TW202231269A - Kras protein degraders, pharmaceutical compositions thereof, and their therapeutic applications - Google Patents
Kras protein degraders, pharmaceutical compositions thereof, and their therapeutic applications Download PDFInfo
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Abstract
Description
本文提供KRAS蛋白降解劑及其醫藥組合物。本文亦提供其用於治療、預防或改善KRAS介導之病症、疾病或病狀之一或多個症狀之方法。Provided herein are KRAS protein degraders and pharmaceutical compositions thereof. Also provided herein are their methods for treating, preventing or ameliorating one or more symptoms of a KRAS-mediated disorder, disease or condition.
三種RAS致癌基因( KRAS、 HRAS及 NRAS)來自癌症中最頻繁突變的致癌基因家族。Milburn等人, Science 1990, 247, 939-45；Cox等人, Nat. Rev. Drug Discov. 2014, 13, 828-51；Papke及Der, Science 2017, 355, 1158-63。已在高達30%之所有人類癌症中偵測到 RAS突變。Cox等人, Nat. Rev. Drug Discov. 2014, 13, 828-51。在該三種中， KRAS突變為最常見的，單獨佔所有RAS相關癌症之85%且全世界每年約一百萬例死亡。Prior等人, Cancer Res. 2012, 72, 2457-67；Cox等人, Nat. Rev. Drug Discov. 2014, 13, 828-51；Simanshu等人, Cell 2017, 170, 17-33；McCarthy等人, ACS Omega 2019, 4, 2921-30。特定言之， KRAS G12C佔攜帶 KRAS突變之所有非小細胞肺癌(non-small cell lung cancer；NSCLC)之44%。Santana-Codina等人, Cell Rep. 2020, 30, 4584-99。 Three RAS oncogenes ( KRAS , HRAS and NRAS ) are from the most frequently mutated oncogene family in cancer. Milburn et al., Science 1990 , 247 , 939-45; Cox et al., Nat. Rev. Drug Discov. 2014 , 13 , 828-51; Papke and Der, Science 2017 , 355, 1158-63. RAS mutations have been detected in up to 30% of all human cancers. Cox et al, Nat. Rev. Drug Discov. 2014 , 13 , 828-51. Of the three, KRAS mutations are the most common, alone accounting for 85% of all RAS-related cancers and approximately one million deaths worldwide each year. Prior et al., Cancer Res. 2012 , 72 , 2457-67; Cox et al., Nat. Rev. Drug Discov. 2014 , 13 , 828-51; Simanshu et al., Cell 2017 , 170 , 17-33; McCarthy et al. , ACS Omega 2019 , 4 , 2921-30. Specifically, KRAS G12C accounts for 44% of all non-small cell lung cancers (NSCLC) harboring KRAS mutations. Santana-Codina et al, Cell Rep. 2020 , 30 , 4584-99.
RAS蛋白為由 RAS致癌基因編碼之小GTP酶。Papke及Der, Science 2017, 355, 1158-63。RAS蛋白充當活性鳥苷三磷酸(GTP)結合狀態與非活性鳥苷二磷酸(GDP)結合狀態之間的分子開關循環。Milburn等人, Science 1990, 247, 939-45。GTP結合之活性RAS活化下游效應路徑，包括大鼠纖維肉瘤/促分裂原活化蛋白激酶激酶/細胞外調節激酶(RAF/MEK/ERK)及磷酸肌醇3-激酶/蛋白激酶B/雷帕黴素激酶之機制目標(PI3K/AKT/mTOR)。Rebocho及Marais, Cancer Discov. 2011, 1, 98-9。RAS蛋白中之致癌突變削弱其GTP水解之能力，導致GTP結合之活性RAS之積累及下游傳訊級聯之過度活化，從而導致不受控的細胞增殖及存活。Uras等人, Int. J. Mol. Sci. 2020, 21, 4325。 RAS proteins are small GTPases encoded by the RAS oncogene. Papke and Der, Science 2017 , 355, 1158-63. The RAS protein acts as a molecular switch cycle between the active guanosine triphosphate (GTP) bound state and the inactive guanosine diphosphate (GDP) bound state. Milburn et al., Science 1990 , 247 , 939-45. GTP-bound active RAS activates downstream effector pathways including rat fibrosarcoma/mitogen-activated protein kinase kinase/extracellular regulated kinase (RAF/MEK/ERK) and phosphoinositide 3-kinase/protein kinase B/rapamycin Mechanistic target of prion kinases (PI3K/AKT/mTOR). Rebocho and Marais, Cancer Discov. 2011 , 1 , 98-9. Oncogenic mutations in RAS proteins impair their ability to hydrolyze GTP, leading to accumulation of GTP-bound active RAS and hyperactivation of downstream signaling cascades, resulting in uncontrolled cell proliferation and survival. Uras et al, Int. J. Mol. Sci. 2020 , 21 , 4325.
儘管在癌症治療方面取得了進展，但癌症仍為全世界範圍內主要的公共健康問題。據估計，2021年僅在美國就將有1,898,160例新診斷的癌症病例及608,570例癌症死亡病例。 Cancer Facts & Figures2021。因此，需要用於癌症治療之有效療法。 Despite advances in cancer treatment, cancer remains a major public health problem worldwide. It is estimated that there will be 1,898,160 new cancer diagnoses and 608,570 cancer deaths in the United States alone in 2021. Cancer Facts & Figures 2021. Therefore, there is a need for effective therapies for cancer treatment.
本文提供一種式(A)化合物：
本文亦提供一種式(I)化合物：
此外，本文提供一種式(IA)化合物：
此外，本文提供一種醫藥組合物，其包含式(A)化合物或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體；或其醫藥學上可接受之鹽、溶劑合物、水合物或前藥；及醫藥學上可接受之賦形劑。In addition, provided herein is a pharmaceutical composition comprising a compound of formula (A) or an enantiomer, a mixture of enantiomers, an enantiomer, a mixture of two or more enantiomers, Tautomers, mixtures of two or more tautomers, or isotopic variants; or pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof; and pharmaceutically acceptable excipients Form.
本文提供一種治療、預防或改善個體之由KRAS介導之病症、疾病或病狀之一或多個症狀的方法，其包含向有需要之該個體投與治療有效量之式(A)化合物或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體；或其醫藥學上可接受之鹽、溶劑合物、水合物或前藥。Provided herein is a method of treating, preventing or ameliorating one or more symptoms of a KRAS-mediated disorder, disease or condition in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound of formula (A) or Enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.
本文提供一種治療、預防或改善個體之增生性疾病之一或多個症狀之方法，其包含向有需要之該個體投與治療有效量之式(A)化合物或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體；或其醫藥學上可接受之鹽、溶劑合物、水合物或前藥。Provided herein is a method of treating, preventing or ameliorating one or more symptoms of a proliferative disease in an individual, comprising administering to the individual in need thereof a therapeutically effective amount of a compound of formula (A) or a mirror isomer, spiegelmer mixtures of structures, non-spiroisomers, mixtures of two or more non-spiroisomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or medicines thereof A pharmaceutically acceptable salt, solvate, hydrate or prodrug.
本文提供一種抑制細胞生長之方法，其包含使該細胞與有效量之式(A)化合物或其鏡像異構物、鏡像異構物之混合物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體；或其醫藥學上可接受之鹽、溶劑合物、水合物或前藥接觸。Provided herein is a method of inhibiting the growth of a cell, comprising exposing the cell to an effective amount of a compound of formula (A) or a mirror isomer thereof, a mixture of enantiomers, a mixture of two or more diastereomers , a tautomer, a mixture or isotopic variant of two or more tautomers; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.
本文提供一種誘導KRAS降解之方法，其包含使KRAS與有效量之式(A)化合物或其鏡像異構物、鏡像異構物之混合物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體；或其醫藥學上可接受之鹽、溶劑合物、水合物或前藥接觸。Provided herein is a method of inducing the degradation of KRAS, comprising combining KRAS with an effective amount of a compound of formula (A) or its enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, A tautomer, a mixture or isotopic variant of two or more tautomers; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof is contacted.
對相關申請案之交叉參考Cross-reference to related applications
本申請案主張2020年10月23日提交之美國臨時申請案第63/105,117號及2021年6月3日提交之美國臨時申請案第63/196,669號之優先權的權益；其中之每一者之揭示內容以全文引用之方式併入本文中。This application claims the benefit of priority from US Provisional Application No. 63/105,117, filed October 23, 2020, and US Provisional Application No. 63/196,669, filed June 3, 2021; each of which The disclosure is incorporated herein by reference in its entirety.
為了有助於理解本文中所闡述之揭示內容，下文定義多個術語。To facilitate understanding of the disclosure set forth herein, a number of terms are defined below.
一般而言，本文所使用之命名法及本文所描述之有機化學、藥物化學、生物化學、生物學及藥理學中之實驗室程序為此項技術中熟知且常用的。除非另外定義，否則本文所用之所有技術及科學術語具有與本發明所屬領域之一般熟習此項技術者通常所理解相同之含義。In general, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, biochemistry, biology, and pharmacology described herein are those well known and commonly used in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
術語「個體」係指動物，包括但不限於靈長類動物(例如人類)、牛、豬、綿羊、山羊、馬、狗、貓、兔、大鼠或小鼠。術語「個體」及「患者」在本文中可互換使用，其指例如哺乳動物個體，諸如人類個體。在一個實施例中，個體為人類。The term "individual" refers to animals including, but not limited to, primates (eg, humans), cows, pigs, sheep, goats, horses, dogs, cats, rabbits, rats, or mice. The terms "subject" and "patient" are used interchangeably herein to refer, for example, to a mammalian subject, such as a human subject. In one embodiment, the individual is a human.
術語「治療(treat/treating/treatment)」意欲包括緩解或消除病症、疾病或病狀或與病症、疾病或病狀相關之症狀中之一或多者；或緩解或根除病症、疾病或病狀本身之起因。The term "treat/treating/treatment" is intended to include alleviation or elimination of one or more of a disorder, disease or condition or symptoms associated with a disorder, disease or condition; or alleviation or eradication of a disorder, disease or condition its own cause.
術語「預防(prevent/preventing/prevention)」意欲包括以下之方法：延遲及/或排除病症、疾病或病狀及/或其伴隨症狀之發作；防止個體罹患病症、疾病或病狀；或降低個體罹患病症、疾病或病狀之風險。The term "prevent/preventing/prevention" is intended to include methods of: delaying and/or eliminating the onset of a disorder, disease, or condition and/or its accompanying symptoms; preventing an individual from suffering from a disorder, disease, or condition; or reducing an individual's Risk of illness, disease or condition.
術語「緩解(alleviate/alleviating)」指減輕或減少病症、疾病或病狀之一或多個症狀(例如疼痛)。該等術語亦可指減少與活性成分相關之副作用。有時，個體自預防劑或治療劑獲得之有益效果不會引起病症、疾病或病狀之治癒。The term "alleviate/alleviating" refers to alleviating or reducing one or more symptoms (eg, pain) of a disorder, disease or condition. These terms may also refer to the reduction of side effects associated with the active ingredient. Sometimes the beneficial effects an individual receives from a prophylactic or therapeutic agent do not result in a cure for the disorder, disease or condition.
術語「接觸(contacting/contact)」意指將治療劑與生物分子(例如，蛋白質、酶、RNA或DNA)、細胞或組織結合在一起以使得由於此類接觸而發生生理及/或化學作用。接觸可活體外、離體或活體內進行。在一個實施例中，使治療劑與生物分子活體外接觸以測定治療劑對生物分子之效果。在另一實施例中，使治療劑與細胞培養物中之細胞(活體外)接觸以測定治療劑對細胞之效果。在又另一實施例中，使治療劑與生物分子、細胞或組織接觸包括向生物分子、細胞或組織待接觸之個體投與治療劑。The term "contacting/contacting" means binding a therapeutic agent to a biomolecule (eg, protein, enzyme, RNA or DNA), cell or tissue such that a physiological and/or chemical effect occurs as a result of such contact. Contacting can be performed in vitro, ex vivo or in vivo. In one embodiment, the therapeutic agent is contacted with the biomolecule in vitro to determine the effect of the therapeutic agent on the biomolecule. In another embodiment, the therapeutic agent is contacted with cells in cell culture (in vitro) to determine the effect of the therapeutic agent on the cells. In yet another embodiment, contacting the therapeutic agent with the biomolecule, cell or tissue comprises administering the therapeutic agent to the individual to whom the biomolecule, cell or tissue is to be contacted.
術語「治療有效量」或「有效量」意欲包括在投與時足以阻止所治療之病症、疾病或病狀之一或多個症狀之發展或在一定程度上緩解該一或多個症狀的化合物之量。術語「治療有效量」或「有效量」亦指足以引起由研究人員、獸醫、醫學醫生或臨床醫師所尋求之生物分子(例如，蛋白質、酶、RNA或DNA)、細胞、組織、系統、動物或人類之生物或醫學反應的化合物之量。The term "therapeutically effective amount" or "effective amount" is intended to include a compound that, when administered, is sufficient to prevent the development of, or to alleviate to some extent, one or more symptoms of the disorder, disease or condition being treated amount. The term "therapeutically effective amount" or "effective amount" also refers to a biomolecule (eg, protein, enzyme, RNA, or DNA), cell, tissue, system, animal, and biological molecule (eg, protein, enzyme, RNA, or DNA) that is sufficient to cause the or the amount of a compound that is biologically or medically reactive in humans.
術語「IC 50」或「EC 50」係指在量測此類反應之分析中實現最大反應之50%抑制所需的化合物之量、濃度或劑量。 The term " IC50 " or " EC50 " refers to the amount, concentration or dose of compound required to achieve 50% inhibition of the maximal response in an assay measuring such a response.
術語「醫藥學上可接受之載劑」、「醫藥學上可接受之賦形劑」、「生理學上可接受之載劑」或「生理學上可接受之賦形劑」係指醫藥學上可接受之材料、組合物或媒劑，諸如液體或固體填充劑、稀釋劑、溶劑或包封材料。在一個實施例中，各組分在以下意義上為「醫藥學上可接受的」：與醫藥調配物之其他成分相容且適合用於與個體(例如人類)之組織或器官接觸而無過度毒性、刺激、過敏反應、免疫原性或其他問題或併發症，與合理益處/風險比相稱。參見例如， Remington: The Science and Practice of Pharmacy, 第23版；Adejare編; Academic Press, 2020； Handbook of Pharmaceutical Excipients, 第9版；Sheskey等人,編; Pharmaceutical Press, 2020； Handbook of Pharmaceutical Additives, 第3版; Ash及Ash編; Synapse Information Resources, 2007； Pharmaceutical Preformulation and Formulation, 第1版; Gibson編; CRC Press, 2015。 The terms "pharmaceutically acceptable carrier", "pharmaceutically acceptable excipient", "physiologically acceptable carrier" or "physiologically acceptable excipient" refer to a pharmaceutical acceptable materials, compositions or vehicles, such as liquid or solid fillers, diluents, solvents or encapsulating materials. In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical formulation and suitable for use in contact with a tissue or organ of a subject (eg, a human) without undue extent Toxicity, irritation, allergic reactions, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy , 23rd ed.; Adejare, ed.; Academic Press, 2020; Handbook of Pharmaceutical Excipients , 9th ed.; Sheskey et al., ed.; Pharmaceutical Press, 2020; Handbook of Pharmaceutical Additives , pp. 3 editions; Ash and Ash eds; Synapse Information Resources, 2007; Pharmaceutical Preformulation and Formulation , 1st edition; Gibson eds; CRC Press, 2015.
術語「約」或「大致」意謂如由一般熟習此項技術者所測定之特定值之可接受誤差，其部分視如何量測或測定該值而定。在某些實施例中，術語「約」或「大致」意謂在1、2或3個標準差內。在某些實施例中，術語「約」或「大致」意謂在既定值或範圍之25%、20%、15%、10%、9%、8%、7%、6%、5%、4%、3%、2%、1%、0.5%或0.05%內。The terms "about" or "approximately" mean an acceptable error in a particular value as determined by one of ordinary skill in the art, depending in part on how the value is measured or determined. In certain embodiments, the terms "about" or "approximately" mean within 1, 2, or 3 standard deviations. In certain embodiments, the term "about" or "approximately" means within 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, Within 4%, 3%, 2%, 1%, 0.5% or 0.05%.
術語「烷基」係指直鏈或分支鏈飽和單價烴基，其中該烷基視情況經一或多個如本文所描述之取代基Q取代。舉例而言，C 1-6烷基係指1至6個碳原子之直鏈飽和單價烴基或3至6個碳原子之分支鏈飽和單價烴基。在某些實施例中，烷基為具有1至20個(C 1-20)、1至15個(C 1-15)、1至10個(C 1-10)或1至6個(C 1-6)碳原子之直鏈飽和單價烴基，或3至20個(C 3-20)、3至15個(C 3-15)、3至10個(C 3-10)或3至6個(C 3-6)碳原子之分支鏈飽和單價烴基。如本文所用，直鏈C 1-6及分支鏈C 3-6烷基亦稱為「低級烷基」。烷基之實例包括但不限於甲基、乙基、丙基(包括所有異構形式，例如正丙基及異丙基)、丁基(包括所有異構形式，例如正丁基、異丁基、二級丁基及三級丁基)、戊基(包括所有異構體形式，例如正戊基、異戊基、二級戊基、新戊基及三級戊基)及己基(包括所有異構體形式，例如正己基、異己基及二級己基)。 The term "alkyl" refers to a straight or branched chain saturated monovalent hydrocarbon group, wherein the alkyl group is optionally substituted with one or more substituents Q as described herein. For example, C1-6 alkyl refers to a straight chain saturated monovalent hydrocarbon group of 1 to 6 carbon atoms or a branched chain saturated monovalent hydrocarbon group of 3 to 6 carbon atoms. In certain embodiments, the alkyl group has 1 to 20 (C 1-20 ), 1 to 15 (C 1-15 ), 1 to 10 (C 1-10 ), or 1 to 6 (C 1-10 ) 1-6 ) Linear saturated monovalent hydrocarbon group of carbon atoms, or 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ) or 3 to 6 A branched chain saturated monovalent hydrocarbon group of (C 3-6 ) carbon atoms. As used herein, straight-chain C1-6 and branched C3-6 alkyl groups are also referred to as "lower alkyls". Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (including all isomeric forms such as n-propyl and isopropyl), butyl (including all isomeric forms such as n-butyl, isobutyl) , secondary and tertiary butyl), pentyl (including all isomeric forms such as n-pentyl, isopentyl, secondary pentyl, neopentyl and tertiary pentyl) and hexyl (including all isomeric forms such as n-hexyl, isohexyl and secondary hexyl).
術語「雜烷基」係指在其主鏈上含有一或多個雜原子的直鏈或分支鏈飽和單價烴基，該一或多個雜原子各自獨立地選自O、S及N。雜烷基視情況經一或多個如本文所描述之取代基Q取代。舉例而言，C 1-6雜烷基係指1至6個碳原子之直鏈飽和單價烴基或3至6個碳原子之分支鏈飽和單價烴基。在某些實施例中，雜烷基為具有1至20個(C 1-20)、1至15個(C 1-15)、1至10個(C 1-10)或1至6個(C 1-6)碳原子之直鏈飽和單價烴基，或3至20個(C 3-20)、3至15個(C 3-15)、3至10個(C 3-10)或3至6個(C 3-6)碳原子之分支鏈飽和單價烴基。如本文所用，直鏈C 1-6及分支鏈C 3-6雜烷基亦稱為「低級雜烷基」。雜烷基之實例包括但不限於-OCH 3、-OCH 2CH 3、-CH 2OCH 3、-NHCH 3、-ONHCH 3、-NHOCH 3、-SCH 3、-CH 2NHCH 2CH 3及-NHCH 2CH 2CH 3。經取代之雜烷基之實例包括但不限於-CH 2NHC(O)CH 3及-NHC(O)CH 2CH 3。 The term "heteroalkyl" refers to a straight or branched chain saturated monovalent hydrocarbon radical containing one or more heteroatoms, each independently selected from O, S, and N, in its backbone. Heteroalkyl is optionally substituted with one or more substituents Q as described herein. For example, C1-6 heteroalkyl refers to a straight chain saturated monovalent hydrocarbon group of 1 to 6 carbon atoms or a branched chain saturated monovalent hydrocarbon group of 3 to 6 carbon atoms. In certain embodiments, the heteroalkyl group has 1 to 20 (C 1-20 ), 1 to 15 (C 1-15 ), 1 to 10 (C 1-10 ), or 1 to 6 ( C 1-6 ) linear saturated monovalent hydrocarbon group of carbon atoms, or 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ), or 3 to 20 (C 3-20 ) A branched chain saturated monovalent hydrocarbon group of 6 (C 3-6 ) carbon atoms. As used herein, straight-chain C1-6 and branched C3-6 heteroalkyl groups are also referred to as "lower heteroalkyl groups." Examples of heteroalkyl include, but are not limited to, -OCH3 , -OCH2CH3 , -CH2OCH3 , -NHCH3 , -ONHCH3 , -NHOCH3 , -SCH3 , -CH2NHCH2CH3 , and - NHCH 2 CH 2 CH 3 . Examples of substituted heteroalkyl include, but are not limited to, -CH2NHC(O) CH3 and -NHC ( O ) CH2CH3 .
術語「伸烷基」與「烷二基」在本文中可互換使用，指代直鏈或分支鏈飽和二價烴基，其中該烷二基視情況經一或多個如本文所描述之取代基Q取代。舉例而言，C 1-6烷二基係指1至6個碳原子之直鏈飽和二價烴基或3至6個碳原子之分支鏈飽和二價烴基。在某些實施例中，烷二基為具有1至30個(C 1-30)、1至20個(C 1-20)、1至15個(C 1-15)、1至10個(C 1-10)或1至6個(C 1-6)碳原子之直鏈飽和二價烴基，或3至30個(C 3-30)、3至20個(C 3-20)、3至15個(C 3-15)、3至10個(C 3-10)或3至6個(C 3-6)碳原子之分支鏈飽和二價烴基。如本文所用，直鏈C 1-6及分支鏈C 3-6烷二基亦稱為「低級烷二基」。烷二基之實例包括但不限於甲烷二基、乙烷二基(包括所有異構形式，例如乙烷-1,1-二基及乙烷-1,2-二基)、丙烷二基(包括所有異構形式，例如丙烷-1,1-二基、丙烷-1,2-二基及丙烷-1,3-二基)、丁烷二基(包括所有異構形式，例如丁烷-1,1-二基、丁烷-1,2-二基、丁烷-1,3-二基及丁烷-1,4-二基)、戊烷二基(包括所有異構形式，例如戊烷-1,1-二基、戊烷-1,2-二基、戊烷-1,3-二基及戊烷-1,5-二基)及己烷二基(包括所有異構形式，例如己烷-1,1-二基、己烷-1,2-二基、己烷-1,3-二基及己烷-1,6-二基)。經取代之烷二基之實例包括但不限於-C(O)CH 2-、-C(O)(CH 2) 2-、-C(O)(CH 2) 3-、-C(O)(CH 2) 4-、-C(O)(CH 2) 5-、-C(O)(CH 2) 6-、-C(O)(CH 2) 7-、-C(O)(CH 2) 8-、-C(O)(CH 2) 9-、-C(O)(CH 2) 10-、-C(O)CH 2C(O)-、-C(O)(CH 2) 2C(O)-、-C(O)(CH 2) 3C(O)-、-C(O)(CH 2) 4C(O)-或-C(O)(CH 2) 5C(O)-。 The terms "alkylene" and "alkanediyl" are used interchangeably herein to refer to a straight or branched chain saturated divalent hydrocarbon radical, wherein the alkanediyl is optionally substituted with one or more substituents as described herein Q replaces. For example, C 1-6 alkanediyl refers to a straight chain saturated divalent hydrocarbon group of 1 to 6 carbon atoms or a branched chain saturated divalent hydrocarbon group of 3 to 6 carbon atoms. In certain embodiments, the alkanediyl group has 1 to 30 (C 1-30 ), 1 to 20 (C 1-20 ), 1 to 15 (C 1-15 ), 1 to 10 ( C 1-10 ) or 1 to 6 (C 1-6 ) straight-chain saturated divalent hydrocarbon groups of carbon atoms, or 3 to 30 (C 3-30 ), 3 to 20 (C 3-20 ), 3 A branched chain saturated divalent hydrocarbon group of to 15 (C 3-15 ), 3 to 10 (C 3-10 ) or 3 to 6 (C 3-6 ) carbon atoms. As used herein, straight-chain C1-6 and branched C3-6 alkanediyl groups are also referred to as "lower alkanediyl groups." Examples of alkanediyl include, but are not limited to, methanediyl, ethanediyl (including all isomeric forms such as ethane-1,1-diyl and ethane-1,2-diyl), propanediyl ( including all isomeric forms such as propane-1,1-diyl, propane-1,2-diyl and propane-1,3-diyl), butanediyl (including all isomeric forms such as butane- 1,1-diyl, butane-1,2-diyl, butane-1,3-diyl and butane-1,4-diyl), pentanediyl (including all isomeric forms such as Pentane-1,1-diyl, pentane-1,2-diyl, pentane-1,3-diyl and pentane-1,5-diyl) and hexanediyl (including all isomeric forms such as hexane-1,1-diyl, hexane-1,2-diyl, hexane-1,3-diyl and hexane-1,6-diyl). Examples of substituted alkanediyl groups include, but are not limited to, -C(O)CH2-, -C(O)( CH2 ) 2- , -C(O)( CH2 ) 3- , -C(O) (CH 2 ) 4 -, -C(O)(CH 2 ) 5 -, -C(O)(CH 2 ) 6 -, -C(O)(CH 2 ) 7 -, -C(O)(CH 2 ) 8 -, -C(O)(CH 2 ) 9 -, -C(O)(CH 2 ) 10 -, -C(O)CH 2 C(O)-, -C(O)(CH 2 ) 2 C(O)-, -C(O)(CH 2 ) 3 C(O)-, -C(O)(CH 2 ) 4 C(O)- or -C(O)(CH 2 ) 5 C(O)-.
術語「伸雜烷基」與「雜烷二基」在本文中可互換使用，指代在其主鏈中含有一或多個雜原子的直鏈或分支鏈飽和二價烴基，該一或多個雜原子各自獨立地選自O、S及N。伸雜烷基視情況經一或多個如本文所描述之取代基Q取代。舉例而言，C 1-6伸雜烷基係指1至6個碳原子之直鏈飽和二價烴基或3至6個碳原子之分支鏈飽和二價烴基。在某些實施例中，伸雜烷基為具有1至20個(C 1-20)、1至15個(C 1-15)、1至10個(C 1-10)或1至6個(C 1-6)碳原子之直鏈飽和二價烴基，或3至20個(C 3-20)、3至15個(C 3-15)、3至10個(C 3-10)或3至6個(C 3-6)碳原子之分支鏈飽和二價烴基。如本文所用，直鏈C 1-6及分支鏈C 3-6伸雜烷基亦稱為「低級伸雜烷基」。伸雜烷基之實例包括但不限於-CH 2O-、-(CH 2) 2O-、-(CH 2) 3O-、-(CH 2) 4O-、-(CH 2) 5O-、-(CH 2) 6O-、-(CH 2) 7O-、-(CH 2) 8O-、-(CH 2) 9O-、-(CH 2) 10O-、-CH 2OCH 2-、-CH 2CH 2O-、-(CH 2CH 2O) 2-、-(CH 2CH 2O) 3-、-(CH 2CH 2O) 4-、-(CH 2CH 2O) 5-、-CH 2NH-、-CH 2NHCH 2-、-CH 2CH 2NH-、-CH 2S-、-CH 2SCH 2-及-CH 2CH 2S-。經取代之伸雜烷基之實例包括但不限於-C(O)CH 2O-、-C(O)(CH 2) 2O-、-C(O)(CH 2) 3O-、-C(O)(CH 2) 4O-、-C(O)(CH 2) 5O-、-C(O)(CH 2) 6O-、-C(O)(CH 2) 7O-、-C(O)(CH 2) 8O-、-C(O)(CH 2) 9O-、-C(O)(CH 2) 10O-、-C(O)CH 2OCH 2CH 2O-、-C(O)CH 2O(CH 2CH 2O) 2-、-C(O)CH 2O(CH 2CH 2O) 3-、-C(O)CH 2O(CH 2CH 2O) 4、-C(O)CH 2O(CH 2CH 2O) 5-、-CH 2NHC(O)CH 2-或-CH 2CH 2C(O)NH-。 The terms "heteroalkylene" and "heteroalkanediyl" are used interchangeably herein to refer to a straight or branched chain saturated divalent hydrocarbon radical containing one or more heteroatoms in its backbone, the one or more The heteroatoms are each independently selected from O, S, and N. Heteroalkylene is optionally substituted with one or more substituents Q as described herein. For example, C 1-6 heteroalkylene refers to a straight chain saturated divalent hydrocarbon group of 1 to 6 carbon atoms or a branched chain saturated divalent hydrocarbon group of 3 to 6 carbon atoms. In certain embodiments, the heteroalkylene group has 1 to 20 (C 1-20 ), 1 to 15 (C 1-15 ), 1 to 10 (C 1-10 ), or 1 to 6 (C 1-6 ) linear saturated divalent hydrocarbon group of carbon atoms, or 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ) or Branched chain saturated divalent hydrocarbon radical of 3 to 6 (C 3-6 ) carbon atoms. As used herein, straight-chain C 1-6 and branched C 3-6 heteroalkylene groups are also referred to as "lower heteroalkylene groups." Examples of heteroalkylene include, but are not limited to, -CH2O-, -( CH2 )2O-, -( CH2 ) 3O- , -( CH2 ) 4O- , -( CH2 ) 5O -, -(CH 2 ) 6 O-, -(CH 2 ) 7 O-, -(CH 2 ) 8 O-, -(CH 2 ) 9 O-, -(CH 2 ) 10 O-, -CH 2 OCH 2 -, -CH 2 CH 2 O-, -(CH 2 CH 2 O) 2 -, -(CH 2 CH 2 O) 3 -, -(CH 2 CH 2 O) 4 -, -(CH 2 CH 2O ) 5- , -CH2NH- , -CH2NHCH2- , -CH2CH2NH- , -CH2S- , -CH2SCH2- and -CH2CH2S- . Examples of substituted heteroalkyl include but are not limited to -C(O) CH2O- , -C(O)( CH2 )2O-, -C(O)( CH2 ) 3O- , - C(O)(CH 2 ) 4 O-, -C(O)(CH 2 ) 5 O-, -C(O)(CH 2 ) 6 O-, -C(O)(CH 2 ) 7 O- , -C(O)(CH 2 ) 8 O-, -C(O)(CH 2 ) 9 O-, -C(O)(CH 2 ) 10 O-, -C(O)CH 2 OCH 2 CH 2 O-, -C(O)CH 2 O(CH 2 CH 2 O) 2 -, -C(O)CH 2 O(CH 2 CH 2 O) 3 -, -C(O)CH 2 O(CH 2CH2O ) 4 , -C (O)CH2O( CH2CH2O ) 5- , -CH2NHC (O ) CH2- or -CH2CH2C ( O ) NH-.
術語「烯基」係指含有一或多個，在一個實施例中，一個、兩個、三個、或四個，在另一實施例中，一個碳-碳雙鍵之直鏈或分支鏈單價烴基。烯基視情況經一或多個如本文所描述之取代基Q取代。如一般熟習此項技術者所瞭解，術語「烯基」涵蓋具有「 順式」或「 反式」組態或其混合物，或替代地，「 Z」或「 E」組態或其混合物之基團。舉例而言，C 2-6烯基係指2至6個碳原子之直鏈不飽和單價烴基或3至6個碳原子之分支鏈不飽和單價烴基。在某些實施例中，烯基為2至20個(C 2-20)、2至15個(C 2-15)、2至10個(C 2-10)或2至6個(C 2-6)碳原子之直鏈單價烴基，或3至20個(C 3-20)、3至15個(C 3-15)、3至10個(C 3-10)或3至6個(C 3-6)碳原子之分支鏈單價烴基。烯基之實例包括但不限於乙烯基、丙烯基(包括所有異構形式，例如丙烯-1-基、丙烯-2-基及烯丙基)及丁烯基(包括所有異構形式，例如丁烯-1-基、丁烯-2-基、丁烯-3-基及2-丁烯-1-基)。 The term "alkenyl" refers to a straight or branched chain containing one or more, in one embodiment, one, two, three, or four, in another embodiment, a carbon-carbon double bond Monovalent hydrocarbon group. The alkenyl group is optionally substituted with one or more substituents Q as described herein. As understood by those of ordinary skill in the art, the term "alkenyl" encompasses groups having the " cis " or " trans " configuration or mixtures thereof, or alternatively, the " Z " or " E " configuration or mixtures thereof group. For example, C2-6 alkenyl refers to a straight chain unsaturated monovalent hydrocarbon group of 2 to 6 carbon atoms or a branched chain unsaturated monovalent hydrocarbon group of 3 to 6 carbon atoms. In certain embodiments, the alkenyl groups are 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 10 (C 2-10 ), or 2 to 6 (C 2 ) -6 ) Linear monovalent hydrocarbon group of carbon atoms, or 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ) or 3 to 6 ( C 3-6 ) branched chain monovalent hydrocarbon group of carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, propenyl (including all isomeric forms such as propen-1-yl, propen-2-yl, and allyl) and butenyl (including all isomeric forms such as butyl) alken-1-yl, buten-2-yl, buten-3-yl and 2-buten-1-yl).
術語「伸烯基」與「烯二基」在本文中可互換使用，指代含有一或多個，在一個實施例中，一個、兩個、三個或四個，在另一實施例中，一個碳-碳雙鍵的直鏈或分支鏈二價烴基。烯二基視情況經一或多個如本文所描述之取代基Q取代。如一般熟習此項技術者所瞭解，術語「烯二基」涵蓋具有「 順式」或「 反式」組態或其混合物，或替代地，「 Z」或「 E」組態或其混合物之基團。舉例而言，C 2-6烯二基係指2至6個碳原子之直鏈不飽和二價烴基或3至6個碳原子之分支鏈不飽和二價烴基。在某些實施例中，烯二基為2至30個(C 2-30)、2至20個(C 2-20)、2至15個(C 2-15)、2至10個(C 2-10)或2至6個(C 2-6)碳原子之直鏈二價烴基，或3至30個(C 3-30)、3至20個(C 3-20)、3至15個(C 3-15)、3至10個(C 3-10)或3至6個(C 3-6)碳原子之分支鏈二價烴基。烯二基之實例包括但不限於乙烯二基(包括所有異構形式，例如乙烯-1,1-二基及乙烯-1,2-二基)、丙烯二基(包括所有異構形式，例如1-丙烯-1,1-二基、1-丙烯-1,2-二基及1-丙烯-1,3-二基)、丁烯二基(包括所有異構形式，例如1-丁烯-1,1-二基、1-丁烯-1,2-二基及1-丁烯-1,4-二基)、戊烯二基(包括所有異構形式，例如1-戊烯-1,1-二基、1-戊烯-1,2-二基及1-戊烯-1,5-二基)及己烯二基(包括所有異構形式，例如1-己烯-1,1-二基、1-己烯-1,2-二基、1-己烯-1,3-二基、1-己烯-1,4-二基、1-己烯-1,5-二基及1-己烯-1,6-二基)。 The terms "alkenylene" and "alkenediyl" are used interchangeably herein to refer to containing one or more, in one embodiment, one, two, three or four, in another embodiment , a linear or branched divalent hydrocarbon radical with a carbon-carbon double bond. Alkendiyl is optionally substituted with one or more substituents Q as described herein. As understood by those of ordinary skill in the art, the term "alkenediyl" encompasses those having the " cis " or " trans " configuration or mixtures thereof, or alternatively, the " Z " or " E " configuration or mixtures thereof group. For example, C 2-6 alkenediyl refers to a linear unsaturated divalent hydrocarbon group of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon group of 3 to 6 carbon atoms. In certain embodiments, the alkenediyl group is 2 to 30 (C 2-30 ), 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 10 (C 2-15 ) 2-10 ) or 2 to 6 (C 2-6 ) linear divalent hydrocarbon groups of carbon atoms, or 3 to 30 (C 3-30 ), 3 to 20 (C 3-20 ), 3 to 15 A branched chain divalent hydrocarbon group of (C 3-15 ), 3 to 10 (C 3-10 ) or 3 to 6 (C 3-6 ) carbon atoms. Examples of alkenediyl include, but are not limited to, ethylenediyl (including all isomeric forms, such as ethylene-1,1-diyl and ethylene-1,2-diyl), propylenediyl (including all isomeric forms, such as 1-propene-1,1-diyl, 1-propene-1,2-diyl and 1-propene-1,3-diyl), butenediyl (including all isomeric forms such as 1-butene) -1,1-diyl, 1-butene-1,2-diyl and 1-butene-1,4-diyl), pentenediyl (including all isomeric forms, such as 1-pentene- 1,1-diyl, 1-pentene-1,2-diyl and 1-pentene-1,5-diyl) and hexenediyl (including all isomeric forms such as 1-hexene-1 ,1-diyl, 1-hexene-1,2-diyl, 1-hexene-1,3-diyl, 1-hexene-1,4-diyl, 1-hexene-1,5 -diyl and 1-hexene-1,6-diyl).
術語「伸雜烯基」與「雜烯二基」在本文中可互換使用，指代含有一或多個，在一個實施例中，一個、兩個、三個或四個，在另一實施例中，一個碳-碳雙鍵，且在烴鏈中含有一或多個各自獨立地選自O、S及N之雜原子的直鏈或分支鏈二價烴基。伸雜烯基視情況經一或多個如本文所描述之取代基Q取代。如一般熟習此項技術者所瞭解，術語「伸雜烯基」涵蓋具有「 順式」或「 反式」組態或其混合物，或替代地，「 Z」或「 E」組態或其混合物之基團。舉例而言，C 2-6伸雜烯基係指2至6個碳原子之直鏈不飽和二價烴基或3至6個碳原子之分支鏈不飽和二價烴基。在某些實施例中，雜伸烯基為2至20個(C 2-20)、2至15個(C 2-15)、2至10個(C 2-10)或2至6個(C 2-6)碳原子之直鏈二價烴基，或3至20個(C 3-20)、3至15個(C 3-15)、3至10個(C 3-10)或3至6個(C 3-6)碳原子之分支鏈二價烴基。伸雜烯基之實例包括但不限於-CH=CHO-、-CH=CHOCH 2-、-CH=CHCH 2O-、-CH=CHS-、-CH=CHSCH 2-、-CH=CHCH 2S-或-CH=CHCH 2NH-。 The terms "heteroalkenyl" and "heteroalkenediyl" are used interchangeably herein to refer to a group containing one or more, in one embodiment, one, two, three or four, in another embodiment In one example, a carbon-carbon double bond and a straight or branched divalent hydrocarbon group containing one or more heteroatoms each independently selected from O, S and N in the hydrocarbon chain. The heteroalkenyl group is optionally substituted with one or more substituents Q as described herein. As will be understood by those of ordinary skill in the art, the term "heteroalkenyl" encompasses having the " cis " or " trans " configuration or mixtures thereof, or alternatively, the " Z " or " E " configuration or mixtures thereof the group. For example, C 2-6 heteroalkenyl refers to a linear unsaturated divalent hydrocarbon group of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon group of 3 to 6 carbon atoms. In certain embodiments, the heteroalkenyl groups are 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 10 (C 2-10 ), or 2 to 6 ( C 2-6 ) linear divalent hydrocarbon group of carbon atoms, or 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ), or 3 to 20 (C 3-20 ) A branched chain divalent hydrocarbon group of 6 (C 3-6 ) carbon atoms. Examples of heteroalkenyl include but are not limited to -CH=CHO-, -CH= CHOCH2- , -CH= CHCH2O- , -CH=CHS-, -CH= CHSCH2- , -CH= CHCH2S -or -CH= CHCH2NH- .
術語「炔基」係指含有一或多個，在一個實施例中，一個、兩個、三個、或四個，在另一實施例中，一個碳-碳參鍵之直鏈或分支鏈單價烴基。炔基不含碳-碳雙鍵。炔基視情況經一或多個如本文所描述之取代基Q取代。舉例而言，C 2-6炔基係指2至6個碳原子之直鏈不飽和單價烴基或4至6個碳原子之分支鏈不飽和單價烴基。在某些實施例中，炔基為2至20個(C 2-20)、2至15個(C 2-15)、2至10個(C 2-10)或2至6個(C 2-6)碳原子之直鏈單價烴基，或4至20個(C 4-20)、4至15個(C 4-15)、4至10個(C 4-10)或4至6個(C 4-6)碳原子之分支鏈單價烴基。炔基之實例包括但不限於乙炔基(-C≡CH)、丙炔基(包括所有異構形式，例如1-丙炔基(-C≡CCH 3)及炔丙基(-CH 2C≡CH))、丁炔基(包括所有異構形式，例如1-丁炔-1-基及2-丁炔-1-基)、戊炔基(包括所有異構形式，例如1-戊炔-1-基及1-甲基-2-丁炔-1-基)及己炔基(包括所有異構形式，例如1-己炔-1-基及2-己炔-1-基)。 The term "alkynyl" refers to a straight or branched chain containing one or more, in one embodiment, one, two, three, or four, in another embodiment, a carbon-carbon linkage Monovalent hydrocarbon group. Alkynyl groups do not contain carbon-carbon double bonds. The alkynyl group is optionally substituted with one or more substituents Q as described herein. For example, C2-6 alkynyl refers to a straight chain unsaturated monovalent hydrocarbon group of 2 to 6 carbon atoms or a branched chain unsaturated monovalent hydrocarbon group of 4 to 6 carbon atoms. In certain embodiments, the alkynyl groups are 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 10 (C 2-10 ), or 2 to 6 (C 2 ) -6 ) Linear monovalent hydrocarbon group of carbon atoms, or 4 to 20 (C 4-20 ), 4 to 15 (C 4-15 ), 4 to 10 (C 4-10 ) or 4 to 6 ( C 4-6 ) branched chain monovalent hydrocarbon group of carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propynyl (including all isomeric forms such as 1-propynyl ( -C≡CCH3 ), and propargyl ( -CH2C≡ CH)), butynyl (including all isomeric forms such as 1-butyn-1-yl and 2-butyn-1-yl), pentynyl (including all isomeric forms such as 1-pentyn- 1-yl and 1-methyl-2-butyn-1-yl) and hexynyl (including all isomeric forms such as 1-hexyn-1-yl and 2-hexyn-1-yl).
術語「伸炔基」與「炔二基」在本文中可互換使用，指代含有一或多個，在一個實施例中，一個、兩個、三個或四個，在另一實施例中，一個碳-碳參鍵的直鏈或分支鏈二價烴基。伸炔基不含碳-碳雙鍵。炔二基視情況經一或多個如本文所描述之取代基Q取代。舉例而言，C 2-6炔二基係指2至6個碳原子之直鏈不飽和二價烴基或4至6個碳原子之分支鏈不飽和二價烴基。在某些實施例中，炔二基為2至30個(C 2-30)、2至20個(C 2-20)、2至15個(C 2-15)、2至10個(C 2-10)或2至6個(C 2-6)碳原子之直鏈二價烴基，或4至30個(C 4-30)、4至20個(C 4-20)、4至15個(C 4-15)、4至10個(C 4-10)或4至6個(C 4-6)碳原子之分支鏈二價烴基。炔二基之實例包括但不限於乙炔二基、丙炔二基(包括所有異構形式，例如1-丙炔-1,3-二基及1-丙炔-3,3-二基)、丁炔二基(包括所有異構形式，例如1-丁炔-1,3-二基、1-丁炔-1,4-二基及2-丁炔-1,1-二基)、戊炔二基(包括所有異構形式，例如1-戊炔-1,3-二基、1-戊炔-1,4-二基及2-戊炔-1,1-二基)及己炔二基(包括所有異構形式，例如1-己炔-1,3-二基、1-己炔-1,4-二基及2-己炔-1,1-二基)。 The terms "alkynylene" and "alkynediyl" are used interchangeably herein to refer to a group containing one or more, in one embodiment, one, two, three or four, in another embodiment , a linear or branched divalent hydrocarbon group with a carbon-carbon bond. Alkynylene groups do not contain carbon-carbon double bonds. Alkyndiyl is optionally substituted with one or more substituents Q as described herein. For example, C 2-6 alkynediyl refers to a straight-chain unsaturated divalent hydrocarbon group of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon group of 4 to 6 carbon atoms. In certain embodiments, the alkynediyl group is 2 to 30 (C 2-30 ), 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 10 (C 2-15 ) 2-10 ) or 2 to 6 (C 2-6 ) straight-chain divalent hydrocarbon groups of carbon atoms, or 4 to 30 (C 4-30 ), 4 to 20 (C 4-20 ), 4 to 15 A branched chain divalent hydrocarbon group of (C 4-15 ), 4 to 10 (C 4-10 ) or 4 to 6 (C 4-6 ) carbon atoms. Examples of alkynediyl include, but are not limited to, ethynediyl, propynediyl (including all isomeric forms such as 1-propyne-1,3-diyl and 1-propyne-3,3-diyl), Butynediyl (including all isomeric forms such as 1-butyne-1,3-diyl, 1-butyne-1,4-diyl and 2-butyne-1,1-diyl), pentyne Alkyndiyl (including all isomeric forms such as 1-pentyne-1,3-diyl, 1-pentyne-1,4-diyl and 2-pentyne-1,1-diyl) and hexyne Diyl (including all isomeric forms such as 1-hexyn-1,3-diyl, 1-hexyn-1,4-diyl and 2-hexyn-1,1-diyl).
術語「伸雜炔基」與「雜炔二基」在本文中可互換使用，指代含有一或多個，在一個實施例中，一個、兩個、三個或四個，在另一實施例中，一個碳-碳參鍵，且在其主鏈中含有一或多個各自獨立地選自O、S及N之雜原子的直鏈或分支鏈二價烴基。伸雜炔基不含碳-碳雙鍵。伸雜炔基視情況經一或多個如本文所描述之取代基Q取代。舉例而言，C 2-6伸雜炔基係指2至6個碳原子之直鏈不飽和二價烴基或4至6個碳原子之分支鏈不飽和二價烴基。在某些實施例中，伸雜炔基為2至30個(C 2-30)、2至20個(C 2-20)、2至15個(C 2-15)、2至10個(C 2-10)或2至6個(C 2-6)碳原子之直鏈二價烴基，或4至30個(C 4-30)、4至20個(C 4-20)、4至15個(C 4-15)、4至10個(C 4-10)或4至6個(C 4-6)碳原子之分支鏈二價烴基。伸雜炔基之實例包括但不限於-C≡CCH 2O-、-C≡CCH 2S-或-C≡CCH 2NH-。 The terms "heteroalkynyl" and "heteroalkynyl" are used interchangeably herein to refer to a group containing one or more, in one embodiment, one, two, three or four, in another embodiment In one example, a carbon-carbon junction bond and containing one or more heteroatoms each independently selected from the group consisting of O, S, and N in its backbone, a straight or branched chain divalent hydrocarbon group. Heteroalkynyl groups do not contain carbon-carbon double bonds. Heteroalkynyl is optionally substituted with one or more substituents Q as described herein. For example, C2-6heteroalkynyl refers to a linear unsaturated divalent hydrocarbon group of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon group of 4 to 6 carbon atoms. In certain embodiments, the heteroalkynyl group is 2 to 30 (C 2-30 ), 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 10 ( C 2-10 ) or linear divalent hydrocarbon groups of 2 to 6 (C 2-6 ) carbon atoms, or 4 to 30 (C 4-30 ), 4 to 20 (C 4-20 ), 4 to A branched chain divalent hydrocarbon group of 15 (C 4-15 ), 4 to 10 (C 4-10 ) or 4 to 6 (C 4-6 ) carbon atoms. Examples of heteroalkynyl include, but are not limited to, -C≡CCH2O- , -C≡CCH2S- , or -C≡CCH2NH- .
術語「環烷基」係指環狀單價烴基，其視情況經一或多個如本文所描述之取代基Q取代。在一個實施例中，環烷基為飽和或不飽和但非芳族，及/或橋聯或非橋聯，及/或稠合雙環基團。在某些實施例中，環烷基具有3至20個(C 3-20)、3至15個(C 3-15)、3至10個(C 3-10)或3至7個(C 3-7)碳原子。在一個實施例中，環烷基為單環的。在另一實施例中，環烷基為雙環的。在又另一實施例中，環烷基為三環的。在再一實施例中，環烷基為多環的。環烷基之實例包括但不限於環丙基、環丁基、環戊基、環戊烯基、環己基、環己烯基、環己二烯基、環庚基、環庚烯基、雙環[1.1.1]戊基、雙環[2.1.1]己基、雙環[2.2.1]庚基、雙環[2.2.2]辛基、十氫萘基及金剛烷基。 The term "cycloalkyl" refers to a cyclic monovalent hydrocarbon group optionally substituted with one or more substituents Q as described herein. In one embodiment, cycloalkyl groups are saturated or unsaturated but non-aromatic, and/or bridged or non-bridged, and/or fused bicyclic groups. In certain embodiments, the cycloalkyl group has 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ), or 3 to 7 (C 3-10 ) 3-7 ) carbon atoms. In one embodiment, the cycloalkyl group is monocyclic. In another embodiment, the cycloalkyl group is bicyclic. In yet another embodiment, the cycloalkyl group is tricyclic. In yet another embodiment, the cycloalkyl group is polycyclic. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptenyl, bicyclic [1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, decalinyl and adamantyl.
術語「伸環烷基」與「環烷二基」在本文中可互換使用，指代可視情況經一或多個如本文所描述之取代基Q取代的環狀二價烴基。在一個實施例中，環烷二基可為飽和或不飽和但非芳族，及/或橋聯，及/或非橋聯，及/或稠合雙環基團。在某些實施例中，環烷二基具有3至30個(C 3-30)、3至20個(C 3-20)、3至15個(C 3-15)、3至10個(C 3-10)或3至7個(C 3-7)碳原子。環烷二基之實例包括但不限於環丙烷二基(包括所有異構形式，例如環丙烷-1,1-二基及環丙烷-1,2-二基)、環丁烷二基(包括所有異構形式，例如環丁烷-1,1-二基、環丁烷-1,2-二基及環丁烷-1,3-二基)、環戊烷二基(包括所有異構形式，例如環戊烷-1,1-二基、環戊烷-1,2-二基及環戊烷-1,3-二基)、環己烷二基(包括所有異構形式，例如環己烷-1,1-二基、環己烷-1,2-二基、環己烷-1,3-二基及環己烷-1,4-二基)、環庚烷二基(包括所有異構形式，例如環庚烷-1,1-二基、環庚烷-1,2-二基、環庚烷-1,3-二基及環庚烷-1,4-二基)、十氫萘二基(包括所有異構形式，例如十氫萘-1,1-二基、十氫萘-1,2-二基及十氫萘-1,8-二基)及金剛烷二基(包括所有異構形式，例如金剛烷-1,2-二基、金剛烷-1,3-二基及金剛烷-1,8-二基)。 The terms "cycloalkylene" and "cycloalkanediyl" are used interchangeably herein to refer to a cyclic divalent hydrocarbon group optionally substituted with one or more substituents Q as described herein. In one embodiment, a cycloalkanediyl group can be saturated or unsaturated but non-aromatic, and/or bridged, and/or non-bridged, and/or a fused bicyclic group. In certain embodiments, the cycloalkanediyl group has 3 to 30 (C 3-30 ), 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 ( C 3-10 ) or 3 to 7 (C 3-7 ) carbon atoms. Examples of cycloalkanediyl include, but are not limited to, cyclopropanediyl (including all isomeric forms such as cyclopropane-1,1-diyl and cyclopropane-1,2-diyl), cyclobutanediyl (including All isomeric forms such as cyclobutane-1,1-diyl, cyclobutane-1,2-diyl and cyclobutane-1,3-diyl), cyclopentanediyl (including all isomeric forms forms such as cyclopentane-1,1-diyl, cyclopentane-1,2-diyl and cyclopentane-1,3-diyl), cyclohexanediyl (including all isomeric forms such as cyclohexane-1,1-diyl, cyclohexane-1,2-diyl, cyclohexane-1,3-diyl and cyclohexane-1,4-diyl), cycloheptanediyl (including all isomeric forms such as cycloheptane-1,1-diyl, cycloheptane-1,2-diyl, cycloheptane-1,3-diyl and cycloheptane-1,4-diyl base), decalindiyl (including all isomeric forms such as decalin-1,1-diyl, decalin-1,2-diyl and decalin-1,8-diyl) and Adamantanediyl (including all isomeric forms such as adamantane-1,2-diyl, adamantane-1,3-diyl and adamantane-1,8-diyl).
術語「芳基」係指含有至少一個芳族碳環之單價單環芳族烴基及/或單價多環芳族烴基。在某些實施例中，芳基具有6至20個(C 6-20)、6至15個(C 6-15)或6至10個(C 6-10)環碳原子。芳基之實例包括但不限於苯基、萘基、茀基、薁基、蒽基、菲基、芘基、聯二苯及聯三苯。芳基亦指雙環或三環碳環，其中環中之一者為芳族且其他環可為飽和、部分不飽和或芳族，例如二氫萘基、茚基、二氫茚基或四氫萘基(tetrahydronaphthyl/tetralinyl)。在一個實施例中，芳基為單環的。在另一實施例中，芳基為雙環的。在又另一實施例中，芳基為三環的。在再一實施例中，芳基為多環的。在某些實施例中，芳基視情況經一或多個如本文所描述之取代基Q取代。 The term "aryl" refers to a monovalent monocyclic aromatic hydrocarbon group and/or a monovalent polycyclic aromatic hydrocarbon group containing at least one aromatic carbocyclic ring. In certain embodiments, aryl groups have 6 to 20 (C 6-20 ), 6 to 15 (C 6-15 ), or 6 to 10 (C 6-10 ) ring carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, perylene, azulenyl, anthracenyl, phenanthryl, pyrenyl, biphenyl, and triphenyl. Aryl also refers to a bicyclic or tricyclic carbocyclic ring wherein one of the rings is aromatic and the other ring may be saturated, partially unsaturated or aromatic, such as dihydronaphthyl, indenyl, indenyl or tetrahydro Naphthyl (tetrahydronaphthyl/tetralinyl). In one embodiment, the aryl group is monocyclic. In another embodiment, the aryl group is bicyclic. In yet another embodiment, the aryl group is tricyclic. In yet another embodiment, the aryl group is polycyclic. In certain embodiments, the aryl group is optionally substituted with one or more substituents Q as described herein.
術語「伸芳基」與「芳二基」在本文中可互換使用，指代含有至少一種芳族烴環之二價單環芳族烴基或二價多環芳族烴基。在某些實施例中，伸芳基具有6至20個(C 6-20)、6至15個(C 6-15)或6至10個(C 6-10)環原子。伸芳基之實例包括但不限於伸苯基(包括所有異構形式，例如苯-1,2-二基、苯-1,3-二基及苯-1,4-二基)、伸萘基(包括所有異構形式，例如萘-1,2-二基、萘-1,3-二基及萘-1,8-二基)、伸茀基(包括所有異構形式，例如茀-1,2-二基、茀-1,3-二基及茀-1,8-二基)、伸薁基(包括所有異構形式，例如薁-1,2-二基、薁-1,3-二基及薁-1,8-二基)、伸蒽基(包括所有異構形式，例如蒽-1,2-二基、蒽-1,3-二基及蒽-1,8-二基)、伸菲基(包括所有異構形式，例如菲-1,2-二基、菲-1,3-二基及菲-1,8-二基)、伸芘基(包括所有異構形式，例如芘-1,2-二基、芘-1,3-二基及芘-1,8-二基)、伸聯苯基(包括所有異構形式，例如聯苯-2,3-二基、聯苯-3,4'-二基及聯苯-4,4'-二基)及伸聯三苯基(包括所有異構形式，例如聯三苯-2,3-二基、聯三苯-3,4'-二基及聯三苯-4,4'-二基)。伸芳基亦指雙環或三環碳環，其中環中之一者為芳族且其他可為飽和、部分不飽和的，或為芳族的，例如，伸二氫萘基(包括所有異構形式，例如二氫萘-1,2-二基及二氫萘-1,8-二基)、伸茚基(包括所有異構形式，例如茚-1,2-二基、茚-1,5-二基及茚-1,7-二基)、伸二氫茚基(包括所有異構形式，例如二氫茚-1,2-二基、二氫茚-1,5-二基及二氫茚-1,7-二基)或伸四氫萘基(tetrahydronaphthylene/tetralinylene) (包括所有異構形式，例如四氫萘-1,2-二基、四氫萘-1,5-二基及四氫萘-1,8-二基)。在某些實施例中，伸芳基視情況經一或多個如本文所描述之取代基Q取代。 The terms "arylene" and "ardiyl" are used interchangeably herein to refer to a bivalent monocyclic aromatic hydrocarbon group or a bivalent polycyclic aromatic hydrocarbon group containing at least one aromatic hydrocarbon ring. In certain embodiments, the arylidene group has 6 to 20 (C 6-20 ), 6 to 15 (C 6-15 ), or 6 to 10 (C 6-10 ) ring atoms. Examples of arylidene groups include, but are not limited to, phenylene groups (including all isomeric forms such as benzene-1,2-diyl, benzene-1,3-diyl, and benzene-1,4-diyl), naphthalene base (including all isomeric forms, such as naphthalene-1,2-diyl, naphthalene-1,3-diyl and naphthalene-1,8-diyl), phenylene (including all isomeric forms, such as phenyl- 1,2-diyl, perylene-1,3-diyl and perylene-1,8-diyl), azulenyl (including all isomeric forms, such as azulen-1,2-diyl, azulen-1, 3-diyl and azulen-1,8-diyl), anthracenyl (including all isomeric forms, such as anthracene-1,2-diyl, anthracene-1,3-diyl and anthracene-1,8-diyl) diyl), phenanthrene (including all isomeric forms, such as phenanthrene-1,2-diyl, phenanthrene-1,3-diyl and phenanthrene-1,8-diyl), pyrene (including all isomeric forms) structural forms, such as pyrene-1,2-diyl, pyrene-1,3-diyl and pyrene-1,8-diyl), biphenyl (including all isomeric forms, such as biphenyl-2,3 -diyl, biphenyl-3,4'-diyl and biphenyl-4,4'-diyl) and triphenyl (including all isomeric forms, such as triphenyl-2,3-diyl) , bis-triphenyl-3,4'-diyl and bis-triphenyl-4,4'-diyl). Arylene also refers to a bicyclic or tricyclic carbocyclic ring wherein one of the rings is aromatic and the other can be saturated, partially unsaturated, or aromatic, for example, dihydronaphthyl (including all isomeric forms) , such as dihydronaphthalene-1,2-diyl and dihydronaphthalene-1,8-diyl), indenyl (including all isomeric forms, such as indene-1,2-diyl, indene-1,5 -diyl and indene-1,7-diyl), dihydroindenyl (including all isomeric forms such as dihydroindene-1,2-diyl, dihydroindene-1,5-diyl and dihydroindenyl) Indene-1,7-diyl) or tetrahydronaphthylene/tetralinylene (including all isomeric forms such as tetrahydronaphthalene-1,2-diyl, tetrahydronaphthalene-1,5-diyl and tetrahydronaphthalene-1,8-diyl). In certain embodiments, arylidene is optionally substituted with one or more substituents Q as described herein.
術語「芳烷基」或「芳基烷基」係指經一或多個芳基取代之單價烷基。在某些實施例中，芳烷基具有7至30個(C 7-30)、7至20個(C 7-20)或7至16個(C 7-16)碳原子。芳烷基之實例包括但不限於苯甲基、苯乙基(包括所有異構形式，例如1-苯乙基及2-苯乙基)及苯丙基(包括所有異構形式，例如1-苯丙基、2-苯丙基及3-苯丙基)。在某些實施例中，芳烷基視情況經一或多個如本文所描述之取代基Q取代。 The term "aralkyl" or "arylalkyl" refers to a monovalent alkyl group substituted with one or more aryl groups. In certain embodiments, the aralkyl group has 7 to 30 (C 7-30 ), 7 to 20 (C 7-20 ), or 7 to 16 (C 7-16 ) carbon atoms. Examples of aralkyl groups include, but are not limited to, benzyl, phenethyl (including all isomeric forms such as 1-phenethyl and 2-phenethyl), and phenylpropyl (including all isomeric forms such as 1- phenylpropyl, 2-phenylpropyl and 3-phenylpropyl). In certain embodiments, aralkyl groups are optionally substituted with one or more substituents Q as described herein.
術語「伸芳烷基」及「芳基伸烷基」係指經一或多個芳基取代之二價烷基。在某些實施例中，伸芳烷基具有7至30個(C 7-30)、7至20個(C 7-20)或7至16個(C 7-16)碳原子。伸芳烷基之實例包括但不限於伸苄基(包括所有異構形式，例如苯基甲二基)、苯基伸乙基(包括所有異構形式，例如2-苯基-乙-1,1-二基及2-苯基-乙-1,2-二基)及苯基伸丙基(包括所有異構形式，例如3-苯基-丙-1,1-二基、3-苯基-丙-1,2-二基及3-苯基-丙-1,3-二基)。在某些實施例中，伸芳烷基視情況經一或多個如本文所描述之取代基Q取代。 The terms "aralkylene" and "arylalkylene" refer to a divalent alkyl group substituted with one or more aryl groups. In certain embodiments, the aralkylene group has 7 to 30 (C 7-30 ), 7 to 20 (C 7-20 ), or 7 to 16 (C 7-16 ) carbon atoms. Examples of aralkylene include, but are not limited to, benzylidene (including all isomeric forms such as phenylmethyldiyl), phenylethylidene (including all isomeric forms such as 2-phenyl-ethane-1,1 -diyl and 2-phenyl-ethane-1,2-diyl) and phenylpropylidene (including all isomeric forms such as 3-phenyl-prop-1,1-diyl, 3-phenyl- propan-1,2-diyl and 3-phenyl-propan-1,3-diyl). In certain embodiments, aralkylene is optionally substituted with one or more substituents Q as described herein.
術語「雜芳基」係指含有至少一個芳族環之單價單環芳族基或單價多環芳族基，其中至少一個芳族環在環中含有一或多個各自獨立地選自O、S及N之雜原子。對於含有雜芳環及非芳族雜環之雜芳基，該雜芳基不經由其非芳族雜環鍵合至分子之其餘部分。雜芳基之各環可含有一或兩個O原子、一或兩個S原子及/或一至四個N原子，其限制條件為各環中之雜原子之總數為四個或更少且各環含有至少一個碳原子。在某些實施例中，雜芳基具有5至20個、5至15個或5至10個環原子。在一個實施例中，雜芳基為單環的。單環雜芳基之實例包括但不限於呋喃基、咪唑基、異噻唑基、異㗁唑基、㗁二唑基、㗁唑基、吡𠯤基、吡唑基、嗒𠯤基、吡啶基、嘧啶基、吡咯基、噻二唑基、噻唑基、噻吩基、四唑基、三𠯤基及三唑基。在另一實施例中，雜芳基為雙環的。雙環雜芳基之實例包括但不限於苯并呋喃基、苯并咪唑基、苯并異㗁唑基、苯并哌喃基、苯并噻二唑基、苯并噻唑基、苯并噻吩基、苯并三唑基、苯并㗁唑基、呋喃吡啶基(包括所有異構形式，例如呋喃并[2,3- b]吡啶基、呋喃并[2,3- c]吡啶基、呋喃并[3,2- b]吡啶基、呋喃并[3,2- c]吡啶基、呋喃并[3,4- b]吡啶基及呋喃并[3,4- c]吡啶基)、咪唑并吡啶基(包括所有異構形式，例如咪唑并[1,2- a]吡啶基、咪唑并[4,5- b]吡啶基及咪唑并[4,5- c]吡啶基)、咪唑并噻唑基(包括所有異構形式，例如咪唑并[2,1- b]噻唑基及咪唑并[4,5- d]噻唑基)、吲唑基、吲吊基、吲哚基、異苯并呋喃基、異苯并噻吩基(亦即，苯并[ c]噻吩基)、異吲哚基、異喹啉基、㖠啶基(包括所有異構形式，例如1,5-㖠啶基、1,6-㖠啶基、1,7-㖠啶基及1,8-㖠啶基)、㗁唑并吡啶基(包括所有異構形式，例如㗁唑并[4,5- b]吡啶基、㗁唑并[4,5- c]吡啶基、㗁唑并[5,4- b]吡啶基及㗁唑并[5,4- c]吡啶基)、呔𠯤基、喋啶基、嘌呤基、吡咯并吡啶基(包括所有異構形式，例如吡咯并[2,3- b]吡啶基、吡咯并[2,3- c]吡啶基、吡咯并[3,2- b]吡啶基及吡咯并[3,2- c]吡啶基)、喹啉基、喹㗁啉基、喹唑啉基、噻二唑并嘧啶基(包括所有異構形式，例如[1,2,5]噻二唑并[3,4- d]嘧啶基及[1,2,3]噻二唑并[4,5- d]嘧啶基)及噻吩并吡啶基(包括所有異構形式，例如噻吩并[2,3- b]吡啶基、噻吩并[2,3- c]吡啶基、噻吩[3,2- b]吡啶基及噻吩[3,2- c]吡啶基)。在又另一實施例中，雜芳基為三環的。三環雜芳基之實例包括但不限於吖啶基、苯并吲哚基、咔唑基、二苯并呋喃基、𠰐啶基、啡啶基、啡啉基(包括所有異構形式，例如1,5-啡啉基、1,6-啡啉基、1,7-啡啉基、1,9-啡啉基及2,10-啡啉基)、啡呻𠯤基、啡𠯤基、啡噻𠯤基、啡㗁 𠯤基及𠮿基。在某些實施例中，雜芳基視情況經一或多個如本文所描述之取代基Q取代。 The term "heteroaryl" refers to a monovalent monocyclic aromatic group or a monovalent polycyclic aromatic group containing at least one aromatic ring, wherein the at least one aromatic ring contains one or more in the ring each independently selected from O, Heteroatoms of S and N. For a heteroaryl group containing a heteroaromatic ring and a non-aromatic heterocyclic ring, the heteroaryl group is not bonded to the rest of the molecule through its non-aromatic heterocyclic ring. Each ring of a heteroaryl group may contain one or two O atoms, one or two S atoms, and/or one to four N atoms, with the proviso that the total number of heteroatoms in each ring is four or less and each Rings contain at least one carbon atom. In certain embodiments, heteroaryl groups have 5 to 20, 5 to 15, or 5 to 10 ring atoms. In one embodiment, the heteroaryl group is monocyclic. Examples of monocyclic heteroaryl groups include, but are not limited to, furyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyridyl, pyrazolyl, pyridoxyl, pyridyl, Pyrimidyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazolyl and triazolyl. In another embodiment, the heteroaryl group is bicyclic. Examples of bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyridyl (including all isomeric forms such as furo[2,3- b ]pyridyl, furo[2,3- c ]pyridyl, furo[ 3,2- b ]pyridyl, furo[3,2- c ]pyridyl, furo[3,4- b ]pyridyl and furo[3,4- c ]pyridyl), imidazopyridyl (including all isomeric forms such as imidazo[1,2- a ]pyridyl, imidazo[4,5- b ]pyridyl and imidazo[4,5- c ]pyridyl), imidazothiazolyl ( Including all isomeric forms such as imidazo[2,1- b ]thiazolyl and imidazo[4,5- d ]thiazolyl), indazolyl, indazolyl, indolyl, isobenzofuranyl, Isobenzothienyl (ie, benzo[ c ]thienyl), isoindolyl, isoquinolinyl, ethidyl (including all isomeric forms such as 1,5-ethidyl, 1,6 -ethidyl, 1,7-ethidyl and 1,8-ethidyl), ethazolopyridyl (including all isomeric forms, e.g. ethazolo[4,5- b ]pyridyl, oxazole [4,5- c ]pyridyl, oxazolo[5,4- b ]pyridyl and oxazolo[5,4- c ]pyridyl), pyridyl, pteridyl, purinyl, pyrrole pyridyl (including all isomeric forms such as pyrrolo[2,3- b ]pyridyl, pyrrolo[2,3- c ]pyridyl, pyrrolo[3,2- b ]pyridyl and pyrrolo[ 3,2- c ]pyridyl), quinolinyl, quinolinyl, quinazolinyl, thiadiazolopyrimidyl (including all isomeric forms such as [1,2,5]thiadiazolo[ 3,4- d ]pyrimidinyl and [1,2,3]thiadiazolo[4,5- d ]pyrimidinyl) and thienopyridyl (including all isomeric forms such as thieno[2,3- b ]pyridyl, thieno[2,3- c ]pyridyl, thiophene[3,2- b ]pyridyl and thiophene[3,2- c ]pyridyl). In yet another embodiment, the heteroaryl group is tricyclic. Examples of tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, pyridinyl, phenidinyl, phenanthrolinyl (including all isomeric forms such as 1,5-phenanthroline, 1,6-phenanthroline, 1,7-phenanthroline, 1,9-phenanthroline and 2,10-phenanthroline), phenanthroline, phenanthroline, Phosphatidyl 𠯤-based, coffee 㗁𠯤-based and 𠮿-based. In certain embodiments, the heteroaryl group is optionally substituted with one or more substituents Q as described herein.
術語「伸雜芳基」與「雜芳二基」在本文中可互換使用，指代含有至少一個芳族環之二價單環芳族基或二價多環芳族基，其中至少一個芳族環在環中含有一或多個雜原子，該一或多個雜原子中之每一者獨立地選自O、S及N。對於含有雜芳環及非芳族雜環之伸雜芳基，該伸雜芳基不經由其非芳族雜環鍵合至分子之其餘部分。伸雜芳基之各環可含有一或兩個O原子、一或兩個S原子及/或一至四個N原子，其限制條件為各環中之雜原子之總數為四個或更少且各環含有至少一個碳原子。在某些實施例中，伸雜芳基具有5至20個、5至15個或5至10個環原子。單環伸雜芳基之實例包括但不限於呋喃二基、咪唑二基、異噻唑二基、異㗁唑二基、㗁二唑二基、㗁唑二基、吡𠯤二基、吡唑二基、嗒𠯤二基、吡啶二基、嘧啶二基、吡咯二基、噻二唑二基、噻唑二基、噻吩二基、四唑二基、三𠯤二基及三唑二基。雙環伸雜芳基之實例包括但不限於苯并呋喃二基、苯并咪唑二基、苯并異㗁唑二基、苯并哌喃二基、苯并噻二唑二基、苯并噻唑二基、苯并噻吩二基、苯并三唑二基、苯并㗁唑二基、呋喃吡啶二基(包括所有異構形式，例如呋喃并[2,3- b]吡啶二基、呋喃并[2,3- c]吡啶二基、呋喃并[3,2- b]吡啶二基、呋喃并[3,2- c]吡啶二基、呋喃并[3,4- b]吡啶二基及呋喃并[3,4- c]吡啶二基)、咪唑并吡啶二基(包括所有異構形式，例如咪唑并[1,2- a]吡啶二基、咪唑并[4,5- b]吡啶二基及咪唑并[4,5- c]吡啶二基)、咪唑并噻唑二基(包括所有異構形式，例如咪唑并[2,1- b]噻唑二基及咪唑并[4,5- d]噻唑二基)、吲唑二基、吲吊二基、吲哚二基、異苯并呋喃二基、異苯并噻吩二基(亦即，苯并[ c]噻吩二基)、異吲哚二基、異喹啉二基、㖠啶二基(包括所有異構形式，例如1,5-㖠啶二基、1,6-㖠啶二基、1,7-㖠啶二基及1,8-㖠啶二基)、㗁唑并吡啶二基(包括所有異構形式，例如㗁唑并[4,5- b]吡啶二基、㗁唑并[4,5- c]吡啶二基、㗁唑并[5,4- b]吡啶二基及㗁唑并[5,4- c]吡啶二基)、呔𠯤二基、喋啶二基、嘌呤二基、吡咯并吡啶二基(包括所有異構形式，例如吡咯并[2,3- b]吡啶二基、吡咯并[2,3- c]吡啶二基、吡咯并[3,2- b]吡啶二基及吡咯并[3,2- c]吡啶二基)、喹啉二基、喹㗁啉二基、喹唑啉二基、噻二唑并嘧啶二基(包括所有異構形式，例如[1,2,5]噻二唑并[3,4- d]嘧啶二基及[1,2,3]噻二唑并[4,5- d]嘧啶二基)及噻吩并吡啶二基(包括所有異構形式，例如噻吩并[2,3- b]吡啶二基、噻吩并[2,3- c]吡啶二基、噻吩[3,2- b]吡啶二基及噻吩[3,2- c]吡啶二基)。三環伸雜芳基之實例包括但不限於吖啶二基、苯并吲哚二基、咔唑二基、二苯并呋喃二基、𠰐啶二基、啡啉二基(包括所有異構形式，例如1,5-啡啉二基、1,6-啡啉二基、1,7-啡啉二基、1,9-啡啉二基及2,10-啡啉二基)、啡啶二基、啡呻𠯤二基、啡𠯤二基、啡噻𠯤二基、啡㗁 𠯤二基及𠮿二基。在某些實施例中，伸雜芳基視情況經一或多個如本文所描述之取代基Q取代。 The terms "heteroaryl" and "heteroaryldiyl" are used interchangeably herein to refer to a bivalent monocyclic aromatic group or a bivalent polycyclic aromatic group containing at least one aromatic ring, wherein at least one aromatic ring A ring family contains one or more heteroatoms in the ring, each of the one or more heteroatoms independently selected from O, S, and N. For a heteroaryl group containing a heteroaromatic ring and a non-aromatic heterocyclic ring, the heteroaryl group is not bonded to the rest of the molecule through its non-aromatic heterocyclic ring. Each ring of a heteroaryl group may contain one or two O atoms, one or two S atoms, and/or one to four N atoms, with the proviso that the total number of heteroatoms in each ring is four or less and Each ring contains at least one carbon atom. In certain embodiments, the heteroaryl group has 5 to 20, 5 to 15, or 5 to 10 ring atoms. Examples of monocyclic heteroaryl include, but are not limited to, furandiyl, imidazolediyl, isothiazolediyl, isoxazolediyl, oxadiazolediyl, oxazolediyl, pyridinediyl, pyrazolediyl base, pyridinediyl, pyridinediyl, pyrimidinediyl, pyrrolediyl, thiadiazolediyl, thiazolediyl, thiophenediyl, tetrazolediyl, triazolediyl and triazolediyl. Examples of bicycloheteroaryl include, but are not limited to, benzofurandiyl, benzimidazolediyl, benzisoxazolediyl, benzopyrandiyl, benzothiadiazolediyl, benzothiazolediyl base, benzothiophenediyl, benzotriazolediyl, benzoxazolediyl, furanpyridinediyl (including all isomeric forms such as furo[2,3- b ]pyridinediyl, furo[ 2,3- c ]pyridinediyl, furo[3,2- b ]pyridinediyl, furo[3,2- c ]pyridinediyl, furo[3,4- b ]pyridinediyl and furan azo[3,4- c ]pyridinediyl), imidazopyridinediyl (including all isomeric forms, such as imidazo[1,2- a ]pyridinediyl, imidazo[4,5- b ]pyridinediyl and imidazo[4,5- c ]pyridinediyl), imidazothiazolediyl (including all isomeric forms, such as imidazo[2,1- b ]thiazolediyl and imidazo[4,5- d ]thiazolediyl), indazolediyl, indolediyl, indolediyl, isobenzofurandiyl, isobenzothiophenediyl (ie, benzo[ c ]thiophenediyl), isoindium Indoldiyl, isoquinolinediyl, ethylenediyl (including all isomeric forms, such as 1,5-ethylenediyl, 1,6-ethylenediyl, 1,7-ethylenediyl and 1 ,8-ethidyl), ethazolo[4,5- c ]pyridinediyl (including all isomeric forms, e.g. ethazolo[4,5- b ]pyridinediyl, ( _ All isomeric forms are included, such as pyrrolo[2,3- b ]pyridinediyl, pyrrolo[2,3- c ]pyridinediyl, pyrrolo[3,2- b ]pyridinediyl and pyrrolo[3 ,2- c ]pyridinediyl), quinolinediyl, quinolinediyl, quinazolinediyl, thiadiazolopyrimidinediyl (including all isomeric forms such as [1,2,5]thiadiyl Diazolo[3,4- d ]pyrimidinediyl and [1,2,3]thiadiazolo[4,5- d ]pyrimidinediyl) and thienopyridinediyl (including all isomeric forms such as Thieno[2,3- b ]pyridinediyl, thieno[2,3- c ]pyridinediyl, thiophene[3,2- b ]pyridinediyl and thiophene[3,2- c ]pyridinediyl) . Examples of tricycloheteroaryl include, but are not limited to, acridinediyl, benzoindolediyl, carbazolediyl, dibenzofurandiyl, azidinediyl, phenanthroline (including all isomeric form, such as 1,5-phenanthroline, 1,6-phenantholindiyl, 1,7-phenantholindiyl, 1,9-phenanthroline and 2,10-phenanthroline), phenanthrene Pyridinyl dibase, brown moan 𠯤 two bases, brown 𠯤 two bases, phenothia 𠯤 two bases, brown 㗁 𠯤 two bases and 𠮿 two bases. In certain embodiments, heteroaryl is optionally substituted with one or more substituents Q as described herein.
術語「雜環基」或「雜環」係指含有至少一個非芳族環之單價單環非芳族環系統或單價多環環系統，其中非芳族環原子中之一或多者為各自獨立地選自O、S及N之雜原子；且其餘環原子為碳原子。對於含有雜芳環及非芳族雜環之雜環基，該雜環基不經由雜芳環鍵合至分子之其餘部分。在某些實施例中，雜環基(heterocyclyl/heterocyclic group)具有3至20個、3至15個、3至10個、3至8個、4至7個或5至6個環原子。在某些實施例中，雜環基為單環、雙環、三環或四環環系統，其可稠合或橋聯，且其中氮或硫原子可視情況氧化，氮原子可視情況四級銨化，且一些環可部分或完全飽和，或為芳族環。雜環基可在任何引起產生穩定化合物之雜原子或碳原子處連接至主結構。雜環基(heterocyclyl/heterocyclic group)之實例包括但不限於氮呯基、苯并二㗁烷基、苯并二氧呃基、苯并呋喃酮基、𠳭基、十氫異喹啉基、二氫苯并呋喃基、二氫苯并異噻唑基、二氫苯并異㗁 𠯤基(包括所有異構形式，例如1,4-二氫苯并[d][1,3]㗁 𠯤基、3,4-二氫苯并[c][1,2]-㗁 𠯤基及3,4-二氫苯并[d][1,2]㗁 𠯤基)、二氫苯并噻吩基、二氫異苯并呋喃基、二氫苯并[c]噻吩基、二氫呋喃基、二氫異吲哚基、二氫哌喃基、二氫吡唑基、二氫吡𠯤基、二氫吡啶基、二氫嘧啶基、二氫吡咯基、二氧戊環基、1,4-二噻烷基、呋喃酮基、四氫咪唑基、咪唑啉基、吲哚啉基、異𠳭基、異吲哚啉基、異噻唑啶基、異㗁唑啶基、𠰌啉基、八氫吲哚基、八氫異吲哚基、㗁唑啶酮基、㗁唑啶基、環氧乙基、哌𠯤基、哌啶基、4-哌啶酮基、吡唑啶基、吡唑啉基、吡咯啶基、吡咯啉基、
術語「伸雜環基」係指含有至少一個非芳族環之二價單環非芳族環系統或二價多環環系統，其中非芳族環原子中之一或多者為獨立地選自O、S及N之雜原子；且其餘環原子為碳原子。對於含有雜芳族環及非芳族雜環之伸雜環基，該伸雜環基經由其非芳族雜環與分子之其餘部分具有至少一個鍵。在某些實施例中，伸雜環基具有3至20個、3至15個、3至10個、3至8個、4至7個或5至6個環原子。在某些實施例中，伸雜環基為單環、雙環、三環或四環環系統，其可稠合或橋聯，且其中氮或硫原子可視情況氧化，氮原子可視情況四級銨化，且一些環可部分或完全飽和，或為芳族環。伸雜環基可在任何引起產生穩定化合物之雜原子或碳原子處連接至主結構。此類伸雜環基之實例包括但不限於氮呯二基、苯并二㗁烷二基、苯并二氧呃二基、苯并呋喃酮二基、𠳭二基、十氫異喹啉二基、二氫苯并呋喃二基、二氫苯并異噻唑二基、二氫苯并異㗁 𠯤二基(包括所有異構形式，例如1,4-二氫苯并[d][1,3]㗁 𠯤二基、3,4-二氫苯并[c][1,2]-㗁 𠯤二基及3,4-二氫苯并[d][1,2]㗁 𠯤二基)、二氫苯并噻吩二基、二氫異苯并呋喃二基、二氫苯并[c]噻吩二基、二氫呋喃二基、二氫異吲哚二基、二氫哌喃二基、二氫吡唑二基、二氫吡𠯤二基、二氫吡啶二基、二氫嘧啶二基、二氫吡咯二基、二氧戊環二基、1,4-二噻烷二基、呋喃酮二基、四氫咪唑二基、咪唑啉二基、吲哚啉二基、異𠳭二基、異吲哚啉二基、異噻唑啶二基、異㗁唑啶二基、𠰌啉二基、八氫吲哚二基、八氫異吲哚二基、㗁唑啶酮二基、㗁唑啶二基、環氧乙二基、哌𠯤二基、哌啶二基、4-哌啶酮二基、吡唑啶二基、吡唑啉二基、吡咯啶二基、吡咯啉二基、
術語「鹵素」、「鹵化物」或「鹵基」係指氟、氯、溴及/或碘。The terms "halogen", "halide" or "halo" refer to fluorine, chlorine, bromine and/or iodine.
術語「視情況經取代」意欲意謂，基團或取代基，諸如烷基、雜烷基、伸烷基、伸雜烷基、烯基、伸烯基、伸雜烯基、炔基、伸炔基、伸雜炔基、環烷基、伸環烷基、芳基、伸芳基、芳烷基、伸芳烷基、雜芳基、伸雜芳基、雜環基或伸雜環基可經一或多個，在一個實施例中，一個、兩個、三個或四個取代基Q取代，其中之每一者獨立地選自例如(a)氘(-D)、氰基(-CN)、鹵基、亞胺基(=NH)、硝基(-NO 2)及側氧基(=O)；(b) C 1-6烷基、C 1-6雜烷基、C 2-6烯基、C 2-6炔基、C 3-10環烷基、C 6-14芳基、C 7-15芳烷基、雜芳基及雜環基，其中之每一者進一步視情況經一或多個，在一個實施例中，一個、兩個、三個或四個取代基Q a取代；及(c) -C(O)R a、-C(O)OR a、-C(O)NR bR c、-C(O)SR a、-C(NR a)NR bR c、-C(S)R a、-C(S)OR a、-C(S)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、-OC(O)SR a、-OC(NR a)NR bR c、-OC(S)R a、-OC(S)OR a、-OC(S)NR bR c、-OP(O)(OR b)OR c、-OS(O)R a、-OS(O) 2R a、-OS(O)NR bR c、-OS(O) 2NR bR c、-NR bR c、-NR aC(O)R d、-NR aC(O)OR d、-NR aC(O)NR bR c、-NR aC(O)SR d、-NR aC(NR d)NR bR c、-NR aC(S)R d、-NR aC(S)OR d、-NR aC(S)NR bR c、-NR aS(O)R d、-NR aS(O) 2R d、-NR aS(O)NR bR c、-NR aS(O) 2NR bR c、-SR a、-S(O)R a、-S(O) 2R a、-S(O)NR bR c及-S(O) 2NR bR c，其中各R a、R b、R c及R d獨立地為(i)氫或氘；(ii) C 1-6烷基、C 1-6雜烷基、C 2-6烯基、C 2-6炔基、C 3-10環烷基、C 6-14芳基、C 7-15芳烷基、雜芳基或雜環基，其中之每一者視情況經一或多個，在一個實施例中，一個、兩個、三個或四個取代基Q a取代；或(iii) R b及R c與其所連接之N原子一起形成視情況經一或多個，在一個實施例中，一個、兩個、三個或四個取代基Q a取代的雜環基。如本文所用，所有可以經取代之基團「視情況經取代」。 The term "optionally substituted" is intended to mean, a group or substituent such as alkyl, heteroalkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenyl, alkynyl, alkene alkynyl, heteroalkynylene, cycloalkyl, cycloalkylene, aryl, arylidene, aralkyl, aralkylene, heteroaryl, heteroaryl, heterocyclylene, or heterocyclylene Can be substituted with one or more, in one embodiment, one, two, three or four substituents Q, each of which is independently selected from, for example, (a) deuterium (-D), cyano ( -CN), halo, imino (=NH), nitro (-NO 2 ) and pendant oxy (=O); (b) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl and heterocyclyl, each of which further Optionally substituted with one or more, in one embodiment, one, two, three or four substituents Q a ; and (c) -C(O)R a , -C(O)OR a , -C(O)NR b R c , -C(O)SR a , -C(NR a )NR b R c , -C(S)R a , -C(S)OR a , -C(S) NR b R c , -OR a , -OC(O)R a , -OC(O)OR a , -OC(O)NR b R c , -OC(O)SR a , -OC(NR a )NR b R c , -OC(S)R a , -OC(S)OR a , -OC(S)NR b R c , -OP(O)(OR b )OR c , -OS(O)R a , -OS(O) 2 R a , -OS(O)NR b R c , -OS(O) 2 NR b R c , -NR b R c , -NR a C(O)R d , -NR a C (O)OR d , -NR a C(O)NR b R c , -NR a C(O)SR d , -NR a C(NR d )NR b R c , -NR a C(S)R d , -NR a C(S)OR d , -NR a C(S)NR b R c , -NR a S(O)R d , -NR a S(O) 2 R d , -NR a S(O) ) NR b R c , -NR a S(O) 2 NR b R c , -SR a , -S(O) R a , -S(O) 2 R a , -S(O)NR b R c and -S(O) 2 NR b R c , wherein each of R a , R b , R c and R d is independently (i) hydrogen or deuterium; (ii) C 1-6 alkyl, C 1-6 heteroalkane base, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl radical, C 7-15 aralkyl, heteroaryl or heterocyclyl, each of which is optionally modified by one or more, in one embodiment, one, two, three or four substituents Q or (iii) Rb and Rc taken together with the N atom to which they are attached form optionally substituted with one or more, in one embodiment, one, two, three or four substituents Qa Heterocyclyl. As used herein, all groups that may be substituted are "optionally substituted."
在一個實施例中，各Q a獨立地選自：(a)氘、氰基、鹵基、硝基、亞胺基及側氧基；(b) C 1-6烷基、C 1-6雜烷基、C 2-6烯基、C 2-6炔基、C 3-10環烷基、C 6-14芳基、C 7-15芳烷基、雜芳基及雜環基；及(c) -C(O)R e、-C(O)OR e、-C(O)NR fR g、-C(O)SR e、-C(NR e)NR fR g、-C(S)R e、-C(S)OR e、-C(S)NR fR g、-OR e、-OC(O)R e、-OC(O)OR e、-OC(O)NR fR g、-OC(O)SR e、-OC(NR e)NR fR g、-OC(S)R e、-OC(S)OR e、-OC(S)NR fR g、-OP(O)(OR f)OR g、-OS(O)R e、-OS(O) 2R e、-OS(O)NR fR g、-OS(O) 2NR fR g、-NR fR g、-NR eC(O)R h、-NR eC(O)OR f、-NR eC(O)NR fR g、-NR eC(O)SR f、-NR eC(NR h)NR fR g、-NR eC(S)R h、-NR eC(S)OR f、-NR eC(S)NR fR g、-NR eS(O)R h、-NR eS(O) 2R h、-NR eS(O)NR fR g、-NR eS(O) 2NR fR g、-SR e、-S(O)R e、-S(O) 2R e、-S(O)NR fR g及-S(O) 2NR fR g；其中各R e、R f、R g及R h獨立地為(i)氫或氘；(ii) C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10環烷基、C 6-14芳基、C 7-15芳烷基、雜芳基或雜環基；或(iii) R f及R g與其所連接之N原子一起形成雜環基。 In one embodiment, each Q a is independently selected from: (a) deuterium, cyano, halo, nitro, imino, and pendant oxy; (b) C 1-6 alkyl, C 1-6 Heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl and heterocyclyl; and (c) -C(O)R e , -C(O)OR e , -C(O)NR f R g , -C(O)SR e , -C(NR e )NR f R g , -C (S)R e , -C(S)OR e , -C(S)NR f R g , -OR e , -OC(O)R e , -OC(O)OR e , -OC(O)NR f R g , -OC(O)SR e , -OC(NR e )NR f R g , -OC(S)R e , -OC(S)OR e , -OC(S)NR f R g , - OP(O)(OR f )OR g , -OS(O)R e , -OS(O) 2 R e , -OS(O)NR f R g , -OS(O) 2 NR f R g , - NR f R g , -NR e C(O)R h , -NR e C(O)OR f , -NR e C(O)NR f R g , -NR e C(O)SR f , -NR e C(NR h )NR f R g , -NR e C(S)R h , -NR e C(S)OR f , -NR e C(S)NR f R g , -NR e S(O)R h , -NR e S(O) 2 Rh , -NR e S(O)NR f R g , -NR e S(O) 2 NR f R g , -SR e , -S(O)R e , -S(O) 2 R e , -S(O)NR f R g and -S(O) 2 NR f R g ; wherein each R e , R f , R g and Rh is independently (i) hydrogen or deuterium; (ii) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, Heteroaryl or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form a heterocyclyl.
在某些實施例中，「光學活性」及「鏡像異構活性」係指分子之集合，其鏡像異構物過量不小於約80%、不小於約90%、不小於約91%、不小於約92%、不小於約93%、不小於約94%、不小於約95%、不小於約96%、不小於約97%、不小於約98%、不小於約99%、不小於約99.5%或不小於約99.8%。在某些實施例中，按所討論之鏡像異構混合物之總重量計，光學活性化合物包含約95%或更多之一種鏡像異構物及約5%或更少之另一種鏡像異構物。在某些實施例中，按所討論之鏡像異構混合物之總重量計，光學活性化合物包含約98%或更多之一種鏡像異構物及約2%或更少之另一種鏡像異構物。在某些實施例中，按所討論之鏡像異構混合物之總重量計，光學活性化合物包含約99%或更多之一種鏡像異構物及約1%或更少之另一種鏡像異構物。In certain embodiments, "optically active" and "enantiomerically active" refer to a collection of molecules whose enantiomer excess is not less than about 80%, not less than about 90%, not less than about 91%, not less than About 92%, not less than about 93%, not less than about 94%, not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5% % or not less than about 99.8%. In certain embodiments, the optically active compound comprises about 95% or more of one enantiomer and about 5% or less of the other enantiomer, based on the total weight of the enantiomer mixture in question . In certain embodiments, the optically active compound comprises about 98% or more of one enantiomer and about 2% or less of the other enantiomer, based on the total weight of the enantiomer mixture in question . In certain embodiments, the optically active compound comprises about 99% or more of one enantiomer and about 1% or less of the other enantiomer, based on the total weight of the enantiomer mixture in question .
