白色固體之5-羥基-1,3-雙((2-(三甲基矽烷基)乙氧基)甲基)-1H-苯并[d]咪唑-2(3H)-酮(680 mg，產率86%)。LC-MS: 411 (M+H)+ 。To 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3-bis((2-(trimethyl) at 0 °C silyl)ethoxy)methyl)-1H-benzo[d]imidazol-2(3H)-one (1 g, 1.9 mmol, 1.0 equiv) and NaOH (1 M in H2O , 1.9 mL , 1.9 mmol, 1.0 equiv) in THF (15 mL) was added H2O2 (330 mg, 2.9 mmol, 30% wt/wt in H2O ) . The reaction mixture was stirred at room temperature for 30 min. The mixture was adjusted to pH about 7 with 1 N aqueous HCl and extracted with EtOAc (60 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4 and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography to give 5-hydroxy-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole as a white solid -2(3H)-one (680 mg, 86% yield). LC-MS: 411 (M+H) + .
步驟D：(1r,3r)-3-((2-側氧基-1,3-雙((2-(三甲基矽烷基)乙氧基)甲基)-2,3-二氫-1H-苯并[d]咪唑-5-基)氧基)環丁烷-1-甲酸甲酯及(1s,3s)-3-((2-側氧基-1,3-雙((2-(三甲基矽烷基)乙氧基)甲基)-2,3-二氫-1H-苯并[d]咪唑-5-基)氧基)環丁烷-1-甲酸甲酯Step D: (1r,3r)-3-((2-oxy-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro- 1H-Benzo[d]imidazol-5-yl)oxy)cyclobutane-1-carboxylic acid methyl ester and (1s,3s)-3-((2-oxy-1,3-bis((2 -(Trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)oxy)cyclobutane-1-carboxylic acid methyl ester
向25 mL微波小瓶中裝入磁性攪拌棒、5-羥基-1,3-雙((2-(三甲基矽烷基)乙氧基)甲基)-1H-苯并[d]咪唑-2(3H)-酮(800 mg，1.9 mmol)、(1s,3s)-3-((甲基磺醯基)氧基)環丁烷-1-甲酸甲酯(527 mg，2.5 mmol；Ref: WO2018/69863, 2018, A1)、Cs2 CO3 (1.9 g，5.8 mmol)、KI (323 mg，1.9 mmol)及DMSO (15 mL)接著在100℃下照射反應物50 min。將混合物倒入水(50 mL)中且用EtOAc (2×30 mL)萃取。合併之有機層用鹽水(30 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮至乾燥。藉由急驟層析純化殘餘物，得到呈黃色油狀物之(1r,3r)-甲基3-(2-側氧基-1,3-雙((2-(三甲基矽烷基)乙氧基)甲基)-2,3-二氫-1H-苯并[d]咪唑-5-基氧基)環丁烷甲酸甲酯(130 mg，產率13%)，LC-MS: 523(M+H)+ ；及呈黃色油狀物之(1s,3s)-3-(2-側氧基-1,3-雙((2-(三甲基矽烷基)乙氧基)甲基)-2,3-二氫-1H-苯并[d]咪唑-5-基氧基)環丁烷甲酸甲酯(125 mg，產率13%)，LC-MS: 523(M+H)+ 。A 25 mL microwave vial was charged with a magnetic stir bar, 5-hydroxy-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2 (3H)-ketone (800 mg, 1.9 mmol), methyl (1s,3s)-3-((methylsulfonyl)oxy)cyclobutane-1-carboxylate (527 mg, 2.5 mmol; Ref: WO2018/69863, 2018, A1), Cs2CO3 ( 1.9 g, 5.8 mmol), KI (323 mg, 1.9 mmol) and DMSO (15 mL) followed by irradiating the reaction at 100 °C for 50 min. The mixture was poured into water (50 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over Na 2 SO 4 and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography to give (1r,3r)-methyl 3-(2-oxy-1,3-bis((2-(trimethylsilyl)ethyl) as a yellow oil Methyl oxy)methyl)-2,3-dihydro-1H-benzo[d]imidazol-5-yloxy)cyclobutanecarboxylate (130 mg, 13% yield), LC-MS: 523 (M+H) + ; and (1s,3s)-3-(2-oxy-1,3-bis((2-(trimethylsilyl)ethoxy)methyl) as a yellow oil yl)-2,3-dihydro-1H-benzo[d]imidazol-5-yloxy)cyclobutanecarboxylate (125 mg, 13% yield), LC-MS: 523 (M+H ) + .
步驟E：5-((1r,3r)-3-(羥基甲基)環丁氧基)-1,3-雙((2-(三甲基矽烷基)乙氧基)甲基)-1,3-二氫-2H-苯并[d]咪唑-2-酮Step E: 5-((1r,3r)-3-(hydroxymethyl)cyclobutoxy)-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1 ,3-Dihydro-2H-benzo[d]imidazol-2-one
在-40℃下向(1r,3r)-3-((2-側氧基-1,3-雙((2-(三甲基矽烷基)乙氧基)甲基)-2,3-二氫-1H-苯并[d]咪唑-5-基)氧基)環丁烷-1-甲酸甲酯(120 mg，0.23 mmol)於THF (5 mL)中之溶液中添加LiAlH4 (1 M於THF中，0.34 mL，0.34 mmol)。在此溫度下攪拌混合物30 min且用Na2 SO4 .10H2 O (1 g)淬滅。接著將EtOAc (50 mL)添加至混合物中且過濾。經Na2 SO4 乾燥濾液且在減壓下濃縮至乾燥。藉由急驟層析純化殘餘物，得到呈黃色油狀物之5-((1r,3r)-3-(羥甲基)環丁氧基)-1,3-雙((2-(三甲基矽烷基)乙氧基)甲基)-1,3-二氫-2H-苯并[d]咪唑-2-酮(100 mg，產率88%)。LC-MS: 495(M+H)+ 。at -40°C to (1r,3r)-3-((2-oxy-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3- To a solution of methyl dihydro-1H-benzo[d]imidazol-5-yl)oxy)cyclobutane-1-carboxylate (120 mg, 0.23 mmol) in THF (5 mL) was added LiAlH4 ( 1 M in THF, 0.34 mL, 0.34 mmol). The mixture was stirred at this temperature for 30 min and quenched with Na2SO4.10H2O ( 1 g ). Then EtOAc (50 mL) was added to the mixture and filtered. The filtrate was dried over Na2SO4 and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography to give 5-((1r,3r)-3-(hydroxymethyl)cyclobutoxy)-1,3-bis((2-(trimethyl) as a yellow oil silyl)ethoxy)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (100 mg, 88% yield). LC-MS: 495(M+H) + .
步驟F：甲烷磺酸((1r,3r)-3-((2-側氧基-1,3-雙((2-(三甲基矽烷基)乙氧基)甲基)-2,3-二氫-1H-苯并[d]咪唑-5-基)氧基)環丁基)甲酯Step F: Methanesulfonic acid ((1r,3r)-3-((2-oxy-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3 -Dihydro-1H-benzo[d]imidazol-5-yl)oxy)cyclobutyl)methyl ester
在0℃下向5-((1r,3r)-3-(羥基甲基)環丁氧基)-1,3-雙((2-(三甲基矽烷基)乙氧基)甲基)-1,3-二氫-2H-苯并[d]咪唑-2-酮(100 mg，0.20 mmol)及TEA (0.04 mL，0.30 mmol)於DCM (3 mL)中之溶液中添加MsCl (0.02 mL，0.22 mmol)。在室溫下攪拌混合物1.5小時。將混合物倒入水(20 mL)中且用DCM (30 mL×2)萃取。合併之有機層用鹽水(20 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮至乾燥。藉由急驟層析純化殘餘物，得到呈黃色油狀物之甲烷磺酸((1r,3r)-3-((2-側氧基-1,3-雙((2-(三甲基矽烷基)乙氧基)甲基)-2,3-二氫-1H-苯并[d]咪唑-5-基)氧基)環丁基)甲酯(90 mg，產率65%)。LC-MS: 573(M+H)+ 。To 5-((1r,3r)-3-(hydroxymethyl)cyclobutoxy)-1,3-bis((2-(trimethylsilyl)ethoxy)methyl) at 0 °C To a solution of -1,3-dihydro-2H-benzo[d]imidazol-2-one (100 mg, 0.20 mmol) and TEA (0.04 mL, 0.30 mmol) in DCM (3 mL) was added MsCl (0.02 mL, 0.22 mmol). The mixture was stirred at room temperature for 1.5 hours. The mixture was poured into water (20 mL) and extracted with DCM (30 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4 and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography to give methanesulfonic acid ((1r,3r)-3-((2-oxy-1,3-bis((2-(trimethylsilane) as a yellow oil (90 mg, 65% yield). LC-MS: 573 (M+H) + .