在描述光學活性化合物時，前綴 R及 S用於表示化合物關於其對掌性中心之絕對組態。(+)及(-)用於指示化合物之旋光度，亦即偏光平面藉由光活性化合物旋轉之方向。(-)前綴指示化合物為左旋性，亦即化合物向左或逆時針旋轉偏光平面。(+)前綴指示化合物為右旋性，亦即化合物向右或順時針旋轉偏光平面。然而，旋光符號(+)及(-)與化合物之絕對組態 R及 S無關。 In describing optically active compounds, the prefixes R and S are used to denote the absolute configuration of the compound with respect to its chiral center. (+) and (-) are used to indicate the optical rotation of the compound, ie the direction in which the plane of polarization is rotated by the photoactive compound. The (-) prefix indicates that the compound is levorotatory, ie the compound rotates the plane of polarization to the left or counterclockwise. The (+) prefix indicates that the compound is dextrorotatory, ie the compound rotates the plane of polarization to the right or clockwise. However, the optical rotation signs (+) and (-) are independent of the absolute configuration R and S of the compound.
術語「經同位素富集」係指在構成此類化合物之原子中之一或多者處含有非天然比例之同位素的化合物。在某些實施例中，經同位素富集的化合物含有非天然比例之一或多種同位素，包括但不限於氫( 1H)、氘( 2H)、氚( 3H)、碳-11 ( 11C)、碳-12 ( 12C)、碳-13 ( 13C)、碳-14 ( 14C)、氮-13 ( 13N)、氮-14 ( 14N)、氮-15 ( 15N)、氧-14 ( 14O)、氧-15 ( 15O)、氧-16 ( 16O)、氧-17 ( 17O)、氧-18 ( 18O)、氟-17 ( 17F)、氟-18 ( 18F)、磷-31 ( 31P)、磷-32 ( 32P)、磷-33 ( 33P)、硫-32 ( 32S)、硫-33 ( 33S)、硫-34 ( 34S)、硫-35 ( 35S)、硫-36 ( 36S)、氯-35 ( 35Cl)、氯-36 ( 36Cl)、氯-37 ( 37Cl)、溴-79 ( 79Br)、溴-81 ( 81Br)、碘-123 ( 123I)、碘-125 ( 125I)、碘-127 ( 127I)、碘-129 ( 129I)及碘-131 ( 131I)。在某些實施例中，經同位素富集的化合物係呈穩定形式，亦即非放射性。在某些實施例中，經同位素富集的化合物含有非天然比例之一或多種同位素，包括但不限於氫( 1H)、氘( 2H)、碳-12 ( 12C)、碳-13 ( 13C)、氮-14 ( 14N)、氮-15 ( 15N)、氧-16 ( 16O)、氧-17 ( 17O)、氧-18 ( 18O)、氟-17 ( 17F)、磷-31 ( 31P)、硫-32 ( 32S)、硫-33 ( 33S)、硫-34 ( 34S)、硫-36 ( 36S)、氯-35 ( 35Cl)、氯-37 ( 37Cl)、溴-79 ( 79Br)、溴-81 ( 81Br)及碘-127 ( 127I)。在某些實施例中，經同位素富集的化合物係呈不穩定形式，亦即放射性。在某些實施例中，經同位素富集的化合物含有非天然比例之一或多種同位素，包括但不限於氚( 3H)、碳-11 ( 11C)、碳-14 ( 14C)、氮-13 ( 13N)、氧-14 ( 14O)、氧-15 ( 15O)、氟-18 ( 18F)、磷-32 ( 32P)、磷-33 ( 33P)、硫-35 ( 35S)、氯-36 ( 36Cl)、碘-123 ( 123I)、碘-125 ( 125I)、碘-129 ( 129I)及碘-131 ( 131I)。應理解，在如本文所提供之化合物中，任何氫可為 2H，作為實例，或任何碳可為 13C，作為實例，或任何氮可為 15N，作為實例，或任何氧可為 18O，作為實例，其中根據熟習此項技術者之判斷為可行的。 The term "isotopically enriched" refers to compounds that contain unnatural proportions of isotopes at one or more of the atoms that make up such compounds. In certain embodiments, isotopically enriched compounds contain unnatural proportions of one or more isotopes including, but not limited to, hydrogen ( 1 H), deuterium ( 2 H), tritium ( 3 H), carbon-11 ( 11 ) C), carbon-12 ( 12 C), carbon-13 ( 13 C), carbon-14 ( 14 C), nitrogen-13 ( 13 N), nitrogen-14 ( 14 N), nitrogen-15 ( 15 N) , Oxygen-14 ( 14 O), Oxygen-15 ( 15 O), Oxygen-16 ( 16 O), Oxygen-17 ( 17 O), Oxygen-18 ( 18 O), Fluorine-17 ( 17 F), Fluorine -18 ( 18 F), Phosphorus-31 ( 31 P), Phosphorus-32 ( 32 P), Phosphorus-33 ( 33 P), Sulfur-32 ( 32 S), Sulfur-33 ( 33 S), Sulfur-34 ( 34 S), sulfur-35 ( 35 S), sulfur-36 ( 36 S), chlorine-35 ( 35 Cl), chlorine-36 ( 36 Cl), chlorine-37 ( 37 Cl), bromine-79 ( 79 Br), bromine-81 ( 81 Br), iodine-123 ( 123 I), iodine-125 ( 125 I), iodine-127 ( 127 I), iodine-129 ( 129 I) and iodine-131 ( 131 I) . In certain embodiments, isotopically enriched compounds are in stable form, ie, non-radioactive. In certain embodiments, isotopically enriched compounds contain unnatural proportions of one or more isotopes including, but not limited to, hydrogen ( 1 H), deuterium ( 2 H), carbon-12 ( 12 C), carbon-13 ( 13 C), nitrogen-14 ( 14 N), nitrogen-15 ( 15 N), oxygen-16 ( 16 O), oxygen-17 ( 17 O), oxygen-18 ( 18 O), fluorine-17 ( 17 F), phosphorus-31 ( 31 P), sulfur-32 ( 32 S), sulfur-33 ( 33 S), sulfur-34 ( 34 S), sulfur-36 ( 36 S), chlorine-35 ( 35 Cl) , chloro-37 ( 37 Cl), bromo-79 ( 79 Br), bromo-81 ( 81 Br) and iodo-127 ( 127 I). In certain embodiments, the isotopically enriched compound is in an unstable form, ie, radioactive. In certain embodiments, isotopically enriched compounds contain unnatural proportions of one or more isotopes, including but not limited to tritium ( 3 H), carbon-11 ( 11 C), carbon-14 ( 14 C), nitrogen -13 ( 13 N), Oxygen-14 ( 14 O), Oxygen-15 ( 15 O), Fluorine-18 ( 18 F), Phosphorus-32 ( 32 P), Phosphorus-33 ( 33 P), Sulfur-35 ( 35 S), chloro-36 ( 36 Cl), iodine-123 ( 123 I), iodine-125 ( 125 I), iodine-129 ( 129 I) and iodine-131 ( 131 I). It should be understood that in compounds as provided herein, any hydrogen can be 2H, as an example, or any carbon can be 13C , as an example, or any nitrogen can be 15N , as an example, or any oxygen can be 18 O, by way of example, where feasible according to the judgment of those skilled in the art.
術語「同位素富集度」係指元素之較不普遍同位素(例如，用於氘或氫-2之D)在分子中之給定位置處代替元素之較普遍同位素(例如，用於氕或氫-1之 1H)的併入百分比。如本文所用，當將在分子中之特定位置處的原子表示為特定較不普遍同位素時，應理解，在該位置處的該同位素之豐度實質上大於其天然豐度。 The term "isotopic enrichment" refers to the substitution of a less prevalent isotope of an element (for example, D for deuterium or hydrogen-2) for a more prevalent isotope of an element (for example, for protium or hydrogen-2) at a given position in the molecule -1 percent of 1 H) incorporated. As used herein, when an atom at a particular position in a molecule is referred to as a particular less prevalent isotope, it is understood that the isotope at that position is substantially more abundant than its natural abundance.
術語「同位素富集因子」係指經同位素富集之化合物中的同位素豐度與特定同位素之天然豐度之間的比率。The term "isotopic enrichment factor" refers to the ratio between the isotopic abundance in an isotopically enriched compound and the natural abundance of a particular isotope.
術語「氫」或符號「H」係指天然存在之氫同位素之組成，其包括在其天然豐度中的氕( 1H)、氘( 2H或D)及氚( 3H)。氕為最常見的氫同位素，其具有超過99.98%之天然豐度。氘為較不普遍的氫同位素，其具有約0.0156%之天然豐度。 The term "hydrogen" or the symbol "H" refers to the composition of naturally occurring hydrogen isotopes including protium ( 1H ), deuterium (2H or D), and tritium ( 3H ) in their natural abundance. Protium is the most common hydrogen isotope with a natural abundance of over 99.98%. Deuterium is a less common hydrogen isotope with a natural abundance of about 0.0156%.
術語「氘富集」係指在分子中給定位置處代替氫的氘之併入的百分比。舉例而言，在給定位置處的1%之氘富集意謂在給定樣品中有1%之分子在該指定位置處含有氘。因為天然存在的氘之分佈平均為約0.0156%，在使用非富集起始材料合成之化合物中之任何位置處的氘富集平均為約0.0156%。如本文所用，當將在經同位素富集之化合物中之特定位置指定為具有氘時，應理解，在該化合物中的該位置處的氘之豐度實質上大於其天然豐度(0.0156%)。The term "deuterium enrichment" refers to the percentage of deuterium incorporated in place of hydrogen at a given position in the molecule. For example, a 1% deuterium enrichment at a given position means that 1% of the molecules in a given sample contain deuterium at that given position. Because the distribution of naturally occurring deuterium averages about 0.0156%, the deuterium enrichment at any position in a compound synthesized using non-enriched starting materials averages about 0.0156%. As used herein, when a particular position in an isotopically enriched compound is designated as having deuterium, it is understood that the abundance of deuterium at that position in the compound is substantially greater than its natural abundance (0.0156%) .
術語「碳」或符號「C」係指天然存在之碳同位素之組成，其包括在其天然豐度中的碳-12 ( 12C)及碳-13 ( 13C)。碳-12為最常見的碳同位素，其具有超過98.89%之天然豐度。碳-13為較不普遍的碳同位素，其具有約1.11%之天然豐度。 The term "carbon" or the symbol "C" refers to the composition of naturally occurring carbon isotopes including carbon-12 ( 12 C) and carbon-13 ( 13 C) in their natural abundance. Carbon-12 is the most common carbon isotope with a natural abundance of over 98.89%. Carbon-13 is a less common carbon isotope with a natural abundance of about 1.11%.
術語「碳-13富集」或「 13C富集」係指碳-13在分子中之給定位置處代替碳的併入百分比。舉例而言，在給定位置處的10%之碳-13富集意謂在給定樣品中有10%之分子在該指定位置處含有碳-13。因為天然存在的碳-13之分佈平均為約1.11%，在使用非富集起始材料合成之化合物中之任何位置處的碳-13富集平均為約1.11%。如本文所用，當將在經同位素富集之化合物中之特定位置指定為具有碳-13時，應理解，在該化合物中的該位置處的碳-13之豐度實質上大於其天然豐度(1.11%)。 The term "carbon-13 enrichment" or " 13C enrichment" refers to the percent incorporation of carbon-13 in place of carbon at a given position in the molecule. For example, a 10% carbon-13 enrichment at a given position means that 10% of the molecules in a given sample contain carbon-13 at that given position. Because the distribution of naturally occurring carbon-13 averages about 1.11%, carbon-13 enrichment at any location in a compound synthesized using non-enriched starting materials averages about 1.11%. As used herein, when a particular position in an isotopically enriched compound is designated as having carbon-13, it is understood that the abundance of carbon-13 at that position in the compound is substantially greater than its natural abundance (1.11%).
當提及物質時，術語「實質上純」及「實質上均質」意謂足夠均質以呈現不含易於偵測的雜質，如藉由一般熟習此項技術者所使用之標準分析方法所測定，該標準分析方法包括但不限於：薄層層析(thin layer chromatography；TLC)、凝膠電泳、高效液相層析(high performance liquid chromatography；HPLC)、氣相層析(gas chromatography；GC)、核磁共振(nuclear magnetic resonance；NMR)及質譜(mass spectrometry；MS)；或足夠純以使得進一步的純化將不可偵測地更改物質之物理、化學、生物學及/或藥理學特性，諸如酶促及生物學活性。在某些實施例中，「實質上純」或「實質上均質」係指分子之集合，其中至少約95重量%、至少約96重量%、至少約97重量%、至少約98重量%、至少約99重量%、或至少約99.5重量%之分子為單一化合物，包括單一鏡像異構物、外消旋混合物或鏡像異構物之混合物，如藉由標準分析方法所測定。如本文所用，當將在經同位素富集的分子中之特定位置的原子特指為特定的不普遍同位素時，含有除在該指定位置的特指同位素之外的分子為相對於該經同位素富集的化合物之雜質。因此，對於在特定位置具有特指為氘之原子之氘化化合物而言，在相同位置含有氕之化合物為雜質。When referring to a substance, the terms "substantially pure" and "substantially homogeneous" mean sufficiently homogeneous to appear free of readily detectable impurities, as determined by standard analytical methods used by those of ordinary skill in the art, The standard analytical methods include but are not limited to: thin layer chromatography (TLC), gel electrophoresis, high performance liquid chromatography (HPLC), gas chromatography (GC), nuclear magnetic resonance (NMR) and mass spectrometry (MS); or sufficiently pure that further purification would undetectably alter the physical, chemical, biological and/or pharmacological properties of the substance, such as enzymatic and biological activity. In certain embodiments, "substantially pure" or "substantially homogeneous" refers to a collection of molecules of which at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about About 99%, or at least about 99.5%, by weight of the molecules are single compounds, including single enantiomers, racemic mixtures, or mixtures of enantiomers, as determined by standard analytical methods. As used herein, when an atom at a particular position in an isotopically enriched molecule is designated as a particular uncommon isotope, a molecule containing other than the specified isotope at the designated position is relative to the isotopically enriched molecule. Impurities of the collected compounds. Thus, for a deuterated compound having an atom designated as deuterium at a particular position, the compound containing protium at the same position is an impurity.
術語「溶劑合物」係指由一或多種溶質分子(例如本文提供之化合物)及一或多種溶劑分子(其以化學計量或非化學計量之量存在)形成的複合物或聚集物。適合的溶劑包括但不限於水、甲醇、乙醇、正丙醇、異丙醇及乙酸。在某些實施例中，溶劑為醫藥學上可接受的。在一個實施例中，複合物或聚集物呈結晶形式。在另一實施例中，複合物或聚集物呈非結晶形式。在溶劑為水之情況下，溶劑合物為水合物。水合物之實例包括但不限於半水合物、一水合物、二水合物、三水合物、四水合物及五水合物。The term "solvate" refers to a complex or aggregate formed from one or more solute molecules, such as the compounds provided herein, and one or more solvent molecules, which are present in stoichiometric or non-stoichiometric amounts. Suitable solvents include, but are not limited to, water, methanol, ethanol, n-propanol, isopropanol, and acetic acid. In certain embodiments, the solvent is pharmaceutically acceptable. In one embodiment, the complex or aggregate is in crystalline form. In another embodiment, the complex or aggregate is in an amorphous form. In the case where the solvent is water, the solvate is a hydrate. Examples of hydrates include, but are not limited to, hemihydrates, monohydrates, dihydrates, trihydrates, tetrahydrates, and pentahydrates.
對於本文所描述之二價基團而言，二價基團所呈現之方向不暗示定向。舉例而言，除非指定特定定向，否則式-C(O)NH-表示-C(O)NH-及-NHC(O)-兩者。For divalent groups described herein, the orientation presented by the divalent group does not imply orientation. For example, unless a specific orientation is specified, the formula -C(O)NH- represents both -C(O)NH- and -NHC(O)-.
片語「其鏡像異構物、鏡像異構物之混合物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體；或其醫藥學上可接受之鹽、溶劑合物、水合物或前藥」具有與片語「(i)其中提及之化合物之鏡像異構物、鏡像異構物之混合物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體；或(ii)其中提及之化合物之醫藥學上可接受之鹽、溶劑合物、水合物或前藥；或(iii)其中提及之化合物之鏡像異構物、鏡像異構物之混合物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體的醫藥學上可接受之鹽、溶劑合物、水合物或前藥」相同的含義。 化合物 The phrase "the enantiomer, mixture of enantiomers, mixture of two or more non-enantiomers, tautomer, mixture of two or more tautomers, or isotopic variation thereof" or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof" having the enantiomer, a mixture of enantiomers, a mixture of two enantiomers of the compound referred to in the phrase "(i) A mixture of or more diastereoisomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant; or (ii) a pharmaceutically acceptable form of the compound referred to therein salts, solvates, hydrates or prodrugs; or (iii) enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers, tautomers of the compounds mentioned therein A tautomer, a mixture of two or more tautomers, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug of an isotopic variant" has the same meaning. compound
在一個實施例中，本文提供一種式(A)化合物：
在一個實施例中，R 4A為-A-L-R E且R 4B為R 4；其中R 4、R E、A及L各自如本文所定義。在另一實施例中，R 4A為R 4且R 4B為-A-L-R E；其中R 4、R E、A及L各自為如本文所定義。 In one embodiment, R 4A is -ALR E and R 4B is R 4 ; wherein R 4 , R E , A and L are each as defined herein. In another embodiment, R 4A is R 4 and R 4B is -ALRE ; wherein R 4 , RE , A and L are each as defined herein.
在一個實施例中，本文提供一種式(I)化合物：
在某些實施例中，在式(I)中，A為(i)鍵；或(ii) C 1-6伸烷基、C 3-10伸環烷基、C 6-14伸芳基、伸雜芳基或伸雜環基；其中之每一者視情況經一或多個取代基Q取代。在某些實施例中，在式(I)中，A為鍵或視情況經一或多個取代基Q取代之C 1-6伸烷基。在某些實施例中，在式(I)中，A為鍵或亞甲基。在某些實施例中，在式(I)中，A為C 3-10伸環烷基或伸雜環基；各自視情況經一或多個取代基Q取代。在某些實施例中，在式(I)中，A為視情況經一或多個取代基Q取代之C 3-10伸環烷基。在某些實施例中，在式(I)中，A為視情況經一或多個取代基Q取代之單環C 3-10伸環烷基。在某些實施例中，在式(I)中，A為視情況經一或多個取代基Q取代之伸雜環基。在某些實施例中，在式(I)中，A為視情況經一或多個取代基Q取代之單環伸雜環基。在某些實施例中，在式(I)中，A為各自視情況經一或多個取代基Q取代之5員或6員伸雜環基。在某些實施例中，在式(I)中，A為各自視情況經一或多個取代基Q取代之哌啶二基或哌𠯤二基。在某些實施例中，在式(I)中，A為各自視情況經一或多個取代基Q取代之哌啶-1,4-二基或哌𠯤-1,4-二基。在某些實施例中，在式(I)中，A為各自視情況經一或多個取代基Q取代之C 6-14伸芳基或伸雜芳基。在某些實施例中，在式(I)中，A為視情況經一或多個取代基Q取代之C 6-14伸芳基。在某些實施例中，在式(I)中，A為視情況經一或多個取代基Q取代之伸苯基。在某些實施例中，在式(I)中，A為各自視情況經一或多個取代基Q取代之苯-1,3-二基或苯-1,4-二基。在某些實施例中，在式(I)中，A為視情況經一或多個取代基Q取代之苯-1,3-二基。在某些實施例中，在式(I)中，A為視情況經一或多個取代基Q取代之苯-1,4-二基。在某些實施例中，在式(I)中，A為視情況經一或多個取代基Q取代之伸雜芳基。在某些實施例中，在式(I)中，A為視情況經一或多個取代基Q取代之單環伸雜芳基。在某些實施例中，在式(I)中，A為各自視情況經一或多個取代基Q取代之5員或6員伸雜芳基。 In certain embodiments, in formula (I), A is (i) a bond; or (ii) C 1-6 alkylene, C 3-10 cycloalkyl, C 6-14 aryl, Heteroarylidene or heterocyclylene; each of which is optionally substituted with one or more substituents Q. In certain embodiments, in formula (I), A is a bond or a C 1-6 alkylene optionally substituted with one or more substituents Q . In certain embodiments, in formula (I), A is a bond or methylene. In certain embodiments, in formula (I), A is C 3-10 cycloalkylene or heterocyclylene; each optionally substituted with one or more substituents Q. In certain embodiments, in formula (I), A is C 3-10 cycloextended alkyl optionally substituted with one or more substituents Q . In certain embodiments, in formula (I), A is a monocyclic C 3-10 cycloalkylene optionally substituted with one or more substituents Q . In certain embodiments, in formula (I), A is a heterocyclylene optionally substituted with one or more substituents Q. In certain embodiments, in formula (I), A is a monocyclic heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, in formula (I), A is a 5- or 6-membered heterocyclyl group each optionally substituted with one or more substituents Q. In certain embodiments, in formula (I), A is piperidinediyl or piperidinediyl, each optionally substituted with one or more substituents Q, Q. In certain embodiments, in formula (I), A is piperidine-1,4-diyl or piperidine-1,4-diyl, each optionally substituted with one or more substituents Q. In certain embodiments, in formula (I), A is C 6-14 aryl or heteroaryl, each optionally substituted with one or more substituents Q . In certain embodiments, in formula (I), A is C6-14 arylidene optionally substituted with one or more substituents Q. In certain embodiments, in formula (I), A is phenylene optionally substituted with one or more substituents Q. In certain embodiments, in formula (I), A is benzene-1,3-diyl or benzene-1,4-diyl, each optionally substituted with one or more substituents Q. In certain embodiments, in formula (I), A is benzene-1,3-diyl optionally substituted with one or more substituents Q. In certain embodiments, in formula (I), A is benzene-1,4-diyl optionally substituted with one or more substituents Q. In certain embodiments, in formula (I), A is heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, in formula (I), A is a monocyclic heteroarylidene optionally substituted with one or more substituents Q. In certain embodiments, in formula (I), A is a 5- or 6-membered heteroaryl group, each optionally substituted with one or more substituents Q.
在一個實施例中，在式(I)中， A為鍵、C 1-6伸烷基、C 6-14伸芳基、伸雜芳基或伸雜環基； R 1及R 3各自獨立地為氫、氘、鹵基或C 1-6烷基； R 2為C 3-10環烷基或雜環基；及 R 4為C 6-14芳基或雜芳基； 其中各烷基、伸烷基、環烷基、芳基、伸芳基、雜芳基、伸雜芳基、雜環基及伸雜環基視情況經一或多個取代基Q取代。 In one embodiment, in formula (I), A is a bond, C 1-6 alkylene, C 6-14 aryl, heteroaryl or heterocyclic; R 1 and R 3 are each independently R is hydrogen, deuterium, halo or C 1-6 alkyl; R 2 is C 3-10 cycloalkyl or heterocyclyl; and R 4 is C 6-14 aryl or heteroaryl; wherein each alkyl group , alkylene, cycloalkyl, aryl, aryl, heteroaryl, heteroaryl, heterocyclyl, and heterocyclylene are optionally substituted with one or more substituents Q.
在另一實施例中，在式(I)中， A為鍵、C 1-6伸烷基、C 6-14伸芳基或伸雜芳基； R 1及R 3各自獨立地為氫、氘、鹵基或C 1-6烷基； R 2為C 3-10環烷基或雜環基；及 R 4為C 6-14芳基或雜芳基； 其中各烷基、伸烷基、環烷基、芳基、伸芳基、雜芳基、伸雜芳基及雜環基視情況經一或多個取代基Q取代。 In another embodiment, in formula (I), A is a bond, C 1-6 alkylene, C 6-14 aryl or heteroaryl; R 1 and R 3 are each independently hydrogen, deuterium, halo or C 1-6 alkyl; R 2 is C 3-10 cycloalkyl or heterocyclyl; and R 4 is C 6-14 aryl or heteroaryl; wherein each alkyl, alkylene , cycloalkyl, aryl, arylidene, heteroaryl, heteroarylidene, and heterocyclyl are optionally substituted with one or more substituents Q.
在又另一實施例中，在式(I)中， A為鍵、C 1-6伸烷基、伸苯基、單環伸雜芳基或單環伸雜環基； R 1及R 3各自獨立地為氫、氘、鹵基或C 1-6烷基； R 2為單環C 3-10環烷基或單環雜環基；及 R 4為苯基或單環雜芳基； 其中各烷基、伸烷基、環烷基、苯基、伸苯基、雜芳基、伸雜芳基、雜環基及伸雜環基視情況經一或多個取代基Q取代。 In yet another embodiment, in formula (I), A is a bond, C 1-6 alkylene, phenylene, monocycloheteroaryl or monocycloheterocyclo; R 1 and R 3 each independently hydrogen, deuterium, halo or C 1-6 alkyl; R 2 is monocyclic C 3-10 cycloalkyl or monocyclic heterocyclyl; and R 4 is phenyl or monocyclic heteroaryl; wherein each alkyl, alkylene, cycloalkyl, phenyl, phenylene, heteroaryl, heteroaryl, heterocyclyl, and heterocyclylene is optionally substituted with one or more substituents Q.
在又另一實施例中，在式(I)中， A為鍵、C 1-6伸烷基、伸苯基或單環伸雜芳基； R 1及R 3各自獨立地為氫、氘、鹵基或C 1-6烷基； R 2為單環C 3-10環烷基或單環雜環基；及 R 4為苯基或單環雜芳基； 其中各烷基、伸烷基、環烷基、苯基、伸苯基、雜芳基、伸雜芳基及雜環基視情況經一或多個取代基Q取代。 In yet another embodiment, in formula (I), A is a bond, C 1-6 alkylene, phenylene or monocyclic heteroaryl; R 1 and R 3 are each independently hydrogen, deuterium , halogen or C 1-6 alkyl; R 2 is monocyclic C 3-10 cycloalkyl or monocyclic heterocyclic group; and R 4 is phenyl or monocyclic heteroaryl; wherein each alkyl, alkane radical, cycloalkyl, phenyl, phenylene, heteroaryl, heteroaryl and heterocyclyl are optionally substituted with one or more substituents Q.
在又另一實施例中，在式(I)中， A為鍵、C 1-6伸烷基、伸苯基、5員或6員伸雜芳基或5員或6員伸雜環基； R 1及R 3各自獨立地為氫、氘、鹵基或C 1-6烷基； R 2為單環C 3-10環烷基或5員或6員雜環基；及 R 4為苯基或5員或6員雜芳基； 其中各烷基、伸烷基、環烷基、苯基、伸苯基、雜芳基、伸雜芳基、雜環基及伸雜環基視情況經一或多個取代基Q取代。 In yet another embodiment, in formula (I), A is a bond, C 1-6 alkylene, phenylene, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclyl R 1 and R 3 are each independently hydrogen, deuterium, halo or C 1-6 alkyl; R 2 is monocyclic C 3-10 cycloalkyl or 5- or 6-membered heterocyclyl; and R 4 is Phenyl or 5- or 6-membered heteroaryl; wherein each alkyl, alkylene, cycloalkyl, phenyl, phenylene, heteroaryl, heteroaryl, heterocyclyl and heterocyclylene is considered is substituted with one or more substituents Q.
在又另一實施例中，在式(I)中， A為鍵、C 1-6伸烷基、伸苯基或5員或6員伸雜芳基； R 1及R 3各自獨立地為氫、氘、鹵基或C 1-6烷基； R 2為單環C 3-10環烷基或5員或6員雜環基；及 R 4為苯基或5員或6員雜芳基； 其中各烷基、伸烷基、環烷基、苯基、伸苯基、雜芳基、伸雜芳基及雜環基視情況經一或多個取代基Q取代。 In yet another embodiment, in formula (I), A is a bond, C 1-6 alkylene, phenylene, or 5- or 6-membered heteroaryl; R 1 and R 3 are each independently hydrogen, deuterium, halo or C 1-6 alkyl; R 2 is monocyclic C 3-10 cycloalkyl or 5- or 6-membered heterocyclyl; and R 4 is phenyl or 5- or 6-membered heteroaryl wherein each alkyl, alkylene, cycloalkyl, phenyl, phenylene, heteroaryl, heteroaryl and heterocyclyl is optionally substituted with one or more substituents Q.
在又另一實施例中，在式(I)中， A為鍵、亞甲基、伸苯基、哌𠯤二基或哌啶二基； R 1為氫、氘或鹵基； R 2為各自視情況經一或多個取代基Q取代之5員或6員雜環基； R 3為C 1-6烷基；及 R 4為苯基。 In yet another embodiment, in formula (I), A is a bond, methylene, phenylene, piperidinediyl or piperidinediyl; R 1 is hydrogen, deuterium or halo; R 2 is 5- or 6-membered heterocyclyl, each optionally substituted with one or more substituents Q; R 3 is C 1-6 alkyl; and R 4 is phenyl.
在再一實施例中，在式(I)中， A為鍵、亞甲基或伸苯基； R 1為氫、氘或鹵基； R 2為各自視情況經一或多個取代基Q取代之5員或6員雜環基； R 3為C 1-6烷基；及 R 4為苯基。 In yet another embodiment, in formula (I), A is a bond, methylene or phenylene; R 1 is hydrogen, deuterium or halo; R 2 is each optionally via one or more substituents Q substituted 5- or 6-membered heterocyclyl; R 3 is C 1-6 alkyl; and R 4 is phenyl.
在另一實施例中，本文提供一種式(II)化合物：
在又另一實施例中，本文提供一種式(III)化合物：
在又另一實施例中，本文提供一種式(IV)化合物：
在一個實施例中，在式(II)、(III)或(IV)中， R 1及R 3各自獨立地為氫、氘、鹵基或C 1-6烷基； R 2為C 3-10環烷基或雜環基； R 4為C 6-14芳基或雜芳基； 各R 5獨立地為氘、鹵基或C 1-6烷基；及 a為0、1、2、3或4之整數； 其中各烷基、環烷基、芳基、雜芳基及雜環基視情況經一或多個取代基Q取代。 In one embodiment, in formula (II), (III) or (IV), R 1 and R 3 are each independently hydrogen, deuterium, halo or C 1-6 alkyl; R 2 is C 3- 10 cycloalkyl or heterocyclyl; R 4 is C 6-14 aryl or heteroaryl; each R 5 is independently deuterium, halo or C 1-6 alkyl; and a is 0, 1, 2, an integer of 3 or 4; wherein each alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally substituted with one or more substituents Q.
在另一實施例中，在式(II)、(III)或(IV)中， R 1及R 3各自獨立地為氫、氘、鹵基或C 1-6烷基； R 2為單環C 3-10環烷基或單環雜環基； R 4為苯基或單環雜芳基； 各R 5獨立地為氘、鹵基或C 1-6烷基；及 a為0、1或2之整數； 其中各烷基、環烷基、苯基、雜芳基及雜環基視情況經一或多個取代基Q取代。 In another embodiment, in formula (II), (III) or (IV), R 1 and R 3 are each independently hydrogen, deuterium, halo or C 1-6 alkyl; R 2 is monocyclic C 3-10 cycloalkyl or monocyclic heterocyclyl; R 4 is phenyl or monocyclic heteroaryl; each R 5 is independently deuterium, halo or C 1-6 alkyl; and a is 0, 1 or an integer of 2; wherein each alkyl, cycloalkyl, phenyl, heteroaryl and heterocyclyl is optionally substituted with one or more substituents Q.
在又另一實施例中，在式(II)、(III)或(IV)中， R 1為氫、氘、鹵基或C 1-6烷基； R 2為單環C 3-10環烷基或5員或6員雜環基； R 3為氫、氘、鹵基或C 1-6烷基； R 4為苯基或5員或6員雜芳基； 各R 5獨立地為氘、鹵基或C 1-6烷基；及 a為0、1或2之整數； 其中各烷基、環烷基、苯基、雜芳基及雜環基視情況經一或多個取代基Q取代。 In yet another embodiment, in formula (II), (III) or (IV), R 1 is hydrogen, deuterium, halo or C 1-6 alkyl; R 2 is a monocyclic C 3-10 ring Alkyl or 5- or 6-membered heterocyclic group; R 3 is hydrogen, deuterium, halo or C 1-6 alkyl; R 4 is phenyl or 5- or 6-membered heteroaryl; each R 5 is independently deuterium, halo, or C1-6 alkyl; and a is an integer of 0, 1, or 2; wherein each alkyl, cycloalkyl, phenyl, heteroaryl, and heterocyclyl is optionally substituted with one or more Base Q is substituted.
在再一實施例中，在式(II)、(III)或(IV)中， R 1為氫； R 2為4-甲基哌𠯤基或4-(2-羥基乙基)哌𠯤基； R 3為甲基； R 4為苯基；及 a為0之整數。 In yet another embodiment, in formula (II), (III) or (IV), R 1 is hydrogen; R 2 is 4-methylpiperazyl or 4-(2-hydroxyethyl)piperazyl ; R 3 is methyl; R 4 is phenyl; and a is an integer of 0.
在某些實施例中，在式(I)、(II)、(III)或(IV)中，R 2為C 3-10環烷基、C 6-14芳基、雜芳基、雜環基或C 1-6烷基-伸雜環基，其中之每一者視情況經一或多個取代基Q取代。在某些實施例中，在式(I)、(II)、(III)或(IV)中，R 2為各自視情況經一或多個取代基Q取代之C 3-10環烷基或雜環基。在某些實施例中，在式(I)、(II)、(III)或(IV)中，R 2為視情況經一或多個取代基Q取代之C 3-10環烷基。在某些實施例中，在式(I)、(II)、(III)或(IV)中，R 2為視情況經一或多個取代基Q取代之單環C 3-10環烷基。在某些實施例中，在式(I)、(II)、(III)或(IV)中，R 2為環丙基、環丁基、環戊基、環己基或環庚基，其中之每一者視情況經一或多個取代基Q取代。在某些實施例中，在式(I)、(II)、(III)或(IV)中，R 2為環丁基、環戊基或環己基，其中之每一者視情況經一或多個取代基Q取代。在某些實施例中，在式(I)、(II)、(III)或(IV)中，R 2為視情況經一或多個取代基Q取代之環己基。在某些實施例中，在式(I)、(II)、(III)或(IV)中，R 2為視情況經一或多個取代基Q取代之雜環基。在某些實施例中，在式(I)、(II)、(III)或(IV)中，R 2為視情況經一或多個取代基Q取代之單環雜環基。在某些實施例中，在式(I)、(II)、(III)或(IV)中，R 2為各自視情況經一或多個取代基Q取代之5員或6員雜環基。在某些實施例中，在式(I)、(II)、(III)或(IV)中，R 2為視情況經一或多個取代基Q取代之5員雜環基。在某些實施例中，在式(I)、(II)、(III)或(IV)中，R 2為視情況經一或多個取代基Q取代之6員雜環基。在某些實施例中，在式(I)、(II)、(III)或(IV)中，R 2為各自視情況經一或多個取代基Q取代之哌啶基或哌𠯤基。在某些實施例中，在式(I)、(II)、(III)或(IV)中，R 2為各自視情況經一或多個取代基Q取代之哌啶-1-基、哌啶-4-基或哌𠯤-1-基。在某些實施例中，在式(I)、(II)、(III)或(IV)中，R 2為視情況經一或多個取代基Q取代之哌𠯤-1-基。在某些實施例中，在式(I)、(II)、(III)或(IV)中，R 2為各自視情況經一或多個取代基Q取代之C 6-14芳基或雜芳基。某些實施例中，在式(I)、(II)、(III)或(IV)中，R 2為視情況經一或多個取代基Q取代之C 6-14芳基。某些實施例中，在式(I)、(II)、(III)或(IV)中，R 2為視情況經一或多個取代基Q取代之雜芳基。 In certain embodiments, in formula (I), (II), (III) or (IV), R 2 is C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl, heterocycle or C 1-6 alkyl-heterocyclylene, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in formula (I), (II), (III), or (IV), R 2 is C 3-10 cycloalkyl, each optionally substituted with one or more substituents Q, or Heterocyclyl. In certain embodiments, in formula (I), (II), (III) or (IV), R 2 is C 3-10 cycloalkyl optionally substituted with one or more substituents Q . In certain embodiments, in formula (I), (II), (III) or (IV), R 2 is a monocyclic C 3-10 cycloalkyl optionally substituted with one or more substituents Q . In certain embodiments, in formula (I), (II), (III) or (IV), R 2 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, wherein Each is optionally substituted with one or more substituents Q. In certain embodiments, in formula (I), (II), (III), or (IV), R 2 is cyclobutyl, cyclopentyl, or cyclohexyl, each of which is optionally modified by one or Multiple substituents Q are substituted. In certain embodiments, in formula (I), (II), (III) or (IV), R 2 is cyclohexyl optionally substituted with one or more substituents Q. In certain embodiments, in formula (I), (II), (III) or (IV), R 2 is heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, in formula (I), (II), (III) or (IV), R 2 is a monocyclic heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, in formula (I), (II), (III) or (IV), R 2 is a 5- or 6-membered heterocyclyl, each optionally substituted with one or more substituents Q . In certain embodiments, in formula (I), (II), (III) or (IV), R 2 is a 5-membered heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, in formula (I), (II), (III) or (IV), R 2 is a 6-membered heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, in formula (I), (II), (III), or (IV), R 2 is piperidinyl or piperazyl, each optionally substituted with one or more substituents Q. In certain embodiments, in formula (I), (II), (III) or (IV), R 2 is piperidin-1-yl, piperidine, each optionally substituted with one or more substituents Q pyridin-4-yl or piperidine-1-yl. In certain embodiments, in formula (I), (II), (III), or (IV), R 2 is piperazine-1-yl optionally substituted with one or more substituents Q. In certain embodiments, in formula (I), (II), (III) or (IV), R 2 is C 6-14 aryl or hetero, each optionally substituted with one or more substituents Q Aryl. In certain embodiments, in formula (I), (II), (III), or (IV), R 2 is C 6-14 aryl optionally substituted with one or more substituents Q . In certain embodiments, in formula (I), (II), (III) or (IV), R 2 is heteroaryl optionally substituted with one or more substituents Q.
在又另一實施例中，本文提供一種式(V)化合物：
在某些實施例中，在式(V)中，A為(i)鍵；或(ii) C 1-6伸烷基、C 3-10伸環烷基、C 6-14伸芳基、伸雜芳基或伸雜環基；其中之每一者視情況經一或多個取代基Q取代。在某些實施例中，在式(V)中，A為鍵或視情況經一或多個取代基Q取代之C 1-6伸烷基。在某些實施例中，在式(V)中，A為鍵或亞甲基。在某些實施例中，在式(V)中，A為C 3-10伸環烷基或伸雜環基；各自視情況經一或多個取代基Q取代。在某些實施例中，在式(V)中，A為視情況經一或多個取代基Q取代之C 3-10伸環烷基。在某些實施例中，在式(V)中，A為視情況經一或多個取代基Q取代之單環C 3-10伸環烷基。在某些實施例中，在式(V)中，A為視情況經一或多個取代基Q取代之伸雜環基。在某些實施例中，在式(V)中，A為視情況經一或多個取代基Q取代之單環伸雜環基。在某些實施例中，在式(V)中，A為各自視情況經一或多個取代基Q取代之5員或6員伸雜環基。在某些實施例中，在式(V)中，A為各自視情況經一或多個取代基Q取代之C 6-14伸芳基或伸雜芳基。在某些實施例中，在式(V)中，A為視情況經一或多個取代基Q取代之C 6-14伸芳基。在某些實施例中，在式(V)中，A為視情況經一或多個取代基Q取代之伸苯基。在某些實施例中，在式(V)中，A為各自視情況經一或多個取代基Q取代之苯-1,3-二基或苯-1,4-二基。在某些實施例中，在式(V)中，A為視情況經一或多個取代基Q取代之苯-1,3-二基。在某些實施例中，在式(V)中，A為視情況經一或多個取代基Q取代之苯-1,4-二基。在某些實施例中，在式(V)中，A為視情況經一或多個取代基Q取代之伸雜芳基。在某些實施例中，在式(V)中，A為視情況經一或多個取代基Q取代之單環伸雜芳基。在某些實施例中，在式(V)中，A為各自視情況經一或多個取代基Q取代之5員或6員伸雜芳基。 In certain embodiments, in formula (V), A is (i) a bond; or (ii) C 1-6 alkylene, C 3-10 cycloalkyl, C 6-14 aryl, Heteroarylidene or heterocyclylene; each of which is optionally substituted with one or more substituents Q. In certain embodiments, in formula (V), A is a bond or a C 1-6 alkylene optionally substituted with one or more substituents Q . In certain embodiments, in formula (V), A is a bond or methylene. In certain embodiments, in formula (V), A is C 3-10 cycloalkylene or heterocyclylene; each optionally substituted with one or more substituents Q. In certain embodiments, in formula (V), A is C 3-10 cycloextended alkyl optionally substituted with one or more substituents Q . In certain embodiments, in formula (V), A is a monocyclic C 3-10 cycloalkylene optionally substituted with one or more substituents Q . In certain embodiments, in formula (V), A is a heterocyclylene optionally substituted with one or more substituents Q. In certain embodiments, in formula (V), A is a monocyclic heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, in formula (V), A is a 5- or 6-membered heterocyclyl group, each optionally substituted with one or more substituents Q. In certain embodiments, in formula (V), A is C 6-14 aryl or heteroaryl, each optionally substituted with one or more substituents Q . In certain embodiments, in formula (V), A is C 6-14 arylidene optionally substituted with one or more substituents Q . In certain embodiments, in formula (V), A is phenylene optionally substituted with one or more substituents Q. In certain embodiments, in formula (V), A is benzene-1,3-diyl or benzene-1,4-diyl, each optionally substituted with one or more substituents Q. In certain embodiments, in formula (V), A is benzene-1,3-diyl optionally substituted with one or more substituents Q. In certain embodiments, in formula (V), A is benzene-1,4-diyl optionally substituted with one or more substituents Q. In certain embodiments, in formula (V), A is heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, in formula (V), A is a monocyclic heteroarylidene optionally substituted with one or more substituents Q. In certain embodiments, in formula (V), A is a 5- or 6-membered heteroaryl group, each optionally substituted with one or more substituents Q.
在一個實施例中，在式(V)中， A為鍵、C 1-6伸烷基、C 6-14伸芳基、伸雜芳基或伸雜環基； X及Y各自獨立地為N或CR 2b，其中R 2b為氫、氘或鹵基； R 1及R 3各自獨立地為氫、氘、鹵基或C 1-6烷基； R 4為C 6-14芳基或雜芳基； R 2a為氫、氘、C 1-6烷基、-C(O)OR 1a、-OR 1a或-NR 1bR 1c，其中各R 1a、R 1b及R 1c如本文所定義； 各R 2c獨立地為氘、鹵基、側氧基或C 1-6烷基； b為1、2或3之整數；及 c為0、1、2、3、4、5或6之整數； 其中各烷基、伸烷基、芳基、伸芳基、雜芳基、伸雜芳基及伸雜環基視情況經一或多個取代基Q取代。 In one embodiment, in formula (V), A is a bond, C 1-6 alkylene, C 6-14 aryl, heteroaryl or heterocyclylene; X and Y are each independently N or CR 2b , wherein R 2b is hydrogen, deuterium or halo; R 1 and R 3 are each independently hydrogen, deuterium, halo or C 1-6 alkyl; R 4 is C 6-14 aryl or hetero Aryl; R 2a is hydrogen, deuterium, C 1-6 alkyl, -C(O)OR 1a , -OR 1a , or -NR 1b R 1c , wherein each R 1a , R 1b and R 1c are as defined herein; Each R 2c is independently deuterium, halo, pendant oxy, or C 1-6 alkyl; b is an integer of 1, 2, or 3; and c is an integer of 0, 1, 2, 3, 4, 5, or 6 ; wherein each alkyl, alkylene, aryl, aryl, heteroaryl, heteroaryl and heterocyclylene is optionally substituted with one or more substituents Q.
在另一實施例中，在式(V)中， A為鍵、C 1-6伸烷基、C 6-14伸芳基或伸雜芳基； X及Y各自獨立地為N或CR 2b，其中R 2b為氫、氘或鹵基； R 1及R 3各自獨立地為氫、氘、鹵基或C 1-6烷基； R 4為C 6-14芳基或雜芳基； R 2a為氫、氘、C 1-6烷基、-C(O)OR 1a、-OR 1a或-NR 1bR 1c，其中各R 1a、R 1b及R 1c如本文所定義； 各R 2c獨立地為氘、鹵基、側氧基或C 1-6烷基； b為1、2或3之整數；及 c為0、1、2、3、4、5或6之整數； 其中各烷基、伸烷基、芳基、伸芳基、雜芳基及伸雜芳基視情況經一或多個取代基Q取代。 In another embodiment, in formula (V), A is a bond, C 1-6 alkylene, C 6-14 aryl or heteroaryl; X and Y are each independently N or CR 2b , wherein R 2b is hydrogen, deuterium or halo; R 1 and R 3 are each independently hydrogen, deuterium, halo or C 1-6 alkyl; R 4 is C 6-14 aryl or heteroaryl; R 2a is hydrogen, deuterium, C 1-6 alkyl, -C(O)OR 1a , -OR 1a or -NR 1b R 1c , wherein each R 1a , R 1b and R 1c are as defined herein; each R 2c is independent is deuterium, halo, pendant oxy, or C1-6 alkyl; b is an integer of 1, 2, or 3; and c is an integer of 0, 1, 2, 3, 4, 5, or 6; wherein each alkane Alkyl, alkylene, aryl, aryl, heteroaryl, and heteroaryl are optionally substituted with one or more substituents Q.
在又另一實施例中，在式(V)中， A為鍵、C 1-6伸烷基、伸苯基、單環伸雜芳基或單環伸雜環基； X及Y各自獨立地為N或CR 2b，其中R 2b為氫、氘或鹵基； R 1及R 3各自獨立地為氫、氘、鹵基或C 1-6烷基； R 4為苯基或單環雜芳基； R 2a為氫、氘、C 1-6烷基、-C(O)OH、-OH或-NH 2； 各R 2c獨立地為氘、鹵基、側氧基或C 1-6烷基； b為1、2或3之整數；及 c為0、1、2、3或4之整數； 其中各烷基、伸烷基、苯基、伸苯基、雜芳基、伸雜芳基及伸雜環基視情況經一或多個取代基Q取代。 In yet another embodiment, in formula (V), A is a bond, C 1-6 alkylene, phenylene, monocyclic heteroaryl or monocyclic heterocyclylene; X and Y are each independently is N or CR 2b , wherein R 2b is hydrogen, deuterium or halo; R 1 and R 3 are each independently hydrogen, deuterium, halo or C 1-6 alkyl; R 4 is phenyl or monocyclic hetero Aryl; R 2a is hydrogen, deuterium, C 1-6 alkyl, -C(O)OH, -OH, or -NH 2 ; each R 2c is independently deuterium, halo, pendant oxy, or C 1-6 alkyl; b is an integer of 1, 2, or 3; and c is an integer of 0, 1, 2, 3, or 4; wherein each alkyl, alkylene, phenyl, phenylene, heteroaryl, heterodyne Aryl and heterocyclylene are optionally substituted with one or more substituents Q.
在又另一實施例中，在式(V)中， A為鍵、C 1-6伸烷基、伸苯基或單環伸雜芳基； X及Y各自獨立地為N或CR 2b，其中R 2b為氫、氘或鹵基； R 1及R 3各自獨立地為氫、氘、鹵基或C 1-6烷基； R 4為苯基或單環雜芳基； R 2a為氫、氘、C 1-6烷基、-C(O)OH、-OH或-NH 2； 各R 2c獨立地為氘、鹵基、側氧基或C 1-6烷基； b為1、2或3之整數；及 c為0、1、2、3或4之整數； 其中各烷基、伸烷基、苯基、伸苯基、雜芳基及伸雜芳基視情況經一或多個取代基Q取代。 In yet another embodiment, in formula (V), A is a bond, C 1-6 alkylene, phenylene or monocyclic heteroaryl; X and Y are each independently N or CR 2b , wherein R 2b is hydrogen, deuterium or halo; R 1 and R 3 are each independently hydrogen, deuterium, halo or C 1-6 alkyl; R 4 is phenyl or monocyclic heteroaryl; R 2a is hydrogen , deuterium, C 1-6 alkyl, -C(O)OH, -OH or -NH 2 ; each R 2c is independently deuterium, halo, pendant oxy or C 1-6 alkyl; b is 1, an integer of 2 or 3; and c is an integer of 0, 1, 2, 3, or 4; wherein each alkyl, alkylene, phenyl, phenylene, heteroaryl, and heteroaryl, as the case may be, is represented by one or more Multiple substituents Q are substituted.
在又另一實施例中，在式(V)中， A為鍵、C 1-6伸烷基、伸苯基、5員或6員伸雜芳基或5員或6員伸雜環基； X及Y各自獨立地為N或CH； R 1及R 3各自獨立地為氫、氘、鹵基或C 1-6烷基； R 4為苯基或5員或6員雜芳基； R 2a為氫、氘、C 1-6烷基、-C(O)OH、-OH或-NH 2； 各R 2c獨立地為氘、鹵基、側氧基或C 1-6烷基； b為1、2或3之整數；及 c為0、1或2之整數； 其中各烷基、伸烷基、苯基、伸苯基、雜芳基、伸雜芳基及伸雜環基視情況經一或多個取代基Q取代。 In yet another embodiment, in formula (V), A is a bond, C 1-6 alkylene, phenylene, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclyl ; X and Y are each independently N or CH; R 1 and R 3 are each independently hydrogen, deuterium, halo or C 1-6 alkyl; R 4 is phenyl or 5-membered or 6-membered heteroaryl; R 2a is hydrogen, deuterium, C 1-6 alkyl, -C(O)OH, -OH or -NH 2 ; each R 2c is independently deuterium, halo, pendant oxy or C 1-6 alkyl; b is an integer of 1, 2, or 3; and c is an integer of 0, 1, or 2; wherein each alkyl, alkylene, phenyl, phenylene, heteroaryl, heteroaryl, and heterocyclylene Optionally substituted with one or more substituents Q.
在又另一實施例中，在式(V)中， A為鍵、C 1-6伸烷基、伸苯基或5員或6員伸雜芳基； X及Y各自獨立地為N或CH； R 1及R 3各自獨立地為氫、氘、鹵基或C 1-6烷基； R 4為苯基或5員或6員雜芳基； R 2a為氫、氘、C 1-6烷基、-C(O)OH、-OH或-NH 2； 各R 2c獨立地為氘、鹵基、側氧基或C 1-6烷基； b為1、2或3之整數；及 c為0、1或2之整數； 其中各烷基、伸烷基、苯基、伸苯基、雜芳基及伸雜芳基視情況經一或多個取代基Q取代。 In yet another embodiment, in formula (V), A is a bond, C 1-6 alkylene, phenylene, or 5- or 6-membered heteroaryl; X and Y are each independently N or CH; R 1 and R 3 are each independently hydrogen, deuterium, halo or C 1-6 alkyl; R 4 is phenyl or 5- or 6-membered heteroaryl; R 2a is hydrogen, deuterium, C 1- 6 alkyl, -C(O)OH, -OH or -NH 2 ; each R 2c is independently deuterium, halo, pendant oxy or C 1-6 alkyl; b is an integer of 1, 2 or 3; and c is an integer of 0, 1 or 2; wherein each alkyl, alkylene, phenyl, phenylene, heteroaryl and heteroaryl is optionally substituted with one or more substituents Q.
在又另一實施例中，在式(V)中， A為鍵、亞甲基、苯-1,3-二基、苯-1,4-二基、哌𠯤-1,4-二基或哌啶-1,4-二基； X及Y各自獨立地為N或CH； R 1為氫； R 3為甲基； R 4B為苯基； R 2a為甲基或2-羥基乙基； b為1或2之整數；及 c為0之整數。 In yet another embodiment, in formula (V), A is a bond, methylene, benzene-1,3-diyl, benzene-1,4-diyl, piperazine-1,4-diyl or piperidine-1,4-diyl; X and Y are each independently N or CH; R 1 is hydrogen; R 3 is methyl; R 4B is phenyl; R 2a is methyl or 2-hydroxyethyl ; b is an integer of 1 or 2; and c is an integer of 0.
在再一實施例中，在式(V)中， A為鍵、亞甲基、苯-1,3-二基或苯-1,4-二基； X及Y各自獨立地為N或CH； R 1為氫； R 3為甲基； R 4為苯基； R 2a為甲基或2-羥基乙基； b為1或2之整數；及 c為0之整數。 In yet another embodiment, in formula (V), A is a bond, methylene, benzene-1,3-diyl or benzene-1,4-diyl; X and Y are each independently N or CH R 1 is hydrogen; R 3 is methyl; R 4 is phenyl; R 2a is methyl or 2-hydroxyethyl; b is an integer of 1 or 2; and c is an integer of 0.
在又另一實施例中，本文提供一種式(VI)化合物：
在又另一實施例中，本文提供一種式(VII)化合物：
在又另一實施例中，本文提供一種式(VIII)化合物：
在一個實施例中，在式(VI)、(VII)或(VIII)中， X及Y各自獨立地為N或CR 2b，其中R 2b為氫、氘或鹵基； R 1及R 3各自獨立地為氫、氘、鹵基或C 1-6烷基； R 4為C 6-14芳基或雜芳基； 各R 5獨立地為氘、鹵基或C 1-6烷基； R 2a為氫、氘、C 1-6烷基、-C(O)OR 1a、-OR 1a或-NR 1bR 1c，其中各R 1a、R 1b及R 1c如本文所定義； 各R 2c獨立地為氘、鹵基、側氧基或C 1-6烷基； a為0、1、2、3或4之整數； b為1、2或3之整數；及 c為0、1、2、3、4、5或6之整數； 其中各烷基、芳基及雜芳基視情況經一或多個取代基Q取代。 In one embodiment, in formula (VI), (VII) or (VIII), X and Y are each independently N or CR 2b , wherein R 2b is hydrogen, deuterium or halo; R 1 and R 3 are each independently hydrogen, deuterium, halo or C 1-6 alkyl; R 4 is C 6-14 aryl or heteroaryl; each R 5 is independently deuterium, halo or C 1-6 alkyl; R 2a is hydrogen, deuterium, C 1-6 alkyl, -C(O)OR 1a , -OR 1a or -NR 1b R 1c , wherein each R 1a , R 1b and R 1c are as defined herein; each R 2c is independent is deuterium, halo, pendant oxy or C 1-6 alkyl; a is an integer of 0, 1, 2, 3 or 4; b is an integer of 1, 2 or 3; and c is 0, 1, 2 , an integer of 3, 4, 5, or 6; wherein each alkyl, aryl, and heteroaryl group is optionally substituted with one or more substituents Q.
在另一實施例中，在式(VI)、(VII)或(VIII)中， X及Y各自獨立地為N或CR 2b，其中R 2b為氫、氘或鹵基； R 1及R 3各自獨立地為氫、氘、鹵基或C 1-6烷基； R 4為苯基或單環雜芳基； 各R 5獨立地為氘、鹵基或C 1-6烷基； R 2a為氫、氘、C 1-6烷基、-C(O)OH、-OH或-NH 2； 各R 2c獨立地為氘、鹵基、側氧基或C 1-6烷基； a為0、1或2之整數； b為1、2或3之整數；及 c為0、1、2、3或4之整數； 其中各烷基、苯基及雜芳基視情況經一或多個取代基Q取代。 In another embodiment, in formula (VI), (VII) or (VIII), X and Y are each independently N or CR 2b , wherein R 2b is hydrogen, deuterium or halo; R 1 and R 3 each independently hydrogen, deuterium, halo or C 1-6 alkyl; R 4 is phenyl or monocyclic heteroaryl; each R 5 is independently deuterium, halo or C 1-6 alkyl; R 2a is hydrogen, deuterium, C 1-6 alkyl, -C(O)OH, -OH or -NH 2 ; each R 2c is independently deuterium, halo, pendant oxy or C 1-6 alkyl; a is an integer of 0, 1, or 2; b is an integer of 1, 2, or 3; and c is an integer of 0, 1, 2, 3, or 4; wherein each alkyl, phenyl, and heteroaryl group is optionally modified by one or more A substituent Q is substituted.
在又另一實施例中，在式(VI)、(VII)或(VIII)中， X及Y各自獨立地為N或CH； R 1及R 3各自獨立地為氫、氘、鹵基或C 1-6烷基； R 4為苯基或5員或6員雜芳基； 各R 5獨立地為氘、鹵基或C 1-6烷基； R 2a為氫、氘、C 1-6烷基、-C(O)OH、-OH或-NH 2； 各R 2c獨立地為氘、鹵基、側氧基或C 1-6烷基； a為0、1或2之整數； b為1、2或3之整數；及 c為0、1或2之整數； 其中各烷基、苯基及雜芳基視情況經一或多個取代基Q取代。 In yet another embodiment, in formula (VI), (VII) or (VIII), X and Y are each independently N or CH; R 1 and R 3 are each independently hydrogen, deuterium, halo or C 1-6 alkyl; R 4 is phenyl or 5- or 6-membered heteroaryl; each R 5 is independently deuterium, halo or C 1-6 alkyl; R 2a is hydrogen, deuterium, C 1- 6 alkyl, -C(O)OH, -OH or -NH 2 ; each R 2c is independently deuterium, halo, pendant oxy or C 1-6 alkyl; a is an integer of 0, 1 or 2; b is an integer of 1, 2, or 3; and c is an integer of 0, 1, or 2; wherein each alkyl, phenyl, and heteroaryl group is optionally substituted with one or more substituents Q.
在再一實施例中，在式(VI)、(VII)或(VIII)中， X及Y各自獨立地為N或CH； R 1為氫； R 3為甲基； R 4為苯基； R 2a為甲基或2-羥基乙基； a及c各自為0之整數；及 b為1或2之整數。 In yet another embodiment, in formula (VI), (VII) or (VIII), X and Y are each independently N or CH; R 1 is hydrogen; R 3 is methyl; R 4 is phenyl; R 2a is methyl or 2-hydroxyethyl; a and c are each an integer of 0; and b is an integer of 1 or 2.
在又另一實施例中，本文提供一種式(IX)化合物：
在又另一實施例中，本文提供一種式(X)化合物：
在再一實施例中，本文提供一種式(XI)化合物：
在一個實施例中，在式(IX)、(X)或(XI)中， R 1及R 3各自獨立地為氫、氘、鹵基或C 1-6烷基； R 4為C 6-14芳基或雜芳基； 各R 5獨立地為氘、鹵基或C 1-6烷基； R 2a為C 1-6烷基； 各R 2c獨立地為氘、鹵基、側氧基或C 1-6烷基； a為0、1、2、3或4之整數；及 c為0、1、2、3、4、5或6之整數； 其中各烷基、芳基及雜芳基視情況經一或多個取代基Q取代。 In one embodiment, in formula (IX), (X) or (XI), R 1 and R 3 are each independently hydrogen, deuterium, halo or C 1-6 alkyl; R 4 is C 6- 14 Aryl or heteroaryl; each R 5 is independently deuterium, halo or C 1-6 alkyl; R 2a is C 1-6 alkyl; each R 2c is independently deuterium, halo, pendant oxy or C 1-6 alkyl; a is an integer of 0, 1, 2, 3 or 4; and c is an integer of 0, 1, 2, 3, 4, 5 or 6; wherein each alkyl, aryl and hetero Aryl is optionally substituted with one or more substituents Q.
在另一實施例中，在式(IX)、(X)或(XI)中， R 1及R 3各自獨立地為氫、氘、鹵基或C 1-6烷基； R 4為苯基或單環雜芳基； 各R 5獨立地為氘、鹵基或C 1-6烷基； R 2a為C 1-6烷基； 各R 2c獨立地為氘、鹵基、側氧基或C 1-6烷基； a為0、1或2之整數；及 c為0、1、2、3或4之整數； 其中各烷基、苯基及雜芳基視情況經一或多個取代基Q取代。 In another embodiment, in formula (IX), (X) or (XI), R 1 and R 3 are each independently hydrogen, deuterium, halo or C 1-6 alkyl; R 4 is phenyl or monocyclic heteroaryl; each R 5 is independently deuterium, halo or C 1-6 alkyl; R 2a is C 1-6 alkyl; each R 2c is independently deuterium, halo, pendant oxy or C 1-6 alkyl; a is an integer of 0, 1, or 2; and c is an integer of 0, 1, 2, 3, or 4; wherein each alkyl, phenyl, and heteroaryl is optionally modified by one or more Substituent Q is substituted.
在又另一實施例中，在式(IX)、(X)或(XI)中， R 1及R 3各自獨立地為氫、氘、鹵基或C 1-6烷基； R 4為苯基或5員或6員雜芳基； 各R 5獨立地為氘、鹵基或C 1-6烷基； R 2a為C 1-6烷基； 各R 2c獨立地為氘、鹵基、側氧基或C 1-6烷基； a為0、1或2之整數；及 c為0、1或2之整數； 其中各烷基、苯基及雜芳基視情況經一或多個取代基Q取代。 In yet another embodiment, in formula (IX), (X) or (XI), R 1 and R 3 are each independently hydrogen, deuterium, halo or C 1-6 alkyl; R 4 is benzene each R 5 is independently deuterium, halo or C 1-6 alkyl; R 2a is C 1-6 alkyl; each R 2c is independently deuterium, halo, pendant oxy or C 1-6 alkyl; a is an integer of 0, 1 or 2; and c is an integer of 0, 1 or 2; wherein each alkyl, phenyl and heteroaryl is optionally modified by one or more Substituent Q is substituted.
在再一實施例中，在式(IX)、(X)或(XI)中， R 1為氫； R 3為甲基； R 4為苯基； R 2a為甲基或2-羥基乙基；及 a及c各自為0之整數。 In yet another embodiment, in formula (IX), (X) or (XI), R 1 is hydrogen; R 3 is methyl; R 4 is phenyl; R 2a is methyl or 2-hydroxyethyl ; and a and c are each an integer of 0.
在一個實施例中，本文提供之化合物為以下之化合物：
在另一實施例中，本文提供之化合物為以下之化合物：
在又另一實施例中，本文提供之化合物為以下之化合物：
在一個實施例中，本文提供一種式(IA)化合物：
在某些實施例中，在式(A)或(IA)中，A為(i)鍵；或(ii) C 1-6伸烷基、C 3-10伸環烷基、C 6-14伸芳基、伸雜芳基或伸雜環基，其中之每一者視情況經一或多個取代基Q取代。在某些實施例中，在式(A)或(IA)中，A為鍵或視情況經一或多個取代基Q取代之C 1-6伸烷基。在某些實施例中，在式(A)或(IA)中，A為鍵或亞甲基。在某些實施例中，在式(A)或(IA)中，A為C 3-10伸環烷基或伸雜環基；各自視情況經一或多個取代基Q取代。在某些實施例中，在式(A)或(IA)中，A為視情況經一或多個取代基Q取代之C 3-10伸環烷基。在某些實施例中，在式(A)或(IA)中，A為視情況經一或多個取代基Q取代之單環C 3-10伸環烷基。在某些實施例中，在式(A)或(IA)中，A為視情況經一或多個取代基Q取代之伸雜環基。在某些實施例中，在式(A)或(IA)中，A為視情況經一或多個取代基Q取代之單環伸雜環基。在某些實施例中，在式(A)或(IA)中，A為各自視情況經一或多個取代基Q取代之5員或6員伸雜環基。在某些實施例中，在式(A)或(IA)中，A為各自視情況經一或多個取代基Q取代之哌啶二基或哌𠯤二基。在某些實施例中，在式(A)或(IA)中，A為各自視情況經一或多個取代基Q取代之哌啶-1,4-二基或哌𠯤-1,4-二基。在某些實施例中，在式(A)或(IA)中，A為各自視情況經一或多個取代基Q取代之C 6-14伸芳基或伸雜芳基。在某些實施例中，在式(A)或(IA)中，A為視情況經一或多個取代基Q取代之C 6-14伸芳基。在某些實施例中，在式(A)或(IA)中，A為視情況經一或多個取代基Q取代之伸苯基。在某些實施例中，在式(A)或(IA)中，A為各自視情況經一或多個取代基Q取代之苯-1,3-二基或苯-1,4-二基。在某些實施例中，在式(A)或(IA)中，A為視情況經一或多個取代基Q取代之苯-1,3-二基。在某些實施例中，在式(A)或(IA)中，A為視情況經一或多個取代基Q取代之苯-1,4-二基。在某些實施例中，在式(A)或(IA)中，A為視情況經一或多個取代基Q取代之伸雜芳基。在某些實施例中，在式(A)或(IA)中，A為視情況經一或多個取代基Q取代之單環伸雜芳基。在某些實施例中，在式(A)或(IA)中，A為各自視情況經一或多個取代基Q取代之5員或6員伸雜芳基。 In certain embodiments, in formula (A) or (IA), A is (i) a bond; or (ii) C 1-6 alkylene, C 3-10 cycloalkylene, C 6-14 Arylene, heteroaryl, or heterocyclylene, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in formula (A) or (IA), A is a bond or C1-6 alkylene optionally substituted with one or more substituents Q. In certain embodiments, in formula (A) or (IA), A is a bond or a methylene group. In certain embodiments, in formula (A) or (IA), A is C 3-10 cycloalkylene or heterocyclylene; each optionally substituted with one or more substituents Q. In certain embodiments, in formula (A) or (IA), A is C 3-10 cycloalkylene optionally substituted with one or more substituents Q . In certain embodiments, in formula (A) or (IA), A is a monocyclic C 3-10 cycloextended alkyl group optionally substituted with one or more substituents Q . In certain embodiments, in formula (A) or (IA), A is a heterocyclylene optionally substituted with one or more substituents Q. In certain embodiments, in formula (A) or (IA), A is a monocyclic heterocyclylene optionally substituted with one or more substituents Q. In certain embodiments, in formula (A) or (IA), A is a 5- or 6-membered heterocyclyl group, each optionally substituted with one or more substituents Q. In certain embodiments, in formula (A) or (IA), A is piperidinediyl or piperidinediyl, each optionally substituted with one or more substituents Q. In certain embodiments, in formula (A) or (IA), A is piperidine-1,4-diyl or piperidine-1,4- each optionally substituted with one or more substituents Q, Q Two bases. In certain embodiments, in formula (A) or (IA), A is C 6-14 aryl or heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, in formula (A) or (IA), A is C6-14 arylidene substituted with one or more substituents Q, as appropriate. In certain embodiments, in formula (A) or (IA), A is phenylene optionally substituted with one or more substituents Q. In certain embodiments, in formula (A) or (IA), A is benzene-1,3-diyl or benzene-1,4-diyl, each optionally substituted with one or more substituents Q . In certain embodiments, in formula (A) or (IA), A is benzene-1,3-diyl optionally substituted with one or more substituents Q. In certain embodiments, in formula (A) or (IA), A is benzene-1,4-diyl optionally substituted with one or more substituents Q. In certain embodiments, in formula (A) or (IA), A is heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, in formula (A) or (IA), A is a monocyclic heteroarylidene optionally substituted with one or more substituents Q. In certain embodiments, in formula (A) or (IA), A is a 5- or 6-membered heteroaryl, each optionally substituted with one or more substituents Q.
在一個實施例中，在式(A)或(IA)中， A為鍵、C 1-6伸烷基、C 6-14伸芳基、伸雜芳基或伸雜環基； R 1及R 3各自獨立地為氫、氘、鹵基或C 1-6烷基； R 2為C 3-10環烷基或雜環基；及 R 4為C 6-14芳基或雜芳基； 其中各烷基、伸烷基、環烷基、芳基、伸芳基、雜芳基、伸雜芳基、雜環基及伸雜環基視情況經一或多個取代基Q取代。 In one embodiment, in formula (A) or (IA), A is a bond, C 1-6 alkylene, C 6-14 aryl, heteroaryl or heterocyclylene; R 1 and R 3 is each independently hydrogen, deuterium, halo or C 1-6 alkyl; R 2 is C 3-10 cycloalkyl or heterocyclyl; and R 4 is C 6-14 aryl or heteroaryl; wherein each alkyl, alkylene, cycloalkyl, aryl, aryl, heteroaryl, heteroaryl, heterocyclylene, and heterocyclylene is optionally substituted with one or more substituents Q.
在另一實施例中，在式(A)或(IA)中， A為鍵、C 1-6伸烷基、伸苯基、單環伸雜芳基或單環伸雜環基； R 1及R 3各自獨立地為氫、氘、鹵基或C 1-6烷基； R 2為單環C 3-10環烷基或單環雜環基；及 R 4為苯基或單環雜芳基； 其中各烷基、伸烷基、環烷基、苯基、伸苯基、雜芳基、伸雜芳基、雜環基及伸雜環基視情況經一或多個取代基Q取代。 In another embodiment, in formula (A) or (IA), A is a bond, C 1-6 alkylene, phenylene, monocycloheteroaryl or monocycloheterocyclo; R 1 and R 3 are each independently hydrogen, deuterium, halo or C 1-6 alkyl; R 2 is monocyclic C 3-10 cycloalkyl or monocyclic heterocyclyl; and R 4 is phenyl or monocyclic heterocyclyl Aryl; wherein each alkyl, alkylene, cycloalkyl, phenyl, phenylene, heteroaryl, heteroaryl, heterocyclyl, and heterocyclylene is optionally substituted by one or more substituents Q replace.
在又另一實施例中，在式(A)或(IA)中， A為鍵、C 1-6伸烷基、伸苯基、5員或6員伸雜芳基或5員或6員伸雜環基； R 1及R 3各自獨立地為氫、氘、鹵基或C 1-6烷基； R 2為單環C 3-10環烷基或5員或6員雜環基；及 R 4B為苯基或5員或6員雜芳基； 其中各烷基、伸烷基、環烷基、苯基、伸苯基、雜芳基、伸雜芳基、雜環基及伸雜環基視情況經一或多個取代基Q取代。 In yet another embodiment, in formula (A) or (IA), A is a bond, C 1-6 alkylene, phenylene, 5- or 6-membered heteroaryl, or 5- or 6-membered Heterocyclic group; R 1 and R 3 are each independently hydrogen, deuterium, halo or C 1-6 alkyl; R 2 is monocyclic C 3-10 cycloalkyl or 5- or 6-membered heterocyclic group; and R 4B is phenyl or 5-membered or 6-membered heteroaryl; wherein each alkyl, alkylene, cycloalkyl, phenyl, phenylene, heteroaryl, heteroaryl, heterocyclyl and Heterocyclyl is optionally substituted with one or more substituents Q.
在再一實施例中，在式(A)或(IA)中， A為鍵、亞甲基、伸苯基、哌𠯤二基或哌啶二基； R 1為氫、氘或鹵基； R 2為各自視情況經一或多個取代基Q取代之5員或6員雜環基； R 3為C 1-6烷基；及 R 4B為苯基。 In yet another embodiment, in formula (A) or (IA), A is a bond, methylene, phenylene, piperidinediyl or piperidinediyl; R 1 is hydrogen, deuterium or halo; R 2 is a 5- or 6-membered heterocyclyl group, each optionally substituted with one or more substituents Q; R 3 is C 1-6 alkyl; and R 4B is phenyl.
在另一實施例中，本文提供一種式(IIA)化合物：
在又另一實施例中，本文提供一種式(IIIA)化合物：
在又另一實施例中，本文提供一種式(IVA)化合物：
在一個實施例中，在式(IIA)、(IIIA)或(IVA)中， R 1及R 3各自獨立地為氫、氘、鹵基或C 1-6烷基； R 2為C 3-10環烷基或雜環基； R 4為C 6-14芳基或雜芳基； 各R 6獨立地為氘、鹵基或C 1-6烷基；及 d為0、1、2、3或4之整數； 其中各烷基、環烷基、芳基、雜芳基及雜環基視情況經一或多個取代基Q取代。 In one embodiment, in formula (IIA), (IIIA) or (IVA), R 1 and R 3 are each independently hydrogen, deuterium, halo or C 1-6 alkyl; R 2 is C 3- 10 cycloalkyl or heterocyclyl; R 4 is C 6-14 aryl or heteroaryl; each R 6 is independently deuterium, halo or C 1-6 alkyl; and d is 0, 1, 2, an integer of 3 or 4; wherein each alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally substituted with one or more substituents Q.
在另一實施例中，在式(IIA)、(IIIA)或(IVA)中， R 1及R 3各自獨立地為氫、氘、鹵基或C 1-6烷基； R 2為單環C 3-10環烷基或單環雜環基； R 4B為苯基或單環雜芳基； 各R 6獨立地為氘、鹵基或C 1-6烷基；及 d為0、1或2之整數； 其中各烷基、環烷基、苯基、雜芳基及雜環基視情況經一或多個取代基Q取代。 In another embodiment, in formula (IIA), (IIIA) or (IVA), R 1 and R 3 are each independently hydrogen, deuterium, halo or C 1-6 alkyl; R 2 is monocyclic C 3-10 cycloalkyl or monocyclic heterocyclyl; R 4B is phenyl or monocyclic heteroaryl; each R 6 is independently deuterium, halo or C 1-6 alkyl; and d is 0, 1 or an integer of 2; wherein each alkyl, cycloalkyl, phenyl, heteroaryl and heterocyclyl is optionally substituted with one or more substituents Q.
在又另一實施例中，在式(IIA)、(IIIA)或(IVA)中， R 1為氫、氘、鹵基或C 1-6烷基； R 2為單環C 3-10環烷基或5員或6員雜環基； R 3為氫、氘、鹵基或C 1-6烷基； R 4B為苯基或5員或6員雜芳基； 各R 6獨立地為氘、鹵基或C 1-6烷基；及 d為0、1或2之整數； 其中各烷基、環烷基、苯基、雜芳基及雜環基視情況經一或多個取代基Q取代。 In yet another embodiment, in formula (IIA), (IIIA) or (IVA), R 1 is hydrogen, deuterium, halo or C 1-6 alkyl; R 2 is a monocyclic C 3-10 ring Alkyl or 5- or 6-membered heterocyclic group; R 3 is hydrogen, deuterium, halo or C 1-6 alkyl; R 4B is phenyl or 5- or 6-membered heteroaryl; each R 6 is independently deuterium, halo, or C1-6 alkyl; and d is an integer of 0, 1, or 2; wherein each alkyl, cycloalkyl, phenyl, heteroaryl, and heterocyclyl is optionally substituted with one or more Base Q is substituted.
在再一實施例中，在式(IIA)、(IIIA)或(IVA)中， R 1為氫； R 2為4-甲基哌𠯤基或4-(2-羥基乙基)哌𠯤基； R 3為甲基； R 4B為苯基；及 d為0之整數。 In yet another embodiment, in formula (IIA), (IIIA) or (IVA), R 1 is hydrogen; R 2 is 4-methylpiperazyl or 4-(2-hydroxyethyl)piperazyl ; R 3 is methyl; R 4B is phenyl; and d is an integer of 0.
在某些實施例中，在式(A)、(IA)、(IIA)、(IIIA)或(IVA)中，R 2為C 3-10環烷基、C 6-14芳基、雜芳基、雜環基或C 1-6烷基-伸雜環基，其中之每一者視情況經一或多個取代基Q取代。在某些實施例中，在式(A)、(IA)、(IIA)、(IIIA)或(IVA)中，R 2為各自視情況經一或多個取代基Q取代之C 3-10環烷基或雜環基。在某些實施例中，在式(A)、(IA)、(IIA)、(IIIA)或(IVA)中，R 2為視情況經一或多個取代基Q取代之C 3-10環烷基。在某些實施例中，在式(A)、(IA)、(IIA)、(IIIA)或(IVA)中，R 2為視情況經一或多個取代基Q取代之單環C 3-10環烷基。在某些實施例中，在式(A)、(IA)、(IIA)、(IIIA)或(IVA)中，R 2為環丙基、環丁基、環戊基、環己基或環庚基，其中之每一者視情況經一或多個取代基Q取代。在某些實施例中，在式(A)、(IA)、(IIA)、(IIIA)或(IVA)中，R 2為環丁基、環戊基或環己基，其中之每一者視情況經一或多個取代基Q取代。在某些實施例中，在式(A)、(IA)、(IIA)、(IIIA)或(IVA)中，R 2為視情況經一或多個取代基Q取代之環己基。在某些實施例中，在式(A)、(IA)、(IIA)、(IIIA)或(IVA)中，R 2為視情況經一或多個取代基Q取代之雜環基。在某些實施例中，在式(A)、(IA)、(IIA)、(IIIA)或(IVA)中，R 2為視情況經一或多個取代基Q取代之單環雜環基。在某些實施例中，在式(A)、(IA)、(IIA)、(IIIA)或(IVA)中，R 2為各自視情況經一或多個取代基Q取代之5員或6員雜環基。在某些實施例中，在式(A)、(IA)、(IIA)、(IIIA)或(IVA)中，R 2為視情況經一或多個取代基Q取代之5員雜環基。在某些實施例中，在式(A)、(IA)、(IIA)、(IIIA)或(IVA)中，R 2為視情況經一或多個取代基Q取代之6員雜環基。在某些實施例中，在式(A)、(IA)、(IIA)、(IIIA)或(IVA)中，R 2為各自視情況經一或多個取代基Q取代之哌啶基或哌𠯤基。在某些實施例中，在式(A)、(IA)、(IIA)、(IIIA)或(IVA)中，R 2為各自視情況經一或多個取代基Q取代之哌啶-1-基、哌啶-4-基或哌𠯤-1-基。在某些實施例中，在式(A)、(IA)、(IIA)、(IIIA)或(IVA)中，R 2為視情況經一或多個取代基Q取代之哌𠯤-1-基。在某些實施例中，在式(A)、(IA)、(IIA)、(IIIA)或(IVA)中，R 2為各自視情況經一或多個取代基Q取代之C 6-14芳基或雜芳基。在某些實施例中，在式(A)、(IA)、(IIA)、(IIIA)或(IVA)中，R 2為視情況經一或多個取代基Q取代之C 6-14芳基。在某些實施例中，在式(A)、(IA)、(IIA)、(IIIA)或(IVA)中，R 2為視情況經一或多個取代基Q取代之雜芳基。 In certain embodiments, in formula (A), (IA), (IIA), (IIIA) or (IVA), R 2 is C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl , heterocyclyl, or C 1-6 alkyl-heterocyclylene, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in formula (A), (IA), (IIA), (IIIA) or (IVA), R 2 is C 3-10 each optionally substituted with one or more substituents Q Cycloalkyl or heterocyclyl. In certain embodiments, in formula (A), (IA), (IIA), (IIIA) or (IVA), R 2 is C 3-10 ring optionally substituted with one or more substituents Q alkyl. In certain embodiments, in formula (A), (IA), (IIA), (IIIA) or (IVA), R 2 is a monocyclic C 3- optionally substituted with one or more substituents Q 10 cycloalkyl. In certain embodiments, in formula (A), (IA), (IIA), (IIIA) or (IVA ) , R is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl groups, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in formula (A), (IA), (IIA), (IIIA) or (IVA), R 2 is cyclobutyl, cyclopentyl, or cyclohexyl, each of which is considered is substituted with one or more substituents Q. In certain embodiments, in formula (A), (IA), (IIA), (IIIA) or (IVA), R 2 is cyclohexyl optionally substituted with one or more substituents Q. In certain embodiments, in formula (A), (IA), (IIA), (IIIA) or (IVA), R 2 is heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, in formula (A), (IA), (IIA), (IIIA) or (IVA), R 2 is a monocyclic heterocyclyl optionally substituted with one or more substituents Q . In certain embodiments, in formula (A), (IA), (IIA), (IIIA) or (IVA), R is 5 -membered or 6-membered, each optionally substituted with one or more substituents Q Member heterocyclyl. In certain embodiments, in formula (A), (IA), (IIA), (IIIA) or (IVA), R 2 is a 5-membered heterocyclyl optionally substituted with one or more substituents Q . In certain embodiments, in formula (A), (IA), (IIA), (IIIA) or (IVA), R 2 is a 6-membered heterocyclyl optionally substituted with one or more substituents Q . In certain embodiments, in formula (A), (IA), (IIA), (IIIA), or (IVA ) , R is piperidinyl, each optionally substituted with one or more substituents Q, or Piper 𠯤 base. In certain embodiments, in formula (A), (IA), (IIA), (IIIA) or (IVA), R 2 is piperidine-1 each optionally substituted with one or more substituents Q -yl, piperidin-4-yl or piperidine-1-yl. In certain embodiments, in formula (A), (IA), (IIA), (IIIA) or (IVA), R 2 is piperidine-1- optionally substituted with one or more substituents Q base. In certain embodiments, in formula (A), (IA), (IIA), (IIIA) or (IVA), R 2 is C 6-14 each optionally substituted with one or more substituents Q Aryl or Heteroaryl. In certain embodiments, in formula (A), (IA), (IIA), (IIIA) or (IVA), R 2 is C 6-14 aryl optionally substituted with one or more substituents Q base. In certain embodiments, in formula (A), (IA), (IIA), (IIIA) or (IVA), R 2 is heteroaryl optionally substituted with one or more substituents Q.
在又另一實施例中，本文提供一種式(VA)化合物：
在某些實施例中，在式(VA)中，A為(i)鍵；或(ii)C 1-6伸烷基、C 3-10伸環烷基、C 6-14伸芳基、伸雜芳基或伸雜環基，其中之每一者視情況經一或多個取代基Q取代。在某些實施例中，在式(VA)中，A為鍵或視情況經一或多個取代基Q取代之C 1-6伸烷基。在某些實施例中，在式(VA)中，A為鍵或亞甲基。在某些實施例中，在式(VA)中，A為C 3-10伸環烷基或伸雜環基；各自視情況經一或多個取代基Q取代。在某些實施例中，在式(VA)中，A為視情況經一或多個取代基Q取代之C 3-10伸環烷基。在某些實施例中，在式(VA)中，A為視情況經一或多個取代基Q取代之單環C 3-10伸環烷基。在某些實施例中，在式(VA)中，A為視情況經一或多個取代基Q取代之伸雜環基。在某些實施例中，在式(VA)中，A為視情況經一或多個取代基Q取代之單環伸雜環基。在某些實施例中，在式(VA)中，A為各自視情況經一或多個取代基Q取代之5員或6員伸雜環基。在某些實施例中，在式(VA)中，A為各自視情況經一或多個取代基Q取代之哌啶二基或哌𠯤二基。在某些實施例中，在式(VA)中，A為各自視情況經一或多個取代基Q取代之哌啶-1,4-二基或哌𠯤-1,4-二基。在某些實施例中，在式(VA)中，A為各自視情況經一或多個取代基Q取代之C 6-14伸芳基或伸雜芳基。在某些實施例中，在式(VA)中，A為視情況經一或多個取代基Q取代之C 6-14伸芳基。在某些實施例中，在式(VA)中，A為視情況經一或多個取代基Q取代之伸苯基。在某些實施例中，在式(VA)中，A為各自視情況經一或多個取代基Q取代之苯-1,3-二基或苯-1,4-二基。在某些實施例中，在式(VA)中，A為視情況經一或多個取代基Q取代之苯-1,3-二基。在某些實施例中，在式(VA)中，A為視情況經一或多個取代基Q取代之苯-1,4-二基。在某些實施例中，在式(VA)中，A為視情況經一或多個取代基Q取代之伸雜芳基。在某些實施例中，在式(VA)中，A為視情況經一或多個取代基Q取代之單環伸雜芳基。在某些實施例中，在式(VA)中，A為各自視情況經一或多個取代基Q取代之5員或6員伸雜芳基。 In certain embodiments, in formula (VA), A is (i) a bond; or (ii) C 1-6 alkylene, C 3-10 cycloalkyl, C 6-14 aryl, Heteroarylidene or heterocyclylene, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in formula (VA), A is a bond or a C1-6 alkylene optionally substituted with one or more substituents Q. In certain embodiments, in formula (VA), A is a bond or methylene. In certain embodiments, in Formula (VA), A is C3-10 cycloalkylene or heterocyclylene; each optionally substituted with one or more substituents Q. In certain embodiments, in formula (VA), A is C3-10 cycloextended alkyl optionally substituted with one or more substituents Q. In certain embodiments, in formula (VA), A is a monocyclic C 3-10 cycloalkylene optionally substituted with one or more substituents Q . In certain embodiments, in formula (VA), A is a heterocyclylene optionally substituted with one or more substituents Q. In certain embodiments, in formula (VA), A is a monocyclic heterocyclyl group optionally substituted with one or more substituents Q. In certain embodiments, in formula (VA), A is a 5- or 6-membered heterocyclyl group, each optionally substituted with one or more substituents Q. In certain embodiments, in formula (VA), A is piperidinediyl or piperidinediyl, each optionally substituted with one or more substituents Q. In certain embodiments, in formula (VA), A is piperidine-1,4-diyl or piperidine-1,4-diyl, each optionally substituted with one or more substituents Q. In certain embodiments, in formula (VA), A is C6-14 aryl or heteroaryl, each optionally substituted with one or more substituents Q, Q. In certain embodiments, in formula (VA), A is C6-14 arylidene optionally substituted with one or more substituents Q. In certain embodiments, in formula (VA), A is phenylene optionally substituted with one or more substituents Q. In certain embodiments, in formula (VA), A is benzene-1,3-diyl or benzene-1,4-diyl, each optionally substituted with one or more substituents Q. In certain embodiments, in formula (VA), A is benzene-1,3-diyl optionally substituted with one or more substituents Q. In certain embodiments, in formula (VA), A is benzene-1,4-diyl optionally substituted with one or more substituents Q. In certain embodiments, in formula (VA), A is heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, in formula (VA), A is a monocyclic heteroarylidene optionally substituted with one or more substituents Q. In certain embodiments, in formula (VA), A is a 5- or 6-membered heteroaryl group, each optionally substituted with one or more substituents Q.
在一個實施例中，在式(VA)中， A為鍵、C 1-6伸烷基、C 6-14伸芳基、伸雜芳基或伸雜環基； X及Y各自獨立地為N或CR 2b，其中R 2b為氫、氘或鹵基； R 1及R 3各自獨立地為氫、氘、鹵基或C 1-6烷基； R 4B為C 6-14芳基或雜芳基； R 2a為氫、氘、C 1-6烷基、-C(O)OR 1a、-OR 1a或-NR 1bR 1c，其中各R 1a、R 1b及R 1c如本文所定義； 各R 2c獨立地為氘、鹵基、側氧基或C 1-6烷基； b為1、2或3之整數；及 c為0、1、2、3、4、5或6之整數； 其中各烷基、伸烷基、芳基、伸芳基、雜芳基、伸雜芳基及伸雜環基視情況經一或多個取代基Q取代。 In one embodiment, in formula (VA), A is a bond, C 1-6 alkylene, C 6-14 aryl, heteroaryl or heterocyclylene; X and Y are each independently N or CR 2b , wherein R 2b is hydrogen, deuterium or halo; R 1 and R 3 are each independently hydrogen, deuterium, halo or C 1-6 alkyl; R 4B is C 6-14 aryl or hetero Aryl; R 2a is hydrogen, deuterium, C 1-6 alkyl, -C(O)OR 1a , -OR 1a , or -NR 1b R 1c , wherein each R 1a , R 1b and R 1c are as defined herein; Each R 2c is independently deuterium, halo, pendant oxy, or C 1-6 alkyl; b is an integer of 1, 2, or 3; and c is an integer of 0, 1, 2, 3, 4, 5, or 6 ; wherein each alkyl, alkylene, aryl, aryl, heteroaryl, heteroaryl and heterocyclylene is optionally substituted with one or more substituents Q.
在另一實施例中，在式(VA)中， A為鍵、C 1-6伸烷基、伸苯基、單環伸雜芳基或單環伸雜環基； X及Y各自獨立地為N或CR 2b，其中R 2b為氫、氘或鹵基； R 1及R 3各自獨立地為氫、氘、鹵基或C 1-6烷基； R 4B為苯基或單環雜芳基； R 2a為氫、氘、C 1-6烷基、-C(O)OH、-OH或-NH 2； 各R 2c獨立地為氘、鹵基、側氧基或C 1-6烷基； b為1、2或3之整數；及 c為0、1、2、3或4之整數； 其中各烷基、伸烷基、苯基、伸苯基、雜芳基、伸雜芳基及伸雜環基視情況經一或多個取代基Q取代。 In another embodiment, in formula (VA), A is a bond, C 1-6 alkylene, phenylene, monocycloheteroarylidene, or monocycloheterocyclylene; X and Y are each independently is N or CR 2b , wherein R 2b is hydrogen, deuterium or halo; R 1 and R 3 are each independently hydrogen, deuterium, halo or C 1-6 alkyl; R 4B is phenyl or monocyclic heteroaryl R 2a is hydrogen, deuterium, C 1-6 alkyl, -C(O)OH, -OH or -NH 2 ; each R 2c is independently deuterium, halo, pendant oxy or C 1-6 alkane b is an integer of 1, 2, or 3; and c is an integer of 0, 1, 2, 3, or 4; wherein each alkyl, alkylene, phenyl, phenylene, heteroaryl, heteroaryl and heterocyclylene are optionally substituted with one or more substituents Q.
在又另一實施例中，在式(VA)中， A為鍵、C 1-6伸烷基、伸苯基、5員或6員伸雜芳基或5員或6員伸雜環基； X及Y各自獨立地為N或CH； R 1及R 3各自獨立地為氫、氘、鹵基或C 1-6烷基； R 4B為苯基或5員或6員雜芳基； R 2a為氫、氘、C 1-6烷基、-C(O)OH、-OH或-NH 2； 各R 2c獨立地為氘、鹵基、側氧基或C 1-6烷基； b為1、2或3之整數；及 c為0、1或2之整數； 其中各烷基、伸烷基、苯基、伸苯基、雜芳基、伸雜芳基及伸雜環基視情況經一或多個取代基Q取代。 In yet another embodiment, in formula (VA), A is a bond, C 1-6 alkylene, phenylene, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclyl X and Y are each independently N or CH; R 1 and R 3 are each independently hydrogen, deuterium, halo or C 1-6 alkyl; R 4B is phenyl or 5-membered or 6-membered heteroaryl; R 2a is hydrogen, deuterium, C 1-6 alkyl, -C(O)OH, -OH or -NH 2 ; each R 2c is independently deuterium, halo, pendant oxy or C 1-6 alkyl; b is an integer of 1, 2, or 3; and c is an integer of 0, 1, or 2; wherein each alkyl, alkylene, phenyl, phenylene, heteroaryl, heteroaryl, and heterocyclylene Optionally substituted with one or more substituents Q.
在再一實施例中，在式(VA)中， A為鍵、亞甲基、苯-1,3-二基、苯-1,4-二基、哌𠯤-1,4-二基或哌啶-1,4-二基； X及Y各自獨立地為N或CH； R 1為氫； R 3為甲基； R 4B為苯基； R 2a為甲基或2-羥基乙基； b為1或2之整數；及 c為0之整數。 In yet another embodiment, in formula (VA), A is a bond, methylene, benzene-1,3-diyl, benzene-1,4-diyl, piperazine-1,4-diyl or Piperidine-1,4-diyl; X and Y are each independently N or CH; R 1 is hydrogen; R 3 is methyl; R 4B is phenyl; R 2a is methyl or 2-hydroxyethyl; b is an integer of 1 or 2; and c is an integer of 0.
在又另一實施例中，本文提供一種式(VIA)化合物：
在又另一實施例中，本文提供一種式(VIIA)化合物：
在又另一實施例中，本文提供一種式(VIIIA)化合物：
在一個實施例中，在式(VIA)、(VIIA)或(VIIIA)中， X及Y各自獨立地為N或CR 2b，其中R 2b為氫、氘或鹵基； R 1及R 3各自獨立地為氫、氘、鹵基或C 1-6烷基； R 4B為C 6-14芳基或雜芳基； 各R 5獨立地為氘、鹵基或C 1-6烷基； R 2a為氫、氘、C 1-6烷基、-C(O)OR 1a、-OR 1a或-NR 1bR 1c，其中各R 1a、R 1b及R 1c如本文所定義； 各R 2c獨立地為氘、鹵基、側氧基或C 1-6烷基； b為1、2或3之整數； c為0、1、2、3、4、5或6之整數；及 d為0、1、2、3或4之整數； 其中各烷基、芳基及雜芳基視情況經一或多個取代基Q取代。 In one embodiment, in formula (VIA), (VIIA) or (VIIIA), X and Y are each independently N or CR 2b , wherein R 2b is hydrogen, deuterium or halo; R 1 and R 3 are each independently hydrogen, deuterium, halo or C 1-6 alkyl; R 4B is C 6-14 aryl or heteroaryl; each R 5 is independently deuterium, halo or C 1-6 alkyl; R 2a is hydrogen, deuterium, C 1-6 alkyl, -C(O)OR 1a , -OR 1a or -NR 1b R 1c , wherein each R 1a , R 1b and R 1c are as defined herein; each R 2c is independent is deuterium, halo, pendant oxy, or C1-6 alkyl; b is an integer of 1, 2, or 3; c is an integer of 0, 1, 2, 3, 4, 5, or 6; and d is 0 , an integer of 1, 2, 3, or 4; wherein each alkyl, aryl, and heteroaryl group is optionally substituted with one or more substituents Q.
在另一實施例中，在式(VIA)、(VIIA)或(VIIIA)中， X及Y各自獨立地為N或CR 2b，其中R 2b為氫、氘或鹵基； R 1及R 3各自獨立地為氫、氘、鹵基或C 1-6烷基； R 4B為苯基或單環雜芳基； 各R 5獨立地為氘、鹵基或C 1-6烷基； R 2a為氫、氘、C 1-6烷基、-C(O)OH、-OH或-NH 2； 各R 2c獨立地為氘、鹵基、側氧基或C 1-6烷基； b為1、2或3之整數； c為0、1、2、3或4之整數；及 d為0、1或2之整數； 其中各烷基、苯基及雜芳基視情況經一或多個取代基Q取代。 In another embodiment, in formula (VIA), (VIIA) or (VIIIA), X and Y are each independently N or CR 2b , wherein R 2b is hydrogen, deuterium or halo; R 1 and R 3 each independently hydrogen, deuterium, halo or C 1-6 alkyl; R 4B is phenyl or monocyclic heteroaryl; each R 5 is independently deuterium, halo or C 1-6 alkyl; R 2a is hydrogen, deuterium, C 1-6 alkyl, -C(O)OH, -OH or -NH 2 ; each R 2c is independently deuterium, halo, pendant oxy or C 1-6 alkyl; b is an integer of 1, 2, or 3; c is an integer of 0, 1, 2, 3, or 4; and d is an integer of 0, 1, or 2; wherein each alkyl, phenyl, and heteroaryl group is optionally modified by one or more A substituent Q is substituted.
在又另一實施例中，在式(VIA)、(VIIA)或(VIIIA)中， X及Y各自獨立地為N或CH； R 1及R 3各自獨立地為氫、氘、鹵基或C 1-6烷基； R 4B為苯基或5員或6員雜芳基； 各R 5獨立地為氘、鹵基或C 1-6烷基； R 2a為氫、氘、C 1-6烷基、-C(O)OH、-OH或-NH 2； 各R 2c獨立地為氘、鹵基、側氧基或C 1-6烷基； b為1、2或3之整數； c為0、1或2之整數；及 d為0、1或2之整數； 其中各烷基、苯基及雜芳基視情況經一或多個取代基Q取代。 In yet another embodiment, in formula (VIA), (VIIA) or (VIIIA), X and Y are each independently N or CH; R 1 and R 3 are each independently hydrogen, deuterium, halo or C 1-6 alkyl; R 4B is phenyl or 5- or 6-membered heteroaryl; each R 5 is independently deuterium, halo or C 1-6 alkyl; R 2a is hydrogen, deuterium, C 1- 6 alkyl, -C(O)OH, -OH or -NH 2 ; each R 2c is independently deuterium, halo, pendant oxy or C 1-6 alkyl; b is an integer of 1, 2 or 3; c is an integer of 0, 1 or 2; and d is an integer of 0, 1 or 2; wherein each alkyl, phenyl and heteroaryl is optionally substituted with one or more substituents Q.
在再一實施例中，在式(VIA)、(VIIA)或(VIIIA)中， X及Y各自獨立地為N或CH； R 1為氫； R 3為甲基； R 4B為苯基； R 2a為甲基或2-羥基乙基； b為1或2之整數；及 c及d各自為0之整數。 In yet another embodiment, in formula (VIA), (VIIA) or (VIIIA), X and Y are each independently N or CH; R 1 is hydrogen; R 3 is methyl; R 4B is phenyl; R 2a is methyl or 2-hydroxyethyl; b is an integer of 1 or 2; and c and d are each an integer of 0.
在又另一實施例中，本文提供一種式(IXA)化合物：
在又另一實施例中，本文提供一種式(XA)化合物：
在再一實施例中，本文提供一種式(XIA)化合物：
在一個實施例中，在式(IXA)、(XA)或(XIA)中， R 1及R 3各自獨立地為氫、氘、鹵基或C 1-6烷基； 各R 5獨立地為氘、鹵基或C 1-6烷基； R 4B為C 6-14芳基或雜芳基； R 2a為C 1-6烷基； 各R 2c獨立地為氘、鹵基、側氧基或C 1-6烷基； c為0、1、2、3、4、5或6之整數；及 d為0、1、2、3或4之整數； 其中各烷基、芳基及雜芳基視情況經一或多個取代基Q取代。 In one embodiment, in formula (IXA), (XA) or (XIA), R 1 and R 3 are each independently hydrogen, deuterium, halo or C 1-6 alkyl; each R 5 is independently deuterium, halo or C 1-6 alkyl; R 4B is C 6-14 aryl or heteroaryl; R 2a is C 1-6 alkyl; each R 2c is independently deuterium, halo, pendant oxy or C 1-6 alkyl; c is an integer of 0, 1, 2, 3, 4, 5 or 6; and d is an integer of 0, 1, 2, 3 or 4; wherein each alkyl, aryl and hetero Aryl is optionally substituted with one or more substituents Q.
在另一實施例中，在式(IXA)、(XA)或(XIA)中， R 1及R 3各自獨立地為氫、氘、鹵基或C 1-6烷基； 各R 5獨立地為氘、鹵基或C 1-6烷基； R 2a為C 1-6烷基； R 4B為苯基或單環雜芳基； 各R 2c獨立地為氘、鹵基、側氧基或C 1-6烷基； c為0、1、2、3或4之整數；及 d為0、1或2之整數；及 其中各烷基、苯基及雜芳基視情況經一或多個取代基Q取代。 In another embodiment, in formula (IXA), (XA) or (XIA), R 1 and R 3 are each independently hydrogen, deuterium, halo or C 1-6 alkyl; each R 5 is independently is deuterium, halo or C 1-6 alkyl; R 2a is C 1-6 alkyl; R 4B is phenyl or monocyclic heteroaryl; each R 2c is independently deuterium, halo, pendant oxy or C 1-6 alkyl; c is an integer of 0, 1, 2, 3, or 4; and d is an integer of 0, 1, or 2; A substituent Q is substituted.
在又另一實施例中，在式(IXA)、(XA)或(XIA)中， R 1及R 3各自獨立地為氫、氘、鹵基或C 1-6烷基； 各R 6獨立地為氘、鹵基或C 1-6烷基； R 4B為苯基或5員或6員雜芳基； R 2a為C 1-6烷基； 各R 2c獨立地為氘、鹵基、側氧基或C 1-6烷基； c為0、1或2之整數；及 d為0、1或2之整數； 其中各烷基、苯基及雜芳基視情況經一或多個取代基Q取代。 In yet another embodiment, in formula (IXA), (XA) or (XIA), R 1 and R 3 are each independently hydrogen, deuterium, halo or C 1-6 alkyl; each R 6 is independently Deuterium is deuterium, halo or C 1-6 alkyl; R 4B is phenyl or 5-membered or 6-membered heteroaryl; R 2a is C 1-6 alkyl; each R 2c is independently deuterium, halo, pendant oxy or C 1-6 alkyl; c is an integer of 0, 1, or 2; and d is an integer of 0, 1, or 2; wherein each alkyl, phenyl, and heteroaryl is optionally modified by one or more Substituent Q is substituted.
在再一實施例中，在式(IXA)、(XA)或(XIA)中， R 1為氫； R 3為甲基； R 4B為苯基； R 2a為甲基或2-羥基乙基；及 c及d各自為0之整數。 In yet another embodiment, in formula (IXA), (XA) or (XIA), R 1 is hydrogen; R 3 is methyl; R 4B is phenyl; R 2a is methyl or 2-hydroxyethyl ; and c and d are each an integer of 0.
在一個實施例中，本文提供一種KRAS蛋白降解劑，其包含KRAS結合部分及E3泛蛋白連接酶結合部分(R
E)。在另一實施例中，本文提供一種KRAS蛋白降解劑，其包含KRAS結合部分、E3泛蛋白連接酶結合部分(R
E)及連接子(L)，其中KRAS結合部分及E3泛蛋白連接酶結合部分(R
E)經由連接子(L)連接在一起。在一個實施例中，KRAS結合部分具有
在某些實施例中，本文提供之KRAS蛋白降解劑為式(I)至(XI)中之任一者之化合物或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體；或其醫藥學上可接受之鹽、溶劑合物、水合物或前藥；其中KRAS結合部分為經由連接子(L)與E3泛蛋白連接酶結合部分(R E)連接之結構部分。在某些實施例中，本文提供之KRAS蛋白降解劑為式(IA)至(XIA)中之任一者之化合物或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體；或其醫藥學上可接受之鹽、溶劑合物、水合物或前藥；其中KRAS結合部分為經由連接子(L)與E3泛蛋白連接酶結合部分(R E)連接之結構部分。 In certain embodiments, the KRAS protein degrading agent provided herein is a compound of any one of formulae (I) to (XI) or a mirror isomer, a mixture of enantiomers, a non-spiroisomer, A mixture of two or more diastereoisomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant; or a pharmaceutically acceptable salt, solvate, A hydrate or prodrug; wherein the KRAS binding moiety is a moiety linked to an E3 ubiquitin ligase binding moiety (R E ) via a linker (L). In certain embodiments, the KRAS protein degrading agent provided herein is a compound of any one of formulae (IA) to (XIA) or a mirror isomer, a mixture of enantiomers, a non-spiroisomer, A mixture of two or more diastereoisomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant; or a pharmaceutically acceptable salt, solvate, A hydrate or prodrug; wherein the KRAS binding moiety is a moiety linked to an E3 ubiquitin ligase binding moiety (R E ) via a linker (L).
在一個實施例中，KRAS結合部分為具有以下結構之KRAS抑制劑之部分：
在一個實施例中，本文提供之化合物為以下之化合物：
在另一實施例中，本文提供之化合物為以下之化合物：
在又另一實施例中，本文提供之化合物為以下之化合物：
在一個實施例中，本文提供之化合物為以下之化合物：
在另一實施例中，本文提供之化合物為以下之化合物：
在又另一實施例中，本文提供之化合物為以下之化合物：
在某些實施例中，R E為塞勒布隆(CRBN) E3配體、細胞凋亡蛋白抑制劑(IAP) E3配體、小鼠雙微體2同源物(MDM2) E3配體或凡希培-林道(von Hippel-Lindau；VHL) E3配體之部分。 In certain embodiments, R E is a celeblon (CRBN) E3 ligand, an inhibitor of apoptosis protein (IAP) E3 ligand, a mouse double microbody 2 homolog (MDM2) E3 ligand, or Part of the von Hippel-Lindau (VHL) E3 ligand.
在某些實施例中，R E為CRBN E3配體之部分。 In certain embodiments, R E is part of a CRBN E3 ligand.
在某些實施例中，R
E為具有式(EC-I)之結構之部分：
在某些實施例中，R
E為具有式(EC-II)之結構之部分：
在某些實施例中，R
E為具有式(EC-III)之結構之部分：
在某些實施例中，R
E為具有式(EC-IV)之結構之部分：
在某些實施例中，R
E為具有式(EC-V)之結構之部分：
在某些實施例中，R
E為具有式(EC-VI)之結構之部分：
在某些實施例中，R
E為具有式(EC-VII)之結構之部分：
在某些實施例中，R
E為具有式(EC-VIII)之結構之部分：
在某些實施例中，R
E為具有式(EC-IX)之結構之部分：
在某些實施例中，R
E為具有式(EC-X)之結構之部分：
在某些實施例中，R
E為具有式(EC-XI)之結構之部分：
在某些實施例中，R
E為具有式(EC-XII)之結構之部分：
在某些實施例中，R
E為具有式(EC-XIII)之結構之部分：
在某些實施例中，R
E為具有式(EC-XIV)之結構之部分：
在某些實施例中，R
E為具有式(EC-XV)之結構之部分：
在某些實施例中，R
E為具有式(EC-XVI)之結構之部分：
在某些實施例中，R
E為具有式(EC-XVII)之結構之部分：
在某些實施例中，R
E為具有式(EC-XVIII)之結構之部分：
在某些實施例中，R
E為具有式(EC-XIX)之結構之部分：
在某些實施例中，R
E為具有式(EC-XX)之結構之部分：
在某些實施例中，R
E為具有式(EC-XXI)之結構之部分：
在某些實施例中，R
E為具有式(EC-XXII)之結構之部分：
在某些實施例中，R
E為具有式(EC-XXIII)之結構之部分：
在某些實施例中，R
E為具有式(EC-XXIV)之結構之部分：
在某些實施例中，R
E為具有式(EC-XXV)之結構之部分：
在某些實施例中，R
E為具有式(EC-XXVI)之結構之部分：
在某些實施例中，R
E為具有式(EC-XXVII)之結構之部分：
在某些實施例中，R E為以下中揭示之E3泛蛋白連接酶結合子之部分：US 9,938,302 B2、US 10,336,771 B2、US 10,406,165 B2、US 10,513,515 B2、US 2019/0322682 A1、US 2020/0000814 A1、US 2020/0148663 A1、US 2020/0369679 A1及WO 2019/173224 A1；其中之每一者之揭示內容以全文引用之方式併入本文中。在某些實施例中，R E為US 9,938,302 B2中揭示之E3泛蛋白連接酶結合子之部分，在一個實施例中，其中第108至137行中揭示之化合物1至57中之一者，其以全文引用之方式併入本文中。在某些實施例中，R E為US 10,336,771 B2中揭示之E3泛蛋白連接酶結合子之部分，在一個實施例中，其中第113至161及169至172行中揭示之化合物1至57及64至66中之一者，其以全文引用之方式併入本文中。在某些實施例中，R E為US 10,406,165 B2中揭示之E3泛蛋白連接酶結合子之部分，在一個實施例中，其中第40至64行中揭示之化合物1至27中之一者，其以全文引用之方式併入本文中。在某些實施例中，R E為US 10,513,515 B2中揭示之E3泛蛋白連接酶結合子之部分，在一個實施例中，其中第97至104、106至112、114至117、122、126及132行中揭示之化合物1至5、7至12、14至16、19、23及27中之一者，其以全文引用之方式併入本文中。在某些實施例中，R E為US 2019/0322682 A1中揭示之E3泛蛋白連接酶結合子之部分，在一個實施例中，其中第31至36頁中揭示之化合物1至15中之一者，其以全文引用之方式併入本文中。在某些實施例中，R E為US 2020/0000814 A1中揭示之E3泛蛋白連接酶結合子之部分，在一個實施例中，其中第26至41頁中揭示之化合物1至21中之一者，其以全文引用之方式併入本文中。在某些實施例中，R E為US 2020/0148663 A1中揭示之E3泛蛋白連接酶結合子之部分，在一個實施例中，其中第18至34頁中揭示之化合物1至21中之一者，其以全文引用之方式併入本文中。在某些實施例中，R E為WO 2019/173224 A1中揭示之E3泛蛋白連接酶結合子之部分，在一個實施例中，其中第62至65頁中揭示之化合物1至3以及其中第78頁中揭示之化合物中之一者，其以全文引用之方式併入本文中。在某些實施例中，R E為US 2020/0369679 A1中揭示之E3泛蛋白連接酶結合子之部分，在一個實施例中，其中第50至101頁中揭示之化合物I-1至I-106及II-1至II-164中之一者，其以全文引用之方式併入本文中。 In certain embodiments, RE is part of an E3 ubiquitin ligase binder disclosed in: US 9,938,302 B2, US 10,336,771 B2, US 10,406,165 B2, US 10,513,515 B2, US 2019/0322682 A1, US 2020/0000814 A1, US 2020/0148663 A1, US 2020/0369679 A1, and WO 2019/173224 A1; the disclosures of each of these are incorporated herein by reference in their entirety. In certain embodiments, RE is part of the E3 ubiquitin ligase binder disclosed in US 9,938,302 B2, in one embodiment, wherein one of compounds 1-57 disclosed in lines 108-137, It is incorporated herein by reference in its entirety. In certain embodiments, RE is part of the E3 ubiquitin ligase binder disclosed in US 10,336,771 B2, in one embodiment, wherein compounds 1-57 and One of 64 to 66, which is incorporated herein by reference in its entirety. In certain embodiments, RE is part of the E3 ubiquitin ligase binder disclosed in US 10,406,165 B2, in one embodiment, wherein one of compounds 1-27 disclosed in lines 40-64, It is incorporated herein by reference in its entirety. In certain embodiments, R E is part of the E3 ubiquitin ligase binder disclosed in US 10,513,515 B2, in one embodiment, wherein 97-104, 106-112, 114-117, 122, 126 and One of Compounds 1 to 5, 7 to 12, 14 to 16, 19, 23, and 27 disclosed in line 132, which is incorporated herein by reference in its entirety. In certain embodiments, RE is part of the E3 ubiquitin ligase binder disclosed in US 2019/0322682 A1, and in one embodiment, one of compounds 1-15 disclosed on pages 31-36 , which is incorporated herein by reference in its entirety. In certain embodiments, RE is part of the E3 ubiquitin ligase binder disclosed in US 2020/0000814 A1, and in one embodiment, one of compounds 1-21 disclosed on pages 26-41 , which is incorporated herein by reference in its entirety. In certain embodiments, RE is part of the E3 ubiquitin ligase binder disclosed in US 2020/0148663 A1, in one embodiment, one of compounds 1-21 disclosed on pages 18-34 , which is incorporated herein by reference in its entirety. In certain embodiments, R E is part of the E3 ubiquitin ligase binder disclosed in WO 2019/173224 A1, in one embodiment, Compounds 1 to 3 disclosed on pages 62-65 and One of the compounds disclosed on page 78, which is incorporated herein by reference in its entirety. In certain embodiments, RE is part of the E3 ubiquitin ligase binder disclosed in US 2020/0369679 A1, in one embodiment, wherein compounds I-1 to I- disclosed in pages 50-101 106 and one of II-1 to II-164, which are incorporated herein by reference in their entirety.
在某些實施例中，R E為US 2020/0199073 A1中揭示之E3泛蛋白連接酶結合子之部分，其揭示內容以全文引用之方式併入本文中。在某些實施例中，R E為美國申請案第US 2020/0199073 A1號中揭示之E3泛蛋白連接酶結合子之部分，在一個實施例中，其中第118至193頁中揭示之化合物1至291中之一者，其以全文引用之方式併入本文中。 In certain embodiments, RE is part of the E3 ubiquitin ligase binder disclosed in US 2020/0199073 Al, the disclosure of which is incorporated herein by reference in its entirety. In certain embodiments, R E is part of the E3 ubiquitin ligase binder disclosed in US Application No. US 2020/0199073 A1, in one embodiment, Compound 1 disclosed on pages 118-193 to one of 291, which are incorporated herein by reference in their entirety.
在某些實施例中，在式(EC-I)至(EC-XXVII)中之任一者中， A E為鍵、-O-、-N(R 1b)-、C 2-6伸炔基、伸雜環基、C 1-6伸雜烷基-C 6-14伸芳基或C 2-6伸炔基-伸雜環基，其中各伸雜烷基、伸炔基、伸芳基及伸雜環基視情況經一或多個，在一個實施例中，一個、兩個、三個或四個取代基Q取代； Z (若存在)為-CH 2-或-C(O)-； m為0、1或2之整數； R E1及R E2各自為氫；及 R E5(若存在)獨立地為氫或氟。 In certain embodiments, in any one of formulae (EC-I) to (EC-XXVII), AE is a bond, -O-, -N(R 1b )-, C 2-6 alkyne base, heterocyclylene, C 1-6 heteroalkylene-C 6-14 aryl or C 2-6 alkynylene-heterocyclylene, wherein each heteroalkyl, alkynylene, aryl radical and heterocyclylene are optionally substituted with one or more, in one embodiment, one, two, three or four substituents Q; Z (if present) is -CH2- or -C(O )-; m is an integer of 0, 1, or 2; R E1 and R E2 are each hydrogen; and R E5 (if present) is independently hydrogen or fluorine.
在某些實施例中，在式(EC-I)至(EC-XXVII)中之任一者中， A E為鍵、-O-、-NH-、乙炔二基、哌啶二基、哌𠯤二基、(苯二基)氧基甲烷二基或(哌啶二基)乙炔二基； Z (若存在)為-CH 2-或-C(O)-； m為0、1或2之整數； R E1及R E2各自為氫；及 R E5(若存在)獨立地為氫或氟。 In certain embodiments, in any one of formulae (EC-I) to (EC-XXVII), AE is a bond, -O-, -NH-, acetylene diyl, piperidine diyl, piperidine 𠯤diyl, (phenylenediyl)oxymethanediyl or (piperidinediyl)acetylenediyl; Z (if present) is -CH 2 - or -C(O)-; m is 0, 1 or 2 R E1 and R E2 are each hydrogen; and R E5 , if present, are independently hydrogen or fluorine.
在某些實施例中，在式(EC-I)至(EC-XXVII)中之任一者中， A E為鍵、-NH-、哌啶-1,3-二基、哌啶-1,4-二基、哌𠯤-1,4-二基、(苯-1,4-二基)氧基甲烷二基或(哌啶-1,4-二基)乙炔二基； Z (若存在)為-CH 2-或-C(O)-； m為0、1或2之整數； R E1及R E2各自為氫；及 R E5(若存在)獨立地為氫或氟。 In certain embodiments, in any of formulae (EC-I) to (EC-XXVII), AE is a bond, -NH-, piperidine-1,3-diyl, piperidine-1 ,4-diyl, piperidine-1,4-diyl, (benzene-1,4-diyl)oxymethanediyl or (piperidine-1,4-diyl)ethynediyl; Z (if present) is -CH2- or -C(O)-; m is an integer of 0, 1, or 2; R E1 and R E2 are each hydrogen; and R E5 , if present, is independently hydrogen or fluorine.
在一個實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式(EC-I)之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式(EC-II)之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式(EC-III)之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式(EC-IV)之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式(EC-V)之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式(EC-VI)之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式(EC-VII)之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式(EC-VIII)之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式(EC-IX)之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式(EC-X)之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式(EC-XI)之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式(EC-XII)之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式(EC-XIII)之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在再一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式(EC-XIV)之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。 In one embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb), and (XIV), R E is having the formula ( Part of the structure of EC-I) or its enantiomer, mixture of enantiomers, non-enantiomer, mixture of two or more non-enantiomers, tautomer, two or more Mixtures or isotopic variants of more tautomers. In another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb), and (XIV), R E is of formula Part of the structure of (EC-II) or its enantiomer, mixture of enantiomers, non-enantiomer, mixture of two or more non-enantiomers, tautomer, two mixtures or isotopic variants of or more tautomers. In yet another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb) and (XIV), R E is having Portions of the structures of formula (EC-III) or enantiomers, mixtures of enantiomers, non-spiroisomers, mixtures of two or more non-spiroisomers, tautomers, two A mixture or isotopic variant of one or more tautomers. In yet another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb) and (XIV), R E is having Portions of structures of formula (EC-IV) or enantiomers, mixtures of enantiomers, non-spiroisomers, mixtures of two or more non-spiroisomers, tautomers, two A mixture or isotopic variant of one or more tautomers. In yet another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb) and (XIV), R E is having Portions of structures of formula (EC-V) or enantiomers, mixtures of enantiomers, non-spiroisomers, mixtures of two or more non-spiroisomers, tautomers, two A mixture or isotopic variant of one or more tautomers. In yet another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb) and (XIV), R E is having Portions of structures of formula (EC-VI) or enantiomers, mixtures of enantiomers, non-spiroisomers, mixtures of two or more non-spiroisomers, tautomers, two A mixture or isotopic variant of one or more tautomers. In yet another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb) and (XIV), R E is having Portions of the structures of formula (EC-VII) or enantiomers, mixtures of enantiomers, non-spiroisomers, mixtures of two or more non-spiroisomers, tautomers, two A mixture or isotopic variant of one or more tautomers. In yet another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb) and (XIV), R E is having Portions of the structures of formula (EC-VIII) or enantiomers, mixtures of enantiomers, non-spiroisomers, mixtures of two or more non-spiroisomers, tautomers, two A mixture or isotopic variant of one or more tautomers. In yet another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb) and (XIV), R E is having A portion of a structure of formula (EC-IX) or its enantiomers, mixtures of enantiomers, non-spiroisomers, mixtures of two or more non-spiroisomers, tautomers, two A mixture or isotopic variant of one or more tautomers. In yet another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb) and (XIV), R E is having Portions of structures of formula (EC-X) or enantiomers, mixtures of enantiomers, non-spiroisomers, mixtures of two or more non-spiroisomers, tautomers, two A mixture or isotopic variant of one or more tautomers. In yet another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb) and (XIV), R E is having Portions of structures of formula (EC-XI) or enantiomers, mixtures of enantiomers, non-spiroisomers, mixtures of two or more non-spiroisomers, tautomers, two A mixture or isotopic variant of one or more tautomers. In yet another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb) and (XIV), R E is having Portions of the structures of formula (EC-XII) or enantiomers, mixtures of enantiomers, non-spiroisomers, mixtures of two or more non-spiroisomers, tautomers, two A mixture or isotopic variant of one or more tautomers. In yet another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb) and (XIV), R E is having Portions of the structures of formula (EC-XIII) or enantiomers, mixtures of enantiomers, non-spiroisomers, mixtures of two or more non-spiroisomers, tautomers, two A mixture or isotopic variant of one or more tautomers. In yet another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb) and (XIV), R E is of formula A portion of the structure of (EC-XIV) or its enantiomer, mixture of enantiomers, non-enantiomer, mixture of two or more non-enantiomers, tautomer, two mixtures or isotopic variants of or more tautomers.
在一個實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式(EC-XV)之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式(EC-XVI)之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式(EC-XVII)之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式(EC-XVIII)之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式(EC-XIX)之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式(EC-XX)之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式(EC-XXI)之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式(EC-XXII)之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式(EC-XXIII)之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式(EC-XXIV)之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式(EC-XXV)之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式(EC-XXVI)之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在再一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式(EC-XXVII)之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。 In one embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb), and (XIV), R E is having the formula ( Part of the structure of EC-XV) or its enantiomer, mixture of enantiomers, non-enantiomer, mixture of two or more non-enantiomers, tautomer, two or more Mixtures or isotopic variants of more tautomers. In another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb), and (XIV), R E is of formula Part of the structure of (EC-XVI) or enantiomers, mixtures of enantiomers, non-enantiomers, mixtures of two or more non-enantiomers, tautomers, two mixtures or isotopic variants of or more tautomers. In yet another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb) and (XIV), R E is having Portions of structures of formula (EC-XVII) or enantiomers, mixtures of enantiomers, non-spiroisomers, mixtures of two or more non-spiroisomers, tautomers, two A mixture or isotopic variant of one or more tautomers. In yet another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb) and (XIV), R E is having Part of the structure of formula (EC-XVIII) or enantiomers, mixtures of enantiomers, non-spiroisomers, mixtures of two or more non-spiroisomers, tautomers, two A mixture or isotopic variant of one or more tautomers. In yet another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb) and (XIV), R E is having Portions of structures of formula (EC-XIX) or enantiomers, mixtures of enantiomers, non-spiroisomers, mixtures of two or more non-spiroisomers, tautomers, two A mixture or isotopic variant of one or more tautomers. In yet another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb) and (XIV), R E is having Portions of structures of formula (EC-XX) or enantiomers, mixtures of enantiomers, non-spiroisomers, mixtures of two or more non-spiroisomers, tautomers, two A mixture or isotopic variant of one or more tautomers. In yet another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb) and (XIV), R E is having Portions of structures of formula (EC-XXI) or enantiomers, mixtures of enantiomers, non-spiroisomers, mixtures of two or more non-spiroisomers, tautomers, two A mixture or isotopic variant of one or more tautomers. In yet another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb) and (XIV), R E is having Portions of structures of formula (EC-XXII) or enantiomers, mixtures of enantiomers, non-spiroisomers, mixtures of two or more non-spiroisomers, tautomers, two A mixture or isotopic variant of one or more tautomers. In yet another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb) and (XIV), R E is having Portions of structures of formula (EC-XXIII) or enantiomers, mixtures of enantiomers, non-spiroisomers, mixtures of two or more non-spiroisomers, tautomers, two A mixture or isotopic variant of one or more tautomers. In yet another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb) and (XIV), R E is having Portions of structures of formula (EC-XXIV) or enantiomers, mixtures of enantiomers, non-spiroisomers, mixtures of two or more non-spiroisomers, tautomers, two A mixture or isotopic variant of one or more tautomers. In yet another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb) and (XIV), R E is having Portions of structures of formula (EC-XXV) or enantiomers, mixtures of enantiomers, non-spiroisomers, mixtures of two or more non-spiroisomers, tautomers, two A mixture or isotopic variant of one or more tautomers. In yet another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb) and (XIV), R E is having Portions of structures of formula (EC-XXVI) or enantiomers, mixtures of enantiomers, non-spiroisomers, mixtures of two or more non-spiroisomers, tautomers, two A mixture or isotopic variant of one or more tautomers. In yet another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb) and (XIV), R E is of formula Portion of the structure of (EC-XXVII) or enantiomers, mixtures of enantiomers, non-enantiomers, mixtures of two or more non-enantiomers, tautomers, two mixtures or isotopic variants of or more tautomers.
在一個實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式(EC-I)之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在另一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式(EC-II)之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式(EC-III)之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式(EC-IV)之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式(EC-V)之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式(EC-VI)之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式(EC-VII)之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式(EC-VIII)之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式(EC-IX)之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式(EC-X)之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式(EC-XI)之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式(EC-XII)之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式(EC-XIII)之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在再一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式(EC-XIV)之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。 In one embodiment, in the compound of any one of formulae (IA) to (XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is having the formula ( Part of the structure of EC-I) or its enantiomer, mixture of enantiomers, non-enantiomer, mixture of two or more non-enantiomers, tautomer, two or more Mixtures or isotopic variants of more tautomers. In another embodiment, in a compound of any one of formulae (IA)-(XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is of formula Part of the structure of (EC-II) or its enantiomer, mixture of enantiomers, non-enantiomer, mixture of two or more non-enantiomers, tautomer, two mixtures or isotopic variants of or more tautomers. In yet another embodiment, in the compound of any one of formulae (IA)-(XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is having Portions of the structures of formula (EC-III) or enantiomers, mixtures of enantiomers, non-spiroisomers, mixtures of two or more non-spiroisomers, tautomers, two A mixture or isotopic variant of one or more tautomers. In yet another embodiment, in the compound of any one of formulae (IA)-(XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is having Portions of structures of formula (EC-IV) or enantiomers, mixtures of enantiomers, non-spiroisomers, mixtures of two or more non-spiroisomers, tautomers, two A mixture or isotopic variant of one or more tautomers. In yet another embodiment, in the compound of any one of formulae (IA)-(XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is having Portions of structures of formula (EC-V) or enantiomers, mixtures of enantiomers, non-spiroisomers, mixtures of two or more non-spiroisomers, tautomers, two A mixture or isotopic variant of one or more tautomers. In yet another embodiment, in the compound of any one of formulae (IA)-(XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is having Portions of structures of formula (EC-VI) or enantiomers, mixtures of enantiomers, non-spiroisomers, mixtures of two or more non-spiroisomers, tautomers, two A mixture or isotopic variant of one or more tautomers. In yet another embodiment, in the compound of any one of formulae (IA)-(XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is having Portions of the structures of formula (EC-VII) or enantiomers, mixtures of enantiomers, non-spiroisomers, mixtures of two or more non-spiroisomers, tautomers, two A mixture or isotopic variant of one or more tautomers. In yet another embodiment, in the compound of any one of formulae (IA)-(XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is having Portions of the structures of formula (EC-VIII) or enantiomers, mixtures of enantiomers, non-spiroisomers, mixtures of two or more non-spiroisomers, tautomers, two A mixture or isotopic variant of one or more tautomers. In yet another embodiment, in the compound of any one of formulae (IA)-(XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is having A portion of a structure of formula (EC-IX) or its enantiomers, mixtures of enantiomers, non-spiroisomers, mixtures of two or more non-spiroisomers, tautomers, two A mixture or isotopic variant of one or more tautomers. In yet another embodiment, in the compound of any one of formulae (IA)-(XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is having Portions of structures of formula (EC-X) or enantiomers, mixtures of enantiomers, non-spiroisomers, mixtures of two or more non-spiroisomers, tautomers, two A mixture or isotopic variant of one or more tautomers. In yet another embodiment, in the compound of any one of formulae (IA)-(XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is having Portions of structures of formula (EC-XI) or enantiomers, mixtures of enantiomers, non-spiroisomers, mixtures of two or more non-spiroisomers, tautomers, two A mixture or isotopic variant of one or more tautomers. In yet another embodiment, in the compound of any one of formulae (IA)-(XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is having Portions of the structures of formula (EC-XII) or enantiomers, mixtures of enantiomers, non-spiroisomers, mixtures of two or more non-spiroisomers, tautomers, two A mixture or isotopic variant of one or more tautomers. In yet another embodiment, in the compound of any one of formulae (IA)-(XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is having Portions of the structures of formula (EC-XIII) or enantiomers, mixtures of enantiomers, non-spiroisomers, mixtures of two or more non-spiroisomers, tautomers, two A mixture or isotopic variant of one or more tautomers. In yet another embodiment, in a compound of any one of formulae (IA)-(XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is of formula A portion of the structure of (EC-XIV) or its enantiomer, mixture of enantiomers, non-enantiomer, mixture of two or more non-enantiomers, tautomer, two mixtures or isotopic variants of or more tautomers.
在一個實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式(EC-XV)之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在另一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式(EC-XVI)之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式(EC-XVII)之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式(EC-XVIII)之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式(EC-XIX)之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式(EC-XX)之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式(EC-XXI)之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式(EC-XXII)之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式(EC-XXIII)之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式(EC-XXIV)之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式(EC-XXV)之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式(EC-XXVI)之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在再一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式(EC-XXVII)之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。 In one embodiment, in the compound of any one of formulae (IA) to (XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is having the formula ( Part of the structure of EC-XV) or its enantiomer, mixture of enantiomers, non-enantiomer, mixture of two or more non-enantiomers, tautomer, two or more Mixtures or isotopic variants of more tautomers. In another embodiment, in a compound of any one of formulae (IA)-(XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is of formula Part of the structure of (EC-XVI) or enantiomers, mixtures of enantiomers, non-enantiomers, mixtures of two or more non-enantiomers, tautomers, two mixtures or isotopic variants of or more tautomers. In yet another embodiment, in the compound of any one of formulae (IA)-(XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is having Portions of structures of formula (EC-XVII) or enantiomers, mixtures of enantiomers, non-spiroisomers, mixtures of two or more non-spiroisomers, tautomers, two A mixture or isotopic variant of one or more tautomers. In yet another embodiment, in the compound of any one of formulae (IA)-(XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is having Part of the structure of formula (EC-XVIII) or enantiomers, mixtures of enantiomers, non-spiroisomers, mixtures of two or more non-spiroisomers, tautomers, two A mixture or isotopic variant of one or more tautomers. In yet another embodiment, in the compound of any one of formulae (IA)-(XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is having Portions of structures of formula (EC-XIX) or enantiomers, mixtures of enantiomers, non-spiroisomers, mixtures of two or more non-spiroisomers, tautomers, two A mixture or isotopic variant of one or more tautomers. In yet another embodiment, in the compound of any one of formulae (IA)-(XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is having Portions of structures of formula (EC-XX) or enantiomers, mixtures of enantiomers, non-spiroisomers, mixtures of two or more non-spiroisomers, tautomers, two A mixture or isotopic variant of one or more tautomers. In yet another embodiment, in the compound of any one of formulae (IA)-(XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is having Portions of structures of formula (EC-XXI) or enantiomers, mixtures of enantiomers, non-spiroisomers, mixtures of two or more non-spiroisomers, tautomers, two A mixture or isotopic variant of one or more tautomers. In yet another embodiment, in the compound of any one of formulae (IA)-(XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is having Portions of structures of formula (EC-XXII) or enantiomers, mixtures of enantiomers, non-spiroisomers, mixtures of two or more non-spiroisomers, tautomers, two A mixture or isotopic variant of one or more tautomers. In yet another embodiment, in the compound of any one of formulae (IA)-(XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is having Portions of structures of formula (EC-XXIII) or enantiomers, mixtures of enantiomers, non-spiroisomers, mixtures of two or more non-spiroisomers, tautomers, two A mixture or isotopic variant of one or more tautomers. In yet another embodiment, in the compound of any one of formulae (IA)-(XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is having Portions of structures of formula (EC-XXIV) or enantiomers, mixtures of enantiomers, non-spiroisomers, mixtures of two or more non-spiroisomers, tautomers, two A mixture or isotopic variant of one or more tautomers. In yet another embodiment, in the compound of any one of formulae (IA)-(XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is having Portions of structures of formula (EC-XXV) or enantiomers, mixtures of enantiomers, non-spiroisomers, mixtures of two or more non-spiroisomers, tautomers, two A mixture or isotopic variant of one or more tautomers. In yet another embodiment, in the compound of any one of formulae (IA)-(XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is having Portions of structures of formula (EC-XXVI) or enantiomers, mixtures of enantiomers, non-spiroisomers, mixtures of two or more non-spiroisomers, tautomers, two A mixture or isotopic variant of one or more tautomers. In yet another embodiment, in a compound of any one of formulae (IA)-(XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is of formula Portion of the structure of (EC-XXVII) or enantiomers, mixtures of enantiomers, non-enantiomers, mixtures of two or more non-enantiomers, tautomers, two mixtures or isotopic variants of or more tautomers.
在某些實施例中，R
E為具有以下結構之部分：
在一個實施例中，在式 EC-1至 EC-6中之任一者中，A E為鍵、-O-、-NH-、乙炔二基、哌啶二基、哌𠯤二基、(苯二基)氧基甲烷二基或(哌啶二基)乙炔二基。在另一實施例中，在式 EC-1至 EC-6中之任一者中，A E為鍵。在另一實施例中，在式 EC-1至 EC-6中之任一者中，A E為-O-。在又另一實施例中，在式 EC-1至 EC-6中之任一者中，A E為-NH-。在又另一實施例中，在式 EC-1至 EC-6中之任一者中，A E為乙炔二基。在又另一實施例中，在式 EC-1至 EC-6中之任一者中，A E為哌啶二基。在又另一實施例中，在式 EC-1至 EC-6中之任一者中，A E為哌𠯤二基。在又另一實施例中，在式 EC-1至 EC-6中之任一者中，A E為(苯二基)氧基甲烷二基。在再一實施例中，在式 EC-1至 EC-6中之任一者中，A E為(哌啶二基)乙炔基。 In one embodiment, in any one of formulae EC-1 to EC-6 , A E is a bond, -O-, -NH-, acetylenediyl, piperidinediyl, piperidinediyl, ( phenylenediyl)oxymethanediyl or (piperidinediyl)acetylenediyl. In another embodiment, in any of formulae EC-1 to EC-6 , AE is a bond. In another embodiment, in any of formulae EC-1 to EC-6 , AE is -O-. In yet another embodiment, in any one of formulae EC-1 to EC-6 , AE is -NH-. In yet another embodiment, in any one of formulae EC-1 to EC-6 , AE is acetylenediyl. In yet another embodiment, in any one of formulae EC-1 to EC-6 , AE is piperidinediyl. In yet another embodiment, in any one of formulae EC-1 to EC-6 , AE is piperazine diyl. In yet another embodiment, in any one of formulae EC-1 to EC-6 , AE is (phenylenediyl)oxymethanediyl. In yet another embodiment, in any of formulae EC-1 to EC-6 , AE is (piperidinediyl)ethynyl.
在一個實施例中，在式 EC-1至 EC-6中之任一者中，A E為鍵、-O-、-NH-、乙炔二基、哌啶-1,3-二基、哌啶-1,4-二基、哌𠯤-1,4-二基、(苯-1,4-二基)氧基甲烷二基或(哌啶-1,4-二基)乙炔二基。在另一實施例中，在式 EC-1至 EC-6中之任一者中，A E為哌啶-1,3-二基。在又另一實施例中，在式 EC-1至 EC-6中之任一者中，A E為哌啶-1,4-二基。在又另一實施例中，在式 EC-1至 EC-6中之任一者中，A E為哌𠯤-1,4-二基。在又另一實施例中，在式 EC-1至 EC-6中之任一者中，A E為(苯-1,4-二基)氧基甲烷二基。在再一實施例中，在式 EC-1至 EC-6中之任一者中，A E為(哌啶-1,4-二基)乙炔二基。 In one embodiment, in any one of formulae EC-1 to EC-6 , A E is a bond, -O-, -NH-, acetylenediyl, piperidine-1,3-diyl, piperidine pyridine-1,4-diyl, piperidine-1,4-diyl, (benzene-1,4-diyl)oxymethanediyl or (piperidine-1,4-diyl)ethynyldiyl. In another embodiment, in any one of formulae EC-1 to EC-6 , AE is piperidine-1,3-diyl. In yet another embodiment, in any one of formulae EC-1 to EC-6 , AE is piperidine-1,4-diyl. In yet another embodiment, in any one of formulae EC-1 to EC-6 , AE is piperazine-1,4-diyl. In yet another embodiment, in any one of formulae EC-1 to EC-6 , AE is (benzene-1,4-diyl)oxymethanediyl. In yet another embodiment, in any one of formulae EC-1 to EC-6 , AE is (piperidine-1,4-diyl)ethynediyl.
在一個實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式 EC-1之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式 EC-2之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式 EC-3之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式 EC-4之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式 EC-5之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在再一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式 EC-6之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。 In one embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), ( XIIIb ) and (XIV), RE is of formula EC - Part of the structure of 1 or its enantiomer, mixture of enantiomers, non-enantiomer, mixture of two or more non-enantiomers, tautomer, two or more A mixture or isotopic variant of a tautomer. In another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb), and (XIV), R E is of formula Portion of the structure of EC-2 or its enantiomer, mixture of enantiomers, non-enantiomer, mixture of two or more non-enantiomers, tautomer, two or more Mixtures or isotopic variants of multiple tautomers. In yet another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb) and (XIV), R E is having A portion of the structure of formula EC-3 or its enantiomer, mixture of enantiomers, non-enantiomer, mixture of two or more non-enantiomers, tautomer, two or more Mixtures or isotopic variants of more tautomers. In yet another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb) and (XIV), R E is having A portion of a structure of formula EC-4 or an enantiomer, mixture of enantiomers, non-enantiomer, mixture of two or more non-enantiomers, tautomer, two or more Mixtures or isotopic variants of more tautomers. In yet another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb) and (XIV), R E is having A portion of a structure of formula EC-5 or an enantiomer, mixture of enantiomers, non-enantiomer, mixture of two or more non-enantiomers, tautomer, two or more Mixtures or isotopic variants of more tautomers. In yet another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb) and (XIV), R E is of formula Part of the structure of EC-6 or its enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, two or more diastereomers Mixtures or isotopic variants of multiple tautomers.
在一個實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式 EC-1之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在另一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式 EC-2之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式 EC-3之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式 EC-4之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式 EC-5之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在再一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式 EC-6之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。 In one embodiment, in a compound of any one of formulae (IA) to (XIA), (XIIAa), (XIIAb), (XIIIAa), ( XIIIAb ), and (XIVA), RE is of formula EC - Part of the structure of 1 or its enantiomer, mixture of enantiomers, non-enantiomer, mixture of two or more non-enantiomers, tautomer, two or more A mixture or isotopic variant of a tautomer. In another embodiment, in a compound of any one of formulae (IA)-(XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is of formula Portion of the structure of EC-2 or its enantiomer, mixture of enantiomers, non-enantiomer, mixture of two or more non-enantiomers, tautomer, two or more Mixtures or isotopic variants of multiple tautomers. In yet another embodiment, in the compound of any one of formulae (IA)-(XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is having A portion of the structure of formula EC-3 or its enantiomer, mixture of enantiomers, non-enantiomer, mixture of two or more non-enantiomers, tautomer, two or more Mixtures or isotopic variants of more tautomers. In yet another embodiment, in the compound of any one of formulae (IA)-(XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is having A portion of a structure of formula EC-4 or an enantiomer, mixture of enantiomers, non-enantiomer, mixture of two or more non-enantiomers, tautomer, two or more Mixtures or isotopic variants of more tautomers. In yet another embodiment, in the compound of any one of formulae (IA)-(XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is having A portion of a structure of formula EC-5 or an enantiomer, mixture of enantiomers, non-enantiomer, mixture of two or more non-enantiomers, tautomer, two or more Mixtures or isotopic variants of more tautomers. In yet another embodiment, in a compound of any one of formulae (IA)-(XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is of formula Part of the structure of EC-6 or its enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, two or more diastereomers Mixtures or isotopic variants of multiple tautomers.
在某些實施例中，R
E為具有以下結構之部分：
在一個實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式 EC-7之結構的部分或其鏡像異構物、鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式 EC-8之結構的部分或其鏡像異構物、鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式 EC-9之結構的部分或其鏡像異構物、鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式 EC-10之結構的部分或其鏡像異構物、鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式 EC-11之結構的部分或其鏡像異構物、鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式 EC-12之結構的部分或其鏡像異構物、鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式 EC-13之結構的部分或其鏡像異構物、鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式 EC-14之結構的部分或其鏡像異構物、鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式 EC-15之結構的部分或其鏡像異構物、鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式 EC-16之結構的部分或其鏡像異構物、鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式 EC-17之結構的部分或其鏡像異構物、鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式 EC-18之結構的部分或其鏡像異構物、鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式 EC-19之結構的部分或其鏡像異構物、鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式 EC-20之結構的部分或其鏡像異構物、鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在再一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式 EC-21之結構的部分或其鏡像異構物、鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。 In one embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), ( XIIIb ) and (XIV), RE is of formula EC A portion of the structure of -7 or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb), and (XIV), R E is of formula A portion of the structure of EC-8 or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb) and (XIV), R E is having A portion of a structure of formula EC-9 or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb) and (XIV), R E is having A portion of a structure of Formula EC-10 or an enantiomer, mixture of enantiomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof. In yet another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb) and (XIV), R E is having A portion of a structure of formula EC-11 or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb) and (XIV), R E is having A portion of a structure of formula EC-12 or an enantiomer, mixture of enantiomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof. In yet another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb) and (XIV), R E is having A portion of a structure of formula EC-13 or an enantiomer, mixture of enantiomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof. In yet another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb) and (XIV), R E is having A portion of a structure of formula EC-14 or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb) and (XIV), R E is having A portion of a structure of formula EC-15 or an enantiomer, mixture of enantiomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof. In yet another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb) and (XIV), R E is having A portion of a structure of formula EC-16 or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb) and (XIV), R E is having A portion of a structure of formula EC-17 or an enantiomer, mixture of enantiomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof. In yet another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb) and (XIV), R E is having A portion of a structure of formula EC-18 or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb) and (XIV), R E is having A portion of a structure of formula EC-19 or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb) and (XIV), R E is having A portion of a structure of formula EC-20 or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb) and (XIV), R E is of formula A portion of the structure of EC-21 or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
在一個實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式 EC-7之結構的部分或其鏡像異構物、鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在另一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式 EC-8之結構的部分或其鏡像異構物、鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式 EC-9之結構的部分或其鏡像異構物、鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式 EC-10之結構的部分或其鏡像異構物、鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式 EC-11之結構的部分或其鏡像異構物、鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式 EC-12之結構的部分或其鏡像異構物、鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式 EC-13之結構的部分或其鏡像異構物、鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式 EC-14之結構的部分或其鏡像異構物、鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式 EC-15之結構的部分或其鏡像異構物、鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式 EC-16之結構的部分或其鏡像異構物、鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式 EC-17之結構的部分或其鏡像異構物、鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式 EC-18之結構的部分或其鏡像異構物、鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式 EC-19之結構的部分或其鏡像異構物、鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式 EC-20之結構的部分或其鏡像異構物、鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在再一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式 EC-21之結構的部分或其鏡像異構物、鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。 In one embodiment, in a compound of any one of formulae (IA) to (XIA), (XIIAa), (XIIAb), (XIIIAa), ( XIIIAb ), and (XIVA), RE is of formula EC A portion of the structure of -7 or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In another embodiment, in a compound of any one of formulae (IA)-(XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is of formula A portion of the structure of EC-8 or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in the compound of any one of formulae (IA)-(XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is having A portion of a structure of formula EC-9 or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in the compound of any one of formulae (IA)-(XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is having A portion of a structure of Formula EC-10 or an enantiomer, mixture of enantiomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof. In yet another embodiment, in the compound of any one of formulae (IA)-(XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is having A portion of a structure of formula EC-11 or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in the compound of any one of formulae (IA)-(XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is having A portion of a structure of formula EC-12 or an enantiomer, mixture of enantiomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof. In yet another embodiment, in the compound of any one of formulae (IA)-(XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is having A portion of a structure of formula EC-13 or an enantiomer, mixture of enantiomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof. In yet another embodiment, in the compound of any one of formulae (IA)-(XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is having A portion of a structure of formula EC-14 or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in the compound of any one of formulae (IA)-(XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is having A portion of a structure of formula EC-15 or an enantiomer, mixture of enantiomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof. In yet another embodiment, in the compound of any one of formulae (IA)-(XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is having A portion of a structure of formula EC-16 or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in the compound of any one of formulae (IA)-(XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is having A portion of a structure of formula EC-17 or an enantiomer, mixture of enantiomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof. In yet another embodiment, in the compound of any one of formulae (IA)-(XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is having A portion of a structure of formula EC-18 or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in the compound of any one of formulae (IA)-(XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is having A portion of a structure of formula EC-19 or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in the compound of any one of formulae (IA)-(XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is having A portion of a structure of formula EC-20 or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in the compound of any one of formulae (IA)-(XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is of formula A portion of the structure of EC-21 or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
在某些實施例中，R
E為具有以下結構之部分：
在一個實施例中，在式 EC-22或 EC-23中，A E為鍵、-O-、-NH-、乙炔二基、哌啶二基、哌𠯤二基、(苯二基)氧基甲烷二基或(哌啶二基)乙炔二基。在另一實施例中，在式 EC-22或 EC-23中，A E為鍵。在另一實施例中，在式 EC-22或 EC-23中，A E為-O-。在又另一實施例中，在式 EC-22或 EC-23中，A E為-NH-。在又另一實施例中，在式 EC-22或 EC-23中，A E為乙炔二基。在又另一實施例中，在式 EC-22或 EC-23中，A E為哌啶二基。在又另一實施例中，在式 EC-22或 EC-23中，A E為哌𠯤二基。在又另一實施例中，在式 EC-22或 EC-23中，A E為(苯二基)氧基甲烷二基。在再一實施例中，在式 EC-22或 EC-23中，A E為(哌啶二基)乙炔基。 In one embodiment, in formula EC-22 or EC-23 , A E is a bond, -O-, -NH-, acetylenediyl, piperidinediyl, piperidinediyl, (phenylenediyl)oxy Methanediyl or (piperidinediyl)acetylenediyl. In another embodiment, in formula EC-22 or EC-23 , AE is a bond. In another embodiment, in formula EC-22 or EC-23 , AE is -O-. In yet another embodiment, in Formula EC-22 or EC-23 , AE is -NH-. In yet another embodiment, in formula EC-22 or EC-23 , AE is acetylenediyl. In yet another embodiment, in formula EC-22 or EC-23 , AE is piperidinediyl. In yet another embodiment, in formula EC-22 or EC-23 , AE is piperazine diyl. In yet another embodiment, in Formula EC-22 or EC-23 , AE is (phenylenediyl)oxymethanediyl. In yet another embodiment, in formula EC-22 or EC-23 , AE is (piperidinediyl)ethynyl.
在一個實施例中，在式 EC-22或 EC-23中，A E為鍵、-O-、-NH-、乙炔二基、哌啶-1,3-二基、哌啶-1,4-二基、哌𠯤-1,4-二基、(苯-1,4-二基)氧基甲烷二基或(哌啶-1,4-二基)乙炔二基。在另一實施例中，在式 EC-22或 EC-23中，A E為哌啶-1,3-二基。在又另一實施例中，在式 EC-22或 EC-23中，A E為哌啶-1,4-二基。在又另一實施例中，在式 EC-22或 EC-23中，A E為哌𠯤-1,4-二基。在又另一實施例中，在式 EC-22或 EC-23中，A E為(苯-1,4-二基)氧基甲烷二基。在再一實施例中，在式 EC-22或 EC-23中，A E為(哌啶-1,4-二基)乙炔二基。 In one embodiment, in formula EC-22 or EC-23 , A E is a bond, -O-, -NH-, acetylene diyl, piperidine-1,3-diyl, piperidine-1,4 -diyl, piperidine-1,4-diyl, (benzene-1,4-diyl)oxymethanediyl or (piperidine-1,4-diyl)ethynediyl. In another embodiment, in formula EC-22 or EC-23 , AE is piperidine-1,3-diyl. In yet another embodiment, in Formula EC-22 or EC-23 , AE is piperidine-1,4-diyl. In yet another embodiment, in formula EC-22 or EC-23 , AE is piperidine-1,4-diyl. In yet another embodiment, in Formula EC-22 or EC-23 , AE is (benzene-1,4-diyl)oxymethanediyl. In yet another embodiment, in Formula EC-22 or EC-23 , AE is (piperidine-1,4-diyl)ethynyldiyl.
在一個實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)、(XIV)、(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式 EC-22之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)、(XIV)、(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式 EC-23之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。 In one embodiment, in formulas (I) to (XI), (XIIa), (XIIb), (XIIIa), (XIIIb), (XIV), (IA) to (XIA), (XIIAa), (XIIAb ), (XIIIAa), (XIIIAb) and (XIVA) in any one of the compounds, R E is a moiety having the structure of formula EC-22 or its enantiomer, a mixture of enantiomers, a non-mirror image Isomers, mixtures of two or more diastereoisomers, tautomers, mixtures of two or more tautomers, or isotopic variants. In another embodiment, in formulas (I) to (XI), (XIIa), (XIIb), (XIIIa), (XIIIb), (XIV), (IA) to (XIA), (XIIAa), ( In the compound of any one of XIIAb), (XIIIAa), (XIIIAb) and (XIVA), R E is a moiety having the structure of formula EC-23 or its enantiomer, mixture of enantiomers, non-enantiomer Enantiomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants.
在某些實施例中，R
E為具有以下結構之部分：
在一個實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)、(XIV)、(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式 EC-24之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)、(XIV)、(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式 EC-25之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)、(XIV)、(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式 EC-26之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在再一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)、(XIV)、(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式 EC-27之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。 In one embodiment, in formulas (I) to (XI), (XIIa), (XIIb), (XIIIa), (XIIIb), (XIV), (IA) to (XIA), (XIIAa), (XIIAb ), (XIIIAa), (XIIIAb) and (XIVA) in any one of the compounds, R E is a moiety having the structure of formula EC-24 or its enantiomer, a mixture of enantiomers, a non-mirror image Isomers, mixtures of two or more diastereoisomers, tautomers, mixtures of two or more tautomers, or isotopic variants. In another embodiment, in formulas (I) to (XI), (XIIa), (XIIb), (XIIIa), (XIIIb), (XIV), (IA) to (XIA), (XIIAa), ( In the compound of any one of XIIAb), (XIIIAa), (XIIIAb) and (XIVA), R E is a moiety having the structure of formula EC-25 or its enantiomer, mixture of enantiomers, non-enantiomer Enantiomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants. In yet another embodiment, in formulas (I) to (XI), (XIIa), (XIIb), (XIIIa), (XIIIb), (XIV), (IA) to (XIA), (XIIAa), In the compound of any one of (XIIAb), (XIIIAa), (XIIIAb) and (XIVA), R E is a moiety having the structure of formula EC-26 or its enantiomer, a mixture of enantiomers, Astereoisomers, mixtures of two or more diastereoisomers, tautomers, mixtures of two or more tautomers, or isotopic variants. In yet another embodiment, in formulas (I) to (XI), (XIIa), (XIIb), (XIIIa), (XIIIb), (XIV), (IA) to (XIA), (XIIAa), ( In the compound of any one of XIIAb), (XIIIAa), (XIIIAb) and (XIVA), R E is a moiety having the structure of formula EC-27 or its enantiomer, mixture of enantiomers, non-enantiomer Enantiomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants.
在某些實施例中，R
E為具有以下結構之部分：
在一個實施例中，在式 EC-28或 EC-29中，A E為鍵、-O-、-NH-、乙炔二基、哌啶二基、哌𠯤二基、(苯二基)氧基甲烷二基、(哌啶二基)-乙炔二基或3,9-二氮雜螺[5.5]十一烷二基。在另一實施例中，在式 EC-28或 EC-29中，A E為鍵、-O-、-NH-、乙炔二基、哌啶二基、哌𠯤二基、(苯二基)氧基-甲烷二基或(哌啶二基)乙炔二基。在另一實施例中，在式 EC-28或 EC-29中，A E為鍵。在另一實施例中，在式 EC-28或 EC-29中，A E為-O-。在又另一實施例中，在式 EC-28或 EC-29中，A E為-NH-。在又另一實施例中，在式 EC-28或 EC-29中，A E為乙炔二基。在又另一實施例中，在式 EC-28或 EC-29中，A E為哌啶二基。在又另一實施例中，在式 EC-28或 EC-29中，A E為哌𠯤二基。在又另一實施例中，在式 EC-28或 EC-29中，A E為(苯二基)氧基甲烷二基。在又另一實施例中，在式 EC-28或 EC-29中，A E為(哌啶二基)乙炔基。在再一實施例中在式 EC-28或 EC-29中，A E為3,9-二氮雜螺[5.5]十一烷二基。 In one embodiment, in formula EC-28 or EC-29 , A E is a bond, -O-, -NH-, acetylenediyl, piperidinediyl, piperidinediyl, (phenylenediyl)oxy methanediyl, (piperidinediyl)-acetylenediyl or 3,9-diazaspiro[5.5]undecandiyl. In another embodiment, in formula EC-28 or EC-29 , A E is a bond, -O-, -NH-, acetylenediyl, piperidinediyl, piperidinediyl, (phenylenediyl) Oxy-methanediyl or (piperidinediyl)ethynediyl. In another embodiment, in formula EC-28 or EC-29 , AE is a bond. In another embodiment, in formula EC-28 or EC-29 , AE is -O-. In yet another embodiment, in formula EC-28 or EC-29 , AE is -NH-. In yet another embodiment, in formula EC-28 or EC-29 , AE is acetylenediyl. In yet another embodiment, in formula EC-28 or EC-29 , AE is piperidinediyl. In yet another embodiment, in formula EC-28 or EC-29 , AE is piperidinediyl. In yet another embodiment, in Formula EC-28 or EC-29 , AE is (phenylenediyl)oxymethanediyl. In yet another embodiment, in Formula EC-28 or EC-29 , AE is (piperidinediyl)ethynyl. In yet another embodiment, in formula EC-28 or EC-29 , AE is 3,9-diazaspiro[5.5]undecanediyl.
在一個實施例中，在式 EC-28或 EC-29中，A E為鍵、-O-、-NH-、乙炔二基、哌啶-1,3-二基、哌啶-1,4-二基、哌𠯤-1,4-二基、(苯-1,4-二基)氧基-甲烷二基、(哌啶-1,4-二基)乙炔二基或3,9-二氮雜螺[5.5]十一烷-3,9-二基。在另一實施例中，在式 EC-28或 EC-29中，A E為鍵、-O-、-NH-、乙炔二基、哌啶-1,3-二基、哌啶-1,4-二基、哌𠯤-1,4-二基、(苯-1,4-二基)氧基甲烷二基或(哌啶-1,4-二基)乙炔二基。在另一實施例中，在式 EC-28或 EC-29中，A E為哌啶-1,3-二基。在又另一實施例中，在式 EC-28或 EC-29中，A E為哌啶-1,4-二基。在又另一實施例中，在式 EC-28或 EC-29中，A E為哌𠯤-1,4-二基。在又另一實施例中，在式 EC-28或 EC-29中，A E為(苯-1,4-二基)氧基甲烷二基。在又另一實施例中，在式 EC-28或 EC-29中，A E為(哌啶-1,4-二基)乙炔二基。在再一實施例中，在式 EC-28或 EC-29中，A E為3,9-二氮雜螺[5.5]十一烷-3,9-二基。 In one embodiment, in formula EC-28 or EC-29 , A E is a bond, -O-, -NH-, acetylene diyl, piperidine-1,3-diyl, piperidine-1,4 -diyl, piperidine-1,4-diyl, (benzene-1,4-diyl)oxy-methanediyl, (piperidine-1,4-diyl)ethynediyl or 3,9-diyl Diazaspiro[5.5]undecan-3,9-diyl. In another embodiment, in formula EC-28 or EC-29 , A E is a bond, -O-, -NH-, acetylene diyl, piperidine-1,3-diyl, piperidine-1, 4-diyl, piperidine-1,4-diyl, (benzene-1,4-diyl)oxymethanediyl or (piperidine-1,4-diyl)ethynediyl. In another embodiment, in formula EC-28 or EC-29 , AE is piperidine-1,3-diyl. In yet another embodiment, in formula EC-28 or EC-29 , AE is piperidine-1,4-diyl. In yet another embodiment, in formula EC-28 or EC-29 , AE is piperidine-1,4-diyl. In yet another embodiment, in Formula EC-28 or EC-29 , AE is (benzene-1,4-diyl)oxymethanediyl. In yet another embodiment, in formula EC-28 or EC-29 , AE is (piperidine-1,4-diyl)ethynyldiyl. In yet another embodiment, in Formula EC-28 or EC-29 , AE is 3,9-diazaspiro[5.5]undecan-3,9-diyl.
在一個實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)、(XIV)、(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式 EC-28之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)、(XIV)、(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式 EC-29之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。 In one embodiment, in formula (I) to (XI), (XIIa), (XIIb), (XIIIa), (XIIIb), (XIV), (IA) to (XIA), (XIIAa), (XIIAb ), (XIIIAa), (XIIIAb) and (XIVA) in any one of the compounds, R E is a moiety having the structure of formula EC-28 or its enantiomer, a mixture of enantiomers, a non-mirror image Isomers, mixtures of two or more diastereoisomers, tautomers, mixtures of two or more tautomers, or isotopic variants. In another embodiment, in formulas (I) to (XI), (XIIa), (XIIb), (XIIIa), (XIIIb), (XIV), (IA) to (XIA), (XIIAa), ( In the compound of any one of XIIAb), (XIIIAa), (XIIIAb) and (XIVA), R E is a moiety having the structure of formula EC-29 or its enantiomer, mixture of enantiomers, non-enantiomer Enantiomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants.
在某些實施例中，R
E為具有以下結構之部分：
在一個實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)、(XIV)、(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式 EC-30之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)、(XIV)、(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式 EC-31之結構的部分或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。 In one embodiment, in formula (I) to (XI), (XIIa), (XIIb), (XIIIa), (XIIIb), (XIV), (IA) to (XIA), (XIIAa), (XIIAb ), (XIIIAa), (XIIIAb) and (XIVA) in any one of the compounds, R E is a moiety having the structure of formula EC-30 or its enantiomer, a mixture of enantiomers, a non-mirror image Isomers, mixtures of two or more diastereoisomers, tautomers, mixtures of two or more tautomers, or isotopic variants. In another embodiment, in formulas (I) to (XI), (XIIa), (XIIb), (XIIIa), (XIIIb), (XIV), (IA) to (XIA), (XIIAa), ( In the compound of any one of XIIAb), (XIIIAa), (XIIIAb) and (XIVA), R E is a moiety having the structure of formula EC-31 or its enantiomer, mixture of enantiomers, non-enantiomer Enantiomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants.
在一個實施例中，本文提供一種式(XV)化合物：
在另一實施例中，本文提供一種式(XVI)化合物：
在又另一實施例中，本文提供一種式(XVII)化合物：
在再一實施例中，本文提供一種式(XVIII)化合物：
在一個實施例中，本文提供一種式(XVA)化合物：
在另一實施例中，本文提供一種式(XVIA)化合物：
在又另一實施例中，本文提供一種式(XVIIA)化合物：
在再一實施例中，本文提供一種式(XVIIIA)化合物：
在一個實施例中，本文提供一種式(XIX)化合物：
在另一實施例中，本文提供一種式(XX)化合物：
在又另一實施例中，本文提供一種式(XXI)化合物：
在一個實施例中，本文提供一種式(XIXA)化合物：
在另一實施例中，本文提供一種式(XXA)化合物：
在又另一實施例中，本文提供一種式(XXIA)化合物：
在某些實施例中，R E為IAP E3配體之部分。 In certain embodiments, R E is part of an IAP E3 ligand.
在某些實施例中，R
E為具有式(EI-I)之結構之部分：
在某些實施例中，R
E為具有式(EI-II)之結構之部分：
在某些實施例中，R
E為具有式(EI-III)之結構之部分：
在一個實施例中，在式(EI-I)、(EI-II)或(EI-III)中，R I1為氫；R I2為C 1-6烷基；R I3為C 1-6烷基；R I4為C 1-6烷基或C 3-10環烷基；R I5為-OR 1a；R I6為鹵基；及p及q各自獨立地為0或1之整數。在另一實施例中，在式(EI-I)、(EI-II)或(EI-III)中，R I1為氫；R I2為C 1-6烷基；R I3為C 1-6烷基；R I4為C 3-10環烷基；R I5為-OR 1a；R I6為鹵基；及p及q各自獨立地為0或1之整數。在又另一實施例中，在式(EI-I)、(EI-II)或(EI-III)中，R I1為氫；R I2及R I3各自為甲基；R I4為環己基；R I5為羥基；R I6為氟；及p及q各自獨立地為0或1之整數。 In one embodiment, in formula (EI-I), (EI-II) or (EI-III), R I1 is hydrogen; R I2 is C 1-6 alkyl; R I3 is C 1-6 alkane R I4 is C 1-6 alkyl or C 3-10 cycloalkyl; R I5 is -OR 1a ; R I6 is halo; and p and q are each independently an integer of 0 or 1. In another embodiment, in formula (EI-I), (EI-II) or (EI-III), R I1 is hydrogen; R I2 is C 1-6 alkyl; R I3 is C 1-6 R I4 is C 3-10 cycloalkyl; R I5 is -OR 1a ; R I6 is halo; and p and q are each independently an integer of 0 or 1. In yet another embodiment, in formula (EI-I), (EI-II) or (EI-III), R I1 is hydrogen; R I2 and R I3 are each methyl; R I4 is cyclohexyl; R I5 is hydroxy; R I6 is fluoro; and p and q are each independently an integer of 0 or 1.
在某些實施例中，R
E為具有式(EI-IV)之結構之部分：
在一個實施例中，在式(EI-IV)中，R I1為氫；R I2為C 1-6烷基；R I3為C 1-6烷基；R I4為C 1-6烷基或C 3-10環烷基；及R I7為C 3-10環烷基或C 6-14芳基。在另一實施例中，在式(EI-IV)中，R I1為氫；R I2為C 1-6烷基；R I3為C 1-6烷基；R I4為C 3-10環烷基；及R I7為C 3-10環烷基或C 6-14芳基。在又另一實施例中，在式(EI-IV)中，R I1為氫；R I2為甲基；R I3為甲基；R I4為環己基；及R I7為1,2,3,4-四氫萘基。在再一實施例中，在式(EI-IV)中，R I1為氫；R I2為甲基；R I3為甲基；R I4為環己基；及R I7為1,2,3,4-四氫萘-1-基。 In one embodiment, in formula (EI-IV), R I1 is hydrogen; R I2 is C 1-6 alkyl; R I3 is C 1-6 alkyl; R I4 is C 1-6 alkyl or C 3-10 cycloalkyl; and R I7 is C 3-10 cycloalkyl or C 6-14 aryl. In another embodiment, in formula (EI-IV), R I1 is hydrogen; R I2 is C 1-6 alkyl; R I3 is C 1-6 alkyl; R I4 is C 3-10 cycloalkane and R I7 is C 3-10 cycloalkyl or C 6-14 aryl. In yet another embodiment, in formula (EI-IV), R I1 is hydrogen; R I2 is methyl; R I3 is methyl; R I4 is cyclohexyl; and R I7 is 1,2,3, 4-Tetrahydronaphthyl. In yet another embodiment, in formula (EI-IV), R I1 is hydrogen; R I2 is methyl; R I3 is methyl; R I4 is cyclohexyl; and R I7 is 1,2,3,4 -Tetrahydronaphthalene-1-yl.
在某些實施例中，R
E為具有式(EI-V)之結構之部分：
在一個實施例中，在式(EI-V)中，R I8為C 1-6烷基或C 3-10環烷基；及r為0或1之整數。在另一實施例中，在式(EI-V)中，R I8為C 1-6烷基及r為0之整數。在又另一實施例中，在式(EI-V)中，R I8為異丁基及r為0之整數。 In one embodiment, in formula (EI-V), R I8 is C 1-6 alkyl or C 3-10 cycloalkyl; and r is an integer of 0 or 1. In another embodiment, in formula (EI-V), R I8 is C 1-6 alkyl and r is an integer of 0. In yet another embodiment, in formula (EI-V), R I8 is isobutyl and r is an integer of 0.
在一個實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)、(XIV)、(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式(EI-I)之結構的部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)、(XIV)、(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式(EI-II)之結構的部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)、(XIV)、(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式(EI-III)之結構的部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)、(XIV)、(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式(EI-IV)之結構的部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在再一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)、(XIV)、(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式(EI-V)之結構的部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。 In one embodiment, in formula (I) to (XI), (XIIa), (XIIb), (XIIIa), (XIIIb), (XIV), (IA) to (XIA), (XIIAa), (XIIAb ), (XIIIAa), (XIIIAb) and (XIVA), wherein R E is a moiety having the structure of formula (EI-I) or a diastereoisomer, two or more thereof A mixture of diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant. In another embodiment, in formulas (I) to (XI), (XIIa), (XIIb), (XIIIa), (XIIIb), (XIV), (IA) to (XIA), (XIIAa), ( In the compound of any one of XIIAb), (XIIIAa), (XIIIAb) and (XIVA), R E is a moiety having the structure of formula (EI-II) or a diastereoisomer, two or more thereof A mixture of diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant. In yet another embodiment, in formulas (I) to (XI), (XIIa), (XIIb), (XIIIa), (XIIIb), (XIV), (IA) to (XIA), (XIIAa), In the compound of any one of (XIIAb), (XIIIAa), (XIIIAb) and (XIVA), RE is a moiety having the structure of formula ( EI -III) or a diastereoisomer, two or more thereof A mixture of diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant. In yet another embodiment, in formulas (I) to (XI), (XIIa), (XIIb), (XIIIa), (XIIIb), (XIV), (IA) to (XIA), (XIIAa), In the compound of any one of (XIIAb), (XIIIAa), (XIIIAb) and (XIVA), R E is a moiety having the structure of formula (EI-IV) or a diastereoisomer, two or more thereof A mixture of diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant. In yet another embodiment, in formulas (I) to (XI), (XIIa), (XIIb), (XIIIa), (XIIIb), (XIV), (IA) to (XIA), (XIIAa), ( In the compound of any one of XIIAb), (XIIIAa), (XIIIAb) and (XIVA), R E is a moiety having the structure of formula (EI-V) or a diastereoisomer, two or more thereof A mixture of diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant.
在某些實施例中，R
E為具有以下結構之IAP E3配體之部分：
在某些實施例中，R
E為具有以下結構之部分：
在一個實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為化合物 EI-1之部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為化合物 EI-2之部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式 EI-3之結構的部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式 EI-4之結構的部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。 In one embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb) and (XIV), R E is compound EI- A part of 1 or an enantiomer, a mixture of two or more enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant. In another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb) and (XIV), R E is compound EI A portion of -2 or its diastereoisomer, a mixture of two or more diastereoisomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant. In yet another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb) and (XIV), R E is having A portion of the structure of formula EI-3 or its diastereoisomer, a mixture of two or more diastereoisomers, a tautomer, a mixture of two or more tautomers, or an isotopic variation body. In yet another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb) and (XIV), R E is having Parts of the structures of formula EI-4 or their diastereoisomers, mixtures of two or more diastereoisomers, tautomers, mixtures of two or more tautomers, or isotopic variations body.
在一個實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為化合物 EI-1之部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在另一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為化合物 EI-2之部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式 EI-3之結構的部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在再一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式 EI-4之結構的部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。 In one embodiment, in the compound of any one of formulae (IA) to (XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb) and (XIVA), R E is compound EI- A part of 1 or an enantiomer, a mixture of two or more enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant. In another embodiment, in the compound of any one of formulae (IA) to (XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb) and (XIVA), R E is compound EI A part of -2 or its diastereoisomer, a mixture of two or more diastereoisomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant. In yet another embodiment, in the compound of any one of formulae (IA)-(XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is having Portions of the structures of formula EI-3 or their diastereoisomers, mixtures of two or more diastereoisomers, tautomers, mixtures of two or more tautomers, or isotopic variations body. In yet another embodiment, in the compound of any one of formulae (IA)-(XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is of formula Part of the structure of EI-4 or its diastereoisomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant .
在某些實施例中，R
E為具有以下結構之部分：
在一個實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)、(XIV)、(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為化合物 EI-5之部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)、(XIV)、(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為化合物 EI-6之部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。 In one embodiment, in formula (I) to (XI), (XIIa), (XIIb), (XIIIa), (XIIIb), (XIV), (IA) to (XIA), (XIIAa), (XIIAb ), (XIIIAa), (XIIIAb) and (XIVA), wherein R E is part of compound EI-5 or its diastereomer, two or more diastereomers mixtures, tautomers, mixtures of two or more tautomers, or isotopic variants. In another embodiment, in formulas (I) to (XI), (XIIa), (XIIb), (XIIIa), (XIIIb), (XIV), (IA) to (XIA), (XIIAa), ( In the compound of any one of XIIAb), (XIIIAa), (XIIIAb) and (XIVA), R E is a part of compound EI-6 or its diastereomer, two or more diastereomers mixtures, tautomers, mixtures of two or more tautomers, or isotopic variants.
在一個實施例中，本文提供一種式(XXII)化合物：
在另一實施例中，本文提供一種式(XXIII)化合物：
在再一實施例中，本文提供一種式(XXIV)化合物：
在一個實施例中，本文提供一種式(XXIIA)化合物：
在另一實施例中，本文提供一種式(XXIIIA)化合物：
在又另一實施例中，本文提供一種式(XXIVA)化合物：
在某些實施例中，R E為MDM2 E3配體之部分。 In certain embodiments, R E is part of an MDM2 E3 ligand.
在某些實施例中，R
E為具有式(EM-I)之結構之部分：
在一個實施例中，在式(EM-I)中，R M1及R M2各自獨立地為C 1-6烷基；各R M3及R M4獨立地為氘或鹵基；及s及t各自獨立地為0、1或2之整數。在另一實施例中，在式(EM-I)中，R M1及R M2各自獨立地為甲基或2,2-二甲基丙基；各R M3及R M4獨立地為氟或氯；及s及t各自獨立地為2之整數。 In one embodiment, in formula (EM-I), R M1 and R M2 are each independently C 1-6 alkyl; each R M3 and R M4 are independently deuterium or halo; and s and t are each independently independently an integer of 0, 1 or 2. In another embodiment, in formula (EM-I), R M1 and R M2 are each independently methyl or 2,2-dimethylpropyl; each R M3 and R M4 are independently fluorine or chlorine ; and s and t are each independently an integer of 2.
在某些實施例中，R
E為具有式(EM-II)之結構之部分：
在一個實施例中，在式(EM-II)中，R M1及R M2各自獨立地為C 1-6烷基；及各R M3及R M4獨立地為氘或鹵基。在另一實施例中，在式(EM-II)中，R M1及R M2各自獨立地為甲基或2,2-二甲基丙基；及各R M3及R M4獨立地為氟或氯。 In one embodiment, in formula (EM-II), R M1 and R M2 are each independently C 1-6 alkyl; and each R M3 and R M4 are independently deuterium or halo. In another embodiment, in formula (EM-II), R M1 and R M2 are each independently methyl or 2,2-dimethylpropyl; and each R M3 and R M4 are independently fluoro or chlorine.
在某些實施例中，R
E為具有式(EM-III)之結構之部分：
在一個實施例中，在式(EM-III)中，R M5為氫或側氧基；各R M6獨立地為氫、氘或C 1-6烷基；各R M7獨立地為鹵基；各R M8獨立地為C 1-6烷基或-OC 1-6烷基；及各u及v獨立地為0、1、2之整數。在另一實施例中，在式(EM-III)中，R M5為氫或側氧基；各R M6獨立地為氫或甲基；各R M7為氯；各R M8獨立地為三級丁基、甲氧基、乙氧基或異丙氧基；u為0或1之整數；及v為1或2之整數。在又另一實施例中，在式(EM-III)中，R M5為氫或側氧基；各R M6獨立地為氫或甲基；各R M7為氯；各R M8獨立地為三級丁基、甲氧基、乙氧基或異丙氧基；u為1之整數；及v為2之整數。 In one embodiment, in formula (EM-III), R M5 is hydrogen or pendant oxy; each R M6 is independently hydrogen, deuterium or C 1-6 alkyl; each R M7 is independently halo; Each R M8 is independently C 1-6 alkyl or -OC 1-6 alkyl; and each u and v is independently an integer of 0, 1, 2. In another embodiment, in formula (EM-III), R M5 is hydrogen or pendant oxy; each R M6 is independently hydrogen or methyl; each R M7 is chlorine; each R M8 is independently tertiary butyl, methoxy, ethoxy or isopropoxy; u is an integer of 0 or 1; and v is an integer of 1 or 2. In yet another embodiment, in formula (EM-III), R M5 is hydrogen or pendant oxy; each R M6 is independently hydrogen or methyl; each R M7 is chloro; each R M8 is independently three tert-butyl, methoxy, ethoxy, or isopropoxy; u is an integer of 1; and v is an integer of 2.
在某些實施例中，R
E為具有式(EM-IV)之結構之部分：
在一個實施例中，在式(EM-IV)中，R M5為氫或側氧基；各R M6獨立地為氫、氘或C 1-6烷基；各R M7獨立地為鹵基；及各R M8獨立地為C 1-6烷基或-OC 1-6烷基。在另一實施例中，在式(EM-IV)中，R M5為氫或側氧基；各R M6獨立地為氫或甲基；各R M7為氯；及各R M8獨立地為三級丁基、甲氧基、乙氧基或異丙氧基。 In one embodiment, in formula (EM-IV), R M5 is hydrogen or pendant oxy; each R M6 is independently hydrogen, deuterium or C 1-6 alkyl; each R M7 is independently halo; and each R M8 is independently C 1-6 alkyl or -OC 1-6 alkyl. In another embodiment, in formula (EM-IV), R M5 is hydrogen or pendant oxy; each R M6 is independently hydrogen or methyl; each R M7 is chloro; and each R M8 is independently three tert-butyl, methoxy, ethoxy or isopropoxy.
在一個實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)、(XIV)、(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式(EM-I)之結構的部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)、(XIV)、(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式(EM-II)之結構的部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)、(XIV)、(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式(EM-III)之結構的部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在再一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)、(XIV)、(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式(EM-IV)之結構的部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。 In one embodiment, in formula (I) to (XI), (XIIa), (XIIb), (XIIIa), (XIIIb), (XIV), (IA) to (XIA), (XIIAa), (XIIAb ), (XIIIAa), (XIIIAb) and (XIVA), wherein R E is a moiety having the structure of formula (EM-I) or a diastereoisomer, two or more thereof A mixture of diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant. In another embodiment, in formulas (I) to (XI), (XIIa), (XIIb), (XIIIa), (XIIIb), (XIV), (IA) to (XIA), (XIIAa), ( In the compound of any one of XIIAb), (XIIIAa), (XIIIAb) and (XIVA), R E is a moiety having the structure of formula (EM-II) or a diastereoisomer, two or more thereof A mixture of diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant. In yet another embodiment, in formulas (I) to (XI), (XIIa), (XIIb), (XIIIa), (XIIIb), (XIV), (IA) to (XIA), (XIIAa), In the compound of any one of (XIIAb), (XIIIAa), (XIIIAb) and (XIVA), R E is a moiety having the structure of formula (EM-III) or a diastereoisomer, two or more thereof A mixture of diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant. In yet another embodiment, in formulas (I) to (XI), (XIIa), (XIIb), (XIIIa), (XIIIb), (XIV), (IA) to (XIA), (XIIAa), ( In the compound of any one of XIIAb), (XIIIAa), (XIIIAb) and (XIVA), R E is a moiety having the structure of formula (EM-IV) or a diastereoisomer, two or more thereof A mixture of diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant.
在某些實施例中，R
E為具有以下結構之MDM2 E3配體之部分：
在一個實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為化合物 EM-1之部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在另一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為化合物 EM-1之部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。 In one embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb) and (XIV), R E is compound EM- A part of 1 or an enantiomer, a mixture of two or more enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant. In another embodiment, in the compound of any one of formulae (IA) to (XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb) and (XIVA), R E is compound EM A part of -1 or an enantiomer, a mixture of two or more enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant.
在某些實施例中，R
E為具有以下結構之MDM2 E3配體之部分：
在一個實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)、(XIV)、(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為化合物 EM-2之部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)、(XIV)、(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為化合物 EM-3之部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。 In one embodiment, in formulas (I) to (XI), (XIIa), (XIIb), (XIIIa), (XIIIb), (XIV), (IA) to (XIA), (XIIAa), (XIIAb ), (XIIIAa), (XIIIAb) and (XIVA), wherein R E is part of compound EM-2 or its diastereomer, two or more diastereomers mixtures, tautomers, mixtures of two or more tautomers, or isotopic variants. In another embodiment, in formulas (I) to (XI), (XIIa), (XIIb), (XIIIa), (XIIIb), (XIV), (IA) to (XIA), (XIIAa), ( In the compound of any one of XIIAb), (XIIIAa), ( XIIIAb ) and (XIVA), RE is a part of compound EM-3 or its diastereomer, two or more diastereomers mixtures, tautomers, mixtures of two or more tautomers, or isotopic variants.
在某些實施例中，R
E為具有以下結構之部分：
在一個實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)、(XIV)、(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式 EM-4之結構的部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)、(XIV)、(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式 EM-5之結構的部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)、(XIV)、(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式 EM-6之結構的部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。 In one embodiment, in formulas (I) to (XI), (XIIa), (XIIb), (XIIIa), (XIIIb), (XIV), (IA) to (XIA), (XIIAa), (XIIAb ), (XIIIAa), (XIIIAb), and (XIVA), wherein R E is a moiety having the structure of formula EM-4 or a non-mirror isomer, two or more non-mirror images A mixture of isomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant. In another embodiment, in formulas (I) to (XI), (XIIa), (XIIb), (XIIIa), (XIIIb), (XIV), (IA) to (XIA), (XIIAa), ( In the compound of any one of XIIAb), (XIIIAa), (XIIIAb) and (XIVA), R E is a moiety having the structure of formula EM-5 or a diastereoisomer thereof, two or more non- A mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant. In yet another embodiment, in formulas (I) to (XI), (XIIa), (XIIb), (XIIIa), (XIIIb), (XIV), (IA) to (XIA), (XIIAa), In the compound of any one of (XIIAb), (XIIIAa), (XIIIAb) and (XIVA), R E is a moiety having the structure of formula EM-6 or a diastereoisomer, two or more thereof A mixture of diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant.
在一個實施例中，本文提供一種式(XXV)化合物：
在另一實施例中，本文提供一種式(XXVI)化合物：
在一個實施例中，本文提供一種式(XXVA)化合物：
在另一實施例中，本文提供一種式(XXVIA)化合物：
在某些實施例中，R E為VHL E3配體之部分。 In certain embodiments, RE is part of a VHL E3 ligand.
在某些實施例中，R
E具有式(EV-I)之結構：
在某些實施例中，R
E具有式(EV-II)之結構：
在某些實施例中，R
E具有式(EV-III)之結構：
在某些實施例中，在式(EV-I)至(EV-III)中之任一者中， R V1為甲基； R V2(若存在)為氫； R V3為氫； R V4(若存在)為丙基、丁基或環丙基；及 R V5(若存在)為乙醯胺基、環丙醯胺基或異吲哚啉基； 其中丙基、丁基、環丙基、乙醯胺基、環丙醯胺基及異吲哚啉基各自視情況經氰基、氟或三氟甲基取代。 In certain embodiments, in any one of formulae (EV-I) to (EV-III), R V1 is methyl; R V2 (if present) is hydrogen; R V3 is hydrogen; R V4 ( If present) is propyl, butyl or cyclopropyl; and R V5 (if present) is acetamido, cyclopropamido or isoindolinyl; wherein propyl, butyl, cyclopropyl, The acetamido, cyclopropamido and isoindolinyl groups are each optionally substituted with cyano, fluoro or trifluoromethyl.
在某些實施例中，在式(EV-I)至(EV-III)中之任一者中， R V1為甲基； R V2(若存在)為氫； R V3為氫； R V4(若存在)為異丙基、三級丁基、環丙基、1-氟環丙基或1-三氟甲基環丙基；及 R V5(若存在)為乙醯胺基、環丙醯胺基、1-氰基環丙醯胺基、1-氟環丙醯胺基或1-側氧基異吲哚啉-2-基。 In certain embodiments, in any one of formulae (EV-I) to (EV-III), R V1 is methyl; R V2 (if present) is hydrogen; R V3 is hydrogen; R V4 ( if present) is isopropyl, tert-butyl, cyclopropyl, 1-fluorocyclopropyl, or 1-trifluoromethylcyclopropyl; and R V5 (if present) is acetamido, cyclopropyl amine, 1-cyanocyclopropionamido, 1-fluorocyclopropamido, or 1-oxyisoindolin-2-yl.
在一個實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式(EV-I)之結構的部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式(EV-II)之結構的部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式(EV-III)之結構的部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。 In one embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb), and (XIV), R E is having the formula ( A portion of the structure of EV-I) or its diastereoisomer, a mixture of two or more diastereoisomers, a tautomer, a mixture of two or more tautomers, or an isotopic variation body. In another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb), and (XIV), R E is of formula A portion of the structure of (EV-II) or its diastereoisomer, mixture of two or more diastereoisomers, tautomer, mixture of two or more tautomers or isotopes Variants. In yet another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb) and (XIV), R E is having A portion of a structure of formula (EV-III) or a diastereoisomer, a mixture of two or more diastereoisomers, a tautomer, a mixture of two or more tautomers, or isotopic variants.
在一個實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式(EV-I)之結構的部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在另一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式(EV-II)之結構的部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式(EV-III)之結構的部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。 In one embodiment, in a compound of any one of formulae (IA)-(XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is having the formula ( A portion of the structure of EV-I) or its diastereoisomer, a mixture of two or more diastereoisomers, a tautomer, a mixture of two or more tautomers, or an isotopic variation body. In another embodiment, in a compound of any one of formulae (IA)-(XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is of formula A portion of the structure of (EV-II) or its diastereoisomer, mixture of two or more diastereoisomers, tautomer, mixture of two or more tautomers or isotopes Variants. In yet another embodiment, in the compound of any one of formulae (IA)-(XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is having A portion of a structure of formula (EV-III) or a diastereoisomer, a mixture of two or more diastereoisomers, a tautomer, a mixture of two or more tautomers, or isotopic variants.