步驟G：((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(((1r,3S)-3-((2-側氧基-1,3-雙((2-(三甲基矽烷基)乙氧基)甲基)-2,3-二氫-1H-苯并[d]咪唑-5-基)氧基)環丁基)甲基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯Step G: ((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1-( ((1r,3S)-3-((2-oxy-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H- Benzo[d]imidazol-5-yl)oxy)cyclobutyl)methyl)piperidin-4-yl)ethyl)cyclopentyl)carbamate
在室溫下向((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(哌啶-4-基)乙基)環戊基)胺基甲酸甲酯(E5) (70 mg，0.18 mmol)及甲烷磺酸((1r,3r)-3-((2-側氧基-1,3-雙((2-(三甲基矽烷基)乙氧基)甲基)-2,3-二氫-1H-苯并[d]咪唑-5-基)氧基)環丁基)甲酯(90 mg，0.18 mmol)於MeCN (5 mL)中之溶液中添加K2 CO3 (52 mg，0.37 mmol)及KI (62 mg，0.37 mmol)。在80℃下攪拌混合物18 h。冷卻且過濾混合物。將濾液在減壓下濃縮至乾燥。藉由製備型TLC純化殘餘物，得到呈黃色固體之((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(((1r,3S)-3-((2-側氧基-1,3-雙((2-(三甲基矽烷基)乙氧基)甲基)-2,3-二氫-1H-苯并[d]咪唑-5-基)氧基)環丁基)甲基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯(40 mg，產率24%)。LC-MS: 905 (M+H)+ 。To ((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(piperidine) at room temperature Methyl pyridin-4-yl)ethyl)cyclopentyl)carbamate (E5) (70 mg, 0.18 mmol) and methanesulfonic acid ((1r,3r)-3-((2-oxo-1 ,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)oxy)cyclobutyl) To a solution of methyl ester (90 mg, 0.18 mmol) in MeCN ( 5 mL) was added K2CO3 ( 52 mg, 0.37 mmol) and KI (62 mg, 0.37 mmol). The mixture was stirred at 80 °C for 18 h. Cool and filter the mixture. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by preparative TLC to give ((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazole-) as a yellow solid 1-yl)-1-(1-(((1r,3S)-3-((2-oxy-1,3-bis((2-(trimethylsilyl)ethoxy)methyl) )-2,3-dihydro-1H-benzo[d]imidazol-5-yl)oxy)cyclobutyl)methyl)piperidin-4-yl)ethyl)cyclopentyl)carbamate Ester (40 mg, 24% yield). LC-MS: 905 (M+H) + .
步驟H：((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(((1r,3S)-3-((2-側氧基-2,3-二氫-1H-苯并[d]咪唑-5-基)氧基)環丁基)甲基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯(化合物136)Step H: ((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1-( ((1r,3S)-3-((2-Oxy-2,3-dihydro-1H-benzo[d]imidazol-5-yl)oxy)cyclobutyl)methyl)piperidine- Methyl 4-yl)ethyl)cyclopentyl)carbamate (Compound 136)
在室溫下向((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(((1r,3S)-3-((2-側氧基-1,3-雙((2-(三甲基矽烷基)乙氧基)甲基)-2,3-二氫-1H-苯并[d]咪唑-5-基)氧基)環丁基)甲基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯(40 mg，0.044 mmol)於DCM (3 mL)中之溶液中添加TFA (1 mL)。在此溫度下攪拌混合物1.5小時且在減壓下濃縮至乾燥。將殘餘物溶解於MeOH (2 mL)中且在室溫下添加NH4 OH (28%於H2 O中，2 mL)。在此溫度下攪拌混合物1.5h。將混合物在減壓下濃縮至乾燥。藉由RP-製備型HPLC純化殘餘物，得到呈白色固體之化合物136 (4.3 mg，產率15%)。LC-MS: 645 (M+H)+ 。1 H NMR (400 MHz, MeOD-d4 ) δ 7.49 - 7.40 (m, 2H), 7.39 - 7.31 (m, 1H), 7.13 - 7.05 (m, 1H), 6.88 (dd, 1H), 6.70 (d, 1H), 6.65 (d, 1H), 6.54 - 6.47 (m, 2H), 4.71 - 4.65 (m, 1H), 4.53 (d, 1H), 4.33 (d, 1H), 4.05 - 3.96 (m, 1H), 3.60 (s, 3H), 3.02 - 2.93 (m, 1H), 2.90 - 2.81 (m, 1H), 2.65 - 2.55 (m, 2H), 2.53 - 2.47 (m, 2H), 2.43 (s, 3H), 2.30 - 2.13 (m, 4H), 2.05 - 1.94 (m, 4H), 1.91 - 1.81 (m, 1H), 1.71 - 1.60 (m, 1H), 1.55 - 1.42 (m, 1H), 1.40 - 1.10 (m, 5H), 0.85 - 0.70 (m, 1H)。 實例22To ((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1 -(((1r,3S)-3-((2-oxy-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro- Methyl 1H-benzo[d]imidazol-5-yl)oxy)cyclobutyl)methyl)piperidin-4-yl)ethyl)cyclopentyl)carbamate (40 mg, 0.044 mmol) in To a solution in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at this temperature for 1.5 hours and concentrated to dryness under reduced pressure. The residue was dissolved in MeOH (2 mL) and NH4OH (28% in H2O, 2 mL) was added at room temperature. The mixture was stirred at this temperature for 1.5 h. The mixture was concentrated to dryness under reduced pressure. The residue was purified by RP-preparative HPLC to give compound 136 (4.3 mg, 15% yield) as a white solid. LC-MS: 645 (M+H) + . 1 H NMR (400 MHz, MeOD- d 4 ) δ 7.49 - 7.40 (m, 2H), 7.39 - 7.31 (m, 1H), 7.13 - 7.05 (m, 1H), 6.88 (dd, 1H), 6.70 (d , 1H), 6.65 (d, 1H), 6.54 - 6.47 (m, 2H), 4.71 - 4.65 (m, 1H), 4.53 (d, 1H), 4.33 (d, 1H), 4.05 - 3.96 (m, 1H) ), 3.60 (s, 3H), 3.02 - 2.93 (m, 1H), 2.90 - 2.81 (m, 1H), 2.65 - 2.55 (m, 2H), 2.53 - 2.47 (m, 2H), 2.43 (s, 3H) ), 2.30 - 2.13 (m, 4H), 2.05 - 1.94 (m, 4H), 1.91 - 1.81 (m, 1H), 1.71 - 1.60 (m, 1H), 1.55 - 1.42 (m, 1H), 1.40 - 1.10 (m, 5H), 0.85 - 0.70 (m, 1H). Example 22
製備((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(((1s,3R)-3-((2-側氧基-2,3-二氫-1H-苯并[d]咪唑-5-基)氧基)環丁基)甲基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯(化合物137)
步驟A：5-((1s,3s)-3-(羥甲基)環丁氧基)-1,3-雙((2-(三甲基矽烷基)乙氧基)甲基)-1,3-二氫-2H-苯并[d]咪唑-2-酮Step A: 5-((1s,3s)-3-(hydroxymethyl)cyclobutoxy)-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1 ,3-Dihydro-2H-benzo[d]imidazol-2-one
在-40℃下向如實例21中所闡述製備的(1s,3s)-3-((2-側氧基-1,3-雙((2-(三甲基矽烷基)乙氧基)甲基)-2,3-二氫-1H-苯并[d]咪唑-5-基)氧基)環丁烷-1-甲酸甲酯(120 mg，0.23 mmol)於THF (5 mL)中之溶液中添加LiAlH4 (1 M於THF中，0.34 mL，0.34 mmol)。在此溫度下攪拌混合物30 min且用Na2 SO4 .10H2 O (1 g)淬滅。接著將EtOAc (50 mL)添加至混合物中且過濾。經Na2 SO4 乾燥濾液且在減壓下濃縮至乾燥。藉由急驟層析純化殘餘物，得到呈黃色油狀物之5-((1s,3s)-3-(羥基甲基)環丁氧基)-1,3-雙((2-(三甲基矽烷基)乙氧基)甲基)-1,3-二氫-2H-苯并[d]咪唑-2-酮(105 mg，產率88%)。LC-MS: 495(M+H)+ 。To (1s,3s)-3-((2-oxy-1,3-bis((2-(trimethylsilyl)ethoxy)) prepared as described in Example 21 at -40°C Methyl)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)oxy)cyclobutane-1-carboxylic acid methyl ester (120 mg, 0.23 mmol) in THF (5 mL) To this solution was added LiAlH4 ( 1 M in THF, 0.34 mL, 0.34 mmol). The mixture was stirred at this temperature for 30 min and quenched with Na2SO4.10H2O ( 1 g ). Then EtOAc (50 mL) was added to the mixture and filtered. The filtrate was dried over Na2SO4 and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography to give 5-((1s,3s)-3-(hydroxymethyl)cyclobutoxy)-1,3-bis((2-(trimethyl) as a yellow oil (silyl)ethoxy)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (105 mg, 88% yield). LC-MS: 495(M+H) + .
步驟B：甲烷磺酸((1s,3s)-3-((2-側氧基-1,3-雙((2-(三甲基矽烷基)乙氧基)甲基)-2,3-二氫-1H-苯并[d]咪唑-5-基)氧基)環丁基)甲酯Step B: Methanesulfonic acid ((1s,3s)-3-((2-oxy-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3 -Dihydro-1H-benzo[d]imidazol-5-yl)oxy)cyclobutyl)methyl ester
在0℃下向5-((1s,3s)-3-(羥甲基)環丁氧基)-1,3-雙((2-(三甲基矽烷基)乙氧基)甲基)-1,3-二氫-2H-苯并[d]咪唑-2-酮(100 mg，0.20 mmol)及TEA (0.04 mL，0.30 mmol)於DCM (3 mL)之溶液中添加MsCl (0.02 mL，0.22 mmol)。在室溫下攪拌混合物1.5小時。將混合物倒入水(20 mL)中且用DCM (30 mL×2)萃取。合併之有機層用鹽水(20 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮至乾燥。藉由急驟層析純化殘餘物，得到呈黃色油狀物之甲烷磺酸((1s,3s)-3-((2-側氧基-1,3-雙((2-(三甲基矽烷基)乙氧基)甲基)-2,3-二氫-1H-苯并[d]咪唑-5-基)氧基)環丁基)甲酯(93 mg，產率65%)。LC-MS: 573(M+H)+ 。To 5-((1s,3s)-3-(hydroxymethyl)cyclobutoxy)-1,3-bis((2-(trimethylsilyl)ethoxy)methyl) at 0 °C -1,3-Dihydro-2H-benzo[d]imidazol-2-one (100 mg, 0.20 mmol) and TEA (0.04 mL, 0.30 mmol) in DCM (3 mL) were added MsCl (0.02 mL) , 0.22 mmol). The mixture was stirred at room temperature for 1.5 hours. The mixture was poured into water (20 mL) and extracted with DCM (30 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4 and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography to give methanesulfonic acid ((1s,3s)-3-((2-oxy-1,3-bis((2-(trimethylsilane) as a yellow oil (93 mg, 65% yield). LC-MS: 573 (M+H) + .