在某些實施例中，R
E為具有以下結構之VHL E3配體之部分：
在一個實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為化合物 EV-1之部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為化合物 EV-2之部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為化合物 EV-3之部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為化合物 EV-4之部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為化合物 EV-5之部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為化合物 EV-6之部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在再一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為化合物 EV-7之部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。 In one embodiment, in the compound of any one of formulae (I) to (XI), (XIIa), (XIIb), (XIIIa), (XIIIb) and (XIV), R E is compound EV- A part of 1 or an enantiomer, a mixture of two or more enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant. In another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), ( XIIIb ) and (XIV), RE is compound EV A part of -2 or its diastereoisomer, a mixture of two or more diastereoisomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant. In yet another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb) and (XIV), R E is the compound A portion of EV-3 or a non-spiroisomer, a mixture of two or more non-spiroisomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant. In yet another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb) and (XIV), R E is the compound A portion of EV-4 or its diastereoisomer, a mixture of two or more diastereoisomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant. In yet another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb) and (XIV), R E is the compound A portion of EV-5 or its diastereoisomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant. In yet another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb) and (XIV), R E is the compound A portion of EV-6 or its diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant. In yet another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb) and (XIV), R E is compound EV A portion of -7 or an enantiomer, a mixture of two or more enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant.
在一個實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為化合物 EV-1之部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在另一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為化合物 EV-2之部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為化合物 EV-3之部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為化合物 EV-4之部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為化合物 EV-5之部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為化合物 EV-6之部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在再一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為化合物 EV-7之部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。 In one embodiment, in the compound of any one of formulae (IA) to (XIA), (XIIAa), (XIIAb), (XIIIAa), ( XIIIAb ) and (XIVA), RE is compound EV- A part of 1 or an enantiomer, a mixture of two or more enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant. In another embodiment, in the compound of any one of formulae (IA) to (XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is compound EV A portion of -2 or its diastereoisomer, a mixture of two or more diastereoisomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant. In yet another embodiment, in the compound of any one of formulae (IA) to (XIA), (XIIAa), (XIIAb), (XIIIAa), ( XIIIAb ), and (XIVA), RE is the compound A portion of EV-3 or a non-spiroisomer, a mixture of two or more non-spiroisomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant. In yet another embodiment, in the compound of any one of formulae (IA) to (XIA), (XIIAa), (XIIAb), (XIIIAa), ( XIIIAb ), and (XIVA), RE is the compound A portion of EV-4 or its diastereoisomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant. In yet another embodiment, in the compound of any one of formulae (IA) to (XIA), (XIIAa), (XIIAb), (XIIIAa), ( XIIIAb ), and (XIVA), RE is the compound A portion of EV-5 or its diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant. In yet another embodiment, in the compound of any one of formulae (IA) to (XIA), (XIIAa), (XIIAb), (XIIIAa), ( XIIIAb ), and (XIVA), RE is the compound A portion of EV-6 or its diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant. In yet another embodiment, in the compound of any one of formulae (IA) to (XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb) and (XIVA), R E is compound EV A part of -7 or its diastereoisomer, a mixture of two or more diastereoisomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant.
在某些實施例中，R
E為具有以下結構之部分：
在某些實施例中，R
E為具有以下結構之部分：
在一個實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式 EV-8之結構的部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式 EV-9之結構的部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式 EV-10之結構的部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式 EV-11之結構的部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式 EV-12之結構的部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式 EV-13之結構的部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式 EV-14之結構的部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在再一實施例中，在式(I)至(XI)、(XIIa)、(XIIb)、(XIIIa)、(XIIIb)及(XIV)中之任一者之化合物中，R E為具有式 EV-15之結構的部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。 In one embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), ( XIIIb ), and (XIV), RE is of formula EV - A portion of the structure of 8 or a non-spiroisomer, a mixture of two or more non-spiroisomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant. In another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb), and (XIV), R E is of formula A portion of the structure of EV-9 or its diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant . In yet another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb) and (XIV), R E is having A portion of a structure of formula EV-10 or a non-enantiomer, mixture of two or more non-enantiomers, tautomer, mixture of two or more tautomers, or isotopic variation body. In yet another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb) and (XIV), R E is having Parts of the structures of formula EV-11 or their diastereoisomers, mixtures of two or more diastereoisomers, tautomers, mixtures of two or more tautomers, or isotopic variations body. In yet another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb) and (XIV), R E is having A portion of a structure of formula EV-12 , or its diastereoisomer, mixture of two or more diastereoisomers, tautomer, mixture of two or more tautomers, or isotopic variation body. In yet another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb) and (XIV), R E is having Parts of the structures of formula EV-13 or their diastereoisomers, mixtures of two or more diastereoisomers, tautomers, mixtures of two or more tautomers, or isotopic variations body. In yet another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb) and (XIV), R E is having A portion of a structure of formula EV-14 , or its diastereoisomer, mixture of two or more diastereoisomers, tautomer, mixture of two or more tautomers, or isotopic variation body. In yet another embodiment, in the compound of any one of formulae (I)-(XI), (XIIa), (XIIb), (XIIIa), (XIIIb) and (XIV), R E is of formula A portion of the structure of EV-15 or its diastereoisomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant .
在一個實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式 EV-8之結構的部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在另一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式 EV-9之結構的部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式 EV-10之結構的部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式 EV-11之結構的部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式 EV-12之結構的部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式 EV-13之結構的部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在又另一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式 EV-14之結構的部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。在再一實施例中，在式(IA)至(XIA)、(XIIAa)、(XIIAb)、(XIIIAa)、(XIIIAb)及(XIVA)中之任一者之化合物中，R E為具有式 EV-15之結構的部分或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體。 In one embodiment, in the compound of any one of formulae (IA) to (XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is of formula EV - A portion of the structure of 8 or a non-spiroisomer, a mixture of two or more non-spiroisomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant. In another embodiment, in a compound of any one of formulae (IA)-(XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is of formula A portion of the structure of EV-9 or its diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant . In yet another embodiment, in the compound of any one of formulae (IA)-(XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is having A portion of a structure of formula EV-10 or a non-enantiomer, mixture of two or more non-enantiomers, tautomer, mixture of two or more tautomers, or isotopic variation body. In yet another embodiment, in the compound of any one of formulae (IA)-(XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is having Parts of the structures of formula EV-11 or their diastereoisomers, mixtures of two or more diastereoisomers, tautomers, mixtures of two or more tautomers, or isotopic variations body. In yet another embodiment, in the compound of any one of formulae (IA)-(XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is having A portion of a structure of formula EV-12 , or its diastereoisomer, mixture of two or more diastereoisomers, tautomer, mixture of two or more tautomers, or isotopic variation body. In yet another embodiment, in the compound of any one of formulae (IA)-(XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is having Parts of the structures of formula EV-13 or their diastereoisomers, mixtures of two or more diastereoisomers, tautomers, mixtures of two or more tautomers, or isotopic variations body. In yet another embodiment, in the compound of any one of formulae (IA)-(XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is having A portion of a structure of formula EV-14 , or its diastereoisomer, mixture of two or more diastereoisomers, tautomer, mixture of two or more tautomers, or isotopic variation body. In yet another embodiment, in the compound of any one of formulae (IA)-(XIA), (XIIAa), (XIIAb), (XIIIAa), (XIIIAb), and (XIVA), R E is of formula A portion of the structure of EV-15 or its diastereoisomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant .
在一個實施例中，本文提供一種式(XXVII)化合物：
在另一實施例中，本文提供一種式(XXVIII)化合物：
在一個實施例中，本文提供一種式(XXVIIA)化合物：
在另一實施例中，本文提供一種式(XXVIIIA)化合物：
在某些實施例中，L為C 1-20伸烷基、C 1-20伸雜烷基、C 2-20伸烯基、C 2-20伸雜烯基、C 2-20伸炔基、C 2-20伸雜炔基、C 3-10伸環烷基、C 6-14伸芳基、伸雜芳基或伸雜環基，其中之每一者視情況經一或多個取代基Q取代。在某些實施例中，L為C 1-20伸烷基、C 1-20伸雜烷基、C 2-20伸烯基、C 2-20伸雜烯基、C 2-20伸炔基或C 2-20伸雜炔基，其中之每一者視情況經一或多個取代基Q取代。在某些實施例中，L為C 1-20伸烷基或C 1-20伸雜烷基，其中之每一者視情況經一或多個取代基Q取代。 In certain embodiments, L is C 1-20 alkylene, C 1-20 heteroalkylene, C 2-20 alkenylene, C 2-20 heteroalkenyl, C 2-20 alkynylene , C 2-20 heteroalkyne, C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl or heterocyclylene, each of which is optionally substituted by one or more Base Q is substituted. In certain embodiments, L is C 1-20 alkylene, C 1-20 heteroalkylene, C 2-20 alkenylene, C 2-20 heteroalkenyl, C 2-20 alkynylene or C2-20heteroalkynyl , each of which is optionally substituted with one or more substituents Q. In certain embodiments, L is C 1-20 alkylene or C 1-20 heteroalkyl, each of which is optionally substituted with one or more substituents Q .
在某些實施例中，L為視情況經一個、兩個或三個取代基Q取代之C 1-20伸烷基。在某些實施例中，L為視情況經一個、兩個或三個取代基Q取代之C 4-16伸烷基。在某些實施例中，L為視情況經一個、兩個或三個取代基Q取代之C 4-12伸烷基。在某些實施例中，L為視情況經一或兩個側氧基取代之C 1-20伸烷基。在某些實施例中，L為視情況經一或兩個側氧基取代之C 4-16伸烷基。在某些實施例中，L為視情況經一或兩個側氧基取代之C 4-12伸烷基。在某些實施例中，L為視情況經一或兩個側氧基取代之-(CH 2) x-；其中x為1、2、3、4、5、6、7、8、9、10、11、12、13、14、15或16之整數。在某些實施例中，L為視情況經一或兩個側氧基取代之-(CH 2)x-；其中x為2、3、4、5、6、7、8、9、10、11或12之整數。在某些實施例中，L為視情況經一或兩個側氧基取代之-(CH 2) x-；其中x為5、6、7、8或9之整數。 In certain embodiments, L is a C 1-20 alkylene optionally substituted with one, two or three substituents Q, as appropriate. In certain embodiments, L is C 4-16 alkylene optionally substituted with one, two or three substituents Q. In certain embodiments, L is C 4-12 alkylene optionally substituted with one, two, or three substituents Q, as appropriate. In certain embodiments, L is C 1-20 alkylene optionally substituted with one or two pendant oxy groups. In certain embodiments, L is C 4-16 alkylene optionally substituted with one or two pendant oxy groups. In certain embodiments, L is C 4-12 alkylene optionally substituted with one or two pendant oxy groups. In certain embodiments, L is -( CH2 ) x- optionally substituted with one or two pendant oxy groups; wherein x is 1, 2, 3, 4, 5, 6, 7, 8, 9, An integer of 10, 11, 12, 13, 14, 15 or 16. In certain embodiments, L is -( CH2 )x- optionally substituted with one or two pendant oxy groups; wherein x is 2, 3, 4, 5, 6, 7, 8, 9, 10, An integer of 11 or 12. In certain embodiments, L is -( CH2 ) x- optionally substituted with one or two pendant oxy groups; wherein x is an integer of 5, 6, 7, 8, or 9.
在某些實施例中，L為視情況經一個、兩個或三個取代基Q取代之C 1-20伸雜烷基。在某些實施例中，L為視情況經一個、兩個或三個取代基Q取代之C 4-16伸雜烷基。在某些實施例中，L為視情況經一個、兩個或三個取代基Q取代之C 4-12伸雜烷基。在某些實施例中，L為視情況經一個、兩個或三個側氧基取代之C 1-20伸雜烷基。在某些實施例中，L為視情況經一個、兩個或三個側氧基取代之C 4-16伸雜烷基。在某些實施例中，L為視情況經一個、兩個或三個側氧基取代之C 4-12伸雜烷基。 In certain embodiments, L is C 1-20 heteroalkyl substituted with one, two, or three substituents Q, as appropriate. In certain embodiments, L is C 4-16 heteroalkyl substituted with one, two, or three substituents Q, as appropriate. In certain embodiments, L is C 4-12 heteroalkyl substituted with one, two, or three substituents Q, as appropriate. In certain embodiments, L is C 1-20 heteroalkyl, optionally substituted with one, two, or three pendant oxy groups. In certain embodiments, L is C 4-16 heteroalkyl, optionally substituted with one, two, or three pendant oxy groups. In certain embodiments, L is C 4-12 heteroalkyl, optionally substituted with one, two, or three pendant oxy groups.
在某些實施例中，L為視情況經一或多個取代基Q取代之包含伸乙氧基(-CH 2CH 2O-)之C 2-20伸雜烷基。在某些實施例中，L為視情況經一或多個取代基Q取代之包含伸乙氧基之C 2-14伸雜烷基。在某些實施例中，L為視情況經一或多個取代基Q取代之包含伸乙氧基之C 2-10伸雜烷基。在某些實施例中，L為視情況經一或多個取代基Q取代之包含伸丙氧基(-CH 2CH 2CH 2O-)之C 3-20伸雜烷基。在某些實施例中，L為視情況經一或多個取代基Q取代之包含伸丙氧基之C 3-14伸雜烷基。在某些實施例中，L為視情況經一或多個取代基Q取代之包含伸丙氧基之C 3-10伸雜烷基。 In certain embodiments, L is a C2-20 heteroalkylene comprising ethoxy ( -CH2CH2O- ) optionally substituted with one or more substituents Q. In certain embodiments, L is C 2-14 heteroalkylene including ethoxy, optionally substituted with one or more substituents Q, Q. In certain embodiments, L is a C 2-10 heteroalkylene containing ethoxy, optionally substituted with one or more substituents Q, Q. In certain embodiments, L is a C3-20 heteroalkylene group comprising propoxyl ( -CH2CH2CH2O- ) optionally substituted with one or more substituents Q. In certain embodiments, L is C 3-14 heteroalkylene including propoxy, optionally substituted with one or more substituents Q. In certain embodiments, L is C 3-10 heteroalkylene including propoxy, optionally substituted with one or more substituents Q, Q.
在某些實施例中，L為C 1-20伸烷基、C 1-20伸雜烷基、C 2-20伸烯基、C 2-20伸雜烯基、C 2-20伸炔基或C 2-20伸雜炔基，其中一或多個亞甲基各自獨立地經二價基團置換，且各二價基團獨立地為C 3-10伸環烷基、C 6-14伸芳基、伸雜芳基或伸雜環基；且其中伸烷基、伸雜烷基、伸烯基、伸雜烯基、伸炔基、伸雜炔基、伸環烷基、伸芳基、伸雜芳基及伸雜環基各自視情況經一或多個取代基Q取代。在某些實施例中，L為C 1-20伸烷基或C 1-20伸雜烷基，其中一或多個亞甲基各自獨立地經二價基團置換，且各二價基團獨立地為C 3-10伸環烷基、C 6-14伸芳基、伸雜芳基或伸雜環基；且其中伸烷基、伸雜烷基、伸環烷基、伸芳基、伸雜芳基及伸雜環基各自視情況經一或多個取代基Q取代。 In certain embodiments, L is C 1-20 alkylene, C 1-20 heteroalkyl, C 2-20 alkenylene, C 2-20 heteroalkenyl, C 2-20 alkynylene or C 2-20 heteroalkynyl, wherein one or more methylene groups are each independently replaced by a divalent group, and each divalent group is independently C 3-10 cycloalkylene, C 6-14 Arylene, heteroaryl, or heterocyclylene; and wherein alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, cycloalkylene, arylene Each of radical, heteroarylidene, and heterocyclylene is optionally substituted with one or more substituents Q. In certain embodiments, L is a C 1-20 alkylene group or a C 1-20 heteroalkylene group, wherein one or more methylene groups are each independently replaced with a diradical, and each diradical independently C 3-10 cycloalkylene, C 6-14 aryl, heteroaryl, or heterocyclylene; and wherein alkylene, heteroalkyl, cycloalkyl, aryl, Each of heteroarylidene and heterocyclylene is optionally substituted with one or more substituents Q.
在某些實施例中，L為C 1-20伸烷基，其中一或多個亞甲基各自獨立地經二價基團置換，且各二價基團獨立地為C 3-10伸環烷基、C 6-14伸芳基、伸雜芳基或伸雜環基；且其中伸烷基、伸環烷基、伸芳基、伸雜芳基及伸雜環基各自視情況經一或多個取代基Q取代。在某些實施例中，L為C 1-20伸烷基，其中一或多個亞甲基各自獨立地經C 3-10伸環烷基置換；且其中伸烷基及伸環烷基各自視情況經一或多個取代基Q取代。在某些實施例中，L為C 1-20伸烷基，其中一或多個亞甲基各自獨立地經C 6-14伸芳基置換；且其中伸烷基及伸芳基各自視情況經一或多個取代基Q取代。在某些實施例中，L為C 1-20伸烷基，其中一或多個亞甲基各自獨立地經伸雜芳基置換；且其中伸烷基及伸雜芳基各自視情況經一或多個取代基Q取代。在某些實施例中，L為C 1-20伸烷基，其中一或多個亞甲基各自獨立地經伸雜環基置換；且其中伸烷基及伸雜環基各自視情況經一或多個取代基Q取代。 In certain embodiments, L is a C 1-20 alkylene group, wherein one or more methylene groups are each independently replaced with a divalent group, and each divalent group is independently a C 3-10 ring extended group Alkylene, C 6-14 arylidene, heteroarylidene or heterocyclylene; and wherein alkylene, cycloalkylene, arylidene, heteroarylidene, and heterocyclidene are each optionally modified by a or multiple substituents Q substituted. In certain embodiments, L is C 1-20 alkylene, wherein one or more methylene groups are each independently replaced with C 3-10 cycloalkylene; and wherein each alkylene and cycloalkylene Optionally substituted with one or more substituents Q. In certain embodiments, L is a C 1-20 alkylene group, wherein one or more methylene groups are each independently replaced with a C 6-14 aryl group; and wherein each of the alkylene and aryl groups is as appropriate Substituted with one or more substituents Q. In certain embodiments, L is a C 1-20 alkylene group, wherein one or more methylene groups are each independently replaced by a heteroaryl group; and wherein each of the alkylene groups and heteroaryl groups are optionally replaced by a or multiple substituents Q substituted. In certain embodiments, L is a C 1-20 alkylene group, wherein one or more methylene groups are each independently replaced by a heterocyclylene group; and wherein each of the alkylene group and the heterocyclylene group is optionally replaced by a or multiple substituents Q substituted.
在某些實施例中，L為C 1-20伸烷基，其中一個、兩個或三個亞甲基各自獨立地經二價基團置換；其中各二價基團獨立地為環己烷二基、苯二基、1,2,3-三唑二基、2,5-二側氧基吡咯啶二基、哌𠯤二基或哌啶二基。在某些實施例中，L為C 1-20伸烷基，其中一個、兩個或三個亞甲基各自獨立地經二價基團置換；其中各二價基團獨立地為環己烷-1,4-二基、苯-1,3-二基、苯-1,4-二基、1,2,3-三唑-1,4-二基、2,5-二側氧基吡咯啶-1,3-二基、哌𠯤-1,4-二基或哌啶-1,4-二基。 In certain embodiments, L is a C 1-20 alkylene group, wherein one, two, or three methylene groups are each independently replaced with a divalent group; wherein each divalent group is independently cyclohexane Diyl, phenylenediyl, 1,2,3-triazolediyl, 2,5-dioxypyrrolidinediyl, piperidinediyl or piperidinediyl. In certain embodiments, L is a C 1-20 alkylene group, wherein one, two, or three methylene groups are each independently replaced with a divalent group; wherein each divalent group is independently cyclohexane -1,4-diyl, benzene-1,3-diyl, benzene-1,4-diyl, 1,2,3-triazole-1,4-diyl, 2,5-dioxygen Pyrrolidine-1,3-diyl, piperidine-1,4-diyl or piperidine-1,4-diyl.
在某些實施例中，L為C 1-20伸烷基，其中一或兩個亞甲基各自獨立地經二價基團置換；其中各二價基團獨立地為C 3-10伸環烷基、C 6-14伸芳基、伸雜芳基或伸雜環基；且其中伸烷基、伸環烷基、伸芳基、伸雜芳基及伸雜環基各自視情況經一或多個取代基Q取代。在某些實施例中，L為C 1-20伸烷基，其中一或兩個亞甲基各自獨立地經二價基團置換；其中各二價基團獨立地為環己烷二基、苯二基、1,2,3-三唑二基、2,5-二側氧基吡咯啶二基、哌𠯤二基或哌啶二基。在某些實施例中，L為C 1-20伸烷基，其中一或兩個亞甲基各自獨立地經二價基團置換；其中各二價基團獨立地為環己烷-1,4-二基、苯-1,3-二基、苯-1,4-二基、1,2,3-三唑-1,4-二基、2,5-二側氧基吡咯啶-1,3-二基、哌𠯤-1,4-二基或哌啶-1,4-二基。 In certain embodiments, L is a C 1-20 alkylene group, wherein one or two methylene groups are each independently replaced with a divalent group; wherein each divalent group is independently a C 3-10 ring extended group Alkylene, C 6-14 arylidene, heteroarylidene or heterocyclylene; and wherein alkylene, cycloalkylene, arylidene, heteroarylidene, and heterocyclidene are each optionally modified by a or multiple substituents Q substituted. In certain embodiments, L is a C 1-20 alkylene group, wherein one or two methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently cyclohexanediyl, phenylenediyl, 1,2,3-triazolediyl, 2,5-dioxypyrrolidinediyl, piperidinediyl or piperidinediyl. In certain embodiments, L is a C 1-20 alkylene group, wherein one or two methylene groups are each independently replaced with a divalent group; wherein each divalent group is independently cyclohexane-1, 4-diyl, benzene-1,3-diyl, benzene-1,4-diyl, 1,2,3-triazole-1,4-diyl, 2,5-dioxypyrrolidine- 1,3-diyl, piperidine-1,4-diyl or piperidine-1,4-diyl.
在某些實施例中，L為C 1-20伸烷基，其中亞甲基經二價基團置換；其中二價基團為C 3-10伸環烷基、C 6-14伸芳基、伸雜芳基或伸雜環基；且其中伸烷基、伸環烷基、伸芳基、伸雜芳基及伸雜環基各自視情況經一或多個取代基Q取代。在某些實施例中，L為C 1-20伸烷基，其中亞甲基經二價基團置換；其中二價基團為環己烷二基、苯二基、1,2,3-三唑二基、2,5-二側氧基吡咯啶二基、哌𠯤二基或哌啶二基。在某些實施例中，L為C 1-20伸烷基，其中亞甲基經二價基團置換；其中各二價基團獨立地為環己烷-1,4-二基、苯-1,3-二基、苯-1,4-二基、1,2,3-三唑-1,4-二基、2,5-二側氧基吡咯啶-1,3-二基、哌𠯤-1,4-二基或哌啶-1,4-二基。 In certain embodiments, L is a C 1-20 alkylene group, wherein the methylene group is replaced by a divalent group; wherein the divalent group is a C 3-10 cycloalkylene group, a C 6-14 aryl group , heteroarylidene, or heterocyclylene; and wherein alkylene, cycloalkylene, arylidene, heteroarylidene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, L is a C 1-20 alkylene group, wherein the methylene group is replaced by a divalent group; wherein the divalent group is cyclohexanediyl, phenylenediyl, 1,2,3- Triazolediyl, 2,5-dioxypyrrolidinediyl, piperidinediyl or piperidinediyl. In certain embodiments, L is a C 1-20 alkylene group, wherein the methylene group is replaced by a divalent group; wherein each divalent group is independently cyclohexane-1,4-diyl, benzene- 1,3-diyl, benzene-1,4-diyl, 1,2,3-triazole-1,4-diyl, 2,5-dioxypyrrolidine-1,3-diyl, Piperidine-1,4-diyl or piperidine-1,4-diyl.
在某些實施例中，L為C 1-20伸雜烷基，其中一或多個亞甲基各自獨立地經二價基團置換，且各二價基團獨立地為C 3-10伸環烷基、C 6-14伸芳基、伸雜芳基或伸雜環基；且其中伸雜烷基、伸環烷基、伸芳基、伸雜芳基及伸雜環基各自視情況經一或多個取代基Q取代。在某些實施例中，L為C 1-20伸雜烷基，其中一或多個亞甲基各自獨立地經C 3-10伸環烷基置換；且其中伸雜烷基及伸環烷基各自視情況經一或多個取代基Q取代。在某些實施例中，L為C 1-20伸雜烷基，其中一或多個亞甲基各自獨立地經C 6-14伸芳基置換；且其中伸雜烷基及伸芳基各自視情況經一或多個取代基Q取代。在某些實施例中，L為C 1-20伸雜烷基，其中一或多個亞甲基各自獨立地經伸雜芳基置換；且其中伸雜烷基及伸雜芳基各自為視情況經一或多個取代基Q取代。在某些實施例中，L為C 1-20伸雜烷基，其中一或多個亞甲基各自獨立地經伸雜環基置換；且其中伸雜烷基及伸雜環基各自視情況經一或多個取代基Q取代。 In certain embodiments, L is C 1-20 heteroalkyl, wherein one or more methylene groups are each independently replaced with a divalent group, and each divalent group is independently C 3-10 alkyl cycloalkyl, C 6-14 arylidene, heteroarylidene, or heterocyclylene; and wherein heteroalkylene, cycloalkylene, arylidene, heteroarylidene, and heterocyclidene are each as appropriate Substituted with one or more substituents Q. In certain embodiments, L is C 1-20 heteroalkylene, wherein one or more methylene groups are each independently replaced with C 3-10 cycloalkylene; and wherein heteroalkylene and cycloalkylene Each group is optionally substituted with one or more substituents Q. In certain embodiments, L is C 1-20 heteroalkylene, wherein one or more methylene groups are each independently replaced with C 6-14 arylidene ; and wherein each of heteroalkylene and arylidene Optionally substituted with one or more substituents Q. In certain embodiments, L is C 1-20 heteroalkylene, wherein one or more methylene groups are each independently replaced with heteroaryl; and wherein each of heteroalkyl and heteroaryl is treated as is substituted with one or more substituents Q. In certain embodiments, L is C 1-20 heteroalkylene, wherein one or more methylene groups are each independently replaced with heterocyclylene; and wherein each of heteroalkylene and heterocyclylene is as appropriate Substituted with one or more substituents Q.
在某些實施例中，L為C 1-20伸雜烷基，其中一個、兩個或三個亞甲基各自獨立地經二價基團置換；其中各二價基團獨立地為環己烷二基、苯二基、1,2,3-三唑二基、2,5-二側氧基吡咯啶二基、哌𠯤二基或哌啶二基。在某些實施例中，L為C 1-20伸雜烷基，其中一個、兩個或三個亞甲基各自獨立地經二價基團置換；其中各二價基團獨立地為環己烷-1,4-二基、苯-1,3-二基、苯-1,4-二基、1,2,3-三唑-1,4-二基、2,5-二側氧基吡咯啶-1,3-二基、哌𠯤-1,4-二基或哌啶-1,4-二基。 In certain embodiments, L is C 1-20 heteroalkyl, wherein one, two or three methylene groups are each independently replaced with a divalent group; wherein each divalent group is independently cyclohexane Alkanediyl, phenylenediyl, 1,2,3-triazolediyl, 2,5-dioxypyrrolidinediyl, piperidinediyl or piperidinediyl. In certain embodiments, L is C 1-20 heteroalkyl, wherein one, two or three methylene groups are each independently replaced with a divalent group; wherein each divalent group is independently cyclohexane Alkane-1,4-diyl, benzene-1,3-diyl, benzene-1,4-diyl, 1,2,3-triazole-1,4-diyl, 2,5-dioxygen pyrrolidine-1,3-diyl, piperidine-1,4-diyl or piperidine-1,4-diyl.
在某些實施例中，L為C 1-20伸雜烷基，其中一或兩個亞甲基各自獨立地經二價基團置換；其中各二價基團獨立地為C 3-10伸環烷基、C 6-14伸芳基、伸雜芳基或伸雜環基；且其中伸雜烷基、伸環烷基、伸芳基、伸雜芳基及伸雜環基各自視情況經一或多個取代基Q取代。在某些實施例中，L為C 1-20伸雜烷基，其中一或兩個亞甲基各自獨立地經二價基團置換；其中各二價基團獨立地為環己烷二基、苯二基、1,2,3-三唑二基、2,5-二側氧基吡咯啶二基、哌𠯤二基或哌啶二基。在某些實施例中，L為C 1-20伸雜烷基，其中一或兩個亞甲基各自獨立地經二價基團置換；其中各二價基團獨立地為環己烷-1,4-二基、苯-1,3-二基、苯-1,4-二基、1,2,3-三唑-1,4-二基、2,5-二側氧基吡咯啶-1,3-二基、哌𠯤-1,4-二基或哌啶-1,4-二基。 In certain embodiments, L is a C 1-20 heteroalkyl group, wherein one or two methylene groups are each independently replaced with a divalent group; wherein each divalent group is independently a C 3-10 alkyl group cycloalkyl, C 6-14 arylidene, heteroarylidene, or heterocyclylene; and wherein heteroalkylene, cycloalkylene, arylidene, heteroarylidene, and heterocyclylene are each as appropriate Substituted with one or more substituents Q. In certain embodiments, L is C 1-20 heteroalkyl, wherein one or two methylene groups are each independently replaced with a divalent group; wherein each divalent group is independently cyclohexanediyl , phenylenediyl, 1,2,3-triazolediyl, 2,5-dioxypyrrolidinediyl, piperidinediyl or piperidinediyl. In certain embodiments, L is C 1-20 heteroalkyl, wherein one or two methylene groups are each independently replaced with a divalent group; wherein each divalent group is independently cyclohexane-1 ,4-diyl, benzene-1,3-diyl, benzene-1,4-diyl, 1,2,3-triazole-1,4-diyl, 2,5-dioxypyrrolidine -1,3-diyl, piperidine-1,4-diyl or piperidine-1,4-diyl.
在某些實施例中，L為C 1-20伸雜烷基，其中亞甲基經二價基團置換；其中二價基團為C 3-10伸環烷基、C 6-14伸芳基、伸雜芳基或伸雜環基；且其中伸雜烷基、伸環烷基、伸芳基、伸雜芳基及伸雜環基各自視情況經一或多個取代基Q取代。在某些實施例中，L為C 1-20伸雜烷基，其中亞甲基經二價基團置換；其中二價基團為環己烷二基、苯二基、1,2,3-三唑二基、2,5-二側氧基吡咯啶二基、哌𠯤二基或哌啶二基。在某些實施例中，L為C 1-20伸雜烷基，其中亞甲基經二價基團置換；其中各二價基團獨立地為環己烷-1,4-二基、苯-1,3-二基、苯-1,4-二基、1,2,3-三唑-1,4-二基、2,5-二側氧基吡咯啶-1,3-二基、哌𠯤-1,4-二基或哌啶-1,4-二基。 In certain embodiments, L is a C 1-20 heteroalkylene group, wherein the methylene group is replaced by a divalent group; wherein the divalent group is a C 3-10 cycloalkylene group, a C 6-14 aryl group and wherein heteroalkylene, cycloalkylene, arylidene, heteroarylidene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, L is a C 1-20 heteroalkylene group, wherein the methylene group is replaced by a divalent group; wherein the divalent group is cyclohexanediyl, benzenediyl, 1,2,3 - triazolediyl, 2,5-dioxypyrrolidinediyl, piperidinediyl or piperidinediyl. In certain embodiments, L is C 1-20 heteroalkylene, wherein the methylene group is replaced by a divalent group; wherein each divalent group is independently cyclohexane-1,4-diyl, benzene -1,3-diyl, benzene-1,4-diyl, 1,2,3-triazole-1,4-diyl, 2,5-dioxypyrrolidine-1,3-diyl , piperidine-1,4-diyl or piperidine-1,4-diyl.
在某些實施例中，L為C 1-15伸烷基-C 3-10伸環烷基、C 1-15伸雜烷基-C 3-10伸環烷基、C 1-15伸烷基-C 6-14伸芳基、C 1-15伸雜烷基-C 6-14伸芳基、C 1-15伸烷基-伸雜芳基、C 1-15伸雜烷基-伸雜芳基、C 1-15伸烷基-伸雜環基、C 1-15伸雜烷基-伸雜環基或伸雜芳基-伸雜環基，其中各伸烷基、伸雜烷基、伸環烷基、伸芳基、伸雜芳基及伸雜環基視情況經一或多個取代基Q取代。在某些實施例中，L為C 1-15伸烷基-C 3-10伸環烷基，其中伸烷基及伸環烷基各自視情況經一或多個取代基Q取代。在某些實施例中，L為C 1-15伸雜烷基-C 3-10伸環烷基，其中伸雜烷基及伸環烷基各自視情況經一或多個取代基Q取代。在某些實施例中，L為C 1-15伸烷基-C 6-14伸芳基，其中伸烷基及伸芳基各自視情況經一或多個取代基Q取代。在某些實施例中，L為C 1-15伸雜烷基-C 6-14伸芳基，其中伸雜烷基及伸芳基各自視情況經一或多個取代基Q取代。在某些實施例中，L為C 1-15伸烷基-伸雜芳基，其中伸烷基及伸雜芳基各自視情況經一或多個取代基Q取代。在某些實施例中，L為C 1-15伸雜烷基-伸雜芳基，其中伸雜烷基及伸雜芳基各自視情況經一或多個取代基Q取代。在某些實施例中，L為C 1-15伸烷基-伸雜環基，其中伸烷基及伸雜環基各自視情況經一或多個取代基Q取代。在某些實施例中，L為C 1-15伸雜烷基-伸雜環基，其中伸雜烷基及伸雜環基各自視情況經一或多個取代基Q取代。在某些實施例中，L為C 1-15伸雜芳基-伸雜環基，其中伸雜芳基及伸雜環基各自視情況經一或多個取代基Q取代。 In certain embodiments, L is C 1-15 alkylene-C 3-10 cycloalkylene, C 1-15 heteroalkylene-C 3-10 cycloalkylene, C 1-15 alkylene base-C 6-14 aryl, C 1-15 heteroalkyl-C 6-14 aryl, C 1-15 alkyl-heteroaryl, C 1-15 heteroalkyl- Heteroaryl, C 1-15 alkylene-heterocyclic group, C 1-15 heteroalkylene-heterocyclic group or heteroaryl-heterocyclic group, wherein each alkylene, heteroalkane , cycloalkylene, arylidene, heteroarylidene, and heterocyclylene are optionally substituted with one or more substituents Q. In certain embodiments, L is C 1-15 alkylene-C 3-10 cycloalkylene, wherein each of the alkylene and cycloalkylene is optionally substituted with one or more substituents Q . In certain embodiments, L is C 1-15 heteroalkylene-C 3-10 cycloalkylene, wherein each of heteroalkylene and cycloalkylene is optionally substituted with one or more substituents Q . In certain embodiments, L is C 1-15 alkylene-C 6-14 arylidene, wherein each of alkylene and arylidene is optionally substituted with one or more substituents Q. In certain embodiments, L is C 1-15 heteroalkylene-C 6-14 arylidene, wherein each of heteroalkylene and arylidene is optionally substituted with one or more substituents Q. In certain embodiments, L is C 1-15 alkylene-heteroaryl, wherein alkylene and heteroaryl are each optionally substituted with one or more substituents Q. In certain embodiments, L is C 1-15 heteroalkylene-heteroaryl, wherein each of heteroalkyl and heteroaryl is optionally substituted with one or more substituents Q. In certain embodiments, L is C 1-15 alkylene-heterocyclylene, wherein alkylene and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, L is C 1-15 heteroalkylidene-heterocyclylene, wherein heteroalkylene and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, L is C 1-15 heteroarylidene-heterocyclylene, wherein heteroaryl and heterocyclylene are each optionally substituted with one or more substituents Q.
在某些實施例中，L為具有L 1-L 2-L 3之結構之連接子，其中： L 1為鍵、C 1-10伸烷基、C 1-10伸雜烷基或伸雜環基； L 2為C 3-10伸環烷基、C 6-14伸芳基、伸雜芳基或伸雜環基；及 L 3為C 1-10伸烷基、C 1-10伸雜烷基、伸雜芳基或伸雜環基； 其中各伸烷基、伸雜烷基、伸環烷基、伸芳基、伸雜芳基及伸雜環基視情況經一或多個取代基Q取代。 In certain embodiments, L is a linker having the structure of L 1 -L 2 -L 3 , wherein: L 1 is a bond, C 1-10 alkylene, C 1-10 heteroalkylene or heteroalkylene cyclic group; L 2 is C 3-10 cycloalkylene, C 6-14 aryl group, heteroaryl or heterocyclic group; and L 3 is C 1-10 alkylene, C 1-10 alkylene Heteroalkylene, heteroarylidene, or heterocyclylene; wherein each alkylene, heteroalkylene, cycloalkylene, arylidene, heteroaryl, and heterocyclidene is optionally modified by one or more Substituent Q is substituted.
在某些實施例中，L 2為視情況經一或多個取代基Q取代之C 3-10伸環烷基。在某些實施例中，L 2為視情況經一或多個取代基Q取代之單環C 3-10伸環烷基。在某些實施例中，L 2為各自視情況經一或多個取代基Q取代之環戊烷二基或環己烷二基。在某些實施例中，L 2為各自視情況經一或多個取代基Q取代之環戊烷-1,3-二基或環己烷-1,4-二基。 In certain embodiments, L 2 is C 3-10 cycloextended alkyl optionally substituted with one or more substituents Q . In certain embodiments, L 2 is a monocyclic C 3-10 cycloextended alkyl group optionally substituted with one or more substituents Q. In certain embodiments, L 2 is cyclopentanediyl or cyclohexanediyl, each optionally substituted with one or more substituents Q. In certain embodiments, L 2 is cyclopentane-1,3-diyl or cyclohexane-1,4-diyl, each optionally substituted with one or more substituents Q, Q.
在某些實施例中，L 2為視情況經一或多個取代基Q取代之C 6-14伸芳基。在某些實施例中，L 2為視情況經一或多個取代基Q取代之苯二基。在某些實施例中，L 2為視情況經一或多個取代基Q取代之苯-1,3-二基。在某些實施例中，L 2為視情況經一或多個取代基Q取代之苯-1,4-二基。 In certain embodiments, L 2 is C 6-14 arylidene optionally substituted with one or more substituents Q . In certain embodiments, L 2 is phenylenediyl optionally substituted with one or more substituents Q. In certain embodiments, L 2 is benzene-1,3-diyl optionally substituted with one or more substituents Q. In certain embodiments, L 2 is benzene-1,4-diyl optionally substituted with one or more substituents Q.
在某些實施例中，L 2為視情況經一或多個取代基Q取代之伸雜芳基。在某些實施例中，L 2為視情況經一或多個取代基Q取代之單環伸雜芳基。在某些實施例中，L 2為各自視情況經一或多個取代基Q取代之5員或6員伸雜芳基。在某些實施例中，L 2為視情況經一或多個取代基Q取代之三唑二基。在某些實施例中，L 2為視情況經一或多個取代基Q取代之1,2,3-三唑-1,4-二基。 In certain embodiments, L 2 is heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, L 2 is a monocyclic heteroarylidene optionally substituted with one or more substituents Q. In certain embodiments, L 2 is a 5- or 6-membered heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, L 2 is triazolediyl optionally substituted with one or more substituents Q. In certain embodiments, L 2 is 1,2,3-triazole-1,4-diyl optionally substituted with one or more substituents Q.
在某些實施例中，L 2為視情況經一或多個取代基Q取代之伸雜環基。在某些實施例中，L 2為視情況經一或多個取代基Q取代之單環伸雜環基。在某些實施例中，L 2為各自視情況經一或多個取代基Q取代之5員或6員伸雜環基。在某些實施例中，L 2為各自視情況經一或多個取代基Q取代之哌𠯤二基或哌啶二基。在某些實施例中，L 2為各自視情況經一或多個取代基Q取代之哌𠯤-1,4-二基、哌啶-1,3-二基或哌啶-1,4-二基。 In certain embodiments, L 2 is heterocyclylene optionally substituted with one or more substituents Q. In certain embodiments, L 2 is a monocyclic heterocyclylene optionally substituted with one or more substituents Q. In certain embodiments, L 2 is a 5- or 6-membered heterocyclyl group, each optionally substituted with one or more substituents Q. In certain embodiments, L 2 is piperidinediyl or piperidinediyl, each optionally substituted with one or more substituents Q. In certain embodiments, L 2 is piperidine-1,4-diyl, piperidine-1,3-diyl, or piperidine-1,4-diyl, each optionally substituted with one or more substituents Q, Q Two bases.
在某些實施例中，L為具有-Z L-(R L-Z L) z-之結構之連接子，其中： 各R L獨立地為C 1-10伸烷基、C 1-10伸烷基、C 2-10伸烯基、C 2-10伸炔基、C 3-10伸環烷基、C 6-14伸芳基、伸雜芳基或伸雜環基； 各Z L獨立地為鍵、-C(O)-、-C(O)O-、-C(O)NR 1b-、-C(O)S-、-C(NR 1a)NR 1b-、-C(S)-、-C(S)O-、-C(S)NR 1b-、-O-、-OC(O)O-、-OC(O)NR 1b-、-OC(O)S-、-OC(NR 1a)NR 1b-、-OC(S)-、-OC(S)O-、-OC(S)NR 1b-、-OS(O)-、-OS(O) 2-、-OS(O)NR 1b-、-OS(O) 2NR 1b-、-NR 1b-、-NR 1aC(O)NR 1b-、-NR 1aC(O)S-、-NR 1aC(NR 1d)NR 1b-、-NR 1aC(S)NR 1b-、-NR 1aS(O)NR 1b-、-NR 1aS(O) 2NR 1b-、-S-、-S(O)-、-S(O) 2-、-S(O)NR 1b-或-S(O) 2NR 1b-；其中各R 1a、R 1b及R 1d如本文所定義；及 z為1、2、3、4、5、6、7、8、9或10之整數； 其中各伸烷基、伸烯基、伸炔基、伸環烷基、伸芳基、伸雜芳基及伸雜環基視情況經一或多個取代基Q取代。 In certain embodiments, L is a linker having the structure -Z L -(R L -Z L ) z -, wherein: each R L is independently C 1-10 alkylene, C 1-10 alkylene Alkyl, C 2-10 alkenylene, C 2-10 alkynylene, C 3-10 cycloalkylene, C 6-14 aryl, heteroaryl or heterocyclylene; each Z L is independent Ground is bond, -C(O)-, -C(O)O-, -C(O)NR 1b -, -C(O)S-, -C(NR 1a )NR 1b -, -C(S )-, -C(S)O-, -C(S)NR 1b -, -O-, -OC(O)O-, -OC(O)NR 1b -, -OC(O)S-, - OC(NR 1a )NR 1b -, -OC(S)-, -OC(S)O-, -OC(S)NR 1b -, -OS(O)-, -OS(O) 2 -, -OS (O)NR 1b -, -OS(O) 2 NR 1b -, -NR 1b -, -NR 1a C(O)NR 1b -, -NR 1a C(O)S-, -NR 1a C(NR 1d )NR 1b -, -NR 1a C(S)NR 1b -, -NR 1a S(O)NR 1b -, -NR 1a S(O) 2 NR 1b -, -S-, -S(O)-, -S(O) 2 -, -S(O)NR 1b - or -S(O) 2 NR 1b -; wherein each R 1a , R 1b and R 1d are as defined herein; and z is 1, 2, 3 , an integer of 4, 5, 6, 7, 8, 9 or 10; wherein each alkylene, alkenylene, alkynylene, cycloalkylene, aryl, heteroaryl and heterocyclylene is regarded as is substituted with one or more substituents Q.
在某些實施例中，各R L獨立地為各自視情況經一或多個取代基Q取代之C 1-10伸烷基、C 2-10伸炔基、C 3-10伸環烷基、C 6-14伸芳基、伸雜芳基或伸雜環基；各Z L獨立地為鍵、-C(O)-、-C(O)NR 1b-、-C(NR 1a)NR 1b-、-O-、-OC(O)NR 1b-、-NR 1b-、-NR 1aC(O)NR 1b-、-NR 1aC(NR 1d)NR 1b-、-NR 1aS(O)NR 1b-、-NR 1aS(O) 2NR 1b-、-S-、-S(O)-、-S(O) 2-、-S(O)NR 1b-或-S(O) 2NR 1b-；及z為1、2、3、4、5、6、7、8、9或10之整數；其中各R 1a、R 1b及R 1d如本文所定義。 In certain embodiments, each R L is independently C 1-10 alkylene, C 2-10 alkynylene, C 3-10 cycloalkylene, each optionally substituted with one or more substituents Q, Q , C 6-14 arylidene, heteroaryl or heterocyclide; each Z L is independently a bond, -C(O)-, -C(O)NR 1b -, -C(NR 1a )NR 1b -, -O-, -OC(O)NR 1b -, -NR 1b -, -NR 1a C(O)NR 1b -, -NR 1a C(NR 1d )NR 1b -, -NR 1a S(O )NR 1b -, -NR 1a S(O) 2 NR 1b -, -S-, -S(O)-, -S(O) 2 -, -S(O)NR 1b - or -S(O) 2 NR 1b -; and z is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; wherein each of R 1a , R 1b and R 1d is as defined herein.
在某些實施例中，各R L獨立地為各自視情況經一或多個取代基Q取代之C 1-10伸烷基、C 2-10伸炔基、C 3-10伸環烷基、C 6-14伸芳基、伸雜芳基或伸雜環基；各Z L獨立地為鍵、-C(O)-、-C(O)NR 1b-、-O-、-OC(O)NR 1b-、-NR 1b-、-NR 1aC(O)NR 1b-、-NR 1aC(NR 1d)NR 1b-；及z為1、2、3、4、5、6、7或8之整數；其中各R 1a、R 1b及R 1d如本文所定義。 In certain embodiments, each R L is independently C 1-10 alkylene, C 2-10 alkynylene, C 3-10 cycloalkylene, each optionally substituted with one or more substituents Q, Q , C 6-14 arylidene, heteroarylidene or heterocyclidene group; each Z L is independently a bond, -C(O)-, -C(O)NR 1b -, -O-, -OC( O)NR 1b -, -NR 1b -, -NR 1a C(O)NR 1b -, -NR 1a C(NR 1d )NR 1b -; and z is 1, 2, 3, 4, 5, 6, 7 or an integer of 8; wherein each R 1a , R 1b and R 1d are as defined herein.
在某些實施例中，各R L獨立地為甲烷二基、乙烷二基、丙烷二基、丁烷二基、戊烷二基、己烷二基、庚烷二基、辛烷二基、乙炔二基、環戊烷二基、環己烷二基、雙環[2.2.2]辛烷二基、苯二基、吡唑二基、咪唑二基、四唑二基、嘧啶二基、5,6,7,8,9,10-六氫環辛并[ d]嗒𠯤二基、1,3-二㗁烷二基、哌𠯤二基、哌啶二基或3,9-二氮雜螺[5.5]十一烷二基，其各自視情況經一或多個取代基Q取代；各Z L獨立地為鍵、-C(O)-、-C(O)O-、-C(O)NH-、-OC(O)NH-、-O-、-NH-、-N(CH 3)-、-NHC(O)NH-；及z為1、2、3、4、5、6、7或8之整數。 In certain embodiments, each R L is independently methanediyl, ethanediyl, propanediyl, butanediyl, pentanediyl, hexanediyl, heptanediyl, octanediyl , acetylenediyl, cyclopentanediyl, cyclohexanediyl, bicyclo[2.2.2]octanediyl, benzenediyl, pyrazolediyl, imidazolediyl, tetrazolediyl, pyrimidinediyl, 5,6,7,8,9,10-Hexahydrocyclooctano[ d ] pyridinediyl, 1,3-dioxanediyl, piperidinediyl, piperidinediyl or 3,9-diyl azaspiro[5.5]undecanediyl, each of which is optionally substituted with one or more substituents Q; each Z L is independently a bond, -C(O)-, -C(O)O-, - C(O)NH-, -OC(O)NH-, -O-, -NH-, -N( CH3 )-, -NHC(O)NH-; and z is 1, 2, 3, 4, An integer of 5, 6, 7 or 8.
在某些實施例中，各R L獨立地為甲烷二基、乙烷-1,2-二基、丙烷-1,3-二基、丁烷-1,4-二基、戊烷-1,5-二基、己烷-1,6-二基、庚烷-1,7-二基、辛烷-1,8-二基、乙炔-1,2-二基、環戊烷-1,3-二基、環己烷-1,3-二基、環己烷-1,4-二基、雙環[2.2.2]辛烷-1,4-二基、苯-1,3-二基、苯-1,4-二基、吡唑-1,3-二基、吡唑-1,4-二基、咪唑-1,4-二基、1,2,3-三唑-1,4-二基、嘧啶-2,4-二基、嘧啶-2,5-二基、5,6,7,8,9,10-六氫環辛并[ d]嗒𠯤-1,7-二基、吡唑啶-1,3-二基、吡唑啶-1,4-二基、1,3-二㗁烷-2,5-二基、哌𠯤-1,4-二基、哌啶-1,3-二基、哌啶-1,4-二基或3,9-二氮雜螺[5.5]-十一烷-3,9-二基，其各自視情況經一或多個取代基Q取代；各Z L獨立地為鍵、-C(O)-、-C(O)O-、-C(O)NH-、-OC(O)NH-、-O-、-NH-、-N(CH 3)-、-NHC(O)NH-；及z為1、2、3、4、5、6、7或8之整數。 In certain embodiments, each RL is independently methanediyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1 ,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, acetylene-1,2-diyl, cyclopentane-1 ,3-diyl, cyclohexane-1,3-diyl, cyclohexane-1,4-diyl, bicyclo[2.2.2]octane-1,4-diyl, benzene-1,3-diyl diyl, benzene-1,4-diyl, pyrazole-1,3-diyl, pyrazole-1,4-diyl, imidazole-1,4-diyl, 1,2,3-triazole- 1,4-diyl, pyrimidine-2,4-diyl, pyrimidine-2,5-diyl, 5,6,7,8,9,10-hexahydrocyclooctano[ d ] pyridine-1, 7-diyl, pyrazolidine-1,3-diyl, pyrazolidine-1,4-diyl, 1,3-dioxane-2,5-diyl, piperidine-1,4-diyl base, piperidine-1,3-diyl, piperidine-1,4-diyl or 3,9-diazaspiro[5.5]-undecan-3,9-diyl, each of which is optionally One or more substituents Q are substituted; each Z L is independently a bond, -C(O)-, -C(O)O-, -C(O)NH-, -OC(O)NH-, -O -, -NH-, -N( CH3 )-, -NHC(O)NH-; and z is an integer of 1, 2, 3, 4, 5, 6, 7, or 8.
在某些實施例中，L為：
在某些實施例中，L為：
在某些實施例中，L為：
在某些實施例中，L為
在某些實施例中，L為：
在某些實施例中，L為戊-1,5-二基、己-1,6-二基、庚-1,7-二基、辛-1,8-二基、壬-1,9-二基、癸-1,10-二基、十一烷-1,11-二基、哌𠯤-1,4-二基、
在某些實施例中，L為丙烷-1,3-二基、丁烷-1,4-二基、戊烷-1,5-二基、己烷-1,6-二基、庚烷-1,7-二基、辛烷-1,8-二基、壬-1,9-二基、癸烷-1,10-二基、十一烷-1,11-二基、十二烷-1,12-二基、十三烷-1,13-二基、
在某些實施例中，L為丙烷-1,3-二基、戊烷-1,5-二基、庚烷-1,7-二基、壬-1,9-二基、十一烷-1,11-二基、十三烷-1,13-二基、
在一個實施例中，本文提供： 3-(6-氟-4-(1-(7-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基-吡唑并[1,5- a]嘧啶-5-基)苯基)庚基)哌啶-4-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮 A1； 3-(6-氟-4-(1-(7-(4-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基-吡唑并[1,5- a]嘧啶-5-基)苯基)庚基)哌啶-4-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮 A2； 2-(2,6-二側氧基哌啶-3-基)-4-((2-(2-(2-(3-(4-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5- a]嘧啶-5-基)苯基)丙氧基)乙氧基)乙氧基)乙基)-胺基)異吲哚啉-1,3-二酮 A3； 3-(6-氟-4-(1-(9-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基-吡唑并[1,5- a]嘧啶-5-基)苯基)壬基)哌啶-4-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮 A4； 3-(6-氟-4-(1-(9-(4-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基-吡唑并[1,5- a]嘧啶-5-基)苯基)壬基)哌啶-4-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮 A5； 3-(6-氟-4-(1-(5-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基-吡唑并[1,5- a]嘧啶-5-基)苯基)戊基)哌啶-4-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮 A6； 3-(6-氟-4-(1-(5-(4-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基-吡唑并[1,5- a]嘧啶-5-基)苯基)戊基)哌啶-4-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮 A7； 3-(1-((4-(((7-(4-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基-吡唑并[1,5- a]嘧啶-5-基)苯基)庚基)胺基)甲基)苯氧基)甲基)-4-側氧基-4 H-噻吩并[3,4- c]吡咯-5(6 H)-基)哌啶-2,6-二酮 A8； 3-(1-((4-(((7-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基-吡唑并[1,5- a]嘧啶-5-基)苯基)庚基)胺基)甲基)苯氧基)甲基)-4-側氧基-4 H-噻吩并[3,4- c]吡咯-5(6 H)-基)哌啶-2,6-二酮 A9； 3-(6-氟-4-(1-(3-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基-吡唑并[1,5- a]嘧啶-5-基)苯基)丙基)哌啶-4-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮 A10； 3-(6-氟-4-(1-(4-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基-吡唑并[1,5- a]嘧啶-5-基)苯基)丁基)哌啶-4-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮 A11； 3-(6-氟-4-(4-(2-(4-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5- a]嘧啶-5-基)苯乙基)-1 H-1,2,3-三唑-1-基)乙基)哌𠯤-1-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮 A12； 3-(6-氟-4-(1-(2-(4-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5- a]嘧啶-5-基)苯乙基)-1H-1,2,3-三唑-1-基)乙基)哌啶-4-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮 A13； 3-(6-氟-4-(1-(2-(4-(3-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5- a]嘧啶-5-基)苯基)丙基)-1 H-1,2,3-三唑-1-基)乙基)哌啶-4-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮 A14； 3-(6-氟-4-(1-(2-(4-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5- a]嘧啶-5-基)苯乙基)哌𠯤-1-基)乙基)哌啶-4-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮 A15； 3-(6-氟-4-(1-(2-(4-(3-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5- a]嘧啶-5-基)苯基)丙基)哌𠯤-1-基)乙基)哌啶-4-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮 A16； 3-(6-氟-4-(4-(7-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基-吡唑并[1,5- a]嘧啶-5-基)苯基)庚基)哌𠯤-1-基)-1-側氧基異吲哚啉-2-基)-哌啶-2,6-二酮 A17； 3-(4-((1-(6-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基-吡唑并[1,5- a]嘧啶-5-基)苯基)己醯基)哌啶-4-基)乙炔基)-1-側氧基異吲哚啉-2-基)-哌啶-2,6-二酮 A18； 3-(4-((4-(((7-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基-吡唑并[1,5- a]嘧啶-5-基)苯基)庚基)胺基)甲基)苯甲基)氧基)-1-側氧基異吲哚啉-2-基)-哌啶-2,6-二酮 A19； 3-(6-氟-4-((2-(4-(4-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5- a]嘧啶-5-基)苯基)丁基)哌𠯤-1-基)-2-側氧基乙基)胺基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮 A20； 3-(4-((4-(((9-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基-吡唑并[1,5- a]嘧啶-5-基)苯基)壬基)胺基)甲基)苯甲基)氧基)-1-側氧基異吲哚啉-2-基)-哌啶-2,6-二酮 A21； 3-(6-氟-5-(1-(5-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基-吡唑并[1,5- a]嘧啶-5-基)苯基)戊基)哌啶-4-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮 A22； 3-(6-氟-5-(1-(7-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基-吡唑并[1,5- a]嘧啶-5-基)苯基)庚基)哌啶-4-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮 A23； 2-(2,6-二側氧基哌啶-3-基)-4-((2-(2-(3-(4-(7-(4-(2-羥基乙基)-哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5- a]嘧啶-5-基)苯基)丙氧基)乙氧基)乙基)胺基)-異吲哚啉-1,3-二酮 A24； 2-(2,6-二側氧基哌啶-3-基)-5-氟-6-(4-((1-(7-(3-(7-(4-(2-羥基乙基)-哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5- a]嘧啶-5-基)苯基)庚醯基)哌啶-4-基)甲基)哌𠯤-1-基)異吲哚啉-1,3-二酮 A25； 2-(2,6-二側氧基哌啶-3-基)-5-氟-6-(4-((1-(9-(3-(7-(4-(2-羥基乙基)-哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5- a]嘧啶-5-基)苯基)壬醯基)哌啶-4-基)甲基)哌𠯤-1-基)異吲哚啉-1,3-二酮 A26； 2-(2,6-二側氧基哌啶-3-基)-5-氟-6-(4-((1-(11-(3-(7-(4-(2-羥基乙基)-哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5- a]嘧啶-5-基)苯基)十一醯基)哌啶-4-基)甲基)哌𠯤-1-基)異吲哚啉-1,3-二酮 A27； 3-(1-((4-(((5-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基-吡唑并[1,5- a]嘧啶-5-基)苯基)戊基)胺基)甲基)苯氧基)甲基)-4-側氧基-4 H-噻吩并[3,4- c]吡咯-5(6 H)-基)哌啶-2,6-二酮 A28； 3-(6-氟-4-(6-(4-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5- a]嘧啶-5-基)苯乙基)哌𠯤-1-基)己-1-炔-1-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮 A29； 3-(1-((4-(((9-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基-吡唑并[1,5- a]嘧啶-5-基)苯基)壬基)胺基)甲基)苯氧基)甲基)-4-側氧基-4 H-噻吩并[3,4- c]吡咯-5(6 H)-基)哌啶-2,6-二酮 A30； 3-(1-((4-(((9-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基-吡唑并[1,5- a]嘧啶-5-基)苯基)壬基)(甲基)胺基)甲基)苯氧基)甲基)-4-側氧基-4 H-噻吩并[3,4- c]吡咯-5(6 H)-基)哌啶-2,6-二酮 A31； N-(5-(2,6-二側氧基哌啶-3-基)-4-側氧基-5,6-二氫-4 H-噻吩并[3,4- c]吡咯-1-基)-2-(4-(9-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5- a]嘧啶-5-基)苯基)壬基)哌𠯤-1-基)乙醯胺 A32； 3-(6-氟-4-(4-(5-(4-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基-吡唑并[1,5- a]嘧啶-5-基)哌啶-1-基)戊基)哌𠯤-1-基)-1-側氧基異吲哚啉-2-基)-哌啶-2,6-二酮 A33； 3-(6-氟-4-(4-(9-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基-吡唑并[1,5- a]嘧啶-5-基)壬基)哌𠯤-1-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮 A34； 2-((2-(2,6-二側氧基哌啶-3-基)-1-側氧基異吲哚啉-4-基)氧基)- N-(7-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5- a]嘧啶-3-基)苯基)庚基)-乙醯胺 A35； 3-(6-氟-4-(1-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基-吡唑并[1,5- a]嘧啶-5-基)苯乙基)哌啶-4-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮 A36； 3-(6-氟-4-(1-(5-(4-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5- a]嘧啶-5-基)哌啶-1-基)戊基)哌啶-4-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮 A37； 3-(6-氟-4-(1-(9-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基-吡唑并[1,5- a]嘧啶-5-基)壬基)哌啶-4-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮 A38； 3-(6-氟-4-(1-(9-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基-吡唑并[1,5- a]嘧啶-5-基)壬基)哌啶-4-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮 A39； 3-(6-氟-4-((2-(4-(6-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5- a]嘧啶-5-基)苯基)己基)哌𠯤-1-基)-2-側氧基乙基)胺基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮 A40； 2-((2-(2,6-二側氧基哌啶-3-基)-1-側氧基異吲哚啉-4-基)氧基)- N-(9-(4-(7-(4-(2-羥基乙基)哌啶-1-基)-2-甲基-5-苯基吡唑并[1,5- a]嘧啶-3-基)苯基)壬基)-乙醯胺 A41； 2-((2-(2,6-二側氧基哌啶-3-基)-1-側氧基異吲哚啉-4-基)氧基)- N-(7-(4-(7-(4-(2-羥基乙基)哌啶-1-基)-2-甲基-5-苯基吡唑并[1,5- a]嘧啶-3-基)苯基)庚基)-乙醯胺 A42； 2-((2-(2,6-二側氧基哌啶-3-基)-1-側氧基異吲哚啉-4-基)氧基)- N-(11-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5- a]嘧啶-3-基)苯基)十一基)-乙醯胺 A43； 2-((2-(2,6-二側氧基哌啶-3-基)-1-側氧基異吲哚啉-4-基)氧基)-N-(9-(4-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5- a]嘧啶-3-基)苯基)壬基)-乙醯胺 A44； 2-((2-(2,6-二側氧基哌啶-3-基)-1-側氧基異吲哚啉-4-基)氧基)- N-(9-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5- a]嘧啶-3-基)苯基)壬基)-乙醯胺 A45； 2-((2-(2,6-二側氧基哌啶-3-基)-1-側氧基異吲哚啉-4-基)氧基)- N-(11-(4-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5- a]嘧啶-3-基)苯基)十一基)-乙醯胺 A46； 2-(2,6-二側氧基哌啶-3-基)-5-氟-6-(4-((1-(8-(3-(7-(4-(2-羥基乙基)-哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5- a]嘧啶-3-基)苯基)-3-甲基辛醯基)-哌啶-4-基)甲基)哌𠯤-1-基)異吲哚啉-1,3-二酮 A47； 2-((2-(2,6-二側氧基哌啶-3-基)-1-側氧基異吲哚啉-4-基)氧基)- N-(9-(2-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5- a]嘧啶-3-基)苯基)壬基)-乙醯胺 A48； 2-((2-(2,6-二側氧基哌啶-3-基)-1-側氧基異吲哚啉-4-基)氧基)- N-(11-(2-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5- a]嘧啶-3-基)苯基)十一基)-乙醯胺 A49； 2-((2-(2,6-二側氧基哌啶-3-基)-1-側氧基異吲哚啉-4-基)氧基)- N-(7-(2-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5- a]嘧啶-3-基)苯基)庚基)-乙醯胺 A50； 3-(5-((9-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基-吡唑并[1,5- a]嘧啶-3-基)苯基)壬基)胺基)-2-甲基-4-側氧基喹唑啉-3(4 H)-基)-哌啶-2,6-二酮 A51； 3-(5-((7-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基-吡唑并[1,5- a]嘧啶-3-基)苯基)庚基)胺基)-2-甲基-4-側氧基喹唑啉-3(4 H)-基)-哌啶-2,6-二酮 A52； 3-(5-((11-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基-吡唑并[1,5- a]嘧啶-3-基)苯基)十一基)胺基)-2-甲基-4-側氧基喹唑啉-3(4 H)-基)哌啶-2,6-二酮 A53； 3-(6-((4-(((7-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基-吡唑并[1,5- a]嘧啶-5-基)苯基)庚基)胺基)甲基)苯甲基)氧基)-1-側氧基異吲哚啉-2-基)-哌啶-2,6-二酮 A54； 2-(2,6-二側氧基哌啶-3-基)-5-氟-6-(4-((1-(6-(3-(7-(4-(2-羥基乙基)-哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5- a]嘧啶-3-基)苯基)-3-甲基己醯基)-哌啶-4-基)甲基)哌𠯤-1-基)異吲哚啉-1,3-二酮 A55；或 2-(2,6-二側氧基哌啶-3-基)-5-氟-6-(4-((1-(10-(3-(7-(4-(2-羥基乙基)-哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5- a]嘧啶-3-基)苯基)-3-甲基癸醯基)-哌啶-4-基)甲基)哌𠯤-1-基)異吲哚啉-1,3-二酮 A56； 或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體；或其醫藥學上可接受之鹽、溶劑合物、水合物或前藥。 In one embodiment, provided herein: 3-(6-Fluoro-4-(1-(7-(3-(7-(4-(2-hydroxyethyl)piperidin-1-yl)-2- Methyl-3-phenyl-pyrazolo[1,5- a ]pyrimidin-5-yl)phenyl)heptyl)piperidin-4-yl)-1-oxyisoindoline-2- yl)piperidine-2,6-dione A1 ; 3-(6-fluoro-4-(1-(7-(4-(7-(4-(2-hydroxyethyl)piperidin-1-yl)) )-2-methyl-3-phenyl-pyrazolo[1,5- a ]pyrimidin-5-yl)phenyl)heptyl)piperidin-4-yl)-1-oxoisoindole Lino-2-yl) piperidine-2,6-dione A2 ; 2-(2,6-dioxypiperidin-3-yl)-4-((2-(2-(2-(3 -(4-(7-(4-(2-Hydroxyethyl)piperidin-1-yl)-2-methyl-3-phenylpyrazolo[1,5- a ]pyrimidin-5-yl) Phenyl)propoxy)ethoxy)ethoxy)ethyl)-amino)isoindoline-1,3-dione A3 ; 3-(6-fluoro-4-(1-(9- (3-(7-(4-(2-hydroxyethyl)piperidin-1-yl)-2-methyl-3-phenyl-pyrazolo[1,5- a ]pyrimidin-5-yl) Phenyl)nonyl)piperidin-4-yl)-1-oxyisoindolin-2-yl)piperidine-2,6-dione A4 ; 3-(6-fluoro-4-(1 -(9-(4-(7-(4-(2-hydroxyethyl)piperidin-1-yl)-2-methyl-3-phenyl-pyrazolo[1,5- a ]pyrimidine- 5-yl)phenyl)nonyl)piperidin-4-yl)-1-oxyisoindolin-2-yl)piperidine-2,6-dione A5 ; 3-(6-fluoro- 4-(1-(5-(3-(7-(4-(2-hydroxyethyl)piperidin-1-yl)-2-methyl-3-phenyl-pyrazolo[1,5- a ]pyrimidin-5-yl)phenyl)pentyl)piperidin-4-yl)-1-oxyisoindolin-2-yl)piperidine-2,6-dione A6 ; 3-( 6-Fluoro-4-(1-(5-(4-(7-(4-(2-hydroxyethyl)piperidin-1-yl)-2-methyl-3-phenyl-pyrazolo[ 1,5- a ]pyrimidin-5-yl)phenyl)pentyl)piperidin-4-yl)-1-oxyisoindolin-2-yl)piperidine-2,6-dione A7 ; 3-(1-((4-(((7-(4-(7-(4-(2-hydroxyethyl)piperidin-1-yl)-2-methyl-3-phenyl-pyridine azolo[1,5- a ]pyrimidin-5-yl)phenyl)heptyl)amino)methyl)phenoxy)methyl)-4-oxy- 4H -thieno[3,4 - c ]pyrrol-5( 6H )-yl)piperidine-2,6-dione A8 ; 3-(1-((4-(((7-(3-(7-(4-(2- Hydroxyethyl)piperan-1-yl)-2-methyl-3-phenyl-pyrazolo[1,5- a ]pyrimidin-5-yl)phenyl)heptyl)amino)methyl)phenoxy)methyl)-4-pendoxyloxy- 4H -thieno[3,4- c ]pyrrole-5( 6H )-yl)piperidine-2,6-dione A9 ; 3-(6-fluoro-4-(1-(3-(3-(7-(4-(2-hydroxyethyl)piperidine) -1-yl)-2-methyl-3-phenyl-pyrazolo[1,5- a ]pyrimidin-5-yl)phenyl)propyl)piperidin-4-yl)-1-oxygen ylisoindolin-2-yl)piperidine-2,6-dione A10 ; 3-(6-fluoro-4-(1-(4-(3-(7-(4-(2-hydroxyethyl) yl)piperidin-1-yl)-2-methyl-3-phenyl-pyrazolo[1,5- a ]pyrimidin-5-yl)phenyl)butyl)piperidin-4-yl)- 1-oxyisoindolin-2-yl) piperidine-2,6-dione A11 ; 3-(6-fluoro-4-(4-(2-(4-(3-(7-( 4-(2-Hydroxyethyl)piperidin-1-yl)-2-methyl-3-phenylpyrazolo[1,5- a ]pyrimidin-5-yl)phenethyl) -1H- 1,2,3-triazol-1-yl)ethyl)piperidine-1-yl)-1-oxyisoindolin-2-yl)piperidine-2,6-dione A12 ; 3 -(6-Fluoro-4-(1-(2-(4-(3-(7-(4-(2-hydroxyethyl)piperidin-1-yl)-2-methyl-3-phenyl) Pyrazolo[1,5- a ]pyrimidin-5-yl)phenethyl)-1H-1,2,3-triazol-1-yl)ethyl)piperidin-4-yl)-1-side Oxyisoindolin-2-yl)piperidine-2,6-dione A13 ; 3-(6-Fluoro-4-(1-(2-(4-(3-(3-(7-( 4-(2-Hydroxyethyl)piperidin-1-yl)-2-methyl-3-phenylpyrazolo[1,5- a ]pyrimidin-5-yl)phenyl)propyl)-1 H -1,2,3-triazol-1-yl)ethyl)piperidin-4-yl)-1-oxyisoindolin-2-yl)piperidine-2,6-dione A14 ; 3-(6-Fluoro-4-(1-(2-(4-(3-(7-(4-(2-hydroxyethyl)piperidin-1-yl)-2-methyl-3- Phenylpyrazolo[1,5- a ]pyrimidin-5-yl)phenethyl)piperidin-4-yl)ethyl)piperidin-4-yl)-1-oxyisoindoline- 2-yl)piperidine-2,6-dione A15 ; 3-(6-fluoro-4-(1-(2-(4-(3-(3-(7-(4-(2-hydroxyethyl) yl)piperidin-1-yl)-2-methyl-3-phenylpyrazolo[1,5- a ]pyrimidin-5-yl)phenyl)propyl)piperidin-1-yl)ethyl ) piperidin-4-yl)-1-oxyisoindolin-2-yl)piperidine-2,6-dione A16 ; 3-(6-fluoro-4-(4-(7-( 3-(7-(4-(2-hydroxyethyl)piperidin-1-yl)-2 -Methyl-3-phenyl-pyrazolo[1,5- a ]pyrimidin-5-yl)phenyl)heptyl)piperidin-1-yl)-1-oxyisoindoline-2 -yl)-piperidine-2,6-dione A17 ; 3-(4-((1-(6-(3-(7-(4-(2-hydroxyethyl)piperidine-1-yl)) -2-Methyl-3-phenyl-pyrazolo[1,5- a ]pyrimidin-5-yl)phenyl)hexyl)piperidin-4-yl)ethynyl)-1-side oxy Isoindolin-2-yl)-piperidine-2,6-dione A18 ; 3-(4-((4-(((7-(3-(7-(4-(2-hydroxyethyl )piperidin-1-yl)-2-methyl-3-phenyl-pyrazolo[1,5- a ]pyrimidin-5-yl)phenyl)heptyl)amino)methyl)benzyl )oxy)-1-oxyisoindolin-2-yl)-piperidine-2,6-dione A19 ; 3-(6-fluoro-4-((2-(4-(4- (3-(7-(4-(2-Hydroxyethyl)piperidin-1-yl)-2-methyl-3-phenylpyrazolo[1,5- a ]pyrimidin-5-yl)benzene (yl)butyl)piperidin-1-yl)-2-oxyethyl)amino)-1-oxyisoindolin-2-yl)piperidine-2,6-dione A20 ; 3-(4-((4-((((9-(3-(7-(4-(2-hydroxyethyl)piperidin-1-yl)-2-methyl-3-phenyl-pyrazole) [1,5- a ]pyrimidin-5-yl)phenyl)nonyl)amino)methyl)benzyl)oxy)-1-oxyisoindolin-2-yl)-piperidine Pyridin-2,6-dione A21 ; 3-(6-Fluoro-5-(1-(5-(3-(7-(4-(2-hydroxyethyl)piperidine-1-yl)-2 -Methyl-3-phenyl-pyrazolo[1,5- a ]pyrimidin-5-yl)phenyl)pentyl)piperidin-4-yl)-1-oxyisoindoline-2 -yl)piperidine-2,6-dione A22 ; 3-(6-fluoro-5-(1-(7-(3-(7-(4-(2-hydroxyethyl)piperidine)-1- yl)-2-methyl-3-phenyl-pyrazolo[1,5- a ]pyrimidin-5-yl)phenyl)heptyl)piperidin-4-yl)-1-side oxyisoindole Doolin-2-yl)piperidine-2,6-dione A23 ; 2-(2,6-dioxypiperidin-3-yl)-4-((2-(2-(3-( 4-(7-(4-(2-Hydroxyethyl)-piperidin-1-yl)-2-methyl-3-phenylpyrazolo[1,5- a ]pyrimidin-5-yl)benzene 2-(2,6- dioxypiperidin -3-yl)-5 -Fluoro-6-(4-((1-(7-(3-(7-(4-(2-hydroxyethyl)-piperidin-1-yl)-2-methyl-3-phenylpyridine azolo[1,5- a ]pyrimidin-5-yl)phenyl)heptanyl)piperidin-4-yl)methyl) pipe𠯤-1-yl)isoindoline-1,3-dione A25 ; 2-(2,6-dioxypiperidin-3-yl)-5-fluoro-6-(4-(( 1-(9-(3-(7-(4-(2-hydroxyethyl)-piperidin-1-yl)-2-methyl-3-phenylpyrazolo[1,5- a ]pyrimidine -5-yl)phenyl)nonanoyl)piperidin-4-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione A26 ; 2-(2,6-dione Pendant oxypiperidin-3-yl)-5-fluoro-6-(4-((1-(11-(3-(7-(4-(2-hydroxyethyl)-piperidin-1-yl) )-2-methyl-3-phenylpyrazolo[1,5- a ]pyrimidin-5-yl)phenyl)undecyl)piperidin-4-yl)methyl)piperidine-1- Base) isoindoline-1,3-dione A27 ; 3-(1-((4-(((5-(3-(7-(4-(2-hydroxyethyl)piperidine)-1- yl)-2-methyl-3-phenyl-pyrazolo[1,5- a ]pyrimidin-5-yl)phenyl)pentyl)amino)methyl)phenoxy)methyl)-4 -Pendant oxy- 4H -thieno[3,4- c ]pyrrol-5(6H)-yl)piperidine-2,6-dione A28 ; 3-(6-fluoro-4-(6- (4-(3-(7-(4-(2-hydroxyethyl)piperidin-1-yl)-2-methyl-3-phenylpyrazolo[1,5- a ]pyrimidine-5- base)phenethyl)piperidine-1-yl)hex-1-yn-1-yl)-1-oxyisoindolin-2-yl)piperidine-2,6-dione A29 ; 3 -(1-((4-(((9-(3-(7-(4-(2-hydroxyethyl)piperidin-1-yl)-2-methyl-3-phenyl-pyrazolo) [1,5- a ]pyrimidin-5-yl)phenyl)nonyl)amino)methyl)phenoxy)methyl)-4-oxo- 4H -thieno[3,4- c ]pyrrol-5( 6H )-yl)piperidine-2,6-dione A30 ; 3-(1-((4-(((9-(3-(7-(4-(2-hydroxyethyl) yl)piperidin-1-yl)-2-methyl-3-phenyl-pyrazolo[1,5- a ]pyrimidin-5-yl)phenyl)nonyl)(methyl)amino)methyl yl)phenoxy)methyl)-4-oxo- 4H -thieno[3,4- c ]pyrrol-5( 6H )-yl)piperidine-2,6-dione A31 ; N -(5-(2,6-Dioxypiperidin-3-yl)-4-oxy-5,6-dihydro- 4H -thieno[3,4- c ]pyrrole-1- yl)-2-(4-(9-(3-(7-(4-(2-hydroxyethyl)piperidin-1-yl)-2-methyl-3-phenylpyrazolo[1, 5- a ]pyrimidin-5-yl)phenyl)nonyl)piperidin-1-yl)acetamide A32 ; 3-(6-fluoro-4-(4-(5-(4-(7-( 4-(2-Hydroxyethyl yl)piperidin-1-yl)-2-methyl-3-phenyl-pyrazolo[1,5- a ]pyrimidin-5-yl)piperidin-1-yl)pentyl)piperidin-1 -yl)-1-oxyisoindolin-2-yl)-piperidine-2,6-dione A33 ; 3-(6-fluoro-4-(4-(9-(7-(4 -(2-Hydroxyethyl)piperidin-1-yl)-2-methyl-3-phenyl-pyrazolo[1,5- a ]pyrimidin-5-yl)nonyl)piperidin-1- base)-1-oxyisoindolin-2-yl)piperidine-2,6-dione A34 ; 2-((2-(2,6-dioxypiperidin-3-yl) -1- Oxyisoindolin -4-yl)oxy)-N-(7-(3-(7-(4-(2-hydroxyethyl)piperidin-1-yl)-2- Methyl-5-phenylpyrazolo[1,5- a ]pyrimidin-3-yl)phenyl)heptyl)-acetamide A35 ; 3-(6-fluoro-4-(1-(3- (7-(4-(2-Hydroxyethyl)piperidin-1-yl)-2-methyl-3-phenyl-pyrazolo[1,5- a ]pyrimidin-5-yl)phenethyl ) piperidin-4-yl)-1-oxyisoindolin-2-yl)piperidine-2,6-dione A36 ; 3-(6-fluoro-4-(1-(5-( 4-(7-(4-(2-Hydroxyethyl)piperidin-1-yl)-2-methyl-3-phenylpyrazolo[1,5- a ]pyrimidin-5-yl)piperidine -1-yl)pentyl)piperidin-4-yl)-1-oxyisoindolin-2-yl)piperidine-2,6-dione A37 ; 3-(6-fluoro-4- (1-(9-(7-(4-(2-hydroxyethyl)piperidin-1-yl)-2-methyl-3-phenyl-pyrazolo[1,5- a ]pyrimidine-5 -yl)nonyl)piperidin-4-yl)-1-side oxyisoindolin-2-yl)piperidine-2,6-dione A38 ; 3-(6-fluoro-4-(1 -(9-(7-(4-(2-Hydroxyethyl)piperidin-1-yl)-2-methyl-3-phenyl-pyrazolo[1,5- a ]pyrimidin-5-yl ) nonyl)piperidin-4-yl)-1-oxyisoindolin-2-yl)piperidine-2,6-dione A39 ; 3-(6-fluoro-4-((2- (4-(6-(3-(7-(4-(2-hydroxyethyl)piperidin-1-yl)-2-methyl-3-phenylpyrazolo[1,5- a ]pyrimidine -5-yl)phenyl)hexyl)piperidin-1-yl)-2-oxyethyl)amino)-1-oxyisoindolin-2-yl)piperidine-2,6 -diketone A40 ; 2-((2-(2,6-dioxypiperidin-3-yl)-1- oxyisoindolin -4-yl)oxy)-N-(9 -(4-(7-(4-(2-hydroxyethyl)piperidin-1-yl)-2-methyl-5-phenylpyrazolo[1,5- a ]pyrimidin-3-yl) Phenyl)nonyl)-acetamide A41 ; 2-((2-(2,6-di pendant oxypiperidin-3-yl)-1- pendant oxyisoindolin -4-yl)oxy)-N-(7-(4-(7-(4-(2-hydroxyethyl)) Piperidin-1-yl)-2-methyl-5-phenylpyrazolo[1,5- a ]pyrimidin-3-yl)phenyl)heptyl)-acetamide A42 ; 2-((2 -(2,6-Dioxypiperidin-3-yl)-1- oxyisoindolin -4-yl)oxy)-N-(11-(3-(7-(4- (2-Hydroxyethyl)piperidin-1-yl)-2-methyl-5-phenylpyrazolo[1,5- a ]pyrimidin-3-yl)phenyl)undecyl)-acetylene Amine A43 ; 2-((2-(2,6-dioxypiperidin-3-yl)-1-oxyisoindolin-4-yl)oxy)-N-(9-( 4-(7-(4-(2-Hydroxyethyl)piperidin-1-yl)-2-methyl-5-phenylpyrazolo[1,5- a ]pyrimidin-3-yl)phenyl ) nonyl)-acetamide A44 ; 2-((2-(2,6-dioxypiperidin-3-yl)-1-oxyisoindolin-4-yl)oxy) - N- (9-(3-(7-(4-(2-hydroxyethyl)piperidin-1-yl)-2-methyl-5-phenylpyrazolo[1,5- a ]pyrimidine -3-yl)phenyl)nonyl)-acetamide A45 ; 2-((2-(2,6-dioxypiperidin-3-yl)-1-oxyisoindoline- 4 - yl)oxy)-N-(11-(4-(7-(4-(2-hydroxyethyl)piperidin-1-yl)-2-methyl-5-phenylpyrazolo[ 1,5- a ]pyrimidin-3-yl)phenyl)undecyl)-acetamide A46 ; 2-(2,6-dioxypiperidin-3-yl)-5-fluoro-6- (4-((1-(8-(3-(7-(4-(2-hydroxyethyl)-piperidin-1-yl)-2-methyl-5-phenylpyrazolo[1, 5- a ]pyrimidin-3-yl)phenyl)-3-methyloctanyl)-piperidin-4-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione A47 ; 2-((2-(2,6-Dioxypiperidin-3-yl)-1- oxyisoindolin -4-yl)oxy)-N-(9-(2- (7-(4-(2-Hydroxyethyl)piperidin-1-yl)-2-methyl-5-phenylpyrazolo[1,5- a ]pyrimidin-3-yl)phenyl)nonan base)-acetamide A48 ; 2-((2-(2,6-dioxypiperidin-3-yl)-1-oxyisoindolin-4-yl)oxy) -N -(11-(2-(7-(4-(2-hydroxyethyl)piperidin-1-yl)-2-methyl-5-phenylpyrazolo[1,5- a ]pyrimidine-3 -yl)phenyl)undecyl)-acetamide A49 ; 2-((2-(2,6-dioxypiperidin-3-yl)-1-oxyisoindoline-4 -yl)oxy)-N-(7-( 2- (7 -(4-(2-Hydroxyethyl)piperidin-1-yl)-2-methyl-5-phenylpyrazolo[1,5- a ]pyrimidin-3-yl)phenyl)heptyl) - Acetamide A50 ; 3-(5-((9-(3-(7-(4-(2-hydroxyethyl)piperidin-1-yl)-2-methyl-5-phenyl-pyridine azolo[1,5- a ]pyrimidin-3-yl)phenyl)nonyl)amino)-2-methyl-4-oxoquinazolin-3( 4H )-yl)-piperidine -2,6-dione A51 ; 3-(5-((7-(3-(7-(4-(2-hydroxyethyl)piperidine-1-yl)-2-methyl-5-benzene yl-pyrazolo[1,5- a ]pyrimidin-3-yl)phenyl)heptyl)amino)-2-methyl-4-oxoquinazolin-3( 4H )-yl) -piperidine-2,6-dione A52 ; 3-(5-((11-(3-(7-(4-(2-hydroxyethyl)piperidine-1-yl)-2-methyl- 5-Phenyl-pyrazolo[1,5- a ]pyrimidin-3-yl)phenyl)undecyl)amino)-2-methyl-4-oxoquinazoline-3( 4H )-yl)piperidine-2,6-dione A53 ; 3-(6-((4-(((7-(3-(7-(4-(2-hydroxyethyl)piperidine)-1- yl)-2-methyl-3-phenyl-pyrazolo[1,5- a ]pyrimidin-5-yl)phenyl)heptyl)amino)methyl)benzyl)oxy)-1 - side oxyisoindolin-2-yl)-piperidine-2,6-dione A54 ; 2-(2,6- side oxypiperidin-3-yl)-5-fluoro-6- (4-((1-(6-(3-(7-(4-(2-hydroxyethyl)-piperidin-1-yl)-2-methyl-5-phenylpyrazolo[1, 5- a ]pyrimidin-3-yl)phenyl)-3-methylhexyl)-piperidin-4-yl)methyl)piperidin-1-yl)isoindoline-1,3-di Ketone A55 ; or 2-(2,6-di-oxypiperidin-3-yl)-5-fluoro-6-(4-((1-(10-(3-(7-(4-(2 -Hydroxyethyl)-piperidin-1-yl)-2-methyl-5-phenylpyrazolo[1,5- a ]pyrimidin-3-yl)phenyl)-3-methyldecanoyl )-piperidin-4-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione A56 ; or its enantiomer, mixture of enantiomers, diastereomer compound, a mixture of two or more diastereoisomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant; or a pharmaceutically acceptable salt, solvate thereof compounds, hydrates or prodrugs.
在另一實施例中，本文提供： ( S)- N-(( S)-1-環己基-2-(( S)-2-(4-(3-((7-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5- a]嘧啶-5-基)苯基)庚基)氧基)苯甲醯基)噻唑-2-基)-吡咯啶-1-基)-2-側氧基乙基)-2-(甲基胺基)丙醯胺 B1； ( S)- N-(( S)-1-環己基-2-(( S)-2-(4-(3-((9-(3-(7-(4-(2-羥基乙基)-哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5- a]嘧啶-5-基)苯基)壬基)氧基)苯甲醯基)噻唑-2-基)-吡咯啶-1-基)-2-側氧基乙基)-2-(甲基胺基)丙醯胺 B2； ( S)- N-(( S)-1-環己基-2-(( S)-2-(4-(3-((11-(3-(7-(4-(2-羥基乙基)-哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5- a]嘧啶-5-基)苯基)十一基)氧基)苯甲醯基)噻唑-2-基)吡咯啶-1-基)-2-側氧基乙基)-2-(甲基胺基)丙醯胺 B3； ( S)- N-(( S)-1-環己基-2-(( S)-2-(4-(3-((13-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5- a]嘧啶-5-基)苯基)十三基)氧基)苯甲醯基)噻唑-2-基)-吡咯啶-1-基)-2-側氧基乙基)-2-(甲基胺基)丙醯胺 B4； ( S)-2-((2 S,3 R)-3-胺基-2-羥基-4-苯基丁醯胺基)- N-(7-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5- a]嘧啶-5-基)苯基)庚基)-4-甲基戊醯胺 B5； ( S)-2-((2 S,3 R)-3-胺基-2-羥基-4-苯基丁醯胺基)- N-(9-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5- a]嘧啶-5-基)苯基)壬基)-4-甲基戊醯胺 B6； ( S)-2-((2 S,3 R)-3-胺基-2-羥基-4-苯基丁醯胺基)- N-(11-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5- a]嘧啶-5-基)苯基)十一基)-4-甲基戊醯胺 B7； ( S)-2-((2 S,3 R)-3-胺基-2-羥基-4-苯基丁醯胺基)- N-(13-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5- a]嘧啶-5-基)苯基)十三基)-4-甲基戊醯胺 B8； (2 S,4 S)-1-(( S)-2-環己基-2-(( S)-2-(甲基胺基)丙醯胺基)乙醯基)-4-(7-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5- a]嘧啶-3-基)苯基)-庚醯胺基)- N-(( R)-1,2,3,4-四氫萘-1-基)吡咯啶-2-甲醯胺 B9； ( S)-2-((2 S,3 R)-3-胺基-2-羥基-4-苯基丁醯胺基)- N-(7-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5- a]嘧啶-3-基)苯基)庚基)-4-甲基戊醯胺 B10； ( S)-2-((2 S,3 R)-3-胺基-2-羥基-4-苯基丁醯胺基)- N-(11-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5- a]嘧啶-3-基)苯基)十一基)-4-甲基戊醯胺 B11； (2 S,4 S)-1-(( S)-2-環己基-2-(( S)-2-(甲基胺基)丙醯胺基)乙醯基)-4-(9-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5- a]嘧啶-3-基)苯基)-壬醯胺基)- N-(( R)-1,2,3,4-四氫萘-1-基)吡咯啶-2-甲醯胺 B12； (2 S,4 S)-1-(( S)-2-環己基-2-(( S)-2-(甲基胺基)丙醯胺基)乙醯基)-4-(11-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5- a]嘧啶-3-基)-苯基)十一醯胺基)- N-(( R)-1,2,3,4-四氫萘-1-基)吡咯啶-2-甲醯胺 B13； (2 S,4 S)-1-(( S)-2-環己基-2-(( S)-2-(甲基胺基)丙醯胺基)乙醯基)-4-(13-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5- a]嘧啶-3-基)-苯基)十三醯胺基)- N-(( R)-1,2,3,4-四氫萘-1-基)吡咯啶-2-甲醯胺 B14； ( S)-2-((2 S,3 R)-3-胺基-2-羥基-4-苯基丁醯胺基)- N-(9-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5- a]嘧啶-3-基)苯基)壬基)-4-甲基戊醯胺 B15； ( S)- N-(( S)-1-環己基-2-(( S)-2-(4-(3-((11-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5- a]嘧啶-5-基)苯基)十一碳-10-炔-1-基)氧基)苯甲醯基)-噻唑-2-基)吡咯啶-1-基)-2-側氧基乙基)-2-(甲基胺基)丙醯胺 B16； ( S)- N-(( S)-1-環己基-2-(( S)-2-(4-(3-((13-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5- a]嘧啶-5-基)苯基)十三碳-12-炔-1-基)氧基)-苯甲醯基)噻唑-2-基)吡咯啶-1-基)-2-側氧基乙基)-2-(甲基胺基)丙醯胺 B17； ( S)- N-(( S)-1-環己基-2-(( S)-2-(4-(3-((13-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5- a]嘧啶-3-基)苯基)十三基)氧基)苯甲醯基)噻唑-2-基)吡咯啶-1-基)-2-側氧基乙基)-2-(甲基胺基)丙醯胺 B18； ( S)- N-(( S)-1-環己基-2-(( S)-2-(4-(3-((11-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5- a]嘧啶-3-基)苯基)十一基)氧基)苯甲醯基)噻唑-2-基)吡咯啶-1-基)-2-側氧基乙基)-2-(甲基胺基)丙醯胺 B19； ( S)- N-(( S)-1-環己基-2-(( S)-2-(4-(3-((9-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5- a]嘧啶-3-基)苯基)壬基)氧基)苯甲醯基)噻唑-2-基)-吡咯啶-1-基)-2-側氧基乙基)-2-(甲基胺基)丙醯胺 B20；或 ( S)- N-(( S)-1-環己基-2-(( S)-2-(4-(3-((7-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5- a]嘧啶-3-基)苯基)庚基)氧基)苯甲醯基)噻唑-2-基)-吡咯啶-1-基)-2-側氧基乙基)-2-(甲基胺基)丙醯胺 B21； 或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體；或其醫藥學上可接受之鹽、溶劑合物、水合物或前藥。 In another embodiment, provided herein is: ( S ) -N -(( S )-1-cyclohexyl-2-(( S )-2-(4-(3-((7-(3-(7 -(4-(2-Hydroxyethyl)piperidin-1-yl)-2-methyl-3-phenylpyrazolo[1,5- a ]pyrimidin-5-yl)phenyl)heptyl) Oxy)benzyl)thiazol-2-yl)-pyrrolidin-1-yl)-2-oxyethyl)-2-(methylamino)propionamide B1 ; ( S ) -N -(( S )-1-cyclohexyl-2-(( S )-2-(4-(3-((9-(3-(7-(4-(2-hydroxyethyl)-piperidine)- 1-yl)-2-methyl-3-phenylpyrazolo[1,5- a ]pyrimidin-5-yl)phenyl)nonyl)oxy)benzyl)thiazol-2-yl) -pyrrolidin-1-yl)-2-oxyethyl)-2-(methylamino)propionamide B2 ; ( S ) -N -(( S )-1-cyclohexyl-2-( ( S )-2-(4-(3-((11-(3-(7-(4-(2-hydroxyethyl)-piperidin-1-yl)-2-methyl-3-phenyl Pyrazolo[1,5- a ]pyrimidin-5-yl)phenyl)undecyl)oxy)benzyl)thiazol-2-yl)pyrrolidin-1-yl)-2-side oxy Ethyl)-2-(methylamino)propionamide B3 ; ( S ) -N -(( S )-1-cyclohexyl-2-(( S )-2-(4-(3-(( 13-(3-(7-(4-(2-hydroxyethyl)piperidin-1-yl)-2-methyl-3-phenylpyrazolo[1,5- a ]pyrimidin-5-yl )phenyl)tridecyl)oxy)benzyl)thiazol-2-yl)-pyrrolidin-1-yl)-2-oxyethyl)-2-(methylamino)propionyl Amine B4 ; ( S )-2-(( 2S , 3R )-3 - amino-2-hydroxy-4-phenylbutanamido)-N-(7-(3-(7-(4 -(2-Hydroxyethyl)piperidin-1-yl)-2-methyl-3-phenylpyrazolo[1,5- a ]pyrimidin-5-yl)phenyl)heptyl)-4- Methylpentamide B5 ; ( S )-2-(( 2S , 3R )-3 - amino-2-hydroxy-4-phenylbutanamide)-N-(9-(3-( 7-(4-(2-Hydroxyethyl)piperidin-1-yl)-2-methyl-3-phenylpyrazolo[1,5- a ]pyrimidin-5-yl)phenyl)nonyl )-4-methylpentanamide B6 ; ( S )-2-(( 2S , 3R )-3 - amino-2-hydroxy-4-phenylbutanamide)-N-(11- (3-(7-(4-(2-Hydroxyethyl)piperidin-1-yl)-2-methyl-3-phenylpyrazolo[1,5- a ]pyrimidin-5-yl)benzene ( S ) -2 -((2 S ,3 R )-3 - amino-2-hydroxy-4-phenylbutanamido)-N-(13-(3-(7-(4-(2-hydroxyethyl)) pipe𠯤-1-yl)-2-methyl-3-phenylpyrazolo[1,5- a ]pyrimidin-5-yl)phenyl)tridecyl)-4-methylpentanamide B8 ; (2 S ,4 S )-1-(( S )-2-cyclohexyl-2-(( S )-2-(methylamino)propionamido)acetyl)-4-(7- (3-(7-(4-(2-Hydroxyethyl)piperidin-1-yl)-2-methyl-5-phenylpyrazolo[1,5- a ]pyrimidin-3-yl)benzene ( S ) -2 -(( (S ) -2-(( 2 S ,3 R )-3-amino-2-hydroxy-4-phenylbutanamido)-N-(7-(3-(7-(4-(2-hydroxyethyl) piperyl )- 1-yl)-2-methyl-5-phenylpyrazolo[1,5- a ]pyrimidin-3-yl)phenyl)heptyl)-4-methylpentamamide B10 ; ( S )- 2-((2 S ,3 R )-3 - amino-2-hydroxy-4-phenylbutanamido)-N-(11-(3-(7-(4-(2-hydroxyethyl) )piperidin-1-yl)-2-methyl-5-phenylpyrazolo[1,5- a ]pyrimidin-3-yl)phenyl)undecyl)-4-methylpentanamide B11 ; ( 2S , 4S )-1-(( S )-2-cyclohexyl-2-(( S )-2-(methylamino)propionamido)acetyl)-4-(9 -(3-(7-(4-(2-hydroxyethyl)piperidin-1-yl)-2-methyl-5-phenylpyrazolo[1,5- a ]pyrimidin-3-yl) Phenyl)-nonylamino) -N -(( R )-1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxamide B12 ; ( 2S,4S ) -1-(( S )-2-cyclohexyl-2-(( S )-2-(methylamino)propionamido)acetyl)-4-(11-(3-(7-( 4-(2-Hydroxyethyl)piperidin-1-yl)-2-methyl-5-phenylpyrazolo[1,5- a ]pyrimidin-3-yl)-phenyl)undecamide base) -N -(( R )-1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-2-carboxamide B13 ; ( 2S , 4S)-1-(((S ) -2-Cyclohexyl-2-(( S )-2-(methylamino)propionamido)acetyl)-4-(13-(3-(7-(4-(2-hydroxyethyl) yl)piperidin-1-yl)-2-methyl-5-phenylpyrazolo[1,5- a ]pyrimidin-3-yl)-phenyl)tridecamino) -N -(( R )-1,2,3,4-tetrahydronaphthalene-1 -yl)pyrrolidine-2-carboxamide B14 ; ( S )-2-(( 2S , 3R )-3 - amino-2-hydroxy-4-phenylbutanamide)-N-( 9-(3-(7-(4-(2-hydroxyethyl)piperidin-1-yl)-2-methyl-5-phenylpyrazolo[1,5- a ]pyrimidin-3-yl )phenyl)nonyl)-4-methylpentamamide B15 ; ( S ) -N -(( S )-1-cyclohexyl-2-(( S )-2-(4-(3-(( 11-(3-(7-(4-(2-hydroxyethyl)piperidin-1-yl)-2-methyl-3-phenylpyrazolo[1,5- a ]pyrimidin-5-yl )Phenyl)undec-10-yn-1-yl)oxy)benzyl)-thiazol-2-yl)pyrrolidin-1-yl)-2-endoxyethyl)-2- (Methylamino)propionamide B16 ; ( S ) -N -(( S )-1-cyclohexyl-2-(( S )-2-(4-(3-((13-(3-( 7-(4-(2-Hydroxyethyl)piperidin-1-yl)-2-methyl-3-phenylpyrazolo[1,5- a ]pyrimidin-5-yl)phenyl)tridecane Carbo-12-yn-1-yl)oxy)-benzyl)thiazol-2-yl)pyrrolidin-1-yl)-2-side oxyethyl)-2-(methylamino) Propionamide B17 ; ( S ) -N -(( S )-1-cyclohexyl-2-(( S )-2-(4-(3-((13-(3-(7-(4-( 2-Hydroxyethyl)piperidin-1-yl)-2-methyl-5-phenylpyrazolo[1,5- a ]pyrimidin-3-yl)phenyl)tridecyl)oxy)benzene Carboxy)thiazol-2-yl)pyrrolidin-1-yl)-2-oxyethyl)-2-(methylamino)propionamide B18 ; ( S ) -N -(( S ) -1-Cyclohexyl-2-(( S )-2-(4-(3-((11-(3-(7-(4-(2-hydroxyethyl)piperidin-1-yl)-2 -Methyl-5-phenylpyrazolo[1,5- a ]pyrimidin-3-yl)phenyl)undecyl)oxy)benzyl)thiazol-2-yl)pyrrolidine-1- ( S ) -N -(( S )-1-cyclohexyl-2-( (S ) -2- (4-(3-((9-(3-(7-(4-(2-hydroxyethyl)piperidin-1-yl)-2-methyl-5-phenylpyrazolo[1,5 - a ]pyrimidin-3-yl)phenyl)nonyl)oxy)benzyl)thiazol-2-yl)-pyrrolidin-1-yl)-2-endoxyethyl)-2-( Methylamino)propionamide B20 ; or ( S ) -N -(( S )-1-cyclohexyl-2-(( S )-2-(4-(3-((7-(3-( 7-(4-(2-hydroxyethyl)piperidin-1-yl )-2-methyl-5-phenylpyrazolo[1,5- a ]pyrimidin-3-yl)phenyl)heptyl)oxy)benzyl)thiazol-2-yl)-pyrrolidine -1-yl)-2-side oxyethyl)-2-(methylamino)propionamide B21 ; or its diastereoisomer, a mixture of two or more diastereoisomers, A tautomer, a mixture of two or more tautomers, or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
在又另一實施例中，本文提供： 2-(4-((4 S,5 R)-4,5-雙(4-氯苯基)-2-(2-異丙氧基-4-甲氧基苯基)-4,5-二氫-1 H-咪唑-1-羰基)哌𠯤-1-基)- N-(9-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5- a]嘧啶-3-基)苯基)壬基)乙醯胺 C1； 2-(4-((4 S,5 R)-4,5-雙(4-氯苯基)-2-(2-異丙氧基-4-甲氧基苯基)-4,5-二氫-1 H-咪唑-1-羰基)哌𠯤-1-基)- N-(11-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5- a]嘧啶-3-基)苯基)十一基)乙醯胺 C2； 2-(4-((4 S,5 R)-4,5-雙(4-氯苯基)-2-(2-異丙氧基-4-甲氧基苯基)-4,5-二氫-1 H-咪唑-1-羰基)哌𠯤-1-基)- N-(13-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5- a]嘧啶-3-基)苯基)十三基)乙醯胺 C3； 2-(4-((4 R,5 S)-4,5-雙(4-氯苯基)-2-(2-異丙氧基-4-甲氧基苯基)-4,5-二氫-1 H-咪唑-1-羰基)-2-側氧基哌𠯤-1-基)- N-(8-(4-(7-(4-(2-羥基乙基)-哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5- a]嘧啶-3-基)苯基)辛基)乙醯胺 C4； 2-(4-((4 S,5 R)-4,5-雙(4-氯苯基)-2-(2-異丙氧基-4-甲氧基苯基)-4,5-二氫-1 H-咪唑-1-羰基)哌𠯤-1-基)- N-(9-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5- a]嘧啶-5-基)苯基)壬基)乙醯胺 C5； 2-(4-((4 S,5 R)-4,5-雙(4-氯苯基)-2-(2-異丙氧基-4-甲氧基苯基)-4,5-二氫-1 H-咪唑-1-羰基)哌𠯤-1-基)- N-(11-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5- a]嘧啶-5-基)苯基)十一基)乙醯胺 C6； 2-(4-((4 S,5 R)-4,5-雙(4-氯苯基)-2-(2-異丙氧基-4-甲氧基苯基)-4,5-二氫-1 H-咪唑-1-羰基)哌𠯤-1-基)- N-(13-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5- a]嘧啶-5-基)苯基)十三基)乙醯胺 C7； 2-(4-((4 R,5 S)-4,5-雙(4-氯苯基)-2-(2-異丙氧基-4-甲氧基苯基)-4,5-二氫-1 H-咪唑-1-羰基)-2-側氧基哌𠯤-1-基)- N-(8-(3-(7-(4-(2-羥基乙基)-哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5- a]嘧啶-3-基)苯基)辛基)乙醯胺 C8； 3-(4-((4 S,5 R)-2-(4-(三級丁基)-2-乙氧基苯基)-4,5-雙(4-氯苯基)-4,5-二甲基-4,5-二氫-1 H-咪唑-1-羰基)哌𠯤-1-基)- N-(5-(3-(7-(4-(2-羥基乙基)-哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5- a]嘧啶-3-基)苯基)戊基)丙醯胺 C9； 3-(4-((4 S,5 R)-2-(4-(三級丁基)-2-乙氧基苯基)-4,5-雙(4-氯苯基)-4,5-二甲基-4,5-二氫-1 H-咪唑-1-羰基)哌𠯤-1-基)- N-(11-(3-(7-(4-(2-羥基-乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5- a]嘧啶-3-基)苯基)十一基)-丙醯胺 C10； 4-((4 S,5 R)-2-(4-(三級丁基)-2-((11-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5- a]嘧啶-3-基)苯基)十一碳-10-炔-1-基)氧基)苯基)-4,5-雙(4-氯苯基)-4,5-二甲基-4,5-二氫-1 H-咪唑-1-羰基)哌𠯤-2-酮 C11； 3-(4-((4 S,5 R)-2-(4-(三級丁基)-2-乙氧基苯基)-4,5-雙(4-氯苯基)-4,5-二甲基-4,5-二氫-1 H-咪唑-1-羰基)哌𠯤-1-基)- N-(7-(3-(7-(4-(2-羥基乙基)-哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5- a]嘧啶-3-基)苯基)庚基)丙醯胺 C12； 3-(4-((4 S,5 R)-2-(4-(三級丁基)-2-乙氧基苯基)-4,5-雙(4-氯苯基)-4,5-二甲基-4,5-二氫-1 H-咪唑-1-羰基)哌𠯤-1-基)- N-(9-(3-(7-(4-(2-羥基-乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5- a]嘧啶-3-基)苯基)壬基)-丙醯胺 C13； 4-((4 S,5 R)-2-(4-(三級丁基)-2-((9-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5- a]嘧啶-3-基)苯基)壬基)氧基)苯基)-4,5-雙(4-氯-苯基)-4,5-二甲基-4,5-二氫-1 H-咪唑-1-羰基)哌𠯤-2-酮 C14； 4-((4 S,5 R)-2-(4-(三級丁基)-2-((11-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5- a]嘧啶-3-基)苯基)十一基)氧基)苯基)-4,5-雙(4-氯-苯基)-4,5-二甲基-4,5-二氫-1 H-咪唑-1-羰基)哌𠯤-2-酮 C15；或 4-((4 S,5 R)-2-(4-(三級丁基)-2-((7-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5- a]嘧啶-3-基)苯基)庚基)氧基)苯基)-4,5-雙(4-氯-苯基)-4,5-二甲基-4,5-二氫-1 H-咪唑-1-羰基)哌𠯤-2-酮 C16； 或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體；或其醫藥學上可接受之鹽、溶劑合物、水合物或前藥。 In yet another embodiment, provided herein: 2-(4-(( 4S , 5R )-4,5-bis(4-chlorophenyl)-2-(2-isopropoxy-4- Methoxyphenyl)-4,5-dihydro- 1H -imidazole-1-carbonyl)piperidin - 1-yl)-N-(9-(3-(7-(4-(2-hydroxyethyl)) yl)piperidin-1-yl)-2-methyl-5-phenylpyrazolo[1,5- a ]pyrimidin-3-yl)phenyl)nonyl)acetamide C1 ; 2-(4 -((4 S ,5 R )-4,5-bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydro-1 H -imidazol-1-carbonyl)piperidin - 1-yl)-N-(11-(3-(7-(4-(2-hydroxyethyl)piperidin-1-yl)-2-methyl- 5-Phenylpyrazolo[1,5- a ]pyrimidin-3-yl)phenyl)undecyl)acetamide C2 ; 2-(4-(( 4S , 5R )-4,5- Bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydro- 1H -imidazole-1-carbonyl)piperidin-1-yl )-N-(13-(3-(7-(4-(2 - hydroxyethyl)piperidin-1-yl)-2-methyl-5-phenylpyrazolo[1,5- a ] pyrimidin-3-yl)phenyl)tridecyl)acetamide C3 ; 2-(4-(( 4R , 5S )-4,5-bis(4-chlorophenyl)-2-(2- Isopropoxy-4-methoxyphenyl)-4,5-dihydro- 1H -imidazole-1-carbonyl)-2 - oxypiperidin-1-yl)-N-(8-( 4-(7-(4-(2-Hydroxyethyl)-piperidin-1-yl)-2-methyl-5-phenylpyrazolo[1,5- a ]pyrimidin-3-yl)benzene yl)octyl)acetamide C4 ; 2-(4-(( 4S , 5R )-4,5-bis(4-chlorophenyl)-2-(2-isopropoxy-4-methyl) Oxyphenyl)-4,5-dihydro- 1H -imidazol-1-carbonyl)piperidin - 1-yl)-N-(9-(3-(7-(4-(2-hydroxyethyl) ) pipe𠯤-1-yl)-2-methyl-3-phenylpyrazolo[1,5- a ]pyrimidin-5-yl)phenyl)nonyl)acetamide C5 ; 2-(4- (( 4S , 5R )-4,5-bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydro- 1H -Imidazol-1-carbonyl)piperidin - 1-yl)-N-(11-(3-(7-(4-(2-hydroxyethyl)piperidin-1-yl)-2-methyl-3 -Phenylpyrazolo[1,5- a ]pyrimidin-5-yl)phenyl)undecyl)acetamide C6 ; 2-(4-(( 4S , 5R )-4,5-bis (4-Chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydro- 1H -Imidazol-1-carbonyl)piperidin - 1-yl)-N-(13-(3-(7-(4-(2-hydroxyethyl)piperidin-1-yl)-2-methyl-3 -Phenylpyrazolo [1,5- a ]pyrimidin-5-yl)phenyl)tridecyl)acetamide C7 ; 2-(4-((4R, 5S )-4,5-bis (4-Chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydro- 1H -imidazole-1-carbonyl)-2-side oxypiperyl 𠯤 -1-yl)-N-(8-(3-(7-(4-(2-hydroxyethyl)-piperidin-1-yl)-2-methyl-5-phenylpyrazolo[ 1,5- a ]pyrimidin-3-yl)phenyl)octyl)acetamide C8 ; 3-(4-(( 4S , 5R )-2-(4-(tertiary butyl)-2 -Ethoxyphenyl)-4,5-bis(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro- 1H -imidazole-1-carbonyl)piperidine-1- yl)-N-(5-(3-(7-(4-(2 - hydroxyethyl)-piperidin-1-yl)-2-methyl-5-phenylpyrazolo[1,5- a ] pyrimidin-3-yl)phenyl)pentyl)propionamide C9 ; 3-(4-(( 4S , 5R )-2-(4-(tertiarybutyl)-2-ethoxy Phenyl)-4,5-bis(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro- 1H -imidazole-1-carbonyl)piperidine-1-yl) -N -(11-(3-(7-(4-(2-Hydroxy-ethyl)piperidin-1-yl)-2-methyl-5-phenylpyrazolo[1,5- a ]pyrimidine- 3-yl)phenyl)undecyl)-propionamide C10 ; 4-(( 4S , 5R )-2-(4-(tertiary butyl)-2-((11-(3-( 7-(4-(2-Hydroxyethyl)piperidin-1-yl)-2-methyl-5-phenylpyrazolo[1,5- a ]pyrimidin-3-yl)phenyl)undecane Carbo-10-yn-1-yl)oxy)phenyl)-4,5-bis(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro- 1H -imidazole- 1-Carbonyl) piperazine-2-one C11 ; 3-(4-(( 4S , 5R )-2-(4-(tertiary butyl)-2-ethoxyphenyl)-4,5 -Bis(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro- 1H -imidazole-1-carbonyl)piperidin - 1-yl)-N-(7-(3- (7-(4-(2-Hydroxyethyl)-piperidin-1-yl)-2-methyl-5-phenylpyrazolo[1,5- a ]pyrimidin-3-yl)phenyl) Heptyl)propionamide C12 ; 3-(4-(( 4S , 5R )-2-(4-(tertiarybutyl)-2-ethoxyphenyl)-4,5-bis(4 -Chlorophenyl)-4,5-dimethyl-4,5-dihydro- 1H -imidazole-1-carbonyl)piperidine-1-yl) -N -(9-(3-(7-(4-(2-Hydroxy-ethyl)piperidin-1-yl)-2-methyl-5-phenylpyrazolo[1,5- a ]pyrimidine- 3-yl)phenyl)nonyl)-propionamide C13 ; 4-(( 4S , 5R )-2-(4-(tertiary butyl)-2-(((9-(3-(7) -(4-(2-Hydroxyethyl)piperidin-1-yl)-2-methyl-5-phenylpyrazolo[1,5- a ]pyrimidin-3-yl)phenyl)nonyl) Oxy)phenyl)-4,5-bis(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro- 1H -imidazole-1-carbonyl)piperidine-2- Ketone C14 ; 4-( ( 4S ,5R)-2-(4-(tertiary butyl)-2-((11-(3-(7-(4-(2-hydroxyethyl)piperidine) -1-yl)-2-methyl-5-phenylpyrazolo[1,5- a ]pyrimidin-3-yl)phenyl)undecyl)oxy)phenyl)-4,5-bis (4-Chloro-phenyl)-4,5-dimethyl-4,5-dihydro- 1H -imidazole-1-carbonyl)piperazol-2-one C15 ; or 4-(( 4S ,5 R )-2-(4-(tertiarybutyl)-2-((7-(3-(7-(4-(2-hydroxyethyl)piperidin-1-yl)-2-methyl- 5-Phenylpyrazolo[1,5- a ]pyrimidin-3-yl)phenyl)heptyl)oxy)phenyl)-4,5-bis(4-chloro-phenyl)-4,5 -Dimethyl-4,5-dihydro- 1H -imidazol-1-carbonyl)piperazol-2-one C16 ; or its diastereoisomer, a mixture of two or more diastereoisomers , a tautomer, a mixture of two or more tautomers, or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
在再一實施例中，本文提供： (2 S,4 R)-4-羥基-1-(( S)-2-(9-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5- a]嘧啶-5-基)苯基)壬醯胺基)-3,3-二甲基丁醯基)- N-(4-(4-甲基噻唑-5-基)苯甲基)吡咯啶-2-甲醯胺 D1； (2 S,4 R)-4-羥基-1-(( S)-2-(9-(4-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5- a]嘧啶-5-基)苯基)壬醯胺基)-3,3-二甲基丁醯基)- N-(4-(4-甲基噻唑-5-基)苯甲基)吡咯啶-2-甲醯胺 D2； (2 S,4 R)-1-(( S)-2-乙醯胺基-3,3-二甲基丁醯基)-4-羥基- N-(2-((7-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5- a]嘧啶-5-基)苯基)-庚基)氧基)-4-(4-甲基噻唑-5-基)苯甲基)吡咯啶-2-甲醯胺 D3； (2 S,4 R)-4-羥基-1-(( S)-2-(8-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5- a]嘧啶-3-基)苯基)辛醯胺基)-3,3-二甲基丁醯基)- N-(4-(4-甲基噻唑-5-基)苯甲基)吡咯啶-2-甲醯胺 D4； (2 S,4 R)-4-羥基-1-(( S)-2-(10-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5- a]嘧啶-3-基)苯基)癸醯胺基)-3,3-二甲基丁醯基)- N-(4-(4-甲基噻唑-5-基)苯甲基)吡咯啶-2-甲醯胺 D5； (2 S,4 R)-4-羥基-1-(( S)-2-(12-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5- a]嘧啶-3-基)苯基)十二烷醯胺基)-3,3-二甲基丁醯基)- N-(4-(4-甲基噻唑-5-基)苯甲基)吡咯啶-2-甲醯胺 D6； (2 S,4 R)-4-羥基-1-(( S)-2-(14-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5- a]嘧啶-3-基)苯基)十四烷醯胺基)-3,3-二甲基丁醯基)- N-(4-(4-甲基噻唑-5-基)苯甲基)吡咯啶-2-甲醯胺 D7； (2 S,4 R)-1-(( S)-2-乙醯胺基-3,3-二甲基丁醯基)-4-羥基- N-(2-((7-(4-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5- a]嘧啶-3-基)苯基)-庚基)氧基)-4-(4-甲基噻唑-5-基)苯甲基)吡咯啶-2-甲醯胺 D8； (2 S,4 R)-1-(( S)-2-乙醯胺基-3,3-二甲基丁醯基)-4-羥基- N-(2-((9-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5- a]嘧啶-3-基)苯基)-壬基)氧基)-4-(4-甲基噻唑-5-基)苯甲基)吡咯啶-2-甲醯胺 D9； (2 S,4 R)-1-(( S)-2-乙醯胺基-3,3-二甲基丁醯基)-4-羥基- N-(2-((11-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5- a]嘧啶-3-基)苯基)-十一基)氧基)-4-(4-甲基噻唑-5-基)苯甲基)吡咯啶-2-甲醯胺 D10； (2 S,4 R)-1-(( S)-2-乙醯胺基-3,3-二甲基丁醯基)-4-羥基- N-(2-((13-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5- a]嘧啶-3-基)苯基)-十三基)氧基)-4-(4-甲基噻唑-5-基)苯甲基)吡咯啶-2-甲醯胺 D11； (2 S,4 R)-4-羥基-1-(( S)-2-(10-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5- a]嘧啶-3-基)苯基)癸醯胺基)-3,3-二甲基丁醯基)- N-(4-(4-甲基噻唑-5-基)苯甲基)吡咯啶-2-甲醯胺 D12； (2 S,4 R)-4-羥基-1-(( S)-2-(9-(4-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5- a]嘧啶-3-基)苯基)壬醯胺基)-3,3-二甲基丁醯基)- N-(4-(4-甲基噻唑-5-基)苯甲基)吡咯啶-2-甲醯胺 D13； (2 S,4 R)-1-(( S)-2-乙醯胺基-3,3-二甲基丁醯基)-4-羥基- N-(2-((13-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5- a]嘧啶-3-基)-苯基)-十三碳-12-炔-1-基)氧基)-4-(4-甲基噻唑-5-基)苯甲基)吡咯啶-2-甲醯胺 D14； (2 S,4 R)-1-(( S)-2-乙醯胺基-3,3-二甲基丁醯基)-4-羥基- N-(2-((11-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5- a]嘧啶-3-基)-苯基)-十一碳-10-炔-1-基)氧基)-4-(4-甲基噻唑-5-基)苯甲基)吡咯啶-2-甲醯胺 D15；或 (2 S,4 R)-1-(( S)-2-乙醯胺基-3,3-二甲基丁醯基)-4-羥基- N-(2-((7-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5- a]嘧啶-3-基)苯基)-庚基)氧基)-4-(4-甲基噻唑-5-基)苯甲基)吡咯啶-2-甲醯胺 D16； 或其非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體；或其醫藥學上可接受之鹽、溶劑合物、水合物或前藥。 In yet another embodiment, provided herein: ( 2S,4R)-4-hydroxy-1-((S ) -2- (9-(3-(7-(4-(2-hydroxyethyl)) pipe𠯤-1-yl)-2-methyl-3-phenylpyrazolo[1,5- a ]pyrimidin-5-yl)phenyl)nonanamido)-3,3-dimethylbutanoyl )-N-(4-(4 - methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide D1 ; ( 2S , 4R )-4-hydroxy-1-(( S ) -2-(9-(4-(7-(4-(2-hydroxyethyl)piperidin-1-yl)-2-methyl-3-phenylpyrazolo[1,5- a ]pyrimidine -5-yl)phenyl)nonylamino)-3,3- dimethylbutyryl )-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-methyl Acetamide D2 ; ( 2S,4R)-1-((S ) -2 -acetamido-3,3-dimethylbutyryl)-4-hydroxy- N- (2-((7-( 3-(7-(4-(2-Hydroxyethyl)piperidin-1-yl)-2-methyl-3-phenylpyrazolo[1,5- a ]pyrimidin-5-yl)phenyl )-heptyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide D3 ; ( 2S , 4R )-4-hydroxy-1- (( S )-2-(8-(3-(7-(4-(2-hydroxyethyl)piperidin-1-yl)-2-methyl-5-phenylpyrazolo[1,5 - a ]pyrimidin-3-yl)phenyl)octanamido)-3,3- dimethylbutanyl )-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine -2-Carboxamide D4 ; ( 2S,4R)-4-hydroxy-1-((S ) -2- (10-(3-(7-(4-(2-hydroxyethyl)piperidine) -1-yl)-2-methyl-5-phenylpyrazolo[1,5- a ]pyrimidin-3-yl)phenyl)decanamido)-3,3-dimethylbutyryl)- N- (4-(4-Methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide D5 ; ( 2S,4R)-4-hydroxy-1-((S ) -2 -(12-(3-(7-(4-(2-hydroxyethyl)piperidin-1-yl)-2-methyl-5-phenylpyrazolo[1,5- a ]pyrimidine-3 -yl)phenyl)dodecylamino)-3,3- dimethylbutyryl )-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-methyl Amide D6 ; ( 2S,4R)-4-hydroxy-1-((S ) -2- (14-(3-(7-(4-(2-hydroxyethyl)piperidin-1-yl) )-2-Methyl-5-phenylpyrazolo[1,5- a ]pyrimidin-3-yl)phenyl)tetradecylamino)-3,3- dimethylbutyryl )-N- (4-(4-methyl) Thiazol-5-yl)benzyl)pyrrolidin-2-carboxamide D7 ; ( 2S,4R)-1-((S ) -2 -acetamido-3,3-dimethylbutanamide )-4-Hydroxy- N- (2-((7-(4-(7-(4-(2-hydroxyethyl)piperidin-1-yl)-2-methyl-5-phenylpyrazole [1,5- a ]pyrimidin-3-yl)phenyl)-heptyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide D8 ; ( 2S,4R)-1-((S ) -2 -acetamido-3,3-dimethylbutanoyl)-4-hydroxy- N- (2-((9-(3- (7-(4-(2-Hydroxyethyl)piperidin-1-yl)-2-methyl-5-phenylpyrazolo[1,5- a ]pyrimidin-3-yl)phenyl)- Nonyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)pyrrolidin-2-carboxamide D9 ; ( 2S,4R)-1-((S ) -2 -Acetylamino-3,3-dimethylbutyryl)-4-hydroxy- N- (2-((11-(3-(7-(4-(2-hydroxyethyl)piperyl)-1- yl)-2-methyl-5-phenylpyrazolo[1,5- a ]pyrimidin-3-yl)phenyl)-undecyl)oxy)-4-(4-methylthiazole-5 -yl)benzyl)pyrrolidine-2-carboxamido D10 ; ( 2S,4R)-1-((S ) -2 -acetamido-3,3-dimethylbutanoyl)-4 -Hydroxy- N- (2-((13-(3-(7-(4-(2-hydroxyethyl)piperidin-1-yl)-2-methyl-5-phenylpyrazolo[1 ,5- a ]pyrimidin-3-yl)phenyl)-tridecyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide D11 ; (2 S ,4 R )-4-hydroxy-1-(( S )-2-(10-(3-(7-(4-(2-hydroxyethyl)piperidin-1-yl)-2- Methyl-5-phenylpyrazolo[1,5- a ]pyrimidin-3-yl)phenyl)decanamido)-3,3- dimethylbutanyl )-N-(4-(4- Methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide D12 ; ( 2S,4R)-4-hydroxy-1-((S ) -2- (9-(4-( 7-(4-(2-Hydroxyethyl)piperidin-1-yl)-2-methyl-5-phenylpyrazolo[1,5- a ]pyrimidin-3-yl)phenyl)nonanyl Amino)-3,3- dimethylbutanyl )-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide D13 ; ( 2S , 4R )-1-(( S )-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxy- N- (2-((13-(3-(7-(4-(2 -hydroxyethyl) Piper (1-yl)-2-methyl-5-phenylpyrazolo[1,5- a ]pyrimidin-3-yl)-phenyl)-tridec-12-yn-1-yl) Oxy)-4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide D14 ; ( 2S,4R)-1-((S ) -2 -acetamide Amino-3,3-dimethylbutyryl)-4-hydroxy- N- (2-((11-(3-(7-(4-(2-hydroxyethyl)piperidin-1-yl)- 2-Methyl-5-phenylpyrazolo[1,5- a ]pyrimidin-3-yl)-phenyl)-undec-10-yn-1-yl)oxy)-4-(4 -Methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamido D15 ; or ( 2S,4R)-1-((S ) -2 -acetamido-3,3- Dimethylbutanyl)-4-hydroxy- N- (2-((7-(3-(7-(4-(2-hydroxyethyl)piperidin-1-yl)-2-methyl-5- Phenylpyrazolo[1,5- a ]pyrimidin-3-yl)phenyl)-heptyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2 - formamide D16 ; or its diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.
在某些實施例中，本文所提供之化合物為氘富集的。在某些實施例中，本文提供之化合物為碳-13富集的。在某些實施例中，本文提供之化合物為碳-14富集的。在某些實施例中，本文提供之化合物含有一或多種對於其他元素之較不普遍同位素，包括但不限於對於氮之 15N；對於氧之 17O或 18O；及對於硫之 34S、 35S或 36S。 In certain embodiments, the compounds provided herein are deuterium-enriched. In certain embodiments, the compounds provided herein are carbon-13 enriched. In certain embodiments, the compounds provided herein are carbon-14 enriched. In certain embodiments, the compounds provided herein contain one or more less common isotopes for other elements, including but not limited to15N for nitrogen; 17O or18O for oxygen; and34S ,34S for sulfur, 35S or 36S .
在某些實施例中，本文提供之化合物之同位素富集因子不小於約5、不小於約10、不小於約20、不小於約50、不小於約100、不小於約200、不小於約500、不小於約1,000、不小於約2,000、不小於約5,000或不小於約10,000。然而，在任何事件中，指定同位素之同位素富集因子不大於指定同位素之最大同位素富集因子，其為在給定位置處之化合物經指定同位素100%富集時的同位素富集因子。因此，不同同位素之最大同位素富集因子為不同的。氘之最大同位素富集因子為6,410且碳-13之最大同位素富集因子為90。In certain embodiments, the compounds provided herein have an isotopic enrichment factor of not less than about 5, not less than about 10, not less than about 20, not less than about 50, not less than about 100, not less than about 200, not less than about 500 , not less than about 1,000, not less than about 2,000, not less than about 5,000, or not less than about 10,000. However, in any event, the isotopic enrichment factor for a given isotope is not greater than the maximum isotopic enrichment factor for the given isotope, which is the isotopic enrichment factor at which the compound at a given location is 100% enriched with the given isotope. Therefore, the maximum isotopic enrichment factors for different isotopes are different. The maximum isotopic enrichment factor for deuterium is 6,410 and the maximum isotopic enrichment factor for carbon-13 is 90.
在某些實施例中，本文提供之化合物具有不小於約64 (約1%氘富集)、不小於約130 (約2%氘富集)、不小於約320 (約5%氘富集)、不小於約640 (約10%氘富集)、不小於約1,300 (約20%氘富集)、不小於約3,200 (約50%氘富集)、不小於約4,800 (約75%氘富集)、不小於約5,130 (約80%氘富集)、不小於約5,450 (約85%氘富集)、不小於約5,770 (約90%氘富集)、不小於約6,090 (約95%氘富集)、不小於約6,220 (約97%氘富集)、不小於約6,280 (約98%氘富集)、不小於約6,350 (約99%氘富集)或不小於約6,380 (約99.5%氘富集)之氘富集因子。氘富集可使用一般熟習此項技術者已知的習知分析方法，包括質譜法及核磁共振光譜法來測定。在某些實施例中，在指定為經氘富集時，本文所提供之化合物之原子中之至少一者具有不小於約50%、不小於約70%、不小於約80%、不小於約90%或不小於約98%之氘富集。In certain embodiments, the compounds provided herein have no less than about 64 (about 1% deuterium enrichment), no less than about 130 (about 2% deuterium enrichment), no less than about 320 (about 5% deuterium enrichment) , not less than about 640 (about 10% deuterium enriched), not less than about 1,300 (about 20% deuterium enriched), not less than about 3,200 (about 50% deuterium enriched), not less than about 4,800 (about 75% deuterium enriched) not less than about 5,130 (about 80% deuterium enriched), not less than about 5,450 (about 85% deuterium enriched), not less than about 5,770 (about 90% deuterium enriched), not less than about 6,090 (about 95% deuterium enriched) deuterium enriched), not less than about 6,220 (about 97% deuterium enriched), not less than about 6,280 (about 98% deuterium enriched), not less than about 6,350 (about 99% deuterium enriched), or not less than about 6,380 (about 99% deuterium enriched) 99.5% deuterium enrichment) deuterium enrichment factor. Deuterium enrichment can be determined using conventional analytical methods known to those of ordinary skill in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy. In certain embodiments, at least one of the atoms of the compounds provided herein has no less than about 50%, no less than about 70%, no less than about 80%, no less than about 90% or not less than about 98% deuterium enrichment.
在某些實施例中，本文提供之化合物經分離或純化。在某些實施例中，本文提供之化合物具有至少約90重量%、至少約95重量%、至少約98重量%、至少約99重量%或至少約99.5重量%之純度。In certain embodiments, the compounds provided herein are isolated or purified. In certain embodiments, the compounds provided herein have a purity of at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 99.5% by weight.
除非指定特定立體化學，否則本文所提供之化合物意欲涵蓋所有可能立體異構物。在本文提供之化合物含有烯基的情況下，化合物可以一種幾何順式/反式(或 Z/ E)異構物或其混合物之形式存在。在結構異構物可互相轉化的情況下，化合物可以單一互變異構物或互變異構物之混合物的形式存在。其在含有例如亞胺基、酮基或肟基之化合物中可呈質子互變異構形式；或在含有芳族部分之化合物中可呈所謂的價互變異構形式。因此，單一化合物可呈現超過一種異構類型。 Unless a specific stereochemistry is specified, the compounds provided herein are intended to encompass all possible stereoisomers. Where a compound provided herein contains an alkenyl group, the compound may exist as a geometric cis/trans (or Z / E ) isomer or a mixture thereof. Where the structural isomers are interconvertible, the compound may exist as a single tautomer or as a mixture of tautomers. It may be in protic tautomeric form in compounds containing, for example, imino, keto or oxime groups; or in so-called valence tautomeric form in compounds containing aromatic moieties. Thus, a single compound may exhibit more than one isomeric type.
本文中提供之化合物可為鏡像異構純的，諸如單一鏡像異構物或單一非鏡像異構物，或為立體異構混合物，諸如鏡像異構物之混合物，例如兩種鏡像異構物之外消旋混合物；或兩種或更多種非鏡像異構物之混合物。因此，熟習此項技術者將認識到，對於經歷活體內差向異構化之化合物，化合物以其( R)形式投與等效於化合物以其( S)形式投與。製備/分離個別鏡像異構物之習知技術包括由適合的光學純前驅體合成、由非對掌性起始材料不對稱合成或解析鏡像異構混合物，例如對掌性層析、再結晶、解析、非鏡像異構鹽形成，或衍生成非鏡像異構加合物接著分離。 The compounds provided herein may be enantiomerically pure, such as a single enantiomer or a single non-enantiomer, or a stereoisomeric mixture, such as a mixture of enantiomers, eg, a mixture of two enantiomers a racemic mixture; or a mixture of two or more diastereoisomers. Accordingly, those skilled in the art will recognize that, for compounds that undergo epimerization in vivo, administration of the compound in its ( R ) form is equivalent to administration of the compound in its ( S ) form. Known techniques for the preparation/isolation of individual enantiomers include synthesis from suitable optically pure precursors, asymmetric synthesis from non-chiral starting materials, or resolution of enantiomer mixtures, such as para-chiral chromatography, recrystallization, Resolved, Astereomeric salts formed, or derivatized as Astereomeric adducts followed by isolation.
當本文提供之化合物含有酸性或鹼性部分時，其亦可以醫藥學上可接受之鹽形式提供。參見，Berge等人, J. Pharm. Sci. 1977, 66, 1-19; Handbook of Pharmaceutical Salts: Properties, Selection, and Use, 第2版；Stahl及Wermuth編；John Wiley & Sons，2011。在某些實施例中，本文提供之化合物之醫藥學上可接受之鹽為溶劑合物。在某些實施例中，本文提供之化合物之醫藥學上可接受之鹽為水合物。 When a compound provided herein contains an acidic or basic moiety, it can also be provided in the form of a pharmaceutically acceptable salt. See, Berge et al., J. Pharm. Sci. 1977 , 66 , 1-19; Handbook of Pharmaceutical Salts: Properties, Selection, and Use , 2nd Ed.; Stahl and Wermuth eds; John Wiley & Sons, 2011. In certain embodiments, the pharmaceutically acceptable salts of the compounds provided herein are solvates. In certain embodiments, the pharmaceutically acceptable salts of the compounds provided herein are hydrates.
適用於製備本文提供之化合物之醫藥學上可接受之鹽的酸包括但不限於乙酸、2,2-二氯乙酸、醯基化胺基酸、己二酸、褐藻酸、抗壞血酸、L-天冬胺酸、苯磺酸、苯甲酸、4-乙醯胺基苯甲酸、硼酸(boric acid)、(+)-樟腦酸、樟腦磺酸、(+)-(1 S)-樟腦-10-磺酸、癸酸、己酸、辛酸、肉桂酸、檸檬酸、環己胺磺酸、環己烷胺基磺酸、十二基硫酸、乙烷-1,2-二磺酸、乙烷磺酸、2-羥基-乙磺酸、甲酸、反丁烯二酸、半乳糖二酸、龍膽酸、葡糖庚酸、D-葡萄糖酸、D-葡糖醛酸、L-麩胺酸、α-氧代戊二酸、乙醇酸、馬尿酸、氫溴酸、鹽酸、氫碘酸、(+)-L-乳酸、(±)-DL-乳酸、乳糖酸、月桂酸、順丁烯二酸、(-)-L-蘋果酸、丙二酸、(±)-DL-杏仁酸、甲磺酸、萘-2-磺酸、萘-1,5-二磺酸、1-羥基-2-萘甲酸、菸鹼酸、硝酸、油酸、乳清酸、草酸、棕櫚酸、雙羥萘酸、過氯酸、磷酸、L-焦麩胺酸、葡萄糖二酸、柳酸、4-胺基-柳酸、癸二酸、硬脂酸、丁二酸、硫酸、鞣酸、(+)-L-酒石酸、硫氰酸、對甲苯磺酸、十一碳烯酸及戊酸。 Acids suitable for use in preparing pharmaceutically acceptable salts of the compounds provided herein include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, glycated amino acids, adipic acid, alginic acid, ascorbic acid, L-day Partic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1 S )-camphor-10- Sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclohexylaminesulfonic acid, cyclohexaneaminosulfonic acid, dodecyl sulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptanoic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, α-Oxoglutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, lauric acid, maleic acid acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2 - Naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid, glucaric acid, salicylic acid, 4-amine salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid and valeric acid.
適用於製備本文提供之化合物之醫藥學上可接受之鹽的鹼包括但不限於無機鹼，諸如氫氧化鎂、氫氧化鈣、氫氧化鉀、氫氧化鋅或氫氧化鈉；及有機鹼，諸如一級胺、二級胺、三級胺及四級胺、脂族胺及芳族胺，包括但不限於L-精胺酸、苯明(benethamine)、苯乍生(benzathine)、膽鹼、二甲基乙醇胺(deanol)、二乙醇胺、二乙胺、二甲胺、二丙胺、二異丙胺、2-(二乙胺基)-乙醇、乙醇胺、乙胺、乙二胺、異丙胺、
N-甲基-葡糖胺、海卓胺(hydrabamine)、1
H-咪唑、L-離胺酸、𠰌啉、4-(2-羥基乙基)-𠰌啉、甲胺、哌啶、哌𠯤、丙胺、吡咯啶、1-(2-羥基乙基)-吡咯啶、吡啶、
本文提供之化合物亦可以前藥形式提供，其為化合物之官能性衍生物，且可易於活體內轉化成母體化合物。前藥通常適用，此係因為在一些情況下其可比母體化合物更易於投與。其可例如藉由經口投與而生物利用，而母體化合物不能。前藥亦可在醫藥組合物中相較於母體化合物具有增強的溶解性。前藥可藉由各種機制轉化成母體藥物，包括酶促方法及代謝水解。 醫藥組合物 The compounds provided herein can also be provided as prodrugs, which are functional derivatives of the compounds and can be readily converted to the parent compound in vivo. Prodrugs are generally suitable because in some cases they may be easier to administer than the parent compound. It is bioavailable, for example, by oral administration, whereas the parent compound is not. Prodrugs may also have enhanced solubility in pharmaceutical compositions compared to the parent compound. Prodrugs can be converted to the parent drug by a variety of mechanisms, including enzymatic methods and metabolic hydrolysis. pharmaceutical composition
在一個實施例中，本文提供一種醫藥組合物，其包含本文提供之化合物(例如式(A)化合物)或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體；或其醫藥學上可接受之鹽、溶劑合物、水合物或前藥；及醫藥學上可接受之賦形劑。In one embodiment, provided herein is a pharmaceutical composition comprising a compound provided herein (eg, a compound of formula (A)) or an enantiomer, a mixture of enantiomers, a diastereomer, both or A mixture of more diastereoisomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate or prodrugs; and pharmaceutically acceptable excipients.
本文提供之醫藥組合物可調配成各種劑型，包括但不限於用於經口、非經腸及局部投與之劑型。醫藥組合物亦可調配為修飾釋放劑型，包括延遲釋放、延緩釋放、延長釋放、持續釋放、脈衝釋放、控制釋放、加速釋放、快速釋放、定向釋放、程控釋放，及胃滯留劑型。此等劑型可根據熟習此項技術者已知之習知方法及技術來製備。參見例如 Remington: The Science and Practice of Pharmacy, 見上文; Modified-Release Drug Delivery Technology, 第2版.; Rathbone等人編; Drugs and the Pharmaceutical Sciences 184; CRC Press: Boca Raton, FL, 2008。 The pharmaceutical compositions provided herein can be formulated into various dosage forms including, but not limited to, dosage forms for oral, parenteral, and topical administration thereof. Pharmaceutical compositions can also be formulated into modified release dosage forms, including delayed release, delayed release, prolonged release, sustained release, pulsed release, controlled release, accelerated release, rapid release, targeted release, programmed release, and gastric retention dosage forms. Such dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art. See, eg, Remington: The Science and Practice of Pharmacy , supra; Modified-Release Drug Delivery Technology , 2nd ed.; Rathbone et al., eds.; Drugs and the Pharmaceutical Sciences 184; CRC Press: Boca Raton, FL, 2008.
在一個實施例中，本文所提供之醫藥組合物調配成用於經口投與之劑型。在另一實施例中，本文所提供之醫藥組合物在調配成用於非經腸投與之劑型。在又另一實施例中，本文所提供之醫藥組合物調配成用於靜脈內投與之劑型。在又另一實施例中，本文所提供之醫藥組合物調配成用於肌肉內投與之劑型。在又另一實施例中，本文所提供之醫藥組合物調配成用於皮下投與之劑型。在再一實施例中，本文所提供之醫藥組合物調配成用於局部投與之劑型。In one embodiment, the pharmaceutical compositions provided herein are formulated in a dosage form for oral administration thereof. In another embodiment, the pharmaceutical compositions provided herein are formulated in a dosage form for parenteral administration thereof. In yet another embodiment, the pharmaceutical compositions provided herein are formulated in a dosage form for intravenous administration. In yet another embodiment, the pharmaceutical compositions provided herein are formulated for intramuscular administration in a dosage form. In yet another embodiment, the pharmaceutical compositions provided herein are formulated in a dosage form for subcutaneous administration thereof. In yet another embodiment, the pharmaceutical compositions provided herein are formulated for topical administration in a dosage form.
本文所提供之醫藥組合物可以單位劑型或多個劑型提供。如本文所用，單位劑型係指實體上離散適合於投與個體之單元，且如此項技術中已知個別地經包裝。各單位劑量含有預定量之活性成分(例如本文所提供之化合物)，其與所需醫藥賦形劑結合足以產生所需治療效果。單位劑型之實例包括但不限於安瓿、注射器及個別包裝之錠劑及膠囊。單位劑型可以其部分或倍數投與。多個劑型為包裝於單一容器中待以分離之單位劑型投與的複數個相同單位劑型。多個劑型之實例包括(不限於)小瓶、錠劑或膠囊之瓶，或品脫或加侖之瓶。The pharmaceutical compositions provided herein can be provided in unit dosage form or in multiple dosage forms. As used herein, unit dosage form refers to physically discrete units suitable for administration to an individual, and individually packaged as is known in the art. Each unit dose contains a predetermined quantity of active ingredient (eg, a compound provided herein) sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical excipient. Examples of unit dosage forms include, but are not limited to, ampoules, syringes, and individually packaged lozenges and capsules. Unit dosage forms can be administered in fractions or multiples thereof. A plurality of dosage forms is a plurality of identical unit dosage forms packaged in a single container to be administered in separate unit dosage forms. Examples of dosage forms include, without limitation, vials, bottles of lozenges or capsules, or bottles of pints or gallons.
本文所提供之醫藥組合物可以一次投與或以時間間隔多次投與。應理解，精確劑量及治療持續時間可隨所治療之個體之年齡、體重及病狀而變化，且可使用已知測試方案憑經驗判定或藉由自活體內或活體外測試或診斷資料外推來判定。應進一步理解，對於任何特定個體，應根據個體需求及投與或監督醫藥組合物之投與的人員之專業判斷隨時間調整特定給藥方案。 A.經口投與 The pharmaceutical compositions provided herein can be administered once or multiple times at timed intervals. It should be understood that the precise dose and duration of treatment may vary with the age, weight and condition of the individual being treated, and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro testing or diagnostic data. determination. It will be further understood that for any particular individual, a particular dosing regimen should be adjusted over time according to the individual's needs and the professional judgment of the person administering or supervising the administration of the pharmaceutical composition. A. Oral administration
本文提供之用於經口投與之醫藥組合物可以用於經口投與之固體、半固體或液體劑型提供。如本文所用，經口投與亦包括頰內、經舌及舌下投與。適合的口服劑型包括但不限於錠劑、速融劑、咀嚼錠、膠囊、丸劑、帶狀物、糖衣錠、口含錠、丸粒、扁囊劑、小丸、藥用口嚼錠、散裝粉末、發泡或非發泡粉末或顆粒、口服噴霧、溶液、乳液、懸浮液、粉片、撒劑、酏劑及糖漿。除活性成分以外，醫藥組合物可含有一或多種醫藥學上可接受之載劑或賦形劑，包括但不限於黏合劑、填充劑、稀釋劑、崩解劑、潤濕劑、潤滑劑、滑動劑、著色劑、染料遷移抑制劑、甜味劑、調味劑、乳化劑、懸浮及分散劑、防腐劑、溶劑、非水性液體、有機酸及二氧化碳源。The pharmaceutical compositions provided herein for oral administration may be provided in solid, semi-solid or liquid dosage forms for oral administration. As used herein, oral administration also includes buccal, translingual, and sublingual administration. Suitable oral dosage forms include, but are not limited to, lozenges, fast-dissolving tablets, chewable lozenges, capsules, pills, ribbons, dragees, lozenges, pellets, cachets, pellets, medicated lozenges, bulk powders, Foaming or non-foaming powders or granules, oral sprays, solutions, emulsions, suspensions, powders, sprinkles, elixirs and syrups. In addition to the active ingredient, the pharmaceutical composition may contain one or more pharmaceutically acceptable carriers or excipients, including but not limited to binders, fillers, diluents, disintegrants, wetting agents, lubricants, Slip agents, colorants, dye transfer inhibitors, sweeteners, flavors, emulsifiers, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids and carbon dioxide sources.
黏合劑或粒化劑賦予錠劑內聚性以確保錠劑在壓縮之後保持完整。適合的黏合劑或粒化劑包括但不限於澱粉，諸如玉米澱粉、馬鈴薯澱粉及預膠凝化澱粉(例如STARCH 1500®)；明膠；糖，諸如蔗糖、葡萄糖、右旋糖、糖蜜及乳糖；天然及合成膠，諸如阿拉伯膠、褐藻酸、褐藻酸鹽、角叉菜(Irish moss)提取物、龐沃膠(Panwar gum)、哥地膠(Ghatti gum)、洋車前子(isabgol)殼之黏液、羧甲基纖維素、甲基纖維素、聚乙烯吡咯啶酮(PVP)、VEEGUM®、落葉松阿拉伯半乳聚糖(larch arabogalactan)、粉末狀黃蓍及瓜爾豆膠；纖維素，諸如乙基纖維素、乙酸纖維素、羧甲基纖維素鈣、羧甲基纖維素鈉、甲基纖維素、羥乙基纖維素(HEC)、羥丙基纖維素(HPC)、羥丙基甲基纖維素(HPMC)；微晶纖維素，諸如AVICEL® PH-101、AVICEL® PH-103、AVICEL® PH-105及AVICEL® RC-581。適合的填充劑包括但不限於滑石、碳酸鈣、微晶纖維素、粉末狀纖維素、葡萄糖結合劑、高嶺土、甘露醇、矽酸、山梨醇、澱粉及預膠凝化澱粉。本文提供之醫藥組合物中之黏合劑或填充劑之量視調配物類型而變化，且可由一般熟習此項技術者容易地辨別。本文提供之醫藥組合物中可存在約50重量%至約99重量%之黏合劑或填充劑。Binder or granulating agents impart cohesion to the tablet to ensure that the tablet remains intact after compression. Suitable binders or granulating agents include, but are not limited to, starches, such as corn starch, potato starch, and pregelatinized starch (eg, STARCH 1500®); gelatin; sugars, such as sucrose, glucose, dextrose, molasses, and lactose; Natural and synthetic gums such as acacia, alginic acid, alginate, carrageenan (Irish moss) extract, Panwar gum, Ghatti gum, isabgol shell mucilage, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), VEEGUM®, larch arabogalactan, powdered tragacanth and guar gum; cellulose, Such as ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl Methylcellulose (HPMC); microcrystalline cellulose, such as AVICEL® PH-101, AVICEL® PH-103, AVICEL® PH-105, and AVICEL® RC-581. Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, glucose binders, kaolin, mannitol, silicic acid, sorbitol, starch, and pregelatinized starch. The amount of binder or filler in the pharmaceutical compositions provided herein varies depending on the type of formulation and can be readily discerned by one of ordinary skill in the art. About 50% to about 99% by weight of binders or fillers can be present in the pharmaceutical compositions provided herein.
適合之稀釋劑包括但不限於磷酸二鈣、硫酸鈣、乳糖、山梨醇、蔗糖、肌醇、纖維素、高嶺土、甘露醇、氯化鈉、無水澱粉及粉糖。當以足夠量存在時，某些稀釋劑，諸如甘露醇、乳糖、山梨醇、蔗糖及肌醇，可賦予一些壓縮錠劑可藉由咀嚼而在口中崩解之特性。此類壓縮錠劑可用作咀嚼錠。本文提供之醫藥組合物中之稀釋劑之量視調配物類型而變化，且可由一般熟習此項技術者容易地辨別。Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, anhydrous starch, and powdered sugar. When present in sufficient amounts, certain diluents, such as mannitol, lactose, sorbitol, sucrose, and inositol, can impart the property of some compressed lozenges to disintegrate in the mouth by chewing. Such compressed lozenges can be used as chewable lozenges. The amount of diluent in the pharmaceutical compositions provided herein varies depending on the type of formulation and can be readily discerned by one of ordinary skill in the art.
適合的崩解劑包括但不限於瓊脂；膨潤土；纖維素，諸如甲基纖維素及羧甲基纖維素；木材產品；天然海綿；陽離子交換樹脂；褐藻酸；膠，諸如瓜爾豆膠及VEEGUM® HV；柑桔渣；交聯纖維素，諸如交聯羧甲纖維素；交聯聚合物，諸如交聯聚維酮；交聯澱粉；碳酸鈣；微晶纖維素，諸如羥基乙酸澱粉鈉；波拉克林鉀(polacrilin potassium)；澱粉，諸如玉米澱粉、馬鈴薯澱粉、木薯澱粉及預膠凝化澱粉；黏土；及褐藻素(algin)。本文提供之醫藥組合物中之崩解劑之量視調配物類型而變化，且可由一般熟習此項技術者容易地辨別。本文所提供之醫藥組合物可含有約0.5重量%至約15重量%或約1重量%至約5重量%之崩解劑。Suitable disintegrants include, but are not limited to, agar; bentonite; celluloses such as methylcellulose and carboxymethylcellulose; wood products; natural sponges; cation exchange resins; alginic acid; gums such as guar gum and VEEGUM ® HV; citrus pulp; cross-linked cellulose, such as croscarmellose; cross-linked polymers, such as crospovidone; cross-linked starch; calcium carbonate; microcrystalline cellulose, such as sodium starch glycolate; polacrilin potassium; starches, such as corn starch, potato starch, tapioca starch, and pregelatinized starch; clay; and algin. The amount of disintegrant in the pharmaceutical compositions provided herein varies depending on the type of formulation and can be readily discerned by one of ordinary skill in the art. The pharmaceutical compositions provided herein can contain from about 0.5% to about 15% by weight or from about 1% to about 5% by weight of a disintegrant.
適合的潤滑劑包括但不限於硬脂酸鈣；硬脂酸鎂；礦物油；輕質礦物油；甘油；山梨醇；甘露醇；二醇，諸如甘油二十二酸酯及聚乙二醇(PEG)；硬脂酸；月桂基硫酸鈉；滑石；氫化植物油，諸如花生油、棉籽油、葵花籽油、芝麻油、橄欖油、玉米油及大豆油；硬脂酸鋅；油酸乙酯；月桂酸乙酯；瓊脂；澱粉；石松；及二氧化矽或矽膠，諸如AEROSIL ®200及CAB-O-SIL ®。本文所提供之醫藥組合物中之潤滑劑之量視調配物類型而變化，且可由一般熟習此項技術者容易地辨別。本文所提供之醫藥組合物可含有約0.1重量%至約5重量%之潤滑劑。 Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oils such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil; zinc stearate; ethyl oleate; lauric acid ethyl ester; agar; starch; lycopodium; and silica or silica gel, such as AEROSIL ® 200 and CAB-O-SIL ® . The amount of lubricant in the pharmaceutical compositions provided herein varies depending on the type of formulation and can be readily discerned by one of ordinary skill in the art. The pharmaceutical compositions provided herein can contain from about 0.1% to about 5% by weight of lubricant.
適合的滑動劑包括但不限於膠態二氧化矽、CAB-O-SIL ®及無石棉滑石。適合的著色劑包括但不限於任何經批准、經檢定、可溶於水之FD&C染料，及懸浮於氧化鋁水合物上之水不溶性FD&C染料，以及其色澱。色澱為由水溶性染料吸附至重金屬之含水氧化物而形成之組合，產生染料之不可溶形式。適合的調味劑包括但不限於自植物(諸如果實)提取之天然調味劑，及產生合意的口感之化合物(諸如胡椒薄荷及柳酸甲酯)之合成摻合物。適合的甜味劑包括但不限於蔗糖、乳糖、甘露醇、糖漿、甘油及人工甜味劑，諸如糖精及阿斯巴甜糖(aspartame)。適合的乳化劑包括但不限於明膠、阿拉伯膠、黃蓍、膨潤土及界面活性劑，諸如聚氧乙烯山梨糖醇酐單油酸酯(TWEEN ®20)、聚氧乙烯山梨糖醇酐單油酸酯80 (TWEEN ®80)及油酸三乙醇胺。適合的懸浮及分散劑包括但不限於羧甲基纖維素鈉、果膠、黃蓍、VEEGUM®、阿拉伯膠、羧甲基纖維素鈉、羥丙基甲基纖維素及聚乙烯吡咯啶酮。適合的防腐劑包括但不限於甘油、對羥基苯甲酸甲酯及對羥基苯甲酸丙酯、苯甲酸添加劑、苯甲酸鈉及醇。適合的潤濕劑包括但不限於丙二醇單硬脂酸酯、山梨糖醇酐單油酸酯、二乙二醇單月桂酸酯及聚氧乙烯月桂基醚。適合的溶劑包括但不限於甘油、山梨醇、乙醇及糖漿。乳液中使用之適合的非水性液體包括但不限於礦物油及棉籽油。適合的有機酸包括但不限於檸檬酸及酒石酸。適合的二氧化碳源包括但不限於碳酸氫鈉及碳酸鈉。 Suitable slip agents include, but are not limited to, colloidal silica, CAB-O-SIL ® and asbestos-free talc. Suitable colorants include, but are not limited to, any approved, certified, water-soluble FD&C dyes, and water-insoluble FD&C dyes suspended on alumina hydrate, and lakes thereof. Lakes are combinations formed by the adsorption of water-soluble dyes to hydrous oxides of heavy metals, resulting in insoluble forms of dyes. Suitable flavors include, but are not limited to, natural flavors extracted from plants, such as fruits, and synthetic blends of compounds that impart a desirable mouthfeel, such as peppermint and methyl salicylate. Suitable sweeteners include, but are not limited to, sucrose, lactose, mannitol, syrups, glycerol, and artificial sweeteners such as saccharin and aspartame. Suitable emulsifiers include, but are not limited to, gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate ( TWEEN® 20), polyoxyethylene sorbitan monooleate Ester 80 (TWEEN ® 80) and triethanolamine oleate. Suitable suspending and dispersing agents include, but are not limited to, sodium carboxymethylcellulose, pectin, tragacanth, VEEGUM®, acacia, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Suitable preservatives include, but are not limited to, glycerin, methyl and propyl parabens, benzoic acid additives, sodium benzoate, and alcohols. Suitable humectants include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Suitable solvents include, but are not limited to, glycerol, sorbitol, ethanol, and syrup. Suitable non-aqueous liquids for use in the emulsion include, but are not limited to, mineral oil and cottonseed oil. Suitable organic acids include, but are not limited to, citric acid and tartaric acid. Suitable carbon dioxide sources include, but are not limited to, sodium bicarbonate and sodium carbonate.
應理解，即使在相同調配物內，許多載劑及賦形劑可提供數種功能。It will be appreciated that many carriers and excipients can serve several functions, even within the same formulation.
本文所提供之用於經口投與之醫藥組合物可以壓縮錠劑、研製錠劑、咀嚼口含錠、快速溶解錠劑、多重壓縮錠劑或腸包衣錠劑、包覆糖衣或包覆膜衣錠劑形式提供。包覆腸溶包衣錠劑為壓縮錠劑，其包覆有抵抗胃酸作用但在腸中溶解或崩解之物質，由此保護活性成分不受胃之酸性環境影響。腸溶包衣包括但不限於脂肪酸、脂肪、柳酸苯基酯、蠟、蟲膠、氨化蟲膠及鄰苯二甲酸乙酸纖維素。糖衣錠劑為由糖衣包覆之壓縮錠劑，其可有利地遮蓋令人不快的口味或氣味且保護錠劑免於氧化。包覆膜衣錠劑為壓縮錠劑，其由水溶性材料之薄層或薄膜覆蓋。膜包衣包括但不限於羥乙基纖維素、羧甲基纖維素鈉、聚乙二醇4000及鄰苯二甲酸乙酸纖維素。膜包衣提供與糖衣相同的一般特徵。多重壓縮錠劑為藉由超過一個壓縮循環製備之壓縮錠劑，包括分層錠劑及壓縮包衣或乾燥包衣錠劑。The pharmaceutical compositions provided herein for oral administration can be compressed lozenges, triturated lozenges, chewable lozenges, fast-dissolving lozenges, multiple compressed lozenges or enteric-coated lozenges, sugar-coated or coated Supplied in film-coated tablet form. Coated enteric-coated tablets are compressed tablets coated with a substance that resists the action of gastric acid but dissolves or disintegrates in the intestine, thereby protecting the active ingredient from the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Dragee are compressed lozenges coated with sugar, which advantageously masks unpleasant tastes or odors and protects the lozenge from oxidation. Film-coated tablets are compressed tablets which are covered by a thin layer or film of water-soluble material. Film coatings include, but are not limited to, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings provide the same general characteristics as sugar coatings. Multiple compressed lozenges are compressed lozenges prepared by more than one compression cycle, including layered lozenges and compression-coated or dry-coated lozenges.
錠劑劑型可由呈粉末、結晶或顆粒形式之活性成分單獨或與本文所描述之一或多種載劑或賦形劑(包括黏合劑、崩解劑、控制釋放聚合物、潤滑劑、稀釋劑及/或著色劑)組合來製備。調味劑及甜味劑尤其適用於形成咀嚼錠及口含錠。Tablet dosage forms may consist of the active ingredient in powder, crystalline or granular form, alone or in combination with one or more of the carriers or excipients described herein (including binders, disintegrants, controlled release polymers, lubricants, diluents and and/or colorant) in combination. Flavoring and sweetening agents are particularly useful in the formation of chewable and buccal lozenges.
本文所提供之用於經口投與之醫藥組合物可以軟或硬膠囊形式提供，其可由明膠、甲基纖維素、澱粉或褐藻酸鈣製備。硬明膠膠囊，亦稱為乾式填充膠囊(dry-filled capsule；DFC)，由兩部分組成，一部分在另一部分上滑動，由此完全包裹活性成分。軟彈性膠囊(soft elastic capsule；SEC)為軟的球狀殼，諸如明膠殼，其藉由添加甘油、山梨醇或類似多元醇而塑化。軟明膠殼可含有防腐劑以防止微生物生長。適合的防腐劑為如本文所描述之彼等防腐劑，包括對羥苯甲酸甲酯及對羥苯甲酸丙酯、及山梨酸。本文所提供之液體、半固體及固體劑型可包封在膠囊中。適合的液體及半固體劑型包括於碳酸伸丙酯、植物油或三酸甘油酯中之溶液及懸浮液。含有此類溶液之膠囊可如美國專利第4,328,245號、第4,409,239號及第4,410,545號中所描述製備。如熟習此項技術者已知，亦可包覆膠囊以改良或維持活性成分之溶解。The pharmaceutical compositions provided herein for oral administration may be provided in soft or hard capsules, which may be prepared from gelatin, methylcellulose, starch, or calcium alginate. Hard gelatin capsules, also known as dry-filled capsules (DFCs), consist of two parts, one sliding over the other, thereby completely encapsulating the active ingredient. Soft elastic capsules (SEC) are soft spherical shells, such as gelatin shells, which are plasticized by the addition of glycerol, sorbitol or similar polyols. Soft gelatin shells may contain preservatives to prevent microbial growth. Suitable preservatives are those as described herein, including methyl and propyl parabens, and sorbic acid. Liquid, semi-solid, and solid dosage forms provided herein can be encapsulated in capsules. Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils or triglycerides. Capsules containing such solutions can be prepared as described in US Pat. Nos. 4,328,245, 4,409,239 and 4,410,545. Capsules may also be coated to improve or maintain dissolution of the active ingredient, as known to those skilled in the art.
本文所提供之用於經口投與之醫藥組合物可以液體及半固體劑型提供，包括乳液、溶液、懸浮液、酏劑及糖漿。乳液為兩相系統，其中一種液體以小球體形式分散於另一種液體中，其可為水包油或油包水。乳液可包括醫藥學上可接受之非水性液體或溶劑、乳化劑及防腐劑。懸浮液可包括醫藥學上可接受之懸浮劑及防腐劑。水溶液醇性溶液可包括醫藥學上可接受之縮醛，諸如低級烷基醛之二(低級烷基)縮醛，例如乙醛二乙醇縮乙醛；及具有一或多個羥基之水混溶性溶劑，諸如丙二醇及乙醇。酏劑為澄清、加糖及水醇性溶液。糖漿為糖(例如蔗糖)之濃縮水溶液且亦可含有防腐劑。對於液體劑型，例如於聚乙二醇中之溶液，可用足量的用於投與之可方便地量測之醫藥學上可接受之液體載劑(例如水)稀釋。The pharmaceutical compositions for oral administration provided herein can be provided in liquid and semi-solid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. Emulsions are two-phase systems in which one liquid is dispersed in another liquid in the form of small spheres, which can be oil-in-water or water-in-oil. Emulsions may include pharmaceutically acceptable non-aqueous liquids or solvents, emulsifiers and preservatives. Suspensions may include pharmaceutically acceptable suspending agents and preservatives. Aqueous alcoholic solutions may include pharmaceutically acceptable acetals, such as di(lower alkyl) acetals of lower alkyl aldehydes, such as acetaldehyde diethanol acetal; and water miscibility with one or more hydroxyl groups Solvents such as propylene glycol and ethanol. Elixirs are clear, sweetened and hydroalcoholic solutions. Syrups are concentrated aqueous solutions of sugars such as sucrose and may also contain a preservative. For liquid dosage forms, eg, solutions in polyethylene glycol, can be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier (eg, water) for administration to which it is conveniently measured.
其他適用液體及半固體劑型包括但不限於含有活性成分及以下物質之劑型：二烷基化單伸烷基二醇或聚伸烷基二醇，包括1,2-二甲氧甲烷、二乙二醇二甲醚、三乙二醇二甲醚、四乙二醇二甲醚、聚乙二醇-350-二甲醚、聚乙二醇-550-二甲醚、聚乙二醇-750-二甲醚，其中350、550及750係指聚乙二醇之大致平均分子量。此等劑型可進一步包含一或多種抗氧化劑，諸如丁基化羥基甲苯(BHT)、丁基化羥基大茴香醚(BHA)、沒食子酸丙酯、維生素E、對苯二酚、羥基香豆素、乙醇胺、卵磷脂、腦磷脂、抗壞血酸、蘋果酸、山梨醇、磷酸、亞硫酸氫鹽、偏亞硫酸氫鈉、硫二丙酸及其酯及二硫胺甲酸。Other suitable liquid and semi-solid dosage forms include, but are not limited to, dosage forms containing the active ingredient and the following: dialkylated monoalkylene glycols or polyalkylene glycols, including 1,2-dimethoxymethane, diethylene glycol Glycol dimethyl ether, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750 - Dimethyl ether, where 350, 550 and 750 refer to the approximate average molecular weight of polyethylene glycol. Such dosage forms may further comprise one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxy vanilla Lecithin, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithicarbamic acid.
本文所提供之用於經口投與之醫藥組合物亦可以脂質體、膠束、微球體或奈米系統形式提供。膠束劑型可如美國專利第6,350,458號中所描述製備。The pharmaceutical compositions provided herein for oral administration may also be provided in the form of liposomes, micelles, microspheres, or nanosystems. Micellar dosage forms can be prepared as described in US Patent No. 6,350,458.
本文所提供之用於經口投與之醫藥組合物可以待復原成液體劑型之非發泡或發泡、顆粒及粉末形式提供。用於非發泡顆粒或粉末中的醫藥學上可接受之載劑及賦形劑可包括稀釋劑、甜味劑及潤濕劑。用於發泡顆粒或粉末之醫藥學上可接受之載劑及賦形劑可包括有機酸及二氧化碳源。The pharmaceutical compositions provided herein for oral administration can be provided in non-foamed or foamed, granular and powder forms to be reconstituted into liquid dosage forms. Pharmaceutically acceptable carriers and excipients for use in non-expanded granules or powders may include diluents, sweeteners and wetting agents. Pharmaceutically acceptable carriers and excipients for the foamed granules or powders can include organic acids and carbon dioxide sources.
著色劑及調味劑可用於本文所描述之所有劑型中。Coloring and flavoring agents can be used in all dosage forms described herein.
本文所提供之用於經口投與之醫藥組合物可以立即或修飾釋放劑型調配，包括延遲釋放形式、持續釋放形式、脈衝釋放形式、控制釋放形式、定向釋放形式及程控釋放形式。 B.非經腸投與 The pharmaceutical compositions provided herein for oral administration can be formulated in immediate or modified release dosage forms, including delayed release, sustained release, pulsed release, controlled release, directed release, and programmed release. B. Parenteral Administration
本文所提供之醫藥組合物可藉由注射、灌注或植入而非經腸投與，以用於局部或全身投與。如本文所用，非經腸投與包括靜脈內、動脈內、腹膜內、鞘內、心室內、尿道內、胸骨內、顱內、肌肉內、滑膜內、膀胱內及皮下投與。The pharmaceutical compositions provided herein can be administered by injection, infusion or implantation rather than enterally, for local or systemic administration. As used herein, parenteral administration includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, intravesical, and subcutaneous administration.
本文所提供之用於非經腸投與之醫藥組合物可調配成任何適合於非經腸投與之劑型(包括但不限於溶液、懸浮液、乳液、膠束、脂質體、微球體、奈米系統)及適合於在注射之前溶解或懸浮於液體中之固體。可根據熟習醫藥科學技術者已知之習知方法製備此類劑型。參見例如 Remington: The Science and Practice of Pharmacy,見上文。 The pharmaceutical compositions for parenteral administration provided herein can be formulated into any dosage form suitable for parenteral administration (including but not limited to solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanoparticle Mi system) and solids suitable for solution or suspension in liquid prior to injection. Such dosage forms can be prepared according to conventional methods known to those skilled in the medical sciences. See, eg, Remington: The Science and Practice of Pharmacy , supra.
本文所提供之用於非經腸投與之醫藥組合物可包括一或多種醫藥學上可接受之載劑及賦形劑，包括但不限於水性媒劑、水可混溶性媒劑、非水性媒劑、對抗微生物生長之抗微生物劑或防腐劑、穩定劑、溶解性增強劑、等張劑、緩衝劑、抗氧化劑、局部麻醉劑、懸浮劑及分散劑、潤濕劑或乳化劑、錯合劑、鉗合劑或螯合劑、低溫保護劑、凍乾保護劑、增稠劑、pH調節劑及惰性氣體。The pharmaceutical compositions provided herein for parenteral administration may include one or more pharmaceutically acceptable carriers and excipients, including but not limited to aqueous vehicles, water-miscible vehicles, non-aqueous vehicles Vehicles, antimicrobial or preservative agents against microbial growth, stabilizers, solubility enhancers, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents , chelating or chelating agents, cryoprotectants, lyoprotectants, thickeners, pH adjusters and inert gases.
適合的水性媒劑包括但不限於水、鹽水、生理鹽水或磷酸鹽緩衝鹽水(phosphate buffered saline；PBS)、氯化鈉注射液、林格氏注射液(Ringer's injection)、等張右旋糖注射液、無菌水注射液、右旋糖及乳酸林格氏注射液。適合的非水性媒劑包括但不限於植物來源之非揮發性油，蓖麻油、玉米油、棉籽油、橄欖油、花生油、薄荷油、紅花油、芝麻油、大豆油、氫化植物油、氫化大豆油及椰子油之中鏈三酸甘油酯，及棕櫚籽油。適合的水可混溶性媒劑包括但不限於乙醇、1,3-丁二醇、液體聚乙二醇(例如聚乙二醇300及聚乙二醇400)、丙二醇、甘油、 N-甲基-2-吡咯啶酮、 N,N-二甲基乙醯胺及二甲亞碸。 Suitable aqueous vehicles include, but are not limited to, water, saline, physiological saline or phosphate buffered saline (PBS), sodium chloride injection, Ringer's injection, isotonic dextrose injection, Sterile water injection, dextrose and lactated Ringer's injection. Suitable non-aqueous vehicles include, but are not limited to, non-volatile oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oil, hydrogenated soybean oil and Medium Chain Triglycerides in Coconut Oil, and Palm Seed Oil. Suitable water-miscible vehicles include, but are not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycols (eg, polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerol, N -methyl -2-pyrrolidone, N,N -dimethylacetamide and dimethylsulfoxide.
適合的抗微生物劑或防腐劑包括但不限於苯酚、甲酚、汞劑、苯甲醇、氯丁醇、對羥基苯甲酸甲酯及對羥基苯甲酸丙酯、硫柳汞、苯紮氯銨(例如苄索氯銨)、對羥基苯甲酸甲酯及對羥基苯甲酸丙酯以及山梨酸。適合的等張劑包括但不限於氯化鈉、甘油及右旋糖。適合的緩衝劑包括但不限於磷酸鹽及檸檬酸鹽。適合的抗氧化劑包括本文所描述之彼等抗氧化劑，諸如亞硫酸氫鹽及偏亞硫酸氫鈉。適合的局部麻醉劑包括但不限於鹽酸普魯卡因(procaine hydrochloride)。適合的懸浮劑及分散劑包括本文所描述之彼等，諸如羧甲基纖維素鈉、羥丙基甲基纖維素及聚乙烯吡咯啶酮。適合的乳化劑包括本文所描述之彼等乳化劑，諸如聚氧化烯山梨糖醇酐單月桂酸酯、聚氧乙烯山梨糖醇酐單油酸酯80及油酸三乙醇胺。適合的鉗合劑或螯合劑包括但不限於EDTA。適合的pH調節劑包括但不限於氫氧化鈉、鹽酸、檸檬酸及乳酸。適合的錯合劑包括但不限於環糊精，包括α-環糊精、β-環糊精、羥丙基-β-環糊精、磺基丁醚-β-環糊精及磺基丁醚7-β-環糊精(CAPTISOL ®)。 Suitable antimicrobial agents or preservatives include, but are not limited to, phenol, cresol, amalgam, benzyl alcohol, chlorobutanol, methyl and propyl parabens, thimerosal, benzalkonium chloride (e.g., benzyl alcohol). oxonium chloride), methyl and propyl parabens, and sorbic acid. Suitable isotonic agents include, but are not limited to, sodium chloride, glycerol, and dextrose. Suitable buffers include, but are not limited to, phosphates and citrates. Suitable antioxidants include those described herein, such as bisulfite and sodium metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents include those described herein, such as sodium carboxymethylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Suitable emulsifiers include those described herein, such as polyoxyalkylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate. Suitable sequestering or chelating agents include, but are not limited to, EDTA. Suitable pH adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid. Suitable complexing agents include, but are not limited to, cyclodextrins, including alpha-cyclodextrin, beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, sulfobutyl ether-beta-cyclodextrin, and sulfobutyl ether 7-beta-cyclodextrin (CAPTISOL ® ).
當本文所提供之醫藥組合物經調配用於多劑量投與時，該等多劑量非經腸調配物必須含有抑細菌或抑真菌濃度之抗微生物劑。如此項技術中已知及實踐的，所有非經腸調配物必須為無菌的。When the pharmaceutical compositions provided herein are formulated for multiple dose administration, such multiple dose parenteral formulations must contain bacteriostatic or fungistatic concentrations of the antimicrobial agent. As known and practiced in the art, all parenteral formulations must be sterile.
在一個實施例中，用於非經腸投與之醫藥組合物以即用型無菌溶液形式提供。在另一實施例中，醫藥組合物以在使用之前用媒劑復原之無菌乾燥可溶產品形式提供，包括凍乾粉末及皮下錠劑。在又另一實施例中，醫藥組合物以即用型無菌懸浮液形式提供。在又另一實施例中，醫藥組合物以在使用之前用媒劑復原之無菌乾燥不可溶產品形式提供。在再一實施例中，醫藥組合物以即用型無菌乳液形式提供。In one embodiment, the pharmaceutical composition for parenteral administration is provided as a ready-to-use sterile solution. In another embodiment, the pharmaceutical composition is provided as a sterile dry soluble product for reconstitution with a vehicle prior to use, including lyophilized powders and subcutaneous lozenges. In yet another embodiment, the pharmaceutical composition is provided as a ready-to-use sterile suspension. In yet another embodiment, the pharmaceutical composition is provided as a sterile dry insoluble product for reconstitution with a vehicle prior to use. In yet another embodiment, the pharmaceutical composition is provided as a ready-to-use sterile emulsion.
本文所提供之用於非經腸投與之醫藥組合物可以立即或修飾釋放劑型調配，包括延遲釋放形式、持續釋放形式、脈衝釋放形式、控制釋放形式、定向釋放形式及程控釋放形式。The pharmaceutical compositions provided herein for parenteral administration may be formulated in immediate or modified release dosage forms, including delayed release, sustained release, pulsed release, controlled release, directed release, and programmed release.
本文所提供之用於非經腸投與之醫藥組合物可以懸浮液、固體、半固體或搖溶性液體形式調配，以用於以植入儲槽形式投與。在一個實施例中，將本文所提供之醫藥組合物分散於固體內部基質中，該固體內部基質由在體液中不可溶但允許醫藥組合物中之活性成分擴散通過之外部聚合膜包裹。The pharmaceutical compositions provided herein for parenteral administration can be formulated in suspension, solid, semisolid, or thixotropic liquid forms for administration in implantable reservoirs. In one embodiment, the pharmaceutical compositions provided herein are dispersed in a solid inner matrix surrounded by an outer polymeric membrane that is insoluble in body fluids but allows the active ingredient in the pharmaceutical composition to diffuse therethrough.
適合的內部基質包括但不限於聚甲基丙烯酸甲酯、聚甲基丙烯酸丁酯、塑化或非塑化聚氯乙烯、塑化耐綸(plasticized nylon)、塑化聚對苯二甲酸伸乙酯、天然橡膠、聚異戊二烯、聚異丁烯、聚丁二烯、聚乙烯、乙烯-乙酸乙烯酯共聚物、聚矽氧橡膠、聚二甲基矽氧烷、聚矽氧碳酸酯共聚物、親水性聚合物(諸如丙烯酸及甲基丙烯酸之酯之水凝膠)、膠原蛋白、交聯聚乙烯醇及交聯部分水解的聚乙酸乙烯酯。Suitable internal matrices include, but are not limited to, polymethyl methacrylate, polybutyl methacrylate, plasticized or non-plasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate Ester, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene vinyl acetate, polysiloxane, polydimethylsiloxane, polysiloxane carbonate , hydrophilic polymers (such as hydrogels of esters of acrylic acid and methacrylic acid), collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate.
適合的外部聚合膜包括但不限於聚乙烯、聚丙烯、乙烯/丙烯共聚物、乙烯/丙烯酸乙酯共聚物、乙烯/乙酸乙烯酯共聚物、聚矽氧橡膠、聚二甲基矽氧烷、氯丁橡膠、氯化聚乙烯、聚氯乙烯、氯乙烯與乙酸乙烯酯、偏二氯乙烯、乙烯及丙烯之共聚物、離聚物聚對苯二甲酸伸乙酯、丁基橡膠表氯醇橡膠、乙烯/乙烯醇共聚物、乙烯/乙酸乙烯酯/乙烯醇三元共聚物及乙烯/乙烯氧基乙醇共聚物。 C.局部投與 Suitable outer polymeric films include, but are not limited to polyethylene, polypropylene, ethylene/propylene copolymer, ethylene/ethyl acrylate copolymer, ethylene/vinyl acetate copolymer, polysiloxane, polydimethylsiloxane, Neoprene, chlorinated polyethylene, polyvinyl chloride, vinyl chloride and vinyl acetate, vinylidene chloride, copolymers of ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber, epichlorohydrin Rubber, ethylene/vinyl alcohol copolymers, ethylene/vinyl acetate/vinyl alcohol terpolymers and ethylene/vinyloxyethanol copolymers. C. Partial delivery
本文所提供之醫藥組合物可局部投與至皮膚、毛孔或黏膜。如本文所用，局部投與包括經皮(皮內)、經結膜、角膜內、眼內、經眼、經耳、透皮、經鼻、經陰道、經尿道、經呼吸道及經直腸投與。The pharmaceutical compositions provided herein can be administered topically to the skin, pores, or mucous membranes. As used herein, topical administration includes transdermal (intradermal), transconjunctival, intracorneal, intraocular, transocular, transauricular, transdermal, nasal, transvaginal, transurethral, transrespiratory, and rectal administration.
本文所提供之醫藥組合物可調配成任何適合於局部投與之劑型以獲得局部或全身作用，包括但不限於乳液、溶液、懸浮液、乳膏、凝膠、水凝膠、軟膏、敷粉、敷料、酏劑、洗劑、懸浮液、酊劑、糊劑、發泡體、薄膜、氣霧劑、沖洗劑、噴霧劑、栓劑、繃帶及經皮貼片。本文所提供之醫藥組合物之局部調配物亦可包含脂質體、膠束、微球體及奈米系統。The pharmaceutical compositions provided herein can be formulated into any dosage form suitable for topical administration thereof for local or systemic effect, including but not limited to emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, powders , dressings, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, rinses, sprays, suppositories, bandages and transdermal patches. Topical formulations of the pharmaceutical compositions provided herein may also include liposomes, micelles, microspheres, and nanosystems.
適用於局部調配物之醫藥學上可接受之載劑及賦形劑包括但不限於水性媒劑、水可混溶性媒劑、非水性媒劑、對抗微生物生長之抗微生物劑或防腐劑、穩定劑、溶解性增強劑、等張劑、緩衝劑、抗氧化劑、局部麻醉劑、懸浮劑及分散劑、潤濕劑或乳化劑、錯合劑、鉗合劑或螯合劑、穿透增強劑、低溫保護劑、凍乾保護劑、增稠劑及惰性氣體。Pharmaceutically acceptable carriers and excipients suitable for topical formulations include, but are not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against microbial growth, stable agents, solubility enhancers, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, penetration enhancers, cryoprotectants , lyophilization protective agent, thickener and inert gas.
醫藥組合物亦可藉由電穿孔、離子導入療法、超音波藥物透入療法、超音波電滲法、或微針或無針注射(諸如POWDERJECT™及BIOJECT™)局部投與。Pharmaceutical compositions can also be administered topically by electroporation, iontophoresis, sonication, sonication, or microneedle or needleless injection such as POWDERJECT™ and BIOJECT™.
本文所提供之醫藥組合物可以軟膏、乳膏及凝膠形式提供。適合的軟膏媒劑包括油性或烴媒劑，包括豬油、安息香豚脂(benzoinated lard)、橄欖油、棉籽油及其他油、白凡士林；可乳化或吸收媒劑，諸如親水性凡士林、羥基硬脂硫酸鹽及無水羊毛蠟；水可移除型媒劑，諸如親水性軟膏；水溶性軟膏媒劑，包括不同分子量之聚乙二醇；乳液媒劑，油包水(W/O)乳液或水包油(O/W)乳液，包括鯨蠟基醇、單硬脂酸甘油酯、羊毛蠟及硬脂酸。參見例如 Remington: The Science and Practice of Pharmacy,見上文。此等媒劑為潤膚劑，但通常需要添加抗氧化劑及防腐劑。 The pharmaceutical compositions provided herein can be provided in the form of ointments, creams, and gels. Suitable ointment vehicles include oily or hydrocarbon vehicles including lard, benzoinated lard, olive oil, cottonseed oil and other oils, white petrolatum; emulsifiable or absorbent vehicles such as hydrophilic petrolatum, hydroxy Lipid sulfates and anhydrous wool waxes; water-removable vehicles, such as hydrophilic ointments; water-soluble ointment vehicles, including polyethylene glycols of various molecular weights; emulsion vehicles, water-in-oil (W/O) emulsions or Oil-in-water (O/W) emulsions including cetyl alcohol, glycerol monostearate, wool wax and stearic acid. See, eg, Remington: The Science and Practice of Pharmacy , supra. These vehicles are emollients, but usually require the addition of antioxidants and preservatives.
適合的乳膏基質可為水包油或油包水。適合的乳膏媒劑可為水可洗的，且含有油相、乳化劑及水相。油相亦稱為「內部」相，其一般由凡士林及脂肪醇(諸如鯨蠟醇或硬脂醇)構成。水相通常(但未必)在體積上超過油相，且一般含有保濕劑。乳膏調配物中之乳化劑可為非離子、陰離子、陽離子或兩性界面活性劑。Suitable cream bases may be oil-in-water or water-in-oil. Suitable cream vehicles can be water-washable, and contain an oily phase, an emulsifying agent, and an aqueous phase. The oily phase, also referred to as the "internal" phase, typically consists of petrolatum and fatty alcohols such as cetyl or stearyl alcohol. The aqueous phase typically (but not necessarily) exceeds the oil phase in volume and typically contains a humectant. Emulsifiers in cream formulations can be nonionic, anionic, cationic or amphoteric surfactants.
凝膠為半固體、懸浮液型系統。單相凝膠含有實質上均勻分佈於液體載劑中之有機大分子。適合的膠凝劑包括但不限於交聯丙烯酸聚合物，諸如卡波姆(carbomer)、羧基聚伸烷基及CARBOPOL ®；親水性聚合物，諸如聚氧化乙烯、聚氧乙烯-聚氧丙烯共聚物及聚乙烯醇；纖維素聚合物，諸如羥丙基纖維素、羥乙基纖維素、羥丙基甲基纖維素、鄰苯二甲酸羥丙基甲基纖維素及甲基纖維素；膠，諸如黃蓍膠及三仙膠；褐藻酸鈉；及明膠。為了製備均勻凝膠，可添加諸如乙醇或甘油之分散劑，或可藉由研磨、機械混合及/或攪拌來使膠凝劑分散。 Gels are semi-solid, suspension-type systems. Single-phase gels contain organic macromolecules distributed substantially uniformly in a liquid carrier. Suitable gelling agents include, but are not limited to, cross-linked acrylic polymers, such as carbomers, carboxypolyalkylenes, and CARBOPOL® ; hydrophilic polymers, such as polyethylene oxide, polyoxyethylene-polyoxypropylene copolymers and polyvinyl alcohol; cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methylcellulose; gums , such as tragacanth and Sanxian gum; sodium alginate; and gelatin. To prepare a uniform gel, dispersing agents such as ethanol or glycerol can be added, or the gelling agent can be dispersed by grinding, mechanical mixing, and/or stirring.
本文所提供之醫藥組合物可以栓劑、子宮托、桿劑、泥罨劑或熱罨劑、糊劑、粉末、敷料、乳膏、石膏、避孕藥、軟膏、溶液、乳液、懸浮液、棉塞、凝膠、發泡體、噴霧劑或灌腸劑形式經直腸、經尿道、經陰道或在陰道周圍投與。此等劑型可使用如 Remington: The Science and Practice of Pharmacy, 見上文中所描述之習知方法製造。 The pharmaceutical compositions provided herein can be suppositories, pessaries, rods, poultices or hot poultices, pastes, powders, dressings, creams, casts, contraceptives, ointments, solutions, lotions, suspensions, tampons , gel, foam, spray or enema form for rectal, transurethral, vaginal or perivaginal administration. Such dosage forms can be manufactured using conventional methods such as those described in Remington: The Science and Practice of Pharmacy , supra.