步驟C：((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(((1s,3R)-3-((2-側氧基-1,3-雙((2-(三甲基矽烷基)乙氧基)甲基)-2,3-二氫-1H-苯并[d]咪唑-5-基)氧基)環丁基)甲基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯Step C: ((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1-( ((1s,3R)-3-((2-oxy-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H- Benzo[d]imidazol-5-yl)oxy)cyclobutyl)methyl)piperidin-4-yl)ethyl)cyclopentyl)carbamate
在室溫下向((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(哌啶-4-基)乙基)環戊基)胺基甲酸甲酯(E5) (70 mg，0.18 mmol)及甲烷磺酸((1s,3s)-3-((2-側氧基-1,3-雙((2-(三甲基矽烷基)乙氧基)甲基)-2,3-二氫-1H-苯并[d]咪唑-5-基)氧基)環丁基)甲酯(93 mg，0.18 mmol)於MeCN (5 mL)及K2 CO3 (52 mg，0.37 mmol)中之混合物中添加KI (62 mg，0.37 mmol)。在80℃下攪拌混合物18小時。冷卻且過濾混合物。將濾液在減壓下濃縮至乾燥。藉由製備型TLC純化殘餘物，得到呈黃色固體之((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(((1s,3R)-3-((2-側氧基-1,3-雙((2-(三甲基矽烷基)乙氧基)甲基)-2,3-二氫-1H-苯并[d]咪唑-5-基)氧基)環丁基)甲基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯(38 mg，產率23%)。LC-MS: 905 (M+H)+ 。To ((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(piperidine) at room temperature Methyl pyridin-4-yl)ethyl)cyclopentyl)carbamate (E5) (70 mg, 0.18 mmol) and methanesulfonic acid ((1s,3s)-3-((2-oxo-1 ,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)oxy)cyclobutyl) To a mixture of methyl ester (93 mg, 0.18 mmol) in MeCN ( 5 mL) and K2CO3 ( 52 mg, 0.37 mmol) was added KI (62 mg, 0.37 mmol). The mixture was stirred at 80°C for 18 hours. Cool and filter the mixture. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by preparative TLC to give ((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazole-) as a yellow solid 1-yl)-1-(1-(((1s,3R)-3-((2-oxy-1,3-bis((2-(trimethylsilyl)ethoxy)methyl) )-2,3-dihydro-1H-benzo[d]imidazol-5-yl)oxy)cyclobutyl)methyl)piperidin-4-yl)ethyl)cyclopentyl)carbamate Ester (38 mg, 23% yield). LC-MS: 905 (M+H) + .
步驟D：((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(((1s,3R)-3-((2-側氧基-2,3-二氫-1H-苯并[d]咪唑-5-基)氧基)環丁基)甲基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯(化合物137)Step D: ((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1-( ((1s,3R)-3-((2-Oxy-2,3-dihydro-1H-benzo[d]imidazol-5-yl)oxy)cyclobutyl)methyl)piperidine- 4-yl)ethyl)cyclopentyl)carbamate (compound 137)
在室溫下向((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(((1s,3R)-3-((2-側氧基-1,3-雙((2-(三甲基矽烷基)乙氧基)甲基)-2,3-二氫-1H-苯并[d]咪唑-5-基)氧基)環丁基)甲基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯(38 mg，0.04 mmol)於DCM (3 mL)中之溶液中添加TFA (1 mL)。在此溫度下攪拌混合物1.5小時且在減壓下濃縮至乾燥。將殘餘物溶解於MeOH (2 mL)中且在室溫下添加NH4 OH (28%於H2 O中，2 mL)。在此溫度下攪拌混合物1.5 h。將混合物在減壓下濃縮至乾燥。藉由RP-製備型HPLC純化殘餘物，得到呈白色固體之化合物137 (8.2 mg，產率19%)。LC-MS: 645 (M+H)+ 。1 H NMR (400 MHz, MeOD-d4 ) δ 7.49 - 7.40 (m, 2H), 7.39 - 7.31 (m, 1H), 7.13 - 7.05 (m, 1H), 6.88 (d, 1H), 6.70 (d, 1H), 6.65 (d, 1H), 6.57 - 6.47 (m, 2H), 4.62 - 4.45 (m, 1H), 4.53 (d, 1H), 4.33 (d, 1H), 4.05 - 3.96 (m, 1H), 3.60 (s, 3H), 3.00 - 2.90 (m, 1H), 2.89 - 2.80 (m, 1H), 2.65 - 2.55 (m, 2H), 2.47 - 2.37 (m, 2H), 2.43 (s, 3H), 2.25 - 2.08 (m, 2H), 2.03 - 1.91 (m, 3H), 1.90 - 1.81 (m, 2H), 1.77 - 1.61 (m, 3H), 1.55 - 1.43 (m, 1H), 1.42 - 1.12 (m, 5H), 0.84 - 0.70 (m, 1H)。 實例23To ((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1 -(((1s,3R)-3-((2-oxy-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro- Methyl 1H-benzo[d]imidazol-5-yl)oxy)cyclobutyl)methyl)piperidin-4-yl)ethyl)cyclopentyl)carbamate (38 mg, 0.04 mmol) in To a solution in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at this temperature for 1.5 hours and concentrated to dryness under reduced pressure. The residue was dissolved in MeOH (2 mL) and NH4OH (28% in H2O, 2 mL) was added at room temperature. The mixture was stirred at this temperature for 1.5 h. The mixture was concentrated to dryness under reduced pressure. The residue was purified by RP-preparative HPLC to give compound 137 (8.2 mg, 19% yield) as a white solid. LC-MS: 645 (M+H) + . 1 H NMR (400 MHz, MeOD- d 4 ) δ 7.49 - 7.40 (m, 2H), 7.39 - 7.31 (m, 1H), 7.13 - 7.05 (m, 1H), 6.88 (d, 1H), 6.70 (d , 1H), 6.65 (d, 1H), 6.57 - 6.47 (m, 2H), 4.62 - 4.45 (m, 1H), 4.53 (d, 1H), 4.33 (d, 1H), 4.05 - 3.96 (m, 1H) ), 3.60 (s, 3H), 3.00 - 2.90 (m, 1H), 2.89 - 2.80 (m, 1H), 2.65 - 2.55 (m, 2H), 2.47 - 2.37 (m, 2H), 2.43 (s, 3H) ), 2.25 - 2.08 (m, 2H), 2.03 - 1.91 (m, 3H), 1.90 - 1.81 (m, 2H), 1.77 - 1.61 (m, 3H), 1.55 - 1.43 (m, 1H), 1.42 - 1.12 (m, 5H), 0.84 - 0.70 (m, 1H). Example 23
製備((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(2-(2-(甲基磺醯基)異吲哚啉-5-基)乙基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯(化合物134)
步驟A：5-溴-2-(甲基磺醯基)異吲哚啉Step A: 5-Bromo-2-(methylsulfonyl)isoindoline
在0℃下向5-溴異吲哚啉鹽酸鹽(500 mg，2.13 mmol)於DCM (10 mL)中之混合物中添加TEA (1.18 mL，8.52 mmol)及MsCl (0.18 mL，2.35 mmol)。在室溫下攪拌反應混合物2小時。接著用H2 O (20 mL)稀釋混合物且用DCM (20 mL×3)萃取。經合併之有機層用鹽水(30 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮。藉由矽膠急驟管柱層析純化殘餘物，得到呈白色固體之5-溴-2-(甲基磺醯基)異吲哚啉(560 mg，產率95%)。LC-MS: 276, 278 (M+H)+ 。To a mixture of 5-bromoisoindoline hydrochloride (500 mg, 2.13 mmol) in DCM (10 mL) at 0 °C was added TEA (1.18 mL, 8.52 mmol) and MsCl (0.18 mL, 2.35 mmol) . The reaction mixture was stirred at room temperature for 2 hours. The mixture was then diluted with H2O (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give 5-bromo-2-(methylsulfonyl)isoindoline (560 mg, 95% yield) as a white solid. LC-MS: 276, 278 (M+H) + .
步驟B：(E)-5-(2-乙氧基乙烯基)-2-(甲基磺醯基)異吲哚啉Step B: (E)-5-(2-Ethoxyvinyl)-2-(methylsulfonyl)isoindoline
在N2 氛圍下，於90℃攪拌5-溴-2-(甲基磺醯基)異吲哚啉(300 mg，1.08 mmol)、(E)-2-(2-乙氧基乙烯基)-4,4,5,5-四甲基-1,3,2-二氧雜硼戊烷(258 mg，1.31 mmol)、Pd(dppf)Cl2 (79 mg，0.11 mmol)及Na2 CO3 (345 mg，3.25 mmol)於二㗁烷(10 mL)及H2 O (1 mL)中之混合物3小時。接著用H2 O (20 mL)稀釋混合物且用EtOAc (20 mL×3)萃取。經合併之有機層用鹽水(20 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮。藉由矽膠急驟管柱層析純化殘餘物，得到呈白色固體之(E)-5-(2-乙氧基乙烯基)-2-(甲基磺醯基)異吲哚啉(240 mg，產率82%)。LC-MS: 268 (M+H)+ 。Stir 5-bromo-2-(methylsulfonyl)isoindoline (300 mg, 1.08 mmol), (E)-2-( 2 -ethoxyvinyl) at 90 °C under N atmosphere -4,4,5,5-Tetramethyl-1,3,2-dioxaborolane (258 mg, 1.31 mmol), Pd(dppf)Cl2 (79 mg , 0.11 mmol) and Na2CO A mixture of 3 (345 mg, 3.25 mmol) in diethane (10 mL) and H2O (1 mL) for 3 h. The mixture was then diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give (E)-5-(2-ethoxyvinyl)-2-(methylsulfonyl)isoindoline as a white solid (240 mg, yield 82%). LC-MS: 268 (M+H) + .