經直腸、經尿道及經陰道栓劑為用於插入身體孔口之固態物體，其在常溫下為固體，但在體溫下熔融或軟化以在孔口內部釋放活性成分。經直腸及經陰道栓劑中所用的醫藥學上可接受之載劑包括基質或媒劑，諸如硬化劑，其在與活性成分調配時產生接近體溫之熔點；及如本文所描述之抗氧化劑，包括亞硫酸氫鹽及偏亞硫酸氫鈉。適合的媒劑包括但不限於可可豆油(可可油)、甘油-明膠、聚乙二醇(聚氧乙二醇)、鯨蠟、石蠟、白色及黃色蠟，及脂肪酸之單甘油酯、二甘油酯及三甘油酯之適當混合物，及水凝膠，諸如聚乙烯醇、甲基丙烯酸羥基乙酯及聚丙烯酸。亦可使用各種媒劑之組合。可藉由壓縮或模製來製備經直腸及經陰道栓劑。經直腸及經陰道栓劑之典型重量為約2至約3 g。Transrectal, transurethral, and transvaginal suppositories are solid objects for insertion into body orifices that are solid at ordinary temperatures but melt or soften at body temperature to release the active ingredient inside the orifice. Pharmaceutically acceptable carriers for use in rectal and vaginal suppositories include bases or vehicles, such as hardeners, which when formulated with the active ingredients produce a melting point near body temperature; and antioxidants as described herein, including Bisulfite and sodium metabisulfite. Suitable vehicles include, but are not limited to, cocoa butter (Cocoa butter), glycerin-gelatin, polyethylene glycol (polyoxyethylene glycol), spermaceti, paraffin, white and yellow waxes, and mono-, diglycerides of fatty acids Suitable mixtures of esters and triglycerides, and hydrogels such as polyvinyl alcohol, hydroxyethyl methacrylate, and polyacrylic acid. Combinations of various vehicles can also be used. Rectal and vaginal suppositories can be prepared by compression or molding. Typical weights for rectal and vaginal suppositories are from about 2 to about 3 g.
本文所提供之醫藥組合物可以溶液、懸浮液、軟膏、乳液、膠凝溶液、用於溶液之粉末、凝膠、眼部插入物及植入劑形式經眼投與。The pharmaceutical compositions provided herein can be administered ocularly in the form of solutions, suspensions, ointments, emulsions, gel solutions, powders for solutions, gels, ocular inserts, and implants.
本文所提供之醫藥組合物可鼻內或藉由吸入投與呼吸道。醫藥組合物可以氣霧劑或溶液形式(單獨或與適合的推進劑(諸如1,1,1,2-四氟乙烷或1,1,1,2,3,3,3-七氟丙烷)組合)提供，以用於使用加壓容器、泵、噴霧器、霧化器(諸如使用電流體動力學以產生細霧之霧化器)或噴霧器遞送。醫藥組合物亦可以用於吹入之乾粉(單獨或與惰性載劑(諸如乳糖或磷脂)組合)；及鼻滴劑形式提供。對於鼻內使用而言，粉末可包含生物黏著劑，包括聚葡萄胺糖或環糊精。The pharmaceutical compositions provided herein can be administered to the respiratory tract intranasally or by inhalation. Pharmaceutical compositions may be in aerosol or solution form, alone or in combination with a suitable propellant such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane ) is provided for delivery using a pressurized container, pump, nebulizer, nebulizer (such as one that uses electrohydrodynamics to generate a fine mist) or nebulizer. The pharmaceutical compositions may also be provided as dry powders for insufflation (alone or in combination with inert carriers such as lactose or phospholipids); and as nasal drops. For intranasal use, powders may contain bioadhesives, including polyglucosamine or cyclodextrin.
用於加壓容器、泵、噴霧器、霧化器或噴霧器中之溶液或懸浮液可經調配以含有乙醇、乙醇水溶液或適合的用於活性成分之分散、溶解或延長釋放之替代性藥劑；作為溶劑之推進劑；及/或界面活性劑，諸如山梨糖醇酐三油酸酯、油酸或寡聚乳酸。Solutions or suspensions for use in pressurized containers, pumps, nebulizers, nebulizers, or nebulizers may be formulated to contain ethanol, aqueous ethanol, or a suitable alternative for dispersion, dissolution, or prolonged release of the active ingredient; as A propellant for a solvent; and/or a surfactant such as sorbitan trioleate, oleic acid or oligomeric lactic acid.
本文所提供之醫藥組合物微米化為適合於藉由吸入遞送之大小，諸如約50微米或更小、或約10微米或更小。此類大小之粒子可使用熟習此項技術者已知之粉碎方法製備，諸如螺旋噴射研磨、流化床噴射研磨、用於形成奈米粒子之超臨界流體加工、高壓均質化或噴霧乾燥。The pharmaceutical compositions provided herein are micronized to a size suitable for delivery by inhalation, such as about 50 microns or less, or about 10 microns or less. Particles of this size can be prepared using pulverization methods known to those skilled in the art, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing for nanoparticle formation, high pressure homogenization, or spray drying.
用於吸入器或吹入器之膠囊、泡殼及料筒可經調配以含有以下物質之粉末混合物：本文所提供之醫藥組合物；適合的粉末基質，諸如乳糖或澱粉；及效能改良劑，諸如 l-白胺酸、甘露醇或硬脂酸鎂。乳糖可為無水的或呈一水合物形式。其他適合的賦形劑或載劑包括但不限於聚葡萄糖、葡萄糖、麥芽糖、山梨醇、木糖醇、果糖、蔗糖及海藻糖。本文所提供之用於吸入/鼻內投與之醫藥組合物可進一步包含適合的香料，諸如薄荷醇及左薄荷腦；及/或甜味劑，諸如糖精及糖精鈉。 Capsules, blisters, and cartridges for use in an inhaler or insufflator can be formulated to contain a powder mix of: a pharmaceutical composition provided herein; a suitable powder base, such as lactose or starch; and a potency modifier, Such as l -leucine, mannitol or magnesium stearate. Lactose can be anhydrous or in the form of a monohydrate. Other suitable excipients or carriers include, but are not limited to, polydextrose, dextrose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose. The pharmaceutical compositions provided herein for inhalation/intranasal administration may further comprise suitable flavoring agents, such as menthol and levomenthol; and/or sweetening agents, such as saccharin and sodium saccharin.
本文所提供之用於局部投與之醫藥組合物可經調配以立即釋放或修飾釋放，包括延遲釋放、持續釋放、脈衝釋放、控制釋放、定向釋放及程控釋放。 D.修飾釋放 The pharmaceutical compositions provided herein for topical administration may be formulated for immediate release or modified release, including delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release. D. Modified release
本文所提供之醫藥組合物可調配為修飾釋放劑型。如本文所用，術語「修飾釋放」係指其中在藉由相同途徑投與時，活性成分之釋放速率或位置與立即劑型不同的劑型。修飾釋放劑型包括但不限於延遲釋放、延緩釋放、延長釋放、持續釋放、脈衝釋放、控制釋放、加速釋放及快速釋放、定向釋放、程控釋放，及胃滯留劑型。呈修飾釋放劑型之醫藥組合物可使用熟習此項技術者已知之多種修飾釋放裝置及方法製備，包括但不限於基質控制釋放裝置、滲透控制釋放裝置、多微粒控制釋放裝置、離子交換樹脂、腸溶衣、多層包衣、微球體、脂質體及其組合。活性成分之釋放速率亦可藉由改變活性成分之粒度及多形現象來修飾。 1.基質控制釋放裝置 The pharmaceutical compositions provided herein can be formulated into modified release dosage forms. As used herein, the term "modified release" refers to a dosage form in which the rate or location of release of the active ingredient, when administered by the same route, is different from that of an immediate dosage form. Modified release dosage forms include, but are not limited to, delayed release, delayed release, prolonged release, sustained release, pulsed release, controlled release, accelerated release and rapid release, targeted release, programmed release, and gastric retention dosage forms. Pharmaceutical compositions in modified release dosage forms can be prepared using a variety of modified release devices and methods known to those skilled in the art, including but not limited to matrix controlled release devices, osmotic controlled release devices, multiparticulate controlled release devices, ion exchange resins, intestinal Solvent coatings, multilayer coatings, microspheres, liposomes, and combinations thereof. The release rate of the active ingredient can also be modified by changing the particle size and polymorphism of the active ingredient. 1. Matrix Controlled Release Device
呈修飾釋放劑型之本文所提供之醫藥組合物可使用熟習此項技術者已知之基質控制釋放裝置來製造。參見例如Takada等人之 Encyclopedia of Controlled Drug Delivery, Mathiowitz版; Wiley, 1999;第2卷。 The pharmaceutical compositions provided herein in modified release dosage forms can be manufactured using matrix controlled release devices known to those skilled in the art. See, eg, Takada et al., Encyclopedia of Controlled Drug Delivery , Mathiowitz Edition; Wiley, 1999; Vol.
在某些實施例中，呈修飾釋放劑型之本文所提供之醫藥組合物係使用可侵蝕基質裝置調配，該可侵蝕基質裝置為水可膨脹、可侵蝕或可溶聚合物，包括但不限於合成聚合物，及天然存在之聚合物及衍生物，諸如多醣及蛋白質。In certain embodiments, the pharmaceutical compositions provided herein in modified release dosage forms are formulated using erodible matrix devices that are water-swellable, erodable, or soluble polymers, including but not limited to synthetic Polymers, and naturally occurring polymers and derivatives such as polysaccharides and proteins.
適用於形成可侵蝕基質之材料包括但不限於幾丁質、聚葡萄胺糖、聚葡萄糖及普魯蘭(pullulan)；瓊脂膠、阿拉伯膠、加拉亞膠(gum karaya)、刺槐豆膠、黃蓍膠、角叉菜膠、哥地膠(gum Ghatti)、瓜爾豆膠、三仙膠及硬葡聚糖；澱粉，諸如糊精及麥芽糊精；親水性膠體，諸如果膠；磷脂，諸如卵磷脂；褐藻酸鹽；丙二醇褐藻酸酯；明膠；膠原蛋白；纖維素材料，諸如乙基纖維素(EC)、甲基乙基纖維素(MEC)、羧甲基纖維素(CMC)、CMEC、羥乙基纖維素(HEC)、羥丙基纖維素(HPC)、乙酸纖維素(CA)、丙酸纖維素(CP)、丁酸纖維素(CB)、乙酸丁酸纖維素(CAB)、CAP、CAT、羥丙基甲基纖維素(HPMC)、HPMCP、HPMCAS、乙酸苯偏三酸羥丙基甲基纖維素(HPMCAT)及乙基羥乙基纖維素(EHEC)；聚乙烯吡咯啶酮；聚乙烯醇；聚乙酸乙烯酯；甘油脂肪酸酯；聚丙烯醯胺；聚丙烯酸；乙基丙烯酸或甲基丙烯酸之共聚物(EUDRAGIT ®)；聚(2-羥乙基-甲基丙烯酸酯)；聚乳酸交酯；L-麩胺酸與乙基-L-麩胺酸酯之共聚物；可降解乳酸-乙醇酸共聚物；聚-D-(-)-3-羥基丁酸；及其他丙烯酸衍生物，諸如甲基丙烯酸丁酯、甲基丙烯酸甲酯、甲基丙烯酸乙酯、丙烯酸乙酯、(2-二甲基胺基乙基)甲基丙烯酸酯及(三甲基胺基乙基)甲基丙烯酸酯氯化物之均聚物及共聚物。 Materials suitable for forming an erodible matrix include, but are not limited to, chitin, polyglucosamine, polydextrose, and pullulan; agar, gum arabic, gum karaya, locust bean gum, Gum tragacanth, carrageenan, gum Ghatti, guar gum, succulent gum, and sclerodextran; starches, such as dextrins and maltodextrins; hydrophilic colloids, such as pectin; Phospholipids such as lecithin; alginates; propylene glycol alginates; gelatin; collagen; cellulosic materials such as ethyl cellulose (EC), methyl ethyl cellulose (MEC), carboxymethyl cellulose (CMC) ), CMEC, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methyl cellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose acetate trimellitate (HPMCAT) and ethyl hydroxyethyl cellulose (EHEC); polyvinylpyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerol fatty acid ester; polyacrylamide; polyacrylic acid; copolymers of ethacrylic acid or methacrylic acid (EUDRAGIT ® ); -methacrylate); polylactide; copolymer of L-glutamic acid and ethyl-L-glutamic acid ester; degradable lactic acid-glycolic acid copolymer; poly-D-(-)-3- Hydroxybutyric acid; and other acrylic derivatives such as butyl methacrylate, methyl methacrylate, ethyl methacrylate, ethyl acrylate, (2-dimethylaminoethyl) methacrylate and ( Homopolymers and copolymers of trimethylaminoethyl)methacrylate chloride.
在某些實施例中，用非可侵蝕基質裝置來調配本文所提供之醫藥組合物。將活性成分溶解或分散於惰性基質中且在投與後主要藉由擴散通過惰性基質來釋放。適用作非可侵蝕基質裝置之材料包括但不限於不可溶塑膠，諸如聚乙烯、聚丙烯、聚異戊二烯、聚異丁烯、聚丁二烯、聚甲基丙烯酸甲酯、聚甲基丙烯酸丁酯、氯化聚乙烯、聚氯乙烯、丙烯酸甲酯-甲基丙烯酸甲酯共聚物、乙烯-乙酸乙烯酯共聚物、乙烯/丙烯共聚物、乙烯/丙烯酸乙酯共聚物、氯乙烯與乙酸乙烯酯、偏二氯乙烯、乙烯及丙烯之共聚物、離聚物聚對苯二甲酸伸乙酯、丁基橡膠、表氯醇橡膠、乙烯/乙烯醇共聚物、乙烯/乙酸乙烯酯/乙烯醇三元共聚物、乙烯/乙烯氧基乙醇共聚物、聚氯乙烯、塑化耐綸、塑化聚對苯二甲酸伸乙酯、天然橡膠、聚矽氧橡膠、聚二甲基矽氧烷及聚矽氧碳酸酯共聚物；親水性聚合物，諸如乙基纖維素、乙酸纖維素、交聯聚維酮及交聯部分水解的聚乙酸乙烯酯；及脂肪化合物，諸如巴西棕櫚蠟、微晶蠟及三酸甘油酯。In certain embodiments, a non-erodible matrix device is used to formulate the pharmaceutical compositions provided herein. The active ingredient is dissolved or dispersed in an inert matrix and after administration is released primarily by diffusion through the inert matrix. Materials suitable for use as non-erodible matrix devices include, but are not limited to, insoluble plastics such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethyl methacrylate, polybutyl methacrylate Esters, Chlorinated Polyethylene, Polyvinyl Chloride, Methyl Acrylate-Methyl Methacrylate Copolymer, Ethylene Vinyl Acetate Copolymer, Ethylene/Propylene Copolymer, Ethylene/Ethyl Acrylate Copolymer, Vinyl Chloride & Vinyl Acetate Ester, vinylidene chloride, copolymers of ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber, epichlorohydrin rubber, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol Terpolymer, ethylene/ethylene oxyethanol copolymer, polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polysiloxane, polydimethylsiloxane and Polysiloxane carbonate copolymers; hydrophilic polymers such as ethyl cellulose, cellulose acetate, crospovidone, and cross-linked partially hydrolyzed polyvinyl acetate; and fatty compounds such as carnauba wax, microcrystalline Waxes and triglycerides.
在基質控制釋放系統中，可例如經由所採用之聚合物類型、聚合物黏度、聚合物及/或活性成分之粒度、活性成分與聚合物之比率及組合物中之其他賦形劑或載劑來控制所要之釋放動力學。In matrix controlled release systems, this can be achieved, for example, by the type of polymer employed, the viscosity of the polymer, the particle size of the polymer and/or active ingredient, the ratio of active ingredient to polymer, and other excipients or carriers in the composition. to control the desired release kinetics.
呈修飾釋放劑型之本文所提供之醫藥組合物可藉由熟習此項技術者已知之方法製備，包括直接壓縮、乾式或濕式造粒接著壓縮，及熔融造粒接著壓縮。 2.滲透控制釋放裝置 The pharmaceutical compositions provided herein in modified release dosage forms can be prepared by methods known to those skilled in the art, including direct compression, dry or wet granulation followed by compression, and melt granulation followed by compression. 2. Osmotic controlled release device
呈修飾釋放劑型之本文所提供之醫藥組合物可使用滲透控制釋放裝置來製造，包括但不限於單腔室系統、二腔室系統、不對稱膜技術(asymmetric membrane technology；AMT)及擠壓核心系統(extruding core system；ECS)。一般而言，此類裝置具有至少兩個組件：(a)含有活性成分之核心；及(b)具有至少一個遞送埠之半透膜，其包封核心。半透膜控制水自水性使用環境流入核心，以便藉由擠壓通過遞送埠來引起藥物釋放。The pharmaceutical compositions provided herein in modified release dosage forms can be manufactured using osmotic controlled release devices, including but not limited to single-chamber systems, two-chamber systems, asymmetric membrane technology (AMT), and extruded cores System (extruding core system; ECS). Generally, such devices have at least two components: (a) a core containing the active ingredient; and (b) a semipermeable membrane with at least one delivery port that encapsulates the core. The semipermeable membrane controls the flow of water into the core from the aqueous use environment to induce drug release by extrusion through the delivery port.
除活性成分以外，滲透裝置之核心視情況包括滲透劑，其產生用於使水自使用環境運輸至裝置核心中之驅動力。一類滲透劑為水可膨脹型親水性聚合物，其亦稱為「滲透聚合物」及「水凝膠」。作為滲透劑之適合的水可膨脹型親水性聚合物包括但不限於親水性乙烯基及丙烯酸聚合物、多醣(諸如褐藻酸鈣)、聚氧化乙烯(PEO)、聚乙二醇(PEG)、聚丙二醇(PPG)、聚(2-甲基丙烯酸羥基乙酯)、聚(丙烯)酸、聚(甲基丙烯)酸、聚乙烯吡咯啶酮(PVP)、交聯PVP、聚乙烯醇(PVA)、PVA/PVP共聚物、PVA/PVP與疏水性單體(諸如甲基丙烯酸甲酯及乙酸乙烯酯)之共聚物、含有大型PEO嵌段之親水性聚胺脂、交聯羧甲纖維素鈉、角叉菜膠、羥乙基纖維素(HEC)、羥丙基纖維素(HPC)、羥丙基甲基纖維素(HPMC)、羧甲基纖維素(CMC)及羧乙基纖維素(CEC)、褐藻酸鈉、聚卡波非(polycarbophil)、明膠、三仙膠及羥基乙酸澱粉鈉。In addition to the active ingredient, the core of an osmotic device optionally includes an osmotic agent, which creates a driving force for transporting water from the environment of use into the core of the device. One class of osmotic agents are water-swellable hydrophilic polymers, also known as "osmopolymers" and "hydrogels." Suitable water-swellable hydrophilic polymers as penetrants include, but are not limited to, hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), Polypropylene glycol (PPG), poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic) acid, polyvinylpyrrolidone (PVP), cross-linked PVP, polyvinyl alcohol (PVA) ), PVA/PVP copolymers, copolymers of PVA/PVP with hydrophobic monomers such as methyl methacrylate and vinyl acetate, hydrophilic polyurethanes containing large PEO blocks, croscarmellose Sodium, carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) and carboxyethyl cellulose (CEC), sodium alginate, polycarbophil, gelatin, sanxian gum and sodium starch glycolate.
另一類滲透劑為滲透原，其能夠吸取水以跨越周圍包衣之障壁影響滲透壓梯度。適合的滲透原包括但不限於無機鹽，諸如硫酸鎂、氯化鎂、氯化鈣、氯化鈉、氯化鋰、硫酸鉀、磷酸鉀、碳酸鈉、亞硫酸鈉、硫酸鋰、氯化鉀及硫酸鈉；糖，諸如右旋糖、果糖、葡萄糖、肌醇、乳糖、麥芽糖、甘露醇、棉子糖、山梨醇、蔗糖、海藻糖及木糖醇；有機酸，諸如抗壞血酸、苯甲酸、反丁烯二酸、檸檬酸、順丁烯二酸、癸二酸、山梨酸、己二酸、依地酸(edetic acid)、麩胺酸、對甲苯磺酸、丁二酸及酒石酸；尿素；及其混合物。Another class of osmotic agents are osmogenes, which are capable of absorbing water to affect the osmotic pressure gradient across the barrier surrounding the coating. Suitable osmogens include, but are not limited to, inorganic salts such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphate, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, and sodium sulfate; Sugars, such as dextrose, fructose, glucose, inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose, and xylitol; organic acids, such as ascorbic acid, benzoic acid, fumaric acid acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamic acid, p-toluenesulfonic acid, succinic acid and tartaric acid; urea; and mixtures thereof .
可使用不同溶解速率之滲透劑以影響活性成分最初自劑型遞送之速率。舉例而言，非晶形糖(諸如MANNOGEM ™EZ)可用於在最初的數小時期間提供更快的遞送以迅速地產生所需治療效果，且逐漸及持續釋放剩餘量以在延長時段內維持治療或防治性效果之所需含量。在此情況下，活性成分以此類速率釋放以置換代謝及排泄之活性成分之量。 Osmotic agents with different dissolution rates can be used to affect the rate at which the active ingredient is initially delivered from the dosage form. For example, amorphous sugars such as MANNOGEM ™ EZ can be used to provide faster delivery during the first few hours to rapidly produce the desired therapeutic effect, and gradual and sustained release of the remaining amount to maintain the treatment over an extended period of time or The required content for the control effect. In this case, the active ingredient is released at such rates to displace the amount of active ingredient that is metabolized and excreted.
核心亦可包括廣泛多種如本文所描述之其他賦形劑及載劑，以增強劑型之效能或促進穩定性或加工。The core may also include a wide variety of other excipients and carriers, as described herein, to enhance the efficacy of the dosage form or to facilitate stability or processing.
適用於形成半透膜之材料包括不同等級之水可滲透且在生理學上相關pH下不溶於水，或對藉由化學變化(諸如交聯)使得不溶於水敏感之丙烯酸聚合物、聚乙烯、醚、聚醯胺、聚酯及纖維素衍生物。適用於形成包衣之適合的聚合物之實例包括塑化、非塑化及強化乙酸纖維素(CA)、二乙酸纖維素、三乙酸纖維素、丙酸CA、硝酸纖維素、乙酸丁酸纖維素(CAB)、乙基胺基甲酸CA、CAP、甲基胺基甲酸CA、丁二酸CA、苯偏三酸乙酸纖維素(CAT)、二甲基胺基乙酸CA、乙基碳酸CA、氯乙酸CA、乙基草酸CA、甲基磺酸CA、丁基磺酸CA、對甲苯磺酸CA、乙酸瓊脂、三乙酸直鏈澱粉、乙酸β葡聚糖、三乙酸β葡聚糖、二甲基乙酸乙醛、刺槐豆膠之三乙酸酯、羥化乙烯-乙酸乙烯酯、EC、PEG、PPG、PEG/PPG共聚物、PVP、HEC、HPC、CMC、CMEC、HPMC、HPMCP、HPMCAS、HPMCAT、聚(丙烯)酸及酯及聚-(甲基丙烯)酸及酯以及其共聚物、澱粉、聚葡萄糖、糊精、聚葡萄胺糖、膠原蛋白、明膠、聚烯烴、聚醚、聚碸、聚醚碸、聚苯乙烯、聚鹵乙烯、聚乙烯酯及醚、天然蠟及合成蠟。Materials suitable for forming semipermeable membranes include acrylic polymers, polyethylenes of varying grades that are water permeable and insoluble in water at physiologically relevant pH, or sensitive to water insolubility by chemical changes such as cross-linking , ethers, polyamides, polyesters and cellulose derivatives. Examples of suitable polymers suitable for use in forming the coating include plasticized, non-plasticized and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, cellulose acetate butyrate (CAB), ethylcarbamate CA, CAP, methylcarbamate CA, succinate CA, trimellitic acid cellulose acetate (CAT), dimethylaminoacetic acid CA, ethyl carbonate CA, Chloroacetic acid CA, ethyl oxalic acid CA, methanesulfonic acid CA, butylsulfonic acid CA, p-toluenesulfonic acid CA, acetic agar, triacetate amylose, acetate beta glucan, triacetate beta glucan, diacetate Methylacetaldehyde, Locust Bean Gum Triacetate, Hydroxyethylene Vinyl Acetate, EC, PEG, PPG, PEG/PPG Copolymer, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS , HPMCAT, poly(acrylic) acid and ester and poly-(methacrylic) acid and ester and their copolymers, starch, polydextrose, dextrin, polyglucosamine, collagen, gelatin, polyolefin, polyether, Polyethylene, polyether ash, polystyrene, polyvinyl halide, polyvinyl ester and ether, natural wax and synthetic wax.
半透膜亦可為疏水性微孔膜，其中孔實質上填充有氣體且不由水性介質潤濕但對水蒸氣為可透的，如美國專利第5,798,119號中所揭示。此類疏水性但水蒸氣滲透膜典型地由疏水性聚合物(諸如聚烯烴、聚乙烯、聚丙烯、聚四氟乙烯、聚丙烯酸衍生物、聚醚、聚碸、聚醚碸、聚苯乙烯、聚鹵乙烯、聚偏二氟乙烯、聚乙烯酯及醚、天然蠟及合成蠟)構成。Semipermeable membranes can also be hydrophobic microporous membranes in which the pores are substantially filled with gas and are not wetted by an aqueous medium but are permeable to water vapor, as disclosed in US Pat. No. 5,798,119. Such hydrophobic but water vapor permeable membranes are typically made of hydrophobic polymers such as polyolefins, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polystilbene, polyethersauce, polystyrene , polyvinyl halide, polyvinylidene fluoride, polyvinyl ester and ether, natural wax and synthetic wax).
半透膜上之遞送埠可在包覆包衣後藉由機械或雷射鑽孔形成。遞送埠亦可藉由水可溶材料之栓塞之沖蝕或藉由核心中凹口上膜之較薄部分之破裂原位形成。另外，遞送埠可在包覆過程期間形成，如在美國專利第5,612,059號及第5,698,220號中所揭示之類型之不對稱膜包衣的情況下。Delivery ports on the semipermeable membrane can be formed by mechanical or laser drilling after the coating has been applied. Delivery ports can also be formed in situ by erosion of a plug of water-soluble material or by rupture of the thinner portion of the membrane over a recess in the core. Additionally, delivery ports can be formed during the coating process, as in the case of asymmetric film coatings of the type disclosed in US Pat. Nos. 5,612,059 and 5,698,220.
所釋放之活性成分的總量及釋放速率可實質上經由半透膜之厚度及孔隙度、核心之組成及遞送埠之數目、大小及位置來調節。The total amount and rate of release of active ingredient released can be substantially modulated by the thickness and porosity of the semipermeable membrane, the composition of the core, and the number, size and location of delivery ports.
呈滲透控制釋放劑型之醫藥組合物可進一步包含其他如本文所描述之習知賦形劑或載劑以有助於調配物之效能或加工。Pharmaceutical compositions in osmotic controlled release dosage forms may further comprise other conventional excipients or carriers as described herein to aid in the performance or processing of the formulation.
滲透控制釋放劑型可根據熟習此項技術者已知之習知方法及技術來製備。參見例如 Remington: The Science and Practice of Pharmacy,見上文；Santus及Baker, J. Controlled Release, 1995, 35, 1-21；Verma等人, Drug Dev. Ind. Pharm., 2000, 26, 695-708；Verma等人, J. Controlled Release, 2002, 79, 7-27。 Osmotic controlled release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art. See, eg, Remington: The Science and Practice of Pharmacy , supra; Santus and Baker, J. Controlled Release , 1995 , 35 , 1-21; Verma et al., Drug Dev. Ind. Pharm. , 2000 , 26 , 695- 708; Verma et al, J. Controlled Release , 2002 , 79 , 7-27.
在某些實施例中，本文所提供之醫藥組合物調配為AMT控制釋放劑型，其包含包覆核心之不對稱滲透膜，該核心包含活性成分及其他醫藥學上可接受之賦形劑或載劑。參見例如美國專利第5,612,059號及WO 2002/17918。AMT控制釋放劑型可根據熟習此項技術者已知之習知方法及技術來製備，包括直接壓縮、乾式造粒、濕式造粒及浸塗方法。In certain embodiments, the pharmaceutical compositions provided herein are formulated as AMT controlled release dosage forms comprising an asymmetric osmotic membrane coating a core comprising the active ingredient and other pharmaceutically acceptable excipients or carriers agent. See, eg, US Patent No. 5,612,059 and WO 2002/17918. AMT controlled release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art, including direct compression, dry granulation, wet granulation, and dip coating methods.
在某些實施例中，本文所提供之醫藥組合物調配為ESC控制釋放劑型，其包含包覆核心之滲透膜，該核心包含活性成分、羥乙基纖維素及其他醫藥學上可接受之賦形劑或載劑。 3.多微粒控制釋放裝置 In certain embodiments, the pharmaceutical compositions provided herein are formulated as ESC controlled release dosage forms comprising an osmotic membrane surrounding a core comprising the active ingredient, hydroxyethylcellulose and other pharmaceutically acceptable excipients excipient or carrier. 3. Multiparticulate controlled release device
呈修飾釋放劑型之本文所提供之醫藥組合物可以多微粒控制釋放裝置形式製造，其包含大量直徑在約10 µm至約3 mm、約50 µm至約2.5 mm或約100 µm至約1 mm範圍內之粒子、顆粒或小丸。此類多顆粒物可藉由熟習此項技術者已知之方法製備，包括濕式及乾式造粒、擠壓/滾圓、輥壓、熔融凝結及藉由噴塗種子核心進行。參見例如 Multiparticulate Oral Drug Delivery; Ghebre-Sellassie編；Drugs and the Pharmaceutical Sciences 65; CRC Press: 1994；及 Pharmaceutical Palletization Technology; Ghebre-Sellassie編；Drugs and the Pharmaceutical Sciences 37; CRC Press: 1989。 The pharmaceutical compositions provided herein in modified release dosage forms can be manufactured in the form of multiparticulate controlled release devices comprising a plurality of diameters ranging from about 10 μm to about 3 mm, about 50 μm to about 2.5 mm, or about 100 μm to about 1 mm particles, granules or pellets. Such multiparticulates can be prepared by methods known to those skilled in the art, including wet and dry granulation, extrusion/spheronization, rolling, melt coagulation, and by spraying seed cores. See, e.g., Multiparticulate Oral Drug Delivery ; Ghebre-Sellassie, ed.; Drugs and the Pharmaceutical Sciences 65; CRC Press: 1994; and Pharmaceutical Palletization Technology ;
如本文所描述之其他賦形劑或載劑可與醫藥組合物摻合以幫助加工及形成多顆粒物。所得粒子本身可構成多微粒裝置或可由不同成膜材料(諸如腸聚合物、水可膨脹及水可溶聚合物)包覆。多顆粒物可進一步加工成膠囊或錠劑。 4.定向遞送 Other excipients or carriers as described herein can be admixed with the pharmaceutical composition to aid in processing and formation of multiparticulates. The resulting particles may themselves constitute multiparticulate devices or may be coated with different film-forming materials such as enteric polymers, water-swellable and water-soluble polymers. The multiparticulates can be further processed into capsules or lozenges. 4. Targeted Delivery
本文所提供之醫藥組合物亦可經調配以靶向特定組織、受體或所治療之個體之身體之其他區域，包括基於脂質體、再密封紅血球及抗體之遞送系統。實例包括但不限於美國專利第6,316,652號、第6,274,552號、第6,271,359號、第6,253,872號、第6,139,865號、第6,131,570號、第6,120,751號、第6,071,495號、第6,060,082號、第6,048,736號、第6,039,975號、第6,004,534號、第5,985,307號、第5,972,366號、第5,900,252號、第5,840,674號、第5,759,542號及第5,709,874號中揭示之彼等。 使用方法 The pharmaceutical compositions provided herein can also be formulated to target specific tissues, receptors, or other areas of the body of the individual being treated, including liposome-based, resealed red blood cell, and antibody-based delivery systems. Examples include, but are not limited to, US Patent Nos. 6,316,652; 6,274,552; 6,271,359; 6,253,872; 6,139,865; 6,131,570; 6,120,751; 6,071,495; 6,060,082; , 6,004,534, 5,985,307, 5,972,366, 5,900,252, 5,840,674, 5,759,542 and 5,709,874. Instructions
在一個實施例中，本文提供一種治療、預防或改善個體之由KRAS介導之病症、疾病或病狀之一或多個症狀的方法，其包含向有需要之個體投與治療有效量之本文提供之化合物(例如式(A)化合物)或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體；或其醫藥學上可接受之鹽、溶劑合物、水合物或前藥。In one embodiment, provided herein is a method of treating, preventing or ameliorating one or more symptoms of a KRAS-mediated disorder, disease or condition in an individual comprising administering to the individual in need thereof a therapeutically effective amount of the herein Provided compounds (eg, compounds of formula (A)) or enantiomers, mixtures of enantiomers, non-enantiomers, mixtures of two or more non-enantiomers, tautomers, A mixture or isotopic variant of two or more tautomers; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.
在某些實施例中，由KRAS介導之病症、疾病或病狀為增生性疾病。In certain embodiments, the disorder, disease or condition mediated by KRAS is a proliferative disease.
在另一實施例中，本發明提供一種治療、預防或改善個體之增生性疾病之一或多個症狀的方法，其包含向有需要之個體投與治療有效量之本文提供之化合物(例如式(A)化合物)或其鏡像異構物、鏡像異構物之混合物、非鏡像異構物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體；或其醫藥學上可接受之鹽、溶劑合物、水合物或前藥。In another embodiment, the present invention provides a method of treating, preventing or ameliorating one or more symptoms of a proliferative disease in an individual comprising administering to an individual in need thereof a therapeutically effective amount of a compound provided herein (e.g., formula (A) Compound) or its enantiomer, mixture of enantiomers, non-enantiomer, mixture of two or more non-enantiomers, tautomer, two or more A mixture or isotopic variant of a tautomer; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.
在某些實施例中，增生性疾病為癌症。在某些實施例中，癌症為實體腫瘤。在某些實施例中，癌症為肝癌或肺癌。在某些實施例中，癌症為非小細胞肺癌(non-small cell lung cancer；NSCLC)。在某些實施例中，癌症為不可切除性實體腫瘤。在某些實施例中，癌症為惡性血液病。在某些實施例中，癌症為白血病。在某些實施例中，癌症為急性骨髓白血病(acute myeloid leukemia；AML)。In certain embodiments, the proliferative disease is cancer. In certain embodiments, the cancer is a solid tumor. In certain embodiments, the cancer is liver or lung cancer. In certain embodiments, the cancer is non-small cell lung cancer (NSCLC). In certain embodiments, the cancer is an unresectable solid tumor. In certain embodiments, the cancer is a hematological malignancy. In certain embodiments, the cancer is leukemia. In certain embodiments, the cancer is acute myeloid leukemia (AML).
在某些實施例中，癌症為難治性及/或復發性的。在某些實施例中，癌症為難治性的。在某些實施例中，癌症為復發性的。在某些實施例中，癌症為轉移性的。在某些實施例中，癌症為不可切除性的。在某些實施例中，癌症為轉移性的。In certain embodiments, the cancer is refractory and/or relapsed. In certain embodiments, the cancer is refractory. In certain embodiments, the cancer is recurrent. In certain embodiments, the cancer is metastatic. In certain embodiments, the cancer is unresectable. In certain embodiments, the cancer is metastatic.
在某些實施例中，癌症為抗藥性的。在某一實施例中，癌症為多重抗藥性的。在某些實施例中，癌症對化學療法具有抗性。在某些實施例中，癌症對免疫療法具有抗性。在某些實施例中，癌症對標準癌症療法具有抗性。In certain embodiments, the cancer is drug-resistant. In a certain embodiment, the cancer is multi-drug resistant. In certain embodiments, the cancer is resistant to chemotherapy. In certain embodiments, the cancer is resistant to immunotherapy. In certain embodiments, the cancer is resistant to standard cancer therapy.
在某些實施例中，癌症攜帶KRAS突變。在某些實施例中，癌症在G12或G13位置處攜帶KRAS突變。在某些實施例中，癌症攜帶G12C、G12D、G12V、G12A、G12S或G12R之KRAS突變。在某些實施例中，癌症攜帶G12C之KRAS突變。在某些實施例中，癌症攜帶G12D之KRAS突變。在某些實施例中，癌症攜帶G12V之KRAS突變。在某些實施例中，癌症攜帶G12A之KRAS突變。在某些實施例中，癌症攜帶G12S之KRAS突變。在某些實施例中，癌症攜帶G12R之KRAS突變。在某些實施例中，癌症在G13位置處攜帶KRAS突變。在某些實施例中，癌症攜帶G13D之KRAS突變。In certain embodiments, the cancer carries a KRAS mutation. In certain embodiments, the cancer carries a KRAS mutation at the G12 or G13 position. In certain embodiments, the cancer carries a KRAS mutation of G12C, G12D, G12V, G12A, G12S, or G12R. In certain embodiments, the cancer carries the KRAS mutation of G12C. In certain embodiments, the cancer carries the KRAS mutation of G12D. In certain embodiments, the cancer carries the KRAS mutation of G12V. In certain embodiments, the cancer carries the KRAS mutation of G12A. In certain embodiments, the cancer carries the KRAS mutation of G12S. In certain embodiments, the cancer carries a KRAS mutation of G12R. In certain embodiments, the cancer carries a KRAS mutation at the G13 position. In certain embodiments, the cancer carries the G13D KRAS mutation.
在某些實施例中，癌症為攜帶KRAS突變之實體腫瘤。在某些實施例中，癌症為在G12或G13位置處攜帶KRAS突變之實體腫瘤。在某些實施例中，癌症為攜帶G12C、G12D、G12V、G12A、G12S或G12R之KRAS突變之實體腫瘤。在某些實施例中，癌症為攜帶G12C之KRAS突變之實體腫瘤。在某些實施例中，癌症為攜帶G12D之KRAS突變之實體腫瘤。在某些實施例中，癌症為攜帶G12V之KRAS突變之實體腫瘤。在某些實施例中，癌症為攜帶G12A之KRAS突變之實體腫瘤。在某些實施例中，癌症為攜帶G12S之KRAS突變之實體腫瘤。在某些實施例中，癌症為攜帶G12R之KRAS突變之實體腫瘤。在某些實施例中，癌症為在G13位置處攜帶KRAS突變之實體腫瘤。在某些實施例中，癌症為攜帶G13D之KRAS突變之實體腫瘤。In certain embodiments, the cancer is a solid tumor carrying a KRAS mutation. In certain embodiments, the cancer is a solid tumor carrying a KRAS mutation at the G12 or G13 position. In certain embodiments, the cancer is a solid tumor carrying a KRAS mutation of G12C, G12D, G12V, G12A, G12S or G12R. In certain embodiments, the cancer is a solid tumor carrying a KRAS mutation of G12C. In certain embodiments, the cancer is a solid tumor carrying a KRAS mutation of G12D. In certain embodiments, the cancer is a solid tumor carrying a KRAS mutation of G12V. In certain embodiments, the cancer is a solid tumor carrying a KRAS mutation of G12A. In certain embodiments, the cancer is a solid tumor carrying a KRAS mutation of G12S. In certain embodiments, the cancer is a solid tumor carrying a KRAS mutation of G12R. In certain embodiments, the cancer is a solid tumor carrying a KRAS mutation at position G13. In certain embodiments, the cancer is a solid tumor carrying a KRAS mutation of G13D.
在某些實施例中，個體為哺乳動物。在某些實施例中，個體為人類。In certain embodiments, the individual is a mammal. In certain embodiments, the individual is a human.
在某些實施例中，本文提供之化合物之治療有效量在約0.1至約100 mg/kg/天、約0.1至約50 mg/kg/天、約0.1至約60 mg/kg/天、約0.1至約50 mg/kg/天、約0.1至約25 mg/kg/天、約0.1至約20 mg/kg/天、約0.1至約15 mg/kg/天、約0.1至約10 mg/kg/天或約0.1至約5 mg/kg/天範圍內。在一個實施例中，本文提供之化合物之治療有效量在約0.1至約100 mg/kg/天範圍內。在另一實施例中，本文提供之化合物之治療有效量在約0.1至約50 mg/kg/天範圍內。在又另一實施例中，本文提供之化合物之治療有效量在約0.1至約60 mg/kg/天範圍內。在又另一實施例中，本文提供之化合物之治療有效量在約0.1至約50 mg/kg/天範圍內。在又另一實施例中，本文提供之化合物之治療有效量在約0.1至約25 mg/kg/天範圍內。在又另一實施例中，本文提供之化合物之治療有效量在約0.1至約20 mg/kg/天範圍內。在又另一實施例中，本文提供之化合物之治療有效量在約0.1至約15 mg/kg/天範圍內。在又另一實施例中，本文提供之化合物之治療有效量在約0.1至約10 mg/kg/天範圍內。在再一實施例中，本文提供之化合物之治療有效量在約0.1至約5 mg/kg/天範圍內。In certain embodiments, a therapeutically effective amount of a compound provided herein is about 0.1 to about 100 mg/kg/day, about 0.1 to about 50 mg/kg/day, about 0.1 to about 60 mg/kg/day, about 0.1 to about 50 mg/kg/day, about 0.1 to about 25 mg/kg/day, about 0.1 to about 20 mg/kg/day, about 0.1 to about 15 mg/kg/day, about 0.1 to about 10 mg/day kg/day or in the range of about 0.1 to about 5 mg/kg/day. In one embodiment, a therapeutically effective amount of a compound provided herein ranges from about 0.1 to about 100 mg/kg/day. In another embodiment, a therapeutically effective amount of a compound provided herein ranges from about 0.1 to about 50 mg/kg/day. In yet another embodiment, a therapeutically effective amount of a compound provided herein ranges from about 0.1 to about 60 mg/kg/day. In yet another embodiment, a therapeutically effective amount of a compound provided herein ranges from about 0.1 to about 50 mg/kg/day. In yet another embodiment, a therapeutically effective amount of a compound provided herein ranges from about 0.1 to about 25 mg/kg/day. In yet another embodiment, a therapeutically effective amount of a compound provided herein ranges from about 0.1 to about 20 mg/kg/day. In yet another embodiment, a therapeutically effective amount of a compound provided herein ranges from about 0.1 to about 15 mg/kg/day. In yet another embodiment, a therapeutically effective amount of a compound provided herein ranges from about 0.1 to about 10 mg/kg/day. In yet another embodiment, a therapeutically effective amount of a compound provided herein ranges from about 0.1 to about 5 mg/kg/day.
應理解，所投與之劑量亦可以除mg/kg/天以外之單位表示。舉例而言，非經腸投與之劑量可表示為mg/m 2/天。在個體之身高或體重或兩者給定的情況下，一般熟習此項技術者將易知如何將劑量由mg/kg/天換算為mg/m 2/天。例如，65 kg人類之1 mg/m 2/天之劑量約等於58 mg/kg/天。 It should be understood that the dose administered may also be expressed in units other than mg/kg/day. For example, a dose for parenteral administration may be expressed in mg/ m2 /day. One of ordinary skill in the art will readily know how to convert doses from mg/kg/day to mg/ m2 /day, given the individual's height or weight, or both. For example, a dose of 1 mg/ m2 /day for a 65 kg human is approximately equal to 58 mg/kg/day.
視待治療之病症、疾病或病狀及個體之病狀而定，本文提供之化合物可藉由以下投與途徑投與：經口、非經腸(例如，肌肉內、腹膜內、靜脈內、CIV、腦池內注射或輸注、皮下注射或植入)、吸入、經鼻、經陰道、經直腸、經舌下或局部(topical) (例如，透皮或局部(local))。本文提供之化合物可與醫藥學上可接受之賦形劑、載劑、佐劑或媒劑調配成適合於各投與途徑的適合劑量單位。Depending on the disorder, disease or condition to be treated and the condition of the individual, the compounds provided herein can be administered by the following routes of administration: oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, CIV, intracisternal injection or infusion, subcutaneous injection or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (eg, transdermal or local). The compounds provided herein can be formulated with pharmaceutically acceptable excipients, carriers, adjuvants or vehicles in suitable dosage units suitable for each route of administration.
在一個實施例中，經口投與本文提供之化合物。在另一實施例中，非經腸投與本文提供之化合物。在又另一實施例中，靜脈內投與本文提供之化合物。在又另一實施例中，肌肉內投與本文提供之化合物。在又另一實施例中，皮下投與本文提供之化合物。在再一實施例中，局部投與本文提供之化合物。In one embodiment, the compounds provided herein are administered orally. In another embodiment, the compounds provided herein are administered parenterally. In yet another embodiment, the compounds provided herein are administered intravenously. In yet another embodiment, the compounds provided herein are administered intramuscularly. In yet another embodiment, the compounds provided herein are administered subcutaneously. In yet another embodiment, the compounds provided herein are administered topically.
本文提供之化合物可以單一劑量(諸如單一彈丸注射或口服錠劑或丸劑)遞送；或隨時間(諸如隨時間連續輸液或隨時間分次彈丸給藥)遞送。必要時，本文提供之化合物可重複投與，例如直至個體經歷穩定疾病或消退，或直至個體經歷疾病進展或不可接受的毒性。The compounds provided herein can be delivered in a single dose (such as a single bolus injection or oral lozenge or pill); or over time (such as continuous infusion over time or divided bolus administration over time). The compounds provided herein can be administered repeatedly as necessary, eg, until the subject experiences stable disease or regression, or until the subject experiences disease progression or unacceptable toxicity.
本文提供之化合物可每天一次(QD)投與，或分為多個日劑量，諸如每天兩次(BID)及每天三次(TID)。另外，投與可為連續性的，亦即每天或間歇地。如本文所用，術語「間歇性」或「間歇地」意欲意謂以規則或不規則間隔停止及起始。舉例而言，本文提供之化合物之間歇投與為每週一至六天之投與，循環投與(例如，二至八個連續週每天投與，接著為長達一週之不投與的停藥期)，或在隔天投與。The compounds provided herein can be administered once daily (QD), or divided into multiple daily doses, such as twice daily (BID) and three times daily (TID). Additionally, administration may be continuous, ie, daily or intermittently. As used herein, the terms "intermittently" or "intermittently" are intended to mean stopping and starting at regular or irregular intervals. For example, intermittent administration of a compound provided herein is administration one to six days per week, cyclic administration (eg, daily administration for two to eight consecutive weeks, followed by a week-long cessation of no administration) period), or the next day.
在某些實施例中，向個體循環投與本文提供之化合物。循環療法涉及投與活性劑一段時間、繼之停藥一段時間及重複此依序投與。循環療法可降低對一或多種療法產生抗性、避免或減少療法中之一者的副作用，及/或改善治療之療效。In certain embodiments, a compound provided herein is administered to a subject's circulation. Cyclic therapy involves administration of the active agent for a period of time, followed by a period of withdrawal and repetition of this sequential administration. Cycling therapy can reduce resistance to one or more therapies, avoid or reduce side effects of one of the therapies, and/or improve the efficacy of the therapy.
本文提供之化合物亦可與適用於治療及/或預防本文所描述之病狀、病症或疾病的其他治療劑合併或組合使用。The compounds provided herein may also be used in combination or in combination with other therapeutic agents useful in the treatment and/or prevention of the conditions, disorders or diseases described herein.
如本文所用，術語「組合」包括使用超過一種療法(例如，一或多種防治劑及/或治療劑)。然而，術語「組合」之使用不會限制向患有疾病或病症之個體投與療法(例如防治劑及/或治療劑)的次序。第一療法(例如預防劑或治療劑，諸如本文提供之化合物)可在向個體投與第二療法(例如預防劑或治療劑)之前(例如5分鐘、15分鐘、50分鐘、65分鐘、1小時、2小時、6小時、6小時、12小時、26小時、68小時、72小時、96小時、1週、2週、5週、6週、8週或12週前)、同時或之後(例如5分鐘、15分鐘、50分鐘、65分鐘、1小時、2小時、6小時、12小時、26小時、68小時、72小時、96小時、1週、2週、5週、6週、8週或12週後)投與。本文中亦考慮三合一療法。As used herein, the term "combination" includes the use of more than one therapy (eg, one or more prophylactic and/or therapeutic agents). However, the use of the term "combination" does not limit the order in which therapies (eg, prophylactic and/or therapeutic agents) are administered to an individual suffering from a disease or disorder. The first therapy (eg, a prophylactic or therapeutic agent, such as a compound provided herein) can be administered to an individual before (eg, 5 minutes, 15 minutes, 50 minutes, 65 minutes, 1 hours, 2 hours, 6 hours, 6 hours, 12 hours, 26 hours, 68 hours, 72 hours, 96 hours, 1 week, 2 weeks, 5 weeks, 6 weeks, 8 weeks or 12 weeks ago), at the same time or after ( e.g. 5 minutes, 15 minutes, 50 minutes, 65 minutes, 1 hour, 2 hours, 6 hours, 12 hours, 26 hours, 68 hours, 72 hours, 96 hours, 1 week, 2 weeks, 5 weeks, 6 weeks, 8 weeks or 12 weeks later) administration. Three-in-one therapy is also contemplated herein.
本文提供之化合物之投與途徑獨立於第二療法之投與途徑。在一個實施例中，經口投與本文提供之化合物。在另一實施例中，靜脈內投與本文提供之化合物。因此，根據此等實施例，經口或靜脈內投與本文提供之化合物，且可經口、非經腸、腹膜內、靜脈內、動脈內、透皮、舌下、肌肉內、經直腸、經頰、鼻內、經脂質體、經由吸入、經陰道、眼內、經由導管或支架局部遞送、皮下、脂肪內、關節內、鞘內或以緩釋劑型投與第二療法。在一個實施例中，本文提供之化合物及第二療法係藉由相同投與模式(經口或藉由IV)投與。在另一實施例中，藉由一種投與模式(例如藉由IV)投與本文提供之化合物，而藉由另一種投與模式(例如經口)投與第二藥劑(抗癌劑)。The route of administration of the compounds provided herein is independent of the route of administration of the second therapy. In one embodiment, the compounds provided herein are administered orally. In another embodiment, the compounds provided herein are administered intravenously. Thus, according to these embodiments, the compounds provided herein are administered orally or intravenously, and can be orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, The second therapy is administered buccally, intranasally, via liposomes, via inhalation, vaginally, intraocularly, locally via catheter or stent, subcutaneously, intrafatally, intraarticularly, intrathecally, or in a sustained release dosage form. In one embodiment, the compounds provided herein and the second therapy are administered by the same mode of administration (oral or by IV). In another embodiment, the compounds provided herein are administered by one mode of administration (eg, by IV) and the second agent (the anticancer agent) is administered by another mode of administration (eg, orally).
在一個實施例中，本文提供一種抑制細胞生長之方法，其包含使細胞與有效量之本文提供之化合物(例如式(A)化合物)或其鏡像異構物、鏡像異構物之混合物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體；或其醫藥學上可接受之鹽、溶劑合物、水合物或前藥接觸。In one embodiment, provided herein is a method of inhibiting cell growth comprising exposing a cell to an effective amount of a compound provided herein (eg, a compound of formula (A)), or a mirror isomer, a mixture of spiantiomers, two A mixture of one or more diastereoisomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrated thereof exposure to substances or prodrugs.
在某些實施例中，細胞為癌細胞。在某些實施例中，細胞為人類細胞。在某些實施例中，細胞為人類癌細胞。In certain embodiments, the cells are cancer cells. In certain embodiments, the cells are human cells. In certain embodiments, the cells are human cancer cells.
在另一實施例中，本文提供一種誘導KRAS降解之方法，其包含使KRAS與有效量之本文提供之化合物(例如式(A)化合物)或其鏡像異構物、鏡像異構物之混合物、兩種或更多種非鏡像異構物之混合物、互變異構物、兩種或更多種互變異構物之混合物或同位素變體；或其醫藥學上可接受之鹽、溶劑合物、水合物或前藥接觸。In another embodiment, provided herein is a method of inducing KRAS degradation, comprising combining KRAS with an effective amount of a compound provided herein (eg, a compound of formula (A)) or a mirror isomer, a mixture of enantiomers, A mixture of two or more diastereoisomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant; or a pharmaceutically acceptable salt, solvate, Hydrate or prodrug contact.
本文提供之化合物亦可使用熟習此項技術者熟知之包裝材料以製品形式提供。參見例如美國專利第5,525,907號、第5,052,558號及第5,055,252號。醫藥包裝材料之實例包括但不限於泡殼包裝、瓶子、管、吸入器、泵、袋、小瓶、包裝箱、針筒及適合於所選調配物及預期投與及治療模式之任何包裝材料。The compounds provided herein can also be provided in an article of manufacture using packaging materials well known to those skilled in the art. See, eg, US Patent Nos. 5,525,907, 5,052,558, and 5,055,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, boxes, syringes, and any packaging material suitable for the formulation selected and the intended mode of administration and treatment.
在某些實施例中，本文提供一種套組，當由開業醫師使用時，其可簡化向個體投與適當量之本文提供之化合物作為活性成分。在某些實施例中，本文提供之套組包括容器及本文提供之化合物之劑型。In certain embodiments, provided herein is a kit that, when used by a medical practitioner, simplifies administration to an individual of an appropriate amount of a compound provided herein as an active ingredient. In certain embodiments, a kit provided herein includes a container and a dosage form of a compound provided herein.
本文提供之套組可進一步包括用於投與活性成分之裝置。此類裝置之實例包括但不限於針筒、無針注射器滴液袋、貼片及吸入器。本文提供之套組亦可包括用於投與活性成分之保險套。The kits provided herein can further include a device for administering the active ingredient. Examples of such devices include, but are not limited to, syringes, needle-free syringe drop bags, patches, and inhalers. The kits provided herein may also include condoms for administration of the active ingredient.
本文提供之套組可進一步包括可用於投與一或多種活性成分之醫藥學上可接受之媒劑。舉例而言，若活性成分以必須經復原以用於非經腸投與之固體形式提供，則套組可包含適合媒劑之密封容器，其中活性成分可溶解以形成適合於非經腸投與之不含粒子的無菌溶液。醫藥學上可接受之媒劑之實例包括但不限於：水性媒劑，包括但不限於注射用水USP、氯化鈉注射液、林格氏注射液、右旋糖注射液、右旋糖及氯化鈉注射液及乳酸林格氏注射液；水可混溶性媒劑，包括但不限於乙醇、聚乙二醇及聚丙二醇；及非水性媒劑，包括但不限於玉米油、棉籽油、花生油、芝麻油、油酸乙酯、肉豆蔻酸異丙酯及苯甲酸苯甲酯。The kits provided herein can further include a pharmaceutically acceptable vehicle that can be used to administer one or more active ingredients. For example, if the active ingredient is provided in a solid form that must be reconstituted for parenteral administration, the kit can include a sealed container with a suitable vehicle in which the active ingredient can be dissolved to form a suitable vehicle for parenteral administration. A sterile, particle-free solution. Examples of pharmaceutically acceptable vehicles include, but are not limited to, aqueous vehicles including, but not limited to, Water for Injection USP, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Chloride Sodium Phosphate Injection and Lactated Ringer's Injection; water-miscible vehicles, including but not limited to ethanol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles, including but not limited to corn oil, cottonseed oil, peanut oil , sesame oil, ethyl oleate, isopropyl myristate and benzyl benzoate.
將藉由以下非限制性實例進一步理解本發明。 實例 The invention will be further understood by the following non-limiting examples. Example
如本文所用，無論是否具體地定義特定縮寫，此等方法、方案及實例中所用之符號及慣例均與當代科學文獻(例如美國化學會志(Journal of the American Chemical Society)、藥物化學雜誌(Journal of Medicinal Chemistry)或生物化學雜誌(Journal of Biological Chemistry))中所用一致。具體言之，在實例及本說明書通篇中可使用以下縮寫：g (公克)；mg (毫克)；mL (毫升)；μL (微升)；mM (毫莫耳)；μM (微莫耳)；mmol (毫莫耳)；min (分鐘(minute/minutes))；h (小時hour/hours)；Bn (苯甲基)；Boc (三級丁氧基羰基)；Et (乙基)；Me (甲基)；Ph (苯基)；ACN (乙腈)；AcOH (乙酸)；DCM (二氯甲烷)；DMF (二甲基甲醯胺)；DMSO (二甲亞碸)；MeOH (甲醇)；EtOAc (乙酸乙酯)；NMP (1-甲基-2-吡咯啶酮)；PE (石油醚)；THF (四氫呋喃)；AIBN (偶氮二異丁腈)；Boc 2O (二碳酸二三級丁酯)；BTC (碳酸雙(三氯甲酯)或三光氣)；CDI (1,1'-羰基二咪唑)；DCC ( N,N'-二環己基碳二亞胺)；DIPEA ( N, N-二異丙基-乙胺)；DMAP (4-二甲胺基-吡啶)；EDCI (1-乙基-3-(3-二甲胺基丙基)-碳化二亞胺)；MTBE (甲基三級丁基醚)；NBS ( N-溴琥珀醯亞胺)；TEA或Et 3N (三乙胺)；TFA (三氟乙酸)；NaOAc (乙酸鈉)；MS (質譜)；及NMR (核磁共振)，但不限於此。 As used herein, whether or not specific abbreviations are specifically defined, the symbols and conventions used in these methods, protocols, and examples are consistent with contemporary scientific literature (eg, Journal of the American Chemical Society, Journal of Medicinal Chemistry). of Medicinal Chemistry) or the Journal of Biological Chemistry). In particular, the following abbreviations may be used in the examples and throughout this specification: g (grams); mg (milligrams); mL (milliliters); μL (microliters); ); mmol (mmol); min (minute/minutes); h (hour/hours); Bn (benzyl); Boc (tertiary butoxycarbonyl); Et (ethyl); Me (methyl); Ph (phenyl); ACN (acetonitrile); AcOH (acetic acid); DCM (dichloromethane); DMF (dimethylformamide); DMSO (dimethylsulfoxide); MeOH (methanol) ); EtOAc (ethyl acetate); NMP (1-methyl- 2 -pyrrolidone); PE (petroleum ether); THF (tetrahydrofuran); AIBN (azobisisobutyronitrile); Di-tertiary butyl ester); BTC (bis(trichloromethyl carbonate) or triphosgene); CDI (1,1'-carbonyldiimidazole); DCC ( N,N' -dicyclohexylcarbodiimide); DIPEA ( N,N -diisopropyl-ethylamine); DMAP (4-dimethylamino-pyridine); EDCI (1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide) amine); MTBE (methyl tertiary butyl ether); NBS ( N -bromosuccinimide); TEA or Et3N (triethylamine); TFA (trifluoroacetic acid); NaOAc (sodium acetate); MS (Mass Spectrometry); and NMR (Nuclear Magnetic Resonance), but not limited thereto.
對於所有以下實例，可使用熟習此項技術者已知之標準處理及純化方法。除非另外指示，否則所有溫度均以℃ (攝氏度)表示。除非另外規定，否則所有反應均在室溫進行。本文所說明之合成方法意欲經由使用具體實例來例示可適用的化學方法且不指示本發明之範疇。
實例1
製備2-(2,6-二側氧基哌啶-3-基)-4-((2-(2-(2-(3-(4-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5-
a]嘧啶-5-基)苯基)丙氧基)乙氧基)乙氧基)乙基)-胺基)異吲哚啉-1,3-二酮A3
如方案1中所示合成化合物 A3。 Compound A3 was synthesized as shown in Scheme 1 .
(2-(2-(2-((3-(4-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5-
a]嘧啶-5-基)苯基)丙-2-炔-1-基)氧基)乙氧基)乙氧基)乙基)-胺基甲酸三級丁酯
3。在氮氣下，在室溫，向2-(4-(5-(4-碘苯基)-2-甲基-3-苯基吡唑并[1,5-
a]-嘧啶-7-基)-哌𠯤-1-基)乙醇
1(460 mg，0.854 mmol)、(2-(2-(2-(丙-2-炔-1-基氧基)乙氧基)乙氧基)乙基)胺基甲酸三級丁酯
2(490 mg，1.71 mmol)及TEA (259 mg，2.56 mmol)於DMF (10 mL)中之溶液中，添加CuI (33 mg，0.171 mmol)及Pd(PPh
3)Cl
2(120 mg，0.171 mmol)。在氮氣下在50℃攪拌隔夜之後，混合物用水(30 mL)稀釋且用EtOAc (3 × 30 mL)萃取。經合併之有機層經無水Na
2SO
4乾燥，過濾且濃縮。藉由矽膠層析，用MeOH/DCM (1:30)溶離來純化殘餘物，得到化合物
3(170 mg，27%)。MS (ESI)
m/z：699.3 [M+H]
+。
方案1
(2-(2-(2-(3-(4-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5- a]嘧啶-5-基)苯基)丙氧基)乙氧基)乙氧基)乙基)胺基甲酸三級丁酯 4 。向化合物 3(170 mg，0.244 mmol)於THF (10 mL)中之溶液中添加Pd(OH) 2/C (40 mg)。在氫氣下在室溫攪拌24 h之後，過濾混合物且濃縮，得到化合物 4(170 mg，粗物質)，其未經進一步純化即直接用於下一步驟中。MS (ESI) m/z: 703.4[M+H] +。 (2-(2-(2-(3-(4-(7-(4-(2-hydroxyethyl)piperidin-1-yl)-2-methyl-3-phenylpyrazolo[1 ,5- a ]pyrimidin-5-yl)phenyl)propoxy)ethoxy)ethoxy)ethyl)carbamate tert-butyl ester 4 . To a solution of compound 3 (170 mg, 0.244 mmol) in THF (10 mL) was added Pd(OH) 2 /C (40 mg). After stirring at room temperature under hydrogen for 24 h, the mixture was filtered and concentrated to give compound 4 (170 mg, crude), which was used directly in the next step without further purification. MS (ESI) m/z : 703.4[M+H] + .
2-(4-(5-(4-(3-(2-(2-(2-胺基乙氧基)乙氧基)乙氧基)丙基)苯基)-2-甲基-3-苯基吡唑并[1,5- a]嘧啶-7-基)哌𠯤-1-基)乙醇 5 。在室溫，向化合物 4(170 mg，粗物質)於DCM (2.4 mL)中之溶液中添加TFA (0.8 mL)。在室溫攪拌1 h之後，濃縮混合物，得到呈TFA鹽形式之粗產物。將鹽溶解於THF (4 mL)中，且添加碳酸鈉(78 mg，0.729 mmol)。在室溫攪拌30 min之後，混合物用水(10 mL)稀釋且用EtOAc (3 × 15 mL)萃取。經合併之有機層經無水Na 2SO 4乾燥，過濾且濃縮。藉由製備型TLC (MeOH/DCM：1/10)純化殘餘物，得到化合物 5(125 mg，85%產率)。MS (ESI) m/z: 603.3[M+H] +。 2-(4-(5-(4-(3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)propyl)phenyl)-2-methyl-3 - Phenylpyrazolo[1,5- a ]pyrimidin-7-yl)piperidin-1-yl) ethanol5 . To a solution of compound 4 (170 mg, crude material) in DCM (2.4 mL) was added TFA (0.8 mL) at room temperature. After stirring at room temperature for 1 h, the mixture was concentrated to give the crude product as TFA salt. The salt was dissolved in THF (4 mL) and sodium carbonate (78 mg, 0.729 mmol) was added. After stirring at room temperature for 30 min, the mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were dried over anhydrous Na2SO4 , filtered and concentrated. The residue was purified by preparative TLC (MeOH/DCM: 1/10) to give compound 5 (125 mg, 85% yield). MS (ESI) m/z : 603.3[M+H] + .
2-(2,6-二側氧基哌啶-3-基)-4-((2-(2-(2-(3-(4-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5-
a]嘧啶-5-基)苯基)丙氧基)乙氧基)乙氧基)乙基)-胺基)異吲哚啉-1,3-二酮
A3。在氮氣下，向化合物
5(125 mg，0.208 mmol)、DIPEA (81 mg，0.628 mmol)於NMP (4 mL)中之溶液中添加2-(2,6-二側氧基哌啶-3-基)-4-氟-異吲哚啉-1,3-二酮
6(63 mg，0.228 mmol)。在微波反應器中在150℃攪拌2.5 h之後，混合物用EtOAc (20 mL)稀釋且用1N LiCl水溶液(3 × 15 mL)洗滌。有機層經無水Na
2SO
4乾燥，過濾且濃縮。藉由製備型TLC (MeOH/DCM：1/20)純化殘餘物，得到化合物
A3(17.8 mg，14%產率)。
1HNMR (400 MHz, DMSO-
d
6 )
δ11.08 (s, 1H), 8.09 (d,
J= 8.4 Hz, 2H), 7.83 (d,
J= 7.6 Hz, 2H), 7.54 (t,
J= 8.0 Hz, 1H), 7.47 (t,
J= 8.0 Hz, 2H), 7.33 (d,
J= 8.4 Hz, 1H), 7.27 (t,
J= 7.6 Hz, 2H), 7.09 (d,
J= 8.4 Hz, 1H), 7.00 (d,
J= 6.8 Hz, 1H), 6.80 (s, 1H), 6.58 (t,
J= 5.6 Hz, 1H), 5.04 (dd,
J= 5.2, 8.4 Hz, 1H), 4.48 (t,
J= 5.6 Hz, 1H), 3.85 (s, 4H), 3.65-3.50 (m, 10H), 3.49-3.40 (m, 4H), 3.39-3.35 (m, 2H), 2.92-2.80 (m, 1H), 2.72-2.62 (m, 6H), 2.60-2.53 (m, 4H), 2.52-2.51 (m, 1H), 2.04-1.95 (m, 2H), 1.85-1.76 (m, 2H); MS (ESI)
m/z:
859.4 [M+H]
+。
實例2
製備3-(1-((4-(((7-(4-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基-吡唑并[1,5-
a]嘧啶-5-基)苯基)庚基)胺基)甲基)苯氧基)甲基)-4-側氧基-4
H-噻吩并[3,4-
c]吡咯-5(6
H)-基)哌啶-2,6-二酮A8
如方案2及3中所示合成化合物
A8。
方案2
7-(4-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5- a]嘧啶-5-基)苯基)庚醛 7。在N 2下，在-78℃，向7-(4-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5- a]嘧啶-5-基)苯基)- N-甲氧基- N-甲基庚醯胺 6(80 mg，0.137 mmol)於THF (6 mL)中之溶液中添加LiAlH 4(0.28 mL，0.28 mmol，1 M於THF中)。在-78℃攪拌1 h之後，反應物用飽和NH 4Cl (水溶液，5 mL)淬滅，且混合物用EtOAc萃取。經合併之有機層經無水Na 2SO 4乾燥，過濾且濃縮，得到化合物 7(70 mg)。MS (ESI) m/z: 526.3 [M+H] +。 7-(4-(7-(4-(2-hydroxyethyl)piperidin-1-yl)-2-methyl-3-phenylpyrazolo[1,5- a ]pyrimidin-5-yl )phenyl)heptanal 7 . Under N at -78 °C, 7-(4-(7-(4-( 2 -hydroxyethyl)piperidin-1-yl)-2-methyl-3-phenylpyrazolo[ 1,5- a ]pyrimidin-5-yl)phenyl) -N -methoxy- N -methylheptanamide 6 (80 mg, 0.137 mmol) in THF ( 6 mL) was added LiAlH4 (0.28 mL, 0.28 mmol, 1 M in THF). After stirring at -78°C for 1 h, the reaction was quenched with saturated NH4Cl (aq, 5 mL), and the mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated to give compound 7 (70 mg). MS (ESI) m/z : 526.3 [M+H] + .
5-胺基-4-(1-(氯甲基)-4-側氧基-4
H-噻吩并[3,4-
c]吡咯-5(6
H)-基)-5-側氧基戊酸三級丁酯
9 。向5-胺基-4-(1-(羥基甲基)-4-側氧基-4
H-噻吩并[3,4-
c]吡咯-5(6
H)-基)-5-側氧基戊酸三級丁酯
8(400 mg，1.13 mmol)於DCM (5 mL)中之溶液中添加甲磺醯氯(194 mg，1.69 mmol)及TEA (226 mg，2.26 mmol)。在1 h之後，混合物用H
2O稀釋且用DCM萃取。經合併之有機層經無水Na
2SO
4乾燥，過濾且濃縮，得到化合物
9(420 mg)。MS (ESI)
m/z: 373.1 [M+H]
+。
5-胺基-4-(1-((4-氰基苯氧基)甲基)-4-側氧基-4 H-噻吩并[3,4- c]吡咯-5(6 H)-基)-5-側氧基戊酸三級丁酯 10 。向化合物 9(420 mg)於DMF (8 mL)中之溶液中添加4-羥基苯甲腈(166 mg，1.40 mmol)及K 2CO 3(297 mg，2.15 mmol)。在80℃攪拌2 h且接著冷卻至室溫之後，混合物用H 2O稀釋且用EtOAc萃取。經合併之有機層經無水Na 2SO 4乾燥，過濾且濃縮。使用矽膠，用DCM/MeOH (20:1)溶離來純化殘餘物，得到化合物 10(380 mg，78%產率)。MS (ESI) m/z: 456.2[M+H] +。 5-Amino-4-(1-((4-cyanophenoxy)methyl)-4-oxy- 4H -thieno[3,4- c ]pyrrole-5( 6H )- base)-5-oxypentanoic acid tertiary butyl ester 10 . To a solution of compound 9 (420 mg) in DMF (8 mL) was added 4 -hydroxybenzonitrile (166 mg, 1.40 mmol) and K2CO3 (297 mg , 2.15 mmol). After stirring at 80°C for 2 h and then cooling to room temperature, the mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4 , filtered and concentrated. The residue was purified using silica gel and eluted with DCM/MeOH (20:1) to give compound 10 (380 mg, 78% yield). MS (ESI) m/z : 456.2[M+H] + .
5-胺基-4-(1-((4-氰基苯氧基)甲基)-4-側氧基-4 H-噻吩并[3,4- c]吡咯-5(6 H)-基)-5-側氧基戊酸 11 。向化合物 10(380 mg，0.84 mmol)於DCM (10 mL)中之溶液中添加TFA (3 mL)。在16 h之後，濃縮混合物，得到化合物 11(350 mg)。MS (ESI) m/z: 400.1 [M+H] +。 5-Amino-4-(1-((4-cyanophenoxy)methyl)-4-oxy- 4H -thieno[3,4- c ]pyrrole-5( 6H )- base)-5-oxovaleric acid 11 . To a solution of compound 10 (380 mg, 0.84 mmol) in DCM (10 mL) was added TFA (3 mL). After 16 h, the mixture was concentrated to give compound 11 (350 mg). MS (ESI) m/z : 400.1 [M+H] + .
4-((5-(2,6-二側氧基哌啶-3-基)-4-側氧基-5,6-二氫-4 H-噻吩并[3,4- c]吡咯-1-基)甲氧基)苯甲腈 12 。向化合物 11(350 mg，粗物質)於ACN (10 mL)中之溶液中添加CDI (486 mg，3.0 mmol)。在95℃攪拌4 h且冷卻至室溫之後，混合物用H 2O稀釋且用EtOAc萃取。經合併之有機層經無水Na 2SO 4乾燥，過濾且濃縮。使用矽膠，用DCM/MeOH (20:1)溶離來純化殘餘物，得到化合物 12(330 mg，91%產率)。MS (ESI) m/z: 382.1 [M+H] +。 4-((5-(2,6-Dioxypiperidin-3-yl)-4-oxy-5,6-dihydro- 4H -thieno[3,4- c ]pyrrole- 1-yl)methoxy)benzonitrile 12 . To a solution of compound 11 (350 mg, crude material) in ACN (10 mL) was added CDI (486 mg, 3.0 mmol). After stirring at 95°C for 4 h and cooling to room temperature, the mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4 , filtered and concentrated. The residue was purified using silica gel and eluted with DCM/MeOH (20:1) to give compound 12 (330 mg, 91% yield). MS (ESI) m/z : 382.1 [M+H] + .
4-((5-(2,6-二側氧基哌啶-3-基)-4-側氧基-5,6-二氫-4 H-噻吩并[3,4- c]吡咯-1-基)甲氧基)苯甲基胺基甲酸三級丁酯 13 。向化合物 12(330 mg，0.867 mmol)於THF (10 mL)中之溶液中添加雷氏鎳(Raney-Ni) (50 mg)及Boc 2O (283 mg，1.30 mmol)。在H 2下16 h之後，過濾混合物且用EtOAc洗滌。濃縮經合併之濾液，且使用製備型TLC，用DCM/MeOH (20:1)溶離來純化殘餘物，得到47%產率之化合物 13。MS (ESI) m/z: 485.2 [M+H] +。 4-((5-(2,6-Dioxypiperidin-3-yl)-4-oxy-5,6-dihydro- 4H -thieno[3,4- c ]pyrrole- 1-yl)methoxy)benzyl tertiary butylcarbamate 13 . To a solution of compound 12 (330 mg, 0.867 mmol) in THF (10 mL) was added Raney-Ni (50 mg) and Boc2O (283 mg , 1.30 mmol). After 16 h under H2 , the mixture was filtered and washed with EtOAc. The combined filtrates were concentrated and the residue was purified using preparative TLC, eluting with DCM/MeOH (20:1) to give compound 13 in 47% yield. MS (ESI) m/z : 485.2 [M+H] + .
3-(1-((4-(胺基甲基)苯氧基)甲基)-4-側氧基-4 H-噻吩并[3,4- c]吡咯-5(6 H)-基)哌啶-2,6-二酮 14 。向化合物 13(70 mg，0.144 mmol)於DCM (1.5 mL)中之溶液中添加TFA (0.5 mL)。在1 h之後，將混合物濃縮為化合物 14(60 mg)。MS (ESI) m/z: 385.2 [M+H] +。 3-(1-((4-(aminomethyl)phenoxy)methyl)-4-oxy- 4H -thieno[3,4- c ]pyrrol-5( 6H )-yl ) piperidine-2,6-dione 14 . To a solution of compound 13 (70 mg, 0.144 mmol) in DCM (1.5 mL) was added TFA (0.5 mL). After 1 h, the mixture was concentrated to compound 14 (60 mg). MS (ESI) m/z : 385.2 [M+H] + .
3-(1-((4-(((7-(4-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基-吡唑并[1,5-
a]嘧啶-5-基)苯基)庚基)胺基)甲基)苯氧基)甲基)-4-側氧基-4
H-噻吩并[3,4-
c]吡咯-5(6
H)-基)哌啶-2,6-二酮
A8。在0℃，向化合物
14(60 mg，粗物質)於DCM (1.6 mL)及MeOH (0.4 mL)中之溶液中添加DIPEA (3滴)至pH 7。添加化合物
7(70 mg，粗物質)於DCM (1.6 mL)及MeOH (0.4 mL)中之溶液，隨後在0℃添加AcOH酸(1滴)及NaBH
3CN (35 mg，0.55 mmol)。在室溫攪拌16 h之後，濃縮混合物，且使用矽膠，用DCM/MeOH (20:1)溶離，且接著藉由製備型HPLC，用ACN (0.1% TFA)/水(0.1% TFA) (5%至95%)溶離，來純化殘餘物，得到3%產率的化合物
A8(3.6 mg)。
1HNMR (400 MHz, DMSO-
d 6)
δ10.98 (brs, 1H), 8.10 (d,
J= 8.0 Hz, 2H), 8.02 (s, 1H), 7.83 (d,
J= 7.6 Hz, 2H), 7.48 (t,
J= 7.6 Hz, 2H), 7.40 (d,
J= 8.4 Hz, 2H), 7.33 (d,
J= 8.0 Hz, 2H), 7.28 (t,
J= 7.6 Hz, 1H), 7.07 (d,
J= 8.4 Hz, 2H), 6.81 (s, 1H), 5.33 (s, 2H), 5.02 (dd,
J= 5.2, 13.2 Hz, 1H), 4.49 (brs, 1H), 4.37-4.20 (m, 2H), 4.01 (s, 2H), 3.85 (s, 4H), 3.62-3.55 (m, 3H), 2.95-2.80 (m, 2H), 2.75-2.60 (m, 6H), 2.60-2.50 (m, 4H), 2.40-2.25 (m, 1H), 2.05-1.95 (m, 2H), 1.65-1.50 (m, 4H), 1.29-1.23 (m, 7H); MS (ESI)
m/z: 895.4 [M+H]
+。
實例3
製備3-(6-氟-4-(1-(3-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5-
a]嘧啶-5-基)苯基)丙基)哌啶-4-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮A10
如方案4中所示合成化合物 A10。 Compound A10 was synthesized as shown in Scheme 4.
N-甲氧基- N-甲基丙炔醯胺 15 。向丙炔酸(600 mg，4.28 mmol)於DCM (50 mL)中之溶液中添加DCC (2.6 g，12.84 mmol)及 N, O-二甲基羥基-胺(1.0 g，10.28 mmol)。在25℃攪拌16 h之後，濃縮混合物。藉由矽膠管柱層析，用EtOAc/PE (1:20)溶離，來純化殘餘物，得到化合物 15(1.3 g，粗物質)，其未經進一步純化即直接用於下一步驟中。 N -Methoxy- N -methylpropynamide 15 . To a solution of propyolic acid (600 mg, 4.28 mmol) in DCM (50 mL) was added DCC (2.6 g, 12.84 mmol) and N , O -dimethylhydroxy-amine (1.0 g, 10.28 mmol). After stirring at 25 °C for 16 h, the mixture was concentrated. The residue was purified by silica gel column chromatography eluting with EtOAc/PE (1:20) to give compound 15 (1.3 g, crude material), which was used directly in the next step without further purification.
3-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5-
a]-嘧啶-5-基)苯基)-
N-甲氧基-
N-甲基丙炔醯胺
16 。向化合物
15(296 mg，2.62 mmol，粗物質)於DMF (30 mL)中之溶液中添加CuI (40 mg，0.21 mmol)、TEA (318 mg，3.15 mmol)、Pd(PPh
3)
2Cl
2(148 mg，0.21 mmol)及2-(4-(5-(3-碘苯基)-2-甲基-3-苯基吡唑并[1,5-
a]嘧啶-7-基)哌𠯤-1-基)乙-1-醇
1(250 mg，1.05 mmol)。在N
2下在50℃攪拌16 h之後，濃縮混合物，且藉由製備型TLC (DCM/MeOH：20/1)來純化殘餘物，得到94%產率之化合物
16(273 mg)。MS (ESI)
m/z:
525.2 [M+H]
+。
方案4
3-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5- a]-嘧啶-5-基)苯基)- N-甲氧基- N-甲基丙醯胺 17 。向化合物 16(120 mg，0.23 mmol)於THF (10 mL)中之溶液中添加Pd/C (120 mg)。在H 2下在25℃攪拌16 h之後，過濾混合物且濃縮濾液。藉由製備型TLC (DCM/MeOH：20/1)來純化殘餘物，得到化合物 17(50 mg，41%產率)。MS (ESI) m/z: 529.2 [M+H] +。 3-(3-(7-(4-(2-hydroxyethyl)piperidin-1-yl)-2-methyl-3-phenylpyrazolo[1,5- a ]-pyrimidine-5- yl)phenyl) -N -methoxy- N -methylpropionamide 17 . To a solution of compound 16 (120 mg, 0.23 mmol) in THF (10 mL) was added Pd/C (120 mg). After stirring at 25 °C for 16 h under H2 , the mixture was filtered and the filtrate was concentrated. The residue was purified by preparative TLC (DCM/MeOH: 20/1) to give compound 17 (50 mg, 41% yield). MS (ESI) m/z : 529.2 [M+H] + .
3-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5- a]-嘧啶-5-基)苯基)丙醛 18 。在N 2下，在-78℃，向化合物 17(50 mg，0.095 mmol)於THF (7 mL)中之溶液中添加LiAlH 4(0.285 mL，0.282 mmol)。在-78℃攪拌30 min之後，反應物用水(15 mL)淬滅，且混合物用EtOAc (20 mL × 2)萃取。經合併之有機層用鹽水(20 mL)洗滌，經無水Na 2SO 4乾燥，過濾且濃縮，得到化合物 18(45 mg，99%產率)。MS (ESI) m/z: 470.5 [M+H] +。 3-(3-(7-(4-(2-hydroxyethyl)piperidin-1-yl)-2-methyl-3-phenylpyrazolo[1,5- a ]-pyrimidine-5- yl)phenyl)propanal 18 . To a solution of compound 17 (50 mg, 0.095 mmol) in THF ( 7 mL) was added LiAlH4 (0.285 mL, 0.282 mmol) at -78 °C under N2 . After stirring at -78 °C for 30 min, the reaction was quenched with water (15 mL) and the mixture was extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated to give compound 18 (45 mg, 99% yield). MS (ESI) m/z : 470.5 [M+H] + .
3-(6-氟-4-(1-(3-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5-a]嘧啶-5-基)苯基)丙基)哌啶-4-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮
A10 。向化合物
18(45 mg，0.095 mmol)於DCM (4 mL)中之溶液中添加DIPEA (37 mg，0.285 mmol)、NaBH
3CN (24 mg，0.380 mmol)、AcOH (1滴)及3-(6-氟-1-側氧基-4-(哌啶-4-基)異吲哚啉-2-基)哌啶-2,6-二酮
19(43 mg，0.124 mmol)。在室溫攪拌16 h之後，濃縮混合物，且藉由製備型HPLC純化殘餘物，得到化合物
A10(34 mg，45%產率)。
1HNMR (400 MHz, DMSO-
d
6 )
δ11.00 (s, 1H), 8.05 (s, 1H), 8.01 (d,
J= 7.6 Hz, 1H), 7.84 (d,
J= 7.6 Hz, 2H), 7.49-7.42 (m, 4H), 7.36 (t,
J= 7.2 Hz, 2H), 7.26 (t,
J= 7.2 Hz, 1H), 6.85 (s, 1H), 5.13 (dd,
J= 5.2, 13.6 Hz, 1H), 4.52-4.31 (m, 3H), 3.89 (s, 4H), 3.62-3.52 (m, 3H), 2.99-2.88 (m, 3H), 2.72-2.69 (m, 7H), 2.68 (s, 3H), 2.63-2.62 (m, 1H), 2.41-2.34 (m, 3H), 2.02-1.97 (m, 3H), 1.91-1.89 (m, 1H), 1.85-1.83 (m, 2H), 1.79-1.74 (m, 4H); MS (ESI)
m/z: 799.4 [M+H]
+。
實例4
製備3-(6-氟-5-(1-(7-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5-
a]嘧啶-5-基)苯基)庚基)哌啶-4-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮A23
如方案5及6中所示合成化合物
A23。
方案5
4-溴-2-(溴甲基)-5-氟苯甲酸甲酯 21 。向在室溫之4-溴-5-氟-2-甲基苯甲酸甲酯 20(20 g，80.95 mmol)於CCl 4(200 mL)中之溶液中添加NBS (15.84 g，89.05 mmol)及AIBN (2.65 g，16.2 mmol)。在80℃攪拌隔夜之後，過濾混合物且藉由矽膠管柱層析，用EtOAc/PE (1:80)溶離來純化濾液，得到化合物 21(24.4 g，97%產率)。 Methyl 4-bromo-2-(bromomethyl)-5-fluorobenzoate 21 . To a solution of methyl 4-bromo-5-fluoro-2-methylbenzoate 20 (20 g, 80.95 mmol) in CCl4 (200 mL) at room temperature was added NBS (15.84 g, 89.05 mmol) and AIBN (2.65 g, 16.2 mmol). After stirring at 80°C overnight, the mixture was filtered and the filtrate was purified by silica gel column chromatography eluting with EtOAc/PE (1:80) to give compound 21 (24.4 g, 97% yield).
3-(5-溴-6-氟-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮
23。向在室溫之化合物
21(24.4 g，76.9 mmol)於ACN (240 mL)中之溶液中添加DIPEA (30 g，230.70 mmol)及3-胺基哌啶-2,6-二酮
22(15.2 g，92.30 mmol)。在90℃攪拌隔夜之後，過濾混合物。濾餅用DCM (80 mL)洗滌且真空乾燥，得到化合物
23(9.6 g，37%產率)。MS (ESI)
m/z: 341.2, 343.1 [M+1, M+3]
+。
4-(2-(2,6-二側氧基哌啶-3-基)-6-氟-1-側氧基異吲哚啉-5-基)-哌𠯤-1-甲酸三級丁酯 25 。向在室溫之化合物 23(300 mg，0.88 mmol)於1,4-二㗁烷(6 mL)中之溶液中添加哌𠯤-1-甲酸三級丁酯 24(210 mg，1.14 mmol)、Pd-PEPPSi (87.6 mg，0.088 mmol)及碳酸銫(852 mg，20.64 mmol)。在100℃攪拌4 h之後，過濾混合物且濃縮濾液。藉由矽膠管柱層析，用MeOH/DCM (0%至3%)溶離來純化殘餘物，得到化合物 25(278 mg，61%產率)。MS (ESI) m/z: 447.2 [M+H] +。 4-(2-(2,6-Dioxypiperidin-3-yl)-6-fluoro-1-oxyisoindolin-5-yl)-piperidine-1-carboxylic acid tertiary butyl Ester 25 . To a solution of compound 23 (300 mg, 0.88 mmol) in 1,4-dioxane (6 mL) at room temperature was added tertiary butyl piperazine-1-carboxylate 24 (210 mg, 1.14 mmol), Pd-PEPPSi (87.6 mg, 0.088 mmol) and cesium carbonate (852 mg, 20.64 mmol). After stirring at 100 °C for 4 h, the mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography eluting with MeOH/DCM (0% to 3%) to give compound 25 (278 mg, 61% yield). MS (ESI) m/z : 447.2 [M+H] + .
3-(6-氟-1-側氧基-5-(哌𠯤-1-基)異吲哚啉-2-基)哌啶-2,6-二酮 26。向在室溫之化合物 25(100 mg，0.224 mmol)於DCM/MeOH (4:1，5 mL)中之溶液中緩慢添加HCl-EtOAc。在室溫攪拌1 h之後，濃縮混合物且乾燥，得到化合物 26(130 mg，粗物質)，其未經進一步純化即直接用於下一步驟中。MS (ESI) m/z: 347 [M+H] +。 3-(6-Fluoro-1-oxo-5-(piperidine-1-yl)isoindolin-2-yl)piperidine-2,6-dione 26 . To a solution of compound 25 (100 mg, 0.224 mmol) in DCM/MeOH (4:1, 5 mL) at room temperature was slowly added HCl-EtOAc. After stirring at room temperature for 1 h, the mixture was concentrated and dried to give compound 26 (130 mg, crude material), which was used directly in the next step without further purification. MS (ESI) m/z : 347 [M+H] + .
N-甲氧基- N-甲基庚-6-炔醯胺 27。向庚-6-炔酸(5.0 g，39.6 mmol)於DCM (80 mL)中之溶液中添加EDCI (11.4 g，59.4 mmol)、 N, O-二甲基羥基-胺(4.65 g，47.56 mmol)、TEA (10 g，99 mmol)及DMAP (483 mg，3.96 mmol)。在室溫攪拌隔夜之後，濃縮混合物，且藉由矽膠管柱層析，用PE/EtOAc (3/1)溶離來純化殘餘物，得到化合物 27(3.0 g，45%產率)。 N -Methoxy- N -methylhept-6-ynamide 27 . To a solution of hept-6-ynoic acid (5.0 g, 39.6 mmol) in DCM (80 mL) was added EDCI (11.4 g, 59.4 mmol), N , O -dimethylhydroxy-amine (4.65 g, 47.56 mmol) ), TEA (10 g, 99 mmol) and DMAP (483 mg, 3.96 mmol). After stirring at room temperature overnight, the mixture was concentrated and the residue was purified by silica gel column chromatography eluting with PE/EtOAc (3/1) to give compound 27 (3.0 g, 45% yield).
7-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5- a]-嘧啶-5-基)苯基)- N-甲氧基- N-甲基庚-6-炔醯胺 28 。向2-(4-(5-(3-碘苯基)-2-甲基-3-苯基吡唑并[1,5- a]嘧啶-7-基)哌𠯤-1-基)乙醇 1(1.0 g，1.9 mmol)於DMF (10 mL)中之溶液中添加CuI (72.4 mg，0.38 mmol)、TEA (479.8 mg，4.75 mmol)、Pd(PPh 3) 2Cl 2(266.8 mg，0.38 mmol)及化合物 27(483 mg，2.85 mmol)。在氮氣下在50℃攪拌隔夜之後，濃縮混合物，且藉由矽膠管柱層析，用MeOH/DCM (1:80至1:30)溶離來純化殘餘物，得到化合物 28(1.14 g，粗物質)，其未經進一步純化即直接用於下一步驟中。MS (ESI) m/z: 581.3 [M+H] +。 7-(3-(7-(4-(2-hydroxyethyl)piperidin-1-yl)-2-methyl-3-phenylpyrazolo[1,5- a ]-pyrimidine-5- yl)phenyl) -N -methoxy- N -methylhept-6-ynamide 28 . To 2-(4-(5-(3-iodophenyl)-2-methyl-3-phenylpyrazolo[1,5- a ]pyrimidin-7-yl)piperidin-1-yl)ethanol To a solution of 1 (1.0 g, 1.9 mmol) in DMF (10 mL) was added CuI (72.4 mg, 0.38 mmol), TEA (479.8 mg, 4.75 mmol), Pd( PPh3 )2Cl2 ( 266.8 mg , 0.38 mmol) and compound 27 (483 mg, 2.85 mmol). After stirring overnight at 50°C under nitrogen, the mixture was concentrated and the residue was purified by silica gel column chromatography eluting with MeOH/DCM (1:80 to 1:30) to give compound 28 (1.14 g, crude material) ), which was used directly in the next step without further purification. MS (ESI) m/z : 581.3 [M+H] + .
7-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5- a]-嘧啶-5-基)苯基)- N-甲氧基- N-甲基庚醯胺 29 。在室溫，向化合物 28(666.0 mg，1.15 mmol，粗物質)於MeOH (20 mL)中之溶液中添加Pd(OH) 2/C (100.0 mg)。在氫氣下在室溫攪拌16 h之後，過濾混合物且濃縮濾液。藉由矽膠管柱層析，用MeOH/DCM (1:80至1:20)溶離來純化殘餘物，得到化合物 29(560.0 mg，84%產率)。MS (ESI) m/z: 585.3 [M+H] +。 7-(3-(7-(4-(2-hydroxyethyl)piperidin-1-yl)-2-methyl-3-phenylpyrazolo[1,5- a ]-pyrimidine-5- yl)phenyl) -N -methoxy- N -methylheptanamide 29 . To a solution of compound 28 (666.0 mg, 1.15 mmol, crude material) in MeOH (20 mL) was added Pd(OH) 2 /C (100.0 mg) at room temperature. After stirring at room temperature for 16 h under hydrogen, the mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography eluting with MeOH/DCM (1:80 to 1:20) to give compound 29 (560.0 mg, 84% yield). MS (ESI) m/z : 585.3 [M+H] + .
7-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5- a]-嘧啶-5-基)苯基)庚醛 30 。在氮氣下，在-78℃，向化合物 29(280 mg，0.478 mmol)於THF (5 mL)中之溶液中添加LiAlH 4(1 M於THF中) (1.2 mL，1.2 mmol)。在氮氣下在-78℃攪拌30 min之後，反應物藉由飽和NH 4Cl (水溶液，5 mL)淬滅，且混合物用EtOAc (20 mL)萃取。有機層經無水Na 2SO 4乾燥過濾且濃縮，得到化合物 30(246 mg，98%產率)。MS (ESI) m/z: 526.3 [M+H] +。 7-(3-(7-(4-(2-hydroxyethyl)piperidin-1-yl)-2-methyl-3-phenylpyrazolo[1,5- a ]-pyrimidine-5- yl)phenyl)heptanal 30 . To a solution of compound 29 (280 mg, 0.478 mmol) in THF (5 mL) was added LiAlH4 ( 1 M in THF) (1.2 mL, 1.2 mmol) at -78 °C under nitrogen. After stirring at -78 °C for 30 min under nitrogen, the reaction was quenched by saturated NH4Cl (aq, 5 mL), and the mixture was extracted with EtOAc (20 mL). The organic layer was dried, filtered over anhydrous Na 2 SO 4 and concentrated to give compound 30 (246 mg, 98% yield). MS (ESI) m/z : 526.3 [M+H] + .
3-(6-氟-5-(4-(7-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基-吡唑并[1,5-a]嘧啶-5-基)苯基)庚基)哌𠯤-1-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮
A23。向化合物
26(120 mg，0.20 mmol，粗物質)於DCM/MeOH (4:1，5 mL)中之溶液中添加DIPEA (26.0 mg，0.20 mmol)、化合物
30(106.0 mg，020 mmol)、NaBH
3CN (62.0 mg，1.0 mmol)及AcOH (1滴)。在室溫攪拌隔夜之後，濃縮混合物，且藉由製備型HPLC純化殘餘物，得到化合物
A23(58.0 mg，34%產率)。
1HNMR (400 MHz, DMSO-
d
6 )
δ10.96 (s, 1H), 8.03-7.99 (m, 2H), 7.84 (d,
J= 7.6 Hz, 2H), 7.49-7.38 (m, 4H), 7.32-7.25 (m, 2H), 7.16 (d,
J= 7.6 Hz, 1H), 6.83 (s, 1H), 5.06 (dd,
J= 13.6, 5.2 Hz, 1H), 4.47 (t,
J=10.4 Hz, 1H), 4.34-4.18 (m, 2H), 3.85 (s, 4H), 3.59-3.55 (m, 2H), 3.04 (s, 4H), 2.93-2.85 (m, 1H), 2.70-2.67 (m, 6H), 2.60-2.53 (m, 4H), 2.49-2.24 (m, 8H), 2.02-1.95 (m, 2H), 1.66-1.63 (m, 2H), 1.44-1.39 (m, 2H), 1.33-1.27 (m, 6H); MS (ESI)
m/z: 856.6 [M+H]
+。
實例5
製備2-(2,6-二側氧基哌啶-3-基)-5-氟-6-(4-((1-(7-(3-(7-(4-(2-羥基乙基)-哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5-
a]嘧啶-5-基)苯基)庚醯基)哌啶-4-基)甲基)哌𠯤-1-基)異吲哚啉-1,3-二酮A25
如方案7中所示合成化合物
A25。
如方案8中所示合成化合物 A30及 A31。 Compounds A30 and A31 were synthesized as shown in Scheme 8.
3-(1-((4-(((9-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基-吡唑并[1,5- a]嘧啶-5-基)苯基)壬基)胺基)甲基)苯氧基)甲基)-4-側氧基-4 H-噻吩并-[3,4- c]吡咯-5(6 H)-基)哌啶-2,6-二酮 A30。向4-((5-(2,6-二側氧基哌啶-3-基)-4-側氧基-5,6-二氫-4 H-噻吩并[3,4- c]吡咯-1-基)甲氧基)苯甲醛 35(38 mg，0.1 mmol)及含2-(4-(5-(3-(9-胺基壬基)苯基)-2-甲基-3-苯基吡唑并[1,5- a]嘧啶-7-基)-哌𠯤-1-基)乙醇 36(55.4 mg，0.1 mmol)於DCM (2 mL)及MeOH (0.5 mL)之溶液中添加DIPEA (13 mg，0.1 mmol)、NaBH 3CN (19 mg，0.3 mmol)及AcOH (1滴)。在室溫攪拌2天之後，濃縮混合物，且藉由製備型TLC (DCM/MeOH：14/1)來純化殘餘物，得到化合物 A30(60 mg，54%產率)。MS (ESI) m/z: 923.5 [M+H] +。 3-(1-((4-(((9-(3-(7-(4-(2-hydroxyethyl)piperidin-1-yl)-2-methyl-3-phenyl-pyrazole [1,5- a ]pyrimidin-5-yl)phenyl)nonyl)amino)methyl)phenoxy)methyl)-4-oxo- 4H -thieno-[3,4 - c ]pyrrol-5( 6H )-yl)piperidine-2,6-dione A30 . To 4-((5-(2,6-Dioxypiperidin-3-yl)-4-oxy-5,6-dihydro- 4H -thieno[3,4- c ]pyrrole -1-yl)methoxy)benzaldehyde 35 (38 mg, 0.1 mmol) with 2-(4-(5-(3-(9-aminononyl)phenyl)-2-methyl-3 - Phenylpyrazolo[1,5- a ]pyrimidin-7-yl)-piperidin-1-yl)ethanol 36 (55.4 mg, 0.1 mmol) in DCM (2 mL) and MeOH (0.5 mL) To this was added DIPEA (13 mg, 0.1 mmol), NaBH3CN (19 mg, 0.3 mmol) and AcOH (1 drop). After stirring at room temperature for 2 days, the mixture was concentrated and the residue was purified by preparative TLC (DCM/MeOH: 14/1) to give compound A30 (60 mg, 54% yield). MS (ESI) m/z : 923.5 [M+H] + .
3-(1-((4-(((9-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基-吡唑并[1,5-
a]嘧啶-5-基)苯基)壬基)(甲基)胺基)甲基)苯氧基)甲基)-4-側氧基-4
H-噻吩并[3,4-
c]吡咯-5(6
H)-基)哌啶-2,6-二酮
A31。向化合物
A30(50 mg，0.054 mmol)及甲醛(12 mg，0.16 mmol)於DCM (2 mL)及MeOH (0.5 mL)中之溶液中添加NaBH
3CN (10 mg，0.16 mmol)及AcOH (1滴)。在室溫攪拌隔夜之後，濃縮混合物，且藉由製備型TLC (DCM/MeOH：11/1)來純化殘餘物，得到化合物
A31(29.3 mg，57%產率)。
1HNMR (400 MHz, DMSO-
d
6 )
δ10.98 (s, 1H), 9.91 (s, 1H), 9.38 (s, 1H), 8.10-8.03 (m, 3H), 7.88-7.82 (m, 2H), 7.50-7.42 (m, 5H), 7.34-7.28 (m, 2H), 7.13-7.11 (m, 2H), 6.98 (s, 1H), 5.51-5.41 (m, 1H), 5.34 (s, 2H), 5.02 (dd,
J= 4.8, 13.2 Hz, 1H), 4.83-4.70 (m, 2H), 4.37-4.28 (m, 2H), 4.23-4.11 (m, 2H), 3.83-3.79 (m, 2H), 3.72-3.69 (m, 2H), 3.62-3.51 (m, 4H), 2.94-2.85 (m, 2H), 2.71-2.67 (m, 3H), 2.64-2.62 (m, 3H), 2.59 (s, 3H), 2.56-2.55 (m, 1H), 2.33-2.29 (m, 1H), 2.01-1.96 (m, 1H), 1.71-1.58 (m, 4H), 1.38-1.26 (m, 10H); MS (ESI)
m/z: 937.7 [M+H]
+。
方案8
如方案9及10中所示合成化合物
A35。
方案9
5-胺基-4-(4-(2-(苯甲氧基)-2-側氧基乙氧基)-1-側氧基異吲哚啉-2-基)-5-側氧基戊酸三級丁酯
38 。向5-胺基-4-(4-羥基-1-側氧基異吲哚啉-2-基)-5-側氧基戊酸三級丁酯
37(1.87 g，5.61 mmol)於ACN (30 mL)中之溶液中添加2-溴乙酸苯甲酯(1.29 g，5.61 mmol)及K
2CO
3(2.32 g，16.83 mmol)。在80℃攪拌隔夜之後，濃縮混合物，且藉由矽膠管柱層析，用EtOAc/PE (50%至100%)溶離來純化殘餘物，得到化合物
38(1.98 g，73%產率)。MS (ESI)
m/z: 483.2 [M+H]
+。
方案10
5-胺基-4-(4-(2-(苯甲氧基)-2-側氧基乙氧基)-1-側氧基異吲哚啉-2-基)-5-側氧基戊酸 39 。向化合物 38(1.85 g，3.84 mmol)於DCM (5 mL)中之溶液中添加TFA (5 mL)。在室溫攪拌1 h之後，濃縮混合物且乾燥，得到化合物 39(粗物質)，其未經進一步純化即直接用於下一步驟中。 5-Amino-4-(4-(2-(benzyloxy)-2-oxyethoxy)-1-oxyisoindolin-2-yl)-5-oxy Valeric acid 39 . To a solution of compound 38 (1.85 g, 3.84 mmol) in DCM (5 mL) was added TFA (5 mL). After stirring at room temperature for 1 h, the mixture was concentrated and dried to give compound 39 (crude material), which was used directly in the next step without further purification.
2-((2-(2,6-二側氧基哌啶-3-基)-1-側氧基異吲哚啉-4-基)氧基)乙酸苯甲酯 40 。向化合物 39(3.84 mmol，粗物質)於ACN (20 mL)中之溶液中添加CDI (1.91 g，11.52 mmol)。在85℃攪拌隔夜之後，混合物用水(20 mL)稀釋且用EtOAc (30 mL × 2)萃取。經合併之有機層經無水Na 2SO 4乾燥，過濾且濃縮。藉由矽膠管柱層析，用EtOAc/PE (50%至100%)溶離來純化殘餘物，得到化合物 40(630 mg，39%產率)。MS (ESI) m/z: 410.1 [M+H] +。 Benzyl methyl 2-((2-(2,6-dioxypiperidin-3-yl)-1-oxyisoindolin-4-yl)oxy)acetate 40 . To a solution of compound 39 (3.84 mmol, crude material) in ACN (20 mL) was added CDI (1.91 g, 11.52 mmol). After stirring at 85°C overnight, the mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were dried over anhydrous Na2SO4 , filtered and concentrated. The residue was purified by silica gel column chromatography eluting with EtOAc/PE (50% to 100%) to give compound 40 (630 mg, 39% yield). MS (ESI) m/z : 410.1 [M+H] + .
2-((2-(2,6-二側氧基哌啶-3-基)-1-側氧基異吲哚啉-4-基)氧基)乙酸 41 。在80℃攪拌化合物 40(528 mg，1.29 mmol)於TFA (5 mL)中之溶液隔夜。接著濃縮混合物，得到化合物 41(450 mg，粗物質)，其未經進一步純化即直接用於下一步驟中。MS (ESI) m/z: 319.1 [M+H] +。 2-((2-(2,6-Dioxypiperidin-3-yl)-1-oxyisoindolin-4-yl)oxy)acetic acid 41 . A solution of compound 40 (528 mg, 1.29 mmol) in TFA (5 mL) was stirred at 80 °C overnight. The mixture was then concentrated to give compound 41 (450 mg, crude material), which was used directly in the next step without further purification. MS (ESI) m/z : 319.1 [M+H] + .
2-(3-碘苯基)-3-側氧基丁腈 43 。向在0℃之2-(3-碘苯基)-乙腈 42(30.0 g，120 mmol)於THF (300 mL)中之溶液中逐份添加NaH (9.6 g，240 mmol，60%礦物油)。在0℃攪拌2 h之後，在0℃逐滴添加EtOAc (50 g，568 mmol)。在室溫另外攪拌反應混合物3 h，用H 2O (150 mL)淬滅且用MTBE (3 × 100 mL)萃取。在分離之後，水層用1N HCl調整至pH 3且用EtOAc (3 × 100 mL)萃取。經合併之有機層經無水Na 2SO 4乾燥，過濾且濃縮，得到化合物 43(粗物質)，其未經進一步純化即直接用於下一步驟中。 1HNMR (400 MHz, CDCl 3) δ7.76 (d, J= 10.4 Hz, 1H), 7.75 (s, 1H), 7.38 (d, J= 10.4 Hz, 1H), 7.18 (t, J= 10.4 Hz, 1H), 4.60 (s, 1H), 2.31 (s, 3H)。 2-(3-Iodophenyl)-3-oxybutyronitrile 43 . To a solution of 2-(3-iodophenyl)-acetonitrile 42 (30.0 g, 120 mmol) in THF (300 mL) at 0 °C was added NaH (9.6 g, 240 mmol, 60% mineral oil) in portions . After stirring at 0 °C for 2 h, EtOAc (50 g, 568 mmol) was added dropwise at 0 °C. The reaction mixture was stirred for an additional 3 h at room temperature, quenched with H2O (150 mL) and extracted with MTBE (3 x 100 mL). After separation, the aqueous layer was adjusted to pH 3 with IN HCl and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4 , filtered and concentrated to give compound 43 (crude material), which was used directly in the next step without further purification. 1 HNMR (400 MHz, CDCl 3 ) δ 7.76 (d, J = 10.4 Hz, 1H), 7.75 (s, 1H), 7.38 (d, J = 10.4 Hz, 1H), 7.18 (t, J = 10.4 Hz, 1H), 4.60 (s, 1H), 2.31 (s, 3H).
4-(3-碘苯基)-5-甲基-1 H-吡唑-3-胺 44 。在0℃，向化合物 43(31 g，110 mmol，粗物質)於甲苯(300 mL)中之溶液中添加N 2H 4.H 2O (11 g，220 mmol)及AcOH (19.8 g，330 mmol)。在110℃攪拌3 h之後，濃縮混合物，用1N HCl調整至pH 1，且用MTBE (50 mL)萃取。水層用NH 3∙H 2O調整至pH 10。藉由過濾收集沈澱，得到化合物 44(24.58 g，75%產率)。MS (ESI) m/z: 300.0 [M+H] +。 4-(3-Iodophenyl)-5-methyl- 1H -pyrazol-3-amine 44 . To a solution of compound 43 (31 g, 110 mmol, crude) in toluene (300 mL) at 0 °C was added N2H4.H2O ( 11 g , 220 mmol) and AcOH (19.8 g, 330 mmol). After stirring at 110 °C for 3 h, the mixture was concentrated, adjusted to pH 1 with 1 N HCl, and extracted with MTBE (50 mL). The aqueous layer was adjusted to pH 10 with NH3 ∙ H2O . The precipitate was collected by filtration to give compound 44 (24.58 g, 75% yield). MS (ESI) m/z : 300.0 [M+H] + .
3-(3-碘苯基)-2-甲基-5-苯基吡唑并[1,5- a]嘧啶-7(4 H)-酮 46 。在室溫，向化合物 44(24.85 g，82 mmol)於AcOH (200 mL)中之攪拌溶液中添加3-側氧基-3-苯基丙酸甲酯 45(20.5 g，107 mmol)。在室溫攪拌4 h且在120℃攪拌隔夜之後，將混合物冷卻至室溫且用MTBE (500 mL)稀釋。在0℃攪拌混合物15 min。藉由過濾收集所得沈澱且用MTBE (25 mL)洗滌，得到化合物 46(23.23 g，66%產率)。MS (ESI) m/z: 428.1 [M+H] +。 3-(3-Iodophenyl)-2-methyl-5-phenylpyrazolo[1,5- a ]pyrimidin-7( 4H )-one 46 . To a stirred solution of compound 44 (24.85 g, 82 mmol) in AcOH (200 mL) was added methyl 3-oxy-3-phenylpropanoate 45 (20.5 g, 107 mmol) at room temperature. After stirring at room temperature for 4 h and at 120 °C overnight, the mixture was cooled to room temperature and diluted with MTBE (500 mL). The mixture was stirred at 0 °C for 15 min. The resulting precipitate was collected by filtration and washed with MTBE (25 mL) to give compound 46 (23.23 g, 66% yield). MS (ESI) m/z : 428.1 [M+H] + .
7-氯-3-(3-碘苯基)-2-甲基-5-苯基吡唑并[1,5- a]嘧啶 47 。在120℃攪拌化合物 46(18 g，42.2 mmol)於POCl 3(500 mL)中之溶液3 h。濃縮混合物，得到化合物 47(粗物質)，其未經進一步純化即直接用於下一步驟中。MS (ESI) m/z: 446.0[M+H] +。 7-Chloro-3-(3-iodophenyl)-2-methyl-5-phenylpyrazolo[1,5- a ]pyrimidine 47 . A solution of compound 46 (18 g, 42.2 mmol) in POCl3 (500 mL) was stirred at 120 °C for 3 h. The mixture was concentrated to give compound 47 (crude material), which was used directly in the next step without further purification. MS (ESI) m/z : 446.0[M+H] + .
2-(4-(3-(3-碘苯基)-2-甲基-5-苯基吡唑并[1,5-a]嘧啶-7-基)哌𠯤-1-基)乙醇 1 。向在室溫之化合物 47(粗物質)及DIPEA (27.3 g，210 mmol)於DMSO (100 mL)中之溶液中添加2-(哌𠯤-1-基)乙醇(28.7 g，223 mmol)。在室溫攪拌隔夜之後，混合物用水(35 mL)稀釋。過濾所得沈澱且用H 2O (3 × 25 mL)洗滌，得到化合物 1(23 g，92%產率)。 1HNMR (400 MHz, DMSO- d 6) δ8.39 (t, J= 1.6 Hz, 1H), 8.23 (dd, J= 8.0 Hz, 1.6 Hz, 2H), 7.84 (d, J= 7.6 Hz, 1H), 7.83 (d, J= 7.6 Hz, 1H), 7.56-7.48 (m, 3H), 7.28 (t, J= 8.0 Hz, 1H), 6.89 (s, 1H), 4.48 (t, J= 7.2 Hz, 1H), 3.88 (t, J= 4.0 Hz, 4H), 3.58 (q, J= 7.6 Hz, 2H), 2.68 (t, J= 4.4 Hz, 4H), 2.58 (s, 3H), 2.53-2.51 (m, 2H); MS (ESI) m/z: 539.9 [M+H] +。 2-(4-(3-(3-Iodophenyl)-2-methyl-5-phenylpyrazolo[1,5-a]pyrimidin-7-yl)piperidin-1-yl)ethanol 1 . To a solution of compound 47 (crude) and DIPEA (27.3 g, 210 mmol) in DMSO (100 mL) at room temperature was added 2-(piperimeni-l-yl)ethanol (28.7 g, 223 mmol). After stirring at room temperature overnight, the mixture was diluted with water (35 mL). The resulting precipitate was filtered and washed with H2O (3 x 25 mL) to give compound 1 (23 g, 92% yield). 1 HNMR (400 MHz, DMSO- d 6 ) δ 8.39 (t, J = 1.6 Hz, 1H), 8.23 (dd, J = 8.0 Hz, 1.6 Hz, 2H), 7.84 (d, J = 7.6 Hz, 1H) , 7.83 (d, J = 7.6 Hz, 1H), 7.56-7.48 (m, 3H), 7.28 (t, J = 8.0 Hz, 1H), 6.89 (s, 1H), 4.48 (t, J = 7.2 Hz, 1H), 3.88 (t, J = 4.0 Hz, 4H), 3.58 (q, J = 7.6 Hz, 2H), 2.68 (t, J = 4.4 Hz, 4H), 2.58 (s, 3H), 2.53-2.51 ( m, 2H); MS (ESI) m/z : 539.9 [M+H] + .
(7-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基-吡唑并[1,5- a]嘧啶-3-基)苯基)庚-6-炔-1-基)胺基甲酸三級丁酯 49 。在氮氣下，在室溫，向化合物 1(215 mg，0.399 mmol)、庚-6-炔-1-基胺基甲酸三級丁酯 48(253 mg，1.20 mmol)及TEA (101 mg，1.00 mmol)於DMF (5 mL)中之溶液中添加CuI (15 mg，0.08 mmol)及Pd(PPh 3)Cl 2(56 mg，0.08 mmol)。在50℃攪拌隔夜之後，混合物用水(15 mL)稀釋且用EtOAc (3 × 15 mL)萃取。經合併之有機層經無水Na 2SO 4乾燥，過濾且濃縮。藉由矽膠層析，用MeOH/DCM (1:30)溶離來純化殘餘物，得到化合物 49(194 mg，90%產率)。MS (ESI) m/z: 623.4 [M+H] +。 (7-(3-(7-(4-(2-hydroxyethyl)piperidin-1-yl)-2-methyl-5-phenyl-pyrazolo[1,5- a ]pyrimidine-3 -yl)phenyl)hept-6-yn-1-yl)carbamic acid tertiary butyl ester 49 . To compound 1 (215 mg, 0.399 mmol), hept-6-yn-1-ylcarbamate 48 (253 mg, 1.20 mmol) and TEA (101 mg, 1.00 mmol) in DMF (5 mL) was added CuI (15 mg, 0.08 mmol) and Pd( PPh3 )Cl2 (56 mg , 0.08 mmol). After stirring at 50 °C overnight, the mixture was diluted with water (15 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were dried over anhydrous Na2SO4 , filtered and concentrated. The residue was purified by silica gel chromatography eluting with MeOH/DCM (1:30) to give compound 49 (194 mg, 90% yield). MS (ESI) m/z : 623.4 [M+H] + .
(7-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基-吡唑并[1,5- a]嘧啶-3-基)苯基)庚基)胺基甲酸三級丁酯 50 。在氮氣下，在室溫，向化合物 49(194 mg，0.309 mmol)於THF/MeOH (1:1，10 mL)中之溶液中添加Pd/C (50 mg)及Pd(OH) 2/C (50 mg)。在氫氣下在室溫攪拌隔夜之後，過濾混合物，且濃縮濾液且藉由矽膠層析，用MeOH/DCM (0%至5%)溶離來純化，得到化合物 50(110 mg，56%產率)。MS (ESI) m/z: 627.5 [M+H] +。 (7-(3-(7-(4-(2-hydroxyethyl)piperidin-1-yl)-2-methyl-5-phenyl-pyrazolo[1,5- a ]pyrimidine-3 -yl)phenyl)heptyl)carbamate tertiary butyl ester 50 . To a solution of compound 49 (194 mg, 0.309 mmol) in THF/MeOH (1:1, 10 mL) was added Pd/C (50 mg) and Pd(OH) 2 /C at room temperature under nitrogen (50 mg). After stirring overnight at room temperature under hydrogen, the mixture was filtered, and the filtrate was concentrated and purified by silica gel chromatography eluting with MeOH/DCM (0% to 5%) to give compound 50 (110 mg, 56% yield) . MS (ESI) m/z : 627.5 [M+H] + .
2-(4-(3-(3-(7-胺基庚基)苯基)-2-甲基-5-苯基吡唑并[1,5- a]嘧啶-7-基)哌𠯤-1-基)乙醇 51 。在室溫，向化合物 50(55 mg，0.837 mmol)於DCM (2 mL)中之溶液中添加TFA (0.5 mL)。在室溫攪拌1 h之後，濃縮混合物且乾燥，得到呈TFA鹽之化合物 51(粗物質)，其未經進一步純化即直接用於下一步驟中。MS (ESI) m/z: 527.4 [M+H] +。 2-(4-(3-(3-(7-Aminoheptyl)phenyl)-2-methyl-5-phenylpyrazolo[1,5- a ]pyrimidin-7-yl)piperidin -1-yl)ethanol 51 . To a solution of compound 50 (55 mg, 0.837 mmol) in DCM (2 mL) was added TFA (0.5 mL) at room temperature. After stirring at room temperature for 1 h, the mixture was concentrated and dried to give compound 51 as a TFA salt (crude material), which was used directly in the next step without further purification. MS (ESI) m/z : 527.4 [M+H] + .
2-((2-(2,6-二側氧基哌啶-3-基)-1-側氧基異吲哚啉-4-基)氧基)-
N-(7-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5-
a]嘧啶-3-基)苯基)-庚基)乙醯胺
A35 。向化合物
51(0.088 mmol，粗物質)於DMF (3mL)中之溶液中添加DIEPA (34 mg，0.263 mmol)、2-((2-(2,6-二側氧基哌啶-3-基)-1-側氧基異吲哚啉-4-基)氧基)乙酸
52(42 mg粗物質，0.132 mmol)、HOBt (24 mg，0.175 mmol)及EDCI∙HCl (34 mg，0.175 mmol)。在室溫攪拌隔夜之後，濃縮混合物，且藉由矽膠層析，用MeOH/DCM (0%至5%)溶離來純化並且藉由製備型HPLC進一步純化，得到呈甲酸鹽之化合物
A35。將鹽溶解於ACN/H
2O (1:6，7 mL)中，且接著使用1/3N HCl水溶液調整至pH 2。將溶液凍乾，得到呈HCl鹽之化合物
A35(36.3 mg，50%產率)。
1HNMR (400 MHz, DMSO-
d 6)
δ11.00 (s, 1H), 10.35 (brs, 1H), 8.28-8.24 (m, 2H), 8.04 (t,
J= 5.6 Hz, 1H), 7.72 (s, 1H), 7.60 (d,
J= 8.8Hz, 1H), 7.54-7.51 (m, 3H), 7.43 (t,
J= 8.0 Hz, 1H), 7.38 (t,
J= 8.8 Hz, 1H), 7.31 (d,
J= 7.2 Hz, 1H), 7.13-7.08 (m, 2H), 7.02 (s, 1H), 5.12 (dd,
J= 13.2 Hz, 4.8 Hz, 1H), 4.77 (d,
J= 13.6 Hz, 2H), 4.60 (s, 2H), 4.46-4.30 (m, 2H), 3.86 (t,
J= 5.2 Hz, 2H), 3.75-3.60 (m, 4H), 3.45-3.38 (m, 2H), 3.35-3.28 (m, 2H), 3.10 (q,
J= 6.0 Hz, 2H), 2.97-2.85 (m, 1H), 2.70-2.60 (m, 3H), 2.58 (s, 3H), 2.45-2.30 (m, 1H), 2.03-1.95 (m, 1H), 1.70-1.60 (m, 2H), 1.45-1.38 (m, 2H), 1.38-1.20 (m, 6H); MS (ESI)
m/z: 827.2 [M+H]
+。
實例8
製備(
S)-
N-((
S)-1-環己基-2-((
S)-2-(4-(3-((7-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5-
a]嘧啶-5-基)苯基)庚基)氧基)苯甲醯基)噻唑-2-基)吡咯啶-1-基)-2-側氧基乙基)-2-(甲基胺基)丙醯胺B1
如方案11中所示合成化合物
B1。
方案11
如方案12中所示合成化合物
B5。
方案12
如方案13中所示合成化合物
B9。
方案13
(( S)-1-((( S)-1-環己基-2-((2 S,4 S)-4-(7-(3-(7-(4-(2-羥基乙基)-哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5- a]嘧啶-3-基)苯基)庚醯胺基)-2-((( R)-1,2,3,4-四氫萘-1-基)胺甲醯基)吡咯啶-1-基)-2-側氧基乙基)胺基)-1-側氧基丙-2-基)(甲基)胺基甲酸三級丁酯 58 。向7-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基-吡唑并[1,5- a]嘧啶-3-基)苯基)庚酸 33(100 mg，0.18 mmol)及(( S)-1-((( S)-2-((2 S,4 S)-4-胺基-2-((( R)-1,2,3,4-四氫萘-1-基)-胺甲醯基)吡咯啶-1-基)-1-環己基-2-側氧基乙基)胺基)-1-側氧基丙-2-基)(甲基)-胺基甲酸三級丁酯 57(110 mg，0.18 mmol)於DMF (5 mL)中之溶液中添加HOBt (28.5 mg，0.21 mmol)、EDCI (40.3 mg，0.21 mmol)及DIPEA (46.5 mg，0.21 mmol)。在室溫攪拌混合物2 h之後，添加水(10 mL)，且混合物用EtOAc (15 mL × 2)萃取。經合併之有機層用鹽水洗滌，經無水Na 2SO 4乾燥，過濾且濃縮。藉由製備型TLC來純化殘餘物，得到化合物 58(86 mg，43%產率)。MS (ESI) m/z: 1107.7 [M+H] +。 (( S )-1-(((( S )-1-cyclohexyl-2-(( 2S , 4S )-4-(7-(3-(7-(4-(2-hydroxyethyl)) -Pipi?-1-yl)-2-methyl-5-phenylpyrazolo[1,5- a ]pyrimidin-3-yl)phenyl)heptanamido)-2-(((( R ) -1,2,3,4-Tetrahydronaphthalen-1-yl)aminocarbinyl)pyrrolidin-1-yl)-2-oxyethyl)amino)-1-oxypropan-2 - tertiary butyl)(methyl)carbamate 58 . To 7-(3-(7-(4-(2-hydroxyethyl)piperidin-1-yl)-2-methyl-5-phenyl-pyrazolo[1,5- a ]pyrimidine-3 -yl)phenyl)heptanoic acid 33 (100 mg, 0.18 mmol) and (( S )-1-((( S )-2-(( 2S , 4S )-4-amino-2-(( ( R )-1,2,3,4-Tetrahydronaphthalen-1-yl)-aminocarbamoyl)pyrrolidin-1-yl)-1-cyclohexyl-2-side oxyethyl)amino) To a solution of -1-oxypropan-2-yl)(methyl)-carbamic acid tertiary butyl ester 57 (110 mg, 0.18 mmol) in DMF (5 mL) was added HOBt (28.5 mg, 0.21 mmol) ), EDCI (40.3 mg, 0.21 mmol) and DIPEA (46.5 mg, 0.21 mmol). After the mixture was stirred at room temperature for 2 h, water (10 mL) was added, and the mixture was extracted with EtOAc (15 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 , filtered and concentrated. The residue was purified by preparative TLC to give compound 58 (86 mg, 43% yield). MS (ESI) m/z : 1107.7 [M+H] + .
(2
S,4
S)-1-((
S)-2-環己基-2-((
S)-2-(甲基胺基)丙醯胺基)乙醯基)-4-(7-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5-
a]嘧啶-3-基)苯基)-庚醯胺基)-
N-((
R)-1,2,3,4-四氫萘-1-基)吡咯啶-2-甲醯胺
B9 。向化合物
58(86 mg，0.08 mmol)於DCM (4 mL)中之溶液中添加HCl-EtOAc (2 mL)。在室溫攪拌1 h之後，濃縮混合物，且將殘餘物與甲苯一起共蒸發，得到呈HCl鹽之化合物
B9。
1HNMR (400 MHz, DMSO-
d 6)
δ11.34 (s, 1H), 9.67 (s, 1H), 8.91 (s, 1H), 8.80 (d,
J= 7.6 Hz, 1H), 8.45 (d,
J= 8.8 Hz, 1H), 8.29-8.27 (m, 2H), 7.28 (t,
J= 8.0 Hz, 1H), 8.21 (d,
J= 7.2 Hz, 1H), 7.72 (s, 1H), 7.61 (d,
J= 8.0 Hz, 1H), 7.55-7.51 (m, 3H), 7.38 (t,
J= 7.6 Hz, 1H), 7.26 (d,
J= 7.2 Hz, 1H), 7.16-7.04 (m, 5H), 5.44 (s, 1H), 4.92-4.89 (m, 1H), 4.76 (d,
J= 13.2 Hz, 2H), 4.37-4.33 (m, 1H), 4.31-4.24 (m, 2H), 4.10-4.06 (m, 1H), 3.89-3.87 (m, 2H), 3.84-3.81 (m, 1H), 3.74-3.68 (m, 4H), 3.40-3.38 (m, 2H), 3.33-3.29 (m, 3H), 2.71-2.64 (m, 4H), 2.57 (s, 3H), 2.44-2.42 (m, 3H), 2.39-2.33 (m, 1H), 2.08-2.05 (m, 2H), 1.90-1.79 (m, 4H), 1.75-1.62 (m, 8H), 1.59-1.50 (m, 4H), 1.37-1.33 (m, 5H), 1.17-1.11 (m, 2H), 1.05-0.99 (m, 2H); MS (ESI)
m/z:
1007.8 [M+H]
+。
實例11
製備2-(4-((4
R,5
S)-4,5-雙(4-氯苯基)-2-(2-異丙氧基-4-甲氧基苯基)-4,5-二氫-1
H-咪唑-1-羰基)-2-側氧基哌𠯤-1-基)-
N-(8-(4-(7-(4-(2-羥基乙基)-哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5-
a]嘧啶-3-基)苯基)辛基)乙醯胺C4
如方案14及15中所示合成化合物
C4。
方案14
(7-(甲氧基(甲基)胺基)-7-側氧基庚基)胺基甲酸三級丁酯 60 。向7-((三級丁氧基羰基)胺基)庚酸(3.0 g，11.49 mmol)於DCM (30 mL)中之溶液中添加 N, O-二甲基羥基胺(1.68 g，17.24 mmol)、TEA (2.32 g，22.98 mmol)、DMAP (141 mg，1.14 mmol)及EDCI (2.64 g，17.24 mmol)。在室溫攪拌隔夜之後，混合物用H 2O (60 mL)稀釋且用EtOAc (30 mL × 2)萃取。經合併之有機層經無水Na 2SO 4乾燥，過濾且濃縮。藉由矽膠管柱層析，用EtOAc/PE (0%至40%)溶離來純化殘餘物，得到化合物 60(3.30 g，99.96%)。MS (ESI) m/z: 289.3[M+H] +。 (7-(Methoxy(methyl)amino)-7-pendant oxyheptyl)carbamate tertiary butyl ester 60 . To a solution of 7-((tertiary butoxycarbonyl)amino)heptanoic acid (3.0 g, 11.49 mmol) in DCM (30 mL) was added N , O -dimethylhydroxylamine (1.68 g, 17.24 mmol) ), TEA (2.32 g, 22.98 mmol), DMAP (141 mg, 1.14 mmol) and EDCI (2.64 g, 17.24 mmol). After stirring at room temperature overnight, the mixture was diluted with H2O (60 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were dried over anhydrous Na2SO4 , filtered and concentrated. The residue was purified by silica gel column chromatography eluting with EtOAc/PE (0% to 40%) to give compound 60 (3.30 g, 99.96%). MS (ESI) m/z : 289.3[M+H] + .
(7-側氧基庚基)胺基甲酸三級丁酯 61 。向在氮氣下在-78℃之化合物 60(3.30 g，11.48 mmol)於THF (3 mL)中之溶液中逐滴添加LiAlH 4(17 mL，1 M於THF中)。在此溫度攪拌1 h之後，反應物用氯化銨(10 mL)淬滅，且混合物用EtOAc (30 mL × 2)萃取。經合併之有機層經無水Na 2SO 4乾燥，過濾且濃縮，得到化合物 61(粗物質)，其未經進一步純化即直接用於下一步驟中。MS (ESI) m/z: 230.1 [M+H] +。 (7-Pendant oxyheptyl)carbamate tertiary butyl ester 61 . To a solution of compound 60 (3.30 g, 11.48 mmol) in THF (3 mL) at -78 °C under nitrogen was added LiAlH4 (17 mL, 1 M in THF) dropwise. After stirring at this temperature for 1 h, the reaction was quenched with ammonium chloride (10 mL), and the mixture was extracted with EtOAc (30 mL x 2). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated to give compound 61 (crude material), which was used directly in the next step without further purification. MS (ESI) m/z : 230.1 [M+H] + .
辛-7-炔-1-基胺基甲酸三級丁酯 62。向在室溫之化合物 61(11.48 mmol，粗物質)於MeOH (8 mL)中之溶液中添加K 2CO 3(4.73 g，34.35 mmol)及(1-重氮-2-側氧基丙基)膦酸二甲酯(3.29 g，17.17 mmol)。之後在室溫攪拌隔夜，濃縮混合物，且藉由矽膠管柱層析，用EtOAc/PE (0%至15%)溶離來純化殘餘物，得到化合物 62(1.44 g，56%產率)。MS (ESI) m/z: 226.3 [M+H] +。 Oct-7-yn-1-ylcarbamate tertiary butyl ester 62 . To a solution of compound 61 (11.48 mmol, crude material) in MeOH (8 mL) at room temperature was added K2CO3 (4.73 g , 34.35 mmol) and ( 1 -diazo-2-pendoxyloxypropyl) ) dimethyl phosphonate (3.29 g, 17.17 mmol). After stirring at room temperature overnight, the mixture was concentrated and the residue was purified by silica gel column chromatography eluting with EtOAc/PE (0% to 15%) to give compound 62 (1.44 g, 56% yield). MS (ESI) m/z : 226.3 [M+H] + .
2-異丙氧基-4-甲氧基苯甲醛 64 。向2-羥基-4-甲氧基苯甲醛 63(5.0 g，32.89 mmol)及K 2CO 3(9.08 g，65.78 mmol)於DMF (50 mL)中之溶液中添加2-溴丙烷(6.02 g，49.34 mmol)及KI (1.09 g，6.58 mmol)。在室溫攪拌8 h之後，過濾混合物且用MeOH洗滌。濃縮濾液，且藉由矽膠管柱層析，用EtOAc/PE (0%至25%)溶離來純化殘餘物，得到化合物 64(6.2 g，97%產率)。MS (ESI) m/z: 195.2 [M+H] +。 2-Isopropoxy-4-methoxybenzaldehyde 64 . To a solution of 2-hydroxy- 4 -methoxybenzaldehyde 63 (5.0 g, 32.89 mmol) and K2CO3 (9.08 g , 65.78 mmol) in DMF (50 mL) was added 2-bromopropane (6.02 g) , 49.34 mmol) and KI (1.09 g, 6.58 mmol). After stirring at room temperature for 8 h, the mixture was filtered and washed with MeOH. The filtrate was concentrated and the residue was purified by silica gel column chromatography eluting with EtOAc/PE (0% to 25%) to give compound 64 (6.2 g, 97% yield). MS (ESI) m/z : 195.2 [M+H] + .
(4 R,5 S)-4,5-雙(4-氯苯基)-2-(2-異丙氧基-4-甲氧基苯基)-4,5-二氫-1 H-咪唑 66。在0℃向(1 R,2 S)-1,2-雙(4-氯苯基)乙烷-1,2-二胺 65(8.26 g，29.48 mmol)於DCM (20 mL)中之溶液中添加化合物 64(5.2 g，26.80 mmol)持續30 min，隨後逐滴添加含NBS (5.72 g，32.16 mmol)之DCM。在室溫攪拌8 h之後，過濾混合物且用苯基醚洗滌。將殘餘物乾燥，得到化合物 66(13.5 g，92%產率)。MS (ESI) m/z: 456.3 [M+H] +。 ( 4R , 5S )-4,5-bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydro- 1H- Imidazole 66 . To a solution of ( 1R , 2S )-1,2-bis(4-chlorophenyl)ethane-1,2-diamine 65 (8.26 g, 29.48 mmol) in DCM (20 mL) at 0 °C Compound 64 (5.2 g, 26.80 mmol) was added for 30 min followed by dropwise addition of NBS (5.72 g, 32.16 mmol) in DCM. After stirring at room temperature for 8 h, the mixture was filtered and washed with phenyl ether. The residue was dried to give compound 66 (13.5 g, 92% yield). MS (ESI) m/z : 456.3 [M+H] + .
4-((4 R,5 S)-4,5-雙(4-氯苯基)-2-(2-異丙氧基-4-甲氧基苯基)-4,5-二氫-1 H-咪唑-1-羰基)哌𠯤-2-酮 67。在0℃，向化合物 66(5 g，11.01 mmol)於DCM (100 mL)中之溶液中逐滴添加含TEA (11.91 mL，82.58 mmol)及BTC (8.17 g，27.5 mmol)之DCM (20 mL)。在攪拌2 h之後，濃縮混合物，且接著逐滴添加含哌𠯤-2-酮(2.2 g，22.02 mmol)之DCM (20 mL)。在0℃攪拌1 h之後，濃縮混合物，且藉由矽膠管柱層析，用EtOAc/PE (0%至25%)溶離來純化殘餘物，得到化合物 67(4.94 g，77%產率)。MS (ESI) m/z: 581.4 [M+H] +。 4-((4 R ,5 S )-4,5-bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydro- 1 H -imidazol-1-carbonyl)piperazol-2-one 67 . To a solution of compound 66 (5 g, 11.01 mmol) in DCM (100 mL) at 0 °C was added TEA (11.91 mL, 82.58 mmol) and BTC (8.17 g, 27.5 mmol) in DCM (20 mL) dropwise ). After stirring for 2 h, the mixture was concentrated and then piperazine-2-one (2.2 g, 22.02 mmol) in DCM (20 mL) was added dropwise. After stirring at 0°C for 1 h, the mixture was concentrated and the residue was purified by silica gel column chromatography eluting with EtOAc/PE (0% to 25%) to give compound 67 (4.94 g, 77% yield). MS (ESI) m/z : 581.4 [M+H] + .
2-(4-((4 R,5 S)-4,5-雙(4-氯苯基)-2-(2-異丙氧基-4-甲氧基-苯基)-4,5-二氫-1H-咪唑-1-羰基)-2-側氧基哌𠯤-1-基)乙酸三級丁酯 68。在0℃，向化合物 67(4.94 g，8.52 mmol)於DMF (30 mL)中之溶液中添加NaH (682 mg，17.04 mmol，60%)持續1 h，隨後逐滴添加含2-溴乙酸三級丁酯(2.16 g，11.07 mmol)之DMF (10 mL)。在室溫攪拌8 h之後，反應物用水(30 mL)淬滅，且混合物用EtOAc (50 mL × 2)萃取。濃縮經合併之有機層且藉由矽膠管柱層析，用EtOAc/PE (20%至40%)溶離來純化，得到化合物 68(3.26 g，55%產率)。MS (ESI) m/z: 695.6 [M+H] +。 2-(4-((4 R ,5 S )-4,5-bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5 -Dihydro-1H-imidazole-1-carbonyl)-2-oxypiperidine-1-yl)acetate tertiary butyl ester 68 . To a solution of compound 67 (4.94 g, 8.52 mmol) in DMF (30 mL) was added NaH (682 mg, 17.04 mmol, 60%) for 1 h at 0 °C followed by dropwise addition of tris-2-bromoacetic acid butyl ester (2.16 g, 11.07 mmol) in DMF (10 mL). After stirring at room temperature for 8 h, the reaction was quenched with water (30 mL), and the mixture was extracted with EtOAc (50 mL x 2). The combined organic layers were concentrated and purified by silica gel column chromatography eluting with EtOAc/PE (20% to 40%) to give compound 68 (3.26 g, 55% yield). MS (ESI) m/z : 695.6 [M+H] + .
2-(4-((4 R,5 S)-4,5-雙(4-氯苯基)-2-(2-異丙氧基-4-甲氧基苯基)-4,5-二氫-1 H-咪唑-1-羰基)-2-側氧基哌𠯤-1-基)乙酸 69。向化合物 68(1.5 g，2.16 mmol)於DCM (6 mL)中之溶液中添加TFA (6 mL)。在室溫攪拌3 h之後，濃縮混合物且與甲苯一起共蒸發，得到化合物 69(1.24 g，89%產率)。MS (ESI) m/z: 639.5 [M+H] +。 2-(4-((4 R ,5 S )-4,5-bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5- Dihydro- 1H -imidazole-1-carbonyl)-2-oxypiperidine-1-yl)acetic acid 69 . To a solution of compound 68 (1.5 g, 2.16 mmol) in DCM (6 mL) was added TFA (6 mL). After stirring at room temperature for 3 h, the mixture was concentrated and co-evaporated with toluene to give compound 69 (1.24 g, 89% yield). MS (ESI) m/z : 639.5 [M+H] + .
(8-(4-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基-吡唑并[1,5- a]嘧啶-3-基)苯基)辛-7-炔-1-基)胺基甲酸三級丁酯 70。向在室溫之化合物 1(200 mg，0.37 mmol)於DMF (4 mL)中之溶液中添加辛-7-炔-1-基胺基甲酸三級丁酯 62(208 mg，0.93 mmol)、TEA (112 mg，1.11 mmol)、CuI (14 mg，0.074 mmol)及Pd(PPh 3) 2Cl 2(54 mg，0.074 mmol)。在氮氣下在50℃攪拌4 h之後，濃縮混合物，且藉由矽膠管柱層析，用MeOH/DCM (0%至10%)溶離來純化殘餘物，得到化合物 70(182 mg，77%產率)。MS (ESI) m/z: 637.8 [M+H] +。 (8-(4-(7-(4-(2-hydroxyethyl)piperidin-1-yl)-2-methyl-5-phenyl-pyrazolo[1,5- a ]pyrimidine-3 -yl)phenyl)oct-7-yn-1-yl)carbamic acid tertiary butyl ester 70 . To a solution of compound 1 (200 mg, 0.37 mmol) in DMF (4 mL) at room temperature was added oct-7-yn-1-ylcarbamate 62 (208 mg, 0.93 mmol), TEA (112 mg, 1.11 mmol), CuI (14 mg, 0.074 mmol) and Pd( PPh3 ) 2Cl2 (54 mg , 0.074 mmol). After stirring at 50 °C for 4 h under nitrogen, the mixture was concentrated and the residue was purified by silica gel column chromatography eluting with MeOH/DCM (0% to 10%) to give compound 70 (182 mg, 77% yield). Rate). MS (ESI) m/z : 637.8 [M+H] + .
(8-(4-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5- a]嘧啶-3-基)苯基)辛基)胺基甲酸三級丁酯 71 。向化合物 70(182 mg，0.286 mmol)於THF (3 mL)及MeOH (3 mL)中之溶液中添加Pd/C (100 mg)及Pd(OH) 2(100 mg)。在H 2下在室溫攪拌隔夜之後，過濾混合物，且濃縮濾液，得到化合物 71(180 mg，粗物質)，其未經進一步純化即直接用於下一步驟中。MS (ESI) m/z: 641.1[M+H] +。 (8-(4-(7-(4-(2-hydroxyethyl)piperidin-1-yl)-2-methyl-5-phenylpyrazolo[1,5- a ]pyrimidine-3- tertiary butyl) phenyl) octyl) carbamate 71 . To a solution of compound 70 (182 mg, 0.286 mmol) in THF (3 mL) and MeOH (3 mL) was added Pd/C (100 mg) and Pd(OH) 2 (100 mg). After stirring overnight at room temperature under H2 , the mixture was filtered, and the filtrate was concentrated to give compound 71 (180 mg, crude material), which was used directly in the next step without further purification. MS (ESI) m/z : 641.1[M+H] + .
2-(4-(3-(4-(8-胺基辛基)苯基)-2-甲基-5-苯基吡唑并[1,5- a]嘧啶-7-基)哌𠯤-1-基)乙醇 72。在0℃，向化合物 71(0.165 mmol，粗物質)於DCM (2 mL)中之溶液中添加HCl (1 mL，1M於EtOAc中)。在室溫攪拌3 h之後，濃縮混合物且乾燥，得到化合物 72(120 mg，粗物質)，其未經進一步純化即直接用於下一步驟中。MS (ESI) m/z: 541.6[M+H] +。 2-(4-(3-(4-(8-Aminooctyl)phenyl)-2-methyl-5-phenylpyrazolo[1,5- a ]pyrimidin-7-yl)piperidin -1-yl) ethanol72 . To a solution of compound 71 (0.165 mmol, crude material) in DCM (2 mL) at 0 °C was added HCl (1 mL, 1 M in EtOAc). After stirring at room temperature for 3 h, the mixture was concentrated and dried to give compound 72 (120 mg, crude material), which was used directly in the next step without further purification. MS (ESI) m/z : 541.6[M+H] + .
2-(4-((4 R,5 S)-4,5-雙(4-氯苯基)-2-(2-異丙氧基-4-甲氧基苯基)-4,5-二氫-1 H-咪唑-1-羰基)-2-側氧基哌𠯤-1-基)- N-(8-(4-(7-(4-(2-羥基乙基)-哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5- a]嘧啶-3-基)苯基)辛基)乙醯胺 C4 。向在0℃之化合物 72(0.165 mol，粗物質)於DMF (3 mL)中之溶液中添加化合物 69(105 mg，0.164 mmol)、DIPEA (63 mg，0.49 mmol)、HOBt (44 mg，328 mmol)及EDCI (62 mg，0.328 mmol)。在室溫攪拌隔夜之後，混合物用H 2O (10 mL)稀釋且用EtOAc (20 mL × 2)萃取。經合併之有機層經無水Na 2SO 4乾燥，過濾且濃縮。藉由製備型HPLC來純化殘餘物，得到化合物 C4(25 mg，13%產率)。 1HNMR (400 MHz, DMSO- d 6) δ8.19 (d, J= 6.8 Hz, 2H), 7.80 (t, J= 5.2 Hz, 1H), 7.73 (d, J= 8.0 Hz, 2H), 7.54-7.47 (m, 4H) ,7.43-7.36 (m, 6H), 7.29 (d, J= 8.4 Hz, 2H), 7.22 (d, J= 8.4 Hz, 2H), 6.83 (s, 1H), 6.59-6.57 (m, 2H), 4.97 (d, J= 8.0 Hz, 1H), 4.84 (d, J= 8.0 Hz, 1H), 4.69-4.63 (m, 1H), 4.54-4.44 (m, 1H), 3.91-3.85 (m, 4 H), 3.81 (s, 3H), 3.77 (s, 1H), 3.71-3.66 (m, 3H), 3.59-3.55 (m, 5H), 3.12-3.07 (m, 2H), 3.02-2.88 (m, 4H), 2.72-2.68 (m, 4H), 2.61(t, J= 7.6 Hz, 2H), 2.55 (s, 3H), 2.03-1.95 (m, 1H), 1.67-1.58 (m, 2H), 1.42-1.31 (m, 6H), 1.24-1.20 (m, 8H); MS (ESI) m/z: 1163.3 [M+H] +。 2-(4-((4 R ,5 S )-4,5-bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5- Dihydro- 1H -imidazole-1-carbonyl)-2 - oxypiperidine-1-yl)-N-(8-(4-(7-(4-(2-hydroxyethyl)-piperazol) -1-yl)-2-methyl-5-phenylpyrazolo[1,5- a ]pyrimidin-3-yl)phenyl)octyl)acetamide C4 . To a solution of compound 72 (0.165 mol, crude material) in DMF (3 mL) at 0 °C was added compound 69 (105 mg, 0.164 mmol), DIPEA (63 mg, 0.49 mmol), HOBt (44 mg, 328 mmol) and EDCI (62 mg, 0.328 mmol). After stirring at room temperature overnight, the mixture was diluted with H2O (10 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were dried over anhydrous Na2SO4 , filtered and concentrated. The residue was purified by preparative HPLC to give compound C4 (25 mg, 13% yield). 1 HNMR (400 MHz, DMSO- d 6 ) δ 8.19 (d, J = 6.8 Hz, 2H), 7.80 (t, J = 5.2 Hz, 1H), 7.73 (d, J = 8.0 Hz, 2H), 7.54- 7.47 (m, 4H) , 7.43-7.36 (m, 6H), 7.29 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H), 6.83 (s, 1H), 6.59-6.57 (m, 2H), 4.97 (d, J = 8.0 Hz, 1H), 4.84 (d, J = 8.0 Hz, 1H), 4.69-4.63 (m, 1H), 4.54-4.44 (m, 1H), 3.91- 3.85 (m, 4H), 3.81 (s, 3H), 3.77 (s, 1H), 3.71-3.66 (m, 3H), 3.59-3.55 (m, 5H), 3.12-3.07 (m, 2H), 3.02 -2.88 (m, 4H), 2.72-2.68 (m, 4H), 2.61(t, J = 7.6 Hz, 2H), 2.55 (s, 3H), 2.03-1.95 (m, 1H), 1.67-1.58 (m , 2H), 1.42-1.31 (m, 6H), 1.24-1.20 (m, 8H); MS (ESI) m/z : 1163.3 [M+H] + .
以下化合物係類似地製備。The following compounds were prepared similarly.
3-(6-氟-4-(1-(7-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5-
a]嘧啶-5-基)苯基)庚基)哌啶-4-基)-1-側氧基異吲哚啉-2-基)-哌啶-2,6-二酮
A1 。 1HNMR (400 MHz, DMSO-
d 6)
δ11.04 (s, 1H), 10.84 (brs, 1H), 10.58 (brs, 1H), 8.07 (s, 1H), 8.06 (d,
J= 8.0 Hz, 1H), 7.85 (d,
J= 7.6 Hz, 2H), 7.49 (t,
J= 8.0 Hz, 2H), 7.46-7.40 (m, 2H), 7.37-7.23 (m, 3H), 7.00 (s, 1H), 5.17 (dd,
J= 4.8, 13.2 Hz, 1H), 4.76 (d,
J= 13.2 Hz, 2H), 4.58-4.35 (m, 2H), 3.87 (t,
J= 4.0 Hz, 2H), 3.76-3.60 (m, 3H), 3.54 (d,
J= 11.6 Hz, 2H), 3.47-3.34 (m, 2H), 3.30-3.27 (m, 2H), 3.06-2.87 (m, 6H), 2.71 (t,
J= 7.2 Hz, 2H), 2.68-2.62 (m, 1H), 2.59 (s, 3H), 2.53-2.50 (m, 1H), 2.41-2.27 (m, 1H), 2.26-2.10 (m, 2H), 2.08-1.92 (m, 3H),1.78-1.62 (m, 4H), 1.43-1.26 (m, 6H); MS (ESI)
m/z:
855.5 [M+H]
+。
3-(6-氟-4-(1-(7-(4-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5-
a]嘧啶-5-基)苯基)庚基)哌啶-4-基)-1-側氧基異吲哚啉-2-基)-哌啶-2,6-二酮
A2。
1HNMR (400 MHz, DMSO-
d
6 )
δ11.02 (s, 1H), 8.11 (d,
J= 8.0 Hz, 2H), 7.83 (d,
J= 8.0 Hz, 2H), 7.47 (t,
J= 7.6 Hz, 2H), 7.39-7.25 (m, 5H), 6.82 (s, 1H), 5.13 (dd,
J= 5.2, 13.2 Hz, 1H), 4.50-4.29 (m, 3H), 3.84 (s, 4H), 3.57 (s, 2H), 2.95-2.87 (m, 3H), 2.67-2.60 (m, 7H), 2.56 (s, 4H), 2.48-2.38 (m, 2H), 2.26 (t,
J= 6.8 Hz, 2H), 2.05-1.90 (m, 4H), 1.75-1.60 (m, 6H), 1.50-1.41 (m, 2H), 1.35-1.20 (m, 6H); MS (ESI)
m/z:
855.5 [M+H]
+。
3-(6-氟-4-(1-(9-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5-
a]嘧啶-5-基)苯基)壬基)哌啶-4-基)-1-側氧基異吲哚啉-2-基)-哌啶-2,6-二酮
A4。
1HNMR (400 MHz, DMSO-
d
6 )
δ8.02 (t,
J= 8.4 Hz, 2H), 7.85 (d,
J= 8.0 Hz, 2H), 7.47 (t,
J= 7.6 Hz, 2H), 7.44-7.28 (m, 5H), 6.84 (s, 1H), 5.14 (dd,
J= 5.2, 13.6 Hz, 1H), 4.51-4.30 (m, 3H), 3.85 (s, 4H), 3.59-3.54 (m, 2H), 2.92-2.67 (m, 3H), 2.70-2.66 (m, 6H), 2.62-2.60 (m, 2H), 2.56 (s, 3H), 2.45-2.33 (m, 2H), 2.24-2.21 (m, 2H), 2.01-1.87 (m, 4H), 1.69-1.64 (m, 6H), 1.39-1.16 (m, 12H); MS (ESI)
m/z:
883.6 [M+H]
+。
3-(6-氟-4-(1-(9-(4-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5-
a]嘧啶-5-基)苯基)壬基)哌啶-4-基)-1-側氧基異吲哚啉-2-基)-哌啶-2,6-二酮
A5。
1HNMR (400 MHz, DMSO-
d
6 )
δ11.01 (s, 1H), 8.11(d,
J= 8.0 Hz, 2H), 7.83 (d,
J= 6.8 Hz, 2H), 7.47 (t,
J= 7.6 Hz, 2H), 7.40-7.33 (m, 4H), 7.27 (t,
J= 7.2 Hz, 1H), 6.82 (s, 1H), 5.13 (dd,
J= 4.8, 13.2 Hz, 1H), 4.51-4.30 (m, 3H), 3.85 (s, 4H), 3.60-3.55 (m, 2H), 2.95-2.92 (m, 3H), 2.67-2.61 (m, 6H), 2.56 (s, 4H), 2.44-2.40 (m, 1H), 2.27-2.23 (m, 2H), 2.00-1.90 (m, 4H), 1.70-1.61 (m, 6H), 1.46-1.38 (m, 2H), 1.29-1.23 (m, 12 H); MS (ESI)
m/z:
883.6 [M+H]
+。
3-(6-氟-4-(1-(5-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5-
a]嘧啶-5-基)苯基)戊基)哌啶-4-基)-1-側氧基異吲哚啉-2-基)-哌啶-2,6-二酮
A6。
1HNMR (400 MHz, DMSO-
d
6 )
δ11.01 (s, 1H), 8.03-7.99 (m, 2H), 7.84 (d,
J= 6.8 Hz, 2H), 749-7.41 (m, 3H), 7.37-7.31 (m, 3H), 7.27 (t,
J= 6.8 Hz, 1H), 6.83 (s, 1H), 5.13 (dd,
J= 4.8, 13.2 Hz, 1H), 4.50-4.46 (m, 2H), 4.34-4.29 (m, 1H), 3.85 (s, 4H), 3.57 (m, 2H), 2.96-2.90 (m, 3H), 2.71-2.68 (m, 6H), 2.62-2.58 (m, 2H), 2.57 (s, 3H), 2.44-2.41(m, 1H), 2.28 (t,
J= 7.2 Hz, 2H), 2.00-1.95 (m, 5H), 1.69-1.62(m, 6H), 1.51-1.48 (m, 2H), 1.36-1.33 (m, 2H); MS (ESI)
m/z:
827.4 [M+H]
+。
3-(6-氟-4-(1-(5-(4-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基-吡唑并[1,5-
a]嘧啶-5-基)苯基)戊基)哌啶-4-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮
A7。
1HNMR (400 MHz, DMSO-
d
6 )
δ10.99 (s, 1H), 8.11 (d,
J= 8.4 Hz, 2H), 7.83 (d,
J= 7.6 Hz, 2H), 7.49-7.45 (m, 2H), 7.39-7.31 (m, 4H), 7.28 (t,
J= 7.6 Hz, 1H), 6.81 (s, 1H), 5.13 (dd,
J= 8.4, 13.2 Hz, 1H), 4.52-4.31 (m, 3H), 3.84 (s, 4H), 3.57 (s, 2H), 2.97-2.91 (m, 3H), 2.67-2.64 (m, 6H), 2.59-2.56 (m, 2H), 2.50 (s, 3H), 2.43-2.40 (m, 1H), 2.80 (t,
J= 7.2 Hz, 2H), 2.02-1.95 (m, 5H), 1.72-1.60 (m, 6H), 1.50-1.44 (m, 2H), 1.35-1.30 (m, 2H); MS (ESI)
m/z:
827.5 [M+H]
+。
3-(1-((4-(((7-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基-吡唑并[1,5-
a]嘧啶-5-基)苯基)庚基)胺基)甲基)苯氧基)甲基)-4-側氧基-4
H-噻吩并[3,4-
c]吡咯-5(6
H)-基)哌啶-2,6-二酮
A9 。 1HNMR (400 MHz, DMSO-
d
6 )
δ8.02-7.98 (m, 3H), 7.85 (s, 1H), 7.83 (s, 1H), 7.47 (t,
J= 7.6 Hz, 2H), 7.41 (t,
J= 7.6 Hz, 1H), 7.32-7.26 (m, 2H), 7.21 (d,
J= 8.4 Hz, 2H), 6.93 (d,
J= 8.8 Hz, 2H), 6.83 (s, 1H), 5.25 (s, 2H), 5.01 (dd,
J= 4.8, 13.6 Hz, 1H), 4.47 (brs, 1H), 4.35-4.19 (m, 2H), 3.85 (s, 4H), 3.60-3.56 (m, 4H), 2.92-2.82 (m, 1H), 2.70-2.66 (m, 6H), 2.60-2.55 (m, 5H), 2.46-2.30 (m, 3H), 2.02-1.92 (m, 2H), 1.68-1.58 (m, 2H), 142-1.28 (m, 8H); MS (ESI)
m/z:
895.4 [M+H]
+。
3-(6-氟-4-(4-(2-(4-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5-
a]嘧啶-5-基)苯乙基)-1
H-1,2,3-三唑-1-基)乙基)哌𠯤-1-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮
A12 。 1HNMR (400 MHz, DMSO-
d
6 )
δ10.99(s, 1H), 8.02-8.00 (m, 2H), 7.83-7.80 (m, 3H), 7.48-7.40 (m, 3H), 7.36-7.34 (m, 1H), 7.26 (t,
J= 14.8 Hz, 1H), 6.99 (dd,
J= 2.4, 7.2 Hz, 1H), 6.87 (dd,
J= 2.0, 12.0 Hz, 1H), 6.80 (s, 1H), 5.09 (dd,
J= 5.2, 13.2 Hz , 1H), 4.47-4.24 (m, 5H), 3.84 (s, 4H), 3.57 (q,
J= 6.0 Hz, 2H), 3.27-3.25 (m, 1H), 3.03-3.00 (m, 10H), 2.74-2.66 (m, 7H), 2.60-2.56 (m, 1H), 2.55 (s, 3H), 2.43-2.33 (m, 2H), 2.33-2.32 (m, 1H), 2.01-1.97 (m, 2H); MS (ESI)
m/z:
881.7 [M+H]
+。
3-(6-氟-4-(1-(2-(4-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5-
a]嘧啶-5-基)苯乙基)-1H-1,2,3-三唑-1-基)乙基)哌啶-4-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮
A13 。 1HNMR (400 MHz, DMSO-
d
6 )
δ11.01 (s, 1H), 8.02-8.01 (m, 2H), 7.83-7.81 (m, 3H), 7.47 (t,
J= 7.6 Hz, 2H), 7.42 (d,
J= 8.0 Hz, 1H), 7.37-7.32 (m, 3H), 7.26 (t,
J= 7.6 Hz, 1H), 6.82 (s, 1H), 5.13 (dd,
J= 5.2, 13.2 Hz, 1H), 4.50-4.46 (m, 2H), 4.40 (t,
J= 6.0 Hz, 2H), 4.34-4.30 (m, 1H), 3.85 (s, 4H), 3.60-3.56 (m, 2H), 3.07-3.00 (m, 5H), 2.94-2.87 (m, 3H), 2.68-2.56 (m, 8H), 2.55 (s, 3H), 2.33-2.32 (m, 1H), 2.06-1.97 (m, 4H), 1.69-1.59 (m, 4H); MS (ESI)
m/z:
880.7 [M+H]
+。
3-(6-氟-4-(1-(2-(4-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5-
a]嘧啶-5-基)苯乙基)哌𠯤-1-基)乙基)哌啶-4-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮
A15 。 1HNMR (400 MHz, DMSO-
d 6)
δ10.99 (s, 1H), 8.05-8.00 (m, 2H), 7.84 (d,
J= 7.2 Hz, 2H), 7.49-7.45 (m, 2H), 7.45-7.38 (m, 2H), 7.35-7.33 (m, 2H), 7.29-7.28 (m, 1H), 6.83 (s , 1H), 5.13 (dd,
J= 5.2, 13.2 Hz, 1H), 4.52-4.31 (m, 3H), 3.87-3.85 (m, 4H), 3.58 (d,
J= 6.0 Hz, 2H), 3.00-2.81 (m, 5H), 2.69-2.61 (m, 6H), 2.57-2.52 (m, 7H), 2.49-2.43 (m, 11H), 2.06-1.99 (m, 3H), 1.72-1.67 (m, 4H); MS (ESI)
m/z: 897.7 [M+H]
+。
3-(6-氟-4-(1-(2-(4-(3-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5-
a]嘧啶-5-基)苯基)丙基)哌𠯤-1-基)乙基)哌啶-4-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮
A16 。 1HNMR (400 MHz, DMSO-
d
6 )
δ10.99 (s, 1H), 8.02-7.99 (m, 2H), 7.84 (d,
J= 7.6 Hz, 2H), 7.49-7.40 (m, 4H), 7.38-7.28 (m, 4H), 6.83 (s, 1H), 5.13 (dd,
J= 5.2, 13.2 Hz, 1H), 4.52-4.31 (m, 3H), 3.85 (s, 4H), 3.57 (t,
J= 6.0 Hz, 2H), 2.99-2.87 (m, 3H), 2.73-2.67 (m, 6H), 2.62-2.60 (m, 1H), 2.57 (s, 3H), 2.54-2.51 (m, 1H), 2.45-2.27 (m, 16H), 2.02-1.99 (m, 3H), 1.80-1.71 (m, 6H); MS (ESI)
m/z: 911.7 [M+H]
+。
3-(6-氟-4-(4-(7-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基-吡唑并[1,5-
a]嘧啶-5-基)苯基)庚基)哌𠯤-1-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮
A17 。 1HNMR (400 MHz, DMSO-
d
6 )
δ10.99 (s, 1H), 8.03-7.99 (m, 2H), 7.84 (d,
J= 6 .4Hz, 2H), 7.49-7.40 (m, 3H), 7.32-7.25 (m, 2H), 7.00 (dd,
J= 2.0, 7.6 Hz,, 1H), 6.87 (dd,
J= 2.0, 12.0 Hz, 1H), 6.83 (s, 1H), 5.11 (dd,
J= 5.2, 13.6 Hz, 1H), 4.48 (t,
J= 5.2 Hz 1H), 4.44-4.25 (m, 2H), 3.85 (s, 4H), 3.59-3.55 (q,
J= 6.4 Hz,2H), 3.05-3.04 (m, 4H), 2.90-2.87 (m, 1H), 2.68-2.67 (m, 6H), 2.62-2.43 (m, 9H), 2.32-2.26 (m, 2H), 2.01-1.97 (m, 3H), 1.66-1.63 (m, 2H), 1.45-1.27 (m, 8H); MS (ESI)
m/z: 856.5 [M+H]
+。
3-(4-((1-(6-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基-吡唑并[1,5-
a]嘧啶-5-基)苯基)己醯基)哌啶-4-基)乙炔基)-1-側氧基異吲哚啉-2-基)-哌啶-2,6-二酮
A18 。 1HNMR (400 MHz, DMSO-
d
6 )
δ10.99 (s, 1H), 9.86 (brs, 1H), 8.05-8.04 (m, 2H), 7.85 (d,
J= 7.2 Hz, 2H), 7.72 (d,
J= 7.6 Hz, 1H), 7.63 (d,
J= 7.6 Hz, 1H), 7.54-7.42 (m, 4H), 7.35 (d,
J= 7.2 Hz, 1H), 7.29 (d,
J= 6.8 Hz, 1H), 6.98 (s, 1H), 5.13 (dd,
J= 5.2, 13.6 Hz, 1H), 4.78 (d,
J= 14.0 Hz, 1H), 4.46-4.28 (m, 2H), 3.89-3.80 (m, 2H), 3.71-3.62 (m, 3H), 3.33-3.29 (m, 5H), 3.19-3.15 (m, 2H), 2.97-2.87 (m, 2H), 2.69 (t,
J= 7.6 Hz, 2H), 2.59 (s, 3H), 2.56-2.55 (m, 1H), 2.44-2.39 (m, 1H), 2.31 (t,
J= 7.2 Hz, 3H), 2.03-1.95 (m, 3H), 1.88-1.79 (m, 2H), 1.68-1.62 (m, 3H), 1.57-1.45 (m, 4H), 1.38-1.29 (m, 2H); MS (ESI)
m/z: 861.5 [M+H]
+。
3-(4-((4-(((7-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基-吡唑并[1,5-
a]嘧啶-5-基)苯基)庚基)胺基)甲基)苯甲基)氧基)-1-側氧基異吲哚啉-2-基)-哌啶-2,6-二酮
A19 。 1HNMR (400 MHz, DMSO-
d
6 )
δ8.01-7.99 (m, 2H), 7.84 (d,
J= 6.8 Hz, 2H), 7.49-7.40 (m, 6H), 7.36-7.25 (m, 6H), 6.83 (s, 1H), 5.75 (s, 1H), 5.21 (s, 1H), 5.10 (dd,
J= 5.2,
J= 13.2 Hz, 1H), 4.48 (brs, 1H), 4.42-4.22 (m, 2H), 3.85 (s, 4H), 3.76-3.72 (m, 1H), 3.59-3.56 (m, 2H), 3.29 (s, 4H), 2.94-2.86 (m, 1H), 2.69-2.64 (m, 6H), 2.59-2.54 (m, 4H), 2.45-2.41 (m, 1H), 2.33-2.32 (m, 1H), 2.01-1.96 (m, 2H), 1.64-1.62 (m, 2H), 1.47-1.43 (m, 2H), 1.31-1.28 (m, 5H); MS (ESI)
m/z: 890.3 [M+H]
+。
3-(6-氟-4-((2-(4-(4-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5-
a]嘧啶-5-基)苯基)丁基)哌𠯤-1-基)-2-側氧基乙基)胺基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮
A20。
1HNMR (400 MHz, DMSO-
d 6)
δ11.02 (s, 1H), 8.16 (s, 1H), 8.03 (s, 1H), 8.02 (d,
J= 11.2 Hz, 1H), 7.84 (d,
J= 11.2 Hz, 2H), 7.48 (t,
J= 8.0 Hz, 2H), 7.43 (t,
J= 8.0 Hz, 1H), 7.33 (d,
J= 7.6 Hz, 1H), 7.28 (t,
J= 7.6 Hz, 1H), 6.84 (s, 1H), 6.87 (dd,
J= 2.0, 7.6 Hz, 1H), 6.60 (dd,
J= 2.0, 12.4 Hz, 1H), 5.88 (t,
J= 4.0 Hz, 1H),5.10 (dd,
J= 7.2, 13.2 Hz, 1H), 4.47 (brs, 1H), 4.30-4.13 (m, 2H), 4.01 (d,
J= 5.2 Hz, 2H), 3.91-3.80 (m, 4H), 3.58 (t,
J= 6.0 Hz, 2H), 3.50-3.40 (m, 4H), 2.97-2.83 (m, 1H), 2.75-2.64 (m, 6H), 2.64-2.60 (m, 1H), 2.57 (s, 3H), 2.54-2.52 (m, 1H), 2.40-2.25 (m, 9H), 2.06-1.98 (m, 1H), 1.72-1.61 (m, 2 H), 1.55-1.43 (m, 2H); MS (ESI)
m/z: 871.2 [M+H]
+。
3-(4-((4-(((9-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基-吡唑并[1,5-
a]嘧啶-5-基)苯基)壬基)胺基)甲基)苯甲基)氧基)-1-側氧基異吲哚啉-2-基)-哌啶-2,6-二酮
A21 。 1HNMR (400 MHz, DMSO-
d
6 )
δ10.96 (brs, 1H), 8.05-7.97 (m, 2H), 7.87-7.81 (m, 2H), 7.51-7.36 (m, 6H), 7.32-7.25 (m, 6H), 6.83 (s, 1H), 5.34-5.31 (m, 1H), 5.20 (s, 2H), 5.10 (dd,
J= 5.2, 13.2 Hz, 1H), 4.49 (brs, 1H), 4.42-4.22 (m, 2H), 4.04-3.98 (m, 4H), 3.86 (s, 2H), 3.56 (t, J = 6。4 Hz, 2H), 2.96-2.82 (m, 1H), 2.73-2.64 (m, 8H), 2.63-2.58 (m, 1H), 2.57 (s, 3H), 2.46-2.37 (m, 3H), 2.02-1.95 (m, 3H), 1.67-1.57 (m, 2H), 1.51-1.34 (m, 4H),1.34-1.28 (m, 6H); MS (ESI)
m/z: 917.8 [M+H]
+。
3-(6-氟-5-(1-(5-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基-吡唑并[1,5-
a]嘧啶-5-基)苯基)戊基)哌啶-4-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮
A22。
1HNMR (400 MHz, DMSO-
d
6 )
δ10.99 (s, 1H), 8.02-7.99 (m, 2H), 7.85 (d,
J=7.2 Hz, 2H), 7.56-7.25 (m, 7H), 6.83 (s, 1H), 5.10 (dd,
J= 5.2, 13.6 Hz, 1H), 4.49 (s, 1H), 4.40-4.23 (m, 2H), 3.85 (s, 4H), 3.57-3.56 (m, 4H), 2.97-2.94 (m, 3H), 2.68-2.56 (m, 7H), 2.57 (s, 3H), 2.39-2.27 (m, 3H),2.00-1.97(m, 4H), 1.68-1.65 (m, 6H), 1.51-1.46 (m, 2H), 1.36-1.32 (m, 2H); MS (ESI)
m/z: 827.5 [M+H]
+。
2-(2,6-二側氧基哌啶-3-基)-4-((2-(2-(3-(4-(7-(4-(2-羥基乙基)-哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5-
a]嘧啶-5-基)苯基)丙氧基)乙氧基)乙基)胺基)-異吲哚啉-1,3-二酮
A24 。 1HNMR (400 MHz, DMSO-
d
6 )
δ11.09 (s, 1H), 8.08 (d,
J= 8.0 Hz, 2H), 7.83 (d,
J= 7.6 Hz, 2H), 7.55 (t,
J= 7.2 Hz, 1H), 7.48 (t,
J= 8.0 Hz, 2H), 7.35-7.24 (m, 3H), 7.13 (d,
J= 8.4 Hz, 1H), 7.01 (d,
J= 7.2 Hz, 1H), 6.80 (s, 1H), 6.65-6.57 (m, 1H), 5.02 (dd,
J= 5.6, 12.8 Hz, 1H), 4.49 (t,
J= 5.2 Hz, 1H), 3.91-3.81 (m, 4H), 3.66-3.62 (m, 2H), 3.61-3.55 (m, 4H), 3.53-3.50 (m, 2H), 3.48-3.45 (m, 2H), 3.43-3.40 (m, 6H), 2.91-2.78 (m, 2H), 2.71-2.67 (m, 4H), 2.57 (s, 3H), 2.03-1.93 (m, 2H), 1.86-1.75 (m, 2H); MS (ESI)
m/z:
815.4 [M+H]
+。
3-(1-((4-(((5-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基-吡唑并[1,5-
a]嘧啶-5-基)苯基)戊基)胺基)甲基)苯氧基)甲基)-4-側氧基-4
H-噻吩并[3,4-
c]吡咯-5(6
H)-基)哌啶-2,6-二酮
A28 。 1HNMR (400 MHz, DMSO-
d
6 )
δ10.97 (s, 1H), 9.96 (brs, 1H), 8.69 (s, 2H), 8.06-8.04 (m, 2H), 8.02 (s, 1H), 7.85 (d,
J= 7.2 Hz, 2H), 7.51-7.40 (m, 5H), 7.36-7.28 (m, 2H), 7.09 (d,
J= 8.8 Hz, 2H), 6.98 (s, 1H), 5.33 (s, 2H), 5.02 (dd,
J= 5.2, 13.2 Hz, 1H), 4.78-4.75 (m, 2H), 4.37-4.20 (m, 2H), 4.06 (t,
J= 4.8 Hz, 2H), 3.82 (t,
J= 4.8 Hz, 2H), 3.69-3.63 (m, 2H), 3.58-3.51 (m, 4H), 2.93-2.85 (m, 4H), 2.69 (t,
J= 7.6 Hz, 2H), 2.59-2.55 (m, 5H), 2.35-2.31 (m, 1H), 2.01-1.97 (m, 2H), 1.68-1.60 (m, 4H), 1.38-1.34 (m, 2H); MS (ESI)
m/z:
867.4 [M+H]
+。
3-(6-氟-4-(6-(4-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5-
a]嘧啶-5-基)苯乙基)哌𠯤-1-基)己-1-炔-1-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮
A29 。 1HNMR (400 MHz, DMSO-
d
6 )
δ11.03 (s, 1H), 8.25 (s, 1H), 8.11-7.98 (m, 2H), 7.84 (d,
J= 7.2 Hz, 2H), 7.58-7.38 (m, 5H), 7.36-7.23 (m, 2H), 6.83 (s, 1H), 5.15 (dd, J = 4.8, 12.8 Hz, 1H), 4.45-4.28 (m, 2H), 3.86 (s, 4H), 3.58 (t,
J= 6.4 Hz, 2H), 2.96-2.79 (m, 3H), 2.69 (s, 4H), 2.63-2.52 (m, 9H), 2.49-2.27 (m, 12H), 2.06-1.99 (m, 1H), 1.58 (s, 4H); MS (ESI)
m/z:
866.6[M+H]
+。
N-(5-(2,6-二側氧基哌啶-3-基)-4-側氧基-5,6-二氫-4
H-噻吩并[3,4-
c]吡咯-1-基)-2-(4-(9-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5-
a]嘧啶-5-基)苯基)壬基)哌𠯤-1-基)乙醯胺
A32 。 1HNMR (400 MHz, DMSO-
d
6 )
δ10.97 (s, 1H), 8.01-7.98 (m, 2H), 7.84 (d,
J= 7.6 Hz, 2H), 7.48-7.39 (m, 4H), 7.31-7.25 (m, 2H), 6.82 (s, 1H), 5.01 (dd,
J= 4.8, 13.2 Hz, 1H), 4.48 (brs, 1H), 4.30-4.15 (m, 2H), 3.85 (s, 4H), 3.57 (t,
J= 6.0 Hz, 2H), 3.17 (s, 2H), 2.92-2.83 (m, 1H), 2.70-2.67 (m, 6H), 2.60-2.58 (m, 1H), 2.57 (s, 3H), 2.32-2.17 (m, 13H), 2.01-1.99 (m, 1H), 1.62-1.61 (m, 2H), 1.35-1.23 (m, 12H); MS (ESI)
m/z: 929.3 [M+H]
+。
3-(6-氟-4-(1-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基-吡唑并[1,5-
a]嘧啶-5-基)苯乙基)哌啶-4-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮
A36。
1HNMR (400 MHz, DMSO-
d 6)
δ11.02 (s, 1H), 8.07-8.04 (m, 2H), 7.85-7.83 (m, 2H), 7.49-7.35 (m, 6H), 7.25 (t,
J= 7.2 Hz, 1H), 6.84 (s, 1H), 5.14 (dd,
J= 5.2, 13.6 Hz, 1H), 4.54-4.32 (m, 3H), 3.87-3.85 (m, 4H), 3.58-3.57 (m, 2H), 3.11-3.09 (m, 2H), 2.97-2.86 (m, 3H), 2.68-2.60 (m, 8H), 2.57 (s, 3H), 2.49-2.48 (m, 2H), 2.45-2.41 (m, 1H), 2.12-2.07 (m, 2H), 2.02-1.99 (m, 1H), 1.75-1.73 (m, 4H); MS (ESI)
m/z: 785.4 [M+H]
+。
3-(6-氟-4-(1-(5-(4-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5-
a]嘧啶-5-基)哌啶-1-基)戊基)哌啶-4-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮
A37。
1HNMR (400 MHz, DMSO-
d 6)
δ11.07 (s, 1H), 10.10 (s, 1H), 9.01 (s, 1H), 9.62 (s, 1H), 7.78-7.79 (m, 2H), 7.48-7.44 (m, 3H), 7.34-7.27 (m, 2H), 6.52 (s, 1H), 5.19 (dd,
J= 4.8, 13.6 Hz, 1H), 4.63 (s, 1H), 4.58-4.37 (m, 2H), 3.93-3.82 (m, 6H), 3.44-3.33 (m, 10H), 3.11-2.93 (m, 11H), 2.67-2.56 (m, 4H), 2.46-2.28 (m, 1H), 2.19-2.05 (m, 9H), 1.76-1.67 (m, 4H), 1.39-1.36 (m, 2H); MS (ESI)
m/z: 834.5 [M+H]
+。
3-(6-氟-4-(1-(9-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基-吡唑并[1,5-
a]嘧啶-5-基)壬基)哌啶-4-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮
A38 。 1HNMR (400 MHz, DMSO-
d
6 )
δ10.97 (s, 1H), 7.74 (d,
J= 7.2 Hz, 2H), 7.44-7.34 (m, 4H), 7.24 (t,
J= 4.6 Hz, 1H), 6.27 (s, 1H), 5.13 (dd,
J= 5.2, 13.2 Hz, 1H), 4.52-4.31 (m, 3H), 3.72 (s, 4H), 3.56 (t,
J= 6.0 Hz, 2H), 2.95-2.89 (m, 4H), 2.78-2.54 (m, 9H), 2.51-2.49 (m, 3H), 2.26 (t,
J= 7.2 Hz, 2H), 2.02-1.97 (m, 3H), 1.77-1.62 (m, 6H), 1.41-1.27(m, 13H); MS (ESI)
m/z:
807.5 [M+H]
+。
3-(6-氟-4-(1-(9-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基-吡唑并[1,5-
a]嘧啶-5-基)壬基)哌啶-4-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮
A39 。 1HNMR (400 MHz, DMSO-
d 6)
δ8.00-7.85 (m, 3H), 7.85-7.83 (m, 2H), 7.48-7.39 (m, 3H), 7.31-7.20 (m, 4H), 6.95 (d,
J= 7.6 Hz, 1H), 6.91 (d,
J= 8.8 Hz, 1H), 6.82 (s, 1H), 5.34-5.32 (m, 1H), 5.23 (s, 2H), 5.08 (dd,
J= 4.8, 13.2 Hz, 1H), 4.34-4.17 (m, 3H), 3.86-3.84 (m, 4H), 3.60-3.58 (m, 4H), 2.99 (s, 3H), 2.98-2.96 (m, 1H), 2.74-2.65 (m, 7H), 2.58 (s, 3H), 2.49-2.44 (m, 2H), 2.33-2.29 (m, 1H), 2.02-1.97 (m, 3H), 1.63-1.60 (m, 2H), 1.48-1.45 (m, 2H), 1.35-1.29 (m, 2H); MS (ESI)
m/z: 881.6 [M+H]
+。
3-(6-氟-4-((2-(4-(6-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5-
a]嘧啶-5-基)苯基)己基)哌𠯤-1-基)-2-側氧基乙基)胺基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮
A40 。 1HNMR (400 MHz, DMSO-
d
6 )
δ11.00 (s, 1H), 8.02 (s, 1H), 8.01 (d,
J= 9.2 Hz, 1H), 7.84 (d,
J= 7.2 Hz, 1H), 7.48 (t,
J= 8.0 Hz, 2H), 7.43 (t,
J= 7.6 Hz, 1H), 7.32 (d,
J= 7.2 Hz, 1H), 7.28 (t,
J= 7.6 Hz, 1H), 6.83 (s, 1H), 6.68 (dd,
J= 2.0, 7.6 Hz, 1H), 6.60 (dd,
J=1.6, 12.4 Hz, 1H), 5.86 (t,
J= 4.8 Hz, 1H), 5.10 (dd,
J= 4.8, 13.2 Hz, 1H), 4.47 (t,
J= 5.2 Hz, 1H), 4.30-4.13 (m, 2H), 4.02 (d,
J= 5.6 Hz, 2H), 3.91-3.80 (m, 4H), 3.58 (q,
J= 5.6 Hz, 2H), 3.00-3.39 (m, 4H), 2.97-2.84 (m, 1H), 2.74-2.64 (m, 6H), 2.64-2.60 (m, 1H), 2.57 (s, 3H), 2.40-2.20 (m, 8H), 2.06-1.94 (m, 2H), 1.72-1.57 (m, 2H), 1.49-1.38 (m, 2H), 1.38-1.29 (m, 4H); MS (ESI)
m/z:
899.2 [M+H]
+。
2-((2-(2,6-二側氧基哌啶-3-基)-1-側氧基異吲哚啉-4-基)氧基)-
N-(9-(4-(7-(4-(2-羥基乙基)哌啶-1-基)-2-甲基-5-苯基吡唑并[1,5-
a]嘧啶-3-基)苯基)壬基)-乙醯胺
A41 。 1HNMR (400 MHz, DMSO-
d 6)
δ11.00 (s, 1H), 8.19 (dd,
J= 1.6, 8.0 Hz, 2H), 8.06 (t,
J= 5.2 Hz, 1H), 7.75 (d,
J= 8.4 Hz, 2H), 7.54-7.44 (m, 4H), 7.35-7.28 (m, 3H), 7.12 (d,
J= 5.2 Hz, 1H), 6.81 (s, 1H), 5.13 (dd,
J= 5.2, 13.6 Hz, 1H), 4.65-4.57 (m, 4H),4.48-4.32 (m, 3H), 3.51 (q,