步驟C：2-(2-(甲基磺醯基)異吲哚啉-5-基)乙醛Step C: 2-(2-(Methylsulfonyl)isoindolin-5-yl)acetaldehyde
在60℃下攪拌(E)-5-(2-乙氧基乙烯基)-2-(甲基磺醯基)異吲哚啉(200 mg，0.74 mmol)及1N HCl水溶液(2 mL)於THF (2 mL)中之混合物1小時。接著用NaHCO3 飽和水溶液將反應混合物調整至pH約7且用EtOAc (20 mL×3)萃取。經合併之有機層用鹽水(20 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮，得到呈黃色固體之2-(2-(甲基磺醯基)異吲哚啉-5-基)乙醛(100 mg，粗物質)。LC-MS: 240 (M+H)+ 。(E)-5-(2-ethoxyvinyl)-2-(methylsulfonyl)isoindoline (200 mg, 0.74 mmol) and 1N aqueous HCl (2 mL) were stirred at 60 °C The mixture in THF (2 mL) for 1 hour. The reaction mixture was then adjusted to pH about 7 with saturated aqueous NaHCO3 and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4 and concentrated under reduced pressure to give 2-(2-(methylsulfonyl)isoindoline-5- as a yellow solid base) acetaldehyde (100 mg, crude). LC-MS: 240 (M+H) + .
步驟D：((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(2-(2-(甲基磺醯基)異吲哚啉-5-基)乙基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯(化合物134)Step D: ((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1-( Methyl 2-(2-(methylsulfonyl)isoindolin-5-yl)ethyl)piperidin-4-yl)ethyl)cyclopentyl)carbamate (Compound 134)
在室溫下攪拌((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(哌啶-4-基)乙基)環戊基)胺基甲酸甲酯(70 mg，0.16 mmol)、2-(2-(甲基磺醯基)異吲哚啉-5-基)乙醛(97 mg，0.32 mmol)及AcOH (20 mg，0.32 mmol)於DCM (10 mL)中之混合物1小時。接著添加NaBH(OAc)3 (69 mg，0.32 mmol)，且在室溫下攪拌反應混合物16小時。用H2 O (10 mL)稀釋混合物，用NaHCO3 飽和水溶液調整至pH約7且用DCM (10 mL×3)萃取。經合併之有機層用鹽水(10 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮。藉由製備型TLC及RP-製備型HPLC純化殘餘物，得到呈白色固體之化合物134 (7 mg，產率6%)。LC-MS: 652 (M+H)+ 。1 H NMR (400 MHz, MeOD-d4 ) δ 7.49 - 7.43 (m, 2H), 7.39 - 7.32 (m, 1H), 7.20 (d, 1H), 7.14 - 7.06 (m, 3H), 6.70 (d, 1H), 6.66 (d, 1H), 4.63 (s, 4H), 4.54 (d, 1H), 4.35 (d, 1H), 4.07 - 3.96 (m, 1H), 3.60 (s, 3H), 3.09 - 3.01 (m, 1H), 2.99 - 2.93 (m, 1H), 2.90 (s, 3H), 2.78 - 2.68 (m, 2H), 2.66 - 2.56 (m, 1H), 2.54 - 2.43 (m, 2H), 2.44 (s, 3H), 2.27 - 2.16 (m, 1H), 2.09 - 1.98 (m, 3H), 1.93 - 1.82 (m, 1H), 1.75 - 1.63 (m, 1H), 1.56 - 1.43 (m, 1H), 1.42 - 1.10 (m, 5H), 0.85 - 0.70 (m, 1H)。 實例24Stir ((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(piperidine) at room temperature pyridin-4-yl)ethyl)cyclopentyl)carbamate (70 mg, 0.16 mmol), 2-(2-(methylsulfonyl)isoindolin-5-yl)acetaldehyde ( 97 mg, 0.32 mmol) and AcOH (20 mg, 0.32 mmol) in DCM (10 mL) for 1 hour. Then NaBH(OAc) 3 (69 mg, 0.32 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with H 2 O (10 mL), adjusted to pH about 7 with saturated aqueous NaHCO 3 and extracted with DCM (10 mL×3). The combined organic layers were washed with brine (10 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by preparative TLC and RP-preparative HPLC to give compound 134 (7 mg, 6% yield) as a white solid. LC-MS: 652 (M+H) + . 1 H NMR (400 MHz, MeOD- d 4 ) δ 7.49 - 7.43 (m, 2H), 7.39 - 7.32 (m, 1H), 7.20 (d, 1H), 7.14 - 7.06 (m, 3H), 6.70 (d , 1H), 6.66 (d, 1H), 4.63 (s, 4H), 4.54 (d, 1H), 4.35 (d, 1H), 4.07 - 3.96 (m, 1H), 3.60 (s, 3H), 3.09 - 3.01 (m, 1H), 2.99 - 2.93 (m, 1H), 2.90 (s, 3H), 2.78 - 2.68 (m, 2H), 2.66 - 2.56 (m, 1H), 2.54 - 2.43 (m, 2H), 2.44 (s, 3H), 2.27 - 2.16 (m, 1H), 2.09 - 1.98 (m, 3H), 1.93 - 1.82 (m, 1H), 1.75 - 1.63 (m, 1H), 1.56 - 1.43 (m, 1H) ), 1.42 - 1.10 (m, 5H), 0.85 - 0.70 (m, 1H). Example 24
製備((1S,2R)-2-((S)-1-(3-氟苯基)-1-(1-(2-(2-甲基-1,1-二氧離子基-3-側氧基-2,3-二氫苯并[d]異噻唑-6-基)乙基)哌啶-4-基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯(化合物128)
步驟A：6-溴-2-甲基苯并[d]異噻唑-3(2H)-酮1,1-二氧化物Step A: 6-Bromo-2-methylbenzo[d]isothiazol-3(2H)-one 1,1-dioxide
在室溫下攪拌6-溴苯并[d]異噻唑-3(2H)-酮1,1-二氧化物(500 mg，1.91 mmol)及K2 CO3 (132 mg，0.96 mmol)於10 mL H2 O 中之混合物15 min，且接著在減壓下濃縮。在室溫下，向含殘餘物之DMF (10 mL)中添加CH3 I (0.12 mL，1.91 mmol)，且接著在90℃下攪拌混合物16小時。接著用H2 O (50 mL)稀釋混合物且用EtOAc (50 mL×3)萃取。經合併之有機層用鹽水(100 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮。藉由矽膠急驟管柱層析純化殘餘物，得到呈白色固體之6-溴-2-甲基苯并[d]異噻唑-3(2H)-酮1,1-二氧化物(380 mg，產率72%)。LC-MS: 276, 278 (M+H)+ 。Stir 6-bromobenzo[d]isothiazol- 3 (2H)-one 1,1-dioxide (500 mg, 1.91 mmol) and K2CO3 (132 mg , 0.96 mmol) in 10 at room temperature The mixture in mL H2O for 15 min, and then concentrated under reduced pressure. To the residue in DMF (10 mL) was added CH3I (0.12 mL, 1.91 mmol) at room temperature, and the mixture was then stirred at 90°C for 16 hours. The mixture was then diluted with H2O (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give 6-bromo-2-methylbenzo[d]isothiazol-3(2H)-one 1,1-dioxide as a white solid (380 mg, yield 72%). LC-MS: 276, 278 (M+H) + .
步驟B-D係遵循實例23中所述之步驟B-D的程序來完成，得到呈白色固體之((1S,2R)-2-((S)-1-(3-氟苯基)-1-(1-(2-(2-甲基-1,1-二氧離子基-3-側氧基-2,3-二氫苯并[d]異噻唑-6-基)乙基)哌啶-4-基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯(化合物128)。LC-MS: 652 (M+H)+ 。1 H NMR (400 MHz, MeOD-d4 ) δ 8.01 - 7.95 (m, 2H), 7.76 (d, 1H), 7.50 - 7.36 (m, 3H), 7.14 - 7.05 (m, 1H), 6.79 (s, 1H), 6.72 (s, 1H), 4.59 (d, 1H), 4.38 (d, 1H), 4.08 - 3.98 (m, 1H), 3.61 (s, 3H), 3.19 (s, 3H), 3.15 - 3.00 (m, 4H), 2.85 - 2.71 (m, 2H), 2.68 - 2.56 (m, 1H), 2.48 (s, 3H), 2.39 - 2.18 (m, 3H), 2.15 - 2.03 (m, 1H), 1.94 - 1.83 (m, 1H), 1.80 - 1.70 (m, 1H), 1.57 - 1.45 (m, 1H), 1.40 - 1.15 (m, 5H), 0.85 - 0.72 (m, 1H)。 實例25Step BD was completed following the procedure of Step BD described in Example 23 to give ((1S,2R)-2-((S)-1-(3-fluorophenyl)-1-(1 as a white solid -(2-(2-Methyl-1,1-dioxionyl-3-oxy-2,3-dihydrobenzo[d]isothiazol-6-yl)ethyl)piperidine-4 -yl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate (compound 128). LC-MS: 652 (M+H) + . 1 H NMR (400 MHz, MeOD- d 4 ) δ 8.01 - 7.95 (m, 2H), 7.76 (d, 1H), 7.50 - 7.36 (m, 3H), 7.14 - 7.05 (m, 1H), 6.79 (s , 1H), 6.72 (s, 1H), 4.59 (d, 1H), 4.38 (d, 1H), 4.08 - 3.98 (m, 1H), 3.61 (s, 3H), 3.19 (s, 3H), 3.15 - 3.00 (m, 4H), 2.85 - 2.71 (m, 2H), 2.68 - 2.56 (m, 1H), 2.48 (s, 3H), 2.39 - 2.18 (m, 3H), 2.15 - 2.03 (m, 1H), 1.94 - 1.83 (m, 1H), 1.80 - 1.70 (m, 1H), 1.57 - 1.45 (m, 1H), 1.40 - 1.15 (m, 5H), 0.85 - 0.72 (m, 1H). Example 25
製備((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(4-(2-(甲基磺醯胺基)乙基)苯乙基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯(化合物130)
步驟A：N-(4-溴苯乙基)甲烷磺醯胺Step A: N-(4-Bromophenethyl)methanesulfonamide
在0℃下向2-(4-溴苯基)乙-1-胺鹽酸鹽(822 mg，3.5 mmol)於DCM (8 mL)中之混合物中添加TEA (1.9 mL，14.0 mmol)及MsCl (0.3 mL，3.85 mmol)。在室溫下攪拌反應混合物1.5小時。接著用H2 O (20 mL)稀釋混合物且用DCM (20 mL×3)萃取。經合併之有機層用鹽水(30 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮。藉由矽膠急驟管柱層析純化殘餘物，得到呈黃色固體之N-(4-溴苯乙基)甲烷磺醯胺(570 mg，產率59%)。LC-MS: 278, 280 (M+H)+ 。To a mixture of 2-(4-bromophenyl)ethan-1-amine hydrochloride (822 mg, 3.5 mmol) in DCM (8 mL) at 0 °C was added TEA (1.9 mL, 14.0 mmol) and MsCl (0.3 mL, 3.85 mmol). The reaction mixture was stirred at room temperature for 1.5 hours. The mixture was then diluted with H2O (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give N-(4-bromophenethyl)methanesulfonamide (570 mg, 59% yield) as a yellow solid. LC-MS: 278, 280 (M+H) + .
步驟B-D係遵循實例23中所述之步驟B-D的程序來完成，得到呈白色固體之((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(4-(2-(甲基磺醯胺基)乙基)苯乙基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯(化合物130)。LC-MS: 654 (M+H)+ 。1 H NMR (400 MHz, MeOD-d4 ) δ 7.49 - 7.37 (m, 3H), 7.20 - 7.12 (m, 5H), 6.73 (d, 1H), 6.69 (d, 1H), 4.57 (d, 1H), 4.38 (d, 1H), 4.08 - 3.98 (m, 1H), 3.61 (s, 3H), 3.27 (t, 2H), 3.18 - 3.10 (m, 1H), 3.07 - 2.98 (m, 1H), 2.84 - 2.78 (m, 5H), 2.77 - 2.71 (m, 2H), 2.69 - 2.61 (m, 1H), 2.60 - 2.51 (m, 2H), 2.47 (s, 3H), 2.33 - 2.23 (m, 1H), 2.17 - 2.00 (m, 3H), 1.95 - 1.85 (m, 1H), 1.77 - 1.65 (m, 1H), 1.56 - 1.47 (m, 1H), 1.45 - 1.15 (m, 5H), 0.87 - 0.72 (m, 1H)。 實例26Step BD was completed following the procedure of Step BD described in Example 23 to give ((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2) as a white solid -Methyl-1H-imidazol-1-yl)-1-(1-(4-(2-(methylsulfonamido)ethyl)phenethyl)piperidin-4-yl)ethyl)cycle Amyl) methyl carbamate (compound 130). LC-MS: 654 (M+H) + . 1 H NMR (400 MHz, MeOD- d 4 ) δ 7.49 - 7.37 (m, 3H), 7.20 - 7.12 (m, 5H), 6.73 (d, 1H), 6.69 (d, 1H), 4.57 (d, 1H) ), 4.38 (d, 1H), 4.08 - 3.98 (m, 1H), 3.61 (s, 3H), 3.27 (t, 2H), 3.18 - 3.10 (m, 1H), 3.07 - 2.98 (m, 1H), 2.84 - 2.78 (m, 5H), 2.77 - 2.71 (m, 2H), 2.69 - 2.61 (m, 1H), 2.60 - 2.51 (m, 2H), 2.47 (s, 3H), 2.33 - 2.23 (m, 1H) ), 2.17 - 2.00 (m, 3H), 1.95 - 1.85 (m, 1H), 1.77 - 1.65 (m, 1H), 1.56 - 1.47 (m, 1H), 1.45 - 1.15 (m, 5H), 0.87 - 0.72 (m, 1H). Example 26
製備((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(4-(1-(甲基磺醯基)氮雜環丁烷-3-基)苯乙基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯(化合物131)
步驟A：3-(4-溴苯基)-1-(甲基磺醯基)氮雜環丁烷Step A: 3-(4-Bromophenyl)-1-(methylsulfonyl)azetidine
在0℃下向3-(4-溴苯基)氮雜環丁烷(170 mg，0.81 mmol)於DCM (5 mL)中之混合物中添加TEA (0.22 mL，1.61 mmol)及MsCl (0.08 mL，0.97 mmol)。在室溫下攪拌反應混合物2小時。接著，用H2 O (10 mL)稀釋混合物且用DCM (10 mL×3)萃取。經合併之有機層用鹽水(15 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮。藉由矽膠急驟管柱層析純化殘餘物，得到呈黃色油狀物之3-(4-溴苯基)-1-(甲基磺醯基)氮雜環丁烷(200 mg，產率86%)。LC-MS: 290, 292 (M+H)+ 。To a mixture of 3-(4-bromophenyl)azetidine (170 mg, 0.81 mmol) in DCM (5 mL) was added TEA (0.22 mL, 1.61 mmol) and MsCl (0.08 mL) at 0 °C , 0.97 mmol). The reaction mixture was stirred at room temperature for 2 hours. Then, the mixture was diluted with H2O (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (15 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give 3-(4-bromophenyl)-1-(methylsulfonyl)azetidine (200 mg, yield 86) as a yellow oil %). LC-MS: 290, 292 (M+H) + .
步驟B-D係遵循實例23中所述之步驟B-D的程序來完成，得到呈白色固體之((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(4-(1-(甲基磺醯基)氮雜環丁烷-3-基)苯乙基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯(化合物131)。LC-MS: 666 (M+H)+ 。1 H NMR (400 MHz, MeOD-d4 ) δ 7.40 - 7.31 (m, 2H), 7.30 - 7.25 (m, 1H), 7.20 (d, 2H), 7.09 (d, 2H), 7.04 - 6.95 (m, 1H), 6.62 (d, 1H), 6.58 (d, 1H), 4.45 (d, 1H), 4.26 (d, 1H), 4.15 (t, 2H), 3.98 - 3.88 (m, 1H), 3.86 (t, 2H), 3.79 - 3.67 (m, 1H), 3.50 (s, 3H), 3.08 - 3.00 (m, 2H), 2.99 - 2.90 (m, 1H), 2.88 (s, 3H), 2.70 - 2.62 (m, 2H), 2.59 - 2.43 (m, 3H), 2.35 (s, 3H), 2.22 - 2.12 (m, 1H), 2.10 - 1.92 (m, 3H), 1.85 - 1.74 (m, 1H), 1.66 - 1.57 (m, 1H), 1.45 - 1.33 (m, 1H), 1.31 - 1.00 (m, 4H), 0.78 - 0.67 (m, 1H)。 實例27Step BD was completed following the procedure of Step BD described in Example 23 to give ((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2) as a white solid -Methyl-1H-imidazol-1-yl)-1-(1-(4-(1-(methylsulfonyl)azetidin-3-yl)phenethyl)piperidine-4- yl)ethyl)cyclopentyl)carbamate (compound 131). LC-MS: 666 (M+H) + . 1 H NMR (400 MHz, MeOD- d 4 ) δ 7.40 - 7.31 (m, 2H), 7.30 - 7.25 (m, 1H), 7.20 (d, 2H), 7.09 (d, 2H), 7.04 - 6.95 (m , 1H), 6.62 (d, 1H), 6.58 (d, 1H), 4.45 (d, 1H), 4.26 (d, 1H), 4.15 (t, 2H), 3.98 - 3.88 (m, 1H), 3.86 ( t, 2H), 3.79 - 3.67 (m, 1H), 3.50 (s, 3H), 3.08 - 3.00 (m, 2H), 2.99 - 2.90 (m, 1H), 2.88 (s, 3H), 2.70 - 2.62 ( m, 2H), 2.59 - 2.43 (m, 3H), 2.35 (s, 3H), 2.22 - 2.12 (m, 1H), 2.10 - 1.92 (m, 3H), 1.85 - 1.74 (m, 1H), 1.66 - 1.57 (m, 1H), 1.45 - 1.33 (m, 1H), 1.31 - 1.00 (m, 4H), 0.78 - 0.67 (m, 1H). Example 27
製備((1S,2R)-2-((S)-1-(3-氟苯基)-1-(1-(2-(2-甲基-1,1-二氧離子基-3-側氧基-2,3-二氫苯并[d]異噻唑-5-基)乙基)哌啶-4-基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯(化合物133)
步驟A：5-溴-2-甲基苯并[d]異噻唑-3(2H)-酮1,1-二氧化物Step A: 5-Bromo-2-methylbenzo[d]isothiazol-3(2H)-one 1,1-dioxide
在室溫下攪拌5-溴苯并[d]異噻唑-3(2H)-酮1,1-二氧化物(1.38 g，5.27 mmol)及K2 CO3 (0.36 g，2.64 mmol)於10 mL H2 O 中之混合物15 min，且接著在減壓下濃縮。在室溫下，向含殘餘物之DMF (15 mL)中添加CH3 I (0.33 mL，5.27 mmol)，且接著在90℃下攪拌混合物16小時。接著用H2 O (50 mL)稀釋混合物且用EtOAc (50 mL×3)萃取。經合併之有機層用鹽水(100 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮。藉由矽膠急驟管柱層析來純化殘餘物，得到呈白色固體之5-溴-2-甲基苯并[d]異噻唑-3(2H)-酮1,1-二氧化物(1.1 g，產率76%)。LC-MS: 276, 278 (M+H)+ 。Stir 5-bromobenzo[d]isothiazol- 3 (2H)-one 1,1-dioxide (1.38 g, 5.27 mmol) and K2CO3 (0.36 g , 2.64 mmol) in 10 at room temperature The mixture in mL H2O for 15 min, and then concentrated under reduced pressure. To the residue in DMF (15 mL) was added CH3I (0.33 mL, 5.27 mmol) at room temperature, and the mixture was then stirred at 90°C for 16 hours. The mixture was then diluted with H2O (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give 5-bromo-2-methylbenzo[d]isothiazol-3(2H)-one 1,1-dioxide (1.1 g) as a white solid , the yield is 76%). LC-MS: 276, 278 (M+H) + .