J= 6.4 Hz, 2H), 3.13-3.04 (m, 4H), 2.97-2.87 (m, 1H), 2.68-2.57 (m, 3H), 2.55 (s, 3H), 2.47-2.32 (m, 2H), 2.03-1.96 (m, 2H), 1.86-1.80 (m, 2H), 1.79-1.74 (m, 1H), 1.63-1.60 (m, 2H), 1.48-1.24 (m, 14H); MS (ESI)
m/z: 854.2 [M+H]
+。
2-((2-(2,6-二側氧基哌啶-3-基)-1-側氧基異吲哚啉-4-基)氧基)-
N-(7-(4-(7-(4-(2-羥基乙基)哌啶-1-基)-2-甲基-5-苯基吡唑并[1,5-
a]嘧啶-3-基)苯基)庚基)-乙醯胺
A42。
1HNMR (400 MHz, DMSO-
d 6)
δ10.99 (s, 1H), 8.18 (d,
J= 7.2 Hz, 2H), 8.07 (t,
J= 4.8 Hz, 1H), 7.75 (d,
J= 8.0 Hz, 2H), 7.54-7.43 (m, 4H), 7.34-7.28 (m, 3H), 7.12 (d,
J= 8.0 Hz, 1H), 6.82 (s, 1H), 5.12 (dd,
J= 5.2, 13.2 Hz, 1H), 4.62-4.58 (m, 4H), 4.47-4.32 (m, 2H), 3.53-3.48 (m, 2H), 3.14-3.05 (m, 4H), 2.96-2.87 (m, 1H), 2.67-2.57 (m, 3H), 2.55 (s, 3H), 2.43-2.31 (m, 2H), 2.02-1.95 (m, 3H), 1.86-1.83 (m, 2H), 1.81-1.74 (m, 1H), 1.63-1.56 (m, 2H), 1.48-1.24 (m, 10H); MS (ESI)
m/z: 826.2 [M+H]
+。
2-((2-(2,6-二側氧基哌啶-3-基)-1-側氧基異吲哚啉-4-基)氧基)-
N-(11-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5-
a]嘧啶-3-基)苯基)十一基)-乙醯胺
A43 。 1HNMR (400 MHz, DMSO-
d
6 )
δ11.00 (s, 1H), 10.20 (s, 1H), 8.26 (dd,
J= 4.0, 8.0 Hz, 2H), 8.04 (t,
J= 4.8 Hz, 1H), 7.73 (s, 1H), 7.55 (d,
J= 4.4 Hz, 1H), 7.53-7.34 (m, 6H), 7.10 (d,
J= 3.2 Hz, 2H), 7.01 (s, 1H), 5.44 (s, 1H), 5.12 (dd,
J= 5.2, 13.2 Hz, 1H), 4.79 (d,
J= 5.6 Hz, 2H), 4.61 (s, 2H), 4.47-4.31 (m, 2H), 3.99-3.97 (m, 2H), 3.72-3.61 (m, 4H), 3.11-3.05 (m, 2H), 2.97-2.88 (m, 1H), 2.68-2.61 (m, 3H), 2.59 (s, 3H), 2.42-2.39 (m, 2H), 2.03-1.97 (m, 2H), 1.68-1.63 (m, 2H), 1.42-1.20 (m, 18H); MS (ESI)
m/z: 883.3 [M+H]
+。
2-((2-(2,6-二側氧基哌啶-3-基)-1-側氧基異吲哚啉-4-基)氧基)-N-(9-(4-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5-
a]嘧啶-3-基)苯基)壬基)-乙醯胺
A44 。 1HNMR (400 MHz, DMSO-
d 6)
δ11.00 (s, 1H), 10.23 (s, 1H), 8.24 (dd,
J= 1.6, 8.0 Hz, 2H), 8.05 (t,
J= 6.0 Hz, 1H), 7.74 (d,
J= 8.4 Hz, 2H), 7.57-7.52 (m, 3H), 7.46 (t,
J= 7.6 Hz, 1H), 7.34-7.29 (m, 3H), 7.11 (d,
J= 7.6 Hz, 1H), 7.00 (s, 1H), 5.43 (s, 1H), 5.13 (dd,
J= 5.2, 13.6 Hz, 1H), 4.78 (d,
J= 14.0 Hz, 2H), 4.61 (s, 2H), 4.47-4.32 (m, 2H), 3.82 (t,
J= 4.4 Hz, 2H), 3.72-3.57 (m, 4H), 3.13-3.08 (m, 2H), 2.93-2.87 (m, 1H), 2.67-2.57 (m, 6H), 2.43-2.32 (m, 2H), 2.03-1.97 (m, 2H), 1.64-1.60 (m, 2H), 1.45-1.38 (m, 2H), 1.31-1.24 (m, 12H); MS (ESI)
m/z: 855.2 [M+H]
+。
2-((2-(2,6-二側氧基哌啶-3-基)-1-側氧基異吲哚啉-4-基)氧基)-
N-(9-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5-
a]嘧啶-3-基)苯基)壬基)-乙醯胺
A45 。 1HNMR (400 MHz, DMSO-
d
6 )
δ11.00 (s, 1H), 10.44 (s, 1H), 8.27-8.26 (m, 2H), 8.05 (t,
J= 5.2 Hz, 1H), 7.73 (s, 1H), 7.60 (d,
J= 7.6 Hz, 1H), 7.53-7.51 (m, 3H), 7.45 (t,
J= 7.6 Hz, 1H), 7.39 (t,
J= 7.6 Hz, 1H), 7.33 (d,
J= 7.6 Hz, 1H), 7.12-7.09 (m, 2H), 7.02 (s, 1H), 5.12 (dd,
J= 5.2, 13.2 Hz, 1H), 4.77 (d,
J= 13.2 Hz, 2H), 4.61 (s, 2H), 4.47-4.31 (m, 2H), 3.86-3.83 (m, 3H), 3.73-3.60 (m, 8H), 3.12-3.07 (m, 2H), 2.96-2.87 (m, 1H), 2.68-2.64 (m, 2H), 2.59 (s, 4 H), 2.42-2.38 (m, 1H), 2.01-1.98 (m, 1H), 1.68-1.65 (m, 2H), 1.39-1.33 (m, 4H), 1.28-1.22 (m, 8H); MS (ESI)
m/z:
855.6 [M+H]
+。
2-((2-(2,6-二側氧基哌啶-3-基)-1-側氧基異吲哚啉-4-基)氧基)-
N-(11-(4-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5-
a]嘧啶-3-基)苯基)十一基)-乙醯胺
A46 。 1HNMR (400 MHz, DMSO-
d
6 )
δ11.00 (s, 1H), 10.39 (brs, 1H), 8.25 (d,
J= 9.6 Hz, 2H), 8.05 (t,
J= 5.6 Hz, 1H), 7.74 (d, J = 8.0 Hz, 2H), 7.56-7.51 (m, 3H), 7.46 (t,
J= 7.6 Hz, 1H), 7.35-7.29 (m, 3H), 7.11 (d,
J= 8.0 Hz, 1H), 7.00 (s, 1H), 5.13 (dd,
J= 5.2, 13.2 Hz, 1H), 4.77 (d,
J= 12.4 Hz, 2H), 4.61 (s, 2H), 4.48-4.32 (m, 2H), 3.84 (t,
J= 4.8 Hz, 2H), 3.71 (d,
J= 12.4 Hz, 2H), 3.62 (t,
J= 12.0 Hz, 3H), 3.36-3.19 (m, 4H), 3.10 (q,
J= 6.4 Hz, 2H), 2.98-2.88 (m, 1H), 2.68-2.66 (m, 1H), 2.64-2.60 (m, 4H), 2.57 (s, 3H), 2.49-2.37 (m, 2H), 2.33-2.32 (m, 1H), 2.03-1.99 (m, 1H), 1.64-1.60 (m, 2H), 1.42-1.39 (m, 2H), 1.37-1.32 (m, 4H), 1.27-1.23 (m, 6H); MS (ESI)
m/z:
883.7 [M+H]
+。
2-(2,6-二側氧基哌啶-3-基)-5-氟-6-(4-((1-(8-(3-(7-(4-(2-羥基乙基)-哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5-
a]嘧啶-3-基)苯基)-3-甲基辛醯基)-哌啶-4-基)甲基)哌𠯤-1-基)異吲哚啉-1,3-二酮
A47 。 1HNMR (400 MHz, DMSO-
d
6 )
δ11.10 (s, 1H), 8.27-8.14 (m, 2H), 7.73 (s, 1H), 7.70 (d,
J= 11.2 Hz, 1H), 7.59 (d,
J= 7.6 Hz, 1H), 7.55-7.45 (m, 3H), 7.42 (d,
J= 7.2 Hz, 1H), 7.37 (t,
J= 7.6 Hz, 1H), 7.09 (d,
J= 7.6 Hz, 1H), 8.86 (s, 1H), 5.10 (dd,
J= 5.6 Hz, 12.8 Hz, 1H), 4.47 (brs, 1H), 4.34 (d,
J= 12.4 Hz, 1H), 3.90-3.82 (m, 4H), 3.78 (d,
J= 12.4 Hz, 1H). 3.57 (t,
J= 1.2 Hz, 2H), 3.24-3.12 (m, 4H), 3.04-2.82 (m, 2H), 2.74-2.59 (m, 7H), 2.57 (s, 3H), 2.54-2.52 (m, 1H), 2.49-2.36 (m, 7H), 2.30-2.19 (m, 2H), 2.14 (d,
J= 6.8 Hz, 2H), 2.06-1.95 (m, 1H), 1.80-1.59 (m, 5H), 1.49-1.39 (m, 2H), 1.40-1.16 (m, 8H), 1.02-0.78 (m, 2H); MS (ESI)
m/z:
1009.3[M+H]
+。
2-((2-(2,6-二側氧基哌啶-3-基)-1-側氧基異吲哚啉-4-基)氧基)-
N-(9-(2-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5-
a]嘧啶-3-基)苯基)壬基)-乙醯胺
A48。
1H NMR (400 MHz, DMSO-
d
6 )
δ10.99 (s, 1H), 8.14 (s, 0.4 H), 8.07-7.99 (m, 3H), 7.46-7.42 (m, 4H), 7.35-7.19 (m, 5H), 7.10 (d,
J= 8.4 Hz, 1H), 6.79 (s, 1H), 5.12 (dd,
J= 5.1, 13.6 Hz, 1H), 4.60 (s, 2H), 4.48-4.31 (m, 3H), 3.91-3.81 (m, 4H), 3.60-3.54 (m, 2H), 3.09-3.01 (m, 2H), 2.96-2.87 (m, 1H), 2.69 (t,
J= 4.0 Hz, 4H), 2.61-2.56 (m, 3H), 2.45-2.38 (m, 3H), 2.26 (s, 3H), 2.02-1.97 (m, 1H), 1.31-1.26 (m, 4H), 1.02-0.87 (m, 10H); MS (ESI)
m/z: 855.2 [M+H]
+。
2-((2-(2,6-二側氧基哌啶-3-基)-1-側氧基異吲哚啉-4-基)氧基)-
N-(11-(2-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5-
a]嘧啶-3-基)苯基)十一基)-乙醯胺
A49 。 1HNMR (400 MHz, DMSO-
d
6 )
δ10.99 (s, 1H), 8.08-8.02 (m, 3H), 7.50-7.40 (m, 4H), 7.35-7.19 (m, 5H), 7.11 (d,
J= 8.0 Hz, 1H), 6.78 (s, 1H), 5.12 (dd,
J= 4.8, 13.6 Hz, 1H), 4.61 (s, 2H), 4.50-4.31 (m, 3H), 3.94-3.78 (m, 4H), 3.62-3.53 (m, 2H), 3.10-3.05 (m, 2H), 2.97-2.85 (m, 1H), 2.68 (s, 4H), 2.61-2.56 (m, 4H), 2.45-2.39 (m, 2H), 2.28 (s, 3H), 2.02-1.98 (m, 1H), 1.43-1.20 (m, 6H), 1.14-1.10 (m, 4H), 0.93-0.85 (m, 8H); MS (ESI)
m/z: 883.6 [M+H]
+。
2-((2-(2,6-二側氧基哌啶-3-基)-1-側氧基異吲哚啉-4-基)氧基)-
N-(7-(2-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5-
a]嘧啶-3-基)苯基)庚基)-乙醯胺
A50 。 1HNMR (400 MHz, DMSO-
d 6)
δ11.00 (s, 1H), 8.24 (s, 0.4H), 8.10-8.00 (m, 2H), 7.95 (t,
J= 5.2 Hz, 1H), 7.53-7.13 (m, 9H), 7.07 (d,
J= 8.0 Hz, 1H), 6.77 (s, 1H), 5.12 (dd,
J= 4.8, 13.2 Hz, 1H), 4.58 (s, 2H), 4.45-4.30 (m, 2H), 3.94-3.78 (m, 5H), 3.57 (t,
J= 6.0 Hz, 3H), 3.02-2.88 (m, 3H), 2.74-2.64 (m, 4H), 2.61-2.55 (m, 2H), 2.44-2.33 (m, 2H), 2.26 (s, 3H), 2.12-1.84 (m, 2H), 1.49-1.26 (m, 2H), 1.21-1.10 (m, 2H), 1.02-0.76 (m, 6H); MS (ESI)
m/z:
827.2 [M+H]
+。
3-(5-((9-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基-吡唑并[1,5-
a]嘧啶-3-基)苯基)壬基)胺基)-2-甲基-4-側氧基喹唑啉-3(4
H)-基)-哌啶-2,6-二酮
A51 。 1HNMR (400 MHz, DMSO-
d
6 )
δ11.05 (s, 1H), 10.69 (s, 1H), 8.28-8.25 (m, 2H), 7.73 (s, 1H), 7.60 (d,
J= 8.0 Hz, 1H), 7.55-7.48 (m, 4H), 7.38 (t,
J= 7.6 Hz, 1H), 7.11 (d,
J= 7.6 Hz, 1H), 7.02 (s, 1H), 6.73 (d,
J= 7.6 Hz, 1H), 6.56 (d,
J= 8.4 Hz, 1H), 5.27-5.22 (m, 1H), 4.83-4.72 (m, 2H), 3.85 (t,
J= 5.2 Hz, 2H), 3.75-3.66 (m, 4H), 3.65-3.61 (m, 4H), 3.33-3.30 (m, 3H), 3.14 (t,
J= 7.2 Hz, 2H), 2.88-2.79 (m, 1H), 2.71-2.64 (m, 5H), 2.61-2.58 (m, 4H), 2.22-2.12 (m, 1H), 1.72-1.62 (m, 2H), 1.60-1.52 (m, 2H), 1.41-1.26(m, 10H); MS (ESI)
m/z:
824.3 [M+H]
+。
3-(5-((7-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基-吡唑并[1,5-
a]嘧啶-3-基)苯基)庚基)胺基)-2-甲基-4-側氧基喹唑啉-3(4
H)-基)-哌啶-2,6-二酮
A52。
1HNMR (400 MHz, DMSO-
d
6 )
δ10.97 (s, 1H), 8.29 (t,
J= 5.2 Hz, 1H), 8.22 (dd, J = 1.6 Hz, 8.0 Hz, 2H), 7.73 (s, 1H), 7.59 (d,
J= 8.0 Hz, 1H), 7.52-7.43 (m, 4H), 7.36 (t,
J= 7.6 Hz, 1H), 7.09 (d,
J= 7.6 Hz, 1H), 6.85 (s, 1H), 6.62 (d,
J= 7.6 Hz, 1H), 6.45 (d,
J= 8.4 Hz, 1H), 5.18-2.13 (m, 1H), 4.47 (t,
J= 5.2 Hz, 1H), 3.92-3.80 (m, 4H), 3.57 (q,
J= 6.0 Hz, 2H), 3.11 (q,
J= 6.8 Hz, 2H), 2.86-2.71 (m, 1H), 2.73-2.59 (m, 7 H), 2.56 (s, 3H), 2.54 (s, 3H), 2.52-2.51 (m, 2H), 2.49-2.47 (m, 1H), 2.16-2.07 (m, 1H), 1.73-1.63 (m, 2H), 1.62-1.52 (m, 2H), 1.42-1.34(m, 6H); MS (ESI)
m/z:
796.2 [M+H]
+。
3-(5-((11-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基-吡唑并[1,5-
a]嘧啶-3-基)苯基)十一基)胺基)-2-甲基-4-側氧基喹唑啉-3(4
H)-基)哌啶-2,6-二酮
A53。
1HNMR (400 MHz, DMSO-
d
6 )
δ11.00 (s, 1H), 8.29 (t,
J= 5.2 Hz, 1H), 8.23-8.21 (m, 2H), 7.74 (s, 1H), 7.59 (d,
J= 7.6 Hz, 1H), 7.52-7.44 (m, 4H), 7.37 (t,
J= 8.0 Hz, 1H),7.09 (d,
J= 8.0 Hz, 1H), 6.86 (s, 1H), 6.62 (d,
J= 7.6 Hz, 1H), 6.46 (d,
J= 8.4 Hz, 1H), 5.19-5.15 (m, 1H), 4.51 (t,
J= 5.6 Hz, 1H), 3.88-3.84 (m, 6H), 3.57 (q,
J= 6.0 Hz, 4H), 3.10 (q,
J= 6.8 Hz, 2H), 2.85-2.78 (m, 2H), 2.67-2.63 (m, 6H), 2.57 (s, 3H), 2.54 (s, 3H), 1.68-1.65 (m, 2H), 1.56-1.51 (m, 2H), 1.32-1.23 (m, 14 H); MS (ESI)
m/z:
852.6 [M+H]
+。
3-(6-((4-(((7-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基-吡唑并[1,5-
a]嘧啶-5-基)苯基)庚基)胺基)甲基)苯甲基)氧基)-1-側氧基異吲哚啉-2-基)-哌啶-2,6-二酮
A54 。 1HNMR (400 MHz, DMSO-
d 6)
δ8.29 (s, 1H), 8.01-7.98 (m, 2H), 7.84 (d,
J= 7.2 Hz, 2H), 7.48-7.21 (m, 12H), 6.82 (s, 1H), 5.21 (s, 2H), 5.09 (dd,
J= 5.2, 13.2 Hz, 1H), 4.42-4.22 (m, 2H), 3.85-3.83 (m, 5H), 3.79 (s, 2H), 3.59-3.56 (m, 4H), 2.95-2.85 (m, 2H), 2.73-2.65 (m, 6H), 2.52-2.50 (m, 6H), 2.47-2.42 (m, 1H), 2.03-1.89 (m, 2H), 1.69-1.54 (m, 2 H), 1.49-1.40 (m, 2 H), 1.37-1.26 (m, 6H); MS (ESI)
m/z:
889.3 [M+H]
+。
2-(2,6-二側氧基哌啶-3-基)-5-氟-6-(4-((1-(6-(3-(7-(4-(2-羥基乙基)-哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5-
a]嘧啶-3-基)苯基)-3-甲基己醯基)-哌啶-4-基)甲基)哌𠯤-1-基)異吲哚啉-1,3-二酮
A55 。 1HNMR (400 MHz, DMSO-
d 6)
δ11.10 (s, 1H), 8.23-8.21 (m, 2H), 7.73-7.70 (m, 2H), 7.61-7.59 (m, 1H), 7.53-7.47 (m, 2H), 7.43 (d,
J= 7.2 Hz, 1H), 7.37 (t,
J= 7.6 Hz, 1H), 7.10 (d,
J= 8.0 Hz, 1H), 6.86 (s, 1H), 5.10 (dd,
J= 5.2, 12.8 Hz, 1H), 4.47 (s, 1H), 4.33 (d,
J= 7.6 Hz, 2H), 3.86-3.75 (m, 5H), 3.60-3.55 (m, 2H), 3.21 (s, 4H), 2.93-2.85 (m, 2H), 2.68-2.60 (m, 7H), 2.57 (s, 3H), 2.54-2.51 (m, 1H), 2.49-2.41 (m, 6H), 2.13-2.11 (m, 2H), 2.06-1.96 (m, 2H), 1.69-1.65 (m, 2H), 1.69-1.65 (m, 5H), 1.51-1.46 (m, 2H), 1.37-1.36 (m, 4H), 0.96-0.84 (m, 2H); MS (ESI)
m/z: 981.7 [M+H]
+。
2-(2,6-二側氧基哌啶-3-基)-5-氟-6-(4-((1-(10-(3-(7-(4-(2-羥基乙基)-哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5-
a]嘧啶-3-基)苯基)-3-甲基癸醯基)-哌啶-4-基)甲基)哌𠯤-1-基)異吲哚啉-1,3-二酮
A56。
1HNMR (400 MHz, DMSO-
d 6)
δ11.12 (s, 1H), 10.70-10.43 (m, 2H), 8.28 (d,
J= 4.4 Hz, 2H), 7.83 (d,
J= 10.2 Hz, 1H), 7.75 (s, 1H), 7.59 (t,
J= 8.8 Hz 2H), 7.53 (d,
J= 4.0 Hz, 3H), 7.39 (t,
J= 7.2 Hz, 1H), 7.13 (d,
J= 7.2 Hz, 1H), 7.03 (s, 1H), 5.13 (dd,
J= 5.6, 13.2 Hz, 1H), 4.76 (d,
J= 11.2 Hz, 2H), 4.38-4.33 (m, 1H), 3.86-3.84 (m, 3H), 3.77-3.17 (m, 15H), 3.01-2.84 (m, 4H), 2.68-2.55 (m, 7H), 2.26 (t,
J= 7.2 Hz, 2H), 2.16-1.96 (m, 3H), 1.88-1.77 (m, 2H), 1.67-1.62 (m, 2H), 1.47-1.16 (m, 18H); MS (ESI)
m/z: 1037.3 [M+H]
+。
(
S)-2-((2
S,3
R)-3-胺基-2-羥基-4-苯基丁醯胺基)-
N-(13-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5-
a]嘧啶-5-基)苯基)十三基)-4-甲基戊醯胺
B8。
1HNMR (400 MHz, DMSO-
d 6)
δ10.69 (s, 1H), 8.28-8.26 (m, 2H), 8.06 (t,
J= 5.6 Hz, 1H), 8.00-7.91 (m, 4H), 7.73 (s, 1H), 7.60 (d,
J= 8.0 Hz, 1H), 7.55-7.49 (m, 3H), 7.40-7.19 (m, 5H), 7.11 (d,
J= 7.6 Hz, 1H), 7.02 (s, 1H), 6.63 (d,
J= 6.0 Hz, 1H), 5.42 (s, 1H), 4.75 (s, 2H), 4.27-4.22 (m, 1H), 4.00-3.98 (m, 1H), 3.84 (s, 2H), 3.73-3.61 (m, 3H), 3.54 (s, 1H), 3.41-3.38 (m, 4H), 3.07-3.00 (m, 1H), 2.99-2.90 (m, 2H), 2.86 (d,
J= 6.0 Hz, 1H), 2.65 (t,
J= 7.2 Hz, 2H), 2.58 (s, 3H), 2.51-2.49 (m, 2H), 2.02-1.95 (m, 1H), 1.70-1.63 (m, 2H), 1.61-1.41 (m, 4H), 1.38-1.33 (m, 6H), 1.27-1.18 (m, 12H), 0.89-0.81 (m, 6H); MS (ESI)
m/z: 902.3 [M+H]
+。
(
S)-2-((2
S,3
R)-3-胺基-2-羥基-4-苯基丁醯胺基)-
N-(7-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5-
a]嘧啶-3-基)苯基)庚基)-4-甲基戊醯胺
B10 。 1HNMR (400 MHz, DMSO-
d 6)
δ10.23 (s, 1H), 8.26 (d,
J= 5.2 Hz, 2H), 8.06 (t,
J= 4.8 Hz, 1H), 7.99 (d,
J= 4.4 Hz, 1H), 7.89-7.87 (m, 3H), 7.71 (s, 1H), 7.61 (d,
J= 7.2 Hz, 1H), 7.53-7.52 (m, 3H), 7.39 (t,
J= 7.2 Hz, 1H), 7.33 (d,
J= 7.2 Hz, 2H), 7.27-7.24 (m, 3H), 7.11 (d,
J= 7.2 Hz, 1H), 7.02 (s, 1H), 6.58 (d,
J= 5.6 Hz, 1H), 5.44 (s, 1H), 4.78-4.75 (m, 2H), 4.28-4.22 (m, 1H), 3.99-3.97 (m, 1H), 3.85-3.80 (m, 1H), 3.72-3.70 (m, 2H), 3.57-3.41 (m, 4H), 3.08-3.03 (m, 1H), 2.98-2.93 (m, 2H), 2.83-2.78 (m, 1H), 2.67-2.63 (m, 3H), 2.58 (s, 3H), 2.02-1.96 (m, 2H), 1.67-1.63 (m, 2H), 1.50-1.44 (m, 4H), 1.39-1.31 (m, 8H), 0.87-0.83 (m, 6H); MS (ESI)
m/z: 818.3 [M+H]
+。
(
S)-2-((2
S,3
R)-3-胺基-2-羥基-4-苯基丁醯胺基)-
N-(11-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5-
a]嘧啶-3-基)苯基)十一基)-4-甲基戊醯胺
B11 。 1HNMR (400 MHz, DMSO-
d
6 )
δ8.24-8.21 (m, 2H), 8.06 (t,
J= 5.2 Hz, 1H), 7.76-7.70 (m, 2H), 7.59 (d,
J= 8.0 Hz, 1H), 7.53-7.49 (m, 3H), 7.37 (t,
J= 7.6 Hz, 1H), 7.30-7.27 (m, 2H), 7.23-7.17 (m, 3H), 7.09 (d,
J= 7.6 Hz, 1H), 6.86 (s, 1H), 4.49 (s, 1H), 4.30-4.24 (m, 1H), 3.90-3.87 (m, 4H), 3.80-3.79 (m, 1H), 3.63-3.54 (m, 4H), 3.22-3.18 (m, 2H), 3.05-2.94 (m, 3H), 2.82-2.77 (m, 1H), 2.70-2.63 (m, 8H), 2.57-2.55 (m, 2H), 2.03-1.96 (m, 1H), 1.68-1.60 (m, 2H), 1.49-1.46 (m, 2H), 1.44-1.40 (m, 2H), 1.35-1.11 (m, 15H), 0.87-0.83 (m, 6H); MS (ESI)
m/z:
873.3 [M+H]
+。
(2
S,4
S)-1-((
S)-2-環己基-2-((
S)-2-(甲基胺基)丙醯胺基)乙醯基)-4-(9-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5-
a]嘧啶-3-基)苯基)-壬醯胺基)-
N-((
R)-1,2,3,4-四氫萘-1-基)吡咯啶-2-甲醯胺
B12 。 1HNMR (400 MHz, DMSO-
d
6 )
δ10.49 (s, 1H), 9.03 (brs, 1H), 8.81 (brs, 1H), 8.76 (d,
J= 8.8 Hz, 1H), 8.41 (d,
J= 8.8 Hz, 1H), 8.30-8.25 (m, 2H), 8.13 (d,
J= 7.6 Hz, 1H), 7.72 (s, 1H), 7.60 (d,
J= 8.0 Hz, 1H), 7.55-7.50 (m, 3H), 7.38 (t,
J= 8.0 Hz, 1H), 7.28 (d,
J= 7.6 Hz, 1H), 7.18-7.05 (m, 4H), 7.03 (s, 1H), 5.42 (brs, 1H), 4.97-4.89 (m, 1H), 4.77 (d,
J= 13.2 Hz, 2H), 4.38 (t,
J= 8.0 Hz, 1H), 4.30-4.22 (m, 2H), 4.12-4.04 (m, 1H), 3.87-3.80 (m, 3H), 3.83 (t,
J= 12.4 Hz, 2H), 3.45-3.40 (m, 2H), 3.31-3.27 (m, 3H), 2.78-2.62 (m, 5H), 2.59 (s, 3H), 2.48-2.44 (m, 2H), 2.40-2.32 (m, 1H), 2.04 (t,
J= 7.2 Hz, 2H), 1.94-1.56 (m, 14H), 1.53-1.43 (m, 14H), 1.40-0.92 (m, 5H); MS (ESI)
m/z:
1035.9 [M+H]
+。
(2
S,4
S)-1-((
S)-2-環己基-2-((
S)-2-(甲基胺基)丙醯胺基)乙醯基)-4-(11-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5-
a]嘧啶-3-基)-苯基)十一醯胺基)-
N-((
R)-1,2,3,4-四氫萘-1-基)吡咯啶-2-甲醯胺
B13 。 1HNMR (400 MHz, DMSO-
d 6)
δ8.44 (d,
J= 8.8 Hz, 1H), 8.24-8.21 (m, 2H), 8.14 (d,
J= 7.2 Hz, 1H), 7.69 (d,
J= 10.0 Hz, 1H), 7.73 (s, 1H), 7.60 (d,
J= 7.6 Hz, 1H), 7.52 (m, 3H), 7.37 (t,
J= 7.6 Hz, 1H), 7.32 (d,
J= 7.2 Hz, 1H), 7.16-7.05 (m,
4H), 6.86 (s, 1H), 4.93-4.92 (m, 1H), 4.37 (t,
J= 8.0 Hz, 1H), 4.31-4.24 (m, 2H), 4.07-4.03 (m, 1H), 3.86 (s, 4H), 3.58 (t,
J= 6.4 Hz, 2H), 3.32-3.30 (m, 4H), 3.01-2.96 (m, 1H), 2.69-2.57 (m, 9H), 2.57 (s, 3H), 2.38-2.33 (m, 1H), 2.17 (s, 3H), 2.05-1.99 (m, 2H), 1.86-1.82 (m, 3H),1.74-1.58 (m, 12H), 1.47 (t,
J= 6.4 Hz, 2H),1.33-1.02 (m, 19H); MS (ESI)
m/z: 1063.7 [M+H]
+。
(2
S,4
S)-1-((
S)-2-環己基-2-((
S)-2-(甲基胺基)丙醯胺基)乙醯基)-4-(13-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5-
a]嘧啶-3-基)-苯基)十三醯胺基)-
N-((
R)-1,2,3,4-四氫萘-1-基)吡咯啶-2-甲醯胺
B14 。 1HNMR (400 MHz, DMSO-
d
6 )
δ8.43 (d,
J= 8.8 Hz, 1H), 8.23-8.12 (m, 4H), 7.73 (s, 1H), 7.59 (d,
J= 7.2 Hz, 1H), 7.51-7.50 (m, 3H), 7.38-7.29 (m, 2H), 7.14-7.01 (m, 4H), 6.87 (s, 1H), 4.93 (s, 1H), 4.37 (t,
J= 13.2 Hz, 1H), 4.29-4.27 (m, 4H), 4.08-4.06 (m, 1H), 3.87 (s, 4H), 3.58 (t,
J= 11.2 Hz, 2H), 3.38-3.28 (m, 5H), 2.69-2.57 (m, 4H), 2.63-2.61 (m, 2H), 2.57 (s, 3H), 2.36-2.27 (m, 4H), 2.03-2.01 (m, 2H), 1.85-1.83 (m, 2H), 1.66-1.60 (m, 10H), 1.48-1.45 (m, 2H), 1.37-1.27 (m, 2H), 1.21-1.12 (m, 20H); MS (ESI)
m/z:
1093.5[M+H]
+。
(
S)-2-((2
S,3
R)-3-胺基-2-羥基-4-苯基丁醯胺基)-
N-(9-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5-
a]嘧啶-3-基)苯基)壬基)-4-甲基戊醯胺
B15 。 1HNMR (400 MHz, DMSO-
d 6)
δ10.54 (s, 1H), 8.28-8.25 (m, 2H), 8.05 (t,
J= 5.6 Hz, 1H), 7.99-7.94 (m, 4H), 7.72 (s, 1H), 7.60 (d,
J= 7.6 Hz, 1H), 7.53-7.51 (m, 3H), 7.40-7.24 (m, 5H), 7.11 (d,
J= 7.6 Hz, 1H), 7.02 (s, 1H), 6.61 (d,
J= 5.2 Hz, 1H), 5.42 (s, 1H), 4.27-4.23 (m, 2H), 3.99-3.97 (m, 1H), 3.84 (s, 2H), 3.72-3.60 (m, 3H), 3.54 (s, 1H), 3.41-3.38 (m, 4H), 3.06-3.00 (m, 1H), 2.97-2.90 (m, 2H), 2.85 (d,
J= 6.0 Hz, 1H), 2.65 (t,
J= 8.0 Hz, 2H), 2.58 (s, 3H), 2.51-2.49 (m, 2H), 2.02-1.97 (m, 1H), 1.69-1.62 (m, 2H), 1.58-1.43 (m, 4H), 1.48-1.21 (m, 10H), 1.27-1.21 (m, 4H), 0.88-0.84 (m, 6H); MS (ESI)
m/z: 845.3 [M+H]
+。
(
S)-
N-((
S)-1-環己基-2-((
S)-2-(4-(3-((11-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5-
a]嘧啶-5-基)苯基)十一碳-10-炔-1-基)氧基)苯甲醯基)-噻唑-2-基)吡咯啶-1-基)-2-側氧基乙基)-2-(甲基胺基)丙醯胺
B16 。 1HNMR (400 MHz, DMSO-
d
6 )
δ10.48 (s, 1H), 9.15 (s, 1H), 8.92 (d,
J= 8.0 Hz, 1H), 8.81(s, 1H), 8.58 (s, 1H), 8.43 (s, 1H), 8.26-- -8.24 (m, 2H), 7.93 (s, 1H), 7.79 (d,
J= 8.0 Hz, 1H), 7.67-7.56 (m, 2H), 7.53-7.52 (m, 3H), 7.49-7.42 (m, 2H), 7.28 (d,
J= 7.6 Hz, 1H), 7.21-7.19 (m, 1H), 7.03 (s, 1H), 5.43-5.36 (m, 2H), 4.78-4.72 (m, 2H), 4.28 (t,
J= 8.8 Hz, 1H), 4.00-3.97 (m, 3H), 3.83 (s, 3H), 3.73-3.61 (m, 5H), 3.57-3.50 (m, 2H), 2.58 (s, 3H), 2.46-2.43 (m, 2H), 2.39 (s, 3H), 2.36-2.17 (m, 3H), 2.08-1.97 (m, 3H), 1.75-1.66 (m, 6H), 1.59-1.56 (m, 4H), 1.49-1.41 (m, 4H),1.37-1.16 (m, 10H); MS (ESI)
m/z: 1062.3 [M+H]
+。
(
S)-
N-((
S)-1-環己基-2-((
S)-2-(4-(3-((13-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5-
a]嘧啶-5-基)苯基)十三碳-12-炔-1-基)氧基)-苯甲醯基)噻唑-2-基)吡咯啶-1-基)-2-側氧基乙基)-2-(甲基胺基)丙醯胺
B17 。 1HNMR (400 MHz, DMSO-
d
6 )
δ10.76 (s, 1H), 9.34 (s, 1H), 8.98-8.89 (m, 1H), 8.82 (s, 1H), 8.43 (s, 1H), 8.31-8.22 (m, 2H), 7.94 (s, 1H), 7.79 (d,
J= 8.0 Hz, 1H), 7.67-7.50 (m, 5H), 7.48-7.43 (m, 2H),7.29 (d,
J= 7.6 Hz, 1H), 7.22-7.17 (m, 1H), 5.50-5.28 (m, 2H), 4.76 (s, 1H), 4.43 (t,
J= 8.4 Hz, 1H), 3.99 (t,
J= 6.0 Hz, 3H), 3.89-3.79 (m, 4H), 3.75-3.64 (m, 5H), 3.58-3.53 (m, 2H), 3.25-3.20 (m, 2H), 2.59 (s, 3H), 2.48-2.43 (m, 5H), 2.41-2.36 (m, 2H), 2.08-1.94 (m, 3H), 1.81-1.67 (m, 5H), 1.63-1.51 (m, 5H), 1.48-1.36 (m, 9H), 1.34-1.24 (m, 12H); MS (ESI)
m/z:
1088.3 [M+H]
+。
(
S)-
N-((
S)-1-環己基-2-((
S)-2-(4-(3-((13-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5-
a]嘧啶-3-基)苯基)十三基)氧基)苯甲醯基)噻唑-2-基)吡咯啶-1-基)-2-側氧基乙基)-2-(甲基胺基)丙醯胺
B18 。 1HNMR (400 MHz, DMSO-
d
6 )
δ8.43 (s, 1H), 8.23-8.20 (m, 2H),7.99 (d,
J= 9.2 Hz, 1H), 7.74 (s, 1H), 7.64-7.57 (m, 3H), 7.52-7.48 (m, 3H), 7.44 (t,
J= 8.0 Hz, 1H), 7.36 (t,
J= 7.6 Hz, 1H),7.21-7.19 (m, 1H), 7.12-7.05 (m, 1H), 6.85 (s, 1H), 5.38-5.31 (m, 2H), 4.56-4.41 (m, 2H), 4.03-3.98 (m, 3H), 3.88-3.83 (m, 4H), 3.69-3.62 (m, 2H), 3.59-3.54 (m, 5H), 3.02-2.96 (m, 2H), 2.72-2.63 (m, 9H), 2.56 (s, 3H), 2.28-2.21 (m, 2H), 2.12 (s, 3H), 2.04-1.98 (m, 4H), 1.74-1.65 (m, 8H), 1.43-1.36 (m, 4H), 1.29-1.23 (m, 16H); MS (ESI)
m/z:
1092.4 [M+H]
+。
(
S)-
N-((
S)-1-環己基-2-((
S)-2-(4-(3-((11-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5-
a]嘧啶-3-基)苯基)十一基)氧基)苯甲醯基)噻唑-2-基)吡咯啶-1-基)-2-側氧基乙基)-2-(甲基胺基)丙醯胺
B19 。 1HNMR (400 MHz, DMSO-
d
6 )
δ8.43 (s, 1H), 8.35 (s, 1H), 8.23-8.20 (m, 2H), 7.98 (d,
J= 8.8 Hz, 1H), 7.74 (s, 1H), 7.63-7.57 (m, 3H), 7.50-7.48 (m, 3H), 7.43 (t,
J= 8.0 Hz, 1H), 7.36 (t,
J= 7.6 Hz, 1H), 7.21-7.18 (m, 1H), 7.09 (d,
J= 7.6 Hz, 1H), 6.85 (s, 1H), 5.36-5.33 (m, 1H), 4.45-4.41 (m, 2H), 4.00 (t,
J= 6.0 Hz, 2H), 3.86-3.80 (m, 5H), 3.58-3.54 (m, 2H), 3.02-2.97 (m, 2H), 2.67-2.63 (m, 6H), 2.56 (s, 3H), 2.33-2.32 (m, 2H), 2.15-2.12 (m, 5H), 2.02-1.98 (m, 2H), 1.74-1.64 (m, 8H), 1.37-1.30 (m, 8H), 1.24-1.22 (m, 16H); MS (ESI)
m/z: 1065.4 [M+H]
+。
(
S)-
N-((
S)-1-環己基-2-((
S)-2-(4-(3-((9-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5-
a]嘧啶-3-基)苯基)壬基)氧基)苯甲醯基)噻唑-2-基)-吡咯啶-1-基)-2-側氧基乙基)-2-(甲基胺基)丙醯胺
B20 。 1HNMR (400 MHz, DMSO-
d
6 )
δ11.02 (s, 1H), 9.56 (s, 1H), 8.95 (d,
J= 8.4 Hz, 1H), 8.85 (s, 1H), 8.43 (s, 1H), 8.27 (dd,
J= 2.0, 7.2 Hz, 2H), 7.73 (s, 1H), 7.68-7.56 (m, 3H), 7.55-7.48 (m, 3H), 7.45 (t,
J= 8,0 Hz, 1H), 7.38 (t,
J= 7.6 Hz, 1H), 7.25-7.18 (m, 1H), 7.11 (d,
J= 7.6 Hz, 1H), 7.02 (s, 1H), 5.52-5.27 (m, 2H), 4.76 (d,
J= 12.8 Hz, 2H), 4.41 (t,
J= 8.8 Hz, 1H), 4.01-3.98 (m, 3H), 3.86-3.66 (m, 8H), 2.66 (t, J = 6.8 Hz, 2H), 2.58 (s, 3H), 2.37-2.19 (m, 3H), 2.10-1.99 (m, 3H), 1.77-1.56 (m, 9H), 1.40-1.18 (m, 24H); MS (ESI)
m/z:
1036.4 [M+H]
+。
(
S)-
N-((
S)-1-環己基-2-((
S)-2-(4-(3-((7-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5-
a]嘧啶-3-基)苯基)庚基)氧基)苯甲醯基)噻唑-2-基)-吡咯啶-1-基)-2-側氧基乙基)-2-(甲基胺基)丙醯胺
B21 。 1HNMR (400 MHz, DMSO-
d 6)
δ10.28 (s, 1H), 9.02 (s, 1H), 8.91 (d,
J= 8.0 Hz, 1H), 8.79 (s, 1H), 8.42 (s, 1H), 8.25 (d,
J= 6.8 Hz, 2H), 7.73 (s, 1H), 7.65-7.57 (m, 3H), 7.55-7.48 (m, 3H), 7.46-7.40 (m, 2H),7.38 (t,
J= 7.6 Hz, 1H), 7.20 (dd,
J= 2.4, 8.4 Hz, 2H), 7.11 (d,
J= 7.6 Hz, 1H), 7.01 (s, 1H), 5.46 (s, 1H), 5.37 (dd,
J= 1.6, 7.6 Hz, 1H), 5.32 (t,
J= 4.4 Hz, 2H), 4.77 (d,
J= 13.6 Hz, 2H), 4.42 (t,
J= 8.8 Hz, 1H), 4.05-3.93 (m, 4H), 3.86-3.76 (m, 4H), 3.72-3.68 (m, 2H), 3.61-3.58 (m, 1H), 2.71-2.63 (m, 4H), 2.58 (s, 3H), 2.40 (s, 3H), 2.32-2.21 (m, 3H), 2.02-1.99 (m, 4H), 1.76-1.64 (m, 8H), 1.50-1.39 (m, 10H), 1.38-1.36 (m, 3H); MS (ESI)
m/z:
1008.7 [M+H]
+。
2-(4-((4
S,5
R)-4,5-雙(4-氯苯基)-2-(2-異丙氧基-4-甲氧基苯基)-4,5-二氫-1
H-咪唑-1-羰基)哌𠯤-1-基)-
N-(9-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5-
a]嘧啶-3-基)苯基)壬基)乙醯胺
C1 。 1HNMR (400 MHz, DMSO-
d
6 )
δ8.23-8.21 (m, 2H), 7.72 (s, 1H), 7.63-7.59 (m, 2H), 7.52-7.49 (m, 3H), 7.43 (d,
J= 7.6 Hz, 1H), 7.37 (t,
J= 7.6 Hz, 1H), 7.15-7.09 (m, 5H), 7.02 (d,
J= 8.4 Hz, 2H), 6.94 (d,
J= 8.4 Hz, 2H), 6.86 (s, 1H), 6.63-6.58 (m, 2H), 5.62 (d,
J= 10.0 Hz, 1H), 5.50 (d,
J= 9.6 Hz, 1H), 4.71-4.65 (m, 1H), 4.47 (t,
J= 5.2 Hz, 1H), 3.86 (s, 4H), 3.82 (s, 3H), 3.58 (q,
J= 5.6 Hz, 2H), 3.06 (s, 2H), 3.02-2.97 (m, 2H), 2.70-2.63 (m, 8H), 2.56 (s, 3H), 2.43-2.32 (m, 4H), 2.01-1.91 (m, 6H), 1.68-1.65 (m, 2H), 1.37-1.22 (m, 16H); MS (ESI)
m/z:
1161.4 [M+H]
+。
2-(4-((4
S,5
R)-4,5-雙(4-氯苯基)-2-(2-異丙氧基-4-甲氧基苯基)-4,5-二氫-1
H-咪唑-1-羰基)哌𠯤-1-基)-
N-(11-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5-
a]嘧啶-3-基)苯基)十一基)乙醯胺
C2。
1HNMR (400 MHz, DMSO-
d
6 )
δ10.93 (s, 1H), 8.57 (s, 1H), 8.29-8.27 (m, 2H), 7.73-7.70 (m, 2H), 7.61 (d,
J= 7.6 Hz, 1H), 7.53-7.52 (m, 3H), 7.39 (t,
J= 7.6 Hz, 1H), 7.26 (d,
J= 8.0 Hz, 2H), 7.21 (d,
J= 8.0 Hz, 2H), 7.15-7.10 (m, 3H), 7.06-7.03 (m, 2H), 6.82-6.79 (m, 2H), 6.14 (brs, 1H), , 6.04 (brs, 1H), 4.92-4.86 (m, 1H), 4.77 (d,
J= 12.8 Hz, 2H), 3.92 (s, 3H), 3.88-3.84 (m, 3H), 3.74-3.65 (m, 8H), 3.37-3.23 (m, 8H), 3.06 (q,
J= 6.0 Hz , 3H), 2.66 (t,
J= 7.2 Hz, 3H), 2.59 (s, 3H), 1.69-1.65 (m, 2H), 1.35-1.22 (m, 22H); MS (ESI)
m/z1189.6 [M+H]
+。
2-(4-((4
S,5
R)-4,5-雙(4-氯苯基)-2-(2-異丙氧基-4-甲氧基苯基)-4,5-二氫-1
H-咪唑-1-羰基)哌𠯤-1-基)-
N-(13-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5-
a]嘧啶-3-基)苯基)十三基)乙醯胺
C3。
1HNMR (400 MHz, DMSO-
d
6 )
δ8.23 (d,
J= 8.0 Hz, 2H), 7.73 (s, 1H), 7.64-7.58 (m, 2H), 7.51-7.48 (m, 3H), 7.43 (d,
J= 8.4 Hz, 1H), 7.36 (t,
J= 7.6 Hz, 1H), 7.15 (s, 1H), 7.13 (s, 1H), 7.11-7.08 (m, 3H), 7.02 (d,
J= 8.4 Hz, 2H), 6.94 (d,
J= 8.0 Hz, 2H), 6.86 (s, 1H), 6.63-6.59 (m, 2H), 5.62 (d,
J= 10.0 Hz, 1H), 5.49 (d,
J= 10.0 Hz, 1H), 4.73-4.66 (m, 1H), 4.47 (t,
J= 5.2 Hz, 1H), 3.86 (s, 4H), 3.82 (s, 3H), 3.58 (q,
J= 6.0 Hz, 2H), 3.06 (s, 4H), 3.05-3.00 (m, 2H), 2.71-2.63 (m, 8H), 2.57 (s, 3H), 2.01-1.96 (m, 4H), 1.71-1.66 (m, 2H), 1.35-1.31 (m, 4H), 1.28-1.22(m, 24H); MS (ESI)
m/z: 1217.4 [M+H]
+。
2-(4-((4
S,5
R)-4,5-雙(4-氯苯基)-2-(2-異丙氧基-4-甲氧基苯基)-4,5-二氫-1
H-咪唑-1-羰基)哌𠯤-1-基)-
N-(9-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5-
a]嘧啶-5-基)苯基)壬基)乙醯胺
C5 。 1HNMR (400 MHz, DMSO-
d
6 )
δ10.88 (brs, 1H), 8.56 (brs, 1H), 8.07-8.05 (m, 2H), 7.85 (d,
J= 7.2 Hz, 2H), 7.71-7.69 (m, 1H), 7.49 (t,
J= 7.6 Hz, 2H), 7.44 (
J= 7.6 Hz, 1H), 7.33 (d,
J= 8.8 Hz, 2H), 7.29-7.26 (m, 3H), 7.23-7.21 (m, 2H), 7.15-7.13 (m, 2H), 7.06-7.04 (m, 2H), 7.00 (s, 1H), 6.83-6.80 (m, 2H), 6.17-6.06 (m, 2H), 4.95-4.85 (m, 1H), 4.75 (d,
J= 14.0 Hz, 2H), 3.92 (s, 3H), 3.87-3.85 (m, 4H), 3..74-3.62 (m, 8H), 3.44-3.39 (m, 4H), 3.31 (s, 2H), 3.08-3.05 (m, 2H), 2.70-2.67 (m, 3H), 2.59 (s, 3H), 1.65-1.61 (m, 2H), 1.441-1.39 (m, 2H), 1.36-1.32 (m, 6H), 1.28-1.25 (m, 12H); MS (ESI)
m/z: 1161.6 [M+H]
+。
2-(4-((4
S,5
R)-4,5-雙(4-氯苯基)-2-(2-異丙氧基-4-甲氧基苯基)-4,5-二氫-1
H-咪唑-1-羰基)哌𠯤-1-基)-
N-(11-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5-
a]嘧啶-5-基)苯基)十一基)乙醯胺
C6。
1HNMR (400 MHz, DMSO-
d
6 )
δ8.01 (s, 1H), 8.00 (d,
J= 8.4 Hz, 1H), 7.85 (d,
J= 7.2 Hz, 2H), 7.62 (t,
J= 6.4 Hz, 1H), 7.49-7.40 (m, 4H), 7.31-7.25 (m, 2H), 7.15-7.09 (m, 4H), 7.02 (d,
J= 8.4 Hz, 2H), 6.94 (d,
J= 8.4 Hz, 2H), 6.83 (s, 1H), 6.63-6.59 (m, 2H), 5.63 (d,
J= 10.0 Hz, 1H), 5.50 (d,
J= 9.6 Hz, 1H), 4.72-4.66 (m, 1H), 4.48 (t,
J= 5.6 Hz, 1H), 3.86 (s, 3H), 3.82 (s, 3H), 3.60-3.56 (m, 2H), 3.22-2.96 (m, 13H), 2.75-2.64 (m, 8H), 2.57 (s, 3H), 2.01-1.91 (m, 4H), 1.66-1.59 (m, 2H), 1.36-1.15 (m, 18H); MS (ESI)
m/z:
1189.4[M+H]
+。
2-(4-((4
S,5
R)-4,5-雙(4-氯苯基)-2-(2-異丙氧基-4-甲氧基苯基)-4,5-二氫-1
H-咪唑-1-羰基)哌𠯤-1-基)-
N-(13-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5-
a]嘧啶-5-基)苯基)十三基)乙醯胺
C7。
1HNMR (400 MHz, DMSO-
d 6)
δ11.02 (s, 1H), 8.58 (s, 1H), 8.06 (s, 1H), 8.05 (d,
J= 8.0 Hz, 1H), 7.85 (d,
J= 7.2 Hz, 2H), 7.71 (d,
J= 8.0 Hz, 1H), 7.50-7.41 (m, 3H), 7.33-7.25 (m, 4H), 7.14 (d, J = 8.4 Hz, 2H), 7.21 (d,
J= 8.0 Hz, 4H), 7.05 (d,
J= 8.4 Hz, 2H), 7.00 (s, 1H), 6.85-6.80 (m, 2H), 6.16 (brs, 1H), 6.07 (brs, 1H), 4.92-4.86 (m, 1H), 4.75 (d,
J= 12.4 Hz, 2H), 3.92 (s, 3H), 3.87 (t,
J= 4.8 Hz, 3H), 3.79-3.63 (m, 6H), 3.40-3.35 (s, 6H), 3.13-3.04 (m, 4H), 2.68 (t,
J= 7.6 Hz, 3H), 2.59 (s, 3H), 1.63 (t,
J= 6.4 Hz, 2H), 1.38-1.21 (m, 28H); MS (ESI)
m/z: 1217.7 [M+H]
+。
2-(4-((4
R,5
S)-4,5-雙(4-氯苯基)-2-(2-異丙氧基-4-甲氧基苯基)-4,5-二氫-1
H-咪唑-1-羰基)-2-側氧基哌𠯤-1-基)-
N-(8-(3-(7-(4-(2-羥基乙基)-哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5-
a]嘧啶-3-基)苯基)辛基)乙醯胺
C8。
1HNMR (400 MHz, DMSO-
d
6 )
δ8.23-8.21 (m, 2H), 7.79 (t,
J= 5.2 Hz, 1H), 7.74-7.70 (s, 1H), 7.60 (d,
J= 8.0 Hz, 1H), 7.54-7.47 (m, 4H), 7.44-7.40 (m, 4H), 7.39-7.35 (m, 3H), 7.22 (d,
J= 8.0 Hz, 2H), 7.10 (d,
J= 7.2 Hz, 1H), 6.86 (s, 1H), 6.61-6.56 (m, 2H), 4.97 (d,
J= 7.6 Hz, 1H), 4.84 (d,
J= 8.0 Hz, 1H), 4.70-4.62 (m, 1H), 4.48 (brs, 1H), 3.90-3.83 (m, 4H), 3.81(s, 3H), 3.76 (s, 1H), 3.69-3.65 (m, 2H), 3.61-3.54 (m, 4H), 3.00-2.96 (m, 2H), 2.71-2.61 (m, 7H), 2.57 (s, 3H), 2.03-1.96 (m, 2H), 1.71-1.63 (m, 2H), 1.35-1.31 (m, 4H), 1.25-1.21 (m, 14H); MS (ESI)
m/z: 1161.8 [M+H]
+。
3-(4-((4
S,5
R)-2-(4-(三級丁基)-2-乙氧基苯基)-4,5-雙(4-氯苯基)-4,5-二甲基-4,5-二氫-1
H-咪唑-1-羰基)哌𠯤-1-基)-
N-(5-(3-(7-(4-(2-羥基乙基)-哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5-
a]嘧啶-3-基)苯基)戊基)丙醯胺
C9 。 1HNMR (400 MHz, DMSO-
d 6)
δ11.60 (s, 1H), 11.00 (s, 1H), 8.29-8.27 (m, 2H), 8.18 (t,
J= 5.2 Hz, 1H), 7.63-7.56 (m, 2H), 7.63 (d,
J= 8.0 Hz, 1H), 7.56-7.52 (m, 3H), 7.42 (t,
J= 7.6 Hz, 1H), 7.24-7.03 (m, 11H), 4.78 (d,
J= 13.2 Hz, 2H), 4.32 (t,
J= 6.0 Hz, 1H), 4.11-4.05 (m, 1H), 3.86 (t,
J= 4.8 Hz, 2H), 3.74-3.66 (m, 8H), 3.31-3.17 (m, 10H), 3.11-3.00 (m, 2H), 2.91-2.87 (m, 2H), 2.68-2.51 (m, 7H), 2.04-1.97 (m, 3H), 1.92-1.87 (m, 3H), 1.69-1.66 (m, 2H), 1.52-1.44 (m, 2H), 1.37 (s, 9H), 1.31-1.23 (m, 5H); MS (ESI)
m/z: 1160.3 [M+H]
+。
3-(4-((4
S,5
R)-2-(4-(三級丁基)-2-乙氧基苯基)-4,5-雙(4-氯苯基)-4,5-二甲基-4,5-二氫-1
H-咪唑-1-羰基)哌𠯤-1-基)-
N-(11-(3-(7-(4-(2-羥基-乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5-
a]嘧啶-3-基)苯基)十一基)-丙醯胺
C10 。 1HNMR (400 MHz, DMSO-
d
6 )
δ10.38 (s, 1 H), 8.27 (d,
J= 4.0 Hz, 2H), 7.06 (s, 1H), 7.75-7.52 (m, 7H), 7.39 (t,
J= 8.0 Hz, 1H), 7.18-7.03 (m, 11H), 4.77 (d,
J= 12.4 Hz, 2H), 4.29-4.26 (m, 1H), 4.06-4.01 (m, 1H), 3.85-3.81 (m, 2H), 3.73-3.59 (m, 6H), 3.57-3.20 (m, 6H), 3.05-2.97 (m, 2H), 2.90-2.83 (m, 2H), 2.67-2.59 (m, 6H), 2.40-2.38 (m, 2H), 2.01-1.89 (m, 4H), 1.73-1.60 (m, 4H), 1.36-1.22 (m, 32H); MS (ESI)
m/z:
1243.4 [M+H]
+。
4-((4
S,5
R)-2-(4-(三級丁基)-2-((11-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5-
a]嘧啶-3-基)苯基)十一碳-10-炔-1-基)氧基)苯基)-4,5-雙(4-氯苯基)-4,5-二甲基-4,5-二氫-1
H-咪唑-1-羰基)哌𠯤-2-酮
C11 。 1HNMR (400 MHz, DMSO-
d
6 )
δ8.39 (s, 1H), 8.23-8.21 (m, 2H), 7.93 (s, 1H), 7.81-7.74 (m, 2H), 7.60-7.57 (m, 1H), 7.53-7.42 (m, 4H), 7.28-7.26 (m, 1H), 7.09-7.88 (m, 11H), 4.09 (s, 1H), 3.86 (s, 4H), 3.59-3.54 (m, 4H), 3.16-3.08 (m, 1H), 3.03-2.93 (m, 1H), 2.72-2.67 (m, 4H), 2.58-2.57 (m, 4H), 2.46-2.38 (m, 4H), 1.88 (s, 3H), 1.68-1.64 (m, 2H), 1.57-1.53 (m, 5H), 1.42-1.38 (m, 2H), 1.34-1.25 (m, 20H); MS (ESI)
m/z:
1154.8 [M+H]
+。
3-(4-((4
S,5
R)-2-(4-(三級丁基)-2-乙氧基苯基)-4,5-雙(4-氯苯基)-4,5-二甲基-4,5-二氫-1
H-咪唑-1-羰基)哌𠯤-1-基)-
N-(7-(3-(7-(4-(2-羥基乙基)-哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5-
a]嘧啶-3-基)苯基)庚基)丙醯胺
C12 。 1HNMR (400 MHz, DMSO-
d 6)
δ11.22 (s, 1H), 10.52 (s, 1H), 8.28-8.26 (m, 2H), 8.06 (s, 1H), 7.71-7.60 (m, 1H), 7.54-7.51 (m, 3H), 7.38 (t,
J= 7.6 Hz, 1H), 7.20-7.02 (m, 11H), 4.76 (d,
J= 12.8 Hz, 2H), 4.03 (s, 1H), 4.11-4.00 (m, 1H), 3.84 (t,
J= 5.6 Hz, 2H), 3.72-3.60 (m, 6H), 3.31 (s, 4H), 3.26-3.12 (m, 5H), 3.05-3.01 (m, 2H), 2.88-2.87 (m, 2H), 2.67-2.66 (m, 2H), 2.59-2.57 (m, 4H), 2.02-1.94 (m, 11H), 1.36-1.34 (m, 15H), 1.29-1.27 (m, 6H); MS (ESI)
m/z: 1187.3 [M+H]
+。
3-(4-((4
S,5
R)-2-(4-(三級丁基)-2-乙氧基苯基)-4,5-雙(4-氯苯基)-4,5-二甲基-4,5-二氫-1
H-咪唑-1-羰基)哌𠯤-1-基)-
N-(9-(3-(7-(4-(2-羥基-乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5-
a]嘧啶-3-基)苯基)壬基)-丙醯胺
C13 。 1HNMR (400 MHz, DMSO-
d 6)
δ11.53 (s, 1H), 10.90 (s, 1H), 8.33-8.24 (m, 2H), 8.10 (s, 1H), 7.79-7.70 (m, 2H), 7.61 (d,
J= 8.0 Hz, 1H), 7.55-7.49 (m, 3H), 7.39 (t,
J= 7.6 Hz, 1H), 7.26-7.21 (m, 2H),7.18-6.90 (m, 10H), 4.77 (d,
J= 12.4 Hz, 2H), 4.39-4.25 (m, 2H), 4.15-4.08 (m, 1H), 3.92-3.81 (m, 4H), 3.74-3.64 (m, 6H), 3.26-3.13 (m, 8H), 3.02-2.98 (m, 2H),3.02-2.97 (m, 2H), 2.92-2.85 (m, 2H), 2.66 (t,
J= 6.8 Hz, 2H), 2.62-2.56 (m, 5H), 2.02-1.98 (m, 2H), 1.71-1.62 (m, 2H), 1.46-1.21(m, 28H); MS (ESI)
m/z: 1215.8 [M+H]
+。
4-((4
S,5
R)-2-(4-(三級丁基)-2-((9-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5-
a]嘧啶-3-基)苯基)壬基)氧基)苯基)-4,5-雙(4-氯-苯基)-4,5-二甲基-4,5-二氫-1
H-咪唑-1-羰基)哌𠯤-2-酮
C14 。 1HNMR (400 MHz, DMSO-
d 6)
δ8.29-8.18 (m, 3H),7.76-7.71 (m, 2H),7.62-7.57 (m, 2H),7.53-7.44 (m, 3H),7.36 (t,
J= 7.6 Hz, 1H),7.11-7.00 (m, 6H), 6.93 (s, 4H), 6.86 (s, 1H), 5.32 (t,
J= 4.0 Hz, 1H), 3.85 (s, 4H), 3.69-3.56 (m, 4H), 3.08-3.03 (m, 2H), 2.94-2.87 (m, 2 H), 2.79-2.72 (m, 2H), 2.67-2.61 (m, 8H), 2.56 (s, 3H), 2.02-1.95 (m, 4 H), 1.88 (s, 3H),1.70-1.62 (m, 4H), 1.56 (s, 3H), 1.32-1.23 (m, 15 H); MS (ESI)
m/z:
1130.7 [M+H]
+。
4-((4
S,5
R)-2-(4-(三級丁基)-2-((11-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5-
a]嘧啶-3-基)苯基)十一基)氧基)苯基)-4,5-雙(4-氯-苯基)-4,5-二甲基-4,5-二氫-1
H-咪唑-1-羰基)哌𠯤-2-酮
C15 。 1HNMR (400 MHz, DMSO-
d
6 )
δ8.22 (d,
J= 9.2 Hz, 2H), 7.73 (s, 2H), 7.60-7.57 (m, 2H), 7.51-7.48 (m, 3H), 7.36 (t,
J=7.6 Hz, 1H), 7.09-6.86 (m, 13H), 3.89-3.82 (m, 4H), 3.70-3.66 (m, 2H), 3.59-3.55 (m, 4H), 3.08-3.04 (m, 1H), 2.93-2.88 (m, 1H), 2.80-2.75 (m, 1H), 2.68-2.64 (m, 6H), 2.62-2.57 (m, 4H), 1.89 (s, 3H), 1.67-1.58 (m, 8H), 1.33 (s, 15H), 1.23-1.19 (m, 10H); MS (ESI)
m/z:
1158.8[M+H]
+。
4-((4
S,5
R)-2-(4-(三級丁基)-2-((7-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5-
a]嘧啶-3-基)苯基)庚基)氧基)苯基)-4,5-雙(4-氯-苯基)-4,5-二甲基-4,5-二氫-1
H-咪唑-1-羰基)哌𠯤-2-酮
C16 。 1HNMR (400 MHz, DMSO-
d 6)
δ8.21 (d,
J= 8.0 Hz, 2H), 7.73-7.71 (m, 2H), 7.62-7.57 (m, 2H), 7.50-7.44 (m, 3H), 7.36 (t,
J= 7.6 Hz, 1H), 7.09-6.86 (m, 12 H), 5.32 (t,
J= 4.8 Hz, 1H), 3.87 (s, 4H), 3.68-3.56 (m, 4H), 3.25-3.11 (m, 2H), 3.08-2.81 (m, 4H), 2.80-2.60 (m, 8H), 2.56 (s, 3H), 2.02-1.95 (m, 2H), 1.91-1.83 (m, 3H), 1.75-1.61 (m, 4H),1.58-1.51 (m, 3H),1.47-1.35 (m, 6H), 1.32 (s, 9H), 1.27-1.23 (m, 6H); MS (ESI)
m/z:
1102.6 [M+H]
+。
(2
S,4
R)-4-羥基-1-((
S)-2-(9-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5-
a]嘧啶-5-基)苯基)壬醯胺基)-3,3-二甲基丁醯基)-
N-(4-(4-甲基噻唑-5-基)苯甲基)吡咯啶-2-甲醯胺
D1 。 1HNMR (DMSO-
d
6 , 400 MHz)
δ8.55 (t,
J= 6.0 Hz, 1H), 8.10 (d,
J= 8.4 Hz, 2H), 7.85-7.81 (m, 3H), 7.47 (t,
J= 7.6 Hz, 2H), 7.43-7.37 (m, 5H), 7.32-7.26 (m, 2H), 6.83 (s, 1H), 5.12 (d,
J= 3.2 Hz, 1H), 4.53 (d,
J= 9.2 Hz, 1H), 4.48 (t,
J= 5.6 Hz, 1H), 4.46-4.39 (m, 2H), 4.34 (brs, 1H), 4.21 (dd,
J= 5.2, 14.6 Hz, 1H), 3.86 (s, 4H), 3.65-3.55 (m, 4H), 2.68 - 2.65 (m, 6H), 2.57 (s, 3H), 2.44 (s, 3H), 2.27-2.24 (m, 1H), 2.12-2.02 (m, 2H), 1.92-1.89 (m, 1H), 1.64-1.61 (m, 2H), 1.49-1.45 (m, 2H), 1.29-1.23 (m, 10H), 0.92 (s, 9H); MS (ESI)
m/z:
982.5 [M+H]
+。
(2
S,4
R)-4-羥基-1-((
S)-2-(9-(4-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5-
a]嘧啶-5-基)苯基)壬醯胺基)-3,3-二甲基丁醯基)-
N-(4-(4-甲基噻唑-5-基)苯甲基)吡咯啶-2-甲醯胺
D2。
1HNMR (DMSO-
d
6 , 400 MHz)
δ8.97 (s, 1H), 8.55 (t,
J= 6.0 Hz, 1H), 8.10 (d,
J= 8.4 Hz, 2H), 7.84-7.82 (m, 3H), 7.47 (t,
J= 7.6 Hz, 2H), 7.42-7.36 (m, 4H), 7.33 (d,
J= 8.4 Hz, 2H), 7.27 (t,
J= 7.6 Hz, 1H), 6.82 (s, 1H), 5.12 (d,
J= 3.6 Hz, 1H), 4.53 (d,
J= 9.6 Hz, 1H), 4.48 (t,
J= 5.6 Hz, 1H), 4.46-4.40 (m, 2H), 4.35 (brs, 1H), 4.21(dd,
J= 5.2, 14.6Hz, 1H), 3.84 (s, 4H), 3.69-3.64 (m, 2H), 3.59-3.55 (m, 2H), 2.67-2.61 (m, 6H), 2.58 (s, 3H), 2.49-2.48 (m, 1H), 2.43 (s, 3H), 2.27-2.23 (m, 1H), 2.12-1.90 (m, 3H), 1.93-1.86 (m, 1H), 1.62-1.58 (m, 2H), 1.49-1.45 (m, 2H), 1.28-1.23 (m, 8H), 0.92 (s, 9H); MS (ESI)
m/z:
982.5 [M+H]
+。
(2
S,4
R)-1-((
S)-2-乙醯胺基-3,3-二甲基丁醯基)-4-羥基-
N-(2-((7-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5-
a]嘧啶-5-基)苯基)-庚基)氧基)-4-(4-甲基噻唑-5-基)苯甲基)吡咯啶-2-甲醯胺
D3。
1HNMR (400 MHz, DMSO-
d
6 )
δ8.99 (s, 1H), 8.43 (t,
J= 6.0 Hz, 1H), 8.04-7.95 (m, 3H), 7.85 (d,
J= 7.2 Hz, 2H), 7.50-7.41 (m, 4H), 7.34-7.26 (m, 2H), 6.99 (s, 1H), 6.92 (d,
J= 8.0 Hz 1H), 6.85 (s, 1H), 5.34 (t,
J=5.2 Hz, 1H), 4.56-4.45 (m, 3H), 4.36-4.30 (m, 2H), 4.18-4.17 (m, 1H), 4.05 (t,
J= 6.0 Hz, 2H), 3.89-3.87 (m, 4H), 3.66-3.51 (m, 4H), 2.70-2.67 (m, 6H), 2.52 (s, 3H), 2.46 (s, 3H), 2.07-1.94 (m, 4H), 1.96-1.88 (m, 3H), 1.66-1.47 (m, 4H), 1.46-1.25 (m, 6H), 0.93(s, 9H); MS (ESI)
m/z: 998.7 [M+H]
+。
(2
S,4
R)-4-羥基-1-((
S)-2-(8-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5-
a]嘧啶-3-基)苯基)辛醯胺基)-3,3-二甲基丁醯基)-
N-(4-(4-甲基噻唑-5-基)苯甲基)吡咯啶-2-甲醯胺
D4 。 1HNMR (400 MHz, DMSO-
d
6 )
δ8.98 (s, 1H), 8.54 (t,
J= 5.6 Hz, 1H), 8.23-8.20 (m, 2H), 7.81 (d,
J= 9.2 Hz, 1H), 7.71 (s, 1H), 7.60 (d,
J= 8.0 Hz, 1H), 7.53-7.50 (m, 3H), 7.42-7.35 (m, 5H), 7.09 (d,
J= 7.6 Hz, 1H), 6.86 (s, 1H), 5.10 (d,
J= 3.6 Hz, 1H), 4.53 (d,
J= 9.6 Hz, 1H), 4.48-4.40 (m, 3H), 4.34 (brs, 1H), 4.21 (dd,
J 1= 16.0 Hz,
J 2= 5.6 Hz, 1H), 3.90-3.83 (m, 4H), 3.65-3.64 (m, 2H), 3.57 (q,
J= 6.0 Hz, 2H), 2.69-2.63 (m, 6H), 2.57 (s, 3H), 2.44 (s, 3H), 2.33-2.22 (m, 2H), 2.12-1.97 (m, 4H), 1.93-1.87 (m, 1H), 1.66-1.63 (m, 2H), 1.52-1.43 (m, 3H), 1.34-1.24 (m, 4H), 0.91 (s, 9H); MS (ESI)
m/z:
968.3 [M+H]
+。
(2
S,4
R)-4-羥基-1-((
S)-2-(10-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5-
a]嘧啶-3-基)苯基)癸醯胺基)-3,3-二甲基丁醯基)-
N-(4-(4-甲基噻唑-5-基)苯甲基)吡咯啶-2-甲醯胺
D5 。 1HNMR (400 MHz, DMSO-
d
6 )
δ8.97 (s, 1H), 8.55 (t,
J= 6.4 Hz, 1H), 8.22-8.21 (m, 2H), 7.83 (d,
J= 9.2 Hz, 1H), 7.72 (s, 1H), 7.59 (d,
J= 7.2 Hz, 1H), 7.49 (s, 3H), 7.42-7.34 (m, 5H), 7.09 (d,
J= 7.6 Hz, 1H), 6.86 (s, 1H), 5.11 (s, 1H), 4.54-4.52 (m, 2H), 4.46-4.40 (m, 2H), 4.34 (brs, 1H), 4.23-4.18 (m, 1H), 3.86 (s, 4H), 3.64-3.58 (m, 4H), 2.72-2.63 (m, 6H), 2.56 (s, 3H), 2.43 (s, 3H), 2.24-2.21 (m, 1H), 2.09-2.00 (m, 2H), 1.92-1.88 (m, 1H), 1.65-1.64 (m, 2H), 1.49-1.47 (m, 2H), 1.45-1.43 (m, 3H), 1.41-1.32 (m, 7H), 0.85 (s, 9H); MS (ESI)
m/z:
996.7 [M+H]
+。
(2
S,4
R)-4-羥基-1-((
S)-2-(12-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5-
a]嘧啶-3-基)苯基)十二烷醯胺基)-3,3-二甲基丁醯基)-
N-(4-(4-甲基噻唑-5-基)苯甲基)吡咯啶-2-甲醯胺
D6。
1HNMR (400 MHz, DMSO-
d
6 )
δ8.97 (s, 1H), 8.54 (t,
J= 5.6 Hz, 1H), 8.23-8.20 (m, 2H), 7.81 (d,
J= 9.2 Hz, 1H), 7.73 (s, 1H), 7.59 (d,
J= 8.0 Hz, 1H), 7.53-7.47 (m, 3H), 7.43-7.34 (m, 5H), 7.11-7.06 (d,
J= 7.6 Hz, 1H), 6.86 (s, 1H), 5.11 (brs, 1H), 4.58-4.52 (m, 1H), 4.49-4.40 (m, 2H), 4.37-4.31 (m, 1H), 4.21 (dd,
J= 5.2, 16.0 Hz, 1H), 3.90-3.82 (m, 4H), 3.69-3.65 (m, 2H), 3.59-3.56 (m, 2H), 3.48-3.40 (m, 4H), 2.70-2.63 (m, 6H), 2.57 (s, 3H), 2.44 (s, 3H), 2.28-2.21 (m, 1H), 2.12-2.00 (m, 2H), 1.72-1.60 (m, 2H), 1.52-1.40 (m, 2H), 1.38-1.30 (m, 4H), 1.29-1.21 (m, 10H), 0.92 (s, 9H); MS (ESI)
m/z: 1024.3 [M+H]
+。
(2
S,4
R)-4-羥基-1-((
S)-2-(9-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5-
a]嘧啶-3-基)苯基)壬醯胺基)-3,3-二甲基丁醯基)-
N-(4-(4-甲基噻唑-5-基)苯甲基)吡咯啶-2-甲醯胺
D7。
1HNMR (400 MHz, DMSO-
d
6 )
δ8.97 (s, 1H), 8.55 (t,
J= 5.6 Hz, 1H), 8.23-8.21 (m, 2H), 7.82 (d,
J= 9.2 Hz, 1H), 7.73 (s, 1H), 7.58 (d,
J= 7.6 Hz, 1H), 7.50-7.49 (m, 3H), 7.42-7.34 (m, 5H), 7.08 (d,
J= 7.6 Hz, 1H), 6.86 (s, 1H), 5.11 (brs, 1H), 4.54-4.34 (m, 5H), 4.23-4.18 (m, 1H), 3.86 (s, 4H), 3.65-3.61 (m, 2H), 3.59-3.56 (m, 2H), 2.68-2.64 (m, 6H), 2.56 (s, 3H), 2.43 (s, 3H), 2.26-2.21 (m, 1H), 2.11-2.00 (m, 2H), 1.92-1.89 (m, 1H), 1.67-1.64 (m, 2H), 1.49-1.47 (m, 2H), 1.43-1.32 (m, 4H), 1.23-1.19 (m, 14H), 0.92 (s, 9H); MS (ESI)
m/z:
1052.4 [M+H]
+。
(2
S,4
R)-1-((
S)-2-乙醯胺基-3,3-二甲基丁醯基)-4-羥基-
N-(2-((7-(4-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5-
a]嘧啶-3-基)苯基)-庚基)氧基)-4-(4-甲基噻唑-5-基)苯甲基)吡咯啶-2-甲醯胺
D8。
1HNMR (400 MHz, DMSO-
d 6)
δ8.96 (s, 1 H), 8.42 (t,
J= 6 Hz, 1 H), 8.19 (dd,
J= 1.6, 8.0 Hz, 2 H), 7.94 (d,
J= 9.2 Hz, 1 H), 7.74(d,
J= 8.0 Hz, 2 H), 7.56-7.41 (m, 4 H), 7.29 (d,
J= 8.4 Hz, 2 H), 6.99 (d,
J= 1.2 Hz, 1 H), 6.89 (dd,
J= 0.8, 7.6 Hz, 1 H), 6.83 (s, 1 H), 5.11 (s, 1 H), 4.57-4.41 (m, 3 H), 4.37-4.25 (m, 2 H), 4.15 (dd,
J= 5.2, 16.4 Hz, 1 H), 4.04 (t,
J= 6.0 Hz, 2 H), 3.85 (s, 4 H), 3.68-3.61 (m, 2 H) , 3.57 (t,
J= 6.0 Hz, 2 H), 2.74-2.58 (m, 7 H), 2.54 (s, 3 H), 2.45 (s, 3 H), 2.08-1.97 (m, 2 H), 1.95-1.92 (m, 1 H), 1.88 (s, 3 H),1.79-1.59 (m, 4 H), 1.49-1.35 (m, 6 H), 0.91(s, 9 H); MS (ESI)
m/z:
998.3 [M+H]
+。
(2
S,4
R)-1-((
S)-2-乙醯胺基-3,3-二甲基丁醯基)-4-羥基-
N-(2-((9-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5-
a]嘧啶-3-基)苯基)-壬基)氧基)-4-(4-甲基噻唑-5-基)苯甲基)吡咯啶-2-甲醯胺
D9 。 1HNMR (400 MHz, DMSO-
d
6 )
δ8.96 (s, 1H), 8.41 (t,
J= 6.0 Hz, 1H), 8.21 (dd,
J= 2.0, 7.6 Hz, 2H), 7.94 (d,
J= 9.2 Hz, 1H), 7.72 (s, 1H), 7.59 (d,
J= 8.0 Hz, 1H), 7.54-7.42 (m, 4H), 7.36 (t,
J= 7.6 Hz, 1H), 7.08 (d,
J= 7.6 Hz, 1H), 6.97 (d,
J= 1.2 Hz, 1H), 6.89 (dd,
J= 1.2, 8.0 Hz, 1H), 6.85 (s, 1H), 5.11 (brs, 1H), 4.61-4.40 (m, 3H), 4.37-4.24 (m, 2H), 4.18-4.06 (m, 1H), 4.00 (t,
J= 6.0 Hz, 2H), 3.85 (s, 4H), 3.63 (s, 2H), 3.57 (t,
J= 6.0 Hz, 3H), 2.73-2.60 (m, 6H), 2.56 (s, 3H), 2.44 (s, 3H), 2.07-1.95 (m, 2H), 1.94-1.88 (m, 4H), 1.76-1.62 (m, 4H), 1.45-1.31 (m, 10H), 0.91(s, 9H); MS (ESI)
m/z: 1026.3 [M+H]
+。
(2
S,4
R)-1-((
S)-2-乙醯胺基-3,3-二甲基丁醯基)-4-羥基-
N-(2-((11-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5-
a]嘧啶-3-基)苯基)-十一基)氧基)-4-(4-甲基噻唑-5-基)苯甲基)吡咯啶-2-甲醯胺
D10 。 1HNMR (400 MHz, DMSO-
d
6 )
δ8.96 (s, 1H), 8.42 (t,
J= 5.6 Hz, 1H), 8.23-8.21 (m, 2H), 7.94 (d,
J= 9.6 Hz, 1H), 7.73 (s, 1H), 7.58 (d,
J= 7.6 Hz, 1H), 7.51-7.44 (m, 4H), 7.36 (t,
J= 7.6 Hz, 1H), 7.09 (d,
J= 7.6 Hz, 1H), 6.97 (s, 1H), 6.89 (d,
J= 7.6 Hz, 1H), 6.85 (s, 1H), 5.13 (s，1H), 4.53 (d,
J= 9.2 Hz, 1H), 4.47-4.43 (m, 1H), 4.34-4.28 (m, 2H), 4.16-4.10 (m, 1H), 4.00 (t,
J= 6.0 Hz, 2H), 3.85 (s, 4H), 3.63 (s, 2H), 3.59-3.55 (m, 2H), 2.71-2.63 (m, 7H), 2.60-2.53 (m, 4H), 2.44-2.40 (m, 5H), 2.05-2.01 (m, 1H), 1.88 (s, 3H), 1.74-1.63 (m, 4H), 1.41 -1.37(m, 2H), 1.33 (s,4H), 1.29-1.20 (m, 10H), 0.91 (s, 9H); MS (ESI)
m/z: 1054.3 [M+H]
+。
(2
S,4
R)-1-((
S)-2-乙醯胺基-3,3-二甲基丁醯基)-4-羥基-
N-(2-((13-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5-
a]嘧啶-3-基)苯基)-十三基)氧基)-4-(4-甲基噻唑-5-基)苯甲基)吡咯啶-2-甲醯胺
D11 。 1HNMR (400 MHz, DMSO-
d
6 )
δ8.97 (s, 1H), 8.43-8.41 (m, 1H), 8.23-8.20 (m, 2H), 7.94 (d,
J= 9.2 Hz, 1H), 7.74 (s, 1H), 7.61-7.56 (d,
J= 7.6 Hz, 1H), 7.53-7.45 (m, 4H), 7.36 (t,
J= 7.6 Hz, 1H), 7.09 (d,
J= 7.6 Hz, 1H), 6.97 (s, 1H), 6.90-6.86 (d,
J= 7.2 Hz, 2H), 5.12 (brs, 1H), 4.53 (d,
J= 9.6 Hz, 1H), 4.46 (t,
J= 8.0 Hz, 1H), 4.38-4.28 (m, 2H), 4.19-4.09 (m, 1H), 4.01 (t,
J= 5.6 Hz, 2H), 3.90-3.82 (m, 4H), 3.65-3.63 (m, 2H), 3.58-3.56 (m, 2H),3.17 (s, 1H), 2.72-2.61 (m, 7H), 2.56 (s, 3H), 2.48-2.40 (m, 4H), 2.06-1.99 (m, 2H), 1.88 (s, 3H), 1.73-1.63 (m, 4H), 1.49-1.37(m, 4H), 1.33-1.23 (m, 14H), 0.91 (s, 9H); MS (ESI)
m/z:
1082.6 [M+H]
+。
(2
S,4
R)-4-羥基-1-((
S)-2-(10-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5-
a]嘧啶-3-基)苯基)癸醯胺基)-3,3-二甲基丁醯基)-
N-(4-(4-甲基噻唑-5-基)苯甲基)吡咯啶-2-甲醯胺
D12 。 1HNMR (400 MHz, DMSO-
d
6 )
δ8.98 (s, 1H), 8.54 (t,
J= 6.0 Hz, 1H), 8.24-8.18 (m, 2H), 7.80 (d,
J= 9.6 Hz, 1H), 7.72 (s, 1H), 7.59 (d,
J= 8.8 Hz, 1H), 7.54-7.45 (m, 3H), 7.44-7.32 (m, 5H), 7.09 (d,
J= 7.2 Hz, 1H), 6.86 (s, 1H), 5.10 (d,
J= 3.2 Hz, 1H), 4.53 (d,
J= 9.2 Hz, 1H), 4.50-4.45 (m, 1H), 4.42 (t,
J= 8.4 Hz, 2H), 4.34 (brs, 1H), 4.26-4.16 (m, 1H), 3.90-3.78 (m, 4H), 3.71-3.61 (m, 2H), 3.58 (q,
J= 5.6 Hz, 2H), 2.75-2.60 (m, 6H), 2.56 (s, 3H), 2.55-2.50 (m, 2H), 2.44 (s, 3H), 2.29-2.19 (m, 1H), 2.13-1.97 (m, 2H), 1.94-1.85 (m, 1H), 1.71-1.61 (m, 2H), 1.54-1.38 (m, 2H), 1.38-1.18 (m, 8H), 0.92 (s, 9H); MS (ESI)
m/z:
982.3[M+H]
+。
(2
S,4
R)-4-羥基-1-((
S)-2-(9-(4-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5-
a]嘧啶-3-基)苯基)壬醯胺基)-3,3-二甲基丁醯基)-
N-(4-(4-甲基噻唑-5-基)苯甲基)吡咯啶-2-甲醯胺
D13 。 1HNMR (400 MHz, DMSO-
d 6)
δ8.97 (s, 1H), 8.55 (t,
J= 6.0 Hz, 1H), 8.20-8.19 (m, 2H), 7.85-7.82 (m, 1H), 7.74-7.72 (m, 2H), 7.53-7.48 (m, 3H), 7.42-7.36 (m, 4H), 7.30-7.28 (m, 2H), 6.84 (s, 1H), 5.12 (brs, 1H), 4.55-4.52 (m, 1H), 4.45-4.39 (m, 2H), 4.23-4.22 (m, 1H), 4.19-4.18 (m, 1H), 3.86-3.85 (m, 4H), 3.67-3.64 (m, 2H), 3.62-3.55 (m, 2H), 2.62-2.59 (m, 6H), 2.57-2.52 (m, 5H), 2.43 (s, 3H), 2.27-2.22 (m, 1H), 2.14-2.08 (m, 1H), 2.05-2.00 (m, 1H), 1.92-1.88 (m, 1H), 1.62-1.60 (m, 2H), 1.52-1.43 (m, 2H), 1.30-1.26 (m, 8H), 0.92 (s, 9H); MS (ESI)
m/z: 982.3 [M+H]
+。
(2
S,4
R)-1-((
S)-2-乙醯胺基-3,3-二甲基丁醯基)-4-羥基-
N-(2-((13-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5-
a]嘧啶-3-基)-苯基)十三碳-12-炔-1-基)氧基)-4-(4-甲基噻唑-5-基)苯甲基)吡咯啶-2-甲醯胺
D14 。 1HNMR (400 MHz, DMSO-
d
6 )
δ8.97 (s, 1H), 8.45 (t,
J= 5.6 Hz, 1H), 8.22-8.20 (m, 2H), 7.98-7.95 (m, 2H), 7.78 (d,
J= 7.6 Hz, 1H), 7.52-7.42 (m, 5H), 7.27 (d,
J= 7.6 Hz, 1H), 6.96 (s, 1H), 6.90-6.89 (m, 2H), 5.13 (brs, 1H), 4.53 (d,
J= 9.2 Hz, 1H), 4.46 (t,
J= 7.6 Hz, 1H), 4.37-4.27 (m, 2H), 4.15-4.12 (m, 1H), 3.99 (t,
J= 6.0 Hz, 1H), 3.91-3.81 (m, 4H), 3.68-3.61 (m, 2H), 3.57 (t,
J= 6.0 Hz, 2H), 3.24-3.17 (m, 1H), 2.72-2.63 (m, 4H), 2.57 (s, 3H), 2.47-2.40 (m, 7H), 2.07-2.00(m, 1H), 1.94-1.83 (m, 4H), 1.71-1.65 (m, 2H), 1.60-1.53(m, 2H), 1.47-1.35 (m, 4H), 1.31-1.25 (m, 10H), 0.91 (s, 9H); MS (ESI)
m/z:
1078.3 [M+H]
+。
(2
S,4
R)-1-((
S)-2-乙醯胺基-3,3-二甲基丁醯基)-4-羥基-
N-(2-((11-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5-
a]嘧啶-3-基)-苯基)十一碳-10-炔-1-基)氧基)-4-(4-甲基噻唑-5-基)苯甲基)吡咯啶-2-甲醯胺
D15 。 1HNMR (400 MHz, DMSO-
d
6 )
δ8.97 (s, 1H), 8.45 (t,
J= 5.6 Hz, 1H), 8.22-8.20 (m, 2H), 7.94-7.94 (m, 2H), 7.77 (d,
J= 8.0 Hz, 1H), 7.51-7.50 (m, 3H), 7.47-7.42 (m, 2H), 7.27 (d,
J= 7.2 Hz, 1H), 6.95 (s, 1H), 6.90-6.87 (m, 2H), 5.16 (brs，1H), 4.53 (d,
J= 9.6 Hz, 1H), 4.46 (t,
J= 8.0 Hz, 1H), 4.34-4.28 (m, 2H), 4.15-4.09 (m, 1H), 3.98 (t,
J= 5.6 Hz, 1H), 3.85 (s, 4H), 3.64 (s, 2H), 3.58-3.55 (m, 2H), 2.66 (s, 4H), 2.56 (s, 3H), 2.47-2.43 (m, 4H), 2.06-2.01 (m, 1H), 1.94-1.83 (m, 4H), 1.70-1.66 (m, 2H), 1.60-1.53(m, 2H), 1.45-1.23(m, 10H), 0.91 (s, 9H); MS (ESI)
m/z: 1050.3 [M+H]
+。
(2
S,4
R)-1-((
S)-2-乙醯胺基-3,3-二甲基丁醯基)-4-羥基-
N-(2-((7-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-5-苯基吡唑并[1,5-
a]嘧啶-3-基)苯基)-庚基)氧基)-4-(4-甲基噻唑-5-基)苯甲基)吡咯啶-2-甲醯胺
D16 。 1HNMR (400 MHz, DMSO-
d
6 )
δ8.97 (s, 1H), 8.42 (t,
J= 6.0 Hz, 1H), 8.21 (d,
J= 7.2 Hz, 2H), 7.94 (d,
J= 9.2 Hz, 1H), 7.73 (s, 1H), 7.59 (d,
J= 7.2 Hz, 1H), 7.51-7.44 (m, 4H), 7.37 (t,
J= 7.6 Hz, 1H), 7.09 (d,
J= 7.2 Hz, 1H), 6.96 (s, 1H), 6.89 (d,
J= 8.0 Hz, 1H), 5.12 (d,
J= 3.2 Hz, 1H), 4.54-4.44 (m, 4H), 4.36-4.28 (m, 2H), 4.20-4.08 (m, 2H), 4.01 (t,
J= 6.0 Hz, 2H), 3.90-3.81 (m, 5H), 3.67-3.62 (m, 3H), 3.60-3.56 (m, 3H), 2.70-2.65 (m, 5H), 2.56 (s, 3H), 2.44 (s, 3H), 2.04-2.01 (m, 1H), 1.89 (s, 3H), 1.76-1.66 (m, 4H), 1.49-1.42 (m, 6H), 0.91 (s, 9H); MS (ESI)
m/z: 998.3 [M+H]
+。
以下化合物係類似地製備。The following compounds were prepared similarly.
3-(6-氟-4-(1-(4-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5-
a]嘧啶-5-基)苯基)丁基)哌啶-4-基)-1-側氧基異吲哚啉-2-基)-哌啶-2,6-二酮
A11。
2-(2,6-二側氧基哌啶-3-基)-5-氟-6-(4-((1-(9-(3-(7-(4-(2-羥基乙基)-哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5-
a]嘧啶-5-基)苯基)壬醯基)哌啶-4-基)甲基)哌𠯤-1-基)異吲哚啉-1,3-二酮
A26。
2-(2,6-二側氧基哌啶-3-基)-5-氟-6-(4-((1-(11-(3-(7-(4-(2-羥基乙基)-哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5-
a]嘧啶-5-基)苯基)十一醯基)哌啶-4-基)甲基)哌𠯤-1-基)異吲哚啉-1,3-二酮
A27。
3-(6-氟-4-(4-(5-(4-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基-吡唑并[1,5-
a]嘧啶-5-基)哌啶-1-基)戊基)哌𠯤-1-基)-1-側氧基異吲哚啉-2-基)-哌啶-2,6-二酮
A33。
3-(6-氟-4-(4-(9-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基-吡唑并[1,5-
a]嘧啶-5-基)壬基)哌𠯤-1-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮
A34。
(
S)-
N-((
S)-1-環己基-2-((
S)-2-(4-(3-((9-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5-
a]嘧啶-5-基)苯基)壬基)氧基)苯甲醯基)噻唑-2-基)-吡咯啶-1-基)-2-側氧基乙基)-2-(甲基胺基)丙醯胺
B2。
(
S)-
N-((
S)-1-環己基-2-((
S)-2-(4-(3-((11-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5-
a]嘧啶-5-基)苯基)十一基)氧基)苯甲醯基)噻唑-2-基)吡咯啶-1-基)-2-側氧基乙基)-2-(甲基胺基)丙醯胺
B3。
(
S)-
N-((
S)-1-環己基-2-((
S)-2-(4-(3-((13-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5-
a]嘧啶-5-基)苯基)十三基)氧基)苯甲醯基)噻唑-2-基)吡咯啶-1-基)-2-側氧基乙基)-2-(甲基胺基)丙醯胺
B4。
(
S)-2-((2
S,3
R)-3-胺基-2-羥基-4-苯基丁醯胺基)-
N-(9-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5-
a]嘧啶-5-基)苯基)壬基)-4-甲基戊醯胺
B6。
(
S)-2-((2
S,3
R)-3-胺基-2-羥基-4-苯基丁醯胺基)-
N-(11-(3-(7-(4-(2-羥基乙基)哌𠯤-1-基)-2-甲基-3-苯基吡唑并[1,5-
a]嘧啶-5-基)苯基)十一基)-4-甲基戊醯胺
B7。
在補充有10%胎牛血清、鏈黴素及青黴素之RPMI 1640培養基中培養H358、H23、SW48及AsPC-1細胞。在補充有10%胎牛血清、鏈黴素及青黴素之DMEM培養基中培養Lovo及SW480細胞。將細胞株塗鋪在補充有2.5%胎牛血清、鏈黴素及青黴素之其各別培養基中。將所有細胞株以2,000個細胞/孔塗鋪於白壁96孔盤或以500個細胞/孔塗鋪於384孔盤中，除了Lovo以外，其分別以4,000或1,000個細胞/孔塗鋪。在DMSO (對照)或化合物中在37℃下在5% CO
2下培育細胞3天。接著，將CELLTITER-GLO®試劑(100 µL)添加至各孔中。在振盪下培育10 min之後，使用ENVISION®多模式盤讀取器來量測發光。IC
50值概述於表1中且抑制百分比概述於表2中。
表1.癌細胞之抑制
使H358細胞在補充有10%胎牛血清、鏈黴素及青黴素之RPMI 1640培養基中生長。將細胞塗鋪在10 cm培養盤中之生長培養基中。次日，在1×PBS中沖洗細胞，同時用補充有2.5%胎牛血清、鏈黴素及青黴素之RPMI1640替換培養基。接著用化合物(1 µM)處理細胞24 h。使用免疫沈澱(IP)溶解緩衝液製備全細胞提取物。簡言之，將細胞在PBS中洗滌一次，且將細胞離心塊(cell pellet)再懸浮於IP溶解緩衝液中且在冰上培育15 min。藉由離心移除細胞碎片且將澄清的全細胞溶解物轉移至新試管中用於進一步分析。H358 cells were grown in RPMI 1640 medium supplemented with 10% fetal bovine serum, streptomycin and penicillin. Cells were plated in growth medium in 10 cm culture dishes. The following day, cells were washed in 1×PBS while the medium was replaced with RPMI1640 supplemented with 2.5% fetal bovine serum, streptomycin and penicillin. Cells were then treated with compound (1 µM) for 24 h. Whole cell extracts were prepared using immunoprecipitation (IP) lysis buffer. Briefly, cells were washed once in PBS and cell pellets were resuspended in IP lysis buffer and incubated on ice for 15 min. Cell debris was removed by centrifugation and clarified whole cell lysates were transferred to new tubes for further analysis.
對於西方墨點分析，將全細胞蛋白質提取物在12% SDS-聚丙烯醯胺凝膠上分離，轉移至硝化纖維素且用初級抗體探測。隨後洗滌膜且用IRDYE ®二級抗體探測。使用ODYSSEY ®成像系統偵測訊號。分析中所用之抗體包括抗KRAS；β-肌動蛋白小鼠單株抗體；IRDYE ®680RD山羊抗兔抗體；及IRDYE ®800CW山羊抗小鼠抗體。 * * * * * For Western blot analysis, whole cell protein extracts were separated on 12% SDS-polyacrylamide gels, transferred to nitrocellulose and probed with primary antibodies. Membranes were then washed and probed with IRDYE® secondary antibodies. Use the ODYSSEY ® imaging system to detect signals. Antibodies used in the assay included anti-KRAS; β-actin mouse monoclonal antibody; IRDYE ® 680RD goat anti-rabbit antibody; and IRDYE ® 800CW goat anti-mouse antibody. * * * * *
提供上述實例以向一般熟習此項技術者提供如何製備及使用所主張之實施例之全部揭示內容及描述，且不意欲限制本文中所揭示之內容之範疇。熟習此項技術者顯而易見之修改意欲屬於以下申請專利範圍之範疇內。本說明書中所引用之所有公開案、專利及專利申請案所以引用的方式併入本文中，如同各此類公開案、專利或專利申請案特定地且個別地指示以引用的方式併入一般。The above examples are provided to provide those of ordinary skill in the art with a full disclosure and description of how to make and use the claimed embodiments, and are not intended to limit the scope of what is disclosed herein. Modifications obvious to those skilled in the art are intended to fall within the scope of the following claims. All publications, patents and patent applications cited in this specification are incorporated herein by reference as if each such publication, patent or patent application were specifically and individually indicated to be incorporated by reference.
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