步驟B-D係遵循實例23中所述之步驟B-D的程序來完成，得到呈白色固體之((1S,2R)-2-((S)-1-(3-氟苯基)-1-(1-(2-(2-甲基-1,1-二氧離子基-3-側氧基-2,3-二氫苯并[d]異噻唑-5-基)乙基)哌啶-4-基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯(化合物133)。LC-MS: 652 (M+H)+ 。1 H NMR (400 MHz, MeOD-d4 ) δ 7.96 (d, 1H), 7.91 (d, 1H), 7.79 (dd, 1H), 7.48 - 7.33 (m, 3H), 7.11 - 7.06 (m, 1H), 6.71 (d, 1H), 6.68 (d, 1H), 4.54 (d, 1H), 4.36 (d, 1H), 4.07 - 3.96 (m, 1H), 3.60 (s, 3H), 3.30 (s, 3H), 3.12 - 3.02 (m, 1H), 3.01 - 2.91 (m, 3H), 2.68 - 2.57 (m, 3H), 2.43 (s, 3H), 2.30 - 2.18 (m, 1H), 2.15 - 1.94 (m, 3H), 1.93 - 1.82 (m, 1H), 1.75 - 1.63 (m, 1H), 1.56 - 1.43 (m, 1H), 1.42 - 1.10 (m, 5H), 0.85 - 0.70 (m, 1H)。 實例28Step BD was completed following the procedure of Step BD described in Example 23 to give ((1S,2R)-2-((S)-1-(3-fluorophenyl)-1-(1 as a white solid -(2-(2-Methyl-1,1-dioxionyl-3-oxy-2,3-dihydrobenzo[d]isothiazol-5-yl)ethyl)piperidine-4 -yl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate (compound 133). LC-MS: 652 (M+H) + . 1 H NMR (400 MHz, MeOD- d 4 ) δ 7.96 (d, 1H), 7.91 (d, 1H), 7.79 (dd, 1H), 7.48 - 7.33 (m, 3H), 7.11 - 7.06 (m, 1H) ), 6.71 (d, 1H), 6.68 (d, 1H), 4.54 (d, 1H), 4.36 (d, 1H), 4.07 - 3.96 (m, 1H), 3.60 (s, 3H), 3.30 (s, 3H), 3.12 - 3.02 (m, 1H), 3.01 - 2.91 (m, 3H), 2.68 - 2.57 (m, 3H), 2.43 (s, 3H), 2.30 - 2.18 (m, 1H), 2.15 - 1.94 ( m, 3H), 1.93 - 1.82 (m, 1H), 1.75 - 1.63 (m, 1H), 1.56 - 1.43 (m, 1H), 1.42 - 1.10 (m, 5H), 0.85 - 0.70 (m, 1H). Example 28
製備((1S,2R)-2-((S)-1-(1-(2-(2-氰基-1,4-二甲基-1H-吲哚-5-基)乙基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯(化合物135)
步驟A：5-溴-1,4-二甲基-1H-吲哚-2-甲腈Step A: 5-Bromo-1,4-dimethyl-1H-indole-2-carbonitrile
在室溫下攪拌5-溴-4-甲基-1H-吲哚-2-甲腈(250 mg，1.07 mmol)、CS2 CO3 (1.04 g，3.2 mmol)及MeI (0.13 mL，2.14 mmol)於10 mL DMF中之混合物2小時。接著用H2 O (50 mL)稀釋混合物且用EtOAc (50 mL×3)萃取。經合併之有機層用鹽水(100 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮。藉由矽膠急驟管柱層析純化殘餘物，得到呈白色固體之5-溴-1,4-二甲基-1H-吲哚-2-甲腈(260 mg，產率98%)。LC-MS: 249, 251 (M+H)+ 。Stir 5-bromo-4-methyl-1H-indole- 2 -carbonitrile (250 mg, 1.07 mmol), CS2CO3 (1.04 g, 3.2 mmol) and MeI (0.13 mL, 2.14 mmol) at room temperature ) in 10 mL DMF for 2 hours. The mixture was then diluted with H2O (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give 5-bromo-1,4-dimethyl-1H-indole-2-carbonitrile (260 mg, 98% yield) as a white solid. LC-MS: 249, 251 (M+H) + .
步驟B：(E)-5-(2-乙氧基乙烯基)-1,4-二甲基-1H-吲哚-2-甲腈Step B: (E)-5-(2-Ethoxyvinyl)-1,4-dimethyl-1H-indole-2-carbonitrile
(E)-5-(2-乙氧基乙烯基)-1,4-二甲基-1H-吲哚-2-甲腈係根據實例23中步驟B中所闡述之程序由5-溴-1,4-二甲基-1H-吲哚-2-甲腈合成，得到白色固體(210 mg，產率84%)。LC-MS: 241 (M+H)+ 。(E)-5-(2-Ethoxyvinyl)-1,4-dimethyl-1H-indole-2-carbonitrile was prepared from 5-bromo- 1,4-Dimethyl-1H-indole-2-carbonitrile synthesis gave a white solid (210 mg, 84% yield). LC-MS: 241 (M+H) + .
步驟C：1,4-二甲基-5-(2-側氧基乙基)-1H-吲哚-2-甲腈Step C: 1,4-Dimethyl-5-(2-oxyethyl)-1H-indole-2-carbonitrile
在室溫下攪拌(E)-5-(2-乙氧基乙烯基)-1,4-二甲基-1H-吲哚-2-甲腈(210 mg，0.87 mmol)及TFA (3 mL)於DCM (9 mL)中之混合物2 h。接著用H2 O (20 mL)稀釋混合物，用NaHCO3 飽和水溶液調整至pH約7且用DCM (15 mL×3)萃取。經合併之有機層用鹽水(20 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮。藉由矽膠急驟管柱層析純化殘餘物，得到呈淡黃色固體之1,4-二甲基-5-(2-側氧基乙基)-1H-吲哚-2-甲腈(80 mg，產率43%)。LC-MS: 213 (M+H)+ 。(E)-5-(2-ethoxyvinyl)-1,4-dimethyl-1H-indole-2-carbonitrile (210 mg, 0.87 mmol) and TFA (3 mL) were stirred at room temperature ) in DCM (9 mL) for 2 h. The mixture was then diluted with H 2 O (20 mL), adjusted to pH about 7 with saturated aqueous NaHCO 3 and extracted with DCM (15 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give 1,4-dimethyl-5-(2-oxyethyl)-1H-indole-2-carbonitrile (80 mg) as a pale yellow solid , the yield is 43%). LC-MS: 213 (M+H) + .
步驟D係根據實例23中所述之步驟D的程序完成，得到呈白色固體之((1S,2R)-2-((S)-1-(1-(2-(2-氰基-1,4-二甲基-1H-吲哚-5-基)乙基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯(化合物135)。LC-MS: 625 (M+H)+ 。1 H NMR (400 MHz, MeOD-d4 ) δ 7.50 - 7.35 (m, 3H), 7.25 (s, 1H), 7.24 (d, 1H), 7.18 (d, 1H), 7.14 - 7.06 (m, 1H), 6.70 (d, 1H), 6.66 (d, 1H), 4.56 (d, 1H), 4.35 (d, 1H), 4.04 - 3.96 (m, 1H), 3.86 (s, 3H), 3.60 (s, 3H), 3.17 - 3.06 (m, 1H), 3.05 - 2.96 (m, 1H), 2.90 - 2.80 (m, 2H), 2.68 - 2.57 (m, 1H), 2.50 - 2.39 (m, 2H), 2.46 (s, 6H), 2.25 - 2.10 (m, 1H), 2.00 - 1.95 (m, 3H), 1.93 - 1.81 (m, 1H), 1.75 - 1.63 (m, 1H), 1.56 - 1.43 (m, 1H), 1.42 - 1.10 (m, 5H), 0.85 - 0.70 (m, 1H)。 實例29 本發明之化合物之合成及表徵Step D was completed according to the procedure of Step D described in Example 23 to give ((1S,2R)-2-((S)-1-(1-(2-(2-cyano-1) as a white solid ,4-Dimethyl-1H-indol-5-yl)ethyl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazole-1 -yl)ethyl)cyclopentyl)carbamate (compound 135). LC-MS: 625 (M+H) + . 1 H NMR (400 MHz, MeOD- d 4 ) δ 7.50 - 7.35 (m, 3H), 7.25 (s, 1H), 7.24 (d, 1H), 7.18 (d, 1H), 7.14 - 7.06 (m, 1H) ), 6.70 (d, 1H), 6.66 (d, 1H), 4.56 (d, 1H), 4.35 (d, 1H), 4.04 - 3.96 (m, 1H), 3.86 (s, 3H), 3.60 (s, 3H), 3.17 - 3.06 (m, 1H), 3.05 - 2.96 (m, 1H), 2.90 - 2.80 (m, 2H), 2.68 - 2.57 (m, 1H), 2.50 - 2.39 (m, 2H), 2.46 ( s, 6H), 2.25 - 2.10 (m, 1H), 2.00 - 1.95 (m, 3H), 1.93 - 1.81 (m, 1H), 1.75 - 1.63 (m, 1H), 1.56 - 1.43 (m, 1H), 1.42 - 1.10 (m, 5H), 0.85 - 0.70 (m, 1H). Example 29 Synthesis and Characterization of Compounds of the Invention
其他本發明化合物可使用前述流程及前述實例中所述之方法以及相關方法來製備，參見例如WO 2017/192543、WO 2018/183857、WO 2019/191526、WO 2020/072391及PCT/US2020/053186。藉由此等方法製備之代表性本發明化合物之LCMS (ESI)資料提供於表1、1A、1B及1C中。Other compounds of the invention can be prepared using the methods described in the preceding schemes and in the preceding examples, and related methods, see eg WO 2017/192543, WO 2018/183857, WO 2019/191526, WO 2020/072391 and PCT/US2020/053186. LCMS (ESI) data for representative compounds of the invention prepared by these methods are provided in Tables 1, 1A, 1B and 1C.
另外的本發明化合物之1
H NMR資料提供於表4中。
表4
結合分析法combined analysis 11
使用螢光偏振(FP)競爭性結合分析來測定代表性本發明化合物之結合親和力。FAM標記之螢光探針係基於MLL1肽(FAM-MM2)來進行設計及合成。由蛋白質飽和實驗藉由監測由在固定濃度下之螢光探針及具有直至完全飽和之增加濃度的蛋白質構成之混合物的總螢光偏振，來測定FAM-MM2對於menin蛋白的平衡解離常數(K d )值。將蛋白質之連續稀釋液與FAM-MM2混合於分析緩衝液(PBS與0.02%牛γ-球蛋白及4% DMSO。在分析之前，立刻添加0.01% Triton X-100)中，達到200 μl之最終體積。最終FAM-MM2濃度為2 nM。在室溫下將培養盤培育30分鐘，伴以平緩振盪以確保均衡。使用Infinite M-1000讀盤器(Tecan U.S., Research Triangle Park, NC)在Microfluor 1 96孔黑色v形底培養盤(Thermo Scientific, Waltham, MA)中，於485 nm之激發波長及530 nm之發射波長下，量測微偏振單元(mP)中之FP值。FAM-MM2之K d 值經測定為1.4 nM，該值藉由使用Graphpad Prism 6.0軟體(Graphpad Software, San Diego, CA)將S形劑量依賴型FP增加擬合為蛋白質濃度之函數來進行計算。Binding affinity of representative compounds of the invention was determined using a fluorescence polarization (FP) competitive binding assay. FAM-labeled fluorescent probes were designed and synthesized based on the MLL1 peptide (FAM-MM2). The equilibrium dissociation constant (K) of FAM-MM2 for menin protein was determined from protein saturation experiments by monitoring the total fluorescence polarization of mixtures consisting of fluorescent probes at fixed concentrations and protein with increasing concentrations until complete saturation. d ) value. Serial dilutions of protein were mixed with FAM-MM2 in assay buffer (PBS with 0.02% bovine gamma-globulin and 4% DMSO. 0.01% Triton X-100 was added immediately before analysis) to a final volume of 200 μl volume. The final FAM-MM2 concentration was 2 nM. The plates were incubated at room temperature for 30 minutes with gentle shaking to ensure equilibrium. Excitation at 485 nm and emission at 530 nm in Microfluor 1 96-well black v-bottom dishes (Thermo Scientific, Waltham, MA) using an Infinite M-1000 plate reader (Tecan US, Research Triangle Park, NC) Under the wavelength, the FP value in the micro-polarization unit (mP) was measured. The Kd value for FAM-MM2 was determined to be 1.4 nM, which was calculated by fitting a sigmoidal dose-dependent increase in FP as a function of protein concentration using Graphpad Prism 6.0 software (Graphpad Software, San Diego, CA).
在競爭性結合實驗中測定代表性本發明化合物之IC50 。參見表5。將5 μl含所測試化合物之DMSO與195 μl含預培育蛋白質/探針複合物溶液之分析緩衝液的混合物，添加至在室溫下伴以平緩振盪培育30分鐘之分析盤中。Menin蛋白之最終濃度為4 nM，且最終探針濃度為2 nM。各分析培養盤中包括僅含有蛋白質/探針複合物之陰性對照(等效於0%抑制)及僅不含探針之陽性對照(等效於100%抑制)。如上文所描述來量測FP值。藉由競爭曲線之非線性回歸擬合來測定IC50 值。 IC50s of representative compounds of the invention were determined in competitive binding experiments. See Table 5. A mixture of 5 μl of DMSO containing the test compound and 195 μl of assay buffer containing the pre-incubated protein/probe complex solution was added to an assay dish incubated for 30 minutes at room temperature with gentle shaking. The final concentration of Menin protein was 4 nM and the final probe concentration was 2 nM. A negative control containing only the protein/probe complex (equivalent to 0% inhibition) and a positive control containing no probe alone (equivalent to 100% inhibition) were included in each assay plate. FP values were measured as described above. IC50 values were determined by nonlinear regression fitting of competition curves.
結合分析法combined analysis 22 及and 33
化合物結合效能亦藉由使用兩種探針36或37中之一者的基於螢光之偏振配位體移位分析法針對重組menin蛋白量測，如Zhou(2013)中所描述，具有以下修改。參見Zhou等人，對高親和力巨環肽模擬物之基於結構之設計以阻斷Menin混合系白血病1 (MLL1)蛋白質之間的相互作用(Structure-Based Design of High-Affinity Macrocyclic Peptidomimetics to Block theMenin-Mixed Lineage Leukemia 1 (MLL1) Protein-Protein Interaction.)，J. Med. Chem., 2013; 56(3):1113-23。所有混合物係在DMSO中以10 mM儲備溶液形式製備。Compound binding potency was also measured against recombinant menin protein by a fluorescence-based polarized ligand shift assay using one of the two probes 36 or 37, as described in Zhou (2013), with the following modifications . See Zhou et al., Structure-Based Design of High-Affinity Macrocyclic Peptidomimetics to Block the Menin-Mixed Lineage Leukemia 1 (MLL1) Protein Interaction Mixed Lineage Leukemia 1 (MLL1) Protein-Protein Interaction.), J. Med. Chem., 2013;56(3):1113-23. All mixtures were prepared as 10 mM stock solutions in DMSO.
對於使用探針36之化合物分析(結合分析法2)，在含有100 mM磷酸鉀(pH 7.5)、100 μg/ml牛γ球蛋白、0.02%疊氮化鈉、0.005% Triton X-100及2% DMSO之緩衝液中進行結合研究。首先將化合物之10點劑量反應曲線添加至孔中，隨後添加含有90 nM重組menin蛋白及6 nM探針36之緩衝溶液。使系統在室溫下在暗處平衡60分鐘，且接著在Ex480/Em530下讀取FP信號。將FP信號資料與四參數劑量方程式擬合以允許IC50資料之提取。For compound analysis using probe 36 (Binding Assay 2), in a solution containing 100 mM potassium phosphate (pH 7.5), 100 μg/ml bovine gamma globulin, 0.02% sodium azide, 0.005% Triton X-100 and 2 Binding studies were performed in % DMSO buffer. A 10-point dose-response curve of compounds was added to the wells first, followed by a buffer solution containing 90 nM recombinant menin protein and 6 nM probe 36. The system was allowed to equilibrate at room temperature for 60 minutes in the dark, and then the FP signal was read at Ex480/Em530. The FP signal data were fitted to a four parameter dose equation to allow extraction of IC50 data.
對於使用探針37之化合物分析(結合分析法3)，分析緩衝液為100 mM磷酸鉀7.5、100 μg/ml牛γ球蛋白、0.01% triton ×100、5% DMSO。首先將化合物之10點劑量反應曲線添加至孔中，隨後添加含有4 nM重組menin蛋白及4 nM探針37之分析緩衝液。使系統在室溫下在暗處平衡一小時，且接著在Ex480/Em530下讀取FP信號。將FP信號資料與四參數劑量反應方程式擬合以允許IC50資料之提取。For compound analysis using probe 37 (binding assay 3), the assay buffer was 100 mM potassium phosphate 7.5, 100 μg/ml bovine gamma globulin, 0.01% triton x 100, 5% DMSO. A 10-point dose-response curve of compounds was added to the wells first, followed by assay buffer containing 4 nM recombinant menin protein and 4 nM probe 37. The system was allowed to equilibrate for one hour at room temperature in the dark, and then the FP signal was read at Ex480/Em530. The FP signal data were fitted to a four parameter dose response equation to allow extraction of IC50 data.
在前述結合分析法中測試本文所揭示之特定化合物，且根據以下評分測定其IC50：(A)小於50 nM，(B)在50 nM與100 nM之間，(C)大於100 nM，且(NT)未測試，如下表5中所示。
表5
程序1program 1
在4天或7天增殖分析中測定代表性本發明化合物對於細胞生存力之影響。在37℃及5% CO2 之氛圍下，將細胞維持於具有10% FBS之適當培養基中。The effect of representative compounds of the invention on cell viability was determined in a 4-day or 7-day proliferation assay. Cells were maintained in appropriate medium with 10% FBS at 37°C in an atmosphere of 5% CO2 .
在100 μl之培養基中，以2,000至3,000個細胞/孔之密度，將細胞接種於96孔平坦底部(Corning COSTAR, Corning, NY, 目錄號3595)中。將化合物連續稀釋於適當培養基中，且將100 μl之稀釋化合物添加至細胞培養盤之適當孔中。在添加化合物之後，在37℃下於5% CO2 之氛圍中培育細胞4或7天。在7天分析中，根據製造商之說明書使用WST (2-(2-甲氧基-4-硝基苯基)-3-(4-硝基苯基)-5-(2,4-二磺基苯基)-2H-四唑鎓單鈉鹽)細胞計數-8套組(Dojindo Molecular Technologies,Inc., Rockville, MD)來測定細胞生存力。在4天分析中，細胞生存力係根據製造商之說明書使用CellTiter-Glo®發光細胞生存力試劑來測定。Cells were seeded in 96-well flat bottom (Corning COSTAR, Corning, NY, cat. no. 3595) at a density of 2,000 to 3,000 cells/well in 100 μl of medium. Compounds were serially diluted in appropriate media and 100 μl of diluted compound was added to appropriate wells of cell culture plates. Following compound addition, cells were incubated for 4 or 7 days at 37°C in an atmosphere of 5% CO 2 . In the 7-day assay, WST (2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-di Sulfophenyl)-2H-tetrazolium monosodium salt) Cell Count-8 Kit (Dojindo Molecular Technologies, Inc., Rockville, MD) was used to determine cell viability. In the 4 day assay, cell viability was determined using CellTiter-Glo® Luminescent Cell Viability Reagent according to the manufacturer's instructions.
將細胞生存力試劑以10% (v/v)之最終濃度添加至各孔中，且隨後在37℃下培育培養盤1至2小時用於顯色。使用SPECTRAmax PLUS讀盤器(Molecular Devices，Sunnyvale，CA)來量測在450 nm下之吸光度。按經DMSO處理之細胞來標準化讀數，且使用GraphPad Prism 5軟體(GraphPad Software, La Jolla, CA)，藉由非線性回歸(與可變斜率擬合、最小平方擬合且無約束條件之四參數S型)分析，來計算半數最大抑制濃度(IC50 )。Cell viability reagents were added to each well at a final concentration of 10% (v/v), and the plates were then incubated at 37°C for 1 to 2 hours for color development. Absorbance at 450 nm was measured using a SPECTRAmax PLUS disk reader (Molecular Devices, Sunnyvale, CA). Readings were normalized to DMSO-treated cells and analyzed by nonlinear regression (fit with variable slope, least squares, and four parameters without constraints) using GraphPad Prism 5 software (GraphPad Software, La Jolla, CA). S-type) analysis to calculate the half maximal inhibitory concentration ( IC50 ).
在前述分析中測試本文所揭示之特定化合物，且根據以下評分測定其以IC50 抑制細胞增殖：(A)小於100 nM，(B)在100 nM與500 nM之間，(C)在500 nM與1 µM之間，(D)大於1 µM，(E)無擬合，且(NT)未測試，如下表6中所示。Particular compounds disclosed herein were tested in the aforementioned assays and were determined to inhibit cell proliferation with IC50s according to the following scores: (A) less than 100 nM, (B) between 100 nM and 500 nM, (C) at 500 nM and 1 µM, (D) was greater than 1 µM, (E) was not fitted, and (NT) was not tested, as shown in Table 6 below.
程序2program 2
在4天或7天增殖分析中測定代表性本發明化合物對於細胞生存力之影響。在37℃及5% CO2 之氛圍下，將細胞維持於具有10% FBS之適當培養基中。The effect of representative compounds of the invention on cell viability was determined in a 4-day or 7-day proliferation assay. Cells were maintained in appropriate medium with 10% FBS at 37°C in an atmosphere of 5% CO2 .
在50 μl之培養基中，以4,000至7,500個細胞/孔之密度，將細胞接種於96孔平坦底部(Corning COSTAR, Corning, NY,目錄號3903)中。將化合物連續稀釋於適當培養基中，且將50 μl之稀釋化合物添加至細胞培養盤之適當孔中。在添加化合物之後，在37℃下於5% CO2 之氛圍中培育細胞4或7天。根據製造商之說明書使用CellTiter-Glo®發光細胞生存力試劑測定細胞生存力。Cells were seeded in 96-well flat bottom (Corning COSTAR, Corning, NY, Cat. No. 3903) at a density of 4,000 to 7,500 cells/well in 50 μl of medium. Compounds were serially diluted in appropriate media, and 50 μl of diluted compound was added to appropriate wells of cell culture plates. Following compound addition, cells were incubated for 4 or 7 days at 37°C in an atmosphere of 5% CO 2 . Cell viability was determined using CellTiter-Glo® Luminescent Cell Viability Reagent according to the manufacturer's instructions.
將CellTiter-Glo®發光細胞生存力試劑添加至各孔中且在室溫下在定軌振盪器上培育10分鐘。使用EnSpire®讀盤器(PerkinElmer，Waltham, MA)量測發光信號。按經DMSO處理之細胞來標準化讀數，且使用GraphPad Prism 5軟體(GraphPad Software, La Jolla, CA)，藉由非線性回歸(與可變斜率擬合、最小平方擬合且無約束條件之四參數S型)分析，來計算半數最大抑制濃度(IC50 )。CellTiter-Glo® Luminescent Cell Viability Reagent was added to each well and incubated on an orbital shaker for 10 minutes at room temperature. Luminescence signals were measured using an EnSpire® disc reader (PerkinElmer, Waltham, MA). Readings were normalized to DMSO-treated cells and analyzed by nonlinear regression (fit with variable slope, least squares, and four parameters without constraints) using GraphPad Prism 5 software (GraphPad Software, La Jolla, CA). S-type) analysis to calculate the half maximal inhibitory concentration ( IC50 ).
在前述分析中測試本文所揭示之特定化合物，且根據以下評分測定其以IC50
抑制細胞增殖：(A)小於100 nM，(B)在100 nM與500 nM之間，(C)在501 nM與1 µM之間，(D)大於1 µM，(E)無擬合，且(NT)未測試，如下表6中所示。
表6
現已完整描述本文中提供之方法、化合物及物質組成，熟習此項技術者將理解，在不影響本文中或其任一實施例所提供之方法、化合物及組合物之範疇的情況下，該等方法、化合物及物質組成可在病狀、調配物及其他參數之廣泛且等效範圍內執行。Now that the methods, compounds, and compositions of matter provided herein are fully described, those skilled in the art will understand that without affecting the scope of the methods, compounds, and compositions provided herein or in any of the examples The methods, compounds and compositions of matter can be performed within a broad and equivalent range of conditions, formulations and other parameters.
本文中引用之所有專利、專利申請案及公開案全部均以其全文引用之方式併入本文中。All patents, patent applications, and publications cited herein are incorporated by reference in their entirety.
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| US8242078B2 (en) | 2006-10-19 | 2012-08-14 | The University Of Chicago | Therapeutics to inhibit MLL-menin interaction for treating leukemia |
| EP2473054B1 (en) | 2009-09-04 | 2017-06-14 | The Regents of the University of Michigan | Compositions and methods for treatment of leukemia |
| CN105188705A (en) | 2013-03-13 | 2015-12-23 | 密歇根大学董事会 | Compositions comprising thienopyrimidine and thienopyridine compounds and methods of use thereof |
| US9212180B2 (en) | 2013-06-12 | 2015-12-15 | The Regents Of The University Of Michigan | Menin-MLL inhibitors and methods of use thereof |
| CA3022868A1 (en) | 2016-05-02 | 2017-11-09 | Shaomeng Wang | Piperidines as menin inhibitors |
| JOP20190072A1 (en) | 2016-10-13 | 2019-04-07 | Glaxosmithkline Ip Dev Ltd | 1,3 di-substituted cyclobutane or azetidine derivatives as hematopoietic prostaglandin d synthase inhibitors |
| CN110691779B (en) * | 2017-03-24 | 2023-10-10 | 库拉肿瘤学公司 | Method for treating hematological malignancies and ewing's sarcoma |
| SG11201909083UA (en) | 2017-03-31 | 2019-10-30 | Univ Michigan Regents | Piperidines as covalent menin inhibitors |
| JP2021519785A (en) | 2018-03-30 | 2021-08-12 | ザ リージェンツ オブ ザ ユニヴァシティ オブ ミシガン | Piperidine compounds as covalent menin inhibitors |
| CA3112340A1 (en) | 2018-10-03 | 2020-04-09 | The Regents Of The University Of Michigan | Small molecule menin inhibitors |
-
2021
- 2021-04-07 TW TW110112602A patent/TW202204334A/en unknown
- 2021-04-07 WO PCT/US2021/026111 patent/WO2021207310A1/en active Application Filing
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| Publication number | Publication date |
|---|---|
| WO2021207310A1 (en) | 2021-10-14 |
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